Handelsman D.J. Editorial: hormonal male contraception - lessons from the East when the Western market fails. J Clin Endocrinol Metab. 2003;88(2):559-61.
The development of hormonal contraception was surely among the highest achievements of applied biomedical science during the 20th century. Combining the biological insight that pregnancy created a reversible anovulatory state via negative hormonal feedback with innovative steroid chemistry, the introduction of hormonal contraception in 1960 transformed society quietly but fundamentally. By providing women with the fifth freedom (1), that from incessant and unpredictable pregnancy (2), this peerless product of human ingenuity allowed women to participate more fully in work and society outside the home. Historically, men’s participation in deliberate family planning was always substantial, having been instrumental in the demographic transition from high to low fertility societies. Moreover, it remains substantial with 150 million couples, over one quarter of all using contraception, employing methods that rely on male participation (3). Yet, whereas the last few decades saw the introduction of a variety of reliable and reversible contraceptives for women, not a single new contraceptive method for men was introduced during the last century (4). Consequently, over the last few decades the responsibility for reliable family planning shifted heavily onto women. For men to resume a greater responsibility for family planning, more reliable reversible male contraceptive methods need to be available.
Novel targets for male contraception continue to be identified (5, 6, 7) but their clinical development remains well into the future. The closest to practical implementation for a new male contraceptive is the hormonal approach. Curiously, it has long been known that hormonal suppression of gamete production was as feasible for men as it was for women (8). Yet, the proof of principle that hormonal male contraception was feasible for men was delayed by 3 decades until the landmark World Health Organization (WHO) male contraceptive studies reported in 1990 (9) and 1996 (10). These studies showed that hormonal suppression of sperm output in the ejaculate to less than 3 million sperm per milliliter provided highly effective, reversible, and well tolerated male contraception. In studies involving over 670 men in 10 countries, the contraceptive failure (pregnancy) rate was proportional to residual sperm output, reinforcing the desirability of azoospermia as the surrogate goal for a hormonal male contraceptive. Importantly, these studies also established a reliable safety monitoring system based on monthly semen samples to minimize the risk of unwanted pregnancies during male contraceptive efficacy studies. The limitations of the WHO studies were that the prototype regimen used, weekly im injections of testosterone enanthate, did not achieve universal azoospermia and that weekly injections would not be widely acceptable.
In this issue of JCEM, Gu et al. (11) report a large, multicenter male contraceptive efficacy study, the first completed since the WHO studies, involving 308 healthy men in six centers and showing clearly that an androgen alone regimen, a monthly injection of 500 mg testosterone undecanoate (TU) after a loading dose of 1000 mg, is a highly effective and reversible contraceptive in Chinese men. No pregnancies were recorded among men who were azoospermic or severely oligozoospermic (<3 million sperm per milliliter), providing a 95% upper confidence limit of pregnancy (contraceptive failure) rate of 2.5% per year. A more stringent criterion of success takes into account men who fail to suppress and those who escape from suppression who might create pregnancies if not detected by the regular semen monitoring of the study. In this study, 9 of 308 (<3%) patients exhibited primary failure to suppress and another 6 (2%) had secondary failure with escape from suppression including one pregnancy. After discounting four of the six patients who escaped while on a suboptimal testosterone maintenance dosage (500 mg at 45 d, rather than monthly), the secondary failure rate of the monthly maintenance regimen was less than 1%, giving an overall failure rate of less than 4% as judged by suppression of spermatogenesis. By either criterion, these findings compare favorably with the first year failure rates of condoms (12%) or oral contraception (3%) (12). Tolerability was good with only expected side effects of injection site discomfort and androgenic effects (acne, weight gain, hemoglobin, lipids), which were modest in magnitude and reversible. No adverse mood or behavioral effects were reported. Limitations of this Chinese study are that the testosterone dose may not yet be optimized nor is the large volume (4 ml) and monthly frequency of injections ideal. With ongoing support from WHO and the Chinese National Family Planning Program, the same investigators are undertaking a Phase III style study involving 1000 men completing an extended efficacy period of 24 months. If successful, these studies promise to achieve the first registration of a practical hormonal male contraceptive.
An interesting but important caveat is that, despite the highly promising findings in Chinese men, androgen alone regimens are unlikely to be adequate for men of Western origin.Hormonal regimens show consistently higher rates of azoospermia among men in Asian centers (95%) than in those of European background (60–70%). The environmental and/or genetic basis for such within and between population differences in susceptibility to testosterone-induced azoospermia remains uncertain (13). Variations in androgen sensitivity due to genetic polymorphisms in androgen receptor or metabolism (14) or in spermatogenic organization (15) do not explain these differences. The lower endogenous testosterone production rate of Chinese men living in China compared with Chinese and American-born men residing in the United States (16), together with the higher sensitivity to negative testosterone feedback of Asian-American men (17), suggests that Chinese men may be more sensitive to fixed doses of exogenous testosterone. This highlights the need for dose optimization in such regimens. The practical consequence, however, is that an androgen alone regimen is considered impractical for Western populations where second generation, combination hormonal regimens using testosterone in conjunction with a nonandrogenic gonadotropin suppressing agent, notably progestins or GnRH antagonists, have proved more promising among men of European background (4). The current working objective for a second generation, hormonal regimen is an optimized progestin/androgen combination administered at 3- to 4-month intervals with sufficient predictability to dispense with regular semen monitoring other than to verify attainment of azoospermia, analogous to standard postvasectomy practice. Several very promising depot regimens involving progestins such as etonogestrel (18) and norethisterone acetate (19) together with TU are in development, and the first depot combination contraceptive efficacy study has been successfully completed (20). By contrast, an oral "pill" seems less feasible or desirable given the uncertain tolerance for compliance, the greater difficulty of dose optimization for a combination, and the first-pass hepatotoxicity of oral synthetic androgens.
The lengthy gestation of an effective hormonal male contraceptive remains inexplicable. The major practical obstacle has been the disinterest of the pharmaceutical industry contrasting vividly with their enthusiastic adoption of hormonal contraception and replacement therapy for women. In practical terms, only large pharmaceutical companies can develop products although public sector researchers and agencies have made great advances in proof of principle and logistics for a hormonal male contraceptive. Indeed, far more mechanistic, efficacy, and safety information is now available about male methods compared with when female methods were introduced in 1960 to an eager market. Now, even companies that developed from the steroidal contraception boom avoid commitment to developing a male-oriented product. Undoubtedly, the dearth of andrology expertise has not helped—even now very few centers have expertise in male reproductive health in contrast to gynecology, which is represented in virtually every medical school and teaching hospital. Indeed, the misplacement of responsibility for andrology research onto gynecologists who lack expertise can lead to misguided nihilism (21). Whatever the reasons for the strike by large pharmaceutical companies—fear of predatory class action suits, low profit margins on contraceptive products, exaggerated fear of side effects—the disconnect between the lay and medical perception of both a need and a niche for such products, on the one hand, and the failure of the pharmaceutical market to deliver a product, despite the demonstration of feasibility, is puzzling, indeed. Clearly, male hormonal contraceptive methods are designed for couples in stable relationships—thought of as a reversible chemical sterilization—rather than for singles or men without regular partners, for whom the need for dual protection against sexually transmitted disease as well as unwanted pregnancy, favors the use of barrier methods. For suitable couples, however, a hormonal male contraceptive would occupy niches such as the postpartum period, delaying vasectomy, intolerance of female methods, replacing less effective male methods, and boutique contraception. Recent surveys suggest that not only are men from a wide variety of cultural backgrounds willing to use a hormonal male contraceptive (22, 23), but that their regular partners in stable relationships are quite willing to trust them (24). From birth and vasectomy rates together with realistic uptake estimates, a real commercial opportunity is being overlooked. Perhaps, however, this variant of pharmaceutical market failure corresponds to the neglected development of new drugs for malaria and tuberculosis or to the reluctance to make available low-cost HIV drugs where the predominant market exists in developing countries.
The silver lining in the cloud of tardy development is that the pathway for clinical development is lit up by history. Larger and longer studies need to define the efficacy relative to appropriate benchmarks and safety based on real clinical endpoints, rather than surrogate variables. The relevant efficacy endpoints are condoms, as the reversible male method, and oral contraception, as the standard female hormonal method (25). Regarding safety, expanded studies need to focus on cardiovascular and prostate disease as well as idiosyncratic androgenic effects, notably polycythemia and sleep apnea. Crucial medical and regulatory issues will include dose optimization, identifying the tolerance margin for irregular compliance as well as defining noncontraceptive benefits. The development of male contraceptive regimens containing testosterone will prove an interesting challenge to International Olympic Committee-style urinary drug screening for elite competitive sports, because urine tests will consistently demonstrate elevated testosterone to epitestosterone ratios, the hallmark of exogenous testosterone usage.
The successful organization of this Chinese multicenter study owes much to the joint efforts of the WHO Male Task Force and the Chinese National Family Planning Program in providing training, funding, local expertise and facilitation, and, above all, sufficiently high priority when pharmaceutical companies have shown scant interest. Interestingly, the injectable TU was developed by a Chinese pharmaceutical company using an off-patent ester (26), long marketed as an oral oil-filled capsule in most Western countries excluding the United States. Subsequently, a Western pharmaceutical company following that lead has shown that TU may be an excellent depot testosterone product suitable for androgen replacement therapy with injections at 2- to 3-month intervals (27). Nevertheless, the progress continues, and prospects look brighter (21), while the pharmaceutical companies continue to frown. Perhaps smaller, more agile, and adventurous pharmaceutical companies may now take up the lead provided by academic researchers, public sector agencies, and the National Programs of China and Indonesia. For the population seeking new male contraceptive methods, in the unequal contest between lay needs and unfilled medical niches vs. commercial priorities of large pharmaceutical companies, the leadership of public sector agencies and national family planning program remain the best hope at least until a real entrepreneur emerges.
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