Update on Male Hormonal Contraception: Is the Vasectomy in Jeopardy?

GJ Manetti and SC Honig

Disclosures

Int J Impot Res. 2010;22(3):159-170. 

In This Article

Testosterone Alone

In 1939, independent studies on male contraception were performed by Heckel[33] and McCullagh and McGurl[34] and with short-acting testosterone propionate. Subsequent studies revealed reversible azoospermia by 60 days in some patients with daily use of 25 mg i.m. testosterone propionate.[44] Improved frequency and dosage were achieved with the advent of longer-acting testosterone enanthate (TE), spurring interest in studies with an improved delivery frequency.

The WHO (World Health Organization) in conjunction with the Contraceptive Research and Development program conducted two large multicenter studies on TE. In the initial multicenter study conducted in seven countries, subjects received 200 mg TE i.m. weekly and used no other contraception for 1 year once sperm concentrations fell below 3 million per ml.[45] This study revealed that 70% of 271 patients became azoospermic after 6 months of treatment. The mean time to azoospermia was 3 months. The azoospermic patients were enrolled in a 12-month efficacy phase, where one pregnancy occurred. Sperm reappeared in the ejaculate in 11 patients. Once the testosterone was discontinued, the mean time to sperm recovery was 3.7 months. Of note, this international study revealed that 91% of Asian and 60% of Caucasian patients became azoospermic, suggesting an ethnic difference in endocrine response. This difference has been seen in subsequent studies. Possible explanations include fivefold differences α-reductase levels in these groups,[46] lower baseline testosterone levels, differing susceptibility of the gonadotropic axis to testosterone and/or the rate of metabolic clearance of this hormone. One recent study by Kornmann et al.[47] suggest that differences in body fat content may have a central role in the discrepancy between the sperm suppression rates of Asians and Caucasians. This investigation evaluated 40 Caucasian men and showed that men with high fat mass had an impaired relative decline in LH and FSH in response to testosterone administration (testosterone propionate and testosterone undecanoate (TU)). They suggest that fat content may be important in differences that occur. Adjustments in the dosing or frequency of injections in obese men may overcome this problem. This may explain why suppression differs in different ethnic populations. Although semen analysis was not performed in this relatively small study, it provides insight that may assist in the development of patient-specific male contraceptives that will be more universally marketable.

The second WHO testosterone study was performed as a 15-center, 9-country study with 399 volunteers. Among them, 98% suppressed spermatogenesis to <3 million sperms per ml with weekly 100 mg i.m. TE after induction phase with 200 mg i.m. TE.[48] There was a significant difference in pregnancy rates between azoospermic patients (1.4 pregnancy per 100 person-years) and patients between 0.1 and 3 million sperms per ml (8.1 pregnancies per 100 person-years). Approximately 25% of patients discontinued the study due to personal reasons, dislike of injections or for medical reasons. This study confirmed the relative efficacy of treatment and was the groundwork for further studies with different longer-acting testosterone regimens.

A phase 2, multicenter study was performed with a longer-acting monthly injections of TU in 380 Chinese men. Among them, 76% of patients suppressed enough to enter the initiation phase. If suppression was to azoospermia or <3 million sperms per ml, there were no pregnancies. However, there was reappearance of sperm in azoospermic patients, with one pregnancy.[49]

A phase 3, multicenter study was recently performed in 1045 Chinese men undergoing monthly injections of 500 mg TU in tea seed oil for 30 months. All subjects had fathered at least one child in the past 2 years and had two normal semen analyses. Suppression was defined as azoospermia or <1 million sperms per ml. The cumulative contraception failure rate was 1.1 per 100 men (nine pregnancies), 4.8% patients did not achieve suppression and 1.3% of subjects had post-suppression sperm rebound. Treatment was well tolerated and spermatogenesis recovered to normal reference levels in all but two subjects following a 15-month recovery period. The authors concluded that monthly injection of TU is a safe, very effective and reversible contraceptive method in a high proportion of healthy fertile Chinese men.[50]

Studies with testosterone buciclate, another long-acting testosterone derivative were initially performed by the WHO collaborating center and showed moderate suppression of spermatogenesis at a dose of 1200 mg i.m. per month. This study, which was conducted in 1995, was among the first to show minimal side effects from this long-acting, easily administered testosterone derivative. This trial helped to set the stage for future investigation combining long-acting testosterone with progesterone derivatives.[51]

Synthetic androgens have been tested as well. A dose response trial of 7α-methyl-19-nortestosterone (MENT) was initiated in 35 healthy volunteers to assess effects of serum gonadotropins and sperm production.[52] This synthetic androgen is more potent than testosterone, is resistant to 5 α-reduction and has diffusion characteristics that make it well-suited for a depot implant. Initial data showed relatively good efficacy, but typical testosterone-related side effects. Suvisaari et al.[53] and others have shown that MENT has a short half-life and is not suitable for long-term injection and does not show significant FSH suppression. Dimethandrolone undecanoate is another potent synthetic androgen with some progestational activity that represents an orally active substance that appears to suppress LH levels in vitro and in rabbit models. Structurally similar to MENT, it may be resistant to breakdown by 5α-reductase allowing it to maintain muscle mass without stimulating prostate growth. Preliminary animal data suggest that due to its combined androgen and progestin effects, dimethandrolone undecanoate may offer a single, reversible contraceptive agent for men.[54]

Newer delivery systems have been approved by the US Food and Drug Administration for the treatment of hypogonadism. Whether men would tolerate daily gel application of testosterone may be a barrier to its widespread use, however recent studies combining testosterone gel with other agents will be presented later.

Testosterone alone has side effects, including acne and oily skin, mood changes, increased hemoglobin and hematocrit, weight gain, decrease in testicular volume, sleep apnea, gynecomastia and possible effects on cholesterol. There are no long-term data with testosterone use and normal men regarding prostate symptoms, growth or cancer. In an era of fear of using medications on relatively healthy individuals, acceptability of routine use may be a major concern, given recent data on medical treatment of menopause with estrogen/progestin therapy. In addition, anabolic steroids are a controlled substance and regulation of this industry is very strict at this time. Abuse of these drugs could easily become prevalent with its widespread use and availability for contraception.

Although data suggest that testosterone therapy will create a milieu of oligospermia and/or azoospermia in most cases, its reliability is clearly uncertain at this point. The efficacy bar has been set very high with 'the pill'. Higher efficacy with fewer short- and long-term side effects will need to be achieved to make use of testosterone alone a viable option. In addition, close follow-up with regular semen analyses is necessary as there may be breakthroughs in sperm suppression. However, the use of testosterone with other agents may have more promise. It is not, completely clear why either testosterone alone, or in combination does not suppress spermatogenesis completely or why it results in evidence of 'breakthrough' sperm production. Theories suggested are incomplete suppression of FSH and persistent or episodic incomplete suppression of intratesticular testosterone that allows for low levels of sperm production.[42] Recent studies have shown increased levels of insulin-like factor 3 (INSL-3)[55] or increased fat content[49] in incompletely suppressed patients.

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