The synthetic progestin norgestrel modulates Nrf2 signaling and acts as an antioxidant in a model of retinal degeneration

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Ashleigh M. Byrne

2016-12-01

Full Text Available Retinitis pigmentosa (RP is one of the most common retinal degenerative conditions affecting people worldwide, and is currently incurable. It is characterized by the progressive loss of photoreceptors, in which the death of rod cells leads to the secondary death of cone cells; the cause of eventual blindness. As rod cells die, retinal-oxygen metabolism becomes perturbed, leading to increased levels of reactive oxygen species (ROS and thus oxidative stress; a key factor in the secondary death of cones. In this study, norgestrel, an FDA-approved synthetic analog of progesterone, was found to be a powerful neuroprotective antioxidant, preventing light-induced ROS in photoreceptor cells, and subsequent cell death. Norgestrel also prevented light-induced photoreceptor morphological changes that were associated with ROS production, and that are characteristic of RP. Further investigation showed that norgestrel acts via post-translational modulation of the major antioxidant transcription factor Nrf2; bringing about its phosphorylation, subsequent nuclear translocation, and increased levels of its effector protein superoxide dismutase 2 (SOD2. In summary, these results demonstrate significant protection of photoreceptor cells from oxidative stress, and underscore the potential of norgestrel as a therapeutic option for RP.

Synthesis of [14α, 15α-3H]-norgestrel

International Nuclear Information System (INIS)

Wagner, H.

1988-01-01

The preparation of the well-known gestogen norgestrel in a tritium labelled form is described. Starting material was 18-methyl-3-methoxy-estra-1,3,5(10),8,14-pentaen-17β-o1 acetate. In a four step synthesis 17α-ethinyl-17β-hydroxy-18-methyl-[14α,15α- 3 H]-estr-4-en-3-one was obtained with a specific activity of 52 Ci/mmol and a radiochemical purity > 99%. (author)

Radioimmunoassay of serum d-Norgestrel in women following oral and intravaginal administration

International Nuclear Information System (INIS)

Stanczyk, F.Z.; Hiroi, M.; Goebelsmann, U.; Brenner, P.F.; Lumkin, M.E.; Mishell, D.R. Jr.

1975-01-01

A radioimmunoassay (RIA) method for measuring d-Norgestrel (d-Ng) in serum has been developed utilizing petroleum ether extraction, an antiserum raised against d-Norgestrel-3-(0-carboxymethyl) oxime-epsilon-aminocaproic acid--boxine serum albumin, d-Norgestrel-3-(0-carboxymethyl) imino-[ 125 I]-iodohistamine, and dextran-coated charcoal separation. Control serum blanks were undetectable, 6 pg of d-Ng was measurable in 0.1 ml of serum with a high reliability, and intra- and interassay coefficients of variation were 4.4 and 4.9 percent, respectively. d-Ng added to control serum was quantitatively recovered. This RIA proved to be highly specific for d-Ng, cross-reacting less than 0.01 percent with 1-Ng and some 4 to 8 percent with 5α- and 5β-tetrahydro-d-Ng. Serum d-Ng levels measured in 3 women after ingestion of 75 μg of dl-Ng rose to 1.5 to 2 ng/ml within 1/2 to 2-3 hours after oral intake and fell rapidly thereafter to 0.2 to 0.4 ng/ml within 24 hours. Insertion of Silastic intravaginal rings (IVRs), containing 50 or 100 mg of dl-Ng, into 3 women for periods of 3 weeks resulted in a rapid rise of serum d-Ng after insertion. Serum d-Ng levels were highest 24 to 48 hours after the first insertion of each IVR, reaching peak levels of about 5 and 7 to 11 ng/ml, respectively, and declined gradually during the ensuing 15 to 20 days to some 30 to 40 percent of the peak serum d-Ng concentration. Serum d-Ng levels attained after IVR reinsertion remained relatively constant at 1 to 3 ng/ml during each subsequent cycle in all subjects and fell rapidly after each IVR removal. Serum estradiol and progesterone concentrations, measured about 3 times a week in these patients, indicated that ovulation was consistently inhibited

Effects of d-norgestrel on lipid metabolism in the rat

Energy Technology Data Exchange (ETDEWEB)

Khokha, R.

1985-01-01

The effects of the progestin d-norgestrel (d-Ng) on lipid and lipoprotein metabolism and elucidate its mechanism of action using the rat as the experimental model were investigated. d-Ng fed to female rats (18 days) in conventional doses, significantly lowered the plasma total and very low density lipoprotein (VLDL)-triglycerides. In contrast, the plasma total and low density lipoprotein (LDL)-cholesterol rose significantly. The triglyceride synthesis was studied using isolated rate hepatocytes. d-Ng (0.1 mM), in the presence of 0.1% dimethylsulfoxide concentration of the medium, significantly inhibited the incorporation of both (9,10-/sup 3/H) palmitate and (U-/sup 14/C) glycerol into triglycerides synthesized and triglycerides released by the hepatocytes. The inhibition of triglyceride synthesis by d-Ng was dose-dependent. Further studies of the effect of d-Ng on the rate limiting enzymes of triglyceride synthesis showed a significant reduction in the specific activity of hepatic glycerol phosphate acyltransferase (GPAT) and phosphatidic acid aqueous dependent phosphatidic acid phosphatase (PAPase) specifically in the microsomes. However, the specific activity of mitochondrial GPAT and phosphatidic acid membrane bound dependent PAPase in microsomes as well as cytosol remained unchanged. These findings suggest that d-Ng acts by inhibiting specifically the hepatic lipogenic enzymes in the microsomes. This subsequently reduces the triglyceride synthesis and secretion by the liver resulting in lower plasma and VLDL triglycerides levels in d-Ng-treated rats.

The radioimmunoassay of biologically active compounds in parotid fluid and plasma

International Nuclear Information System (INIS)

Walker, R.F.; Read, G.F.; Riad-Fahmy, D.

1977-01-01

The potential value of parotid fluid estimations of clomipramine, d-norgestrel, and cortisol have been evaluated for assessment of clinical status and patient compliance. Excellent agreement (r > 0.9) was observed when parotid fluid samples were assayed with and without chromatographic purification. Clomipramine levels following oral dosage (150mg) rose steadily to a maximum in plasma but showed wide fluctuations in parotid fluid. Following an oral dose of d-norgestrel(0.3mg), parotid fluid levels rose steadily to a maximum but plasma response was biphasic making correlation impossible. The sensitivity and high throughput of the d-norgestrel methodology suggests its use in evaluating patient compliance in large scale fertility control programmes. Changes in circulating cortisol concentrations were rapidly and accurately reflected in parotid fluid in normal volunteers. Parotid fluid cortisol showed a market diurnal rythm, suppression to low levels after dexamethasone, and elevation following Synacthen. Low levels after Synacthen stimulation in a patient with secondary adrenal atrophy and constant high levels in Cushingoid patients indicate that parotid fluid cortisol levels could be used for accurate adrenocortical evaluation. The value in rapid screening procedures is stressed since the assay can be performed directly on only 10μl of parotid fluid. (orig./AJ) [de

Individual levels of plasma alpha 2-antiplasmin and alpha 2-macroglobulin during the normal menstrual cycle and in women on oral contraceptives low in oestrogen

DEFF Research Database (Denmark)

Jespersen, J; Sidelmann, Johannes Jakobsen

1983-01-01

Determinations of alpha 2-antiplasmin and alpha 2-macroglobulin were made in plasma samples collected during one normal or hormone induced cycle in 15 normal women and 11 women using oral contraceptives containing 30 micrograms ethinyl oestradiol and 150 micrograms levo-norgestrel. The immediate ...

The radioimmunoassay of biologically active compounds in parotid fluid and plasma

International Nuclear Information System (INIS)

Walker, R.F.; Read, G.F.; Riad-Fahmy, D.

1978-01-01

Parotid fluid collection is a simple stress-free procedure. The potential value of parotid fluid estimations of clomipramine, a tricyclic antidepressant, d-norgestrel, a synthetic contraceptive steroid and cortisol have been evaluated for assessment of clinical status and patient compliance. These compounds circulate bound largely to plasma proteins. Their concentration in parotid fluid, which reflects the non-protein bound fraction, is low but assay sensitivity (10, 1 and 30 pg/tube respectively) is adequate. Excellent agreement (r>0.9) was observed when parotid fluid samples were assayed with and without chromatographic purification. Clomipramine levels following oral dosage (150 mg) rose steadily to a maximum in plasma but showed wide fluctuations in parotid fluid. Clomipramine therapy can only be assessed by plasma assays, but patient compliance may be checked by parotid fluid concentrations. Following an oral dose of d-norgestrel (0.3 mg), parotid fluid levels rose steadily to a maximum but plasma response was biphasic making correlation impossible. The sensitivity and high throughput of the d-norgestrel methodology suggests its use in evaluating patient compliance in large-scale fertility control programmes. Changes in circulating cortisol concentrations were rapidly and accurately reflected in parotid fluid in normal volunteers. Parotid fluid cortisol showed a marked diurnal rhythm, suppression to low levels after dexamethasone, and elevation following Synacthen. Low levels after Synacthen stimulation in a patient with secondary adrenal atrophy and constant high levels in Cushingoid patients indicate that parotid fluid cortisol levels could be used for accurate adrenocortical evaluation. The value in rapid screening procedures is stressed since the assay can be performed directly on only 10 μl of parotid fluid. (author)

Analysis of sex hormones in groundwater using electron impact ionization

International Nuclear Information System (INIS)

Gonschorowski, Graciele Pereira da Cruz; Gonschorowski, Juliano dos Santos; Shihomatsu, Helena M.; Bustillos, Jose Oscar Vega; Limeira, Larissa

2013-01-01

A wide range of estrogenic contaminants has been detected in the aquatic environment, both in natural and synthetic forms. Steroid hormones are endocrine-disrupting compounds, which affect the endocrine system at very low concentrations. This work presents the development of an analytical procedure for the determination of five sexual steroid hormones, 17β-estradiol, estrone, progesterone, and the synthetics contraceptives, 17α-ethynylestradiol and norgestrel in groundwater from Sao Paulo University campus, specifically at Institute of Energy and Nuclear Research (IPEN). The analytical procedure starting with the sample pre-treatment, where the samples were first filtered and then extracted through solid-phase extraction, using Strata-X cartridges, and ending with detection. The separation method used was gas chromatography (GC), and the detection method was mass spectrometry (MS). The ion source used was electron impact ionization which produced an electron beam generated by an incandescent tungsten/thorium filament, which collide with molecules of gas sample. This interaction between the electrons and molecules, produce ions of the sample. The detection limits 0.06μg.L -1 for estrone, 0.13 μg. L -1 for 17β-estradiol, 0.13 μg.L -1 for 17α-ethynylestradiol, 0.49 μg.L -1 for norgestrel and 0.02 μg.L -1 for progesterone were detected in assays matrix. Validating tests were also used in this work. (author)

Analysis of sex hormones in groundwater using electron impact ionization

Energy Technology Data Exchange (ETDEWEB)

Gonschorowski, Graciele Pereira da Cruz, E-mail: graci_ju@yahoo.com.br [Universidade Estadual do Centro-Oeste (UNICENTRO), Guarapuava, PR (Brazil); Gonschorowski, Juliano dos Santos, E-mail: jgsantosbr@yahoo.com.br [Universidade Federal Tecnologica do Parana (UTFPR), Guarapuava, PR (Brazil); Shihomatsu, Helena M.; Bustillos, Jose Oscar Vega, E-mail: hmatsu@ipen.br, E-mail: ovega@ipen.br [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil); Limeira, Larissa, E-mail: larissa.limeira07@gmail.com [Centro Universitario FIEO (UNIFIEO), Sao Paulo, SP (Brazil)

2013-07-01

A wide range of estrogenic contaminants has been detected in the aquatic environment, both in natural and synthetic forms. Steroid hormones are endocrine-disrupting compounds, which affect the endocrine system at very low concentrations. This work presents the development of an analytical procedure for the determination of five sexual steroid hormones, 17β-estradiol, estrone, progesterone, and the synthetics contraceptives, 17α-ethynylestradiol and norgestrel in groundwater from Sao Paulo University campus, specifically at Institute of Energy and Nuclear Research (IPEN). The analytical procedure starting with the sample pre-treatment, where the samples were first filtered and then extracted through solid-phase extraction, using Strata-X cartridges, and ending with detection. The separation method used was gas chromatography (GC), and the detection method was mass spectrometry (MS). The ion source used was electron impact ionization which produced an electron beam generated by an incandescent tungsten/thorium filament, which collide with molecules of gas sample. This interaction between the electrons and molecules, produce ions of the sample. The detection limits 0.06μg.L{sup -1} for estrone, 0.13 μg. L{sup -1} for 17β-estradiol, 0.13 μg.L{sup -1} for 17α-ethynylestradiol, 0.49 μg.L{sup -1} for norgestrel and 0.02 μg.L{sup -1} for progesterone were detected in assays matrix. Validating tests were also used in this work. (author)

Sometimes You Do Get a Second Chance: Emergency Contraception for Adolescents.

Science.gov (United States)

Rome, Ellen S; Issac, Veronica

2017-04-01

Unplanned or unintended pregnancy remains a significant challenge for adolescents; many teens who plan ahead but opt not to choose long-acting reversible contraceptive methods have high failure rates with condom usage, oral contraceptives, and other less long-acting methods. Emergency contraception (EC) remains a necessity for those adolescents seeking a second chance to prevent the unintended consequences of unplanned sexual activity. At present, 5 postcoital methods remain available as EC globally: intrauterine devices, ulipristal acetate, a selective progesterone modulator, mifepristone; levonorgestrel, and ethinyl estradiol plus levonorgestrel or norgestrel (rarely used now that progestin only methods are more readily available). Copyright © 2017 Elsevier Inc. All rights reserved.

Sex hormone studies by radioimmunoassay in pregnant and non-pregnant women and in women treated with hormonal contraceptives

International Nuclear Information System (INIS)

Tafurt, C.A.

1980-12-01

Blood concentration profiles for follicle-stimulating hormone, luteinizing hormone, chorionic gonadotropin, testosterone, estradiol, estriol, progesterone, cortisol and sex hormonebinding globulin throughout a menstrual cycle were derived from measurements by radioimmunoassay and related procedures on serial blood samples from 16 normal women as controls. Similar studies were then performed on 9 normal women receiving a low-dose oral contraceptive combination of D-norgestrel and ethynlestradiol. Further studies were performed on 9 out of 16 normal women in whom progestational contraception was carried out with orally administered lynestrenol or intramuscularly administered norethindrone enathate and on 12 normal pregnant women from the 28th to the 38th week of pregnancy. Additional studies embracing chorionic gonadotropin progesterone and 17-hydroxyprogesterone were performed on 10 normal pregnant women from the 6th to the 12th week of pregnancy. Detailed results are presented and their significance discussed

Simultaneous Determination of Hormonal Residues in Treated Waters Using Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectrometry

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Rayco Guedes-Alonso

2013-01-01

Full Text Available In the last years, hormone consumption has increased exponentially. Because of that, hormone compounds are considered emerging pollutants since several studies have determinted their presence in water influents and effluents of wastewater treatment plants (WWTPs. In this study, a quantitative method for the simultaneous determination of oestrogens (estrone, 17β-estradiol, estriol, 17α-ethinylestradiol, and diethylstilbestrol, androgens (testosterone, and progestogens (norgestrel and megestrol acetate has been developed to determine these compounds in wastewater samples. Due to the very low concentrations of target compounds in the environment, a solid phase extraction procedure has been optimized and developed to extract and preconcentrate the analytes. Determination and quantification were performed by ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS. The method developed presents satisfactory limits of detection (between 0.15 and 9.35 ng·L−1, good recoveries (between 73 and 90% for the most of compounds, and low relative standard deviations (under 8.4%. Samples from influents and effluents of two wastewater treatment plants of Gran Canaria (Spain were analyzed using the proposed method, finding several hormones with concentrations ranged from 5 to 300 ng·L−1.

A positive feedback loop between progesterone and microsomal prostaglandin E synthase-1-mediated PGE2 promotes production of both in mouse granulosa cells.

Science.gov (United States)

Tamura, Kazuhiro; Naraba, Hiroaki; Hara, Takahiko; Nakamura, Kota; Yoshie, Mikihiro; Kogo, Hiroshi; Tachikawa, Eiichi

2016-03-01

Microsomal prostaglandin E synthase-1 (mPGES-1) is primarily expressed in granulosa cells (GCs) in the preovulatory follicle. Both prostaglandin E2 (PGE2) and progesterone (P4) are implicated in various reproductive functions. Here, we demonstrate that mPges-1 may be a direct downstream target gene of the P4 receptor and P4-stimulated PGE2 secretion can stimulate P4 production in a newly generated mouse GC line (GtsT). Treatment of GtsT cells with a P4 receptor agonist, norgestrel, markedly increased mPGES-1 expression detected by RT-PCR analysis. PGE2 secretion measured by an enzyme-linked immunosorbent assay was enhanced by P4 treatment. Luciferase assays revealed that the proximal promoter region of the mPges-1 gene was responsible for the effects of P4 treatment. Conversely, PGE2 treatment stimulated P4 secretion, which coordinated with mRNA expression of steroidogenic acute regulatory protein. Taken together, P4 may regulate mPGES-1 expression to increase PGE2 secretion and in turn P4 production. An autocrine loop between P4 and PGE2 might function to maintain the increased levels of both in GCs. Copyright © 2016 Elsevier Inc. All rights reserved.

Ultrasound assisted destruction of estrogen hormones in aqueous solution: Effect of power density, power intensity and reactor configuration

International Nuclear Information System (INIS)

Suri, Rominder P.S.; Nayak, Mohan; Devaiah, Uthappa; Helmig, Edward

2007-01-01

There are many reports documenting the adverse effects, such as feminization of fish, of estrogen hormones in the environment. One of the major sources of these compounds is from municipal wastewater effluents. The biological processes at municipal wastewater treatment plants cannot completely remove these compounds. This paper discusses the use of ultrasound to destroy estrogen compounds in water. The study examines the effect of ultrasound power density and power intensity on the destruction of various estrogen compounds which include: 17α-estradiol, 17β-estradiol, estrone, estriol, equilin, 17α-dihydroequilin, 17α-ethinyl estradiol and norgestrel. These tests were conducted in single component batch and flow through reactors using 0.6, 2 and 4 kW ultrasound sources. The sonolysis process produced 80-90% destruction of individual estrogens at initial concentration of 10 μg/L within 40-60 min of contact time. First order rate constants for the individual compounds under different conditions are presented. The estrogen degradation rates increase with increase in power intensity. However, the energy efficiency of the reactor was higher at lower power density. The 4 kW ultrasound reactor was more energy efficient compared to the 0.6 and 2 kW sonicators

Luteal blood flow in patients undergoing GnRH agonist long protocol

Directory of Open Access Journals (Sweden)

Takasaki Akihisa

2011-01-01

Full Text Available Abstract Background Blood flow in the corpus luteum (CL is closely related to luteal function. It is unclear how luteal blood flow is regulated. Standardized ovarian-stimulation protocol with a gonadotropin-releasing hormone agonist (GnRHa long protocol causes luteal phase defect because it drastically suppresses serum LH levels. Examining luteal blood flow in the patient undergoing GnRHa long protocol may be useful to know whether luteal blood flow is regulated by LH. Methods Twenty-four infertile women undergoing GnRHa long protocol were divided into 3 groups dependent on luteal supports; 9 women were given ethinylestradiol plus norgestrel (Planovar orally throughout the luteal phase (control group; 8 women were given HCG 2,000 IU on days 2 and 4 day after ovulation induction in addition to Planovar (HCG group; 7 women were given vitamin E (600 mg/day orally throughout the luteal phase in addition to Planovar (vitamin E group. Blood flow impedance was measured in each CL during the mid-luteal phase by transvaginal color-pulsed-Doppler-ultrasonography and was expressed as a CL-resistance index (CL-RI. Results Serum LH levels were remarkably suppressed in all the groups. CL-RI in the control group was more than the cutoff value (0.51, and only 2 out of 9 women had CL-RI values Conclusion Patients undergoing GnRHa long protocol had high luteal blood flow impedance with very low serum LH levels. HCG administration improved luteal blood flow impedance. This suggests that luteal blood flow is regulated by LH.

A model for evaluating steroids acting at the hypothalamus-pituitary axis using radioimmunoassay and related procedures

International Nuclear Information System (INIS)

Spona, J.; Bieglmayer, Ch.; Schroeder, R.; Poeckl, E.

1978-01-01

The relative affinity constants for binding of estrone (E 1 ), estriol (E 3 ), 17β-estradiol(E 2 ) and 17α-ethinyl-17β-estradiol(EE 2 ) to cytosol estrogen-receptors of rat hypothalamus and pituitary were estimated by a radioligand-receptor assay procedure. The relative affinity constants in the hypothalamic system were 6.5x10 -10 M for E 2 , 1x10 -9 M for EE 2 and 2x10 -8 M for E 1 and E 3 . The affinity constants were 1x10 -9 M for E 2 and E 3 and 7x10 -9 M for E 1 and E 3 when pituitary cytosol samples were used. Some discrepancies between biological activity and affinity for the estrogen-receptor were noted. These may be due to differences in the metabolism and cellular uptake of the estrogens. The radioligand-receptor assay procedure may be useful in evaluating the action of estrogens and anti-estrogens acting at the hypothalamic and pituitary level. Sedimentation patterns of cytosol samples labelled with the estrogens used in this study revealed, upon ultracentrifugation, protein moieties sedimenting in the 8 S region. The potency of progesterone and D-Norgestrel to modulate the release of LH and FSH stimulated by luteinizing hormone-releasing hormone (LH-RH) in castrated female rats was found to correlate well with the biological activity of the progestogens. It is concluded that the radioligand-receptor assay procedure for estrogens and the in-vivo model for the evaluation of the central action of progestogens may be valuable tools for testing new steroids to be used in oral contraceptives. (author)

Role of the levonorgestrel intrauterine system in effective contraception

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Attia AM

2013-08-01

Full Text Available Abdelhamid M Attia,1 Magdy M Ibrahim,1 Ahmed M Abou-Setta21Department of Obstetrics and Gynecology, Cairo University, Cairo, Egypt; 2George and Fay Yee Centre for Healthcare Innovation, University of Manitoba/Winnipeg Regional Health Authority, Winnipeg, MB, CanadaAbstract: Norgestrel, a synthetic progestin chemically derived from 19-nortestosterone, is six times more potent than progesterone, with variable binding affinity to various steroid receptors. The levonorgestrel-releasing intrauterine system (LNG IUS provides a long-acting, highly effective, and reversible form of contraception, with a pearl index of 0.18 per 100 women-years. The locally released hormone leads to endometrial concentrations that are 200–800 times those found after daily oral use and a plasma level that is lower than that with other forms of levonorgestrel-containing contraception. The contraceptive effect of the LNG IUS is achieved mainly through its local suppressive effect on the endometrium, leading to endometrial thinning, glandular atrophy, and stromal decidualization without affecting ovulation. The LNG IUS is generally well tolerated. The main side effects are related to its androgenic activity, which is usually mild and transient, resolving after the first few months. Menstrual abnormalities are also common but well tolerated, and even become desirable (eg, amenorrhea, hypomenorrhea, and oligomenorrhea with proper counseling of the patient during the choice of the method of contraception. The satisfaction rates after 3 years of insertion are high, reaching between 77% and 94%. The local effect of the LNG IUS on the endometrium and low rates of systemic adverse effects have led to its use in other conditions rather than contraception, as for the treatment of endometrial hyperplasia, benign menorrhagia, endometriosis, adenomyosis, and uterine fibroids.Keywords: levonorgestrel, intrauterine device, contraception, family planning, Mirena, Skyla

Safety, efficacy and patient satisfaction with continuous daily administration of levonorgestrel/ethinylestradiol oral contraceptives

Directory of Open Access Journals (Sweden)

Giuseppe Benagiano

2009-04-01

Full Text Available Giuseppe Benagiano, Sabina Carrara, Valentina FilippiDepartment of Gynaecology and Obstetrics, Sapienza University, Rome, ItalyAbstract: The progestational steroid norgestrel was synthesized and tested between 1960 and 1965 through an international cooperation between Wyeth, USA and Schering, Berlin. It is a mixture of two “enantiomers,” with only one form (designated as levonorgestrel biologically active. When taken orally, it is rapidly absorbed, not subjected to a “first-pass” effect and is approximately 90% bioavailable, with a circulating half-life around 15 hours. Its contraceptive action is exerted at the central (hypothalamic and peripheral (cervical mucus and endometrium levels. Levonorgestrel (LNG, alone or in combination with ethinyl estradiol (EE, is the most widely employed contraceptive progestin: it is used in combined oral contraceptives, progestogen-only pills, long-acting contraceptive implants, intrauterine contraceptive systems and in emergency contraception. It is also the steroid of choice for new oral contraceptive regimens aimed at reducing the frequency of bleeding episodes. This novel approach, already tried more than 30 years ago, gained interest around the year 2000 when surveys of women’s attitudes toward monthly menstrual bleeding started to show a major change: more and more women declared that they would welcome a hormonal contraceptive method that reduced bleeding episodes to 4, 2 or even 1 per year. At this point, while the debate on the significance and “usefulness” of menstruation went on, attention focused on new regimens. The first new modality consisted of changing the 7-day medication-free interval, either shortening it to fewer than 7 days, or by the administration of low-dose estrogens during the interval between packages. Then, continuous administration regimens started to be investigated. This, however, did not happen suddenly, since, in specific situations, doctors had for years