ABSTRACT

Men continue to have a strong interest and commitment to effective family planning. Traditional methods of male contraception have long included periodic abstinence, non-vaginal ejaculation, condoms, and vasectomy, the latter two representing physical methods to prevent sperm from reaching the site of fertilization. However, for male contraception the reversible methods are not reliable, and the only reliable method, vasectomy, is not intended as reversible. During the 20^th century, a wide array of reversible and highly reliable female hormonal contraceptive methods was marketed; however, no new methods for male fertility regulation have been introduced for centuries. For men to share more equally the burdens as well as the benefits of family planning, more effective reversible male contraceptive methods need to be available. Most studies into male contraception have been conducted with hormonal methods, analogous to well-known female hormonal contraceptives, making them the closest to introducing a reliable, reversible male contraceptive method. The most promising hormonal approach is the combination of an androgen (usually testosterone) with a progestin and multiple studies have shown such combinations of depot steroids displays high contraceptive efficacy, based on reliable and reversible suppression of sperm output, with few side effects. While research into novel methods for male fertility regulation has continued in the public sector, private sector research into male contraception, essential for effective commercial product development, has stalled in recent decades. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

BACKGROUND

A male contraceptive must reduce the number of fertile sperm ejaculated into the vagina to levels that reliably prevent fertilization (1). Conception can be prevented by diverting or suppressing sperm output and/or inhibiting sperm fertilizing capacity. So far, all male methods depend on mechanical means to reduce female exposure to sperm using either traditional drug and device-free methods (abstinence, withdrawal, non-vaginal intercourse) or contemporary male methods comprising condoms and vasectomy. Unfortunately, among current male contraceptive options, the reversible methods are not reliable, and the reliable method is not intended as reversible. No new male contraceptive methods were introduced during the 20^th century contrasting with highly reliable, reversible hormonal contraceptives developed for women over the last half century. Yet male involvement in family planning remains extensive. Globally, one third of couples using contraception rely on methods requiring active male participation (2) and current male methods remain (together with medicated intrauterine devices) the most cost-effective contraceptive methods in the USA (3). While reflecting traditional and ongoing reliance of family planning on male involvement, greater participation by men in sharing the burdens as well as the benefits of effective family planning require developing more effective, reversible male methods. Such greater participation could ameliorate the still large unmet need for contraception globally as 40% of pregnancies are still unintended with half of unintended pregnancies ending in abortion and those rates are higher among developed countries (4). Family planning must always remain a matter of personal choice by couples. This is highlighted by the human rights abuses of coercive national family planning programs enforcing family limitation (“one-child family”), including through forced sterilization and abortion, in India and China (5, 6). Such coercive national programs originated in the 1970’s prompted by uncritical belief in the “population explosion”, notably from influential publications such as the Club of Rome’s “Limits to Growth” and Ehrlich’s “Population Bomb”, now discredited by their failed, alarmist predictions. India’s forced sterilization program was overturned by popular democratic action within a few years of its imposition whereas China’s one-child family policy operated for nearly 4 decades before its ending in 2016. These issues echo in medical mistrust as a barrier to acceptance of male contraception among the Black American minority (7).

Extensive public sector clinical research over the last 4 decades (8), despite minimal pharmaceutical industry involvement, has proven in principle that hormonal male contraception is feasible. Proof-of-principle is established for androgen-based hormonal suppression of spermatogenesis (9) achieving full reversibility (10), sufficient short-term safety (11) and acceptability to men and women (12, 13) culminating in the crucial proof of reliable contraceptive efficacy using androgen alone (14-17) or depot (18) or daily use (19) androgen-progestin combinations. Demographic modelling shows that introducing new male contraceptive methods, even if adopted by only a minority of men, would significantly reduce unintended pregnancies in Nigeria, South Africa, and the USA (20). Surveys of participants in clinical male contraceptive studies suggest that men may prefer a male contraceptive to be provided by their family doctor rather than specialists (21); however, the practical knowledge of non-specialists remains unsatisfactory and would require specific training (22). In addition to boutique contraception for adventurous early adopters, practical niches for male contraception include contraception after birth, during breast-feeding, or after abortion (23). Nevertheless, despite the proof-of-principle, strong community interest, and medical priority on the need for new, reversible male contraceptives, pharmaceutical industry development has ceased. This market failure reflects pharmaceutical industry perceptions of low profitability coupled with high risk in the context where a better return on investment is expected for developing drugs in more lucrative, less risky areas of chronic disease compared with the higher product liability risk of developing novel contraceptives for healthy men to compete with existing low-cost female methods. The possibility that Western market failure might be overcome if the growing perception of needs for voluntary family planning as a national priority in rapidly industrializing countries such as China, India and Brazil (24), has proved a failed hope. Novel approaches to finance further research such as philanthropic private sector funding (25) and public-private partnerships (26) have been developed. The 2022 overturning by the US Supreme Court of what was long accepted as a constitutional right to abortion has refreshed interest in developing wider coverage of effective contraception, including for men, to reduce the demand for abortion.

NON-HORMONAL METHODS

HORMONAL METHODS

Hormonal methods are the closest to meeting the requirement for a reliable, reversible, safe, and acceptable male contraceptive. Although reliability is judged by the efficacy in preventing pregnancy in fertile female partners, as a hormonal male contraceptive aims to prevent pregnancy by reversible inhibition of sperm output, the suppression of spermatogenesis constitutes a useful surrogate marker for development and evaluation of prototype male contraceptive regimens. This makes defining the degree of suppression of sperm output required a key strategic issue in developing a hormonal male contraceptive (228).

Two landmark WHO studies, the first ever male contraceptive efficacy studies, involving 671 men from 16 centers in 10 countries established the proof of principle that hormonally-induced azoospermia provides highly reliable, reversible contraception (14, 15). Among the minority (~25%) of men who remained severe oligozoospermic (0.1-3 million sperm/ml) using weekly testosterone enanthate injections, contraceptive failure rate (~8% per annum) was directly proportional to their sperm output. Hence to achieve highly effective contraception, azoospermia is analogous to anovulation as a sufficient, but not necessary, requirement. Nevertheless, reliable contraception by modern standards (29) requires uniform azoospermia as the desirable target for male contraceptive regimens (229). No regimen yet achieves this consistently in all men, although in some Asian countries (e.g. China (15), Indonesia (230, 231)) an approximation to uniform azoospermia can be achieved by a variety of regimens. A study involving 308 Chinese men in 6 centers has shown that monthly injections of testosterone undecanoate provides highly effective and reversible contraception (17). No pregnancies were recorded among men who were azoospermic or severely oligozoospermic (≤3 million sperm per mL) providing a 95% upper confidence limit of pregnancy (contraceptive failure) rate of 2.5% per annum. The overall failure rate based on suppression of spermatogenesis was <4%. The prototype regimen was well tolerated apart from injection site discomfort due to large oil injection volume (4 mL) and reversible androgenic effects (acne, weight gain, hemoglobin, lipids). Nevertheless, despite these promising findings, non-Chinese men require combination hormonal regimens involving a 2^nd gonadotropin suppressing agent, notably progestins, together with testosterone to ensure uniformly adequate spermatogenic suppression. Proof-of-principle for this combination approach was provided by a depot androgen/progestin regimen that observed no pregnancies among 55 couples during 35.5 person-years of exposure (95% upper limit of failure rate ~8%) in a study with satisfactory tolerability and reversibility for a prototype regimen (18). Hence, contraceptive efficacy studies show that highly effective contraception can be achieved with suppression of sperm output to near azoospermia (≤1 million per mL) (229). Ultimately, the efficacy of male contraception must be established by enumerating pregnancies prevented, and not counting sperm. The present paucity of male contraceptive efficacy studies, for which placebo controls are ethically impossible (232), makes systematic evaluations comparing practical clinical regimens a task for the future (233).

The reversibility of hormonal male contraceptive regimens is clearly established by an integrated re-analysis that pooled primary data from over 90% of all hormonal male contraceptive studies reported to show that all regimens show full reversibility within a predictable time course (234). This comprehensive review of the recovery of 1549 healthy eugonadal men, aged 18-51 years, who underwent 1283.5 man-years of treatment and 705 man-years of post-treatment recovery, showed the median times for recover to sperm densities of 10 and 20 million per mL were 2.5 months (2.4-2.7) and 3.0 months (2.9-3.1), respectively. Covariables such as age, ethnicity and hormonal or sperm output kinetics had significant but minor influence on the rate, but not the extent, of recovery.

Acceptability of a hormonal male contraceptive is high across a wide range of countries and cultures in potential male as well as female users (12). Willingness to use a hypothetical hormonal male contraceptive averaged 55% (range 29-71%) in an extensive, population representative survey of 9342 men aged 18-50 yr from 9 countries (4 Europe, 3 South America, Indonesia and USA) with consistency across a wide range of socio-economic and cultural settings (235, 236). Similar findings are reported in a 4-country study (UK, South Africa, Hong Kong, Shanghai) with 44-83% in each center (237) as well as 75% in Australia willing to try a hormonal male contraceptive (238). A majority of men in a US study were satisfied with and would recommend a transdermal gel-based hormonal contraceptive (239) and a majority of Chinese men were satisfied with monthly injections (240). Female partners from a variety of cultures also indicate high acceptability in a survey of 1894 women in 4 countries, among whom 40-78% would support and trust their male partners in stable relationships to use a hormonal male contraceptive (241). Corroborating the acceptability of hormonal male contraception are findings from experimental studies of prototype regimens for up to 12 months usage in which most participants confirm high levels of satisfaction and willingness to try a commercial product (239, 240, 242, 243).

Modern safety evaluation for hormonal contraceptive methods requires long-term, large scale studies of marketed products (244). Consequently, in the absence of any marketed male contraceptive, no long-term safety profile can be discerned. Nevertheless, 4 decades of clinical trials have consistently identified mainly minor adverse effects in short- or medium-term studies of prototype male hormonal contraception regimens (1, 8, 228). This was verified in an unique, placebo-controlled study of a combined androgen-progestin regimen which again proved highly effective at reversible suppression of sperm output although the inclusion of a placebo arm rendered it ethically impossible to evaluate contraceptive efficacy but provided insight into drug-related side effects (11). The study confirmed the benign medium-term safety profile for this prototype regimen in observing few serious adverse effects, none attributable to the steroid regimen, and, among the non-serious adverse effects reported, expected androgenic effects (acne, weight gain, sweating, changes in mood or libido) were more frequent than placebo but mild and rarely led to discontinuation (11). Nevertheless, the long-term safety evaluation of novel contraceptives requires large scale observational studies of extensively used drugs to define low frequency risks but can only occur after the marketing of suitable products.

Hence, prototype hormonal methods have proven reliability and reversibility and reasonable prospects for being well accepted and safe. Although they are the most likely opportunity in the foreseeable future to develop a practical contraceptive method for men, progress depends on pharmaceutical industry development. However, leadership in male contraceptive development has come almost exclusively from university-based investigators working with public sector organizations (8), notably WHO (245), CONRAD (246), and the Population Council (247). By contrast, commitment from pharmaceutical companies, including those that flourished in the post-war decades through developing female hormonal contraception, continued to languish over recent decades (24, 248) and is effectively ceased (249).

Steroidal Methods

ANDROGEN ALONE

Testosterone provides both gonadotropin suppression and androgen replacement making it an obvious first choice as a single agent for a reversible hormonal male contraceptive. Although androgen-induced, reversible suppression of human spermatogenesis has long been known (250-253), systematic studies of androgens for male contraception began in the 1970's (254, 255). Feasibility and dose-finding studies (256), mostly using testosterone enanthate (TE) in an oil vehicle as a prototype, showed that weekly im injections of 100-200 mg TE induce azoospermia in most Caucasian men (257) but less frequent or lower doses fail to sustain suppression (258-261). The largest experience with an androgen alone regimen arises from the two WHO studies in which over 670 men from 16 centers in 10 countries received weekly injections of 200 mg TE. In these studies ~60% of non-Chinese and >90% of Chinese men became azoospermic and the remainder were severely oligozoospermic (14, 15) (Figure 1). The high efficacy among Chinese men has also been replicated using monthly TU injections (16, 17). Effective gonadotropin suppression is a prerequisite for effective testosterone-induced spermatogenic suppression in human (18, 262-266) and non-human primates (267, 268). However, the reasons for within and between population differences in susceptibility to hormonally-induced azoospermia remain largely unexplained (269). Possible factors include population differences in reproductive physiology of environmental (270, 271), genetic (272-274) or uncertain (275, 276) origin that may lead to differences in rate and extent of suppression of circulating gonadotropins and/or depletion of intratesticular androgens. Limited invasive studies measuring intratesticular testosterone (and DHT) suggest that the degree of depletion may not predict reliably complete suppression of sperm output (277-279) but other more widely applicable, non-invasive markers of endogenous Leydig cell function such as circulating epitestosterone (262) or 17-hydroxyprogesterone (280) or non-steroidal testicular products such as INSL3 (281) may be more analytically informative as to the relative roles of gonadotropin suppression and intratesticular androgen depletion. Exogenous testosterone causes suppression of sperm output with an average of 13 weeks to reach severe oligozoospermia (<1 million per mL) or azoospermia with suppression being maintained consistently during ongoing treatment (282) (Figure 2). Following cessation of treatment, sperm reappear within 3 months to reach sperm densities of 10 and 20 million per mL at an average of 11.5 and 13.6 weeks, respectively (282) with ultimately full recovery (10) (Figure 3). Apart from intolerance of weekly injections, there were few discontinuations due to acne, weight gain, polycythemia, or behavioral effects and these were reversible as were changes in hemoglobin, testis size, and plasma urea. There was no evidence of liver, prostate, or cardiovascular disorders (14, 15, 283).

Figure 1.

Pooled summary of contraceptive efficacy from two WHO male contraceptive efficacy studies (14, 15) where contraceptive failure rate (pregnancy rate) is plotted against the current sperm concentration in the ejaculate. This illustrates a summation of all data pooled from both studies. Data comprise monthly observations of the mean sperm concentration (averaging monthly sperm counts) and whether a pregnancy occurred in that month or not. Pregnancy rate (per 100 person-years, Pearl index) on the y-axis is plotted against the cumulative sperm density (in million sperm per ml) indicating that contraceptive failure rates are proportional to sperm output. The inset is the same data re-plotted in discrete sperm concentration bands rather than cumulatively. For comparison, the average contraceptive failure rates in the first year of use (33, 407) of modern reliable contraceptive methods are indicated by diamond symbols.

Figure 2.

Plot of suppression (left panel) and recovery (right panel) of sperm output from the WHO Studies 85921 (15) and 89903 (14) involved pooling ~14,000 semen samples from 16 centers in 10 countries (282). Data-points represent mean and SE (error bar) of semen samples grouped within weeks with between six and 383 samples per time-point. Note cube-root scale on y-axis. For suppression, the smooth line is the two-parameter, single term exponential decay function plotted to fit the data by non-linear regression. For recovery, the smooth line is the three-parameter sigmoidal curve plotted to fit the data by non-linear regression.

Figure 3.

Recovery of spermatogenesis after cessation of treatment with hormonal male contraceptive regimens modified after an integrated re-analysis of over 90% of all reported studies (234). Data is plotted as a Kaplan-Meier survival plot of the increasing proportion of men recovering to various thresholds over time since last treatment. The data of last treatment is defined as the time elapsed from the end of the last treatment cycle, that is the latest date of the first missed treatment dose. The thresholds are a sperm concentration of 3, 10 or 20 million sperm per mL in the ejaculate or a return to their own pre-treatment baseline sperm concentration. The median time to achieving each threshold is tabulated together with its 95% confidence interval.

The pharmacokinetics of testosterone products are crucial for suppressing sperm output. Oral androgens have major first-pass hepatic effects producing prominent route-dependent effects on hepatic protein secretion (e.g., SHBG, HDL cholesterol) and inconsistent bioavailability. Short-acting testosterone products requiring daily or more frequent administration (oral, transdermal patches or gels) which may be acceptable for androgen replacement therapy present serious feasibility challenges in compliance for effective long-term hormonal contraception. Weekly TE injections required for maximal suppression of spermatogenesis (256) are far from ideal (284) and cause supraphysiological blood testosterone levels risking both excessive androgenic side effects and preventing maximal depletion of intratesticular testosterone for optimal efficacy (285, 286). Other currently available oil-based testosterone esters (cypionate, cyclohexane-carboxylate, propionate) do not differ from the enanthate ester (287), but longer-acting depot preparations such as injectable testosterone undecanoate are a substantial improvement. Subdermal testosterone pellets sustain physiological testosterone levels for 4-6 months (288) and the newer injectable preparations testosterone undecanoate (17), testosterone-loaded biodegradable microspheres (289) and testosterone buciclate (290) provide 2-3 months duration of action. Depot androgens suppress spermatogenesis faster, at lower doses and with fewer metabolic side effects than TE injections but azoospermia is still not achieved uniformly (291) although when combined with a depot progestin, this goal is achievable (18).

Oral synthetic 17-α alkylated androgens such as methyltestosterone (292), fluoxymesterone (293), methandienone (294) and danazol (295, 296) suppress spermatogenesis but azoospermia is rarely achieved and the inherent hepatotoxicity of the 17-α alkyl substitutent (297, 298) renders them unsuitable for long-term use. Athletes self-administering supratherapeutic doses of androgens also exhibit suppression of spermatogenesis (294, 299). Synthetic androgens lacking the 17-α alkyl substituent have been little studied although injectable nandrolone esters produce azoospermia in 88% of European men (300, 301) whereas oral mesterolone is ineffective (302). On the other hand, nandrolone hexyloxyphenylpropionate alone was unable to maintain spermatogenic suppression induced by a GnRH antagonist (303) in a prototype hybrid regime (where induction and maintenance treatment differ) whereas testosterone appears more promising (304). A 7-methyl derivative of nandrolone (MeNT), which is partly aromatisable but resistant to 5α-reductive amplification of androgenic potency, has been studied as a non-oral androgen for hormonal male contraceptive regimens (305). While its non-amplification by 5α reduction may be theoretically prostate-sparing (306), dose titration to achieve essential androgen replacement at each relevant tissue might be more difficult to achieve than for testosterone (307) or impossible. Non-aromatisable androgens which lack estrogen- receptor-mediated effects such as on bone density maintenance (308) and sexual function (309, 310) may not be ideal for long-term hormonal contraception. More potent, synthetic androgens lacking 17-α alkyl groups (311, 312) remain to be evaluated.

Adverse effects due to testosterone administration in prototype hormonal contraceptive regimens include (asymptomatic) polycythemia, weight (muscle) gain, and acne as well as changes in mood or sexual behavior. These are usually minor in severity, reversible upon cessation of treatment and of minimal clinical significance (11).

The safety of androgen administration concerns mainly potential effects on cardiovascular and prostatic disease As the explanation for the higher male susceptibility to cardiovascular disease is not well understood, the risks of exogenous androgens are not clear (313, 314). In clinical trials, lipid changes are minimal with depot (non-oral) hormonal regimens (18, 291, 315, 316). Changes in blood cholesterol fractions observed during high hepatic exposure to testosterone and/or progestins, due to either oral first pass effects or high parenteral doses, have unknown clinical significance but, in any case, maintenance of physiological blood testosterone concentrations is the prudent and preferred objective. The real cardiovascular risks or benefits of hormonal male contraception will require long-term surveillance of cardiovascular outcomes (317).

The long-term effects of exogenous androgens on the prostate also require monitoring since prostatic diseases are both age and androgen dependent. Exposure to adult testosterone levels is required for prostate development and disease (318-320). The precise relationship of androgens to prostatic disease and in particular any influence of exogenous androgens remains poorly understood. Ambient blood testosterone or DHT levels do not predict development of prostatic cancer over future decades in prospective studies of adults (321). A genetic polymorphism, the CAG (polyglutamine) triplet repeat in exon 1 of the androgen receptor, is an important determinant of prostate sensitivity to circulating testosterone with short repeat lengths leading to increased androgen sensitivity (322), however the relationship of the CAG triplet repeat length polymorphism to late-life prostate diseases remains unclear (323). Among androgen deficient men, prostate size and PSA concentrations are reduced and returned towards normal by testosterone replacement without exceeding age-matched eugonadal controls (322, 324-326). In healthy middle-aged men without known prostate disease, very high doses of the potent natural androgen DHT for 2 years did not increase prostate size or age-related growth rate compared with placebo indicating that effects of even high dose exogenous androgen treatment has much less effect than age on the human prostate (308). Similarly, self-administration of massive androgen over-dosage does not increase total prostate volume or PSA in anabolic steroid abusers although central prostate zone volumes increases (327). In-situ prostate cancer is common in all populations of older men whereas rates of invasive prostate cancer differ many-fold between populations despite similar blood testosterone concentrations. This suggests that early and prolonged exposure to androgens may initiate in-situ prostate cancer, but later androgen-independent environmental factors promote the outbreak of invasive prostate cancer. Therefore, it is prudent to maintain physiological androgen levels with exogenous testosterone, which then might be no more hazardous than exposure to endogenous testosterone. Prolonged surveillance comparable with that for cardiovascular and breast disease in users of female hormonal contraception would be equally essential to monitor both cardiovascular and prostatic disease risk in men receiving exogenous androgens for hormonal contraception.

Extensive experience with testosterone in doses equivalent to replacement therapy in normal men indicates minimal effects on mood or behavior (14, 15, 256, 328-330). A careful placebo-controlled, cross-over study showed that a 1000 mg TU injection in healthy young men produces minor mood changes without any detectable increase in self or partner-reported aggressive, non-aggressive or sexual behaviors (331). By contrast, extreme androgen doses used experimentally in healthy men can produce idiosyncratic hypomanic reactions in a minority (332). Aberrant behavior in observational studies of androgen-abusing athletes or prisoners are difficult to interpret particularly to distinguished genuine androgen effects from the influence of self-selection for underlying psychological morbidity (333).

ANTI-ANDROGENS

Antiandrogens have been used to selectively inhibit epididymal and testicular effects of testosterone without impeding systemic androgenic effects (334). Cyproterone acetate, a steroidal antiandrogen with progestational activity, suppresses gonadotropin secretion without achieving azoospermia but leads to androgen deficiency when used alone (335). In contrast, pure non-steroidal antiandrogens lacking androgenic or gestagenic effects such as flutamide, nilutamide and casodex fail to suppress spermatogenesis when used alone (336, 337). Two studies evaluating the hypothesis that incomplete suppression of spermatogenesis is due to persistence of testicular DHT have reported no additional suppression from administration of finasteride, a type II 5α reductase inhibitor (338, 339); however as testes express predominantly the type I isoforms (340), further studies are required to conclusively test this hypothesis using an inhibitor of type I 5-α reductase (341).

ANDROGEN COMBINATION REGIMENS

Combination steroid regimens use non-androgenic steroids (estrogens, progestins) to suppress gonadotropins, in conjunction with testosterone for androgen replacement, have shown the most promising efficacy with enhanced rate and extent of spermatogenic suppression compared with androgen alone regimens (315, 342, 343). Synergistic combinations reduce the effective dose of each steroid and minimizing testosterone dosage could enhance spermatogenic suppression if high blood testosterone levels counteract the necessary maximal depletion of intratesticular testosterone (344, 345) as well as reducing androgenic side-effects (Figure 4).

Figure 4.

Plot of time course of sperm output (expressed as sperm density in millions of sperm per mL) before and after implantation of two 200-mg testosterone pellets (400 mg total; closed circles), four 200-mg testosterone pellets (800 mg total; closed squares), four testosterone pellets plus depot progestin (800 mg total testosterone plus 300 mg DMPA; closed diamonds) and six 200 mg testosterone pellets mg (1200 mg total; open hexagons) in healthy fertile men (262). Results expressed as the mean and SEM. Note the cube root transformed scale on the y-axis.

Progesterone is a key precursor and steroidogenic intermediate for all bioactive natural steroids and the progesterone receptors A and B are structurally and evolutionarily the closest members of the nuclear receptor superfamily to the androgen receptor. Yet, although progesterone has crucial gestational and lactational roles in female reproductive physiology, it has no well-established role in male reproductive physiology apart from a possible role in sperm function (200, 346), possibly via non-genomic rather than a classically genomic mechanism (347). Nevertheless functional nuclear progesterone receptors are expressed in male brain, smooth muscle and reproductive, but not most non-reproductive, tissues (348). Synthetic progestins, steroidal structural agonistic analogs of progesterone, are potent inhibitors of pituitary gonadotropin secretion used widely for female contraception and hormonal treatment of disorders such as endometriosis, uterine myoma and mastalgia. Used alone, progestins suppress spermatogenesis but cause androgen deficiency including impotence (349, 350) so androgen replacement is necessary. Non-human primate studies indicate that this is mediated via a central hypothalamic-pituitary site of action rather than direct effects on the testis (351). Extensive feasibility studies concluded that progestin-androgen combination regimens had promise as hormonal male contraceptives if more potent and durable agents were developed (256, 352). The largest and most detailed multi-center study of the contraceptive efficacy of a androgen-progestin combination involving 320 healthy men aged 18-45 years together with their 18-38 year old female partners, both without known fertility problems, studied for up to 56 weeks while having intramuscular injections of 200 mg norethisterone acetate and testosterone undecanoate every 8 weeks that produced near-complete suppression (96% declined to <1 million/ml by 24 weeks) and reversible recovery (95% recovered by 52 weeks) of sperm output (353). Four pregnancies occurred in partners of 266 men with a pregnancy failure rate of 1.6% (95% confidence interval 0.6-4.1%). Prior information on androgen/progestin regimens derives from studies with medroxyprogesterone acetate (MPA) combined with testosterone. Monthly injections of both agents or daily oral progestin with dermal androgen gels produce azoospermia in ~60% of fertile men of European background with the remainder having severe oligozoospermia and impaired sperm function (256, 352, 354). Nearly uniform azoospermia is produced in men treated with depot MPA and either of two injectable androgens in Indonesian men (230, 231) or testosterone depot implants in Caucasian men (315). Smaller studies with other oral progestins such as levonorgestrel (342, 355, 356) and norethisterone (357, 358) combined with testosterone demonstrate similar efficacy to oral MPA whereas cyproterone acetate with its additional anti-androgenic activity has higher efficacy in conjunction with TE (343, 359) but not oral testosterone undecanoate (360). Highly effective suppression of spermatogenesis is reported with depot progestins in the form of non-biodegradable implants of norgestrel (361-363) or etonorgestrel (364, 365) or depot injectable medroxyprogesterone acetate (18, 315, 366, 367) or norethisterone enanthate (368, 369) coupled with testosterone (370). A comparative study showed that all four progestins (cyproterone acetate, levonorgestrel, norethisterone acetate and nesterone) displayed significant short-term gonadotrophin suppression when combined with testosterone (371). The pharmacokinetics of the testosterone preparation is critical to efficacy of spermatogenic suppression with long-acting depots being most effective while transdermal delivery is less effective than injectable testosterone (361). Progestin side-effects are few if sexual function and well-being are maintained by adequate doses of testosterone replacement. The metabolic effects depend on specific regimen with oral administration and higher testosterone doses exhibiting more prominent hepatic effects such as lowering SHBG and HDL cholesterol. After treatment ceases with depletion or withdrawal of hormonal depots, spermatogenesis recovers completely but gradually consistent with the time-course of the spermatogenic cycle (234, 282). Steroids with dual androgen and progestin properties may be potentially well suited to male contraception if the balance between these two bioactivities is properly balanced (372). A study comparing a gel combining nesterone (8.3 mg) with testosterone (62.5 mg) with the same dose of testosterone alone for daily transdermal application for 28 days demonstrated suppression of sperm output and serum gonadotropin to levels consistent with contraceptive efficacy and superior to testosterone alone indicating the suitability of the combination gel for further product development (373). Two orally active nandrolone derivatives, dimethandrolone (374-376) and 11-methyl nandrolone dodecylcarbonate (377), are undergoing promising, early stage clinical development showing high acceptability in a short-term, placebo-controlled clinical trials (378, 379). Whether such daily use oral or transdermal gel (239, 380)-based male contraceptives will have sufficient user compliance to attain high contraceptive efficacy remains to be evaluated.

Estradiol augments testosterone-induced suppression of primate spermatogenesis (381) and fertility (382) but estrogenic side-effects (gynecomastia) and modest efficacy at tolerable doses make estradiol-based combinations impractical for male contraception (383). The efficacy and tolerability of newer estrogen analogs in combination with testosterone remain to be evaluated.

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