Non-hormonal Contraception 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.

Learnings From an Innovative Model to Expand Access to a New and Underutilized Nonhormonal Contraceptive Diaphragm.

We document the effort over the last 30 years to respond to the call by women advocates at the International Conference on Population and Development for more woman-initiated single or dual-purpose contraceptive methods by developing the Caya contoured diaphragm, an innovative diaphragm designed to meet the needs of women and their partners and expand options for nonhormonal barrier contraception. We describe the complex and interrelated set of activities undertaken to develop the product using a human-centered design process and how we are working to create a corollary sustainable market. This review includes the evidence generated around improved acceptability among couples in low- and middle-income countries and depicts challenges and practical actions on how to dispel misconceptions about diaphragm use. Importantly, we share programmatic lessons learned on increasing universal access to this new sexual and reproductive health technology. Following our new model for increasing access to new and underutilized methods, Caya is now registered and being marketed in nearly 40 countries worldwide.

The association between lifestyle factors and the composition of the vaginal microbiota: a review.

The vaginal microbiota offers valuable insights into women's sexual health and the risk of developing sexually transmitted infections (STIs) and bacterial vaginosis. Despite the public health implications of changes in the vaginal environment, existing data on this topic remain sparse. Following the PRISMA statement guidelines, we consulted five bibliographic databases, focusing on five main daily habits and behaviors. We included only studies published up to October 2023, investigating the influence of personal hygiene, sexual behaviors, hormonal contraception, smoking, alcohol consumption, and psychosocial stress on the vaginal microbiota using next-generation sequencing. Based on our inclusion criteria, we incorporated 37 studies into this review. Hormonal contraception and personal hygiene were found to promote eubiosis of the vaginal microbiota. In contrast, sexual behaviors, smoking, alcohol consumption, and psychosocial stress were associated with an increased susceptibility to bacterial vaginosis, STIs, and severe pelvic inflammatory diseases due to a modified vaginal microbiota. Black ethnicity emerged as a confounding factor, with this population showing unstable vaginal microbiota. Oral contraception and a stable male sexual partner were found to favor Lactobacillus colonization, acting as a protective factor. Conversely, non-hormonal contraception and unprotected or non-penile/vaginal sexual activity increased the incidence of vaginal inflammation and bacterial vaginosis by disturbing the vaginal microbiota and reducing Lactobacillus abundance. Daily habits and lifestyle can influence the composition of the vaginal microbiota, thereby affecting vaginal health. Disturbances in the vaginal microbiota could be associated factors for STIs and vaginosis. Therefore, prioritizing more appropriate management of the vaginal microbiota is crucial.

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.

David Garbers and the Birth of cAMP Biology in Mammalian Sperm.

Dr. David Garbers made many impactful contributions to science and vastly improved our understanding of sperm biology. In this review, we focus on his identification of a key role for the second messenger cAMP in mammalian sperm. As a graduate student David discovered that sperm motility, which is essential for sperm to fertilize the egg, is under the control of the (at the time) recently identified, prototypical second messenger cAMP. Fast-forwarding to the present, agents which turn off sperm's ability to generate cAMP and block sperm motility are being investigated as potential nonhormonal contraceptives for men and women. Should these efforts prove successful, Dave's discoveries will prove to be the spark which ignited a revolution in human health.

The Effect of Social Media Influencer Warranting Cues on Intentions to Use Non-Hormonal Contraception

ABSTRACT Young women increasingly get sexual health information from social media influencers, who use persuasive communication and can alter attitudes, intentions, and behaviors. Contraception is a commonly discussed health topic among influencers on social media. Previous research suggests that influencers negatively frame and encourage the discontinuation of hormonal contraception. At the same time, influencers also encourage the uptake of less effective non-hormonal options, such as fertility awareness-based methods. Though descriptive content analysis work details these patterns in influencer contraceptive messaging, there is no experimental research that explains message effects. The purpose of this study was to experimentally test the effect of influencer contraceptive-related messaging on behavioral health intentions. This study introduces warranting theory as a potentially valuable model for explaining online health communication message effects. Specifically, this study tested the effect of influencer messages containing sponsorship and medical disclaimers on intentions to use non-hormonal contraception. U.S. females (n = 296) ranging in age from 18–29 years old participated in a survey. Findings suggest that the interaction led to decreased intentions to use non-hormonal contraception. However, findings did not support a relationship between influencer messaging and impressions, which highlights potential boundary conditions for warranting theory and high-risk health behaviors. Additionally, there was a positive relationship between perceived trustworthiness and expertise of the influencer and intention to use non-hormonal contraception. Future research should test influencer messaging using real social media content and consider the effect of parasocial relationships. Practical implications highlight the need for comprehensive contraceptive counseling.

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.

The Impact Of Endorphin Massage On The Efficient Production Of Postpartum Breast Milk In TPMB Sulastri, Pagelaran District, Pringsewu Regency In 2024.

Initiating breastfeeding within the first day of delivery has been shown to decrease the likelihood of newborn mortality. It is specifically demonstrated to provide exclusive protection against diarrhea, respiratory infections, and pneumonia ASI. The project seeks to investigate endorphin massage's impact on smoothness development in postpartum women at TPMB Sulastri, S.ST., M.Kes in 2024.ASI stands for Automatic Speech Recognition. This research employs a quasi-experiment design utilizing a pretest-posttest control group strategy. The sample included of 14 participants in the intervention group and 14 participants in the control group. Purposive sampling techniques were employed. The instrument utilizes Standard Operating Procedures (SOP) and checklist sheets. A three-day Endorphin massage treatment was administered and assessed using the Mann-Whitney test. The study found that 50% of individuals had a moderate frequency of meal intake. The utilization rate of non-hormonal contraceptives was 71.4%. The weight of newborns does not exceed 100% of the BBLR. The gestational age at the time of labor is 100% accurate. The mean milk output of the intervention group was 2.6 before and 7.5 after. The mean of the control group was 2.5 before and 5.2 after. The endorphin massage significantly impacted the efficient production of breast milk in postpartum moms. This was evidenced by a p-value of 0.000 (< 0.05) and a positive Correlation Coefficient value of 0.88, indicating a highly robust association between the two variables. Ultimately, endorphin massage has a significant impact on facilitating the efficient production of breast milk in mothers throughout the postpartum period. It is desirable for lactating postpartum women to regularly engage in endorphin massage to ensure the continuous and unobstructed flow of breast milk during the entire two-year duration of breastfeeding.

Synthesis and Optimization of Small Molecule Inhibitors of Prostate Specific Antigen.

Semen liquefaction is a postejaculation process that transforms semen from a gel-like (coagulated) form to a water-like consistency (liquefied). This process is primarily regulated by serine proteases from the prostate gland, most prominently, prostate-specific antigen (PSA; KLK3). Inhibiting PSA activity has the potential to impede liquefaction of human semen, presenting a promising target for nonhormonal contraception in the female reproductive tract. This study employed triazole B1 as a starting compound. Through systematic design, synthesis, and optimization, we identified compound 20 (CDD-3290) as a 216 nM inhibitor of PSA with better stability in media than triazole B1. Further, we also evaluated the selectivity profile of compound 20 (CDD-3290) by testing against closely related proteases and demonstrated excellent inhibition of PSA versus α-chymotrypsin and elastase and similar potency versus thrombin. Thus, compound 20 is an improved PSA inhibitor that can be tested for efficacy in vitro or in the female reproductive tract.

Sexual function, quality of life, anxiety, and depression in women of reproductive age using hormonal, nonhormonal, and no contraceptive methods.

Hormonal contraceptive use has been related to adverse effects, including impacts on sexual function and sexual satisfaction, although the difference in the effects on sexual function with the use of hormonal vs nonhormonal contraceptive methods remains controversial. In this study we sought to compare the prevalence of dyspareunia, sexual function, sexual satisfaction, quality of life, anxiety, and depression between women using hormonal, nonhormonal, or no contraceptive methods and to compare these outcomes between the most frequently used contraceptive methods. This cross-sectional study included sexually active women of reproductive age who were stratified into 3 groups: women using hormonal, nonhormonal, or no contraceptive methods. Based on the use of questionnaires administered to the study participants, we compared sexual function in the 3 groups and more specifically among users of oral contraceptives, copper and hormonal intrauterine devices, and barrier methods. Participants completed 4 questionnaires to assess sexual function (Female Sexual Function Index), sexual satisfaction (Sexual Quotient-Feminine Version), quality of life (12-item Medical Outcomes Short Form Health Survey), and anxiety and depression (Hospital Anxiety and Depression Scale). This study included 315 women classified into 3 groups on the basis of contraceptive use: 161 in the hormonal contraceptives group (median [interquartile range] age, 24 [23-28] years), 97 in the nonhormonal contraceptives group (age 26 [23-30] years), and 57 in the no contraceptive methods group (age 28 [24-35] years). Dyspareunia prevalence showed no difference between the groups. In the quality of life domain, compared with women in the nonhormonal contraceptive group, women in the hormonal contraceptive group were younger and had lower sexual function satisfaction, reduced arousal, and heightened pain (P< .05), as well as higher anxiety and depression levels (P= .03, for both), increased pain (P= .01), and poorer overall health (P= .01). No difference was found between these groups in other quality of life domains. Regarding contraceptive methods, women using copper intrauterine devices had better sexual function, including higher rates of arousal and lower anxiety, than women using oral contraceptives (P< .05). The results of this study highlight worse sexual function and sexual satisfaction and higher levels of anxiety and depression in women using hormonal contraceptive methods than in women using nonhormonal methods. The findings of this study strengthen the evidence of differences in sexual function between women using oral contraceptives and those using copper intrauterine devices. Sexual function was also compared among users of oral contraceptives, copper and hormonal intrauterine devices, and barrier methods. However, less frequently used contraceptive methods, such as hormonal injections and vaginal rings, could not be compared in this sample. Women using hormonal contraceptive methods were younger, had lower sexual function and satisfaction, and experienced higher anxiety and depression levels than women using nonhormonal contraceptive methods.

S2k-Guideline Non-hormonal Contraception, Part 2: Intrauterine Devices and Sterilization: Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry No. 015 - 095, January 2024).

Aim This official guideline was published and coordinated by the DGGG, OEGGG and SGGG with the involvement of other medical societies. The aim was to provide a consensus-based overview of non-hormonal forms of contraception based on an evaluation of the relevant literature. The first part of these summarized statements and recommendations presents natural family planning methods such as lactational amenorrhea, barrier methods and coitus interruptus. The second part focuses on intrauterine devices and sterilization. Methods This S2k-guideline was developed by representative members from different medical professions on behalf of the guidelines commission of the DGGG, OEGGG and SGGG using a structured consensus process. Recommendations The guideline provides recommendations on the indications for, safety of use, benefits, and limitations of the different methods as well as recommendations on providing advice and other aspects of non-hormonal contraception. This summary presents recommendations and statements about intrauterine devices and female and male sterilization.

S2k-Guideline Non-hormonal Contraception, Part 1: Natural Family Planning, Lactational Amenorrhea, Barrier Methods, Coitus Interruptus: Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry No. 015 - 095, January 2024).

Aim This official guideline was published and coordinated by the DGGG, OEGGG and SGGG with the involvement of other medical societies. The aim was to provide a consensus-based overview of non-hormonal forms of contraception based on an evaluation of the relevant literature. The first part of these summarized statements and recommendations presents natural family planning methods such as lactational amenorrhea, barrier methods and coitus interruptus. The second part will focus on intrauterine devices and sterilization methods. Methods This S2k-guideline was developed by representative members from different medical professions on behalf of the guidelines commission of the DGGG, OEGGG and SGGG using a structured consensus process. Recommendations The guideline provides recommendations on the indications for, safety of use, benefits, and limitations of the different methods as well as recommendations on providing advice and other aspects of non-hormonal contraception. Natural family planning methods, lactational amenorrhea, barrier methods and coitus interruptus are discussed.

Pre-clinical and early clinical considerations for the development of non-hormonal contraceptives for men.

This manuscript presents non-hormonal male contraceptive development in the context of mitigating risk to investigators and investors. The manuscript uses examples to illustrate drug development principles to move a project from discovery to development. The content is intended for those with reproductive biology backgrounds without significant exposure to drug development-particularly early-stage targeted drug development-and those with general interest in developing non-hormonal methods of contraception. The goal of issues addressed in this manuscript is to facilitate the advancement of innovative male contraceptives into late-stage clinical trials, while keeping in mind early recognition of program deficiencies and development of mitigation strategies, or reassignment of limited, valuable resources.

The Relationship Between PUS Knowledge And Husband's Support In Choosing The IUD Contraception Method

IUD is highly affective non-hormonal contraceptives. This research aims to analyze the relationship between the knowledge of PUS and husband's support with the choice of IUD contraception at the Senori Tuban Community Health Center. This research is a cross sectional correlational analytic study, involving 61 respondents selected through a stratified random sampling technique. The independent variable is knowledge of PUS and the husband's support, while the dependent variable is the choice of the IUD contraceptive method. Data were collected using a questionnaire and checklist, and the relationship was analyzed using the chi square test with a significance level of α 0.05. The results showed that most 32 (52.5%) couples had good knowledge about IUD contraception, most 35 (57.4%) husbands provided support, and 35 (57.4%) couples chose the IUD as their contraception method. The analysis concluded a significant relationship between the knowledge of PUS and the husband's support with the choice of IUD contraception. It is recommended that husbands provide positive support to their wives who are KB acceptors. Additionally, they are encouraged to actively seek reliable information directly to health care providers or other sources about their family planning.

Hormone-related side effects in new users of a levonorgestrel 52-mg intrauterine device

Although the levonorgestrel 52 mg intrauterine device is locally active and has low systemic hormone exposure, hormonal intrauterine device users sometimes report hormone-related side effects. Evaluate hormone-related adverse event rates among all participants and compare these among those who used combined hormonal or no hormonal contraception in the month before enrollment. A total of 1714 women aged 16-45 years old received a levonorgestrel 52 mg intrauterine device in a multicenter phase 3 trial to evaluate contraceptive efficacy and safety for up to 10 years. This analysis evaluated a subset of participants who used combined hormonal or no hormonal contraception in the month prior to device placement. We assessed all non-expulsion, non-bleeding-related events with ≥1% incidence at 180 days with a plan to include weight increase regardless of incidence; we excluded events considered non-hormonal. We computed 180-day side effect frequency rates based on the number of days a side effect was reported during the study period. We created a multivariable model for side effect incidence at 180 days based on age, race, ethnicity, body mass index at enrollment, parity, and contraception use in the month before enrollment. For those side effects with a p-value <0.2 on univariate comparison between combined-hormonal and no-hormonal contraception users, we secondarily evaluated 360-day event rates. Overall, 644 participants used combined hormonal contraception (primarily oral [n=499, 77.5%]) and 855 used no hormonal method before IUD placement. Individual side effect rates over the first 180 days did not differ between prior combined-hormonal and no-hormonal contraception users except for acne (84 [13.0%] versus 73 [8.5%], respectively), p=0.006, OR 1.61 (95% CI 1.15-2.24). However, this association was weaker after adjustment for age, race, ethnicity, obesity status, and parity (aOR 1.40, 95% CI 0.99-1.98) At 360 days, prior combined hormonal contraception users were more likely to report acne (101 [15.7%] vs. 91 [10.6%], respectively, p=0.005) and orgasm/libido problems (20 [3.1%] vs. 12 [1.4%], respectively, p=0.03). Over the first 180 days, all side effects other than acne were reported in less than 3% of days; acne was reported an average of 13 days (7.4%) per prior combined hormonal contraception user and 9 days (5.0%) per prior non-hormonal contraception user (p<0.0001). Discontinuation for evaluated side effects occurred in 83 (5.5%) participants with no difference between those who used combined hormonal (36 [5.6%]) or no hormonal contraception (47 [5.5%]), p=1.0) before study entry. Using combined hormonal contraception prior to levonorgestrel 52 mg intrauterine device placement is only weakly associated with reporting hormonally related side effects like acne. Only a small percentage of levonorgestrel 52 mg intrauterine device users experienced potentially hormone-related side effects during the initial 6 months of use that resulted in discontinuation.

Effect of various contraceptives on oocyte yield and maturation in patients undergoing planned oocyte cryopreservation

Research questionDo the various forms of hormonal and non-hormonal contraceptives have any association with ovarian stimulation outcomes, such as oocyte yield and maturation, in patients undergoing planned oocyte cryopreservation (POC)? DesignThis retrospective cohort study included all patients who underwent POC cycles between 2011 and 2023. The use of types of contraception before a POC cycle was recorded. The study evaluated the median number of cumulus–oocyte complexes obtained after vaginal oocyte retrieval and the proportion of metaphase II oocytes that underwent vitrification among all the cohorts. ResultsA total of 4059 oocyte freezing cycles were included in the analysis. Eight types of contraceptive method were recognized in patients undergoing ovarian stimulation: intrauterine device (IUD), copper (n = 84); IUD, levonorgestrel low dose (<52 mg) (n = 37); IUD, levonorgestrel (n = 192); subdermal etonogestrel implant (n = 14); injectable medroxyprogesterone acetate (n = 11); etonogestrel vaginal ring (n = 142); combined oral contraceptive pills (n = 2349); and norelgestromin transdermal patch (n = 10). The control group included patients not using contraceptives or using barrier or calendar methods (n = 1220). Among all the cohorts the median number of cumulus–oocyte complexes retrieved during oocyte retrieval was comparable (P = 0.054), and a significant difference in oocyte maturity rate with median number of vitrified oocytes was found (P = 0.03, P < 0.001, respectively). After adjusting for confounders a multivariate analysis found no association between the type of contraceptive and proportion of metaphase II oocytes available for cryopreservation. ConclusionsAmong the various forms of contraception, none was shown to have an adverse association with oocyte yield or maturation rate in patients undergoing POC.

Relationship between classic indicators of health behaviour and contraceptive choices in women in Flanders

BackgroundIn this study we shed light on ongoing trends in contraceptive use in Flanders (Belgium). Building on the fundamental cause theory and social diffusion of innovation theory, we examine socio-economic gradients in contraceptive use and the relationship to health behaviours.MethodsUsing the unique and recently collected (2020) ISALA data, we used multinomial logistic regression to model the uptake of contraceptives and its association to educational level and health behaviour (N:4316 women).ResultsHigher educated women, and women with a healthy lifestyle especially, tend to use non-hormonal contraceptives or perceived lower-dosage hormonal contraceptives that are still trustworthy from a medical point of view. Moreover, we identified a potentially vulnerable group in terms of health as our results indicate that women who do not engage in preventive health behaviours are more likely to use no, or no modern, contraceptive method.DiscussionThe fact that higher educated women and women with a healthy lifestyle are less likely to use hormonal contraceptive methods is in line with patient empowerment, as women no longer necessarily follow recommendations by healthcare professionals, and there is a growing demand for naturalness in Western societies.ConclusionThe results of this study can therefore be used to inform policy makers and reproductive healthcare professionals, since up-to-date understanding of women’s contraceptive choices is clearly needed in order to develop effective strategies to prevent sexually transmitted infections and unplanned pregnancies, and in which women can take control over their sexuality and fertility in a comfortable and pleasurable way.

The Effect of Hormonal Contraceptive use on Breast Milk Production in Breastfeeding Mothers at Meurah Mulia Health Center, North Aceh Regency

This study aims to determine the effect of using hormonal contraception on breast milk production in breastfeeding mothers at the Meurah Mulia Health Center, North Aceh Regency in 2023. The research was conducted with a retrospective case-control design. The results of the analysis show that the use of hormonal contraception has a significant effect on breast milk production in breastfeeding mothers (p=0.017; OR=2.269), where mothers who use hormonal contraception are twice as likely to have less breast milk production compared to mothers who use non-hormonal contraception. In conclusion, this research shows that there is an influence of the use of hormonal contraception on breast milk production in breastfeeding mothers, so it is recommended that health services provide sufficient information to women who want to use contraception, especially women who are breastfeeding, regarding the effect of contraception on breast milk production.

Spem2, a novel testis-enriched gene, is required for spermiogenesis and fertilization in mice

Spermiogenesis is considered to be crucial for the production of haploid spermatozoa with normal morphology, structure and function, but the mechanisms underlying this process remain largely unclear. Here, we demonstrate that SPEM family member 2 (Spem2), as a novel testis-enriched gene, is essential for spermiogenesis and male fertility. Spem2 is predominantly expressed in the haploid male germ cells and is highly conserved across mammals. Mice deficient for Spem2 develop male infertility associated with spermiogenesis impairment. Specifically, the insufficient sperm individualization, failure of excess cytoplasm shedding, and defects in acrosome formation are evident in Spem2-null sperm. Sperm counts and motility are also significantly reduced compared to controls. In vivo fertilization assays have shown that Spem2-null sperm are unable to fertilize oocytes, possibly due to their impaired ability to migrate from the uterus into the oviduct. However, the infertility of Spem2−/− males cannot be rescued by in vitro fertilization, suggesting that defective sperm–egg interaction may also be a contributing factor. Furthermore, SPEM2 is detected to interact with ZPBP, PRSS21, PRSS54, PRSS55, ADAM2 and ADAM3 and is also required for their processing and maturation in epididymal sperm. Our findings establish SPEM2 as an essential regulator of spermiogenesis and fertilization in mice, possibly in mammals including humans. Understanding the molecular role of SPEM2 could provide new insights into future therapeutic treatment of human male infertility and development of non-hormonal male contraceptives.

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.