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Ischemic stroke remains a significant unmet need causing massive mortality and morbidity due to few treatment options with limited therapeutic window. The progestin Nestorone® (segesterone acetate) displays high affinity for the progesterone receptor in exerting its potent birth control and hormone replacement therapy. Accumulating evidence implicates a new utility of Nestorone in affording neuroprotection in a variety of central nervous system diseases, including stroke. However, the mechanism of action mediating Nestorone's neuroprotection in stroke remains unknown. Here, we showed that stand-alone treatments of Nestorone or human amniotic fluid-derived stem cells (hAFSc), but more pronounced with their combined treatment, led to significant improvements in behavioral function and reductions in infarction and peri-infarct cell loss in adult rats with ischemic stroke. We detected significantly lower levels of pro-inflammatory signals (OX6 and IBA1) coupled with enhanced levels of stem cell proliferation (Ki67) and differentiation (DCX and MAP2) in both brain and spleen of stroke rats that received stand-alone or combined treatments of Nestorone and hAFSc. In concert, the in vitro oxygen-glucose deprivation stroke model revealed that neural stem cells treated with Nestorone exhibited increased stem cell proliferation and differentiation that was accompanied by rescue of the mitochondrial respiratory activity characterized by reduced mitochondrial reactive oxygen species, increased ATP, elevated mitochondrial deacetylase Sirtuin 3 (SIRT3), and a normalized ratio of acetyl-superoxide dismutase 2 (Ac-SOD2)/SOD2, suggesting the key role of mitochondrial metabolism and oxidative protection in Nestorone's therapeutic effects in stroke.

L’amélioration des méthodes contraceptives et la recherche de nouvelles approches innovantes, avec un bénéfice médical ajouté, permettraient de satisfaire plus de couples, aux différentes étapes de leur vie reproductive. Les systèmes de délivrance s’améliorent, visant à une utilisation autonome et à une longue durée d’action, ce qui en facilite ainsi l’observance. Auto-injections, patchs à microaiguilles, anneaux vaginaux multipores, qui délivrent des molécules contraceptives et des molécules anti-infectieuses, promettent ainsi une double prévention, la grossesse non désirée et les maladies sexuellement transmissibles. Enfin, de nouveaux systèmes intra-utérins et de contraception permanente sont à l’étude. La recherche de nouveaux contraceptifs est une nécessité et doit se poursuivre, afin de diminuer la mortalité maternelle liée aux grossesses multiples et aux avortements, qui restent souvent à risque dans beaucoup de pays.

With persistently high global rates of unintended pregnancy and contraceptive non-use, non-adherence and discontinuation, new contraceptive methods must address the needs of women and men who seek alternatives to their current options. Methods under development aim to reduce potential side effects, improve access and ease of use, ensure safety, increase secondary benefits associated with method use and expand options for both women and men. Developmental approaches employed to enhance current methods utilize new delivery systems and novel active pharmaceutical ingredients. This will improve overall user satisfaction with the methods used, while expanding the number of options available to provide choice and value user autonomy in the highly diverse contraceptive markets around the world..

Introduction We previously showed that Nestorone® (NES), a synthetic progestin structurally related to progesterone, stimulated remyelination of the corpus callosum in a Cuprizone (CUP) mouse model of demyelination in intact females by promoting replenishment with mature oligodendrocytes (OL) (Glia. 2015;63:104‐117). Here, we further investigated the underlying mechanisms of this promyelinating effect. Methods We explored whether NES, applied subcutaneously through Alzet mini‐osmotic pumps, regulates specific transcription factors involved in oligodendrocyte progenitor cell (OPC) proliferation and their differentiation into mature OL, using RT‐qPCR and Western Blot analysis. Results Our present data show that in comparison to controls, a one‐week treatment with NES, through Alzet mini‐osmotic pumps, enhanced the production of three relevant transcription factor mRNAs encoding Olig2, Myt1, and Sox17. After 3 weeks, NES treatment reversed the effect of CUP on the levels of corresponding Olig2, Myt1, and Sox17 proteins. Moreover, in mice receiving NES + Estradiol (E2) co‐treatment, levels of Olig2, Myt1, and Sox17 proteins did not change as compared to NES alone. Conclusion NES alone or with E2 increased the levels of transcription factors, essential for myelin synthesis., Schematic view of the first demonstration of the mechanism by which Nestorone® a synthetic progestin structurally related to progesterone stimulates remyelination of the corpus callosum in a mouse model of demyelination, by increasing the levels of transcription factors Olig2, Myt1, and Sox17 proteins, essential for myelin synthesis after one week of treatment.

While the contributions of science, biomedicine, and engineering to contraceptive development offer wonder and promise to the community, what inspires many of us in the not-for-profit sector about the process of contraceptive product development is the integration of consultations with users, providers and policy makers, good clinical and manufacturing practice in product design and development, and the delivery of approved products at affordable prices to those in greatest need. The commitment to have an impact on the reproductive lives of women and men along with the ethical principles embedded in this process of achieving safe, effective, and acceptable options include the respect for persons, i.e., eventual users, beneficence for those using the product and justice in ensuring that it is available to those who are most vulnerable, including those in developing countries. It is the inspiration that drives the scientists and developers to produce public benefit and additional social value.

BACKGROUND: Novel male-based contraceptives are needed to broaden family planning choices. A progestin, Nestorone® (Nes) gel, plus a testosterone (T) gel suppresses sperm concentrations to levels associated with effective contraception in normal men. However, administration of two gels on different parts of the body daily is impractical. OBJECTIVE: Compare the effectiveness of daily application of a single, combined 8.3 mg Nes-62.5 mg T gel (Nes-T) vs. 62.7 mg T gel to suppress serum FSH and LH concentrations to ≤ 1.0 IU/L (a threshold associated with suppression of sperm concentrations to ≤ 1 million and effective contraception) and to compare the pharmacokinetics of serum Nes and T concentrations between the gel groups. DESIGN: We conducted a 28-day, double-blind, controlled trial of 44 healthy men randomized to daily Nes-T or T gel with measurement of hormones at baseline, treatment and recovery and during 24-hour pharmacokinetic studies on days 1 and 28 of treatment. RESULTS: Of the subjects who met pre-defined inclusion criteria, 84% of the Nes-T group suppressed serum gonadotropin concentrations to ≤ 1.0 IU/L at days 21–28 vs. 16.7% in the T group (p < .001). On day 1, Nes concentrations rose significantly above baseline by two hours and continued to rise up to 24 hours after Nes-T gel application. Nes concentrations were not detectable in the T group. Serum total T concentrations rose and were significantly higher in the T gel group compared to the Nes-T group at 24 hours on day 1 and days 11, 14, and 21 (p < 0.01). There were no serious adverse events in either group. About 80% of the subjects reported satisfaction with both gels. CONCLUSION: Daily Nes-T gel effectively and safely suppresses serum gonadotropins and is acceptable to most men. It should be studied further in efficacy trials of hormonal male contraception.

STUDY QUESTION: What is the lowest safe and effective ulipristal acetate (UPA) dose to be released from a copper (Cu) intrauterine system (IUS) that may prevent the copper-induced increase in bleeding and avoid progesterone receptor modulator associated-endometrial changes (PAEC) occurrences in healthy women? SUMMARY ANSWER: The 20 μg/d dose meets the criteria of lowest safe and effective UPA dose that can promote a favorable bleeding profile and avoid PAEC occurrences. WHAT IS KNOWN ALREADY: UPA is a selective progesterone receptor modulator used to reduce the heavy menstrual bleeding associated with uterine fibroids. However, it induces specific benign and reversible histological endometrial changes (PAEC). Very low levels of UPA may decrease the amount of bleeding associated with copper intrauterine device (Cu-IUD) use, without interfering with ovulation and preventing the occurrence of PAEC. STUDY DESIGN, SIZE, AND DURATION: In this single-blinded, randomized, 3-group parallel proof-of-concept study, healthy women were randomized to receive a Cu-IUS releasing a low-dose of UPA (5, 20 and 40 μg/d) for a 12-week treatment period. The study included three periods: baseline, treatment and post-treatment follow-up. Women received a Cu-UPA-IUS between days 2 and 5 of menses and we removed it at 12 weeks of use. The post-treatment follow-up period was equivalent to two cycles starting after IUS removal. The sample size calculation was based on the average bleeding/spotting (B/S) days per cycle expected from ovulatory cycles among women not using any contraceptive and the changes promoted by a Cu-IUD. Considering a relative difference of 40% in the number of B/S days between the baseline period and the end of the third 4-week reference period of Cu-UPA-IUS use, and assuming 80% power, a two-sided 5% level of significance, 8 participants per group were required. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included healthy women, 21–38 years old, with ovulatory cycles, not at risk for pregnancy at the time of inclusion. The primary outcome was the pharmacodynamic effects of a Cu-IUS releasing 5, 20 or 40 μg/d of UPA on bleeding patterns, ovarian function, and the occurrence of PAEC. The secondary outcomes were the pharmacokinetic characteristics and safety profile of the device. Participants filled a daily paper diary about any B/S they experienced. We collected blood and urine samples and performed transvaginal ultrasound. Endometrial biopsies were obtained during the baseline period, at the end of the treatment period and at post-treatment follow-up. For analysis purpose, we divided the 12-week treatment period into three 4-week treatment sequences and called each sequence as “treatment cycle”. We used generalized linear mixed models with orthogonal contrasts to analyze quantitative variables and Chi-Square/Fisher test for categorial variables. The level of significance was set at 5%. RESULTS: We randomized 29 women who had a successful IUS insertion; 27 completed the 12-week treatment period. Compared to baseline, the mean number of B/S days at treatment cycle 3 reduced by 2.6% in the 5 μg/d group (p=0.89), 17.1% in the 20 μg/d group (p=0.24), and 37.8% in the 40 μg/d group (p=0.03). Compared to baseline, the mean number of bleeding-only days at treatment cycle 3 reduced by 16.7% in the 5 μg/d group (p=0.66), 40.5% in the 20 μg/d group (p=0.14), and 77% in the 40 μg/d group (p=0.002). During the 12-week treatment period, ovulation occurred in most of the cycles (5 μg/d: 95.8%, 20 μg/d: 86.7%, 40 μg/d: 81.5%). The frequency of PAECs on the day of IUS removal was 10% (1/10), 10% (1/10) and 44.4% (4/9) in the 5 μg/d, 20 μg/d, and 40 μg/d groups, respectively. Most adverse events (AEs) were mild (87%, 90/104). There were no serious AEs. No AE led to treatment discontinuation. LIMITATIONS, REASONS FOR CAUTION: The results of this small proof-of-concept study will need to be confirmed in larger and long-term trials with a comparator such as a Cu-IUD. WIDER IMPLICATIONS OF THE FINDINGS: The novel Cu-UPA-IUS appears safe and well-tolerated and highly acceptable across all three UPA doses tested in this short-term proof-of-concept study. By preventing copper-induced increase in bleeding, this new IUS could provide a non-contraceptive benefit, especially for women with a low hemoglobin due to poor nutrition. STUDY FUNDING/COMPETING INTEREST(S): RSW, MP, RM, HS, NK, and DL are employees of the Population Council, a not-for-profit organization that developed UPA for contraception. RSW received a research grant from the National Institute of Child Health and Human Development (NICHD) from the National institute of Health (NIH) as Project Director of a Contraception research center U54 HD 29990. CSV serves on Medical Advisory Boards and gives lectures for Bayer and Merck.

ObjectiveTo evaluate serum estradiol (E2) concentrations during use of 90-day contraceptive vaginal rings releasing E2 75, 100, or 200mcg/day and segesterone acetate (SA) 200mcg/day to identify a dose that avoids hypoestrogenism.Study designWe conducted a multicenter dose-finding study in healthy, reproductive-aged women with regular cycles with sequential enrollment to increasing E2 dose groups. We evaluated serum E2 concentrations twice weekly for the primary outcome of median E2 concentrations throughout initial 30-day use (target ≥40pg/mL). In an optional 2-cycle extension substudy, we randomized participants to 2- or 4-day ring-free intervals per 30-day cycle to evaluate bleeding and spotting based on daily diary information.ResultsSixty-five participants enrolled in E2 75 (n=22), 100 (n=21), and 200 (n=22)mcg/day groups; 35 participated in the substudy. Median serum E2 concentrations in 75 and 100mcg/day groups were 40pg/mL throughout 30days; E2 concentrations were 37pg/mL (range 28-62pg/mL) on days 88-90 (n=11). Among the E2 200mcg/day substudy participants, all had withdrawal bleeding following ring removal. The 2-day ring-free interval group reported zero median unscheduled bleeding and two (range 0-16) and three (range 0-19) unscheduled spotting days in extension cycles 1 and 2, respectively. The 4-day ring-free interval group reported zero median unscheduled bleeding or spotting days.ConclusionsEstradiol concentrations with rings releasing E2 200mcg/day and SA 200mcg/day avoid hypoestrogenism over 30-day use.ImplicationsA 90-day contraceptive vaginal ring releasing estradiol 200mcg/day and segesterone acetate 200mcg/day achieves estradiol concentrations that should avoid hypoestrogenism and effectively suppresses ovulation.

Hormone therapy, primarily progesterone and progestins, for central nervous system (CNS) disorders represents an emerging field of regenerative medicine. Following a failed clinical trial of progesterone for traumatic brain injury treatment, attention has shifted to the progestin Nestorone for its ability to potently and selectively transactivate progesterone receptors at relatively low doses, resulting in robust neurogenetic, remyelinating, and anti-inflammatory effects. That CNS disorders, including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), spinal cord injury (SCI), and stroke, develop via demyelinating, cell death, and/or inflammatory pathological pathways advances Nestorone as an auspicious candidate for these disorders. Here, we assess the scientific and clinical progress over decades of research into progesterone, progestins, and Nestorone as neuroprotective agents in MS, ALS, SCI, and stroke. We also offer recommendations for optimizing timing, dosage, and route of the drug regimen, and identifying candidate patient populations, in advancing Nestorone to the clinic.

Objective Neurogenesis is the principal regenerative mechanism to sustain the plasticity potential in adult brains. Decreased neurogenesis parallels the cognition decline with aging, and has been suggested as a common hallmark in the progression of many neurodegeneration diseases. We previously reported that acute exposure to segesterone acetate (ST-1435; Nestorone), alone or in combination with 17β-estradiol (E2), increased human neural stem cells proliferation and survival both in vitro and in vivo. The present study expanded our previous findings to investigate the more clinical related chronic exposure in combination with E2 on the regenerative capacity of adult brain. Methods To mimic the chronic contraception exposure in women, 3-month old female mice (n = 110) were treated with ST-1435, with or without co-administration of E2, for 4 weeks. Neural cell proliferation and survival, and oligodendrocyte generation were assessed. The involvement of insulin-like growth factor 1 signaling was studied. Results Our results demonstrated that chronic ST-1435 and E2 alone or in combination increased neurogenesis by a comparable magnitude, with minimum to no antagonistic or additive effects between ST-1435 and E2. In addition, chronic exposure of ST-1435 or ST-1435 + E2 stimulated oligodendrocyte generation, indicating potential elevated myelination. Insulin-like growth factor-1 (IGF-1) and IGF-1 receptor (IGF-1R) were also up-regulated after chronic ST-1435 and E2 exposure, suggesting the involvement of IGF-1 signaling as the potential underlined regulatory pathway transducing ST-1435 effect. Conclusion These findings provide preclinical evidence and mechanistic insights for the development of ST-1435 as a neuroregenerative therapy to promote intrinsic regenerative capacity in female brains against aging and neurodegenerative disorders.

Progesterone is a steroid hormone that is essential for the regulation of reproductive function. Progesterone has been approved for several indications including the treatment of anovulatory menstrual cycles, assisted reproductive technology, contraception during lactation and, when combined with estrogen, for the prevention of endometrial hyperplasia in postmenopausal hormonal therapy. In addition to its role in reproduction, progesterone regulates a number of biologically distinct processes in other tissues, particularly in the nervous system. This physiological hormone is poorly absorbed when administered in a crystalline form and is not active when given orally, unless in micronized form, or from different non-oral delivery systems that allow a more constant delivery rate. A limited number of preclinical studies have been conducted to document the toxicity, carcinogenicity and overall animal safety of progesterone delivered from different formulations, and these rather old studies showed no safety concern. More recently, it has been shown in animal experiments that progesterone, its metabolite allopregnanolone and structurally related progestins have positive effects on neuroregeneration and repair of brain damage, as well as myelin repair. These recent preclinical findings have the potential to accelerate therapeutic translation for multiple unmet neurological needs.

BACKGROUND: As part of a program to develop a novel estradiol-releasing contraceptive vaginal ring (CVR), we evaluated the pharmacokinetic (PK) profile of CVRs releasing segesterone acetate (Nestorone® (NES)) combined with one of three different estradiol (E(2)) doses. STUDY DESIGN: A prospective, double-blind, randomized, multi-centered study to evaluate a 90-day CVR releasing NES [200μg/day] plus E(2), either 10μg/day, 20μg/day, or 40μg/day in healthy reproductive-age women with regular cycles. Participants provided blood samples twice weekly for NES and E(2) levels during the first 60 days (ring 1) and the last 30 days (ring 2) of use. A subset underwent formal PK assessments at ring initiation, ring exchange (limited PK), and study completion. RESULTS: The main study enrolled 197 women; 22 participated in the PK substudy. Baseline characteristics between the main and PK participants were comparable, with an average BMI of 25.8 kg/m(2) (SD 4.3). In the PK substudy, all three rings showed similar NES PK: mean area under the curve (AUC((0-72))) 34,181 pg*day/mL; concentration maximum (Cmax) 918 pg/mL; time to maximum concentration (Tmax) 3.5 hours. For E(2,) the Cmax occurred at 2 hours, and was significantly higher with the 20 ug/day ring (mean 390 pg/mL); 10ug/day, 189 pg/mL, p = .003; 40 ug/day, 189 pg/mL, p < .001), and declined rapidly to ≤ 50 pg/mL for all doses by 24 hours. For all subjects, the median E(2) levels remained under 35 pg/mL during treatment. CONCLUSION: PK parameters of NES were not affected when paired with different doses of E(2), but E(2) levels from all three doses were lower than anticipated and no dose response was observed. IMPLICATIONS: While these novel estradiol-releasing combination contraceptive vaginal rings provided sustained release of contraceptive levels of Nestorone over 90 days, the E(2) levels achieved were not consistent with bone protection, and a dose-response was not observed.

Global climate change represents a grave threat to the future of human welfare and our natural environment.1 The contentious ongoing policy debate about potential interventions focuses on switching to renewable energy sources and increasing energy use efficiency. But given the urgency of the problem and the lack of political will, other approaches to limit greenhouse gas emissions should be given higher priority. Improving access to effective contraception is one such policy that has thus far been largely ignored by the international climate community.2 This recommendation is based on three simple facts: (1) population growth is a key driver of climate change, (2) higher and more effective use of contraception reduces unplanned pregnancies and hence population growth, and (3) many more women and men would freely choose to use contraception if only it were available and acceptable. The authors’ recommended policy is about improving universal access to reproductive technologies, not about coercion. In 2100, our planet is expected to be home to 10.9 billion people, up from today’s 7.7 billion.3 This expansion of humanity will take place mostly in sub-Saharan Africa and South Asia.3 Rapid population growth has pervasive adverse effects on societies, economies and the natural environment. In particular, with an additional 3 billion people producing greenhouse gases, the global warming problem will become even more intractable in the coming decades. Slower future population growth could reduce emissions globally by an estimated 40% or more in the long term.4 …

Neurological diseases such as ischemic stroke can be debilitating and have limited treatments available. The progestin Nestorone® (segesterone acetate) has been evaluated for use in birth control and hormone replacement therapy due to its potency and high affinity for the progesterone receptor. Interestingly, Nestorone also exerts neuroprotection in animals afflicted with various central nervous system diseases, including stroke, which implicates its potential for treating these maladies in clinical settings. In fact, a recent Brain Research paper by Tanaka and colleagues demonstrates Nestorone's ability to reduce infarct sizes and preclude functional impairments in rats subjected to ischemic stroke. This commentary highlights Nestorone's properties as a progestin, its neuroprotective capabilities in animal studies, and how the Tanaka team's findings and previous clinical trials contribute to Nestorone's translation into a therapeutic agent for stroke and other neurological diseases.

Our previous studies showed that intranasal delivery of progesterone offers a good bioavailability and neuroprotective efficacy after experimental stroke. We have also demonstrated that progesterone receptors (PR) are essential for cerebroprotection by endogenous progesterone and by progesterone treatment. The identification of PR as a potential drug target for stroke therapy opens new therapeutic indications for selective synthetic progestins. Nestorone® (16-methylene-17α-acetoxy-19-nor-pregn-4-ene-3, 20-dione, also known as segesterone acetate) is a 19-norprogesterone derivative that more potently targets PR than progesterone. The objective of this study was to evaluate the cerebroprotective efficiency of intranasal administration of Nestorone after middle cerebral occlusion (MCAO) in mice. We show here that intranasal administration is a very efficient route to achieve a preferential delivery of Nestorone to the brain and confers a slow elimination and a sustained bioavailability. Furthermore, intranasal administration of Nestorone (at 0.08 mg/kg) improved the functional outcomes and decreased the ischemic lesion in male but not in female mice at 48 h post MCAO. Use of PRNesCre mice, selectively lacking expression of PR in neural cells, and their control PRloxP/loxP littermates showed that the cerebroprotective effects of Nestorone in male mice depended on neural PR as they were not observed in PRNesCre mice. Our findings show that intranasal delivery of Nestorone may be an efficient strategy to promote recovery after stroke in males and confirm the key role of PR in cerebroprotection. Furthermore, they point to sex differences in the response to Nestorone treatment and emphasize the necessity to include males and females in experimental studies.

Although several progestins have been tested for hormonal male contraception, the effects of dosage and nature of various progestins on gonadotropin suppression combined with and without additional testosterone has not been performed in a comparative trial. The aim of this study was to evaluate the differential impact of four oral or transdermal progestins on the suppression of gonadotropins in healthy men: oral: cyproterone acetate (CPA), levonorgestrel (LNG), norethisterone acetate (NETA), and transdermal: Nestorone (NES), all in combination with transdermal testosterone (T). Randomized clinical trial testing was performed with four progestins at two doses each. After a 2-week progestin-only treatment, transdermal T was added for further 4 weeks and was followed by a 3-week recovery period. Progestin-dose per day: CPA 10 mg/20 mg, NES 2 mg/3 mg/dose e.g. 200/300 lg/day absorbed, NETA 5 mg/10 mg, LNG 120 lg/240 lg. From an andrology outpatient clinic, 56 healthy men aged 18–50 years, with body mass index ≤33 kg 9 m 2 were included in the study. Serum concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were studied. Secondary outcome measure included were serum testosterone concentrations, sperm concentrations, and safety parameters. Intergroup comparisons demonstrated that CPA and LNG had the strongest effect on LH/FSH suppression. Nevertheless, every substance showed significant inhibitory effects on gonadotropin secretion, especially in combination with transdermal T. A decrease in hematocrit and insulin sensitivity as well as cholesterol subfractions and triglycerides was uniformly seen for every group. The combination of oral or transdermal progestins with a transdermal testosterone preparation is able to suppress gonadotropins. Further dose titration studies with sperm suppression as an end-point should be conducted to determine the lowest effective dose for hormonal male contraception.

OBJECTIVES: Evaluate and compare contraceptive efficacy, safety, continuation rates and duration of lactational amenorrhea (LA) in married lactating women (20–35 years) using the progesterone vaginal ring (PVR) or Copper-T380A intrauterine device (IUD) during the first postpartum year. STUDY DESIGN: We conducted a one-year multicenter, non-randomized, non-inferiority, open-label, comparative trial at 20 centers in India and compared efficacy, safety, continuation and LA plus feeding patterns and growth/well-being of participants’ infants. Women used four 3-month PVRs consecutively (lost PVRs were not replaced) and were to breastfeed at least four times/day. We used Pearl Index (PI) and Kaplan Meier (K-M) rates to analyze pregnancy and K-M for continuation. RESULTS: We enrolled 789 women (459 PVR, 330 IUD). Neither PI nor K-M one-year pregnancy rates differed significantly between groups (PI: PVR-0.62; IUD-0.35); (K-M: PVR-0.7; IUD-0.4, p=0.58). Continuation rates at 12 months were 78.5% (IUD) vs. 56.9% (PVR) (p

A one-year segesterone acetate (SA)/ethinyl estradiol (EE) contraceptive vaginal system (CVS; Annovera™) used to prevent pregnancy in women of reproductive age, was recently approved by the FDA (August 2018). Efficacy (Pearl Index of 2.98) and safety of the CVS were demonstrated in two phase 3, open-label, multicenter studies conducted in the US and internationally. The ring is self-inserted, left in place for 21 days and removed for 7 days in each cycle, and provides contraceptive efficacy for up to 13 cycles of use. It is designed to release 150 mcg SA and 13 mcg EE per day. This report reviews the evidence of systemic serum SA levels required for ovulation inhibition. SA is a potent synthetic progestin when given parenterally (eg, subcutaneous implant, transdermal gel, or vaginal ring), but, due to rapid inactivation by first-pass hepatic metabolism, is not biologically active when administered orally. SA specifically binds to progesterone receptors; it does not bind to sex hormone-binding globulin (SHBG) and has no estrogenic or androgenic activity. The effects of SA on ovulation inhibition were first examined in dose-finding studies of subdermal implants, which showed that the mechanism of ovulation inhibition was concentration dependent.1,2 Another study of subdermal implants releasing 45-50 mcg SA/day, showed ovulation did not occur with SA plasma levels >105 pmol/L; women who ovulated had SA levels ranging from 68 to

Annovera™ is an FDA-approved contraceptive vaginal system (CVS) releasing 150 mcg segesterone acetate (SA), a new chemical entity, and 13 mcg ethinyl estradiol (EE) per day.1 We postulate that as a non-androgenic progestin, SA is unlikely to adversely affect lipids versus androgenic progestins. Here we review the effects of this CVS on lipids, glucose, coagulation factors and sex hormone-binding globulin (SHBG). Two pivotal, open-label, phase 3 trials and one PK trial evaluated women (18-40 years) who received the CVS for 13 cycles of 28 days over 12 months; one phase 3 study examined hepatic proteins in a substudy. The CVS was self-inserted, left in place for 21 days and removed for 7 days in each 28-day cycle. Lipids and glucose were measured at baseline and study end in the 3 trials. As previously reported, factor VIII, protein S (PS), fibrinogen, and SHBG were measured in the hepatic factors substudy.2 A total of 2308 women used the SA/EE CVS. Participants had a mean age of 26.7 years and mean BMI of 24.1 kg/m2. Most women were white (71%) and 14% were black. Women in the substudy (n=129) had similar mean ages and BMIs; 69% were white and 28% were black. In an integrated analysis of the phase 3 and PK studies, levels of total cholesterol increased by a mean +0.236 mmol/L from baseline to study end, as did HDL cholesterol (+0.162 mmol/L) and triglycerides (+0.193 mmol/L). At study end, LDL cholesterol decreased from baseline by a mean of -0.003 mmol/L. Glucose levels increased from baseline to study end by a mean +0.074 mmol/L. A prior study using the CVS showed lipid changes similar in direction and magnitude to other combined oral contraceptives (COC).3 Hepatic protein substudy results showed significant mean changes from baseline to study end for fibrinogen (+0.2±0.66 mg/mL [SD]; P=0.0052), factor VIII activity (+21%±55; P=0.0005), and PS activity (-8%±19; P=0.0043). Mean SHBG levels also significantly increased from baseline to study end by +81.7±94.3 nmol/L (P

Objectives To describe bleeding patterns among users of the segesterone acetate (SA) and ethinyl estradiol (EE) contraceptive vaginal system (CVS), and identify factors associated with unscheduled bleeding/spotting (B/S). Study design We pooled results from two multicenter, single-arm, open-label, pivotal, phase 3 studies of the SA/EE CVS conducted in 17 US and 7 international sites. Participants (age 18–40 years; BMI ≤29 kg/m2) followed a 21/7-day in/out schedule of CVS use for up to 13 cycles and recorded vaginal bleeding daily in paper diaries. Scheduled and unscheduled B/S were summarized by cycle. We used multiple logistic regression to identify factors associated with unscheduled bleeding/spotting, based on the first 4 cycles only. Results Analysis included data from 2070 participants (16,408 cycles). Ninety-eight percent documented scheduled B/S [mean (SD): 4.9 (1.1) days/cycle)]. Absence of scheduled B/S was 5–8% of women/cycle. Unscheduled B/S ranged from 13.2% to 21.7% of women per cycle. Few women (1.8%) discontinued prematurely due to unacceptable bleeding. Black women were more likely to report unscheduled B/S than White women [Adjusted odds ratio (AOR) = 1.49, 95% confidence interval (CI) = 1.14–1.94]. Women with fewer years of schooling [ Conclusions Participants using the SA/EE CVS up to 13 cycles reported good cycle control. Discontinuation due to unacceptable bleeding was very low. Further research into demographic/other differences with reported unscheduled bleeding is warranted. Implications Since good cycle control is a key factor influencing contraceptive selection, adherence and continuation of combined hormonal contraceptives, the favorable bleeding profiles experienced by women during the SA/EE CVS clinical trials provide reassuring information for prospective users.

The safety of combined hormonal contraceptives (CHCs) has been documented by years of follow-up, and the occurrence of venous thromboembolism (VTE) possibly related to their use is rare in the young population exposed to these agents. The balance between the benefits and risks of contraceptive steroids is generally positive, in particular when compared with pregnancy's risks. Epidemiological studies led to different results showing either no difference in VTE risk between CHCs (active surveillance prospective studies) or an increase in risk (observational or database studies). The discrepancy may be explained by different study designs and the fact that important risk factors such as overweight, family history of thrombosis, and smoking were not adjusted for in some observational studies. To improve the safety of CHC, modifying the estrogen dose and type, selecting newer progestins, and alternative routes of delivery were implemented. Ethinyl- E2 (EE) exerts a stronger effect than E2 on estrogen-dependent markers such as liver proteins and coagulation factors. To circumvent the metabolic changes induced by EE, more natural compounds such as E2 and E2 valerate (E2V) were developed, as well as new progestins structurally closer to P. Progestins when given alone do not increase VTE risk, and their risks and benefits depend upon their chemical structure, the type and dose of combined estrogen, and the delivery route. The lower impact of E2-based CHCs on metabolic markers may result in an improved safety profile. A recent study on clinical outcomes supports this hypothesis. In conclusion, CHCs remain a safe and effective choice to prevent unwanted pregnancy, and the risk of VTE is in general low. Careful consideration of individual risk factors should be given before prescribing to avoid cumulative risks and minimize the occurrence of unwanted events.

Objectives Estrogen-sensitive hepatic proteins were assessed in women using a contraceptive vaginal ring (CVR) delivering 150 mcg Nestorone® (NES) and 15 mcg ethinyl estradiol (EE). Study design A substudy of the Contraceptive Clinical Trials Network of the National Institute of Child Health and Human Development enrolled 129 participants, with assessments of factor VIII, fibrinogen, protein S (PS) and sex hormone binding globulin (SHBG). Thirty-six participants had used combined hormonal contraceptives (CHCs) in the cycle preceding first CVR use (recent users) and 70 had no history of recent use (nonusers). Results Mean values at baseline were within the normal range for all four proteins but were higher for factor VIII, fibrinogen and SHBG and significantly lower for PS in recent compared to nonusers. During NES/EE CVR use, factor VIII, fibrinogen and PS were within the normal range; however, SHBG levels were increased by nearly 100% at Cycle 13. The change from baseline to final evaluation was statistically significant for all proteins in nonusers. The change in recent users was significant for factor VIII at Cycle 6 and for SHBG at Cycles 6 and 13, but not for PS or fibrinogen. Conclusion NES/EE CVR for up to 13 cycles was associated with changes from baseline in plasma levels of factor VIII, fibrinogen and PS that were within the normal range, with SHBG levels above the normal range by Cycle 6. Nonusers of CHC before CVR showed wider changes in values versus recent users whose baseline values were increased by previous EE exposure. Implications Recent use of CHCs demonstrated significant changes in all four measured hepatic proteins at baseline compared to nonusers. Use of the NES/EE CVR further changed these hepatic protein markers, but values remained within the normal range. Prebaseline exposure to estrogen can obscure interpretation of hepatic proteins changes associated with a second CHC.

BACKGROUND Testosterone (T)/Nestorone (NES) combination gel is a potential transdermal male contraceptive that suppresses gonadotropins and spermatogenesis. Transfer of transdermal T from men to women can be prevented by washing or covering application sites with clothing. OBJECTIVES We hypothesized that showering or wearing a shirt over gel application sites would prevent secondary exposure of T and NES to a woman after close skin contact. MATERIALS AND METHODS Twelve healthy male and 12 healthy female participants were recruited. Men applied T/NES 62 mg/8 mg gel to their shoulders and upper arms. Two hours after application, female partners rubbed the application site for 15 min. Exposure in the female partner was assessed under three conditions: a shirt covered the application site; the man showered prior to skin contact; or without intervention to reduce transfer. Serum T and NES concentrations were measured by LC-MS/MS in serial blood samples for 24 h after gel exposure. MAIN OUTCOMES Change in female serum T and NES levels as measured by average concentration over 24 h (Cavg ). RESULTS Median female serum T Cavg was 23.9 ng/dL (interquartile range, 19.3, 33.9) with the shirt barrier and 26.7 ng/dL (20.7, 33.9) after showering, which was higher than baseline 20.9 ng/dL (16.7, 25.0), both p

Summary Background A ring-shaped, contraceptive vaginal system designed to last 1 year (13 cycles) delivers an average of 0·15 mg segesterone acetate and 0·013 mg ethinylestradiol per day. We evaluated the efficacy of this contraceptive vaginal system and return to menses or pregnancy after use. Methods In two identically designed, multicentre, open-label, single-arm, phase 3 trials (one at 15 US academic and community sites and one at 12 US and international academic and community sites), participants followed a 21-days-in, 7-days-out segesterone acetate and ethinylestradiol contraceptive vaginal system schedule for up to 13 cycles. Participants were healthy, sexually active, non-pregnant, non-sterilised women aged 18–40 years. Women were cautioned that any removals during the 21 days of cyclic use should not exceed 2 h, and used daily paper diaries to record vaginal system use. Consistent with regulatory requirements for contraceptives, we calculated the Pearl Index for women aged 35 years and younger, excluding adjunctive contraception cycles, as the primary efficacy outcome measure. We also did intention-to-treat Kaplan-Meier life table analyses and followed up women who did not use hormonal contraceptives or desired pregnancy after study completion for 6 months for return to menses or pregnancy. The trials are registered with ClinicalTrials.gov , numbers NCT00455156 and NCT00263341 . Findings Between Dec 19, 2006, and Oct 9, 2009, at the 15 US sites, and between Nov 1, 2006, and July 2, 2009, at the 12 US and international sites we enrolled 2278 women. Our overall efficacy analysis included 2265 participants (1130 in the US study and 1135 in the international study) and 1303 (57·5%) participants completed up to 13 cycles. The Pearl Index for the primary efficacy group was 2·98 (95% CI 2·13–4·06) per 100 woman-years, and was well within the range indicative of efficacy for a contraceptive under a woman's control. The Kaplan-Meier analysis revealed the contraceptive vaginal system was 97·5% effective, which provided further evidence of efficacy. Pregnancy occurrence was similar across cycles. All 290 follow-up participants reported return to menses or became pregnant (24 [63%] of 38 women who desired pregnancy) within 6 months. Interpretation The segesterone acetate and ethinylestradiol contraceptive vaginal system is an effective contraceptive for 13 consecutive cycles of use. This new product adds to the contraceptive method mix and the 1-year duration of use means that women do not need to return to the clinic or pharmacy for refills every few months. Funding Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health, the US Agency for International Development, and the WHO Reproductive Health Research Department.

Emerging science will make an important contribution towards the development of improved contraceptives. While long-acting reversible contraceptives remain the most effective method, new user-controlled, mid-acting methods will avoid the need for procedures requiring trained providers. Contraceptives combined with other agents may bring additional health benefits, such as dual protection against both pregnancy and sexually transmitted infections. Emerging research areas in proteomics allowed the discovery of new reproductive targets that may lead to non-hormonal contraceptives for both men and women. Current research objectives include the improvement of existing contraceptive methods, as well as discovery of new materials able to deliver new molecules more specifically to their target without systemic actions.

Neurological diseases such as ischemic stroke can be debilitating and have limited treatments available. The progestin Nestorone® (segesterone acetate) has been evaluated for use in birth control and hormone replacement therapy due to its potency and high affinity for the progesterone receptor. Interestingly, Nestorone also exerts neuroprotection in animals afflicted with various central nervous system diseases, including stroke, which implicates its potential for treating these maladies in clinical settings. In fact, a recent Brain Research paper by Tanaka and colleagues demonstrates Nestorone's ability to reduce infarct sizes and preclude functional impairments in rats subjected to ischemic stroke. This commentary highlights Nestorone's properties as a progestin, its neuroprotective capabilities in animal studies, and how the Tanaka team's findings and previous clinical trials contribute to Nestorone's translation into a therapeutic agent for stroke and other neurological diseases.

To evaluate changes in the bone turnover markers CTx and P1NP during 6 months' use of novel continuous contraceptive vaginal rings delivering Nestorone (NES) 200 mcg/day and three doses of estradiol (E2) (10, 20, and 40 mcg/day).This randomized trial enrolled 189 women who used two consecutive vaginal rings over 180 days. Frequent blood sampling permitted analysis of NES, E2, CTx and P1NP concentrations. The bone-turnover marker analyses included only women with complete sampling and excluded women with characteristics that might interfere with accurate measurement of bone markers such as afternoon sampling, poor ring compliance or recent pregnancy. We evaluated the change from baseline to 6 months in CTx and P1NP, stratified by ring dose and by average circulating E2 concentrations.One hundred fifty-one women completed the study, and 82 women had complete data available for the bone marker analyses; the three dosage groups were balanced with regard to baseline characteristics. E2 concentrations remained low throughout treatment, regardless of which dose ring the participant used. Individual CTx changes from baseline averaged 27±56% (p.01). Similarly, individual P1NP changes averaged 11±33% (p=.04). These increases were within the premenopausal reference ranges, and unrelated to treatment dose or to circulating E2 concentrations.The low E2 dose of these rings was associated with low E2 concentrations and modest increases in serum bone turnover makers. Because we have only 6-month bone turnover markers and no direct evidence of bone loss or bone density change, these results must be interpreted with caution.Nestorone, a 19-norprogesterone derivative, leads to complete ovarian suppression, which should yield excellent contraceptive effectiveness. To prevent potential adverse effects on bone, the NES contraceptive ring should be combined with higher doses of E2 than were assessed in this study.

Progesterone shows anti-inflammatory and promyelinating effects in mice with experimental autoimmune encephalomyelitis (EAE), a commonly used model for multiple sclerosis (MS). Because neurosteroids have been implicated as protective factors for MS and EAE, we analysed the expression of neurosteroidogenic enzymes in the compromised spinal cord of EAE mice. EAE was induced in female C57Bl6 mice, which were then killed on day 16 after induction. Progesterone was given by pellet implantation 1 week before EAE induction. Untreated EAE mice showed decreased mRNAs for the steroidogenic acute regulatory protein (Star), voltage-dependent anion channel (VDAC), cholesterol side-chain cleavage (P450scc), 5α-reductase, 3α-hydroxysteroid dehydrogenase (3α-HSOR) and aromatase, whereas changes of 3β-hydroxysteroid dehydrogenase (3β-HSD) were not significant. mRNA translocator protein (18 kDa) (TSPO) was elevated, concomitantly with a reactive microgliosis. EAE mice also showed abnormal mitochondrial ultrastructure in axons and neuronal bodies, as well as reduced expression of fission and fusion protein mRNAs. Progesterone pretreatment before EAE induction increased Star, VDAC, P450scc, 5α-reductase type I, 3α-HSOR and aromatase mRNAs and did not modify 3β-HSD. TSPO mRNA was decreased, possibly as a result of reversal of microgliosis. Progesterone pretreatment also improved mitochondrial ultrastructure and increased fission/fusion protein mRNAs. These mitochondrial effects may be part of the progesterone recovery of neurosteroidogenesis. The enzymes 3β-HSD, 3α-HSOR and 5α-reductase are also responsible for the formation of androgens. Because MS patients and EAE rodents show changes of central androgen levels, it is likely that, together with progestins and oestrogens, neuroandrogens afford neuroprotection for EAE and MS. The data reviewed suggest that enhanced synthesis of neurosteroids contributes in an auto/paracrine manner to reinforce the neuroprotective and anti-inflammatory effects of exogenous progesterone given to EAE mice. Fil: de Nicola, Alejandro Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina Fil: Garay, Laura Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina Fil: Meyer, Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Guennoun, Rachida. Université Paris Sud; Francia Fil: Sitruk Ware, R.. The Poputation Council; Estados Unidos Fil: Schumacher, Michael. Inserm; Francia Fil: Gonzalez Deniselle, Maria Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina

Recent data suggests that a "window of opportunity" to decrease the risk of mortality and coronary heart disease (CHD) exists, when initiation hormone replacement therapy (HRT) in menopausal women aged of 50 to 59 years, or within the 10 years following the onset of menopause. The risks of HRT are rare, especially in young postmenopausal women with symptoms who use HRT for long periods of time, and have lower rates of mortality and CHD than comparable postmenopausal women who do not use HRT Newer evidence suggests that there are distinct differences between synthetic molecules and estradiol ; the physiological hormone may be preferable especially from a non-oral delivery system as thrombosis risk is the lowest with such therapy. In addition, natural progesterone does not reverse the benefits of estrogen, particularly in the nervous system and the vessels, and seems to be neutral on breast cancer risk. HRT must be individualized and tailored according to symptoms and each woman's individual risk profile, her preferences and expectations.

Ulipristal acetate (UPA) is a selective progesterone receptor modulator (PRM), which is used as an emergency contraceptive in women. Recent studies demonstrated the efficacy of an UPA contraceptive vaginal ring (UPA-CVR) as a blocker of ovulation. However, the endometrium of women exposed to UPA over a 6-month period display glandular changes, termed PRM-associated endometrial changes (PAECs). We, therefore, investigated whether UPA-induced PAECs are associated with altered expression of the transcription factor heart- and neural crest derivatives-expressed protein 2 (HAND2) whose downregulation is observed in endometrial epithelial hyperplasia and cancer. Our results showed that while exposure to mifepristone, a well-known PRM, leads to suppression of endometrial HAND2 expression, long-term exposure to UPA-CVR did not cause downregulation of this marker. Further studies, using human primary endometrial stromal cells, confirmed that whereas mifepristone-mediated suppression of HAND2 elevated the levels of its downstream target fibroblast growth factor 18, UPA did not significantly alter the expression of this growth factor. A rationale for the differential regulation of HAND2 by these PRMs was provided by our observation that mifepristone-bound progesterone receptors turn over at a faster rate than those bound to UPA. Collectively, these results support the selective effects of different PRMs and indicate that chronic exposure to UPA does not alter the HAND2 pathway whose dysregulation is linked to complex atypical endometrial hyperplasia and cancer. The results from this study involving a limited number of clinical samples should pave the way for a larger study to determine the safety of UPA for long-term use.

Progesterone plays a protective role in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). Besides spinal cord neuropathology, MS patients present a dysfunctional hippocampus. In this work we studied the therapeutic effects of the progestin Nestorone in the brain of mice with chronic EAE. Nestorone decreased clinical grade and enhanced motor behavior. In addition, it increased cell proliferation and doublecortin positive neuroblasts in the hippocampus, increased GABAergic interneurons and attenuated the number of Iba1+ microglia/macrophages, events possibly linked to enhancement of neurogenesis. Therefore, Nestorone protected against hippocampus abnormalities and improved functional outcomes of EAE mice, suggesting its potential value for MS. Fil: Garay, Laura Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina Fil: Gonzalez Deniselle, Maria Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina Fil: Sitruk Ware, Regine. Population Council’s Center for Biomedical Research; Estados Unidos. The Rockefeller University; Estados Unidos Fil: Gennoun, Rachida. Inserm; Francia Fil: Shumacher, Michael. Inserm; Francia Fil: Alejandro de Nicola. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina

Fifty percent of pregnancies in the United States are unintended despite numerous contraceptive methods available to women. The only male contraceptive methods, vasectomy and condoms, are used by 10% and 16% of couples, respectively. Prior studies have shown efficacy of male hormonal contraceptives in development, but few have evaluated patient acceptability and potential use if commercially available. The objective of this study is to determine if a transdermal gel-based male hormonal contraceptive regimen, containing testosterone and Nestorone® gels, would be acceptable to study participants as a primary contraceptive method.As part of a three-arm, 6-month, double-blind, randomized controlled trial of testosterone and nestorone gels at two academic medical centers, subjects completed a questionnaire to assess the acceptability of the regimen. Of the 99 men randomized, 79 provided data for analysis.Overall, 56% (44/79) of men were satisfied or extremely satisfied with this gel-based method of contraception, and 51% (40/79) reported that they would recommend this method to others. One third of subjects (26/79) reported that they would use this as their primary method of contraception if it were commercially available today. However, men with concerns about sexually transmitted disease were significantly less satisfied than men without such concerns (p=0.03).A majority of the men who volunteered to participate in this trial of an experimental male hormonal contraceptive were satisfied with this transdermal male hormonal contraceptive. If commercially available, a combination of topical nesterone and testosterone gels could provide a reversible, effective method of contraception that is appealing to men.A substantial portion of men report they would use this transdermal male contraceptive regimen if commercially available. This method would provide a novel, reversible method of contraception for men, whose current choices are limited to condoms and vasectomy.

Multiple Sclerosis affects mainly women and consists in intermittent or chronic damages to the myelin sheaths, focal inflammation, and axonal degeneration. Current therapies are limited to immunomodulators and antiinflammatory drugs, but there is no efficient treatment for stimulating the endogenous capacity of myelin repair. Progesterone and synthetic progestins have been shown in animal models of demyelination to attenuate myelin loss, reduce clinical symptoms severity, modulate inflammatory responses and partially reverse the age-dependent decline in remyelination. Moreover, progesterone has been demonstrated to promote myelin formation in organotypic cultures of cerebellar slices. In the present study, we show that progesterone and the synthetic 19-nor-progesterone derivative Nestorone® promote the repair of severe chronic demyelinating lesions induced by feeding cuprizone to female mice for up to 12 weeks. Progesterone and Nestorone increase the density of NG2(+) oligodendrocyte progenitor cells and CA II(+) mature oligodendrocytes and enhance the formation of myelin basic protein (MBP)- and proteolipid protein (PLP)-immunoreactive myelin. However, while demyelination in response to cuprizone was less marked in corpus callosum than in cerebral cortex, remyelination appeared earlier in the former. The remyelinating effect of progesterone was progesterone receptor (PR)-dependent, as it was absent in PR-knockout mice. Progesterone and Nestorone also decreased (but did not suppress) neuroinflammatory responses, specifically astrocyte and microglial cell activation. Therefore, some progestogens are promising therapeutic candidates for promoting the regeneration of myelin.

Objective In 2006, the incidence of unintended pregnancy among rural-to-urban migrant women (RUMW) in Shanghai was reported as 12.8 per 100 women-years during the first year postpartum. Among permanent residents of Shanghai, that same rate was 3.8 per 100 women-years. An intervention study was designed to address the unmet need for family planning services among this underserved population of RUMW and reduce their high postpartum unintended pregnancy incidence. Study design We enrolled 840 migrant women into an intervention study that provided free contraceptive counseling and a choice of methods. Subjects were recruited into the study during hospitalization for childbirth and offered a contraceptive method according to their choice prior to discharge. Counseling and further support were offered at 6 weeks and at 3, 6, 9 and 12 months postpartum via scheduled telephone calls and/or clinic visits. Results Among all study participants, the median time to contraceptive initiation and sexual resumption was 2 months postpartum, respectively. The overall contraceptive prevalence at 12 months was 97.1%, and more than half of the women were using long-acting contraception. The incidence rate of unintended pregnancy during the first year postpartum was 2.2 per 100 women-years (95% confidence interval: 1.3–3.6). Conclusions Integrating free family planning services into existing childbirth delivery services in a maternity setting in Shanghai was effective in addressing the unmet need for family planning and reduced the risk of unintended pregnancy during the first year postpartum. Implications The maternity setting at the time of early labor and prior to postpartum hospital discharge is a practical venue and an optimal time to provide contraception counseling and for postpartum women to initiate use of contraceptive methods. Supporting services during the first year postpartum are also essential to encourage women to continue contraceptive use and reduce the incidence of postpartum unintended pregnancy.

Progesterone is commonly considered as a female reproductive hormone and is well-known for its role in pregnancy. It is less well appreciated that progesterone and its metabolite allopregnanolone are also male hormones, as they are produced in both sexes by the adrenal glands. In addition, they are synthesized within the nervous system. Progesterone and allopregnanolone are associated with adaptation to stress, and increased production of progesterone within the brain may be part of the response of neural cells to injury. Progesterone receptors (PR) are widely distributed throughout the brain, but their study has been mainly limited to the hypothalamus and reproductive functions, and the extra-hypothalamic receptors have been neglected. This lack of information about brain functions of PR is unexpected, as the protective and trophic effects of progesterone are much investigated, and as the therapeutic potential of progesterone as a neuroprotective and promyelinating agent is currently being assessed in clinical trials. The little attention devoted to the brain functions of PR may relate to the widely accepted assumption that non-reproductive actions of progesterone may be mainly mediated by allopregnanolone, which does not bind to PR, but acts as a potent positive modulator of γ-aminobutyric acid type A (GABA(A) receptors. The aim of this review is to critically discuss effects of progesterone on the nervous system via PR, and of allopregnanolone via its modulation of GABA(A) receptors, with main focus on the brain. Fil: Schumacher, M.. Inserm; Francia Fil: Mattern, C.. MetP Pharma AG ; Suiza Fil: Ghoumari, A.. Inserm; Francia Fil: Oudinet, J. P.. Inserm; Francia Fil: Liere, P.. Inserm; Francia Fil: Labombarda, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina Fil: Sitruk Ware, Régine. The Rockefeller University; Estados Unidos. Population Council. Center for Biomedical Research ; Estados Unidos Fil: de Nicola, Alejandro Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina Fil: Guennoun, R.. Inserm; Francia

Thank you to Dr Smith for this interesting question1 submitted in response to our commentary article.2 In our view climate should not be discussed in counselling sessions …

Ulipristal acetate (UPA), a progesterone receptor (PR) modulator, is used as an emergency contraceptive in women. Here, using a mouse model, we investigated the mechanism of action of UPA as an ovulation blocker. In mice, ovulation is induced ~12 hours following the treatment with exogenous gonadotropins, including human chorionic gonadotropin (hCG), which mimics the action of luteinizing hormone (LH). When administered within 6 hours of hCG treatment, UPA is a potent blocker of ovulation. However, UPA’s effectiveness declined significantly when it was given at 8 hours post hCG. Our study revealed that, when administered within 6 hours of hCG, UPA blocks ovulation by inhibiting PR-dependent pathways intrinsic to the ovary. At 8 hours post hCG, when the PR signaling has already occurred, UPA is unable to block ovulation efficiently. Collectively, these results indicated that UPA, when administered within a critical time window following the LH surge, blocks PR-dependent pathways in the ovary to function as an effective antiovulatory contraceptive.

Steady progress in contraception research has been achieved over the past 50 years. Hormonal and non-hormonal modern contraceptives have improved women’s lives by reducing different health conditions that contributed to considerable morbidity. However the contraceptives available today are not suitable to all users and the need to expand contraceptive choices still exists. Novel products such as new implants, contraceptive vaginal rings, transdermal patches and newer combinations of oral contraceptives have recently been introduced in family planning programs and hormonal contraception is widely used for spacing and limiting births. Concerns over the adverse effects of hormonal contraceptives have led to research and development of new combinations with improved metabolic profile. Recent developments include use of natural compounds such as estradiol (E2) and estradiol valerate (E2V) with the hope to decrease thrombotic risk, in combination with newer progestins derived from the progesterone structure or from spirolactone, in order to avoid the androgenic effects. Progesterone antagonists and progesterone receptor modulators are highly effective in blocking ovulation and preventing follicular rupture and are undergoing investigations in the form of oral pills and in semi long-acting delivery systems. Future developments also include the combination of a contraceptive with an antiretroviral agent for dual contraception and protection against sexually transmitted diseases, to be used before intercourse or on demand, as well as for continuous use in dual-protection rings. Alhough clinical trials of male contraception have reflected promising results, limited involvement of industry in that area of research has decreased the likelihood of having a male method available in the current decade. Development of non-hormonal methods are still at an early stage of research, with the identification of specific targets within the reproductive system in ovaries and testes, as well as interactions between spermatozoa and ova. It is hoped that the introduction of new methods with additional health benefits would help women and couples with unmet needs to obtain access to a wider range of contraceptives with improved acceptability.

Testosterone is an essential part of all regimens for hormonal male contraception tested to date. Initial efficacy trials revealed that the half-life of the testosterone preparations available at that time was too short to be used for male contraception. The ensuing search for long-acting preparations yielded testosterone buciclate and undecanoate as well as 7α-methyl-19-nortestosterone (MENT). Following description of the principle of male hormonal contraception and the efficacy trials performed to date, the systematic development of MENT for substitution of male hypogonadism and use in male contraception by the Population Council is reviewed here.