TY - JOUR
AU - Blithe, Diana, L
AB - Abstract BACKGROUND Development of new methods of male contraception would address an unmet need for men to control their fertility and could increase contraceptive options for women. Pharmaceutical research and development for male contraception was active in the 1990s but has been virtually abandoned. The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) has supported a contraceptive development program since 1969 and supports the majority of hormonal male contraceptive development. Nonhormonal methods are also in development but are at earlier stages. CONTENT Several hormonal male contraceptive agents have entered clinical trials. Single-agent products being evaluated include dimethandrolone undecanoate, 11β-methyl-nortestosterone dodecyl carbonate, and 7α-methyl-19-nortestosterone. A contraceptive efficacy trial of Nestorone® gel and testosterone gel in a single application will begin in 2018. Potential nonhormonal methods are at preclinical stages of development. Many nonhormonal male contraceptive targets that affect either sperm production or sperm function have been identified. Targeted pathways include the retinoic acid pathway, bromodomain and extraterminal proteins, and pathways for Sertoli cell–germ cell adhesion or sperm motility. Druggable targets include CatSper, the sperm Na+/K+-exchanger, TSSK, HIPK4, EPPIN, and ADAMs family proteins. Development of a procedure to reversibly block the vas deferens (initially developed in India in the 1980s) is undergoing early stage research in the US under the trade name Vasalgel™. SUMMARY NICHD has supported the development of reversible male contraceptive agents. Other organizations such as the World Health Organization and the Population Council are pursuing male contraceptive development, but industry involvement remains dormant. The unintended pregnancy rate in the US is approximately 45% (1), despite a variety of contraceptive options available to women. Male condoms and withdrawal are the only reversible contraceptive methods available to men, with typical failure rates of 13% and 20%, respectively (2). Studies indicate that >50% of men would be interested in using a reversible method, if available (3), and many women would be willing to rely on their partner to use a contraceptive (4). Unplanned pregnancy rates could improve if both partners used a contraceptive method or if men had more options to control their own fertility. Hormonal Male Contraception Hormonal male contraceptive effectiveness has been established (5). However, the search for the “male pill” has been hindered by the lack of a safe, effective oral androgen, which is a necessary component of the method. Hormonal methods in men use a feedback mechanism similar to hormonal methods in women. In healthy men, testicular testosterone concentrations are 40- to 100-fold higher than serum testosterone concentrations. This high intratesticular testosterone concentration is required for spermatogenesis. Exogenous steroid hormone administration, an androgen alone or in combination with a progestin or gonadotropin-releasing hormone agonist or antagonist, suppresses testicular testosterone production through feedback inhibition of the hypothalamic–pituitary axis. Below a threshold amount of testicular testosterone, sperm production does not occur. However, other androgen-dependent functions such as libido, erection, ejaculation, and maintenance of muscle mass are dependent on sufficient serum testosterone concentrations. Therefore, exogenous androgens must be administered to maintain sufficient serum concentrations to support those functions while keeping testicular testosterone below the threshold to initiate sperm production. Studies using this approach have shown high rates of severe oligozoospermia (<1 million/mL) or azoospermia (no sperm), resulting in high contraceptive efficacy with few reported side effects (5, 6). The challenge for developing the “male pill” is that oral testosterone is cleared too rapidly to be effective as a single daily dose regimen even in combination with a progestin. Multiple doses of oral testosterone per day would be impractical for contraception. Although 17-methyl-testosterone has better oral bioavailability, it has been associated with hepatotoxicity when used long term. The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)2 has supported the development of new androgens that also bind to progesterone receptors and potentially may serve as single-agent male contraceptive drugs (7). Two lead candidates are in clinical development: dimethandrolone undecanoate and 11β-methyl-nortestosterone dodecyl carbonate (8, 9). These drugs are not susceptible to 5α-reduction, a characteristic that may be beneficial to prostate health and may lessen male pattern baldness. When administered orally or intramuscularly, dimethandrolone undecanoate is hydrolyzed to the active drug dimethandrolone, a novel derivative of 19-nortestosterone that binds to both androgen and progesterone receptors. Dimethandrolone undecanoate has been evaluated in early phase I clinical trials in the NICHD's Contraceptive Clinical Trials Network and was well tolerated (10). A first-in-man clinical trial of 11β-methyl-nortestosterone dodecyl carbonate is underway in the Contraceptive Clinical Trials Network. Longer term evaluation of progestagenic androgens is necessary to determine if the drugs are safe and can effectively suppress sperm production. These clinical evaluations will demonstrate if either of these drugs can be used as a single-agent hormonal contraceptive for men. Another synthetic androgen, 7α-methyl-19-nortestosterone (MENT), is currently being evaluated as a possible male contraceptive (11). MENT is not a substrate for 5α reduction and may provide selective sparing of the prostate while supporting other androgen-dependent functions. Initial evaluations of MENT implants to suppress sperm production were comparable to initial studies with testosterone, with about two-thirds of men showing dose-dependent spermatogenesis suppression (12). Improvements of the MENT implant resulting in sustained concentrations of MENT release are in development but require further validation in clinical trials. Although an effective oral testosterone product has not yet been developed, transdermal testosterone gels or an injectable androgen may provide an alternate dosing regimen. Testosterone gels are widely used in the US to treat hypoandrogenism. Combining testosterone gel and injections of the progestin depomedroxyprogesterone acetate, used for female contraception, resulted in effective sperm suppression in 90% of participants in one trial (13). Notably, this method involved 2 Food and Drug Administration–approved products, albeit they were used for off-label indications. Of the few hormonal male contraceptive effectiveness trials, the most recent was a phase II, multisite international clinical trial sponsored by the World Health Organization and CONRAD. The study evaluated the contraceptive efficacy and safety of separate intramuscular injections, at 8-week intervals, of a long-acting progesterone, norethisterone enanthate, and a long-acting androgen, testosterone undecanoate (14). Couples (n = 320) were enrolled, with 266 entering the efficacy phase. Per the recommendation of an external safety review committee, the study was terminated early because of the frequency of reported mood changes, depression, pain at the injection site, and increased libido. However, the combined method failure rate, including sperm nonsuppression by the end of the suppression phase, sperm rebound during the efficacy phase, and pregnancy during the efficacy phase, was 7.5%. Importantly, >75% said they would be willing to use the method if it were available. Taking advantage of the transdermal effectiveness of testosterone, another regimen in development includes daily applications of Nestorone gel and testosterone gel. Use of Nestorone gel (8 mg) and testosterone gel (100 mg) suppressed sperm concentration to <1 million/mL or to azoospermia in 89% of men compared to only 23% of men using testosterone gel and a placebo gel (15). Suppression of serum gonadotropins (luteinizing hormone and follicle-stimulating hormone) occurred rapidly. Gonadotropin hormone concentrations that were >1 IU/L after 4 weeks of treatment predicted treatment failure (sperm concentration >1 million/mL) with 97% diagnostic sensitivity (16). Most failure was due to inconsistent or nonuse of the products rather than to nonresponse to the drug regimen. When asked about acceptability of the regimen, over half of participants reported being satisfied or extremely satisfied with this method of contraception (17). A contraceptive efficacy study to evaluate combined Nestorone and testosterone in a single gel preparation for use as a primary method of contraception in couples began enrollment in the Contraceptive Clinical Trials Network in 2018. Hormonal male contraceptive methods have proven effective. Long-term safety will need to be demonstrated before any method would be considered for regulatory approval. Because men do not face the medical risks associated with pregnancy and childbirth, any systemic product for men must have a strong safety profile. The goal of identifying additional health benefits for male methods is especially attractive. Realistically, it will be several years before a product could reach the market because long-term trials with a sufficient numbers of couples are required. Additionally, pharmaceutical investment will be required to achieve that goal. Nonhormonal Male Contraception In contrast to hormonal male contraception, in which the mechanism of action is to suppress testicular testosterone production through feedback inhibition of the hypothalamic–pituitary axis to stop sperm production, the rationale behind the nonhormonal contraceptives is to avoid the hypothalamic–pituitary axis, potentially avoiding some side effects associated with hormones. Nonhormonal male contraceptive research involves targeting proteins that affect either sperm production or sperm function. Although nonhormonal contraceptive targets do not target the hypothalamic–pituitary axis, off-target side effects should still be minimized. This is largely contingent on specificity and potency of inhibitors for the target protein. Nonhormonal male contraceptive development is still in the preclinical phase; however, within the past decade or so, increasing efforts with iterative screening, structural biology, computational modeling, and designer chemistry have been employed to move forward several nonhormonal male contraceptives. First studied and recognized in male rats, vitamin A (retinol) deficiency and its physiologically active metabolite, all-transretinoic acid, have long been recognized for their role in male sterility (18). Retinoic acid is required for normal spermatogenesis. Additionally, retinoic acid receptor α (RARα) mouse knockout models display phenotypic sterility in male mice. The retinoic acid (RA) pathway, including conversion of retinol to retinal and finally to RA, provides places where inhibitors or antagonists can be applied to stop RA synthesis and thereby stop spermatogenesis. Suppression of spermatogenesis involving the RA pathway was demonstrated with a bisdichloroacetyldiamine analog (BDAD) (19). In a clinical study, one BDAD, known as WIN18,446, was used to treat over 60 men for 1 year. The drug was well tolerated and efficacious at inhibition of spermatogenesis. However, consumption of alcohol induced a severe disulfiram reaction, causing termination of development of the drug. The disulfiram reaction caused by BDADs is due to off-target inhibition of a liver enzyme, aldehyde dehydrogenase-2 (ALDH2). This enzyme detoxifies aldehyde during alcohol metabolism and inhibition by BDADs produced toxic aldehyde accumulation. A different aldehyde dehydrogenase subfamily, ALDH1A, is involved in the synthesis of RA, and a testis-specific member includes ALDH1A2. Covalent and noncovalent small-molecule inhibitors of ALDH1A2 have been developed recently. Ternary x-ray cocrystal structures of the inhibitors provide the structural framework for design of potent and selective inhibitors of ALDH1A2 (20). An alternative approach in the RA synthetic pathway is inhibition of RARα. An RARα variant is essential for spermatogenesis, and mouse knock-outs show phenotypic infertility. A study with the pan-retinoic acid receptor antagonist BMS-189453 demonstrated reversible spermatogenesis inhibition in a mouse model (18). Structure-based drug design, with iterative screening, is being employed to develop potent specific antagonists to inhibit RARα activity in the RA synthetic pathway to inhibit sperm production. Another nonhormonal target is bromodomain testis-specific protein (BRDT), a subfamily of bromodomain and extraterminal (BET) proteins, which consists of 4 members: BRD2, BRD3, BRD4, and BRDT. Testis-specific BRDT is critical for chromatin remodeling during spermatogenesis (21). Mice with homozygous BRDT null mutations are viable, but male animals are sterile (22). Validation of BRDT as a nonhormonal male contraceptive target was further strengthened by pharmacological inhibition of BRDT. A study showed that JQ1, a small-molecule inhibitor of BRDT, was able to cross the blood–testis barrier and cause complete, reversible contraceptive activity in male mice (20). Although effective for contraception, JQ1 had off-target binding to other BRD proteins. Efforts are underway with different chemical scaffolds in discovery and optimization of new inhibitors of BRDT. A study entailing virtual screening, analytical testing, structure–activity relationship evaluation, and compound optimization via x-ray cocrystal have resulted in different chemical scaffolds with potent BRDT activity (23). Each BET protein has 2 bromodomain modules, and the second module (BD2) may be a target for enhancing specificity. Focused library screening and subsequent optimization has produced potent BET inhibitor candidates selective for BD2 (24). Mechanistically different drug candidates that target Sertoli cell–germ cell adhesion and cause release of immature spermatids from the seminiferous epithelium have been identified. CDB-4022, an indenopyridine, has been shown to effect inhibition of mature sperm production in primates and stallions. Cessation of the drug treatment brings about full reversibility of sperm production with no apparent side effects (25, 26). Another series of drug candidates targeting Sertoli cell–germ cell interaction are the indazole carboxylic acid derivatives gamendazole, H2-gamendazole, and adjudin. These analogs have shown to affect fertility in animal models. In particular, rats treated with oral doses of H2-gamendazole showed inhibition of fertility (27). Although at low doses the drug effect was reversible, at higher doses the fertility effect was irreversible. The challenge of inhibitors crossing the blood–testis barrier is demonstrated by the difficulty in targeting Sertoli cells. To enhance specificity, adjudin was conjugated to a recombinant follicle-stimulating, hormone-binding fragment to target the testis germ cell–Sertoli cell junction (28). The increase is specificity was offset by the reduction of the oral bioavailability caused by the peptide. In general, for this series of molecules, safety and reversibility should be demonstrated in higher mammals. There are numerous ion channel and kinase protein targets that affect sperm motility. Many of these proteins are produced in the tail region of the sperm. Ion channels such as CatSper (a calcium ion channel) and KSper (a potassium ion channel) are sperm specific and they are required in male fertility (29). Male infertility profile without apparent systemic effects were displayed in gene mutations and deletions in animal models. An in vitro study with HC-056456, an inhibitor of the calcium ion channel, demonstrated that the drug prevented hyperactivation of sperm (30). A sperm-specific potassium channel, KCNU1, controls calcium entry through CatSper. Genetic deletion of SLO3 causes male infertility in mice (31). CatSper is activated by progesterone and prostaglandins through a nonclassical binding domain, causing sperm tail hyperactivation. Under normal function, CatSper is activated in an unconventional pathway involving progesterone binding and activating α/β hydrolase domain-containing protein 2 (ABHD2), causing the depletion of endocannabinoid 2-arachidonoylglycerol from plasma membrane in spermatozoa. The 2-arachidonoylglycerol inhibits CatSper, and the removal by ABHD2 causes calcium influx leading to sperm activation (32). Physiologically, the cumulus–oocyte complex likely provides the source of progesterone after it leaves the ovary, enters the fallopian tube, and migrates toward the ampulla. Sperm enters the tubal isthmus through the uterotubal junction and forms a reservoir (33). Each ejaculate contains millions of sperm, but only a few hundred or less bind to the wall of the oviduct and undergo capacitation (34). Sperm can remain viable in the isthmus for several days until progesterone and other triggers signal them to swim toward the tubal ampulla where fertilization may occur. A recent study demonstrated that the steroidal inhibitor RU1968 causes dysfunction of CatSper's progesterone-mediated motility response. The inhibitor is nontoxic to human sperm and inhibits hSLO3 with approximately 15-fold lower potency than CatSper (35). It is unclear if this approach would be more appropriate for female use as it affects progesterone function in the oviduct, but the targets remain an area of nonhormonal contraceptive research interest. The soluble adenylyl cyclase and a sperm Na+/H+-exchanger Slc9c1 form a complex critical for sperm motility (36). Mouse knockout of Slc9c1 displays infertility phenotype, making the exchanger another potential sperm-specific target for male contraception. In particular, Slc9a8−/− male mice are infertile owing to disruption in acrosome formation (37). The NHE in human sperm is mainly localized to the principal piece of the tail, and the production pattern suggests implication in the regulation of sperm motility (38). The Na+/K+-ATPase (sodium pump) is important in sperm motility and capacitation (39). These ion channels are found in many tissues, but the α4-subunit of the Na+/K+-ATPase is sperm specific and appears to be necessary for sperm function. The α4-subunit knockout male mice are completely infertile (40). One of the first known inhibitors for Na+/K+ pumps are cardenolide analogs. They have been used clinically to treat congestive heart failure. Ouabain, a cardenolide analog, has higher affinity for the Na+/K+-ATPase α4 isoform than the other somatic forms, α1, α2, and α3, in both mice and humans. Optimization using the ouabain scaffold as a starting point may yield derivatives with specificity for the α4 subunit (41, 42). Ouabain derivatives modified at the glycone (C3) and the lactone (C17) domains show picomolar inhibition for the α4 isoform with an excellent selectivity profile against α1, α2, and α3. Additionally, decrease in sperm motility in vitro and in vivo was demonstrated for the new ouabain triazole analogs (43). Several testis-specific serine/threonine kinases (TSSK) are important for spermatogenesis and function. In the human kinome, the TSSKs belong to a 5-member, testis-specific serine/threonine kinase family: TSSK1, TSSK2, TSSK3, TSSK4 (also known as TSSK5), and TSSK6. Male infertility is the phenotype displayed for the double TSSK1/TSSK2 knockout mice, indicating a critical role for TSSK1 and TSSK2 in spermiogenesis (44, 45). Protein production of stable and enzymatically active recombinant human TSSK2 represents a key achievement in progress toward targeting TSSKs as valid male contraceptive target proteins (46). Additionally, evidence from mutation screening in 494 patients with azoospermia or severe oligozoospermia in comparison with those in 357 fertile controls indicate single-nucleotide polymorphisms of TSSK2, associated with idiopathic infertile men with impairment of spermatogenesis (47). High-throughput screening of TSSK2 assays have revealed sub-100 nanomolar inhibitors that show promise for targeting the TSSKs with small-molecule inhibitors (48). The homeodomain-interacting protein kinase 4 (HIPK4) plays a role in later stages of sperm maturation and is another potential nonhormonal target under development (49). HIPK4 knockout mice have impaired spermatogenesis but are otherwise healthy. A sperm surface protein EPPIN (epididymal peptidase inhibitor) is another potentially druggable contraceptive target. A recent study has shown that intravenous infusion of a small-molecule inhibitor of EPPIN, EP055, resulted in dramatic reduction of sperm motility to approximately 20% of pretreatment levels in a monkey model. EP055 is thought to cause a rapid decrease in sperm internal pH and calcium level, affecting sperm motility (50). Numerous protein targets that affect sperm function have been identified. The challenge remains for these nonhormonal proteins targeting sperm function to be developed into effective and reversible contraceptive agents that can safely and permanently inhibit function of the sperm in the female reproductive tract. Several members of a disintegrin and metalloproteinases (ADAMs) family of proteins are produced exclusively or predominately in the testis or epididymis (51). Additionally, related members of ADAMs with thrombospondin motifs (ADAMTS) are also proposed to participate in sperm–egg adhesion (52). An ADAMTS-like protein from sea urchin is proposed to mediate species-specific sperm–egg adhesion (53). A systematic study to identify sperm membrane alloantigens found >20 potential unique sperm membrane and 5 sperm raft proteins. Among these, ADAM1, ADAM2, and ADAM3 were the dominant sperm membrane alloantigens (54). Further, in ADAM3 knockout mice, sperm were unable to enter the oviduct (55). However, it is unclear if human sperm have the same requirement for ADAM3. Numerous ADAM proteins form complexes that are required for sperm–egg binding (51). Additionally, ADAM family of proteases are increasingly the targets for new therapies in many areas of medicine (56). Sperm–egg binding is exemplified by Izumo1, a sperm surface protein that binds to JUNO (Izumo1R) on the egg, leading to sperm–egg fusion (57). Gossypol is a polyphenolic aldehyde-containing compound isolated from the cotton plant (58, 59). The infertility profile of gossypol was discovered in rural areas of China when the farmers begin to press uncooked cotton seeds for oil in the 1950s and 1960s. The eventual outcome of consuming raw untreated oil resulted in infertility for both women and men. Subsequently, a gossypol-free diet resulted in eventual recovery for women. However, some men did not recover from their infertility and impotency. The findings indicated that the rates of recovery and permanent infertility were associated with quantity and duration of cotton oil consumption (58). This information led to the idea that gossypol could be used as a male contraceptive. Thus, clinical studies for gossypol were initiated in China in the 1970s and 1980s as a male contraceptive. In total, >8000 volunteers participated in these studies. Gossypol, as male contraceptive, was highly efficacious; however, the narrow therapeutic window, frequent association with hypokalemia, and irreversible sterility caused termination of further clinical development (60, 61). Extract from Tripterygium wilfordii Hook. f., commonly called thunder god vine, has been used in Chinese herbal medicine for many years. Further, for >50 years, refined extract has been used to treat rheumatoid arthritis, chronic nephritis, chronic hepatitis, and various skin disorders (62, 63). Triptolide, a major component of the extract, belongs to the class of chemicals called diterpene epoxides (64). The first indication of the potential contraceptive effect of triptolide was gleaned from rheumatoid arthritis patients. The rheumatoid arthritis patients treated with the extract showed necrospermia or azoospermia characteristics (63, 65, 66). Subsequent studies in rats showed that T. wilfordii extracts containing diterpene epoxides cause infertility in male rats, with a severe decrease in epididymal sperm count and motility (62, 63, 66–70). Similar to gossypol, prolonged exposure was associated with irreversible infertility in rodents (68, 70). However, triptolide's immunosuppressive properties likely would prevent its long-term use and its development as a contraceptive. A commonly used plant to prepare jamu, an Indonesian traditional medicine, Justicia gendarussa has been used as a male contraceptive in Papua. Additionally, this plant is used as an antiinflammatory, antibacterial, and antifungal agent and is used to treat a variety of ailments including arthritis and cancer. Gendarussa is a commonly used term when referring to the extract of J. gendarussa for male contraception. In particular, gendarusin A and B, flavonoid scaffold analogs, are thought to be the active metabolites responsible for eliciting the contraceptive effect (71), possibly by decreasing human sperm hyaluronidase activity. An unpublished clinical trial performed in Indonesia reported contraceptive efficacy of Justicia gendarussa plant extract if ingested by the male partner daily for at least 20 days before having intercourse during the female's ovulatory period. Fertility was restored within 30 days after last usage, and minimal side effects were reported. Additional study on its mechanism of action and evaluation of longer duration of use will be required before any regulatory approval (unpublished observations). Using a local vs systemic approach to male contraception, development of a nonhormonal method to reversibly block the vas deferens was begun in the late 1970s in India. The procedure is called RISUG (reversible inhibition of sperm under guidance), in which the polymer styrene maleic anhydride is mixed with the solvent dimethyl sulfoxide and injected into the vas deferens (72). The polymer was thought to damage sperm, making them ineffective. The procedure was used in rats, monkeys, and in the first human in 1989. By 2000, RISUG was evaluated in a phase III clinical trial in India with promising results. However, an inspection of the Indian facilities by the World Health Organization produced concerns that studies were not done according to international standards, and further development was stymied. Intellectual property rights to RISUG were acquired by the Parsemus Foundation, a nongovernmental organization, in 2010, which then developed Vasalgel, also a styrene maleic anhydride acid polymer dissolved in dimethyl sulfoxide. Vasalgel does not claim any effect on the sperm and is purported to act as a mechanical barrier to sperm passage. It is thought that sperm flow can be restored by flushing the vas with an injection of sodium bicarbonate solution. The Parsemus Foundation has performed preclinical studies in rabbits and monkeys (73, 74) and intends to begin trials in humans in 2019 or 2020. A competitor to Parsemus, Contraline, is developing a hydrogel called Echo-V that can be injected into the vas deferens to block the flow of sperm but not other fluids (75). The gel ideally could be dissolved when the man is ready to restore fertility. Conclusion Although some nonhormonal natural products have gone into the clinic, nonhormonal male contraceptives are in early stages of development. In addition to the protein targets and small-molecule inhibitors described above, active research is ongoing for nonhormonal contraceptive target discovery and validation. As exemplified above, numerous laboratories are engaged in discovery and optimization of small-molecule inhibitors. It is hoped that some of these small-molecule contraceptive agents would enter preclinical development and further into clinical development in the near future. A variety of new contraceptive methods are under development for men. The introduction of an effective reversible male contraceptive method has the potential to dramatically reduce unplanned pregnancy rates. It would likely represent a new market opportunity rather than creating a significant reduction in the use of existing female contraceptive methods. How a possible risk to one individual may be mitigated by prevention of potential health consequences in another individual provides an interesting regulatory consideration for the evaluation of systemic male contraceptive agents. At the current pace of drug development, regulatory approval for a new male product in the US likely would not occur until at least 2030. 2 Nonstandard abbreviations NICHD Eunice Kennedy Shriver National Institute of Child Health and Human Development MENT 7α-methyl-19-nortestosterone RARα retinoic acid receptor α RA retinoic acid BDAD bisdichloroacetyldiamine analog ALDH aldehyde dehydrogenase BRDT bromodomain testis-specific protein BET bromodomain and extraterminal ABHD2 α/β hydrolase domain-containing protein 2 sNHE sperm Na+/H+-exchanger TSSK testis-specific serine/threonine kinases HIPK4 homeodomain-interacting protein kinase 4 EPPIN epididymal peptidase inhibitor ADAMs a disintegrin and metalloproteinases ADAMTS ADAMs with thrombospondin motifs. 3 Genes Slc9c1 solute carrier family 9, subfamily C (Na+-transporting carboxylic acid decarboxylase), member 1 Slc9a8 solute acarrier family 9 sodium/hydrogen exchanger), member 8 TSSK2 testis specific serine kinase 2. " Author Contributions:All authors confirmed they have contributed to the intellectual content of this paper and have met the following 4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved. " J. Long, administrative support. " Authors' Disclosures or Potential Conflicts of Interest:Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest: " Employment or Leadership: D. Blithe, National Institutes of Health, US Government. " Consultant or Advisory Role: None declared. " Stock Ownership: None declared. 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TI - Male Contraceptive Development: Update on Novel Hormonal and Nonhormonal Methods
JF - Clinical Chemistry
DO - 10.1373/clinchem.2018.295089
DA - 2019-01-01
UR - https://www.deepdyve.com/lp/oxford-university-press/male-contraceptive-development-update-on-novel-hormonal-and-YfZ2ak21sS
SP - 153
VL - 65
IS - 1
DP - DeepDyve
ER -