Male hormonal contraception: a safe, acceptable and reversible choice

Long-acting testosterone/progestin combinations show great promise as contraceptives

MJA 2000; 172: 254-255

	Any suggestion that men cannot be trusted with contraceptive responsibility ignores the widespread use of existing methods which involve their cooperation -- condoms, periodic abstinence and interrupted intercourse are used by millions of couples worldwide.1 For those wanting an alternative to these methods, only female contraceptive methods, permanent sterilisation or "natural" methods have been available. A wider choice of effective methods would be highly desirable, and male hormonal contraception (MHC) is likely to offer a reliable alternative in the near future.
Male hormonal contraception
	The physiological principles of MHC have long been recognised, but the past 20 years have seen important research in this area, notably that sponsored by the World Health Organization (WHO). Real evidence for MHC effectiveness has been provided from trials involving 600 couples in 10 countries, including Australia.2,3 All MHC strategies involve the administration of testosterone, which profoundly reduces serum gonadotropin (follicle-stimulating hormone [FSH] and luteinising hormone [LH]) levels.4 A reduced serum LH level markedly reduces intratesticular testosterone levels, which, in combination with a reduced serum FSH level, reversibly interrupts sperm production. (Following cessation of testosterone treatment, sperm counts return to pretreatment levels in 4-6 months.) In the WHO trials, two-thirds of men were rendered azoospermic (ie, having sperm counts of zero), while 91% of the men achieved sperm counts below 1 x 106/mL (normal value, > 20 x 106/mL).3 The pharmaceutical industry has not been active in the MHC area in the past, perhaps because of a belief that the potential market was small, or because of concerns about product litigation. Very recently, the industry has cautiously entered the area. Fortuitously for MHC development, current pharmaceutical interest in new types of androgen replacement therapies will assist this process.
Marketing male hormonal contraceptives
	Key factors to consider in planning a marketing strategy for male hormonal contraceptives are contraceptive effectiveness, acceptability and safety. Contraceptive effectiveness. No contraceptive is 100% effective. For the female contraceptive pill the failure rate is approximately 3 conceptions per 100 person-years in the first year of use, a figure which represents a reasonable target comparator for MHC. The WHO study showed that azoospermia confers high contraceptive cover (0.8 conceptions/100 person-years; 95% CI, 0.02-4.5).2 While azoospermia continues to be the goal, the WHO data suggest that the suppression of sperm counts to very low levels (eg, less than 1 x 106/mL) may provide contraceptive cover comparable to that of the female contraceptive pill, and would almost certainly be superior to other widely used methods such as condoms.3 No pretreatment marker predicts whether an individual will attain azoospermia using MHC. Apart from interracial variation (eg, 98% of Chinese men become azoospermic2,3), there appear to be no differences in serum gonadotropin or testosterone levels, or in testosterone pharmacokinetics, between those who become azoospermic and those who do not.5 Some data suggest that men in whom sperm production is not fully suppressed have a higher level of 5a-reductase enzyme activity, which converts testosterone to the potent androgen metabolite dihydrotestosterone and thus maintains spermatogenesis.6 Understanding the variability of response to MHC is important in formulating regimens which produce the highest rates of azoospermia. Acceptability. Men's willingness to use MHC will depend upon its effectiveness, convenience of use and side effect profile. Methods which are painful, costly, or inconvenient, or which require extensive monitoring or interfere with sexual function or general health, will be declined or soon discarded. Current MHC treatments encounter problems in this area, particularly the need for frequent testosterone injections (every 1-2 weeks) or testosterone implants (every 4-6 months). Supraphysiological doses of testosterone given by intramuscular injection in the WHO studies led to androgenic side effects (acne, mood change) in 21% of men,2,3 but more physiological testosterone levels achieved with implants can reduce these problems.7 Safety. The effects of male hormonal contraceptives on prostate and cardiovascular health are of prime concern in assessing the safety of MHC. So far, prostate problems have not been encountered in MHC trials of up to 18 months' duration. Furthermore, there is no evidence for the induction or acceleration of benign or malignant prostate disease with androgen replacement therapy in hypogonadal men. A fall of around 15% in HDL-cholesterol levels was observed in MHC trials using injectable testosterone;8,9 however, these changes were not seen with the more physiological profile of testosterone delivery via implants.7 Such physiological androgen delivery should reduce androgenic side effects (eg, polycythaemia) associated with intramuscular testosterone replacement, while maintaining libido and sexual function.
MHC using combined preparations
	Testosterone treatment alone will not reliably suppress sperm production to the point of azoospermia. The addition of a gonadotropin-releasing hormone antagonist to testosterone treatment effectively suppresses sperm production,4 but practical difficulties and expense make this a non-viable option. The combination of testosterone and a progestin promotes rapid and profound suppression of serum gonadotropins and sperm counts, and the search for the ideal testosterone-plus-progestin regimen is now the main focus of MHC research. Recent studies have used levonorgestrel,8 desogestrel and medroxyprogesterone acetate.7 One study using cyproterone acetate, an antiandrogenic progestin, produced azoospermia very rapidly and consistently.10 It was proposed that the efficacy of cyproterone acetate was due to its inhibition of testosterone action within the testis (which has a unique need for high testosterone levels) while not interfering with androgen action elsewhere in the body. The question of whether the progestin component of combined male hormonal contraceptives may have specific effects (eg, mood change) in some men requires further study.
Delivery methods
	Delivery methods providing stable physiological levels of testosterone are critical to male hormonal contraceptive development. Delivery could be either oral or by infrequent injection or implants (the latter perhaps being preferable, to assist with compliance). In this area, there is renewed interest from the pharmaceutical industry to work collaboratively with clinical scientists. Testosterone undecanoate or buciclate are esters which are slowly absorbed from intramuscular injection sites and provide testosterone delivery for 2-3 months. Methylnortestosterone is a more potent androgen than testosterone (reducing the mass of steroid to be delivered),11 and, furthermore, its 5a-reduced metabolite is inactive and thus avoids stimulation of the prostate. Finally, our improved knowledge of steroid ligand/receptor interaction may permit the synthesis of a single agent which activates both androgen and progestin receptors in the male, thereby providing gonadotropin suppression within the testis while maintaining androgen activity elsewhere in the body.
Conclusions	The combination of testosterone and progestin, delivered in the form of a single long-acting injection, shows great promise for providing equally effective (or better) contraception than current widely used male contraception methods. Large and long-term MHC trials are needed to establish the optimal formulations, to provide essential safety and efficacy data, and to spur the interest of industry, which is essential in bringing these products to the market. Robert I McLachlan Associate Professor and Principal Research Fellow Prince Henry's Institute of Medical Research Monash Medical Centre, Clayton, VIC Handelsman DJ. Contraception in the male. In: DeGroot LJ, editor. Endocrinology. 3rd edition. Philadelphia: WB Saunders, 1995: 2449-2458. World Health Organization Task Force on Methods for the Regulation of Male Fertility. Contraceptive efficacy of testosterone-induced azoospermia in normal men. Lancet 1990; 336: 955-959. World Health Organization Task Force on Methods for the Regulation of Male Fertility. Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men. Fertil Steril 1996; 65: 821-829. Amory JK, Bremner WJ. The use of testosterone as a male contraceptive. Baillieres Clin Endocrinol Metab 1998; 12: 471-484. Handelsman DJ, Farley TMM, Peregoudov A, et al. World Health Organization Task Force on Methods for the Regulation of Male Fertility. Factors in non-uniform induction of azoospermia by testosterone enanthate in normal men. Fertil Steril 1995; 63: 125-133. Anderson RA, Wallace AM, Wu FCW. Comparison between testosterone enanthate-induced azoospermia and oligozoospermia in a male contraceptive study. III. Higher 5a-reductase activity in oligozoospermic men administered supraphysiological doses of testosterone. J Clin Endocrinol Metab 1996; 81: 902-908. Handelsman DJ, Conway AJ, Howe CJ, et al. Establishing the minimum effective dose and additive effects of depot progestin in suppression of human spermatogenesis by a testosterone depot. J Clin Endocrinol Metab 1996; 81: 4113-4121. Wu FCW, Farley TMM, Peregoudov A, et al. Effects of testosterone enanthate in normal men: experience from a multicentre contraceptive efficacy study. Fertil Steril 1996; 65: 626-636. Bebb RA, Anawalt BD, Christensen RB, et al. A promising male contraceptive approach: combined administration of testosterone and levonorgestrel. J Clin Endocrinol Metab 1996; 81: 757-762. Meriggiola MC, Bremner WJ, Paulsen CA, et al. Cyproterone acetate and testosterone enanthate as a potentially highly effective male contraceptive. J Clin Endocrinol Metab 1996, 81: 3018-3023. Noe G, Suvisaari J, Martin C, et al. Gonadotropin and testosterone suppression by 7-methyl-19-nortestosterone acetate administered by subdermal implant to healthy men. Hum Reprod 1999, 14: 2200-2206. ©MJA 2000 Make a comment Home | Issues | eMJA shop | My account | Classifieds | More... | Contact | Topics | Search The Medical Journal of Australia    eMJA   Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company. Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/> © 2000 Medical Journal of Australia. We appreciate your comments.