Clear evidence shows that many men and women would welcome new male methods of contraception, but none have become available. The hormonal approach is based on suppression of gonadotropins and thus of testicular function and spermatogenesis, and has been investigated for several decades. This approach can achieve sufficient suppression of spermatogenesis for effective contraception in most men, but not all; the basis for these men responding insufficiently is unclear. Alternatively, the non-hormonal approach is based on identifying specific processes in sperm development, maturation and function. A range of targets has been identified in animal models, and targeted effectively. This approach, however, remains in the pre-clinical domain at present. There are, therefore, grounds for considering that safe, effective and reversible methods of contraception for men can be developed.
Introduction
Childbearing and rearing directly affect women’s health, lifestyle, and economy. As a result, research and efforts in family planning have traditionally focused more on female methods of contraception. A wide range of reversible contraceptive choices have become available to women over the past 50 years; however, male contraceptive methods remain limited. Condoms, introduced 300–400 years ago, provide protection against sexually transmitted diseases when used properly, but are associated with high contraception failure rates, with 12 out of 100 couples conceiving during their first year of use. Vasectomy, a safe and simple outpatient surgical procedure, has a failure rate of less than 1%, but may require several months to achieve full contraceptive efficacy, and vasectomy reversal is costly and unreliable. Recent studies have shown that both men and women of different races, religions, and ethnicities are increasingly interested in novel male methods of contraception . The ideal male contraception would rapidly achieve consistent and fully reversible azoospermia without adverse effects, such as interference with libido or prostatic enlargement. Optimally, it would provide additional health benefits such as chemoprevention or an increase in quality of life.
Hormonal and non-hormonal pharmacological methods are being investigated for male contraception. Hormonally based male contraceptive methods are based on suppression of the hypothalamic–pituitary–gonadal axis and thus of spermatogenesis ( Fig. 1 ). Gonadotropin-releasing hormone (GnRH) secreted from the hypothalamus leads to pulsatile release of luteinising hormone and follicle-stimulating hormone (FSH) from the pituitary gland into the circulation. Luteinising hormone stimulates Leydig cells of the testes, leading to testosterone production. Follicle stimulating hormone interacts with Sertoli cells, supporting spermatogenesis. Both FSH and luteinising hormone are required for normal spermatogenesis to occur in men. Maximal suppression of both hormones usually results in azoospermia , although, in many of the studies described below, a proportion of men continue to produce low concentrations of sperm in the ejaculate. This dual hormonal control of spermatogenesis is regulated by the negative feedback of testosterone (and to a lesser extent of inhibin B) to the hypothalamus and pituitary gland. Therefore, administration of exogenous testosterone suppresses the production of GnRH, luteinising hormone, and FSH, causing a reversible inhibition on endogenous testosterone production and spermatogenesis.
Non-hormonal contraceptive agents aim at disrupting spermatogenesis or the sperm-egg interactions by interfering with sperm motility or processes involved in fertilisation. The theoretical advantages of non-hormonal contraception include target specificity, which could minimise the systemic side-effects that may be associated with the hormonally based agents, and the possibility of having a more rapid onset of action.
In this review, we first summarise recent advances in male contraception, with emphasis on newer regimens that may be introduced into clinical practice in the near future.
Male hormonal contraceptive methods
The goal of male hormonal contraception is the sufficient inhibition of spermatogenesis to result in azoospermia; however, early studies of male hormonal contraception showed that a sperm concentration less than 1 million/ml, classified as ‘severe oligospermia’ is associated with a low pregnancy rate (about 1% per year), an efficacy similar to that of the female hormonal contraceptives . Therefore, severe oligospermia is considered a standard for a male hormonal contraceptive, and is currently used as an end point in clinical development of these methods. An interval of 2–3 months is required for male hormonal contraceptives to reach their full effect, similar to the time required for vasectomy to become fully effective.
Hormonal contraceptive agents lead to the suppression of endogenous testosterone production via negative feedback on the hypothalamus and the pituitary gland. Therefore, it is important to replace peripheral testosterone with sufficient androgen administration to prevent the development of symptoms related to androgen deficiency, such as low libido, erectile dysfunction, changes in mood and behaviours, and disturbance of certain metabolic processes. On the contrary, supraphysiological dosing of testosterone may be associated with unwanted side-effects, such as acne, an increase in haemoglobin concentrations, and a decrease in high-density lipoprotein (HDL) cholesterol. Therefore, it is prudent for hormonal regimens to aim to maintain serum testosterone levels, and, by extension, androgen action at target tissues, within the normal, physiologic range.
Testosterone alone as a male hormonal contraceptive
Testosterone enanthate
After many years of development studies, The World Health Organization (WHO) conducted two large, multicentre, male hormonal contraceptive efficacy trials between the late 1980s and early 1990s, using intramuscular testosterone enanthate as a single agent contraceptive. These ‘proof of concept’ trials showed that testosterone enanthate is a reversible and effective contraceptive regimen in most men. In the first study , 65% of the men became azoospermic after a mean of 4 months, with 0–0.8 pregnancies per 100 person-years, equivalent to an efficacy rate of over 99%. An additional 30% of men became oligospermic (<3 million sperm/ml). The second WHO study enrolled 399 mostly Asian men who were given 200 mg testosterone enanthate by weekly injection . All but eight men (2%) became azoospermic or oligospermic, with overall fertility decreasing to a rate of 8.1 pregnancies per 100 person-years. Notably, none of the men who became azoospermic fathered a pregnancy. After the cessation of testosterone injections, sperm production of all subjects returned to normal.
No serious adverse events occurred in these trials, and well-being, quality of life, sexual function, and cognitive function were maintained or slightly improved in men receiving testosterone enanthate compared with baseline. Several major disadvantages, however, render testosterone enanthate as a single agent hormonal contraceptive impractical: a delay between first dose to contraceptive effectiveness of 3–4 months, the potential for fertility in the few men who fail to suppress their sperm concentration to below 1 million sperm/ml, and the inconvenient frequency of weekly injections. Side-effects seemed to be dose-related and reversible, including acne, weight gain, a decrease in testicular volume, an increase in haemoglobin, and a 10–15% decrease in serum HDL cholesterol reflecting the supraphysiologic levels of serum testosterone from this regimen. Nevertheless, these were important studies that demonstrated reversible contraceptive efficacy in large numbers of men.
Testosterone undecanoate
The development of a long-acting formulation of injectable testosterone took a long time to reach clinical practice. Injectable testosterone undecanoate allows for one injection every 10–12 weeks for testosterone replacement in men with hypogonadism. Two large studies conducted in China showed that testosterone undecanoate is a highly acceptable, effective, and safe agent for male contraception. Both studies administered 500 mg of testosterone undecanoate monthly as a single agent. The first study found that 299 out of 308 men enrolled achieved either azoospermia or oligospermia (<3 million sperm/ml) , and went on use testosterone undecanoate injections as a sole means of contraception for 1 year. Six men were subsequently found to have rising sperm concentrations despite testosterone undecanoate injections, and the overall contraceptive efficacy was 96.7%. A subsequent phase III study conducted in China enrolled 1045 men and showed that 94% of the men in the study attained severe oligospermia, with a fertility rate of 1.1 per 100 men after 30 months of treatment, and a similar overall contraceptive efficacy of 95% .
Testosterone undecanoate treatment resulted in a slower recovery time for spermatogenesis compared with testosterone enanthate. Discomfort at the site of injection was the main adverse effect, followed by acne (reflecting the supraphysiological dose of testosterone), and a small decrease in testis volume. Other dose-related side-effects, including increases in haemoglobin, are of particular concern for the widespread application of this approach.
Most importantly, the contraceptive efficacy of testosterone-only regimens is not uniform. Although Asian men attain high rates of azoospermia (90–100%), only 60% of white men do so . The basis of these ethnic differences has not been elucidated, but adjunctive therapies are clearly required to achieve appropriate efficacy in combination with testosterone across ethnic groups.
Testosterone pellets
Implantable testosterone pellets offer an alternative route of delivery, achieve steady testosterone concentrations, and need to be replaced only every 3–6 months. Testosterone pellets have been investigated alone but, as with injectable testosterone, combinations with progestogens were more effective. Two contraceptive studies have examined the efficacy of testosterone pellets combined with etonogestrel implants, and found an overall rate of azoospermia of 85% (83 out of 98 men) . Similarly, the combination of testosterone pellets and depomedroxyprogesterone (DMPA) was both efficacious and well tolerated in a pilot efficacy study among couples in Australia (discussed below). Testosterone given in the form of pellets seems to have only minor, if any, affect on HDL cholesterol, and these regimens had few side-effects. Although the long-term clinical implications remain unclear, minimising the non-reproductive effects of contraceptive regimens remains desirable for widespread use.
Transdermal testosterone
Transdermal testosterone may be delivered via patches or gels. The former has been used successfully to restore eugonadism in men with hypogonadism. Even when testosterone patches are combined with a progestin, however, they have not proven to be an effective method for male contraception , with fewer than 50% of men achieving oligo- or azoospermia, presumably because lower amounts of testosterone were delivered overall as well as a lack of high peak levels incompletely suppressing the secretion of the gonadotropins. Moreover, patches are associated with a high frequency of skin irritation, leading to the discontinuation in nearly one-quarter of the participants in one study .
Testosterone gel has shown efficacy in the treatment of hypogonadism and superior suppression of spermatogenesis compared with the testosterone patches when combined with a progestin. Testosterone gel alone has not been tested as a contraceptive. The combination of daily testosterone gel and intramuscular DMPA every 3 months resulted in severe oligospermia in 90% of participants (see below). Side-effects of this regimen were well-tolerated and reversible, and included mild acne, mild weight gain, a small decrease in HDL cholesterol and total cholesterol, whereas the haematocrit remained unaffected, the latter reflecting the lack of high peak levels of testosterone .
Contraceptive regimens using testosterone gels cause less skin irritation and are quite acceptable to men . Disadvantages include the need for daily application and the potential for transfer to female partners or children. This can be avoided if these products are used as directed, however, and men are counselled about appropriate timing of application and washing.
Testosterone–progestin combinations
Progestins act as adjunct male contraceptive agent with testosterone, enhancing inhibition of gonadotropin secretion leading to improved sperm suppression . Progestins may also have direct testicular effects, which may further modulate spermatogenesis or spermation .
A variety of progestins have been used in combination with testosterone in contraceptive trials ( Table 1 ). These steroids vary in structure, resulting in degrees of androgenic compared with purely progestational activity. First-and second-generation progestins (estranes and first-generation gonanes, respectively) are derivatives of 19-nortestosterone and tend to be androgenic (although such considerations are more relevant for female administration than for men), whereas third- and fourth-generation progestins have less androgenic activity.
| Preparation | Major features |
|---|---|
| Testosterone alone (injections, pellets, gel) | High doses needed so androgenic side-effects; relatively low rates of azoospermia especially in white men. |
| With levonorgestrel | Good efficacy; HDL-cholesterol changes; oral and implant options for LNG. |
| With etonogestrel | Implant formulation; low metabolic effects. |
| With norethisterone enanthate | Long-acting injectable; potential for co-formulation with testosterone undecanoate; currently being investigated in efficacy trial. |
| With medroxyprogesterone acetate | Used with testosterone pellets and gel; occasional prolonged duration of action. |
| With nestorone | Novel non-androgenic progestogen. |
| With cyproterone acetate | Anti-androgenic activity; may be relevant to metabolic effects and contraceptive efficacy. |
| With GnRH antagonists | Peptides, thus require frequent injection; expensive compared with progestogens; no metabolic effects; potentially useful for initial suppression of spermatogenesis; novel oral agents becoming available. |
Levonorgestrel and testosterone
Levonorgestrel is a first-generation gonane that has been used extensively in women, and has the advantage of good oral bioavailability. It has been used in a number of small male hormonal contraceptive trials in combination with testosterone, including a series of studies examining low-dose titration in an effort to limit side-effects. A randomised-controlled trial that enrolled 36 white men showed that the combination of levonorgestrel and testosterone enanthate led to higher incidence of azoospermia and severe oligospermia compared with testosterone enanthate alone . The levonorgestrel- testosterone enanthate combination group had more weight gain and greater decline in HDL cholesterol. When levonorgestrel was used at a much lower dose, sperm suppression was not compromised, and these side-effects were minimised . Levonorgestrel has also been used successfully as an implant in combination with long-acting testosterone undecanoate injections. A trial enrolling 62 Chinese men used a long-acting levonorgestrel implant with testosterone undecanoate, and found that 90% of the men attained azoospermia, and all became severely oligospermic . In a second study involving both Chinese and non-Chinese men, testosterone implants alone were not effective in non-Chinese men; however, the combination of levonorgestrel with testosterone resulted in nearly 90% of the men achieving severe oligospermia in both groups .
Etonogestrel and testosterone
Etonogestrel, the active metabolite of orally administered desogestrel, is a third-generation progestin originally formulated as a contraceptive agent for women and delivered via an implant, providing 3 years of contraception. A pilot study examined etonogestrel’s potential as part of a male hormonal contraceptive regimen in combination with testosterone pellets was promising , leading to an international multicentre phase II study that enrolled 130 men and used combinations of etonogestrel implants with testosterone decanoate for 48 weeks . A total of 78–85% of the men achieved azoospermia, with a low incidence of side-effects. This regimen was further optimised by using testosterone undecanoate injections evaluated in a trial that included 354 men . In the group who received high-dose etonogestrel, 94% achieved severe oligospermia. This study notably included a placebo group for the etonogestrel arm to allow clearer identification of side-effects. It also used an innovative centralised semen analysis method based on fluorescent detection: this allowed detection of low numbers of sperm, and accounted for the low azoospermia rate in that study. Side-effects associated with the combination were minimal and well-tolerated, with no change in HDL cholesterol concentrations.
Norethisterone enanthate and testosterone
Norethisterone enanthate (NETE) is a long-acting injectable, second-generation progestin with both antiandrogenic and antiestrogenic effects. Pilot studies have shown that testosterone undecanoate combined with NETE given intramuscularly or orally resulted in azoospermia in 90% of the men and severe oligospermia in the remaining 10%. Follow-up studies further investigated the optimal dosing interval for NETE when combined with testosterone undecanoate for the suppression of spermatogenesis , and this combination was selected by WHO and CONRAD for further exploration in a multinational phase II efficacy trial, with the intention of recruiting 400 couples who would use the 80-week injection regimen (200 mg NETE with 1000 mg testosterone undecanoate) for contraception for a year when the man’s sperm concentration had fallen below 1 million per ml. Although the detailed findings have not been published, preliminary reports suggest that the combination of testosterone undecanoate and NETE was well-tolerated and had a high contraceptive efficacy rate.
Depot medroxyprogesterone acetate and testosterone
Depot medroxyprogesterone acetate (DMPA) is a long-acting progestin with a long history of use as a female contraceptive agent. The first testosterone-DMPA male contraceptive efficacy trial enrolled 55 men in Australia and used the combination of testosterone pellets every 4–6 months and DMPA injections every 3 months . Fifty-three men achieved severe oligospermia and entered the efficacy phase, during which no pregnancies occurred. A similar study in China randomised 30 men to receive either alone or testosterone undecanoate with DMPA . Rebound in sperm concentrations occurred only in the testosterone undecanoate-alone group. As mentioned above, a more recent trial randomised 44 men to receive transdermal testosterone gel and DMPA with or without the GnRH antagonist acyline. In this study, 90% of the men developed severe oligospermia. Safety outcomes of all three trials were reassuring, with no severe adverse events. In both the Australian and Chinese studies, an increase in haemoglobin concentration and modest weight gain was observed, whereas transdermal T resulted in minimal changes in weight and serum lipid concentrations. When used in women, DMPA can result in persisting contraceptive effects, making reversibility less predictable. As persisting DMPA may continue to suppress gonadotropins beyond the duration of testosterone administration during the initial recovery phase, this may induce temporary hypogonadism in some men.
Nestorone, cyproterone acetate, and testosterone
Nestorone is a 19-norprogesterone-derived progestin with potent gonadotropin suppression developed as a gel, allowing an ‘all-gel’ approach for male hormonal contraception. Of 99 participants enrolled in a study of this approach, 89% achieved azoospermia or severe oligospermia . A rebound in sperm production during drug exposure was observed in four men. No significant adverse event occurred, and reported side-effects included mild acne in one-fifth of participants, weight gain, a small decrease in serum HDL cholesterol, and a small increase in fasting serum glucose that remained within the normal range in all men. A combined nestorone–testosterone gel is currently being developed, and could be a promising contraceptive option for men.
Cyproterone acetate (CPA) is an anti-androgenic progestin that, when combined with testosterone, yielded profound spermatogenic suppression with few adverse effects. In contrast to other regimens, CPA plus testosterone resulted in mild weight loss and a slight decrease in haemoglobin concentration, both of which are dose-dependent and attributed to CPA’s anti-androgenic properties, with rapid and profound sperm suppression . Although the antiandrogenic properties of CPA may have had a direct testicular affect that enhances sperm suppression, higher doses of testosterone enanthate, when combined with CPA did not further the contraceptive potential of the combination, and, in fact, were associated with lower rates of azoospermia. In a follow-up study, longer acting testosterone undecanoate injections combined with daily, oral, CPA resulted in azoospermia or severe oligospermia in 100% of participants and could be maintained by testosterone undecanoate alone or testosterone undecanoate plus CPA for another 32 weeks. Despite high concentrations of testosterone, a fall in haemoglobin was observed in men receiving the combination of testosterone and CPA. Although these results are promising, CPA has not been available for further evaluation.
The paradoxical lack of enhanced suppression of sperm production in the setting of higher doses of exogenous testosterone combined with CPA highlight a conundrum in male hormonal contraceptive development. Why do a proportion of men fail to completely suppress sperm production despite hormonal manipulation? Initial studies focused on the possibility of incomplete gonadotropin suppression in some individuals, but this has not been borne out . Baseline hormone levels and sperm concentration similarly do not predict men who are treatment ‘failures’ . It is possible that residual, non-gonadotropin dependent intratesticular androgen production might support persistent, low-level spermatogenesis in some men. This hypothesis is supported by work in mice deficient in luteinising hormone, in which low levels of non-LH dependent intratesticular androgens appear to support spermatogenesis . Although small, pilot studies in men have failed to corroborate a linear relationship between intratesticular androgen concentrations and spermatogenesis, recent work has demonstrated the potency of ketoconazole with and without dutasteride (a 5a reductase inhibitor) to lower intratesticular androgens further in men undergoing male hormonal contraceptive treatment. Use of these agents, together with androgen plus progestin regimens, will allow for experimental testing of the effectiveness of further suppression of non-gonadotropin dependent intratesticular androgen production on spermatogenesis in men over the next few years and may provide a target for further treatment of those men who fail to achieve azoospermia.
Gonadotropin-releasing hormone antagonists as adjuncts in male hormonal contraceptive treatment
Despite improved efficacy with the addition of progestins to testosterone, persistent spermatogenesis in a small number of men has been problematic. One potential mechanism whereby men might escape full suppression is via persistent, low level gonadotropin production, below the limit of detection for many gonadotropin assays. Unlike the GnRH agonists that initially increase gonadotropin production, GnRH antagonists are capable of potently suppressing the production of FSH and luteinising hormone within hours of administration. This property has been exploited experimentally to augment the contraceptive effects of hormone-based regimens at the level of the pituitary, particularly as ‘induction’ agents to shut down the gonadal axis in an effort to decrease the time to maximal sperm suppression.
Three trials have evaluated the efficacy of the GnRH antagonist peptide Nal-Glu as an adjunct to testosterone for male contraception . The first two small trials found reversible azoospermia in 14 of the 16 men receiving the combination of testosterone enanthate and daily subcutaneous injections of Nal-Glu; however, one-third trial failed to demonstrate an additive effect of Nal-Glu compared with testosterone enanthate alone. Nal-Glu was also tested as a potential agent for the induction of azoospermia, and, when combined with testosterone enanthate, led to oligospermia or azoospermia in 14 of the 15 men within 12–16 weeks . Another trial showed that the combined administration of 19-nortestosterone and the GnRH antagonist cetrorelix effectively suppressed spermatogenesis to azoospermia in all six participants within 12 weeks .
Both Nal-Glu and cetrorelix required daily subcutaneous administration, which is not feasible as a part of a long-term contraceptive regimen. Acyline is a longer-acting GnRH antagonist that suppresses gonadotropins for up to 2 weeks , and is also active after oral administration . Although the addition of acyline did not accelerate spermatogenic suppression or improve the rates of severe oligospermia when used in combination with testosterone enanthate and DMPA , the high efficacy of testosterone enanthate plus DMPA might have obscured any benefit of acyline. Oral acyline and other formulations of novel GnRH antagonists have yet to be evaluated as adjuncts to androgens for male contraception. Unlike progestins, the GnRH antagonists are unlikely to be associated with additional metabolic side effects when used with testosterone and thus deserve further evaluation in this context.
Alternative androgens for hormonal contraception
7-Alpha-methyl-19-nortestosterone
7-Alpha-methyl-19-nortestosterone (MENT) is an androgenic-anabolic steroid, and is five times more androgenic than testosterone in vitro . It has been successfully formulated as an implant, with a goal to develop implants requiring only annual, or even less frequent, placement. The addition of a methyl group at the 7-carbon position renders MENT resistant to 5-alpha-reduction, a potentially attractive property in an androgen for male hormonal contraception as it renders MENT relatively ‘prostate-sparing’ in animal models. 5α-reductases are highly expressed in the prostate, and reduction of androgens by these enzymes can result in more potent metabolites, such as dihydrotestosterone in the case of testosterone, which may amplify androgen action in these tissues. In addition, MENT is aromatised to an oestrogen, which may be important for supporting bone health in long-term users .
The first dose-finding study in healthy men showed that MENT implants can provide a sustained release of MENT sufficient to suppress gonadotropins and spermatogenesis for 1 year . In this study, eight out of the 11 men receiving four implants achieved and maintained azoospermia for 12 months, with recovery to normal levels of spermatogenesis within 3 months of implant removal. Results from trials combining MENT implants with etonogestrel and levonorgestrel implants, however, have been disappointing, with low rates of azoospermia (50–60%) and inconsistent maintenance of sperm suppression . This lack of efficacy, however, may be specific to the MENT implants used, as they did not provide sufficient and sustained release of MENT into the circulation, compared with earlier formulations. New MENT implants are in development to improve delivery, and will be tested in future trials.
Dimethandrolone undecanoate
Dimethandrolone undecanoate (DMAU) (7α, 11β-dimethyl-19-nortestosterone 17β-undecanoate) is a potent synthetic 19-norandrogen. Both DMAU and its more potent metabolite dimethandrolone (DMA) bind androgen and progesterone receptors, resulting in androgenic and progestational activity in vitro and in vivo . This dual activity gives DMAU and DMA the potential to serve as a single agent for male contraception. Moreover, DMAU is both orally and intramuscularly bioavailable, giving it the potential to be either a single agent ‘male pill’ or a long-acting, single agent injectable. A promising study in rabbits demonstrated reversible contraception with daily, oral, DMAU . Moreover, DMAU administered to rats had favourable anabolic effects, including maintenance of lean body mass and bone mineral density and prevention of fat mass accumulation and weight gain.
On the basis of these promising results in animals, evaluation of DMAU in men is currently under way. A Phase 1, single-dose, dose-ranging safety study in healthy men demonstrated that a single dose of oral DMAU partially suppressed gonadotropins and testosterone (Page et al.: manuscript submitted). Effective drug concentrations were only achieved when this formulation of DMAU was ingested with a fatty meal. This is similar to observations with oral testosterone undecanoate, which requires lymphatic absorption to optimise serum concentrations. Efforts are currently under way to improve the bioavailability of oral DMAU and to examine the effectiveness of intramuscular DMAU as a long acting, reversible, single-agent male hormonal contraceptive.
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