Reversible Male Contraception Research Articles

Hierarchically Dual-Targeted Casein-Coated Iron Oxide Nanoparticles as Oral Thermal Agents for Noninvasive and Reversible Male Contraception

Hierarchically Dual-Targeted Casein-Coated Iron Oxide Nanoparticles as Oral Thermal Agents for Noninvasive and Reversible Male Contraception

Reversible male contraception by targeted inhibition of serine/threonine kinase 33.

Men or mice with homozygous serine/threonine kinase 33 (STK33) mutations are sterile owing to defective sperm morphology and motility. To chemically evaluate STK33 for male contraception with STK33-specific inhibitors, we screened our multibillion-compound collection of DNA-encoded chemical libraries, uncovered potent STK33-specific inhibitors, determined the STK33 kinase domain structure bound with a truncated hit CDD-2211, and generated an optimized hit CDD-2807 that demonstrates nanomolar cellular potency (half-maximal inhibitory concentration = 9.2 nanomolar) and favorable metabolic stability. In mice, CDD-2807 exhibited no toxicity, efficiently crossed the blood-testis barrier, did not accumulate in brain, and induced a reversible contraceptive effect that phenocopied genetic STK33 perturbations without altering testis size. Thus, STK33 is a chemically validated, nonhormonal contraceptive target, and CDD-2807 is an effective tool compound.

Shared risk and shared responsibility: the ethics of male contraceptives.

Efforts to develop reversible male contraceptives analogous to female oral contraceptives are underway and may be introduced in the next decade. The advent of novel male contraceptives provides an opportunity for an ethical reformulation of the contraceptive paradigm given the relational, rather than individual, nature of sexual relationships, and family planning. For individuals in any sexual relationship that could result in pregnancy, issues of reproductive autonomy, freedom, equality in reproductive decision-making and risks-both of side effects and of unintended pregnancies-are significant. Historically, however, women have been attributed the greatest responsibilities simultaneously with the most restrictions on their freedom of choice and access to reproductive care. In this paper, we extend our prior "shared risk" model of male contraception to one of "shared risk and responsibility" to ethically inform this discourse. This updated framework more fully captures the complexity of this novel technology and may be of use to regulatory and legal agencies grappling with an intervention that poses medical risks to the member of the relationship who does not face risks of becoming pregnant.

Targeting nuclear receptor corepressors for reversible male contraception

Despite numerous female contraceptive options, nearly half of all pregnancies are unintended. Family planning choices for men are currently limited to unreliable condoms and invasive vasectomies with questionable reversibility. Here, we report the development of an oral contraceptive approach based on transcriptional disruption of cyclical gene expression patterns during spermatogenesis. Spermatogenesis involves a continuous series of self-renewal and differentiation programs of spermatogonial stem cells (SSCs) that is regulated by retinoic acid (RA)-dependent activation of receptors (RARs), which control target gene expression through association with corepressor proteins. We have found that the interaction between RAR and the corepressor silencing mediator of retinoid and thyroid hormone receptors (SMRT) is essential for spermatogenesis. In a genetically engineered mouse model that negates SMRT-RAR binding (SMRTmRID mice), the synchronized, cyclic expression of RAR-dependent genes along the seminiferous tubules is disrupted. Notably, the presence of an RA-resistant SSC population that survives RAR de-repression suggests that the infertility attributed to the loss of SMRT-mediated repression is reversible. Supporting this notion, we show that inhibiting the action of the SMRT complex with chronic, low-dose oral administration of a histone deacetylase inhibitor reversibly blocks spermatogenesis and fertility without affecting libido. This demonstration validates pharmacologic targeting of the SMRT repressor complex for non-hormonal male contraception.

Evaluation of Knowledge and Attitude to Uptake of Vasectomy among Male Health Care Workers in a Tertiary Health Facility: A Cross-sectional Study

Vasectomy is a safe and effective permanent male contraceptive, although its acceptance remains low in low-income countries. A cross-sectional study was conducted at the University of Ilorin Teaching Hospital, Ilorin, Nigeria, between 1st July and 31st August 2020. Participants were 247 consenting male health care workers recruited using systematic sampling based on their profession. Data collection was through a self-administered questionnaire, and analysis was performed using IBM-SSPS Version 23.0; p-value<0.05 was significant. The modal age group was 31-39 years (61.1%), 96.8% had tertiary education, 63.2% were Doctors, 21.5% were Laboratory Scientists, 12.1% Pharmacists, 1.6% Nurses, and 1.6% Physiotherapists; 68.0% had two or more children. Awareness about vasectomy was 93.5%, the commonest source of information was the health facility (55.3%), 76.5% supports the role of men in family planning while 84.0% were willing to share family planning responsibility with their partners 16.6% intend to undergo vasectomy on completion of their family size. The identified hindrances to the uptake of vasectomy were fear that it may lead to sexual dysfunction (87.0%), fear of other side effects (70.3%), irreversibility of the procedure (37.0%), cultural factors (25.0%), and concerns about possible infidelity (20.9%). Knowledge about vasectomy was negatively associated with its uptake (p<0.001). This study reports aversion to vasectomy among male health workers despite adequate awareness and Knowledge due to concerns about possible side effects, including the irreversibility of the procedure. Therefore, while advocacy for vasectomy continues, researchers should expedite actions to make reversible male contraceptives readily available.

SPATA33 localizes calcineurin to the mitochondria and regulates sperm motility in mice

Calcineurin is a calcium-dependent phosphatase that plays roles in a variety of biological processes including immune responses. In spermatozoa, there is a testis-enriched calcineurin composed of PPP3CC and PPP3R2 (sperm calcineurin) that is essential for sperm motility and male fertility. Because sperm calcineurin has been proposed as a target for reversible male contraceptives, identifying proteins that interact with sperm calcineurin widens the choice for developing specific inhibitors. Here, by screening the calcineurin-interacting PxIxIT consensus motif in silico and analyzing the function of candidate proteins through the generation of gene-modified mice, we discovered that SPATA33 interacts with sperm calcineurin via a PQIIIT sequence. Spata33 knockout mice exhibit reduced sperm motility because of an inflexible midpiece, leading to impaired male fertility, which phenocopies Ppp3cc and Ppp3r2 knockout mice. Further analysis reveals that sperm calcineurin disappears from the mitochondria in the Spata33 knockout testis. In addition, immunoprecipitation analysis indicates that sperm calcineurin interacts with not only SPATA33 but also the mitochondrial protein VDAC2. These results indicate that SPATA33 localizes calcineurin to the mitochondria and regulates sperm motility.

“Shared risk”: Reframing risk analysis in the ethics of novel male contraceptives,

Novel male contraception has the potential to enhance reproductive autonomy for men [ 1 Campo-Engelstein L. No more larking around! Why we need male LARCs. Hastings Cent Rep. 2011; 41: 22-32 Crossref PubMed Scopus (6) Google Scholar , 2 Martin C.W. Anderson R.A. Cheng L. Ho P.C. van der Spuy Z. Smith K.B. et al. Potential impact of hormonal male contraception: cross-cultural implications for development of novel male preparations. Human Reprod. 2000; 15: 637-645 Crossref PubMed Scopus (174) Google Scholar , 3 Heinemann K. Saad F. Wiesemes M. White S. Heinemann L. Attitudes towards male fertility control: results of a multinational survey on four continents. Human Reprod. 2005; 20: 549-556 Crossref PubMed Scopus (147) Google Scholar , 4 Glasier A.F. Anakwe R. Everington D. Martin C.W. van der Spuy Z. Cheng L. et al. Would women trust their partners to use a male pill?. Human Reprod. 2000; 15: 646-649 Crossref PubMed Scopus (148) Google Scholar ] and offer greater equity in contraceptive responsibility for monogamous or non-monogamous heterosexual relationships [ [1] Campo-Engelstein L. No more larking around! Why we need male LARCs. Hastings Cent Rep. 2011; 41: 22-32 Crossref PubMed Scopus (6) Google Scholar ]. However, novel male contraceptives have been in development for decades, with no method able to reach the market to-date. Technical challenges inherent in the development of novel reversible male contraceptives have been detailed in other publications [ 5 Thirumalai A. Page S.T. Recent developments in male contraception. Drugs. 2019; 79: 11-20 Crossref PubMed Scopus (19) Google Scholar , 6 Plana O. Male contraception: Research, new methods, and implications for marginalized populations. Am J Mens Health. 2017; 11: 1182-1189 Crossref PubMed Scopus (16) Google Scholar ]. The negative impact of gender bias in this setting has also been explored [ [1] Campo-Engelstein L. No more larking around! Why we need male LARCs. Hastings Cent Rep. 2011; 41: 22-32 Crossref PubMed Scopus (6) Google Scholar ]. Moreover, medicolegal issues have presented enormous challenges in female contraception development, leading to the discontinuation of some approved products. Similar concerns are likely to affect the development of novel male contraception, which is thus far unexplored and will require further analysis. For our purposes here, we will focus on one of the key ethical challenges in this domain. How ought medical professionals and researchers assess the balance of nonmaleficence (do no harm or avoid risks) and beneficence (seek the greatest good or benefit) [ [7] Beauchamp T.L. Childress J.F. Principles of biomedical ethics. Oxford University Press, New York2012 Google Scholar ], when male contraception has impacts that extend beyond the user of the contraceptive?

Neem leaves extract (Azadirachta indica A. Juss) on male reproductive system: a mini-review

Neem (Azadirachta indica A. Juss) is the tropical plant of the family Meliaceae that has been used as medicine. Almost all parts, i.e., leaves, stems, bark, roots, seeds, and flowers can be used to medicate multiple diseases. Apart from medicine and other health benefits, neem is a very promising plant as it could be used to reduce the rate of population growth. The aim of this review is to figure out the effect of neem leaves on the male reproductive system which can be developed into safe and reversible male contraception. The article review used online databases to conduct keyword searches and investigate the active compounds in neem leaves that could serve as antifertility, the effect of neem leaves on reproductive hormones and spermatogenesis. Several studies show that neem leaves can affect the male reproductive system by interfering spermatogenesis, e.g., reducing the amount, motility, and morphology of the spermatozoa, affecting the structure and function of the testes which cause a decrease in the quality of spermatozoa. Abnormal spermatozoa could reduce spermatozoa ability to fertilize. Thus neem leaves can be proposed as male contraceptives.

Male Hormonal Contraception.

The economic and public health burdens of unplanned pregnancies are evident globally. Since the introduction of the condom >300 years ago, assumptions about male willingness to participate in contraception, as well as concerns about failure rates and side effects, have stagnated the development of additional reversible male contraceptives. However, changing attitudes and recent research advances have generated renewed interest in developing reversible male contraceptives. To achieve effective and reversible suppression of spermatogenesis, male hormonal contraception relies on suppression of testicular testosterone and sperm production using an androgen-progestin combination. While these may be associated with side effects-changes in libido, weight, hematocrit, and cholesterol-recently, novel androgens and progestins have shown promise for a "male pill" with reduced side effects. Here we summarize landmark studies in male contraceptive development, showcase the most recent advances, and look into the future of this field, which has the potential to greatly impact global public health.

Biologic response of sperm and seminal plasma to transient testicular heating.

Currently, there are few male contraceptive methods that are purely based on prevention of the entry of the sperm into the female reproductive tract. An alternative approach for designing reversible male contraceptive is achieved by transient testicular heating (TTH). This treatment, through massive germ cell apoptosis, causes reversible oligospermia or azoospermia. Here, we describe as how TTH causes DNA damage, oxidative stress, apoptosis, autophagy, sperm protein expression, and alters the biochemical components of seminal plasma. Further understanding of TTH will help design safe and reversible male contraception.

Reversible Male Contraceptives Preferences in Nigeria Survey

Male contraceptive preferences in Nigeria are major pointers to acceptance, demand and sustained use of new reversible male contraceptive technologies. This study is designed to assess the willingness of Nigerian men to become actors in shared reproductive responsibility. A cross-sectional study design with mixed-methodology, which adopted both qualitative and quantitative research – using desk research, in-depth and household interviews, focus group discussions and online polls - was adopted. A total of 1,442 respondents were questioned; 801 from rural areas and 641 from urban areas. Male contraceptive use was defined by factors that influence the desire to practice contraception. 68.85% of the respondents say they would use reversible male contraceptives, if they were available; 54.27% of the respondents who were against it, said they would not use reversible male contraceptives because of the fear of adverse health risks. Our findings show that a considerable proportion of men had knowledge of family planning methods. The results show that there is a demand for reversible male contraceptives among the male population in Nigeria. It is evident that if other types of reversible male contraceptives are made available, they will be readily accepted.

Potent Pyrimidine and Pyrrolopyrimidine Inhibitors of Testis-Specific Serine/Threonine Kinase 2 (TSSK2).

Testis-specific serine/threonine kinase 2 (TSSK2) is an important target for reversible male contraception. A high-throughput screen of ≈17 000 compounds using a mobility shift assay identified two potent series of inhibitors having a pyrrolopyrimidine or pyrimidine core. The pyrrolopyrimidine 10 (IC50 22 nm; GSK2163632A) and the pyrimidine 17 (IC50 31 nm; ALK inhibitor 1) are the most potent TSSK2 inhibitors in these series, which contain the first sub-100 nanomolar inhibitors of any TSSK isoform reported, except for the broad kinase inhibitor staurosporine. The novel, potent pyrimidine TSSK2 inhibitor compound 19 (IC50 66 nm; 2-[[5-chloro-2-[2-methoxy-4-(1-methylpiperidin-4-yl)anilino]pyrimidin-4-yl]amino]-N-methylbenzenesulfonamide) lacks the potential for metabolic activation. Compound 19 had a potency rank order of TSSK1>TSSK2>TSSK3>TSSK6, indicating that potent dual inhibitors of TSSK1/2 can be identified, which may be required for a complete contraceptive effect. The future availability of a TSSK2 crystal structure will facilitate structure-based discovery of selective TSSK inhibitors from these pyrrolopyrimidine and pyrimidine scaffolds.

Relative suitability of DMSO and NaHCO3 for reversal of RISUG® induced long-term contraception.

Among the vas-based methods on trial, reversible inhibition of sperm under guidance (RISUG(®) ), a co-polymer of styrene and maleic anhydride is being projected as an effective alternative to No Scalpel Vasectomy. RISUG offers long-term contraception with safety, efficacy in human trials and can be delivered by no-scalpel injection. Currently, the procedure is under phase-III clinical trial. However, reversal of this vas-based drug-induced contraception needs to be established in animal models prior to clinical trials to ensure its claim as an effective alternative for vasectomy. In the present investigation, the relative suitability of dimethyl sulphoxide (DMSO) and NaHCO3 for RISUG induced long-term vas occlusion reversal was carried out in albino rats. Animals were allocated into four groups (n = 10), viz., sham-operated control (group-I), vas occlusion with RISUG for 360 days (group-II), vas occlusion with RISUG for 360 days and reversal with DMSO (group-III) and vas occlusion with RISUG for 360 days and reversal with NaHCO3 (group-IV). A variable response in fertility was observed in different groups. Absolute sterility in group III at all mating intervals, while, zero percent fertility in groups II and IV following 90 days of occlusion was observed. Following reversal restoration of fertility with DMSO at 45 days, whereas, reversal by NaHCO3 at 30 days was noticed. Ejaculated spermatozoa of RISUG injected and initial intervals of reversed animals exhibited various degrees of abnormalities. The testes exhibited focal degeneration in vas occluded animals. The occluded lumen of the vas deferens contained an eosinated polymer with exfoliated epithelium. Following vas occlusion reversal, a complete regeneration in the vas epithelium was seen. All other parameters remained unaltered. The reversal with NaHCO3 resulted into an early resumption of fertility when compared with DMSO and the procedure found to be successful, feasible and safe up to F1 generation. Thus, RISUG provides a hope for reversible male contraceptives.

Male hormonal contraception: looking back and moving forward.

Despite numerous contraceptive options available to women, approximately half of all pregnancies in the United States and worldwide are unplanned. Women and men support the development of reversible male contraception strategies, but none have been brought to market. Herein we review the physiologic basis for male hormonal contraception, the history of male hormonal contraception development, currents agents in development as well as the potential risks and benefits of male hormonal contraception for men.

Physiology in perspective: cell-cell interactions: the physiological basis of communication.

prompting the discipline of high-altitude physiology. He built the first human decompression chamber and studied the effects of rarified air and hypoxia on humans. He showed how the lung could function as a gas exchanger in the absence of its movement. As curator of the Royal Society for 40 years, he was involved in an enormous number of new findings. His own inventions include the balance spring in a pocket watch, the wheel barometer, and the universal joint. He was a mathematical and engineering genius and formulated the law of elasticity that states that strain is proportional to stress. He was a gifted architect who was heavily involved with rebuilding London after the Great Fire of 1666. His collection of microscopic observations, Micrographia, remains a classic. And yet few of us recognize Hooke’s name. In his review (6), John West gives this polymath the credit he deserves for his many inventions and ideas. Blood vessels carry oxygen and nutrients to all organs and tissues in the body. When the vessels do not form or function properly, disruptions that can contribute to a vast array of diseases occur in normal physiology. Thus understanding how the cells of the vasculature communicate with each other is fundamentally important in both health and disease. Formation and function of blood vessels relies on proper communication between the endothelial cells and smooth muscle cells. These interactions dictate how, when, and where blood vessels form and control their physiological responses to manage blood flow. In her review (3), Lilly highlights the pathways by which endothelial cells and smooth muscle cells communicate during blood vessel formation and discusses how disruptions in these pathways contribute to disease. The cells of the vasculature utilize multiple signaling pathways to communicate. They employ secreted molecules to regulate cell recruitment and proliferation, and engage

Male and female public opinion regarding a possible male contraceptive pill

Reversible male contraception (RMC) is currently limited to the use of barrier methods. A non-hormonal, oral method of RMC is currently on the cusp of clinical trial. Differences in the attitudes and beliefs between men and women towards a RMC have not been examined.

In Vitro Versus In Vivo Effects of NB-DGJ and NB-DNJ as Lead Compounds for Development of Non-Hormonal Reversible Oral Male Contraceptives.

In Vitro Versus In Vivo Effects of NB-DGJ and NB-DNJ as Lead Compounds for Development of Non-Hormonal Reversible Oral Male Contraceptives.

How Close are We in Achieving Safe, Affordable and Reversible Male Contraceptives?

The world population, currently estimated to be over six billions, is expected to double in the next forty years. The projected growth will cause severe over crowding that will have an adverse effect on the ecological health of the planet. A recent survey by the United Nations found that a majority of men in many countries are willing to participate in family planning by taking full control of their fertility. However, the available contraceptives for men have either higher failure rates or they are irreversible. Thus, the contraceptive needs of tens of millions of men go unmet every day resulting in millions of unwanted pregnancies, and hundreds of thousands of abortions. Since the introduction of oral contraceptive (pill) for women over five decades ago, there have been numerous collaborative efforts by scientists and pharmaceutical companies to improve the effectiveness and delivery of contraceptives to women who wish to safely regulate their reproductive physiology. However, the contraceptive options available to men have not changed in several decades and are still limited to the use of condoms and timely withdrawal (coitus interruptus) or under going a minor surgical procedure (vasectomy) that prevents the release of spermatozoa during ejaculation. The first two methods have relatively higher typical-use failure rates, whereas the last approach is largely irreversible and not suitable for younger men. Despite non-stop efforts worldwide, we may still be several years away from providing safe, effective and affordable male contraceptives which will allow both men and women to participate fully in family planning. In this article, we will discuss various contraceptives currently available to regulate male fertility. In addition, we will summarize potentially new contraceptives for men that are at various stages of research and development. Finally, our intention is to discuss details of two safe, reversible and affordable male contraceptive approaches that are inching closure to being approved for use by the masses in India and China, the world's two most populous nations.

Blockade of α 1A-adrenoceptor: A novel possible strategy for male contraception

Worldwide almost one quarter of all couples practicing contraception rely on male methods. However, currently available options for male contraception are limited. Thus, it is urgent to develop safe, effective, and reversible male contraceptives. To date, alpha(1)-blockers are the most widely used agents for the treatment of benign prostatic hyperplasia. Several studies reveal that in elderly patients the alpha(1A)-selective antagonist tamsulosin can induce a notably high incidence of ejaculation dysfunction characterized by low ejaculate volume. Recent clinical trials suggest that tamsulosin may effectively inhibit sperm ejaculation in young volunteers. Since alpha(1A)-adrenoceptor subtype plays a dominant role in mediating the contractions of accessory sex organs contributing to ejaculation, we hypothesize that blockade of alpha(1A)-adrenoceptor may suppress the motility of these organs, thereby inhibiting sperm transport and achieving contraception, and the alpha(1A)-selective antagonists can act as a male contraceptive. If our hypotheses can be further supported with clinical trials it will shift the paradigm for male-based contraception and provide a wider range of choice for all.

Reversible contraception like activity of embelin in male dogs (Canis indicus Linn).

In order to evaluate the long term metabolic effect of embelin on the testes, adult male dogs were fed with embelin (80 mg/kg b.w. each other day) for 100 days. Loss in weights of testes and spermatogenic elements was noticed. The epididymides were devoid of spermatozoa but the functional morphology remain unaltered. 250 days of recovery period brings about normal spermiogenesis with all 1-8 cell stages. Epididymal milieu showed functional physiology. A three tiered finding accompanying histology, tissue biochemistry and blood/serum profile of dogs treated with embelin showed that 100 days therapy inhibits spermatogenesis, whereas 250 days recovery restores it. Sexual potency and libido of the animals did not change. A reversible male contraception with the help of a plant benzoquinone (embelin) is promising.