Nestorone Research Articles

Development of new hormonal male contraception for the couple.

Current options for male contraception are limited to condoms, the withdrawal method, or a vasectomy. Studies indicate that men have expressed growing interest in bearing responsibility for family planning. To review prior studies investigating the role of an androgen-only or androgen with progestin regimen for hormonal male contraception and to provide an update of a promising new hormonal agent, a transdermal gel. Thus far, there have been six studies conducted in couples evaluating the contraceptive efficacy of an androgen-only or androgen co-administered with a progestin regimen for hormonal male contraception. The only ongoing study is by the National Institute of Child Health and Human Development, in collaboration with the Population Council. They have developed a novel transdermal gel containing testosterone and segesterone acetate (Nestorone), a progestin. An ongoing phase II study enrolling more than 460 couples has shown great potential with respect to the product's efficacy, safety, reversibility, and acceptability. As this agent advances in development, a rapid at-home test for sperm concentration will provide couples with immediate feedback regarding their potential for pregnancy. There is promise for the first-of-its-kind hormonal male contraceptive, a transdermal gel, to achieve market approval for distribution in the United States and elsewhere. Its safety, efficacy, reversibility, and user-control are all appealing qualities that make it readily adoptable for clinical practice.

Use of serum evaluation of contraceptive and ovarian hormones to assess reduced risk of pregnancy among women presenting for emergency contraception in a multicenter clinical trial

ObjectiveTo evaluate ovulation risk among women enrolling in an emergency contraception (EC) study by measuring contraceptive steroids and ovarian hormones. Study DesignWe used standard chemoluminescent assays to evaluate endogenous hormones [estradiol (E2), progesterone (P4), FSH, LH] and liquid chromatography-tandem triple quadrupole mass spectrometry (LC-MS/MS) to simultaneously analyze concentrations of ethinylestradiol (EE), dienogest (DNG), norelgestromin (NGMN), norethindrone (NET), gestodene (GSD), levonorgestrel (LNG), etonogestrel (ENG), segesterone acetate (NES), medroxyprogesterone acetate (MPA), and drospirenone (DRSP), in serum samples obtained at the time of enrollment in a recent study comparing oral ulipristal acetate and LNG EC in women with weight ≥ 80kg reporting no recent use of hormonal contraception. ResultsWe enrolled 532 and obtained a valid baseline blood sample from 520 women. Of these, 117 (22.5%) had detectable concentrations of a progestin [MPA (n=58, 11.2%), LNG (50, 9.6%), ENG (11, 2.1%), NET (5, 0.96%), NGMN (3, 0.06%), or DRSP (1, 0.02%)]. LNG was co-detected in all three participants with samples containing NGMN. Multiple progestins were detected in 8 other women: ENG/MPA (1); ENG/LNG (2); MPA/LNG (5). Samples from 55 (10.6%) had concentrations of one or more progestin considered above the minimum level for contraceptive [MPA ≥ 0.1ng/mL, n = 19; NGMN/LNG ≥ 0.2ng/mL, n = 31; ENG ≥ 0.09 ng/mL, n = 8; NET ≥ 0.35 ng/mL, n = 4]. We detected concentrations of serum P4 ≥ 3ng/mL, indicative of luteal phase (post-ovulation) status, in an additional 194 (37.3%) samples. ConclusionsMore than one third of enrolled in our clinical trial of oral emergency contraception had evidence of prior ovulation at the time of enrollment. Additionally, about 23% had evidence of recent use of hormonal contraception recent use of hormonal contraception. This results would have decreased the expected risk of pregnancy in the study. ImplicationsMany participants in a recent clinical trial of oral emergency contraception did not appear to be at risk for pregnancy or would not have benefited from intervention due to cycle timing. Investigators should consider the effects of these findings on expected pregnancy rates when determining sample size in future EC clinical trials, particularly when using non-inferiority designs or historical controls.Keywords

Risk factors for and outcomes of ring expulsions with a 1-year contraceptive vaginal system

The US Food and Drug Administration-approved segesterone acetate and ethinyl estradiol ring-shaped contraceptive vaginal system, known as Annovera (Sever Pharma Solutions/QPharma, Malmö, Sweden), was inserted and removed under a woman's control for a 21 day in and 7 day out regimen for up to 13 cycles of use. We aimed to describe the patterns of ring expulsion over time, to identify potential predictors of expulsion, and to evaluate the impact of expulsions on method discontinuation and pregnancy risk. Using data from 2064 participants who were enrolled in 2 multinational phase 3 clinical trials on the use of this contraceptive vaginal system, we examined data from participants' daily diaries for documentation of complete ring expulsion. We modeled the odds of reported expulsions over time with adjustment for background and demographic characteristics using mixed-effects logistic regression models with random intercepts. We compared the probability of continuation between those who did and those who did not report expulsions in the first cycle of use using survival analysis and hazards modeling. To determine if expulsions during the first cycle of use affected the risk for pregnancy, we calculated Pearl Indices. Most participants (75%) never experienced any expulsions during any cycle of use, and 91% to 97% did not experience an expulsion during any 1 cycle. The incidence of expulsion was highest in cycle 1 (9%). The odds of experiencing expulsions decreased by half in cycles 2 to 8 when compared with cycle 1 (0.48; 95% confidence interval, 0.40-0.58), and in cycles 9 to 13, expulsions were about a third of that in cycle 1 (0.32; 95% confidence interval, 0.26-0.41). Of those who did experience expulsions, most (62%-84%) experienced ≤2 expulsions per cycle. Participants from study sites in Latin America vs those in the United States had higher odds of not experiencing an expulsion (odds ratio, 1.95; 95% confidence interval, 1.45-2.63). Women with a higher education level had higher odds of experiencing an expulsion. Notably, parity, age, and body mass index were not associated with expulsion. Participants who experienced any expulsions in cycle 1 were more likely to discontinue use early (hazard ratio, 1.28; 95% confidence interval, 1.14-1.43) than participants who did not have an expulsion. The Pearl Index for participants who had expulsions during cycle 1 was 3.99 (95% confidence interval, 1.29-9.31), which was higher than that among participants who reported no expulsions (Pearl Index, 2.39; 95% confidence interval, 1.61-3.41), but the overlapping confidence intervals indicate that there is not sufficient evidence to demonstrate an association between expulsions and pregnancy risk. Expulsions were infrequent overall, decreased with subsequent cycles of use, and were not associated with body mass index or parity. Early discontinuation of product use was higher among participants who experienced an expulsion during cycle 1. Although it is unclear whether pregnancy risk was associated with expulsions, early recognition of expulsions among users may identify those at higher risk for discontinuation and may highlight when enhanced anticipatory counselling and guidance may be advantageous.

FRI436 Design Of An International Male Contraceptive Efficacy Trial Using A Self-administered Daily Topical Gel Containing Testosterone And Nestorone™

Abstract Disclosure: S.T. Page: None. Support: Supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) through the Contraceptive Development Program’s Contraceptive Clinical Trials Network and by the Population Council. Background: A self-administered male hormonal contraceptive might be very useful to prevent unintended pregnancy. Prior efficacy studies of male hormonal contraceptives have relied on injections or implants of hormones by medical personnel. Transdermal testosterone gels are widely used to treat hypogonadism. Transdermal administration may have utility for male contraception as well; however, no contraceptive efficacy data from the use of a self-administered transdermal male hormonal contraceptive gel are available. Survey data suggests that men are not only interested in male contraception but that a self-administered transdermal gel is desired by many men as an optimal form of contraceptive delivery. A transdermal male contraceptive raises novel considerations regarding compliance with and absorption of the gel in men as well as concern regarding the potential cutaneous transfer of the hormones to the female partner. Previous studies in men have demonstrated that a combined Nestorone-(segesterone acetate) testosterone transdermal gel is well tolerated, and that it safely and effectively suppresses sperm production to contraceptive levels in men who apply it daily. Here we describe the design of an ongoing Phase 2b safety and efficacy trial of this transdermal male contraceptive gel. We discuss the novel aspects and challenges in the design and evaluation of an international transdermal male contraceptive efficacy study that was conducted during a global pandemic. Methods: We are conducting an international, single-arm, open-label study of self-administration of a daily combined Nestorone (segesterone acetate)-testosterone gel for male contraception. Couples are eligible for the study if they are in a committed relationship, at risk for unintended pregnancy and the men have normal spermatogenesis and are in good health. The primary outcome is the rate of pregnancy in couples during the 52-week efficacy phase of the study. Secondary endpoints include the proportion of men suppressing sperm production and entering the efficacy phase, side effects, hormone concentrations in both men and their female partners, sexual function, urinary symptoms, and regimen acceptability for the men and their female partners. ClinicalTrials.gov: NCT03452111. Results: Approximately 460 couples have been enrolled at 17 sites internationally including sites in North and South America, Europe and Africa. The study is now closed to enrollment. Conclusions: We present the design of the first study to examine contraceptive efficacy, side effect profile and acceptability of a self-administered, reversible, male hormonal contraceptive product. Presentation: Friday, June 16, 2023

Clinical Approaches to Nestorone Subdermal Implant Therapy in Women's Health.

Segesterone acetate (SA) or Nestorone, a fourth-generation progestogen, is a synthetic compound with high progestational activity and no androgenic, glucocorticoid, or anabolic effects. However, due to its oral inactivity, SA must be used by other routes, such as subcutaneous. Thus, considering its peculiar properties, the SA subdermal implant is successfully used in female contraception and postmenopausal hormone replacement therapy (HRT). In recent years, its potential uses in endometriosis, polycystic ovaries syndrome (PCOS), and a new therapeutic possibility for neuroprotection have made this treatment extremely interesting. However, the absence of a standardized dose and the long-term safety of SA implant therapy in women is still controversial. Here, we present the possible indications, doses, limitations, and side effects of SA implant therapy.

Development and validation of an expanded panel of progestins using liquid chromatography-tandem triple quadrupole mass spectrometry to monitor protocol compliance in hormonal contraceptive pharmacokinetic/pharmacodynamic studies

We developed and validated the use of ultra-high-performance liquid chromatography–heated electrospray ionization-tandem triple quadrupole mass spectrometry to simultaneously analyze serum concentrations of ethinylestradiol, dienogest, norelgestromin, norethindrone, gestodene, levonorgestrel, etonogestrel, segesterone acetate, medroxyprogesterone acetate, and drospirenone. The calibration range for all targets was 0.009–10 ng/mL, with lower limit of quantification of 0.009 ng/mL for all analytes except gestodene (0.019 ng/mL). We used our assay to check compliance among participants in a clinical trial, confirmed the use of drospirenone in 11 of 13 study participants, and evidence of noncompliant progestins in 2 (levonorgestrel = 1, norethindrone = 1). We conclude that this approach provides an accurate method to check protocol compliance in contraceptive clinical trials. ImplicationsThe availability of a liquid chromatography-tandem triple quadrupole mass spectrometry multiprogestin analysis panel for simultaneous evaluation of the most common contraceptive steroids approved worldwide could improve monitoring of compliance and protocol adherence in clinical trials.

O-044 The future of contraception

Abstract In 1960, the first hormonal contraceptive agent, Enovid approved by the Food and Drug Administration in the United States. The pill contained mestranol 150 mcg and norethynodrel 10 mg. High dose pills containing >50 mcg of estrogen were discontinued in 1988 due to a higher risk of myocardial infraction and stroke secondary to thrombosis. Until recently, the only estrogens used in combination OCPs were mestranol and ethinyl estradiol (EE). Estetrol (E4) and 17-beta estradiol have been added to newer pill and intravaginal ring (IVR) formulations in order to reduce the risk of thrombosis. Progestins confer the primary contraceptive effect in combination agents and can be used without estrogens. First generation progestins include norethynodrel, ethynodiol diacetate, norethindrone and norethindrone acetate (estranes). Second generation progestins include norgestrel and levonorgestrel (gonanes). Third generation include gestoden, desogrestrel and norgestimate, which are less androgen versions of the second generation progestins. Fourth generation progestins have no androgenicity include drospirenone. The fourth generation progestin is a 17 carbon compound which separates it from the other progestins that are primarily 19 carbon derivatives of androgens. Segesterone acetate (SA) is a newer progestin that is less potent and has no androgenic properties. SA, combined with EE, is currently being used in an IVR. However, clinical trials are ongoing using SA with 17-beta estradiol in an IVR and another with EE as a contraceptive gel. Other new methods of hormonal contraception include progestins in a biodegradable implant, longer acting injectables that can last 6-12 months, transdermal patches that are imbedded with an array of microneedles where either the contraceptive agent is in a reservoir or in the needles themselves. Microchip technology is being developed by the Gates Foundation that would allow levonorgestrel to be released systemically at will over a 16-year period using a remote device. Multipurpose technologies are being developed utilizing contraceptive pills, injectables and IVRs containing hormonal agents as well as medications to prevent STI/HIV acquisition.

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. ImplicationsThe 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.

Evaluations of memory, anxiety, and the growth factor IGF-1R after post-surgical menopause treatment with a highly selective progestin

Progestogens are a key component of menopausal hormone therapies. While some progestogens can be detrimental to cognition, there is preclinical evidence that progestogens with a strong progesterone-receptor affinity benefit some molecular mechanisms believed to underlie cognitive function. Thus, a progestin that maximizes progesterone-receptor affinity and minimizes affinities to other receptors may be cognitively beneficial. We evaluated segesterone-acetate (SGA), a 19-norprogesterone derivative with a strong progesterone-receptor affinity and no androgenic or estrogenic-receptor activity, hypothesizing that it would enhance cognition. Middle-aged rats underwent Sham or Ovariectomy (Ovx) surgery followed by administration of medroxyprogesterone-acetate (MPA; used as a positive control as we have previously shown MPA-induced cognitive deficits), SGA (low or high dose), or vehicle (one Sham and one Ovx group). Spatial working and reference memory, delayed retention, and anxiety-like behavior were assessed, as were memory- and hormone- related protein assays within the frontal cortex, dorsal hippocampus, and entorhinal cortex. Low-dose SGA impaired spatial working memory, while high-dose SGA had a more extensive detrimental impact, negatively affecting spatial reference memory and delayed retention. Replicating previous findings, MPA impaired spatial reference memory and delayed retention. SGA, but not MPA, alleviated Ovx-induced anxiety-like behaviors. On two working memory measures, IGF-1R expression correlated with better working memory only in rats without hormone manipulation; any hormone manipulation or combination of hormone manipulations used herein altered this relationship. These findings suggest that SGA impairs spatial cognition after surgical menopause, and that surgical menopause with or without progestin administration disrupts relationships between a growth factor critical to neuroplasticity.

Advances in contraception: vaginal contraceptive rings.

The vaginal contraceptive ring is very effective and user dependent. In this article, we will discuss the different types of vaginal contraceptive rings, namely, the etonogestrel/ethinyl estradiol (ENG/EE) ring (NuvaRing, Merck, Rahway, NJ, USA) and the segesterone acetate (SA)/EE (Annovera, Mayne Pharma, Raleigh, NC, USA) ring. The details of dosing and administration, indications, advantages, disadvantages, and cost-effectiveness are presented. This literature review was conducted using PubMed and Google Scholar. The search terms included 'vaginal contraceptive ring', 'etonogestrel/ethinyl estradiol ring', and 'segesterone acetate/ethinyl estradiol ring'. The search was then sorted by year from 2000 until present, and the most recent articles were reviewed. The purpose of this article is to provide a comprehensive reference on the two vaginal contraceptive rings widely used in the United States for clinicians to guide management. Both vaginal contraceptive rings are combination of hormonal contraceptives that suppress ovulation and create physiologic conditions unfavorable for pregnancy. The ENG/EE ring is designed to be replaced monthly, while the SA/EE ring is a single device used over the course of 1 year. Common side effects of both devices include headaches, nausea, vomiting, and vaginitis. Serious adverse reactions can occur with the vaginal contraceptive rings including venous thromboembolism, psychiatric events, and hypersensitivity. Both devices are contraindicated in patients at high risk for arterial or venous thrombotic events, patients with a history of breast cancer or other estrogen/progesterone cancers, and patients with severe liver disease. Overall, the vaginal contraceptive ring is well tolerated and liked by patients. Patients should be well counseled on known severe adverse reactions. The vaginal contraceptive ring is more expensive than other forms of contraception and this should be an important point of discussion with patients.

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.

Differential off-target glucocorticoid activity of progestins used in endocrine therapy

The glucocorticoid receptor (GR) regulates transcription of genes involved in multiple processes. Medroxyprogesterone acetate (MPA), widely used in the injectable contraceptive Depo-MPA (DMPA), has off-target effects via the GR, which may result in side-effects in endocrine therapy. However, very little is known about the GR activity of other progestins used in endocrine therapy. This study compared GR activities for several progestins, using whole cell binding, dose–response, and GR phosphorylation assays, in both a cell line model and peripheral blood mononuclear cells (PBMCs). MPA, etonogestrel (ETG) and nestorone (NES) exhibit greater relative binding affinities for the GR than levonorgestrel (LNG) and norethisterone/norethindrone (NET) and are partial GR agonists for transactivation but agonists for transrepression on synthetic promoters in COS-1 cells. MPA is a potent agonist for endogenous GR-regulated GILZ and IL6 genes in PBMCs. While ETG and NES also display agonist activity on IL6, they have little effect on GILZ. In contrast, LNG and NET exhibit little to no activity in transactivation models, while both exhibit some transrepressive activity but are generally less potent and/or efficacious than MPA. Antagonist and phosphorylation assays confirmed that MPA and NES act via the GR on endogenous genes in PBMCs. Our results suggest GR-mediated dose-dependent and gene-specific transcriptional side-effects are likely to occur at physiologically relevant concentrations in vivo for MPA, may possibly occur selectively for ETG and NES, but are unlikely to occur for LNG and NET. This suggests that these progestins will exhibit differential side-effects in endocrine therapy via the GR.

The use of serum segesterone acetate levels to assess adherence of trial participants with a contraceptive vaginal ring

ObjectivesTo determine the incidence of out-of-range segesterone acetate (NES) concentrations in participants of a pharmacokinetic/pharmacodynamic trial of a continuous use contraceptive vaginal ring (CVR) releasing NES and estradiol (E2). We hypothesized that out-of-range concentrations reflect nonadherent ring use and predict ovulation risk. Study DesignWe conducted a secondary analysis of data from a prospective, multi-centered, randomized, Phase IIa dose-finding trial for a CVR releasing NES and E2. Our primary outcome was the risk of ovulation associated with out-of-range NES events. We calculated the 5th and 95th percentile NES concentrations of subjects at steady state to determine high and low cutoffs. We used a Fisher's exact test to determine group differences, and calculated the relative risk of ovulation for each group. ResultsWe analyzed available serum NES data from cycles 2 (n = 172), 3 (n = 156) and 7 (n = 115) to determine the 5th and 95th percentile of all NES concentrations (64, 296 pg/mL). In the 443 cycles of observation, no ovulations occurred in participants with NES concentrations within the expected range. In contrast, we found ovulatory elevations of progesterone in 21 cycles with out-of-range values. Of these, 15 (71%) cycles had evidence of one or more nonadherent low and 6 (29%) one or more unexpected peak. The relative risk of ovulation increased with evidence of multiple non-adherent levels. ConclusionsWe found out-of-range NES concentrations, suggestive of improper use of a CVR associated with an increased risk of ovulation, with a direct relationship between the number of out-of-range events and the relative risk. ImplicationsThe results of this study support the use of out-of-range serum NES values as a marker of adherence in contraceptive clinical trials of continuous vaginal rings, and suggest that nonadherence occurs even in early phase clinical trials with close monitoring.

Nestorone nanosuspension-loaded dissolving microneedles array patch: A promising novel approach for “on-demand” hormonal female-controlled peritcoital contraception

“On demand” hormonal female-controlled pericoital contraception is one strategy which could be used to minimize the impact of unintended pregnancy. Nestorone (NES) is a potent contraceptive, with relatively few side effects in comparison with other contraceptives. NES presents an attractive option for “on demand” pericoital contraceptive. Unfortunately, the drug is inactive if taken orally, but it has high progestational activity and antiovulatory potency if administered parenterally. Current drug delivery systems, such as a transdermal hydrogel are not so satisfactory. Dissolving microneedles array (DMNs) are an attractive alternative, minimally-invasive, delivery system. In this study, we report, for the first time, development of tip-loaded NES-nanosuspension (NES-NS)-loaded bilayer DMNs to deliver NES intradermally for subsequent release. NES-NS was prepared and optimised, freeze-dried and then used to fabricate DMNs using a blend of two biocompatible polymers, namely poly(vinyl alcohol) and poly(vinyl pyrrolidone). Both NES-NS and the NES-NS-loaded DMNs were fully characterised and the performance of the DMNs was evaluated in vivo using Sprague Dawley rats. Results showed that the finalised NES-NS had particle size and PDI values of 666.06 ± 1.86 nm and 0.183 ± 0.01, respectively. The NES-NS-DMNs had relatively high tips-localised drug loading (approximately 2.26 ± 1.98 mg/array) and exhibited satisfactory mechanical and insertion properties. In Sprague Dawley rats, DMNs delivered NES into the skin, with the drug then appearing in blood and rapidly reaching its maximum concentration (Cmax of 32.68 ± 14.06 ng/mL) within 1 h post-DMNs application. Plasma levels above 3.4 ng/mL were maintained for 2 days. This suggests that DMNs are a promising drug delivery system that could be used to deliver NES as an “On demand” hormonal female-controlled pericoital contraceptive.

A DRUG-DRUG INTERACTION STUDY TO EVALUATE THE EFFECTS OF STRONG CYP3A INDUCTION ON THE PHARMACOKINETICS OF SEGESTERONE ACETATE AND ETHINYL ESTRADIOL IN A CONTRACEPTIVE VAGINAL SYSTEM

A contraceptive vaginal system (CVS) containing segesterone acetate (SA) and ethinyl estradiol (EE) was approved in the US (2018) for preventing pregnancy in women. The same ring-shaped CVS is used in a 21-days-in/7-days-out regimen for 13 cycles. Hormones are metabolized by the cytochrome p450A (CYP3A) system and inducers of CYP3A may increase their metabolism. Physiologically based pharmacokinetic (PK) modeling of SA hepatic clearance predicted that systemic exposure to SA would decrease ∼50% in the presence of a strong CYP3A inducer.

A DRUG-DRUG INTERACTION STUDY TO EVALUATE THE EFFECTS OF STRONG CYP3A INHIBITION ON THE PHARMACOKINETICS OF SEGESTERONE ACETATE AND ETHINYL ESTRADIOL IN A CONTRACEPTIVE VAGINAL SYSTEM

A contraceptive vaginal system (CVS) containing segesterone acetate (SA) and ethinyl estradiol (EE) was approved in the US (2018) for the prevention of pregnancy. The same ring-shaped CVS is used in a 21-days-in/7-days-out regimen for up to 13 cycles. Hormones are metabolized by the cytochrome p450A (CYP3A) system and inhibitors of CYP3A may decrease their metabolism. Physiologically based pharmacokinetic (PK) modeling of SA hepatic clearance predicted that systemic exposure to SA would increase up to 1.6-fold in the presence of a strong CYP3A inhibitor.

SATISFACTION WITH THE SEGESTERONE ACETATE AND ETHINYL ESTRADIOL CONTRACEPTIVE VAGINAL SYSTEM AMONG PREVIOUS ORAL CONTRACEPTIVE OR CONTRACEPTIVE VAGINAL RING USERS

To evaluate satisfaction with segesterone acetate and ethinyl estradiol (SA/EE; 0.15 mg/0.013 mg) contraceptive vaginal system (CVS) use among women who had recently used contraceptive vaginal rings or contraceptive pills. The CVS is a ring-shaped contraceptive, used in a 21-days-in/7-days out regimen for up to 13 cycles and indicated for the prevention of pregnancy in women with reproductive potential.

A stability indicating RP-HPLC- PDA method for simultaneous estimation of segesterone acetate and ethinyl estradiol in tablet dosage form

A simple, accurate, precise method was developed for the simultaneous estimation of the Segesterone acetate and Ethinyl estradiol in a tablet dosage form. The chromatogram was run through Discovery C18 150 x 4.6mm, 5mm column and mobile phase containing buffer 0.01N KH2PO4: Acetonitrile taken in the ratio 50:50 was pumped through the column at a flow rate of 1 ml/min. The temperature was maintained at 30°C. The optimized wavelength selected was 240.0 nm. Ethinyl estradiol and Segesterone acetate were eluted at 2.348 min and 3.855 min respectively.

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.

Segesterone acetate serum levels with a regression model of continuous use of the segesterone acetate/ethinyl estradiol contraceptive vaginal system

ObjectiveTo predict serum segesterone (SA) and ethinyl estradiol (EE) levels after 364 days of hypothetical continuous use (without removal) of a cyclic contraceptive vaginal system (CVS) containing 0.15 mg SA and 0.013 mg EE. Study designWe used pharmacokinetic (PK) data (n = 37) from a multicenter, open-label, nonrandomized study of healthy women (18–38 years) that used the CVS for 13 cycles in a 21 days-in/7 days-out regimen to develop a linear regression model to predict daily serum SA and EE levels for 364 days of continuous CVS use. We then determined residual SA/EE levels in vitro from 18 randomly chosen CVS used by women who completed 13 cycles. Serum SA and EE levels were also predicted for 364 days of continuous CVS use in another in vitro study. ResultsAfter a hypothetical 364 days of continuous CVS use, we predicted daily mean serum levels to be 184 pmol/L (95% confidence interval [CI], 102‒332 pmol/L) for SA and 43 pmol/L (95% CI, 19‒95 pmol/L) for EE. We did predict that serum EE levels would not accumulate over time. Residual SA and EE in the CVS were 60% and 80% of the original load after 13 cycles, respectively. ConclusionThe predicted serum SA level after 364 days of hypothetical continuous CVS use was comparable to reported levels at which no pregnancy occurred (>100 pmol/L), showing the potential of the CVS for one year of continuous use. Clinical trials on continuous CVS use are planned. ImplicationsBased on statistical modeling, the long-term, user-controlled contraceptive vaginal system containing segesterone acetate and ethinyl estradiol may have the potential to provide effective pregnancy prevention if used continuously (without removal) for one year. Further investigation is warranted.