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EDITORIAL |
Department of Andrology (P.Y.L.), Concord Hospital and ANZAC and Woolcock Research Institutes, University of Sydney, Concord New South Wales 2139, Australia; Department of Obstetrics and Gynaecology (R.I.M.), Monash Medical Centre and Prince Henry’s Institute of Medical Research, Monash University, and Andrology Australia (P.Y.L., R.I.M.), Monash Medical Centre, Clayton, Victoria 3168, Australia
Address all correspondence and requests for reprints to: Peter Y. Liu, F.R.A.C.P., Ph.D., Department of Andrology, Concord Hospital and ANZAC and Woolcock Research Institutes, University of Sydney, Concord, New South Wales 2139, Australia. E-mail: pliu{at}mail.usyd.edu.au.
Finding a life partner and starting a family are near-universal human desires. Fulfilling these expectations requires effective planning because child rearing imposes major life demands; consequently, fertile couples practice family planning to avoid unintended pregnancies and space and limit desired pregnancies to best fit their personal desires and financial resources. For these reasons, broadening contraceptive choice to allow men and women the option to share family planning responsibilities satisfies important individual and societal needs. To this end, generating male-directed contraceptive methods, vasectomy and condoms, is an important objective because the two currently available methods are not widely acceptable because vasectomy is not easily reversible, whereas condoms have limited user efficacy.
Considerable progress has been made in identifying specific targets (in sperm, testis, and/or epididymis) that might be used to reversibly reduce sperm number or function. These advances have been promoted in part through national health agencies such as the Contraception and Reproductive Health Branch, Center for Population Research, National Institute of Child Health and Development in the United States, which has provided grants, established two Contraceptive Clinical Network Centers (Male Area) in the United Sates, and sponsored two Future of Male Contraception conferences (http://www.futureofmalecontraception.com) to facilitate rapid translation of new male contraceptive targets to the clinic with support from the Contraceptive Research and Development Program, the University of Washington, and the World Health Organization. Nevertheless, these novel approaches, however promising, are years from clinical efficacy trials.
The most comprehensively researched male-directed contraceptives in humans are hormonally based methods of which combined androgen-progestin treatment regimens are the most promising. Male hormonal contraceptive (MHC) methods exploit negative sex hormone feedback suppression of pituitary gonadotropin secretion (1, 2) analogous to inhibition of ovulation by combined estrogen-progestin contraceptives. Landmark World Health Organization-sponsored proof-of-concept studies showing that testosterone treatment profoundly suppressed spermatogenesis and prevented pregnancies are now decades old (3, 4): these observations were later confirmed with a longer-acting testosterone formulation (5). Five years ago, we showed in the as yet only such efficacy study, that a combined androgen-progestin regimen allowed more physiological androgen dosing, sustained suppression of sperm output, and prevented pregnancies (6). More recently the International Hormonal Male Contraception Summit Group reviewed its combined data to demonstrate that androgen-progestin contraceptive regimens: 1) can be widely applied in men of differing ages, ethnicity, and other baseline characteristics (7, 8); 2) are superior to androgens administered alone and compare favorably with vasectomy in terms of time of onset of contraceptive action (8, 9); and, 3) allow spermatogenesis to fully recover to levels consistent with normal male fertility in all men after cessation of androgen with and without progestin treatments (7).
Despite these fundamental advances, driven primarily by public sector agencies and committed academic researchers, the development of marketable MHC remains elusive. The study by Mommers et al. (10) published in the current issue of the Journal addresses this problem by first identifying a lead androgen-progestin combination of testosterone undecanoate and etonorgesterol and then comparing six possible dosing combinations. Novel aspects include the (unprecedented in this field) use of a placebo control group and the prominent involvement of two multinational drug companies in collaboration. Other notable methodological innovations of this large multicenter study were the first-time use of centralized semen analysis, fluorescence methodology to detect low sperm concentrations, and gas chromatography mass-spectroscopy to measure blood steroid concentrations. The hope was to identify the optimal dosing regimen for a definitive large scale contraceptive efficacy study as a stepping stone to product development and registration.
Three hundred fifty-four men were randomized equally to one of seven groups receiving either placebo or six treatments involving differing combinations of long-acting im testosterone undecanoate (750–1000 mg every 10–12 wk) in combination with two doses of etonorgesterol implants for 42–44 wk, and a posttreatment follow-up of at least 24 wk. All treatment regimens were broadly equivalent in terms of suppression of spermatogenesis and safety. About 90% of men had suppressed sperm output to levels consistent with reliable contraception (
1 M/ml) (11) by 16 wk. Challenges in future protocol refinement include the fact that 3% of men in this largely Caucasian European population never suppressed sperm concentration to this threshold, even after 42 wk of treatment, supporting prior data that such combined methods will not be universally applicable (3, 4). Secondly, 17 men (about 6% of all treated) who initially suppressed sperm output adequately did not maintain this throughout the trial (so-called rebound), raising concern about unexpected pregnancies if such couples had been relying solely on this method of contraception.
Safety data were meticulously collected and compared with a placebo group for the first time. Men receiving treatment showed a doubling in the frequency of adverse events (20 vs. 8%, on average) consistent with increased hormone exposure (increased acne, weight gain, night sweats, and more frequent changes in libido or mood), compared with those receiving placebo: these were generally mild but the increase was statistically significant. High-density lipoprotein cholesterol fell by about 10% (consistent with many MHC studies) but proportionally with total cholesterol, and neither change was statistically significant. These minor lipid changes are only a potential surrogate marker of cardiovascular risk and their clinical importance is uncertain, given emerging understanding of reverse cholesterol transport. Adverse events occurred despite using a dosing regimen that probably did not maintain adequate suppression of gonadotropins (their sampling procedures did not allow a critical review of this eventuality) and thus spermatogenesis in all men throughout the trial. Together the data suggests that some degree of supraphysiological androgen exposure and/or alternative progestin dosing and delivery methods is required for sustained and profound negative feedback inhibition.
Further innovations in MHC are needed. Prior information shows that overall androgen exposure can be minimized by using preparations (sc implants or long acting im testosterone formulations) with near constant release pharmacokinetics, which result in more consistent suppression of blood gonadotropin concentrations (12, 13). Androgen exposure may also be reduced after initial suppression of spermatogenesis has been achieved (8, 14). 7
-Methyl-19-nortestosterone is being developed by the Population Council as a modified androgen that may have less prostate stimulating activity (15). And finally, selective androgen receptor modulators, which more profoundly suppress gonadotropin secretion and spermatogenesis (possibly by exhibiting specific progestogenic properties and minimal 5 reducibility) but that also show reduced androgenic side effects, could also be developed.
The history of the development of hormonal methods for women also provides some perspectives wherein lower-dose regimens evolved to minimize side effects without compromising efficacy. Further refinement of MHC regimens is clearly needed, but it seems likely that universal suppression of sperm output will not be achievable using physiological androgen exposure (i.e. no hormone related adverse effects), even when supplemented with progestins or other treatments that rely on inhibition of gonadotropins. Such men may have a degree of gonadotropin-independent spermatogenesis arising from intrinsic testicular androgen production or action. In practice this may indicate the need for verification of adequate sperm suppression, yet this burden (not required for female methods) may be minimal, given the advent of Food and Drug Administration-approved sensitive home semen testing kits (e.g. SpermCheck Vasectomy). As such, many couples may choose MHC as an effective and reversible contraceptive method (16).
Academic investigators, public sector agencies, and more recently the pharmaceutical industry, driven by regulatory authorities, have been searching for an ideal male hormonal contraceptive that is universally effective and free of side effects. Perhaps it is time to recognize that it is more important to allow individuals to make their own informed contraceptive choices while research continues to develop increasingly refined treatments. This is pertinent because some issues cannot be resolved by more research. The outcome of a man’s contraceptive failure, for example, will be literally borne by the female partner. Market research, however, already indicates that this is acceptable to many men and women who are in long-term stable relationships (16). But documenting what individuals do, rather than what they say they will do, requires that such methods first be available. Delayed onset of action is another nuisance, but again this may be acceptable to many men particularly if the alternative is vasectomy. Indeed, given that the spermatogenic cycle is around 70 d, rapid-onset male contraception may not be possible for particular methods that target processes that occur early in this cycle.
The fact is that many men already assume a conscientious role in family planning worldwide. Thus, it is still reasonable to maintain some perspectives in reviewing the strengths and weaknesses of contraceptive methods. Widely used female hormonal methods have side effects, such as mood change, and weight gain similar to those exhibited by men treated with androgen-progestin combinations (17, 18) and are not universally applicable, being contraindicated in some women due to past breast cancer, thromboembolism, migraine headaches, or older age. Breakthrough ovulation, be that a method failure or noncompliance, is analogous to rebound of spermatogenesis and risk of unintended pregnancy. No single method is used universally by all women; in a way this is analogous to the less than 5% of men who may not adequately suppress their sperm output and in whom this method would not be suitable. The need for a range of different options is obvious because no single method can be expected to be ideal for every couple, and MHC would be a useful addition to the current array of contraceptive methods available.
It is disappointing that both pharmaceutical companies involved in this study (10), and the most active in the MHC development, have since decided to withdraw from the field. Their reasons are sure to be multifactorial but probably include the perceived profitability of male hormonal contraception in the context of a shrinking global market and an increasingly adversarial medicolegal climate. To this end, the public needs to clearly articulate its wishes because there is a clear disconnect between what academic clinicians hear from disgruntled couples and what the pharmaceutical industry and governments believe! Another problem hindering progress is the unique circumstances of contraceptive research, which are not always appreciated by experts working in other fields (19). In contraceptive efficacy studies, placebo controls are not ethically justifiable because they would result in unwanted pregnancies, and for this reason, semen analysis is indispensable during MHC development.
Despite these setbacks, progress is continuing and academic researchers remain passionate. Support for male-directed hormonal methods continues to be fostered through internationally focused organizations, such as the World Health Organization and Contraceptive Research and Development Program, who have jointly sponsored the first large-scale androgen-progestin contraceptive efficacy study, involving 400 couples in seven countries (but none in the United States) that will commence shortly, as well as the final publication of results from an important large efficacy study conducted in China. However, what is needed is to reengage the pharmaceutical industry. Perhaps this will occur in countries such as China and India, which have world-class pharmaceutical manufacturing industries, proven innovation, and expertise in conducting these studies and perhaps most importantly, the population drive arising from their enormous and aspiring middle class to make such research a national priority (5). However, rather than rely on the East to show leadership (20), those of us in the West should ask ourselves the importance we place on contraceptive options for couples for whom MHC may represent both their preferred and only effective method.
Footnotes
This work was supported by the Australian National Health and Medical Research Council through Career Development Award 511929 and Research Fellowship 441103.
Abbreviation: MHC, Male hormonal contraceptive.
Received May 9, 2008.
Accepted May 19, 2008.
References
-mathyl-19-nortestosterone implants for possible use as a long-acting contraceptive for men. J Clin Endocrinol Metab 88:5232–5239This article has been cited by other articles:
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  V. Mahabadi, J. K. Amory, R. S. Swerdloff, W. J. Bremner, S. T. Page, R. Sitruk-Ware, P. D. Christensen, N. Kumar, Y.-Y. Tsong, D. Blithe, et al. Combined Transdermal Testosterone Gel and the Progestin Nestorone Suppresses Serum Gonadotropins in Men J. Clin. Endocrinol. Metab., July 1, 2009; 94(7): 2313 - 2320. [Abstract] [Full Text] [PDF]
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