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Sample records for androgen suppression therapy

  1. Nonlinear system identification for prostate cancer and optimality of intermittent androgen suppression therapy.

    Science.gov (United States)

    Suzuki, Taiji; Aihara, Kazuyuki

    2013-09-01

    These days prostate cancer is one of the most common types of malignant neoplasm in men. Androgen ablation therapy (hormone therapy) has been shown to be effective for advanced prostate cancer. However, continuous hormone therapy often causes recurrence. This results from the progression of androgen-dependent cancer cells to androgen-independent cancer cells during the continuous hormone therapy. One possible method to prevent the progression to the androgen-independent state is intermittent androgen suppression (IAS) therapy, which ceases dosing intermittently. In this paper, we propose two methods to estimate the dynamics of prostate cancer, and investigate the IAS therapy from the viewpoint of optimality. The two methods that we propose for dynamics estimation are a variational Bayesian method for a piecewise affine (PWA) system and a Gaussian process regression method. We apply the proposed methods to real clinical data and compare their predictive performances. Then, using the estimated dynamics of prostate cancer, we observe how prostate cancer behaves for various dosing schedules. It can be seen that the conventional IAS therapy is a way of imposing high cost for dosing while keeping the prostate cancer in a safe state. We would like to dedicate this paper to the memory of Professor Luigi M. Ricciardi.

  2. Intermittent versus continuous androgen suppression therapy: do we have consensus yet?

    Science.gov (United States)

    Buchan, N C; Goldenberg, S L

    2010-09-01

    Androgen deprivation therapy (ADT) has been a cornerstone in the management of advanced prostate cancer for more than 50 years, but several aspects of the therapy remain controversial. Research since the mid-1980s has looked at the use of intermittent androgen suppression (IAS) as a way to reduce the side effects and costs of continuous androgen suppression. During that same time, testing for prostate-specific antigen resulted in forward stage migration both at diagnosis and at the time of treatment initiation. Earlier treatment has led to prolonged periods of ADT and increasing recognition of the resultant metabolic complications. With preclinical evidence suggesting a potential benefit for ias in terms of time to androgen independence, with phase II and III studies producing optimistic results, and with the potential for reductions in cost and complications, ias has become a popular modality of therapy around the globe. Large prospective randomized studies, currently ongoing, will ultimately determine the legitimate place of IAS in the treatment of prostate cancer.

  3. Duration of short-course androgen suppression therapy and the risk of death as a result of prostate cancer.

    LENUS (Irish Health Repository)

    D'Amico, Anthony V

    2011-12-10

    We evaluated whether the duration of androgen suppression therapy (AST) had an impact on the risk of prostate cancer-specific mortality (PCSM) in men with unfavorable-risk prostate cancer (PC) within established Gleason score (GS) categories.

  4. A qualitative study evaluating experiences of a lifestyle intervention in men with prostate cancer undergoing androgen suppression therapy

    Directory of Open Access Journals (Sweden)

    Bourke Liam

    2012-11-01

    Full Text Available Abstract Background The severe iatrogenic hypogonadal state induced by medical castration used for treatment of prostate cancer is associated with adverse effects including fatigue, increased fracture risk, and a decrease in skeletal muscle function, which negatively impact quality of life. We have previously reported beneficial changes in healthy lifestyle behaviors, physical function and fatigue as a result of a novel combined exercise and dietary advice intervention (a lifestyle intervention in men with prostate cancer on androgen suppression therapy (AST. The aim of this research was to conduct a qualitative evaluation of the lifestyle intervention in these men with advanced prostate cancer receiving androgen suppression therapy (AST. Methods Twelve men with prostate cancer on AST took part in three focus groups in a UK higher education institution following the 12 week intervention. Sessions lasted between 45 and 60 minutes in duration. All discussions were audio-taped and transcribed. A framework analysis approach was applied to the focus group data. An initial coding framework was developed from a priori issues listed in the topic guide and extended and refined following initial familiarization with the focus group transcripts. Line by line indexing of the transcripts was undertaken iteratively to allow for the incorporation of new codes. Coded sections of text were grouped together (charted into themes and subthemes prior to a further process of comparison and interpretation. Results None of the participants involved in the trial were provided with information on how lifestyle changes might be beneficial to men with prostate cancer during the course of their standard medical treatment. We present novel findings that this intervention was considered beneficial for reducing anxiety around treatment and fear of disease progression. Men were supportive of the benefits of the intervention over conventional cancer survival discussion group

  5. Elucidation of the mechanism of suppressed steroidogenesis during androgen deprivation therapy of prostate cancer patients using a mouse model.

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    Taniguchi, H; Katano, T; Nishida, K; Kinoshita, H; Matsuda, T; Ito, S

    2016-09-01

    Androgen deprivation therapy (ADT) is the standard medical approach to the management of prostate cancer. Patients switched from a GnRH antagonist to a GnRH agonist, did not experience a testosterone surge in spite of the occurrence of luteinizing hormone (LH) surge in our protocol of clinical study. To clarify this observation, male mice pre-treated with two different doses of the GnRH antagonist degarelix for 28 days were further administered the GnRH agonist leuprolide or chorionic gonadotropin, and testosterone production of the mice was studied. Serum LH and testosterone levels, the size of Leydig cells, and expression level of steroidogenesis-related genes in the testis were analyzed. Treatment of mice with a high dose of degarelix (0.1 μg/mouse; HDG), but not a low dose (0.05 μg/mouse; LDG), for 28 days reproduced declined steroidogenesis observed in prostate cancer patients during ADT switched from a GnRH antagonist to a GnRH agonist. The size of the Leydig cells in the HDG mice was not significantly different from that in naive mice. Although expression levels of StAR, P450scc, and 17β HSD increased significantly in the LDH testis, those in the HDG testis did not change. Treatment of mice with a high dose of degarelix for 28 days reproduced the decline in steroidogenesis observed in prostate cancer patients during ADT. In this animal model, we demonstrated that initial ADT may inhibit the ability of Leydig cells to produce testosterone by suppressing the expression of genes involved in steroidogenesis, such as StAR, P450scc, and 17βHSD.

  6. Osteoporosis in men treated with androgen suppression therapy for prostate cancer.

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    Gholz, Ruth Canty; Conde, Francisco; Rutledge, Dana N

    2002-01-01

    Men with advanced or metastatic prostate cancer commonly receive long-term treatment with luteinizing hormone-releasing hormone (LHRH) agonist therapy. This prolonged treatment causes a hypogonadal state of chronic testosterone deficiency. Similar to estrogen deficiency in postmenopausal women, testosterone deficiency among these men negatively affects bone metabolism through a complex self-regulating, negative feedback system and subsequent reduction in bone formation. If left undetected or untreated, the risk for osteoporosis rises. Osteoporosis increases the likelihood of fracture, especially of the hips. Researchers are studying the effects of LHRH agonist therapy on osteoporosis and other related conditions to determine whether interventions, such as pharmacologic agents (e.g., bisphosphonates), dietary supplements (e.g., calcium, vitamin D), and exercise, can slow or prevent the process and assist healthcare providers in knowing how to counsel patients. Current recommendations are found in the literature on glucocorticoid-induced and menopausal osteoporosis. Nurses need to stay abreast of current knowledge in this area, as it is expanding rapidly.

  7. Protein phosphatase 1 suppresses androgen receptor ubiquitylation and degradation.

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    Liu, Xiaming; Han, Weiwei; Gulla, Sarah; Simon, Nicholas I; Gao, Yanfei; Cai, Changmeng; Yang, Hongmei; Zhang, Xiaoping; Liu, Jihong; Balk, Steven P; Chen, Shaoyong

    2016-01-12

    The phosphoprotein phosphatases are emerging as important androgen receptor (AR) regulators in prostate cancer (PCa). We reported previously that the protein phosphatase 1 catalytic subunit (PP1α) can enhance AR activity by dephosphorylating a site in the AR hinge region (Ser650) and thereby decrease AR nuclear export. In this study we show that PP1α increases the expression of wildtype as well as an S650A mutant AR, indicating that it is acting through one or more additional mechanisms. We next show that PP1α binds primarily to the AR ligand binding domain and decreases its ubiquitylation and degradation. Moreover, we find that the PP1α inhibitor tautomycin increases phosphorylation of AR ubiquitin ligases including SKP2 and MDM2 at sites that enhance their activity, providing a mechanism by which PP1α may suppress AR degradation. Significantly, the tautomycin mediated decrease in AR expression was most pronounced at low androgen levels or in the presence of the AR antagonist enzalutamide. Consistent with this finding, the sensitivity of LNCaP and C4-2 PCa cells to tautomycin, as assessed by PSA synthesis and proliferation, was enhanced at low androgen levels or by treatment with enzalutamide. Together these results indicate that PP1α may contribute to stabilizing AR protein after androgen deprivation therapies, and that targeting PP1α or the AR-PP1α interaction may be effective in castration-resistant prostate cancer (CRPC).

  8. A Phase 1/2 Trial of Brief Androgen Suppression and Stereotactic Radiation Therapy (FASTR) for High-Risk Prostate Cancer

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    Bauman, Glenn, E-mail: Glenn.bauman@lhsc.on.ca [Division of Radiation Oncology, Department of Oncology, Western University and London Regional Cancer Program, London, Ontario (Canada); Ferguson, Michelle [Department of Radiation Oncology, Allan Blair Cancer Centre, Regina, Saskatchewan (Canada); Lock, Michael; Chen, Jeff; Ahmad, Belal; Venkatesan, V.M.; Sexton, Tracy; D' Souza, David [Division of Radiation Oncology, Department of Oncology, Western University and London Regional Cancer Program, London, Ontario (Canada); Loblaw, Andrew [Department of Radiation Medicine, University of Toronto and Odette Cancer Center, Toronto, Ontario (Canada); Warner, Andrew; Rodrigues, George [Division of Radiation Oncology, Department of Oncology, Western University and London Regional Cancer Program, London, Ontario (Canada)

    2015-07-15

    Purpose: To initiate a phase 1/2 trial to examine the tolerability of a condensed combined-modality protocol for high-risk prostate cancer. Methods and Materials: Men scoring ≥3 on the Vulnerable Elderly Scale (VES) or refusing conventionally fractionated treatment for high-risk prostate cancer were eligible to participate. Androgen suppression was delivered for 12 months, and radiation therapy was delivered using 25 Gy to pelvic nodes delivered synchronously with 40 Gy to the prostate given as 1 fraction per week over 5 weeks. The phase 1 component included predetermined stopping rules based on 6-month treatment-related toxicity, with trial suspension specified if there were ≥6 of 15 patients (40%) or ≥3 of 15 (20%) who experienced grade ≥2 or ≥3 gastrointestinal (GI) or genitourinary (GU) toxicity, respectively. Results: Sixteen men were enrolled, with 7 men meeting the criteria of VES ≥3 and 9 men having a VES <3 but choosing the condensed treatment. One man was not treated owing to discovery of a synchronous primary rectal cancer. Four patients (26%) experienced grade ≥2 toxicity at 6 weeks after treatment. There were 9 of 15 (60%) who experienced grade ≥2 GI or GU toxicity and 4 of 15 (26%) grade ≥3 GI or GU toxicity at 6 months, and 5 of 15 (30%) grade ≥2 GI and GU toxicity at 6 months. A review of the 15 cases did not identify any remedial changes, thus the phase 1 criteria were not met. Conclusion: This novel condensed treatment had higher than anticipated late toxicities and was terminated before phase 2 accrual. Treatment factors, such as inclusion of pelvic lymph node radiation therapy, planning constraints, and treatment margins, or patient factors related to the specific frail elderly population may be contributing.

  9. Phase II Study of Long-Term Androgen Suppression With Bevacizumab and Intensity-Modulated Radiation Therapy (IMRT) in High-Risk Prostate Cancer

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    Vuky, Jacqueline, E-mail: vukyja@ohsu.edu [Section of Community Hematology/Oncology, Knight Cancer Institute, Oregon Health Sciences University, Portland, OR (United States); Pham, Huong T. [Section of Hematology/Oncology and Radiation Oncology, Virginia Mason Medical Center, Seattle, WA (United States); Warren, Sarah; Douglass, Erika [Benaroya Research Institute, Virginia Mason Medical Center, Seattle, WA (United States); Badiozamani, Kasra [Section of Hematology/Oncology and Radiation Oncology, Virginia Mason Medical Center, Seattle, WA (United States); Madsen, Berit; Hsi, Alex [Peninsula Cancer Center, Poulsbo, WA (United States); Song Guobin [Section of Hematology/Oncology and Radiation Oncology, Virginia Mason Medical Center, Seattle, WA (United States)

    2012-03-15

    Purpose: We report a Phase II trial assessing the acute and late toxicities of intensity-modulated radiation therapy (IMRT), long-term androgen suppression (LTAS), and bevacizumab in patients with high-risk localized prostate cancer. Methods and Materials: We treated 18 patients with LTAS with bicalutamide and goserelin in combination with bevacizumab and IMRT. Bevacizumab (10 mg/kg every 2 weeks) was administered for the first 16 weeks, and 15 mg/kg was then given every 3 weeks for 12 additional weeks, with an IMRT dose of 77.9 Gy to the prostate, 64.6 Gy to the seminal vesicles, and 57 Gy to the pelvic lymph nodes. Patients were eligible if they had clinical stage T2b to T4, a Gleason sum score of 8 to 10, or a prostate- specific antigen level of 20ng/mL or greater. The primary endpoint of the study was evaluation of acute and late toxicities. Results: The median age was 69 years, with a median pretreatment prostate-specific antigen level of 12.5 ng/mL and Gleason score of 8. The pretreatment clinical stage was T1c in 4 patients, T2 in 11, and T3 in 3. All patients completed IMRT with median follow-up of 34 months (range, 28-40 months) The most common Grade 2 or higher toxicities were hypertension (61% of patients with Grade 2 and 11% with Grade 3), proteinuria (28% with Grade 2 and 6% with Grade 3), and leucopenia (28% with Grade 2). No Grade 4 or higher acute toxicities were reported. Late toxicities included proctitis (6% of patients with Grade 2 and 11% with Grade 3), rectal bleeding (6% with Grade 2 and 11% with Grade 3), hematuria (6% with Grade 2), proteinuria (17% with Grade 2), hyponatremia (6% with Grade 3), cystitis (6% with Grade 3), and urinary retention (6% with Grade 2 and 11% with Grade 3). Grade 4 prostatitis occurred in 1 patient (6%). Conclusions: Bevacizumab does not appear to exacerbate the acute effects of IMRT. Late toxicities may have been worsened with this regimen. Further investigations of bevacizumab with LTAS and IMRT should be

  10. Androgen suppresses the proliferation of androgen receptor-positive castration-resistant prostate cancer cells via inhibition of Cdk2, CyclinA, and Skp2.

    Directory of Open Access Journals (Sweden)

    John M Kokontis

    Full Text Available The majority of prostate cancer (PCa patient receiving androgen ablation therapy eventually develop castration-resistant prostate cancer (CRPC. We previously reported that androgen treatment suppresses Skp2 and c-Myc through androgen receptor (AR and induced G1 cell cycle arrest in androgen-independent LNCaP 104-R2 cells, a late stage CRPC cell line model. However, the mechanism of androgenic regulation of Skp2 in CRPC cells was not fully understood. In this study, we investigated the androgenic regulation of Skp2 in two AR-positive CRPC cell line models, the LNCaP 104-R1 and PC-3AR Cells. The former one is an early stage androgen-independent LNCaP cells, while the later one is PC-3 cells re-expressing either wild type AR or mutant LNCaP AR. Proliferation of LNCaP 104-R1 and PC-3AR cells is not dependent on but is suppressed by androgen. We observed in this study that androgen treatment reduced protein expression of Cdk2, Cdk7, Cyclin A, cyclin H, Skp2, c-Myc, and E2F-1; lessened phosphorylation of Thr14, Tyr15, and Thr160 on Cdk2; decreased activity of Cdk2; induced protein level of p27(Kip1; and caused G1 cell cycle arrest in LNCaP 104-R1 cells and PC-3AR cells. Overexpression of Skp2 protein in LNCaP 104-R1 or PC-3AR cells partially blocked accumulation of p27(Kip1 and increased Cdk2 activity under androgen treatment, which partially blocked the androgenic suppressive effects on proliferation and cell cycle. Analyzing on-line gene array data of 214 normal and PCa samples indicated that gene expression of Skp2, Cdk2, and cyclin A positively correlates to each other, while Cdk7 negatively correlates to these genes. These observations suggested that androgen suppresses the proliferation of CRPC cells partially through inhibition of Cyclin A, Cdk2, and Skp2.

  11. Androgen suppresses the proliferation of androgen receptor-positive castration-resistant prostate cancer cells via inhibition of Cdk2, CyclinA, and Skp2.

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    Kokontis, John M; Lin, Hui-Ping; Jiang, Shih Sheng; Lin, Ching-Yu; Fukuchi, Junichi; Hiipakka, Richard A; Chung, Chi-Jung; Chan, Tzu-Min; Liao, Shutsung; Chang, Chung-Ho; Chuu, Chih-Pin

    2014-01-01

    The majority of prostate cancer (PCa) patient receiving androgen ablation therapy eventually develop castration-resistant prostate cancer (CRPC). We previously reported that androgen treatment suppresses Skp2 and c-Myc through androgen receptor (AR) and induced G1 cell cycle arrest in androgen-independent LNCaP 104-R2 cells, a late stage CRPC cell line model. However, the mechanism of androgenic regulation of Skp2 in CRPC cells was not fully understood. In this study, we investigated the androgenic regulation of Skp2 in two AR-positive CRPC cell line models, the LNCaP 104-R1 and PC-3AR Cells. The former one is an early stage androgen-independent LNCaP cells, while the later one is PC-3 cells re-expressing either wild type AR or mutant LNCaP AR. Proliferation of LNCaP 104-R1 and PC-3AR cells is not dependent on but is suppressed by androgen. We observed in this study that androgen treatment reduced protein expression of Cdk2, Cdk7, Cyclin A, cyclin H, Skp2, c-Myc, and E2F-1; lessened phosphorylation of Thr14, Tyr15, and Thr160 on Cdk2; decreased activity of Cdk2; induced protein level of p27(Kip1); and caused G1 cell cycle arrest in LNCaP 104-R1 cells and PC-3AR cells. Overexpression of Skp2 protein in LNCaP 104-R1 or PC-3AR cells partially blocked accumulation of p27(Kip1) and increased Cdk2 activity under androgen treatment, which partially blocked the androgenic suppressive effects on proliferation and cell cycle. Analyzing on-line gene array data of 214 normal and PCa samples indicated that gene expression of Skp2, Cdk2, and cyclin A positively correlates to each other, while Cdk7 negatively correlates to these genes. These observations suggested that androgen suppresses the proliferation of CRPC cells partially through inhibition of Cyclin A, Cdk2, and Skp2.

  12. Effect of androgen suppression compared with androgen receptor blockade on arterial stiffness in men with prostate cancer.

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    Dockery, Frances; Bulpitt, Christopher J; Agarwal, Sanjiv; Vernon, Clare; Rajkumar, Chakravarthi

    2009-01-01

    Endogenous testosterone and estradiol are thought to be cardio-protective in men. We wanted to determine the effects of 2 different anti-androgen therapies on arterial stiffness as one suppresses (goserelin--a gonadotrophin-releasing hormone analog) while the other increases (bicalutamide--an androgen receptor blocker) both testosterone and estradiol. We conducted a randomized trial on 43 men (mean age, 71.2 +/- 6.2 years) with localized prostate cancer. They received either goserelin or bicalutamide for 24 weeks. Carotid-femoral (C-F) and carotid-radial (C-R) pulse wave velocities (PWVs) were measured. Twenty age- and disease-matched men with prostate cancer on no active treatment were studied in a similar manner. After 12 weeks of goserelin, radial artery PWV increased significantly from baseline and a nonsignificant increase was observed in femoral PWV (change from baseline radial: +1.4 m/s, P = .002, femoral: +0.9 m/s, P = .127) Both PWV measures increased significantly with bicalutamide (change from baseline radial: +0.8, femoral: +0.9 m/s, P change from baseline radial: +1.7, femoral: +1.3 m/s, P change from baseline radial: +0.4, femoral: +0.4 m/s, P not significant [NS]); however, comparison of changes between the 2 drugs were not significantly different at either 12 or 24 weeks (P >or= .967 at 12 weeks and P >or= .07 at 24 weeks). The untreated men studied in parallel showed no changes at 12 or 24 weeks in either PWV measure. Anti-androgen treatment in men might increase large artery stiffness, an adverse cardiovascular risk factor; however, the effect was not maintained with testosterone receptor blockade, in the longer term, but tended to be sustained with suppression therapy. This could relate to the different sex hormone effects of the 2 therapies.

  13. Hematological changes during androgen deprivation therapy

    Institute of Scientific and Technical Information of China (English)

    Mathis Grossmann; Jeffrey D Zajac

    2012-01-01

    Androgen deprivation therapy (ADT) has been associated with a plethora of adverse effects,consistent with the androgen dependency of multiple reproductive and somatic tissues.One such tissue is the hemopoietic system,and one of the most predictable consequences of ADT is the development of anemia.Although anemia caused by ADT is rarely severe,ADT is often given to frail,elderly men with increased susceptibility to anemia due to multiple other causes.ADT-associated anemia may contribute to fatigue and reduced quality of life (QoL) in such men,although this requires further study.While anemia is an independent risk factor of mortality in men with prostate cancer,it is not known whether treatment of ADT-associated anemia alters clinically important outcomes,or whether treatment affects mortality.Awareness of the phenomenon of ADT-induced anemia should avoid unnecessary work-up in mild cases of normocytic normochromic anemia.However,assessment and treatment of more severe anemia may be required.This should be determined on an individual basis.In contrast to the well-described actions of ADT on erythrepoiesis,its effect on other hemopoietic lineages has been less well elucidated.While preclinical studies have found roles for androgens in maturation and differentiated function of neutrophils,lymphocytes and platelets,the implications of these findings for men with prostate cancer receiving ADT require further studies.

  14. Androgen deprivation therapy-associated vasomotor symptoms

    Institute of Scientific and Technical Information of China (English)

    Jason M Jones; Manish Kohli; Charles L Loprinzi

    2012-01-01

    Androgen deprivation therapy (ADT) is widely used as standard therapy in the treatment of locally advanced and metastatic prostate cancer.While efficacious,ADT is associated with multiple side effects,including decreased libido,erectile dysfunction,diabetes,loss of muscle tone and altered body composition,osteoporosis,lipid changes,memory loss,gynecomastia and hot flashes.The breadth of literature for the treatment of hot flashes is much smaller in men than that in women.While hormonal therapy of hot flashes has been shown to be effective,multiple non-hormonal medications and treatment methods have also been developed.This article reviews current options for the treatment of hot flashes in patients taking ADT.

  15. Cardiovascular physiology of androgens and androgen testosterone therapy in postmenopausal women.

    Science.gov (United States)

    Ling, Shanhong; Komesaroff, Paul A; Sudhir, Krishnankutty

    2009-03-01

    Women before menopause are at relatively lower risk of cardiovascular disease (CVD) compared with age-matched men and after menopause this gender advantage disappears. Androgen has been known to be an independent factor contributing to the higher male susceptibility to CVD, through adverse effects on lipids, blood pressure, and glucose metabolism. High androgen levels also contribute to CVD development in women with polycystic ovary syndrome as well as androgen abusing athletes and body builders. On the other hand, decline in androgen levels, as a result of ageing in men, is associated with hypertension, diabetes and atherosclerosis. Postmenopausal women, particularly those with oophorectomy are generally in low levels of sex hormones and androgen insufficiency is independently associated with the higher incidence of atherosclerosis in postmenopausal women. Androgen testosterone therapy (ATT) has been commonly used to improve well-being and libido in aging men with low androgen levels. The therapy has been demonstrated also to effectively reduce atherogenesis in these people. The use of ATT in postmenopausal women has increased in recent years and to date, however, the cardiovascular benefits of such therapy in these women remain uncertain. This review focuses on research regarding the impact of endogenous androgens and ATT on the cardiovascular physiology and CVD development in postmenopausal women.

  16. Selective androgen receptor modulators as improved androgen therapy for advanced breast cancer.

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    Coss, Christopher C; Jones, Amanda; Dalton, James T

    2014-11-01

    Androgens were at one time a therapeutic mainstay in the treatment of advanced breast cancer. Despite comparable efficacy, SERMs and aromatase inhibitors eventually became the therapies of choice due to in part to preferred side-effect profiles. Molecular characterization of breast tumors has revealed an abundance of androgen receptor expression but the choice of an appropriate androgen receptor ligand (agonist or antagonist) has been confounded by multiple conflicting reports concerning the role of the receptor in the disease. Modern clinical efforts have almost exclusively utilized antagonists. However, the recent clinical development of selective androgen receptor modulators with greatly improved side-effect profiles has renewed interest in androgen agonist therapy for advanced breast cancer.

  17. A nonlinear competitive model of the prostate tumor growth under intermittent androgen suppression.

    Science.gov (United States)

    Yang, Jing; Zhao, Tong-Jun; Yuan, Chang-Qing; Xie, Jing-Hui; Hao, Fang-Fang

    2016-09-01

    Hormone suppression has been the primary modality of treatment for prostate cancer. However long-term androgen deprivation may induce androgen-independent (AI) recurrence. Intermittent androgen suppression (IAS) is a potential way to delay or avoid the AI relapse. Mathematical models of tumor growth and treatment are simple while they are capable of capturing the essence of complicated interactions. Game theory models have analyzed that tumor cells can enhance their fitness by adopting genetically determined survival strategies. In this paper, we consider the survival strategies as the competitive advantage of tumor cells and propose a new model to mimic the prostate tumor growth in IAS therapy. Then we investigate the competition effect in tumor development by numerical simulations. The results indicate that successfully IAS-controlled states can be achieved even though the net growth rate of AI cells is positive for any androgen level. There is crucial difference between the previous models and the new one in the phase diagram of successful and unsuccessful tumor control by IAS administration, which means that the suggestions from the models for medication can be different. Furthermore we introduce quadratic logistic terms to the competition model to simulate the tumor growth in the environment with a finite carrying capacity considering the nutrients or inhibitors. The simulations show that the tumor growth can reach an equilibrium state or an oscillatory state with the net growth rate of AI cells being androgen independent. Our results suggest that the competition and the restraint of a limited environment can enhance the possibility of relapse prevention.

  18. Quantitative mathematical modeling of PSA dynamics of prostate cancer patients treated with intermittent androgen suppression

    Institute of Scientific and Technical Information of China (English)

    Yoshito Hirata; Koichiro Akakura; Celestia S.Higano; Nicholas Bruchovsky; Kazuyuki Aihara

    2012-01-01

    If a mathematical model is to be used in the diagnosis,treatment,or prognosis of a disease,it must describe the inherent quantitative dynamics of the state.An ideal candidate disease is prostate cancer owing to the fact that it is characterized by an excellent biomarker,prostate-specific antigen (PSA),and also by a predictable response to treatment in the form of androgen suppression therapy.Despite a high initial response rate,the cancer will often relapse to a state of androgen independence which no longer responds to manipulations of the hormonal environment.In this paper,we present relevant background information and a quantitative mathematical model that potentially can be used in the optimal management of patients to cope with biochemical relapse as indicated by a rising PSA.

  19. Androgen Receptor-Mediated Escape Mechanisms from Androgen Ablation Therapy

    Science.gov (United States)

    2005-10-01

    of CAG repeats in the Machado-Joseph disease , spinocerebellar ataxia type 1 and androgen receptor genes. Hum. Mol. Genet. 4, 1585-1590. Rundlett, S . E... diseases such as Huntington disease and spinal and bulbar muscular atro- phy, which is commonly called Kennedy’s disease . This finding has been attributed...STATEMENT: Approved for Public Release; Distribution Unlimited The views, opinions and/or findings contained in this report are those of the author( s ) and

  20. Androgen receptor roles in insulin resistance and obesity in males: the linkage of androgen-deprivation therapy to metabolic syndrome.

    Science.gov (United States)

    Yu, I-Chen; Lin, Hung-Yun; Sparks, Janet D; Yeh, Shuyuan; Chang, Chawnshang

    2014-10-01

    Prostate cancer (PCa) is one of the most frequently diagnosed malignancies in men. Androgen-deprivation therapy (ADT) is the first-line treatment and fundamental management for men with advanced PCa to suppress functions of androgen/androgen receptor (AR) signaling. ADT is effective at improving cancer symptoms and prolonging survival. However, epidemiological and clinical studies support the notion that testosterone deficiency in men leads to the development of metabolic syndrome that increases cardiovascular disease risk. The underlying mechanisms by which androgen/AR signaling regulates metabolic homeostasis in men are complex, and in this review, we discuss molecular mechanisms mediated by AR signaling that link ADT to metabolic syndrome. Results derived from various AR knockout mouse models reveal tissue-specific AR signaling that is involved in regulation of metabolism. These data suggest that steps be taken early to manage metabolic complications associated with PCa patients receiving ADT, which could be accomplished using tissue-selective modulation of AR signaling and by treatment with insulin-sensitizing agents.

  1. A Counterregulatory Mechanism Impacting Androgen Suppression Therapy

    Science.gov (United States)

    2016-03-01

    project activities, for the purpose of enhancing public understanding and increasing interest in learning and careers in science, technology, and the...study questionnaires , and surveys, etc. 15 1 Curriculum Vitae David Brian Wilson, M.D., Ph.D. Date: March 15, 2016 Address and Telephone...Clean-up XS kit (Machrey-Nagel, Düren, Germany). RNA quality was assessed via Bioanalyzer ( Agilent , Santa Clara, CA). Array hy- bridization was

  2. A Counterregulatory Mechanism Impacting Androgen Suppression Therapy

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    2016-08-01

    etc. 11 Curriculum Vitae David B. Wilson, M.D., Ph.D. Date: 7/13/2016 3:23:26 PM Personal Information Birthplace: Berkeley, CA Citizenship: USA ...JP, St Peter S, Sharma M, Davidoff AM, Nottage K, Bernabe K, Wilson DB, Dutta S, Glader B, Crary SE, Dassinger MS, Dunbar L, Islam S, Kumar M, Rescorla...Dunbar L, Islam S, Kumar M, Rescorla F, Bruch S, Campbell A, Austin M, Sidonio R, Blakely ML, Rice HE, Splenectomy in Congenital Hemolytic Anemia

  3. Loss of androgen receptor-dependent growth suppression by prostate cancer cells can occur independently from acquiring oncogenic addiction to androgen receptor signaling.

    Directory of Open Access Journals (Sweden)

    Jason M D'Antonio

    Full Text Available The conversion of androgen receptor (AR signaling as a mechanism of growth suppression of normal prostate epithelial cells to that of growth stimulation in prostate cancer cells is often associated with AR mutation, amplification and over-expression. Thus, down-regulation of AR signaling is commonly therapeutic for prostate cancer. The E006AA cell line was established from a hormone naïve, localized prostate cancer. E006AA cells are genetically aneuploid and grow equally well when xenografted into either intact or castrated male NOG but not nude mice. These cells exhibit: 1 X chromosome duplication and AR gene amplification, although paradoxically not coupled with increased AR expression, and 2 somatic, dominant-negative Serine-599-Glycine loss-of-function mutation within the dimerization surface of the DNA binding domain of the AR gene. No effect on the growth of E006AA cells is observed using targeted knockdown of endogenous mutant AR, ectopic expression of wild-type AR, or treatment with androgens or anti-androgens. E006AA cells represent a prototype for a newly identified subtype of prostate cancer cells that exhibit a dominant-negative AR loss-of-function in a hormonally naïve patient. Such loss-of-function eliminates AR-mediated growth suppression normally induced by normal physiological levels of androgens, thus producing a selective growth advantage for these malignant cells in hormonally naïve patients. These data highlight that loss of AR-mediated growth suppression is an independent process, and that, without additional changes, is insufficient for acquiring oncogene addiction to AR signaling. Thus, patients with prostate cancer cells harboring such AR loss-of-function mutations will not benefit from aggressive hormone or anti-AR therapies even though they express AR protein.

  4. [Androgen-deprivation therapy in prostate cancer: clinical evidence and future perspectives].

    Science.gov (United States)

    Pinto, F; Calarco, A; Totaro, A; Sacco, E; Volpe, A; Racioppi, M; D'Addessi, A; Bassi, P F

    2010-01-01

    Androgens are involved in the development and progression of prostate cancer even if the mechanism is not well-recognized. For this reason androgen-deprivation therapy remains a milestone for the treatment of patients with advanced and metastatic disease and, in the last years, in conjunction with radiotherapy and surgery in locally advanced tumors. Alternative options, such as intermittent deprivation suppression, seem to be promising in terms of clinical benefits and toxicity profile. However, current therapies present side effects, such as testosterone surge with consequent clinical flare-up, metabolic syndrome and hormone-resistance, which develops after a variable number of years. Novel therapies such as LH-RH antagonists and prolonged depot LH-RH analogues have been developed in order to avoid clinical flare-up and testosterone microsurges. Novel androgen synthesis inhibitors, such as abiraterone acetate and MDV3100, have been recently discovered and tested as promising hormonal second-line agents in patients with castration-resistant prostate cancer. Finally, long-term side effects from androgen deprivation, such as osteoporosis, sarcopenic obesity and cardiovascular morbidity should be carefully monitored and properly treated.

  5. Testicular steroidogenesis is locally regulated by androgen via suppression of Nur77.

    Science.gov (United States)

    Song, Chin-Hee; Gong, Eun-Yeung; Park, Ji soo; Lee, Keesook

    2012-06-01

    Steroidogenesis in the testis is regulated by a negative feedback mechanism through the hypothalamus-pituitary-testis axis. Recent studies suggest that besides this long-loop regulation, testicular steroidogenesis is also locally regulated by androgen. However, the molecular mechanism behind this additional regulatory pathway has been poorly addressed. In the present study, we demonstrate that liganded androgen receptor (AR) suppresses the transcriptional activity of Nur77 on steroidogenic enzyme gene promoters, affecting testicular steroidogenesis. AR physically interacts and colocalizes with Nur77 in the nucleus in the presence of androgen. AR inhibits Nur77 transactivation by competing mainly with coactivators such as SRC-1 for Nur77 binding. These results suggest that androgen, through binding to AR, directly acts as a signal inhibiting the expression of steroidogenic enzyme genes in Leydig cells, eventually resulting in decreased testicular steroidogenesis. These findings strongly support the hypothesis that androgen acts locally to regulate testicular steroidogenesis, and may provide its action mechanism.

  6. Impact of androgen deprivation therapy on sexual function

    Institute of Scientific and Technical Information of China (English)

    Clarisse R Mazzola; John P Mulhall

    2012-01-01

    Many patients with prostate cancer for whom androgen deprivation therapy (ADT) is indicated are young and desire to remain sexually active.In such patients,the side effects of androgen therapy on sexual function can be a source of serious reduction in overall quality of life.Providing the appropriate treatment options in this patient population is therefore essential.Nevertheless,treating such patients is challenging and an understanding of the underlying mechanisms of sexual physiology and pathophysiology is crucial to optimal patient care.In this paper,we reviewed what was known regarding the effects of ADT on sexual function in animal models and we also provided a detailed review on the effects of ADT on sexual health in humans and its treatment.

  7. Type I Collagen Synthesis Marker Procollagen I N-Terminal Peptide (PINP) in Prostate Cancer Patients Undergoing Intermittent Androgen Suppression

    Energy Technology Data Exchange (ETDEWEB)

    Hamilton, Gerhard, E-mail: gerhard.hamilton@toc.lbg.ac.at; Olszewski-Hamilton, Ulrike [Ludwig Boltzmann Cluster of Translational of Oncology, Nussdorfer Strasse 64, Vienna A-1090 (Austria); Theyer, Gerhard [Hospital Kittsee, Kittsee A-2421, Burgenland (Austria)

    2011-09-15

    Intermittent androgen suppression (IAS) therapy for prostate cancer patients attempts to maintain the hormone dependence of the tumor cells by cycles alternating between androgen suppression (AS) and treatment cessation till a certain prostate-specific antigen (PSA) threshold is reached. Side effects are expected to be reduced, compared to standard continuous androgen suppression (CAS) therapy. The present study examined the effect of IAS on bone metabolism by determinations of serum procollagen I N-terminal peptide (PINP), a biochemical marker of collagen synthesis. A total of 105 treatment cycles of 58 patients with prostate cancer stages ≥pT2 was studied assessing testosterone, PSA and PINP levels at monthly intervals. During phases of AS lasting for up to nine months PSA levels were reversibly reduced, indicating apoptotic regression of the prostatic tumors. Within the first cycle PINP increased at the end of the AS period and peaked in the treatment cessation phase. During the following two cycles a similar pattern was observed for PINP, except a break in collagen synthesis as indicated by low PINP levels in the first months off treatment. Therefore, measurements of the serum PINP concentration indicated increased bone matrix synthesis in response to >6 months of AS, which uninterruptedly continued into the first treatment cessation phase, with a break into each of the following two pauses. In summary, synthesis of bone matrix collagen increases while degradation decreases during off-treatment phases in patients undergoing IAS. Although a direct relationship between bone matrix turnover and risk of fractures is difficult to establish, IAS for treatment of biochemical progression of prostate tumors is expected to reduce osteoporosis in elderly men often at high risk for bone fractures representing a highly suitable patient population for this kind of therapy.

  8. Emerging potential of parenteral estrogen as androgen deprivation therapy for prostate cancer

    Directory of Open Access Journals (Sweden)

    Syed Imran Ali Shah

    2015-01-01

    Full Text Available Androgen deprivation therapy (ADT is a key management strategy for prostate cancer (PC, achieved commonly by administration of luteinizing hormone-releasing hormone agonist (LHRHa, ADT markedly suppresses both male and female sex hormones which results in "castration syndrome", a constellation of adverse events such as muscle weakness, impairment of glucose and lipid metabolism, impotence, osteoporosis, and fractures. Recent evidence suggests that estrogen, in the parenteral form, may emerge as an alternative to LHRHa as it offers potential benefits of arresting PC growth as well as avoiding some of the estrogen deficiency related toxicities of LHRHa by maintaining endogenous levels of estrogen.

  9. Chemical Suppression of the Reactivated Androgen Signaling Pathway in Androgen-Independent Prostate Cancer

    Science.gov (United States)

    2011-07-01

    of cyclopamine on androgen signaling in LNCaP cells. (A) Real time qPCR was used to measure relative expression of KLK3, KLK2, PGC or SHH mRNA in...response to Shh signaling . Science 1998, 280:1603-1607. 20. Chen JK, Taipale J, Cooper MK, Beachy PA: Inhibition of Hedgehog signaling by direct...body, although all can simi- larly engage with receptor to initiate the signaling process. Shh is synthesized as a propolypeptide that is processed

  10. Catalytic inhibitors of DNA topoisomerase II suppress the androgen receptor signaling and prostate cancer progression.

    Science.gov (United States)

    Li, Haolong; Xie, Ning; Gleave, Martin E; Dong, Xuesen

    2015-08-21

    Although the new generation of androgen receptor (AR) antagonists like enzalutamide (ENZ) prolong survival of metastatic castration-resistant prostate cancer (CRPC), AR-driven tumors eventually recur indicating that additional therapies are required to fully block AR function. Since DNA topoisomerase II (Topo II) was demonstrated to be essential for AR to initiate gene transcription, this study tested whether catalytic inhibitors of Topo II can block AR signaling and suppress ENZ-resistant CRPC growth. Using multiple prostate cancer cell lines, we showed that catalytic Topo II inhibitors, ICRF187 and ICRF193 inhibited transcription activities of the wild-type AR, mutant ARs (F876L and W741C) and the AR-V7 splice variant. ICRF187 and ICRF193 decreased AR recruitment to target promoters and reduced AR nuclear localization. Both ICRF187 and ICRF193 also inhibited cell proliferation and delayed cell cycling at the G2/M phase. ICRF187 inhibited tumor growth of castration-resistant LNCaP and 22RV1 xenografts as well as ENZ-resistant MR49F xenografts. We conclude that catalytic Topo II inhibitors can block AR signaling and inhibit tumor growth of CRPC xenografts, identifying a potential co-targeting approach using these inhibitors in combination with AR pathway inhibitors in CRPC.

  11. Time to raise awareness regarding complications of androgen deprivation therapy

    Institute of Scientific and Technical Information of China (English)

    Shehzad Basaria

    2012-01-01

    No treatment is devoid of adverse effects,and androgen deprivation therapy (ADT) in men with prostate cancer (PCa) bears no exception.PCa is the most common non-cutaneous malignancy in men worldwide.In 2011,approximately 240 890 new cases of PCa were diagnosed in the United States and 33 720 men died because of the disease.1 In intermediate- and high-risk patients with locally advanced disease,ADT,when added to external bean radiation therapy,has shown improved survival,while in men with metastatic PCa,ADT improves quality of life (QoL).2-4 However,patients with localized cancer and those encountering biochemical recurrences after definitive therapy are also being started on ADT,even though survival advantage has not been conclusively demonstrated in these clinical settings.As a result,the use of ADT has significantly increased in the last 15 years.

  12. External Beam Radiation Therapy and Abiraterone in Men With Localized Prostate Cancer: Safety and Effect on Tissue Androgens

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Eunpi [University of Washington School of Medicine, Seattle, Washington (United States); Fred Hutchinson Cancer Research Center, Seattle, Washington (United States); Mostaghel, Elahe A. [Fred Hutchinson Cancer Research Center, Seattle, Washington (United States); Russell, Kenneth J.; Liao, Jay J.; Konodi, Mark A. [University of Washington School of Medicine, Seattle, Washington (United States); Kurland, Brenda F. [University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Marck, Brett T. [Veterans Affairs Puget Sound Health Care System, Seattle, Washington (United States); Matsumoto, Alvin M. [University of Washington School of Medicine, Seattle, Washington (United States); Veterans Affairs Puget Sound Health Care System, Seattle, Washington (United States); Dalkin, Bruce L. [University of Washington School of Medicine, Seattle, Washington (United States); Montgomery, R. Bruce, E-mail: rbmontgo@uw.edu [University of Washington School of Medicine, Seattle, Washington (United States)

    2015-06-01

    Purpose: Optimizing androgen suppression may provide better control of localized prostate cancer (PCa). Numerous trials have supported the benefit of combining androgen deprivation therapy with definitive radiation therapy in men with locally advanced or high-grade disease. Addition of abiraterone to luteinizing hormone-releasing hormone agonist (LHRHa) with radiation has not been reported. We examined the safety of this combination as well as its impact on androgen suppression. Methods and Materials: A prospective, phase 2 study was conducted in men with localized PCa treated with 6 months of neoadjuvant and concurrent abiraterone with LHRHa and radiation. Duration of adjuvant LHRHa was at the discretion of the treating clinician. Prostate biopsy assays were obtained prior to the start of therapy and prior to radiation. Sera and tissue androgen levels were measured by liquid chromatography-tandem mass spectrometry. Results: A total of 22 men with intermediate- (n=3) and high-risk PCa (n=19) received study therapy. Sixteen men completed the intended course of abiraterone, and 19 men completed planned radiation to 77.4 to 81 Gy. Radiation to pelvic nodes was administered in 20 men. The following grade 3 toxicities were reported: lymphopenia (14 patients), fatigue (1 patient), transaminitis (2 patients), hypertension (2 patients), and hypokalemia (1 patient). There were no grade 4 toxicities. All 21 men who complied with at least 3 months of abiraterone therapy had a preradiation prostate-specific antigen (PSA) concentration nadir of <0.3 ng/mL. Median levels of tissue androgen downstream of CYP17A were significantly suppressed after treatment with abiraterone, and upstream steroids were increased. At median follow-up of 21 months (range: 3-37 months), only 1 patient (who had discontinued abiraterone at 3 months) had biochemical relapse. Conclusions: Addition of abiraterone to LHRHa with radiation is safe and achieves effective prostatic androgen suppression

  13. ASC-J9(®) suppresses castration resistant prostate cancer progression via degrading the enzalutamide-induced androgen receptor mutant AR-F876L.

    Science.gov (United States)

    Wang, Ronghao; Lin, Wanying; Lin, Changyi; Li, Lei; Sun, Yin; Chang, Chawnshang

    2016-08-28

    Androgen deprivation therapy (ADT) with the newly developed powerful anti-androgen enzalutamide (Enz, also known as MDV3100) has promising therapeutic effects to suppress castration resistant prostate cancer (CRPC) and extending patients' lives an extra 4.8 months. However, most Enz therapy eventually fails with the development of Enz resistance. The detailed mechanisms how CRPC develops Enz resistance remain unclear and may involve multiple mechanisms. Among them, the induction of the androgen receptor (AR) mutant AR-F876L in some CRPC patients may represent one driving force that confers Enz resistance. Here, we demonstrate that the AR degradation enhancer, ASC-J9(®), not only degrades wild-type AR, but also has the ability to target AR-F876L. The consequence of suppressing AR-F876L may then abrogate AR-F876L mediated CRPC cell proliferation and metastasis. Thus, developing ASC-J9(®) as a new therapeutic approach may represent a novel therapy to better suppress CRPC that has already developed Enz resistance.

  14. A Phase 3 Trial of 2 Years of Androgen Suppression and Radiation Therapy With or Without Adjuvant Chemotherapy for High-Risk Prostate Cancer: Final Results of Radiation Therapy Oncology Group Phase 3 Randomized Trial NRG Oncology RTOG 9902

    Energy Technology Data Exchange (ETDEWEB)

    Rosenthal, Seth A., E-mail: rosents@sutterhealth.org [Radiation Oncology, Sutter Cancer Centers, Roseville, California (United States); Hunt, Daniel [NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania (United States); Sartor, A. Oliver [Tulane University Medical Center, New Orleans, Louisiana (United States); Pienta, Kenneth J. [Johns Hopkins School of Medicine, Baltimore, Maryland (United States); Gomella, Leonard [Thomas Jefferson University Hospital, Philadelphia, Pennsylvania (United States); Grignon, David [Indiana University, Bloomington, Indiana (United States); Rajan, Raghu [McGill University, Montreal, Quebec (Canada); Kerlin, Kevin J. [Community Clinical Oncology Program, Southeast Cancer Control Consortium, Inc, Winston-Salem, North Carolina (United States); Jones, Christopher U. [Radiation Oncology, Sutter Cancer Centers, Roseville, California (United States); Radiological Associates of Sacramento, Sacramento, California (United States); Dobelbower, Michael [University of Alabama at Birmingham Medical Center, Birmingham, Alabama (United States); Shipley, William U. [Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (United States); Zeitzer, Kenneth [Albert Einstein Medical Center, Bronx, New York (United States); Hamstra, Daniel A. [University of Michigan Medical Center, Ann Arbor, Michigan (United States); Donavanik, Viroon [Christiana Care Health Services, Inc, Wilmington, Delaware (United States); Rotman, Marvin [State University of New York Health Science Center–Brooklyn, Brooklyn, New York (United States); Hartford, Alan C. [Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire (United States); Michalski, Jeffrey [Washington University, St. Louis, Missouri (United States); Seider, Michael [Akron City Hospital, Akron, Ohio (United States); Kim, Harold [Wayne State University, Detroit, Michigan (United States); and others

    2015-10-01

    Purpose: Long-term (LT) androgen suppression (AS) with radiation therapy (RT) is a standard treatment of high-risk, localized prostate cancer (PCa). Radiation Therapy Oncology Group 9902 was a randomized trial testing the hypothesis that adjuvant combination chemotherapy (CT) with paclitaxel, estramustine, and oral etoposide plus LT AS plus RT would improve overall survival (OS). Methods and Materials: Patients with high-risk PCa (prostate-specific antigen 20-100 ng/mL and Gleason score [GS] ≥7 or clinical stage ≥T2 and GS ≥8) were randomized to RT and AS (AS + RT) alone or with adjuvant CT (AS + RT + CT). CT was given as four 21-day cycles, delivered beginning 28 days after 70.2 Gy of RT. AS was given as luteinizing hormone-releasing hormone for 24 months, beginning 2 months before RT plus an oral antiandrogen for 4 months before and during RT. The study was designed based on a 6% improvement in OS from 79% to 85% at 5 years, with 90% power and a 2-sided alpha of 0.05. Results: A total of 397 patients (380 eligible) were randomized. The patients had high-risk PCa, 68% with GS 8 to 10 and 34% T3 to T4 tumors, and median prostate-specific antigen of 22.6 ng/mL. The median follow-up period was 9.2 years. The trial closed early because of excess thromboembolic toxicity in the CT arm. The 10-year results for all randomized patients revealed no significant difference between the AS + RT and AS + RT + CT arms in OS (65% vs 63%; P=.81), biochemical failure (58% vs 54%; P=.82), local progression (11% vs 7%; P=.09), distant metastases (16% vs 14%; P=.42), or disease-free survival (22% vs 26%; P=.61). Conclusions: NRG Oncology RTOG 9902 showed no significant differences in OS, biochemical failure, local progression, distant metastases, or disease-free survival with the addition of adjuvant CT to LT AS + RT. The trial results provide valuable data regarding the natural history of high-risk PCa treated with LT AS + RT and have implications for

  15. Hypoxia-Independent Downregulation of Hypoxia-Inducible Factor 1 Targets by Androgen Deprivation Therapy in Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Ragnum, Harald Bull [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Røe, Kathrine [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Division of Medicine, Department of Oncology, Akershus University Hospital, Lørenskog (Norway); Holm, Ruth; Vlatkovic, Ljiljana [Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Nesland, Jahn Marthin [Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Medical Faculty, University of Oslo, Oslo (Norway); Aarnes, Eva-Katrine [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Ree, Anne Hansen [Division of Medicine, Department of Oncology, Akershus University Hospital, Lørenskog (Norway); Medical Faculty, University of Oslo, Oslo (Norway); Flatmark, Kjersti [Department of Tumor Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Department of Gastrointestinal Surgery, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Seierstad, Therese [Department of Radiology and Nuclear Medicine, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Faculty of Health Sciences, Buskerud University College, Drammen (Norway); Lilleby, Wolfgang [Department of Oncology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Lyng, Heidi, E-mail: heidi.lyng@rr-research.no [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway)

    2013-11-15

    Purpose: We explored changes in hypoxia-inducible factor 1 (HIF1) signaling during androgen deprivation therapy (ADT) of androgen-sensitive prostate cancer xenografts under conditions in which no significant change in immunostaining of the hypoxia marker pimonidazole had occurred. Methods and Materials: Gene expression profiles of volume-matched androgen-exposed and androgen-deprived CWR22 xenografts, with similar pimonidazole-positive fractions, were compared. Direct targets of androgen receptor (AR) and HIF1 transcription factors were identified among the differentially expressed genes by using published lists. Biological processes affected by ADT were determined by gene ontology analysis. HIF1α protein expression in xenografts and biopsy samples from 35 patients receiving neoadjuvant ADT was assessed by immunohistochemistry. Results: A total of 1344 genes showed more than 2-fold change in expression by ADT, including 35 downregulated and 5 upregulated HIF1 targets. Six genes were shared HIF1 and AR targets, and their downregulation was confirmed with quantitative RT-PCR. Significant suppression of the biological processes proliferation, metabolism, and stress response in androgen-deprived xenografts was found, consistent with tumor regression. Nineteen downregulated HIF1 targets were involved in those significant biological processes, most of them in metabolism. Four of these were shared AR and HIF1 targets, including genes encoding the regulatory glycolytic proteins HK2, PFKFB3, and SLC2A1. Most of the downregulated HIF1 targets were induced by hypoxia in androgen-responsive prostate cancer cell lines, confirming their role as hypoxia-responsive HIF1 targets in prostate cancer. Downregulation of HIF1 targets was consistent with the absence of HIF1α protein in xenografts and downregulation in patients by ADT (P<.001). Conclusions: AR repression by ADT may lead to downregulation of HIF1 signaling independently of hypoxic fraction, and this may contribute to

  16. Androgens and the breast.

    Science.gov (United States)

    Dimitrakakis, Constantine; Bondy, Carolyn

    2009-01-01

    Androgens have important physiological effects in women while at the same time they may be implicated in breast cancer pathologies. However, data on the effects of androgens on mammary epithelial proliferation and/or breast cancer incidence are not in full agreement. We performed a literature review evaluating current clinical, genetic and epidemiological data regarding the role of androgens in mammary growth and neoplasia. Epidemiological studies appear to have significant methodological limitations and thus provide inconclusive results. The study of molecular defects involving androgenic pathways in breast cancer is still in its infancy. Clinical and nonhuman primate studies suggest that androgens inhibit mammary epithelial proliferation and breast growth while conventional estrogen treatment suppresses endogenous androgens. Abundant clinical evidence suggests that androgens normally inhibit mammary epithelial proliferation and breast growth. Suppression of androgens using conventional estrogen treatment may thus enhance estrogenic breast stimulation and possibly breast cancer risk. Addition of testosterone to the usual hormone therapy regimen may diminish the estrogen/progestin increase in breast cancer risk but the impact of this combined use on mammary gland homeostasis still needs evaluation.

  17. A Phase 3 Protocol of Total Androgen Suppression and Radiation Therapy (RT) vs. TAS and RT Followed by Chemotherapy with Paclitaxel, Estramustine, and Etoposide for Localized, High Risk, Prostate Cancer

    Science.gov (United States)

    2014-05-13

    Paclitaxelkestramustine, and Etopside (TEE) for Localized, High-Risk, Society of Clinical Rajan R, Kerlin K, Prostate Cancer Oncology (ASCO) Michalski J...Therapy and Radiation Therapy (RT) vs. Kerlin K, Michalski J, Long-Term AS+ RT Alone in the Management of High-Risk Prostate Sandler H. Cancer

  18. Androgen-androgen receptor system improves chronic inflammatory conditions by suppressing monocyte chemoattractant protein-1 gene expression in adipocytes via transcriptional regulation.

    Science.gov (United States)

    Morooka, Nobukatsu; Ueguri, Kei; Yee, Karen Kar Lye; Yanase, Toshihiko; Sato, Takashi

    2016-09-02

    Age-related decreases in sex hormones are closely related to chronic inflammation in obesity and metabolic diseases. Particularly, the molecular basis of androgen activity in regulating inflammation and controlling metabolism remains largely unknown. Obese adipocytes secrete monocyte chemoattractant protein-1 (MCP-1), a key chemokine that promotes the infiltration of monocytes/macrophages into adipose tissue, thereby leading to metabolic disorders. Here, we studied the role of androgen-androgen receptor (AR) action in regulating MCP-1 expression in adipose tissue. We observed the induction of Mcp-1 expression in 3T3-L1 adipocytes co-cultured with RAW264.7 macrophages. Additionally, Mcp-1 expression was upregulated by culturing in conditioned medium derived from inflammatory macrophages (M1-Mφ) containing tumor necrosis factor-alpha (TNF-α). We found that sex hormones downregulated TNF-α-induced Mcp-1 and interleukin (Il)-6 expression in 3T3-L1 adipocytes. Furthermore, luciferase-reporter analysis indicated that MCP-1 promoter activity was predominantly suppressed by dihydrotestosterone (DHT)-AR interactions through functional canonical nuclear factor-kappa B (NF-κB) sites, whereas non-canonical NF-κB site containing important flanking sequences exhibited minor contributions to DHT-AR transcriptional repression. These findings suggested that androgen-AR suppressed obesity-induced chronic inflammation in adipose tissue.

  19. Peripheral androgen receptor gene suppression rescues disease in mouse models of spinal and bulbar muscular atrophy.

    Science.gov (United States)

    Lieberman, Andrew P; Yu, Zhigang; Murray, Sue; Peralta, Raechel; Low, Audrey; Guo, Shuling; Yu, Xing Xian; Cortes, Constanza J; Bennett, C Frank; Monia, Brett P; La Spada, Albert R; Hung, Gene

    2014-05-01

    Spinal and bulbar muscular atrophy (SBMA) is caused by the polyglutamine androgen receptor (polyQ-AR), a protein expressed by both lower motor neurons and skeletal muscle. Although viewed as a motor neuronopathy, data from patients and mouse models suggest that muscle contributes to disease pathogenesis. Here, we tested this hypothesis using AR113Q knockin and human bacterial artificial chromosome/clone (BAC) transgenic mice that express the full-length polyQ-AR and display androgen-dependent weakness, muscle atrophy, and early death. We developed antisense oligonucleotides that suppressed AR gene expression in the periphery but not the CNS after subcutaneous administration. Suppression of polyQ-AR in the periphery rescued deficits in muscle weight, fiber size, and grip strength, reversed changes in muscle gene expression, and extended the lifespan of mutant males. We conclude that polyQ-AR expression in the periphery is an important contributor to pathology in SBMA mice and that peripheral administration of therapeutics should be explored for SBMA patients.

  20. Peripheral Androgen Receptor Gene Suppression Rescues Disease in Mouse Models of Spinal and Bulbar Muscular Atrophy

    Directory of Open Access Journals (Sweden)

    Andrew P. Lieberman

    2014-05-01

    Full Text Available Spinal and bulbar muscular atrophy (SBMA is caused by the polyglutamine androgen receptor (polyQ-AR, a protein expressed by both lower motor neurons and skeletal muscle. Although viewed as a motor neuronopathy, data from patients and mouse models suggest that muscle contributes to disease pathogenesis. Here, we tested this hypothesis using AR113Q knockin and human bacterial artificial chromosome/clone (BAC transgenic mice that express the full-length polyQ-AR and display androgen-dependent weakness, muscle atrophy, and early death. We developed antisense oligonucleotides that suppressed AR gene expression in the periphery but not the CNS after subcutaneous administration. Suppression of polyQ-AR in the periphery rescued deficits in muscle weight, fiber size, and grip strength, reversed changes in muscle gene expression, and extended the lifespan of mutant males. We conclude that polyQ-AR expression in the periphery is an important contributor to pathology in SBMA mice and that peripheral administration of therapeutics should be explored for SBMA patients.

  1. The androgen receptor is transcriptionally suppressed by proteins that bind single-stranded DNA.

    Science.gov (United States)

    Grossmann, M E; Tindall, D J

    1995-05-01

    The androgen receptor (AR) is a nuclear transcription factor that is essential for development of the male urogenital tract. In the current work, we have characterized the mouse androgen receptor suppressor (mARS). A single, 20-base pair, region (TCCCCCCACCCACCCCC-CCT) was sufficient for suppression in chloramphenicol acetyltransferase assays. Northern analysis indicated that translational regulation is not necessary for the suppression. Analysis of the AR mRNA half-life indicated that the mARS does not affect AR RNA degradation. Gel mobility assays showed that the mARS is bound by multiple proteins that can recognize single-stranded DNA and RNA. In addition, differing proteins are expressed in distinct tissues. Purification of some of these proteins has shown that a doublet of 33 and 35 kDa binds to the G-rich strand and that a 52-kDa protein binds to the C-rich strand. Southwestern blots have confirmed that these proteins are indeed recognized by the mARS. The results of these experiments indicate that the AR 5'-untranslated region contains a suppressor element that can be bound by multiple proteins. The mARS appears to be acting either by altering transcription initiation or blocking transcription elongation. Characterization of this suppressor may provide insight into the physiological means by which the AR is regulated.

  2. Exercise can prevent and even reverse adverse effects of androgen suppression treatment in men with prostate cancer.

    Science.gov (United States)

    Galvão, D A; Taaffe, D R; Spry, N; Newton, R U

    2007-01-01

    Side effects accompanying androgen deprivation therapy (ADT), including sarcopenia, loss of bone mass and reduction in muscle strength, can compromise physical function, particularly in older patients. Exercise, specifically resistance training, may be an effective and cost-efficient strategy to limit or even reverse some of these adverse effects during and following therapy. In this review, we discuss common morphological and physiological ADT-related side effects or 'Androgen Deprivation and Sarcopenia-Related Disorders' and the existing clinical trials incorporating physical exercise in prostate cancer patients receiving active therapy. Further, training concepts and guidelines are provided for prescribing resistance exercise programs for this population.

  3. Male osteoporosis and androgenic therapy: from testosterone to SARMs.

    Science.gov (United States)

    Cilotti, Antonio; Falchetti, Alberto

    2009-09-01

    As in the women, male osteoporosis represents an important social problem, amplified by the increasing life expectance.Differently from women, 50% of male osteoporosis is secondary to treatments and/or diseases that make mandatory their search through an accurate clinical investigations in every newly diagnosed osteoporotic men. Male osteoporosis is frequently underdiagnosed and consequently undertreated, and too often it is revealed only after the occurrence of a fragility fracture. Androgens may prevent the loss of cancellous bone and stimulate periosteal cortical bone apposition. The anabolic effect of testosterone on both bone and muscle, is limited by the high incidence of androgenic side effects. Hypogonadism is the only situation where the benefits of the use of testosterone formulations exceed the side effects. Selective androgen receptor modulators can dissociate androgenic and anabolic effect on different tissues with various strategies. Many compounds have been studied with positive results in vivo and in clinical trials.

  4. Single strand conformation polymorphism analysis of androgen receptor gene mutations in patients with androgen insensitivity syndromes: Application for diagnosis, genetic counseling, and therapy

    Energy Technology Data Exchange (ETDEWEB)

    Hiort, O. (Medizinische Universitaet zu Luebeck (Germany) Tufts-New England Medical Center, Boston, MA (United States)); Huang, Q. (Massachusetts Eye and Ear Infirmary, Boston, MA (United States)); Sinnecker, G.H.G.; Kruse, K. (Medizinische Universitaet zu Luebeck (Germany)); Sadeghi-Nejad, A.; Wolfe, H.J. (Tufts-New England Medical Center, Boston, MA (United States)); Yandell, D.W. (Massachusetts Eye and Ear Infirmary, Boston, MA (United States))(Harvard Medical School, Boston, MA (United States) Harvard School of Public Health, Boston, MA (United States))

    1993-07-01

    Recent studies indicate that mutations in the androgen receptor gene are associated with androgen insensitivity syndromes, a heterogeneous group of related disorders involving defective sexual differentiation in karyotypic males. In this report, the authors address the possibility of rapid mutational analysis of the androgen receptor gene for initial diagnosis, genetic counseling, and molecular subclassification of affected patients and their families. DNA from peripheral blood leukocytes of six patients from five families with various degrees of androgen insensitivity was studied. Exons 2 to 8 of the androgen receptor gene were analyzed using a combination of single strand conformation polymorphism analysis and direct DNA sequencing. Female family members were also studied to identify heterozygote carriers. Point mutations in the AR gene were identified in all six patients, and all mutations caused amino acid substitutions. One patient with incomplete androgen insensitivity was a mosaic for the mutation. Four of the five mothers, as well as a young sister of one patient, were carriers of the mutation present in the affected child. The data show that new mutations may occur in the androgen receptor gene leading to sporadic androgen insensitivity syndrome. Molecular genetic characterization of the variant allele can serve as a primary tool for diagnosis and subsequent therapy, and can provide a basis for distinguishing heterozygous carriers in familial androgen resistance. The identification of carriers is of substantial clinical importance for genetic counseling. 29 refs., 2 figs., 1 tab.

  5. Synthesis of esters of androgens with unsaturated fatty acids for androgen requiring therapy.

    Science.gov (United States)

    Aiello, F; Garofalo, A; Aloisi, A M; Lamponi, S; Magnani, A; Petroni, A

    2013-06-01

    Androgens' metabolism and activity are gaining a more and more important role in human physiology particularly referring to aging and to neurodegenerative diseases. Androgen treatment is often required for long-lasting disorders. In order to improve their duration and effects, androgens can be administered as esters of carboxylic acids. The novelty of our research is the use of esters of androgens with specific unsaturated fatty acids, in order to reduce possible side effects particularly related to chronic pathologies with altered lipid homeostasis such as X-linked adrenoleukodystrophy and cardiovascular disorders. Thus the esters of the main androgenic substances testosterone, dihydrotestosterone (DHT) and their metabolite 5α-androstan-3α,17β-diol were chemically obtained by coupling with different unsaturated fatty acids. To this aim, fatty acids with various degree of unsaturation and belonging to different series were selected. Specifically, oleic acid (18:1, n-9), linoleic acid (18:2, n-6), and the n-3 fatty acids, α-linolenic acid (18:3), eicosapentaenoic acid (EPA, 20:5), and docosahexaenoic acid (DHA, 22:6) were used obtaining corresponding esters with acceptable yields and good degree of purity. All the synthesized compounds were tested for their cytotoxic activities in mouse NIH3T3 and human astrocyte cell lines. The esters demonstrated good tolerability and no in vitro cytotoxic effect in both cell cultures. After these promising preliminary results, the esters will be suitable for in vivo studies in order to ascertain their pharmacokinetic characteristics and their biological effects.

  6. Activin B is produced early in antral follicular development and suppresses thecal androgen production

    Science.gov (United States)

    Young, J M; Henderson, S; Souza, C; Ludlow, H; Groome, N; McNeilly, A S

    2012-01-01

    Little is known about the role of activin B during folliculogenesis. This study investigated the expression levels of activin/inhibin subunits (βA, βB, and α), steroid enzyme, and gonadotrophin receptors in theca (TC) and granulosa cells (GC) by QPCR and activin A and B and inhibin A protein levels in follicular fluid (FF) of developing sheep follicles during estrus and anestrus. The effect of activin B on androgen production from primary TC cultures in vitro was also assessed. During folliculogenesis, in anestrus and estrus, FF activin B concentrations and thecal and GC activin βB mRNA levels decreased as follicle diameter increased from 1–3 to >6 mm regardless of estrogenic status. Estrogenic preovulatory follicles had reduced concentrations of FF activins B and A, and TC and GCs expressed higher levels of activin βA mRNA at 3–4 mm, and TCs more inhibin α mRNA at >4 mm stages of development compared with nonestrogenic follicles. Activin B decreased androstenedione production from primary TCs in vitro, an effect blocked by inhibin A. Thus, sheep follicles 1–3 mm in diameter contained high FF levels of activin B, which decreased as the follicle size increased, and, like activin A, suppressed thecal androgen production in vitro, an effect blocked by inhibin. Furthermore, the theca of large estrogenic follicles expressed high levels of inhibin α and activin βA mRNA suggesting local thecal derived inhibin A production. This would inhibit the negative effects of thecal activins B and A ensuring maximum androgen production for enhanced estradiol production by the preovulatory follicle(s). PMID:22450673

  7. Androgen Deprivation Therapy and Future Alzheimer’s Disease Risk

    Science.gov (United States)

    Gaskin, Greg; Chester, Cariad; Swisher-McClure, Samuel; Dudley, Joel T.; Leeper, Nicholas J.; Shah, Nigam H.

    2016-01-01

    Purpose To test the association of androgen deprivation therapy (ADT) in the treatment of prostate cancer with subsequent Alzheimer’s disease risk. Methods We used a previously validated and implemented text-processing pipeline to analyze electronic medical record data in a retrospective cohort of patients at Stanford University and Mt. Sinai hospitals. Specifically, we extracted International Classification of Diseases-9th revision diagnosis and Current Procedural Terminology codes, medication lists, and positive-present mentions of drug and disease concepts from all clinical notes. We then tested the effect of ADT on risk of Alzheimer’s disease using 1:5 propensity score–matched and traditional multivariable-adjusted Cox proportional hazards models. The duration of ADT use was also tested for association with Alzheimer’s disease risk. Results There were 16,888 individuals with prostate cancer meeting all inclusion and exclusion criteria, with 2,397 (14.2%) receiving ADT during a median follow-up period of 2.7 years (interquartile range, 1.0-5.4 years). Propensity score–matched analysis (hazard ratio, 1.88; 95% CI, 1.10 to 3.20; P = .021) and traditional multivariable-adjusted Cox regression analysis (hazard ratio, 1.66; 95% CI, 1.05 to 2.64; P = .031) both supported a statistically significant association between ADT use and Alzheimer’s disease risk. We also observed a statistically significant increased risk of Alzheimer’s disease with increasing duration of ADT (P = .016). Conclusion Our results support an association between the use of ADT in the treatment of prostate cancer and an increased risk of Alzheimer’s disease in a general population cohort. This study demonstrates the utility of novel methods to analyze electronic medical record data to generate practice-based evidence. PMID:26644522

  8. Impact of age on the biochemical failure and androgen suppression after radical prostatectomy for prostate cancer in chilean men

    Directory of Open Access Journals (Sweden)

    Nigel P Murray

    2016-01-01

    Conclusion: After radical prostatectomy, the older men with pathological features of Gleason score ≥ 8, pT3 tumors, and positive extracapsular extension had higher frequency of biochemical failure and the presence of CPCs. The treatment of androgen blockade was less successful to suppress the disease relapse in the older men than that in the younger man.

  9. Muscle and bone effects of androgen deprivation therapy: current and emerging therapies.

    Science.gov (United States)

    Cheung, Ada S; Zajac, Jeffrey D; Grossmann, Mathis

    2014-10-01

    Prostate cancer and treatment with androgen deprivation therapy (ADT) affect significant numbers of the male population. Endocrine effects of ADT are a critical consideration in balancing the benefits and risks of treatment on long-term survival and quality of life. This review highlights the latest advances in androgen manipulation in prostate cancer with an emphasis on the effects of ADT on muscle and bone, which universally affects the health and well-being of men undergoing ADT for prostate cancer. Muscle mass declines with ADT; however, the evidence that this correlates with a decrease in muscle strength or a decrease in physical performance is discordant. Cortical bone decay also occurs in association with an increase in fracture risk, hence optimization of musculoskeletal health in men undergoing ADT is crucial. The role of exercise, and current and emerging anabolic therapies for muscle as well as various new strategies to prevent loss of bone mass in men undergoing ADT are discussed. Future well-designed, prospective, controlled studies are required to elucidate the effects of ADT on physical performance, which are currently lacking, and larger randomized controlled trials are required to test the efficacy of medical therapies and exercise interventions to target proven deficits and to ensure safety in men with prostate cancer.

  10. Clinical evaluation of women presenting with low libido and determination of whether androgen therapy might be appropriate.

    Science.gov (United States)

    Papalia, Mary-Anne; Burger, Henry

    2006-04-01

    The assessment of female sexual dysfunction (FSD) is often challenging in the clinical setting. Although androgen deficiency is regarded as a major cause for FSD, the causes of this condition are multifactorial. Women presenting with FSD require thorough clinical evaluation to determine the cause of FSD. Androgen therapy should be used in women only when clinical and biochemical parameters indicate that FSD stems from androgen deficiency. This review outlines the various causes of FSD, clinical and biochemical investigations required to diagnose androgen deficiency, and options for treatment of the woman found to have androgen deficiency as a cause of FSD.

  11. Radiation therapy and androgen deprivation in the management of high risk prostate cancer

    Directory of Open Access Journals (Sweden)

    Alan Dal Pra

    2011-04-01

    Full Text Available The combined use of radiation therapy (RT and androgen deprivation for patients with localized high-risk prostate cancer is commonly accepted as the standard treatment among uro-oncologists. Preclinical studies have provided rationale for the use of this combination. Additionally, results of phase 3 studies using conventional doses of RT have supported the combined approach. Other phase 3 studies have also shown a benefit for using higher doses of RT; however, the role of androgen deprivation in this context is not clear. The optimal duration of the androgen deprivation, in both the neoadjuvant and adjuvant setting, is still under investigation. This article critically reviews the data on the use of RT combined with androgen deprivation for the treatment of high-risk prostate cancer with emphasis on the results of phase 3 trials.

  12. Efficiency and safety of androgenic therapies of hypogonadism at patients with considerably eliminated urolithiasis

    Directory of Open Access Journals (Sweden)

    P.I. Shuster

    2009-09-01

    Full Text Available The weakest unit in treatment of urolithiasis is revealing in each specific case etiological factor of lithogenic and carrying out etiotropic therapy, and, hence prevention of urolithiasis relapse. The study of correlation of hypogonadism through osteosinging with urolithiasis at men is the new perspective direction uniting Endocrinology and somatic Urology. In prospective cohort research the patients divided into 2 groups have been included: basic group - patients with considerably cured urolithiasis and hypogonadism, received androgenic therapy (30 persons; comparison group -patients with considerably cured urolithiasis and hypogonadism, not receiving androgen therapy (30 persons. Used: questioning on questionnaire AMS, the International index of erectile functions (IIEF-5, index of weight of a body, haemoglobin, hematocrit, biochemical indicators of blood serum, densitometry, general testosterone, PSA, and ionized calcium. After contra-indications exception (cancer of prostate gland, expressed increase of haemoglobin and hematocrit the basic group patients were prescribed one of testosterone group drug during the period not less than 6 months: Androgel (Solvay Pharma, Nebido (Bayer Schering Pharma, Sustanon-250 (Organon, Omnadren-250 (Polfa. At the moment of the therapy beginning, patients of both groups were comparable in all investigated indices. Relapse of urolithiasis: against androgenic therapy - 28,6%, in comparison group - 63,2%. The obtained data testify to efficiency of androgenic therapy in respect to prevention of urolithiasis at patients with hypogonadism and confirm the role of hypogonadism as one of etiopathogenetic development factors of urolithiasis. Androgenic therapy was safe. All patients had insignificant increase of general PSA level and statistically significant increase of haemoglobin and hematocrit indicators. However, the received changes did not demand cancellation, or therapy correction.

  13. Anemia in patients on combined androgen block therapy for prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Li-XinQian; Li-XinHua; Hong-FeiWu; Yuan-GengSui; Shuang-GuanCheng; WeiZhang,JieLi; Xin-RuWang

    2004-01-01

    Aim: To study the effect of combined androgen block therapy on hemoglobin and hematocrit values in patients with prostate cancer. Methods: One hundred and thirty-six patients with adenocarcinoma of prostate were treated with combined androgen block (orchiectomy and flutamide 250 mg, tid). Complete blood counts were determined before and after 1,2,3,6,9 and 12 months of therapy. Results: The hemoglobin and hematocrit levels declined significantly in all patients and at all the time points after treatment (P<0.05). Conclusion: Prostate cancer patients treated with combined androgen block would develop obvious anemia. Recombinant human erythropoietin can be used to treat patients with severe anemia. (Asian J Androl 2004 Dec;6: 383-384)

  14. Use of androgen deprivation therapy in prostate cancer:indications and prevalence

    Institute of Scientific and Technical Information of China (English)

    Roisin M Connolly; Michael A Carducci; Emmanuel S Antonarakis

    2012-01-01

    Androgens play a prominent role in the development,maintenance and progression of prostate cancer.The introduction of androgen deprivation therapies into the treatment paradigm for prostate cancer patients has resulted in a wide variety of benefits ranging from a survival advantage for those with clinically localized or locally advanced disease,to improvements in symptom control for patients with advanced disease.Controversies remain,however,surrounding the optimal timing,duration and schedule of these hormonal approaches.Newer hormonal manipulations such as abiraterone acetate have also been investigated and will broaden treatment options for men with prostate cancer.This review highlights the various androgen-directed treatment options available to men with prostate cancer,their specific indications and the evidence supporting each approach,as well as patterns of use of hormonal therapies.

  15. Monocyte/macrophage androgen receptor suppresses cutaneous wound healing in mice by enhancing local TNF-alpha expression.

    Science.gov (United States)

    Lai, Jiann-Jyh; Lai, Kuo-Pao; Chuang, Kuang-Hsiang; Chang, Philip; Yu, I-Chen; Lin, Wen-Jye; Chang, Chawnshang

    2009-12-01

    Cutaneous wounds heal more slowly in elderly males than in elderly females, suggesting a role for sex hormones in the healing process. Indeed, androgen/androgen receptor (AR) signaling has been shown to inhibit cutaneous wound healing. AR is expressed in several cell types in healing skin, including keratinocytes, dermal fibroblasts, and infiltrating macrophages, but the exact role of androgen/AR signaling in these different cell types remains unclear. To address this question, we generated and studied cutaneous wound healing in cell-specific AR knockout (ARKO) mice. General and myeloid-specific ARKO mice exhibited accelerated wound healing compared with WT mice, whereas keratinocyte- and fibroblast-specific ARKO mice did not. Importantly, the rate of wound healing in the general ARKO mice was dependent on AR and not serum androgen levels. Interestingly, although dispensable for wound closure, keratinocyte AR promoted re-epithelialization, while fibroblast AR suppressed it. Further analysis indicated that AR suppressed wound healing by enhancing the inflammatory response through a localized increase in TNF-alpha expression. Furthermore, AR enhanced local TNF-alpha expression via multiple mechanisms, including increasing the inflammatory monocyte population, enhancing monocyte chemotaxis by upregulating CCR2 expression, and enhancing TNF-alpha expression in macrophages. Finally, targeting AR by topical application of a compound (ASC-J9) that degrades AR protein resulted in accelerated healing, suggesting a potential new therapeutic approach that may lead to better treatment of wound healing.

  16. Recovery of spermatogenesis following testosterone replacement therapy or anabolic-androgenic steroid use.

    Science.gov (United States)

    McBride, J Abram; Coward, Robert M

    2016-01-01

    The use of testosterone replacement therapy (TRT) for hypogonadism continues to rise, particularly in younger men who may wish to remain fertile. Concurrently, awareness of a more pervasive use of anabolic-androgenic steroids (AAS) within the general population has been appreciated. Both TRT and AAS can suppress the hypothalamic-pituitary-gonadal (HPG) axis resulting in diminution of spermatogenesis. Therefore, it is important that clinicians recognize previous TRT or AAS use in patients presenting for infertility treatment. Cessation of TRT or AAS use may result in spontaneous recovery of normal spermatogenesis in a reasonable number of patients if allowed sufficient time for recovery. However, some patients may not recover normal spermatogenesis or tolerate waiting for spontaneous recovery. In such cases, clinicians must be aware of the pathophysiologic derangements of the HPG axis related to TRT or AAS use and the pharmacologic agents available to reverse them. The available agents include injectable gonadotropins, selective estrogen receptor modulators, and aromatase inhibitors, but their off-label use is poorly described in the literature, potentially creating a knowledge gap for the clinician. Reviewing their use clinically for the treatment of hypogonadotropic hypogonadism and other HPG axis abnormalities can familiarize the clinician with the manner in which they can be used to recover spermatogenesis after TRT or AAS use.

  17. Recovery of spermatogenesis following testosterone replacement therapy or anabolic-androgenic steroid use

    Directory of Open Access Journals (Sweden)

    J Abram McBride

    2016-01-01

    Full Text Available The use of testosterone replacement therapy (TRT for hypogonadism continues to rise, particularly in younger men who may wish to remain fertile. Concurrently, awareness of a more pervasive use of anabolic-androgenic steroids (AAS within the general population has been appreciated. Both TRT and AAS can suppress the hypothalamic-pituitary-gonadal (HPG axis resulting in diminution of spermatogenesis. Therefore, it is important that clinicians recognize previous TRT or AAS use in patients presenting for infertility treatment. Cessation of TRT or AAS use may result in spontaneous recovery of normal spermatogenesis in a reasonable number of patients if allowed sufficient time for recovery. However, some patients may not recover normal spermatogenesis or tolerate waiting for spontaneous recovery. In such cases, clinicians must be aware of the pathophysiologic derangements of the HPG axis related to TRT or AAS use and the pharmacologic agents available to reverse them. The available agents include injectable gonadotropins, selective estrogen receptor modulators, and aromatase inhibitors, but their off-label use is poorly described in the literature, potentially creating a knowledge gap for the clinician. Reviewing their use clinically for the treatment of hypogonadotropic hypogonadism and other HPG axis abnormalities can familiarize the clinician with the manner in which they can be used to recover spermatogenesis after TRT or AAS use.

  18. Patients receiving androgen deprivation therapy for prostate cancer have an increased risk of depressive disorder

    Science.gov (United States)

    Chung, Shiu-Dong; Xirasagar, Sudha

    2017-01-01

    Androgen deprivation therapy (ADT) results in testosterone suppression, a hypothesized mechanism linking ADT to depressive symptoms. This study investigated the relationship between ADT and the risk of subsequently being diagnosed with depressive disorder (DD) during a 3-year follow-up period. The patient sample for this population-based, retrospective cohort study was retrieved from the Taiwan Longitudinal Health Insurance Database 2005. We included all 1714 patients aged over 40 years with a first-time diagnosis of prostate cancer (PC) during 2001 to 2010 who did not have an orchiectomy. Among them, we defined 868 patients who received ADT during the 3-year follow-up period as the study group, and 846 patients who did not receive ADT as the comparison group. The incidence rates of DD per 1000 person-years were 13.9 (95% confidence interval (CI): 9.5~19.6) and 6.7 (95% CI: 3.7~11.0), respectively. Cox proportional hazard regressions showed that the adjusted hazard ratio for DD for ADT recipients was 1.93 (95% CI: 1.03~3.62) relative to the comparison group. This study presents epidemiological evidence of an association between ADT and a subsequent DD diagnosis. PMID:28253340

  19. The use of exercise interventions to overcome adverse effects of androgen deprivation therapy

    DEFF Research Database (Denmark)

    Østergren, Peter Busch; Kistorp, Caroline; Bennedbæk, Finn Noe;

    2016-01-01

    Androgen deprivation therapy (ADT) induces severe hypogonadism and is associated with several adverse effects that negatively affect health and quality of life in patients with prostate cancer. ADT changes body composition characterized by an increase in fat mass and a reduction in muscle mass an...

  20. High dose androgen therapy in male pseudohermaphroditism due to 5 alpha-reductase deficiency and disorders of the androgen receptor.

    OpenAIRE

    Price, P; Wass, J. A.; Griffin, J E; Leshin, M; Savage, M O; Large, D. M.; Bu'Lock, D E; Anderson, D. C.; Wilson, J. D.; Besser, G M

    1984-01-01

    We describe the clinical and biochemical features of six men with male pseudohermaphroditism due to androgen resistance. Each of the subjects had male-gender behavior but incomplete virilization. The underlying defects in androgen metabolism were defined by studies of the 5 alpha-reductase enzyme and the androgen receptor in fibroblasts cultured from biopsies of genital skin. Four of the six have 5 alpha-reductase deficiency, and two have defects of the androgen receptor (the Reifenstein synd...

  1. Androgen deficiency in older men: indications, advantages, and pitfalls of testosterone replacement therapy.

    Science.gov (United States)

    McGill, John J; Shoskes, Daniel A; Sabanegh, Edmund S

    2012-11-01

    The decline in testosterone with age has been associated with specific physical changes that affect quality of life and life expectancy, although a cause-and-effect relationship is yet to be established. While female menopause is rapid and well described, "male menopause" or androgen decline in older men is gradual and marked by nonspecific symptoms. This makes diagnosis of true testosterone deficiency and prediction of response to testosterone replacement therapy (TRT) challenging. This article reviews androgen decline in men, focusing on those over age 40, and covers symptoms, indications, contraindications,diagnosis, treatments, and the risks and benefits of treatment [corrected].

  2. RNase L Suppresses Androgen Receptor Signaling, Cell Migration and Matrix Metalloproteinase Activity in Prostate Cancer Cells.

    Science.gov (United States)

    Dayal, Shubham; Zhou, Jun; Manivannan, Praveen; Siddiqui, Mohammad Adnan; Ahmad, Omaima Farid; Clark, Matthew; Awadia, Sahezeel; Garcia-Mata, Rafael; Shemshedini, Lirim; Malathi, Krishnamurthy

    2017-03-01

    The interferon antiviral pathways and prostate cancer genetics converge on a regulated endoribonuclease, RNase L. Positional cloning and linkage studies mapped Hereditary Prostate Cancer 1 (HPC1) to RNASEL. To date, there is no correlation of viral infections with prostate cancer, suggesting that RNase L may play additional roles in tumor suppression. Here, we demonstrate a role of RNase L as a suppressor of androgen receptor (AR) signaling, cell migration and matrix metalloproteinase activity. Using RNase L mutants, we show that its nucleolytic activity is dispensable for both AR signaling and migration. The most prevalent HPC1-associated mutations in RNase L, R462Q and E265X, enhance AR signaling and cell migration. RNase L negatively regulates cell migration and attachment on various extracellular matrices. We demonstrate that RNase L knockdown cells promote increased cell surface expression of integrin β1 which activates Focal Adhesion Kinase-Sarcoma (FAK-Src) pathway and Ras-related C3 botulinum toxin substrate 1-guanosine triphosphatase (Rac1-GTPase) activity to increase cell migration. Activity of matrix metalloproteinase (MMP)-2 and -9 is significantly increased in cells where RNase L levels are ablated. We show that mutations in RNase L found in HPC patients may promote prostate cancer by increasing expression of AR-responsive genes and cell motility and identify novel roles of RNase L as a prostate cancer susceptibility gene.

  3. Variation in Use of Androgen Suppression With External-Beam Radiotherapy for Nonmetastatic Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Swisher-McClure, Samuel, E-mail: Swisher-Mcclure@uphs.upenn.edu [Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA (United States); Pollack, Craig E. [Division of General Internal Medicine, Johns Hopkins University School of Medicine and Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (United States); Christodouleas, John P. [Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA (United States); Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA (United States); Guzzo, Thomas J. [Department of Surgery, Division of Urology, University of Pennsylvania, Philadelphia, PA (United States); Haas, Naomi B. [Department of Medicine, Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, PA (United States); Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA (United States); Vapiwala, Neha [Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA (United States); Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA (United States); Bekelman, Justin E. [Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA (United States); Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA (United States); Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, PA (United States)

    2012-05-01

    Purpose: To describe practice patterns associated with androgen suppression (AS) stratified by disease risk group in patients undergoing external-beam radiotherapy (EBRT) for localized prostate cancer. Methods and Materials: We identified 2,184 low-risk, 2,339 intermediate-risk, and 2,897 high-risk patients undergoing EBRT for nonmetastatic prostate cancer diagnosed between January 1, 2004, and December 31, 2005, in the linked Surveillance, Epidemiology, and End Results-Medicare database. We examined the association of patient, clinical, and demographic characteristics with AS use by multivariate logistic regression. Results: The proportions of patients receiving AS for low-risk, intermediate-risk, and high-risk prostate cancer were 32.2%, 56.3%, and 81.5%, respectively. AS use among men in the low-risk disease category varied widely, ranging from 13.6% in Detroit to 47.8% in Kentucky. We observed a significant decline in AS use between 2004 and 2005 within all three disease risk categories. Men aged {>=}75 years or with elevated comorbidity levels were more likely to receive AS. Conclusion: Our results identified apparent overuse and underuse of AS among men within the low-risk and high-risk disease categories, respectively. These results highlight the need for clinician and patient education regarding the appropriate use of AS. Practice patterns among intermediate-risk patients reflect the clinical heterogeneity of this population and underscore the need for better evidence to guide the treatment of these patients.

  4. Abiraterone and other novel androgen-directed strategies for the treatment of prostate cancer: a new era of hormonal therapies is born.

    Science.gov (United States)

    Schweizer, Michael T; Antonarakis, Emmanuel S

    2012-08-01

    The number of life-prolonging therapies proven effective in the treatment of metastatic castrate-resistant prostate cancer (CRPC) has been limited until recently. In the past 2 years several such therapies have come to market. In 2010, the autologous immunotherapy sipuleucel-T and the next-generation taxane cabazitaxel were approved in this setting. However, abundant evidence has shown that CRPC growth continues to be driven through androgen-dependent signaling. Both of these drugs fail to take advantage of this targetable oncogenic pathway. Potent specific inhibitors of cytochrome P450-17 have been engineered with the aim of suppressing androgen synthesis beyond that seen with the luteinizing hormone-releasing hormone agonists/antagonists. Abiraterone acetate was developed by rational design based on a pregnenolone parent structure. Its approval by the US Food and Drug Administration (FDA) was granted in 2011 based on phase III data demonstrating an overall survival advantage compared with placebo. More recently, other drugs that act along the androgen signaling pathway, such as orteronel (TAK-700), galeterone (TOK-001), enzalutamide (MDV3100) and ARN-509, have shown promise in clinical trials. Some of these are expected to gain FDA approval in the near future. Here, we review abiraterone and other novel androgen-directed therapeutic strategies for the management of advanced prostate cancer.

  5. Cough suppression therapy: does it work?

    Science.gov (United States)

    Chamberlain, Sarah; Garrod, Rachel; Birring, Surinder S

    2013-10-01

    Cough suppression therapy (CST), also known as cough suppression physiotherapy and speech pathology management is a promising non-pharmacological therapeutic option for patients with refractory chronic cough. CST may consist of education, improving laryngeal hygiene and hydration, cough suppression techniques, breathing exercises and counselling. It is an out-patient therapy delivered in 2-4 sessions. There is evidence to support the efficacy of CST: a randomised controlled trial reported a significant reduction in cough symptoms and other studies have reported improved cough related quality of life, reduced cough reflex hypersensitivity and cough frequency. The mechanism of action of CST is not clear, but it has been shown to reduce cough reflex sensitivity, paradoxical vocal fold movement (PVFM) and extrathoracic hyperresponsiveness. Further research is needed to determine the optimal components of CST, the characteristics of patients in whom it is most effective and to increase the understanding of its mechanisms of action. The effectiveness of CST in other respiratory conditions such as asthma, pulmonary fibrosis, chronic obstructive pulmonary disease and sarcoidosis should also be investigated.

  6. Treatment of androgenic disorders in women: acne, hirsutism, and alopecia.

    Science.gov (United States)

    Redmond, G P; Bergfeld, W F

    1990-01-01

    Androgen excess disorders--acne, alopecia, and hirsutism--can be treated effectively with endocrine therapy such as androgen receptor blockers or antagonists, or with androgen suppression. Spironolactone, estrogen, and dexamethasone are considered the most effective approaches to treatment. Whatever the modality, careful planning is key to success, with recognition that response rates vary from patient to patient. A treatment regimen generally continues for at least 2 years.

  7. Are the Endocrine Society's Clinical Practice Guidelines on Androgen Therapy in Women misguided? A commentary.

    Science.gov (United States)

    Traish, Abdulmaged; Guay, Andre T; Spark, Richard F

    2007-09-01

    The Endocrine Society Clinical Guidelines on Androgen Therapy in Women (henceforth referred to as the Guidelines) do not necessarily represent the opinion held by the many health-care professionals and clinicians who are specialized in the evaluation, diagnosis, and treatment of women's health in androgen insufficiency states. The recommendations provided in the published Guidelines are neither accurate nor complete. We disagree with the therapeutic nihilism promoted by these Guidelines. The members of the Guidelines Panel (henceforth referred to as the Panel), in their own disclaimer, stated that the Guidelines do not establish a standard of care. Based on data available in the contemporary literature, on the role of androgens in women's health, we provide in this commentary a point-by-point discussion of the arguments made by the Panel in arriving at their recommendations. It is our view that the Guidelines are not based on the preponderance of scientific evidence. Health-care professionals, physicians, and scientists often disagree when determining how best to address and manage new and emerging clinical issues. This is where we stand now as we endeavor to understand the role of androgens in a woman's health and welfare. Indeed, some basic facts are not in contention. All agree that dehydroepiandrosterone sulfate (DHEA-S) production from the adrenal gland begins during the preteen years, peaks in the mid 20s, then declines progressively over time. In contrast, ovarian androgen (i.e., testosterone) secretion commences at puberty, is sustained during a woman's peak reproductive years and declines as a woman ages, with a more rapid and steep decrease after surgical menopause. However, there are ample data to suggest that adrenal androgens play a role in the development of axillary and pubic hair, and that testosterone is critical for women's libido and sexual function. We take this opportunity to invite members of the Panel on Androgen Therapy in Women to discuss

  8. Role of non-genomic androgen signalling in suppressing proliferation of fibroblasts and fibrosarcoma cells.

    Science.gov (United States)

    Castoria, G; Giovannelli, P; Di Donato, M; Ciociola, A; Hayashi, R; Bernal, F; Appella, E; Auricchio, F; Migliaccio, A

    2014-12-04

    The functions of androgen receptor (AR) in stromal cells are still debated in spite of the demonstrated importance of these cells in organ development and diseases. Here, we show that physiological androgen concentration (10 nM R1881 or DHT) fails to induce DNA synthesis, while it consistently stimulates cell migration in mesenchymal and transformed mesenchymal cells. Ten nanomolar R1881 triggers p27 Ser10 phosphorylation and its stabilization in NIH3T3 fibroblasts. Activation of Rac and its downstream effector DYRK 1B is responsible for p27 Ser10 phosphorylation and cell quiescence. Ten nanomolar androgen also inhibits transformation induced by oncogenic Ras in NIH3T3 fibroblasts. Overexpression of an AR mutant unable to interact with filamin A, use of a small peptide displacing AR/filamin A interaction, and filamin A knockdown indicate that the androgen-triggered AR/filamin A complex regulates the pathway leading to p27 Ser10 phosphorylation and cell cycle arrest. As the AR/filamin A complex is also responsible for migration stimulated by 10 nM androgen, our report shows that the androgen-triggered AR/filamin A complex controls, through Rac 1, the decision of cells to halt cell cycle and migration. This study reveals a new and unexpected role of androgen/AR signalling in coordinating stromal cell functions.

  9. Effects of recreational soccer in men with prostate cancer undergoing androgen deprivation therapy

    DEFF Research Database (Denmark)

    Uth, Jacob; Schmidt, Jakob Friis; Christensen, Jesper Frank;

    2013-01-01

    Androgen deprivation therapy (ADT) is a cornerstone in the treatment of advanced prostate cancer. Adverse musculoskeletal and cardiovascular effects of ADT are widely reported and investigations into the potential of exercise to ameliorate the effects of treatment are warranted. The 'Football Club...... (FC) Prostate' study is a randomized trial comparing the effects of soccer training with standard treatment approaches on body composition, cardiovascular function, physical function parameters, glucose tolerance, bone health, and patient-reported outcomes in men undergoing ADT for prostate cancer....

  10. Clinical review 138: Anabolic-androgenic steroid therapy in the treatment of chronic diseases.

    Science.gov (United States)

    Basaria, S; Wahlstrom, J T; Dobs, A S

    2001-11-01

    The purpose of this study was to review the preclinical and clinical literature relevant to the efficacy and safety of anabolic androgen steroid therapy for palliative treatment of severe weight loss associated with chronic diseases. Data sources were published literature identified from the Medline database from January 1966 to December 2000, bibliographic references, and textbooks. Reports from preclinical and clinical trials were selected. Study designs and results were extracted from trial reports. Statistical evaluation or meta-analysis of combined results was not attempted. Androgenic anabolic steroids (AAS) are widely prescribed for the treatment of male hypogonadism; however, they may play a significant role in the treatment of other conditions as well, such as cachexia associated with human immunodeficiency virus, cancer, burns, renal and hepatic failure, and anemia associated with leukemia or kidney failure. A review of the anabolic effects of androgens and their efficacy in the treatment of these conditions is provided. In addition, the numerous and sometimes serious side effects that have been known to occur with androgen use are reviewed. Although the threat of various side effects is present, AAS therapy appears to have a favorable anabolic effect on patients with chronic diseases and muscle catabolism. We recommend that AAS can be used for the treatment of patients with acquired immunodeficiency syndrome wasting and in severely catabolic patients with severe burns. Preliminary data in renal failure-associated wasting are also positive. Advantages and disadvantages should be weighed carefully when comparing AAS therapy to other weight-gaining measures. Although a conservative approach to the use of AAS in patients with chronic diseases is still recommended, the utility of AAS therapy in the attenuation of severe weight loss associated with disease states such as cancer, postoperative recovery, and wasting due to pulmonary and hepatic disease should be

  11. Can Mathematical Models Predict the Outcomes of Prostate Cancer Patients Undergoing Intermittent Androgen Deprivation Therapy?

    Science.gov (United States)

    Everett, R. A.; Packer, A. M.; Kuang, Y.

    Androgen deprivation therapy is a common treatment for advanced or metastatic prostate cancer. Like the normal prostate, most tumors depend on androgens for proliferation and survival but often develop treatment resistance. Hormonal treatment causes many undesirable side effects which significantly decrease the quality of life for patients. Intermittently applying androgen deprivation in cycles reduces the total duration with these negative effects and may reduce selective pressure for resistance. We extend an existing model which used measurements of patient testosterone levels to accurately fit measured serum prostate specific antigen (PSA) levels. We test the model's predictive accuracy, using only a subset of the data to find parameter values. The results are compared with those of an existing piecewise linear model which does not use testosterone as an input. Since actual treatment protocol is to re-apply therapy when PSA levels recover beyond some threshold value, we develop a second method for predicting the PSA levels. Based on a small set of data from seven patients, our results showed that the piecewise linear model produced slightly more accurate results while the two predictive methods are comparable. This suggests that a simpler model may be more beneficial for a predictive use compared to a more biologically insightful model, although further research is needed in this field prior to implementing mathematical models as a predictive method in a clinical setting. Nevertheless, both models are an important step in this direction.

  12. Improving intermittent androgen deprivation therapy: lessons learned from basic and translational research

    Directory of Open Access Journals (Sweden)

    Rahul A Parikh

    2014-08-01

    Full Text Available Intermittent androgen deprivation therapy (IADT is an alternative to continuous androgen deprivation therapy (ADT in prostate cancer patients with nonmetastatic disease. ADT is associated with numerous side effects such as hot flashes, sexual dysfunction, anemia, fatigue, loss of muscle mass, osteoporosis, metabolic syndrome and premature cardiovascular disease. IADT was developed with the intention of improving the quality of life and to delay progression of prostate cancer to castration resistance. The benefits of slightly improved quality of life by IADT compared to ADT were demonstrated in multiple clinical trials. IADT was noted to be noninferior to ADT in patients with biochemical recurrence of prostate cancer but in studies performed in patients with metastatic prostate cancer, the results were inconclusive. Our recent studies suggested that the administration of 5 alpha-reductase inhibitors during the off-cycle of IADT can significantly prolong the survival of mice bearing androgen-sensitive prostate tumors when off-cycle duration was short. This review discusses the survival benefit of 5 alpha-reductase inhibition in IADT in animal models and the potential translation of this finding into clinic.

  13. Monotherapy of androgen deprivation therapy versus radical prostatectomy among veterans with localized prostate cancer: comparative effectiveness analysis of retrospective cohorts

    Directory of Open Access Journals (Sweden)

    Liu J

    2012-05-01

    Full Text Available Jinan Liu1,2, Lizheng Shi1,2,3, Oliver Sartor31Tulane University, School of Public Health and Tropical Medicine, 2Southeast Louisiana Veterans Health Care System, Tulane University, 3School of Medicine and Tulane Cancer Center, New Orleans, LA, USABackground: This retrospective cohort study aimed to examine the comparative effectiveness of monotherapy of primary androgen deprivation therapy or radical prostatectomy.Methods: Male patients with localized prostate cancer (T1-T2, N0, M0 were identified in the Veterans Affairs Veterans Integrated Service Network 16 data warehouse (January 2003 to June 2006, with one-year baseline and at least three-year follow-up data (until June 2009. Patients were required to be 18–75 years old and without other recorded cancer history. The initiation of primary androgen deprivation therapy or monotherapy of radical prostatectomy within six months after the first diagnosis of prostate cancer was used as the index date. Primary androgen deprivation therapy patients were matched to the radical prostatectomy patients via propensity score, which was predicted from a logistic regression of treatment selection (primary androgen deprivation therapy versus radical prostatectomy on age, race, marital status, insurance type, cancer stage, Charlson comorbidity index, and alcohol and tobacco use. The overall survival from initiation of index treatment was then analyzed using the Kaplan–Meier and Cox proportional hazards model.Results: The two cohorts were well matched at baseline (all P > 0.05. During a median follow-up of 4.3 years, the cumulative incidence of death was 13 (10.57% among 123 primary androgen deprivation therapy patients and four (3.25% among 123 radical prostatectomy patients (P < 0.05. The overall three-year survival rate was 92.68% for primary androgen deprivation therapy and 98.37% for radical prostatectomy (P < 0.05. Patients who received primary androgen deprivation therapy had almost three times as

  14. Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy.

    Science.gov (United States)

    Li, Zhenfei; Alyamani, Mohammad; Li, Jianneng; Rogacki, Kevin; Abazeed, Mohamed; Upadhyay, Sunil K; Balk, Steven P; Taplin, Mary-Ellen; Auchus, Richard J; Sharifi, Nima

    2016-05-26

    Abiraterone blocks androgen synthesis and prolongs survival in patients with castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis. Abiraterone is metabolized in patients to Δ(4)-abiraterone (D4A), which has even greater anti-tumour activity and is structurally similar to endogenous steroidal 5α-reductase substrates, such as testosterone. Here, we show that D4A is converted to at least three 5α-reduced and three 5β-reduced metabolites in human serum. The initial 5α-reduced metabolite, 3-keto-5α-abiraterone, is present at higher concentrations than D4A in patients with prostate cancer taking abiraterone, and is an androgen receptor agonist, which promotes prostate cancer progression. In a clinical trial of abiraterone alone, followed by abiraterone plus dutasteride (a 5α-reductase inhibitor), 3-keto-5α-abiraterone and downstream metabolites were depleted by the addition of dutasteride, while D4A concentrations rose, showing that dutasteride effectively blocks production of a tumour-promoting metabolite and permits D4A accumulation. Furthermore, dutasteride did not deplete the three 5β-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacological 5α-reductase inhibition on abiraterone metabolism. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine-tuning abiraterone metabolism to optimize therapy.

  15. Androgen deprivation therapy and fracture risk in Chinese patients with prostate carcinoma

    Science.gov (United States)

    Lee, Chi-Ho; Huang, Gang; Chan, Pak-Hei; Hai, Jojo; Yeung, Chun-Yip; Fong, Carol Ho-Yi; Woo, Yu-Cho; Ho, Kwan Lun; Yiu, Ming-Kwong; Leung, Frankie; Lau, Tak-Wing; Tse, Hung-Fat; Lam, Karen Siu-Ling; Siu, Chung-Wah

    2017-01-01

    Objective Androgen deprivation therapy (ADT) increases fracture risk in men with carcinoma of the prostate, but little is known about the fracture risk for different types of ADT. We studied the fracture risk amongst Chinese patients with carcinoma of the prostate prescribed different ADT regimens. Subjects and methods This was a single-centered observational study that involved 741 patients with carcinoma of the prostate from January 2001 to December 2011. Results After a median follow-up of 5 years, 71.7% of the study cohort received ADT and the incidence rate of fracture was 8.1%. Multivariable Cox regression analysis revealed that use of ADT was significantly associated with risk of incident fracture (Hazard Ratio [HR] 3.60; 95% Confidence Interval [95% CI] 1.41–9.23; p = 0.008), together with aged >75 years and type 2 diabetes. Compared with no ADT, all three types of ADT were independently associated with the risk of incident fracture: anti-androgen monotherapy (HR 4.47; 95% CI 1.47–13.7; p = 0.009), bilateral orchiectomy ± anti-androgens (HR 4.01; 95% CI 1.46–11.1; p = 0.007) and luteinizing hormone-releasing hormone agonists ± anti-androgens (HR 3.16; 95% CI 1.18–8.43; p = 0.022). However, there was no significant difference in the relative risks among the three types of ADT. Conclusions Fracture risk increases among all types of ADT. Clinicians should take into account the risk-benefit ratio when prescribing ADT, especially in elderly patients with type 2 diabetes. PMID:28158241

  16. New Insights into the Androgen-Targeted Therapies and Epigenetic Therapies in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Abhijit M. Godbole

    2011-01-01

    Full Text Available Prostate cancer is the most common cancer in men in the United States, and it is the second leading cause of cancer-related death in American men. The androgen receptor (AR, a receptor of nuclear family and a transcription factor, is the most important target in this disease. While most efforts in the clinic are currently directed at lowering levels of androgens that activate AR, resistance to androgen deprivation eventually develops. Most prostate cancer deaths are attributable to this castration-resistant form of prostate cancer (CRPC. Recent work has shed light on the importance of epigenetic events including facilitation of AR signaling by histone-modifying enzymes, posttranslational modifications of AR such as sumoylation. Herein, we provide an overview of the structure of human AR and its key structural domains that can be used as targets to develop novel antiandrogens. We also summarize recent findings about the antiandrogens and the epigenetic factors that modulate the action of AR.

  17. Differences in Hypercholesterolemia and Atherogenesis Induced by Common Androgen Deprivation Therapies in Male Mice

    DEFF Research Database (Denmark)

    Poulsen, Christian Bo; Mortensen, Martin Bødtker; Koechling, Wolfgang;

    2016-01-01

    BACKGROUND: Treatment of prostate cancer often involves androgen deprivation therapy (ADT) by gonadotropin-releasing hormone (GnRH) receptor agonists, GnRH receptor antagonists, or orchiectomy. ADT may increase the rate of cardiovascular disease events, but recent clinical studies suggested...... allocated to orchiectomy and/or monthly injections with the GnRH receptor agonist leuprolide or the GnRH receptor antagonist degarelix. Atherosclerosis was quantified at 26 weeks of age in the aortic arch by en face examination and in the aortic root by histology. In intact Apoe-deficient mice, all types...... associated with GnRH agonist-based ADT....

  18. Effects of recreational soccer in men with prostate cancer undergoing androgen deprivation therapy

    DEFF Research Database (Denmark)

    Uth, Jacob; Schmidt, Jakob Friis; Christensen, Jesper Frank;

    2013-01-01

    (FC) Prostate' study is a randomized trial comparing the effects of soccer training with standard treatment approaches on body composition, cardiovascular function, physical function parameters, glucose tolerance, bone health, and patient-reported outcomes in men undergoing ADT for prostate cancer.......Androgen deprivation therapy (ADT) is a cornerstone in the treatment of advanced prostate cancer. Adverse musculoskeletal and cardiovascular effects of ADT are widely reported and investigations into the potential of exercise to ameliorate the effects of treatment are warranted. The 'Football Club...

  19. Football training in men with prostate cancer undergoing androgen deprivation therapy

    DEFF Research Database (Denmark)

    Uth, Jacob; Hornstrup, Therese; Christensen, Jesper F

    2016-01-01

    PURPOSE: To investigate the activity profile of football training and its short-term effects on bone mass, bone turnover markers (BTMs) and postural balance in men with prostate cancer (PCa) undergoing androgen deprivation therapy (ADT). METHODS: This was a randomised 12-week study in which men...... with PCa undergoing ADT were assigned to a football intervention group [FTG, n = 29, 67 ± 7 (±SD) years] training 2‒3 times per week for 45‒60 min or to a control group (n = 28, 66 ± 5 years). The activity profile was measured using a 5-Hz GPS. The outcomes were total body and leg bone mineral content (BMC...

  20. Quality of life issues in men undergoing androgen deprivation therapy: a review

    Institute of Scientific and Technical Information of China (English)

    Rowan G Casey; Niall M Corcoran; S Larry Goldenberg

    2012-01-01

    Androgen deprivation therapy (ADT) has been an essential treatment option for treating prostate cancer (PCa).The role for hormonal treatment initially was restricted to men with metastatic and inoperable,locally advanced disease.Now it has been extended to neoadjuvant or adjuvant therapy for surgery and radiotherapy,for biochemical relapse after surgery or radiation,and even as primary therapy for non-metastatic disease.Fifty percent of PCa patients treated will receive ADT at some point.There is growing concern about the adverse effects and costs associated with more widespread ADT use.The adverse effects on quality of life (QoL),including physical,social and psychological well-being when men are androgen-deprived,may be considerable.This review examines the QoL issues in the following areas:body feminisation,sexual changes,relationship changes,cognitive and affective symptoms,fatigue,sleep disturbance,depression and physical effects.Further suggestions for therapeutic approaches to reduce these alterations are suggested.

  1. Aspects of androgen replacement therapy for the treatment of hypogonadism in men with diabetes and metabolic syndrome.

    Directory of Open Access Journals (Sweden)

    Роман Викторович Роживанов

    2015-04-01

    Full Text Available The article presents the results of studies of efficacy and safety of androgen therapy for hypogonadism, metabolic syndrome and type 2diabetes mellitus in men. In the study was used testosterone undecanoate therapy which causes reduction of obesity, a decrease in theseverity of the other components of the metabolic syndrome, improving glycemic profile without significant side effects. Nevertheless,this therapy requires monitoring and management for risk factors.

  2. [Anti-androgen therapy for spinal and bulbar muscular atrophy (SBMA)].

    Science.gov (United States)

    Katsuno, Masahisa; Banno, Haruhiko; Suzuki, Keisuke; Hashizume, Atsushi; Adachi, Hiroaki; Tanaka, Fumiaki; Sobue, Gen

    2012-01-01

    Spinal and bulbar muscular atrophy (SBMA), or Kennedy's disease, is an adult-onset lower motor neuron disease caused by the expansion of a trinucleotide CAG repeat encoding a polyglutamine tract within the first exon of the androgen receptor (AR) gene. The testosterone-dependent nuclear accumulation of polyglutamine-expanded AR protein is central to the pathogenesis. This hypothesis is supported by pre-clinical studies showing that testosterone deprivation ameliorates motor neuron degeneration in animal modes of SBMA. In a randomized placebo-controlled multi-centric clinical trial, leuprorelin, which suppresses secretion of testosterone, showed no definite effect on motor functions, although there was the improvement of swallowing function in a subgroup of patients whose disease duration was less than 10 years. Elucidation of the entire disease mechanism, early initiation of therapeutic intervention, and sensitive outcome measures to evaluate drug effect appear to be the key to a successful translational research on SBMA.

  3. Riscos cardiovasculares do bloqueio androgênico Riesgos cardiovasculares del bloqueo androgénico Cardiovascular risks of androgen deprivation therapy

    Directory of Open Access Journals (Sweden)

    Adriano Freitas Ribeiro

    2010-09-01

    bien conocidas. Recientemente, una serie de complicaciones metabólicas fue descripta como aumento de la circunferencia abdominal, resistencia a la insulina, hiperglicemia, diabetes, dislipidemia y síndrome metabólico con consecuente aumento del riesgo de eventos coronarios y mortalidad cardiovascular en esa población específica. Este artículo de actualización presenta una revisión bibliográfica realizada en el MEDLINE de toda literatura publicada en inglés en el período de 1966 hasta junio de 2009, con las siguientes palabras-clave: androgen deprivation therapy, androgen supression therapy, hormone treatment, prostate cancer, metabolic syndrome y cardiovascular disease, con el propósito de analizar cuales serían los reales riesgos cardiovasculares de la terapia de deprivación androgénica, también llamada bloqueo androgénico, en los pacientes con cáncer de próstata.Prostate adenocarcinoma is the most common cancer type in the male sex after skin cancer. Among the several types of treatment for prostate cancer, the androgen deprivation therapy has been highly recommended in patients with metastatic or locally advanced disease, which probably results in increased survival. However, the androgen deprivation is the cause of several adverse effects. Complications such as osteoporosis, sexual dysfunction, gynecomastia, anemia and body composition alterations are well-known effects of the therapy. Recently, a number of metabolic complications have been described, such as increase in the abdominal circumference, insulin resistance, hyperglycemia, diabetes, dyslipidemia and metabolic syndrome, with a consequent increase in the risk of coronary events and cardiovascular mortality in this specific population. This update article presents a literature review carried out at MEDLINE database of all literature published in English from 1966 to June 2009, using the following key words: androgen deprivation therapy, androgen suppression therapy, hormone treatment

  4. Adjuvant androgen deprivation therapy augments cure and long-term cancer control in men with poor prognosis, nonmetastatic prostate cancer.

    NARCIS (Netherlands)

    Fleshner, N.; Keane, T.E.; Lawton, C.A.; Mulders, P.F.A.; Payne, H.; Taneja, S.S.; Morris, T.

    2008-01-01

    Historically, adjuvant androgen deprivation therapy has been viewed as a palliative treatment option for patients with poor-prognosis non-metastatic prostate cancer. In addition, guidelines from bodies such as the European Association of Urology and American Society for Clinical Oncology do not spec

  5. Hot flushes in prostatic cancer patients during androgen-deprivation therapy with monthly dose of degarelix or leuprolide

    DEFF Research Database (Denmark)

    Iversen, P; Karup, C; van der Meulen, E;

    2011-01-01

    The aim of the study was to compare the onset, incidence and frequency/intensity of hot flushes during androgen-deprivation therapy with a gonadotropin-releasing hormone antagonist (GnRH) blocker versus an agonist using data from a randomized Phase 3 clinical trial. In total, 610 prostate cancer...

  6. Effect of androgen deprivation therapy on cardiovascular risk factors in prostate cancer

    Directory of Open Access Journals (Sweden)

    Mahnaz Roayaei

    2013-01-01

    Full Text Available Background: Androgen deprivation is the basis of treatment for advanced stages of prostate cancer. Cardiovascular disease may be a risk factor for mortality in prostate cancer. Therefore, we decided to evaluate the effect of androgen deprivation therapy (ADT on the cardiovascular risk factors in patients with prostate cancer. Materials and Methods: In a cross-sectional study on 2011, 35 patients suffering from metastatic prostate cancer as candidates for ADT were enrolled. Serum levels of fasting blood sugar (FBS, triglyceride (TG and total cholesterol (TC were measured at the beginning and after the 5 th month of ADT. Results: The mean level of TG increased significantly from 130.82 ± 41.57 mg/dl to 150.05 ± 48.29 mg/dl (P < 0.012. Furthermore, serum level of TC increased from 197.62 ± 40.71 mg/dl to 212.54 ± 38.25 mg/dl, which is statistically significant (P < 0.001. A non-significant increase in the serum level of FBS from 96.74 ± 14.04 mg/dl to 99.17 ± 15.23 mg/dl was also seen (P = 0.27. Conclusion: ADT in prostate cancer may lead to an increase in TG and TC levels. In patients with a high risk of cardiovascular disease patient′s lipid profile should be considered during ADT.

  7. The use of dietary supplements to alleviate androgen deprivation therapy side effects during prostate cancer treatment.

    Science.gov (United States)

    Dueregger, Andrea; Heidegger, Isabel; Ofer, Philipp; Perktold, Bernhard; Ramoner, Reinhold; Klocker, Helmut; Eder, Iris E

    2014-10-21

    Prostate cancer (PCa), the most commonly diagnosed cancer and second leading cause of male cancer death in Western societies, is typically androgen-dependent, a characteristic that underlies the rationale of androgen deprivation therapy (ADT). Approximately 90% of patients initially respond to ADT strategies, however many experience side effects including hot flashes, cardiotoxicity, metabolic and musculoskeletal alterations. This review summarizes pre-clinical and clinical studies investigating the ability of dietary supplements to alleviate adverse effects arising from ADT. In particular, we focus on herbal compounds, phytoestrogens, selenium (Se), fatty acids (FA), calcium, and Vitamins D and E. Indeed, there is some evidence that calcium and Vitamin D can prevent the development of osteoporosis during ADT. On the other hand, caution should be taken with the antioxidants Se and Vitamin E until the basis underlying their respective association with type 2 diabetes mellitus and PCa tumor development has been clarified. However, many other promising supplements have not yet been subjected large-scale clinical trials making it difficult to assess their efficacy. Given the demographic trend of increased PCa diagnoses and dependence on ADT as a major therapeutic strategy, further studies are required to objectively evaluate these supplements as adjuvant for PCa patients receiving ADT.

  8. Androgen Deprivation Therapy and the Incidence of Inflammatory Bowel Disease in Patients With Prostate Cancer.

    Science.gov (United States)

    Klil-Drori, Adi J; Tascilar, Koray; Yin, Hui; Aprikian, Armen; Bitton, Alain; Azoulay, Laurent

    2016-07-01

    Androgen deprivation therapy (ADT) is the mainstay treatment for advanced prostate cancer. By lowering androgen levels, ADT inhibits the progression of prostate cancer, but it may also affect gut autoimmunity. We investigated the association between ADT and the incidence of inflammatory bowel disease using a cohort of 31,842 men newly diagnosed with prostate cancer between 1988 and 2014, identified in the United Kingdom Clinical Practice Research Datalink. Exposure to ADT was treated as a time-varying variable and lagged by 1 year to account for diagnostic delays, with nonuse as the reference category. During 133,018 person-years of follow-up, 48 men were newly diagnosed with ulcerative colitis (incidence rate (IR) = 36/100,000 person-years (PY)) and 12 were diagnosed with Crohn's disease (IR = 9/100,000 PY). In Cox proportional hazards models, ADT was associated with a decreased risk of ulcerative colitis (IR = 24/100,000 PY vs. IR = 50/100,000 PY; hazard ratio = 0.52, 95% confidence interval: 0.28, 0.99) and a nonsignificant decreased risk of Crohn's disease (hazard ratio = 0.38, 95% confidence interval: 0.11, 1.37). These findings indicate that the use of ADT may be associated with intestinal autoimmunity. Further research is warranted to replicate these findings and assess their clinical significance.

  9. In an Ovine Model of Polycystic Ovary Syndrome (PCOS) Prenatal Androgens Suppress Female Fetal Renal Gluconeogenesis.

    Science.gov (United States)

    Connolly, Fiona; Rae, Michael T; Späth, Katharina; Boswell, Lyndsey; McNeilly, Alan S; Duncan, W Colin

    2015-01-01

    Increased maternal androgen exposure during pregnancy programmes a polycystic ovary syndrome (PCOS)-like condition, with metabolic dysfunction, in adult female offspring. Other in utero exposures associated with the development of insulin resistance, such as intrauterine growth restriction and exposure to prenatal glucocorticoids, are associated with altered fetal gluconeogenesis. We therefore aimed to assess the effect of maternal androgenisation on the expression of PEPCK and G6PC in the ovine fetus. Pregnant Scottish Greyface sheep were treated with twice weekly testosterone propionate (TP; 100mg) or vehicle control from day 62 to day 102 of gestation. At day 90 and day 112 fetal plasma and liver and kidney tissue was collected for analysis. PEPCK and G6PC expression were analysed by quantitative RT-PCR, immunohistochemistry and western blotting. PEPCK and G6PC were localised to fetal hepatocytes but maternal androgens had no effect on female or male fetuses. PEPCK and G6PC were also localised to the renal tubules and renal PEPCK (P<0.01) and G6PC (P = 0.057) were lower in females after prenatal androgenisation with no change in male fetuses. These tissue and sex specific observations could not be explained by alterations in fetal insulin or cortisol. The sexual dimorphism may be related to the increase in circulating estrogen (P<0.01) and testosterone (P<0.001) in females but not males. The tissue specific effects may be related to the increased expression of ESR1 (P<0.01) and AR (P<0.05) in the kidney when compared to the fetal liver. After discontinuation of maternal androgenisation female fetal kidney PEPCK expression normalised. These data further highlight the fetal and sexual dimorphic effects of maternal androgenisation, an antecedent to adult disease and the plasticity of fetal development.

  10. In an Ovine Model of Polycystic Ovary Syndrome (PCOS Prenatal Androgens Suppress Female Fetal Renal Gluconeogenesis.

    Directory of Open Access Journals (Sweden)

    Fiona Connolly

    Full Text Available Increased maternal androgen exposure during pregnancy programmes a polycystic ovary syndrome (PCOS-like condition, with metabolic dysfunction, in adult female offspring. Other in utero exposures associated with the development of insulin resistance, such as intrauterine growth restriction and exposure to prenatal glucocorticoids, are associated with altered fetal gluconeogenesis. We therefore aimed to assess the effect of maternal androgenisation on the expression of PEPCK and G6PC in the ovine fetus. Pregnant Scottish Greyface sheep were treated with twice weekly testosterone propionate (TP; 100mg or vehicle control from day 62 to day 102 of gestation. At day 90 and day 112 fetal plasma and liver and kidney tissue was collected for analysis. PEPCK and G6PC expression were analysed by quantitative RT-PCR, immunohistochemistry and western blotting. PEPCK and G6PC were localised to fetal hepatocytes but maternal androgens had no effect on female or male fetuses. PEPCK and G6PC were also localised to the renal tubules and renal PEPCK (P<0.01 and G6PC (P = 0.057 were lower in females after prenatal androgenisation with no change in male fetuses. These tissue and sex specific observations could not be explained by alterations in fetal insulin or cortisol. The sexual dimorphism may be related to the increase in circulating estrogen (P<0.01 and testosterone (P<0.001 in females but not males. The tissue specific effects may be related to the increased expression of ESR1 (P<0.01 and AR (P<0.05 in the kidney when compared to the fetal liver. After discontinuation of maternal androgenisation female fetal kidney PEPCK expression normalised. These data further highlight the fetal and sexual dimorphic effects of maternal androgenisation, an antecedent to adult disease and the plasticity of fetal development.

  11. The Master Neural Transcription Factor BRN2 Is an Androgen Receptor-Suppressed Driver of Neuroendocrine Differentiation in Prostate Cancer.

    Science.gov (United States)

    Bishop, Jennifer L; Thaper, Daksh; Vahid, Sepideh; Davies, Alastair; Ketola, Kirsi; Kuruma, Hidetoshi; Jama, Randy; Nip, Ka Mun; Angeles, Arkhjamil; Johnson, Fraser; Wyatt, Alexander W; Fazli, Ladan; Gleave, Martin E; Lin, Dong; Rubin, Mark A; Collins, Colin C; Wang, Yuzhuo; Beltran, Himisha; Zoubeidi, Amina

    2017-01-01

    Mechanisms controlling the emergence of lethal neuroendocrine prostate cancer (NEPC), especially those that are consequences of treatment-induced suppression of the androgen receptor (AR), remain elusive. Using a unique model of AR pathway inhibitor-resistant prostate cancer, we identified AR-dependent control of the neural transcription factor BRN2 (encoded by POU3F2) as a major driver of NEPC and aggressive tumor growth, both in vitro and in vivo Mechanistic studies showed that AR directly suppresses BRN2 transcription, which is required for NEPC, and BRN2-dependent regulation of the NEPC marker SOX2. Underscoring its inverse correlation with classic AR activity in clinical samples, BRN2 expression was highest in NEPC tumors and was significantly increased in castration-resistant prostate cancer compared with adenocarcinoma, especially in patients with low serum PSA. These data reveal a novel mechanism of AR-dependent control of NEPC and suggest that targeting BRN2 is a strategy to treat or prevent neuroendocrine differentiation in prostate tumors.

  12. Androgen excess: Investigations and management.

    Science.gov (United States)

    Lizneva, Daria; Gavrilova-Jordan, Larisa; Walker, Walidah; Azziz, Ricardo

    2016-11-01

    Androgen excess (AE) is a key feature of polycystic ovary syndrome (PCOS) and results in, or contributes to, the clinical phenotype of these patients. Although AE will contribute to the ovulatory and menstrual dysfunction of these patients, the most recognizable sign of AE includes hirsutism, acne, and androgenic alopecia or female pattern hair loss (FPHL). Evaluation includes not only scoring facial and body terminal hair growth using the modified Ferriman-Gallwey method but also recording and possibly scoring acne and alopecia. Moreover, assessment of biochemical hyperandrogenism is necessary, particularly in patients with unclear or absent hirsutism, and will include assessing total and free testosterone (T), and possibly dehydroepiandrosterone sulfate (DHEAS) and androstenedione, although these latter contribute limitedly to the diagnosis. Assessment of T requires use of the highest quality assays available, generally radioimmunoassays with extraction and chromatography or mass spectrometry preceded by liquid or gas chromatography. Management of clinical hyperandrogenism involves primarily either androgen suppression, with a hormonal combination contraceptive, or androgen blockade, as with an androgen receptor blocker or a 5α-reductase inhibitor, or a combination of the two. Medical treatment should be combined with cosmetic treatment including topical eflornithine hydrochloride and short-term (shaving, chemical depilation, plucking, threading, waxing, and bleaching) and long-term (electrolysis, laser therapy, and intense pulse light therapy) cosmetic treatments. Generally, acne responds to therapy relatively rapidly, whereas hirsutism is slower to respond, with improvements observed as early as 3 months, but routinely only after 6 or 8 months of therapy. Finally, FPHL is the slowest to respond to therapy, if it will at all, and it may take 12 to 18 months of therapy for an observable response.

  13. Influence of age on androgen deprivation therapy-associated Alzheimer’s disease

    Science.gov (United States)

    Nead, Kevin T.; Gaskin, Greg; Chester, Cariad; Swisher-McClure, Samuel; Dudley, Joel T.; Leeper, Nicholas J.; Shah, Nigam H.

    2016-10-01

    We recently found an association between androgen deprivation therapy (ADT) and Alzheimer’s disease. As Alzheimer’s disease is a disease of advanced age, we hypothesize that older individuals on ADT may be at greatest risk. We conducted a retrospective multi-institutional analysis among 16,888 individuals with prostate cancer using an informatics approach. We tested the effect of ADT on Alzheimer’s disease using Kaplan–Meier age stratified analyses in a propensity score matched cohort. We found a lower cumulative probability of remaining Alzheimer’s disease-free between non-ADT users age ≥70 versus those age Alzheimer’s disease was 2.9%, 1.9% and 0.5% among ADT users ≥70, non-ADT users ≥70 and individuals Alzheimer’s disease risk. Future work should investigate the ADT Alzheimer’s disease association in advanced age populations given the greater potential clinical impact.

  14. Influence of age on androgen deprivation therapy-associated Alzheimer's disease.

    Science.gov (United States)

    Nead, Kevin T; Gaskin, Greg; Chester, Cariad; Swisher-McClure, Samuel; Dudley, Joel T; Leeper, Nicholas J; Shah, Nigam H

    2016-10-18

    We recently found an association between androgen deprivation therapy (ADT) and Alzheimer's disease. As Alzheimer's disease is a disease of advanced age, we hypothesize that older individuals on ADT may be at greatest risk. We conducted a retrospective multi-institutional analysis among 16,888 individuals with prostate cancer using an informatics approach. We tested the effect of ADT on Alzheimer's disease using Kaplan-Meier age stratified analyses in a propensity score matched cohort. We found a lower cumulative probability of remaining Alzheimer's disease-free between non-ADT users age ≥70 versus those age Alzheimer's disease was 2.9%, 1.9% and 0.5% among ADT users ≥70, non-ADT users ≥70 and individuals Alzheimer's disease risk. Future work should investigate the ADT Alzheimer's disease association in advanced age populations given the greater potential clinical impact.

  15. Preferred treatment frequency in patients receiving androgen deprivation therapy for advanced prostate cancer

    DEFF Research Database (Denmark)

    Fode, Mikkel; Nielsen, Torben K; Al-Hamadani, Muhammad;

    2014-01-01

    for analysis. A total of 38.1% of participants preferred frequent treatment ("Every month", "Every third month"), 32.4% preferred infrequent treatment ("Every sixth month", "Every twelfth month") and 29.6% stated that length of the treatment intervals made no difference (p = 0.37). Patients with disease......OBJECTIVE: The aim of this study was to assess patient preference regarding the length of treatment intervals of androgen deprivation therapy (ADT) with gonadotropin-releasing hormone agonists for prostate cancer. MATERIAL AND METHODS: The study was conducted as a questionnaire-based, cross...... satisfaction and side-effects. Overall, 238 men receiving ADT for prostate cancer were presented with the questionnaire between September 2011 and May 2012. Descriptive statistics, the chi-squared test and multiple regression were used for analyses. RESULTS: In total, 176 questionnaires (74%) were available...

  16. Development and exploitation of a novel mutant androgen receptor modelling strategy to identify new targets for advanced prostate cancer therapy.

    Science.gov (United States)

    O'Neill, Daniel; Jones, Dominic; Wade, Mark; Grey, James; Nakjang, Sirintra; Guo, Wenrui; Cork, David; Davies, Barry R; Wedge, Steve R; Robson, Craig N; Gaughan, Luke

    2015-09-22

    The persistence of androgen receptor (AR) signalling in castrate-resistant prostate cancer (CRPC) highlights the unmet clinical need for the development of more effective AR targeting therapies. A key mechanism of therapy-resistance is by selection of AR mutations that convert anti-androgens to agonists enabling the retention of androgenic signalling in CRPC. To improve our understanding of these receptors in advanced disease we developed a physiologically-relevant model to analyse the global functionality of AR mutants in CRPC. Using the bicalutamide-activated AR(W741L/C) mutation as proof of concept, we demonstrate that this mutant confers an androgenic-like signalling programme and growth promoting phenotype in the presence of bicalutamide. Transcriptomic profiling of AR(W741L) highlighted key genes markedly up-regulated by the mutant receptor, including TIPARP, RASD1 and SGK1. Importantly, SGK1 expression was found to be highly expressed in the KUCaP xenograft model and a CRPC patient biopsy sample both of which express the bicalutamide-activated receptor mutant. Using an SGK1 inhibitor, AR(W741L) transcriptional and growth promoting activity was reduced indicating that exploiting functional distinctions between receptor isoforms in our model may provide new and effective therapies for CRPC patients.

  17. The Efficacy of Neoadjuvant Androgen Deprivation Therapy as a Prostate Volume Reduction before Brachytherapy for Clinically Localized Prostate Cancer

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    Miki,Kenta

    2007-12-01

    Full Text Available From September 2003 to December 2005, 188 patients who visited our hospital and allied institutions for the purpose of prostate brachytherapy were administrated hormonal therapy for volume reductions before brachytherapy. The pretreatment and posttreatment of prostate volume using a transrectal ultrasound volumetric study and the types and duration of hormonal therapy were analyzed. We administered 91 patients with Luteinizing hormone-releasing hormone (LH-RH agonist, 49 patients with anti-androgen (bicaltamide/flutamide, and 48 patients with maximum androgen blockade (MAB. The duration of the hormonal therapy was 1-3 months for 49 patients, 4-6 months for 59 patients, 7-9 months for 40 patients, 10-12 months for 32 patients, and over 13 months for 8 patients. Before the initiation of hormonal therapy, the mean prostate volume was 35.12 ml (11.04-78.71 ml, and the average of prostate volume before and after hormonal therapy was 36.79 ml and 24.79 ml, respectively (a 32.4% reduction. The prostate volume reduction rate was 32.0% for the LH-RH agonist only, 18.1% for the anti-androgen only and 41.2% for the MAB. No statistically significant difference was observed for the duration of hormonal therapy between 3 groups. A three-month course of the neoadjuvant LH-RH agonist indicated a sufficient volume reduction effectiveness for a large prostate volume.

  18. Integrating diet and exercise into care of prostate cancer patients on androgen deprivation therapy

    Directory of Open Access Journals (Sweden)

    Moyad MA

    2016-08-01

    Full Text Available Mark A Moyad,1 Robert U Newton,2 Ulf W Tunn,3 Damian Gruca4 1Department of Urology, University of Michigan Medical Center, Ann Arbor, MI, USA; 2Exercise Medicine Research Institute, Edith Cowan University, Joondalup, WA, Australia; 3Urological Clinic, Facharztzentrum Academic Hospital Sana Klinikum Offenbach, Offenbach/Main, 4Global Medical Affairs, AbbVie Deutschland, Ludwigshafen, Germany Abstract: Improved diagnosis and treatment regimens have resulted in greater longevity for men with prostate cancer. This has led to an increase in both androgen deprivation therapy (ADT use and duration of exposure, and therefore to its associated adverse effects, such as sexual dysfunction, osteoporosis, reduced muscle mass, increased fat mass, and increased incidence of cardiovascular disease and type 2 diabetes. Given that the adverse effects of ADT are systemic, often debilitating, and difficult to treat, efforts continue in the development of new strategies for long-term management of prostate cancer. The PubMed database was searched to select trials, reviews, and meta-analyses in English using such search terms as “prostate cancer” and “androgen deprivation therapy”, “cardiovascular risk”, “lean body mass”, “exercise”, and “diet”. The initial searches produced 379 articles with dates 2005 or more recent. Articles published after 2004 were favored. This review utilizes the latest data to provide a status update on the effects of exercise and diet on patients with prostate cancer, focusing on ADT-associated side effects, and it discusses the evidence for such interventions. Since the evidence of large-scale trials in patients with prostate cancer is missing, and an extrapolation of supporting data to all patient subgroups cannot be provided, individualized risk assessments remain necessary before the initiation of exercise and diet programs. Exercise, diet, and nutritional supplementation interventions have the potential to

  19. Muscle function, physical performance and body composition changes in men with prostate cancer undergoing androgen deprivation therapy

    Institute of Scientific and Technical Information of China (English)

    Thomas W Storer; Renee Miciek; Thomas G Travison

    2012-01-01

    Prostate cancer (PCa) is the most common visceral malignancy in men with androgen deprivation therapy (ADT) the preferred therapy to suppress testosterone production and hence tumor growth.Despite its effectiveness in lowering testosterone,ADT is associated with side effects including loss of muscle mass,diminished muscle strength,decrements in physical performance,earlier fatigue and declining quality of life.This review reports a survey of the literature with a focus on changes in muscle strength,physical function and body composition,due to short-term and long-term ADT.Studies in these areas are sparse,especially well-controlled,prospective randomized trials.Cross-sectional and longitudinal data (up to 2 years) for men with PCa treated with ADT as well as patients with PCa not receiving ADT and age-matched healthy men are presented when available.Based on limited longitudinal data,the adverse effects of ADT on muscle function,physical performance and body composition occur shortly after the onset of ADT andtend to persist and worsen over time.Exercise training is a safe and effective intervention for mitigating these changes and initial guidelines for exercise program design for men with PCa have been published by the American College of Sports Medicine.Disparities in study duration,typos of studies and other patient-specific variables such as time since diagnosis,cancer stage and comorbidities may all affect an understanding of the influence of ADT on health,physical performance and mortality.

  20. Inhibition of the Akt, cyclooxygenase-2, and matrix metalloproteinase-9 pathways in combination with androgen deprivation therapy: potential therapeutic approaches for prostate cancer.

    Science.gov (United States)

    Miyamoto, Hiroshi; Altuwaijri, Saleh; Cai, Yi; Messing, Edward M; Chang, Chawnshang

    2005-09-01

    Prostate cancer cells are generally dependent on androgen stimulation mediated by the androgen receptor (AR) for growth and survival, and, therefore, hormonal manipulation, such as castration and/or the use of AR antagonists, results in a regression of the cancer. However, this treatment very rarely leads to the "cure" of advanced disease, and cancers eventually become androgen-independent. A number of genes/pathways have been reported to be activated in prostate cancer, most of which are possibly associated with disease progression. In this article, among them, we focus on Akt (also known as protein kinase B), cyclooxygenase (COX)-2, and matrix metalloproteinase (MMP)-9, whose activities or expressions have been found to be regulated by androgens/AR. Previous studies by us and others, with androgen-sensitive prostate cancer cell lines, have demonstrated that androgen deprivation results in activation/overexpression of Akt, COX-2, and MMP-9 in cells. This suggests that androgen deprivation in clinical settings activates the Akt, COX-2, and MMP-9 pathways in prostate cancer, which may increase cell growth and in turn promote the transition to the androgen-independent state. We hypothesize that androgen deprivation, in combination with inhibition of the Akt, COX-2, and MMP-9 pathways, delays the androgen-independent transition and has more beneficial effects than hormonal therapy alone.

  1. Androgen receptor signaling is required for androgen-sensitive human prostate cancer cell proliferation and survival

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    Day Wanda V

    2005-04-01

    Full Text Available Abstract Background Androgens and androgen receptors (AR regulate normal prostate development and growth. They also are involved in pathological development of prostatic diseases, including benign prostatic hyperplasia (BPH and prostate cancer (PCa. Antiandrogen therapy for PCa, in conjunction with chemical or surgical castration, offers initial positive responses and leads to massive prostate cell death. However, cancer cells later appear as androgen-independent PCa. To investigate the role of AR in prostate cell proliferation and survival, we introduced a vector-based small interfering RNA (siRNA. This siRNA targeted 5'-untranslated region of AR mRNA for extended suppression of AR expression in androgen-sensitive human prostate LNCaP cells. Results The siRNA design successfully suppressed endogenous AR expression, as revealed by western blotting and immunofluorescence staining in LNCaP cells. LNCaP cells did not proliferate in the absence of AR and underwent apoptosis, based on elevated phospho-Histone H2B expression and higher number of apoptotic body as compared to control cells. Conclusion We demonstrated that AR is vital for prostate cell proliferation and survival in this androgen-sensitive prostate cell line. These results further strengthen the hypothesis that AR can be a therapeutic target for treating androgen-sensitive stages of PCa. Unlike antiandorgens, however, siRNA targeting AR provides a direct inactivation of AR function through the suppression of AR protein expression.

  2. Re: Final Report of the Intergroup Randomized Study of Combined AndrogenDeprivation Therapy Plus Radiotherapy Versus Androgen-Deprivation Therapy Alone in Locally Advanced Prostate Cancer

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    Malcolm D. Mason

    2015-06-01

    Full Text Available No certain treatment recommendations were given for locally advanced or high-risk prostate cancer in the European Association of Urology (EAU guidelines (1. In the guidelines, studies supporting surgery or radiotherapy (RT were listed, and the readers were left alone to make their own decisions. In the present study, Mason et al. reported the impact of adding RT to androgen deprivation therapy (ADT. One thousand two hundred and five patients with T3- 4, N0/Nx, M0 prostate cancer or T1-2 disease with either PSA more than 40 μg/L or PSA 20 to 40 μg/L plus Gleason score of 8 to 10 were randomized to ADT alone (n=602 or to ADT+RT (n=603. A lower dose radiation 64 to 69 Gy was used for RT. Overall survival (OS risk reduction was 30% for ADT+RT group (P<0.001 at a median follow-up of 8 years. Cancer-specific survival (CSS was significantly improved by the addition of RT to ADT (HR: 0.46, 95% CI: 0.34 to 0.61; p<0.001. Patients on ADT+RT reported a higher frequency of adverse events related to bowel toxicity. However, reported frequency of ADT-related toxicities (impotence, hot flushes, urinary frequency, ischemia, and hypertension were similar for both arms. The present study provided results of high-risk patients in a longer median follow-up time than SPCG-7 study (2. Because the study took place between 1995 and 2005, less than 70 Gy was used for RT. Even at lower radiation doses, the authors confirmed that adding RT to ADT improved both OS and cancer-specific survival (CSS with minimal general toxicity. In the modern era, improved RT techniques may help achieve better outcomes with much higher radiation doses without increased morbidity in this group of patients

  3. Natural proteasome inhibitor celastrol suppresses androgen-independent prostate cancer progression by modulating apoptotic proteins and NF-kappaB.

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    Yao Dai

    Full Text Available Celastrol is a natural proteasome inhibitor that exhibits promising anti-tumor effects in human malignancies, especially the androgen-independent prostate cancer (AIPC with constitutive NF-κB activation. Celastrol induces apoptosis by means of proteasome inhibition and suppresses prostate tumor growth. However, the detailed mechanism of action remains elusive. In the current study, we aim to test the hypothesis that celastrol suppresses AIPC progression via inhibiting the constitutive NF-κB activity as well as modulating the Bcl-2 family proteins.We examined the efficacy of celastrol both in vitro and in vivo, and evaluated the role of NF-κB in celastrol-mediated AIPC regression. We found that celastrol inhibited cell proliferation in all three AIPC cell lines (PC-3, DU145 and CL1, with IC₅₀ in the range of 1-2 µM. Celastrol also suppressed cell migration and invasion. Celastrol significantly induced apoptosis as evidenced by increased sub-G1 population, caspase activation and PARP cleavage. Moreover, celastrol promoted cleavage of the anti-apoptotic protein Mcl-1 and activated the pro-apoptotic protein Noxa. In addition, celastrol rapidly blocked cytosolic IκBα degradation and nuclear translocation of RelA. Likewise, celastrol inhibited the expression of multiple NF-κB target genes that are involved in proliferation, invasion and anti-apoptosis. Celastrol suppressed AIPC tumor progression by inhibiting proliferation, increasing apoptosis and decreasing angiogenesis, in PC-3 xenograft model in nude mouse. Furthermore, increased cellular IκBα and inhibited expression of various NF-κB target genes were observed in tumor tissues.Our data suggest that, via targeting the proteasome, celastrol suppresses proliferation, invasion and angiogenesis by inducing the apoptotic machinery and attenuating constitutive NF-κB activity in AIPC both in vitro and in vivo. Celastrol as an active ingredient of traditional herbal medicine could thus be

  4. Can prophylactic breast irradiation contribute to cardiac toxicity in patients with prostate cancer receiving androgen suppressing drugs?

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    Molls Michael

    2008-01-01

    Full Text Available Abstract Background Androgen suppression treatment (AST might increase the risk of cardiac morbidity in prostate cancer patients. Possible explanations were provided, however, they disregard the potential contribution of prophylactic radiotherapy to the mamillary regions (PMRT, prescribed to avoid gynecomastia. Methods We studied the exposure of the heart in a typical electron beam PMRT setting by evaluating computed tomography (CT scans in 40 non-cancer patients (age 65 and 75 years in 50% each and 17 prostate cancer patients. Five of the younger, 7 of the older and 4 of the cancer patients had significant cardiac disease. Results The median distance between skin and outer heart contour decreased with age. In all three groups, patients with cardiac morbidity had smaller distances. When using the CT-determined PMRT beam energy, 10% of the younger, 15% of the older and none of the prostate cancer patients would receive approximately 50% of the prescription dose to a part of the heart (2 had no history of cardiac disease. When using the clinically rather than CT-determined beam energy, as often done in daily practice, an additional 12.5% of the non-cancer and 12% of the prostate cancer patients would be exposed to comparably high doses. Conclusion The present data provide preliminary evidence that PMRT might be a factor that contributes to cardiac side effects. Previous studies that established a relationship between AST and cardiac morbidity did not include information on delivery of PMRT.

  5. Androgens and breast cancer in men and women.

    Science.gov (United States)

    Dimitrakakis, Constantine

    2011-09-01

    Abundant clinical evidence suggests that androgens normally inhibit mammary epithelial proliferation and breast growth. Clinical and nonhuman primate studies support the notion that androgens inhibit mammary proliferation and, thus, may protect from breast cancer. On the other hand, administration of conventional estrogen treatment suppresses endogenous androgens and may, thus, enhance estrogenic breast stimulation and possibly breast cancer risk. Addition of testosterone to the usual hormone therapy regimen may diminish the estrogen/progestin increase in breast cancer risk, but the impact of this combined use on mammary gland homeostasis still needs evaluation.

  6. Prognostic significance of genetic polymorphisms in disease progression and survival in prostate cancer after androgen deprivation therapy

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    Tsung-Yi Huang

    2015-06-01

    Full Text Available It is believed that androgens and their receptors regulate normal prostate growth and mediate prostate cancer development. Androgen deprivation therapy is the most commonly used treatment for advanced prostate cancer. Although the therapy is initially effective, progression of the disease to castration-resistant prostate cancer is almost inevitable, leading to treatment failure. Despite the existence of current clinical parameters, new biomarkers are urgently needed to improve the prognosis. Some molecules and DNA-based genetic biomarkers are under investigation as potential prognostic factors. The advancement in molecular cytogenetic research, such as genome-wide association for single-nucleotide polymorphisms, has made possible the detection of genetic mutations. In this study, a literature search from August 1985 to April 2013 was performed through the PubMed database using the keywords “genetic polymorphisms”, “prostate cancer” and “androgen deprivation therapy”. The results revealed that several genome-wide association studies (such as rs16901979, rs7931342, HSD17B4, rs6162 in the CYP17A1, rs4243229 and rs7201637 in the HSD17B2, rs1062577 in the ESR1, SLCO1B3, SLCO2B1, rs2939244 in the ARRDC3, rs9508016 in the FLT1, rs6504145 in the SKAP1, rs7830611 in the FBXO32, rs9508016 in the FLT1, rs12529 in the AKR1C3, rs16934641 in the BNC2, rs3763763 in the TACC2, rs2051778 in the ALPK1, and rs3763763 in the TACC2, AR, ESR1, and ESR2 and single-nucleotide polymorphisms in important pathways (such as androgen signal, biosynthesis, metabolism, androgen receptor binding site, response element, androgen receptor CAG repeat polymorphism length, and estrogen receptor-binding sites involved in prostate cancer occurrence and mechanism could serve as candidate biomarkers for the early detection of castration-resistant prostate cancer after androgen deprivation therapy. Additional investigations are required to decipher precisely the gene

  7. Obesity and the Odds of Weight Gain following Androgen Deprivation Therapy for Prostate Cancer

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    Lior Z. Braunstein

    2014-01-01

    Full Text Available Background. Increasing body mass index (BMI is associated with increased risk of mortality; however, quantifying weight gain in men undergoing androgen deprivation therapy (ADT for prostate cancer (PC remains unexplored. Methods. Between 1995 and 2001, 206 men were enrolled in a randomized trial evaluating the survival difference of adding 6 months of ADT to radiation therapy (RT. BMI measurements were available in 171 men comprising the study cohort. The primary endpoint was weight gain of ≥10 lbs by 6-month followup. Logistic regression analysis was performed to assess whether baseline BMI or treatment received was associated with this endpoint adjusting for known prognostic factors. Results. By the 6-month followup, 12 men gained ≥10 lbs, of which 10 (83% received RT + ADT and, of these, 7 (70% were obese at randomization. Men treated with RT as compared to RT + ADT were less likely to gain ≥10 lbs (adjusted odds ratio (AOR: 0.18 [95% CI: 0.04–0.89]; P=0.04, whereas this risk increased with increasing BMI (AOR: 1.15 [95% CI: 1.01–1.31]; P=0.04. Conclusions. Consideration should be given to avoid ADT in obese men with low- or favorable-intermediate risk PC where improved cancer control has not been observed, but shortened life expectancy from weight gain is expected.

  8. Androgen deprivation therapy of self-identifying, help-seeking pedophiles in the Dunkelfeld.

    Science.gov (United States)

    Amelung, Till; Kuhle, Laura F; Konrad, Anna; Pauls, Alfred; Beier, Klaus M

    2012-01-01

    Androgen deprivation therapy (ADT) is considered an effective strategy in sexual offender treatment. However, the evidence base concerning its effects on sexual arousal control is limited. Past research has focused almost exclusively on men in forensic contexts. The present retrospective observational study provided data on ADT in a sample of self-identifying, help-seeking pedohebephilic men applying for a one-year group therapy program. Factors possibly influencing the readiness to take up or discontinue ADT were presented. Effects of a combination of ADT and group psychotherapy program on changes in paraphilic sexual behavior and associated psychological factors were examined. The proportion of men having taken up ADT was rather small (n=15). Greater awareness of potentially risky situations to commit child sexual offenses and self-rated uncontrollability of sexual urges were identified as characterizing men resorting to ADT. Additionally, these men were initially more open to include medical treatment. Examination of the effects of ADT and psychotherapy was limited to a sample of six men providing complete data sets. Descriptive data demonstrated a reduction of paraphilic sexual behaviors, an increase of risk-awareness and self-efficacy, and a decrease of offense-supportive cognitions and self-esteem. The present study underlined the importance of careful education and monitoring of self-identifying, help-seeking pedohebephilic patients interested in ADT concerning the effects and side effects of the treatment in a clinical context.

  9. Humanized Androgen Receptor Mice: A Genetic Model for Differential Response to Prostate Cancer Therapy

    Science.gov (United States)

    2012-07-01

    address at the International Conference on Hormonal Steroids and Hormones & Cancer, Edinburgh, Scotland , 09/22/2010; Genetic Variation of the Androgen...Ferrell, R.E., Roth , S.M., 2005. Androgen receptor CAG repeat polymorphism is associated with fat-free mass in men. J. Appl. Physiol. 98, 132–137. Wu, C.T

  10. Huntingtin-associated protein 1 (HAP1) interacts with androgen receptor (AR) and suppresses SBMA-mutant-AR-induced apoptosis.

    Science.gov (United States)

    Takeshita, Yukio; Fujinaga, Ryutaro; Zhao, Changjiu; Yanai, Akie; Shinoda, Koh

    2006-08-01

    Huntingtin-associated protein 1 (HAP1), an interactor of huntingtin, has been known as an essential component of the stigmoid body (STB) and recently reported to play a protective role against neurodegeneration in Huntington's disease (HD). In the present study, subcellular association between HAP1 and androgen receptor (AR) with a long polyglutamine tract (polyQ) derived from spinal-and-bulbar-muscular-atrophy (SBMA) was examined using HEp-2 cells cotransfected with HAP1 and/or normal ARQ25, SBMA-mutant ARQ65 or deletion-mutant AR cDNAs. The results provided the first clear evidence that HAP1 interacts with AR through its ligand-binding domain in a polyQ-length-dependent manner and forms prominent inclusions sequestering polyQ-AR, and that addition of dihydrotestosterone reduces the association strength of HAP1 with ARQ25 more dramatically than that with ARQ65. Furthermore, SBMA-mutant-ARQ65-induced apoptosis was suppressed by cotransfection with HAP1. Our findings strongly suggest that HAP1/STB is relevant to polyQ-length-dependent modification on subcellular AR functions and critically involved in pathogenesis of not only HD but also SBMA as an important intrinsic neuroprotectant determining the threshold for cellular vulnerability to apoptosis. Taking together with previous reports that HAP1/STB is selectively expressed in the brain regions spared from degenerative targets in HD and SBMA, the current study might explain the region-specific occurrence of neurodegeneration in both diseases, shedding light on common aspects of their molecular pathological mechanism and yet-to-be-uncovered diagnostic or therapeutic applications for HD and SBMA patients.

  11. Metabolic syndrome in patients with prostate cancer undergoing intermittent androgen-deprivation therapy

    Science.gov (United States)

    Rezaei, Mohammadali Mohammadzadeh; Rezaei, Mohammadhadi Mohammadzadeh; Ghoreifi, Alireza; Kerigh, Behzad Feyzzadeh

    2016-01-01

    Introduction: The presence of metabolic syndrome in men with prostate cancer (PCa) undergoing androgen-deprivation therapy (ADT), especially intermittent type, has not been completely evaluated. The aim of this study is to evaluate metabolic syndrome in men with PCa undergoing intermittent ADT. Methods: In this longitudinal study, we studied the prevalence of metabolic syndrome and its components in 190 patients who were undergoing intermittent ADT. The metabolic syndrome was defined according to the Adult Treatment Panel III criteria. All metabolic parameters, including lipid profile, blood glucose, blood pressures, and waist circumferences of the patients were measured six and 12 months after treatment. Results: Mean age of the patients was 67.5 ± 6.74 years. The incidence of metabolic syndrome after six and 12 months was 6.8% and 14.7%, respectively. Analysis of various components of the metabolic syndrome revealed that patients had significantly higher overall prevalence of hyperglycemia, abdominal obesity, and hypertriglyceridemia in their six- and 12-month followups, but blood pressure has not been changed in the same period except for diastolic blood pressure after six months. Conclusions: Although there was an increased risk of metabolic syndrome in patients receiving intermittent ADT, it was lower than other studies that treated the same patients with continuous ADT. Also it seems that intermittent ADT has less metabolic complications than continuous ADT and could be used as a safe alternative in patients with advanced and metastatic PCa. PMID:27695584

  12. Asian trends in primar y androgen depletion therapy on prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Hideyuki Akaza

    2013-01-01

    hTere are notable differences in the incidence and mortality rates for prostate cancer between Asia and Western countries. It is also recognized that there are differences in thinking with regard to treatment options. Recently it is also the case that opinions have been reported concerning the differences between Asian and Western patients with regard to their reaction to androgen depletion therapy (ADT). Given that ADT is a method of treatment that focuses on the elimination of testosterone, an inevitable symptom of its administration is testosterone losing syndrome. It is for this reason that in Western countries ADT has only been recommended in cases of advanced or metastatic cancer. On the other hand, in Asia, ADT is used in relatively many cases, including non-metastatic localized cancer and invasive localized cancer. To date, however, there has been little substantive discussion concerning this difference in utilization of ADT. ADT-related drugs for prostate cancer and the development of new drugs for castration resistant prostate cancer (CRPC) have been actively tested in recent years. It could be the case that analyzing the differences in concepts about ADT between Asia and the West could contribute to the effective use of ADT-related drugs and also help to build new treatment strategies for prostate cancer.

  13. Changes in neuronal activation patterns in response to androgen deprivation therapy: a pilot study

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    Shelton Amy L

    2010-01-01

    Full Text Available Abstract Background A common treatment option for men with prostate cancer is androgen deprivation therapy (ADT. However, men undergoing ADT may experience physical side effects, changes in quality of life and sometimes psychiatric and cognitive side effects. Methods In this study, hormone naïve patients without evidence of metastases with a rising PSA were treated with nine months of ADT. Functional magnetic resonance imaging (fMRI of the brain during three visuospatial tasks was performed at baseline prior to treatment and after nine months of ADT in five subjects. Seven healthy control patients, underwent neuroimaging at the same time intervals. Results ADT patients showed reduced, task-related BOLD-fMRI activation during treatment that was not observed in control subjects. Reduction in activation in right parietal-occipital regions from baseline was observed during recall of the spatial location of objects and mental rotation. Conclusions Findings, while preliminary, suggest that ADT reduces task-related neural activation in brain regions that are involved in mental rotation and accurate recall of spatial information.

  14. Cardiometabolic and Skeletal Risk Factors in Black Men with Prostate Cancer Starting Androgen Deprivation Therapy

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    Gunnarsson, Orvar, E-mail: orvar.gunnarsson@uphs.upenn.edu [Department of Medicine, Division of Hematology and Oncology, Hospital of the University of Pennsylvania, 3400 Spruce Street, 16 Penn Tower, Philadelphia, PA 19104 (United States); Basaria, Shehzad [Department of Medicine, Section of Men’s Health, Aging and Metabolism, Brigham and Women’s Hospital, Boston, MA 02115 (United States); Gignac, Gretchen A. [Department of Medicine, Section of Hematology and Oncology, Boston University School of Medicine, Boston, MA 02118 (United States)

    2015-04-22

    Background: Androgen deprivation therapy (ADT) for prostate cancer (PCa) is associated with multiple metabolic complications, previously predominantly evaluated in the white population. Methods: A chart-based retrospective review was conducted on black patients with PCa, considered for ADT, from September 2007 to July 2010. Baseline data were collected on body mass index (BMI), vitamin-D status, bone mineral density (BMD), dyslipidemia and diabetes. Overweight and obesity were classified as BMI ≥ 25 and BMI ≥ 30, respectively. Vitamin-D sufficiency was defined as levels ≥30 ng/mL, insufficiency as <30 ng/mL and deficiency as ≤20 ng/mL. Osteopenia was defined as T scores between −1 to −2.5 and osteoporosis when T scores ≤−2.5. Results: Of the initial cohort of 130 black men, 111 (85.4%) patients underwent ADT. At baseline, average BMI was 28.1 ± 5.9 with 43.3% of men being overweight and 30.8% obese. More than one-third of the patients had pre-existing dyslipidemia while 28.8% were diabetics. 50% were vitamin-D deficient while 41% had low bone mass. Conclusions: Black men with PCa presenting for consideration of ADT have a high prevalence of existing metabolic risk factors. Close monitoring of this patient population is needed during ADT to prevent and treat metabolic complications.

  15. Cardiometabolic and Skeletal Risk Factors in Black Men with Prostate Cancer Starting Androgen Deprivation Therapy

    Directory of Open Access Journals (Sweden)

    Orvar Gunnarsson

    2015-04-01

    Full Text Available Background: Androgen deprivation therapy (ADT for prostate cancer (PCa is associated with multiple metabolic complications, previously predominantly evaluated in the white population. Methods: A chart-based retrospective review was conducted on black patients with PCa, considered for ADT, from September 2007 to July 2010. Baseline data were collected on body mass index (BMI, vitamin-D status, bone mineral density (BMD, dyslipidemia and diabetes. Overweight and obesity were classified as BMI ≥ 25 and BMI ≥ 30, respectively. Vitamin-D sufficiency was defined as levels ≥30 ng/mL, insufficiency as <30 ng/mL and deficiency as ≤20 ng/mL. Osteopenia was defined as T scores between −1 to −2.5 and osteoporosis when T scores ≤−2.5. Results: Of the initial cohort of 130 black men, 111 (85.4% patients underwent ADT. At baseline, average BMI was 28.1 ± 5.9 with 43.3% of men being overweight and 30.8% obese. More than one-third of the patients had pre-existing dyslipidemia while 28.8% were diabetics. 50% were vitamin-D deficient while 41% had low bone mass. Conclusions: Black men with PCa presenting for consideration of ADT have a high prevalence of existing metabolic risk factors. Close monitoring of this patient population is needed during ADT to prevent and treat metabolic complications.

  16. A pilot study of exercise in men with prostate cancer receiving androgen deprivation therapy

    Directory of Open Access Journals (Sweden)

    Lee C

    2012-03-01

    Full Text Available Abstract Background Androgen deprivation therapy (ADT is the mainstay therapy for men with prostate cancer. However, there are musculoskeletal side effects from ADT that increase the risk for osteoporosis and fracture, and can compromise the quality of life of these individuals. The objectives of this study are to determine the efficacy of a home-based walking exercise program in promoting bone health, physical function and quality of life in men with prostate cancer receiving ADT. Methods/Design A 12-month prospective, single-blinded, randomized controlled trial will be conducted to compare the Exercise Group with the Control Group. Sixty men with prostate cancer who will be starting ADT will be recruited and randomly assigned to one of the two groups: the Exercise Group will receive instructions in setting up an individualized 12-month home-based walking exercise program, while the Control Group will receive standard medical advice from the attending physician. A number of outcome measures will be used to assess bone health, physical function, and health-related quality of life. At baseline and 12 months, bone health will be assessed using dual-energy X-ray absorptiometry. At baseline and every 3 months up to 12 months, physical function will be evaluated using the Functional Assessment of Chronic Illness Therapy - Fatigue Scale, Activities-specific Balance Confidence Scale, Short Physical Performance Battery, and Six-Minute Walk Test; and health-related quality of life will be assessed using the Functional Assessment of Cancer Therapy Prostate Module and the Medical Outcomes Study 12-item Short Form Health Survey Version 2. A mixed multiple analysis of variance will be used to analyze the data. Discussion Musculoskeletal health management remains a challenge in men with prostate cancer receiving ADT. This study addresses this issue by designing a simple and accessible home-based walking exercise program that will potentially have significant

  17. Androgens and women's health.

    Science.gov (United States)

    Redmond, G P

    1998-01-01

    Androgenic disorders are those conditions in women characterized by excessive androgen action. They are the most common endocrinopathy of women, affecting from 10% to 20%. Signs are: persistent acne, hirsutism and androgenic alopecia, which is the female equivalent of male pattern baldness. A subgroup, those traditionally labeled as having polycystic ovary syndrome (PCOS), additionally have anovulation, as well as menstrual abnormalities and, often, obesity. Although women with androgenic disorders usually present themselves for help with the skin or menstrual changes, there are other important implications regarding their health. Women with PCOS have varying degrees of insulin resistance, and an increased incidence of Type II diabetes mellitus, as well as unfavorable lipid patterns. The presence of these risk factors is suggested by upper segment obesity, darkening of the skin, and the other skin changes that make up acanthosis nigricans. Diagnosis involves measurement of circulating androgens (of which free testosterone is most important), together with prolactin and FSH when menstrual dysfunction is present. Many women with androgenic skin changes have normal serum androgen levels, suggesting increased end organ sensitivity to androgens. Others have hyperandrogenism (of ovarian or adrenal origin). Treatment is usually successful in controlling acne, reducing hirsutism and stabilizing, or partially reversing, androgenic alopecia. Pharmacological approaches involve suppressing androgen levels, for example, the use of an appropriate oral contraceptive, or antagonizing androgen action with several medications that have this activity. Unfortunately, most women with androgenic disorders are frustrated in their efforts to obtain medical help. Understanding androgenic disorders will enable the physician to significantly help the majority of women with these conditions.

  18. Quality-of-life outcomes in high-risk prostate cancer patients treated with helical tomotherapy in a hypofractionated radiation schedule with long-term androgen suppression

    Science.gov (United States)

    Pervez, N.; Krauze, A.V.; Yee, D.; Parliament, M.; Mihai, A.; Ghosh, S.; Joseph, K.; Murtha, A.; Amanie, J.; Kamal, M.; Pearcey, R.

    2012-01-01

    Purpose We examined the impact of hypofractionated radiation therapy and androgen suppression therapy (ast) on quality of life (qol) in high-risk prostate cancer patients. Methods Between March 2005 and March 2007, 60 patients with high-risk prostate cancer were enrolled in a prospective phase ii study. All patients received 68 Gy (2.72 Gy per fraction) to the prostate gland and 45 Gy (1.8 Gy per fraction) to the pelvic lymph nodes in 25 fractions over 5 weeks. Of the 60 patients, 58 received ast. The University of California–Los Angeles Prostate Cancer Index questionnaire was used to prospectively measure qol at baseline (month 0) and at 1, 6, 12, 18, 24, 30, and 36 months after radiation treatment. The generalized estimating equation approach was used to compare the qol scores at 1, 6, 12, 18, 24, 30, and 36 months with those at baseline. Results We observed a significant decrease in qol items related to bowel and sexual function. Several qol items related to bowel function were significantly adversely affected at both 1 and 6 months, with improvement toward 6 months. Although decreased qol scores persisted beyond the 6-month mark, they began to re-approach baseline at the 18- to 24-month mark. Most sexual function items were significantly adversely affected at both 1 and 6 months, but the effects were not considered to be a problem by most patients. A complete return to baseline was not observed for either bowel or sexual function. Urinary function items remained largely unaffected, with overall urinary function being the only item adversely affected at 6 months, but not at 1 month. Urinary function returned to baseline and remained unimpaired from 18 months onwards. Conclusions In our study population, who received hypofractionated radiation delivered using dynamic intensity-modulated radiotherapy with inclusion of the pelvic lymph nodes, and 2–3 years of ast prescription, qol with respect to bowel and sexual function was significantly affected; qol with

  19. Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies.

    Science.gov (United States)

    Moilanen, Anu-Maarit; Riikonen, Reetta; Oksala, Riikka; Ravanti, Laura; Aho, Eija; Wohlfahrt, Gerd; Nykänen, Pirjo S; Törmäkangas, Olli P; Palvimo, Jorma J; Kallio, Pekka J

    2015-07-03

    Activation of androgen receptor (AR) is crucial for prostate cancer growth. Remarkably, also castration-resistant prostate cancer (CRPC) is dependent on functional AR, and several mechanisms have been proposed to explain the addiction. Known causes of CRPC include gene amplification and overexpression as well as point mutations of AR. We report here the pharmacological profile of ODM-201, a novel AR inhibitor that showed significant antitumor activity and a favorable safety profile in phase 1/2 studies in men with CRPC. ODM-201 is a full and high-affinity AR antagonist that, similar to second-generation antiandrogens enzalutamide and ARN-509, inhibits testosterone-induced nuclear translocation of AR. Importantly, ODM-201 also blocks the activity of the tested mutant ARs arising in response to antiandrogen therapies, including the F876L mutation that confers resistance to enzalutamide and ARN-509. In addition, ODM-201 reduces the growth of AR-overexpressing VCaP prostate cancer cells both in vitro and in a castration-resistant VCaP xenograft model. In contrast to other antiandrogens, ODM-201 shows negligible brain penetrance and does not increase serum testosterone levels in mice. In conclusion, ODM-201 is a potent AR inhibitor that overcomes resistance to AR-targeted therapies by antagonizing both overexpressed and mutated ARs. ODM-201 is currently in a phase 3 trial in CRPC.

  20. Is neoadjuvant androgen deprivation therapy beneficial in prostate cancer treated with definitive radiotherapy?

    Energy Technology Data Exchange (ETDEWEB)

    Eom, Keun Yong; Ha, Sung W.; Lee, Eun Sik; Kwak, Cheol [Seoul National University College of Medicine, Seoul (Korea, Republic of); Lee, Sang Eun [Dept.of Urology, Seoul National University Bundang Hospital, Seongam (Korea, Republic of)

    2014-12-15

    To determine whether neoadjuvant androgen deprivation therapy (NADT) improves clinical outcomes in patients with prostate cancer treated with definitive radiotherapy. We retrospectively reviewed medical records of 201 patients with prostate cancer treated with radiotherapy between January 1991 and December 2008. Of these, 156 patients with more than 3 years of follow-up were the subjects of this study. The median duration of follow-up was 91.2 months. NADT was given in 103 patients (66%) with median duration of 3.3 months (range, 1.0 to 7.7 months). Radiation dose was escalated gradually from 64 Gy to 81 Gy using intensity-modulated radiotherapy technique. Biochemical relapse-free survival (BCRFS) and overall survival (OS) of all patients were 72.6% and 90.7% at 5 years, respectively. BCRFS and OS of NADT group were 79.5% and 89.8% at 5 years and those of radiotherapy alone group were 58.8% and 92.3% at 5 years, respectively. Risk group (p = 0.010) and radiation dose > or =70 Gy (p = 0.017) affected BCRFS independently. NADT was a significant prognostic factor in univariate analysis, but not in multivariate analysis (p = 0.073). Radiation dose > or =70 Gy was only an independent factor for OS (p = 0.007; hazard ratio, 0.261; 95% confidence interval, 0.071-0.963). NADT prior to definitive radiotherapy did not result in significant benefit in terms of BCRFS and OS. NADT should not be performed routinely in the era of dose-escalated radiotherapy.

  1. Positive effects of early androgen therapy on the behavioral phenotype of boys with 47,XXY.

    Science.gov (United States)

    Samango-Sprouse, Carole; Stapleton, Emily J; Lawson, Patrick; Mitchell, Francie; Sadeghin, Teresa; Powell, Sherida; Gropman, Andrea L

    2015-06-01

    47, XXY occurs in up to 1 in 650 male births and is associated with androgen deficiency, neurodevelopmental delays, and atypical social-behaviors. Previously, we showed that young boys with 47, XXY who received early hormonal therapy (EHT) had significantly improved neurodevelopment. The objective of this follow-up study was to examine the effects of EHT on social behavior in boys with 47, XXY. The study consisted of boys prenatally diagnosed with 47, XXY who were referred for evaluations. Twenty-nine boys received three injections of 25 mg testosterone enanthate and 57 controls did not receive EHT. Behavioral functioning was assessed using the Behavior Rating Inventory of Executive Function, Social Responsiveness Scale, 2nd Ed., and the Child Behavior Checklist for Ages 6-18. The hypothesis that EHT may affect behavior was formulated prior to data collection. Questionnaire data was prospectively obtained and analyzed to test for significance between two groups. Significant differences were identified between group's scores over time in Social Communication (P=0.007), Social Cognition (P=0.006), and Total T-score (P=0.001) on the SRS-2; Initiation (P=0.05) on the BRIEF; and Externalizing Problems (P=0.024), Affective Problems (P=0.05), and Aggressive Behaviors (P=0.031) on the CBCL. This is the third study revealing positive effects of EHT on boys with XXY. There was a significant improvements associated with the 47, XXY genotype in boys who received EHT. Research is underway on the neurobiological mechanisms, and later developmental effects of EHT.

  2. Androgen Deprivation Therapy and the Risk of Dementia in Patients With Prostate Cancer.

    Science.gov (United States)

    Khosrow-Khavar, Farzin; Rej, Soham; Yin, Hui; Aprikian, Armen; Azoulay, Laurent

    2017-01-10

    Purpose Recent observational studies have associated the use of androgen deprivation therapy (ADT) with an increased risk of dementia and Alzheimer's disease, but these studies had limitations. The objective of this study was to determine whether the use of ADT is associated with an increased risk of dementia, including Alzheimer's disease, in patients with prostate cancer. Patients and Methods Using the United Kingdom's Clinical Practice Research Datalink, we assembled a cohort of 30,903 men newly diagnosed with nonmetastatic prostate cancer between April 1, 1988 and April 30, 2015, and observed them until April 30, 2016. Time-dependent Cox proportional hazards models were used to estimate adjusted hazard ratios with 95% CIs of dementia associated with the use of ADT compared with nonuse. ADT exposure was lagged by 1 year to account for delays associated with the diagnosis of dementia and to minimize reverse causality. Secondary analyses assessed whether the risk varied with cumulative duration of use and by ADT type. Results During a mean (standard deviation) follow-up of 4.3 (3.6) years, 799 patients were newly diagnosed with dementia (incidence, 6.0; 95% CI, 5.6 to 6.4) per 1,000 person-years. Compared with nonuse, ADT use was not associated with an increased risk of dementia (incidence, 7.4 v 4.4 per 1,000 person-years, respectively; adjusted hazard ratio, 1.02; 95% CI, 0.87 to 1.19). In secondary analyses, cumulative duration of use ( P for heterogeneity = .78) and no single type of ADT were associated with an increased risk of dementia. Conclusion In this population-based study, the use of ADT was not associated with an increased risk of dementia. Additional studies in different settings are needed to confirm these findings.

  3. PI3K-AKT-mTOR signaling in prostate cancer progression and androgen deprivation therapy resistance

    Institute of Scientific and Technical Information of China (English)

    Merritt P Edlind; Andrew C Hsieh

    2014-01-01

    Prostate cancer (PCa) is the second most common malignancy among men in the world. Castration-resistant prostate cancer (CRPC) is the lethal form of the disease, which develops upon resistance to ifrst line androgen deprivation therapy (ADT). Emerging evidence demonstrates a key role for the PI3K-AKT-mTOR signaling axis in the development and maintenance of CRPC. This pathway, which is deregulated in the majority of advanced PCas, serves as a critical nexus for the integration of growth signals with downstream cellular processes such as protein synthesis, proliferation, survival, metabolism and differentiation, thus providing mechanisms for cancer cells to overcome the stress associated with androgen deprivation. Furthermore, preclinical studies have elucidated a direct connection between the PI3K-AKT-mTOR and androgen receptor (AR) signaling axes, revealing a dynamic interplay between these pathways during the development of ADT resistance. Thus, there is a clear rationale for the continued clinical development of a number of novel inhibitors of the PI3K pathway, which offer the potential of blocking CRPC growth and survival. In this review, we will explore the relevance of the PI3K-AKT-mTOR pathway in PCa progression and castration resistance in order to inform the clinical development of speciifc pathway inhibitors in advanced PCa. In addition, we will highlight current deifciencies in our clinical knowledge, most notably the need for biomarkers that can accurately predict for response to PI3K pathway inhibitors.

  4. Androgen deprivation therapy for volume reduction, lower urinary tract symptom relief and quality of life improvement in patients with prostate cancer

    DEFF Research Database (Denmark)

    Axcrona, Karol; Aaltomaa, Sirpa; da Silva, Carlos Martins

    2012-01-01

    Study Type--Therapy (RCT) Level of Evidence 1b. What's known on the subject? and What does the study add? Androgen deprivation therapy (ADT) is commonly used as a primary treatment for patients with prostate cancer (PCa) who are not eligible for radical treatment options. ADT is also used in pati...

  5. Identification of a new androgen receptor (AR) co-regulator BUD31 and related peptides to suppress wild-type and mutated AR-mediated prostate cancer growth via peptide screening and X-ray structure analysis.

    Science.gov (United States)

    Hsu, Cheng-Lung; Liu, Jai-Shin; Wu, Po-Long; Guan, Hong-Hsiang; Chen, Yuh-Ling; Lin, An-Chi; Ting, Huei-Ju; Pang, See-Tong; Yeh, Shauh-Der; Ma, Wen-Lung; Chen, Chung-Jung; Wu, Wen-Guey; Chang, Chawnshang

    2014-12-01

    Treatment with individual anti-androgens is associated with the development of hot-spot mutations in the androgen receptor (AR). Here, we found that anti-androgens-mt-ARs have similar binary structure to the 5α-dihydrotestosterone-wt-AR. Phage display revealed that these ARs bound to similar peptides, including BUD31, containing an Fxx(F/H/L/W/Y)Y motif cluster with Tyr in the +5 position. Structural analyses of the AR-LBD-BUD31 complex revealed formation of an extra hydrogen bond between the Tyr+5 residue of the peptide and the AR. Functional studies showed that BUD31-related peptides suppressed AR transactivation, interrupted AR N-C interaction, and suppressed AR-mediated cell growth. Combination of peptide screening and X-ray structure analysis may serve as a new strategy for developing anti-ARs that simultaneously suppress both wt and mutated AR function.

  6. Exercise improves quality of life in androgen deprivation therapy-treated prostate cancer: systematic review of randomised controlled trials.

    Science.gov (United States)

    Teleni, Laisa; Chan, Raymond J; Chan, Alexandre; Isenring, Elisabeth A; Vela, Ian; Inder, Warrick J; McCarthy, Alexandra L

    2016-02-01

    Men receiving androgen deprivation therapy (ADT) for prostate cancer (PCa) are likely to develop metabolic conditions such as diabetes, cardiovascular disease, abdominal obesity and osteoporosis. Other treatment-related side effects adversely influence quality of life (QoL) including vasomotor distress, depression, anxiety, mood swings, poor sleep quality and compromised sexual function. The objective of this study was to systematically review the nature and effects of dietary and exercise interventions on QoL, androgen deprivation symptoms and metabolic risk factors in men with PCa undergoing ADT. An electronic search of CINAHL, CENTRAL, Medline, PsychINFO and reference lists was performed to identify peer-reviewed articles published between January 2004 and December 2014 in English. Eligible study designs included randomised controlled trials (RCTs) with pre- and post-intervention data. Data extraction and assessment of methodological quality with the Cochrane approach was conducted by two independent reviewers. Seven exercise studies were identified. Exercise significantly improved QoL, but showed no effect on metabolic risk factors (weight, waist circumference, lean or fat mass, blood pressure and lipid profile). Two dietary studies were identified, both of which tested soy supplements. Soy supplementation did not improve any outcomes. No dietary counselling studies were identified. No studies evaluated androgen-deficiency symptoms (libido, erectile function, sleep quality, mood swings, depression, anxiety and bone mineral density). Evidence from RCTs indicates that exercise enhances health- and disease-specific QoL in men with PCa undergoing ADT. Further studies are required to evaluate the effect of exercise and dietary interventions on QoL, androgen deprivation symptoms and metabolic risk factors in this cohort.

  7. Endurance training improves insulin sensitivity and body composition in prostate cancer patients treated with androgen deprivation therapy

    DEFF Research Database (Denmark)

    Hvid, Thine; Winding, Kamilla; Rinnov, Anders;

    2013-01-01

    Insulin resistance and changes in body composition are side effects of androgen deprivation therapy (ADT) given to prostate cancer patients. The present study investigated whether endurance training improves insulin sensitivity and body composition in ADT-treated prostate cancer patients. Nine men...... and magnetic resonance imaging). The secondary endpoint was systemic inflammation. Statistical analysis was carried out using two-way ANOVA. Endurance training increased VO2max (ml(O2)/min per kg) by 11 and 13% in the patients and controls respectively (P...

  8. Kaposi's sarcoma following immune suppressive therapy for Wegener's granulomatosis.

    Science.gov (United States)

    Deschênes, Isabelle; Dion, Louise; Beauchesne, Claude; de Brum-Fernandes, Artur

    2003-03-01

    The association between Kaposi's sarcoma and infection with human herpesvirus 8 is now well recognized. Immunologic impairment is associated with 2 forms of Kaposi's sarcoma, epidemic [associated with human immunodeficiency virus (HIV) infection] and iatrogenic (associated with immunosuppressive treatment); both forms have become more common during the last decade. We describe an HIV negative 54-year-old man who developed Kaposi's sarcoma 2 months after the beginning of immuno-suppressive therapy for Wegener's granulomatosis (WG). With tapering of medication, complete remission of Kaposi's sarcoma was achieved in one year. To our knowledge, this is the second reported case of iatrogenic Kaposi's sarcoma in a patient with WG.

  9. [A potential of selective androgen receptor modulator(SARM)for the therapy of osteoporosis].

    Science.gov (United States)

    Yanase, Toshihiko

    2016-07-01

    In recent years, the drugs, which show anabolic, effect on bone and muscle without stimulating prostate has been developed. They show tissue-specific selective androgen actions and called selective androgen receptor modulators(SARMs). The development of drug targeting bone and muscle in male is very promising as a treatment tool for osteoporosis and sarcopenia in the near future. The clinical study is under going especially in the field of cachexia associated with cancer, but unfortunately there is no drug in the current market at present. The current situation of the development of SARMs will be reviewed.

  10. Locally advanced prostate cancer: combination of high-dose high-precision radiotherapy and androgen deprivation therapy%Locally advanced prostate cancer:combination of high-dose high-precision radiotherapy and androgen deprivation therapy

    Institute of Scientific and Technical Information of China (English)

    Michel Bolla; René-Olivier Mirimanoff

    2014-01-01

    Locally advanced prostate cancer entails a risk of local,regional and systemic relapse requiring the combination of a Ioco-regional treatment,namely external beam radiotherapy(EBRT) to control the pelvic-confined disease,combined with a systemic therapy,namely androgen-deprivation therapy(ADT),to potentiate irradiation and to destroy the infra-clinical androgen-dependant disease outside the irradiated volume.Many phases Ⅲ randomized trials have paved the way in establishing the indications of this combined approach,which requires a long term ADT(≥2 years) with LHRH agonists.The duration of ADT may be reduced to 6 months should there be a significant comorbidity,a reluctance from the patient or a poor tolerance.A multidisciplinary approach will enable physicians to tailor the treatment strategy and a close cooperation between the specialists and the general practitioners will be set up to prevent as much as possible the side-effects of ADT.

  11. Risk factors for bone loss with prostate cancer in Korean men not receiving androgen deprivation therapy

    Directory of Open Access Journals (Sweden)

    Sun-Ouck Kim

    2009-04-01

    Full Text Available PURPOSE: Preexisting bone loss in men with prostate cancer is an important issue due to the accelerated bone loss during androgen deprivation therapy (ADT. In addition, a high prostate-specific antigen (PSA level has been reported to be related to bone metabolism. This study assessed the factors associated with osteoporosis in Korean men with non-metastatic prostate cancer before undergoing ADT. MATERIAL AND METHODS: The study enrolled patients admitted for a prostate biopsy because of a high PSA or palpable nodule on a digital rectal examination. We divided the patients (n = 172 according to the results of the biopsy: group I, non-metastatic prostate cancer (n = 42 and group II, benign prostatic hypertrophy (BPH; n = 130. The lumbar bone mineral density (BMD was evaluated using quantitative computed tomography. The demographic, health status, lifestyle, body mass index (BMI, serum testosterone concentration, and disease variables in prostate cancer (Gleason score, clinical stage, and PSA were analyzed prospectively to determine their effect on the BMD. RESULTS: The estimated mean T-score was higher in group I than in group II (-1.96 ± 3.35 vs. -2.66 ± 3.20, but without statistic significance (p = 0.235. The significant factors correlated with BMD in group I were a high serum PSA (ß = -0.346, p = 0.010 and low BMI (ß = 0.345, p = 0.014 in the multiple linear regression model. Also old age (r = -0.481, p = 0.001, a high serum PSA (r = -0.571, p < 0.001, low BMI (r = 0.598, p < 0.001, and a high Gleason’s score (r = -0.319, p = 0.040 were the factors related to BMD in the correlation. The significant factors correlated with BMD in group II were old age (ß = -0.324, p = 0.001 and BMI (ß = 0.143, p = 0.014 in the multiple linear regression model. CONCLUSIONS: The risk factors for osteoporosis in men with prostate cancer include a low BMI, and elevated serum PSA. Monitoring BMD from the outset of ADT is a logical first step in the clinical

  12. High-Dose Adjuvant Radiotherapy After Radical Prostatectomy With or Without Androgen Deprivation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Ost, Piet, E-mail: piet.ost@ugent.be [Department of Radiotherapy, Ghent University Hospital (Belgium); Cozzarini, Cesare [Department of Radiotherapy, Hospital San Raffaele, Milan (Italy); De Meerleer, Gert [Department of Radiotherapy, Ghent University Hospital (Belgium); Fiorino, Claudio [Department of Radiotherapy, Hospital San Raffaele, Milan (Italy); De Potter, Bruno [Department of Radiotherapy, Ghent University Hospital (Belgium); Briganti, Alberto [Department of Urology, San Raffaele Hospital, Vita-Salute University, Milan (Italy); Nagler, Evi V.T. [Department of Nephrology, Ghent University Hospital (Belgium); Montorsi, Francesco [Department of Urology, San Raffaele Hospital, Vita-Salute University, Milan (Italy); Fonteyne, Valerie [Department of Radiotherapy, Ghent University Hospital (Belgium); Di Muzio, Nadia [Department of Radiotherapy, Hospital San Raffaele, Milan (Italy)

    2012-07-01

    Purpose: To retrospectively evaluate the outcome and toxicity in patients receiving high-dose (>69 Gy) adjuvant radiotherapy (HD-ART) and the impact of androgen deprivation therapy (ADT). Methods and Materials: Between 1999 and 2008, 225 node-negative patients were referred for HD-ART with or without ADT to two large academic institutions. Indications for HD-ART were extracapsular extension, seminal vesicle invasion (SVI), and/or positive surgical margins at radical prostatectomy (RP). A dose of at least 69.1 Gy was prescribed to the prostate bed and seminal vesicle bed. The ADT consisted of a luteinizing hormone-releasing hormone analog. The duration and indication of ADT was left at the discretion of the treating physician. The effect of HD-ART and ADT on biochemical (bRFS) and clinical (cRFS) relapse-free survival was examined through univariate and multivariate analysis, with correction for known patient- and treatment-related variables. Interaction terms were introduced to evaluate effect modification. Results: After a median follow-up time of 5 years, the 7-year bRFS and cRFS were 84% and 88%, respectively. On multivariate analysis, the addition of ADT was independently associated with an improved bRFS (hazard ratio [HR] 0.4, p = 0.02) and cRFS (HR 0.2, p = 0.008). Higher Gleason scores and SVI were associated with decreased bRFS and cRFS. A lymphadenectomy at the time of RP independently improved cRFS (HR 0.09, p = 0.009). The 7-year probability of late Grade 2-3 toxicity was 29% and 5% for genitourinary (GU) and gastrointestinal (GI) symptoms, respectively. The absolute incidence of Grade 3 toxicity was <1% and 10% for GI and GU symptoms, respectively. The study is limited by its retrospective design and the lack of a standardized use of ADT. Conclusions: This retrospective study shows significantly improved bRFS and cRFS rates with the addition of ADT to HD-ART, with low Grade 3 gastrointestinal toxicity and 10% Grade 3 genitourinary toxicity.

  13. AB125. Androgen deprivation therapy for prostate cancer is associated with cardiovascular morbidity and mortality

    Science.gov (United States)

    Niu, Yuanjie; Zhu, Shimiao

    2015-01-01

    Background There is no consensus regarding whether androgen deprivation therapy (ADT) is associated with cardiovascular disease (CVD) and cardiovascular mortality (CVM). The objective of this study was to determine the role of ADT for prostate cancer (PCa) in development of cardiovascular events (CVD and CVM). Methods and findings We performed a meta-analysis from population-based observational studies comparing ADT vs control aimed at treating PCa in patients with PCa, reporting either CVD or CVM as outcome. Publications were searched using Medline, Embase, Cochrane Library Central Register of observational studies database up to May 31th 2014, and supplementary searches in publications from potentially relevant journals. 6 studies were identified with a total of 129,802 ADT users and 165,605 controls investigating the relationship between ADT and CVD. The incidence of CVD was 10% higher in ADT groups, although no significant association was observed (HR =1.10, 95% CIs: 1.00-1.21; P=0.06). For different types of ADT, CVD was related with gonadotropin-releasing hormone (GnRH) (HR =1.19, 95% CIs: 1.04-1.36; P<0.001) and GnRH plus oral antiandrogen (AA) (HR =1.46, 95% CIs: 1.03-2.08; P=0.04), but not with AA alone or orchiectomy. For CVM, 119,625 ADT users and 150,974 controls from 6 eligible studies were included, pooled result suggested that ADT was associated with CVM (HR =1.17, 95% CIs: 1.04-1.32; P=0.01). Significantly increased CVM was also detected in GnRH and GnRH plus AA groups. When patients received other treatments (e.g., prostatectomy and radiotherapy) were ruled out of consideration, more increased CVD (HR =1.19, 95% CIs: 1.08-1.30; P<0.001) and CVM (HR =1.30, 95% CIs: 1.13-1.50; P<0.001) were found in men treated with ADT monotherapy. Conclusions ADT is associated with both CVD and CVM. Particularly, GnRH alone and GnRH plus AA can significantly increase the incidence of cardiovascular events in patients with PCa.

  14. AB187. Androgen deprivation therapy for prostate cancer is associated with cardiovascular morbidity and mortality

    Science.gov (United States)

    Niu, Yuanjie; Zhu, Shimiao

    2016-01-01

    Objectives There is no consensus regarding whether androgen deprivation therapy (ADT) is associated with cardiovascular disease (CVD) and cardiovascular mortality (CVM). The objective of this study was to determine the role of ADT for prostate cancer (PCa) in development of cardiovascular events (CVD and CVM). Methods We performed a meta-analysis from population-based observational studies comparing ADT vs. control aimed at treating PCa in patients with PCa, reporting either CVD or CVM as outcome. Publications were searched using Medline, Embase, Cochrane Library Central Register of observational studies database up to May 31th 2014, and supplementary searches in publications from potentially relevant journals. Six studies were identified with a total of 129,802 ADT users and 165,605 controls investigating the relationship between ADT and CVD. Result The incidence of CVD was 10% higher in ADT groups, although no significant association was observed (HR =1.10, 95% CIs, 1.00–1.21; P=0.06). For different types of ADT, CVD was related with gonadotropin-releasing hormone (GnRH) (HR =1.19, 95% CIs, 1.04–1.36; P<0.001) and GnRH plus oral antiandrogen (AA) (HR =1.46, 95% CIs, 1.03–2.08; P=0.04), but not with AA alone or orchiectomy. For CVM, 119,625 ADT users and 150,974 controls from 6 eligible studies were included, pooled result suggested that ADT was associated with CVM (HR=1.17, 95% CIs, 1.04–1.32; P=0.01). Significantly increased CVM was also detected in GnRH and GnRH plus AA groups. When patients received other treatments (e.g., prostatectomy and radiotherapy) were ruled out of consideration, more increased CVD (HR =1.19, 95% CIs, 1.08–1.30; P<0.001) and CVM (HR =1.30, 95% CIs, 1.13–1.50; P<0.001) were found in men treated with ADT monotherapy. Conclusions ADT is associated with both CVD and CVM. Particularly, GnRH alone and GnRH plus AA can significantly increase the incidence of cardiovascular events in patients with PCa.

  15. Role of androgen receptor in prostate cancer

    Institute of Scientific and Technical Information of China (English)

    HiroyoshiSuzuki; HaruoIto

    1999-01-01

    The growth of prostate cancer is sensitive to androgen, and hormonal therapy has been used for treatment of ad-vanced cancer. About 80 % of prostate cancers initially respond to hormonal therapy, howcrver, more than half of the re-sponders gradtmlly become resistant to this therapy. Changes in tumors from an androgen-responsive to an androgen-unre-sponsive state have been widely discussed. Since androgen action is mediated by androgen receptor (AR), abnonnalitiesof AR is believed to play an important role of the loss of androgen responsiveness in prostate cancer. "Ilais article focusedon the role of AR in the progression of prostate cancer.

  16. Markers and Time Course of Neurodegenerative Risk with Androgen Deprivation Therapy

    Science.gov (United States)

    2009-01-01

    Androgen deprivation is associated with an increased risk for neurodegeneration in both animal models and humans. Therefore the overall objective of this...increased risk for neurodegeneration in both animal models and humans(Moffat et al., 2004; Rosario & Pike, 2008). Therefore, we examined white matter...Imaging. Neuropsychol.Rev. Moffat, S. D., Zonderman, A. B., Metter, E. J., Kawas , C., Blackman, M. R., Harman, S. M. et al. (2004). Free testosterone

  17. Sipuleucel-T and Androgen Receptor-Directed Therapy for Castration-Resistant Prostate Cancer: A Meta-Analysis

    Directory of Open Access Journals (Sweden)

    Renliang Yi

    2016-01-01

    Full Text Available New treatments, such as sipuleucel-T and androgen receptor- (AR- directed therapies (enzalutamide (Enz and abiraterone acetate (AA, have emerged and been approved for the management of castration-resistant prostate cancer (CRPC. There are still debates over their efficacy and clinical benefits. This meta-analysis aimed to investigate the efficacy and safety of sipuleucel-T and AR-directed therapies in patients with CRPC. RevMan 5.1 was used for pooled analysis and analysis of publication bias. Seven studies were included in the meta-analysis, with three studies in sipuleucel-T (totally 737 patients, 488 patients in treatment group, and 249 patients in placebo group and four in AR-directed therapies (totally 5,199 patients, 3,015 patients in treatment group, and 2,184 patients in placebo group. Treatment with sipuleucel-T significantly improved overall survival in patients with CRPC and was not associated with increased risk of adverse event of grade ≥3 (p>0.05. However, treatment with sipuleucel-T did not improve time-to-progression and reduction of prostate-specific antigen (PSA level ≥50% was not significantly different from that with placebo. AR-directed therapies significantly improved overall survival in patients with CRPC and improved time-to-progression and reduction of PSA level ≥50%. AR-directed therapies did not increase risk of adverse event of grade ≥3 (p>0.05.

  18. Sipuleucel-T and Androgen Receptor-Directed Therapy for Castration-Resistant Prostate Cancer: A Meta-Analysis.

    Science.gov (United States)

    Yi, Renliang; Chen, Baoxin; Duan, Peng; Zheng, Chanjiao; Shen, Huanyu; Liu, Qun; Yuan, Chen; Ou, Weilin; Zhou, Zhiheng

    2016-01-01

    New treatments, such as sipuleucel-T and androgen receptor- (AR-) directed therapies (enzalutamide (Enz) and abiraterone acetate (AA)), have emerged and been approved for the management of castration-resistant prostate cancer (CRPC). There are still debates over their efficacy and clinical benefits. This meta-analysis aimed to investigate the efficacy and safety of sipuleucel-T and AR-directed therapies in patients with CRPC. RevMan 5.1 was used for pooled analysis and analysis of publication bias. Seven studies were included in the meta-analysis, with three studies in sipuleucel-T (totally 737 patients, 488 patients in treatment group, and 249 patients in placebo group) and four in AR-directed therapies (totally 5,199 patients, 3,015 patients in treatment group, and 2,184 patients in placebo group). Treatment with sipuleucel-T significantly improved overall survival in patients with CRPC and was not associated with increased risk of adverse event of grade ≥3 (p > 0.05). However, treatment with sipuleucel-T did not improve time-to-progression and reduction of prostate-specific antigen (PSA) level ≥50% was not significantly different from that with placebo. AR-directed therapies significantly improved overall survival in patients with CRPC and improved time-to-progression and reduction of PSA level ≥50%. AR-directed therapies did not increase risk of adverse event of grade ≥3 (p > 0.05).

  19. Brachyury as a potential modulator of androgen receptor activity and a key player in therapy resistance in prostate cancer

    Science.gov (United States)

    Pinto, Filipe; Pértega-Gomes, Nelma; Vizcaíno, José R.; Andrade, Raquel P.; Cárcano, Flavio M.; Reis, Rui Manuel

    2016-01-01

    Prostate cancer (PCa) is the most commonly diagnosed neoplasm and the second leading cause of cancer-related deaths in men. Acquisition of resistance to conventional therapy is a major problem for PCa patient management. Several mechanisms have been described to promote therapy resistance in PCa, such as androgen receptor (AR) activation, epithelial-to-mesenchymal transition (EMT), acquisition of stem cell properties and neuroendocrine transdifferentiation (NEtD). Recently, we identified Brachyury as a new biomarker of PCa aggressiveness and poor prognosis. In the present study we aimed to assess the role of Brachyury in PCa therapy resistance. We showed that Brachyury overexpression in prostate cancer cells lines increased resistance to docetaxel and cabazitaxel drugs, whereas Brachyury abrogation induced decrease in therapy resistance. Through ChiP-qPCR assays we further demonstrated that Brachyury is a direct regulator of AR expression as well as of the biomarker AMACR and the mesenchymal markers Snail and Fibronectin. Furthermore, in vitro Brachyury was also able to increase EMT and stem properties. By in silico analysis, clinically human Brachyury-positive PCa samples were associated with biomarkers of PCa aggressiveness and therapy resistance, including PTEN loss, and expression of NEtD markers, ERG and Bcl-2. Taken together, our results indicate that Brachyury contributes to tumor chemotherapy resistance, constituting an attractive target for advanced PCa patients. PMID:27049720

  20. Adverse effects of androgen deprivation therapy in men with prostate cancer: a focus on metabolic and cardiovascular complications

    Institute of Scientific and Technical Information of China (English)

    Lauren Collins; Shehzad Basaria

    2012-01-01

    Prostate cancer (PCa) is the most common malignancy in men.Prostate being an androgen responsive tissue,androgen deprivation therapy (ADT) is used in the management of locally advanced (improves survival) and metastatic (improves pain and quality of life) PCa.Over the past two decades,the use of ADT has significantly increased as it is also being used in patients with localized disease and those experiencing biochemical recurrences,though without any evidence of survival advantage.Hypogonadism resulting from ADT is associated with decreased muscle mass and strength,increased fat mass,sexual dysfunction,vasomotor symptoms,decreased quality of life,anemia and bone loss.Insulin resistance,diabetes and cardiovascular disease have recently been added to the list of these complications.As the majority of men with PCa die of conditions other than their primary malignancy,recognition and management of these adverse effects is paramount.Here we review data evaluating metabolic and cardiovascular complications of ADT.

  1. Androgen resistance.

    Science.gov (United States)

    Hughes, Ieuan A; Deeb, Asma

    2006-12-01

    Androgen resistance causes the androgen insensitivity syndrome in its variant forms and is a paradigm of clinical syndromes associated with hormone resistance. In its complete form, the syndrome causes XY sex reversal and a female phenotype. Partial resistance to androgens is a common cause of ambiguous genitalia of the newborn, but a similar phenotype may result from several other conditions, including defects in testis determination and androgen biosynthesis. The biological actions of androgens are mediated by a single intracellular androgen receptor encoded by a gene on the long arm of the X chromosome. Mutations in this gene result in varying degrees of androgen receptor dysfunction and phenotypes that often show poor concordance with the genotype. Functional characterization and three-dimensional modelling of novel mutant receptors has been informative in understanding the mechanism of androgen action. Management issues in syndromes of androgen insensitivity include decisions on sex assignment, timing of gonadectomy in relation to tumour risk, and genetic and psychological counselling.

  2. Castration induces up-regulation of intratumoral androgen biosynthesis and androgen receptor expression in an orthotopic VCaP human prostate cancer xenograft model.

    Science.gov (United States)

    Knuuttila, Matias; Yatkin, Emrah; Kallio, Jenny; Savolainen, Saija; Laajala, Teemu D; Aittokallio, Tero; Oksala, Riikka; Häkkinen, Merja; Keski-Rahkonen, Pekka; Auriola, Seppo; Poutanen, Matti; Mäkelä, Sari

    2014-08-01

    Androgens are key factors involved in the development and progression of prostate cancer (PCa), and PCa growth can be suppressed by androgen deprivation therapy. In a considerable proportion of men receiving androgen deprivation therapy, however, PCa progresses to castration-resistant PCa (CRPC), making the development of efficient therapies challenging. We used an orthotopic VCaP human PCa xenograft model to study cellular and molecular changes in tumors after androgen deprivation therapy (castration). Tumor growth was monitored through weekly serum prostate-specific antigen measurements, and mice with recurrent tumors after castration were randomized to treatment groups. Serum prostate-specific antigen concentrations showed significant correlation with tumor volume. Castration-resistant tumors retained concentrations of intratumoral androgen (androstenedione, testosterone, and 5α-dihydrotestosterone) at levels similar to tumors growing in intact hosts. Accordingly, castration induced up-regulation of enzymes involved in androgen synthesis (CYP17A1, AKR1C3, and HSD17B6), as well as expression of full-length androgen receptor (AR) and AR splice variants (AR-V1 and AR-V7). Furthermore, AR target gene expression was maintained in castration-resistant xenografts. The AR antagonists enzalutamide (MDV3100) and ARN-509 suppressed PSA production of castration-resistant tumors, confirming the androgen dependency of these tumors. Taken together, the findings demonstrate that our VCaP xenograft model exhibits the key characteristics of clinical CRPC and thus provides a valuable tool for identifying druggable targets and for testing therapeutic strategies targeting AR signaling in CRPC.

  3. Laparoscopic gonedectomy in a case of complete androgen insensitivity syndrome.

    Science.gov (United States)

    Bhaskararao, G; Himabindu, Y; Nayak, Samir Rajan; Sriharibabu, M

    2014-07-01

    Complete Androgen insensitivity syndrome is a disorder of hormone resistance characterized by a female phenotype in an individual with an XY karyotype. The pathogenesis of CAIS involves a defective androgen receptor gene located on X-chromosome at Xq11-12and end organ insensitivity to androgens, although androgen concentrations are appropriate for the age of the patient. There are three major types of androgen insensitivity syndrome: Complete androgen insensitivity syndrome, minimal androgen insensitivity syndrome, and partial androgen insensitivity syndrome. Management of androgen insensitivity syndrome includes multidisciplinary approach and involves gonedectomy to avoid gonadal tumors in later life. Hormone replacement therapy (HRT) and psychological support are required in long-term basis.

  4. Abiraterone and other novel androgen-directed strategies for the treatment of prostate cancer: a new era of hormonal therapies is born

    OpenAIRE

    Schweizer, Michael T.; Antonarakis, Emmanuel S.

    2012-01-01

    The number of life-prolonging therapies proven effective in the treatment of metastatic castrate-resistant prostate cancer (CRPC) has been limited until recently. In the past 2 years several such therapies have come to market. In 2010, the autologous immunotherapy sipuleucel-T and the next-generation taxane cabazitaxel were approved in this setting. However, abundant evidence has shown that CRPC growth continues to be driven through androgen-dependent signaling. Both of these drugs fail to ta...

  5. Selective Androgen Receptor Down-Regulators (SARDs): A New Prostate Cancer Therapy

    Science.gov (United States)

    2007-10-01

    sensitive as well as in androgen independent prostate cancer cells. J Steroid Biochem Mol Biol, 96: 251-258, 2005. 18. Hung, T. T. and Gibbons, W. E...G-G., Suh, S.W., Stern, P.H. Prostate cancer cell conditioned media have anabolic effects on bone in vitro. Second Joint Meeting of the American...Stern, P.H. Mechanisms of anabolic action of LNCaP prostate cancer cells on bone. 24 nnual Meeting of the American Society for Bone and Mineral

  6. An alternative pharmacological approach to the detection of anti-androgenic drugs for acne therapy.

    Science.gov (United States)

    Clanachan, I; Devitt, H; Foreman, M I; Picton, W

    1985-03-01

    Both testosterone and dihydrotestosterone may be able to stimulate sebaceous glands, and the glandular function may continue under direct testosterone control in the presence of 5 alpha-reductase blockade. Antagonism of sebaceous gland hypertrophy, induced by exogenous testosterone or dihydrotestosterone, has been studied in the hairless hamster using established and experimental drugs applied topically. The results support the proposition that testosterone plays a direct role in mediating sebaceous gland response. This suggests possibilities for the design of sebum inhibitory drugs with minimal systemic anti-androgenic side effects.

  7. ASC-J9 Suppresses Castration-Resistant Prostate Cancer Growth through Degradation of Full-length and Splice Variant Androgen Receptors

    Directory of Open Access Journals (Sweden)

    Shinichi Yamashita

    2012-01-01

    Full Text Available Early studies suggested androgen receptor (AR splice variants might contribute to the progression of prostate cancer (PCa into castration resistance. However, the therapeutic strategy to target these AR splice variants still remains unresolved. Through tissue survey of tumors from the same patients before and after castration resistance, we found that the expression of AR3, a major AR splice variant that lacks the AR ligand-binding domain, was substantially increased after castration resistance development. The currently used antiandrogen, Casodex, showed little growth suppression in CWR22Rv1 cells. Importantly, we found that AR degradation enhancer ASC-J9 could degrade both full-length (fAR and AR3 in CWR22Rv1 cells as well as in C4-2 and C81 cells with addition of AR3. The consequences of such degradation of both fAR and AR3 might then result in the inhibition of AR transcriptional activity and cell growth in vitro. More importantly, suppression of AR3 specifically by short-hairpin AR3 or degradation of AR3 by ASC-J9 resulted in suppression of AR transcriptional activity and cell growth in CWR22Rv1-fARKD (fAR knockdown cells in which DHT failed to induce, suggesting the importance of targeting AR3. Finally, we demonstrated the in vivo therapeutic effects of ASC-J9 by showing the inhibition of PCa growth using the xenografted model of CWR22Rv1 cells orthotopically implanted into castrated nude mice with undetectable serum testosterone. These results suggested that targeting both fAR- and AR3-mediated PCa growth by ASC-J9 may represent the novel therapeutic approach to suppress castration-resistant PCa. Successful clinical trials targeting both fAR and AR3 may help us to battle castration-resistant PCa in the future.

  8. PLCε knockdown inhibits prostate cancer cell proliferation via suppression of Notch signalling and nuclear translocation of the androgen receptor.

    Science.gov (United States)

    Wang, Yin; Wu, Xiaohou; Ou, Liping; Yang, Xue; Wang, Xiaorong; Tang, Min; Chen, E; Luo, Chunli

    2015-06-28

    Phospholipase Cε (PLCε), a key regulator of diverse cellular functions, has been implicated in various malignancies. Indeed, PLCε functions include cell proliferation, apoptosis and malignant transformation. Here, we show that PLCε expression is elevated in prostate cancer (PCa) tissues compared to benign prostate tissues. Furthermore, PLCε depletion using an adenovirally delivered shRNA significantly decreased cell growth and colony formation, arresting the PC3 and LNCaP cell lines in the S phase of the cell cycle. We also observed that PLCε was significantly correlated with Notch1 and androgen receptor (AR). Additionally, we demonstrate that the activation of both the Notch and AR signalling pathways is involved in PLCε-mediated oncogenic effects in PCa. Our findings suggest that PLCε is a putative oncogene and prognostic marker, potentially representing a novel therapeutic target for PCa.

  9. Suppression of rat and human androgen biosynthetic enzymes by apigenin: Possible use for the treatment of prostate cancer.

    Science.gov (United States)

    Wang, Xiudi; Wang, Guimin; Li, Xiaoheng; Liu, Jianpeng; Hong, Tingting; Zhu, Qiqi; Huang, Ping; Ge, Ren-Shan

    2016-06-01

    Apigenin is a natural flavone. It has recently been used as a chemopreventive agent. It may also have some beneficial effects to treat prostate cancer by inhibiting androgen production. The objective of the present study was to investigate the effects of apigenin on the steroidogenesis of rat immature Leydig cells and some human testosterone biosynthetic enzyme activities. Rat immature Leydig cells were incubated for 3h with 100μM apigenin without (basal) or with 1ng/ml luteinizing hormone (LH), 10mM 8-bromoadenosine 3',5'-cyclic monophosphate (8BR), and 20μM of the following steroid substrates: 22R-hydroxychloesterol (22R), pregnenolone (P5), progesterone (P4), and androstenedione (D4). The medium levels of 5α-androstane-3α, 17β-diol (DIOL), the primary androgen produced by rat immature Leydig cells, were measured. Apigenin significantly inhibited basal, 8BR, 22R, PREG, P4, and D4 stimulated DIOL production in rat immature Leydig cells. Further study showed that apigenin inhibited rat 3β-hydroxysteroid dehydrogenase, 17α-hydroxylase/17, 20-lyase, and 17β-hydroxysteroid dehydrogenase 3 with IC50 values of 11.41±0.7, 8.98±0.10, and 9.37±0.07μM, respectively. Apigenin inhibited human 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase 3 with IC50 values of 2.17±0.04 and 1.31±0.09μM, respectively. Apigenin is a potent inhibitor of rat and human steroidogenic enzymes, being possible use for the treatment of prostate cancer.

  10. External beam radiation therapy and a low-dose-rate brachytherapy boost without or with androgen deprivation therapy for prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Strom, Tobin J.; Hutchinson, Sean Z.; Shrinath, Kushagra; Cruz, Alex A.; Figura, Nicholas B.; Nethers, Kevin; Biagioli, Matthew C.; Fernandez, Daniel C.; Heysek, Randy V.; Wilder, Richard B., E-mail: richard.wilder@moffitt.org [Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL (United States)

    2014-07-15

    Purpose: To assess outcomes with external beam radiation therapy (EBRT) and a low-dose-rate (LDR) brachytherapy boost without or with androgen deprivation therapy (ADT) for prostate cancer. Materials and Methods: From January 2001 through August 2011, 120 intermediate-risk or high-risk prostate cancer patients were treated with EBRT to a total dose of 4,500 cGy in 25 daily fractions and a palladium-103 LDR brachytherapy boost of 10,000 cGy (n = 90) or an iodine-125 LDR brachytherapy boost of 11,000 cGy (n = 30). ADT, consisting of a gonadotropin-releasing hormone agonist ± an anti-androgen, was administered to 29/92 (32%) intermediate-risk patients for a median duration of 4 months and 26/28 (93%) high-risk patients for a median duration of 28 months. Results: Median follow-up was 5.2 years (range, 1.1-12.8 years). There was no statistically-significant difference in biochemical disease-free survival (bDFS), distant metastasis-free survival (DMFS), or overall survival (OS) without or with ADT. Also, there was no statistically-significant difference in bDFS, DMFS, or OS with a palladium-103 vs. an iodine-125 LDR brachytherapy boost. Conclusions: There was no statistically-significant difference in outcomes with the addition of ADT, though the power of the current study was limited. The Radiation Therapy Oncology Group 0815 and 0924 phase III trials, which have accrual targets of more than 1,500 men, will help to clarify the role ADT in locally-advanced prostate cancer patients treated with EBRT and a brachytherapy boost. Palladium-103 and iodine-125 provide similar bDFS, DMFS, and OS. (author)

  11. Optimal duration of androgen deprivation therapy following radiation therapy in intermediate- or high-risk non-metastatic prostate cancer: a systematic review and meta-analysis

    Energy Technology Data Exchange (ETDEWEB)

    Leal, Frederico; Figueiredo, Maximiliano Augusto Novis de; Sasse, Andre Deeke, E-mail: sasse@cevon.com.br [Universidade Estadual de Campinas (UNICAMP), SP (Brazil)

    2015-05-15

    Objectives: to investigate current evidence on the optimal duration of adjuvant hormone deprivation for prostate cancer treated with radiation therapy with curative intent. Materials and Methods: A systematic search was performed in electronic databases. Data from randomized trials comparing different durations of hormone blockade was collected for pooled analysis. Overall survival, disease-free survival, disease-specific survival and toxicity were the outcomes of interest. Meta-analyses were performed using random-effects model. Results: Six studies met the eligibility criteria. For overall survival, the pooled data from the studies demonstrated a statistically significant benefit for longer hormone deprivation (Hazard Ratio 0.84; 95% CI 0.74 - 0.96). A statistically significant benefit was also found for disease-free survival (Hazard Ratio 0.74; 95% CI 0.62 - 0.89), and disease-specific survival (Hazard Ratio 0.73; 95% CI 0.62 - 0.85). Studies with longer blockade duration arm demonstrated greater benefit. Toxicity was low, with no increase in cardiovascular events. Conclusions: Longer duration of androgen deprivation combined to radiotherapy prolongs OS, DFS and DSS in patients with intermediate and high-risk non-metastatic prostate cancer. However, this evidence is based on trials using older radiation techniques, and further research of combination of androgen deprivation and new RT technologies may be warranted. (author)

  12. Testosterone and cardiovascular risk: myths and new truth about cardiological safety of androgen replacement therapy in men

    Directory of Open Access Journals (Sweden)

    S. Yu. Kalinchenko

    2014-12-01

    Full Text Available In a critical review of the literature highlights issues cardiological safety of testosterone therapy in men with cardiovascular diseases, based on research evidence over the past 25 years, as well as a detailed analysis of a number of recent publications, was summoned by the ambiguous attitude of experts and researchers in connection with them demonstrated high frequency of adverse cardiological outcomes in men on the background of androgen replacement therapy. Most modern randomized studies have proven a link between low testosterone levels and the poor state of the cardiovascular system in older men, so early detection and proper correction of hypogonadism in them can be regarded as an effective preventive and therapeutic cardioprotective option. Results improperly designed studies that have low probative due to errors in design and statistical treatment of the material and, more recently published, it should be, no matter what, to actively explore and analyze in order to not only criticize, but also to learn from them scientific practical use to a more correct understanding of the problem as a whole. The authors present their views on this issue and try to uncover the possible causes of the mixed results of recent publications on cardiological safety of testosterone drugs, a high degree of which they themselves have no doubt.

  13. Testosterone and cardiovascular risk: myths and new truth about cardiological safety of androgen replacement therapy in men

    Directory of Open Access Journals (Sweden)

    S. Yu. Kalinchenko

    2014-01-01

    Full Text Available In a critical review of the literature highlights issues cardiological safety of testosterone therapy in men with cardiovascular diseases, based on research evidence over the past 25 years, as well as a detailed analysis of a number of recent publications, was summoned by the ambiguous attitude of experts and researchers in connection with them demonstrated high frequency of adverse cardiological outcomes in men on the background of androgen replacement therapy. Most modern randomized studies have proven a link between low testosterone levels and the poor state of the cardiovascular system in older men, so early detection and proper correction of hypogonadism in them can be regarded as an effective preventive and therapeutic cardioprotective option. Results improperly designed studies that have low probative due to errors in design and statistical treatment of the material and, more recently published, it should be, no matter what, to actively explore and analyze in order to not only criticize, but also to learn from them scientific practical use to a more correct understanding of the problem as a whole. The authors present their views on this issue and try to uncover the possible causes of the mixed results of recent publications on cardiological safety of testosterone drugs, a high degree of which they themselves have no doubt.

  14. Androgen-deprivation therapy versus radical prostatectomy as monotherapy among clinically localized prostate cancer patients

    Directory of Open Access Journals (Sweden)

    Liu J

    2013-06-01

    Full Text Available Jinan Liu,1 Lizheng Shi,2,3 Oliver Sartor,3 Richard Culbertson2,31HealthCore, Wilmington, DE, USA; 2School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA; 3School of Medicine, Tulane University, New Orleans, LA, USABackground: The most recent randomized controlled trial in a predominantly prostate-specific antigen-detected prostate cancer (PC population found a nonsignificant reduction in mortality from radical prostatectomy (RP compared to conservative management. The optimal treatment for clinically localized prostate cancer is anything but clear. The PC-specific mortality and all-cause mortality were compared between primary androgen-deprivation treatment (PADT and RP, both as monotherapy, among clinically localized PC patients.Methods: A retrospective cohort study among PC patients in Surveillance, Epidemiology and End Results-Medicare data with a median follow up of 2.87 years in the PADT cohort and 2.95 years in the RP cohort. Propensity score-matching was employed to adjust for the observed selection bias. PC-specific mortality and all-cause mortality were modeled using the Fine and Gray competing risk model and Cox proportional hazards model, respectively. The independent variables in these models included age, race, Gleason score risk groups, T-score, prostate-specific antigen, Charlson comorbidity, and index year of treatment initiation.Results: After propensity score-matching, there were 1624 in the PADT cohort and 1624 in the RP cohort. All baseline values were comparable (all P-values >0.35. There were a total of 266 deaths (16.38% and 60 (3.69% PC-specific deaths among PADT recipients, while there were 56 (3.45% deaths and four (0.25% PC-specific deaths among RP recipients. According to the Kaplan–Meier estimation, the 8-year survival rate was 43.39% in the PADT cohort and 79.62% in the RP cohort. PADT was associated with increased risk of overall mortality (hazard ratio = 2.98, 95% confidence

  15. MR Guided Pulsed High Intensity Focused Ultrasound Enhancement of Gene Therapy Combined with Androgen Deprivation and Radiotherapy for Prostate Cancer Treatment

    Science.gov (United States)

    2012-09-01

    the observed enhancement are not well understood. It is thought mainly due to the nonthermal effects of ultrasound —mechanical streaming and cavitation ...AD ________________ Award Number: W81XWH-08-1-0469 TITLE: MR Guided Pulsed High Intensity Focused Ultrasound Enhancement of (Enter title of award...Intensity Focused Ultrasound Enhancement of 5b. GRANT NUMBER Gene Therapy Combined with Androgen Deprivation and Radiotherapy W81XWH-08-1-0469 for Prostate

  16. Sunitinib Plus Androgen Deprivation and Radiation Therapy for Patients With Localized High-Risk Prostate Cancer: Results From a Multi-institutional Phase 1 Study

    Energy Technology Data Exchange (ETDEWEB)

    Corn, Paul G., E-mail: pcorn@mdanderson.org [Department of Genitourinary Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas (United States); Song, Danny Y. [Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland (United States); Heath, Elisabeth; Maier, Jordan [Karmanos Cancer Institute, Wayne State University, Detroit, Michigan (United States); Meyn, Raymond [Department of Experimental Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas (United States); Kuban, Deborah [Department of Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas (United States); DePetrillo, Thomas A. [Department of Radiation Oncology, Tufts Medical Center, Boston, Massachusetts (United States); Mathew, Paul, E-mail: pmathew@tuftsmedicalcenter.org [Department of Hematology-Oncology, Tufts Medical Center, University of Texas M. D. Anderson Cancer Center, Houston, Texas (United States)

    2013-07-01

    Purpose: To evaluate the feasibility of administering sunitinib in combination with androgen deprivation therapy and external-beam intensity modulated radiation therapy (XRT) in patients with localized high-risk prostate cancer. Methods and Materials: Seventeen men with localized adenocarcinoma of the prostate with cT2c-cT4 or Gleason 8-10 or prostate-specific antigen >20 ng/mL received initial androgen deprivation (leuprolide 22.5 mg every 12 weeks plus oral bicalutamide 50 mg daily) for 4-8 weeks before oral sunitinib 12.5, 25, or 37.5 mg daily for 4 weeks as lead-in, then concurrently with and 4 weeks after XRT (75.6 Gy in 42 fractions to prostate and seminal vesicles). A 3+3 sequential dose-escalation design was used to assess the frequency of dose-limiting toxicity (DLT) and establish a maximal tolerated dose of sunitinib. Results: Sunitinib at 12.5- and 25-mg dose levels was well tolerated. The first 4 patients enrolled at 37.5 mg experienced a DLT during lead-in, and a drug interaction between sunitinib and bicalutamide was suspected. The protocol was revised and concurrent bicalutamide omitted. Of the next 3 patients enrolled at 37.5 mg, 2 of 3 receiving concurrent therapy experienced DLTs during radiation: grade 3 diarrhea and grade 3 proctitis, respectively. Only 1 of 7 patients completed sunitinib at 37.5 mg daily, whereas 3 of 3 patients (25 mg as starting dose) and 3 of 4 patients (25 mg as reduced dose) completed therapy. Conclusions: The feasibility of combined vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR) inhibitor therapy, androgen deprivation, and radiation therapy for prostate cancer was established. Using a daily dosing regimen with lead-in, concurrent, and post-XRT therapy, the recommended phase 2 dose of sunitinib is 25 mg daily.

  17. Changes within the thyroid axis after long-term TSH-suppressive levothyroxine therapy.

    NARCIS (Netherlands)

    Verburg, F.A.; Smit, J.W.A.; Grelle, I.; Visser, T.J.; Peeters, R.P.; Reiners, C.

    2012-01-01

    OBJECTIVE: The effects of long-term TSH-suppressive levothyroxine (LT4) therapy on thyroid hormone metabolism in patients with differentiated thyroid carcinoma (DTC) are unknown. The aim of the study was to investigate the changes in thyroid hormone metabolism after long-term TSH-suppressive LT4 the

  18. One and the same androgen for all? towards designer androgens

    Institute of Scientific and Technical Information of China (English)

    LouisJGGooren; NhuThanhNguyen

    1999-01-01

    The introduction of designer oestrogens as a treatment medality in hormone replacement in women has invited to consider the concept of compounds with selective androgenic effects for male honnone replacement therapy. The full spectrum of the actions of testosterone may not be necessary of even undesired for certain indications for testosterone treatment, To define for what indications certain androgenic properties are desired and undesired more insight in basic androgen (patho)physiology is required. There is convincing evidence that aromatization of androgenic compounds to nestrogens might be an advantage for maintenance of bone mass and it might also mitigate negative effects of androgens on bichemical parameters of cardiovascular risks: the potentially negative effects of oestmgens on prostate pathology in ageing men needs further elucidation. While the role of dihydro-testosterone (DHT) for the male sexual differentiation and for pubertal sexual maturation is evident, its role in mature and ageing males seems less significant or may even be harmful. It is, however, of note that a negative effect of DHT on prostate pathophysiolog~ is certainly not proven.For male contraception a progestational agent with strong androgenic properties might be an asset. For most of the androgenic actions the critical levels of androgens are not well established. The latter is relevant since the large amount of androgen molecules required for its biological actions (as compared to oestrogens) is an impediment in androgen replacement medalities. There may be room for more biopotent androgens since delivery of large amounts of androgen molecules to the circulation poses problems fur treatment modalities. ( Asian J Andro11999 Jun; 1:21 -28)

  19. The Prevalence of Cardiac Risk Factors in Men with Localized Prostate Cancer Undergoing Androgen Deprivation Therapy in British Columbia, Canada

    Directory of Open Access Journals (Sweden)

    Margot K. Davis

    2015-01-01

    Full Text Available Background. While androgen deprivation therapy (ADT reduces the risk of prostate cancer-specific mortality in high-risk localized prostate cancer, it adversely affects cardiovascular (CV risk factor profiles in treated men. Methods. We retrospectively reviewed the charts of 100 consecutive men with intermediate- or high-risk localized prostate cancer referred to the British Columbia Cancer Agency for ADT. Data on CV risk factors and disease were collected and Framingham risk scores were calculated. Results. The median age of the study cohort was 73 years. Established cardiovascular disease was present in 25% of patients. Among patients without established CV disease, calculated Framingham risk was high in 65%, intermediate in 33%, and low in 1%. Baseline hypertension was present in 58% of patients, dyslipidemia in 51%, and diabetes or impaired glucose tolerance in 24%. Hypertension was more prevalent in the study cohort than in an age- and sex-matched population sample (OR 1.74, P=0.006; diabetes had a similar prevalence (OR 0.93, P=0.8. Conclusions. Patients receiving ADT have a high prevalence of cardiovascular disease and risk factors and are more likely to be hypertensive than population controls. Low rates of CV risk screening suggest opportunities for improved primary and secondary prevention of CV disease in this population.

  20. Expanded risk groups help determine which prostate radiotherapy sub-group may benefit from adjuvant androgen deprivation therapy

    Directory of Open Access Journals (Sweden)

    Williams Scott G

    2008-04-01

    Full Text Available Abstract Purpose To assess whether an expanded (five level risk stratification system can be used to identify the sub-group of intermediate risk patients with prostate cancer who benefit from combining androgen deprivation therapy (ADT with external beam radiotherapy (EBRT. Materials and methods Using a previously validated 5-risk group schema, a prospective non-randomized data set of 1423 men treated at the British Columbia Cancer Agency was assessed for the primary end point of biochemical control (bNED with the RTOG-ASTRO "Phoenix" definition (lowest PSA to date + 2 ng/mL, both with and without adjuvant ADT. The median follow-up was 5 years. Results There was no bNED benefit for ADT in the low or low intermediate groups but there was a statistically significant bNED benefit in the high intermediate, high and extreme risk groups. The 5-year bNED rates with and without ADT were 70% and 73% respectively for the low intermediate group (p = non-significant and 72% and 58% respectively for the high intermediate group (p = 0.002. Conclusion There appears to be no advantage to ADT where the Gleason score is 6 or less and PSA is 15 or less. ADT is beneficial in patients treated to standard dose radiation with Gleason 6 disease and a PSA greater than 15 or where the Gleason score is 7 or higher.

  1. Predictors of Fracture Risk and Bone Mineral Density in Men with Prostate Cancer on Androgen Deprivation Therapy

    Directory of Open Access Journals (Sweden)

    Katherine Neubecker

    2011-01-01

    Full Text Available Decrease of bone mineral density (BMD and fracture risk is increased in men with prostate cancer receiving androgen deprivation therapy (ADT. We looked at possible predictors of decreased BMD and increased fracture risk in men with prostate cancer; most of whom were on ADT. In a retrospective study, we analyzed serum, BMD, and clinical risk factors used in the Fracture Risk Assessment (FRAX tool and others in 78 men with prostate cancer with reported height loss. The subjects were divided in two groups: 22 men with and 56 without vertebral fractures. 17 of the 22 men with vertebral fractures on spine X-rays did not know they had a vertebral fracture. Of those 17 men, 9 had not previously qualified for treatment based on preradiograph FRAX score calculated with BMD, and 6 based on FRAX calculated without BMD. Performing spine films increased the predictive ability of FRAX for vertebral fracture. Vertebral fracture was better predicted by FRAX for other osteoporotic fractures than FRAX for hip fractures. The inclusion of BMD in FRAX calculations did not affect the predictive ability of FRAX. The PSA level showed a positive correlation with lumbar spine BMD and accounted for about 9% of spine BMD.

  2. Randomized, Double-Blinded, Placebo-Controlled, Trial of Risedronate for the Prevention of Bone Mineral Density Loss in Nonmetastatic Prostate Cancer Patients Receiving Radiation Therapy Plus Androgen Deprivation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Choo, Richard [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Lukka, Himu [Department of Radiation Oncology, Juravinski Cancer Center, McMaster University, Hamilton (Canada); Cheung, Patrick [Department of Radiation Oncology, Odette Cancer Centre, University of Toronto, Toronto (Canada); Corbett, Tom [Department of Radiation Oncology, Juravinski Cancer Center, McMaster University, Hamilton (Canada); Briones-Urbina, Rosario [Department of Medicine, Women' s College Hospital, University of Toronto, Toronto (Canada); Vieth, Reinhold [Departments of Nutritional Sciences and Laboratory Medicine and Pathology, Mount Sinai Hospital, University of Toronto, Toronto (Canada); Ehrlich, Lisa [Department of Radiology, Sunnybrook Health Sciences Center, University of Toronto (Canada); Kiss, Alex [Department of Health Policy, Management, and Evaluation, Sunnybrook Health Sciences Center, University of Toronto, Toronto (Canada); Danjoux, Cyril, E-mail: Cyril.danjoux@sunnybrook.ca [Department of Radiation Oncology, Odette Cancer Centre, University of Toronto, Toronto (Canada)

    2013-04-01

    Purpose: Androgen deprivation therapy (ADT) has been used as an adjuvant treatment to radiation therapy (RT) for the management of locally advanced prostate carcinoma. Long-term ADT decreases bone mineral density (BMD) and increases the risk of osteoporosis. The objective of this clinical trial was to evaluate the efficacy of risedronate for the prevention of BMD loss in nonmetastatic prostate cancer patients undergoing RT plus 2 to 3 years of ADT. Methods and Materials: A double-blinded, placebo-controlled, randomized trial was conducted for nonmetastatic prostate cancer patients receiving RT plus 2 to 3 years of ADT. All had T scores > −2.5 on dual energy x-ray absorptiometry at baseline. Patients were randomized 1:1 between risedronate and placebo for 2 years. The primary endpoints were the percent changes in the BMD of the lumbar spine at 1 and 2 years from baseline, measured by dual energy x-ray absorptiometry. Analyses of the changes in BMD and bone turnover biomarkers were carried out by comparing mean values of the intrapatient changes between the 2 arms, using standard t tests. Results: One hundred four patients were accrued between 2004 and 2007, with 52 in each arm. Mean age was 66.8 and 67.5 years for the placebo and risedronate, respectively. At 1 and 2 years, mean (±SE) BMD of the lumbar spine decreased by 5.77% ± 4.66% and 13.55% ± 6.33%, respectively, in the placebo, compared with 0.12% ± 1.29% at 1 year (P=.2485) and 0.85% ± 1.56% (P=.0583) at 2 years in the risedronate. The placebo had a significant increase in serum bone turnover biomarkers compared with the risedronate. Conclusions: Weekly oral risedronate prevented BMD loss at 2 years and resulted in significant suppression of bone turnover biomarkers for 24 months for patients receiving RT plus 2 to 3 years of ADT.

  3. Recovery of serum testosterone following neoadjuvant and adjuvant androgen deprivation therapy in men treated with prostate brachytherapy

    Institute of Scientific and Technical Information of China (English)

    Hideyasu Tsumura; Takefumi Satoh; Hiromichi Ishiyama; Shuhei Hirano; Kenichi Tabata; Shinji Kurosaka; Kazumasa Matsumoto; Tetsuo Fujita; Masashi Kitano; Shiro Baba; Kazushige Hayakawa; Masatsugu Iwamura

    2015-01-01

    AIM: To investigate the time course of testosterone(T) recovery after cessation of androgen deprivation therapy(ADT) in patients treated with brachytherapy. METHODS: One-hundred and seventy-four patients treated between June 1999 and February 2009 were studied. Patients were divided into a short-term usage group(≤ 12 mo, n = 91) and a long-term usage group(≥ 36 mo, n = 83) according to the duration of gonadotropin-releasing hormone agonist therapy. Median follow-up was 29 mo in the short-term group and was 60 mo in the long-term group.RESULTS: Cumulative incidence rates of T recovery to normal and supracastrate levels at 24 mo after cessationwere 28.8% and 74.6%, respectively, in the long-term usage group, whereas these values were 96.4% and 98.8% in the short-term usage group. T recovery to normal and supracastrate levels occurred significantly more rapidly in the short-term than in the long-term usage group(P < 0.001 and P < 0.001, respectively). Five years after cessation, 22.6% of patients maintained a castrate T level in the long-term usage group. On multivariate analysis, lower T levels(< 10 ng/d L) at cessation of ADT was significantly associated with prolonged T recovery to supracastrate levels in the longterm usage group(P = 0.002). CONCLUSION: Lower T levels at cessation of ADT were associated with prolonged T recovery in the longterm usage group. Five years after cessation of longterm ADT, approximately one-fifth of patients still had castrate T levels. When determining the therapeutic effect, especially biochemical control, we should consider this delay in T recovery.

  4. Efficacy of walking exercise in promoting cognitive-psychosocial functions in men with prostate cancer receiving androgen deprivation therapy

    Directory of Open Access Journals (Sweden)

    Lee C

    2012-07-01

    Full Text Available Abstract Background Prostate cancer is the most commonly diagnosed non-melanoma cancer among men. Androgen deprivation therapy (ADT has been the core therapy for men with advanced prostate cancer. It is only in recent years that clinicians began to recognize the cognitive-psychosocial side effects from ADT, which significantly compromise the quality of life of prostate cancer survivors. The objectives of the study are to determine the efficacy of a simple and accessible home-based, walking exercise program in promoting cognitive and psychosocial functions of men with prostate cancer receiving ADT. Methods A 6-month prospective, single-blinded, randomized controlled trial will be conducted to compare the Exercise Group with the Control Group. Twenty men with prostate cancer starting ADT will be recruited and randomly assigned to one of the two groups: the Exercise Group will receive instructions in setting up an individualized 6-month home-based, walking exercise program, while the Control Group will receive standard medical advice from the attending physician. The primary outcomes will be psychosocial and cognitive functions. Cognitive functions including memory, attention, working memory, and executive function will be assessed using a battery of neurocognitive tests at baseline and 6 months. Psychosocial functions including depression, anxiety and self-esteem will be assessed at baseline, 3 and 6 months using the Center for Epidemiological Studies Depression Scale, Spielberger State-Trait Anxiety Inventory, and Rosenberg Self-Esteem Scale. Discussion The significance of the cognitive-psychosocial side effects of ADT in men with prostate cancer has only been recently recognized, and the management remains unclear. This study addresses this issue by designing a simple and accessible home-based, exercise program that may potentially have significant impact on reducing the cognitive and psychosocial side effects of ADT, and ultimately

  5. The effect of vitamin D replacement therapy on insulin resistance and androgen levels in women with polycystic ovary syndrome.

    Science.gov (United States)

    Selimoglu, H; Duran, C; Kiyici, S; Ersoy, C; Guclu, M; Ozkaya, G; Tuncel, E; Erturk, E; Imamoglu, S

    2010-04-01

    Insulin resistance (IR) is one of the common features of the polycystic ovary syndrome (PCOS), and recent studies indicate the possible role of vitamin D in the pathogenesis of IR and glucose metabolism. Aim of this study was aimed to determine the effect of vitamin D replacement therapy on glucose metabolism, insulin, and androgen levels in obese, insulin-resistant women with PCOS. Eleven women with PCOS were included in the study. Mean age of the patients was 23.6+/-5.7 yr, body mass index 33.9+/-5.1 kg/m(2). Six patients (54.5%) had acantosis nigricans and 10 (90.9%) oligoamenorrhea. The mean Ferriman Gallwey score was 14.1+/-4.6. Only 2 women were within the normal limits of vitamin D levels as >20 ng/ml. Three weeks after the administration of the single dose of 300,000 units of vitamin D3 orally, 25-hydroxyvitamin D3 significantly increased from 16.9+/-16 ng/ml to 37.1+/-14.6 ng/ml (p: 0.027) and only 2 women were detected to have vitamin D3 levels <20 ng/ml. Although glucose and insulin levels were decreased non-significantly, homeostasis model assessment (HOMA)-IR significantly decreased from 4.41+/-1.38 to 3.67+/-1.48 (p: 0.043). No significant alterations were witnessed at the levels of DHEAS, total and free testosterone, androstenedione. No correlation was found between vitamin D with HOMA and other hormonal parameters. In conclusion, women with PCOS have mostly insufficient vitamin D levels, and vitamin D replacement therapy may have a beneficial effect on IR in obese women with PCOS.

  6. Short-term Androgen-Deprivation Therapy Improves Prostate Cancer-Specific Mortality in Intermediate-Risk Prostate Cancer Patients Undergoing Dose-Escalated External Beam Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Zumsteg, Zachary S.; Spratt, Daniel E.; Pei, Xin; Yamada, Yoshiya; Kalikstein, Abraham [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Kuk, Deborah; Zhang, Zhigang [Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Zelefsky, Michael J., E-mail: zelefskm@mskcc.org [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States)

    2013-03-15

    Purpose: We investigated the benefit of short-term androgen-deprivation therapy (ADT) in patients with intermediate-risk prostate cancer (PC) receiving dose-escalated external beam radiation therapy. Methods and Materials: The present retrospective study comprised 710 intermediate-risk PC patients receiving external beam radiation therapy with doses of ≥81 Gy at a single institution from 1992 to 2005, including 357 patients receiving neoadjuvant and concurrent ADT. Prostate-specific antigen recurrence-free survival (PSA-RFS) and distant metastasis (DM) were compared using the Kaplan-Meier method and Cox proportional hazards models. PC-specific mortality (PCSM) was assessed using competing-risks analysis. Results: The median follow-up was 7.9 years. Despite being more likely to have higher PSA levels, Gleason score 4 + 3 = 7, multiple National Comprehensive Cancer Network intermediate-risk factors, and older age (P≤.001 for all comparisons), patients receiving ADT had improved PSA-RFS (hazard ratio [HR], 0.598; 95% confidence interval [CI], 0.435-0.841; P=.003), DM (HR, 0.424; 95% CI, 0.219-0.819; P=.011), and PCSM (HR, 0.380; 95% CI, 0.157-0.921; P=.032) on univariate analysis. Using multivariate analysis, ADT was an even stronger predictor of improved PSA-RFS (adjusted HR [AHR], 0.516; 95% CI, 0.360-0.739; P<.001), DM (AHR, 0.347; 95% CI, 0.176-0.685; P=.002), and PCSM (AHR, 0.297; 95% CI, 0.128-0.685; P=.004). Gleason score 4 + 3 = 7 and ≥50% positive biopsy cores were other independent predictors of PCSM. Conclusions: Short-term ADT improves PSA-RFS, DM, and PCSM in patients with intermediate-risk PC undergoing dose-escalated external beam radiation therapy.

  7. The majority of Danish nontoxic goitre patients are ineligible for Levothyroxine suppressive therapy

    DEFF Research Database (Denmark)

    Fast, Søren; Bonnema, Steen Joop; Hegedüs, Laszlo

    2008-01-01

    OBJECTIVE: Levothyroxine suppressive therapy (LT4-therapy), aimed at shrinking thyroid nodules is controversial. Despite evidence of limited effect and long-term side-effects, questionnaire surveys indicate widespread use. Our aim was to determine, in consecutive nontoxic goitre patients, the pro......OBJECTIVE: Levothyroxine suppressive therapy (LT4-therapy), aimed at shrinking thyroid nodules is controversial. Despite evidence of limited effect and long-term side-effects, questionnaire surveys indicate widespread use. Our aim was to determine, in consecutive nontoxic goitre patients......, the proportion ineligible for LT4-therapy. Exclusion criteria were set up in agreement with recent guidelines. SETTING: Secondary/tertiary referral centre at University Clinic. SUBJECTS AND METHODS: During 1997-2001, 822 patients were referred to our endocrine unit on suspicion of nontoxic goitre. Patients were...... is contraindicated. Exclusion criteria included (1) Serum TSH goitre, (5) Clinical suspicion of malignancy, (6) Dominant thyroid cyst, (7) Nondiagnostic FNA, (8) Previous ineffective LT4-therapy...

  8. Survival benefit of early androgen receptor inhibitor therapy in locally advanced prostate cancer

    DEFF Research Database (Denmark)

    Thomsen, Frederik B; Brasso, Klaus; Christensen, Ib J

    2015-01-01

    -metastatic PCa. Kaplan-Meier analysis was used to estimate overall survival (OS) and multivariate Cox proportional hazard model was performed to analyse time-to-event (death). FINDINGS: A total of 1218 patients were included into the Scandinavian Prostate Cancer Group (SPCG)-6 study of which 607 were randomised......BACKGROUND: The optimal timing of endocrine therapy in non-metastatic prostate cancer (PCa) is still an issue of debate. METHODS: A randomised, double-blind, parallel-group trial comparing bicalutamide 150mg once daily with placebo in addition to standard care in patients with hormone-naïve, non...... disease (HR=1.19 (95% CI: 1.00-1.43), p=0.056). However, a survival gain from bicalutamide therapy was present in patients with localised disease and a baseline PSA greater than 28ng/mL at randomisation. In multivariate Cox proportional hazard model, only including patients managed on watchful waiting...

  9. Dosimetric impact of a CT metal artefact suppression algorithm for proton, electron and photon therapies.

    Science.gov (United States)

    Wei, Jikun; Sandison, George A; Hsi, Wen-Chien; Ringor, Michael; Lu, Xiaoyi

    2006-10-21

    Accurate dose calculation is essential to precision radiation treatment planning and this accuracy depends upon anatomic and tissue electron density information. Modern treatment planning inhomogeneity corrections use x-ray CT images and calibrated scales of tissue CT number to electron density to provide this information. The presence of metal in the volume scanned by an x-ray CT scanner causes metal induced image artefacts that influence CT numbers and thereby introduce errors in the radiation dose distribution calculated. This paper investigates the dosimetric improvement achieved by a previously proposed x-ray CT metal artefact suppression technique when the suppressed images of a patient with bilateral hip prostheses are used in commercial treatment planning systems for proton, electron or photon therapies. For all these beam types, this clinical image and treatment planning study reveals that the target may be severely underdosed if a metal artefact-contaminated image is used for dose calculations instead of the artefact suppressed one. Of the three beam types studied, the metal artefact suppression is most important for proton therapy dose calculations, intermediate for electron therapy and least important for x-ray therapy but still significant. The study of a water phantom having a metal rod simulating a hip prosthesis indicates that CT numbers generated after image processing for metal artefact suppression are accurate and thus dose calculations based on the metal artefact suppressed images will be of high fidelity.

  10. Quantitative assessment of quality of life in New Zealand prostate cancer survivors: the effect of androgen deprivation therapy

    Directory of Open Access Journals (Sweden)

    Keogh JW

    2013-04-01

    Full Text Available Men with prostate cancer experience many challenges to their quality of life (QOL. While some of these challenges reflect the direct effects of the cancer, additional side-effects and symptoms are also associated with common treatments especially androgen deprivation therapy (ADT. While several studies have examined the effects of ADT on the QOL of men with prostate cancer, much of this research is between 10-20 years old and was conducted in North America or Europe. This study therefore examined the effects of ADT on QOL in prostate cancer patients (survivors in the Southern hemisphere. The registries of two New Zealand based hospitals were sourced to identify men with prostate cancer who were using ADT for at least six months (ADT group, n=205 and those who had never used ADT (non-ADT group, n=143. Participants in both groups were mailed a letter of invitation, the WHOQOL-BREF and three facets of the WHOQOL-OLD QOL questionnaire. Response rates of 41% and 40% were obtained for the ADT and non-ADT groups, respectively. QOL scores were generally similar between the groups, with the exception of physical QOL, which was significantly lower in the ADT group. Such results suggest that cancer clinicians, allied health professionals and cancer researchers should not just concentrate on the physical effect of ADT on their survivors’ risk of developing osteoporosis, falls-related fracture and cardio-metabolic syndrome, but also devote time to ensure their survivors’ perception of their physical QOL is not compromised.

  11. A low carbohydrate, high protein diet suppresses intratumoral androgen synthesis and slows castration-resistant prostate tumor growth in mice.

    Science.gov (United States)

    Fokidis, H Bobby; Yieng Chin, Mei; Ho, Victor W; Adomat, Hans H; Soma, Kiran K; Fazli, Ladan; Nip, Ka Mun; Cox, Michael; Krystal, Gerald; Zoubeidi, Amina; Tomlinson Guns, Emma S

    2015-06-01

    likely to be mechanistic drivers behind the observed tumor growth suppression.

  12. Therapeutic effect of androgen therapy in a mouse model of aplastic anemia produced by short telomeres.

    Science.gov (United States)

    Bär, Christian; Huber, Nicolas; Beier, Fabian; Blasco, Maria A

    2015-10-01

    Aplastic anemia is a rare but life-threatening disorder characterized by cytopenia in at least two of the three blood lineages. A frequent feature of patients with aplastic anemia is that they have shorter telomeres than those of age-matched controls. Testosterone has been used for over half a century in the treatment of aplastic anemia. However, although remissions are frequent following hormone therapy, the molecular mechanism underlying the response to treatment has remained unknown. Here we explored the possibility that the recently described regulation of telomerase activity by sex hormones may be the mechanism responsible. To this end, we used a mouse model of aplastic anemia induced by short telomeres in the bone marrow compartment. We found that testosterone therapy results in telomerase up-regulation, improved blood counts, and a significant extension of life-span of these mice. Importantly, longitudinal follow-up studies revealed longer telomeres in peripheral blood in mice subjected to hormone treatment. Our results demonstrate that testosterone-mediated telomerase activation can attenuate or reverse aplastic anemia disease progression associated with the presence of short telomeres.

  13. Is Androgen Deprivation Therapy Necessary in All Intermediate-Risk Prostate Cancer Patients Treated in the Dose Escalation Era?

    Energy Technology Data Exchange (ETDEWEB)

    Castle, Katherine O., E-mail: kocastle@mdanderson.org [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Hoffman, Karen E.; Levy, Lawrence B.; Lee, Andrew K.; Choi, Seungtaek; Nguyen, Quynh N.; Frank, Steven J.; Pugh, Thomas J.; McGuire, Sean E.; Kuban, Deborah A. [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States)

    2013-03-01

    Purpose: The benefit of adding androgen deprivation therapy (ADT) to dose-escalated radiation therapy (RT) for men with intermediate-risk prostate cancer is unclear; therefore, we assessed the impact of adding ADT to dose-escalated RT on freedom from failure (FFF). Methods: Three groups of men treated with intensity modulated RT or 3-dimensional conformal RT (75.6-78 Gy) from 1993-2008 for prostate cancer were categorized as (1) 326 intermediate-risk patients treated with RT alone, (2) 218 intermediate-risk patients treated with RT and ≤6 months of ADT, and (3) 274 low-risk patients treated with definitive RT. Median follow-up was 58 months. Recursive partitioning analysis based on FFF using Gleason score (GS), T stage, and pretreatment PSA concentration was applied to the intermediate-risk patients treated with RT alone. The Kaplan-Meier method was used to estimate 5-year FFF. Results: Based on recursive partitioning analysis, intermediate-risk patients treated with RT alone were divided into 3 prognostic groups: (1) 188 favorable patients: GS 6, ≤T2b or GS 3+4, ≤T1c; (2) 71 marginal patients: GS 3+4, T2a-b; and (3) 68 unfavorable patients: GS 4+3 or T2c disease. Hazard ratios (HR) for recurrence in each group were 1.0, 2.1, and 4.6, respectively. When intermediate-risk patients treated with RT alone were compared to intermediate-risk patients treated with RT and ADT, the greatest benefit from ADT was seen for the unfavorable intermediate-risk patients (FFF, 74% vs 94%, respectively; P=.005). Favorable intermediate-risk patients had no significant benefit from the addition of ADT to RT (FFF, 94% vs 95%, respectively; P=.85), and FFF for favorable intermediate-risk patients treated with RT alone approached that of low-risk patients treated with RT alone (98%). Conclusions: Patients with favorable intermediate-risk prostate cancer did not benefit from the addition of ADT to dose-escalated RT, and their FFF was nearly as good as patients with low-risk disease

  14. Suppressive therapy versus episodic therapy with oral valacyclovir for recurrent herpes labialis: efficacy and tolerability in an open-label, crossover study.

    Science.gov (United States)

    Gilbert, Stanley C

    2007-04-01

    Oral valacyclovir's efficacy and tolerability as suppressive therapy versus episodic therapy were compared for recurrent herpes labialis (RHL). Subjects with a history of at least 3 RHL episodes in the past year were randomized to receive 6 months of oral valacyclovir episodic therapy at the first sign of prodrome (two 2-g doses separated by 12 hours) and 6 months of oral valacyclovir suppressive therapy (1 g once daily) for 6 months in open-label, crossover fashion. The mean +/- SE number of recurrences per 120 days of follow-up (primary endpoint) was lower with suppressive therapy (0.30 +/- 0.41) than episodic therapy (0.71 +/- 0.79) (P 180 days) for suppressive therapy (P = 0.021). Data for secondary efficacy endpoints (pain severity score, mean duration of recurrences, maximal total lesion area) showed approximately a 30% to 50% reduction in mean values with suppressive therapy compared with episodic therapy, but results were statistically significantly different between the regimens for pain severity only. The percentage of subjects with at least one adverse event over 6 months of treatment that was considered to be drug related was 3% with suppressive therapy and 6% with episodic therapy. Suppressive therapy with oral valacyclovir was more effective than episodic therapy with oral valacyclovir in reducing the frequency of recurrences of herpes labialis and prolonging the time to first recurrence and was also similarly well-tolerated.

  15. Androgen-deprivation therapy alone versus combined with radiation therapy or chemotherapy for nonlocalized prostate cancer: a systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    Jun-Hao Lei

    2016-01-01

    Full Text Available In this paper, we reviewed the long-term survival outcomes, safety, and quality-of-life of androgen-deprivation therapy (ADT alone versus combined with radiation therapy (RT or chemotherapy for locally advanced and metastatic prostate cancer (PCa. A literature search was performed using OvidSP. Randomized controlled trials (RCTs that met the following criteria were included: including locally advanced or metastatic PCa, comparing ADT alone versus combined with any treatment method and reporting quantitative data of disease control or survival outcomes. Finally, eight RCTs met the inclusion criteria. Among these, three compared ADT versus ADT plus RT (n = 2344 and one compared ADT versus ADT plus docetaxel-estramustine (n = 413 in locally advanced PCa; two compared ADT versus ADT plus docetaxel (n = 1175 and two compared ADT versus ADT plus estramustine (n = 114 in metastatic PCa. For locally advanced PCa, the addition of RT to long-term ADT can improve the outcomes of survival and tumor control with fully acceptable adverse effects. Specially, the pooled odds ratio (OR of overall survival (OS was 1.43 (95% confidence interval 1.20-1.71 when compared ADT plus RT with ADT alone (P < 0.0001. For metastatic hormonally sensitive PCa, the concurrent use of docetaxel plus ADT was effective and safe (pooled OR of OS: 1.29 [1.01-1.65]: P = 0.04. In all, long-term ADT plus RT and long-term ADT plus docetaxel should be considered as proper treatment option in locally advanced and metastatic hormonally sensitive PCa, respectively. The major limitation for the paper was that only eight RCTs were available.

  16. Differential regulation of LncRNA-SARCC suppresses VHL-mutant RCC cell proliferation yet promotes VHL-normal RCC cell proliferation via modulating androgen receptor/HIF-2α/C-MYC axis under hypoxia.

    Science.gov (United States)

    Zhai, W; Sun, Y; Jiang, M; Wang, M; Gasiewicz, T A; Zheng, J; Chang, C

    2016-09-15

    It is well established that hypoxia contributes to tumor progression in a hypoxia inducible factor-2α (HIF-2α)-dependent manner in renal cell carcinoma (RCC), yet the role of long noncoding RNAs (LncRNAs) involved in hypoxia-mediated RCC progression remains unclear. Here we demonstrate that LncRNA-SARCC (Suppressing Androgen Receptor in Renal Cell Carcinoma) is differentially regulated by hypoxia in a von Hippel-Lindau (VHL)-dependent manner both in RCC cell culture and clinical specimens. LncRNA-SARCC can suppress hypoxic cell cycle progression in the VHL-mutant RCC cells while derepress it in the VHL-restored RCC cells. Mechanism dissection reveals that LncRNA-SARCC can post-transcriptionally regulate androgen receptor (AR) by physically binding and destablizing AR protein to suppress AR/HIF-2α/C-MYC signals. In return, HIF-2α can transcriptionally regulate the LncRNA-SARCC expression via binding to hypoxia-responsive elements on the promoter of LncRNA-SARCC. The negative feedback modulation between LncRNA-SARCC/AR complex and HIF-2α signaling may then lead to differentially modulated RCC progression in a VHL-dependent manner. Together, these results may provide us a new therapeutic approach via targeting this newly identified signal from LncRNA-SARCC to AR-mediated HIF-2α/C-MYC signals against RCC progression.

  17. Cardiovascular Adaptations to Recreational Football Training in Men with Type 2 Diabetes, Untrained Elderly Men and in Men with Prostate Cancer Receiving Androgen Deprivation Therapy

    DEFF Research Database (Denmark)

    Schmidt, Jakob Friis

    Numerous people in the general population are not suffuciently physically active and the use of new exercise training modalities which could promote physically active lifestyles are important. The present PhD thesis includes studies , which investigated the effect of recreational football training...... in middle-aged men with type 2 diabetes, 65-75-year-old untrained men, men with prostate cancer receiving androgen deprivation therapy and the effect of life-long participation in football training in veteran football players. The primary purpose was to evaluate the structure and function of the heart...

  18. Growth Suppression and Therapy Sensitization of Breast Cancer

    Science.gov (United States)

    2001-07-01

    23 B -24 DLD-1 T47D PC-3 T98G::.25 :_26 2 100 A .27 80 I Ad-p53 7-.28 6-5 60- =29 _ 40 -󈧢 ® 20 __31 . 0 + + + + -- 32 5FU dox CDDP CDDP =-.33 -34 Fig...41 ments 1 d postinfection were as follows: 5-fluorouracil ( 5FU ), 10 p.M 1 h;, doxorubi- -42 cin (dox) 3.7 pM I h, cisplatin (CDDP), 30 4aM for I h for...100 • 80 Ad-Bgal ,-0 "r---l Ad-p53•- 6- 60 0 Z 40 W 05 20 - 0 -4 -4 + + 5FU dox CDDP CDDP Figure 1. Viability assay showing that Ad-p53 suppresses

  19. Short androgenic suppression and high dose radiotherapy (80 Gy) for prostate cancer with intermediate risk: interim analysis of randomized trial 14 by the Group of uro-genital tumour investigations (Getug); Suppression androgenique courte et radiotherapie de haute dose (80 Gy) pour cancer prostatique de risque intermediaire: analyse interimaire de l'essai randomise 14 du Groupe d'etudes des tumeurs urogenitales (Getug)

    Energy Technology Data Exchange (ETDEWEB)

    Dubray, B. [CRLCC Henri-Becquerel, Rouen (France); Beckendorf, V.; Harter, V. [CRLCCAIexis-Vautrin, Vandceuvre- les-Nancy (France); Guerif, S. [CHU La Miletrie, Poitiers (France); Le Prise, E. [CRLCCEugene-Marquis, Rennes (France); Reynaud-Bougnoux, A. [Corad Henry-S.-Kaplan, Tours (France); Hannoun Levi, J.M. [CRLCCAntoine-Lacassagne, Nice (France); Nguyeng, T.D. [InstitutJean-Godinot, Reims (France); Hennequin, C. [CHU Saint-Louis, Paris (France); Cretin, J. [Clinique de Valdegour, Nimes (France)

    2011-10-15

    The authors report an interim analysis of a randomized trial for the assessment of the contribution of a short androgenic suppression to a high-dose irradiation on patients suffering from an intermediate risk localized prostate cancer. The study concerned a bit less than 400 patients treated between 2003 and 2010. About half of them had hormonotherapy, and the other half not. Results are discussed in terms of biochemical or clinical control probability, of cumulative grade-3 and grade-4 toxicity rates. The benefit of androgenic suppression does not reach a statistic significant threshold. Short communication

  20. Causes of Mortality After Dose-Escalated Radiation Therapy and Androgen Deprivation for High-Risk Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Tendulkar, Rahul D., E-mail: tendulr@ccf.org [Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio (United States); Hunter, Grant K. [Department of Radiation Oncology, Intermountain Healthcare, Salt Lake City, Utah (United States); Reddy, Chandana A.; Stephans, Kevin L.; Ciezki, Jay P.; Abdel-Wahab, May [Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio (United States); Stephenson, Andrew J.; Klein, Eric A. [Department of Urology, Glickman Urological Institute, Cleveland Clinic, Cleveland, Ohio (United States); Mahadevan, Arul [Seacoast Cancer Center New Hampshire, Dover, New Hampshire (United States); Kupelian, Patrick A. [Department of Radiation Oncology, University of California Los Angeles Health System, Los Angeles, California (United States)

    2013-09-01

    Purpose: Men with high-risk prostate cancer have other competing causes of mortality; however, current risk stratification schema do not account for comorbidities. We aim to identify the causes of death and factors predictive for mortality in this population. Methods and Materials: A total of 660 patients with high-risk prostate cancer were treated with definitive high-dose external beam radiation therapy (≥74 Gy) and androgen deprivation (AD) between 1996 and 2009 at a single institution. Cox proportional hazards regression analysis was conducted to determine factors predictive of survival. Results: The median radiation dose was 78 Gy, median duration of AD was 6 months, and median follow-up was 74 months. The 10-year overall survival (OS) was 60.6%. Prostate cancer was the leading single cause of death, with 10-year mortality of 14.1% (95% CI 10.7-17.6), compared with other cancers (8.4%, 95% CI 5.7-11.1), cardiovascular disease (7.3%, 95% CI 4.7-9.9), and all other causes (10.4%, 95% CI 7.2-13.6). On multivariate analysis, older age (HR 1.55, P=.002) and Charlson comorbidity index score (CS) ≥1 (HR 2.20, P<.0001) were significant factors predictive of OS, whereas Gleason score, T stage, prostate-specific antigen, duration of AD, radiation dose, smoking history, and body mass index were not. Men younger than 70 years of age with CS = 0 were more likely to die of prostate cancer than any other cause, whereas older men or those with CS ≥1 more commonly suffered non-prostate cancer death. The cumulative incidences of prostate cancer-specific mortality were similar regardless of age or comorbidities (P=.60). Conclusions: Men with high-risk prostate cancer are more likely to die of causes other than prostate cancer, except for the subgroup of men younger than 70 years of age without comorbidities. Only older age and presence of comorbidities significantly predicted for OS, whereas prostate cancer- and treatment-related factors did not.

  1. Prevention of Gynecomastia and Breast Pain Caused by Androgen Deprivation Therapy in Prostate Cancer: Tamoxifen or Radiotherapy?

    Energy Technology Data Exchange (ETDEWEB)

    Arruda Viani, Gustavo, E-mail: gusviani@gmail.com [Department of Radiation Oncology, Marilia Medical School, Marilia, Sao Paulo (Brazil); Bernardes da Silva, Lucas Godoi; Stefano, Eduardo Jose [Department of Radiation Oncology, Marilia Medical School, Marilia, Sao Paulo (Brazil)

    2012-07-15

    Purpose: To determine, in a meta-analysis, whether gynecomastia and breast pain rates in men with prostate cancer treated with androgen deprivation therapy (ADT) are reduced if treated with prophylactic radiotherapy (RT) or tamoxifen (TMX). Methods and Materials: The MEDLINE, EMBASE, CANCERLIT, and Cochrane Library databases, as well as proceedings of annual meetings, were systematically searched to identify randomized, controlled studies comparing RT or TMX with observation for men with prostate cancer using ADT. Results: Six RCTs (three RT trials and three TMX trials, N = 777 patients total) were identified that met the study criteria. Pooled results from these RCTs comparing RT vs. observation showed a significant reduction in the incidence of gynecomastia and breast pain rates in patients treated with RT (odds ratio [OR] = 0.21, 95% confidence interval [CI] = 0.12-0.37, p < 0.0001, and OR = 0.34, 95% CI 0.20-0.57, p < 0.0001, respectively). Use of RT resulted in an absolute risk reduction (ARR) of 29.4% and 19.9%, with a number needed to treat (NNT) of 3.4 and 5 to avoid one case of gynecomastia and breast pain, respectively. Pooled results from trials comparing TMX vs. observation showed a statistical benefit for breast pain and gynecomastia in favor of TMX arms (OR = 0.04, 95% CI = 0.02-0.08, p < 0.0001 and OR = 0.07, 95% CI = 0.0-0.14, p < 0.00001). TMX resulted in an ARR = 64.1% and 47.6%, with an NNT of 1.56 and 2.1 to avoid one case of gynecomastia and breast pain, respectively. Considering adverse effects, TMX was 6 times more adverse effects than RT. Conclusions: Our data have shown that both TMX and RT prevented gynecomastia and breast pain in patients with prostate cancer receiving ADT for prostate cancer. Although TMX was two times more effective in preventing gynecomastia, RT should represent an effective and safe treatment option, to take into account mainly in patients with cardiovascular risk factors or thrombotic diathesis.

  2. Androgen receptor non-nuclear regulation of prostate cancer cell invasion mediated by Src and matriptase.

    Science.gov (United States)

    Zarif, Jelani C; Lamb, Laura E; Schulz, Veronique V; Nollet, Eric A; Miranti, Cindy K

    2015-03-30

    Castration-resistant prostate cancers still depend on nuclear androgen receptor (AR) function despite their lack of dependence on exogenous androgen. Second generation anti-androgen therapies are more efficient at blocking nuclear AR; however resistant tumors still develop. Recent studies indicate Src is highly active in these resistant tumors. By manipulating AR activity in several different prostate cancer cell lines through RNAi, drug treatment, and the use of a nuclear-deficient AR mutant, we demonstrate that androgen acting on cytoplasmic AR rapidly stimulates Src tyrosine kinase via a non-genomic mechanism. Cytoplasmic AR, acting through Src enhances laminin integrin-dependent invasion. Active Matriptase, which cleaves laminin, is elevated within minutes after androgen stimulation, and is subsequently shed into the medium. Matriptase activation and shedding induced by cytoplasmic AR is dependent on Src. Concomitantly, CDCP1/gp140, a Matriptase and Src substrate that controls integrin-based migration, is activated. However, only inhibition of Matriptase, but not CDCP1, suppresses the AR/Src-dependent increase in invasion. Matriptase, present in conditioned medium from AR-stimulated cells, is sufficient to enhance invasion in the absence of androgen. Thus, invasion is stimulated by a rapid but sustained increase in Src activity, mediated non-genomically by cytoplasmic AR, leading to rapid activation and shedding of the laminin protease Matriptase.

  3. Bone marrow suppression caused by whole body electron therapy for mycosis fungoides

    Energy Technology Data Exchange (ETDEWEB)

    Koga, K.; Nishikawa, K.; Kuroki, Y.; Asada, Y.; Sumiyoshi, A.; Ogata, K.; Kusuhara, T.; Watanabe, K. (Miyazaki Medical Coll. (Japan))

    1985-06-01

    A case reported is presented of bone marrow suppression in a 62 year old women, who was given six courses of electron therapy between 1979 and 1982 for mycosis fungoides over the whole body. X-ray contamination in the electron beam is discussed.

  4. Use of acid-suppressive therapy before anti-reflux surgery in 2922 patients

    DEFF Research Database (Denmark)

    Lødrup, A; Pottegård, A; Hallas, J;

    2015-01-01

    inhibitors and H2 -receptor antagonists in the year before anti-reflux surgery. METHODS: A nationwide retrospective study of all patients aged ≥18 undergoing first-time anti-reflux surgery in Denmark during 2000-2012 using data from three different sources: the Danish National Register of Patients......, the Danish National Prescription Register, and the Danish Person Register. RESULTS: The study population thus included 2922 patients (median age: 48 years, 55.7% male). The annual proportion of patients redeeming ≥180 DDD of acid-suppressive therapy increased from 17.0% 5 years before anti-reflux surgery......BACKGROUND: Guidelines recommend that patients with gastro-oesophageal reflux disease are adequately treated with acid-suppressive therapy before undergoing anti-reflux surgery. Little is known of the use of acid-suppressive drugs before anti-reflux surgery. AIM: To determine the use of proton pump...

  5. Evaluation of RU58841 as an anti-androgen in prostate PC3 cells and a topical anti-alopecia agent in the bald scalp of stumptailed macaques.

    Science.gov (United States)

    Pan, H J; Wilding, G; Uno, H; Inui, S; Goldsmith, L; Messing, E; Chang, C

    1998-08-01

    The effect of androgen receptor transcriptional activation by RU58841, a nonsteroidal anti-androgen, was studied in the human prostate cancer PC3 cell line by cotransfection with wild-type androgen receptor (wt AR) and an androgen-responsive reporter (MMTV-ARE-CAT) construct. Anti-and rogens, hydroxyflutamide, and Casodex, and the antiestrogen, genistein, were studied in parallel for comparison with RU58841. The wt AR was activated only by the androgen dihydrotestosterone (DHT). Neither the anti-androgens nor antiestrogen can enhance AR transcriptional activity at 10(-11)-10(-7)M in PC3 cells. Hydroxyflutamide, RU58841, and Casodex, but not genistein, displayed competitively suppressive effects on DHT activation of wt AR. The potency of RU58841 was comparable to that of hydroxyflutamide. From this result, topical application of RU58841, which is considered to be a potential therapy for skin diseases, may induce systemic side effects. However, RU58841, on topical application, revealed a potent increase in density, thickening, and length of hair in the macaque model of androgenetic alopecia, whereas no systemic effects were detected. Together our results suggest that RU58841 may have potent antagonism to the wt AR and could be considered as a topically applied active anti-androgen for the treatment of androgen-dependent skin disorders, such as acne, androgenetic alopecia, and hirsutism.

  6. Laparoscopic gonedectomy in a case of complete androgen insensitivity syndrome

    Directory of Open Access Journals (Sweden)

    G Bhaskararao

    2014-01-01

    Full Text Available Complete Androgen insensitivity syndrome is a disorder of hormone resistance characterized by a female phenotype in an individual with an XY karyotype. The pathogenesis of CAIS involves a defective androgen receptor gene located on X-chromosome at Xq11-12and end organ insensitivity to androgens, although androgen concentrations are appropriate for the age of the patient. There are three major types of androgen insensitivity syndrome: Complete androgen insensitivity syndrome, minimal androgen insensitivity syndrome, and partial androgen insensitivity syndrome. Management of androgen insensitivity syndrome includes multidisciplinary approach and involves gonedectomy to avoid gonadal tumors in later life. Hormone replacement therapy (HRT and psychological support are required in long-term basis.

  7. Antarlides: A New Type of Androgen Receptor (AR) Antagonist that Overcomes Resistance to AR-Targeted Therapy.

    Science.gov (United States)

    Saito, Shun; Fujimaki, Takahiro; Panbangred, Watanalai; Igarashi, Yasuhiro; Imoto, Masaya

    2016-02-18

    Prostate cancer is treated with androgen receptor (AR) antagonists but most patients experience disease progression after long-term treatment with these compounds. Therefore, new AR antagonists are required for patient follow-up treatment. In the course of screening for a new AR antagonist, we isolated the novel compounds antarlides A-E (1-5) from Streptomyces sp. BB47. Antarlides are mutually isomeric with respect to the double bond and have a 22-membered-ring macrocyclic structure. The full stereostructure of 1 was established by chemical modifications, including methanolysis, the Trost method, acetonide formation, and the PGME method. 1-5 inhibited the binding of androgen to ARs in vitro. In addition, 2 inhibited the transcriptional activity of not only wild-type AR but also mutant ARs, which are seen in patients with acquired resistance to clinically used AR antagonists. Therefore, antarlides are a potent new generation of AR antagonists that overcome resistance.

  8. Expanding the therapeutic use of androgens via selective androgen receptor modulators (SARMs).

    Science.gov (United States)

    Gao, Wenqing; Dalton, James T

    2007-03-01

    Selective androgen receptor modulators (SARMs) are a novel class of androgen receptor (AR) ligands that might change the future of androgen therapy dramatically. With improved pharmacokinetic characteristics and tissue-selective pharmacological activities, SARMs are expected to greatly extend the clinical applications of androgens to osteoporosis, muscle wasting, male contraception and diseases of the prostate. Mechanistic studies with currently available SARMs will help to define the contributions of differential tissue distribution, tissue-specific expression of 5alpha-reductase, ligand-specific regulation of gene expression and AR interactions with tissue-specific coactivators to their observed tissue selectivity, and lead to even greater expansion of selective anabolic therapies.

  9. Three linked nomograms for predicting biochemical failure in prostate cancer treated with radiotherapy plus androgen deprivation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Lopez-Torrecilla, Jose [Hospital General Universitario, Servicio Oncologia Radioterapica- ERESA, Valencia (Spain); Boladeras, Anna [Institut Catala d' Oncologia, S.Oncologia Radioterapica, Hospitalet (Spain); Angeles Cabeza, Maria [Hospital Universitario Doce de Octubre, S.Oncologia Radioterapica, Madrid (Spain); Zapatero, Almudena [Hospital Universitario de la Princesa, S.Oncologia Radioterapica, Madrid (Spain); Jove, Josep [Institut Catala d' Oncologia, S.Oncologia Radioterapica, Badalona (Spain); Esteban, Luis M. [Universidad de Zaragoza, Escuela Universitaria Politecnica de La Almunia, Zaragoza (Spain); Henriquez, Ivan [Hospital Universitari Sant Joan de Reus, S.Oncologia Radioterapica, Reus (Spain); Casana, Manuel; Mengual, Jose Luis [Fundacion Instituto Valenciano de Oncologia, S.Oncologia Radioterapica, Valencia (Spain); Gonzalez-San Segundo, Carmen [Hospital Universitario Gregorio Maranon, S.Oncologia Radioterapica, Madrid (Spain); Gomez-Caamano, Antonio [Hospital Clinico Universitario de Santiago, S.Oncologia Radioterapica, Santiago de Compostela (Spain); Hervas, Asuncion [Hospital Universitario Ramon y Cajal, S.Oncologia Radioterapica, Madrid (Spain); Munoz, Julia Luisa [Hospital Infanta Cristina, S.Oncologia Radioterapica, Badajoz (Spain); Sanz, Gerardo [Universidad de Zaragoza, Departamento de Metodos Estadisticos, Zaragoza (Spain)

    2015-10-15

    Nomograms were established to predict biochemical recurrence (BCR) after radiotherapy (RT) with a low weight of the characteristic variables of RT and androgen deprivation therapy (ADT). Our aim is to provide a new stratified tool for predicting BCR at 4 and 7 years in patients treated using RT with radical intent. A retrospective, nonrandomized analysis was performed on 5044 prostate cancer (PCa) patients with median age 70 years, who received RT - with or without ADT - between November 1992 and May 2007. Median follow-up was 5.5 years. BCR was defined as a rise in serum prostate-specific antigen (PSA) of 2 ng/ml over the post-treatment PSA nadir. Univariate association between predictor variables and BCR was assessed by the log-rank test, and three linked nomograms were created for multivariate prognosis of BCR-free survival. Each nomogram corresponds to a category of the Gleason score - either 6,7, or 8-10 - and all of them were created from a single proportional hazards regression model stratified also by months of ADT (0, 1-6, 7-12, 13-24, 25-36, 36-60). The performance of this model was analyzed by calibration, discrimination, and clinical utility. Initial PSA, clinical stage, and RT dose were significant variables (p < 0.01). The model showed a good calibration. The concordance probability was 0.779, improving those obtained with other nomograms (0.587, 0.571, 0.554) in the database. Survival curves showed best clinical utility in a comparison with National Comprehensive Cancer Network (NCCN) risk groups. For each Gleason score category, the nomogram provides information on the benefit of adding ADT to a specific RT dose. (orig.) [German] Es wurden Nomogramme etabliert, um ein biochemisches Rezidiv (BCR) nach einer Strahlentherapie (RT) vorhersagen zu koennen und den Einfluss der charakteristischen Variablen der RT und der Androgendeprivationstherapie (ADT) dabei moeglichst gering zu halten. Unser Ziel ist es, ein neues stratifiziertes Instrument

  10. Is the detection rate of 18F-choline PET/CT influenced by androgen-deprivation therapy?

    Energy Technology Data Exchange (ETDEWEB)

    Chondrogiannis, Sotirios; Marzola, Maria Cristina; Grassetto, Gaia; Maffione, Anna Margherita; Rampin, Lucia; Rubello, Domenico [' ' Santa Maria della Misericordia' ' Hospital, Rovigo (Italy). PET/CT Centre; Ferretti, Alice [' ' San Giacomo Apostolo' ' Hospital, Castelfranco Veneto, Treviso (Italy). Service of Medical Physics; Fanti, Stefano [Azienda Ospedaliero-Univ. Policlinico S. Orsola-Malpighi, Bologna (Italy). Dept. of Nuclear Medicine; Giammarile, Francesco [Lyon 1 Univ. Centre Hospitalier Lyon Sud Biophysique, Villeurbanne (Italy). Dept. of Nuclear Medicine

    2014-07-15

    To evaluate if the detection rate (DR) of {sup 18}F-choline (18F-CH) PET/CT is influenced by androgen-deprivation therapy (ADT) in patients with prostate cancer (PC) already treated with radical intent and presenting biochemical relapse. We have retrospectively evaluated {sup 18}F-CH PET/CT scans of 325 consecutive PC patients enrolled in the period November 2009 to December 2012 previously treated with radical intent and referred to our centre to perform {sup 18}F-CH PET/CT for biochemical relapse. Two different groups of patients were evaluated. group A included the whole sample of 325 patients (mean age 70 years, range: 49-86) who presented trigger PSA between 0.1 and 80 ng/ml (mean 5.5 ng/ml), and group B included 187 patients (mean age 70 years, range 49-86) with medium-low levels of trigger PSA ranging between 0.5 and 5 ng/ml (mean PSA 2.1 ng/ml); group B was chosen in order to obtain a more homogeneous group of patients in terms of PSA values also excluding both very low and very high PSA levels avoiding the ''a priori'' higher probability of negative or positive PET scan, respectively. At the time of examination, 139 patients from group A and 72 patients from group B were under ADT: these patients were considered to be hormone-resistant PC patients because from their oncologic history (>18 months) an increase of PSA levels emerged despite the ongoing ADT. The relationship between {sup 18}F-CH PET/CT findings and possible clinical predictors was investigated using both univariate and multivariate binary logistic regression analyses, including trigger PSA and ADT. Considering the whole population, overall DR of {sup 18}F-CH PET was 58.2 % (189/325 patients). In the whole sample of patients (group A), both at the univariate and multivariate logistic regression analysis, trigger PSA and ADT were significantly correlated with the DR of {sup 18}F-CH PET (p < 0.05). Moreover, the DR in patients under ADT (mean PSA 7.8 ng/ml) was higher than in

  11. Discovery and therapeutic promise of selective androgen receptor modulators.

    Science.gov (United States)

    Chen, Jiyun; Kim, Juhyun; Dalton, James T

    2005-06-01

    Androgens are essential for male development and the maintenance of male secondary characteristics, such as bone mass, muscle mass, body composition, and spermatogenesis. The main disadvantages of steroidal androgens are their undesirable physicochemical and pharmacokinetic properties. The recent discovery of nonsteroidal selective androgen receptor modulators (SARMs) provides a promising alternative for testosterone replacement therapies with advantages including oral bioavailability, flexibility of structural modification, androgen receptor specificity, tissue selectivity, and the lack of steroid-related side effects.

  12. Group-based exercise in daily clinical practice to improve physical fitness in men with prostate cancer undergoing androgen deprivation therapy

    DEFF Research Database (Denmark)

    Østergren, Peter; Ragle, Anne-Mette; Jakobsen, Henrik

    2016-01-01

    . This article describes the design of an ongoing prospective observational study to evaluate the potential benefits of exercise in daily clinical practice. METHODS AND ANALYSIS: Men diagnosed with prostate cancer starting or already receiving ADT at our facility are invited to participate in a 12-week exercise......INTRODUCTION: Level 1 evidence supports the use of supervised exercise to mitigate the adverse effects of androgen deprivation therapy (ADT) in men with prostate cancer. The data, however, have been generated in controlled research settings and might not be transferable to daily clinical practice...... programme implemented as the standard of care. Exclusion criteria are opioid-demanding treatment for skeletal pain, an Eastern Cooperative Oncology Group (ECOG) performance status above 2 or the inability to perform floor and machine exercises independently. The intervention consists of an initial...

  13. Efficacy of recreational football on bone health, body composition, and physical functioning in men with prostate cancer undergoing androgen deprivation therapy

    DEFF Research Database (Denmark)

    Uth, J.; Hornstrup, T.; Christensen, J. F.

    2016-01-01

    Androgen deprivation therapy (ADT) for prostate cancer (PCa) impairs musculoskeletal health. We evaluated the efficacy of 32-week football training on bone mineral density (BMD) and physical functioning in men undergoing ADT for PCa. Football training improved the femoral shaft and total hip BMD...... and physical functioning parameters compared to control. INTRODUCTION: ADT is a mainstay in PCa management. Side effects include decreased bone and muscle strength and increased fracture rates. The purpose of the present study was to evaluate the effects of 32 weeks of football training on BMD, bone turnover...... markers (BTMs), body composition, and physical functioning in men with PCa undergoing ADT. METHODS: Men receiving ADT >6 months (n = 57) were randomly allocated to a football training group (FTG) (n = 29) practising 2-3 times per week for 45-60 min or to a standard care control group (CON) (n = 28) for 32...

  14. Up-regulation of insulin-like growth factor-binding protein 3 by 5-fluorouracil (5-FU) leads to the potent anti-proliferative effect of androgen deprivation therapy combined with 5-FU in human prostate cancer cell lines.

    Science.gov (United States)

    Kawabata, Rumi; Oie, Shinji; Takahashi, Masayuki; Kanayama, Hiroomi; Oka, Toshinori; Itoh, Kohji

    2011-06-01

    In this study, we investigated the synergistic mechanism of anti-androgen and 5-fluorouracil (5-FU) combination therapy against castration-resistant prostate cancer (CRPC). Four prostate cancer cell lines, LNCaP, 22Rv1, DU145 and PC3, were examined for their growth dependency on androgens and the insulin-like growth factor 1 (IGF1). We assessed the expression changes of certain growth factor receptors and regulating proteins when treated with 5-FU, and found that 5-FU increased the expression of the IGF-binding protein 3 (IGFBP3). Furthermore, 5-FU inhibited the phosphorylation of Akt and p70 S6K, while the knockdown of IGFBP3 reduced the levels of poly (ADP-ribose) polymerase cleaved by 5-FU in PC3 cells. Therefore, the up-regulation of IGFBP3 by 5-FU not only inhibits cell growth by reducing the IGF1 signal but also induces apoptosis in PC3 cells. The synergistic effect of bicalutamide and 5-FU on 22Rv1 cells was reduced by IGFBP3 gene silencing using small-interfering RNA. These results suggest that the up-regulation of IGFBP3 induced by 5-FU plays an important role in the potent anti-tumor effect of 5-FU combined with anti-androgens on CRPC. Androgen-deprivation therapy combined with 5-FU could therefore be an appropriate therapy for CRPC patients.

  15. Labda-8(17),12,14-trien-19-oic acid contained in fruits of Cupressus sempervirens suppresses benign prostatic hyperplasia in rat and in vitro human models through inhibition of androgen and STAT-3 signaling.

    Science.gov (United States)

    Verma, Vikas; Sharma, Vikas; Singh, Vishal; Kumar, Rajeev; Khan, Mohammad F; Singh, Anil K; Sharma, Rolee; Arya, Kamal R; Maikhuri, J P; Dalela, Diwakar; Maurya, Rakesh; Gupta, Gopal

    2014-08-01

    Fruit extract of Cupressus sempervirens (CS), which is used traditionally to treat Benign Prostatic Hyperplasia (BPH)-like urinary symptoms in patients, was scientifically validated for anti-BPH activity. The ethanolic fruit extract of CS inhibited proliferation of human BPH-stromal cells and the activity was localized to its chloroform-soluble, diterpene-rich fraction. Eight major diterpenes isolated from this fraction exhibited moderate to potent activity and the most active diterpene (labda-8(17),12,14-trien-19-oic acid) exhibited an IC50 of 37.5 μM (antiproliferative activity against human BPH-stromal cells). It significantly inhibited activation (phosphorylation) of Stat-3 in BPH-stromal cells and prevented transactivation of androgen sensitive KLK3/PSA and TMPRSS2 genes in LNCaP cells. Labda-8(17),12,14-trien-19-oic acid-rich CS fraction prevented prostatic hyperplasia in rat model and caused TUNEL labeling of stromal cells with lower expressions of IGF-I, TGF-ß and PCNA, and bcl-2/bax ratio. Human BPH tissues exhibited precise lowering of stromal component after incubation in labda-8(17),12,14-trien-19-oic acid, ex vivo. We conclude that labda-8(17),12,14-trien-19-oic acid contained in CS exhibits anti-BPH activity through inhibition of stromal proliferation and suppression of androgen action in the prostate, presenting a unique lead structure for further optimization of anti-BPH activity.

  16. Acid suppression therapy does not predispose to Clostridium difficile infection: the case of the potential bias.

    Directory of Open Access Journals (Sweden)

    Lena Novack

    Full Text Available OBJECTIVE: An adverse effect of acid-suppression medications on the occurrence of Clostridium difficile infection (CDI has been a common finding of many, but not all studies. We hypothesized that association between acid-suppression medications and CDI is due to the residual confounding in comparison between patients with infection to those without, predominantly from non-tested and less sick subjects. We aimed to evaluate the effect of acid suppression therapy on incidence of CDI by comparing patients with CDI to two control groups: not tested patients and patients suspected of having CDI, but with a negative test. METHODS: We conducted a case-control study of adult patients hospitalized in internal medicine department of tertiary teaching hospital between 2005-2010 for at least three days. Controls from each of two groups (negative for CDI and non-tested were individually matched (1:1 to cases by primary diagnosis, Charlson comorbidity index, year of hospitalization and gender. Primary outcomes were diagnoses of International Classification of Diseases (ICD-9-coded CDI occurring 72 hours or more after admission. RESULTS: Patients with CDI were similar to controls with a negative test, while controls without CDI testing had lower clinical severity. In multivariable analysis, treatment by acid suppression medications was associated with CDI compared to those who were not tested (OR = 1.88, p-value = 0.032. Conversely, use of acid suppression medications in those who tested negative for the infection was not associated with CDI risk as compared to the cases (OR = 0.66; p = 0.059. CONCLUSIONS: These findings suggest that the reported epidemiologic associations between use of acid suppression medications and CDI risk may be spurious. The control group choice has an important impact on the results. Clinical differences between the patients with CDI and those not tested and not suspected of having the infection may explain the different conclusions

  17. Nrf1 and Nrf2 transcription factors regulate androgen receptor transactivation in prostate cancer cells.

    Directory of Open Access Journals (Sweden)

    Michelle A Schultz

    Full Text Available Despite androgen deprivation therapy (ADT, persistent androgen receptor (AR signaling enables outgrowth of castration resistant prostate cancer (CRPC. In prostate cancer (PCa cells, ADT may enhance AR activity through induction of oxidative stress. Herein, we investigated the roles of Nrf1 and Nrf2, transcription factors that regulate antioxidant gene expression, on hormone-mediated AR transactivation using a syngeneic in vitro model of androgen dependent (LNCaP and castration resistant (C4-2B PCa cells. Dihydrotestosterone (DHT stimulated transactivation of the androgen response element (ARE was significantly greater in C4-2B cells than in LNCaP cells. DHT-induced AR transactivation was coupled with higher nuclear translocation of p65-Nrf1 in C4-2B cells, as compared to LNCaP cells. Conversely, DHT stimulation suppressed total Nrf2 levels in C4-2B cells but elevated total Nrf2 levels in LNCaP cells. Interestingly, siRNA mediated silencing of Nrf1 attenuated AR transactivation while p65-Nrf1 overexpression enhanced AR transactivation. Subsequent studies showed that Nrf1 physically interacts with AR and enhances AR's DNA-binding activity, suggesting that the p65-Nrf1 isoform is a potential AR coactivator. In contrast, Nrf2 suppressed AR-mediated transactivation by stimulating the nuclear accumulation of the p120-Nrf1 which suppressed AR transactivation. Quantitative RT-PCR studies further validated the inductive effects of p65-Nrf1 isoform on the androgen regulated genes, PSA and TMPRSS2. Therefore, our findings implicate differential roles of Nrf1 and Nrf2 in regulating AR transactivation in PCa cells. Our findings also indicate that the DHT-stimulated increase in p65-Nrf1 and the simultaneous suppression of both Nrf2 and p120-Nrf1 ultimately facilitates AR transactivation in CRPC cells.

  18. Complete androgen insensitivity syndrome

    Directory of Open Access Journals (Sweden)

    Tančić-Gajić Milina

    2015-01-01

    Full Text Available Introduction. Androgen insensitivity syndrome (AIS belongs to disorders of sex development, resulting from complete or partial resistance to the biological actions of androgens in persons who are genetically males (XY with normally developed testes and age-appropriate for males of serum testosterone concentration. Case Outline. A 21-year-old female patient was admitted at our Clinic further evaluation and treatment of testicular feminization syndrome, which was diagnosed at the age of 16 years. The patient had never menstruated. On physical examination, her external genitalia and breast development appeared as completely normal feminine structures but pubic and axillary hair was absent. Cytogenetic analysis showed a 46 XY karyotype. The values of sex hormones were as in adult males. The multisliced computed tomography (MSCT showed structures on both sides of the pelvic region, suggestive of testes. Bilateral orchiectomy was performed. Hormone replacement therapy was prescribed after gonadectomy. Vaginal dilatation was advised to avoid dyspareunia. Conclusion. The diagnosis of complete androgen insensitivity is based on clinical findigs, hormonal analysis karyotype, visualization methods and genetic analysis. Bilateral gonadectomy is generally recommended in early adulthood to avoid the risk of testicular malignancy. Vaginal length may be short requiring dilatation in an effort to avoid dyspareunia. Vaginal surgery is rarely indicated for the creation of a functional vagina. [Projekat Ministarstva nauke Republike Srbije, br. 175067

  19. The selection of hormonal therapy in prostate cancer: who, when, and for how long?

    Science.gov (United States)

    Ryan, Charles J; Small, Eric J

    2004-05-01

    Androgen deprivation is the foundation for the systemic therapy of advanced prostate cancer. Multiple trials have tested combined androgen blockade versus androgen deprivation alone in patients with advanced disease. These studies suggest a slight advantage to the combined approaches that contain flutamide and bicalutamide, but the lack of dramatic differences in outcome makes monotherapy reasonable, especially in patients with more indolent disease. Intermittent androgen deprivation is an alternative that may allow patients to reduce the total time on androgen suppression as well as possibly delay the onset of androgen independence. A number of secondary hormonal therapies, including deferred and secondary antiandrogens, ketoconazole, and estrogens have shown modest response proportions. Patients with less advanced disease such as a rising prostate-specific antigen have varied outcomes, and no standard approach exists. In this group, noncastrating forms of hormonal therapy are being evaluated. Patients undergoing definitive local therapy who have high-risk features may benefit from early, as opposed to deferred, androgen deprivation. This review examines the evidence for the current state of the art in hormonal therapy in patients with prostate cancer and focuses, in particular, on treatment composition and timing as well as the rationale for the use of hormonal therapy in early stage disease.

  20. A qualitative study evaluating experiences of a lifestyle intervention in men with prostate cancer undergoing androgen suppression therapy

    OpenAIRE

    Bourke, Liam; Sohanpal, Ratna; Nanton, Veronica; Crank, Helen; Rosario, Derek J.; Saxton, John

    2012-01-01

    Abstract Background The severe iatrogenic hypogonadal state induced by medical castration used for treatment of prostate cancer is associated with adverse effects including fatigue, increased fracture risk, and a decrease in skeletal muscle function, which negatively impact quality of life. We have previously reported beneficial changes in healthy lifestyle behaviors, physical function and fatigue as a result of a novel combined exercise and dietary advice intervention (a lifestyle interventi...

  1. Androgen and bone mass in men

    Institute of Scientific and Technical Information of China (English)

    AnnieW.C.Kung

    2003-01-01

    Androgens have multiple actions on the skeleton throughout life. Androgens promote skeletal growth and accumulation of minerals during puberty and adolescence and stimulate osteoblast but suppress osteoclast function,activity and lifespan through complex mechanisms. Also androgens increase periosteal bone apposition, resulting in larger bone size and thicker cortical bone in men. There is convincing evidence to show that aromatization to estrogens was an important pathway for mediating the action of testosterone on bone physiology. Estrogen is probably the dominant sex steroid regulating bone resorption in men, but both testosterone and estrogen are important in maintaining bone formation. ( Asian J Androl 2003 Jun; 5: 148-154)

  2. Relation of androgen receptor gene polymorphism to bone mineral density and fracture risk in early postmenopausal women during a 5-year randomized hormone replacement therapy trial.

    Science.gov (United States)

    Salmén, Timo; Heikkinen, Anna-Mari; Mahonen, Anitta; Kröger, Heikki; Komulainen, Marja; Pallonen, Heli; Saarikoski, Seppo; Honkanen, Risto; Mäenpää, Pekka H

    2003-02-01

    In women, the influence of androgens on bone health is not clear. It has been suggested that the androgen receptor (AR) genotype is associated with bone mineral density and serum androgen levels in pre- and perimenopausal women, but the association between AR genotype, bone mineral density, and fracture risk has not been studied in postmenopausal women. Therefore, we studied whether AR polymorphism affects bone mineral density, bone mineral density change, or fracture risk in a 5-year randomized hormone replacement therapy (HRT) trial on 331 early postmenopausal women (mean baseline age, 52.7 +/- 2.3 years). The participants consisted of two treatment groups: the HRT group (n = 151) received a sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate with or without vitamin D3, 100-300 IU + 93 mg calcium as lactate/day, and the non-HRT group (n = 180) received 93 mg calcium alone or in combination with vitamin D3, 100-300 IU/day for 5 years. Bone mineral density was measured from lumbar spine and proximal femur (DXA) before and after the 5-year trial. All new symptomatic, radiographically defined fractures were recorded during the follow-up. The length of CAG repeat in exon 1 of AR gene was evaluated after polymerase chain reaction (PCR) amplification. The subjects were divided into three repeat groups according to AR alleles. None of the baseline characteristics were associated with AR gene polymorphism and HRT treatment. The polymorphism did not influence the calculated annual changes of lumbar or femoral neck bone mineral density during the 5-year follow-up in the HRT (p = 0.926 and 0.146, respectively) or non-HRT (p = 0.818 and 0.917, respectively) groups. In all, 28 women sustained 33 fractures during the follow-up. Thus, the numbers of fractures were limited. The AR repeat length variation was not significantly associated with fracture risk in the HRT or non-HRT groups (p = 0.632 and 0.459, respectively; Cox proportional hazards model

  3. Androgen-mediated regulation of skeletal muscle protein balance.

    Science.gov (United States)

    Rossetti, Michael L; Steiner, Jennifer L; Gordon, Bradley S

    2017-02-22

    Androgens significantly alter muscle mass in part by shifting protein balance in favor of net protein accretion. During various atrophic conditions, the clinical impact of decreased production or bioavailability of androgens (termed hypogonadism) is important as a loss of muscle mass is intimately linked with survival outcome. While androgen replacement therapy increases muscle mass in part by restoring protein balance, this is not a comprehensive treatment option due to potential side effects. Therefore, an understanding of the mechanisms by which androgens alter protein balance is needed for the development of androgen-independent therapies. While the data in humans suggest androgens alter protein balance (both synthesis and breakdown) in the fasted metabolic state, a predominant molecular mechanism(s) behind this observation is still lacking. This failure is likely due in part to inconsistent experimental design between studies including failure to control nutrient/feeding status, the method of altering androgens, and the model systems utilized.

  4. A phase II trial of docetaxel and erlotinib as first-line therapy for elderly patients with androgen-independent prostate cancer

    Directory of Open Access Journals (Sweden)

    Green Erica

    2007-07-01

    Full Text Available Abstract Background Docetaxel is the standard first-line agent for the treatment of androgen-independent prostate cancer (AIPC. The combination of docetaxel with molecularly targeted therapies may offer the potential to increase the efficacy and decrease the toxicity of cytotoxic chemotherapy for prostate cancer. Previous studies demonstrate activation of the human epidermal growth factor receptor (EGFR in prostate cancer. Erlotinib is a specific inhibitor of the tyrosine-kinase activity of EGFR. The goal of this study is to determine the anti-cancer activity docetaxel combined with erlotinib for the treatment of elderly subjects with AIPC. Methods This is a multi-institutional Phase II study in patients with histologically confirmed adenocarcinoma of the prostate and age ≥ 65 years. Patients were requred to have progressive disease despite androgen-deprivation therapy as determined by: (1 measurable lesions on cross-sectional imaging; (2 metastatic disease by radionucleotide bone imaging; or (3 elevated prostate specific antigen (PSA. Treatment cycles consisted of docetaxel 60 mg/m2 IV on day 1 and erlotinib 150 mg PO days 1–21. Patients with responding or stable disease after 9 cycles were eligible to continue on erlotinib alone as maintenance therapy. Results Characteristics of 22 patients enrolled included: median age 73.5 years (range, 65–80; median Karnofsky Performance Status 90 (range 70–100; median hemoglobin 12.1 g/dl (range, 10.0–14.3; median PSA 218.3 ng/ml (range, 9–5754. A median of 6 treatment cycles were delivered per patient (range 1–17. No objective responses were observed in 8 patients with measurable lesions (0%, 95% CI 0–31%. Bone scan improvement and PSA decline was seen in 1 patient (5%, 95% CI 0.1–25%. Five of 22 patients experienced ≥ 50 % decline in PSA (23%, 95% CI 8–45%. Hematologic toxicity included grade 3 neutropenia in 9 patients and neutropenic fever in 2 patients. Common non

  5. Outcome of patients over 80 years of age on prolonged suppressive antibiotic therapy for at least 6 months for prosthetic joint infection

    Directory of Open Access Journals (Sweden)

    Virginie Prendki

    2014-12-01

    Conclusions: Prolonged suppressive antibiotic therapy is an alternative therapy in elderly patients with PJI when surgery is contraindicated and when the bacteria are susceptible to well-tolerated oral antimicrobial therapy such as beta-lactams.

  6. Prostate cancer: assessing the effects of androgen-deprivation therapy using quantitative diffusion-weighted and dynamic contrast-enhanced MRI

    Energy Technology Data Exchange (ETDEWEB)

    Hoetker, Andreas M. [Memorial Sloan-Kettering Cancer Center, Department of Radiology, New York, NY (United States); Universitaetsmedizin Mainz, Department of Diagnostic and Interventional Radiology, Mainz (Germany); Mazaheri, Yousef [Memorial Sloan-Kettering Cancer Center, Department of Medical Physics, New York, NY (United States); Zheng, Junting; Moskowitz, Chaya S. [Memorial Sloan-Kettering Cancer Center, Department of Epidemiology and Biostatistics, New York, NY (United States); Berkowitz, Joshua; Pei, Xin; Zelefsky, Michael J. [Memorial Sloan-Kettering Cancer Center, Department of Radiation Oncology, New York, NY (United States); Lantos, Joshua E.; Hricak, Hedvig; Akin, Oguz [Memorial Sloan-Kettering Cancer Center, Department of Radiology, New York, NY (United States)

    2015-09-15

    To investigate the effects of androgen-deprivation therapy (ADT) on MRI parameters and evaluate their associations with treatment response measures. The study included 30 men with histopathologically confirmed prostate cancer who underwent MRI before and after initiation of ADT. Thirty-four tumours were volumetrically assessed on DW-MRI (n = 32) and DCE-MRI (n = 18), along with regions of interest in benign prostatic tissue, to calculate apparent diffusion coefficient (ADC) and transfer constant (K{sup trans}) values. Changes in MRI parameters and correlations with clinical parameters (change in prostate-specific antigen [PSA], treatment duration, PSA nadir) were assessed. Prostate volume and PSA values decreased significantly with therapy (p < 0.001). ADC values increased significantly in tumours and decreased in benign prostatic tissue (p < 0.05). Relative changes in ADC and absolute post-therapeutic ADC values differed significantly between tumour and benign tissue (p < 0.001). K{sup trans} decreased significantly only in tumours (p < 0.001); relative K{sup trans} changes and post-therapeutic values were not significantly different between tumour and benign tissue. The relative change in tumour ADC correlated significantly with PSA decrease. No changes were associated with treatment duration or PSA nadir. Multi-parametric MRI shows significant measurable changes in tumour and benign prostate caused by ADT and may help in monitoring treatment response. (orig.)

  7. Androgen receptor gene mutation, rearrangement, polymorphism.

    Science.gov (United States)

    Eisermann, Kurtis; Wang, Dan; Jing, Yifeng; Pascal, Laura E; Wang, Zhou

    2013-09-01

    Genetic aberrations of the androgen receptor (AR) caused by mutations, rearrangements, and polymorphisms result in a mutant receptor that has varied functions compared to wild type AR. To date, over 1,000 mutations have been reported in the AR with most of these being associated with androgen insensitivity syndrome (AIS). While mutations of AR associated with prostate cancer occur less often in early stage localized disease, mutations in castration-resistant prostate cancer (CRPC) patients treated with anti-androgens occur more frequently with 10-30% of these patients having some form of mutation in the AR. Resistance to anti-androgen therapy usually results from gain-of-function mutations in the LBD such as is seen with bicalutamide and more recently with enzalutamide (MDV3100). Thus, it is crucial to investigate these new AR mutations arising from drug resistance to anti-androgens and other small molecule pharmacological agents.

  8. The prognostic value of expression of HIF1α, EGFR and VEGF-A, in localized prostate cancer for intermediate- and high-risk patients treated with radiation therapy with or without androgen deprivation therapy

    Directory of Open Access Journals (Sweden)

    Weber Damien C

    2012-04-01

    Full Text Available Abstract Purpose Androgens stimulate the production of hypoxia-inducible factor (HIF1α and ultimately vascular endothelial growth factor (VEGF-A. Additionally, epithelial growth factor (EGF mediates HIF1α production. Carbonic anhydrase IX (CAIX expression is associated with tumor cell hypoxia in a variety of malignancies. This study assesses the prognostic relation between HIF1α, VEGF-A, EGF Receptor and CAIX expression by immunochemistry in diagnostic samples of patients with intermediate- and high-risk localized prostate cancer treated with radiation therapy, with or without androgen deprivation therapy (ADT. Materials and methods Between 1994 and 2004, 103 prostate cancer patients (mean age, 68.7 ± 6.2, with prostate cancer (mean PSA, 13.3 ± 3.7, were treated with radiation therapy (RT, median dose, 74 Gy. Fifty seven (55.3% patients received ADT (median duration, 6 months; range, 0 – 24. Median follow-up was 97.6 months (range, 5.9 – 206.8. Results Higher EGFR expression was significantly (p = 0.04 correlated with higher Gleason scores. On univariate analysis, HIF1α nuclear expression was a significant (p = 0.02 prognostic factor for biological progression-free survival (bPFS. A trend towards significance (p = 0.05 was observed with EGFR expression and bPFS. On multivariate analysis, low HIF1α nuclear (p = 0.01 and high EGFR (p = 0.04 expression remained significant adverse prognostic factors. Conclusions Our study suggests that high nuclear expression of HIF1α and low EGFR expression in diagnostic biopsies of prostate cancer patients treated with RT ± ADT is associated with a good prognosis.

  9. Transcriptional network of androgen receptor in prostate cancer progression.

    Science.gov (United States)

    Takayama, Ken-ichi; Inoue, Satoshi

    2013-08-01

    The androgen receptor belongs to the nuclear receptor superfamily and functions as a ligand-dependent transcription factor. It binds to the androgen responsive element and recruits coregulatory factors to modulate gene transcription. In addition, the androgen receptor interacts with other transcription factors, such as forkhead box A1, and other oncogenic signaling pathway molecules that bind deoxyribonucleic acid and regulate transcription. Androgen receptor signaling plays an important role in the development of prostate cancer. Prostate cancer cells proliferate in an androgen-dependent manner, and androgen receptor blockade is effective in prostate cancer therapy. However, patients often progress to castration-resistant prostate cancer with elevated androgen receptor expression and hypersensitivity to androgen. Recently, comprehensive analysis tools, such as complementary DNA microarray, chromatin immunoprecipitation-on-chip and chromatin immunoprecipitation-sequence, have described the androgen-mediated diverse transcriptional program and gene networks in prostate cancer. Furthermore, functional and clinical studies have shown that some of the androgen receptor-regulated genes could be prognostic markers and potential therapeutic targets for the treatment of prostate cancer, particularly castration-resistant prostate cancer. Thus, identifying androgen receptor downstream signaling events and investigating the regulation of androgen receptor activity is critical for understanding the mechanism of carcinogenesis and progression to castration-resistant prostate cancer.

  10. Evaluation of primary androgen deprivation therapy in prostate cancer patients using the J-CAPRA risk score

    Directory of Open Access Journals (Sweden)

    Hideyuki Akaza

    2013-06-01

    Conclusions: Based on large-scale registry data, this report is the first to analyze the outcomes of MAB therapy in patients with prostate cancer at a wide range of disease stages. MAB therapy may provide significant survival benefits in intermediate- and high-risk patients.

  11. Anti-coreceptor therapy drives selective T cell egress by suppressing inflammation-dependent chemotactic cues

    Science.gov (United States)

    Martin, Aaron J.; Clark, Matthew; Gojanovich, Gregory; Manzoor, Fatima; Miller, Keith; Kline, Douglas E.; Morillon, Y. Maurice; Wang, Bo

    2016-01-01

    There continues to be a need for immunotherapies to treat type 1 diabetes in the clinic. We previously reported that nondepleting anti-CD4 and -CD8 Ab treatment effectively reverses diabetes in new-onset NOD mice. A key feature of the induction of remission is the egress of the majority of islet-resident T cells. How this occurs is undefined. Herein, the effects of coreceptor therapy on islet T cell retention were investigated. Bivalent Ab binding to CD4 and CD8 blocked TCR signaling and T cell cytokine production, while indirectly downregulating islet chemokine expression. These processes were required for T cell retention, as ectopic IFN-γ or CXCL10 inhibited Ab-mediated T cell purging. Importantly, treatment of humanized mice with nondepleting anti–human CD4 and CD8 Ab similarly reduced tissue-infiltrating human CD4+ and CD8+ T cells. These findings demonstrate that Ab binding of CD4 and CD8 interrupts a feed-forward circuit by suppressing T cell–produced cytokines needed for expression of chemotactic cues, leading to rapid T cell egress from the islets. Coreceptor therapy therefore offers a robust approach to suppress T cell–mediated pathology by purging T cells in an inflammation-dependent manner.

  12. Postmenopausal serum androgens, oestrogens and breast cancer risk: the European prospective investigation into cancer and nutrition

    NARCIS (Netherlands)

    Kaaks, R.; Rinaldi, S.; Key, T.J.; Berrino, F.; Peeters, P.H.M.; Biessy, C.; Dossus, L.; Lukanova, A.; Bingham, S.; Khaw, K-T.; Allen, N.E.; Bueno-de-Mesquita, H.B.; Gils, C.H. van; Grobbee, D.E.; Boeing, H.; Lahmann, P.H.; Nagel, G.; Chang-Claude, J.; Clavel-Chapelon, F.; Fournier, A.; Thiébaut, A.; Gonzalez, C.A.; Quirós, J.R.; Tormo, M-J.; Ardanaz, E.; Amiano, P.; Krogh, V.; Palli, D.; Panico, S.; Tumino, R.; Vineis, P.; Trichopoulou, A.; Kalapothaki, V.; Trichopoulos, D.; Ferrari, P.; Norat, T.; Saracci, R.; Riboli, E.

    2005-01-01

    Considerable experimental and epidemiological evidence suggests that elevated endogenous sex steroids — notably androgens and oestrogens — promote breast tumour development. In spite of this evidence, postmenopausal androgen replacement therapy with dehydroepiandrosterone (DHEA) or testosterone has

  13. Postmenopausal serum androgens, oestrogens and breast cancer risk : the European prospective investigation into cancer and nutrition

    NARCIS (Netherlands)

    Kaaks, R; Rinaldi, S; Key, TJ; Berrino, F; Peeters, PHM; Biessy, C; Dossus, L; Lukanova, A; Binghan, S; Khaw, KTG; Allen, NE; Bueno-De-Mesquita, HB; van Gils, CH; Grobbee, D; Boeing, H; Lahmann, PH; Nagel, G; Chang-Claude, J; Clavel-Chapelon, F; Fournier, A; Thiebaut, A; Gonzalez, CA; Quiros, [No Value; Tormo, MJ; Ardanaz, E; Amiano, P; Krogh, [No Value; Palli, D; Panico, S; Tumino, R; Vineis, P; Trichopoulou, A; Kalapothaki, [No Value; Trichopoulos, D; Ferrari, P; Norat, T; Saracci, R; Riboli, E

    2005-01-01

    Considerable experimental and epidemiological evidence suggests that elevated endogenous sex steroids - notably androgens and oestrogens - promote breast tumour development. In spite of this evidence, postmenopausal androgen replacement therapy with dehydroepiandrosterone (DHEA) or testosterone has

  14. Abiraterone acetate for prostate cancer: a new era of hormonal therapies

    Institute of Scientific and Technical Information of China (English)

    Emmanuel S Antonarakis

    2011-01-01

    @@ Therapies targeting the androgen receptor (AR) axis have constituted the Holy Grail in the management of advanced prostate cancer for seven decades.1 These hormonal therapies have traditionally taken two main forms: those that suppress gonadal androgen synthesis (e.g.,the gonadotropin releasing hormone agonists/antagonists,such as leuprolide),and those that inhibit the AR directly (e.g.,the anti-androgens,such asbicalutamide).However,although the vast majority of patients with prostate cancer initially respond favorably to androgen-ablative therapies (manifested by tumor regressions and symptomatic improvements),all patients will eventually develop further disease progression after a median of 18-24 months.This transformed disease state,known as castration-resistant prostate cancer (CRPC),is invariably fatal.

  15. Dehydroepiandrosterone substitution in female adrenal failure: no impact on endothelial function and cardiovascular parameters despite normalization of androgen status

    DEFF Research Database (Denmark)

    Christiansen, Jens Juel; Andersen, Niels Holmark; Sørensen, Keld E;

    2007-01-01

    BACKGROUND: Female adrenal insufficiency implicates reduced production of the adrenal androgen precursor dehydroepiandrosterone (DHEA) and low androgen levels. Oral DHEA restores androgen deficit but the clinical implications and safety of substitution therapy is uncertain. A putative DHEA receptor...... androgen levels using 6 months of DHEA replacement in this pilot study did not affect cardiovascular parameters and endothelial function in female adrenal insufficiency...

  16. The efficacy of antioxidant therapy against oxidative stress and androgen rise in ethylene glycol induced nephrolithiasis in Wistar rats.

    Science.gov (United States)

    Naghii, M R; Jafari, M; Mofid, M; Eskandari, E; Hedayati, M; Khalagie, K

    2015-07-01

    Administration of natural antioxidants has been used to protect against nephrolithiasis. Urolithiasis was induced by ethylene glycol (EG) in Wistar rats. For 4 weeks, group 1 (control) was fed with a standard commercial diet. Group 2 received the same diet with 0.75% of EG. Group 3 received EG plus the diet and water added with antioxidant nutrients and lime juice as the dietary source of citrate (EG + AX). Group 4 same as group 3 with no EG in water. For 8 weeks, group 5 was fed the standard diet with EG in water for the first 28 days, followed by no EG. Group 6 received the diet with EG for the first 28 days, followed by discontinuation of EG and addition of antioxidant nutrients. Group 7 were provided the diet with antioxidant nutrients for 8 weeks. Group 8 received the diet with antioxidant nutrients for 4 weeks, followed by antioxidant nutrients with EG for the next 4 weeks. Blood samples were collected and kidneys were removed. The size and the mean number of crystal deposits in EG-treated groups was significantly higher than the EG-treated groups, added with antioxidant nutrients and lime juice. After 4 weeks, the mean concentration of malondialdehyde in group 2 was higher than the group 3, and significantly lower in group 4; and in groups 7 after 8 weeks, as well. After 8 weeks, supplementation developed less mean number of deposits in group 6 as compared to group 5; and in group 8, the crystal deposits was substantially less than either group 2 or group 5 (EG-treated rats). Elevated concentration of androgens (as promoters of the formation of renal calculi) as a result of EG consumption decreased following antioxidant supplementations. Results showed a beneficial effect of antioxidant and provided superior renal protection on treating and preventing stone deposition in the rat kidney.

  17. A randomised controlled trial to evaluate the efficacy of a 6 month dietary and physical activity intervention for prostate cancer patients receiving androgen deprivation therapy

    Directory of Open Access Journals (Sweden)

    Haseen Farhana

    2010-08-01

    Full Text Available Abstract Background Treatment with Androgen Deprivation Therapy (ADT for prostate cancer is associated with changes in body composition including increased fat and decreased lean mass; increased fatigue, and a reduction in quality of life. No study to date has evaluated the effect of dietary and physical activity modification on the side-effects related to ADT. The aim of this study is to evaluate the efficacy of a 6-month dietary and physical activity intervention for prostate cancer survivors receiving ADT to minimise the changes in body composition, fatigue and quality of life, typically associated with ADT. Methods Men are recruited to this study if their treatment plan is to receive ADT for at least 6 months. Men who are randomised to the intervention arm receive a home-based tailored intervention to meet the following guidelines a ≥ 5 servings vegetables and fruits/day; b 30%-35% of total energy from fat, and Discussion The results of this study will provide detailed information on diet and physical activity levels in prostate cancer patients treated with ADT and will test the feasibility and efficacy of a diet and physical activity intervention which could provide essential information to develop guidelines for prostate cancer patients to minimise the side effects related to ADT. Trial registration ISRCTN trial number ISCRTN75282423

  18. 前列腺癌雄激素剥夺治疗与骨质丢失%Androgen deprivation therapy for prostate cancer and bone loss

    Institute of Scientific and Technical Information of China (English)

    吴燕华; 刘伟

    2013-01-01

    Prostate cancer is one of the common malignant tumors of the urinary system in the male. The incidence of prostate cancer in China is rising rapidly. At present, the vast majority of patients are receiving androgen deprivation therapy (ADT). Compared with chemotherapy, ADT has less toxic side effect, and it is more likely to be accepted by patients. However, ADT causes a range of adverse reactions. This paper reviews the risk of bone loss after ADT and the prevention and treatment strategies in patients with prostate cancer.%目的 前列腺癌是男性泌尿系统常见的恶性肿瘤之一.我国前列腺癌的发病率在迅速上升.目前绝大多数患者采取雄激素剥夺治疗,与化疗相比,雄激素剥夺治疗的毒副作用较轻,更容易被患者接受,但仍会引起一系列的不良反应,本文将对前列腺癌雄激素剥夺治疗后骨质丢失的情况及防治策略进行综述.

  19. CD4 cell count and the risk of AIDS or death in HIV-Infected adults on combination antiretroviral therapy with a suppressed viral load

    DEFF Research Database (Denmark)

    Obel, Niels

    2012-01-01

    Most adults infected with HIV achieve viral suppression within a year of starting combination antiretroviral therapy (cART). It is important to understand the risk of AIDS events or death for patients with a suppressed viral load.......Most adults infected with HIV achieve viral suppression within a year of starting combination antiretroviral therapy (cART). It is important to understand the risk of AIDS events or death for patients with a suppressed viral load....

  20. Ovarian overproduction of androgens

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/article/001165.htm Ovarian overproduction of androgens To use the sharing features on this page, please enable JavaScript. Ovarian overproduction of androgens is a condition in which the ...

  1. Androgen inhibits the growth of carcinoma cell lines established from prostate cancer xenografts that escape androgen treatment.

    Science.gov (United States)

    Joly-Pharaboz, Marie-Odile; Kalach, Jean-Jacques; Pharaboz, Julie; Chantepie, Jacqueline; Nicolas, Brigitte; Baille, Marie-Laurence; Ruffion, Alain; Benahmed, Mohamed; André, Jean

    2008-07-01

    Most prostate cancers escape endocrine therapy by diverse mechanisms. One of them might be growth repression by androgen. We reported that androgen represses the growth in culture of MOP cells (a sub-line of LNCaP cells) and that of MOP cell xenografts, although tumor growth becomes androgen-independent (AI). Here we explore whether AI tumors contain androgen-responsive cells. ME carcinoma cells were established from AI tumors. The responses to androgen were examined by cell counting, DAPI labeling, flow cytometry, PSA immunoassay and tumor size follow-up. Androgen receptors (AR) were analyzed by western blotting and DNA sequencing. The pattern of responses of these cells to androgen was compared to that of MOP cells and that of JAC cells established from LNCaP-like MOP cells. R1881, a synthetic androgen: (1) repressed the growth of all the six ME cell lines obtained, MOP and JAC cells, (2) augmented the secretion of PSA, (3) induced spectacular cell bubbling/fragmentation and (4) blocked the cell cycle and induced a modest increase of apoptosis. All the androgen-repressed cells expressed the same level of mutated AR as LNCaP cells. In nude mice, the growth of ME-2 cell xenografts displayed transient androgen repression similar to that of MOP cells. In culture neither fibroblasts nor extra-cellular matrix altered the effects of R1881 on cell proliferation. These results demonstrate that androgen-independent tumors contain androgen-responsive cells. The apparent discrepancy between the responses to androgen of tumors and those of carcinoma cells in culture suggests that microenvironmental factors contribute to the androgen responsiveness of tumor cells in vivo. These modifications, albeit unspecified, could be suitable targets for restoring the androgen responsiveness of AI tumors.

  2. Decreased HIV type 1 transcription in CCR5-Δ32 heterozygotes during suppressive antiretroviral therapy.

    Science.gov (United States)

    Wang, Charlene; Abdel-Mohsen, Mohamed; Strain, Matthew C; Lada, Steven M; Yukl, Steven; Cockerham, Leslie R; Pilcher, Christopher D; Hecht, Frederick M; Sinclair, Elizabeth; Liegler, Teri; Richman, Douglas D; Deeks, Steven G; Pillai, Satish K

    2014-12-01

    Individuals who are heterozygous for the CCR5-Δ32 mutation provide a natural model to examine the effects of reduced CCR5 expression on human immunodeficiency virus (HIV) persistence. We evaluated the HIV reservoir in 18 CCR5-Δ32 heterozygotes and 54 CCR5 wild-type individuals during suppressive antiretroviral therapy. Cell-associated HIV RNA levels (P=.035), RNA to DNA transcriptional ratios (P=.013), and frequency of detectable HIV 2-long terminal repeat circular DNA (P=.013) were significantly lower in CD4+ T cells from CCR5-Δ32 heterozygotes. Cell-associated HIV RNA was significantly correlated with CCR5 surface expression on CD4+ T cells (r2=0.136; P=.002). Our findings suggest that curative strategies should further explore manipulation of CCR5.

  3. Androgens and the ageing male

    DEFF Research Database (Denmark)

    Juul, Anders; Skakkebaek, Niels E

    2002-01-01

    Hypogonadal men share a variety of signs and symptoms such as decreased muscle mass, osteopoenia, increased fat mass, fatigue, decreased libido and cognitive dysfunctions. Controlled trials have demonstrated favourable effects of androgen substitution therapy on these signs and symptoms in men wi...... in some elderly males with low-normal testosterone levels. However, at this point in time, widespread use of testosterone in an elderly male population outside controlled clinical trials seems inappropriate....

  4. Androgen receptor mutations

    NARCIS (Netherlands)

    A.O. Brinkmann (Albert); G.W. Jenster (Guido); C. Ris-Stalpers (Carolyn); J.A.G.M. van der Korput (J. A G M); H.T. Brüggenwirth (Hennie); A.L.M. Boehmer (Annemie); J. Trapman (Jan)

    1995-01-01

    textabstractMale sexual differentiation and development proceed under direct control of androgens. Androgen action is mediated by the intracellular androgen receptor, which belongs to the superfamily of ligand-dependent transcription factors. At least three pathological situations are associated wit

  5. Small molecule screening reveals a transcription-independent pro-survival function of androgen receptor in castration-resistant prostate cancer.

    Science.gov (United States)

    Narizhneva, Natalia V; Tararova, Natalia D; Ryabokon, Petro; Shyshynova, Inna; Prokvolit, Anatoly; Komarov, Pavel G; Purmal, Andrei A; Gudkov, Andrei V; Gurova, Katerina V

    2009-12-15

    In prostate cancer (PCa) patients, initial responsiveness to androgen deprivation therapy is frequently followed by relapse due to development of treatment-resistant androgen-independent PCa. This is typically associated with acquisition of mutations in AR that allow activity as a transcription factor in the absence of ligand, indicating that androgen-independent PCa remains dependent on AR function. Our strategy to effectively target AR in androgen-independent PCa involved using a cell-based readout to isolate small molecules that inhibit AR transactivation function through mechanisms other than modulation of ligand binding. A number of the identified inhibitors were toxic to AR-expressing PCa cells regardless of their androgen dependence. Among these, some only suppressed PCa cell growth (ARTIS), while others induced cell death (ARTIK). ARTIK, but not ARTIS, compounds caused disappearance of AR protein from treated cells. siRNA against AR behaved like ARTIK compounds, while a dominant negative AR mutant that prevents AR-mediated transactivation but does not eliminate the protein showed only a growth suppressive effect. These observations reveal a transcription-independent function of AR that is essential for PCa cell viability and, therefore, is an ideal target for anti-PCa treatment. Indeed, several of the identified AR inhibitors demonstrated in vivo efficacy in mouse models of PCa and are candidates for pharmacologic optimization.

  6. Comparison of the efficacy on serum androgenic hormone levels between isotretinoin, cyproterone acetate/ethynil estradiol and combination therapies in females with acne vulgaris

    OpenAIRE

    Hilal Gökalp; Ahmet Burhan Aksakal

    2012-01-01

    Objective: Acne vulgaris is one of the most common skin disorders, and is a multifactorial disease characterized by androgenic stimulation of sebaceous glands. This study aimed to further understand the antiandrogenic effects of isotretinoin by using isotretinoin, cyproterone acetate/ethynil estradiol (CTA/EE) and isotretinoin+CTA/EE combination treatments with analyzing their effects on serum androgenic hormon levels. Materials and methods: 60 females that were clinically evaluated as grade ...

  7. Androgen Depletion Induces Senescence in Prostate Cancer Cells through Down-regulation of Skp2

    Directory of Open Access Journals (Sweden)

    Zuzana Pernicová

    2011-06-01

    Full Text Available Although the induction of senescence in cancer cells is a potent mechanism of tumor suppression, senescent cells remain metabolically active and may secrete a broad spectrum of factors that promote tumorigenicity in neighboring malignant cells. Here we show that androgen deprivation therapy (ADT, a widely used treatment for advanced prostate cancer, induces a senescence-associated secretory phenotype in prostate cancer epithelial cells, indicated by increases in senescence-associated β-galactosidase activity, heterochromatin protein 1β foci, and expression of cathepsin B and insulin-like growth factor binding protein 3. Interestingly, ADT also induced high levels of vimentin expression in prostate cancer cell lines in vitro and in human prostate tumors in vivo. The induction of the senescence-associated secretory phenotype by androgen depletion was mediated, at least in part, by down-regulation of S-phase kinase-associated protein 2, whereas the neuroendocrine differentiation of prostate cancer cells was under separate control. These data demonstrate a previously unrecognized link between inhibition of androgen receptor signaling, down-regulation of S-phase kinase-associated protein 2, and the appearance of secretory, tumor-promoting senescent cells in prostate tumors. We propose that ADT may contribute to the development of androgen-independent prostate cancer through modulation of the tissue microenvironment by senescent cells.

  8. Androgens and bone.

    Science.gov (United States)

    Vanderschueren, Dirk; Vandenput, Liesbeth; Boonen, Steven; Lindberg, Marie K; Bouillon, Roger; Ohlsson, Claes

    2004-06-01

    Loss of estrogens or androgens increases the rate of bone remodeling by removing restraining effects on osteoblastogenesis and osteoclastogenesis, and also causes a focal imbalance between resorption and formation by prolonging the lifespan of osteoclasts and shortening the lifespan of osteoblasts. Conversely, androgens, as well as estrogens, maintain cancellous bone mass and integrity, regardless of age or sex. Although androgens, via the androgen receptor (AR), and estrogens, via the estrogen receptors (ERs), can exert these effects, their relative contribution remains uncertain. Recent studies suggest that androgen action on cancellous bone depends on (local) aromatization of androgens into estrogens. However, at least in rodents, androgen action on cancellous bone can be directly mediated via AR activation, even in the absence of ERs. Androgens also increase cortical bone size via stimulation of both longitudinal and radial growth. First, androgens, like estrogens, have a biphasic effect on endochondral bone formation: at the start of puberty, sex steroids stimulate endochondral bone formation, whereas they induce epiphyseal closure at the end of puberty. Androgen action on the growth plate is, however, clearly mediated via aromatization in estrogens and interaction with ERalpha. Androgens increase radial growth, whereas estrogens decrease periosteal bone formation. This effect of androgens may be important because bone strength in males seems to be determined by relatively higher periosteal bone formation and, therefore, greater bone dimensions, relative to muscle mass at older age. Experiments in mice again suggest that both the AR and ERalpha pathways are involved in androgen action on radial bone growth. ERbeta may mediate growth-limiting effects of estrogens in the female but does not seem to be involved in the regulation of bone size in males. In conclusion, androgens may protect men against osteoporosis via maintenance of cancellous bone mass and

  9. Preferential suppression of CXCR4-specific strains of HIV-1 by antiviral therapy.

    Science.gov (United States)

    Philpott, S; Weiser, B; Anastos, K; Kitchen, C M; Robison, E; Meyer, W A; Sacks, H S; Mathur-Wagh, U; Brunner, C; Burger, H

    2001-02-01

    To initiate infection, HIV-1 requires a primary receptor, CD4, and a secondary receptor, principally the chemokine receptor CCR5 or CXCR4. Coreceptor usage plays a critical role in HIV-1 disease progression. HIV-1 transmitted in vivo generally uses CCR5 (R5), but later CXCR4 (X4) strains may emerge; this shift heralds CD4+ cell depletion and clinical deterioration. We asked whether antiretroviral therapy can shift HIV-1 populations back to R5 viruses after X4 strains have emerged, in part because treatment has been successful in slowing disease progression without uniformly suppressing plasma viremia. We analyzed the coreceptor usage of serial primary isolates from 15 women with advanced disease who demonstrated X4 viruses. Coreceptor usage was determined by using a HOS-CD4+ cell system, biological and molecular cloning, and sequencing the envelope gene V3 region. By constructing a mathematical model to measure the proportion of virus in a specimen using each coreceptor, we demonstrated that the predominant viral population shifted from X4 at baseline to R5 strains after treatment. Multivariate analyses showed that the shift was independent of changes in plasma HIV-1 RNA level and CD4+ cell count. Hence, combination therapy may lead to a change in phenotypic character as well as in the quantity of HIV-1. Shifts in coreceptor usage may thereby contribute to the clinical efficacy of anti-HIV drugs.

  10. Molecular cell biology of androgen receptor signalling.

    Science.gov (United States)

    Bennett, Nigel C; Gardiner, Robert A; Hooper, John D; Johnson, David W; Gobe, Glenda C

    2010-06-01

    The classical action of androgen receptor (AR) is to regulate gene transcriptional processes via AR nuclear translocation, response element binding and recruitment of, or crosstalk with, transcription factors. AR also utilises non-classical, non-genomic mechanisms of signal transduction. These precede gene transcription or protein synthesis, and involve steroid-induced modulation of cytoplasmic or cell membrane-bound regulatory proteins. Despite many decades of investigation, the role of AR in gene regulation of cells and tissues remains only partially characterised. AR exerts most of its effects in sex hormone-dependent tissues of the body, but the receptor is also expressed in many tissues not previously thought to be androgen sensitive. Thus it is likely that a complex, more over-arching, role for AR exists. Each AR domain co-ordinates a multitude of individual and vital roles via a diverse array of interacting partner molecules that are necessary for cellular and tissue development and maintenance. Aberrant AR activity, promoted by mutations or binding partner misregulation, can present as many clinical manifestations including androgen insensitivity syndrome and prostate cancer. In the case of malignant prostate cancer, treatment generally revolves around androgen deprivation therapies designed to interfere with AR action and the androgen signalling axis. Androgen therapies for prostate cancer often fail, highlighting a real need for increased research into AR function.

  11. Upfront Androgen Deprivation Therapy With Salvage Radiation May Improve Biochemical Outcomes in Prostate Cancer Patients With Post-Prostatectomy Rising PSA

    Energy Technology Data Exchange (ETDEWEB)

    Jang, Joanne W. [Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA (United States); Hwang, Wei-Ting [Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA (United States); Guzzo, Thomas J.; Wein, Alan J. [Department of Urology, University of Pennsylvania School of Medicine, Philadelphia, PA (United States); Haas, Naomi B. [Department of Medical Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA (United States); Both, Stefan [Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA (United States); Vapiwala, Neha, E-mail: vapiwala@uphs.upenn.edu [Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA (United States)

    2012-08-01

    Purpose: The addition of androgen deprivation therapy (ADT) to definitive external beam radiation therapy (RT) improves outcomes in higher-risk prostate cancer patients. However, the benefit of ADT with salvage RT in post-prostatectomy patients is not clearly established. Our study compares biochemical outcomes in post-prostatectomy patients who received salvage RT with or without concurrent ADT. Methods and Materials: Of nearly 2,000 post-prostatectomy patients, we reviewed the medical records of 191 patients who received salvage RT at University of Pennsylvania between 1987 and 2007. Follow-up data were obtained by chart review and electronic polling of the institutional laboratory database and Social Security Death Index. Biochemical failure after salvage RT was defined as a prostate-specific antigen of 2.0 ng/mL above the post-RT nadir or the initiation of ADT after completion of salvage RT. Results: One hundred twenty-nine patients received salvage RT alone, and 62 patients received combined ADT and salvage RT. Median follow-up was 5.4 years. Patients who received combined ADT and salvage RT were younger, had higher pathologic Gleason scores, and higher rates of seminal vesicle invasion, lymph node involvement, and pelvic nodal irradiation compared with patients who received salvage RT alone. Patients who received combined therapy had improved biochemical progression-free survival (bPFS) compared with patients who received RT alone (p = 0.048). For patients with pathologic Gleason scores {<=}7, combined RT and ADT resulted in significantly improved bPFS compared to RT alone (p = 0.013). Conclusions: These results suggest that initiating ADT during salvage RT in the post-prostatectomy setting may improve bPFS compared with salvage RT alone. However, prospective randomized data are necessary to definitively determine whether hormonal manipulation should be used with salvage RT. Furthermore, the optimal nature and duration of ADT and the patient subgroups in

  12. Effects of androgen deprivation therapy and bisphosphonate treatment on bone in patients with metastatic castration-resistant prostate cancer: results from the University of Washington Rapid Autopsy Series.

    Science.gov (United States)

    Morrissey, Colm; Roudier, Martine P; Dowell, Alex; True, Lawrence D; Ketchanji, Melanie; Welty, Christopher; Corey, Eva; Lange, Paul H; Higano, Celestia S; Vessella, Robert L

    2013-02-01

    Qualitative and quantitative bone features were determined in nondecalcified and decalcified bone from 20 predetermined bone sites in each of 44 patients who died with castration-resistant prostate cancer (CRPC), some of which received bisphosphonate treatment (BP) in addition to androgen-deprivation therapy (ADT). Thirty-nine of the 44 patients (89%) had evidence of bone metastases. By histomorphometric analysis, these bone metastases were associated with a range of bone responses from osteoblastic to osteolytic with a wide spectrum of bone responses often seen within an individual patient. Overall, the average bone volume/tissue volume (BV/TV) was 25.7%, confirming the characteristic association of an osteoblastic response to prostate cancer bone metastasis when compared with the normal age-matched weighted mean BV/TV of 14.7%. The observed new bone formation was essentially woven bone, and this was a localized event. In comparing BV/TV at metastatic sites between patients who had received BP treatment and those who had not, there was a significant difference (28.6% versus 19.3%, respectively). At bone sites that were not invaded by tumor, the average BV/TV was 10.1%, indicating significant bone loss owing to ADT that was not improved (11%) in those patients who had received BPs. Surprisingly, there was no significant difference in the number of osteoclasts present at the metastatic sites between patients treated or not treated with BPs, but in bone sites where the patient had been treated with BPs, giant osteoclasts were observed. Overall, 873 paraffin-embedded specimens and 661 methylmethacrylate-embedded specimens were analyzed. Our results indicate that in CRPC patients, ADT induces serious bone loss even in patients treated with BP. Furthermore, in this cohort of patients, BP treatment increased BV and did not decrease the number of osteoclasts in prostate cancer bone metastases compared with bone metastases from patients who did not receive BP.

  13. Effect of Whole Pelvic Radiotherapy for Patients With Locally Advanced Prostate Cancer Treated With Radiotherapy and Long-Term Androgen Deprivation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Mantini, Giovanna [Department of Radiotherapy, Policlinico Universitario A. Gemelli, Catholic University, Rome (Italy); Tagliaferri, Luca, E-mail: luca.tagliaferri@rm.unicatt.it [Department of Radiotherapy, Policlinico Universitario A. Gemelli, Catholic University, Rome (Italy); Mattiucci, Gian Carlo; Balducci, Mario; Frascino, Vincenzo; Dinapoli, Nicola [Department of Radiotherapy, Policlinico Universitario A. Gemelli, Catholic University, Rome (Italy); Di Gesu, Cinzia; Ippolito, Edy; Morganti, Alessio G. [Department of Radiotherapy, John Paul II Center for High Technology Research and Education in Biomedical Sciences, Catholic University, Campobasso (Italy); Cellini, Numa [Department of Radiotherapy, Policlinico Universitario A. Gemelli, Catholic University, Rome (Italy)

    2011-12-01

    Purpose: To evaluate the effect of whole pelvic radiotherapy (WPRT) in prostate cancer patients treated with RT and long-term (>1 year) androgen deprivation therapy (ADT). Methods and materials: Prostate cancer patients with high-risk features (Stage T3-T4 and/or Gleason score {>=}7 and/or prostate-specific antigen level {>=}20 ng/mL) who had undergone RT and long-term ADT were included in the present analysis. Patients with bowel inflammatory disease, colon diverticula, and colon diverticulitis were excluded from WPRT and treated with prostate-only radiotherapy (PORT). Patients were grouped according to nodal risk involvement as assessed by the Roach formula using different cutoff levels (15%, 20%, 25%, and 30%). Biochemical disease-free survival (bDFS) was analyzed in each group according to the RT type (WPRT or PORT). Results: A total of 358 patients treated between 1994 and 2007 were included in the analysis (46.9% with WPRT and 53.1% with PORT). The median duration of ADT was 24 months (range, 12-38). With a median follow-up of 52 months (range, 20-150), the overall 4-year bDFS rate was 90.5%. The 4-year bDFS rate was similar between the patients who had undergone WPRT or PORT (90.4% vs. 90.5%; p = NS). However, in the group of patients with the greatest nodal risk (>30%), a significant bDFS improvement was recorded for the patients who had undergone WPRT (p = .03). No differences were seen in acute toxicity among the patients treated with WPRT or PORT. The late gastrointestinal toxicity was similar in patients treated with PORT or WPRT (p = NS). Conclusions: Our analysis has supported the use of WPRT in association with long-term ADT for patients with high-risk nodal involvement (>30%), although a definitive recommendation should be confirmed by a randomized trial.

  14. Impact of initial time to prostate-specific antigen nadir on survival in prostate cancer with bone metastasis initially treated with maximum androgen blockade therapy

    Directory of Open Access Journals (Sweden)

    Yamamoto Y

    2013-10-01

    Full Text Available Background: The objective of this study is to provide certain data on clinical outcomes and their predictors of traditional maximum androgen blockade (MAB in prostate cancer with bone metastasis. Methods: Subjects were patients with prostate adenocarcinoma with bone metastasis initiated to treat with MAB as a primary treatment without any local therapy at our hospital between January 2003 and December 2010. Time to prostate specific antigen (PSA progression, overall survival (OS time, and association of clinical factors and outcomes were retrospectively evaluated. Results: A total of 57 patients were evaluable. The median age was 70 years. The median primary PSA was 203 ng/ml. Luteinizing hormone-releasing hormone agonists had been administered in 96.5% of the patients. Bicalutamide had been chosen in 89.4 % of the patients as the initial antiandrogen. The median time to PSA progression with MAB was 11.3 months (95% confidence interval [CI], 10.4 to 13.0. The median OS was 47.3 months (95% CI, 30.7 to 81.0. Gleason score 9 or greater, decline of PSA level equal to or higher than 1.0 ng/ml with MAB, and time to PSA nadir equal to or shorter than six months after initiation of MAB were independent risk factors for time to PSA progression (P=0.010, P=0.005, and P=0.001; respectively. Time to PSA nadir longer than six months was the only independent predictor for longer OS (HR, 0.255 [95% CI, 0.109 to 0.597]; P=0.002. Conclusions: Initial time to PSA nadir should be emphasized for clinical outcome analyses in future studies on prostate cancer with bone metastasis.

  15. SIMBOSPROST: Prevalence of metabolic syndrome and osteoporosis in prostate cancer patients treated with radiotherapy and androgen deprivation therapy: A multicentre, cross-sectional study

    Science.gov (United States)

    Samper Ots, Pilar Ma; Muñoz García, Julia Luisa; Ríos Kavadoy, Yesika; Couselo Paniagua, Ma Luz; Villafranca Iturre, Elena; Rodríguez Liñán, Milagrosa; Pérez Casas, Ana María; Soria, Rodrigo Muelas; Martínez, Blanca Ludeña; Torrecilla, José López; Giner, Manuel Casaña; Laborda, Almudena Zapatero; García-Salazar, Ma Magdalena Márquez

    2015-01-01

    Aim To assess the prevalence of metabolic syndrome (MetS) and osteoporosis in patients with prostate cancer (PCa) treated with radical radiotherapy (RT) with or without androgen deprivation therapy (ADT). Background Worldwide, the prevalence of MetS is estimated to range from 20% to 25% of the adult population. However, prevalence rates are much higher in PCa patients (pts) who undergo ADT. Materials and methods Multicentre cross-sectional study of 270 pts in Spain with PCa. Patients were divided into 3 groups based on the duration of ADT (6, 12–18, ≥24 months) and compared to a control group without ADT. MetS was defined according to NCEP ATP III criteria. Osteoporosis was assessed by DEXA. Results A total of 270 pts, treated from November 2011 to October 2012, were included. Of these, 122 pts (47%) fulfilled the criteria for MetS. The median age of this group was significantly higher (71.3 vs. 69.38 years, p = 0.028). MetS prevalence was 50% in the control group. In pts who received ADT, prevalence was 44.8% after 6 months of ADT, 45.3% after 12–18 months, and 50% after ≥24 months (pns). Most pts (168/270; 62%) underwent DEXA. Of those tested, 78 (46.4%) had osteopenia and only 11 (6.5%) had osteoporosis. Conclusions The prevalence of MetS in pts with PCa treated with radical RT was higher (47%) than in the general population. However, there were no significant differences in the duration of ADT administration. The prevalence of osteoporosis was low. These findings suggest that the prevalence of MetS in PCa patients may be higher than previously reported. PMID:26549995

  16. First Line Androgen Deprivation Therapy Duration Is Associated with the Efficacy of Abiraterone Acetate Treated Metastatic Castration-Resistant Prostate Cancer after Docetaxel

    Science.gov (United States)

    Li, Jian-Ri; Wang, Shian-Shiang; Yang, Cheng-Kuang; Chen, Chuan-Su; Ho, Hao-Chung; Chiu, Kun-Yuan; Hung, Chi-Feng; Cheng, Chen-Li; Yang, Chi-Rei; Chen, Cheng-Che; Wang, Shu-Chi; Lin, Chia-Yen; Ou, Yen-Chuan

    2017-01-01

    Introduction: We performed a chart review study in our castration-resistant prostate cancer (CRPC) patients who received Abiraterone acetate (AA) treatment after docetaxel and identified clinical markers which can predict treatment outcome. Materials and Methods: From 2012 to 2016, 64 patients who received docetaxel after CRPC followed by AA treatment were included. Clinical parameters were recorded and analysis was performed to identify associations between pre-treatment variables and treatment outcome. Results: Thirty three patients (51.6%) achieved a decrease in PSA of 50%. The median PSA progression-free survival and overall survival in the total cohort of 64 patients were 6.6 and 24 months, respectively. Adverse events (AEs) in all grades developed in 35.9% (23/64) patients and mostly were grade 1 or 2. The most common AEs were gastric upset, hypokalemia and elevated liver function tests. Of the eight variables analyzed, first line androgen deprivation therapy (ADT) duration showed positive association to progression free survival (HR 0.98, 95% CI [0.96–0.99], p = 0.012) and overall survival (HR 0.97, 95% CI [0.94–0.99], p = 0.019). Pre-AA PSA and PSA progression ratio showed negative association only to progression free survival (HR 1.0, 95% CI [1.000–1.002], p = 0.025, HR 1.01, 95% CI [1.00–1.01], p < 0.001, respectively). Conclusion: First line ADT duration was positively associated with AA treatment efficacy in progression free survival and overall survival. It can be used as a pre-treatment predictor. PMID:28243202

  17. Lack of benefit for the addition of androgen deprivation therapy to dose-escalated radiotherapy in the treatment of intermediate- and high-risk prostate cancer.

    LENUS (Irish Health Repository)

    Krauss, Daniel

    2012-02-01

    PURPOSE: Assessment of androgen deprivation therapy (ADT) benefits for prostate cancer treated with dose-escalated radiotherapy (RT). METHODS AND MATERIALS: From 1991 to 2004, 1,044 patients with intermediate- (n = 782) or high-risk (n = 262) prostate cancer were treated with dose-escalated RT at William Beaumont Hospital. Patients received external-beam RT (EBRT) alone, brachytherapy (high or low dose rate), or high dose rate brachytherapy plus pelvic EBRT. Intermediate-risk patients had Gleason score 7, prostate-specific antigen (PSA) 10.0-19.9 ng\\/mL, or Stage T2b-T2c. High-risk patients had Gleason score 8-10, PSA >\\/=20, or Stage T3. Patients were additionally divided specifically by Gleason score, presence of palpable disease, and PSA level to further define subgroups benefitting from ADT. RESULTS: Median follow-up was 5 years; 420 patients received ADT + dose-escalated RT, and 624 received dose-escalated RT alone. For all patients, no advantages in any clinical endpoints at 8 years were associated with ADT administration. No differences in any endpoints were associated with ADT administration based on intermediate- vs. high-risk group or RT modality when analyzed separately. Patients with palpable disease plus Gleason >\\/=8 demonstrated improved clinical failure rates and a trend toward improved survival with ADT. Intermediate-risk patients treated with brachytherapy alone had improved biochemical control when ADT was given. CONCLUSION: Benefits of ADT in the setting of dose-escalated RT remain poorly defined. This question must continue to be addressed in prospective study.

  18. Development of a nomogram model predicting current bone scan positivity in patients treated with androgen-deprivation therapy for prostate cancer

    Directory of Open Access Journals (Sweden)

    Michael eKattan

    2014-10-01

    Full Text Available Purpose: To develop a nomogram predictive of current bone scan positivity in patients receiving androgen-deprivation therapy (ADT for advanced prostate cancer; to augment clinical judgment and highlight patients in need of additional imaging investigations.Materials and Methods: A retrospective chart review of bone scan records (conventional 99mTc-scintigraphy of 1,293 patients who received ADT at the Memorial Sloan-Kettering Cancer Center from 2000 to 2011. Multivariable logistic regression analysis was used to identify variables suitable for inclusion in the nomogram. The probability of current bone scan positivity was determined using these variables and the predictive accuracy of the nomogram was quantified by concordance index.Results: In total, 2,681 bone scan records were analyzed and 636 patients had a positive result. Overall, the median pre-scan prostate-specific antigen (PSA level was 2.4 ng/ml; median PSA doubling time (PSADT was 5.8 months. At the time of a positive scan, median PSA level was 8.2 ng/ml; 53% of patients had PSA <10 ng/ml; median PSADT was 4.0 months. Five variables were included in the nomogram: number of previous negative bone scans after initiating ADT, PSA level, Gleason grade sum, and history of radical prostatectomy and radiotherapy. A concordance index value of 0.721 was calculated for the nomogram. This was a retrospective study based on limited data in patients treated in a large cancer centre who underwent conventional 99mTc bone scans, which themselves have inherent limitations. Conclusions: This is the first nomogram to predict current bone scan positivity in ADT-treated prostate cancer patients, providing high predictive accuracy.

  19. Sequencing of Sipuleucel-T and Androgen Deprivation Therapy in Men with Hormone-Sensitive Biochemically Recurrent Prostate Cancer: A Phase II Randomized Trial.

    Science.gov (United States)

    Antonarakis, Emmanuel S; Kibel, Adam S; Yu, Evan Y; Karsh, Lawrence I; Elfiky, Aymen; Shore, Neal D; Vogelzang, Nicholas J; Corman, John M; Millard, Frederick E; Maher, Johnathan C; Chang, Nancy N; DeVries, Todd; Sheikh, Nadeem A; Drake, Charles G

    2016-11-10

    Purpose: STAND, a randomized, phase II, open-label trial (NCT01431391), assessed sequencing of sipuleucel-T (an autologous cellular immunotherapy) with androgen deprivation therapy (ADT) in biochemically recurrent prostate cancer (BRPC) patients at high risk for metastasis.Experimental Design: Men with BRPC following prostatectomy and/or radiotherapy, a PSA doubling time ≤12 months, and no metastasis were enrolled. Patients were randomized (34/arm) to sipuleucel-T followed by ADT (started 2 weeks after sipuleucel-T completion), or ADT followed by sipuleucel-T (started 12 weeks after ADT initiation); ADT continued for 12 months in both arms. The primary endpoint was PA2024-specific T-cell response [enzyme-linked immunospot (ELISPOT)] over time.Results: PA2024-specific ELISPOT responses over time were similar between groups, except at week 6, where responses were higher with sipuleucel-T→ADT versus ADT→sipuleucel-T (P = 0.013). PA2024-specific T-cell proliferation responses, averaged across time points, were approximately 2-fold higher with sipuleucel-T→ADT versus ADT→sipuleucel-T (P = 0.001). PA2024-specific cellular and humoral responses and prostatic acid phosphatase-specific humoral responses increased significantly versus baseline (P Sipuleucel-T with ADT was generally well tolerated.Conclusions: Sipuleucel-T→ADT appears to induce greater antitumor immune responses than the reverse sequence. These results warrant further investigation to determine whether this sequence leads to improved clinical outcomes, as well as the independent contribution of ADT alone in terms of immune activation. Clin Cancer Res; 1-9. ©2016 AACR.

  20. Targeted-cryosurgical ablation of the prostate with androgen deprivation therapy: quality of life in high-risk prostate cancer patients

    Institute of Scientific and Technical Information of China (English)

    Seok-Ho Kang; Jin-Wook Kim; Jae-Hyun Bae; Hong-Seok Park; Du-Geon Moon; Duck-Ki Yoon; Jun Cheon; Je-Jong Kim

    2006-01-01

    Aim: To present preliminary results on health-related quality of life (QoL), prostate-associated symptoms and therapeutic effects of targeted-cryosurgical ablation of the prostate (TCSAP) with androgen deprivation therapy (ADT) in high-risk prostate cancer (PCa) patients. Methods: Thirty-four men with high-risk PCa features underwent TCSAP,and ADT was added to improve the treatment outcomes. High-risk parameters were defined as either prostatespecific antigen (PSA) ≥ 10ng/mL, or Gleason score ≥ 8, or both. The Genito-Urinary Group of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) with prostate-cancer-specific module (QLQ-PR25) was used for evaluating morbidities and PSA levels were recorded every 3 months. PSA failure was defined as the inability to reach a nadir of 0.4 ng/mL or less. Results: Although it was not statistically significant, the global health status scores increased after TCSAP with ADT. The scores for five functional scales also became higher after treatment. The most prominent symptom after treatment was sexual dysfunction, followed by treatment-related and irritative voiding symptoms. Conclusion: TCSAP with ADT appears to be minimally invasive with high QoL except for sexual dysfunction. Long-term follow-up of PSA data and survival is necessary before any conclusions can be made on the efficacy of this promising new therapeutic modality in the treatment of PCa.

  1. Androgens and the skeleton.

    Science.gov (United States)

    Lindberg, M K; Vandenput, L; Movèrare Skrtic, S; Vanderschueren, D; Boonen, S; Bouillon, R; Ohlsson, C

    2005-03-01

    Loss of estrogens or androgens causes bone loss by increasing the rate of bone remodeling, and also causes an imbalance between resorption and formation by prolonging the lifespan of osteoclasts and shortening the lifespan of osteoblasts. Conversely, treatment with androgens, as well as estrogens, maintains cancellous bone mass and integrity, regardless of age or sex. Both androgens, via the androgen receptor (AR), and estrogens, via the estrogen receptors (ERs) can exert these effects, but the relative contribution of these 2 pathways remains uncertain. Androgens, like estrogens, stimulate endochondral bone formation at the start of puberty, whereas they induce epiphyseal closure at the end of puberty, thus, they have a biphasic effect. Androgen action on the growth plate is, however, clearly mediated via aromatization into estrogens and interaction with ER alpha. Androgens increase, while estrogens decrease radial growth. This differential effect of the sex steroids may be important because bone strength in males seems to be determined by higher periosteal bone formation and, therefore, greater bone dimensions. Experiments in mice suggest that both the AR and ER alpha pathways are involved in androgen action on radial bone growth. ER beta may mediate growth-limiting effects of estrogens in the female but does not seem to be involved in the regulation of bone size in males. In conclusion, androgens may protect men against osteoporosis via maintenance of cancellous bone mass and expansion of cortical bone. This androgen action on bone is mediated by the AR and ER alpha.

  2. The predictive value of ERG protein expression for development of castration-resistant prostate cancer in hormone-naïve advanced prostate cancer treated with primary androgen deprivation therapy

    DEFF Research Database (Denmark)

    Berg, Kasper Drimer; Røder, Martin A; Thomsen, Frederik B;

    2015-01-01

    BACKGROUND: Biomarkers predicting response to primary androgen deprivation therapy (ADT) and risk of castration-resistant prostate cancer (CRPC) is lacking. We aimed to analyse the predictive value of ERG expression for development of CRPC. METHODS: In total, 194 patients with advanced and....../or metastatic prostate cancer (PCa) treated with first-line castration-based ADT were included. ERG protein expression was analysed in diagnostic specimens using immunohistochemistry (anti-ERG, EPR3864). Time to CRPC was compared between ERG subgroups using multiple cause-specific Cox regression stratified...

  3. High-dose-rate interstitial brachytherapy in combination with androgen deprivation therapy for prostate cancer. Are high-risk patients good candidates

    Energy Technology Data Exchange (ETDEWEB)

    Yoshida, Ken; Narumi, Yoshifumi [Osaka Medical College, Department of Radiology, Takatsuki, Osaka (Japan); Yamazaki, Hideya; Masui, Koji [Kyoto Prefectural University of Medicine, Department of Radiology, Kyoto (Japan); Takenaka, Tadashi [National Hospital Organization Osaka National Hospital, Department of Radiology, Osaka city, Osaka (Japan); Kotsuma, Tadayuki; Yoshida, Mineo; Tanaka, Eiichi [National Hospital Organization Osaka National Hospital, Department of Radiation Oncology, Osaka city, Osaka (Japan); Yoshioka, Yasuo [Osaka University Graduate School of Medicine, Department of Radiation Oncology, Suita, Osaka (Japan); Oka, Toshitsugu [National Hospital Organization Osaka National Hospital, Department of Urology, Osaka city, Osaka (Japan)

    2014-11-15

    To evaluate the effectiveness of high-dose-rate interstitial brachytherapy (HDR-ISBT) as the only form of radiotherapy for high-risk prostate cancer patients. Between July 2003 and June 2008, we retrospectively evaluated the outcomes of 48 high-risk patients who had undergone HDR-ISBT at the National Hospital Organization Osaka National Hospital. Risk group classification was according to the criteria described in the National Comprehensive Cancer Network (NCCN) guidelines. Median follow-up was 73 months (range 12-109 months). Neoadjuvant androgen deprivation therapy (ADT) was administered to all 48 patients; 12 patients also received adjuvant ADT. Maximal androgen blockade was performed in 37 patients. Median total treatment duration was 8 months (range 3-45 months). The planned prescribed dose was 54 Gy in 9 fractions over 5 days for the first 13 patients and 49 Gy in 7 fractions over 4 days for 34 patients. Only one patient who was over 80 years old received 38 Gy in 4 fractions over 3 days. The clinical target volume (CTV) was calculated for the prostate gland and the medial side of the seminal vesicles. A 10-mm cranial margin was added to the CTV to create the planning target volume (PTV). The 5-year overall survival and biochemical control rates were 98 and 87 %, respectively. Grade 3 late genitourinary and gastrointestinal complications occurred in 2 patients (4 %) and 1 patient (2 %), respectively; grade 2 late genitourinary and gastrointestinal complications occurred in 5 patients (10 %) and 1 patient (2 %), respectively. Even for high-risk patients, HDR-ISBT as the only form of radiotherapy combined with ADT achieved promising biochemical control results, with acceptable late genitourinary and gastrointestinal complication rates. (orig.) [German] Beurteilung der Wirksamkeit von interstitieller Brachytherapie mit Hochdosisraten (''high-dose-rate interstitial brachytherapy'', HDR-ISBT) als einzige Form der Radiotherapie fuer Hochrisiko

  4. Up-regulation of Bcl-2 is required for the progression of prostate cancer cells from an androgen-dependent to an androgen-independent growth stage

    Institute of Scientific and Technical Information of China (English)

    Yuting Lin; Junichi Fukuchi; Richard A Hiipakka; John M Kokontis; Jialing Xiang

    2007-01-01

    Bcl-2 is an anti-apoptotic oncoprotein and its protein levels are inversely correlated with prognosis in many cancers.However, the role of Bcl-2 in the progression of prostate cancer is not clear. Here we report that Bcl-2 is required for the progression of LNCaP prostate cancer cells from an androgen-dependent to an androgen-independent growth stage. The mRNA and protein levels of Bcl-2 are significantly increased in androgen-independent prostate cancer cells, shRNA-mediated gene silencing of Bcl-2 in androgen-independent prostate cancer cells promotes UV-induced apoptosis and suppresses the growth of prostate tumors in vivo. Growing androgen-dependent cells under androgen-deprivation conditions results in formation of androgen-independent colonies; and the transition from androgen-dependent to androgen-independent growth is blocked by ectopic expression of the Bcl-2 antagonist Bax or Bcl-2 shRNA. Thus, our results demonstrate that Bcl-2 is not only critical for the survival of androgen-independent prostate cancer cells, but is also required for the progression of prostate cancer cells from an androgen-dependent to an androgen-independent growth stage.

  5. Development of selective androgen receptor modulators and their therapeutic applications.

    Science.gov (United States)

    Chen, Fang; Rodan, Gideon A; Schmidt, Azi

    2002-01-01

    Androgens control a broad range of physiological functions. The androgen receptor (AR), a steroid receptor that mediates the diverse biological actions of androgens, is a ligand inducible transcription factor. Abnormalities in the androgen signaling system result in many disturbances ranging from changes in gender determination and sexual development to psychiatric and emotional disorders. Androgen replacement therapy can improve many clinical conditions including hypogonadism and osteoporosis, but is limited by the lack of efficacious and safe therapeutic agents with easy delivery options. Recent progress in the area of gene regulation by steroid receptors and by selective receptor modulators provides an opportunity to examine if selective androgen receptor modulators (SARMs) could address some of the problems associated with current androgen therapy. Since the composition of the transcriptional initiation complex recruited by liganded AR determines the specificity of gene regulation, synthetic ligands aimed at initiating transcription of tissue and promoter specific genes offers hope for developing better androgen therapy. Establishment of assays that predict synthetic ligand activity is critical for SARM development. Advancement in high throughput compound screening and gene fingerprinting technologies, such as microarrays and proteomics, will facilitate and accelerate identification of effective SARMs.

  6. Clinical markers of androgenicity in acne vulgaris.

    Science.gov (United States)

    Sheehan-Dare, R A; Hughes, B R; Cunliffe, W J

    1988-12-01

    Androgenic stimulation of sebaceous glands is necessary for development of acne. If hyperandrogenaemia were a major determinant of acne in women, the frequency of other clinical markers of androgenicity should increase with acne severity. To investigate this, 268 female subjects (aged 12-44 years) were studied. Subjects were divided into groups on the basis of acne severity: physiological, moderate, and severe. With exclusion of women taking oral contraceptives or anti-androgen therapy, subjects in each group were similar with respect to age at menarche and incidence of menstrual irregularity of amenorrhoea. Reports of excessive body hair, and clinical hirsutes on examination were few and there were no significant differences between acne severity groups. No correlation was observed between acne and hirsutes grades in all subjects (rank correlation coefficient = 0.096). Mild male pattern androgenic alopecia occurred in similar proportions of subjects in the three groups. Female pattern androgenic alopecia was observed in only two subjects. We have shown no correlation between acne severity and clinical markers of androgenicity in women. This suggests that in most cases factors other than hyperandrogenaemia are necessary for the development of acne.

  7. Androgen receptor expression in gastrointestinal stromal tumor.

    Science.gov (United States)

    Lopes, Lisandro F; Bacchi, Carlos E

    2009-03-01

    The aim of this study was to evaluate the expression of estrogen, progesterone, and androgen receptors in a large series of gastrointestinal stromal tumors. Clinical and pathologic data were reviewed in 427 cases of gastrointestinal stromal tumor and the expression of such hormone receptors was investigated by immunohistochemistry using tissue microarray technique. All tumors were negative for estrogen receptor expression. Progesterone and androgen receptors expression was observed in 5.4% and 17.6% of tumors, respectively. We found the higher average age at diagnosis, the lower frequency of tumors located in the small intestine, and the higher frequency of extragastrointestinal tumors to be statistically significant in the group of tumors with androgen receptor expression in contrast to the group showing no androgen receptor expression. There was no statistic difference between such groups regarding sex, tumor size, mitotic count, cell morphology, and risk of aggressive behavior. Considering that the expression of androgen receptors in gastrointestinal stromal tumors is not negligible, further studies are encouraged to establish the role of androgen deprivation therapy for gastrointestinal stromal tumors.

  8. High-Dose Radiotherapy With or Without Androgen Deprivation Therapy for Intermediate-Risk Prostate Cancer: Cancer Control and Toxicity Outcomes

    Energy Technology Data Exchange (ETDEWEB)

    Edelman, Scott [Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA (United States); Liauw, Stanley L. [Department of Radiation Oncology, University of Chicago, Chicago, IL (United States); Rossi, Peter J.; Cooper, Sherrie [Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA (United States); Jani, Ashesh B., E-mail: abjani@emory.edu [Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA (United States)

    2012-08-01

    Purpose: To evaluate the impact of short-course androgen deprivation therapy (ADT) on cancer control outcomes and toxicity in intermediate-risk prostate cancer treated with dose-escalated external beam radiotherapy (high-dose radiotherapy [HDRT]). Methods and Materials: Demographic, disease, and treatment characteristics of prostate cancer patients at 2 institution consortiums were charted. Of 296 men with intermediate-risk prostate cancer (defined as {>=}T2b, prostate-specific antigen level >10 ng/mL, or Gleason score [GS] of 7, with none of the following: {>=}T3, prostate-specific antigen level >20 ng/mL, GS {>=}8, or positive nodes) treated with HDRT to a dose of 72 Gy or greater, 123 received short-course ADT and 173 did not. Univariate and multivariate analyses on biochemical failure-free survival (BFFS) (including subset analysis by disease factors) and on overall survival (OS) were performed, as were comparisons of gastrointestinal (GI) and genitourinary (GU) toxicity rates. Results: For the whole group, the median dose was 75.6 Gy; the minimum follow-up was 2 years, and the median follow-up was 47.4 months. For ADT vs. no ADT, the 5-year BFFS rate was 86% vs. 79% (p = 0.138) and the 5-year OS rate was 87% vs. 80% (p = 0.159). On multivariate analysis, percent positive cores (PPC) (p = 0.002) and GS (p = 0.008) were significantly associated with BFFS, with ADT showing a trend (p = 0.055). The impact of ADT was highest in the subsets with PPC greater than 50% (p = 0.019), GS 4+3 (p = 0.078), and number of risk factors greater than 1 (p = 0.022). Only intensity-modulated radiotherapy use (p = 0.012) and GS (p = 0.023) reached significance for OS, and there were no significant differences in GU or GI toxicity. Conclusions: Although the use of ADT with HDRT did not influence BFFS, our study suggests a benefit in patients with PPC greater than 50%, GS 4+3, or multiple risk factors. No OS benefit was shown, and ADT was not associated with additional radiotherapy

  9. Influence of Androgen Deprivation Therapy on All-Cause Mortality in Men With High-Risk Prostate Cancer and a History of Congestive Heart Failure or Myocardial Infarction

    Energy Technology Data Exchange (ETDEWEB)

    Nguyen, Paul L., E-mail: pnguyen@LROC.harvard.edu [Department of Radiation Oncology, Dana Farber Cancer Institute and Brigham and Women' s Hospital, Harvard Medical School, Boston, MA (United States); Chen, Ming-Hui [Department of Statistics, University of Connecticut, Storrs, CT (United States); Beckman, Joshua A. [Department of Cardiology, Brigham and Women' s Hospital, Harvard Medical School, Boston, MA (United States); Beard, Clair J.; Martin, Neil E. [Department of Radiation Oncology, Dana Farber Cancer Institute and Brigham and Women' s Hospital, Harvard Medical School, Boston, MA (United States); Choueiri, Toni K. [Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA (United States); Hu, Jim C. [Division of Urologic Surgery, Brigham and Women' s/Faulkner Hospital, Harvard Medical School, Boston, MA (United States); Hoffman, Karen E. [Department of Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX (United States); Dosoretz, Daniel E. [21st Century Oncology, Fort Myers, FL (United States); Moran, Brian J. [Chicago Prostate Center, Westmont, IL (United States); Salenius, Sharon A. [21st Century Oncology, Fort Myers, FL (United States); Braccioforte, Michelle H. [Chicago Prostate Center, Westmont, IL (United States); Kantoff, Philip W. [Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA (United States); D' Amico, Anthony V. [Department of Radiation Oncology, Dana Farber Cancer Institute and Brigham and Women' s Hospital, Harvard Medical School, Boston, MA (United States); Ennis, Ronald D. [Department of Radiation Oncology, St. Luke' s-Roosevelt and Beth Israel Hospitals, Continuum Cancer Centers of New York, Albert Einstein College of Medicine, New York, NY (Israel)

    2012-03-15

    Purpose: It is unknown whether the excess risk of all-cause mortality (ACM) observed when androgen deprivation therapy (ADT) is added to radiation for men with prostate cancer and a history of congestive heart failure (CHF) or myocardial infarction (MI) also applies to those with high-risk disease. Methods and Materials: Of 14,594 men with cT1c-T3aN0M0 prostate cancer treated with brachytherapy-based radiation from 1991 through 2006, 1,378 (9.4%) with a history of CHF or MI comprised the study cohort. Of these, 22.6% received supplemental external beam radiation, and 42.9% received a median of 4 months of neoadjuvant ADT. Median age was 71.8 years. Median follow-up was 4.3 years. Cox multivariable analysis tested for an association between ADT use and ACM within risk groups, after adjusting for treatment factors, prognostic factors, and propensity score for ADT. Results: ADT was associated with significantly increased ACM (adjusted hazard ratio [AHR] = 1.76; 95% confidence interval [CI], 1.32-2.34; p = 0.0001), with 5-year estimates of 22.71% with ADT and 11.62% without ADT. The impact of ADT on ACM by risk group was as follows: high-risk AHR = 2.57; 95% CI, 1.17-5.67; p = 0.019; intermediate-risk AHR = 1.75; 95% CI, 1.13-2.73; p = 0.012; low-risk AHR = 1.52; 95% CI, 0.96-2.43; p = 0.075). Conclusions: Among patients with a history of CHF or MI treated with brachytherapy-based radiation, ADT was associated with increased all-cause mortality, even for patients with high-risk disease. Although ADT has been shown in Phase III studies to improve overall survival in high-risk disease, the small subgroup of high-risk patients with a history of CHF or MI, who represented about 9% of the patients, may be harmed by ADT.

  10. Comparison of the efficacy on serum androgenic hormone levels between isotretinoin, cyproterone acetate/ethynil estradiol and combination therapies in females with acne vulgaris

    Directory of Open Access Journals (Sweden)

    Hilal Gökalp

    2012-12-01

    Full Text Available Objective: Acne vulgaris is one of the most common skin disorders, and is a multifactorial disease characterized by androgenic stimulation of sebaceous glands. This study aimed to further understand the antiandrogenic effects of isotretinoin by using isotretinoin, cyproterone acetate/ethynil estradiol (CTA/EE and isotretinoin+CTA/EE combination treatments with analyzing their effects on serum androgenic hormon levels. Materials and methods: 60 females that were clinically evaluated as grade 4-8 on Allen-Smith scale were selected from our patient population for whom isotretinoin, CTA/EE and isotretinoin+CTA/EE combination treatment was planned. Fasting androgenic hormone levels (androstenedion, luteinizing hormone (LH, follicle stimulating hormone (FSH, dehidroepiandrosteron sulfate (DHEAS, free and total testosterone were detected in venous blood before treatment and on the third and the sixth month of study. Results: The statistical analysis showed that similar to the CTA/EE treatment; the decrease of the serum androstenedion and free testosterone levels with isotretinoin treatment in females with acne vulgaris were found to be statistically significant (p0,0056. There is no statistically significant change in LH/FSH ratio in isotretinoin monotherapy, so as in CTA/EE treatment (p>0,0056. Conclusion: Our study demonstrates isotretinoin monotherapy made us to think that antiandrogenic effect may be one of the pathways of antiacne effect of isotretinoin. No statistically significant correlation was found between the severity of acne vulgaris and the androgenic hormone levels.

  11. Use of acid suppressive therapy in hospitalized non-critically ill patients

    Institute of Scientific and Technical Information of China (English)

    Marwan; Sheikh-Taha; Sarah; Alaeddine; Julie; Nassif

    2012-01-01

    AIM: To assess the appropriateness of prescribing acid suppressive therapy (AST) in a general medicine service in a tertiary care hospital. METHODS: In this retrospective observational study, we reviewed the inpatient records of all patients admitted to the general medical service in a tertiary care hospital in Beirut, Lebanon, from April 1 to May 31, 2011. Treatment with AST was considered appropriate if the patient had a specific indication or appropriate treatment purpose [e.g. , gastro-esophageal reflux disease (GERD), peptic ulcer disease, dyspepsia, acute or suspected gastrointestinal (GI) bleeding]. Appropriate administration of stress ulcer prophylaxis (SUP) was derived from an internal guideline that is based on the American Society of Health System Pharmacists guidelines. Prophylaxis was considered appropriate if a patient had 1 absolute indication (coagulopathy or requiring mechanical ventilation), or 2 or more relative indications (sepsis, occult bleeding, use of high dose corticosteroids, recent use of non-steroidal anti-inflammatory drugs for more than 3 mo, renal or liver failure, enteral feeding and anticoagulant use). RESULTS: Of the 153 patient admissions during the study period, 130 patients (85%) were started on AST, out of which 11 (8.5%) had a diagnosis that sup-ports the use of this therapy (GI bleed, gastritis and GERD), 16 (12.3%) had an absolute indication for SUP, 59 (45.4%) had 2 or more relative indications for SUP, and 44 (33.8%) received AST without an appropriate indication. In addition, one patient with an absolute indication for SUP and four with two or more relative indications did not receive AST. Rabeprazole was the most frequently used AST (59.2%), followed by omeprazole (24.6%), esomeprazole (11.6%) and ranitidine (4.6%). The dose of AST was appropriate in 126 patients (96.9%) and the route of administration was appropriate in 123 patients (94.6%). Fifteen of the admitted patients (10%) were discharged on AST, 7 of which (47

  12. Adjudicated morbidity and mortality outcomes by age among individuals with HIV infection on suppressive antiretroviral therapy.

    Directory of Open Access Journals (Sweden)

    Christopher J Miller

    Full Text Available BACKGROUND: Non-AIDS conditions such as cardiovascular disease and non-AIDS defining cancers dominate causes of morbidity and mortality among persons with HIV on suppressive combination antiretroviral therapy. Accurate estimates of disease incidence and of risk factors for these conditions are important in planning preventative efforts. METHODS: With use of medical records, serious non-AIDS events, AIDS events, and causes of death were adjudicated using pre-specified criteria by an Endpoint Review Committee in two large international trials. Rates of serious non-AIDS which include cardiovascular disease, end-stage renal disease, decompensated liver disease, and non-AIDS cancer, and other serious (grade 4 adverse events were determined, overall and by age, over a median follow-up of 4.3 years for 3,570 participants with CD4+ cell count ≥300 cells/mm³ who were taking antiretroviral therapy and had an HIV RNA level ≤500 copies/mL. Cox models were used to examine the effect of age and other baseline factors on risk of a composite outcome of all-cause mortality, AIDS, or serious non-AIDS. RESULTS: Five-year Kaplan-Meier estimates of the composite outcome, overall and by age were 8.3% (overall, 3.6% (<40, 8.7% (40-49 and 16.1% (≥50, respectively (p<0.001. In addition to age, smoking and higher levels of interleukin-6 and D-dimer were significant predictors of the composite outcome. The composite outcome was dominated by serious non-AIDS events (overall 65% of 277 participants with a composite event. Most serious non-AIDS events were due to cardiovascular disease and non-AIDS cancers. CONCLUSIONS: To date, few large studies have carefully collected data on serious non-AIDS outcomes. Thus, reliable estimates of event rates are scarce. Data cited here, from a geographically diverse cohort, will be useful for planning studies of interventions aimed at reducing rates of serious non-AIDS events among people with HIV.

  13. Early mortality and AIDS progression despite high initial antiretroviral therapy adherence and virologic suppression in Botswana.

    Directory of Open Access Journals (Sweden)

    Katherine T Steele

    Full Text Available BACKGROUND: Adverse outcomes occurring early after antiretroviral therapy (ART initiation are common in sub-Saharan Africa, despite reports of high levels of ART adherence in this setting. We sought to determine the relationship between very early ART adherence and early adverse outcomes in HIV-infected adults in Botswana. METHODS: This prospective cohort study of 402 ART-naïve, HIV-infected adults initiating ART at a public HIV clinic in Gaborone, Botswana evaluated the relationship between suboptimal early ART adherence and HIV treatment outcomes in the initial months after ART initiation. Early adherence during the interval between initial ART dispensation and first ART refill was calculated using pill counts. In the primary analysis patients not returning to refill and those with adherence <0.95 were considered to have suboptimal early adherence. The primary outcome was death or loss to follow-up during the first 6 months of ART; a secondary composite outcome included the primary outcome plus incident opportunistic illness (OIs and virologic failure. We also calculated the percent of early adverse outcomes theoretically attributable to suboptimal early adherence using the population attributable risk percent (PAR%. RESULTS: Suboptimal early adherence was independently associated with loss to follow-up and death (adjusted OR 2.3, 95% CI 1.1-4.8 and with the secondary composite outcome including incident OIs and virologic failure (adjusted OR 2.6, 95% CI 1.4-4.7. However, of those with early adverse outcomes, less than one-third had suboptimal adherence and approximately two-thirds achieved virologic suppression. The PAR% relating suboptimal early adherence and primary and secondary outcomes were 14.7% and 17.7%, respectively. CONCLUSIONS: Suboptimal early adherence was associated with poor outcomes, but most early adverse outcomes occurred in patients with optimal early adherence. Clinical care and research efforts should focus on

  14. Hormone therapy for transgender patients

    Science.gov (United States)

    2016-01-01

    Many transgender men and women seek hormone therapy as part of the transition process. Exogenous testosterone is used in transgender men to induce virilization and suppress feminizing characteristics. In transgender women, exogenous estrogen is used to help feminize patients, and anti-androgens are used as adjuncts to help suppress masculinizing features. Guidelines exist to help providers choose appropriate candidates for hormone therapy, and act as a framework for choosing treatment regimens and managing surveillance in these patients. Cross-sex hormone therapy has been shown to have positive physical and psychological effects on the transitioning individual and is considered a mainstay treatment for many patients. Bone and cardiovascular health are important considerations in transgender patients on long-term hormones, and care should be taken to monitor certain metabolic indices while patients are on cross-sex hormone therapy. PMID:28078219

  15. Androgen receptor abnormalities

    NARCIS (Netherlands)

    A.O. Brinkmann (Albert); G.G.J.M. Kuiper (George); C. Ris-Stalpers (Carolyn); H.C.J. van Rooij (Henri); G. Romalo (G.); G. Trifiro (Gianluca); E. Mulder (Eppo); L. Pinsky (L.); H.U. Schweikert (H.); J. Trapman (Jan)

    1991-01-01

    markdownabstract__Abstract__ The human androgen receptor is a member of the superfamily of steroid hormone receptors. Proper functioning of this protein is a prerequisite for normal male sexual differentiation and development. The cloning of the human androgen receptor cDNA and the elucidation of t

  16. New therapy with ASC-J9® to suppress the prostatitis via altering the cytokine CCL2 signals.

    Science.gov (United States)

    Lin, Shin-Jen; Chou, Fu-Ju; Lin, Chang-Yi; Chang, Hong-Chiang; Yeh, Shuyuan; Chang, Chawnshang

    2016-10-11

    Prostatitis is a common disease contributing to 8% of all urologist visits. Yet the etiology and effective treatment remain to be further elucidated. Using a non-obese diabetes mouse model that can be induced by autoimmune response for the spontaneous development of prostatitis, we found that injection of the ASC-J9® at 75 mg/Kg body weight/48 hours led to significantly suppressed prostatitis that was accompanied with reduction of lymphocyte infiltration with reduced CD4+ T cells in prostate. In vitro studies with a co-culture system also confirmed that ASC-J9® treatment could suppress the CD4+ T cell migration to prostate stromal cells. Mechanisms dissection indicated that ASC-J9® can suppress CD4+ T cell migration via decreasing the cytokine CCL2 in vitro and in vivo, and restoring CCL2 could interrupt the ASC-J9® suppressed CD4+ T cell migration. Together, results from in vivo and in vitro studies suggest that ASC-J9® can suppress prostatitis by altering the autoimmune response induced by CD4+ T cell recruitment, and using ASC-J9® may help us to develop a potential new therapy to battle the prostatitis with little side effects.

  17. Improvement in scalp hair growth in androgen-deficient women treated with testosterone: a questionnaire study

    OpenAIRE

    Glaser, RL; Dimitrakakis, C.; Messenger, AG

    2012-01-01

    Background Androgens are thought to have an adverse effect on female scalp hair growth. However, our clinical experience of androgen replacement therapy in women with androgen deficiency, in which hair loss was seldom reported, led us to question this concept. Objectives To evaluate the effect of subcutaneous testosterone therapy on scalp hair growth in female patients. Methods A total of 285 women, treated for a minimum of 1 year with subcutaneous testosterone implants for symptoms of androg...

  18. Neuroendocrine prostate cancer (NEPCa) increased the neighboring PCa chemo-resistance via altering the PTHrP/p38/Hsp27/androgen receptor (AR)/p21 signals

    Science.gov (United States)

    Cui, Yun; Sun, Yin; Hu, Shuai; Luo, Jie; Li, Lei; Li, Xin; Yeh, Shuyuan; Jin, Jie; Chang, Chawnshang

    2016-01-01

    Prostatic neuroendocrine cells (NE) are an integral part of prostate cancer (PCa) that are associated with PCa progression. As the current androgen-deprivation therapy (ADT) with anti-androgens may promote the neuroendocrine PCa (NEPCa) development, and few therapies can effectively suppress NEPCa, understanding the impact of NEPCa on PCa progression may help us to develop better therapies to battle PCa. Here we found NEPCa cells could increase the docetaxel-resistance of their neighboring PCa cells. Mechanism dissection revealed that through secretion of PTHrP, NEPCa cells could alter the p38/MAPK/Hsp27 signals in their neighboring PCa cells that resulted in increased androgen receptor (AR) activity via promoting AR nuclear translocation. The consequences of increased AR function might then increase docetaxel-resistance via increasing p21 expression. In vivo xenograft mice experiments also confirmed NEPCa could increase the docetaxel-resistance of neighboring PCa, and targeting this newly identified PTHrP/p38/Hsp27/AR/p21 signaling pathway with either p38 inhibitor (SB203580) or sh-PTHrP may result in improving/restoring the docetaxel sensitivity to better suppress PCa. PMID:27375022

  19. Intratumoral de novo steroid synthesis activates androgen receptor in castration-resistant prostate cancer and is upregulated by treatment with CYP17A1 inhibitors.

    Science.gov (United States)

    Cai, Changmeng; Chen, Sen; Ng, Patrick; Bubley, Glenn J; Nelson, Peter S; Mostaghel, Elahe A; Marck, Brett; Matsumoto, Alvin M; Simon, Nicholas I; Wang, Hongyun; Chen, Shaoyong; Balk, Steven P

    2011-10-15

    Relapse of castration-resistant prostate cancer (CRPC) that occurs after androgen deprivation therapy of primary prostate cancer can be mediated by reactivation of the androgen receptor (AR). One important mechanism mediating this AR reactivation is intratumoral conversion of the weak adrenal androgens DHEA and androstenedione into the AR ligands testosterone and dihydrotestosterone. DHEA and androstenedione are synthesized by the adrenals through the sequential actions of the cytochrome P450 enzymes CYP11A1 and CYP17A1, so that CYP17A1 inhibitors such as abiraterone are effective therapies for CRPC. However, the significance of intratumoral CYP17A1 and de novo androgen synthesis from cholesterol in CRPC, and the mechanisms contributing to CYP17A1 inhibitor resistance/relapse, remain to be determined. We report that AR activity in castration-resistant VCaP tumor xenografts can be restored through CYP17A1-dependent de novo androgen synthesis, and that abiraterone treatment of these xenografts imposes selective pressure for increased intratumoral expression of CYP17A1, thereby generating a mechanism for development of resistance to CYP17A1 inhibitors. Supporting the clinical relevance of this mechanism, we found that intratumoral expression of CYP17A1 was markedly increased in tumor biopsies from CRPC patients after CYP17A1 inhibitor therapy. We further show that CRPC cells expressing a progesterone responsive T877A mutant AR are not CYP17A1 dependent, but that AR activity in these cells is still steroid dependent and mediated by upstream CYP11A1-dependent intraturmoral pregnenolone/progesterone synthesis. Together, our results indicate that CRPCs resistant to CYP17A1 inhibition may remain steroid dependent and therefore responsive to therapies that can further suppress de novo intratumoral steroid synthesis.

  20. The Efficacy of Thyrotropin Suppression Therapy in Treatment of Differentiated Thyroid Cancer after Total Thyroidectomy

    Directory of Open Access Journals (Sweden)

    Abo-Touk Niveen A.

    2015-06-01

    Full Text Available Background: The aim of this prospective study was to assess the effect of the TSH suppression on both disease-free and overall survivals in patients with nonmetastatic differentiated thyroid cancer (DTC after total thyroidectomy.

  1. A novel approach to breast cancer prevention: reducing excessive ovarian androgen production in elderly women.

    Science.gov (United States)

    Secreto, Giorgio; Sieri, Sabina; Agnoli, Claudia; Grioni, Sara; Muti, Paola; Zumoff, Barnett; Sant, Milena; Meneghini, Elisabetta; Krogh, Vittorio

    2016-08-01

    Minimizing endogenous estrogen production and activity in women at high risk for breast cancer is a prominent approach to prevention of the disease. A number of clinical trials have shown that the administration of selective-estrogen receptor modulators or aromatase inhibitors significantly reduces the incidence of breast cancer in healthy women. Unfortunately, these drugs often produce adverse effects on the quality of life and are, therefore, poorly accepted by many women, even those who are at high risk for breast cancer. We propose a novel alternative approach to decreasing estrogen production: suppression of ovarian synthesis of the androgen precursors of estrogens by administration of long-acting gonadotropin-releasing hormone analogs to women with ovarian stromal hyperplasia. The specific target population would be elderly postmenopausal women, at increased risk of breast cancer, and with high blood levels of testosterone, marker of ovarian hyperandrogenemia, and recognized factor of risk for breast cancer. Testosterone levels are measured at baseline to identify women at risk and during the follow-up to evaluate the effectiveness of therapy. The postmenopausal ovary is an important source of excessive androgen production which originates from the ovarian interstitial cell hyperplasia frequently present in breast cancer patients. We propose to counter the source of androgen excess in women with ovarian stromal hyperplasia, thus reducing the substrate for estrogen formation without completely inhibiting estrogen synthesis. Available evidence indicates that gonadotropin-releasing hormone analogs can be safely used for breast cancer prevention in postmenopausal women.

  2. CD4 changes among virologically suppressed patients on antiretroviral therapy: a systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    Nathan Ford

    2015-08-01

    Full Text Available Introduction: The effectiveness of antiretroviral therapy (ART is assessed by measuring CD4 cell counts and viral load. Recent studies have questioned the added value of routine CD4 cell count measures in patients who are virologically suppressed. Methods: We systematically searched three databases and two conference sites up to 31 October 2014 for studies reporting CD4 changes among patients who were on ART and virologically suppressed. No geographic, language or age restrictions were applied. Results and discussion: We identified 12 published and 1 unpublished study reporting CD4 changes among 20,297 virologically suppressed patients. The pooled proportion of patients who experienced an unexplained, confirmed CD4 decline was 0.4% (95% CI 0.2–0.6%. Results were not influenced by duration of follow-up, age, study design or region of economic development. No studies described clinical adverse events among virologically suppressed patients who experienced CD4 declines. Conclusions: The findings of this review support reducing or stopping routine CD4 monitoring for patients who are immunologically stable on ART in settings where routine viral load monitoring is provided.

  3. History of viral suppression on combination antiretroviral therapy as a predictor of virological failure after a treatment change

    DEFF Research Database (Denmark)

    Reekie, J; Mocroft, A; Ledergerber, B

    2010-01-01

    OBJECTIVES: HIV-infected persons experience different patterns of viral suppression after initiating combination antiretroviral therapy (cART). The relationship between such differences and risk of virological failure after starting a new antiretroviral could help with patient monitoring strategies....... METHODS: A total of 1827 patients on cART starting at least one new antiretroviral from 1 January 2000 while maintaining a suppressed viral load were included in the analysis. Poisson regression analysis identified factors predictive of virological failure after baseline in addition to traditional...... demographic variables. Baseline was defined as the date of starting new antiretrovirals. RESULTS: Four hundred and fifty-one patients (24.7%) experienced virological failure, with an incidence rate (IR) of 7.3 per 100 person-years of follow-up (PYFU) [95% confidence interval (CI) 6.7-8.0]. After adjustment...

  4. Evolutionary strategy for systemic therapy of metastatic breast cancer: balancing response with suppression of resistance.

    Science.gov (United States)

    Kam, Yoonseok; Das, Tuhin; Minton, Susan; Gatenby, Robert A

    2014-07-01

    Conventional systemic therapy for disseminated breast cancer is based on the general assumption that the greatest patient benefit is achieved by killing the maximum number of tumor cells. While this strategy often achieves a significant reduction in tumor burden, most patients with metastatic breast cancer ultimately die from their disease as therapy fails because tumor cells evolve resistance. We propose that the conventional maximum dose/maximum cell kill cancer therapy, when viewed from an evolutionary vantage, is suboptimal and likely even harmful as it accelerates evolution and growth of the resistant phenotypes that ultimately cause patient death. As an alternative, we are investigating evolutionary therapeutic strategies that shift the treatment goal from killing the maximum number of cancer cells to maximizing patient survival. Here we introduce two novel approaches for systemic therapy for metastatic breast cancer, considering the evolutionary nature of tumor progression; adaptive therapy and double-bind therapy.

  5. Alterations in ubiquitin ligase Siah-2 and its corepressor N-CoR after P-MAPA immunotherapy and anti-androgen therapy: new therapeutic opportunities for non-muscle invasive bladder cancer.

    Science.gov (United States)

    Garcia, Patrick Vianna; Apolinário, Letícia Montanholi; Böckelmann, Petra Karla; da Silva Nunes, Iseu; Duran, Nelson; Fávaro, Wagner José

    2015-01-01

    The present study describes the role of the ubiquitin ligase Siah-2 and corepressor N-CoR in controlling androgen receptor (AR) and estrogen receptors (ERα and ERβ) signaling in an appropriate animal model (Fischer 344 female rats) of non-muscle invasive bladder cancer (NMIBC), especially under conditions of anti-androgen therapy with flutamide. Furthermore, this study describes the mechanisms of a promising therapeutic alternative for NMIBC based on Protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride (P-MAPA) intravesical immunotherapy combined with flutamide, involving the interaction among steroid hormone receptors, their regulators and Toll-like receptors (TLRs). Our results demonstrated that increased Siah-2 and AR protein levels and decreased N-CoR, cytochrome P450 (CYP450) and estrogen receptors levels played a critical role in the urothelial carcinogenesis, probably leading to escape of urothelial cancer cells from immune system attack. P-MAPA immunotherapy led to distinct activation of innate immune system TLRs 2 and 4-mediated, resulting in increase of interferon signaling pathway, which was more effective in recovering the immunosuppressive tumor immune microenvironment and in recovering the bladder histology features than BCG (Bacillus Calmette-Guerin) treatments. The AR blockade therapy was important in the modulating of downstream molecules of TLR2 and TLR4 signaling pathway, decreasing the inflammatory cytokines signaling and enhancing the interferon signaling pathway when associated with P-MAPA. Taken together, the data obtained suggest that interferon signaling pathway activation and targeting AR and Siah-2 signals by P-MAPA intravesical immunotherapy alone and/ or in combination with AR blockade may provide novel therapeutic approaches for NMIBC.

  6. Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome.

    Science.gov (United States)

    Hara, Takahito; Miyazaki, Jun-ichi; Araki, Hideo; Yamaoka, Masuo; Kanzaki, Naoyuki; Kusaka, Masami; Miyamoto, Masaomi

    2003-01-01

    Most prostate cancers (PCs) become resistant to combined androgen blockade therapy with surgical or medical castration and antiandrogens after several years. Some of these refractory PCs regress after discontinuation of antiandrogen administration [antiandrogen withdrawal syndrome (AWS)]. Although the molecular mechanisms of the AWS are not fully understood because of the lack of suitable experimental models, one hypothesis of the mechanism is mutation of androgen receptor (AR). However, bicalutamide, which has become the most prevalent pure antiandrogen, does not work as an agonist for any mutant AR detected thus far in PC. To elucidate the mechanisms of the AWS, we established and characterized novel LNCaP cell sublines, LNCaP-cxDs, which were generated in vitro by culturing androgen-dependent LNCaP-FGC human PC cells in androgen-depleted medium with bicalutamide to mimic the combined androgen blockade therapy. LNCaP-FGC cells did not grow at first, but they started to grow after 6-13 weeks of culture. Bicalutamide stimulated LNCaP-cxD cell growth and increased prostate-specific antigen secretion from LNCaP-cxD cells both in vitro and in vivo. Sequencing of AR transcripts revealed that the AR in LNCaP-cxD cells harbors a novel mutation in codon 741, TGG (tryptophan) to TGT (cysteine; W741C), or in codon 741, TGG to TTG (leucine; W741L), in the ligand-binding domain. Transactivation assays showed that bicalutamide worked as an agonist for both W741C and W741L mutant ARs. Importantly, another antiandrogen, hydroxyflutamide, worked as an antagonist for these mutant ARs. In summary, we demonstrate for the first time that within only 6-13 weeks of in vitro exposure to bicalutamide, LNCaP-FGC cells, whose growth had initially been suppressed, came to use bicalutamide as an AR agonist via W741 AR mutation to survive. Our data strongly support the hypothesis that AR mutation is one possible mechanism of the AWS and suggest that flutamide might be effective as a second

  7. Dopa therapy and action impulsivity: subthreshold error activation and suppression in Parkinson's disease

    NARCIS (Netherlands)

    Fluchère, F.; Deveaux, M.; Burle, B.; Vidal, F.; van den Wildenberg, W.P.M.; Witjas, T.; Eusebio, A.; Azulay, J.-P.; Hasbroucq, T.

    2015-01-01

    Rationale: Impulsive actions entail (1) capture of the motor system by an action impulse, which is an urge to act and (2) failed suppression of that impulse in order to prevent a response error. Several studies indicate that dopaminergic treatment can induce action impulsivity in patients diagnosed

  8. The influence of Helicobacter pylori on oesophageal acid exposure in GERD during acid suppressive therapy

    NARCIS (Netherlands)

    Peters, FTM; Kuipers, EJ; Ganesh, S; Sluiter, WJ; Klinkenberg-Knol, EC; Lamers, CBHW; Kleibeuker, JH

    1999-01-01

    Background: Helicobacter pylori exaggerates the effect of acid suppressive drugs on intragastric pH. It is unknown whether this is relevant for the treatment of GERD. Aim: To compare oesophageal acid exposure and symptoms in H. pylori-negative and H. pylori-positive GERD patients during low and prof

  9. A physiological role for androgen actions in the absence of androgen receptor DNA binding activity.

    Science.gov (United States)

    Pang, Tammy P S; Clarke, Michele V; Ghasem-Zadeh, Ali; Lee, Nicole K L; Davey, Rachel A; MacLean, Helen E

    2012-01-01

    We tested the hypothesis that androgens have physiological actions via non-DNA binding-dependent androgen receptor (AR) signaling pathways in males, using our genetically modified mice that express a mutant AR with deletion of the 2nd zinc finger of the DNA binding domain (AR(ΔZF2)) that cannot bind DNA. In cultured genital skin fibroblasts, the mutant AR(ΔZF2) has normal ligand binding ability, phosphorylates ERK-1/2 in response to 1 min DHT treatment (blocked by the AR antagonist bicalutamide), but has reduced androgen-dependent nuclear localization compared to wildtype (WT). AR(ΔZF2) males have normal baseline ERK-1/2 phosphorylation, with a 1.5-fold increase in Akt phosphorylation in AR(ΔZF2) muscle vs WT. To identify physiological actions of non-DNA binding-dependent AR signaling, AR(ΔZF2) males were treated for 6 weeks with dihydrotestosterone (DHT). Cortical bone growth was suppressed by DHT in AR(ΔZF2) mice (6% decrease in periosteal and 7% decrease in medullary circumference vs untreated AR(ΔZF2) males). In conclusion, these data suggest that non-DNA binding dependent AR actions suppress cortical bone growth, which may provide a mechanism to fine-tune the response to androgens in bone.

  10. Prospective assessment of pituitary size and shape on MR imaging after suppressive hormonal therapy in central precocious puberty

    Energy Technology Data Exchange (ETDEWEB)

    Beek, J.T. van; Sharafuddin, M.J.A.; Kao, S.C.S. [Department of Radiology-JPP 3889, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52246 (United States); Luisiri, A. [Cardinal Glennon Children' s Hospital, St. Louis, Missouri (United States); Garibaldi, L.R. [Children' s Hospital of New Jersey, Newark Beth Israel Medical Center, Newark, New Jersey (United States); St. Barnabas Medical Center, Livingston, New Jersey (United States)

    2000-07-01

    Objective. The diagnostic significance of an enlarged pituitary gland regarding both shape and size parameters on MR imaging has previously been demonstrated in children with central precocious puberty. This study was designed to assess changes in these parameters following successful suppressive therapy of central precocious puberty with the gonadotropin-releasing hormone (GnRH) analogue. Materials and methods. Twelve girls (mean age 7.3 years) with central precocious puberty were prospectively enrolled in our study protocol. Sagittal and coronal MR images of the pituitary region were obtained in all patients before treatment and after at least 6 months of GnRH analogue therapy (mean 18.0 months). Parameters measured included pituitary gland height, length, width, sagittal cross-sectional area, and volume. Results. All patients had excellent clinical response to treatment with arrest of secondary sexual development, normalization of serum estradiol levels, and complete obliteration of the LH response to diagnostic GnRH stimulation. No significant change occurred in any pituitary size or shape parameter following GnRH analogue therapy. Conclusion. Favorable clinical response to GnRH analogue therapy in central precocious puberty is not accompanied by significant a change in pituitary gland size and shape. (orig.)

  11. The Effect of Prior Androgen Synthesis Inhibition on Outcomes of Subsequent Therapy with Docetaxel in Patients with Metastatic Castrate Resistant Prostate Cancer: Results from a Retrospective Analysis of a Randomized Phase 3 Clinical Trial (CALGB 90401) (Alliance)

    Science.gov (United States)

    Aggarwal, Rahul; Halabi, Susan; Kelly, William Kevin; George, Daniel; Mahoney, John F.; Millard, Frederick; Stadler, Walter M.; Morris, Michael J.; Kantoff, Philip; Monk, J. Paul; Carducci, Michael; Small, Eric J.

    2013-01-01

    Background Preliminary data suggests a potential decreased benefit of docetaxel in metastatic castration-resistant prostate cancer (mCRPC) patients previously treated with abiraterone acetate, a novel androgen synthesis inhibitor (ASI). CALGB 90401 (Alliance), a phase 3 trial of mCRPC patients treated with docetaxel-based chemotherapy, offered the opportunity to evaluate effect of prior ketoconazole, an earlier generation ASI, on clinical outcomes following docetaxel. Methods CALGB 90401 randomized 1050 men with chemotherapy-naïve, mCRPC to treatment with docetaxel and prednisone with either bevacizumab or placebo. 1005 men (96%) had data available regarding prior ketoconazole therapy. The effect of prior ketoconazole on overall survival (OS), progression-free survival (PFS), PSA decline, and objective response rate (ORR) observed was assessed using proportional hazards and Poisson regression method adjusted for validated prognostic factors and treatment arm. Results Baseline characteristics between patients with (N=277) and without (N=728) prior ketoconazole therapy were similar. There were no statistically significant differences between patients with and without prior ketoconazole therapy with respect to OS (median OS 21.1 vs. 22.3 months, stratified log-rank p-value=0.635); PFS (median PFS 8.1 vs. 8.6 months, stratified log-rank p-value=0.342); ≥50% PSA decline (61% vs. 66%, relative risk=1.09, adjusted p-value=0.129); or ORR (39% vs. 43%, relative risk=1.11, adjusted p-value=0.366). Conclusions As measured by OS, PFS, PSA and ORR, there is no evidence that prior treatment with ketoconazole impacts clinical outcomes in mCRPC patients treated with subsequent docetaxel-based therapy. Prospective studies are needed to assess for potential cross-resistance with novel ASIs and to define the optimal sequence of therapy in mCRPC. PMID:23913744

  12. Androgens and Androgen Derivatives: Science, Myths, and Theories: Explored From a Special Operations Perspective.

    Science.gov (United States)

    Givens, Melissa L; Deuster, Patricia

    2015-01-01

    Androgen use outside of legitimate medical therapy is a perceived concern that is drawing attention across military and specifically Special Operations Forces (SOF) communities. For leadership and the medical community to properly address the issue and relate to those individuals who are using or considering use, it will be crucial to understand the scope of the problem. Limited data suggest that the prevalence of androgen use may be increasing, and inferences made from the scientific literature suggest that SOF may be a population of concern. While risks of androgen use are well known, there are little data specific to military performance that can be applied to a rigorous risk:benefit analysis, allowing myths and poorly supported theories to perpetuate within the community. Further efforts to define the potential benefits balanced against the short- and long-term risks should be undertaken. Providers within the SOF community should arm themselves with information to engage androgen users and leadership in meaningful discussion regarding androgen use.

  13. Selective androgen receptor modulators for frailty and osteoporosis.

    Science.gov (United States)

    Kilbourne, Edward J; Moore, William J; Freedman, Leonard P; Nagpal, Sunil

    2007-10-01

    Androgens play an important role not only in male sexual differentiation, puberty, sexual behavior and spermatogenesis, but also in the maintenance of bone architecture and muscle mass and strength. For decades, steroidal androgens have been used by hypogonadal and aging men as hormone replacement therapy, and abused by prominent athletes as anabolic agents for enhancing physical performance. The use of steroidal androgens is associated with hepatotoxicity, potential for prostate stimulation, virilizing actions and other side effects resulting from their cross-reactivity to related steroid receptors. Therefore, to utilize the therapeutic potential of the androgen receptor for the treatment of indications such as osteoporosis and frailty, several pharmaceutical and biotechnology companies are developing non-steroidal tissue-selective androgen receptor modulators (SARMs) that retain the beneficial properties of natural androgens and exhibit better therapeutic indices. This article reviews the mechanism of androgen action, novel non-steroidal ligands under development and future directions of SARM research for the discovery of novel modulators for frailty and osteoporosis.

  14. Androgen synthesis inhibitors in the treatment of castration-resistant prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Mark N Stein; Neal Patel; Alexander Bershadskiy; Alisa Sokoloff; Eric A Singer

    2014-01-01

    Suppression of gonadal testosterone synthesis represents the standard ifrst line therapy for treatment of metastatic prostate cancer. However, in the majority of patients who develop castration-resistant prostate cancer (CRPC), it is possible to detect persistent activation of the androgen receptor (AR) through androgens produced in the adrenal gland or within the tumor itself. Abiraterone acetate was developed as an irreversible inhibitor of the dual functional cytochrome P450 enzyme CYP17 with activity as a 17α-hydroxylase and 17,20-lyase. CYP17 is necessary for production of nongonadal androgens from cholesterol. Regulatory approval of abiraterone in 2011, based on a phase III trial showing a signiifcant improvement in overall survival (OS) with abiraterone and prednisone versus prednisone, represented proof of principle that targeting AR is essential for improving outcomes in men with CRPC. Inhibition of 17α-hydroxylase by abiraterone results in accumulation of upstream mineralocorticoids due to loss of cortisol-mediated suppression of pituitary adrenocorticotropic hormone (ACTH), providing a rationale for development of CYP17 inhibitors with increased speciifcity for 17,20-lyase (orteronel, galeterone and VT-464) that can potentially be administered without exogenous corticosteroids. In this article, we review the development of abiraterone and other CYP17 inhibitors;recent studies with abiraterone that inform our understanding of clinical parameters such as drug effects on quality-of-life, potential early predictors of response, and optimal sequencing of abiraterone with respect to other agents;and results of translational studies providing insights into resistance mechanisms to CYP17 inhibitors leading to clinical trials with drug combinations designed to prolong abiraterone beneift or restore abiraterone activity.

  15. Update on androgenicity.

    Science.gov (United States)

    Thorneycroft, I H

    1999-02-01

    The development of a new generation of progestins deemed less androgenic than their earlier counterparts has led to a number of misconceptions regarding their possible benefits in combination oral contraceptives. All combination oral contraceptives are beneficial for treating such androgenic conditions as acne and hirsutism. The only expressed androgenic effect of some first- and second-generation combined oral contraceptives are changes in plasma lipid and lipoprotein levels. However, the overall effect of today's low-dose oral contraceptives is largely lipid neutral, and human and monkey studies have shown that oral contraceptive use is associated with reduced, not increased, atherosclerosis rates. Myocardial infarction rates are not increased among oral contraceptive users, except among those who are heavy smokers.

  16. Tumor growth suppression by gadolinium-neutron capture therapy using gadolinium-entrapped liposome as gadolinium delivery agent.

    Science.gov (United States)

    Dewi, Novriana; Yanagie, Hironobu; Zhu, Haito; Demachi, Kazuyuki; Shinohara, Atsuko; Yokoyama, Kazuhito; Sekino, Masaki; Sakurai, Yuriko; Morishita, Yasuyuki; Iyomoto, Naoko; Nagasaki, Takeshi; Horiguchi, Yukichi; Nagasaki, Yukio; Nakajima, Jun; Ono, Minoru; Kakimi, Kazuhiro; Takahashi, Hiroyuki

    2013-07-01

    Neutron capture therapy (NCT) is a promising non-invasive cancer therapy approach and some recent NCT research has focused on using compounds containing gadolinium as an alternative to currently used boron-10 considering several advantages that gadolinium offers compared to those of boron. In this study, we evaluated gadolinium-entrapped liposome compound as neutron capture therapy agent by in vivo experiment on colon-26 tumor-bearing mice. Gadolinium compound were injected intravenously via tail vein and allowed to accumulate into tumor site. Tumor samples were taken for quantitative analysis by ICP-MS at 2, 12, and 24 h after gadolinium compound injection. Highest gadolinium concentration was observed at about 2 h after gadolinium compound injection with an average of 40.3 μg/g of wet tumor tissue. We performed neutron irradiation at JRR-4 reactor facility of Japan Atomic Energy Research Institute in Tokaimura with average neutron fluence of 2×10¹² n/cm². The experimental results showed that the tumor growth suppression of gadolinium-injected irradiated group was revealed until about four times higher compared to the control group, and no significant weight loss were observed after treatment suggesting low systemic toxicity of this compound. The gadolinium-entrapped liposome will become one of the candidates for Gd delivery system on NCT.

  17. Regulation of progesterone-binding breast cyst protein GCDFP-24 secretion by estrogens and androgens in human breast cancer cells: a new marker of steroid action in breast cancer.

    Science.gov (United States)

    Simard, J; Dauvois, S; Haagensen, D E; Lévesque, C; Mérand, Y; Labrie, F

    1990-06-01

    We have previously demonstrated that androgens are potent inhibitors of breast cancer cell proliferation under both basal and estrogen-induced incubation conditions, while they suppress expression of the estrogen and progesterone receptors. To better understand the mechanisms responsible for the antagonism between androgens and estrogens in breast cancer and to obtain a new tumor marker for the actions of these two steroids, we have investigated the effects of androgens and estrogens on expression of the major protein found in human breast gross cystic disease fluid, namely GCDFP-24. This study was performed in ZR-75-1 and MCF-7 human breast cancer cells. After a 9-day incubation period, physiological concentrations of 17 beta-estradiol stimulated proliferation of ZR-75-1 and MCF-7 cells by 2- to 3.5-fold while simultaneously exerting a marked 70-90% inhibition of GCDFP-24 secretion. The estrogenic effects on GCDFP-24 secretion and cell proliferation were both competitively blocked by simultaneous incubation with the new steroidal pure antiestrogen EM-139. On the other hand, a maximal concentration (10 nM) of the nonaromatizable androgen dihydrotestosterone decreased by 50% the proliferation of ZR-75-1 cells; the half-maximal inhibitory effect was exerted at 0.01 nM. The androgen exerted a 3- to 4-fold stimulatory effect on GCDFP-24 secretion at an EC50 value of 0.01 nM. The effect of dihydrotestosterone on these parameters was competitively blocked by simultaneous incubation with the pure antiandrogen OH-flutamide. The present data show that the effects of estrogens and androgens in ZR-75-1 cells on GCDFP-24 secretion and cell growth are opposite. Similarly, in MCF-7 cells, estrogens stimulate cell growth, while GCDFP-24 secretion is inhibited. The present data also suggest that GCDFP-24 could well be a good biochemical marker for monitoring the response to androgenic and antiestrogenic compounds in the therapy of advanced breast cancer.

  18. Reinforcing aspects of androgens.

    Science.gov (United States)

    Wood, Ruth I

    2004-11-15

    Are androgens reinforcing? Androgenic-anabolic steroids (AAS) are drugs of abuse. They are taken in large quantities by athletes and others to increase performance, often with negative long-term health consequences. As a result, in 1991, testosterone was declared a controlled substance. Recently, Brower [K.J. Brower, Anabolic steroid abuse and dependence. Curr. Psychiatry Rep. 4 (2002) 377-387.] proposed a two-stage model of AAS dependence. Users initiate steroid use for their anabolic effects on muscle growth. With continued exposure, dependence on the psychoactive effects of AAS develops. However, it is difficult in humans to separate direct psychoactive effects of AAS from the user's psychological dependence on the anabolic effects of AAS. Thus, studies in laboratory animals are useful to explore androgen reinforcement. Testosterone induces a conditioned place preference in rats and mice, and is voluntarily consumed through oral, intravenous, and intracerebroventricular self-administration in hamsters. Active, gonad-intact male and female hamsters will deliver 1 microg/microl testosterone into the lateral ventricles. Indeed, some individuals self-administer testosterone intracerebroventricularly to the point of death. Male rats develop a conditioned place preference to testosterone injections into the nucleus accumbens, an effect blocked by dopamine receptor antagonists. These data suggest that androgen reinforcement is mediated by the brain. Moreover, testosterone appears to act through the mesolimbic dopamine system, a common substrate for drugs of abuse. Nonetheless, androgen reinforcement is not comparable to that of cocaine or heroin. Instead, testosterone resembles other mild reinforcers, such as caffeine, nicotine, or benzodiazepines. The potential for androgen addiction remains to be determined.

  19. Suppressive therapy using azithromycin in 2 rare cases of recurrent staphylococcal infections.

    Science.gov (United States)

    Grobost, Vincent; Rigal, Emilie; Pavier, Yoann; Vidal, Magali; Mrozek, Natacha; Beytout, Jean; Laurichesse, Henri; Lesens, Olivier

    2014-05-01

    Recurrent staphylococcal skin and soft tissue infections may recur despite decontamination and multiple courses of antibiotic therapy and may dramatically impair the patient's quality of life. We report successful use of long-term azithromycin prophylaxis in a recurrent laryngitis and a scalp folliculitis due to methicillin-susceptible Staphylococcus aureus.

  20. Androgenic Regulation of White Adipose Tissue-Prostate Cancer Interactions

    Science.gov (United States)

    2015-08-01

    oncogenes; inactivation of tumor suppression genes; and interaction between cancer cells and tumor-associated stroma and tumor- associated macrophages ...into inflamed tissue and dif- ferentiate into macrophages , which coordinate inflammatory re- sponses by producing chemokines and clearing debris by...AWARD NUMBER: W81XWH-10-1-0275 TITLE: Androgenic Regulation of White Adipose Tissue-Prostate Cancer Interactions PRINCIPAL INVESTIGATOR

  1. Activation of two mutant androgen receptors from human prostatic carcinoma by adrenal androgens and metabolic derivatives of testosterone.

    Science.gov (United States)

    Culig, Z; Stober, J; Gast, A; Peterziel, H; Hobisch, A; Radmayr, C; Hittmair, A; Bartsch, G; Cato, A C; Klocker, H

    1996-01-01

    The androgen receptor (AR) plays a central regulatory role in prostatic carcinoma and is a target of androgen ablation therapy. Recent detection of mutant receptors in tumor specimens suggest a contribution of AR alterations to progression towards androgen independence. In a specimen derived from metastatic prostate cancer we have reported a point mutation in the AR gene that leads to a single amino acid exchange in the ligand binding domain of the receptor. Another amino acid exchange resulting from a point mutation was also identified 15 amino acids away from our mutation. This mutation was detected in the AR gene isolated from an organ-confined prostatic tumor. Here we report the functional characterization of the two mutant receptors in the presence of adrenal androgens and testosterone metabolites. These studies were performed by cotransfecting androgen-responsive reporter genes and either the wild-type or mutant AR expression vectors into receptor negative DU-145 and CV-1 cells. The indicator genes used consisted of the promoter of the androgen-inducible prostate-specific antigen gene or the C' Delta9 enhancer fragment from the promoter of the mouse sex-limited protein driving the expression of the bacterial chloramphenicol acetyl transferase gene. Cotransfection-transactivation assays revealed that the adrenal androgen androstenedione and two products of testosterone metabolism, androsterone and androstandiol, induced reporter gene activity more efficiently in the presence of the mutant receptors than in the presence of the wild-type receptor. No difference between wild-type and mutant receptors was observed in the presence of the metabolite androstandione. The interaction of receptor-hormone complexes with target DNA was studied in vitro by electrophoretic mobility shift assays (EMSA). Dihydrotestosterone and the synthetic androgen mibolerone induced a faster migrating complex with all receptors, whereas the androgen metabolite androstandione induced this

  2. Androgen receptor drives cellular senescence.

    Directory of Open Access Journals (Sweden)

    Yelena Mirochnik

    Full Text Available The accepted androgen receptor (AR role is to promote proliferation and survival of prostate epithelium and thus prostate cancer progression. While growth-inhibitory, tumor-suppressive AR effects have also been documented, the underlying mechanisms are poorly understood. Here, we for the first time link AR anti-cancer action with cell senescence in vitro and in vivo. First, AR-driven senescence was p53-independent. Instead, AR induced p21, which subsequently reduced ΔN isoform of p63. Second, AR activation increased reactive oxygen species (ROS and thereby suppressed Rb phosphorylation. Both pathways were critical for senescence as was proven by p21 and Rb knock-down and by quenching ROS with N-Acetyl cysteine and p63 silencing also mimicked AR-induced senescence. The two pathways engaged in a cross-talk, likely via PML tumor suppressor, whose localization to senescence-associated chromatin foci was increased by AR activation. All these pathways contributed to growth arrest, which resolved in senescence due to concomitant lack of p53 and high mTOR activity. This is the first demonstration of senescence response caused by a nuclear hormone receptor.

  3. Antiretroviral therapy suppressed participants with low CD4+ T-cell counts segregate according to opposite immunological phenotypes

    Science.gov (United States)

    Pérez-Santiago, Josué; Ouchi, Dan; Urrea, Victor; Carrillo, Jorge; Cabrera, Cecilia; Villà-Freixa, Jordi; Puig, Jordi; Paredes, Roger; Negredo, Eugènia; Clotet, Bonaventura; Massanella, Marta; Blanco, Julià

    2016-01-01

    Background: The failure to increase CD4+ T-cell counts in some antiretroviral therapy suppressed participants (immunodiscordance) has been related to perturbed CD4+ T-cell homeostasis and impacts clinical evolution. Methods: We evaluated different definitions of immunodiscordance based on CD4+ T-cell counts (cutoff) or CD4+ T-cell increases from nadir value (ΔCD4) using supervised random forest classification of 74 immunological and clinical variables from 196 antiretroviral therapy suppressed individuals. Unsupervised clustering was performed using relevant variables identified in the supervised approach from 191 individuals. Results: Cutoff definition of CD4+ cell count 400 cells/μl performed better than any other definition in segregating immunoconcordant and immunodiscordant individuals (85% accuracy), using markers of activation, nadir and death of CD4+ T cells. Unsupervised clustering of relevant variables using this definition revealed large heterogeneity between immunodiscordant individuals and segregated participants into three distinct subgroups with distinct production, programmed cell-death protein-1 (PD-1) expression, activation and death of T cells. Surprisingly, a nonnegligible number of immunodiscordant participants (22%) showed high frequency of recent thymic emigrants and low CD4+ T-cell activation and death, very similar to immunoconcordant participants. Notably, human leukocyte antigen - antigen D related (HLA-DR) PD-1 and CD45RA expression in CD4+ T cells allowed reproducing subgroup segregation (81.4% accuracy). Despite sharp immunological differences, similar and persistently low CD4+ values were maintained in these participants over time. Conclusion: A cutoff value of CD4+ T-cell count 400 cells/μl classified better immunodiscordant and immunoconcordant individuals than any ΔCD4 classification. Immunodiscordance may present several, even opposite, immunological patterns that are identified by a simple immunological follow-up. Subgroup

  4. Successful treatment of metastatic androgen-independent prostate carcinoma in a transsexual patient.

    Science.gov (United States)

    Dorff, Tanya B; Shazer, Ronald L; Nepomuceno, Edward M; Tucker, Steven J

    2007-06-01

    The occurrence of prostate carcinoma in transsexual patients has rarely been reported. These cases present a unique challenge in that such patients are effectively receiving androgen deprivation therapy. By definition, their disease is androgen-independent prostate cancer, and the role of local therapy is undefined. We report on a male-to-female transsexual patient with metastatic prostate cancer treated successfully with combination chemotherapy after previous standard therapy failed.

  5. Androgen replacement therapy improves psychological distress and health-related quality of life in late onset hypogonadism patients in Chinese population

    Institute of Scientific and Technical Information of China (English)

    ZHANG Xiao-wei; LIU Zhen-hua; HU Xiao-wei; YUAN Ye-qing; BAI Wen-jun; WANG Xiao-feng; SHEN Huan; ZHAO Yong-ping

    2012-01-01

    Background Late onset hypogonadism negatively impacts on men's psychological well-being.This study was conducted to examine the interrelationship among symptoms of testosterone deficiency,psychological well-being,and quality of life.Methods Eligible subjects were randomized into active treatment and control groups,and were asked to complete the following questionnaires at baseline and month 6:aging male's symptoms (AMS) rating scale,hospital anxiety and depression scale (HADS),perceived stress scale (PSS) and the short form health survey-12 (SF-12).In this study,men were treated and monitored for 6 months with oral testosterone undecanoate (TU) capsules or vitamin E/C capsules in a single-blinded fashion.All in the active treatment group were administered a total of 120-160 mg TU orally on a daily basis.Total and free T levels between baseline and month 6 were compared.Results One hundred and sixty eligible subjects were recruited and followed up.In the active treatment group,total serum testosterone concentrations before and after intervention were (7.98±0.73) nmol/L and (13.7±1.18) nmol/L.The mean HADS anxiety subscale scores for the subjects at baseline and at month 6 were 3.47±0.4 and 1.72±0.2,respectively (t=1.526,P<0.05).Additionally,the mean HADS depression subscale scores were 4.91±0.6 and 2.39±0.3,respectively (t=3.466,P<0.05).The mean scores on PSS for the subjects at baseline and at month 6 were 12.88±2.1 and 9.83±1.7,respectively (t=4.009,P<0.05).Significantly improved SF-12 could be observed (t=1.433 and 1.118,respectively; both P<0.05).No significant changes were observed in the control group at month 6.Conclusion Androgen replacement not only improves androgen deficiency associated symptoms,but also enhances comprehensive improvement in psychological issues.(No.ChiCTR-TRC-11001811)

  6. Partial Androgen Insensitivity Syndrome

    OpenAIRE

    Sindhu Sharma, Kuldeep Singh, Sanjay Dhar*,Yudhvir Gupta

    2010-01-01

    Androgen insensitivity syndrome (AIS) present at several differentiation from genetic defects to endorgan resistance thereby producing gender dilema dispelled by sex hormones signature.It is quite traumaticfor the patients and family of the affected baby. Extreme sensitivity and awareness on the part of thecaring doctor is necessary for early diagnosis of case of AIS &for successful outcome.

  7. Partial Androgen Insensitivity Syndrome

    Directory of Open Access Journals (Sweden)

    Sindhu Sharma, Kuldeep Singh, Sanjay Dhar*,Yudhvir Gupta

    2010-01-01

    Full Text Available Androgen insensitivity syndrome (AIS present at several differentiation from genetic defects to endorgan resistance thereby producing gender dilema dispelled by sex hormones signature.It is quite traumaticfor the patients and family of the affected baby. Extreme sensitivity and awareness on the part of thecaring doctor is necessary for early diagnosis of case of AIS &for successful outcome.

  8. Androgen insensitivity syndrome

    Science.gov (United States)

    ... syndrome URL of this page: //medlineplus.gov/ency/article/001180.htm Androgen insensitivity syndrome To use the ... a condition in which the opening of the urethra is on the underside of the penis, instead of ... they can develop cancer, just like any undescended testicle. Estrogen replacement is ...

  9. Beyond androgen deprivation: ancillary integrative strategies for targeting the androgen receptor addiction of prostate cancer.

    Science.gov (United States)

    McCarty, Mark F; Hejazi, Jalal; Rastmanesh, Reza

    2014-09-01

    The large majority of clinical prostate cancers remain dependent on androgen receptor (AR) activity for proliferation even as they lose their responsiveness to androgen deprivation or antagonism. AR activity can be maintained in these circumstances by increased AR synthesis--often reflecting increased NF-κB activation; upregulation of signaling pathways that promote AR activity in the absence of androgens; and by emergence of AR mutations or splice variants lacking the ligand-binding domain, which render the AR constitutively active. Drugs targeting the N-terminal transactivating domain of the AR, some of which are now in preclinical development, can be expected to inhibit the activity not only of unmutated ARs but also of the mutant forms and splice variants selected for by androgen deprivation. Concurrent measures that suppress AR synthesis or boost AR turnover could be expected to complement the efficacy of such drugs. A number of nutraceuticals that show efficacy in prostate cancer xenograft models--including polyphenols from pomegranate, grape seed, and green tea, the crucifera metabolite diindolylmethane, and the hormone melatonin--have the potential to suppress AR synthesis via downregulation of NF-κB activity; clinical doses of salicylate may have analogous efficacy. The proteasomal turnover of the AR is abetted by diets with a high ratio of long-chain omega-3 to omega-6 fatty acids, which are beneficial in prostate cancer xenograft models; berberine and sulforaphane, by inhibiting AR's interaction with its chaperone Hsp90, likewise promote AR proteasomal degradation and retard growth of human prostate cancer in nude mice. Hinge region acetylation of the AR is required for optimal transactivational activity, and low micromolar concentrations of the catechin epigallocatechin-3-gallate (EGCG) can inhibit such acetylation--possibly explaining the ability of EGCG administration to suppress androgenic activity and cell proliferation in prostate cancer

  10. Combination Therapy with a Sodium-Glucose Cotransporter 2 Inhibitor and a Dipeptidyl Peptidase-4 Inhibitor Additively Suppresses Macrophage Foam Cell Formation and Atherosclerosis in Diabetic Mice

    Science.gov (United States)

    Hiromura, Munenori; Mori, Yusaku; Kohashi, Kyoko; Kushima, Hideki; Ohara, Makoto; Watanabe, Takuya; Andersson, Olov

    2017-01-01

    Dipeptidyl peptidase-4 inhibitors (DPP-4is), in addition to their antihyperglycemic roles, have antiatherosclerotic effects. We reported that sodium-glucose cotransporter 2 inhibitors (SGLT2is) suppress atherosclerosis in a glucose-dependent manner in diabetic mice. Here, we investigated the effects of combination therapy with SGLT2i and DPP-4i on atherosclerosis in diabetic mice. SGLT2i (ipragliflozin, 1.0 mg/kg/day) and DPP-4i (alogliptin, 8.0 mg/kg/day), either alone or in combination, were administered to db/db mice or streptozotocin-induced diabetic apolipoprotein E-null (Apoe−/−) mice. Ipragliflozin and alogliptin monotherapies improved glucose intolerance; however, combination therapy did not show further improvement. The foam cell formation of peritoneal macrophages was suppressed by both the ipragliflozin and alogliptin monotherapies and was further enhanced by combination therapy. Although foam cell formation was closely associated with HbA1c levels in all groups, DPP-4i alone or the combination group showed further suppression of foam cell formation compared with the control or SGLT2i group at corresponding HbA1c levels. Both ipragliflozin and alogliptin monotherapies decreased scavenger receptors and increased cholesterol efflux regulatory genes in peritoneal macrophages, and combination therapy showed additive changes. In diabetic Apoe−/− mice, combination therapy showed the greatest suppression of plaque volume in the aortic root. In conclusion, combination therapy with SGLT2i and DPP4i synergistically suppresses macrophage foam cell formation and atherosclerosis in diabetic mice.

  11. Antiretroviral treatment switch strategies for lowering the costs of antiretroviral therapy in subjects with suppressed HIV-1 viremia in Spain

    Directory of Open Access Journals (Sweden)

    Llibre JM

    2013-05-01

    Full Text Available Josep M Llibre,1,2 Gloria Cardona,3 José R Santos,2 Angels Andreu,3 Josep O Estrada,4 Jordi Ara,4 Xavier Bonafont,3 Bonaventura Clotet1,21HIV Unit, University Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain; 2Lluita contra la SIDA Foundation, Badalona, Barcelona, Spain; 3Hospital Pharmacy, University Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain; 4Hospital Management, University Hospital Germans Trias i Pujol, Badalona, Barcelona, SpainBackground: The current economic recession in European countries has forced governments to design emergency measures to reduce spending on drugs, including antiretroviral therapy (ART. Switching antiretroviral drugs for others that have the same efficacy and safety profile at a lower cost (cost-reduction measures, CRM could prove to be a valid means of generating savings.Methods: Descriptive study of prospective consensus-based CRM undertaken in 2011 in a Catalonian hospital HIV unit among patients with prolonged plasma HIV-1 RNA <50 copies/mL.Results: During the study period, we made 673 switches (87.5% more than the previous year, of which 378 (56.2% were CRM (16% of all patients treated, leading to a savings of €87,410/month. Switching tenofovir/emtricitabine for abacavir/lamivudine was the most common CRM (129, 31.3%, followed by simplification to boosted protease inhibitor monotherapy (bPImono, 102, 26%. The CRM that generated the greatest saving were switching to bPImono (38%, withdrawal or replacement of raltegravir (24%, switching tenofovir/emtricitabine for abacavir/lamivudine (13%, and switching to nevirapine (5%. Cost savings with CRM were slightly higher than those achieved with medication paid for by clinical trial sponsors (€80,333/month or through discount arrangements (€76,389/month.Conclusion: Proactively switching antiretroviral therapy in selected treated patients with sustained virological suppression can generate significant cost savings in pharmacy spending in

  12. Adrenal suppression: A practical guide to the screening and management of this under-recognized complication of inhaled corticosteroid therapy

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    Ahmet Alexandra

    2011-08-01

    Full Text Available Abstract Inhaled corticosteroids (ICSs are the most effective anti-inflammatory agents available for the treatment of asthma and represent the mainstay of therapy for most patients with the disease. Although these medications are considered safe at low-to-moderate doses, safety concerns with prolonged use of high ICS doses remain; among these concerns is the risk of adrenal suppression (AS. AS is a condition characterized by the inability to produce adequate amounts of the glucocorticoid, cortisol, which is critical during periods of physiological stress. It is a proven, yet under-recognized, complication of most forms of glucocorticoid therapy that can persist for up to 1 year after cessation of corticosteroid treatment. If left unnoticed, AS can lead to significant morbidity and even mortality. More than 60 recent cases of AS have been described in the literature and almost all cases have involved children being treated with ≥500 μg/day of fluticasone. The risk for AS can be minimized through increased awareness and early recognition of at-risk patients, regular patient follow-up to ensure that the lowest effective ICS doses are being utilized to control asthma symptoms, and by choosing an ICS medication with minimal adrenal effects. Screening for AS should be considered in any child with symptoms of AS, children using high ICS doses, or those with a history of prolonged oral corticosteroid use. Cases of AS should be managed in consultation with a pediatric endocrinologist whenever possible. In patients with proven AS, stress steroid dosing during times of illness or surgery is needed to simulate the protective endogenous elevations in cortisol levels that occur with physiological stress. This article provides an overview of current literature on AS as well as practical recommendations for the prevention, screening and management of this serious complication of ICS therapy.

  13. A Novel Epi-drug Therapy Based on the Suppression of BET Family Epigenetic Readers

    Science.gov (United States)

    Shin, Dong-Guk; Bayarsaihan, Dashzeveg

    2017-01-01

    Recent progress in epigenetic research has made a profound influence on pharmacoepigenomics, one of the fastest growing disciplines promising to provide new epi-drugs for the treatment of a broad range of diseases. Histone acetylation is among the most essential chromatin modifications underlying the dynamics of transcriptional activation. The acetylated genomic regions recruit the BET (bromodomain and extra-terminal) family of bromodomains (BRDs), thereby serving as a molecular scaffold in establishing RNA polymerase II specificity. Over the past several years, the BET epigenetic readers have become the main targets for drug therapy. The discovery of selective small-molecule compounds with capacity to inhibit BET proteins has paved a path for developing novel strategies against cancer, cardiovascular, skeletal, and inflammatory diseases. Therefore, further research into small chemicals impeding the regulatory activity of BRDs could offer therapeutic benefits for many health problems including tumor growth, heart disease, oral, and bone disorders. PMID:28356894

  14. Glycogen synthesis correlates with androgen-dependent growth arrest in prostate cancer

    Directory of Open Access Journals (Sweden)

    Gorin Frederic A

    2005-03-01

    Full Text Available Abstract Background Androgen withdrawal in normal prostate or androgen-dependent prostate cancer is associated with the downregulation of several glycolytic enzymes and with reduced glucose uptake. Although glycogen metabolism is known to regulate the intracellular glucose level its involvement in androgen response has not been studied. Methods We investigated the effects of androgen on glycogen phosphorylase (GP, glycogen synthase (GS and on glycogen accumulation in the androgen-receptor (AR reconstituted PC3 cell line containing either an empty vector (PC3-AR-V or vector with HPV-E7 (PC3-AR-E7 and the LNCaP cell line. Results Androgen addition in PC3 cells expressing the AR mimics androgen ablation in androgen-dependent prostate cells. Incubation of PC3-AR-V or PC3-AR-E7 cells with the androgen R1881 induced G1 cell cycle arrest within 24 hours and resulted in a gradual cell number reduction over 5 days thereafter, which was accompanied by a 2 to 5 fold increase in glycogen content. 24 hours after androgen-treatment the level of Glucose-6-P (G-6-P had increased threefold and after 48 hours the GS and GP activities increased twofold. Under this condition inhibition of glycogenolysis with the selective GP inhibitor CP-91149 enhanced the increase in glycogen content and further reduced the cell number. The androgen-dependent LNCaP cells that endogenously express AR responded to androgen withdrawal with growth arrest and increased glycogen content. CP-91149 further increased glycogen content and caused a reduction of cell number. Conclusion Increased glycogenesis is part of the androgen receptor-mediated cellular response and blockage of glycogenolysis by the GP inhibitor CP-91149 further increased glycogenesis. The combined use of a GP inhibitor with hormone therapy may increase the efficacy of hormone treatment by decreasing the survival of prostate cancer cells and thereby reducing the chance of cancer recurrence.

  15. Sexual Activity Without Condoms and Risk of HIV Transmission in Serodifferent Couples When the HIV-Positive Partner Is Using Suppressive Antiretroviral Therapy

    DEFF Research Database (Denmark)

    Rodger, Alison J; Cambiano, Valentina; Bruun, Tina

    2016-01-01

    IMPORTANCE: A key factor in assessing the effectiveness and cost-effectiveness of antiretroviral therapy (ART) as a prevention strategy is the absolute risk of HIV transmission through condomless sex with suppressed HIV-1 RNA viral load for both anal and vaginal sex. OBJECTIVE: To evaluate the rate...

  16. Metabolic syndrome, androgens, and hypertension.

    Science.gov (United States)

    Moulana, Mohadetheh; Lima, Roberta; Reckelhoff, Jane F

    2011-04-01

    Obesity is one of the constellation of factors that make up the definition of the metabolic syndrome. Metabolic syndrome is also associated with insulin resistance, dyslipidemia, hypertriglyceridemia, and type 2 diabetes mellitus. The presence of obesity and metabolic syndrome in men and women is also associated with increased risk of cardiovascular disease and hypertension. In men, obesity and metabolic syndrome are associated with reductions in testosterone levels. In women, obesity and metabolic syndrome are associated with increases in androgen levels. In men, reductions in androgen levels are associated with inflammation, and androgen supplements reduce inflammation. In women, increases in androgens are associated with increases in inflammatory cytokines, and reducing androgens reduces inflammation. This review discusses the possibility that the effects of androgens on metabolic syndrome and its sequelae may differ between males and females.

  17. Toll-Like Receptor 7 Agonist GS-9620 Induces HIV Expression and HIV-Specific Immunity in Cells from HIV-Infected Individuals on Suppressive Antiretroviral Therapy

    Science.gov (United States)

    Tsai, Angela; Irrinki, Alivelu; Kaur, Jasmine; Cihlar, Tomas; Kukolj, George

    2017-01-01

    ABSTRACT Antiretroviral therapy can suppress HIV replication to undetectable levels but does not eliminate latent HIV, thus necessitating lifelong therapy. Recent efforts to target this persistent reservoir have focused on inducing the expression of latent HIV so that infected cells may be recognized and eliminated by the immune system. Toll-like receptor (TLR) activation stimulates antiviral immunity and has been shown to induce HIV from latently infected cells. Activation of TLR7 leads to the production of several stimulatory cytokines, including type I interferons (IFNs). In this study, we show that the selective TLR7 agonist GS-9620 induced HIV in peripheral blood mononuclear cells (PBMCs) from HIV-infected individuals on suppressive antiretroviral therapy. GS-9620 increased extracellular HIV RNA 1.5- to 2-fold through a mechanism that required type I IFN signaling. GS-9620 also activated HIV-specific T cells and enhanced antibody-mediated clearance of HIV-infected cells. Activation by GS-9620 in combination with HIV peptide stimulation increased CD8 T cell degranulation, production of intracellular cytokines, and cytolytic activity. T cell activation was again dependent on type I IFNs produced by plasmacytoid dendritic cells. GS-9620 induced phagocytic cell maturation and improved effector-mediated killing of HIV-infected CD4 T cells by the HIV envelope-specific broadly neutralizing antibody PGT121. Collectively, these data show that GS-9620 can activate HIV production and improve the effector functions that target latently infected cells. GS-9620 may effectively complement orthogonal therapies designed to stimulate antiviral immunity, such as therapeutic vaccines or broadly neutralizing antibodies. Clinical studies are under way to determine if GS-9620 can target HIV reservoirs. IMPORTANCE Though antiretroviral therapies effectively suppress viral replication, they do not eliminate integrated proviral DNA. This stable intermediate of viral infection is

  18. ANDROGEN INSENSITIVITY SYNDROME

    OpenAIRE

    Kanan; Sonali

    2014-01-01

    The condition is inherited as X - linked recessive gene 1 . The underlying pathology is the inability of end organs to respond to androgens. These cases are phenotypically and psychologically female with adequate breast development , normal external genitalia , a vagina with variable depth , absent /sparse pubic hair and axillary hair. The exact incidence in India is not known but the reported incidence is 1 in 2 , 000 to 1 in 62 ,400 worldwi...

  19. Retrospective Evaluation Reveals That Long-term Androgen Deprivation Therapy Improves Cause-Specific and Overall Survival in the Setting of Dose-Escalated Radiation for High-Risk Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Feng, Felix Y., E-mail: ffeng@med.umich.edu [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Department of Radiation Oncology, Veterans Affairs Medical Center, Ann Arbor, Michigan (United States); Blas, Kevin; Olson, Karin; Stenmark, Matthew [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Sandler, Howard [Cedars Sinai Medical Center, Los Angeles, California (United States); Hamstra, Daniel A. [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States)

    2013-05-01

    Purpose: To evaluate the role of androgen deprivation therapy (ADT) and duration for high-risk prostate cancer patients treated with dose-escalated radiation therapy (RT). Methods and Materials: A retrospective analysis of high-risk prostate cancer patients treated with dose-escalated RT (minimum 75 Gy) with or without ADT was performed. The relationship between ADT use and duration with biochemical failure (BF), metastatic failure (MF), prostate cancer-specific mortality (PCSM), non-prostate cancer death (NPCD), and overall survival (OS) was assessed as a function of pretreatment characteristics, comorbid medical illness, and treatment using Fine and Gray's cumulative incidence methodology. Results: The median follow-up time was 64 months. In men with National Comprehensive Cancer Network defined high-risk prostate cancer treated with dose-escalated RT, on univariate analysis, both metastasis (P<.0001; hazard ratio 0.34; 95% confidence interval 0.18-0.67; cumulative incidence at 60 months 13% vs 35%) and PCSM (P=.015; hazard ratio 0.41; 95% confidence interval 0.2-1.0; cumulative incidence at 60 months 6% vs 11%) were improved with the use of ADT. On multivariate analysis for all high-risk patients, Gleason score was the strongest negative prognostic factor, and long-term ADT (LTAD) improved MF (P=.002), PCSM (P=.034), and OS (P=.001). In men with prostate cancer and Gleason scores 8 to 10, on multivariate analysis after adjustment for other risk features, there was a duration-dependent improvement in BF, metastasis, PCSM, and OS, all favoring LTAD in comparison with STAD or RT alone. Conclusion: For men with high-risk prostate cancer treated with dose-escalated EBRT, this retrospective study suggests that the combination of LTAD and RT provided a significant improvement in clinical outcome, which was especially true for those with Gleason scores of 8 to 10.

  20. Next-generation steroidogenesis inhibitors, dutasteride and abiraterone, attenuate but still do not eliminate androgen biosynthesis in 22RV1 cells in vitro.

    Science.gov (United States)

    Pham, Steven; Deb, Subrata; Ming, Dong Sheng; Adomat, Hans; Hosseini-Beheshti, Elham; Zoubeidi, Amina; Gleave, Martin; Guns, Emma S Tomlinson

    2014-10-01

    Castration resistant prostate cancer (CRPC) is often lethal and inevitably develops after androgen ablation therapy. However, in the majority of cases it remains androgen dependent. CRPC tumors have the ability to synthesize their own androgens from cholesterol by engaging in de novo steroidogenesis. We investigated the potential of 22RV1 prostate cancer cells to convert the supplemented steroid precursors within this pathway under the effects of current clinical steroidogenesis inhibitors such as abiraterone and dutasteride, either alone or in combination. Under steroid starved conditions, enzymes responsible for de novo steroidogenesis were upregulated. Testosterone and dihydrotestosterone (DHT) were formed by using both dehydroepiandrosterone (DHEA) and progesterone as substrates. Formation of testosterone and DHT was higher following incubation with DHEA compared to progesterone. Progesterone decreased the mRNA expression of enzymes responsible for steroidogenesis. Abiraterone treatment decreased testosterone production but increased several precursor steroids in both classical and backdoor pathways in the presence of progesterone. In contrast, the DHT levels were elevated following treatment with abiraterone when progesterone was absent. Dutasteride decreased the formation of testosterone, DHT and precursor steroids in the backdoor pathway but increased steroid precursors in the classical steroidogenesis pathway. The combination of abiraterone and dutasteride decreased testosterone and DHT in the presence of progesterone but increased DHT in the absence of progesterone. Abiraterone inhibited androgen receptor (AR) activation but not to the same extent as MDV3100. However, abiraterone and dutasteride treatment, either alone or in combination, were more effective in decreasing prostate specific antigen secretion into the media than MDV3100. Thus, while interventions with these drugs alone or in combination fail to completely inhibit steroidogenesis in the 22RV1

  1. Leuprolide acetate 1-, 3- and 6-monthly depot formulations in androgen deprivation therapy for prostate cancer in nine European countries: evidence review and economic evaluation

    Directory of Open Access Journals (Sweden)

    Wex J

    2013-06-01

    savings resulting from switching eligible patients from 1 M and 3 M to 6 M. Results were stable in univariate and probabilistic sensitivity analyses.Conclusion: Eligard® formulations offer comparable efficacy and safety, but different dosing schedules require different number of visits. The 6 M formulation offers the greatest cost savings and should be considered the treatment of choice in eligible patients in Europe.Keywords: prostate, cancer, androgen, leuprolide, Eligard, cost-effectiveness

  2. Analysis of the molecular networks in androgen dependent and independent prostate cancer revealed fragile and robust subsystems.

    Directory of Open Access Journals (Sweden)

    Ryan Tasseff

    Full Text Available Androgen ablation therapy is currently the primary treatment for metastatic prostate cancer. Unfortunately, in nearly all cases, androgen ablation fails to permanently arrest cancer progression. As androgens like testosterone are withdrawn, prostate cancer cells lose their androgen sensitivity and begin to proliferate without hormone growth factors. In this study, we constructed and analyzed a mathematical model of the integration between hormone growth factor signaling, androgen receptor activation, and the expression of cyclin D and Prostate-Specific Antigen in human LNCaP prostate adenocarcinoma cells. The objective of the study was to investigate which signaling systems were important in the loss of androgen dependence. The model was formulated as a set of ordinary differential equations which described 212 species and 384 interactions, including both the mRNA and protein levels for key species. An ensemble approach was chosen to constrain model parameters and to estimate the impact of parametric uncertainty on model predictions. Model parameters were identified using 14 steady-state and dynamic LNCaP data sets taken from literature sources. Alterations in the rate of Prostatic Acid Phosphatase expression was sufficient to capture varying levels of androgen dependence. Analysis of the model provided insight into the importance of network components as a function of androgen dependence. The importance of androgen receptor availability and the MAPK/Akt signaling axes was independent of androgen status. Interestingly, androgen receptor availability was important even in androgen-independent LNCaP cells. Translation became progressively more important in androgen-independent LNCaP cells. Further analysis suggested a positive synergy between the MAPK and Akt signaling axes and the translation of key proliferative markers like cyclin D in androgen-independent cells. Taken together, the results support the targeting of both the Akt and MAPK

  3. Androgen dependence of hirsutism, acne, and alopecia in women: retrospective analysis of 228 patients investigated for hyperandrogenism.

    Science.gov (United States)

    Karrer-Voegeli, Sandra; Rey, François; Reymond, Marianne J; Meuwly, Jean-Yves; Gaillard, Rolf C; Gomez, Fulgencio

    2009-01-01

    the other diagnostic groups. These included hyperandrogenism (hirsutism or elevated androgens) and eumenorrhea (101 patients; 44.3%); normal androgens (acne or alopecia and eumenorrhea) (51 patients; 22.4%); isolated low SHBG (7 patients; 3.1%); nonclassical congenital adrenal hyperplasia (4 patients; 1.8% of total, 4.9% of patients undergoing cosyntropin stimulation tests); and ovarian tumor (2 patients; 0.9%).Ethinylestradiol and high-dose cyproterone acetate treatment lowered the hirsutism score to 53.5% of baseline at 1 year, and was also effective in treating acne and alopecia. The clinical benefit is ascribed to the peripheral antiandrogenic effect of cyproterone acetate as well as the hormone-suppressive effect of this combination. Salivary testosterone showed the most marked proportional decrease of all the androgens under treatment. Cost-effectiveness and tolerance of ethinylestradiol and high-dose cyproterone acetate compared well with other antiandrogenic drug therapies for hirsutism. The less potent therapy with spironolactone only, a peripheral antiandrogen without hormone-suppressive effect, was effective in treating isolated alopecia in patients with normal androgens.

  4. Structural Determinants of Antiretroviral Therapy Use, HIV Care Attendance, and Viral Suppression among Adolescents and Young Adults Living with HIV.

    Directory of Open Access Journals (Sweden)

    Shoshana Y Kahana

    Full Text Available The authors examined associations between structural characteristics and HIV disease management among a geographically diverse sample of behaviorally and perinatally HIV-infected adolescents and young adults in the United States.The sample included 1891 adolescents and young adults living with HIV (27.8% perinatally infected; 72.2% behaviorally infected who were linked to care through 20 Adolescent Medicine Trials Network for HIV/AIDS Interventions Units. All completed audio computer-assisted self-interview surveys. Chart abstraction or blood draw provided viral load data. Geographic-level variables were extracted from the United States Census Bureau (e.g., socioeconomic disadvantage, percent of Black and Latino households, percent rural and Esri Crime (e.g., global crime index databases as Zip Code Tabulation Areas. AIDSVu data (e.g., prevalence of HIV among youth were extracted at the county-level. Using HLM v.7, the authors conducted means-as-outcomes random effects multi-level models to examine the association between structural-level and individual-level factors and (1 being on antiretroviral therapy (ART currently; (2 being on ART for at least 6 months; (3 missed HIV care appointments (not having missed any vs. having missed one or more appointments over the past 12 months; and (4 viral suppression (defined by the corresponding assay cutoff for the lower limit of viral load at each participating site which denoted nondetectability vs. detectability.Frequencies for the 4 primary outcomes were as follows: current ART use (n = 1120, 59.23%; ART use for ≥6 months (n = 861, 45.53%; at least one missed HIV care appointment (n = 936, 49.50; and viral suppression (n = 577, 30.51%. After adjusting for individual-level factors, youth living in more disadvantaged areas (defined by a composite score derived from 2010 Census indicators including percent poverty, percent receiving public assistance, percent of female, single-headed households, percent

  5. Selective Androgen Receptor Modulator RAD140 Is Neuroprotective in Cultured Neurons and Kainate-Lesioned Male Rats

    OpenAIRE

    2014-01-01

    The decline in testosterone levels in men during normal aging increases risks of dysfunction and disease in androgen-responsive tissues, including brain. The use of testosterone therapy has the potential to increase the risks for developing prostate cancer and or accelerating its progression. To overcome this limitation, novel compounds termed “selective androgen receptor modulators” (SARMs) have been developed that lack significant androgen action in prostate but exert agonist effects in sel...

  6. A place of androgen deficiency in a clinical portrait of the modern urological patient

    Directory of Open Access Journals (Sweden)

    I. A. Tyuzikov

    2013-01-01

    Full Text Available In article on the basis of literary given both own clinical supervision and researches applied aspects of androgen deficiency in urological practice are considered. True androgen deficiency’ frequency in man’s population remains precisely not established as decrease in testosterone synthesis is connected not only with the age, but also varieties of other factors, including features of geography of area of residing, presence or absence of other hormonal and metabolic disorders, accompanying somatic comorbidity etc. Results of the newest foreign epidemiological researches of androgen deficiency prevalence worldwide, and also results of the first Russian pilot epidemiological research of androgen deficiency at men prevalence in practice of urologists and doctors of adjacent specialities (Yaroslavl Study, 2013 present in the article. Intime pathogenetic communication of androgen deficiency both the most widespread uroandrological and somatic diseases at men is shown. On the basis of own clinical experience optimum algorithms of complex diagnostics of androgen deficiency at urological patients are offered and also the necessity of inclusion of testosterone preparations for pharmacotherapy of the majority of male urinogenital diseases is shown. The review of indications, contra-indications, estimations of risk factors and preparations for androgen replacement therapy is spent. Features of transdermal forms of testosterone preparations (Аndrogel are described and the clinical analysis of their present and perspective application within the limits of modern androgen replacement therapy is carried out.

  7. A place of androgen deficiency in a clinical portrait of the modern urological patient

    Directory of Open Access Journals (Sweden)

    I. A. Tyuzikov

    2014-11-01

    Full Text Available In article on the basis of literary given both own clinical supervision and researches applied aspects of androgen deficiency in urological practice are considered. True androgen deficiency’ frequency in man’s population remains precisely not established as decrease in testosterone synthesis is connected not only with the age, but also varieties of other factors, including features of geography of area of residing, presence or absence of other hormonal and metabolic disorders, accompanying somatic comorbidity etc. Results of the newest foreign epidemiological researches of androgen deficiency prevalence worldwide, and also results of the first Russian pilot epidemiological research of androgen deficiency at men prevalence in practice of urologists and doctors of adjacent specialities (Yaroslavl Study, 2013 present in the article. Intime pathogenetic communication of androgen deficiency both the most widespread uroandrological and somatic diseases at men is shown. On the basis of own clinical experience optimum algorithms of complex diagnostics of androgen deficiency at urological patients are offered and also the necessity of inclusion of testosterone preparations for pharmacotherapy of the majority of male urinogenital diseases is shown. The review of indications, contra-indications, estimations of risk factors and preparations for androgen replacement therapy is spent. Features of transdermal forms of testosterone preparations (Аndrogel are described and the clinical analysis of their present and perspective application within the limits of modern androgen replacement therapy is carried out.

  8. Aberrant E2F activation by polyglutamine expansion of androgen receptor in SBMA neurotoxicity.

    Science.gov (United States)

    Suzuki, Eriko; Zhao, Yue; Ito, Saya; Sawatsubashi, Shun; Murata, Takuya; Furutani, Takashi; Shirode, Yuko; Yamagata, Kaoru; Tanabe, Masahiko; Kimura, Shuhei; Ueda, Takashi; Fujiyama, Sally; Lim, Jinseon; Matsukawa, Hiroyuki; Kouzmenko, Alexander P; Aigaki, Toshiro; Tabata, Tetsuya; Takeyama, Ken-ichi; Kato, Shigeaki

    2009-03-10

    Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disorder caused by a polyglutamine repeat (polyQ) expansion within the human androgen receptor (AR). Unlike other neurodegenerative diseases caused by abnormal polyQ expansion, the onset of SBMA depends on androgen binding to mutant human polyQ-AR proteins. This is also observed in Drosophila eyes ectopically expressing the polyQ-AR mutants. We have genetically screened mediators of androgen-induced neurodegeneration caused by polyQ-AR mutants in Drosophila eyes. We identified Rbf (Retinoblastoma-family protein), the Drosophila homologue of human Rb (Retinoblastoma protein), as a neuroprotective factor. Androgen-dependent association of Rbf or Rb with AR was remarkably potentiated by aberrant polyQ expansion. Such potentiated Rb association appeared to attenuate recruitment of histone deacetyltransferase 1 (HDAC1), a corepressor of E2F function. Either overexpression of Rbf or E2F deficiency in fly eyes reduced the neurotoxicity of the polyQ-AR mutants. Induction of E2F function by polyQ-AR-bound androgen was suppressed by Rb in human neuroblastoma cells. We conclude that abnormal expansion of polyQ may potentiate innate androgen-dependent association of AR with Rb. This appears to lead to androgen-dependent onset of SBMA through aberrant E2F transactivation caused by suppressed histone deacetylation.

  9. Novel series of potent, nonsteroidal, selective androgen receptor modulators based on 7H-[1,4]oxazino[3,2-g]quinolin-7-ones.

    Science.gov (United States)

    Higuchi, Robert I; Arienti, Kristen L; López, Francisco J; Mani, Neelakhanda S; Mais, Dale E; Caferro, Thomas R; Long, Yun Oliver; Jones, Todd K; Edwards, James P; Zhi, Lin; Schrader, William T; Negro-Vilar, Andrés; Marschke, Keith B

    2007-05-17

    Recent interest in orally available androgens has fueled the search for new androgens for use in hormone replacement therapy and as anabolic agents. In pursuit of this, we have discovered a series of novel androgen receptor modulators derived from 7H-[1,4]oxazino[3,2-g]quinolin-7-ones. These compounds were synthesized and evaluated in competitive binding assays and an androgen receptor transcriptional activation assay. A number of compounds from the series demonstrated single-digit nanomolar agonist activity in vitro. In addition, lead compound (R)-16e was orally active in established rodent models that measure androgenic and anabolic properties of these agents. In this assay, (R)-16e demonstrated full efficacy in muscle and only partially stimulated the prostate at 100 mg/kg. These data suggest that these compounds may be utilized as selective androgen receptor modulators or SARMs. This series represents a novel class of compounds for use in androgen replacement therapy.

  10. Ameliorative effect of androgen therapy tear on film stability in castrate female rats%雄激素疗法对去势雌性大鼠泪膜稳定性的改善作用

    Institute of Scientific and Technical Information of China (English)

    高阳; 周瑾; 孙晓芳

    2015-01-01

    Background Prevalence of dry eye is significantly inceasing in postmenopausal women than that in men,suggesting that sex hormone plays a role in the pathogenesis of dry eye.In addition,dry eye might become worse following estrogen therapy in postmenopausal women.However,whether application of androgen can ameliorate dry eye is being concerned.Objective This study was to investigate the effect of androgen on tear film of ovariectomized female rats.Methods Forty-eight 3-month-old sexually mature female Wistar rats were randomized into the normal control group,sham group,ovariectomy (OVX) model group and testosterone-injected group.OVX models were established by bilateral ovaries enucleation in the rats of the model group and testosterone-injected group,and then androgen (3.75 mg/kg) was intramuscularly injected since 5 months after OVX at 3-day interval for 6 weeks.Only intraperitoneal fat was cut off in the sham group.In 6 weeks after injection of androgen,serum androgen concentration detected and Schirmer Ⅰ test (S Ⅰ t),tear film break-up time (BUT) were performed.The rats were sacrificed to prepare the corneal and conjunctival samples.The expression of MUC5AC in conjunctival tissue was examined by immunofluorescence staining,and the microstructure of corneal cellular surface was observed under the scanning electron microscope before and 6 weeks after application of androgen.Animals in this study were treated in accordance with Animal Experimentation Ethic Committee Guidelines of Southern Medical University and the study protocol was approved by Ethic Committee of this University.Results The mean serum testosterone concentration was (1.83 ±0.12) ng/ml,and S Ⅰ t or BUT was (3.63-±0.26)mm/5 minutes or (3.73-0.38) seconds,respectively,in the OVX model group,which was significantly declined in comparison with (2.56 ±0.14) ng/ml,(7.47±0.66) mm/5 minutes or (9.57 ±0.76) seconds in the normal control group (all at P =0.000).However,the serum testosterone

  11. MR-Guided Pulsed High-Intensity Focused Ultrasound Enhancement of Gene Therapy Combined With Androgen Deprivation and Radiotherapy for Prostate Cancer Treatment

    Science.gov (United States)

    2009-09-01

    ultrasound . J. Acoust. Soc.Am. 72 1926-1932, (1982) (7) Neppiras E A. Acoustic cavitation . Physics reports 61(3): 159-251, (1980) (8) ter Haar G R, Daniels...Guided Pulsed High-Intensity Focused Ultrasound Enhancement of 5b. GRANT NUMBER W81XWH-08-1-0469 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT...failing to This work is aimed to study MR guided high intensity focused ultrasound (MRgHIFU) enhancement of gene therapy for Prostate Cancer. The

  12. Effects of long-term androgen replacement therapy on the physical and mental statuses of aging males with late-onset hypogonadism: a multicenter randomized controlled trial in Japan (EARTH Study

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    Hiroyuki Konaka

    2016-01-01

    Full Text Available Androgen replacement therapy (ART efficacy on late-onset hypogonadism (LOH has been widely investigated in Western countries; however, it remains controversial whether ART can improve health and prolong active lifestyles. We prospectively assessed long-term ART effects on the physical and mental statuses of aging men with LOH in Japan. The primary endpoint was health-related quality of life assessed by questionnaires. Secondary endpoints included glycemic control, lipid parameters, blood pressure, waist circumference, body composition, muscular strength, International Prostate Symptom Scores (IPSS, International Index of Erectile Function-5 (IIEF-5 scores, and serum prostate-specific antigen levels. Of the 1637 eligible volunteers, 334 patients > 40 years with LOH were randomly assigned to either the ART (n = 169 or control groups (n = 165. Fifty-two weeks after the initial treatment, ART significantly affected the role physical subdomain of the short form-36 health survey (SF-36 scale (P = 0.0318. ART was also associated with significant decreases in waist circumstance (P = 0.002 and serum triglyceride (TG (P = 0.013 and with significant increases in whole-body and leg muscle mass volumes (P = 0.071 and 0.0108, respectively, serum hemoglobin (P < 0.001, IPSS voiding subscore (P = 0.0418, and the second question on IIEF-5 (P = 0.0049. There was no significant difference between the groups in terms of severe adverse events. In conclusion, in patients with LOH, long-term ART exerted beneficial effects on Role Physical subdomain of the SF-36 scale, serum TG, waist circumstance, muscle mass volume, voiding subscore of IPSS, and the second question of IIEF-5. We hope our study will contribute to the future development of this area.

  13. Impact of circulating cholesterol levels on growth and intratumoral androgen concentration of prostate tumors.

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    Elahe A Mostaghel

    Full Text Available Prostate cancer (PCa is the second most common cancer in men. Androgen deprivation therapy (ADT leads to tumor involution and reduction of tumor burden. However, tumors eventually reemerge that have overcome the absence of gonadal androgens, termed castration resistant PCa (CRPC. Theories underlying the development of CRPC include androgen receptor (AR mutation allowing for promiscuous activation by non-androgens, AR amplification and overexpression leading to hypersensitivity to low androgen levels, and/or tumoral uptake and conversion of adrenally derived androgens. More recently it has been proposed that prostate tumor cells synthesize their own androgens through de novo steroidogenesis, which involves the step-wise synthesis of androgens from cholesterol. Using the in vivo LNCaP PCa xenograft model, previous data from our group demonstrated that a hypercholesterolemia diet potentiates prostatic tumor growth via induction of angiogenesis. Using this same model we now demonstrate that circulating cholesterol levels are significantly associated with tumor size (R = 0.3957, p = 0.0049 and intratumoral levels of testosterone (R = 0.41, p = 0.0023 in LNCaP tumors grown in hormonally intact mice. We demonstrate tumoral expression of cholesterol uptake genes as well as the spectrum of steroidogenic enzymes necessary for androgen biosynthesis from cholesterol. Moreover, we show that circulating cholesterol levels are directly correlated with tumoral expression of CYP17A, the critical enzyme required for de novo synthesis of androgens from cholesterol (R = 0.4073, p = 0.025 Since hypercholesterolemia does not raise circulating androgen levels and the adrenal gland of the mouse synthesizes minimal androgens, this study provides evidence that hypercholesterolemia increases intratumoral de novo steroidogenesis. Our results are consistent with the hypothesis that cholesterol-fueled intratumoral androgen synthesis may accelerate the

  14. Androgen receptor promotes abdominal aortic aneurysm development via modulating inflammatory interleukin-1α and transforming growth factor-β1 expression.

    Science.gov (United States)

    Huang, Chiung-Kuei; Luo, Jie; Lai, Kuo-Pao; Wang, Ronghao; Pang, Haiyan; Chang, Eugene; Yan, Chen; Sparks, Janet; Lee, Soo Ok; Cho, Joshua; Chang, Chawnshang

    2015-10-01

    Sex difference is a risk factor for abdominal aortic aneurysm (AAA) formation yet the reason for male predominance remains unclear. Androgen and the androgen receptor (AR) influence the male sex difference, indicating that AR signaling may affect AAA development. Using angiotensin II–induced AAA in apolipoprotein E null mouse models (82.4% AAA incidence), we found that mice lacking AR failed to develop AAA and aorta had dramatically reduced macrophages infiltration and intact elastic fibers. These findings suggested that AR expression in endothelial cells, macrophages, or smooth muscle cells might play a role in AAA development. Selective knockout of AR in each of these cell types further demonstrated that mice lacking AR in macrophages (20% AAA incidence) or smooth muscle cells (12.5% AAA incidence) but not in endothelial cells (71.4% AAA incidence) had suppressed AAA development. Mechanism dissection showed that AR functioned through modulation of interleukin-1α (IL-1α) and transforming growth factor-β1 signals and by targeting AR with the AR degradation enhancer ASC-J9 led to significant suppression of AAA development. These results demonstrate the underlying mechanism by which AR influences AAA development is through IL-1α and transforming growth factor-β1, and provides a potential new therapy to suppress/prevent AAA by targeting AR with ASC-J9.

  15. Activation of HIV transcription with short-course vorinostat in HIV-infected patients on suppressive antiretroviral therapy.

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    Julian H Elliott

    2014-10-01

    Full Text Available Human immunodeficiency virus (HIV persistence in latently infected resting memory CD4+ T-cells is the major barrier to HIV cure. Cellular histone deacetylases (HDACs are important in maintaining HIV latency and histone deacetylase inhibitors (HDACi may reverse latency by activating HIV transcription from latently infected CD4+ T-cells. We performed a single arm, open label, proof-of-concept study in which vorinostat, a pan-HDACi, was administered 400 mg orally once daily for 14 days to 20 HIV-infected individuals on suppressive antiretroviral therapy (ART. The primary endpoint was change in cell associated unspliced (CA-US HIV RNA in total CD4+ T-cells from blood at day 14. The study is registered at ClinicalTrials.gov (NCT01365065. Vorinostat was safe and well tolerated and there were no dose modifications or study drug discontinuations. CA-US HIV RNA in blood increased significantly in 18/20 patients (90% with a median fold change from baseline to peak value of 7.4 (IQR 3.4, 9.1. CA-US RNA was significantly elevated 8 hours post drug and remained elevated 70 days after last dose. Significant early changes in expression of genes associated with chromatin remodeling and activation of HIV transcription correlated with the magnitude of increased CA-US HIV RNA. There were no statistically significant changes in plasma HIV RNA, concentration of HIV DNA, integrated DNA, inducible virus in CD4+ T-cells or markers of T-cell activation. Vorinostat induced a significant and sustained increase in HIV transcription from latency in the majority of HIV-infected patients. However, additional interventions will be needed to efficiently induce virus production and ultimately eliminate latently infected cells.ClinicalTrials.gov NCT01365065.

  16. Efficacy and Safety of Combined Androgen Deprivation Therapy (ADT and Docetaxel Compared with ADT Alone for Metastatic Hormone-Naive Prostate Cancer: A Systematic Review and Meta-Analysis.

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    Tobias Engel Ayer Botrel

    Full Text Available Prostate cancer is the most common nonskin cancer and second most common cause of cancer mortality in older men in the United States (USA and Western Europe. Androgen-deprivation therapy alone (ADT remains the first line of treatment in most cases, for metastatic disease. We performed a systematic review and meta-analysis of all randomized controlled trials (RCT that compared the efficacy and adverse events profile of a chemohormonal therapy (ADT ± docetaxel for metastatic hormone-naive prostate cancer (mHNPC.Several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. The primary endpoint was overall survival. Data extracted from the studies were combined by using the hazard ratio (HR or risk ratio (RR with their corresponding 95% confidence intervals (95% CI.The final analysis included 3 trials comprising 2,264 patients (mHNPC. Patients who received the chemohormonal therapy had a longer clinical progression-free survival interval (HR = 0.64; 95% CI: 0.55 to 0.75; p<0.00001, and no heterogeneity (Chi2 = 0.64; df = 1 [p = 0.42]; I2 = 0%. The biochemical progression-free survival (bPFS also was higher in patients treated with ADT plus docetaxel (HR = 0.63; 95% CI: 0.57 to 0.69; p<0.00001, also with no heterogeneity noted (Chi2 = 0.48; df = 2 [p = 0.79]; I2 = 0%. Finally, the combination of ADT with docetaxel showed a superior overall survival (OS compared with ADT alone (HR = 0.73; 95% CI: 0.64 to 0.84; p<0.0001, with moderate heterogeneity (Chi2 = 3.84; df = 2 [p = 0.15]; I2 = 48%. A random-effects model analysis was performed, and the results remained favorable to the use of ADT plus docetaxel (HR = 0.73; 95% CI: 0.60 to 0.89; p = 0.002. In the final combined analysis of the high-volume disease patients, the use of the combination therapy also favored an increased overall survival (HR = 0.67; 95% CI: 0.54 to 0.83; p = 0.0003. Regarding adverse events and severe toxicity (grade ≥3, the group receiving the combined therapy

  17. ANDROGEN LEVELS IN PREECLAMPSIA

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    M. Valadan

    2006-08-01

    Full Text Available Preeclampsia is a major cause of morbidity and mortality during pregnancy. Several independent investigators have demonstrated the association of androgens with hypertension. The main purpose of this study was to determine whether maternal levels of sex hormones, especially testosterone, are higher in patients with preeclampsia than in matched normotensive control subjects. Serum levels of testosterone, free testosterone, dehydroepiandrosterone sulfate (DHEA-S and estradiol were measured in 60 subjects in the 3rd trimester of pregnancy with documented preeclampsia (including 30 cases of mild and 30 cases of severe preeclampsia and 60 healthy normotensive women with similar maternal and gestational ages and body mass index (BMI and neonatal sex. All subjects were primigravid with singleton pregnancies. Cases of polycystic ovary (PCO, diabetes, chronic hypertension and chronic systemic diseases such as lupus and patients using steroid hormones and anti-hypertensive drugs were excluded. Levels of testosterone, DHEA-S and estradiol were not higher in primigravid women with preeclampsia than in normotensive women with similar gestational and maternal ages, BMI and neonatal sex. There were no significant differences in sex hormones measured between groups of mild and severe preeclampsia and normotensive women. There were also no significant differences in sex hormone levels according to neonatal sex. These findings are against the hypothesis of mediating or amplifying role of high androgen levels in pathophysiology of preeclampsia.

  18. Androgen and prostatic stroma

    Institute of Scientific and Technical Information of China (English)

    Yuan-JieNIU; Teng-XiangMA; IuZHANG; YongXU; Rui-FaHAN; GuangSUN

    2003-01-01

    Aim:To investigate the effect of androgen on the proliferation,differentiation and regression of canine prostatic stromal cells in vivo and human stromal cells in vitro.Methods:Twenty-two dogs,including 15 normal prostate doge and 7 prostatic hyperplasia dogs,had their serum concentration of testosterone and estrodiol determined by radioimmunoassay before and after castration.The expression of androgen receptor(AR)and estrogen receptor(ER)in the prostate were analysed by immunohistochemistry and semi-quantitative RT-PCR before and after castration.Light microscopy,transmission electron microscopy and TUNEL assay were carried out successively before and after castration to evaluate the prostatic histomorphology.In vitro serum-free cell cultures from human prostatic stroma were established and exposed to dihydrotestosterone(DHT).The proliferation of the cell culture was detected by MTT assay.The expression of TGFβ bFGF,AR,and smooth muscle cell(SMC) specific proteins (myosin and/or smoothelin)were detected using immunohistochemistry and RT-PCR.The differentiation from fibroblasts to smooth muscle cells was deduced by measuring the expression of SMC specific proteins.Results:Before castration,the serum concentrations of testosterone and estrodiol were not statistically different between normal and hyperplasia groups.Following castration,the serum concentration of testerone decreased rapidly in 2 days,and the concentration of estrodiol had no significant change compared with the pre-castration data.In the prostate,AR was presented in both the epithelial and stromal cells and the AR mRNA level was higher in hyperplasia than in normal prostate tissues(P<0.05).While ER predominantly existed in the prostate stromal cells and the ER mRNA had no difference between the hyperplasia and the normal group.Within the early phase of castration(

  19. Prostate Cancer in Elderly Croatian Men: 5-HT Genetic Polymorphisms and the Influence of Androgen Deprivation Therapy on Osteopenia—A Pilot Study

    Science.gov (United States)

    Pauković, Paulina; Cvijetić, Selma; Pizent, Alica; Jurasović, Jasna; Milković-Kraus, Sanja; Dodig, Slavica; Mück-Šeler, Dorotea; Mustapić, Maja; Pivac, Nela; Lana-Feher-Turković; Pavlović, Mladen

    2012-01-01

    Background: The aim of this study was to determine the relationship between body mass index, biochemical parameters, and 5-hydroxytryptamine (5-HT) genetic polymorphisms and prostate dysfunction in an elderly general male population. Results: One hundred and seventeen elderly male subjects [60 men without symptoms of prostate hyperplasia, 42 men with untreated benign prostatic hyperplasia (BPH), and 15 men with prostate cancer (PCa)] treated with finasteride or flutamide were included. Multiple comparisons showed significant difference in age, T-score, concentration of phosphorus, calcium, C-reactive protein, and prostate-specific antigen (PSA) between the groups. T-score was the lowest and phosphorus concentration was the highest in the PCa group. Highest PSA, proteins, calcium, and Hekal's formula score were found in the BPH group. Patients with PCa were more frequent GG+GA carriers of 5-HT1B 1997A/G gene polymorphism (p=0.035). Univariate regression analysis showed association of PCa-treated subjects with age (p=0.010) and 5-HT1B genetic polymorphism (p=0.018). Antiandrogen therapy affects T-score (p=0.017), serum phosphorus (p=0.008), glucose (p=0.036), and total proteins (p=0.050). Multivariate-stepwise logistic regression analysis showed the significant association of treated PCa with age (p=0.028) and inorganic phosphorus (p=0.005), and a marginal association with ultrasonographic T-score (p=0.052). Conclusions: Antiandrogen therapy might induce bone mineral loss in elderly PCa patients. Preliminary data imply that the genetic variants of the 5-HT1B receptor might be associated with PCa. PMID:22420486

  20. CD8+ T cells promote proliferation of benign prostatic hyperplasia epithelial cells under low androgen level via modulation of CCL5/STAT5/CCND1 signaling pathway

    Science.gov (United States)

    Yang, Yang; Hu, Shuai; Liu, Jie; Cui, Yun; Fan, Yu; Lv, Tianjing; Liu, Libo; Li, Jun; He, Qun; Han, Wenke; Yu, Wei; Sun, Yin; Jin, Jie

    2017-01-01

    Previous studies by our group have shown that low intra-prostatic dihydrotestosterone (DHT) induced BPH epithelial cells (BECs) to recruit CD8+ T cells. However, the influence of the recruited CD8+ T cells on BECs under a low androgen level is still unknown. Here, we found CD8+ T cells have the capacity to promote proliferation of BECs in low androgen condition. Mechanism dissection revealed that interaction between CD8+ T cells and BECs through secretion of CCL5 might promote the phosphorylation of STAT5 and a higher expression of CCND1 in BECs. Suppressed CCL5/STAT5 signals via CCL5 neutralizing antibody or STAT5 inhibitor Pimozide led to reverse CD8+ T cell-enhanced BECs proliferation. IHC analysis from Finasteride treated patients showed PCNA expression in BECs was highly correlated to the level of CD8+ T cell infiltration and the expression of CCL5. Consequently, our data indicated infiltrating CD8+ T cells could promote the proliferation of BECs in low androgen condition via modulation of CCL5/STAT5/CCND1 signaling. The increased secretion of CCL5 from the CD8+ T cells/BECs interaction might help BECs survive in a low DHT environment. Targeting these signals may provide a new potential therapeutic approach to better treat BPH patients who failed the therapy of 5α-reductase inhibitors. PMID:28216616

  1. In vivo modulation of androgen receptor by androgens

    Institute of Scientific and Technical Information of China (English)

    V·L·Kumar; V·Kumar

    2002-01-01

    Aim:To study the effect of androgen and antiandrogen on the level of androgen receptor(AR)mRNA.Methods:The totalRNA was extracted from the prostate and analyzed by slot blot analysis,The blots were hybrid-ized with ARcDNA probe and 1Aprobe(internal control)and autoradionraphy was performed.The intensity of signal was measured with a densitometer and the ratio of AR RNAand1ARNAwas calculated.Results:Androgenic deprivation produced by castration decreased the weight of the prostate and increased the levels of ARmRNA.Treatment of the castrated rats with testostrone increased the weight of prostate and decreased the levels of ARmRNA.Treatment of normal rats with flutamide decreased the weight of the gland and increased the levels of AR mRNA.Conclusion:Androgens produce proliferative effect on the prostate and negatively regulate the AR transcription.

  2. Dominant-negative androgen receptor inhibition of intracrine androgen-dependent growth of castration-recurrent prostate cancer.

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    Mark A Titus

    Full Text Available BACKGROUND: Prostate cancer (CaP is the second leading cause of cancer death in American men. Androgen deprivation therapy is initially effective in CaP treatment, but CaP recurs despite castrate levels of circulating androgen. Continued expression of the androgen receptor (AR and its ligands has been linked to castration-recurrent CaP growth. PRINCIPAL FINDING: In this report, the ligand-dependent dominant-negative ARΔ142-337 (ARΔTR was expressed in castration-recurrent CWR-R1 cell and tumor models to elucidate the role of AR signaling. Expression of ARΔTR decreased CWR-R1 tumor growth in the presence and absence of exogenous testosterone (T and improved survival in the presence of exogenous T. There was evidence for negative selection of ARΔTR transgene in T-treated mice. Mass spectrometry revealed castration-recurrent CaP dihydrotestosterone (DHT levels sufficient to activate AR and ARΔTR. In the absence of exogenous testosterone, CWR-R1-ARΔTR and control cells exhibited altered androgen profiles that implicated epithelial CaP cells as a source of intratumoral AR ligands. CONCLUSION: The study provides in vivo evidence that activation of AR signaling by intratumoral AR ligands is required for castration-recurrent CaP growth and that epithelial CaP cells produce sufficient active androgens for CaP recurrence during androgen deprivation therapy. Targeting intracrine T and DHT synthesis should provide a mechanism to inhibit AR and growth of castration-recurrent CaP.

  3. Selective androgen receptor modulator activity of a steroidal antiandrogen TSAA-291 and its cofactor recruitment profile.

    Science.gov (United States)

    Hikichi, Yukiko; Yamaoka, Masuo; Kusaka, Masami; Hara, Takahito

    2015-10-15

    Selective androgen receptor modulators (SARMs) specifically bind to the androgen receptor and exert agonistic or antagonistic effects on target organs. In this study, we investigated the SARM activity of TSAA-291, previously known as a steroidal antiandrogen, in mice because TSAA-291 was found to possess partial androgen receptor agonist activity in reporter assays. In addition, to clarify the mechanism underlying its tissue selectivity, we performed comprehensive cofactor recruitment analysis of androgen receptor using TSAA-291 and dihydrotestosterone (DHT), an endogenous androgen. The androgen receptor agonistic activity of TSAA-291 was more obvious in reporter assays using skeletal muscle cells than in those using prostate cells. In castrated mice, TSAA-291 increased the weight of the levator ani muscle without increasing the weight of the prostate and seminal vesicle. Comprehensive cofactor recruitment analysis via mammalian two-hybrid methods revealed that among a total of 112 cofactors, 12 cofactors including the protein inhibitor of activated STAT 1 (PIAS1) were differently recruited to androgen receptor in the presence of TSAA-291 and DHT. Prostate displayed higher PIAS1 expression than skeletal muscle. Forced expression of the PIAS1 augmented the transcriptional activity of the androgen receptor, and silencing of PIAS1 by siRNAs suppressed the secretion of prostate-specific antigen, an androgen responsive marker. Our results demonstrate that TSAA-291 has SARM activity and suggest that TSAA-291 may induce different conformational changes of the androgen receptor and recruitment profiles of cofactors such as PIAS1, compared with DHT, to exert tissue-specific activity.

  4. A novel selective androgen receptor modulator, NEP28, is efficacious in muscle and brain without serious side effects on prostate.

    Science.gov (United States)

    Akita, Kazumasa; Harada, Koichiro; Ichihara, Junji; Takata, Naoko; Takahashi, Yasuhiko; Saito, Koichi

    2013-11-15

    Age-related androgen depletion is known to be a risk factor for various diseases, such as osteoporosis and sarcopenia. Furthermore, recent studies have demonstrated that age-related androgen depletion results in accumulation of β-amyloid protein and thereby acts as a risk factor for the development of Alzheimer's disease. Supplemental androgen therapy has been shown to be efficacious in treating osteoporosis and sarcopenia. In addition, studies in animals have demonstrated that androgens can play a protective role against Alzheimer's disease. However, androgen therapy is not used routinely for these indications, because of side effects. Selective androgen receptor modulators (SARMs) are a new class of compounds. SARMs maintain the beneficial effects of androgens on bone and muscle while reducing unwanted side effects. NEP28 is a new SARM exhibiting high selectivity for androgen receptor. To investigate the pharmacological effects of NEP28, we compared the effects on muscle, prostate, and brain with mice that were androgen depleted by orchidectomy and then treated with either placebo, NEP28, dihydrotestosterone, or methyltestosterone. We demonstrated that NEP28 showed tissue-selective effect equivalent to or higher than existing SARMs. In addition, the administration of NEP28 increased the activity of neprilysin, a known Aβ-degrading enzyme. These results indicate that SARM is efficacious for the treatment of not only osteoporosis and sarcopenia, but also Alzheimer's disease.

  5. Hormone Therapy for Prostate Cancer

    Science.gov (United States)

    ... Galvão DA, Taaffe DR, Spry N, Newton RU. Exercise can prevent and even reverse adverse effects of androgen suppression treatment in men with prostate cancer. Prostate Cancer and Prostatic Diseases 2007; 10(4): ...

  6. Androgen effects on skeletal muscle: implications for the development and management of frailty

    Directory of Open Access Journals (Sweden)

    Matthew DL O'Connell

    2014-04-01

    Full Text Available Androgens have potent anabolic effects on skeletal muscle and decline with age in parallel to losses in muscle mass and strength. This loss of muscle mass and function, known as sarcopenia, is the central event in development of frailty, the vulnerable health status that presages adverse outcomes and rapid functional decline in older adults. The potential role of falling androgen levels in the development of frailty and their utility as function promoting therapies in older men has therefore attracted considerable attention. This review summarizes current concepts and definitions in muscle ageing, sarcopenia and frailty, and evaluates recent developments in the study of androgens and frailty. Current evidence from observational and interventional studies strongly supports an effect of androgens on muscle mass in ageing men, but effects on muscle strength and particularly physical function have been less clear. Androgen treatment has been generally well-tolerated in studies of older men, but concerns remain over higher dose treatments and use in populations with high cardiovascular risk. The first trials of selective androgen receptor modulators (SARMs suggest similar effects on muscle mass and function to traditional androgen therapies in older adults. Important future directions include the use of these agents in combination with exercise training to promote functional ability across different populations of older adults, as well as more focus on the relationships between concurrent changes in hormone levels, body composition and physical function in observational studies.

  7. Androgen effects on skeletal muscle: implications for the development and management of frailty.

    Science.gov (United States)

    O'Connell, Matthew D L; Wu, Frederick C W

    2014-01-01

    Androgens have potent anabolic effects on skeletal muscle and decline with age in parallel to losses in muscle mass and strength. This loss of muscle mass and function, known as sarcopenia, is the central event in development of frailty, the vulnerable health status that presages adverse outcomes and rapid functional decline in older adults. The potential role of falling androgen levels in the development of frailty and their utility as function promoting therapies in older men has therefore attracted considerable attention. This review summarizes current concepts and definitions in muscle ageing, sarcopenia and frailty, and evaluates recent developments in the study of androgens and frailty. Current evidence from observational and interventional studies strongly supports an effect of androgens on muscle mass in ageing men, but effects on muscle strength and particularly physical function have been less clear. Androgen treatment has been generally well-tolerated in studies of older men, but concerns remain over higher dose treatments and use in populations with high cardiovascular risk. The first trials of selective androgen receptor modulators (SARMs) suggest similar effects on muscle mass and function to traditional androgen therapies in older adults. Important future directions include the use of these agents in combination with exercise training to promote functional ability across different populations of older adults, as well as more focus on the relationships between concurrent changes in hormone levels, body composition and physical function in observational studies.

  8. The effect of thyroid stimulating hormone suppressive therapy on bone geometry in the hip area of patients with differentiated thyroid carcinoma.

    Science.gov (United States)

    Moon, Jae Hoon; Jung, Kyong Yeun; Kim, Kyoung Min; Choi, Sung Hee; Lim, Soo; Park, Young Joo; Park, Do Joon; Jang, Hak Chul

    2016-02-01

    Subclinical hyperthyroidism has been reported to increase the fracture risk. However, the effect of thyroid stimulating hormone (TSH) suppressive therapy on bone geometry in the hip area of patients with differentiated thyroid carcinoma (DTC) is still unclear. The aim of this study was to investigate the effect of TSH suppression on bone geometry in the hip area of pre- and postmenopausal women with DTC. We conducted a retrospective cohort study including 99 women with DTC (25 pre- and 74 postmenopausal) who had received TSH suppressive therapy for at least 3years and 297 control subjects (75 and 222, respectively) matched for sex and age. Bone mineral density (BMD) in the spine and hip area and bone geometry at the femoral neck measured by dual energy X-ray absorptiometry (DXA) were compared between patients and controls. The association between thyroid hormone and bone parameters was investigated. All analyses of bone parameters were adjusted for age, body mass index, and serum calcium levels. In premenopausal subjects, TSH suppressive therapy was not associated with poor bone parameters. In postmenopausal subjects, patients with DTC undergoing TSH suppression showed lower cross-sectional moment of inertia (CSMI), cross-sectional area, and section modulus and thinner cortical thickness at the femoral neck than those of control subjects, whereas their femoral neck BMD was comparable with controls. Total hip BMD was lower in postmenopausal patients than in controls. CSMI and section modulus at the femoral neck were independently associated with serum free T4 levels in postmenopausal patients. The difference in femoral neck bone geometry between patients and controls was only apparent in postmenopausal DTC patients with free T4 >1.79ng/dL (23.04pmol/l), and not in those with free T4 levels ≤1.79ng/dL (23.04pmol/l). TSH suppression in postmenopausal DTC patients was associated with decreased bone strength by altering bone geometry rather than BMD in the hip area

  9. The androgen receptor in hormone-refractory prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Hai-Lei Mao; Zhi-Qi Zhu; Charlie Degui Chen

    2009-01-01

    Advanced prostate cancer is responsive to hormone therapy that interferes with androgen receptor (AR) signalling.However,the effect is short-lived,as nearly all tumours progress to a hormone-refractory (HR) state,a lethal stage of the disease.Intuitively,the AR should not be involved because hormone therapy that blocks or reduces AR activity is not effective in treating HR turnouts.However,there is still a consensus that AR plays an essential role in HR prostate cancer (HRPC) because AR signalling is still functional in HR tumours.AR signalling can be activated in HR turnouts through several mechanisms.First,activation of intracellular signal transduction pathways can sensitize the AR to castrate levels of androgens.Also,mutations in the AR can change AR ligand specificity,thereby allowing it to be activated by non-steroids or anti-androgens.Finally,overexpression of the wild-type AR sensitizes itself to low concentrations of androgens.Therefore,drugs targeting AR signalling could still be effective in treating HRPC.

  10. Pathogenetic correlations androgen deficiency and uronephrological kidneys diseases at men (the literary review

    Directory of Open Access Journals (Sweden)

    I. A. Tyuzikov

    2014-11-01

    Full Text Available Mechanisms of pathophysiological interactions of androgen deficiency, associated with it the metabolic disorders (components of a metabolic syndrome and the homeostasis disorders caused by uronephrological kidneys diseases at men based on the modern epidemiological, clinical and experimental investigations are considered in the literary review. There are described either androgen deficiency development mechanisms in kidneys pathology or mutual androgen deficiency influence an anatomic and functional condition of kidneys at men. The information about mechanisms and diagnostics and prognostic role of hyperprolactinaemia in kidneys diseases at men is presented, and also questions of a current state of a problem of expediency and carrying out possibility androgen re-placement therapies at this patients category are covered in the short form too. Kidneys diseases at men represent as the difficult interdisciplinary problem, therefore for the successful decision of modern questions of their early diagnostics, pathogenetic therapy and prevention unconditional interaction of various medical specialties is required.

  11. Pathogenetic correlations androgen deficiency and uronephrological kidneys diseases at men (the literary review

    Directory of Open Access Journals (Sweden)

    I. A. Tyuzikov

    2012-01-01

    Full Text Available Mechanisms of pathophysiological interactions of androgen deficiency, associated with it the metabolic disorders (components of a metabolic syndrome and the homeostasis disorders caused by uronephrological kidneys diseases at men based on the modern epidemiological, clinical and experimental investigations are considered in the literary review. There are described either androgen deficiency development mechanisms in kidneys pathology or mutual androgen deficiency influence an anatomic and functional condition of kidneys at men. The information about mechanisms and diagnostics and prognostic role of hyperprolactinaemia in kidneys diseases at men is presented, and also questions of a current state of a problem of expediency and carrying out possibility androgen re-placement therapies at this patients category are covered in the short form too. Kidneys diseases at men represent as the difficult interdisciplinary problem, therefore for the successful decision of modern questions of their early diagnostics, pathogenetic therapy and prevention unconditional interaction of various medical specialties is required.

  12. 自我管理教育对前列腺癌去势治疗后患者生活质量的影响%Effect of self-management education on the life quality of patients with prostate cancer after androgen deprivation therapy

    Institute of Scientific and Technical Information of China (English)

    杨惠娟

    2012-01-01

    Objective To explore the effects of self - management education on the life quality of patients with prostate cancer after androgen deprivation therapy.Methods Forty - six patients with androgen deprivation were randomly divided into two groups:control group and experimental group.the routine education were used in the control group,while the self - management education were used in the experimental group.Results After implementation of self - management education,the physical function,social function,mental function of experimental group were higher than those in the control group.There were significant difference (P < 0.05).Conclusions Self - management education on patients with prostate cancer after androgen deprivation therapy can improve physical function,social function and mental function,improve the quality of life.%目的 探讨自我管理教育对前列腺癌去势治疗后患者生活质量的影响.方法 将46例前列腺癌行去势治疗患者分为两组,分别为对照组和实验组,对照组采用常规健康教育,实验组实施自我管理教育.结果 实施自我管理教育后,实验组的躯体功能、社会功能、心理功能高于对照组,差异有统计学意义(P<0.05).结论 自我管理教育能提高前列腺癌去势治疗后患者的躯体功能、社会功能、心理功能,从而改善生活质量.

  13. Expression of androgen receptor target genes in skeletal muscle

    Directory of Open Access Journals (Sweden)

    Kesha Rana

    2014-10-01

    Full Text Available We aimed to determine the mechanisms of the anabolic actions of androgens in skeletal muscle by investigating potential androgen receptor (AR-regulated genes in in vitro and in vivo models. The expression of the myogenic regulatory factor myogenin was significantly decreased in skeletal muscle from testosterone-treated orchidectomized male mice compared to control orchidectomized males, and was increased in muscle from male AR knockout mice that lacked DNA binding activity (ARΔZF2 versus wildtype mice, demonstrating that myogenin is repressed by the androgen/AR pathway. The ubiquitin ligase Fbxo32 was repressed by 12 h dihydrotestosterone treatment in human skeletal muscle cell myoblasts, and c-Myc expression was decreased in testosterone-treated orchidectomized male muscle compared to control orchidectomized male muscle, and increased in AR∆ZF2 muscle. The expression of a group of genes that regulate the transition from myoblast proliferation to differentiation, Tceal7 , p57 Kip2, Igf2 and calcineurin Aa, was increased in AR∆ZF2 muscle, and the expression of all but p57 Kip2 was also decreased in testosterone-treated orchidectomized male muscle compared to control orchidectomized male muscle. We conclude that in males, androgens act via the AR in part to promote peak muscle mass by maintaining myoblasts in the proliferative state and delaying the transition to differentiation during muscle growth and development, and by suppressing ubiquitin ligase-mediated atrophy pathways to preserve muscle mass in adult muscle.

  14. Expression of androgen receptor target genes in skeletal muscle

    Institute of Scientific and Technical Information of China (English)

    Kesha Rana; Nicole KL Lee; Jeffrey D Zajac; Helen E MacLean

    2014-01-01

    We aimed to determine the mechanisms of the anabolic actions of androgens in skeletal muscle by investigating potential androgen receptor(AR)‑regulated genes ininvitroandinvivomodels. The expression of the myogenic regulatory factormyogenin was signiifcantly decreased in skeletal muscle from testosterone‑treated orchidectomized male mice compared to control orchidectomized males, and was increased in muscle from male AR knockout mice that lacked DNA binding activity(ARΔZF2) versus wildtype mice, demonstrating thatmyogenin is repressed by the androgen/AR pathway. The ubiquitin ligaseFbxo32 was repressed by 12h dihydrotestosterone treatment in human skeletal muscle cell myoblasts, andc‑Myc expression was decreased in testosterone‑treated orchidectomized male muscle compared to control orchidectomized male muscle, and increased in AR∆ZF2 muscle. The expression of a group of genes that regulate the transition from myoblast proliferation to differentiation, Tceal7, p57Kip2, Igf2 andcalcineurin Aa, was increased in AR∆ZF2 muscle, and the expression of all butp57Kip2was also decreased in testosterone‑treated orchidectomized male muscle compared to control orchidectomized male muscle. We conclude that in males, androgens act via the AR in part to promote peak muscle mass by maintaining myoblasts in the proliferative state and delaying the transition to differentiation during muscle growth and development, and by suppressing ubiquitin ligase‑mediated atrophy pathways to preserve muscle mass in adult muscle.

  15. Expression of androgen receptor target genes in skeletal muscle.

    Science.gov (United States)

    Rana, Kesha; Lee, Nicole K L; Zajac, Jeffrey D; MacLean, Helen E

    2014-01-01

    We aimed to determine the mechanisms of the anabolic actions of androgens in skeletal muscle by investigating potential androgen receptor (AR)-regulated genes in in vitro and in vivo models. The expression of the myogenic regulatory factor myogenin was significantly decreased in skeletal muscle from testosterone-treated orchidectomized male mice compared to control orchidectomized males, and was increased in muscle from male AR knockout mice that lacked DNA binding activity (AR(ΔZF2)) versus wildtype mice, demonstrating that myogenin is repressed by the androgen/AR pathway. The ubiquitin ligase Fbxo32 was repressed by 12 h dihydrotestosterone treatment in human skeletal muscle cell myoblasts, and c-Myc expression was decreased in testosterone-treated orchidectomized male muscle compared to control orchidectomized male muscle, and increased in AR(∆ZF2) muscle. The expression of a group of genes that regulate the transition from myoblast proliferation to differentiation, Tceal7 , p57(Kip2), Igf2 and calcineurin Aa, was increased in AR(∆ZF2) muscle, and the expression of all but p57(Kip2) was also decreased in testosterone-treated orchidectomized male muscle compared to control orchidectomized male muscle. We conclude that in males, androgens act via the AR in part to promote peak muscle mass by maintaining myoblasts in the proliferative state and delaying the transition to differentiation during muscle growth and development, and by suppressing ubiquitin ligase-mediated atrophy pathways to preserve muscle mass in adult muscle.

  16. Long-Term Follow-Up of a Prospective Trial of Trimodality Therapy of Weekly Paclitaxel, Radiation, and Androgen Deprivation in High-Risk Prostate Cancer With or Without Prior Prostatectomy

    Energy Technology Data Exchange (ETDEWEB)

    Hussain, Arif, E-mail: ahussain@som.umaryland.edu [University of Maryland Greenebaum Cancer Center, Baltimore, MD (United States); Department of Medicine, University of Maryland School of Medicine, Baltimore, MD (United States); Baltimore VA Medical Center, Baltimore, MD (United States); Wu, Yin [Department of Medicine, University of Maryland School of Medicine, Baltimore, MD (United States); Mirmiran, Alireza [Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD (United States); DiBiase, Steven [Cooper University Hospital, Camden, NJ (United States); Goloubeva, Olga [University of Maryland Greenebaum Cancer Center, Baltimore, MD (United States); Bridges, Benjamin [University of Maryland Greenebaum Cancer Center, Baltimore, MD (United States); Department of Medicine, University of Maryland School of Medicine, Baltimore, MD (United States); Mannuel, Heather [University of Maryland Greenebaum Cancer Center, Baltimore, MD (United States); Department of Medicine, University of Maryland School of Medicine, Baltimore, MD (United States); Baltimore VA Medical Center, Baltimore, MD (United States); Engstrom, Christine [Baltimore VA Medical Center, Baltimore, MD (United States); Dawson, Nancy [Lombardi Cancer Center, Georgetown University, Washington, D.C (United States); Amin, Pradip; Kwok, Young [Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD (United States)

    2012-01-01

    Purpose: Weekly paclitaxel, concurrent radiation, and androgen deprivation (ADT) were evaluated in patients with high-risk prostate cancer (PC) with or without prior prostatectomy (RP). Methods and Materials: Eligible post-RP patients included: pathological T3 disease, or rising prostate-specific antigen (PSA) {>=}0.5 ng/mL post-RP. Eligible locally advanced PC (LAPC) patients included: 1) cT2b-4N0N+, M0; 2) Gleason score (GS) 8-10; 3) GS 7 + PSA 10-20 ng/mL; or 4) PSA 20-150 ng/mL. Treatment included ADT (4 or 24 months), weekly paclitaxel (40, 50, or 60 mg/m{sup 2}/wk), and pelvic radiation therapy (total dose: RP = 64.8 Gy; LAPC = 70.2 Gy). Results: Fifty-nine patients were enrolled (LAPC, n = 29; RP, n = 30; ADT 4 months, n = 29; 24 months, n = 30; whites n = 29, African Americans [AA], n = 28). Baseline characteristics (median [range]) were: age 67 (45-86 years), PSA 5.9 (0.1-92.1 ng/mL), GS 8 (6-9). At escalating doses of paclitaxel, 99%, 98%, and 95% of doses were given with radiation and ADT, respectively, with dose modifications required primarily in RP patients. No acute Grade 4 toxicities occurred. Grade 3 toxicities were diarrhea 15%, urinary urgency/incontinence 10%, tenesmus 5%, and leukopenia 3%. Median follow-up was 75.3 months (95% CI: 66.8-82.3). Biochemical progression occurred in 24 (41%) patients and clinical progression in 11 (19%) patients. The 5- and 7-year OS rates were 83% and 67%. There were no differences in OS between RP and LAPC, 4- and 24-month ADT, white and AA patient categories. Conclusions: In addition to LAPC, to our knowledge, this is the first study to evaluate concurrent chemoradiation with ADT in high-risk RP patients. With a median follow-up of 75.3 months, this trial also represents the longest follow-up of patients treated with taxane-based chemotherapy with EBRT in high-risk prostate cancer. Concurrent ADT, radiation, and weekly paclitaxel at 40 mg/m{sup 2}/week in RP patients and 60 mg/m{sup 2}/week in LAPC patients is

  17. Androgen deprivation causes truncation of the C-terminal region of androgen receptor in human prostate cancer LNCaP cells.

    Science.gov (United States)

    Harada, Naoki; Inoue, Kaoru; Yamaji, Ryoichi; Nakano, Yoshihisa; Inui, Hiroshi

    2012-06-01

    The androgen receptor (AR) acts as a ligand-dependent transcription factor, whereas mutant AR lacking the C-terminal ligand-binding domain functions in a ligand-independent manner. In the present study we report that the C-terminal truncated AR, which we named AR-NH1 (the N-terminal fragment of AR cleaved in the neighborhood of helix 1 of the ligand-binding domain), is produced in LNCaP prostatic carcinoma cells. The AR-NH1 of ~90 kDa was observed in an androgen-independent LNCaP subline and was further accumulated by the proteasome inhibitor MG132. MG132 treatment caused the accumulation of AR-NH1 even in parent LNCaP cells. AR-NH1 was produced in the absence of ligand or in the presence of the AR antagonist bicalutamide, whereas AR agonists suppressed its production. AR-NH1 was detected with different AR antibodies recognizing amino acid residues 1-20 and 300-316 and was also generated from exogenous AR. Both siRNA-mediated AR knockdown and treatment with a serine protease inhibitor (4-(2-aminoethyl)-benzenesulfonyl fluoride) reduced AR-NH1 levels. According to the predicted cleavage site (between amino acid residues 660-685) and its nuclear localization, it is assumed that AR-NH1 functions as a constitutively active transcription factor. These data suggest that AR-NH1 is produced under hormone therapy and contributes to the development of castration-resistant prostate cancer due to its ligand-independent transcriptional activity.

  18. Effect of HSV-2 Suppressive Therapy on Genital Tract HIV-1 RNA Shedding among Women on HAART: A Pilot Randomized Controlled Trial

    Directory of Open Access Journals (Sweden)

    A. E. Nijhawan

    2012-01-01

    Full Text Available Background. The role of suppressive HSV therapy in women coinfected with HSV-2 and HIV-1 taking highly active antiretroviral therapy (HAART is unclear. Methods. 60 women with HIV-1/HSV-2 coinfection on HAART with plasma HIV-1 viral load (PVL ≤75 copies/mL were randomized to receive acyclovir (N=30 or no acyclovir (N=30. PVL, genital tract (GT HIV-1, and GT HSV were measured every 4 weeks for one year. Results. Detection of GT HIV-1 was not significantly different in the two arms (OR 1.23, P=0.67, although this pilot study was underpowered to detect this difference. When PVL was undetectable, the odds of detecting GT HIV were 0.4 times smaller in the acyclovir arm than in the control arm, though this was not statistically significant (P=0.07. The odds of detecting GT HSV DNA in women receiving acyclovir were significantly lower than in women in the control group, OR 0.38, P<0.05. Conclusions. Chronic suppressive therapy with acyclovir in HIV-1/HSV-2-positive women on HAART significantly reduces asymptomatic GT HSV shedding, though not GT HIV shedding or PVL. PVL was strongly associated with GT HIV shedding, reinforcing the importance of HAART in decreasing HIV sexual transmission.

  19. Severe Bone Marrow Suppression Accompanying Pulmonary Infection and Hemorrhage of the Digestive Tract Associated with Leflunomide and Low-dose Methotrexate Combination Therapy

    Science.gov (United States)

    Qu, Caihong; Lu, Ying; Liu, Weimin

    2017-01-01

    A 60-year-old male patient developed hyperpyrexia, cough, expectoration with blood-stained sputum, mouth ulcers, and suppurative tonsillitis after receiving 35 days of combination treatment with leflunomide (LEF) and low-dose methotrexate (MTX) for active rheumatoid arthritis. On admission, routine blood tests showed severe thrombocytopenia, agranulocytosis, and decreased hemoglobin concentration compared with the relatively normal results of 1 month previously during the first hospitalization. Chest radiography revealed inflammation in both lungs, and a fecal occult blood test was positive. Given this presentation, severe bone marrow suppression accompanying pulmonary infection and hemorrhage of the digestive tract associated with LEF and MTX combination therapy was diagnosed. After 28 days of symptomatic treatment, the patient's complications subsided gradually. This case highlighted that bone marrow suppression associated with MTX and LEF combination therapy could be very serious, even at a normal dose or especially at the beginning of treatment. MTX and LEF combination therapy should be used with caution or be limited in those with a history of pulmonary disease, hemorrhage of the digestive tract, or other relevant diseases.

  20. Systematic review of HIV transmission between heterosexual serodiscordant couples where the HIV-positive partner is fully suppressed on antiretroviral therapy.

    Directory of Open Access Journals (Sweden)

    Mona R Loutfy

    Full Text Available BACKGROUND: The risk of sexual HIV transmission in serodiscordant couples when the HIV-positive partner has full virologic suppression on combination antiretroviral therapy (cART is debated. This study aims to systematically review observational studies and randomized controlled trials (RCTs, evaluating rates of sexual HIV transmission between heterosexual serodiscordant couples when the HIV-positive partner has full suppression on cART. METHODS AND FINDINGS: We searched major bibliographic databases to November 2012 for relevant observational studies and RCTs without language restrictions. Conference proceedings, key journals and bibliographies were also searched. Studies reporting HIV transmission rates, cART histories and viral loads of the HIV-positive partners were included. Two reviewers extracted methodologic characteristics and outcomes. Of 20,252 citations, 3 studies met all eligibility criteria with confirmed full virologic suppression in the HIV-positive partner. We included 3 additional studies (2 cohort studies, 1 RCT that did not confirm viral suppression in the HIV-positive partner at transmission in a secondary meta-analysis. Methodologic quality was reasonable. The rate of transmission in the 3 studies confirming virologic suppression was 0 per 100 person-years (95% CI = 0-0.05, with low heterogeneity (I(2 = 0%. When we included the 3 studies that did not confirm virologic suppression, the rate of transmission was 0.14 per 100 person-years (95%CI = 0.04-0.31 (I(2 = 0%. In a sensitivity analysis including all 6 studies, the rate of transmission was 0 per 100 person-years (95%CI = 0-0.01 after omitting all transmissions with known detectable or unconfirmed viral loads, as full suppression in these cases was unlikely. Limitations included lack of data on same-sex couples, type of sexual intercourse (vaginal vs. anal, direction of HIV transmission, exact viral load at the time of transmission, sexually

  1. Viral suppression and immune restoration in the gastrointestinal mucosa of human immunodeficiency virus type 1-infected patients initiating therapy during primary or chronic infection.

    Science.gov (United States)

    Guadalupe, Moraima; Sankaran, Sumathi; George, Michael D; Reay, Elizabeth; Verhoeven, David; Shacklett, Barbara L; Flamm, Jason; Wegelin, Jacob; Prindiville, Thomas; Dandekar, Satya

    2006-08-01

    Although the gut-associated lymphoid tissue (GALT) is an important early site for human immunodeficiency virus (HIV) replication and severe CD4+ T-cell depletion, our understanding is limited about the restoration of the gut mucosal immune system during highly active antiretroviral therapy (HAART). We evaluated the kinetics of viral suppression, CD4+ T-cell restoration, gene expression, and HIV-specific CD8+ T-cell responses in longitudinal gastrointestinal biopsy and peripheral blood samples from patients initiating HAART during primary HIV infection (PHI) or chronic HIV infection (CHI) using flow cytometry, real-time PCR, and DNA microarray analysis. Viral suppression was more effective in GALT of PHI patients than CHI patients during HAART. Mucosal CD4+ T-cell restoration was delayed compared to peripheral blood and independent of the time of HAART initiation. Immunophenotypic analysis showed that repopulating mucosal CD4+ T cells were predominantly of a memory phenotype and expressed CD11 alpha, alpha(E)beta 7, CCR5, and CXCR4. Incomplete suppression of viral replication in GALT during HAART correlated with increased HIV-specific CD8+ T-cell responses. DNA microarray analysis revealed that genes involved in inflammation and cell activation were up regulated in patients who did not replenish mucosal CD4+ T cells efficiently, while expression of genes involved in growth and repair was increased in patients with efficient mucosal CD4+ T-cell restoration. Our findings suggest that the discordance in CD4+ T-cell restoration between GALT and peripheral blood during therapy can be attributed to the incomplete viral suppression and increased immune activation and inflammation that may prevent restoration of CD4+ T cells and the gut microenvironment.

  2. A novel selective androgen receptor modulator (SARM) MK-4541 exerts anti-androgenic activity in the prostate cancer xenograft R-3327G and anabolic activity on skeletal muscle mass & function in castrated mice.

    Science.gov (United States)

    Chisamore, Michael J; Gentile, Michael A; Dillon, Gregory Michael; Baran, Matthew; Gambone, Carlo; Riley, Sean; Schmidt, Azriel; Flores, Osvaldo; Wilkinson, Hilary; Alves, Stephen E

    2016-10-01

    The androgen receptor (AR) is a member of the nuclear hormone receptor super family of transcription factors. Androgens play an essential role in the development, growth, and maintenance of male sex organs, as well as the musculoskeletal and central nervous systems. Yet with advancing age, androgens can drive the onset of prostate cancer, the second leading cause of cancer death in males within the United States. Androgen deprivation therapy (ADT) by pharmacologic and/or surgical castration induces apoptosis of prostate cells and subsequent shrinkage of the prostate and prostate tumors. However, ADT is associated with significant musculoskeletal and behavioral adverse effects. The unique pharmacological activity of selective androgen receptor modulator (SARM) MK-4541 recently has been reported as an AR antagonist with 5α-reductase inhibitor function. The molecule inhibits proliferation and induces apoptosis in AR positive, androgen dependent prostate cancer cells. Importantly, MK-4541 inhibited androgen-dependent prostate growth in male rats yet maintained lean body mass and bone formation following ovariectomy in female rats. In the present study, we evaluated the effects of SARM MK-4541 in the androgen-dependent Dunning R3327-G prostate carcinoma xenograft mouse model as well as on skeletal muscle mass and function, and AR-regulated behavior in mice. MK-4541 significantly inhibited the growth of R3327-G prostate tumors, exhibited anti-androgen effects on the seminal vesicles, reduced plasma testosterone concentrations in intact males, and inhibited Ki67 expression. MK-4541 treated xenografts appeared similar to xenografts in castrated mice. Importantly, we demonstrate that MK-4541 exhibited anabolic activity in androgen deficient conditions, increasing lean body mass and muscle function in adult castrated mice. Moreover, MK-4541 treatment restored general activity levels in castrated mice. Thus, MK-4541 exhibits an optimum profile as an adjuvant therapy to ADT

  3. ANDROGEN INSENSITIVITY SYNDROME

    Directory of Open Access Journals (Sweden)

    Kanan

    2014-01-01

    Full Text Available The condition is inherited as X - linked recessive gene 1 . The underlying pathology is the inability of end organs to respond to androgens. These cases are phenotypically and psychologically female with adequate breast development , normal external genitalia , a vagina with variable depth , absent /sparse pubic hair and axillary hair. The exact incidence in India is not known but the reported incidence is 1 in 2 , 000 to 1 in 62 ,400 worldwide . These patients have male karyotyping (XY wi th negative sex chromatin with undescended gonads. These cases are rarely diagnosed before puberty. Though rare , these are extremely distressing to the concerned individuals requiring expert handling. Management should include psychological counseling not only to determine the sexual mentation but also to help those individuals to cope with their problems. The chance of malignancy developing in the gonad with Y chromosome are about 20%.Surgical removal of the gonad is mandatory but can be delayed till 18 ye ars to permit breast development and epiphyseal closure. The aim of presenting this case is to develop awareness regarding this rare syndrome X - linked genetic disorder which runs in families

  4. Hypochlorite Oxidation of Select Androgenic Steroids

    Science.gov (United States)

    Steroid hormones are vital for regulation of various biological functions including sexual development. Elevated concentrations of natural and synthetic androgenic steroids have been shown to adversely affect normal development in indigenous aqueous species. Androgens and their s...

  5. Cortical venous thrombosis following exogenous androgen use for bodybuilding.

    Science.gov (United States)

    Sveinsson, Olafur; Herrman, Lars

    2013-02-05

    There are only a few reports of patients developing cerebral venous sinus thrombosis (CVST) after androgen therapy. We present a young man who developed cortical venous thrombosis after using androgens to increase muscle mass. He was hospitalised for parasthesia and dyspraxia in the left hand followed by a generalised tonic-clonic seizure. At admission, he was drowsy, not fully orientated, had sensory inattention, pronation drift and a positive extensor response, all on the left side. The patient had been using anabolic steroids (dainabol 20 mg/day) for the last month for bodybuilding. CT angiography showed a right cortical venous thrombosis. Anticoagulation therapy was started with intravenous heparin for 11 days and oral anticoagulation (warfarin) thereafter. A control CT angiography 4 months later showed resolution of the thrombosis. He recovered fully.

  6. Attenuation of circadian variation by combined antianginal therapy with suppression of morning and evening increases in transient myocardial ischemia

    DEFF Research Database (Denmark)

    Egstrup, K

    1991-01-01

    three 6-hour periods (p less than 0.01); a lesser peak was noted in the evening. The effects of metoprolol and combined therapy with metoprolol and nifedipine on the circadian variation of ischemic activity were studied in two subgroups of patients in a random, double-blind study design (31 patients...... receiving metoprolol and 42 receiving combined therapy). During therapy with metoprolol the morning increase in ischemic activity was attenuated, and the highest frequency of ischemia was then noted in the evening (6 AM to 12 noon compared with 6 PM to 12 midnight; p less than 0.05). Combined therapy...... abolished the morning peak as did metoprolol monotherapy, but even the evening increase in ischemic activity was attenuated (p less than 0.05). The diurnal distribution of the mean heart rate at the onset of ischemia, when patients were off therapy, showed a morning increase similar to the increase...

  7. Targeting Androgen Receptor Aberrations in Castration-Resistant Prostate Cancer.

    Science.gov (United States)

    Sharp, Adam; Welti, Jonathan; Blagg, Julian; de Bono, Johann S

    2016-09-01

    Androgen receptor (AR) splice variants (SV) have been implicated in the development of metastatic castration-resistant prostate cancer and resistance to AR targeting therapies, including abiraterone and enzalutamide. Agents targeting AR-SV are urgently needed to test this hypothesis and further improve the outcome of patients suffering from this lethal disease. Clin Cancer Res; 22(17); 4280-2. ©2016 AACRSee related article by Yang et al., p. 4466.

  8. Androgen receptor roles in the development of benign prostate hyperplasia.

    Science.gov (United States)

    Izumi, Kouji; Mizokami, Atsushi; Lin, Wen-Jye; Lai, Kuo-Pao; Chang, Chawnshang

    2013-06-01

    Benign prostate hyperplasia (BPH) is a major cause of lower urinary tract symptoms, with an increased volume of transitional zone and associated with increased stromal cells. It is known that androgen/androgen receptor (AR) signaling plays a key role in development of BPH, and that blockade of this signaling decreases BPH volume and can relieve lower urinary tract symptoms, but the mechanisms of androgen/AR signaling in BPH development remain unclear, and the effectiveness of current drugs for treating BPH is still limited. The detailed mechanisms of androgen/AR signaling need to be clarified, and new therapies are needed for better treatment of BPH patients. This review focuses on roles of AR in epithelial and stromal cells in BPH development. In epithelial cells, AR may contribute to BPH development via epithelial cell-stromal cell interaction with alterations of epithelial-mesenchymal transition, leading to proliferation of stromal cells. Data from several mouse models with selective knockout of AR in stromal smooth-muscle cells and/or fibroblasts indicate that the AR in stromal cells can also promote BPH development. In prostatic inflammation, AR roles in infiltrating macrophages and epithelial and stromal cells have been linked to BPH development, which has led to discovery of new therapeutic targets. For example, targeting AR with the novel AR degradation enhancer, ASC-J9 offers a potential therapeutic approach against BPH development.

  9. Synthetic anabolic agents: steroids and nonsteroidal selective androgen receptor modulators.

    Science.gov (United States)

    Thevis, Mario; Schänzer, Wilhelm

    2010-01-01

    The central role of testosterone in the development of male characteristics, as well as its beneficial effects on physical performance and muscle growth, has led to the search for synthetic alternatives with improved pharmacological profiles. Hundreds of steroidal analogs have been prepared with a superior oral bioavailability, which should also possess reduced undesirable effects. However, only a few entered the pharmaceutical market due to severe toxicological incidences that were mainly attributed to the lack of tissue selectivity. Prominent representatives of anabolic-androgenic steroids (AAS) are for instance methyltestosterone, metandienone and stanozolol, which are discussed as model compounds with regard to general pharmacological aspects of synthetic AAS. Recently, nonsteroidal alternatives to AAS have been developed that selectively activate the androgen receptor in either muscle tissue or bones. These so-called selective androgen receptor modulators (SARMs) are currently undergoing late clinical trials (IIb) and will be prohibited by the World Anti-Doping Agency from January 2008. Their entirely synthetic structures are barely related to steroids, but particular functional groups allow for the tissue-selective activation or inhibition of androgen receptors and, thus, the stimulation of muscle growth without the risk of severe undesirable effects commonly observed in steroid replacement therapies. Hence, these compounds possess a high potential for misuse in sports and will be the subject of future doping control assays.

  10. Androgen deprivation modulates the inflammatory response induced by irradiation

    Directory of Open Access Journals (Sweden)

    Lin Paul-Yang

    2009-03-01

    Full Text Available Abstract Background The aim of this study was to determine whether radiation (RT-induced inflammatory responses and organ damage might be modulated by androgen deprivation therapies. Methods The mRNA and tissue sections obtained from the lungs, intestines and livers of irradiated mice with or without androgen deprivation were analyzed by real-time PCR and histological analysis. Activation of NF-kappa B was examined by measuring nuclear protein levels in the intestine and lung 24 h after irradiation. We also examined the levels of cyclooxygenase-2 (COX-2, TGF-β1 and p-AKT to elucidate the related pathway responsible to irradiation (RT -induced fibrosis. Results We found androgen deprivation by castration significantly augmented RT-induced inflammation, associated with the increase NF-κB activation and COX-2 expression. However, administration of flutamide had no obvious effect on the radiation-induced inflammation response in the lung and intestine. These different responses were probably due to the increase of RT-induced NF-κB activation and COX-2 expression by castration or lupron treatment. In addition, our data suggest that TGF-β1 and the induced epithelial-mesenchymal transition (EMT via the PI3K/Akt signaling pathway may contribute to RT-induced fibrosis. Conclusion When irradiation was given to patients with total androgen deprivation, the augmenting effects on the RT-induced inflammation and fibrosis should take into consideration for complications associated with radiotherapy.

  11. The clinical benefits of antiretroviral therapy in severely immunocompromised HIV-1-infected patients with and without complete viral suppression

    DEFF Research Database (Denmark)

    Mocroft, Amanda; Bannister, Wendy P; Kirk, Ole

    2012-01-01

    The aim of this study was to determine whether there is a protective effect of combination antiretroviral therapy (cART) on the development of clinical events in patients with ongoing severe immunosuppression.......The aim of this study was to determine whether there is a protective effect of combination antiretroviral therapy (cART) on the development of clinical events in patients with ongoing severe immunosuppression....

  12. IN VIVO AND IN VITRO ANTI-ANDROGENIC EFFECTS OF DE-71

    Science.gov (United States)

    Recently, we showed that the PBDE mixture, DE-71, delayed preputial separation (PPS) and suppressed the growth of androgen-dependent tissues in the Wistar rat following a peri-pubertal exposure. These effects occurred concurrently with hypothyroidism and suggested that in additi...

  13. Progress on the pathologic mechanism and potential therapy of androgenic alopecia%脂溢性脱发的发生机制及治疗研究进展

    Institute of Scientific and Technical Information of China (English)

    巫珊; 张海州

    2012-01-01

    Pathologic mechanism and therapeutic methods of androgenic alopecia were discussed. Pathological representations, pathogenesis and therapeutically active ingredients of androgenic alopecia were introduced, and the relationship between cytokines and androgenic alopecia was disclosed. The active ingredients which may inhibit or stimulate related cytokines with traditional treatment for hairloss are presented and its application prospect is also discussed.%综述了脂溢性脱发的发生机制及活性物治疗研究进展。主要介绍了脂溢性脱发的病理表现、发生机制以及治疗活性物的研究现状。重点揭示了相关细胞因子对脂溢性脱发的影响。提出将具有相应细胞因子激励或抑制作用的活性物与常规的功能性成分联合应用在防脱发个人护理品中,将充分发挥其治疗效果,并对其应用前景进行了展望。

  14. Laparoscopic gonedectomy in a case of complete androgen insensitivity syndrome

    OpenAIRE

    G Bhaskararao; Himabindu, Y; Samir Ranjan Nayak; M Sriharibabu

    2014-01-01

    Complete Androgen insensitivity syndrome is a disorder of hormone resistance characterized by a female phenotype in an individual with an XY karyotype. The pathogenesis of CAIS involves a defective androgen receptor gene located on X-chromosome at Xq11-12and end organ insensitivity to androgens, although androgen concentrations are appropriate for the age of the patient. There are three major types of androgen insensitivity syndrome: Complete androgen insensitivity syndrome, minimal androgen ...

  15. High rate of virological re-suppression among patients failing second-line antiretroviral therapy following enhanced adherence support: A model of care in Khayelitsha, South Africa

    Directory of Open Access Journals (Sweden)

    D B Garone

    2013-12-01

    Full Text Available Objective. To describe and evaluate the outcomes of a support programme for patients with virological failure while receiving second-line antiretroviral therapy (ART in South Africa.Method. We described a comprehensive medical and counselling patient support programme for patients receiving secondline ART and with two consecutive viral loads (VLs >1 000 copies/ml. Patients with >3 months follow-up and at least one VL measurement after inclusion in the programme were eligible for analysis.Results. Of 69 patients enrolled in the programme, 40 had at least one follow-up VL and no known drug resistance at enrolment; 27 (68% of these re-suppressed while remaining on second-line ART following enhanced adherence support. The majority (18/27; 67% achieved re-suppression within the first 3 months in the programme. Five patients with diagnosed second-line drug resistance achieved viral re-suppression (<400 copies/ml after being switched to third-line ART. Seven patients (7/40; 18% did not achieve viral re-suppression after 9 months in the programme: 6 with known adherence problems (4 without drug resistance on genotype and 1 with a VL <1 000 copies/ml. Overall, 3 patients (4% died, 3 (4% were lost to follow-up and 2 (3% were transferred out.Conclusion. Our experience from a routine programme demonstrates that with targeted adherence support, the majority of patients who were viraemic while receiving second-line ART returned to an undetectable VL within 3 months. By increasing the time receiving second-line ART and decreasing the need for genotypes and/or third-line ART, this intervention may reduce costs.

  16. Factors associated with virological failure and suppression after enhanced adherence counselling, in children, adolescents and adults on antiretroviral therapy for HIV in Swaziland.

    Directory of Open Access Journals (Sweden)

    Kiran Jobanputra

    Full Text Available This study explores factors associated with virological detectability, and viral re-suppression after enhanced adherence counselling, in adults and children on antiretroviral therapy (ART in Swaziland.This descriptive study used laboratory data from 7/5/2012 to 30/9/2013, which were linked with the national ART database to provide information on time on ART and CD4 count; information on enhanced adherence counselling was obtained from file review in health facilities. Multivariable logistic regression was used to explore the relationship between viral load, gender, age, time on ART, CD4 count and receiving (or not receiving enhanced adherence counselling.From 12,063 patients undergoing routine viral load monitoring, 1941 (16% had detectable viral loads. Children were more likely to have detectable viral loads (AOR 2.6, 95%CI 1.5-4.5, as were adolescents (AOR 3.2, 95%CI 2.2-4.8, patients with last CD4 1000 copies/ml (AOR 0.3, 95%CI 0.1-0.7, and those with last CD4<350 cells/µl (AOR 0.4, 95%CI 0.2-0.7. Receiving (or not receiving enhanced adherence counselling was not associated with likelihood of re-suppression.Children, adolescents and those with advanced disease were most likely to have high viral loads and least likely to achieve viral suppression at retesting; receiving adherence counselling was not associated with higher likelihood of viral suppression. Although the level of viral resistance was not quantified, this study suggests the need for ART treatment support that addresses the adherence problems of younger people; and to define the elements of optimal enhanced adherence support for patients of all ages with detectable viral loads.

  17. 4-Nitro-3-phenylphenol has both androgenic and anti-androgenic-like effects in rats.

    Science.gov (United States)

    Trisomboon, Jiratthiya; Li, ChunMei; Suzuki, Akira; Watanabe, Gen; Taya, Kazuyoshi

    2015-01-01

    To investigate the effect of endocrine disruption of 4-nitro-3-phenylphenol (PNMPP) on immature male Wistar-Imamichi rats, the rat pituitary was exposed to PNMPP (10(-5)-10(-9) M) for 24 h with or without gonadotropin-releasing hormone (GnRH) in experiment I. In addition, the Leydig cells (10(-5)-10(-9) M) were exposed to PNMPP for 24 h with or without human chronic gonadotropin (hCG) in experiment II. Our results showed that the PNMPP at 10(-5)-10(-7) M suppressed follicle-stimulating hormone (FSH) and luteinizing hormone (LH) productions from GnRH-stimulated pituitary cells. At the same time, PNMPP 10(-5)-10(-7) M induced an increase in testosterone production from the Leydig cells treated with or without hCG. Based on our results, it can be concluded that that PNMPP might have both androgen agonist action by decreasing FSH and LH production in the pituitary and anti-androgenic action by increasing testosterone production in the Leydig cell.

  18. Antiandrogens act as selective androgen receptor modulators at the proteome level in prostate cancer cells.

    Science.gov (United States)

    Brooke, Greg N; Gamble, Simon C; Hough, Michael A; Begum, Shajna; Dart, D Alwyn; Odontiadis, Michael; Powell, Sue M; Fioretti, Flavia M; Bryan, Rosie A; Waxman, Jonathan; Wait, Robin; Bevan, Charlotte L

    2015-05-01

    Current therapies for prostate cancer include antiandrogens, inhibitory ligands of the androgen receptor, which repress androgen-stimulated growth. These include the selective androgen receptor modulators cyproterone acetate and hydroxyflutamide and the complete antagonist bicalutamide. Their activity is partly dictated by the presence of androgen receptor mutations, which are commonly detected in patients who relapse while receiving antiandrogens, i.e. in castrate-resistant prostate cancer. To characterize the early proteomic response to these antiandrogens we used the LNCaP prostate cancer cell line, which harbors the androgen receptor mutation most commonly detected in castrate-resistant tumors (T877A), analyzing alterations in the proteome, and comparing these to the effect of these therapeutics upon androgen receptor activity and cell proliferation. The majority are regulated post-transcriptionally, possibly via nongenomic androgen receptor signaling. Differences detected between the exposure groups demonstrate subtle changes in the biological response to each specific ligand, suggesting a spectrum of agonistic and antagonistic effects dependent on the ligand used. Analysis of the crystal structures of the AR in the presence of cyproterone acetate, hydroxyflutamide, and DHT identified important differences in the orientation of key residues located in the AF-2 and BF-3 protein interaction surfaces. This further implies that although there is commonality in the growth responses between androgens and those antiandrogens that stimulate growth in the presence of a mutation, there may also be influential differences in the growth pathways stimulated by the different ligands. This therefore has implications for prostate cancer treatment because tumors may respond differently dependent upon which mutation is present and which ligand is activating growth, also for the design of selective androgen receptor modulators, which aim to elicit differential proteomic

  19. EPI-001, A Compound Active against Castration-Resistant Prostate Cancer, Targets Transactivation Unit 5 of the Androgen Receptor.

    Science.gov (United States)

    De Mol, Eva; Fenwick, R Bryn; Phang, Christopher T W; Buzón, Victor; Szulc, Elzbieta; de la Fuente, Alex; Escobedo, Albert; García, Jesús; Bertoncini, Carlos W; Estébanez-Perpiñá, Eva; McEwan, Iain J; Riera, Antoni; Salvatella, Xavier

    2016-09-16

    Castration-resistant prostate cancer is the lethal condition suffered by prostate cancer patients that become refractory to androgen deprivation therapy. EPI-001 is a recently identified compound active against this condition that modulates the activity of the androgen receptor, a nuclear receptor that is essential for disease progression. The mechanism by which this compound exerts its inhibitory activity is however not yet fully understood. Here we show, by using high resolution solution nuclear magnetic resonance spectroscopy, that EPI-001 selectively interacts with a partially folded region of the transactivation domain of the androgen receptor, known as transactivation unit 5, that is key for the ability of prostate cells to proliferate in the absence of androgens, a distinctive feature of castration-resistant prostate cancer. Our results can contribute to the development of more potent and less toxic novel androgen receptor antagonists for treating this disease.

  20. Systematic structure-function analysis of androgen receptor Leu 701 mutants explains the properties of the prostate cancer mutant L701H

    NARCIS (Netherlands)

    D.J. van de Wijngaart (Dennis); M. Molier; S.J. Lusher (Scott); R. Hersmus (Remko); G.W. Jenster (Guido); J. Trapman (Hans); H.J. Dubbink (Erik Jan)

    2010-01-01

    textabstractOne mechanism of prostate tumors for escape from androgen ablation therapies is mutation of the androgen receptor (AR). Weinvestigated the unique properties of theARL701H mutant, which is strongly stimulated by cortisol, by a systematic structure-function analysis. Most amino acid substi

  1. Development of an androgen reporter gene assay (AR-LUX) utilizing a human cell line with an endogenously regulated androgen receptor.

    Science.gov (United States)

    Blankvoort, B M; de Groene, E M; van Meeteren-Kreikamp, A P; Witkamp, R F; Rodenburg, R J; Aarts, J M

    2001-11-01

    The aim of the work described in this report is to develop and characterize a cell-based androgen reporter assay. For this purpose, the androgen receptor (AR) expressing human breast cancer cell line T47D was stably transfected with a luciferase gene under transcriptional control of the PB-ARE-2 androgen response element. The application of this cell line in an endogenous Androgen Receptor-mediated LUciferase eXpression assay (AR-LUX) was validated. An EC50 value of 86 pM was determined for the standard androgen R1881 with a detection limit of 46 pM. Other androgens like dihydrotestosterone, 17beta-trenbolone, and bolasterone also induced luciferase expression, while anti-androgens suppressed these responses. As expected, AR-mediated responses were also elicited by high concentrations of the steroids progesterone, 17beta-estradiol, d-aldosterone, and dexamethasone, with observed EC50 values 10 to 350,000 times higher than that for R1881. A unique feature of the AR-LUX assay is that effects on modulation of active endogenous AR-levels are reliably reflected in the luciferase induction response, as exemplified by vitamin D, all-trans-retinoic acid, epigallocatechin gallate, and forskolin. This feature is especially useful when assessing complex mixtures, e.g., environmental samples or natural compound libraries. From these data it is concluded that the AR-LUX assay is a reliable in vitro test system for the detection and quantification of AR-mediated biological effects. The 96-well plate format makes the assay particularly suitable for high-throughput screening.

  2. Identification of an anabolic selective androgen receptor modulator that actively induces death of androgen-independent prostate cancer cells.

    Science.gov (United States)

    Schmidt, Azriel; Meissner, Robert S; Gentile, Michael A; Chisamore, Michael J; Opas, Evan E; Scafonas, Angela; Cusick, Tara E; Gambone, Carlo; Pennypacker, Brenda; Hodor, Paul; Perkins, James J; Bai, Chang; Ferraro, Damien; Bettoun, David J; Wilkinson, Hilary A; Alves, Stephen E; Flores, Osvaldo; Ray, William J

    2014-09-01

    Prostate cancer (PCa) initially responds to inhibition of androgen receptor (AR) signaling, but inevitably progresses to hormone ablation-resistant disease. Much effort is focused on optimizing this androgen deprivation strategy by improving hormone depletion and AR antagonism. However we found that bicalutamide, a clinically used antiandrogen, actually resembles a selective AR modulator (SARM), as it partially regulates 24% of endogenously 5α-dihydrotestosterone (DHT)-responsive genes in AR(+) MDA-MB-453 breast cancer cells. These data suggested that passive blocking of all AR functions is not required for PCa therapy. Hence, we adopted an active strategy that calls for the development of novel SARMs, which induce a unique gene expression profile that is intolerable to PCa cells. Therefore, we screened 3000 SARMs for the ability to arrest the androgen-independent growth of AR(+) 22Rv1 and LNCaP PCa cells but not AR(-) PC3 or DU145 cells. We identified only one such compound; the 4-aza-steroid, MK-4541, a potent and selective SARM. MK-4541 induces caspase-3 activity and cell death in both androgen-independent, AR(+) PCa cell lines but spares AR(-) cells or AR(+) non-PCa cells. This activity correlates with its promoter context- and cell-type dependent transcriptional effects. In rats, MK-4541 inhibits the trophic effects of DHT on the prostate, but not the levator ani muscle, and triggers an anabolic response in the periosteal compartment of bone. Therefore, MK-4541 has the potential to effectively manage prostatic hypertrophic diseases owing to its antitumor SARM-like mechanism, while simultaneously maintaining the anabolic benefits of natural androgens.

  3. Clinical, ultrasound and hormonal markers of androgenicity in acne vulgaris.

    Science.gov (United States)

    Walton, S; Cunliffe, W J; Keczkes, K; Early, A S; McGarrigle, H H; Katz, M; Reese, R A

    1995-08-01

    Androgenic stimulation of sebaceous glands is an important factor in the development of acne. We examined 36 females (aged 14-34 years), selected because none had received oral contraceptives, anti-androgen therapy, or systemic antibiotics during the previous year, or isotretinoin therapy, prior to their participation in the study. Subjects were divided into groups on the basis of acne severity, as follows: physiological, mild and moderate. Only two patients had polycystic ovaries on ultrasound examination. Seven patients had irregular menses; none had evidence of hirsutism. We found that the severity of acne, based on the acne grade, was highly correlated with the inflammatory lesion count, and less correlated with the sebum excretion rate. Either acne grade or inflammatory lesion count could be related to some of the five androgenic hormone determinants; free testosterone (TESTOS), delta 4 androstenedione (DELTA 4), sex hormone binding globulin (SHBG), dehydroepiandrostenedione sulphate (DHEAS) and dihydrotestosterone (DHT). Multiple linear regression analysis determined the best model for predicting ACNE scores as involving DELTA 4 and DHEAS (positive effects), and SHBG (negative effect), P < 0.005, R2 = 0.36). In none of the patients were the levels of DHEAS or SHBG outside the normal range. The findings in the two patients with polycystic ovaries did not differ significantly from those in the remainder of the patients.

  4. The impact of point mutations in the human androgen receptor: classification of mutations on the basis of transcriptional activity.

    Directory of Open Access Journals (Sweden)

    Colin W Hay

    Full Text Available Androgen receptor mediated signaling drives prostate cancer cell growth and survival. Mutations within the receptor occur infrequently in prostate cancer prior to hormonal therapy but become prevalent in incurable androgen independent and metastatic tumors. Despite the determining role played by the androgen receptor in all stages of prostate cancer progression, there is a conspicuous dearth of comparable data on the consequences of mutations. In order to remedy this omission, we have combined an expansive study of forty five mutations which are predominantly associated with high Gleason scores and metastatic tumors, and span the entire length of the receptor, with a literature review of the mutations under investigation. We report the discovery of a novel prevalent class of androgen receptor mutation that possesses loss of function at low levels of androgen yet transforms to a gain of function at physiological levels. Importantly, mutations introducing constitutive gain of function are uncommon, with the majority of mutations leading to either loss of function or no significant change from wild-type activity. Therefore, the widely accepted supposition that androgen receptor mutations in prostate cancer result in gain of function is appealing, but mistaken. In addition, the transcriptional outcome of some mutations is dependent upon the androgen receptor responsive element. We discuss the consequences of these findings and the role of androgen receptor mutations for prostate cancer progression and current treatment options.

  5. Bilateral atypical femoral subtrochanteric fractures in a premenopausal patient receiving prolonged bisphosphonate therapy: evidence of severely suppressed bone turnover.

    Science.gov (United States)

    Kondo, Naoki; Yoda, Takuya; Fujisawa, Junichi; Arai, Katsumitsu; Sakuma, Mayumi; Ninomiya, Hiroshi; Sano, Hiroshige; Endo, Naoto

    2015-01-01

    We report a case of bilateral atypical femoral fractures that occurred in a patient who had been taking bisphosphonate long-term. A 36-year-old premenopausal female diagnosed with systemic lupus erythematosus and dermatomyositis had been treated with glucocorticoid and alendronate (5 mg/day) to prevent glucocorticoid-induced osteoporosis. She was taken to our hospital because she could not walk immediately after falling down from the standing position. A plain radiograph showed a subtrochanteric fracture of the left femur. Four months later, she fell again and sustained a contralateral subtrochanteric fracture. For each fracture, a femoral intramedullary nail was inserted. Delayed union was detected in both sides, and revision surgery with an iliac bone graft was required for implant breakage in the right side. Histomorphometric findings for the ilium revealed remarkably decreased osteoid volume with no osteoclasts and a minimally eroded surface, suggesting that bone turnover was severely suppressed. However, histology of the delayed union site revealed callus formation and some osteoclast appearance, suggesting that fracture healing was occurring. In total, it took 29 months (left) and 24 months (right) until fracture healing was achieved, showing delayed union. This case is extremely rare in that patient who presented with atypical femoral fractures in spite of her premenopausal status. The bone histomorphometric findings from this case suggest that severely suppressed bone turnover is associated with atypical femoral subtrochanteric fracture and can cause delayed union in patients treated with alendronate long-term.

  6. Natural conception in HIV-serodiscordant couples with the infected partner in suppressive antiretroviral therapy: A prospective cohort study.

    Science.gov (United States)

    Del Romero, Jorge; Baza, María Begoña; Río, Isabel; Jerónimo, Adrián; Vera, Mar; Hernando, Victoria; Rodríguez, Carmen; Castilla, Jesús

    2016-07-01

    The potential of antiretroviral treatment (ART) to prevent the sexual transmission of HIV has increased the number of serodiscordant couples who are considering natural conception. We aim to describe the results of a protocol for reproductive counseling aimed at HIV serodiscordant couples who desire natural conception, in which the infected partner, the index case, is receiving suppressive antiretroviral treatment.A prospective cohort included all HIV serodiscordant couples attended a counseling program in the period 2002 to 2013 who opted for natural conception and met the following criteria: index case on ART with persistent plasma viral suppression for at least the previous 6 months, ART compliance over 95%, preserved immune status, undetectable HIV viral and proviral load in semen in male index cases, and absence of genitourinary infections and fertility problems in both members of the couple.Of the 161 HIV serodiscordant couples included, 133 with male index cases, 66% achieved at least 1 pregnancy, 18% a second one, and 5% a third pregnancy. A total of 144 natural pregnancies occurred and 107 babies were born. The pregnancy rate was 1.9 for each 100 acts of vaginal intercourse, and the mean time to conception was 6.1 months, both independently of the sex of the index case. No case of sexual or vertical HIV transmission occurred.In the absence of fertility problems and under controlled conditions, natural conception might be a safe and effective reproductive method for those HIV serodiscordant couples who choose this reproductive option.

  7. CCR5-Δ32 Heterozygosity, HIV-1 Reservoir Size, and Lymphocyte Activation in Individuals Receiving Long-term Suppressive Antiretroviral Therapy.

    Science.gov (United States)

    Henrich, Timothy J; Hanhauser, Emily; Harrison, Linda J; Palmer, Christine D; Romero-Tejeda, Marisol; Jost, Stephanie; Bosch, Ronald J; Kuritzkes, Daniel R

    2016-03-01

    We conducted a case-controlled study of the associations of CCR5-Δ32 heterozygosity with human immunodeficiency virus type 1 (HIV-1) reservoir size, lymphocyte activation, and CCR5 expression in 114 CCR5(Δ32/WT) and 177 wild-type CCR5 AIDS Clinical Trials Group participants receiving suppressive antiretroviral therapy. Overall, no significant differences were found between groups for any of these parameters. However, higher levels of CCR5 expression correlated with lower amounts of cell-associated HIV-1 RNA. The relationship between CCR5-Δ32 heterozygosity, CCR5 expression, and markers of HIV-1 persistence is likely to be complex and may be influenced by factors such as the duration of ART.

  8. Potential role of vascular smooth muscle cell-like progenitor cell therapy in the suppression of experimental abdominal aortic aneurysms.

    Science.gov (United States)

    Park, Hyung Sub; Choi, Geum Hee; Hahn, Soli; Yoo, Young Sun; Lee, Ji Youl; Lee, Taeseung

    2013-02-08

    Abdominal aortic aneurysms (AAA) are a growing problem worldwide, yet there is no known medical therapy. The pathogenesis involves degradation of the elastic lamina by two combined mechanisms: increased degradation of elastin by matrix metalloproteinases (MMP) and decreased formation of elastin due to apoptosis of vascular smooth muscle cells (VSMC). In this study, we set out to examine the potential role of stem cells in the attenuation of AAA formation by inhibition of these pathogenetic mechanisms. Muscle-derived stem cells from murine skeletal muscles were isolated and stimulated with PDGF-BB in vitro for differentiation to VSMC-like progenitor cells (VSMC-PC). These cells were implanted in to elastase-induced AAAs in rats. The cell therapy group had decreased rate of aneurysm formation compared to control, and MMP expression at the genetic, protein and enzymatic level were also significantly decreased. Furthermore, direct implantation of VSMC-PCs in the intima of harvested aortas was visualized under immunofluorescent staining, suggesting that these cells were responsible for the inhibition of MMPs and consequent attenuation of AAA formation. These results show a promising role of stem cell therapy for the treatment of AAAs, and with further studies, may be able to reach clinical significance.

  9. Genotype versus phenotype in families with androgen insensitivity syndrome

    NARCIS (Netherlands)

    Boehmer, ALM; Bruggenwirth, H; Van Assendelft, C; Otten, BJ; Verleun-Mooijman, MCT; Niermeijer, MF; Brunner, HG; Rouwe, CW; Waelkens, JJ; Oostdijk, W; Kleijer, WJ; Van der Kwast, TH; De Vroede, MA; Drop, SLS

    2001-01-01

    Androgen insensitivity syndrome encompasses a wide range of phenotypes, which are caused by numerous different mutations in the AR gene. Detailed information on the genotype/ phenotype relationship in androgen insensitivity syndrome is important for sex assignment, treatment of androgen insensitivit

  10. Reptides and Proteins Interacting with the Androgen Receptor

    NARCIS (Netherlands)

    D.J. van de Wijngaart (Dennis)

    2009-01-01

    textabstractAndrogens are important sex steroid hormones. The androgens testosterone and dihydrotestosterone (DHT) are essential for normal male sexual differentiation and for the development and maintenance of male reproductive tissues, including the prostate. Androgens mediate their effects by bin

  11. Tumor-targeted gene therapy using Adv-AFP-HRPC/IAA prodrug system suppresses growth of hepatoma xenografted in mice.

    Science.gov (United States)

    Dai, M; Liu, J; Chen, D-E; Rao, Y; Tang, Z-J; Ho, W-Z; Dong, C-Y

    2012-02-01

    Clinical efficacy of current therapies for hepatocellular carcinoma (HCC) treatment is limited. Indole-3-acetic acid (IAA) is non-toxic for mammalian cells. Oxidative decarboxylation of IAA by horseradish peroxidase (HRP) leads to toxic effects of IAA. The purpose of this study was to investigate the effects of a novel gene-targeted enzyme prodrug therapy with IAA on hepatoma growth in vitro and in vivo mouse hepatoma models. We generated a plasmid using adenovirus to express HRP isoenzyme C (HRPC) with the HCC marker, alpha-fetoprotein (AFP), as the promoter (pAdv-AFP-HRPC). Hepatocellular cells were infected with pAdv-AFP-HRPC and treated with IAA. Cell death was detected using MTT assay. Hepatoma xenografts were developed in mice by injection of mouse hepatoma cells. The size and weight of tumors and organs were evaluated. Cell death in tumors was assessed using hematoxylin and eosin-stained tissue sections. HRPC expression in tissues was detected using Reverse Transcriptase-Polymerase Chain Reaction. IAA stimulated death of hepatocellular cells infected with pAdv-AFP-HRPC, in a dose- and time-dependent manner, but not in control cells. Growth of hepatoma xenografts, including the size and weight, was inhibited in mice treated with pAdv-AFP-HRPC and IAA, compared with that in control group. pAdv-AFP-HRPC/IAA treatment induced cell death in hepatoma xenografts in mice. HRPC gene expressed only in hepatoma, but not in other normal organs of mice. pAdv-AFP-HRPC/IAA treatment did not cause any side effects on normal organs. These findings suggest that pAdv-AFP-HRPC/IAA enzyme/prodrug system may serve as a strategy for HCC therapy.

  12. Successful tumour necrosis factor (TNF) blocking therapy suppresses oxidative stress and hypoxia-induced mitochondrial mutagenesis in inflammatory arthritis

    LENUS (Irish Health Repository)

    Biniecka, Monika

    2011-07-25

    Abstract Introduction To examine the effects of tumour necrosis factor (TNF) blocking therapy on the levels of early mitochondrial genome alterations and oxidative stress. Methods Eighteen inflammatory arthritis patients underwent synovial tissue oxygen (tpO2) measurements and clinical assessment of disease activity (DAS28-CRP) at baseline (T0) and three months (T3) after starting biologic therapy. Synovial tissue lipid peroxidation (4-HNE), T and B cell specific markers and synovial vascular endothelial growth factor (VEGF) were quantified by immunohistochemistry. Synovial levels of random mitochondrial DNA (mtDNA) mutations were assessed using Random Mutation Capture (RMC) assay. Results 4-HNE levels pre\\/post anti TNF-α therapy were inversely correlated with in vivo tpO2 (P < 0.008; r = -0.60). Biologic therapy responders showed a significantly reduced 4-HNE expression (P < 0.05). High 4-HNE expression correlated with high DAS28-CRP (P = 0.02; r = 0.53), tender joint count for 28 joints (TJC-28) (P = 0.03; r = 0.49), swollen joint count for 28 joints (SJC-28) (P = 0.03; r = 0.50) and visual analogue scale (VAS) (P = 0.04; r = 0.48). Strong positive association was found between the number of 4-HNE positive cells and CD4+ cells (P = 0.04; r = 0.60), CD8+ cells (P = 0.001; r = 0.70), CD20+ cells (P = 0.04; r = 0.68), CD68+ cells (P = 0.04; r = 0.47) and synovial VEGF expression (P = 0.01; r = 063). In patients whose in vivo tpO2 levels improved post treatment, significant reduction in mtDNA mutations and DAS28-CRP was observed (P < 0.05). In contrast in those patients whose tpO2 levels remained the same or reduced at T3, no significant changes for mtDNA mutations and DAS28-CRP were found. Conclusions High levels of synovial oxidative stress and mitochondrial mutation burden are strongly associated with low in vivo oxygen tension and synovial inflammation. Furthermore these significant mitochondrial genome alterations are rescued following successful anti TNF

  13. Abiraterone acetate: oral androgen biosynthesis inhibitor for treatment of castration-resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Rosenberg JE

    2012-01-01

    Full Text Available Yasser Rehman1, Jonathan E Rosenberg21Division of Hospital Medicine, UMass Memorial Healthcare, Worcester, MA, USA; 2Lank Center for Genitourinary Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USAAbstract: Prostate cancer is the second leading cause of cancer death in men in the US and Europe. The treatment of advanced-stage prostate cancer has been androgen deprivation. Medical castration leads to decreased production of testosterone and dihydrotestosterone by the testes, but adrenal glands and even prostate cancer tissue continue to produce androgens, which eventually leads to continued prostate cancer growth despite castrate level of androgens. This stage is known as castrate-resistant prostate cancer (CRPC, which continues to be a challenge to treat. Addition of androgen antagonists to hormonal deprivation has been successful in lowering the prostate-specific antigen levels further, but has not actually translated into life-prolonging options. The results of several contemporary studies have continued to demonstrate activation of the androgen receptor as being the key factor in the continued growth of prostate cancer. Blockade of androgen production by nongonadal sources has led to clinical benefit in this setting. One such agent is abiraterone acetate, which significantly reduces androgen production by blocking the enzyme, cytochrome P450 17 alpha-hydroxylase (CYP17. This has provided physicians with another treatment option for patients with CRPC. The landscape for prostate cancer treatment has changed with the approval of cabazitaxel, sipuleucel-T and abiraterone. Here we provide an overview of abiraterone acetate, its mechanism of action, and its potential place for therapy in CRPC.Keywords: CRPC, abiraterone, CYP17, inhibitors, androgens, castration resistant prostate cancer

  14. Suppression of casein kinase 2 sensitizes tumor cells to antitumor TRAIL therapy by regulating the phosphorylation and localization of p65 in prostate cancer.

    Science.gov (United States)

    Gang, Xiaokun; Wang, Yao; Wang, Yingdi; Zhao, Yu; Ding, Liya; Zhao, Jingwen; Sun, Lin; Wang, Guixia

    2015-09-01

    In the United States, prostate cancer (PCa) is the most commonly diagnosed cancer in males. For PCa at the late hormone-refractory stage, substantial improvement in treatment strategies is critically needed. TNF-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent, but both intrinsic and acquired resistance to TRAIL poses a huge problem in establishing clinically effective TRAIL therapies. In the present study, we examined the role played by casein kinase 2 (CK2) in the TRAIL‑induced nuclear factor κ-light-chain-enhancer of activated B cell (NF-κB) pathway in a PCa cell line. Downregulation of CK2 combined with a sub-dose of TRAIL suppressed p65 phosphorylation at serine 536. The combination treatment of TRAIL and the CK2 inhibitor decreased p65 nuclear translocation. Under the treatment of a sub-dose of TRAIL, downregulation of CK2, using both genetic and pharmacological approaches, decreased the transcriptional activity of NF-κB and the expression of NF-κB downstream anti-apoptosis genes. Therefore, we provided novel molecular mechanistic insight reporting that CK2 regulates the sensitivity of PCa cells to the antitumor effect of TRAIL. This is important for understanding how the TRAIL pathway is disrupted in PCa and may help to develop an effective combinatorial therapy for PCa.

  15. Synthetic Androgens as Designer Supplements

    OpenAIRE

    Joseph, Jan Felix; Parr, Maria Kristina

    2015-01-01

    Anabolic androgenic steroids (AAS) are some of the most common performance enhancing drugs (PED) among society. Despite the broad spectrum of adverse effects and legal consequences, AAS are illicitly marketed and distributed in many countries. To circumvent existing laws, the chemical structure of AAS is modified and these designer steroids are sold as nutritional supplements mainly over the Internet. Several side effects are linked with AAS abuse. Only little is known about the pharmacologic...

  16. Increasing women's sexual desire: The comparative effectiveness of estrogens and androgens.

    Science.gov (United States)

    Cappelletti, Maurand; Wallen, Kim

    2016-02-01

    Both estradiol and testosterone have been implicated as the steroid critical for modulating women's sexual desire. By contrast, in all other female mammals only estradiol has been shown to be critical for female sexual motivation and behavior. Pharmaceutical companies have invested heavily in the development of androgen therapies for female sexual desire disorders, but today there are still no FDA approved androgen therapies for women. Nonetheless, testosterone is currently, and frequently, prescribed off-label for the treatment of low sexual desire in women, and the idea of testosterone as a possible cure-all for female sexual dysfunction remains popular. This paper places the ongoing debate concerning the hormonal modulation of women's sexual desire within a historical context, and reviews controlled trials of estrogen and/or androgen therapies for low sexual desire in postmenopausal women. These studies demonstrate that estrogen-only therapies that produce periovulatory levels of circulating estradiol increase sexual desire in postmenopausal women. Testosterone at supraphysiological, but not at physiological, levels enhances the effectiveness of low-dose estrogen therapies at increasing women's sexual desire; however, the mechanism by which supraphysiological testosterone increases women's sexual desire in combination with an estrogen remains unknown. Because effective therapies require supraphysiological amounts of testosterone, it remains unclear whether endogenous testosterone contributes to the modulation of women's sexual desire. The likelihood that an androgen-only clinical treatment will meaningfully increase women's sexual desire is minimal, and the focus of pharmaceutical companies on the development of androgen therapies for the treatment of female sexual desire disorders is likely misplaced.

  17. Suppression of human breast tumors in NOD/SCID mice by CD44 shRNA gene therapy combined with doxorubicin treatment

    Directory of Open Access Journals (Sweden)

    Pham PV

    2012-05-01

    Full Text Available Phuc Van Pham1, Ngoc Bich Vu1, Thuy Thanh Duong1, Tam Thanh Nguyen1, Nhung Hai Truong1, Nhan Lu Chinh Phan1, Tue Gia Vuong1, Viet Quoc Pham1, Hoang Minh Nguyen1, Kha The Nguyen1, Nhung Thi Nguyen1, Khue Gia Nguyen1, Lam Tan Khat1, Dong Van Le2, Kiet Dinh Truong1, Ngoc Kim Phan11Laboratory of Stem Cell Research and Application, University of Science, Vietnam National University, HCM City, 2Military Medical University, Ha Noi, VietnamBackground: Breast cancer stem cells with a CD44+CD24- phenotype are the origin of breast tumors. Strong CD44 expression in this population indicates its important role in maintaining the stem cell phenotype. Previous studies show that CD44 down-regulation causes CD44+CD24- breast cancer stem cells to differentiate into non-stem cells that are sensitive to antitumor drugs and lose many characteristics of the original cells. In this study, we determined tumor suppression in non-obese severe combined immunodeficiency mice using CD44 shRNA therapy combined with doxorubicin treatment.Methods: Tumor-bearing non-obese severe combined immunodeficiency mice were established by injection of CD44+CD24- cells. To track CD44+CD24- cells, green fluorescence protein was stably transduced using a lentiviral vector prior to injection into mice. The amount of CD44 shRNA lentiviral vector used for transduction was based on CD44 down-regulation by in vitro CD44 shRNA transduction. Mice were treated with direct injection of CD44 shRNA lentiviral vector into tumors followed by doxorubicin administration after 48 hours. The effect was evaluated by changes in the size and weight of tumors compared with that of the control.Results: The combination of CD44 down-regulation and doxorubicin strongly suppressed tumor growth with significant differences in tumor sizes and weights compared with that of CD44 down-regulation or doxorubicin treatment alone. In the combination of CD44 down-regulation and doxorubicin group, the tumor weight was

  18. Identification of androgen-responsive genes that are alternatively regulated in androgen-dependent and androgen-independent rat prostate tumors.

    NARCIS (Netherlands)

    Pfundt, R.; Smit, F.P.; Jansen, Corine; Aalders, T.W.; Straatman, H.M.P.M.; Vliet, W. van der; Isaacs, J.; Geurts van Kessel, A.H.M.; Schalken, J.A.

    2005-01-01

    The vast majority of androgen-dependent prostate tumors progress toward incurable, androgen-independent tumors. The identification of androgen-responsive genes, which are still actively transcribed in the tumors of patients who have undergone androgen ablation, may shed light on the molecular mechan

  19. Impact of chemotherapy for HIV-1 related lymphoma on residual viremia and cellular HIV-1 DNA in patients on suppressive antiretroviral therapy.

    Science.gov (United States)

    Cillo, Anthony R; Krishnan, Supriya; McMahon, Deborah K; Mitsuyasu, Ronald T; Para, Michael F; Mellors, John W

    2014-01-01

    The first cure of HIV-1 infection was achieved through complex, multimodal therapy including myeloablative chemotherapy, total body irradiation, anti-thymocyte globulin, and allogeneic stem cell transplantation with a CCR5 delta32 homozygous donor. The contributions of each component of this therapy to HIV-1 eradication are unclear. To assess the impact of cytotoxic chemotherapy alone on HIV-1 persistence, we longitudinally evaluated low-level plasma viremia and HIV-1 DNA in PBMC from patients in the ACTG A5001/ALLRT cohort on suppressive antiretroviral therapy (ART) who underwent chemotherapy for HIV-1 related lymphoma without interrupting ART. Plasma HIV-1 RNA, total HIV-1 DNA and 2-LTR circles (2-LTRs) in PBMC were measured using sensitive qPCR assays. In the 9 patients who received moderately intensive chemotherapy for HIV-1 related lymphoma with uninterrupted ART, low-level plasma HIV-1 RNA did not change significantly with chemotherapy: median HIV-1 RNA was 1 copy/mL (interquartile range: 1.0 to 20) pre-chemotherapy versus 4 copies/mL (interquartile range: 1.0 to 7.0) post-chemotherapy. HIV-1 DNA levels also did not change significantly, with median pre-chemotherapy HIV-1 DNA of 355 copies/106 CD4+ cells versus 228 copies/106 CD4+ cells post-chemotherapy. 2-LTRs were detectable in 2 of 9 patients pre-chemotherapy and in 3 of 9 patients post-chemotherapy. In summary, moderately intensive chemotherapy for HIV-1 related lymphoma in the context of continuous ART did not have a prolonged impact on HIV-1 persistence. Clinical trials registration unique identifier: NCT00001137.

  20. Impact of chemotherapy for HIV-1 related lymphoma on residual viremia and cellular HIV-1 DNA in patients on suppressive antiretroviral therapy.

    Directory of Open Access Journals (Sweden)

    Anthony R Cillo

    Full Text Available The first cure of HIV-1 infection was achieved through complex, multimodal therapy including myeloablative chemotherapy, total body irradiation, anti-thymocyte globulin, and allogeneic stem cell transplantation with a CCR5 delta32 homozygous donor. The contributions of each component of this therapy to HIV-1 eradication are unclear. To assess the impact of cytotoxic chemotherapy alone on HIV-1 persistence, we longitudinally evaluated low-level plasma viremia and HIV-1 DNA in PBMC from patients in the ACTG A5001/ALLRT cohort on suppressive antiretroviral therapy (ART who underwent chemotherapy for HIV-1 related lymphoma without interrupting ART. Plasma HIV-1 RNA, total HIV-1 DNA and 2-LTR circles (2-LTRs in PBMC were measured using sensitive qPCR assays. In the 9 patients who received moderately intensive chemotherapy for HIV-1 related lymphoma with uninterrupted ART, low-level plasma HIV-1 RNA did not change significantly with chemotherapy: median HIV-1 RNA was 1 copy/mL (interquartile range: 1.0 to 20 pre-chemotherapy versus 4 copies/mL (interquartile range: 1.0 to 7.0 post-chemotherapy. HIV-1 DNA levels also did not change significantly, with median pre-chemotherapy HIV-1 DNA of 355 copies/106 CD4+ cells versus 228 copies/106 CD4+ cells post-chemotherapy. 2-LTRs were detectable in 2 of 9 patients pre-chemotherapy and in 3 of 9 patients post-chemotherapy. In summary, moderately intensive chemotherapy for HIV-1 related lymphoma in the context of continuous ART did not have a prolonged impact on HIV-1 persistence. Clinical trials registration unique identifier: NCT00001137.

  1. In vitro capacity of various cyclooxygenase inhibitors to revert immune suppression caused by radiation therapy for breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Blomgren, H.; Rotstein, S. (Karolinska Sjukhuset, Stockholm (Sweden)); Wasserman, J.; Petrini, B. (Stockholm County Council (Sweden). Central Microbiological Laboratory); Hammarstroem, S. (Linkoeping University Faculty of Health Sciences (Sweden). Department of Cell Biology, Division of Medical and Physical Chemistry)

    1990-12-01

    Radiation therapy triggers blood monocytes to an increased secretion of immunosuppressive prostaglandins (PGs), which in part can explain the post-irradiation impairment of lymphocyte blastogenesis. Since low mitogen responses of lymphocytes in irradiated breast cancer patients is linked to a poor prognosis a clinical trial is planned to examine if treatment with inhibitors of PG-synthesis during irradiation can counteract immunosuppression and increase survival. In the present investigation the authors have compared 9 different inhibitors of PG-synthesis for capacity to enhance phytohemagglutinin responses of blood lymphocytes before and after irradiation for breast cancer. 5 of the drugs (aspisol, indomethacin, meclofenamic acid, ketoprofen and diclofenac) enhanced the reactivity to more than 150 percent. In general, the strongest enhancements were observed in lymphocyte preparations obtained at completion of irradiation when reactivity was most depressed followed by those obtained at one month and before irradiation. (author). 28 refs.; 5 figs.; 1 tab.

  2. Exogenous p16 gene therapy combined with X-ray irradiation suppresses the growth of human glioma cells

    Institute of Scientific and Technical Information of China (English)

    Hongbing Ma; Zhengli Di; Minghua Bai; Hongtao Ren; Zongfang Li

    2011-01-01

    In this study, we infected human glioma U251 cells with a replication-defective recombinant adeno-virus carrying the p16 gene. This adenovirus constructed was able to transfect exogenous p16 into the human glioma cells efficiently, and direct a high level of p16 protein expression. Tumor-inhibition experiments demonstrated that treatment with the adenovirus-p16 significantly inhibited the growth of glioma cells in vitro as well as the in vivo development of tumors in nude mice bearing a brain glioma. The combination of adenovirus-p16 gene treatment and X-ray irradiation resulted in a greater inhibition of tumor growth. Adenovirus-mediated p16 gene therapy conferred a significant antitumor effect against human glioma cells both in vitro and in vivo, and that there was a synergistic effect when X-ray irradiation was also used.

  3. Silencing neuronal mutant androgen receptor in a mouse model of spinal and bulbar muscular atrophy.

    Science.gov (United States)

    Sahashi, Kentaro; Katsuno, Masahisa; Hung, Gene; Adachi, Hiroaki; Kondo, Naohide; Nakatsuji, Hideaki; Tohnai, Genki; Iida, Madoka; Bennett, C Frank; Sobue, Gen

    2015-11-01

    Spinal and bulbar muscular atrophy (SBMA), an adult-onset neurodegenerative disease that affects males, results from a CAG triplet repeat/polyglutamine expansions in the androgen receptor (AR) gene. Patients develop progressive muscular weakness and atrophy, and no effective therapy is currently available. The tissue-specific pathogenesis, especially relative pathological contributions between degenerative motor neurons and muscles, remains inconclusive. Though peripheral pathology in skeletal muscle caused by toxic AR protein has been recently reported to play a pivotal role in the pathogenesis of SBMA using mouse models, the role of motor neuron degeneration in SBMA has not been rigorously investigated. Here, we exploited synthetic antisense oligonucleotides to inhibit the RNA levels of mutant AR in the central nervous system (CNS) and explore its therapeutic effects in our SBMA mouse model that harbors a mutant AR gene with 97 CAG expansions and characteristic SBMA-like neurogenic phenotypes. A single intracerebroventricular administration of the antisense oligonucleotides in the presymptomatic phase efficiently suppressed the mutant gene expression in the CNS, and delayed the onset and progression of motor dysfunction, improved body weight gain and survival with the amelioration of neuronal histopathology in motor units such as spinal motor neurons, neuromuscular junctions and skeletal muscle. These findings highlight the importance of the neurotoxicity of mutant AR protein in motor neurons as a therapeutic target.

  4. A role for the androgen receptor in the treatment of male breast cancer.

    Science.gov (United States)

    Zhu, Jason; Davis, Carter T; Silberman, Sandra; Spector, Neil; Zhang, Tian

    2016-02-01

    Male breast cancer (BC) is relatively rare, making up less than 1% of all breast cancer cases in the United States. Treatment guidelines for male BC are derived from studies on the treatment of female BC, and are based molecular and clinical characteristics, such as hormone receptor positivity. For female estrogen receptor positive (ER+) breast cancers, the standard of care includes three classes of endocrine therapies: selective estrogen receptor modulators, aromatase inhibitors, and pure anti-estrogens. In contrast to female ER+ breast cancers, there is less known about the optimal treatment for male ER+ BC. Furthermore, in contrast to ER, less is known about the role of the androgen receptor (AR) in male and female BC. We report here the treatment of a 28-year-old man with metastatic AR+, ER+ breast cancer otherwise refractory to chemotherapy, who has had a durable clinical response to hormonal suppression with the combination of aromatase inhibition (Letrozole) in conjunction with a GnRH agonist (Leuprolide).

  5. Non-Genomic Actions of the Androgen Receptor in Prostate Cancer

    Science.gov (United States)

    Leung, Jacky K.; Sadar, Marianne D.

    2017-01-01

    Androgen receptor (AR) is a validated drug target for prostate cancer based on its role in proliferation, survival, and metastases of prostate cancer cells. Unfortunately, despite recent improvements to androgen deprivation therapy and the advent of better antiandrogens with a superior affinity for the AR ligand-binding domain (LBD), most patients with recurrent disease will eventually develop lethal metastatic castration-resistant prostate cancer (CRPC). Expression of constitutively active AR splice variants that lack the LBD contribute toward therapeutic resistance by bypassing androgen blockade and antiandrogens. In the canonical pathway, binding of androgen to AR LBD triggers the release of AR from molecular chaperones which enable conformational changes and protein–protein interactions to facilitate its nuclear translocation where it regulates the expression of target genes. However, preceding AR function in the nucleus, initial binding of androgen to AR LBD in the cytoplasm may already initiate signal transduction pathways to modulate cellular proliferation and migration. In this article, we review the significance of signal transduction pathways activated by rapid, non-genomic signaling of the AR during the progression to metastatic CRPC and put into perspective the implications for current and novel therapies that target different domains of AR.

  6. Effect of low-dose oral contraceptives on androgenic markers and acne.

    Science.gov (United States)

    Thorneycroft, I H; Stanczyk, F Z; Bradshaw, K D; Ballagh, S A; Nichols, M; Weber, M E

    1999-11-01

    Oral contraceptives (OC) suppress excess androgen production; however, different progestins in combination with low-dose estrogens produce divergent effects on sex hormone-binding globulin (SHBG) and testosterone that may influence clinical outcomes. This multicenter, open-label, randomized study compared biochemical androgen profiles and clinical outcomes associated with two OC containing the same amounts of ethinyl estradiol (EE, 20 micrograms) but different progestins, levonorgestrel (LNG, 100 micrograms), and norethindrone acetate (NETA, 1000 micrograms). Fifty-eight healthy women (18-28 years old) received three cycles of treatment with LNG/EE (n = 30) or NETA/EE (n = 28). The results showed that LNG reduced androgen levels in three compartments--adrenal, ovarian, and peripheral. NETA reduced only adrenal and peripheral androgens. Despite a 2.2-fold greater relative increase in SHBG with NETA than LNG, bioavailable testosterone (T) was reduced by the same amount with LNG and NETA. Both treatments improved acne and were well tolerated. Low-dose OC (EE, 20 micrograms) are effective in reducing circulating androgens and acne lesions without causing weight gain. Although LNG and NETA affected secondary markers differently, both OC formulations produced an equivalent decrease in bioavailable.

  7. Estren promotes androgen phenotypes in primary lymphoid organs and submandibular glands

    Directory of Open Access Journals (Sweden)

    Gustafsson Jan-Åke

    2005-07-01

    Full Text Available Abstract Background Estrogens and androgens have extensive effects on the immune system, for example they suppress both T and B lymphopoiesis in thymus and bone marrow. Submandibular glands are sexually dimorphic in rodents, resulting in larger granular convoluted tubules in males compared to females. The aim of the present experiments was to investigate the estrogenic and androgenic effects of 4-estren-3α,17β-diol (estren on thymus, bone marrow and submandibular glands, and compare the effects to those of 17β-estradiol (E2 and 5α-dihydrotestosterone (DHT, respectively. Estrogen receptors (ERs were blocked by treatment of mice with the ER-antagonist ICI 182,780; also, knock-out mice lacking one or both ERs were used. Results As expected, the presence of functional ERs was mandatory for all the effects of E2. Similar to DHT-treatment, estren-treatment resulted in decreased thymus weight, as well as decreased frequency of bone marrow B cells. Treatment with estren or DHT also resulted in a shift in submandibular glands towards an androgen phenotype. All the effects of estren and DHT were independent of ERs. Conclusion Our study is the first to show that estren has similar effects as the androgen DHT on lymphopoiesis in thymus and bone marrow, and on submandibular glands, and that these effects are independent of estrogen receptors. This supports the hypothesis of estren being able to signal through the androgen receptor.

  8. Effect of MK-906, a specific 5 alpha-reductase inhibitor, on serum androgens and androgen conjugates in normal men.

    Science.gov (United States)

    Rittmaster, R S; Stoner, E; Thompson, D L; Nance, D; Lasseter, K C

    1989-01-01

    To determine the hormonal effects of MK-906, an orally active 5 alpha-reductase inhibitor, on serum androgens and androgen conjugates, 12 healthy men were given 10, 20, 50, and 100 mg MK-906 2 weeks apart in randomized order in a 4-period crossover design. Serum testosterone (T), dihydrotestosterone (DHT), androstanediol glucuronide, and androsterone glucuronide were measured before and 24 hours after each dose. The effect of MK-906 on glucuronyl transferase activity, the enzyme responsible for androstanediol glucuronide and androsterone glucuronide formation, was assessed in vitro using rat prostate tissue. Serum T levels were unchanged after all doses. Serum DHT, androstanediol glucuronide, and androsterone glucuronide were suppressed by 70, 40, and 56%, respectively, after the 10-mg dose, and by 82, 52, and 66% after the 100-mg dose (P less than 0.02 for the comparison between the 10 and 100-mg doses for all three steroids), respectively. Baseline serum T and DHT levels were strongly correlated (R = 0.89, P = 0.0002), as were androstanediol glucuronide and androsterone glucuronide levels (R = 0.78, P = 0.003), but there was no correlation between DHT levels and the levels of either conjugated steroid. MK-906 had no effect on glucuronyl transferase activity in vitro. It was concluded that single doses of MK-906 suppress both conjugated and unconjugated 5 alpha-reduced androgens. While all three steroids appeared to be good markers of systemic 5 alpha-reductase inhibition, further research will be needed to determine which steroid best reflects tissue DHT levels in patients receiving these inhibitors.

  9. Suppression of Angiogenesis and Therapy of Human Colon Cancer Liver Metastasis by Systemic Administration of Interferon-α

    Directory of Open Access Journals (Sweden)

    Shutaro Ozawa

    2001-01-01

    Full Text Available The purpose of this study was to determine whether systemic administration of interferon-alpha (IFN-α can inhibit liver metastasis produced in nude mice by human colon cancer cells. KM12L4 (IFN-α-sensitive or KM12L4 IFNR (IFN-α-resistant cells were injected into the spleen of nude mice. Seven days later, the mice were treated with subcutaneous (s.c. injections of IFN-α (70,000 units/week at different dosing schedules (1, 2, or 7 times/week. Significant inhibition of tumor growth, vascularization and expression of basic fibroblast growth factor (bFGF or matrix metal loproteinase9 (MMP-9 mRNA and protein occurred in mice given daily injections of IFN-α. Kinetic analysis of therapy showed that daily s.c. administrations of 10,000 units of IFN-α induced apoptosis in liver metastasis-associated endothelial cells, followed by inhibition of tumor cell division and apoptosis of tumor cells. These data suggest that the antiangiogenic activity of IFN-α-2a depends on frequent administration of the optimal biologic dose.

  10. Antibody Therapy Targeting CD47 and CD271 Effectively Suppresses Melanoma Metastasis in Patient-Derived Xenografts.

    Science.gov (United States)

    Ngo, Michael; Han, Arum; Lakatos, Anita; Sahoo, Debashis; Hachey, Stephanie J; Weiskopf, Kipp; Beck, Andrew H; Weissman, Irving L; Boiko, Alexander D

    2016-08-09

    The high rate of metastasis and recurrence among melanoma patients indicates the existence of cells within melanoma that have the ability to both initiate metastatic programs and bypass immune recognition. Here, we identify CD47 as a regulator of melanoma tumor metastasis and immune evasion. Protein and gene expression analysis of clinical melanoma samples reveals that CD47, an anti-phagocytic signal, correlates with melanoma metastasis. Antibody-mediated blockade of CD47 coupled with targeting of CD271(+) melanoma cells strongly inhibits tumor metastasis in patient-derived xenografts. This therapeutic effect is mediated by drastic changes in the tumor and metastatic site immune microenvironments, both of whichwhich exhibit greatly increased density of differentiated macrophages and significantly fewer inflammatory monocytes, pro-metastatic macrophages (CCR2(+)/VEGFR1(+)), and neutrophils, all of which are associated with disease progression. Thus, antibody therapy that activates the innate immune response in combination with selective targeting of CD271(+) melanoma cells represents a powerful therapeutic approach against metastatic melanoma.

  11. Antibody Therapy Targeting CD47 and CD271 Effectively Suppresses Melanoma Metastasis in Patient-Derived Xenografts

    Directory of Open Access Journals (Sweden)

    Michael Ngo

    2016-08-01

    Full Text Available The high rate of metastasis and recurrence among melanoma patients indicates the existence of cells within melanoma that have the ability to both initiate metastatic programs and bypass immune recognition. Here, we identify CD47 as a regulator of melanoma tumor metastasis and immune evasion. Protein and gene expression analysis of clinical melanoma samples reveals that CD47, an anti-phagocytic signal, correlates with melanoma metastasis. Antibody-mediated blockade of CD47 coupled with targeting of CD271+ melanoma cells strongly inhibits tumor metastasis in patient-derived xenografts. This therapeutic effect is mediated by drastic changes in the tumor and metastatic site immune microenvironments, both of whichwhich exhibit greatly increased density of differentiated macrophages and significantly fewer inflammatory monocytes, pro-metastatic macrophages (CCR2+/VEGFR1+, and neutrophils, all of which are associated with disease progression. Thus, antibody therapy that activates the innate immune response in combination with selective targeting of CD271+ melanoma cells represents a powerful therapeutic approach against metastatic melanoma.

  12. Differences in HIV Burden and Immune Activation within the Gut of HIV+ Patients on Suppressive Antiretroviral Therapy

    Science.gov (United States)

    Yukl, Steven; Gianella, Sara; Sinclair, Elizabeth; Epling, Lorrie; Li, Qingsheng; Duan, Lijie; Choi, Alex L. M.; Girling, Valerie; Ho, Terence; Li, Peilin; Fujimoto, Katsuya; Lampiris, Harry; Hare, C. Bradley; Pandori, Mark; Haase, Ashley T.; Günthard, Huldrych F.; Fischer, Marek; Shergill, Amandeep; McQuaid, Kenneth; Havlir, Diane V.; Wong, Joseph K.

    2010-01-01

    Background The gut is a major reservoir for HIV in patients receiving antiretroviral therapy (ART). We hypothesized that distinct immune environments within the gut may support varying levels of HIV. Methods In 8 HIV-1+ adults on ART with CD4>200 and plasma VL<40, levels of HIV and T-cell activation were measured in blood and endoscopic biopsies from the duodenum, ileum, right colon, and rectum. Results HIV DNA and RNA per CD4+T-cell were higher in all four gut sites compared to blood. HIV DNA increased from the duodenum to the rectum, while the median HIV RNA peaked in the ileum. HIV DNA correlated positively with T-cell activation in the PBMC but negatively with T-cell activation in the gut. Multiply-spliced RNA was infrequently detected in gut, and unspliced RNA/DNA ratios were lower in the colon and rectum relative to PBMC, reflecting paradoxically low HIV transcription given the higher T-cell activation in the gut. Conclusions HIV DNA and RNA are both concentrated in the gut, but the inverse relationship between HIV DNA and T-cell activation in the gut and the paradoxically low levels of HIV expression in the large bowel suggest that different processes drive HIV persistence in the blood and gut. PMID:20939732

  13. High levels of adherence and viral suppression in a nationally representative sample of HIV-infected adults on antiretroviral therapy for 6, 12 and 18 months in Rwanda.

    Directory of Open Access Journals (Sweden)

    Batya Elul

    Full Text Available BACKGROUND: Generalizable data are needed on the magnitude and determinants of adherence and virological suppression among patients on antiretroviral therapy (ART in Africa. METHODS: We conducted a cross-sectional survey with chart abstraction, patient interviews and site assessments in a nationally representative sample of adults on ART for 6, 12 and 18 months at 20 sites in Rwanda. Adherence was assessed using 3- and 30-day patient recall. A systematically selected sub-sample had viral load (VL measurements. Multivariable logistic regression examined predictors of non-perfect (40 copies/ml. RESULTS: Overall, 1,417 adults were interviewed and 837 had VL measures. Ninety-four percent and 78% reported perfect adherence for the last 3 and 30 days, respectively. Eighty-three percent had undetectable VL. In adjusted models, characteristics independently associated with higher odds of non-perfect 30-day adherence were: being on ART for 18 months (vs. 6 months; younger age; reporting severe (vs. no or few side effects in the prior 30 days; having no documentation of CD4 cell count at ART initiation (vs. having a CD4 cell count of <200 cells/µL; alcohol use; and attending sites which initiated ART services in 2003-2004 and 2005 (vs. 2006-2007; sites with ≥600 (vs. <600 patients on ART; or sites with peer educators. Participation in an association for people living with HIV/AIDS; and receiving care at sites which regularly conduct home-visits were independently associated with lower odds of non-adherence. Higher odds of having a detectable VL were observed among patients at sites with peer educators. Being female; participating in an association for PLWHA; and using a reminder tool were independently associated with lower odds of having detectable VL. CONCLUSIONS: High levels of adherence and viral suppression were observed in the Rwandan national ART program, and associated with potentially modifiable factors.

  14. Central hemodynamics and androgen status in men with coronary heart disease, and androgen deficiency in its correction of prolonged administration of testosterone

    Directory of Open Access Journals (Sweden)

    L. M. Gaivoronskaya

    2013-01-01

    Full Text Available This work was designed to study the dynamic of the central hemodynamic disorders symptoms at men with coronary heart disease, stable angina, obesity and androgen deficiency under replacement short-term therapy by Testosterone undecanoate (TU. The comparative assessment of central hemodynamic indicators and total and sub-scale AMS score at two groups of men who receiving (the main group and not receiving (control group replacement therapy of TU is carried out. Results showed that in the main group, unlike control group the positive tendency in a number of indicators (stroke volume, left ventricular end- diastolic volume, left ventricular end- systolic volume of the central hemodynamic and indicators of the androgenic status is observed. Positive dynamics of some parameters of the central hemodynamic even at short-term replacement therapy of TU indicates the therapeutic potential of testosterone at cardiovascular pathology which full realization may require longer period of testosterone administration.

  15. Molecular mechanisms of androgen and antiandrogen action

    NARCIS (Netherlands)

    C.W. Kuil (Cor)

    1997-01-01

    textabstractThe steroid hormones testosterone and 5a-dihydrotestosterone (androgens) control the development, differentiation and function of male reproductive and accessory sex tissues, such as seminal vesicle, epididymis and prostate. Changes in cell properties induced by androgens require the pre

  16. Molecular mechanisms of androgen receptor functions

    NARCIS (Netherlands)

    K. Steketee (Karine)

    2007-01-01

    textabstractThe androgens testosterone (T) and dihydrotestosterone (DHT) are steroid hormones, which are necessary for development and maintenance of the functions of the male sex organs, including the prostate. Androgens also play an important role in benign abnormalities of the prostate and in the

  17. Androgens inhibit the osteogenic response to mechanical loading in adult male mice.

    Science.gov (United States)

    Sinnesael, Mieke; Laurent, Michaël R; Jardi, Ferran; Dubois, Vanessa; Deboel, Ludo; Delisser, Peter; Behets, Geert J; D'Haese, Patrick C; Carmeliet, Geert; Claessens, Frank; Vanderschueren, Dirk

    2015-04-01

    Androgens are well known to enhance exercise-induced muscle hypertrophy; however, whether androgens also influence bone's adaptive response to mechanical loading remains unclear. We studied the adaptive osteogenic response to unilateral in vivo mechanical loading of tibia in adult male mice in both a long- and a short-term experimental set-up. Mice were divided into four groups: sham operated, orchidectomized (ORX), T (ORX+T), or nonaromatizable dihydrotestosterone (ORX+DHT) replacement. Significant interactions between androgen status and osteogenic response to mechanical loading were observed. Cortical thickness increased by T (0.14 vs 0.11 mm sham, P<.05) and DHT (0.17 vs 0.11 mm sham, P<.05). However, T partially (+36%) and DHT completely (+10%) failed to exhibit the loading-related increase observed in sham (+107%) and ORX (+131%, all P<.05) mice. ORX decreased periosteal bone formation, which was restored to sham levels by T and DHT. However, both androgens completely suppressed the loading-related increase in periosteal bone formation. Short-term loading decreased the number of sclerostin-positive osteocytes in sham, whereas in control fibulas, ORX decreased and T increased the number of sclerostin-positive osteocytes. Loading no longer down-regulated sclerostin in the ORX or T groups. In conclusion, both T and DHT suppress the osteogenic response to mechanical loading.

  18. A Phase II Study Evaluating the Role of Androgen Receptors as Targets for Therapy of Pre-treated Post-menopausal Patients With ER/PgR-negative/AR-positive or ER and/or PgRpositive/ AR-positive Metastatic Breast Cancer (ARTT)

    Science.gov (United States)

    2016-09-28

    Metastatic Breastcancer; Estrogen Receptor Positive Breast Cancer; Estrogen Receptor Negative Neoplasm; Progesterone Receptor Positive Tumor; Progesterone Receptor Negative Neoplasm; Androgen Receptor Gene Overexpression

  19. Socioeconomic factors explain suboptimal adherence to antiretroviral therapy among HIV-infected Australian adults with viral suppression

    Science.gov (United States)

    Siefried, Krista J.; Mao, Limin; Kerr, Stephen; Cysique, Lucette A.; Gates, Thomas M.; McAllister, John; Maynard, Anthony; de Wit, John; Carr, Andrew

    2017-01-01

    Background Missing more than one tablet of contemporary antiretroviral therapy (ART) per month increases the risk of virological failure. Recent studies evaluating a comprehensive range of potential risk factors for suboptimal adherence are not available for high-income settings. Methods Adults on ART with undetectable viral load (UDVL) were recruited into a national, multi-centre cohort, completing a comprehensive survey assessing demographics, socio-economic indicators, physical health, well-being, life stressors, social supports, HIV disclosure, HIV-related stigma and discrimination, healthcare access, ART regimen, adherence, side effects, costs and treatment beliefs. Baseline data were assessed, and suboptimal adherence was defined as self-reported missing ≥1 ART dose/month over the previous 3-months; associated factors were identified using bivariate and multivariate binary logistic regression. Results We assessed 522 participants (494 [94.5%] men, mean age = 50.8 years, median duration UDVL = 3.3 years [IQR = 1.2–6.8]) at 17 sexual health, hospital, and general practice clinics across Australia. Seventy-eight participants (14.9%) reported missing ≥1 dose/month over the previous three months, which was independently associated with: being Australian-born (AOR [adjusted odds ratio] = 2.4 [95%CI = 1.2–4.9], p = 0.014), not being in a relationship (AOR = 3.3 [95%CI = 1.5–7.3], p = 0.004), reaching the “Medicare safety net” (capping annual medical/pharmaceutical costs) (AOR = 2.2 [95%CI = 1.1–4.5], p = 0.024), living in subsidised housing (AOR = 2.5 [95%CI = 1.0–6.2], p = 0.045), receiving home-care services (AOR = 4.4 [95%CI = 1.0–18.8], p = 0.046), HIV community/outreach services linkage (AOR = 2.4 [95%CI = 1.1–5.4], p = 0.033), and starting ART following self-request (AOR = 3.0 [95%CI = 1.3–7.0], p = 0.012). Conclusions In this population, 15% reported recent suboptimal ART adherence at levels associated in prospective studies with

  20. Immune activation is inversely related to, but does not cause variation in androgen levels in a cichlid fish species

    NARCIS (Netherlands)

    Ros, Albert F. H.; Oliveira, Rui F.; Dijkstra, Peter D.; Groothuis, Ton G. G.

    2012-01-01

    Studies on birds and mammals indicate that sexual traits may signal superior health because active immunity, like inflammatory responses to infections, is suppressive to the production of androgens that facilitate the expression of these traits. Here we test this possible pathway for honest signalin

  1. In Vitro Androgen Bioassays as a Detection Method for Designer Androgens

    Directory of Open Access Journals (Sweden)

    Alison K. Heather

    2013-02-01

    Full Text Available Androgens are the class of sex steroids responsible for male sexual characteristics, including increased muscle mass and decreased fat mass. Illicit use of androgen doping can be an attractive option for those looking to enhance sporting performance and/or physical appearance. The use of in vitro bioassays to detect androgens, especially designer or proandrogens, is becoming increasingly important in combating androgen doping associated with nutritional supplements. The nutritional sports supplement market has grown rapidly throughout the past decade. Many of these supplements contain androgens, designer androgens or proandrogens. Many designer or proandrogens cannot be detected by the standard highly-sensitive screening methods such as gas chromatography-mass spectrometry because their chemical structure is unknown. However, in vitro androgen bioassays can detect designer and proandrogens as these assays are not reliant on knowing the chemical structure but instead are based on androgen receptor activation. For these reasons, it may be advantageous to use routine androgen bioassay screening of nutraceutical samples to help curb the increasing problem of androgen doping.

  2. Chlorin e6-Mediated Photodynamic Therapy Suppresses P. acnes-Induced Inflammatory Response via NFκB and MAPKs Signaling Pathway

    Science.gov (United States)

    Wang, Yoon-Young; Ryu, A-Reum; Jin, Solee; Jeon, Yu-Mi; Lee, Mi-Young

    2017-01-01

    Photodynamic therapy (PDT), consisting of photosensitizer, light, and oxygen has been used for the treatment of various diseases including cancers, microbial infections and skin disorders. In this study, we examined the anti-inflammatory effect of chlorin e6-mediated PDT in P. acnes-infected HaCaT cells using photosensitizer chlorin e6 (Ce6) and halogen light. The live and heat-killed P. acnes triggered an upregulation of inflammatory molecules such as iNOS, NO, and inflammatory cytokine in HaCaT cells and mouse model. Ce6-mediated PDT notably downregulated the expression of these inflammatory molecules in vitro and in vivo. Similarly, chlorin e6-mediated PDT was capable of regulating inflammatory response in both live and heat killed S. epidermidis exposed HaCaT cells. Moreover, phosphorylation of p38, JNK, and ERK were reduced by Ce6-mediated PDT. Ce6-mediated PDT also reduced the phosphorylation of IKKα/β, IĸBα and NFκB p65 in P. acnes-stimulated HaCaT cells. In addition, the dramatic increase in the nuclear translocation of NFκB p65 observed upon stimulation with P. acnes was markedly impaired by Ce6-based PDT. This is the first suggestion that Ce6-mediated PDT suppresses P. acnes-induced inflammation through modulating NFκB and MAPKs signaling pathways. PMID:28118375

  3. Regulation of the transcriptional coactivator FHL2 licenses activation of the androgen receptor in castrate-resistant prostate cancer.

    Science.gov (United States)

    McGrath, Meagan J; Binge, Lauren C; Sriratana, Absorn; Wang, Hong; Robinson, Paul A; Pook, David; Fedele, Clare G; Brown, Susan; Dyson, Jennifer M; Cottle, Denny L; Cowling, Belinda S; Niranjan, Birunthi; Risbridger, Gail P; Mitchell, Christina A

    2013-08-15

    It is now clear that progression from localized prostate cancer to incurable castrate-resistant prostate cancer (CRPC) is driven by continued androgen receptor (AR), signaling independently of androgen. Thus, there remains a strong rationale to suppress AR activity as the single most important therapeutic goal in CRPC treatment. Although the expression of ligand-independent AR splice variants confers resistance to AR-targeted therapy and progression to lethal castrate-resistant cancer, the molecular regulators of AR activity in CRPC remain unclear, in particular those pathways that potentiate the function of mutant AR in CRPC. Here, we identify FHL2 as a novel coactivator of ligand-independent AR variants that are important in CRPC. We show that the nuclear localization of FHL2 and coactivation of the AR is driven by calpain cleavage of the cytoskeletal protein filamin, a pathway that shows differential activation in prostate epithelial versus prostate cancer cell lines. We further identify a novel FHL2-AR-filamin transcription complex, revealing how deregulation of this axis promotes the constitutive, ligand-independent activation of AR variants, which are present in CRPC. Critically, the calpain-cleaved filamin fragment and FHL2 are present in the nucleus only in CRPC and not benign prostate tissue or localized prostate cancer. Thus, our work provides mechanistic insight into the enhanced AR activation, most notably of the recently identified AR variants, including AR-V7 that drives CRPC progression. Furthermore, our results identify the first disease-specific mechanism for deregulation of FHL2 nuclear localization during cancer progression. These results offer general import beyond prostate cancer, given that nuclear FHL2 is characteristic of other human cancers where oncogenic transcription factors that drive disease are activated like the AR in prostate cancer.

  4. Up-Regulation of Hepatic Alpha-2-HS-Glycoprotein Transcription by Testosterone via Androgen Receptor Activation

    Directory of Open Access Journals (Sweden)

    Jakob Voelkl

    2014-06-01

    Full Text Available Background/Aims: Fetuin-A (alpha-2-HS-glycoprotein, AHSG, a liver borne plasma protein, contributes to the prevention of soft tissue calcification, modulates inflammation, reduces insulin sensitivity and fosters weight gain following high fat diet or ageing. In polycystic ovary syndrome, fetuin-A levels correlate with free androgen levels, an observation pointing to androgen sensitivity of fetuin-A expression. The present study thus explored whether the expression of hepatic fetuin-A is modified by testosterone. Methods: HepG2 cells were treated with testosterone and androgen receptor antagonist flutamide, and were silenced with androgen receptor siRNA. To test the in vivo relevance, male mice were subjected to androgen deprivation therapy (ADT for 7 weeks. AHSG mRNA levels were determined by quantitative RT-PCR and fetuin-A protein abundance by Western blotting. Results: In HepG2 cells, AHSG mRNA expression and fetuin-A protein abundance were both up-regulated following testosterone treatment. The human alpha-2-HS-glycoprotein gene harbors putative androgen receptor response elements in the proximal 5 kb promoter sequence relative to TSS. The effect of testosterone on AHSG mRNA levels was abrogated by silencing of the androgen receptor in HepG2 cells. Moreover, treatment of HepG2 cells with the androgen receptor antagonist flutamide in presence of endogenous ligands in the medium significantly down-regulated AHSG mRNA expression and fetuin-A protein abundance. In addition, ADT of male mice was followed by a significant decrease of hepatic Ahsg mRNA expression and fetuin-A protein levels. Conclusions: Testosterone participates in the regulation of hepatic fetuin-A expression, an effect mediated, at least partially, by androgen receptor activation.

  5. Androgen receptor expression in human ovarian and uterine tissue of long term androgen-treated transsexual women

    NARCIS (Netherlands)

    D. Chadha; T.D. Pache; F.J. Huikeshoven (Frans); A.O. Brinkmann (Albert); Th.H. van der Kwast (Theo)

    1994-01-01

    textabstractAndrogen receptor (AR) modulation in human uteri and ovaries of long term androgen-treated transsexual female patients was investigated. Androgen receptor expression was evaluated immunohistochemically in the ovaries of 11 and the endometria and myometria of six androgen-treated transsex

  6. Factors and interventions for mental disorders in patients with prostate cancer after androgen deprivation therapy%前列腺癌患者去势治疗后心理障碍的原因分析及干预策略

    Institute of Scientific and Technical Information of China (English)

    杨艳; 陈莉

    2011-01-01

    Though androgen deprivation therapy is the first choice for patients with advanced prostate cancer, it significantly decreases the quality of life and causes lots of mental disorders in patients, such as self-image disturbance, inferiority, anxiety, phobia, suspicious, fatigue, frustration, depression and so on. Psychological intervention may be an important method to recover from their mental trauma. Nursing staff, who contact with patients most frequently, are responsible for realizing psychological problems of patients in different periods, analyzing the possible causes, mastering the effective countermeasures and providing high-quality psychological care service to improve the quality of life of patients. This paper reviews the causes and corresponding countermeasures for mental disorders of patients with prostate cancer after androgen deprivation therapy, in hopes of helping nurses to conduct effective psychological intervention.%去势治疗是晚期前列腺癌患者首选的治疗方法,但其大大降低了患者的生活质量,易使患者陷入自我形象紊乱、自卑、焦虑、恐惧、多疑、疲劳、情绪低落以及抑郁等多种心理障碍,而心理干预是治疗其心理创伤的有效手段.护理人员作为与患者接触最为频繁的群体应了解患者不同时期的心理问题,分析产生的原因,掌握有效的心理干预手段,为患者提供优质的心理护理服务,提高患者的生活质量.该文就前列腺癌患者接受去势治疗后易产生心理障碍的原因及相应的护理干预措施进行综述,为护理人员进行有效的心理干预提供帮助.

  7. Inhibition of Androgen-Independent Prostate Cancer by Estrogenic Compounds Is Associated with Increased Expression of Immune-Related Genes

    Directory of Open Access Journals (Sweden)

    Ilsa M. Coleman

    2006-10-01

    Full Text Available The clinical utility of estrogens for treating prostate cancer (CaP was established in the 1940s by Huggins. The classic model of the anti-CaP activity of estrogens postulates an indirect mechanism involving the suppression of androgen production. However, clinical, preclinical studies have shown that estrogens exert growth-inhibitory effects on CaP under low-androgen conditions, suggesting additional modes whereby estrogens affect CaP cells and/or the microenvironment. Here we have investigated the activity of 17β estradiol (E2 against androgen-independent CaP, identified molecular alterations in tumors exposed to E2. E2 treatment inhibited the growth of all four androgen-independent CaP xenografts studied (LuCaP 35V, LuCaP 23.1AI, LuCaP 49, LuCaP 58 in castrated male mice. The molecular basis of growth suppression was studied by cDNA microarray analysis, which indicated that multiple pathways are altered by E2 treatment. Of particular interest are changes in transcripts encoding proteins that mediate immune responses, regulate androgen receptor signaling. In conclusion, our data show that estrogens have powerful inhibitory effects on CaP in vivo in androgendepleted environments, suggest novel mechanisms of estrogen-mediated antitumor activity. These results indicate that incorporating estrogens into CaP treatment protocols could enhance therapeutic efficacy even in cases of advanced disease.

  8. Testosterone regulates keratin 33B expression in rat penis growth through androgen receptor signaling.

    Science.gov (United States)

    Ma, Yan-Min; Wu, Kai-Jie; Dang, Qiang; Shi, Qi; Gao, Yang; Guo, Peng; Xu, Shan; Wang, Xin-Yang; He, Da-Lin; Gong, Yong-Guang

    2014-01-01

    Androgen therapy is the mainstay of treatment for the hypogonadotropic hypogonadal micropenis because it obviously enhances penis growth in prepubescent microphallic patients. However, the molecular mechanisms of androgen treatment leading to penis growth are still largely unknown. To clarify this well-known phenomenon, we successfully generated a castrated male Sprague Dawley rat model at puberty followed by testosterone administration. Interestingly, compared with the control group, testosterone treatment stimulated a dose-dependent increase of penis weight, length, and width in castrated rats accompanied with a dramatic recovery of the pathological changes of the penis. Mechanistically, testosterone administration substantially increased the expression of androgen receptor (AR) protein. Increased AR protein in the penis could subsequently initiate transcription of its target genes, including keratin 33B (Krt33b). Importantly, we demonstrated that KRT33B is generally expressed in the rat penis and that most KRT33B expression is cytoplasmic. Furthermore, AR could directly modulate its expression by binding to a putative androgen response element sequence of the Krt33b promoter. Overall, this study reveals a novel mechanism facilitating penis growth after testosterone treatment in precastrated prepubescent animals, in which androgen enhances the expression of AR protein as well as its target genes, such as Krt33b.

  9. Estrogen receptor ligands counteract cognitive deficits caused by androgen deprivation in male rats.

    Science.gov (United States)

    Lagunas, Natalia; Calmarza-Font, Isabel; Grassi, Daniela; Garcia-Segura, Luis M

    2011-04-01

    Androgen deprivation causes impairment of cognitive tasks in rodents and humans, and this deficit can be reverted by androgen replacement therapy. Part of the effects of androgens in the male may be mediated by their local metabolism to estradiol or 3-alpha androstanediol within the brain and the consequent activation of estrogen receptors. In this study we have assessed whether the administration of estradiol benzoate, the estrogen receptor β selective agonist diarylpropionitrile or the estrogen receptor α selective agonist propyl pyrazole triol affect performance of androgen-deprived male Wistar rats in the cross-maze test. In addition, we tested the effect of raloxifene and tamoxifen, two selective estrogen receptor modulators used in clinical practice. The behavior of the rats was assessed 2 weeks after orchidectomy or sham surgery. Orchidectomy impaired acquisition in the cross-maze test. Estradiol benzoate and the selective estrogen receptor β agonist significantly improved acquisition in the cross-maze test compared to orchidectomized animals injected with vehicle. Raloxifene and tamoxifen at a dose of 1mg/kg, but not at doses of 0.5 or 2mg/kg, also improved acquisition of orchidectomized animals. Our findings suggest that estrogenic compounds with affinity for estrogen receptor β and selective estrogen receptor modulators, such as raloxifene and tamoxifen, may represent good candidates to promote cognitive performance in androgen-deprived males.

  10. Selective androgen receptor modulators: in pursuit of tissue-selective androgens.

    Science.gov (United States)

    Omwancha, Josephat; Brown, Terry R

    2006-10-01

    The androgen receptor mediates the androgenic and anabolic activity of the endogenous steroids testosterone and 5alpha-dihydrotestosterone. Current knowledge of the androgen receptor protein structure, and the molecular mechanisms surrounding the binding properties and activities of agonists and antagonists has led to the design and development of novel nonsteroidal ligands with selected tissue-specific androgen receptor agonist and antagonist activities. The activity of these compounds, termed selective androgen receptor modulators (SARMs), is directed toward the maintenance or enhancement of anabolic effects on bone and muscle with minimal androgenic effects on prostate growth. SARMs are of potential therapeutic value in the treatment of male hypogonadism, osteoporosis, frailty and muscle wasting, burn injury and would healing, anemia, mood and depression, benign prostatic hyperplasia and prostate cancer.

  11. Histone deacetylase inhibitor romidepsin induces HIV expression in CD4 T cells from patients on suppressive antiretroviral therapy at concentrations achieved by clinical dosing.

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    Datsen George Wei

    2014-04-01

    Full Text Available Persistent latent reservoir of replication-competent proviruses in memory CD4 T cells is a major obstacle to curing HIV infection. Pharmacological activation of HIV expression in latently infected cells is being explored as one of the strategies to deplete the latent HIV reservoir. In this study, we characterized the ability of romidepsin (RMD, a histone deacetylase inhibitor approved for the treatment of T-cell lymphomas, to activate the expression of latent HIV. In an in vitro T-cell model of HIV latency, RMD was the most potent inducer of HIV (EC50 = 4.5 nM compared with vorinostat (VOR; EC50 = 3,950 nM and other histone deacetylase (HDAC inhibitors in clinical development including panobinostat (PNB; EC50 = 10 nM. The HIV induction potencies of RMD, VOR, and PNB paralleled their inhibitory activities against multiple human HDAC isoenzymes. In both resting and memory CD4 T cells isolated from HIV-infected patients on suppressive combination antiretroviral therapy (cART, a 4-hour exposure to 40 nM RMD induced a mean 6-fold increase in intracellular HIV RNA levels, whereas a 24-hour treatment with 1 µM VOR resulted in 2- to 3-fold increases. RMD-induced intracellular HIV RNA expression persisted for 48 hours and correlated with sustained inhibition of cell-associated HDAC activity. By comparison, the induction of HIV RNA by VOR and PNB was transient and diminished after 24 hours. RMD also increased levels of extracellular HIV RNA and virions from both memory and resting CD4 T-cell cultures. The activation of HIV expression was observed at RMD concentrations below the drug plasma levels achieved by doses used in patients treated for T-cell lymphomas. In conclusion, RMD induces HIV expression ex vivo at concentrations that can be achieved clinically, indicating that the drug may reactivate latent HIV in patients on suppressive cART.

  12. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS, AMERICAN COLLEGE OF ENDOCRINOLOGY, AND ANDROGEN EXCESS AND PCOS SOCIETY DISEASE STATE CLINICAL REVIEW: GUIDE TO THE BEST PRACTICES IN THE EVALUATION AND TREATMENT OF POLYCYSTIC OVARY SYNDROME--PART 1.

    Science.gov (United States)

    Goodman, Neil F; Cobin, Rhoda H; Futterweit, Walter; Glueck, Jennifer S; Legro, Richard S; Carmina, Enrico

    2015-11-01

    , alopecia, and acne. Cycle length >35 days suggests chronic anovulation, but cycle length slightly longer than normal (32 to 35 days) or slightly irregular (32 to 35-36 days) needs assessment for ovulatory dysfunction. Ovulatory dysfunction is associated with increased prevalence of endometrial hyperplasia and endometrial cancer, in addition to infertility. In PCOS, hirsutism develops gradually and intensifies with weight gain. In the neoplastic virilizing states, hirsutism is of rapid onset, usually associated with clitoromegaly and oligomenorrhea. Girls with severe acne or acne resistant to oral and topical agents, including isotretinoin (Accutane), may have a 40% likelihood of developing PCOS. Hair loss patterns are variable in women with hyperandrogenemia, typically the vertex, crown or diffuse pattern, whereas women with more severe hyperandrogenemia may see bitemporal hair loss and loss of the frontal hairline. Oral contraceptives (OCPs) can effectively lower androgens and block the effect of androgens via suppression of ovarian androgen production and by increasing sex hormone-binding globulin. Physiologic doses of dexamethasone or prednisone can directly lower adrenal androgen output. Anti-androgens can be used to block the effects of androgen in the pilosebaceous unit or in the hair follicle. Anti-androgen therapy works through competitive antagonism of the androgen receptor (spironolactone, cyproterone acetate, flutamide) or inhibition of 5α-reductase (finasteride) to prevent the conversion of T to its more potent form, 5α-dihydrotestosterone. The choice of antiandrogen therapy is guided by symptoms. The diagnosis of PCOS in adolescents is particularly challenging given significant age and developmental issues in this group. Management of infertility in women with PCOS requires an understanding of the pathophysiology of anovulation as well as currently available treatments. Many features of PCOS, including acne, menstrual irregularities, and hyperinsulinemia

  13. Androgen-responsive gene database: integrated knowledge on androgen-responsive genes.

    Science.gov (United States)

    Jiang, Mei; Ma, Yunsheng; Chen, Congcong; Fu, Xuping; Yang, Shu; Li, Xia; Yu, Guohua; Mao, Yumin; Xie, Yi; Li, Yao

    2009-11-01

    Androgen signaling plays an important role in many biological processes. Androgen Responsive Gene Database (ARGDB) is devoted to providing integrated knowledge on androgen-controlled genes. Gene records were collected on the basis of PubMed literature collections. More than 6000 abstracts and 950 original publications were manually screened, leading to 1785 human genes, 993 mouse genes, and 583 rat genes finally included in the database. All the collected genes were experimentally proved to be regulated by androgen at the expression level or to contain androgen-responsive regions. For each gene important details of the androgen regulation experiments were collected from references, such as expression change, androgen-responsive sequence, response time, tissue/cell type, experimental method, ligand identity, and androgen amount, which will facilitate further evaluation by researchers. Furthermore, the database was integrated with multiple annotation resources, including National Center for Biotechnology Information, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway, to reveal the biological characteristics and significance of androgen-regulated genes. The ARGDB web site is mainly composed of the Browse, Search, Element Scan, and Submission modules. It is user friendly and freely accessible at http://argdb.fudan.edu.cn. Preliminary analysis of the collected data was performed. Many disease pathways, such as prostate carcinogenesis, were found to be enriched in androgen-regulated genes. The discovered androgen-response motifs were similar to those in previous reports. The analysis results are displayed in the web site. In conclusion, ARGDB provides a unified gateway to storage, retrieval, and update of information on androgen-regulated genes.

  14. Study of RNA interference inhibiting rat ovarian androgen biosynthesis by depressing 17alpha-hydroxylase/17, 20-lyase activity in vivo

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    Yang Xing

    2009-07-01

    Full Text Available Abstract Background 17alpha-hydroxylase/17, 20-lyase encoded by CYP17 is the key enzyme in androgen biosynthesis pathway. Previous studies demonstrated the accentuation of the enzyme in patients with polycystic ovary syndrome (PCOS was the most important mechanism of androgen excess. We chose CYP17 as the therapeutic target, trying to suppress the activity of 17alpha-hydroxylase/17, 20-lyase and inhibit androgen biosynthesis by silencing the expression of CYP17 in the rat ovary. Methods Three CYP17-targeting and one negative control oligonucleotides were designed and used in the present study. The silence efficiency of lentivirus shRNA was assessed by qRT-PCR, Western blotting and hormone assay. After subcapsular injection of lentivirus shRNA in rat ovary, the delivery efficiency was evaluated by GFP fluorescence and qPCR. Total RNA was extracted from rat ovary for CYP17 mRNA determination and rat serum was collected for hormone measurement. Results In total, three CYP17-targeting lentivirus shRNAs were synthesized. The results showed that all of them had a silencing effect on CYP17 mRNA and protein. Moreover, androstenedione secreted by rat theca interstitial cells (TIC in the RNAi group declined significantly compared with that in the control group. Two weeks after rat ovarian subcapsular injection of chosen CYP17 shRNA, the GFP fluorescence of frozen ovarian sections could be seen clearly under fluorescence microscope. It also showed that the GFP DNA level increased significantly, and its relative expression level was 7.42 times higher than that in the control group. Simultaneously, shRNA treatment significantly decreased CYP17 mRNA and protein levels at 61% and 54%, respectively. Hormone assay showed that all the levels of androstenedione, 17-hydroxyprogesterone and testosterone declined to a certain degree, but progesterone levels declined significantly. Conclusion The present study proves for the first time that ovarian androgen

  15. Inhibition of Apoptosis in Prostate Cancer Cells by Androgens Is Mediated through Downregulation of c-Jun N-terminal Kinase Activation

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    Petra Isabel Lorenzo

    2008-05-01

    Full Text Available Androgen deprivation induces the regression of prostate tumors mainly due to an increase in the apoptosis rate; however, the molecular mechanisms underlying the antiapoptotic actions of androgens are not completely understood. We have studied the antiapoptotic effects of androgens in prostate cancer cells exposed to different proapoptotic stimuli. Terminal deoxynucleotidyl transferase-mediated nick-end labeling and nuclear fragmentation analyses demonstrated that androgens protect LNCaP prostate cancer cells from apoptosis induced by thapsigargin, the phorbol ester 12-O-tetradecanoyl-13-phorbol-acetate, or UV irradiation. These three stimuli require the activation of the c-Jun N-terminal kinase (JNK pathway to induce apoptosis and in all three cases, androgen treatment blocks JNK activation. Interestingly, okadaic acid, a phosphatase inhibitor that causes apoptosis in LNCaP cells, induces JNK activation that is also inhibited by androgens. Actinomycin D, the antiandrogen bicalutamide or specific androgen receptor (AR knockdown by small interfering RNA all blocked the inhibition of JNK activation mediated by androgens indicating that this activity requires AR-dependent transcriptional activation. These data suggest that the crosstalk between AR and JNK pathways may have important implications in prostate cancer progression and may provide targets for the development of new therapies.

  16. Retreatment for prostate cancer with stereotactic body radiation therapy (SBRT): Feasible or foolhardy?

    Science.gov (United States)

    Arcangeli, Stefano; Agolli, Linda; Donato, Vittorio

    2015-01-01

    The most popular therapeutic option in the management of radio-recurrent prostatic carcinoma is represented by the androgen deprivation therapy, that however should be considered only palliative and hampered by potential adverse effects of testosterone suppression. Local therapies such as surgery, cryoablation or brachytherapy might be curative choices for patients in good conditions and with a long-life expectancy, but at cost of significant risk of failure and severe toxicity. The administration of stereotactic body radiation therapy (SBRT) in this setting have come about because of tremendous technologic advances in image guidance and treatment delivery techniques that enable the delivery of large doses to tumor with reduced margins and high gradients outside the target, thereby reducing the volume of rectum which already received significant doses from primary radiotherapy. So far, very modest data are available to support its employment. Rationale, clinical experience, and challenges are herein reviewed and discussed.

  17. ABUSE OF ANABOLIC ANDROGENIC STEROIDS

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    Abbas Yavari

    2009-09-01

    Full Text Available According to the International Olympic Committee, the abuse of anabolic androgenic steroids (AASS is found in over 50% of positive doping tests. AASS abuse is not restricted to the organized sports andwidespread use. It remains as an unsolved public-health problem.Lower black market price, easier access to AASS, bodybuilding clubs and internet advertising are factors of this increasingly misuse. There is not real data about the prevalence of AASS abuse in various populations or countries, because most of athletes or students, due to their prohibition or ethical aspects do not admit to AASS abuse. Often they are aware of the risks of their choice and yet, are eager to put themselves at risk without deeper consideration. The abusers use them to improve their physical fitness and appearance.Present article has been collected to elucidate the risks and adverse effects of AASS and explanation of mechanisms of these events.

  18. Synthetic androgens as designer supplements.

    Science.gov (United States)

    Joseph, Jan Felix; Parr, Maria Kristina

    2015-01-01

    Anabolic androgenic steroids (AAS) are some of the most common performance enhancing drugs (PED) among society. Despite the broad spectrum of adverse effects and legal consequences, AAS are illicitly marketed and distributed in many countries. To circumvent existing laws, the chemical structure of AAS is modified and these designer steroids are sold as nutritional supplements mainly over the Internet. Several side effects are linked with AAS abuse. Only little is known about the pharmacological effects and metabolism of unapproved steroids due to the absence of clinical studies. The large number of designer steroid findings in dietary supplements and the detection of new compounds combined with legal loopholes for their distribution in many countries show that stricter regulations and better information policy are needed.

  19. ANABOLIC ANDROGENIC STEROIDS AND DEPENDENCE

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    IHSAN SARI

    2010-12-01

    Full Text Available Anabolic androgenic steroids are used for sportive, cosmetic, therapeutic and occupational reasons and there are many side effects reported (George, 2005; Nieminen et al., 1996; O'Sullivan et al., 2000. Prevalence of anabolic steroids’ use also indicates the importance of this topic. Moreover, it is now known that use of anabolic steroids could lead to dependence which could be psychological or/and physiological (Copeland et al., 2000. It isimportant to know about all aspects of anabolic steroids including dependence. Therefore, this study has attempted to give an insight into use of anabolic steroids and dependence. The discussion will focus on prevalence, reasons, and side effects of use and physiological and psychological dependence

  20. Oestrogen-androgen crosstalk in the pathophysiology of erectile dysfunction

    Institute of Scientific and Technical Information of China (English)

    BSrilatha; PGAdaikan

    2003-01-01

    Ageing in man is associated with a decline in testosterone following changes in the hypothalamo-pituitary-testicular axis. This may offset the physiologic equilibrium between oestrogen and androgen and at some point when the ratio of free testosterone to oestradiol reaches a critical level, the oestrogenic gonadotropin suppressive effect predominates with decreased release of FSH and LH. Adding to this endocrinal complexity is the continued peripheral conversion to oestradiol through aromatisation. Although the androgen deficiency is not the sole cause for impotence in the elderly, there is a gradual decrease in nocturnal penile tumescence (NPT) and spontaneous morning erections with ageing. Despite the age related increase in oestrogen levels, the information on the pathophysiological role of the "female hormone" in erectile dysfunction has been scanty. Together with our identification of oestrogen receptors within the penile cavernosum, we have delineated dysfunctional changes on male erection mediated by oestradiol.These findings parallel the recent concerns over environmental oestrogens on fertility declines in young men. Oestrogenic activity is also present in plants and thereby in human diet. These phytoestrogens are structurally and functionally similar to oestradiol and more potent than the environmental oestrogenic chemicals such as organochlorine and phenolic compounds. Thus in the light of growing concerns of possible compromising effects on sexuality by endogenous and environmental oestrogens, we are faced with the scientific need to delineate their role on the mechanism of male erectile pathway in health and disease for clinical correlates and prognostics.

  1. Acne vulgaris related to androgens - a review.

    Science.gov (United States)

    Khondker, L; Khan, S I

    2014-01-01

    Sebum production is stimulated by androgens and is the key in the development of acne vulgaris. Several investigators have looked for direct relationships between serum androgen levels, sebum secretion rate and the presence of acne. The presence of acne in prepubertal girls and sebum production in both sexes correlate with serum dehydroepiandrosterone sulfate (DHEAS) levels. Although increased serum androgen levels correlate with the presence of severe nodular acne in men and women, these levels are often within the normal range in mild to moderate acne. This raises the question of whether there is an increased local production of androgens within the sebaceous gland of patients with acne vulgaris that leads to increased sebum secretion.

  2. Androgen receptor roles in spermatogenesis and infertility.

    Science.gov (United States)

    O'Hara, Laura; Smith, Lee B

    2015-08-01

    Androgens such as testosterone are steroid hormones essential for normal male reproductive development and function. Mutations of androgen receptors (AR) are often found in patients with disorders of male reproductive development, and milder mutations may be responsible for some cases of male infertility. Androgens exert their action through AR and its signalling in the testis is essential for spermatogenesis. AR is not expressed in the developing germ cell lineage so is thought to exert its effects through testicular Sertoli and peri-tubular myoid (PTM) cells. AR signalling in spermatogenesis has been investigated in rodent models where testosterone levels are chemically supressed or models with transgenic disruption of AR. These models have pinpointed the steps of spermatogenesis that require AR signalling, specifically maintenance of spermatogonial numbers, blood-testis barrier integrity, completion of meiosis, adhesion of spermatids and spermiation, together these studies detail the essential nature of androgens in the promotion of male fertility.

  3. Androgen deficiency and metabolic syndrome in men

    OpenAIRE

    Winter, Ashley G; Zhao, Fujun; Lee, Richard K.

    2014-01-01

    Metabolic syndrome (MetS) is a growing health concern worldwide. Initially a point of interest in cardiovascular events, the cluster of HTN, obesity, dyslipidemia, and insulin resistance known as MetS has become associated with a variety of other disease processes, including androgen deficiency and late-onset hypogonadism (LOH). Men with MetS are at a higher risk of developing androgen deficiency, and routine screening of testosterone (T) is advised in this population. The pathophysiology of ...

  4. The discovery of novel human androgen receptor antagonist chemotypes using a combined pharmacophore screening procedure.

    Science.gov (United States)

    Voet, Arnout; Helsen, Christine; Zhang, Kam Y J; Claessens, Frank

    2013-04-01

    Unraveling the mechanisms involved in castration- and therapy-resistant prostate cancer has led to a renewed interest in androgen receptor (AR)-targeted therapeutics. Anti-androgens that block the activity of the AR therefore remain a valid therapeutic option. However, they must be more effective than, or display a distinct mechanism of action or binding mode from those of bicalutamide and hydroxyflutamide, which are currently in clinical use. For that reason, the second-generation anti-androgen MDV3100 was developed. MDV3100, however, shares its 4-cyano-3-(trifluoromethyl)phenyl group with bicalutamide and hydroxyflutamide required for binding to the AR. In this work, we used a combined strategy to find new antagonist structures distinct from the 4-cyano-3-(trifluoromethyl)phenyl group to avoid cross-resistance for these compounds and to find structures without agonist activity on mutant ARs (AR W741C and AR T877A). We found two novel chemotypes with AR-antagonistic activity (IC(50): 3-6 μM) by virtual screening and confirmed their biological activity in an androgen-responsive reporter assay. The design of our computational approach was validated by the observation of strongly decreased or absence of agonistic activity on the two mutant ARs. Further structural derivatization to optimize the potency of these compounds can render these chemotypes into very promising, alternative AR antagonists for prostate cancer therapy.

  5. Differential effects of genistein on prostate cancer cells depend on mutational status of the androgen receptor.

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    Abeer M Mahmoud

    Full Text Available Blocking the androgen receptor (AR activity is the main goal of therapies for advanced prostate cancer (PCa. However, relapse with a more aggressive, hormone refractory PCa arises, which harbors restored AR activity. One mechanism of such reactivation occurs through acquisition of AR mutations that enable its activation by various steroidal and non-steroidal structures. Thus, natural and chemical compounds that contribute to inappropriate (androgen-independent activation of the AR become an area of intensive research. Here, we demonstrate that genistein, a soy phytoestrogen binds to both the wild and the Thr877Ala (T877A mutant types of AR competitively with androgen, nevertheless, it exerts a pleiotropic effect on PCa cell proliferation and AR activity depending on the mutational status of the AR. Genistein inhibited, in a dose-dependent way, cell proliferation and AR nuclear localization and expression in LAPC-4 cells that have wild AR. However, in LNCaP cells that express the T877A mutant AR, genistein induced a biphasic effect where physiological doses (0.5-5 µmol/L stimulated cell growth and increased AR expression and transcriptional activity, and higher doses induced inhibitory effects. Similar biphasic results were achieved in PC-3 cells transfected with AR mutants; T877A, W741C and H874Y. These findings suggest that genistein, at physiological concentrations, potentially act as an agonist and activate the mutant AR that can be present in advanced PCa after androgen ablation therapy.

  6. Differential effects of genistein on prostate cancer cells depend on mutational status of the androgen receptor.

    Science.gov (United States)

    Mahmoud, Abeer M; Zhu, Tian; Parray, Aijaz; Siddique, Hifzur R; Yang, Wancai; Saleem, Mohammad; Bosland, Maarten C

    2013-01-01

    Blocking the androgen receptor (AR) activity is the main goal of therapies for advanced prostate cancer (PCa). However, relapse with a more aggressive, hormone refractory PCa arises, which harbors restored AR activity. One mechanism of such reactivation occurs through acquisition of AR mutations that enable its activation by various steroidal and non-steroidal structures. Thus, natural and chemical compounds that contribute to inappropriate (androgen-independent) activation of the AR become an area of intensive research. Here, we demonstrate that genistein, a soy phytoestrogen binds to both the wild and the Thr877Ala (T877A) mutant types of AR competitively with androgen, nevertheless, it exerts a pleiotropic effect on PCa cell proliferation and AR activity depending on the mutational status of the AR. Genistein inhibited, in a dose-dependent way, cell proliferation and AR nuclear localization and expression in LAPC-4 cells that have wild AR. However, in LNCaP cells that express the T877A mutant AR, genistein induced a biphasic effect where physiological doses (0.5-5 µmol/L) stimulated cell growth and increased AR expression and transcriptional activity, and higher doses induced inhibitory effects. Similar biphasic results were achieved in PC-3 cells transfected with AR mutants; T877A, W741C and H874Y. These findings suggest that genistein, at physiological concentrations, potentially act as an agonist and activate the mutant AR that can be present in advanced PCa after androgen ablation therapy.

  7. Sexually dimorphic fin regeneration in zebrafish controlled by androgen/GSK3 signaling.

    Science.gov (United States)

    Nachtrab, Gregory; Czerwinski, Michael; Poss, Kenneth D

    2011-11-22

    Certain fish and amphibians regenerate entire fins and limbs after amputation, whereas such potential is absent in birds and limited in mammals to digit tips [1, 2]. Additionally, regenerative success can change during life stages. Anuran tadpoles gradually lose the capacity to regenerate limbs [3, 4], and digit regeneration occurs more effectively in fetal mice and human children than adults [5-8]. Little is known about mechanisms that control regenerative capacity. Here, we identify an unexpected difference between male and female zebrafish in the regenerative potential of a major appendage. Males display regenerative defects in amputated pectoral fins, caused by impaired blastemal proliferation. This regenerative failure emerges after sexual maturity, is mimicked in androgen-treated females, and is suppressed in males by androgen receptor antagonism. Androgen signaling maintains expression of dkk1b and igfbp2a, which encode secreted inhibitors of Wnt and Igf signaling, respectively. Furthermore, the regulatory target of Wnts and Igfs, GSK3β, is inefficiently inactivated in male fin regenerates compared with females. Pharmacological inhibition of GSK3 in males increases blastemal proliferation and restores regenerative pattern. Our findings identify a natural sex bias in appendage regenerative capacity and indicate an underlying regulatory circuit in which androgen locally restricts key morphogenetic programs after amputation.

  8. Transcriptional regulation of myotrophic actions by testosterone and trenbolone on androgen-responsive muscle.

    Science.gov (United States)

    Ye, Fan; McCoy, Sean C; Ross, Heather H; Bernardo, Joseph A; Beharry, Adam W; Senf, Sarah M; Judge, Andrew R; Beck, Darren T; Conover, Christine F; Cannady, Darryl F; Smith, Barbara K; Yarrow, Joshua F; Borst, Stephen E

    2014-09-01

    Androgens regulate body composition and skeletal muscle mass in males, but the molecular mechanisms are not fully understood. Recently, we demonstrated that trenbolone (a potent synthetic testosterone analogue that is not a substrate for 5-alpha reductase or for aromatase) induces myotrophic effects in skeletal muscle without causing prostate enlargement, which is in contrast to the known prostate enlarging effects of testosterone. These previous results suggest that the 5α-reduction of testosterone is not required for myotrophic action. We now report differential gene expression in response to testosterone versus trenbolone in the highly androgen-sensitive levator ani/bulbocavernosus (LABC) muscle complex of the adult rat after 6weeks of orchiectomy (ORX), using real time PCR. The ORX-induced expression of atrogenes (Muscle RING-finger protein-1 [MuRF1] and atrogin-1) was suppressed by both androgens, with trenbolone producing a greater suppression of atrogin-1 mRNA compared to testosterone. Both androgens elevated expression of anabolic genes (insulin-like growth factor-1 and mechano-growth factor) after ORX. ORX-induced increases in expression of glucocorticoid receptor (GR) mRNA were suppressed by trenbolone treatment, but not testosterone. In ORX animals, testosterone promoted WNT1-inducible-signaling pathway protein 2 (WISP-2) gene expression while trenbolone did not. Testosterone and trenbolone equally enhanced muscle regeneration as shown by increases in LABC mass and in protein expression of embryonic myosin by western blotting. In addition, testosterone increased WISP-2 protein levels. Together, these findings identify specific mechanisms by which testosterone and trenbolone may regulate skeletal muscle maintenance and growth.

  9. Suppressed Belief

    Directory of Open Access Journals (Sweden)

    Komarine Romdenh-Romluc

    2009-12-01

    Full Text Available Moran’s revised conception of conscious belief requires us to reconceptualise suppressed belief. The work of Merleau-Ponty offers a way to do this. His account of motor-skills allows us to understand suppressed beliefs as pre-reflective ways of dealing with the world.

  10. Differential effects of androgens on coronary blood flow regulation and arteriolar diameter in intact and castrated swine

    Directory of Open Access Journals (Sweden)

    O’Connor Erin K

    2012-05-01

    Full Text Available Abstract Background Low endogenous testosterone levels have been shown to be a risk factor for the development of cardiovascular disease and cardiovascular benefits associated with testosterone replacement therapy are being advocated; however, the effects of endogenous testosterone levels on acute coronary vasomotor responses to androgen administration are not clear. The objective of this study was to compare the effects of acute androgen administration on in vivo coronary conductance and in vitro coronary microvascular diameter in intact and castrated male swine. Methods Pigs received intracoronary infusions of physiologic levels (1–100 nM of testosterone, the metabolite 5α-dihydrotestosterone, and the epimer epitestosterone while left anterior descending coronary blood flow and mean arterial pressure were continuously monitored. Following sacrifice, coronary arterioles were isolated, cannulated, and exposed to physiologic concentrations (1–100 nM of testosterone, 5α-dihydrotestosterone, and epitestosterone. To evaluate effects of the androgen receptor on acute androgen dilation responses, real-time PCR and immunohistochemistry for androgen receptor were performed on conduit and resistance coronary vessels. Results In vivo, testosterone and 5α-dihydrotestosterone produced greater increases in coronary conductance in the intact compared to the castrated males. In vitro, percent maximal dilation of microvessels was similar between intact and castrated males for testosterone and 5α-dihydrotestosterone. In both studies epitestosterone produced significant increases in conductance and microvessel diameter from baseline in the intact males. Androgen receptor mRNA expression and immunohistochemical staining were similar in intact and castrated males. Conclusions Acute coronary vascular responses to exogenous androgen administration are increased by endogenous testosterone, an effect unrelated to changes in androgen receptor expression.

  11. Androgen-induced cell migration: role of androgen receptor/filamin A association.

    Directory of Open Access Journals (Sweden)

    Gabriella Castoria

    Full Text Available BACKGROUND: Androgen receptor (AR controls male morphogenesis, gametogenesis and prostate growth as well as development of prostate cancer. These findings support a role for AR in cell migration and invasiveness. However, the molecular mechanism involved in AR-mediated cell migration still remains elusive. METHODOLOGY/PRINCIPAL FINDINGS: Mouse embryo NIH3T3 fibroblasts and highly metastatic human fibrosarcoma HT1080 cells harbor low levels of transcriptionally incompetent AR. We now report that, through extra nuclear action, AR triggers migration of both cell types upon stimulation with physiological concentrations of the androgen R1881. We analyzed the initial events leading to androgen-induced cell migration and observed that challenging NIH3T3 cells with 10 nM R1881 rapidly induces interaction of AR with filamin A (FlnA at cytoskeleton. AR/FlnA complex recruits integrin beta 1, thus activating its dependent cascade. Silencing of AR, FlnA and integrin beta 1 shows that this ternary complex controls focal adhesion kinase (FAK, paxillin and Rac, thereby driving cell migration. FAK-null fibroblasts migrate poorly and Rac inhibition by EHT impairs motility of androgen-treated NIH3T3 cells. Interestingly, FAK and Rac activation by androgens are independent of each other. Findings in human fibrosarcoma HT1080 cells strengthen the role of Rac in androgen signaling. The Rac inhibitor significantly impairs androgen-induced migration in these cells. A mutant AR, deleted of the sequence interacting with FlnA, fails to mediate FAK activation and paxillin tyrosine phosphorylation in androgen-stimulated cells, further reinforcing the role of AR/FlnA interaction in androgen-mediated motility. CONCLUSIONS/SIGNIFICANCE: The present report, for the first time, indicates that the extra nuclear AR/FlnA/integrin beta 1 complex is the key by which androgen activates signaling leading to cell migration. Assembly of this ternary complex may control organ development

  12. Sensitivity as outcome measure of androgen replacement: the AMS scale

    Directory of Open Access Journals (Sweden)

    Dinger Juergen C

    2006-03-01

    Full Text Available Abstract Background The capacity of the AMS scale as clinical utility and as outcome measure still needs validation. Methods An open post-marketing study was performed by office-based physicians in Germany in 2004. We analysed data of 1670 androgen-deficient males who were treated with testosterone gel. The AMS scale was applied prior to and after 3 months treatment. Results The improvement of complaints under treatment relative to the baseline score was 30.7% (total score, 27.3% (psychological domain, 30.5% (somatic domain, and 30.7% (sexual domain, respectively. Patients with little or no symptoms before therapy improved by 9%, those with mild complaints at entry by 24%, with moderate by 32%, and with severe symptoms by 39% – compared with the baseline score. We showed that the distribution of complaints of testosterone deficient men before therapy almost returned to norm values after 12 weeks of testosterone treatment. Age, BMI, and total testosterone level at baseline did not modify the positive effect of androgen therapy. We also demonstrated that the AMS results can predict the independent (physician's opinion about the individual treatment effect. Both, sensitivity (correct prediction of a positive assessment by the physician and specificity (correct prediction of a negative assessment by the physician were over 70%, if about 22% improvement of the AMS total score was used as cut-off point. Conclusion The AMS scale showed a convincing ability to measure treatment effects on quality of life across the full range of severity of complaints. Effect modification by other variables at baseline was not observed. In addition, results of the scale can predict the subjective clinical expert opinion on the treatment efficiency.

  13. Rapamycin enhances the susceptibility of both androgen-dependent and-independent prostate carcinoma cells to docetaxel

    Institute of Scientific and Technical Information of China (English)

    LIU Qing-jun; XU Xiu-hong; SHANG Dong-hao; TIAN Ye; L(U) Wen-cheng; ZHANG Yu-hai

    2010-01-01

    Background Docetaxel (DOC) therapy is well tolerated and shows high response rates in patients with hormone refractory prostate cancer (HRPC). There are many reports on the effect of rapamycin (RPM) on the treatment of carcinogenesis. The goal of this study was to test whether RPM could enhance the susceptibility of both androgen-dependent and -independent prostate carcinoma cells to DOC.Methods Prostate cancer (PC) cell lines (LNCap, PC3 and AILNCap) were cultured and treated with RPM and DOC alone or in combination. The effects of therapeutic agents on cells were determined by the WST-1 assay. Apoptosis induction was confirmed by flow cytometric analysis. The apopcyto caspase colorimetric assay kit was applied to measure the activities of caspases 3 and 9. The antitumor effects of RPM and DOC against PC cells were also assessed in nude mice using four randomized groups: control, RPM, DOC and combination drug therapy by measuring tumor size. All the animals tolerated both RPM and DOC without significant weight loss.Results RPM and DOC caused dosage-dependent growth suppression of PC cells. RPM could increase the susceptibility of PC cells to DOC significantly, and combined treatment with RPM and DOC caused synergistic growth suppression in all examined PC cell lines by isobolographic analysis. Both RPM and DOC significantly induced apoptosis in a dosage-dependent manner. RPM (10 nmol/L), DOC (1 nmol/L), and combined treatment induced apoptosis rate were 8%, 17% and 38%, respectively (the control was 2%). RPM could promote the apoptosis induced by DOC in PC cell lines. Both RPM and DOC significantly increased the caspase activity in a dosage-dependent manner. The relative activities of caspase 9 in control, RPM, DOC and RPM+DOC groups were 0.22±0.02, 0.36±0.06, 0.47±0.05 and 0.84±0.08, respectively. The relative activities of cespase 3 were 0.21±0.02, 0.24±0.05, 0.42±0.06 and 0.81±0.09, respectively. Either RPM or DOC alone significantly inhibited the

  14. Effects of anabolic-androgens on brain reward function

    Directory of Open Access Journals (Sweden)

    Emanuela eMhillaj

    2015-08-01

    Full Text Available Androgens are mainly prescribed to treat several diseases caused by testosterone deficiency. However, athletes try to promote muscle growth by manipulating testosterone levels or assuming the so called androgen anabolic steroids (AAS. These substances were originally synthesized to obtain anabolic effects greater than testosterone. Although AAS are rarely prescribed compared to testosterone, the off-label utilization is very wide. Furthermore, combination of different steroids, and doses largely higher than those used in therapy are common. Symptoms of the chronic use of supra-therapeutic doses of AAS include anxiety, depression, aggression, paranoia, distractibility, confusion, amnesia. Interestingly, some studies have shown that AAS elicited electroencephalographic changes similar to those observed with amphetamine abuse. Among the AAS abusers, the frequency of side effects is higher, with psychiatric complications such as labile mood, lack of impulse control and high violence. On the other hand, AAS addiction studies are complex because the collection of data is very difficult due to reticent subjects and can be biased by many variables, including physical exercise, that alter the reward system. Moreover, it has been reported that AAS may imbalance neurotransmitter systems involved in reward process, leading to an increased sensitivity toward opioid narcotics and central stimulants. The aim of this review is to discuss what is present in literature in regard to steroid abuse and alteration of reward system in preclinical and clinical studies.

  15. Cardiovascular risk factors and events in women with androgen excess.

    Science.gov (United States)

    Macut, D; Antić, I B; Bjekić-Macut, J

    2015-03-01

    Androgen excess (AE) was approximated to be present in 7% of the adult population of women. Polycystic ovary syndrome (PCOS) is the most prevalent among them, followed by idiopathic hirsutism (IH), congenital adrenal hyperplasia (CAH), hyperandrogenic insulin-resistant acanthosis nigricans (HAIRAN) syndrome, and androgen-secreting neoplasms (ASNs). Increased cardiovascular risk was implicated in women with AE. Serum testosterone independently increases risk for cardiovascular disease (CVD), and correlates even with indices of subclinical atherosclerosis in various populations of postmenopausal women. Hyperandrogenism in PCOS is closely related to the aggravation of abdominal obesity, and together with insulin resistance forming the metabolic core for the development of CVD. However, phenotypic variability of PCOS generates significant influence on the cardiometabolic risks. Numerous risk factors in PCOS lead to 5-7 times higher risk for CVD and over 2-fold higher risk for coronary heart disease and stroke. However, issue on the cardiometabolic risk in postmenopausal women with hyperandrogenic history is still challenging. There is a significant overlapping in the CVD characteristics of women with PCOS and variants of CAH. Relevant clinical data on the prevalence and cardiometabolic risk and events in women with IH, HAIRAN syndrome or ASNs are scarce. The effects of various oral contraceptives (OCs) and antiandrogenic compounds on metabolic profile are varying, and could be related to the selected populations and different therapy regiments mainly conducted in women with PCOS. It is assumed relation of OCs containing antiandrogenic progestins to the increased risk of cardiovascular and thromboembolic events.

  16. Anabolic-androgenic steroids for alcoholic liver disease

    DEFF Research Database (Denmark)

    Rambaldi, Andrea; Iaquinto, Gaetano; Gluud, Christian

    2002-01-01

    The objectives were to assess the beneficial and harmful effects of anabolic-androgenic steroids for alcoholic liver disease.......The objectives were to assess the beneficial and harmful effects of anabolic-androgenic steroids for alcoholic liver disease....

  17. Longitudinal Magnetic Resonance Imaging-Based Assessment of Vascular Changes and Radiation Response in Androgen-Sensitive Prostate Carcinoma Xenografts under Androgen-Exposed and Androgen-Deprived Conditions

    Directory of Open Access Journals (Sweden)

    Kathrine Røe

    2010-10-01

    Full Text Available Prostate cancer (PCa patients receive androgen-deprivation therapy (ADT to reduce tumor burden. However, complete eradication of PCa is unusual, and recurrent disease is evident within approximately 2 years in high-risk patients. Clinical evidence suggests that combining ADT with radiotherapy improves local control and disease-free survival in these patients compared with radiotherapy alone. We investigated whether vascularization of androgen-sensitive PCa xenografts changed after ADT and whether such therapy affected radiation response. CWR22 xenografts received combinations of ADT by castration (CWR22-cas and 15 Gy of single-dose irradiation. At a shortest tumor diameter of 8 mm, vascularization was visualized by dynamic contrast-enhanced magnetic resonance imaging before radiation and 1 and 9 days after radiation. Voxel-wise quantitative modeling of contrast enhancement curves extracted the hemodynamic parameter Ktrans, reflecting a combination of permeability, density, and blood flow. Tumor volumes and prostate-specific antigen (PSA were monitored during the experiment. The results showed that Ktrans of CWR22-cas tumors 36±4 days after ADT was 47.1% higher than Ktrans of CWR22 tumors (P = .01. CWR22-cas tumors showed no significant changes in Ktrans after radiation, whereas Ktrans of CWR22 tumors at day 1 decreased compared with pretreatment values (P = .04 before a continuous increase from day 1 to day 9 followed (P = .01. Total PSA in blood correlated positively to tumor volume (r = 0.59, P < .01. In conclusion, androgen-exposed xenografts demonstrated radiation-induced reductions in vascularization and tumor volumes, whereas androgen-deprived xenografts showed increased vascularization and growth inhibition, but no significant additive effect of radiation.

  18. BAY 1024767 blocks androgen receptor mutants found in castration-resistant prostate cancer patients.

    Science.gov (United States)

    Sugawara, Tatsuo; Lejeune, Pascale; Köhr, Silke; Neuhaus, Roland; Faus, Hortensia; Gelato, Kathy A; Busemann, Matthias; Cleve, Arwed; Lücking, Ulrich; von Nussbaum, Franz; Brands, Michael; Mumberg, Dominik; Jung, Klaus; Stephan, Carsten; Haendler, Bernard

    2016-02-01

    Androgen receptor (AR) mutations arise in patients developing resistance to hormone deprivation therapies. Here we describe BAY 1024767, a thiohydantoin derivative with strong antagonistic activity against nine AR variants with mutations located in the AR ligand-binding domain (LBD), and against wild-type AR. Antagonism was maintained, though reduced, at increased androgen levels. Anti-tumor efficacy was evidenced in vivo in the KuCaP-1 prostate cancer model which bears the W741C bicalutamide resistance mutation and in the syngeneic prostate cancer rat model Dunning R3327-G. The prevalence of six selected AR mutations was determined in plasma DNA originating from 100 resistant patients and found to be at least 12%. Altogether the results show BAY 1024767 to be a strong antagonist for several AR mutants linked to therapy resistance, which opens the door for next-generation compounds that can benefit patients based on their mutation profile.

  19. Selective androgen receptor modulators for the treatment of late onset male hypogonadism.

    Science.gov (United States)

    Coss, Christopher C; Jones, Amanda; Hancock, Michael L; Steiner, Mitchell S; Dalton, James T

    2014-01-01

    Several testosterone preparations are used in the treatment of hypogonadism in the ageing male. These therapies differ in their convenience, flexibility, regional availability and expense but share their pharmacokinetic basis of approval and dearth of long-term safety data. The brevity and relatively reduced cost of pharmacokinetic based registration trials provides little commercial incentive to develop improved novel therapies for the treatment of late onset male hypogonadism. Selective androgen receptor modulators (SARMs) have been shown to provide anabolic benefit in the absence of androgenic effects on prostate, hair and skin. Current clinical development for SARMs is focused on acute muscle wasting conditions with defi ned clinical endpoints of physical function and lean body mass. Similar regulatory clarity concerning clinical deficits in men with hypogonadism is required before the beneficial pharmacology and desirable pharmacokinetics of SARMs can be employed in the treatment of late onset male hypogonadism.

  20. Selective androgen receptor modulators for the treatment of late onset male hypogonadism

    Directory of Open Access Journals (Sweden)

    Christopher C Coss

    2014-04-01

    Full Text Available Several testosterone preparations are used in the treatment of hypogonadism in the ageing male. These therapies differ in their convenience, flexibility, regional availability and expense but share their pharmacokinetic basis of approval and dearth of long-term safety data. The brevity and relatively reduced cost of pharmacokinetic based registration trials provides little commercial incentive to develop improved novel therapies for the treatment of late onset male hypogonadism. Selective androgen receptor modulators (SARMs have been shown to provide anabolic benefit in the absence of androgenic effects on prostate, hair and skin. Current clinical development for SARMs is focused on acute muscle wasting conditions with defi ned clinical endpoints of physical function and lean body mass. Similar regulatory clarity concerning clinical deficits in men with hypogonadism is required before the beneficial pharmacology and desirable pharmacokinetics of SARMs can be employed in the treatment of late onset male hypogonadism.

  1. Prostate cancer characteristics associated with response to pre-receptor targeting of the androgen axis.

    Directory of Open Access Journals (Sweden)

    Elahe A Mostaghel

    Full Text Available Factors influencing differential responses of prostate tumors to androgen receptor (AR axis-directed therapeutics are poorly understood, and predictors of treatment efficacy are needed. We hypothesized that the efficacy of inhibiting DHT ligand synthesis would associate with intra-tumoral androgen ratios indicative of relative dependence on DHT-mediated growth.We characterized two androgen-sensitive prostate cancer xenograft models after androgen suppression by castration in combination with the SRD5A inhibitor, dutasteride, as well as a panel of castration resistant metastases obtained via rapid autopsy.In LuCaP35 tumors (intra-tumoral T:DHT ratio 2:1 dutasteride suppressed DHT to 0.02 ng/gm and prolonged survival vs. castration alone (337 vs.152 days, HR 2.8, p = 0.0015. In LuCaP96 tumors (T:DHT 10:1, survival was not improved despite similar DHT reduction (0.02 ng/gm. LuCaP35 demonstrated higher expression of steroid biosynthetic enzymes maintaining DHT levels (5-fold higher SRD5A1, 41 fold higher, 99-fold higher RL-HSD, p<0.0001 for both, reconstitution of intra-tumoral DHT (to ∼30% of untreated tumors, and ∼2 fold increased expression of full length AR. In contrast, LuCaP96 demonstrated higher levels of steroid catabolizing enzymes (6.9-fold higher AKR1C2, 3000-fold higher UGT2B15, p = 0.002 and p<0.0001 respectively, persistent suppression of intra-tumoral DHT, and 6-8 fold induction of full length AR and the ligand independent V7 AR splice variant. Human metastases demonstrated bio-active androgen levels and AR full length and AR splice-variant expression consistent with the range observed in xenografts.Intrinsic differences in basal steroidogenesis, as well as variable expression of full length and splice-variant AR, associate with response and resistance to pre-receptor AR ligand suppression. Expression of steroidogenic enzymes and AR isoforms may serve as potential biomarkers of sensitivity to potent AR-axis inhibition and

  2. Androgen circle of polycystic ovary syndrome.

    Science.gov (United States)

    Homburg, Roy

    2009-07-01

    Although the aetiology of polycystic ovary syndrome (PCOS) is still not known and the search for causative genes is proving elusive, it is generally agreed that hyperandrogenism is at the heart of the syndrome. Here, it is proposed that excess androgens are the root cause of PCOS starting from their influence on the female fetus in programming gene expression, producing the characteristic signs and symptoms which are then exacerbated by a propagation of excess ovarian androgen production from multiple small follicles, anovulation and insulin resistance in the reproductive life-span, thus setting up a vicious perpetual circle of androgen excess. This opinion paper, rather than being a full-scale review, is intentionally biased in support of this hypothesis that androgen excess is the 'root of all evil' in PCOS; in the hope that its acceptance could lead to more direct treatment of the syndrome in all its facets rather than the symptomatic treatment of side effects of androgen excess that we are addressing today.

  3. Eurycoma longifolia: Medicinal Plant in the Prevention and Treatment of Male Osteoporosis due to Androgen Deficiency

    OpenAIRE

    2012-01-01

    Osteoporosis in elderly men is now becoming an alarming health issue due to its relation with a higher mortality rate compared to osteoporosis in women. Androgen deficiency (hypogonadism) is one of the major factors of male osteoporosis and it can be treated with testosterone replacement therapy (TRT). However, one medicinal plant, Eurycoma longifolia Jack (EL), can be used as an alternative treatment to prevent and treat male osteoporosis without causing the side effects associated with TRT....

  4. Computational Investigation on the Allosteric Modulation of Androgen Receptor

    Institute of Scientific and Technical Information of China (English)

    OU Min-Rui; LI Jun-Qian

    2012-01-01

    Androgens have similar structures with different biological activities. To identify molecular determinants responsible for the activity difference, we have docked six steroidal androgens to the binding site or the surface of androgen receptor by using molecular docking with computational investigation. The energy was calculated respectively based on the QM (quantum mechanics) and MM (molecular mechanics) methods. The result shows that the allosteric modulation of androgen receptor plays an important role in the binding process between androgens and receptor. The open state receptor is less stable than the close state one, but the latter is more favorable for binding with androgens. It is worthy of note that when the androgen receptors binding or without binding with androgen are in close state, they are difficult to return to their open state. This phenomenon is an exception of the well known two-state model theory in which the two states are reversible. Whether the internal of close state androgen receptor has a combination of androgen or not, the androgen receptor surface can be combined with another androgen, and their surface binding energies could be very close. The result is consistent with the experimental observations, but this phenomenon of continuous combination from open state is also an exception of the two-state model theory.

  5. The transcriptional programme of the androgen receptor (AR) in prostate cancer.

    Science.gov (United States)

    Lamb, Alastair D; Massie, Charlie E; Neal, David E

    2014-03-01

    The androgen receptor (AR) is essential for normal prostate and prostate cancer cell growth. AR transcriptional activity is almost always maintained even in hormone relapsed prostate cancer (HRPC) in the absence of normal levels of circulating testosterone. Current molecular techniques, such as chromatin-immunoprecipitation sequencing (ChIP-seq), have permitted identification of direct AR-binding sites in cell lines and human tissue with a distinct coordinate network evident in HRPC. The effectiveness of novel agents, such as abiraterone acetate (suppresses adrenal androgens) or enzalutamide (MDV3100, potent AR antagonist), in treating advanced prostate cancer underlines the on-going critical role of the AR throughout all stages of the disease. Persistent AR activity in advanced disease regulates cell cycle activity, steroid biosynthesis and anabolic metabolism in conjunction with regulatory co-factors, such as the E2F family, c-Myc and signal transducer and activator of transcription (STAT) transcription factors. Further treatment approaches must target these other factors.

  6. Diferentes respuestas somáticas y densitométricas sobre el hueso cortical y trabecular a la androgenoterapia en varones hipogonádicos Different somatic and densitometric responses of cortical and trabecular bone to androgen therapy in hypogonadal men

    Directory of Open Access Journals (Sweden)

    S. Aszpis

    2007-12-01

    Full Text Available Una consecuencia clínica de la deficiencia de testosterona en el varón es el descenso de la densidad mineral ósea (DMO, asociado a mayor riesgo de fractura (con la consiguiente morbi-mortalidad en el hombre añoso, y cambios de la composición y el contenido de calcio corporal total. Para cuantificar los efectos de la androgenoterapia sobre la composición corporal y el contenido de calcio corporal, correlacionar los cambios hormonales con los densitométricos y de la composición corporal, y constatar posibles diferencias densitométricas regionales, se incluyeron 15 varones hipogonádicos. Se determinaron variables antropométricas, bioquímicas, densitométricas y de la composición corporal en condiciones basales y bajo la terapia sustitutiva. Como resultado, se logró compensar el déficit androgénico y duplicar la concentración de estradiol. El eugonadismo inducido incrementó la DMO como el contenido del calcio corporal total. Además, redujo el porcentaje de masa grasa corporal total (principalmente abdominal y aumentó la masa muscular corporal total, con incremento de la relación masa magra/masa grasa, sin cambios del índice de masa corporal. En conclusión, nuestros resultados afirman el papel preponderante de los esteroides sexuales sobre la composición corporal y su rol en el hueso. El hipogonadismo masculino constituye un factor de riesgo para osteoporosis y enfermedad cardiovascular.A clinical consequence of testosterone deficiency in males is the reduction of bone mineral density (BMD, associated with a higher risk of fracture (and a subsequent increase in morbi-mortality in elderly men and with changes in body composition and total body calcium content. In order to quantify the effects of androgen therapy on body composition and body calcium content, and to correlate changes in hormone levels with densitometric changes and changes in body composition changes, as well as to determine potential regional densitometric

  7. Relationships between androgens, serotonin gene expression and innervation in male macaques.

    Science.gov (United States)

    Bethea, C L; Coleman, K; Phu, K; Reddy, A P; Phu, A

    2014-08-22

    Androgen administration to castrated individuals was purported to decrease activity in the serotonin system. However, we found that androgen administration to castrated male macaques increased fenfluramine-induced serotonin release as reflected by increased prolactin secretion. In this study, we sought to define the effects of androgens and aromatase inhibition on serotonin-related gene expression in the dorsal raphe, as well as serotonergic innervation of the LC. Male Japanese macaques (Macaca fuscata) were castrated for 5-7 months and then treated for 3 months with (1) placebo, (2) testosterone (T), (3) dihydrotestosterone (DHT; non-aromatizable androgen) and ATD (steroidal aromatase inhibitor), or (4) Flutamide (FLUT; androgen antagonist) and ATD (n=5/group). This study reports the expression of serotonin-related genes: tryptophan hydroxylase 2 (TPH2), serotonin reuptake transporter (SERT) and the serotonin 1A autoreceptor (5HT1A) using digoxigenin-ISH and image analysis. To examine the production of serotonin and the serotonergic innervation of a target area underlying arousal and vigilance, we measured the serotonin axon density entering the LC with ICC and image analysis. TPH2 and SERT expression were significantly elevated in T- and DHT + ATD-treated groups over placebo- and FLUT + ATD-treated groups in the dorsal raphe (p expression between the groups. There was a significant decrease in the pixel area of serotonin axons and in the number of varicosities in the LC across the treatment groups with T > placebo > DHT + ATD = FLUT + ATD treatments. Comparatively, T- and DHT + ATD-treated groups had elevated TPH2 and SERT gene expression, but the DHT + ATD group had markedly suppressed serotonin axon density relative to the T-treated group. Further comparison with previously published data indicated that TPH2 and SERT expression reflected yawning and basal prolactin secretion. The serotonin axon density in the LC agreed with the area under the fenfluramine

  8. Using Anabolic Androgenic Steroids in Sport

    Directory of Open Access Journals (Sweden)

    Sefa Lök

    2010-12-01

    Full Text Available It is known that sportsmen especially youngers who engaged in athletism, weight lifting and body building sport have beenusing ‘‘Anabolic Androgenic Steroid’’ (AAS intensively for purpose of doping during world sport history. Used dopingsubstances to increase sport performance differ from sport branches. In some sport branches, it is used to diminish neuralstress while in other sport branches it is used to increase force, endurance and resistance against exhaustion. Today amongsportsmen using ergogenic substances to increase rivalry and physical performance for purpose of doping are increased. Inthis study using anabolic androgenic steroids in sports will be assessed.

  9. Challenges in the sequencing of therapies for the management of metastatic castration-resistant prostate cancer.

    Science.gov (United States)

    Parente, Phillip; Parnis, Francis; Gurney, Howard

    2014-09-01

    Prior to 2010, docetaxel was the standard option for chemotherapy in men with metastatic castration-resistant prostate cancer (mCRPC). Today, the picture is vastly different: several additional therapies have each demonstrated a survival benefit such that we now have chemotherapy (cabazitaxel), androgen suppressive agents (abiraterone acetate and enzalutamide), a cellular vaccine (sipuleucel-T) and radium-233 (for symptomatic bone metastases). With several other agents in the pipeline for late-stage disease, the future looks promising for mCRPC. As the available data are not able to inform as to the optimum sequencing of therapy, this remains a challenge. This paper draws on insights from published and ongoing clinical studies to provide a practical patient-focused approach to maximize the benefits of the current therapeutic armamentarium. Preliminary sequencing suggestions are made based on clinical trial criteria. But until more data become available, clinical gestalt, experience, cost and individual patient preferences will continue to drive choices.

  10. Selective androgen receptor modulator RAD140 is neuroprotective in cultured neurons and kainate-lesioned male rats.

    Science.gov (United States)

    Jayaraman, Anusha; Christensen, Amy; Moser, V Alexandra; Vest, Rebekah S; Miller, Chris P; Hattersley, Gary; Pike, Christian J

    2014-04-01

    The decline in testosterone levels in men during normal aging increases risks of dysfunction and disease in androgen-responsive tissues, including brain. The use of testosterone therapy has the potential to increase the risks for developing prostate cancer and or accelerating its progression. To overcome this limitation, novel compounds termed "selective androgen receptor modulators" (SARMs) have been developed that lack significant androgen action in prostate but exert agonist effects in select androgen-responsive tissues. The efficacy of SARMs in brain is largely unknown. In this study, we investigate the SARM RAD140 in cultured rat neurons and male rat brain for its ability to provide neuroprotection, an important neural action of endogenous androgens that is relevant to neural health and resilience to neurodegenerative diseases. In cultured hippocampal neurons, RAD140 was as effective as testosterone in reducing cell death induced by apoptotic insults. Mechanistically, RAD140 neuroprotection was dependent upon MAPK signaling, as evidenced by elevation of ERK phosphorylation and inhibition of protection by the MAPK kinase inhibitor U0126. Importantly, RAD140 was also neuroprotective in vivo using the rat kainate lesion model. In experiments with gonadectomized, adult male rats, RAD140 was shown to exhibit peripheral tissue-specific androgen action that largely spared prostate, neural efficacy as demonstrated by activation of androgenic gene regulation effects, and neuroprotection of hippocampal neurons against cell death caused by systemic administration of the excitotoxin kainate. These novel findings demonstrate initial preclinical efficacy of a SARM in neuroprotective actions relevant to Alzheimer's disease and related neurodegenerative diseases.

  11. Analysis of cognitive function and its influenced factors in patients with prostate cancer after maximal androgen blockade therapy%最大限度雄激素阻断治疗后前列腺癌患者的认知功能状况及其影响因素分析

    Institute of Scientific and Technical Information of China (English)

    吴楠; 曾胜; 马宇坤; 徐勇; 马志方

    2016-01-01

    patients with prostate cancer after maximal androgen blockade therapy and its influenced factors,and to provide a new way for early prevention strategy.Methods Montreal cognitive assessment (MoCA),hospital anxiety depression scale (HAD),social support rating scale (SSRS) and self-designed questionnaire were used in 56 cases treated with maximum androgen blockade therapy for more than six months and 37 cases who underwent radical prostatectomy treatment to evaluate their cognitive function and collect the observation indexes between January 2013 and October 2015.Based on MoCA score,all patients were divided into cognitive dysfunction group (n =40) and normal cognitive function group (n =53).The observation indexes in two groups were compared and cognitive function with different treatment in two groups were analyzed.The changes on the influencing factors of cognitive function in patients were filtered using multivariable logistic regression analysis.Results In the cognitive dysfunction group and normal group,the proportion of MAB treatment was 80.0% (32/40) vs.45.3% (24/53),the age was 73.7 vs.73.7 years,the proportion of solitary was 32.5% (13/40) vs.13.2% (7/53),the proportion of depressive symptoms was 87.5% (35/40) vs.62.3% (33/53),the social support level was 32.5 vs.41.1 and the proportion of testosterone decreased was 95.0% (38/40) vs.45.3% (24/53).All events showed statistically significant differences (P <0.05).Compared MAB treatment group with radical surgical treatment group,the testosterone level was (0.27-±O.15) vs.(12.14 ± 1.86) nmol/L,visual space and executive function score was 4.18 ±0.79 vs.4.54 ±0.56,attention score was 4.73 ±0.99 vs.5.16 ±0.79,delayed memory score was 3.75 ± 1.21 vs.4.30 ± 1.05 and MoCA score was 26.13 ± 1.48 vs.27.27 ± 1.39,which all showed the statistically significant difference (P < 0.05).The results of multiple regression analysis showed that age (OR =1.183,95% CI 1.135-1.223),depressive symptoms (OR

  12. A novel mutation in the RYR2 gene leading to catecholaminergic polymorphic ventricular tachycardia and paroxysmal atrial fibrillation: dose-dependent arrhythmia-event suppression by β-blocker therapy.

    Science.gov (United States)

    Kazemian, Pedram; Gollob, Michael H; Pantano, Alfredo; Oudit, Gavin Y

    2011-01-01

    Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic condition that presents with exercise-induced polymorphic arrhythmias. We describe a case report of a 25-year-old woman who had a cardiac arrest due to ventricular fibrillation. Genetic analysis revealed a novel missense mutation in exon 90 of the ryanodine receptor (RyR2) gene resulting in substitution of arginine for serine at residue 4153 (S4153R). The patient received an implantable cardioverter-defibrillator and low-dose β-blocker therapy. She had recurrent polymorphic ventricular arrhythmias treated with appropriate cardioverter-defibrillator shocks and paroxysmal atrial fibrillation. Titration of β-blocker to a much higher dose suppressed further episodes of ventricular arrhythmia and paroxysmal atrial fibrillation, resulting in reduction in device therapies.

  13. Antioxidants Abrogate Alpha-Tocopherylquinone-Mediated Down-Regulation of the Androgen Receptor in Androgen-Responsive Prostate Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Alexandra M Fajardo

    Full Text Available Tocopherylquinone (TQ, the oxidation product of alpha-tocopherol (AT, is a bioactive molecule with distinct properties from AT. In this study, AT and TQ are investigated for their comparative effects on growth and androgenic activity in prostate cancer cells. TQ potently inhibited the growth of androgen-responsive prostate cancer cell lines (e.g., LAPC4 and LNCaP cells, whereas the growth of androgen-independent prostate cancer cells (e.g., DU145 cells was not affected by TQ. Due to the growth inhibitory effects induced by TQ on androgen-responsive cells, the anti-androgenic properties of TQ were examined. TQ inhibited the androgen-induced activation of an androgen-responsive reporter and inhibited the release of prostate specific antigen from LNCaP cells. TQ pretreatment was also found to inhibit AR activation as measured using the Multifunctional Androgen Receptor Screening assay. Furthermore, TQ decreased androgen-responsive gene expression, including TM4SF1, KLK2, and PSA over 5-fold, whereas AT did not affect the expression of androgen-responsive genes. Of importance, the antiandrogenic effects of TQ on prostate cancer cells were found to result from androgen receptor protein down-regulation produced by TQ that was not observed with AT treatment. Moreover, none of the androgenic endpoints assessed were affected by AT. The down-regulation of androgen receptor protein by TQ was abrogated by co-treatment with antioxidants. Overall, the biological actions of TQ were found to be distinct from AT, where TQ was found to be a potent inhibitor of cell growth and androgenic activity in androgen-responsive prostate cancer cells.

  14. Androgen receptor modulators: a marriage of chemistry and biology.

    Science.gov (United States)

    McEwan, Iain J

    2013-06-01

    Androgenic steroids are important for male development in utero and secondary sexual characteristics at puberty. In addition, androgens play a role in non-reproductive tissues, such as bone and muscle in both sexes. The actions of the androgens testosterone and dihydrotestosterone are mediated by a single receptor protein, the androgen receptor. Over the last 60-70 years there has been considerable research interest in the development of inhibitors of androgen receptor for the management of diseases such as prostate cancer. However, more recently, there is also a growing appreciation of the need for selective androgen modulators that would demonstrate tissue-selective agonist or antagonist activity. The chemistry and biology of selective agonists, antagonists and selective androgen receptor modulators will be discussed in this review.

  15. CD4 cell count and the risk of AIDS or death in HIV-Infected adults on combination antiretroviral therapy with a suppressed viral load: a longitudinal cohort study from COHERE.

    Directory of Open Access Journals (Sweden)

    Jim Young

    Full Text Available BACKGROUND: Most adults infected with HIV achieve viral suppression within a year of starting combination antiretroviral therapy (cART. It is important to understand the risk of AIDS events or death for patients with a suppressed viral load. METHODS AND FINDINGS: Using data from the Collaboration of Observational HIV Epidemiological Research Europe (2010 merger, we assessed the risk of a new AIDS-defining event or death in successfully treated patients. We accumulated episodes of viral suppression for each patient while on cART, each episode beginning with the second of two consecutive plasma viral load measurements 500 copies/µl, the first of two consecutive measurements between 50-500 copies/µl, cART interruption or administrative censoring. We used stratified multivariate Cox models to estimate the association between time updated CD4 cell co