Testosterone

Various androgen preparations have been used alone for the suppression of spermatogenesis, including early studies performed with weekly or bi-weekly injections of testosterone enanthate and implantable testosterone pellets, both of which demonstrated suppression of spermatogenesis to severe oligospermia in most men (Table Androgens in Male Contraception). Weekly intramuscular injections and the insertion of implants every four months, however, were not considered acceptable and practical methods. testosterone patches did not deliver adequate androgens to allow for adequate suppression of spermatogenesis.

Table Androgens in Male Contraception

Oral testosterone Testosterone undecanoate (not efficacious)
Buccal testosterone Not yet tested
Injectables Testosterone enanthate
Testosterone undecanoate
Implants Testosterone
METN (7-alpha-methyl-19 nor-testosterone)
Transdermal Patches — not efficacious
Gels — not yet tested

The most promising androgen preparation currently being tested is testosterone undecanoate (testosterone undecanoate). Oral testosterone undecanoate has been available for the treatment of hypogonadal men for many years in Europe, Asia, and Canada, as well as in many other regions. testosterone undecanoate administered intramuscularly in oil was first used by Chinese investigators for testosterone replacement in hypogonadal men.

Subsequently, the intramuscular administration of testosterone undecanoate at a dose of 1000 mg every 12 weeks has been shown to provide adequate androgen replacement for hypogonadal men. When testosterone undecanoate was administered to normal Chinese men at a dose of 500 mg or 1000 mg every four weeks, azoospermia was induced in most of the subjects. Subsequently, Gu et al. administered 1000 mg of testosterone undecanoate as a loading dose followed by 500 mg every four weeks intramuscularly to over 300 couples. Azoospermia or severe oligospermia was achieved in 95% of the men. When the couples used only this method for contraception, no pregnancy occurred. Currently, there is an ongoing Phase III study that aims to test the same testosterone undecanoate regimen for two years on a large scale of 1000 male recruits in China. Studies in non-Asian men showed that testosterone undecanoate administered at 1000 mg every six to eight weeks resulted in azoospermia in about 50% to 60% of subjects, and severe oligospermia in 80% to 90% of subjects.

Potential Adverse Effect of Androgens

In these short-term androgen-alone regimens, the adverse events are few and related to the dose of androgen administered. Acne and weight gain were present in the early studies of testosterone enanthate. With long-acting testosterone esters, the side effects are related to androgen actions, including an increase in hematocrit / hemoglobin and a decrease in high-density lipoprotein (HDL) cholesterol. These side effects are usually mild and rarely lead to discontinuation from the clinical trials. If any, the long-term adverse effects of androgens in younger men on the prostate or the cardiovascular system are not known. Long-term epidemiological studies will be able to address these questions only when a male hormonal contraceptive becomes available to the public. Based on current knowledge, however, a lower androgen dose is presumed to be associated with fewer short-term side effects.

Androgens with Selective Actions

Androgens with more selective actions have been studied for male contraceptive development. For example, the selective androgen 7-alpha-methyl-19-nortestosterone (METN) is not converted by 5-alpha-reductase to dihydrotestosterone (dihydrotestosterone). In rodents and monkeys, METN (7-alpha-methyl-19 nor-testosterone) is about 10 times more potent than testosterone in suppressing gonadotropins, and only four times more efficacious than testosterone in supporting unwanted prostate growth in castrated animals. Subcutaneous implants of METN (7-alpha-methyl-19 nor-testosterone) can maintain sexual function but are unable to maintain bone mass in comparison to testosterone enanthate. With four subcutaneous implants of 7-alpha-methyl-19 nor-testosterone, sperm concentration was suppressed after six months of treatment to azoospermia and severe oligospermia in 64% and 82% of men, respectively, without any change in serum prostatic-specific antigen levels or prostate volume. When the subjects were followed for longer periods, all became oligospermic, and five out of six men remained azoospermic. The efficacy of METN (7-alpha-methyl-19 nor-testosterone) alone or in combination with progestogens in male contraceptive studies must still be confirmed with larger, multicenter studies.

To date, many pharmaceutical companies are developing tissue-selective androgen-receptor modulators (SARMs) that may be steroidal or nonsteroidal compounds. The steroidal compounds are designed to have less stimulatory effects on prostate growth while still being aromatizable, thus conferring the beneficial effects of estrogens on bone and lipid profiles. The nonsteroidal SARMs are neither aromatizable nor 5-α-reduced, but may have selective action on tissues. If it possible to develop selective gonadorropin-suppressing SARMs that can maintain androgenic effects on sexual function, bone, muscle, and mood without stimulating the prostate, these SARMs would be the ideal androgens for male hormonal contraception and the treatment of male hypogonadism.

Variation in Responsiveness to Exogenous Androgens

In the multicenter androgen-alone studies, it was noted that azoospermia was achieved in over 90% of Asian men as against approximately 60% of non-Asian men. These observations have been confirmed in studies utilizing androgens plus progestins. The reason for the differences in the suppression of spermatogenesis in response to exogenous hormones is not known. When exogenous testosterone was administered to both Asian and non-Asian men, serum luteinizing-hormone pulse amplitude suppressed at a lower dose of testosterone in Asian men, suggesting that their gonadotropin-releasing hormone-LH axis may be more sensitive to exogenous testosterone. The clearance of testosterone is not different between Asian and white men but testosterone production rates may be slightly lower in Asian men. It has been shown that Asian men have a smaller average tesris volume and seminiferous tubular volume, and fewer number of Sertoli cells, all of which are associated with an increased basal apoptoric rate of germ cells. Other researchers have shown that 5-alpha-reductase activity may be higher in those who failed to achieve near-complete suppression of sperm concentrations in semen, allowing dihydrotestosterone to maintain residual spermatogenesis. It has also been demonstrated that longer CAG repeats in exon 1 of the androgen receptor are more common in nonresponders, indicating lower androgen receptor activity in men who failed to demonstrate severe suppression of spermatogenesis to hormones administered exogenously.

Because of the smaller inhibitory response of non-Asians to androgen-alone male contraceptive regimens, it is generally thought that the addition of another gonadorropin-suppressive agent would be necessary to achieve more significant suppression of spermatogenesis in most men.

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