Male Contraceptive Research Articles

Peculiarity of recovery of the hypothalamic-pituitary-gonadal (hpg) axis, in men after using androgenic anabolic steroids

BACKGROUND: Spontaneous recovery of the hypothalamicpituitarygonadal (HPG) axis after cessation of testosterone replacement therapy or after male contraception may take up to 24 months. There is insufficient data on the duration of recovery of HPG axis after abuse of androgenic anabolic steroids (AAS). AAS users use post-cycle therapy (PCT) to restore HPG axis, the effectiveness of which is unknown and needs further investigation.
 AIMS: To evaluate the recovery of HPG axis in men, AAS users, after a 3-month of cessation of their use and after PCT.
 METHODS: An observational, single-center, prospective, sampling, open, uncontrolled study was conducted among male AAS users. While using of AAS and 3 months after the refusal of their administration and PCT, the clinical symptoms of hypogonadism were evaluated, luteinizing hormone (LH), follicle-stimulating hormone (FSH), total testosterone (Tt), prolactin, estradiol, inhibin B, thyroid-stimulating hormone (TSH) were determined. The scheme of rehabilitation therapy was the same and did not change throughout the study. Recovery criteria: Tt 3.4 ng/ml and LH 1.24 mIU/ml. The study was conducted from January to August 2019. Fishers exact test, Mann-Whitney U-test, and Spearmans rank correlation coefficient were used. The differences were considered statistically significant at p0.05.
 RESULTS: The study included 44 men, their age 29 years [27.75; 34], the duration of the use of AAS is 6 months [3.52; 7]. During the use of AAS: LH 0.2 mIU/ml [0.04; 0.47], Tt 4.34 ng/ml [1.05; 8.81]. In this group, the number of men with a LH level 1.24 mIU / ml was 84% (n=37) and Tt 3.4 ng/ml was 47.7% (n=21). After 3 months, the LH level reached 4.12 mIU/ml [2.58; 5.84], Tt 4.55 ng/ml [3.76; 6.24]. At the same time, the level of Tt 3.4 ng/ml remained in 20.5% (n=9), and LH 1.24 mIU/ml in 4.5% (n=2) men. According to the level of recovery of LH and Tt, patients were divided into two groups: with satisfying (n=35; 79.5%) and poor (n=9; 20.5%) recovery. A clear correlation was established between the duration of use (-0.857; p0.0001), the amount (-0.443; p=0.003), the dose (-0.7825; p0.0001), the type of AAS (-0.698; p0.0001) and testosterone level recovery. A correlation between inhibin B and Tt (0.418; p=0.005) was revealed.
 CONCLUSIONS: A three-month refusal to use AAS with PCT led to the restoration of HPG axis a in 79.5% of the volunteers. In 20.5% of cases, recovery did not occur. The negative effect of the duration of use, the number of simultaneously administered drugs, their dose and type of AAS on the restoration of HPG axis was established. The level of inhibin B may serve as a marker for the restoration of spermatogenic epithelium.

Leaf and Fruit Methanolic Extracts of Azadirachta indica Exhibit Antifertility Activity on Rats' Sperm Quality and Testicular Histology.

The world's population is still growing, having an impact on the environment and the economic growth of developing countries; so that, there is a particular interest in the development of new fertility control methods, focused on male contraception. The objective of this study was to evaluate the effect of methanolic extracts of leaf and fruit of Azadirachta indica on sperm quality and testicular histology of Long Evans rats. Antifertility effects of a methanolic leaf and fruit extracts of A. indica on 24 male rats were investigated. The animals were randomly divided into two control groups and four treatment groups (n=4). Doses of the leaf and fruit extract were given at concentrations of 100 and 200 μg mL-1. A significant decrease in the viability of sperm cells was observed. The leaf extract at a concentration of 200 μg mL-1 inhibited cell viability compared to the negative control (p< 0.001). The percentage of abnormal cells in leaf extract was shown in 100 and 200 μg mL-1, the conditions at which a higher percentage of morphological irregularities of observed (15% and 16% respectively). The results show that there was cellular detachment in the seminiferous epithelium in the experimental groups treated with methanolic extracts. Sperm death was observed without decreasing the number of sperm. The methanolic extracts of Azadirachta indica have a modulating effect on the spermatogenesis of experimental rats through sperm morphological alterations.

Review of Vasectomy Complications and Safety Concerns.

Vasectomy is a simple, safe, effective, and economical method used worldwide for long-term male contraception. As a surgical operation, it has short-term and long-term complications such as hematoma formation, infection, sterilization failure, sperm granulomas, short-term postoperative pain (nodal pain, scrotal pain, and ejaculation pain), and chronic pain syndrome. Whether it increases the risk of autoimmune disease, cardiovascular disease, testicular cancer, or prostate cancer is still controversial. Changes in plasma concentrations of luteinizing hormone, follicle-stimulating hormone, and testosterone after vasectomy have also been studied, as well as the relation between vasectomy and sexual function. Sperm quality decreases very slowly after vasectomy, and vasovasostomy and intracytoplasmic sperm injection could help a couple achieve a pregnancy if they change their minds at any point. We include a follow-up strategy and suggestions for follow-up care at the end of this review.

Filamentous actin disorganization and absence of apical ectoplasmic specialization disassembly during spermiation upon interference with retinoid signaling†

Spermiation is a multiple-step process involving profound cellular changes in both spermatids and Sertoli cells. We have observed spermiation defects, including abnormalities in spermatid orientation, translocation and release, in mice deficient in the retinoic acid receptor alpha (RARA) and upon treatment with a pan-RAR antagonist. To elucidate the role of retinoid signaling in regulating spermiation, we first characterized the time course of appearance of spermiogenic defects in response to treatment with the pan-RAR antagonist. The results revealed that defects in spermiation are indeed among the earliest abnormalities in spermatogenesis observed upon inhibition of retinoid signaling. Using fluorescent dye-conjugated phalloidin to label the ectoplasmic specialization (ES), we showed for the first time that these defects involved improper formation of filamentous actin (F-actin) bundles in step 8–9 spermatids and a failure of the actin-surrounded spermatids to move apically to the lumen and to disassemble the ES. The aberrant F-actin organization is associated with diminished nectin-3 expression in both RARA-deficient and pan-RAR antagonist-treated testes. An abnormal localization of both tyrosinated and detyrosinated tubulins was also observed during spermatid translocation in the seminiferous epithelium in drug-treated testes. These results highlight a crucial role of RAR receptor-mediated retinoid signaling in regulating microtubules and actin dynamics in the cytoskeleton rearrangements, required for proper spermiation. This is critical to understand in light of ongoing efforts to inhibit retinoid signaling as a novel approach for male contraception and may reveal spermiation components that could also be considered as new targets for male contraception.

Retinoic acid receptor antagonists for male contraception: current status†

Retinoic acid receptor alpha (RARA), a nuclear receptor protein, has been validated as a target for male contraception by gene knockout studies and also pharmacologically using a pan-retinoic acid receptor antagonist. Retinoic acid receptor alpha activity is indispensable for the spermatogenic process, and therefore its antagonists have potential as male contraceptive agents. This review discusses the effects of systematic dosing regimen modifications of the orally bioavailable and reversible pan-antagonist BMS-189453 as well as studies with the alpha-selective antagonists BMS-189532 and BMS-189614 in a murine model. We also provide an overview of structure–activity studies of retinoic acid receptor alpha antagonists that provide insight for the design of novel alpha-selective ligands.

Crystal structure of TEX101, a glycoprotein essential for male fertility, reveals the presence of tandemly arranged Ly6/uPAR domains.

Testis-expressed gene 101 (TEX101) is a glycosyl-phosphatidylinositol-anchored glycoprotein essential for sperm fertility and spermatogenesis. TEX101 interacts with lymphocyte antigen 6 complex, locus K (Ly6k) as well as a disintegrin and metallopeptidase domain 3 (ADAM3). Although these proteins are considered essential for fertility, the associated mechanisms remain uncharacterized. Herein, we determined the crystal structure of human and mouse TEX101, revealing that TEX101 contains two tandem Ly6/uPAR (LU) domains. Detailed structural analyses revealed characteristic surfaces of TEX101 that may be involved in the interactions with other proteins or membranes. These results provide the structural basis for the role of TEX101 in fertilization and could contribute to developing diagnostic methods and treatments for infertility or developing male contraceptives.

Synthesis of 2-phenyl-5,6,7,8-tetrahydroquinoxaline derivatives and screening for P2X1-purinoceptor antagonist activity in isolated preparations of rat vas deferens, for translation into a male contraceptive†.

Sympathetically mediated contractions of smooth muscle cells in the vasa deferentia are mediated by neuronally released adenosine 5′-triphosphate (ATP) and noradrenaline, which stimulate P2X1-purinoceptors and α1A-adrenoceptors, respectively. This process is crucial for sperm transport, as demonstrated in knockout mouse studies where simultaneous genetic deletion of P2X1-purinoceptors and α1A-adrenoceptors resulted in male infertility. We hypothesize that dual pharmacological antagonism of these two receptors could inhibit sperm transport sufficiently to provide a novel nonhormonal method of male contraception. To generate a suitable P2X1-purinoceptor antagonist, substituents were introduced on the phenyl moiety of 2-phenyl-5,6,7,8-tetrahydroquinoxaline to create a series of analogues that were tested for P2X1-purinoceptor antagonism in isolated preparations of rat vas deferens. Novel compounds were initially screened for their ability to attenuate contractile responses to electrical field stimulation (EFS: 60 V, 0.5 ms, 0.2 Hz). The addition of polar substituents to the meta, but not ortho, position markedly increased the inhibition of contractions, as did the addition of both polar and aliphatic substituents to the para position. Di-substituted compounds were also synthesized and tested, resulting in a compound 31 (2-hydroxy, 4-fluoro), which exhibited the greatest potency, with an IC50 of 14 μM (95% confidence limits: 12–16 μM). Additionally, compound 31 noncompetitively antagonized contractions mediated by exogenously administered αß-methylene ATP (10 nM–30 μM) but had no inhibitory effect on contractions mediated by exogenously administered noradrenaline (30 nM–100 μM) or acetylcholine (30 nM–100 μM). These results have contributed to a structure–activity relationship profile for the P2X1-purinoceptor that will inform future designs of more potent antagonists.

Discovery of potent thrombin inhibitors from a protease-focused DNA-encoded chemical library

DNA-encoded chemical libraries are collections of compounds individually coupled to unique DNA tags serving as amplifiable identification barcodes. By bridging split-and-pool combinatorial synthesis with the ligation of unique encoding DNA oligomers, million- to billion-member libraries can be synthesized for use in hundreds of healthcare target screens. Although structural diversity and desirable molecular property ranges generally guide DNA-encoded chemical library design, recent reports have highlighted the utility of focused DNA-encoded chemical libraries that are structurally biased for a class of protein targets. Herein, a protease-focused DNA-encoded chemical library was designed that utilizes chemotypes known to engage conserved catalytic protease residues. The three-cycle library features functional moieties such as guanidine, which interacts strongly with aspartate of the protease catalytic triad, as well as mild electrophiles such as sulfonamide, urea, and carbamate. We developed a DNA-compatible method for guanidinylation of amines and reduction of nitriles. Employing these optimized reactions, we constructed a 9.8-million-membered DNA-encoded chemical library. Affinity selection of the library with thrombin, a common protease, revealed a number of enriched features which ultimately led to the discovery of a 1 nM inhibitor of thrombin. Thus, structurally focused DNA-encoded chemical libraries have tremendous potential to find clinically useful high-affinity hits for the rapid discovery of drugs for targets (e.g., proteases) with essential functions in infectious diseases (e.g., severe acute respiratory syndrome coronavirus 2) and relevant healthcare conditions (e.g., male contraception).

Review of rationale and progress toward targeting cyclin-dependent kinase 2 (CDK2) for male contraception†.

Cyclin-dependent kinase 2 (CDK2) is a member of the larger cell cycle regulating CDK family of kinases, activated by binding partner cyclins as its name suggests. Despite its canonical role in mitosis, CDK2 knockout mice are viable but sterile, suggesting compensatory mechanisms for loss of CDK2 in mitosis but not meiosis. Here, we review the literature surrounding the role of CDK2 in meiosis, particularly a cyclin-independent role in complex with another activator, Speedy 1 (SPY1). From this evidence, we suggest that CDK2 could be a viable nonhormonal male contraceptive target. Finally, we review the literature of pertinent CDK2 inhibitors from the preclinical to clinical stages, mostly developed to treat various cancers. To date, there is no potent yet selective CDK2 inhibitor that could be repurposed as a contraceptive without appreciable off-target toxicity. To achieve selectivity for CDK2 over closely related kinases, developing compounds that bind outside the conserved adenosine triphosphate-binding site may be necessary.

The Na+ and K+ transport system of sperm (ATP1A4) is essential for male fertility and an attractive target for male contraception†.

One of the mechanisms that cells have developed to fulfil their specialized tasks is to express different molecular variants of a particular protein that has unique functional properties. Na,K-ATPase (NKA), the ion transport mechanism that maintains the transmembrane Na+ and K+ concentrations across the plasma membrane of cells, is one of such protein systems that shows high molecular and functional heterogeneity. Four different isoforms of the NKA catalytic subunit are expressed in mammalian cells (NKAα1, NKAα2, NKAα3, and NKAα4). NKAα4 (ATP1A4) is the isoform with the most restricted pattern of expression, being solely produced in male germ cells of the testis. NKAα4 is abundant in spermatozoa, where it is required for sperm motility and hyperactivation. This review discusses the expression, functional properties, mechanism of action of NKAα4 in sperm physiology, and its role in male fertility. In addition, we describe the use of NKAα4 as a target for male contraception and a potential approach to pharmacologically block its ion transport function to interfere with male fertility.

Comparative Modulation of the Reproductive System by Ethanolleaf Extracts of Asystasia Gangetica Andanthocleista Vogelli in Male Wistar Rats

A number of medicinal plants have been found to influence the level of reproductive hormones and thus affect fertility in the overall. This work evaluated the effects of ethanol leaf extracts of A. gangetica and A. vogelli respectively on some reproductive system parameters in male Wistar rats. A total of sixteen (16) male albino rats were grouped into four (four rats in each group): group A served as normal control, group B received Immunace (Vitabiotics) group C and D received 400 mg/kg body weight of A. gangetica and A. vogelli extracts respectively. Extracts were administered orally to rats for 21 days, after which they were sacrificed by cervical dislocations and blood samples drawn by cardiac puncture. The effect of the extracts on testosterone, follicle stimulating hormone, luteinizing hormone and semen analysis of the test rats were determined using enzyme linked immunosorbent assay (ELISA) and standard techniques. Data collected were analyzed using Graph pad prism V6 and p values &lt; 0.05 were adopted as significant. There was no significant (p&gt;0.05) change in testosterone, FSH and luteinizing hormones in the group administered A. gangetica plant extract relative to the control. There was also no visible difference in the testes weight and sperm morphology relative to the control group. In contrast, administration of A. vogelli extract caused significant (p&lt;0.05) decrease in testosterone and follicle stimulating hormone concentrations from: 1.12 ± 0.20 to 0.89 ± 0.05 and 1.41 ± 0.07 to 1.35 ± 0.12 respectively relative to the control group. While significant (p&lt;0.05) decrease in luteinizing hormone (1.71 ± 0.15) was observed relative to the standard drug group (1.76 ± 0.05). A significant (p&lt;0.05) decrease in sperm count and testes weight was also observed in rats treated with A. vogelli extract relative to the normal control.The results suggest that, A. vogelli extract may cause decreased fertility in male albino rats and could be developed further into potent male contraceptives. A. gangetica on the other hand, had no effect on male reproductive hormones.

“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?

The role of team science in the future of male contraception†.

Efforts to develop a male contraceptive method beyond condoms and vasectomy have been on-going for nearly 70 years. During this time, there have been ebbs and modest flows of resources available to support product development, but not at a level sufficient to carry research efforts through to market. The small community of researchers that have continued to pursue the development of male contraceptives is comprised of dedicated scientists who have a great deal of knowledge and experience to offer. While collaboration has been an organic outcome of limited resources, competing research objectives and geographically diverse locations have made consistent and sustained progress challenging, particularly for those working in the earliest stages of developing nonhormonal, reversible male contraceptive methods. While the past decade has seen an increase in funding to the field, the levels are still modest when placed in the context of actual costs to bring products to market. In addition, there are challenges still to be identified given that there is no regulatory precedent for these products. These challenges present an excellent use case for the application of design-thinking or human centered design, as a means of generating novel solutions. By engaging those with deep technical expertise in the field of male contraception as well as thought leaders from other fields of practice, design-thinking offers an opportunity to identify potential strategies, including nontraditional approaches, capable of driving the product development process forward, in a faster and more efficient manner.

CRISPR/Cas9-mediated genome-edited mice reveal 10 testis-enriched genes are dispensable for male fecundity.

As the world population continues to increase to unsustainable levels, the importance of birth control and the development of new contraceptives are emerging. To date, male contraceptive options have been lagging behind those available to women, and those few options available are not satisfactory to everyone. To solve this problem, we have been searching for new candidate target proteins for non-hormonal contraceptives. Testis-specific proteins are appealing targets for male contraceptives because they are more likely to be involved in male reproduction and their targeting by small molecules is predicted to have no on-target harmful effects on other organs. Using in silico analysis, we identified Erich2, Glt6d1, Prss58, Slfnl1, Sppl2c, Stpg3, Tex33, and Tex36 as testis-abundant genes in both mouse and human. The genes, 4930402F06Rik and 4930568D16Rik, are testis-abundant paralogs of Glt6d1 that we also discovered in mice but not in human, and were also included in our studies to eliminate the potential compensation. We generated knockout (KO) mouse lines of all listed genes using the CRISPR/Cas9 system. Analysis of all of the individual KO mouse lines as well as Glt6d1/4930402F06Rik/4930568D16Rik TKO mouse lines revealed that they are male fertile with no observable defects in reproductive organs, suggesting that these 10 genes are not required for male fertility nor play redundant roles in the case of the 3 Glt6D1 paralogs. Further studies are needed to uncover protein function(s), but in vivo functional screening using the CRISPR/Cas9 system is a fast and accurate way to find genes essential for male fertility, which may apply to studies of genes expressed elsewhere. In this study, although we could not find any potential protein targets for non-hormonal male contraceptives, our findings help to streamline efforts to find and focus on only the essential genes.

CRISPR/Cas9-based genome editing in mice uncovers 13 testis- or epididymis-enriched genes individually dispensable for male reproduction†.

Developing a safe and effective male contraceptive remains a challenge in the field of medical science. Molecules that selectively target the male reproductive tract and whose targets are indispensable for male reproductive function serve among the best candidates for a novel non-hormonal male contraceptive method. To determine the function of these genes in vivo, mutant mice carrying disrupted testis- or epididymis-enriched genes were generated by zygote microinjection or electroporation of the CRISPR/Cas9 components. Male fecundity was determined by consecutively pairing knockout males with wild-type females and comparing the fecundity of wild-type controls. Phenotypic analyses of testis appearance and weight, testis and epididymis histology, and sperm movement were further carried out to examine any potential spermatogenic or sperm maturation defect in mutant males. In this study, we uncovered 13 testis- or epididymis-enriched evolutionarily conserved genes that are individually dispensable for male fertility in mice. Owing to their dispensable nature, it is not feasible to use these targets for the development of a male contraceptive.

SAT-LB7 Acceptability of Oral 11β-Methyl-19-Nortestosterone Dodecylcarbonate (11β-MNTDC) as a Potential Hormonal Male Contraceptive Pill: Results From a Randomized, Placebo-Controlled Trial

Background: Injectable hormonal male contraceptives (HMC) injectables appear safe and are effective in clinical trials, but global surveys suggest men would prefer an oral pill. 11β-methyl-19-nortestosterone dodecylcarbonate (11β-MNTDC) is orally bioavailable and well-tolerated. When taken daily with food for 28 days, the drug decreases serum gonadotropins and testosterone without significant impact on mood. If ongoing studies demonstrate that daily 11β-MNTDC consistently suppresses spermatogenesis to <1 million/mL in healthy men, oral 11β-MNTDC could be an effective HMC pill. Surveys of participant satisfaction and method acceptability for promising HMC pill prototypes, like oral 11β-MNTDC, are needed. Objective: To determine satisfaction with and acceptability of a daily oral 11β-MNTDC HMC pill Study Design: In a double-blind, randomized, placebo-controlled trial of a 28-day regimen of daily oral 11β-MNTDC at two academic medical centers, healthy male volunteers completed baseline and end-of-treatment surveys assessing their experience, satisfaction with, and willingness to use daily oral 11β-MNTDC. Results: Of 42 participants, 40 (30 11β-MNTDC, 10 placebo) completed end-of-treatment surveys. Respondents were primarily college-educated, sexually active white men between 21-40 years old. Less than 20% of participants cited initial concerns about safety and missing doses. Following treatment, nearly 90% of participants affirmed that taking the pill was easy to remember and did not interfere with their daily routine. Although one-third (37% 11β-MNTDC vs. 20% placebo, p=0.45) reported bothersome side effects, and 28% (30% 11β-MNTDC vs. 20% placebo, p=0.66) reported potential concerns about safety, these rates were neither statistically different in those taking active drug versus placebo nor associated with method satisfaction. The majority of participants reported satisfaction with the method (73% 11β-MNTDC vs. 70% placebo, p=0.84), that they would recommend it to others (90% 11β-MNTDC vs. 100% placebo, p=0.56), and that they would use the drug regimen as their primary contraceptive even if having to pay (67% 11β-MNTDC vs. 50% placebo, p=0.35). Half of participants (50% 11β-MNTDC vs. 67% placebo, p=0.51) affirmed that the method exceeded initial expectations. Respondents who reported being more likely to miss a dose were also more likely to report dissatisfaction with the study drug (p=0.03). Conclusion: The majority of participants in a 28-day trial of daily, oral 11β-MNTDC pills were satisfied with the regimen, would recommend the drug to others, and would pay to use the drug even when adverse or off-target effects (e.g. changes in libido and/or mood) were considered. If 11β-MNTDC is demonstrated to suppress spermatogenesis uniformly to very low levels, it would be acceptable to men desiring reversible contraception.

SAT-040 Changes in Metabolic Parameters After Administration of Novel Oral Androgens with Progestational Activity for 28 Days

Background: While the metabolic effects of testosterone have been well studied, the effects of co-administration of an androgen and progestin are less established. Two novel compounds being investigated for male hormonal contraception, dimethandrolone undecanoate (DMAU) and 11β-methyl-19-nortestosterone dodecylcarbonate (11β-MNTDC), have both androgenic and progestational activity.Aim: Characterize the effects of DMAU and 11β-MNTDC on metabolic parameters including weight, lipid parameters, insulin resistance, and adiponectin.Methods: Two randomized, double-blind, placebo-controlled studies in healthy men were previously performed to assess the safety and tolerability of DMAU and 11β-MNTDC taken orally for 28 days. Insulin and adiponectin assays were performed on a subset of banked samples. Changes in weight, LDL-C, HDL-C, fasting glucose, HOMA-IR, and adiponectin were assessed. Two way ANOVA with post hoc Tukey HSD was performed to assess for dosage (0, 200, or 400mg) and drug (DMAU or 11β-MNTDC) effects.Results: A total of 85 subjects were included in this secondary analysis. There was a statistically significant decrease in HDL-C (mean change -11 and -15 mg/dL) and increase in weight (3 and 2 kg) and LDL-C (18 and 23 mg/dL) in the DMAU and 11β-MNTDC 400mg groups respectively. There was no significant difference between the 200 and 400 mg groups nor differences between the two androgens. There were no statistically significant changes in fasting glucose, adiponectin or HOMA-IR.Conclusion: There were mild changes in weight, HDL-C, and LDL-C after 28 days of DMAU and 11β-MNTDC without significant changes in markers of insulin resistance or differences between the two compounds. Changes in metabolic parameters should be monitored and considered during further development of compounds for male hormonal contraception.

Knowledge and Attitude’s Men in Family Planning with Stop Motion Video Design in the Working Area of Singaparna Health Center of Tasikmalaya District, 2019

Indonesia is facing problems with the quantity and quality of human resources. One of the controls on this population is the family planning program. Currently, implementation of development-oriented to justice and gender equality in Indonesia has been implemented, it needs efforts to increase men's participation in family planning, namely by promoting media using digital marketing, one of which is by stop motion animation video media. The purpose of this study is to know the differences in knowledge and attitudes of men/husbands about male contraception in family planning before and after the screening of stop motion videos and to know the picture of male participation in family planning. The research method used was Pre-Experimental with one group pre-test and post-test design. The statistical test used is Wilcoxon. Based on data in Tasikmalaya in 2017 the coverage of contraceptive use from 8589 active acceptors there were 134 condom users (1.56%) and 10 MOP (0.11%) while in 2018 the contraceptive use coverage of 9376 active acceptors contained users 134 condoms (0.014%) and MOP 14 people (0.10%) the data shows that although there was an increase in the number of active family planning acceptors which was 0.22%, the number of male acceptor users decreased including 0.01% MOP and condom 1,54%. An increase in average knowledge after video viewing to 72.42 with an increase of 16.08 for knowledge and attitude variables to become 33.77 with an increase of 1.65 it illustrates the use of video stop motion media effective in increasing male knowledge.

Testis-specific serine kinase protein family in male fertility and as targets for non-hormonal male contraception†.

Male contraception is a very active area of research. Several hormonal agents have entered clinical trials, while potential non-hormonal targets have been brought to light more recently and are at earlier stages of development. The general strategy is to target genes along the molecular pathways of sperm production, maturation, or function, and it is predicted that these novel approaches will hopefully lead to more selective male contraceptive compounds with a decreased side effect burden. Protein kinases are known to play a major role in signaling events associated with sperm differentiation and function. In this review, we focus our analysis on the testis-specific serine kinase (TSSK) protein family. We have previously shown that members of the family of TSSKs are postmeiotically expressed in male germ cells and in mature mammalian sperm. The restricted postmeiotic expression of TSSKs as well as the importance of phosphorylation in signaling processes strongly suggests that TSSKs have an important role in germ cell differentiation and/or sperm function. This prediction has been supported by the reported sterile phenotype of the Tssk6 knockout (KO) mice and of the double Tssk1 and Tssk2 KO mice and by the male subfertile phenotype observed in a Tssk4 KO mouse model.

CIB4 is essential for the haploid phase of spermatogenesis in mice†.

Spermatogenesis is a complex developmental process that involves the proliferation of diploid cells, meiotic division, and haploid differentiation. Many genes are shown to be essential for male fertility using knockout (KO) mice; however, there still remain genes to be analyzed to elucidate their molecular mechanism and their roles in spermatogenesis. Calcium- and integrin-binding protein 1 (CIB1) is a ubiquitously expressed protein that possesses three paralogs: CIB2, CIB3, and CIB4. It is reported that Cib1 KO male mice are sterile due to impaired haploid differentiation. In this study, we discovered that Cib4 is expressed strongly in mouse and human testis and begins expression during the haploid phase of spermatogenesis in mice. To analyze the function of CIB4 in vivo, we generated Cib4 KO mice using the CRISPR/Cas9 system. Cib4 KO male mice are sterile due to impaired haploid differentiation, phenocopying Cib1 KO male mice. Spermatogenic cells isolated from seminiferous tubules demonstrate an essential function of CIB4 in the formation of the apical region of the sperm head. Further analysis of CIB4 function may shed light on the etiology of male infertility caused by spermatogenesis defects, and CIB4 could be a target for male contraceptives because of its dominant expression in the testis.