Metabolism of progestogens used for contraception and menopausal hormone therapy.

A variety of progestogens are widely used by women for contraception and menopausal hormone therapy. The progestogens undergo extensive metabolism by oral and parenteral routes of administration to form many metabolites. Although a small number of metabolites have been shown to be biologically active, most have not been tested for biologic activity. The present review shows that we know most about progesterone metabolism, followed by the metabolism of levonorgestrel and norethindrone. Very few studies have been carried out on metabolism of most of the progestogens. The clinical significance of this deficiency is that those progestogen metabolites that bind to the progesterone receptors may also bind to other steroid receptors and be responsible for some of the well-documented side effects of administered progestogens. We also discuss how obesity and genetic polymorphisms alter progestogen metabolism, and how development of oral progestogen formulations that are targeted to the colon, where the concentration of steroid-metabolizing enzymes is much lower than in the proximal gut, may have a beneficial effect on progestogen metabolism.

Nestorone (segesterone acetate) effects on neuroregeneration.

Nestorone® (segesterone acetate) is a progestin with a chemical structure closely related to progesterone with high affinity and selectivity for the progesterone receptor without significant interaction with other steroid receptors. It has been developed for female and male contraception and is FDA-approved in a first long-acting contraceptive vaginal system for female contraception. Its safety has been extensively demonstrated in both preclinical and clinical studies for contraceptive indications. Nestorone was found to display neuroprotective and neuroregenerative activity in animal models of various central nervous system diseases, including multiple sclerosis, stroke, and amyotrophic lateral sclerosis. Reviewed herein are neuroprotective and myelin- regenerating properties of Nestorone in various animal models and its translational potential as a therapeutic agent for debilitating neurological diseases for which limited therapeutic options are available (Table 1).

Practice and development of male contraception: European Academy of Andrology and American Society of Andrology guidelines.

BACKGROUNDS: Despite a wide spectrum of contraceptive methods for women, the unintended pregnancy rate remains high (45% in the US), with 50% resulting in abortion. Currently, 20% of global contraceptive use is male-directed, with a wide variation among countries due to limited availability and lack of efficacy. Worldwide studies indicate that >50% of men would opt to use a reversible method, and 90% of women would rely on their partner to use a contraceptive. Additional reasons for novel male contraceptive methods to be available include the increased life expectancy, sharing the reproductive risks among partners, social issues, the lack of pharma industry involvement and the lack of opinion makers advocating for male contraception. AIM: The present guidelines aim to review the status regarding male contraception, the current state of the art to support the clinical practice, recommend minimal requirements for new male contraceptive development and provide and grade updated, evidence-based recommendations from the European Society of Andrology (EAA) and the American Society of Andrology (ASA). METHODS: An expert panel of academicians appointed by the EAA and the ASA generated a consensus guideline according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system. RESULTS: Sixty evidence-based and graded recommendations were produced on couple-centered communication, behaviors, barrier methods, semen analysis and contraceptive efficacy, physical agents, surgical methods, actions before initiating male contraception, hormonal methods, non-hormonal methods, vaccines, and social and ethical considerations. CONCLUSION: As gender roles transform and gender equity is established in relationships, the male contribution to family planning must be facilitated. Efficient and safe male-directed methods must be evaluated and introduced into clinical practice, preferably reversible, either hormonal or non-hormonal. From a future perspective, identifying new hormonal combinations, suitable testicular targets, and emerging vas occlusion methods will produce novel molecules and products for male contraception.

Design of an international male contraceptive efficacy trial using a self-administered daily transdermal gel containing testosterone and segesterone acetate (Nestorone).

Injectable male hormonal contraceptives are effective for preventing pregnancy in clinical trials; however, users may prefer to avoid medical appointments and injections. A self-administered transdermal contraceptive gel may be more acceptable for long-term contraception. Transdermal testosterone gels are widely used to treat hypogonadism and transdermal administration may have utility for male contraception; however, no efficacy data from transdermal male hormonal contraceptive gel are available. We designed and are currently conducting an international, multicenter, open-label study of self-administration of a daily combined testosterone and segesterone acetate (Nestorone) gel for male contraception. The transdermal approach to male contraception raises novel considerations regarding adherence with the daily gel, as well as concern about the potential transfer of the gel and the contraceptive hormones to the female partner. Enrolled couples are in committed relationships. Male partners have baseline normal spermatogenesis and are in good health; female partners are regularly menstruating and at risk for unintended pregnancy. The study's primary outcome is the rate of pregnancy in couples during the study's 52-week efficacy phase. Secondary endpoints include the proportion of male participants suppressing sperm production and entering the efficacy phase, side effects, hormone concentrations in male participants and their female partners, sexual function, and regimen acceptability. Enrollment concluded on November 1, 2022, with 462 couples and enrollment is now closed. This report outlines the strategy and design of the first study to examine the contraceptive efficacy of a self-administered male hormonal contraceptive gel. The results will be presented in future reports. IMPLICATIONS: The development of a safe, effective, reversible male contraceptive would improve contraceptive options and may decrease rates of unintended pregnancy. This manuscript outlines the study design and analysis plan for an ongoing large international trial of a novel transdermal hormone gel for male contraception. Successful completion of this and future studies of this formulation may lead to the approval of a male contraceptive.

Contraceptive drug, Nestorone, enhances stem cell-mediated remodeling of the stroke brain by dampening inflammation and rescuing mitochondria.

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.

[New frontiers in contraception research]. / Contraception au futur - Nouvelles techniques à l'horizon de la prochaine décennie.

Improving current contraceptives and discover novel methods easy to use with added health benefits would meet the needs of couples who seek alternatives to current methods. New delivery systems target user-controlled, longer-acting options to provide choice, user's autonomy and improve compliance. Self-injections, microarray patches, pod rings able to deliver several molecules aim to prevent both pregnancies and sexually transmitted infections. Improved intrauterine systems and non-surgical permanent methods are also on the research agenda. The search for novel methods must continue, to curb maternal mortality led by multiple pregnancies and unsafe abortion, still a burden in many countries.

TITLE: Contraception au futur - Nouvelles techniques à l'horizon de la prochaine décennie. ABSTRACT: 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.

Sex differences in the cerebroprotection by Nestorone intranasal delivery following stroke in mice.

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.

Contraceptive Technologies: Looking Ahead to New Approaches to Increase Options for Family Planning.

With persistently high global rates of unintended pregnancy and contraceptive nonuse, nonadherence 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.

Pharmacodynamics and pharmacokinetics of a copper intrauterine contraceptive system releasing ulipristal acetate: A randomized proof-of-concept study.

OBJECTIVES: To assess pharmacodynamic and pharmacokinetic outcomes of a novel copper (Cu) intrauterine system (IUS) releasing ulipristal acetate (UPA) in healthy women. STUDY DESIGN: In this single-blinded, randomized proof-of-concept study, ovulatory women received one of three Cu-IUSs releasing low-dose UPA (5, 20 or 40 µg/d) for 12 weeks. The study included a baseline cycle, three 4-week treatment-cycles and 2 recovery cycles. Primary outcomes included effects of the IUS on bleeding profile, ovarian function, and the occurrence of progesterone receptor modulator associated endometrial changes (PAEC). Pharmacokinetics and safety profile were secondary outcomes. We compared outcomes in treatment-cycle 3 with baseline, using generalized linear mixed models with orthogonal contrasts. RESULTS: We randomized 29 women (5 µg/d = 10, 20 µg/d = 10, 40 µg/d = 9). All had a successful IUS insertion; 27 completed the 12-week treatment period. Compared to baseline, the mean number of bleeding-only days at treatment-cycle 3 declined by 16.7% in the 5 µg/d group (3.6 vs 3.0, p = 0.66), 40.5% in the 20 µg/d group (4.2 vs 2.5, p = 0.14), and 77% in the 40 µg/d group (3.9 vs 0.9, p = 0.002). Most women reported reduction in the amount of bleeding: 4/8, 8/10, and 7/9 for the 5 µg/d, 20 µg/d, and 40 µg/d groups, respectively. During IUS use, ovulation occurred in most cycles [5 µg/d: 23/24 (96%), 20 µg/d: 26/30 (87%), 40 µg/d: 22/27 (81%)]. The frequency of PAEC at IUS removal was 1/10 (10%), 1/10 (10%) and 4/9 (44%) in the 5 µg/d, 20 µg/d, and 4 0 µg/d groups, respectively. No serious adverse events occurred. CONCLUSIONS: Reduction in bleeding, low incidence of PAEC, and no serious adverse events are reassuring findings of the novel Cu-UPA-IUS. The 20 µg/d seems the lowest dose promoting a favorable bleeding profile and limiting PAEC. IMPLICATIONS: The preliminary results of this short-term study of a novel copper intrauterine system (IUS) delivering ulipristal acetate showed reduction of bleeding, low incidence of progesterone receptor modulator associated endometrial changes, and absence of serious adverse events. By preventing copper-induced increase in bleeding, this IUS could provide a noncontraceptive benefit, especially for women with low hemoglobin.

Nestorone® , a 19nor-progesterone derivative boosts remyelination in an animal model of demyelination.

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.

Progress in progestin-based therapies for neurological disorders.

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.

Dose-finding study of a 90-day contraceptive vaginal ring releasing estradiol and segesterone acetate.

OBJECTIVE: To evaluate serum estradiol (E2) concentrations during use of 90-day contraceptive vaginal rings releasing E2 75, 100, or 200 mcg/day and segesterone acetate (SA) 200 mcg/day to identify a dose that avoids hypoestrogenism. STUDY DESIGN: We 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 ≥40 pg/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. RESULTS: Sixty-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 100 mcg/day groups were <40 pg/mL. In the 200 mcg/day group, median E2 concentrations peaked on days 4-5 of CVR use at 194 pg/mL (range 114-312 pg/mL) and remained >40 pg/mL throughout 30 days; E2 concentrations were 37 pg/mL (range 28-62 pg/mL) on days 88-90 (n = 11). Among the E2 200 mcg/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. CONCLUSIONS: Estradiol concentrations with rings releasing E2 200 mcg/day and SA 200 mcg/day avoid hypoestrogenism over 30-day use. IMPLICATIONS: A 90-day contraceptive vaginal ring releasing estradiol 200 mcg/day and segesterone acetate 200 mcg/day achieves estradiol concentrations that should avoid hypoestrogenism and effectively suppresses ovulation.

Progesterone vaginal ring as a new contraceptive option for lactating mothers: Evidence from a multicenter non-randomized comparative clinical trial in India.

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 < 0.001). Ring expulsions and menorrhagia were the most common discontinuation among PVR/IUD users respectively. The median duration of LA among PVR vs. IUD users was 405 vs. 120 days (p < 0.001). Both groups reported similar adverse events (PVR: 24.2%; IUD: 23.0%); there were no serious adverse events among PVR users. Infants from both groups fed 12-7 times/day and grew at expected rates. CONCLUSIONS: Efficacy and safety outcomes were comparable among women in both groups. Continuation rates for PVR, a woman-controlled method, were shorter than IUD rates while PVR users maintained LA significantly longer than IUD users. Infant breastfeeding and growth patterns/well-being were favorable in both groups. IMPLICATIONS: PVR, a user-controlled device, offers an additional contraceptive choice for lactating women for one-year postpartum use and can help to address the unmet need for contraception among postpartum women while encouraging breastfeeding to enhance infant growth and well-being.

Contraceptive technologies for global health: ethically getting to safe, effective and acceptable options for women and men.

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.

Bleeding profile associated with 1-year use of the segesterone acetate/ethinyl estradiol contraceptive vaginal system: pooled analysis from Phase 3 trials.

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 [

Reprint of: Beyond contraception and hormone replacement therapy: Advancing Nestorone to a neuroprotective drug in the clinic.

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.