OBJECTIVES:To compare discontinuation rates, satisfaction, and bleeding/pain outcomes over 3 years in a nulliparous population randomized to one of two copper IUDs. STUDY DESIGN:We performed secondary analyses of the nulliparous population (n = 927) in a US-based, participant-blinded, randomized trial of the NTCu380-Mini (n = 744) and the TCu380A (n = 183). We calculated overall cumulative Kaplan-Meier IUD discontinuation and reason-specific probabilities by year. At nine timepoints over three years, participants summarized IUD satisfaction (highly satisfied, satisfied, dissatisfied, or highly dissatisfied) and last menstrual bleeding patterns; we analyzed responses over time using generalized linear models and estimating equations (computing odds ratios). On first-year diaries, participants also recorded bleeding and menstrual/intermenstrual pain. RESULTS:Through one and two years, NTCu380-Mini users had lower overall discontinuation probabilities compared to TCu380A users: 24.8% vs. 32.8%, p = 0.03 and 39.6% vs. 48.0%, p = 0.02, respectively. Cumulative three-year rates were 50.1% (NTCu380-Mini) vs. 56.5% (TCu380A), p = 0.06. Through all intervals, NTCu380-Mini users had lower discontinuation rates due to bleeding and/or pain and lower expulsion rates relative to TCu380A users; cumulative three-years rate were 14.5% vs. 26.8%, p < 0.001 and 10.0% vs. 15.1%, p = 0.03, respectively. Participants reported higher satisfaction with the NTCu380-Mini (OR 1.29 [95% CI 1.01-1.64]). In the first year, median number of bleeding/spotting days in a cycle (7.0) did not differ between products, yet some prolonged bleeding outcomes and type of pain showed product differences favoring the NTCu380-Mini. CONCLUSION:Over 3 years, nulliparous NTCu380-Mini users had lower expulsion and discontinuation rates for bleeding and pain, and they reported higher satisfaction than TCu380A users. IMPLICATIONS:The NTCu380-Mini demonstrates comparative benefits in nulliparous users, with lower rates of early discontinuation due to pain and bleeding and expulsions. As copper IUDs are the only non-hormonal, long-acting reversible contraceptives available, future development should prioritize optimizing device design to minimize side effects while maintaining high contraceptive efficacy.

While there are several easy-to-use reversible female contraceptives, little is available for men. Introduction of novel, cost-effective male contraceptives could have important downstream global health and economic benefits. Currently, nearly half of all pregnancies globally are unintended, with many resulting in unsafe abortions, a significant burden for women and families in many countries. Available reversible options for male contraception include male condoms or withdrawal, both with high typical use failure rates, and vasectomy, which is not easily reversible. Advanced methods of male hormonal contraception include combinations of progestin and androgen, generally testosterone itself. Administration of these steroids results in the suppression of gonadotropins leading to the suppression of sperm production with full reversibility within a few months. Importantly, the exogenous androgen replaces the suppressed endogenous testosterone, minimizing side effects for the user. Using the skin to deliver steroids in the systemic circulation is a well-accepted concept both for the treatment of hypogonadism and contraception. A transdermal gel delivering Nestorone (segesterone acetate) and testosterone is under development and is leading the way in advancing novel, self-delivered methods of male hormonal contraception. (c) 2025 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

End-user feedback early in product development is important for optimizing multipurpose prevention technologies for HIV and pregnancy prevention. We evaluated the acceptability of the 90-day dapivirine levonorgestrel ring (DPV-LNG ring) used for 14 days compared to a dapivirine-only ring (DVR-200mg) in MTN-030/IPM 041 (n = 23), and when used for 90 days cyclically or continuously in MTN-044/IPM 053/CCN019 (n = 25). We enrolled healthy, non-pregnant, HIV-negative women aged 18-45 in Pittsburgh, PA and Birmingham, AL (MTN-030 only). Self-reports of vaginal bleeding and adherence (ring removals, expulsions) were collected via daily short message service. Acceptability data were recorded in face-to-face interviews at study exit. We assessed differences in acceptability by product characteristics and adherence; and associations between baseline characteristics/demographics, number of bleeding days, adherence, and overall acceptability. Most (21/23) women in the 14-day MTN-030 study and about half (13/25) in the 90-day MTN-044 study liked their assigned rings. In MTN-030 there were no significant associations between any variables and overall acceptability of either ring. In MTN-044, women who disliked the DPV-LNG ring had a significantly higher incidence of unanticipated vaginal bleeding, and reporting that vaginal bleeding changes were unacceptable than those who liked it. Although we found no overall association between adherence and acceptability, significantly more women who disliked (versus liked) the DPV-LNG ring reported expulsions during toileting. The DPV-LNG ring could meet the needs of women seeking simultaneous protection from HIV and unintended pregnancy. Addressing issues related to vaginal bleeding and expulsions early in product development will likely enhance acceptability of the DPV-LNG ring. Trial registration: Clinical Trial Registration: MTN-030/IPM 041: ClinicalTrials.gov NCT02855346; MTN-044/IPM 053/CCN019: ClinicalTrials.gov NCT03467347.

OBJECTIVE:We sought to develop consensus recommendations for measurement and analysis of data on contraceptive-induced menstrual changes (CIMCs) in contraceptive clinical trials. We built upon previous standardization efforts over the last 50 years and prioritized input from a variety of global experts and current regulatory authority guidance on patient-reported outcomes. STUDY DESIGN:We completed a formal consensus-building process with an interdisciplinary group of 57 experts from 30 organizations and 14 countries in five global regions who work across academia, nonprofit research organizations, the pharmaceutical industry, and funding agencies. Smaller topical working groups drafted and revised recommendations. RESULTS:We developed 44 consensus recommendations, including research approaches to establish the evidence for future improvement in the measurement and analysis of CIMC data and guidance for investigators to implement presently. Priority recommendations call for simplification of terminology to make measurement accessible and patient-centered, accounting for intrinsic and extrinsic factors that may impact outcomes during study design and recruitment, standardized data collection of primary CIMC and acceptability outcomes, and harmonized approaches for analysis of these data, including addressing missing data. CONCLUSION:By virtually convening a large group of global experts working across disciplines and sectors via a formal methodology, we developed consensus recommendations that will improve the current and future measurement and analysis of CIMC data in contraceptive clinical trials. Using these standardized approaches will permit valid and reliable contraceptive product labeling on CIMC outcomes that matter to users and greater comparability across trials that can inform clinical guidance and contraceptive counseling. IMPLICATIONS:Consensus recommendations on measuring bleeding changes and related outcomes in contraceptive clinical trials can improve reporting of standardized, patient-centered outcomes in future product labeling. These improvements can enable healthcare providers to offer more relevant guidance on contraceptives and users to make more informed decisions about their choice of method.

Background Intrauterine devices (IUDs) are highly effective, yet acceptability and continuation differ by user and device characteristics. We evaluated the efficacy of the NTCu380 Mini, a 380-mm2 copper IUD available in Europe and Canada, and compared safety and continuation with the TCu380A IUD, the 380-mm2 copper IUD available in the United States. Methods We randomly assigned participants between 16 and 40 years of age in a 4:1 ratio to the NTCu380 Mini or TCu380A and assessed over 37 months. The primary outcome was NTCu380 Mini efficacy measured by the Pearl Index (defined as the number of pregnancies per 100 woman-years) in participants 35 years of age and under. Additional outcomes included NTCu380 Mini time to pregnancy by survival analysis, and comparative adverse events (AEs) and continuation rates of NTCu380 Mini versus TCu380A. Results We randomly assigned 887 participants to NTCu380 Mini (744 [83.9%] nulliparous) and 218 to TCu380A (183 [83.9%] nulliparous), of whom 875 (98.6%) and 213 (97.7%), respectively, had successful placement. The NTCu380 Mini IUD 3-year cumulative Pearl Index was 1.86 (95% confidence interval [CI], 1.20 to 2.74) pregnancies per 100 women-years; the cumulative rate of pregnancy through year 3 was 4.8% (95% CI, 2.8 to 6.9%). Serious AEs occurred in 31 (3.5%) NTCu380 Mini and 4 (1.9%) TCu380A users (P=0.28). Discontinuation occurred in 449 (51.3%) NTCu380 Mini and 122 (57.3%) TCu380A users (P=0.07). AEs led to discontinuation less frequently among NTCu380 Mini (152 [20.8%]) than TCu380A users (57 [33.2%]) (P=0.001), particularly bleeding or pelvic pain AEs (103 [14.5%] vs. 46 [27.3%], respectively; P<0.001). Conclusions In this predominantly nulliparous population, the NTCu380 Mini IUD had an approximate 5% pregnancy rate over 3 years, with fewer side effects leading to discontinuation than observed among TCu380A users. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT03124160.) The findings and conclusions in this article are those of the authors and do not necessarily reflect the views of the Planned Parenthood Federation of America, Inc.

OBJECTIVES:To evaluate ovulation risk among women enrolling in an emergency contraception (EC) study by measuring contraceptive steroids and ovarian hormones. STUDY DESIGN:We used standard chemiluminescent assays to evaluate endogenous hormones (estradiol, progesterone, follicle stimulating hormone, luteinizing hormone) and liquid chromatography-tandem triple quadrupole mass spectrometry to simultaneously analyze concentrations of ethinylestradiol, dienogest, norelgestromin (NGMN), norethindrone (NET), gestodene, levonorgestrel (LNG), etonogestrel (ENG), segesterone acetate, medroxyprogesterone acetate (MPA), and drospirenone in serum samples obtained at the time of enrollment in a recent study comparing oral ulipristal acetate and LNG EC in women with weight ≥80 kg reporting no recent use of hormonal contraception. RESULTS:We enrolled 532 and obtained a valid baseline blood sample from 520 women. Of these, 117 (22.5%) had detectable concentrations of progestin (MPA [n = 58, 11.2%], LNG [50, 9.6%], ENG [11, 2.1%], NET [5, 0.96%], NGMN [3, 0.06%], or drospirenone [1, 0.02%]). LNG was co-detected in all three participants with samples containing NGMN. Multiple progestins were detected in eight other women: ENG/MPA (1), ENG/LNG (2), and MPA/LNG (5). Samples from 55 (10.6%) had concentrations of one or more progestin considered above the minimum level for contraceptive (MPA ≥ 0.1 ng/mL, n = 19; NGMN/LNG ≥ 0.2 ng/mL, n = 31; ENG ≥ 0.09 ng/mL, n = 8; NET ≥ 0.35 ng/mL, n = 4). We detected concentrations of serum progesterone ≥ 3 ng/mL, indicative of luteal phase (postovulation) status, in an additional 194 (37.3%) samples. CONCLUSIONS:More than one-third of enrolled in our clinical trial of oral EC had evidence of prior ovulation at the time of enrollment. Additionally, about 23% had evidence of recent use of hormonal contraception. These results would have decreased the expected risk of pregnancy in the study. IMPLICATIONS:Many 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 noninferiority designs or historical controls.

BackgroundCurrent 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.ObjectivesTo 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.DiscussionThus 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.ConclusionThere 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.

INTRODCTION:Human spermatogenesis is a complex process that transforms spermatogonial stem cells through mitosis and meiosis to spermatozoa. Testosterone is the key regulator of the terminal stages of meiosis, adherence of spermatids to Sertoli cells, and spermiation. Follicle-stimulating hormone (FSH) may be required for early spermatogenesis and is important for maintaining normal spermatogenesis in men. Hormonal contraception suppresses FSH, luteinizing hormone, and intratesticular testosterone concentration, resulting in marked suppression of sperm output. RESULTS:Clinical trials using testosterone alone or testosterone plus progestin demonstrate that sustained suppression of sperm concentration to ≤1 million/mL is sufficient to prevent pregnancy in the female partner. New agents that target spermatogenesis could use this as a target for contraceptive efficacy while others that block sperm function or transport may require a lower threshold. When sperm concentrations are suppressed to such low levels, measurement of sperm motility and morphology is technically difficult and unnecessary. With current data from fertile and infertile men, it is not possible to establish a lower limit of sperm motility or percent normal morphology that equates to the prevention of conception. New compounds that decrease sperm motility or alter sperm morphology may need to demonstrate a complete absence of sperm motility or altered morphology in all spermatozoa in the ejaculate. Sperm function tests may be useful depending on the mechanism of action of each new compound. CONCLUSION:Monitoring of sperm surrogate markers to ensure effective contraception relies on laboratories experienced in semen analyses. The development of at-home tests to assess sperm parameters has progressed rapidly. Some tests have been assessed in clinical trials and approved by regulatory agencies for at-home use for fertility assessment. However, caution must be exercised in using these tests as many have not been rigorously validated against semen parameters measured in laboratories by trained technologists using standardized tests defined in the World Health Organization Semen Manual.

11β-Methyl-19-nortestosterone dodecylcarbonate (11β-MNTDC) is a prodrug of 11β-MNT and is being considered as a promising male oral contraceptive candidate in clinical development. However, the oral administration of 11β-MNTDC exhibits an ~200-fold lower serum concentration of 11β-MNT compared to 11β-MNTDC, resulting in the poor bioavailability of 11β-MNT. To elucidate the role of the first-pass metabolism of 11β-MNT in its poor bioavailability, we determined the biotransformation products of 11β-MNT and its prodrugs in human in vitro models. 11β-MNT and its two prodrugs 11β-MNTDC and 11β-MNT undecanoate (11β-MNTU) were incubated in cryopreserved human hepatocytes (HHs) and subjected to liquid chromatography–high resolution tandem mass spectrometry analysis, which identified ten 11β-MNT biotransformation products with dehydrogenated and glucuronidation (11β-MNTG) metabolites being the major metabolites. However, 11β-MNTG formation is highly variable and prevalent in human intestinal S9 fractions. A reaction phenotyping study of 11β-MNT using thirteen recombinant UDP-glucuronosyltransferase (UGT) enzymes confirmed the major role of UGT2B17 in 11β-MNTG formation. This was further supported by a strong correlation (R2 > 0.78) between 11β-MNTG and UGT2B17 abundance in human intestinal microsomes, human liver microsomes, and HH systems. These results suggest that 11β-MNT and its prodrugs are rapidly metabolized to 11β-MNTG by the highly polymorphic intestinal UGT2B17, which may explain the poor and variable bioavailability of the drug.

INTRODUCTION: Menstrual cup use for menstrual hygiene is increasingly popular. We evaluated relationship of menstrual cup use and intrauterine device (IUD) expulsion in a prospective trial of two copper IUDs. METHODS: An ongoing 3-year contraceptive efficacy trial randomized women to one of two copper IUDs, with successful placement in 1,092 women. Institutional Review Board approval was obtained, and all subjects provided informed consent. Follow-up visits in the first year occurred at 6 weeks, and then 3, 6, and 12 months after insertion. At nine months after initiating enrollment, we modified the protocol to advise subjects against concurrent menstrual cup use with the IUD. We evaluated the association of menstrual cup use and expulsion risk over the first 24 months of study conduct. RESULTS: Overall, 266 (24.4%) women reported menstrual cup use. At 24 months after initiating enrollment, 46 (17.3%) cup users and 43 (5.2%) non-users experienced expulsion (odds ratio 3.81 [95% CI 2.45-5.92]). Fourteen (30.4%) menstrual cup users with expulsion reported the event occurred during menstrual cup removal. At Year 1 of the study, expulsion rates among menstrual cup users and non-users were 14.3% and 4.7%, respectively (P<.001). By the end of Year 2, these rates were 23.2% and 6.5% (P<.001). CONCLUSION: We found higher than expected IUD expulsion rates in menstrual cup users amongst participants in a prospective trial of two copper IUDs. Copper IUD users should be cautioned that concurrent menstrual cup use increases the risk of IUD expulsion and expulsion risk continues with ongoing menstrual cup use.

Abstract ID 97258Poster Board 038Despite the availability of effective female-centric contraceptives, millions of unintended pregnancies are reported annually.1 Recent developments in the realm of oral male contraceptives are viewed as promising steps to address this reproductive health challenge. The compound 11β-methyl-nortestosterone dodecylcarbonate (11β-MNTDC), a prodrug of 11β-MNT, is being developed as a hormonal male contraceptive.2 However, clinical data of oral 11β-MNTDC show poor and variable bioavailability, highlighting the need to investigate the mechanisms affecting its absorption into the systemic circulation.3 The specific aims of this study were to: i) identify biotransformation products of 11β-MNT and its prodrugs, and ii) characterize ’the isoforms of uridine 5'-diphospho-glucuronosyltransferases (UGTs) involved in glucuronidation of 11β-MNT. To identify biotransformation products, 11β-MNT, 11β-MNTDC, and another prodrug (11β-MNT undecanoate or 11β-MNTU) were incubated in cryopreserved human hepatocytes (n = 4 donors) for 120 min. The reaction was quenched and analyzed by nano-liquid chromatography-high resolution mass spectrometry (nLC-HRMS). The HRMS data were processed using an optimized metabolomics approach with XCMS Online software. This analysis revealed seven biotransformation products of 11β-MNT, including two major metabolites, dehydrogenation and glucuronidation products (11β-MNTG) with >10% relative mass response and five minor metabolites with a relative mass response of <2%. The structures of these metabolites were confirmed by MS/MS fragmentation data. The formation of the dehydrogenation product of 11β-MNT was higher in the hepatocyte incubation compared to 11β-MNTG; however, the latter was highly variable across samples. Retrospective analysis of hepatocyte data revealed a strong correlation (R2>0.99) between 11β-MNTG formation and UGT2B17 protein abundance. Subsequent incubation of 11β-MNT and its prodrugs in S9 fractions of the human intestine (HIS9) and liver (HLS9) showed formation of the same two major metabolites identified in the hepatocyte incubation. Interestingly, 11β-MNTG was higher in HIS9 in comparison to that of the dehydrogenation product, which corresponds to the higher abundance of UGT2B17 in the intestine than in the liver. The reaction phenotyping data, using thirteen different recombinant UGT enzymes, confirmed that UGT2B17 plays a primary role (98%) in the formation of 11β-MNTG, with a minor role played by UGT1A4, 1A8, 1A9 and 2B7 (<2%). Taken together, these findings imply that highly polymorphic intestinal UGT2B17 plays a critical role in the metabolism of 11β-MNT and its prodrug to 11β-MNTG, which could be one of the reasons for the poor and variable bioavailability seen in clinical studies.3Funding source: National Institutes of Child Health and Human Development (Contract No. 75N94020D00003 awarded to SRI International)

BACKGROUND:Dimethandrolone undecanoate (DMAU) is under development as a single agent hormonal male contraceptive. DMAU is a prodrug hydrolyzed by esterase(s) to the active metabolite dimethandrolone (DMA) which has dual androgenic and progestogenic actions. Phase 1 clinical trial results show DMAU to be well-tolerated as an oral contraceptive in healthy men; however, delivery of DMAU as a long-acting injectable rather than a daily oral formulation would provide user compliance benefits and address oral bioavailability concerns. OBJECTIVE:To assess the safety, pharmacokinetics (PK), and long-acting contraceptive potential of DMAU in male non-human primates (NHP) when delivered as an injectable or oral formulation. MATERIALS AND METHODS:DMAU was administered to cynomolgus macaques orally for 9 months or as five weekly intramuscular (IM) injections and to rhesus macaques as a single IM injection. Evaluations of safety, fertility indicators, and serum levels of DMAU and DMA were followed > 2 years post-dose. RESULTS:Repeat dose oral and IM administrations were well-tolerated with no significant toxicological findings. Dramatic reductions in serum testosterone concentration occurred within days of administration followed by sustained suppression of additional fertility indicators (e.g., serum inhibin B, sperm count, and testicular spermatogenesis). Slight body weight increases and reductions in testes weight also occurred. Repeat DMAU injections resulted in DMA serum concentrations above the lower limit of quantification (1 ng/mL) for > 500 days. DMAU PK parameters increased with increasing IM dose, while dose dependence was not seen for serum DMA concentrations suggesting a depot effect with a reservoir of non-circulating prodrug remaining at the injection site which gets slowly hydrolyzed to DMA and absorbed into circulation. Testosterone levels and spermatogenesis returned by the end of the recovery period. CONCLUSIONS:Nonclinical safety, PK, and pharmacodynamic data in male NHP demonstrate the safe, well-tolerated, long-acting, and reversible contraceptive potential of injectable DMAU.

BACKGROUND:Vaginal rings formulated to deliver two drugs simultaneously have potential as user-controlled, long-acting methods for dual prevention of HIV and pregnancy.METHODS:Two phase 1 randomized trials (MTN-030/IPM 041 and MTN-044/IPM 053/CCN019) respectively enrolled 24 and 25 healthy, HIV-negative participants to evaluate safety, pharmacokinetics, and vaginal bleeding associated with use of a vaginal ring containing 200mg dapivirine (DPV) and 320mg levonorgestrel (LNG) designed for 90-day use. MTN-030/IPM 041 compared the DPV/LNG ring to a DPV-only ring (200mg) over 14 days of use. MTN-044/IPM 053/CCN019 compared continuous or cyclic use of the DPV/LNG ring over 90 days of use. Safety was assessed by recording adverse events (AEs). DPV and LNG concentrations were quantified in plasma, cervicovaginal fluid, and cervical tissue. Vaginal bleeding was self-reported.RESULTS:There were no differences in the proportion of participants with grade ≥2 genitourinary AEs or grade ≥3 AEs with DPV/LNG ring vs. DPV ring use (p = .22), or with DPV/LNG ring continuous vs. cyclic use (p = .67). Higher plasma DPV concentrations were observed in users of DPV/LNG compared to DPV-only rings (Cmax p = 0.049; AUC p = 0.091). Plasma DPV and LNG concentrations were comparable with continuous and cyclic use (Cmax p = 0.74; AUC p = 0.25). With cyclic use, median nadir plasma DPV concentration was approximately 300 pg/mL two days after removal and median t1/2 for cervicovaginal fluid DPV concentration was 5.76 hours (n = 3). Overall bleeding experiences did not differ between continuous and cyclic users (p = 0.12).CONCLUSIONS:The extended duration DPV/ LNG rings were well tolerated and the observed DPV concentrations in plasma and cervicovaginal fluid when used continuously exceeded concentrations observed in previous DPV ring efficacy studies. LNG concentrations in plasma were comparable with other efficacious LNG-based contraceptives. Genital DPV concentrations had a short half-life and were thus not well sustained following ring removal.

ObjectiveTo compare the efficacy of oral emergency contraception (EC) regimens used within 72 hours of unprotected intercourse in individuals weighing >80 kg.Study DesignWe enrolled healthy women aged 18-40 years with a weight of at least 80 kg requesting EC in a multi-center, single-blind, randomized study of levonorgestrel 1.5 mg (LNG1X) and 3.0 mg (LNG2X) and ulipristal acetate 30 mg (UPA) (enrollment goal 1200). Key eligibility requirements included regular cycles, unprotected intercourse within 72 hours of enrollment, no use of hormonal contraception since last menstrual period, a negative urine pregnancy test (UPT), and willingness to abstain from intercourse until next menses. Study staff directly observed EC ingestion. To assess our primary outcome of incidence of pregnancy, participants completed home UPTs; if no menses by 2-weeks post-treatment, or a positive UPT, they returned for an in person visit with quantitative serum human chorionic gonadotropin (hCG) and ultrasound.ResultsWe enrolled and randomized 532; 44 were not dosed or not evaluable for primary end-point, leaving an analyzable sample of 488 (173 LNG1X, 158 LNG2X, 157 UPA) with similar demographics between groups [mean age 29.6 years (5.74), BMI 37.09 kg/m2 (6.95)]. Five pregnancies occurred during the study (LNG1X n = 1, LNG2X n = 1, UPA n = 3); none occurred during the highest at-risk window relative to estimated day of ovulation (day of ovulation and the 3 days prior). We closed the study prior to achieving our enrollment goal because the low pregnancy rate in all groups established futility based on an interim blinded analysis.ConclusionAlthough slow enrollment limited our study power, we found no differences in pregnancy rates between oral EC regimens among women weighing 80 kg or more. Our results are not able to refute or support differences between the three treatment arms.ImplicationsWomen weighing 80 kg or more experienced no differences in pregnancy rates between oral EC regimens but due to several significant study limitations including sample size and the lack of a study population at high risk of pregnancy, our results are not able to determine if differences in treatment effectiveness exist.

Male contraceptive development has included use of testosterone (T) with or without a progestin or the use of a single molecule such as progestogenic androgens (PA) for suppression of testicular T production. Expanding upon the vast amount of data accumulated from nortestosterone (NT), NT analogs, and their prodrugs, a new series of PA, the C7 methyl, and ethyl α-substituted T analogs 7α-Methyltestosterone (7α-MT) and 7α-Ethyltestosterone (7α-ET), respectively, were hypothesized and designed to have superior androgenic and progestogenic activities when compared with parent T. Results from androgen receptor and progesterone receptor competitive binding and transcriptional activation assays showed favorable activities for these T analogs. Additionally, 7α-MT and 7α-ET were shown to be active substrates for aromatase in vitro, mitigating a potential negative impact on bone mineral density with long-term use. In conjunction with this observation, the diminished metabolism of these T analogs by 5α-reductase may reduce potential concerns for prostatic growth. In the Hershberger in vivo rat bioassay, 7α-MT and 7α-ET showed superior androgenic and anabolic activities as compared with T. These C7 α-substituted T analogs also showed clear progestogenic activity in the McPhail bioassay which evaluated endometrial glandular arborization in a rabbit model. The discovery of aromatizable molecules with reduced metabolism by 5α-reductase that have androgenic, anabolic, and progestogenic properties indicates that the core and/or prodrugs of 7α-MT and 7α-ET are promising molecules for further development as male contraceptive PAs.

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 contra-ceptive 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 trans-dermal 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 spermato-genesis 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 pro-duction 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 contra-ceptive 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.& COPY; 2023 Elsevier Inc. All rights reserved.

Introduction:With high concurrent global rates of HIV incidence and unintended pregnancy, there is a need to provide options beyond condoms to enable users to simultaneously prevent HIV acquisition and pregnancy. Multiple vaginal rings are in development as "MPTs" (multipurpose prevention technologies) as they are shown to provide several co-occurring benefits such as discretion, convenience, reversibility and user control. Methods:In this Phase 1 trial of a 3-month MPT ring in the U.S., 25 participants (low-risk for HIV and pregnancy) were randomized to use the study ring for 90 days continuously or in 28-day cycles with 2-day removal periods in between. All participants completed in-depth interviews at the end of their study participation. Results:Overall, the ring was well tolerated. Participants resoundingly endorsed the concept of an extended-use, dual-purpose vaginal ring, but reported too many functional challenges and side effects to endorse this particular ring. Participants assigned to the continuous regimen reported more positive experiences with ring use than those in the cyclic group. A minority of participants who experienced minimal side effects and did not experience challenges with vaginal retention of the ring found it appealing. However, the majority of participants experienced challenges (ring slippage, expulsions, side effects, vaginal bleeding changes) with product use that outweighed the potential benefits and led them to report that - in the future - they would not be interested in using this specific version of the ring in its current form. A subset expressed interest in using the current MPT ring under certain conditions (e.g., if fewer expulsions, less bleeding, higher risk for HIV/pregnancy). Discussion:User feedback regarding participant experiences and challenges with the study ring was continuously shared with the product developer, underscoring the value of early-stage end-user feedback in product development.