Return to fertility, toxicology, and transgenerational impact of treatment with WIN 18,446, a potential male contraceptive, in mice.

OBJECTIVES: We examined the return to fertility and transgenerational impact of treatment with WIN 18,446, an experimental male contraceptive, in mice. STUDY DESIGN: We paired male mice treated with WIN 18,446 for 4 weeks to suppress spermatogenesis, followed by a 9-week recovery, and mated them with normal females to assess fertility. F1 generation mice were subsequently mated to ascertain any transgenerational impact of treatment on fertility. Testes were examined histologically. RESULTS: WIN 18,446-treated mice and their progeny produced normally sized litters (6.5 pups per litter after treatment and 7.3 pups per litter from the progeny). However, testes histology revealed rare residual intratesticular foci of mineralization after treatment. CONCLUSIONS: Fertility normalizes after WIN 18,446 treatment, and progeny also have normal fertility.

Male Contraception.

Approximately 40 to 50% of pregnancies are unintended. Contraceptive use significantly reduces the risk of unintended pregnancy. Approximately 70% of couples' contraceptive use is female and 30% is male, attributable to the reliance on condoms and vasectomies. Unfortunately, many women cannot use currently available contraceptives due to medical contraindications or side effects. At the same time, men want additional safe and effective contraceptive methods. Because of this, work to develop novel, safe, and effective male contraceptives is underway. This review will briefly discuss the pros and cons of condoms and vasectomies, and then describe research into the development of novel methods of male contraception, by the mechanism of action of the contraceptive. First, we will discuss male contraceptives that block sperm transmission. Next, we will discuss male contraceptives that impair sperm production. Lastly, we will discuss male contraceptives that impair sperm function.

Nonhormonal Male Contraceptive Development-Strategies for Progress.

Despite the widely demonstrated public health benefits of contraception, limited contraceptive options are available for men, placing both the contraceptive burden and opportunity solely on women. This review outlines the need for an increased focus on male contraceptive development and highlights several related topics, including the perspectives of women and men on male contraceptives, historical challenges, and reasons behind the persistent delays in male contraceptive development. It also discusses the importance of serendipitous observations in drug discovery and the limitations of depleting sperm or spermatogenic cells as a contraceptive approach. It further provides an overview of ongoing research and development on novel methods, with a goal to offer insights into the multifaceted aspects of nonhormonal male contraceptive development, addressing its implications for the health of men and women. SIGNIFICANCE STATEMENT: Despite well over half a century of effort in developing male contraceptives, there are no approved male contraceptive drugs on the market. This review aims to present strategies for progress in nonhormonal male contraception based on lessons learned from history, with the hope of expediting development and bringing a male contraceptive drug closer to reality.

[Male contraception]. / Contraception masculine.

CONTEXT: Contraception is a major global health issue, which is still dominated by female contraception. Developments in male contraception could help redistribute the contraceptive burden. METHODS: A literature search was carried out to review the existing options and the criteria for optimal contraception, to establish the principles of a male pre-contraception consultation, and to review the various research avenues with their advantages and disadvantages. RESULTS: The new male contraception options are detailed, whether hormonal (androgen therapy, combination of progestins and testosterone) or non-hormonal, particularly thermal, with current results and avenues for improvement. Condom use and vasectomy remain the only 2 validated options. The recent development of minimally invasive vasectomy without the need for a scalpel and of occlusion techniques has simplified the procedure, minimised the risk of complications (pain, haematomas, post-vasectomy pain syndrome) and improved efficacy. The issues of regret and the possibility of repermeabilisation are also raised. CONCLUSION: The question of male contraception will become increasingly important in consultations with urologists. The urologist will have to inform the patient, as required by law, before the vasectomy is performed, and provide the best possible advice on the technique, which will often be minimally invasive without the need for a scalpel. New reversible options should also broaden the range of options available on a routine basis, with a view to gradually moving towards contraceptive equity.

Novel progestogenic androgens for male contraception: design, synthesis, and activity of C7 α-substituted testosterone†.

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.

Interactions of the male contraceptive target EPPIN with semenogelin-1 and small organic ligands.

Novel male contraceptives will promote gender equality in sharing contraceptive responsibility. The sperm-associated protein epididymal protease inhibitor (EPPIN) is a promising target for non-hormonal male contraception. EPPIN interacts with the semen coagulum protein semenogelin-1 (SEMG1) on the sperm surface, leading to transient inhibition of sperm motility after ejaculation. Small organic molecules targeting EPPIN's SEMG1-binding are under development as male contraceptives. Here, we combined computational approaches to uncover key aspects underlying EPPIN binding to SEMG1 and small organic ligands. We generated a human EPPIN model showing a typical arrangement of the WFDC (Whey-acid four disulfide core)-type and Kunitz-type domains, connected by a hinge region. Determining the EPPIN model's intrinsic motion by molecular dynamics simulations and normal mode analysis revealed a conformation, presenting a binding pocket that accommodates SEMG1Glu229-Gln247, EP055, and EP012. EPPIN's residues Phe63 and Lys68 (WFDC domain), Asp71 (hinge region), and Asn113, Asn114, and Asn115 (Kunitz domain) were identified as hot spots for SEMG1, EP055, and EP012 binding. Moreover, hydrophobic and hydrophilic residues in the WFDC and Kunitz domains allow plasma membrane anchoring, orienting the EPPIN binding pocket to the solvent. Targeting EPPIN's essential residues for its biomolecular interactions may improve the rational design of EPPIN ligands as spermiostatic compounds.

Advances in non-hormonal male contraception targeting sperm motility.

BACKGROUND: The high rates of unintended pregnancy and the ever-growing world population impose health, economic, social, and environmental threats to countries. Expanding contraceptive options, including male methods, are urgently needed to tackle these global challenges. Male contraception is limited to condoms and vasectomy, which are unsuitable for many couples. Thus, novel male contraceptive methods may reduce unintended pregnancies, meet the contraceptive needs of couples, and foster gender equality in carrying the contraceptive burden. In this regard, the spermatozoon emerges as a source of druggable targets for on-demand, non-hormonal male contraception based on disrupting sperm motility or fertilization. OBJECTIVE AND RATIONALE: A better understanding of the molecules governing sperm motility can lead to innovative approaches toward safe and effective male contraceptives. This review discusses cutting-edge knowledge on sperm-specific targets for male contraception, focusing on those with crucial roles in sperm motility. We also highlight challenges and opportunities in male contraceptive drug development targeting spermatozoa. SEARCH METHODS: We conducted a literature search in the PubMed database using the following keywords: 'spermatozoa', 'sperm motility', 'male contraception', and 'drug targets' in combination with other related terms to the field. Publications until January 2023 written in English were considered. OUTCOMES: Efforts for developing non-hormonal strategies for male contraception resulted in the identification of candidates specifically expressed or enriched in spermatozoa, including enzymes (PP1γ2, GAPDHS, and sAC), ion channels (CatSper and KSper), transmembrane transporters (sNHE, SLC26A8, and ATP1A4), and surface proteins (EPPIN). These targets are usually located in the sperm flagellum. Their indispensable roles in sperm motility and male fertility were confirmed by genetic or immunological approaches using animal models and gene mutations associated with male infertility due to sperm defects in humans. Their druggability was demonstrated by the identification of drug-like small organic ligands displaying spermiostatic activity in preclinical trials. WIDER IMPLICATIONS: A wide range of sperm-associated proteins has arisen as key regulators of sperm motility, providing compelling druggable candidates for male contraception. Nevertheless, no pharmacological agent has reached clinical developmental stages. One reason is the slow progress in translating the preclinical and drug discovery findings into a drug-like candidate adequate for clinical development. Thus, intense collaboration among academia, private sectors, governments, and regulatory agencies will be crucial to combine expertise for the development of male contraceptives targeting sperm function by (i) improving target structural characterization and the design of highly selective ligands, (ii) conducting long-term preclinical safety, efficacy, and reversibility evaluation, and (iii) establishing rigorous guidelines and endpoints for clinical trials and regulatory evaluation, thus allowing their testing in humans.

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.

Men's willingness to use novel male contraception is linked to gender-equitable attitudes: Results from an exploratory online survey.

OBJECTIVES: To explore the association of men's willingness to use a novel male contraceptive with their attitudes toward gender equity. STUDY DESIGN: We conducted an anonymous online survey examining willingness to use male contraception among reproductive-age (18-50 years) cisgender men from the United States and Canada, recruited via online forums, social media ads, and male contraceptive mailing lists from April through July of 2022. We collected sociodemographics and reproductive histories and used a 20-item Gender-Equitable Men Scale to examine men's gender role attitudes. We conducted bivariate analyses to inform a multivariable logistic regression isolating the independent influence of increasingly gender-equitable attitudes on cis-men's willingness to use novel male contraceptives. RESULTS: We received 2066 surveys from primarily white (n = 1192; 58%), heterosexual (n = 1816; 88%), married cis-men (n = 1008; 49%), below age 30 (n = 1010; 49%), and who had not completed a bachelor's degree (n = 1173; 57%). The majority reported sex multiple times per week (n = 946; 46%), but had never gotten someone pregnant (n = 907; 44%); nearly half (n = 994; 48%) identified as parents. Three-quarters of respondents reported being willing to use novel male contraceptives (n = 1545; 75%); willingness was independently linked to having had an abortion (adjOR: 2.04; 95% CI: 1.37-3.02) and increasing total Gender-Equitable Men Scale scores (adjOR: 1.05; 95% CI: 1.02-1.08), even after controlling for age, race/ethnicity, and education. CONCLUSIONS: Three-quarters of cis-men surveyed reported willingness to use new male contraceptives, which was correlated with increasingly gender-equitable attitudes. IMPLICATIONS: As gender-equitable attitudes are linked to men's willingness to use novel male contraceptives, older population surveys may underestimate male contraceptive demand. Further, given the association of abortion experience with willingness to use novel male contraceptives, abortion-providing clinics may be considered for future dissemination of male contraceptives.

On-demand male contraception via acute inhibition of soluble adenylyl cyclase.

Nearly half of all pregnancies are unintended; thus, existing family planning options are inadequate. For men, the only choices are condoms and vasectomy, and most current efforts to develop new contraceptives for men impact sperm development, meaning that contraception requires months of continuous pretreatment. Here, we provide proof-of-concept for an innovative strategy for on-demand contraception, where a man would take a birth control pill shortly before sex, only as needed. Soluble adenylyl cyclase (sAC) is essential for sperm motility and maturation. We show a single dose of a safe, acutely-acting sAC inhibitor with long residence time renders male mice temporarily infertile. Mice exhibit normal mating behavior, and full fertility returns the next day. These studies define sAC inhibitors as leads for on-demand contraceptives for men, and they provide in vivo proof-of-concept for previously untested paradigms in contraception; on-demand contraception after just a single dose and pharmacological contraception for men.

Willingness to Use Male Contraceptive Pill: Spain-Mozambique Comparison.

Previous studies have suggested that social and cultural factors significantly influence people's willingness to use the male contraceptive pill, which is in relatively advanced development. The present study aims at comparing Spanish and Mozambican participants level of willingness to take a male contraceptive pill. Factorial designed scenarios were used to collect data on the two population samples (Spain = 402 participants; Mozambique = 412 participants). One-way analysis of variance (ANOVAs) were performed comparing the average scores of Mozambique and Spain at the levels of each modelled factor: The cost of the pills (30 €/USD 20 for 3 months vs. free); Efficacy (99% vs. 95%); Side effects (none, mild and severe); Context (disease, condom abandonment and diversification of contraceptive methods). The two groups found significant differences in the scores for each of the four factors, in light of the socio-cultural differences between the two countries. In the Spanish sample, the main factor affected the willingness to use male contraceptive pill (MCP) were the side effects, while for Mozambican men it was the context. Along with technological change, an ideological-social change in gender roles is required to ensure equity in contraceptive responsibilities and the participation of men at all socio-demographic levels in reproductive health.

Screening through Lead Optimization of High Affinity, Allosteric Cyclin-Dependent Kinase 2 (CDK2) Inhibitors as Male Contraceptives That Reduce Sperm Counts in Mice.

Although cyclin-dependent kinase 2 (CDK2) is a validated target for both cancer and contraception, developing a CDK2 inhibitor with exquisite selectivity has been challenging due to the structural similarity of the ATP-binding site, where most kinase inhibitors bind. We previously discovered an allosteric pocket in CDK2 with the potential to bind a selective compound and then discovered and structurally confirmed an anthranilic acid scaffold that binds this pocket with high affinity. These allosteric inhibitors are selective for CDK2 over structurally similar CDK1 and show contraceptive potential. Herein, we describe the screening and optimization that led to compounds like EF-4-177 with nanomolar affinity for CDK2. EF-4-177 is metabolically stable, orally bioavailable, and significantly disrupts spermatogenesis, demonstrating this series' therapeutic potential. This work details the discovery of the highest affinity allosteric CDK inhibitors reported and shows promise for this series to yield an efficacious and selective allosteric CDK2 inhibitor.

Why we need more methods for male contraception.

The US Supreme Court decision against abortion has once again triggered the call for male contraception. However, in addition to existing methods, there are further reasons why pharmacological reversible easy-to-use male contraception should be available. Green activists and environmentalists have to recognize that overpopulation consume resources. Medical progress results in increasing life expectancy and must be combined with contraception. Sharing the risks of contraception among partners and "Reproductive Autonomy for All" are ethical issues. The resistance of the pharmacological industry to becoming partners in male contraception must be overcome by public financial subsidies and popular demand.

Male contraception development: monitoring effective spermatogenesis suppression utilizing a user-controlled sperm concentration test compared with standard semen analysis.

OBJECTIVE: To determine whether a user-controlled sperm concentration test compared with standard semen analysis can effectively monitor spermatogenesis suppression for male contraception. DESIGN: Single center, prospective sub study of the ongoing clinical trial: "Study of daily application of Nestorone and testosterone combination gel for male contraception." SETTING: Research institute at an academic medical center. PARTICIPANT(S): Couples participating in the male contraceptive clinical trial. INTERVENTIONS: None. MAIN OUTCOME MEASURE(S): The ability by participants to monitor sperm suppression to a threshold compatible with contraceptive efficacy utilizing a user-controlled test verified by sperm concentration determined by standard laboratory methods. RESULT(S): Thirty-eight men participating in a hormonal male contraceptive clinical trial provided multiple samples during spermatogenesis suppression for this substudy. Participants, employing a user-controlled test, correctly identified the absence of sperm (a negative test) in 100% of their laboratory-confirmed azoospermic samples (n = 122). Participants also identified 100% of samples (n = 73) with sperm >0.2 million/mL as positive. Sperm counts between 0.01 and 0.2 million/mL were identified as negative in 96% of samples. Trial participants noted the overall ease of using the test with respect to sample preparation, test timing, and result interpretation, and that they could accurately use this test at home without difficulty. CONCLUSION(S): Participants undergoing spermatogenesis suppression in a hormonal male contraceptive trial performed user-controlled test to determine whether their semen sperm concentration was ≤ or >0.2 million/mL. Compared with standard semen analyses, participants correctly identified 100% of samples with sperm counts >0.2 million/mL as positive (Sensitivity 100%). A positive result when the couple is using a male contraceptive method triggers the need for semen analysis by a laboratory while the couple uses another method of contraception. Participants correctly diagnosed samples ≤0.2 million sperm/mL as negative in 99% of samples (specificity 99%). A negative result indicates a sperm concentration ≤0.2 million/mL, well below the threshold of ≤1 million/mL offering contraceptive efficacy demonstrated by prior studies. At-home sperm concentration test would minimize the need for users to return to the clinic to monitor suppression of spermatogenesis, decreasing cost and burden of male contraception trials and increasing practicality of the method. CLINICAL TRIAL REGISTRATION NUMBER: NCT: 03452111.

Design, Synthesis, and Pharmacological Evaluation of Second-Generation Soluble Adenylyl Cyclase (sAC, ADCY10) Inhibitors with Slow Dissociation Rates.

Soluble adenylyl cyclase (sAC: ADCY10) is an enzyme involved in intracellular signaling. Inhibition of sAC has potential therapeutic utility in a number of areas. For example, sAC is integral to successful male fertility: sAC activation is required for sperm motility and ability to undergo the acrosome reaction, two processes central to oocyte fertilization. Pharmacologic evaluation of existing sAC inhibitors for utility as on-demand, nonhormonal male contraceptives suggested that both high intrinsic potency, fast on and slow dissociation rates are essential design elements for successful male contraceptive applications. During the course of the medicinal chemistry campaign described here, we identified sAC inhibitors that fulfill these criteria and are suitable for in vivo evaluation of diverse sAC pharmacology.

The world needs better male contraceptives: What is taking so long?

Forty percent of US pregnancies are unintended despite currently available contraceptives. A substantial number of men use the currently available methods of male contraception, condoms and vasectomy, and a large majority would be interested in novel forms of male contraception if available. Research into male contraception has been ongoing for more than 50 years, with hormonal contraceptives nearing clinical utility and non-hormonal methods hopefully becoming available, albeit with a longer time frame. However, uncertainly regarding benchmarks for the efficacy and safety of male contraception continue to be an issue with development and regulatory approval. In addition, pharmaceutical industry support is minimal with the NIH and Foundations being the main research funders. Given the continuing high rates of unintended pregnancy, many of which are now occurring in areas with extremely restricted access to legal abortion, additional focus and investment in male contraceptive development is imperative.

The novel BRDT inhibitor NHWD870 shows potential as a male contraceptive in mice.

Small molecule inhibitors of the bromodomain and extraterminal domain (BET) family proteins have emerged as promising options not only for the treatment of multiple cancers but also for disturbing the process of sperm maturation with potential for use as viable contraceptive targets. In this study, we find that the BET family inhibitor NHWD870 and BRDT can bind well in vitro through bioinformatics software prediction and protein binding inhibition experiments. NHWD870 can produce a good contraceptive effect through animal experiments in vivo, and the fertility can be restored to normal after drug withdrawal. Transcriptomics and proteomics results suggest that NHWD870 affects pathways related to spermatogenesis and maturation, further contributing to the male infertility phenotype. Our results show that NHWD870 can induce a complete and reversible contraceptive effect in mice, which is stronger than that of JQ1 and its synthesized derivatives. This study is expected to eventually lead to clinical trials.