Male Contraceptive Research Articles

The regulation role of calcium channels in mammalian sperm function: a narrative review with a focus on humans and mice.

Mammalian sperm are characterized as specialized cells, as their transcriptional and translational processes are largely inactive. Emerging researches indicate that Ca2+ serves as a crucial second messenger in the modulation of various sperm physiological processes, such as capacitation, hyperactivation, and the acrosome reaction. Specifically, sperm-specific calcium channels, including CatSper, voltage-gated calcium channels (VGCCs), store-operated calcium channels (SOCCs), and cyclic nucleotide-gated (CNG) channels, are implicated in the regulation of calcium signaling in mammalian sperm. Calcium stores located in the sperm acrosomes, along with the IP3 receptors in the neck of the redundant nuclear envelope and the mitochondria in the tail, play significant roles in modulating intracellular Ca2+ levels in sperm. However, the functions and mechanisms of these calcium channels in modulating mammalian sperm physiological functions have not yet been well elucidated. Therefore, by focusing on humans and mice, this study aims to provide a comprehensive review of the current advancements in research regarding the roles of calcium signaling and associated calcium channels in regulating sperm function. This endeavor seeks to enhance the understanding of calcium signaling in sperm regulation and to facilitate the development of drugs for the treatment of infertility or as non-hormonal male contraceptives.

Post-Vasectomy Semen Analysis: What's All the Fuss about?

Vasectomy is a reliable male contraceptive method with a success rate exceeding 98%. Despite its efficacy, vasectomy is not foolproof, with potential early and late failures requiring careful postoperative monitoring via post-vasectomy semen analysis (PVSA). Published guidelines emphasize the necessity of conducting PVSA to ensure clinical sterility. Despite these clear guidelines, discrepancies in adherence and interpretation persist, with significant mismatches between guidelines and actual practice. Recent shifts in societal attitudes toward reproductive autonomy, spurred by significant political events and socioeconomic factors, have increased vasectomy rates, particularly among younger, childless men. This demographic change calls for enhanced PVSA compliance and clear communication about the non-immediate contraceptive effect of vasectomy. Home test kits have emerged as a convenient, though not always reliable, method for conducting PVSAs, which may require reevaluation in clinical practice. Given the variations across clinical guidelines and the challenges in achieving consistent PVSA outcomes, further research is needed to harmonize PVSA protocols across different health systems. PVSA is typically conducted between 8 and 16 weeks post-vasectomy, depending on the surgeon's preference. Success is confirmed when a fresh, uncentrifuged sample exhibits either azoospermia, rare non-motile sperm (RNMS), or fewer than 100,000 non-motile sperm per milliliter. This effort will ensure that both patients and practitioners can rely on vasectomy as a safe and effective form of contraception. Effective patient counseling and strategic follow-up are crucial when it comes to managing expectations and ensuring compliance with post-vasectomy protocols, thereby minimizing the risk of unintended pregnancies post-procedure.

Socioeconomic determinants of male contraceptive use in South Africa: a secondary analysis of the 2016 SADHS data

BackgroundHistorically, family planning discussions have predominantly centred on women, overlooking the crucial role men play in contraception. This is particularly concerning in regions like Sub-Saharan Africa (SSA), where reproductive health challenges are pronounced. South Africa, a key country within SSA, continues to grapple with issues such as high unintended pregnancy rates and increasing pregnancy-related mortality. Understanding the factors that deter male contraceptive use is essential for achieving universal access to sexual and reproductive health (SRH) services. This study investigates the socioeconomic disparities influencing male contraceptive use in South Africa, drawing on data from the 2016 South Africa Demographic Health Survey.MethodsThe study utilised data from the 2016 South African Demographic and Health Survey, which employed a stratified, two-stage sampling design across all provinces based on the 2011 Census. The survey focused on men aged 15–59 using the “Man’s Questionnaire.” Various socio-demographic and attitudinal variables were analysed using STATA 17. The analysis included multinomial logistic regression to identify determinants of male contraceptive use and the Erreygers Normalized Concentration Index to assess socioeconomic inequalities in contraceptive uptake.ResultsAmong the surveyed men, 47% reported not using any contraception, 40% used male methods, and 13% relied on their partners’ contraceptive use. A majority began sexual activity between the ages of 14–17 (54%), resided in urban areas (56%), were unmarried (67%), and had attained secondary education (70%). Notably, 78% disagreed that contraception is solely a woman’s responsibility, and 64% expressed positive attitudes toward contraception. Age, marital status, and education level emerged as significant factors influencing contraceptive use. The study revealed a slight pro-rich inequality in male contraception use, with socioeconomic status (SES) being the most significant contributor to this disparity (223.22%). This suggests that higher SES is associated with increased inequality in the adoption of modern male contraceptive methods.ConclusionThese findings highlight the impact of socioeconomic disparities and entrenched cultural beliefs on male contraceptive use in South Africa. To address these challenges, comprehensive strategies that prioritise education, expand family planning media campaigns and ensure equitable access to contraception are urgently needed.

The role of S-palmitoylation of C4BPA in regulating murine sperm motility and complement resistance

The epididymis and epididymosomes are crucial for regulating sperm motility, a key factor in male fertility. Palmitoylation, a lipid modification involving the attachment of palmitic acid to cysteine residues, is essential for protein function and localization. Additionally, this modification plays a vital role in the sorting of proteins into exosomes. This study investigates the role of S-palmitoylation at the Cys15 residue of the C4b binding protein alpha chain (C4BPA) in murine sperm motility. Our findings revealed high expression of C4BPA mRNA in the caput epididymis, with the protein present across all regions of the epididymis. Palmitoylation of C4BPA in epididymal epithelial cells was essential for its enrichment in epididymosomes and on sperm, thereby maintaining sperm motility. Inhibition of palmitoylation significantly reduced sperm motility and the localization of C4BPA on sperm. Additionally, palmitoylated C4BPA in exosomes resisted complement C4 attacks, preserving motility, unlike mutated C4BPA (C15S). These results highlight the critical role of palmitoylated C4BPA in protecting sperm from complement attacks and maintaining motility, suggesting that reversible palmitoylation of epididymal proteins could be explored as a therapeutic strategy for male contraception. Our study underscores the importance of post-translational modifications in sperm function and presents new insights into potential male contraceptive methods.

Novel Genes of the Male Reproductive System: Potential Roles in Male Reproduction and as Non-hormonal Male Contraceptive Targets.

The development of novel non-hormonal male contraceptives represents a pivotal frontier in reproductive health, driven by the need for safe, effective, and reversible contraceptive methods. This comprehensive review explores the genetic underpinnings of male fertility, emphasizing the crucial roles of specific genes and structural variants (SVs) identified through advanced sequencing technologies such as long-read sequencing (LRS). LRS has revolutionized the detection of structural variants and complex genomic regions, offering unprecedented precision and resolution over traditional next-generation sequencing (NGS). Key genetic targets, including those implicated in spermatogenesis and sperm motility, are highlighted, showcasing their potential as non-hormonal contraceptive targets. The review delves into the systematic identification and validation of male reproductive tract-specific genes, utilizing advanced transcriptomics and genomics studies with validation using novel knockout mouse models. We discuss the innovative application of small molecule inhibitors, developed through platforms like DNA-encoded chemistry technology (DEC-Tec), which have shown significant promise in preclinical models. Notable examples include inhibitors targeting serine/threonine kinase 33 (STK33), soluble adenylyl cyclase (sAC), cyclin-dependent kinase 2 (CDK2), and bromodomain testis associated (BRDT), each demonstrating nanomolar affinity and potential for reversible and specific inhibition of male fertility. This review also honors the contributions of Dr. David L. Garbers whose foundational work has paved the way for these advancements. The integration of genomic, proteomic, and chemical biology approaches, supported by interdisciplinary collaboration, is poised to transform male contraceptive development. Future perspectives emphasize the need for continued innovation and rigorous testing to bring these novel contraceptives from the laboratory to clinical application, promising a new era of male reproductive health management.

A REVIEW STUDY ON ROLE OF CONTRACEPTIVES AND THEIR VARIOUS TYPES.

Contraception is the process used to stop unwanted pregnancy and control birth rate. Contraceptives reduces the chances of pregnancy after sexual intercourse. Contraceptives prevent pregnancies by interfering with the procedure of fertilization. Contraceptives reduces the chances of abortion by preventing unintended pregnancies on their partners, in which 842 million (44%) are modern using modern methods of Contraceptives are accessible in huge varieties and types . Numerous contraceptives are available, 790 million (42%) are traditional method users according the statistical data of 2019. The most common contraceptive techniques that are use of contraceptives are increasing day by day, 922 million of women of reproductive age used worldwide are female sterilization and male condoms, female sterilization are used in 219 million users (24%), male condoms are used in 189 million users (21%) according the data of 2019. The use of traditional methods and IUDs has reduced worldwide since 1994. According to WHO, The only form of birth control is a condom,that can prevent both unintended pregnancies and sexually transmitted diseases. The need of family planning is increased globally up to 77% from 2015 to 2020.. Over the past 20 years, the number of women using family planning methods has grown, rising from 900 million in 2020 to 2000 million. Use of modern contraceptive methods is also increased from 663 million to 851 million with the prevalence rate of 47.7% to 49.0%. Numerous contraceptive methods exist, including hormonal methods like CHC vaginal ring, CHC transdermal patch, and combination hormonal contraceptives. Progestin-only techniques include hormonal male contraceptives, progestin-only pills, DMPA injections, implants, and progestin-only IUDs. The other approach is non-hormonal and consists of vaginal pH modulators, barrier techniques like condoms, and copper IUDs. Traditional methods, such as the LAM method, the fertile cycle method, and the withdrawal approach, comprise the third type of contraception. Herbal contraceptives, which use a variety of herbs and plant preparations, are the fourth technique of birth control.

Pre-Clinical Study of Hydro-Ethanol (60:40) Extract of <i>Areca catechu</i> (L.) on Testicular Androgenesis in Albino Rat: An Approach for Herbal Male Contraceptive Development

The present study was designed to determine the anti-testicular activity of hydro-ethanol seed extract of Areca catechu (10, 20 and 40 mg) in dose-dependent fashion in albino rats. Seminal vesicular fructose (SVF), oxidative stress sensors, gene expression, somatic weight, reproductive organo-somatic indices, spermiological, hormonal profile, and testicular histological examination for qualitative and quantitative investigations of spermatogenesis were observed. In compared to the placebo treated control (PTC), the exposure of the said doses showed a statistical significant downward deviation in the spermiological, hormonal, SVF profile, kinetics of testicular key androgenic dehydrogenase enzymes, and diameters of seminiferous tubules. Anti-oxidant enzyme kinetics were reduced significantly against PTC, and the quantity of malondialdehyde in male gonad and sperm precipitate was elevated in significant level (p<0.05). Expression of apoptotic promoting gene in testis was increased (p<0.05) and anti-apoptotic Bcl-2 gene expression exhibited a significant decrease (p<0.05) in treated group comparison to the PTC. The alterations in the activities of phosphatases in hepatic tissue was not significant from the background of PTC suggesting that the plant has no systematic undesirable effect in physiological processes. The observation highlighted that 10 mg dose as the threshold dose for imposition of such anti- testicular activity leading to male contraception.

Male contraceptive acceptability versus male acceptance of contraceptive responsibility.

Despite the projected impact of new male contraceptives, resources and investments directed at their development remain limited in part due to concerns that men would not actually use them. Now, more than 30 studies have been conducted over the last 30 years-regionally and internationally, within clinical trials, and across populations-examining men and women's attitudes towards new male contraceptive methods, all consistently demonstrating interest in and willingness to use new methods. Yet even these studies, inclusive of competitive contraceptive market projections, seem not to be convincing enough. Rather than study whether men would be willing to use male contraceptives, more resources should be devoted to developing the infrastructure and supporting the cultural changes needed to ensure that when new male contraceptives inevitably emerge, that they will be disseminated quickly and made readily accessible. Men's views on what their roles are in society, families, relationships, and pregnancy prevention are changing in ways that may impact what they consider to be acceptable contraceptive risks. As society moves toward more gender equitable beliefs, men's positive involvement in contraception might organically develop into an expected behavior. Interventions aimed at sensitizing men toward gender equitable beliefs may pay dividends in improving male contraceptive acceptability. The current lack of a reversible male contraceptive method prevents us from collecting data that might disprove presumptions that men would be unwilling to take on responsibility for pregnancy prevention. However, studies of men's involvement in (1) over-the-counter emergency contraception, (2) vasectomy, and (3) abortion offer case studies for men's increasing consciousness of opportunities for shared contraceptive responsibility, the structural and sociopolitical barriers that men face when trying to participate in family planning, and how these might translate into new male contraceptive interest and development.

Population differences in responses to male hormonal contraception (lessons learned from the WHO-CONRAD phase III study)

Population differences in responses to male hormonal contraception (lessons learned from the WHO-CONRAD phase III study)

Population differences in responses to male hormonal contraception (lessons learned from the WHO-CONRAD phase III study)

Population differences in responses to male hormonal contraception (lessons learned from the WHO-CONRAD phase III study)

The male birth control pill - A new approach to family planning and population control.

With the increase in the world's population, contraception is crucial in population control strategies. Majority of contraceptives produced today are targeted at women; many of whom experience side effects, leading to the discontinuation of these contraceptives after a year of use. As the use of condoms and vasectomies has been subjected to scrutiny, it is necessary for the development of male birth control (BC). Attempts to achieve this include hormonal and non-hormonal contraception. Hormonal contraception prevents the production of the sperm in the testes; but this mode of BC has been found to be ineffective while also causing behavioural changes in men. In contrast, non-hormonal male contraception focuses on rendering the sperm immotile to prevent fertilization post-copulation. Soluble adenylate cyclase is an area of research that has shown promise in this field. Furthermore, two inhibitors, TDI-10299 and TDI-11861, have been developed and tested, with the latter, showing greater potency and longer activity, in mice models. Overall, by developing non-hormonal male contraceptives, men will have more control over their reproductive health. Nonetheless, before such contraceptives can be made widely available, it is important that further research takes place to ensure the safety and effectiveness of these methods.

A new vision for male contraception research and development

A new vision for male contraception research and development

Treatment with Terminalia chebula (retz.): possible mechanism of inhibition of spermatogenesis and fertility in albino mice

Background: There has been a continued effort to develop an effective male contraceptive of plant origin due to its ready availability, cost-effectiveness, and fewer side effects. The present study has evaluated the mechanism of inhibitory action of Terminalia chebula Retz. (T. chebula; family: Combretaceae) on spermatogenesis and fertility in albino mice after oral administration of the aqueous bark extract (100, 300, and 500 mg/kg BW daily) of T. chebula for 35 d. Methodology: The effects of the Terminalia treatment on various reproductive endpoints such as sperm parameters, testis histology, activities of 3ß- and 17ß-HSDs, immunoblot expressions of StAR and AR proteins, immunostaining of AR, serum testosterone level, LPO level, activities of SOD and catalase, and fertility indices were investigated. Toxicological and recovery studies have also been performed. Results: Testes in Terminalia-treated mice showed nonuniform histologic alterations. Sperm parameters, activities of 3ß- and 17ß-HSDs, immunoblot expressions of StAR and AR proteins, immunostaining of AR, and serum testosterone level were adversely affected, though activities of SOD and catalase were unchanged. Libido remained unaffected, but fertility was inhibited markedly in treated males without signs of toxicity. By 42 d of treatment discontinuation, Terminalia-induced deviations in the reproductive endpoints recovered to control levels. Conclusion: The results of the present study indicate that T. chebula treatment reversibly inhibits spermatogenesis and fertility without signs of toxicity. Further, antifertility effects result from diminished production of testosterone due to Terminalia-mediated inhibition of testicular steroidogenesis.

Human efferent ductules and epididymis display unique cell lineages with motile and primary cilia.

Previous research has illustrated the role of cilia as mechanical and sensory antennae in various organs within the mammalian male reproductive system across different developmental stages. Despite their significance in both organ development and homeostasis, primary cilia in the human male reproductive excurrent duct have been overlooked due to limited access to human specimens. This study aimed to characterize the unique cellular composition of human efferent and epididymal ducts, with a focus on their association with primary cilia. Human efferent ductules/epididymides from five donors aged 32-47 years, were obtained through our local organ transplant program. Cell lineage specificity and primary cilia features were examined by immunofluorescent staining and confocal microscopy in the efferent ductules and the distinct segments of the epididymis. The epithelium of the human efferent duct exhibited estrogen receptor-positive cells with primary cilia, FoxJ1-positive multiciliated cells with numerous motile cilia, and non-ciliated intraepithelial immune cells. Notably, intraluminal macrophages, identified by CD163/CD68 positivity, were observed to engage in sperm phagocytosis. In all three segments of the human epididymis, primary cilia were found on the surface of principal and basal cells. Our research indicates that the human efferent ductules create a distinct environment, characterized by the presence of two types of ciliated cells that are in contact with immune cells. The discovery of sensory primary cilia exposed on the surface of reabsorptive cells in the efferent ductules, as well as on basal and principal cells in the epididymis, lays the foundation for complementary functional studies. This research uncovers novel characteristics exclusive to human efferent ductules and epididymides, providing a basis for exploring innovative approaches to male contraception and infertility treatment.

Testosterone and male contraception.

Rates of unintended pregnancy have remained relatively stagnant for many years, despite a broad array of female contraceptive options. Recent restrictions on access to abortion in some countries have increased the urgency for expanding contraceptive options. Increasing data suggest men are keen to utilize novel reversible male contraceptives. Despite decades of clinical research in male contraception, no reversible hormonal product currently exists. Nestorone/testosterone, among other novel androgens, shows promise to finally move to pivotal Phase 3 studies and introduction to the marketplace. Hormonal male contraception utilizes androgens or androgen-progestin combinations to exploit negative feedback that regulates the hypothalamic-pituitary-testicular axis. By suppressing release of gonadotropins, these agents markedly decrease endogenous testosterone production, lower intratesticular testosterone and suppress spermatogenesis. The addition of a progestin enhances the degree and speed of sperm suppression. The androgen component preserves a state of symptomatic eugonadism in the male. There is growing demand and acceptance of male contraceptive options in various forms. As these formulations progress through stages of drug development, regulatory oversight and communication with developers around safety and efficacy standards and garnering industry support for advancing the production of male contraceptives will be imperative.

Assessment of demand for male contraceptives: A multi-country study.

As of 2019, high unmet contraceptive needs in low- and middle-income countries result in nearly half of all pregnancies being unintended. Additional male contraceptive options could help, but gaps remain in assessing demand for them. As the development of novel male contraceptives progresses, addressing these gaps would help inform policy and scientific direction. Measure consumer demand for novel male contraceptives and identify product attributes associated with men's preferences. A cross-sectional, probability-based-sample survey was conducted with 12,435 sexually active, fertile cisgender, heterosexual men aged 18-60 years, and 9,122 of their female partners in Bangladesh, Vietnam, Kenya, Nigeria, DR Congo, and Côte d'Ivoire from May 2021 to October 2022. The survey was also conducted in the United States among 3,243 of these men in April 2022. A follow-up with 3,070 men in May 2023 assessed potential changes in demand after the Supreme Court's Dobbs v. Jackson Women's Health Organization decision. The surveys assessed contraceptive use, perceptions, and sociodemographic characteristics, and a discrete choice experiment evaluated preferences for 11 potential product attributes. Data from female partners in the six LMICs indicated their interest and trust in male partners' contraceptive use. On average, 61% of men showed interest in trying novel male contraceptives in their first year of availability, ranging from 39% and 49% (pre- and post-Dobbs) in the United States to 76% in Nigeria and Bangladesh. Form of administration and time of use drove men's product preferences. Female partners' interest and trust in male contraceptive use were high across geographies. This study reveals strong latent demand for novel male contraceptives, highlighting the potential for novel male methods to meet unmet needs, and female partners' trust in men to use them. High demand for novel male contraceptives among men and their partners exists, supporting investment in their development.

Extracellular cAMP elicits contraction of rat vas deferens: Involvement of ecto-5′-nucleotidase and adenosine A1 receptors

AimsIt is well established that intracellular cAMP contributes to the relaxation of vas deferens smooth muscle. In many tissues, intracellular cAMP is actively transported to the extracellular space, where it exerts regulatory functions, via its metabolite adenosine. These actions take place through the cAMP conversion to adenosine by ectoenzymes, a process called “extracellular cAMP-adenosine pathway”. Herein, we investigated whether, in addition to ATP, extracellular cAMP might be an alternative source of adenosine, influencing the contraction of vas deferens smooth muscle. Main methodsThe effects of cAMP, 8-Br-cAMP and adenosine were analyzed in the isometric contractions of rat vas deferens. cAMP efflux was analyzed by measuring extracellular cAMP levels after exposure of vas deferens segments to isoproterenol and forskolin in the presence or absence of MK-571, an inhibitor of MRP/ABCC transporters. Key findingsWhile 8-Br-cAMP, a cell-permeable cAMP analog, induced relaxation of KCl-precontracted vas deferens, the non-permeant cAMP increased the KCl-induced contractile response, which was mimicked by adenosine, but prevented by inhibitors of ecto-5′-nucleotidase or A1 receptors. Our results also showed that isoproterenol and forskolin increases cAMP efflux via an MRP/ABCC transporter-dependent mechanism, since it is inhibited by MK-571. SignificanceOur data show that activation of β-adrenoceptors and adenylyl cyclase increases cAMP efflux from vas deferens tissue, which modulates the vas deferens contractile response via activation of adenosine A1 receptors. Assuming that inhibition of vas deferens contractility has been proposed as a strategy for male contraception, the extracellular cAMP-adenosine pathway emerges as a potential pharmacological target that should be considered in studies of male fertility.

Men's Willingness to Use and Preferences for Novel Male Contraceptive Methods in Malawi.

Evidence is needed in low- and middle-income countries regarding men's willingness to use new male contraceptive methods in development, preferences regarding method attributes, and what shapes willingness/preferences. We analyzed data from cross-sectional surveys with 611 men in Malawi, concerning willingness to use each of four types of new male methods. Mean age was 24.5 years; half (50 percent) were married/cohabiting. Over half (51 percent) of men expressed willingness to use at least one new male method, including a topical contraceptive gel (33 percent), injection (32 percent), pill (29 percent), and implant (14 percent). Many male product attributes were considered important (with 59-67 percent endorsement), including ease of use, comfort of use, side effects, partner approval, type of method, frequency of facility visits, and cost. A prevalent reported reason for willingness was to "share responsibility for family planning with my partner" (44 percent). In multivariate regression analyses, willingness was inversely associated with inequitable gender attitudes (p < 0.001) and was not associated with married/cohabiting status, using condoms, or perceived risk for HIV. These findings add to growing evidence that a majority of men express willingness to use new male contraceptive methods like a topical gel, injectable, or pill. Reflection around gender roles is likely critical within future education about male contraceptive methods.

The role of advocacy in sustaining male contraceptive research and development.

Novel male contraceptives have been in development for well over half a century, and despite a robust predicted global market for new methods, funding for research and development has been extremely limited. While the pharmaceutical industry previously supported male contraceptive research and development, industry partners are only spectators in the current space, awaiting a product that has been de-risked by the public sector before re-entering the field. Current male contraceptive development efforts are thus primarily funded by nonprofit, non-governmental, and government agencies who also act as the primary advocates for the field. Specific organizations include the International Consortium on Male Contraception, the Population Council, the Male Contraceptive Initiative, the World Health Organization, and the US National Institutes of Health. The funding provided by these public agencies, alongside their social and policy-based advocacy efforts such as market research, public education, and calls to action have kept the male contraceptive product development space afloat, resulting in a pipeline of potential products advancing towards market approval. However, as these products mature into more expensive clinical stages of development, they continue to face significant funding challenges, which many programs may not overcome. To fully realize the benefits of novel male contraceptive options, it is incumbent on philanthropic entities, impact investors, venture capital, and/or the pharmaceutical sector to provide significant and timely support for male contraceptive research and development.

Regulatory challenges of new male contraceptive methods.

Progress in male contraception development faces the challenge of a lack of regulatory precedent and guidelines on the evidence (trial design and primary endpoint) required for marketing approval. Moreover, the development of a male contraceptive is complicated by the fact that the clinical treatment effect; prevention of pregnancy, is not measured in the patient receiving the intervention. Regulatory precedent and guidelines exist for female hormonal contraceptives but their applicability to male contraceptive products likely varies based on the mode of action and the anticipated pharmacodynamic effects of the product. The unique attributes of male contraceptives, including the frequent delay between the intervention (e.g., vasectomy and hormonal methods) and ultimate contraceptive effect, sperm suppression near azoospermia, and pregnancy prevention need to be addressed. This article describes the regulatory challenges faced by developers of male contraceptive products and offers proposals, paving the way for the development of both hormonal methods and non-hormonal approaches. Our article intends to suggest the directions but cannot substitute for the advice of regulatory agencies.