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No. 66 Hormones |
An equivalent pharmacological male method is not yet available. This article will discuss why, and the prospects for its introduction sometime during the 21st century. Why male contraception at all? Female contraception is very effective. Nevertheless, 50% of the 1,000,000 conceptions occurring every day worldwide remain unplanned, of which 150,000 are terminated by abortion, an intervention that will end fatally for 500 of these women. Although improved distribution and utilization of female contraceptive methods might ameliorate this situation, the contribution of a male contraceptive is well worth considering (fig. 1). Men enjoy the pleasures of sex, but can do little to contribute to the tasks of family planning – a pharmacological male contraceptive is perhaps long overdue. In addition, the risks of contraception would also be more fairly shared between women and men. Representative surveys have shown that a pharmacological male contraceptive would be acceptable to large segments of the population in industrial nations, and would thus contribute to further stabilization of population dynamics. It might also help developing countries whose exponential population growth endangers economic, social, and medical progress. Last but not least, male contraception can be considered an outstanding issue in the political field of gender equality.  Fig. 1.
Use of contraceptive methods worldwide and in Germany. D/P/S diaphragms, cervical cap, spermicides etc; CI/PA coitus interruptus, periodic abstinence; IUD intrauterine device (UN Population Division, New York, June 1998.)
Castration and abstinence For the male, there are ways to eliminate both procreation and sex at the same time. Such methods have been used in the past and are still being practiced on a limited scale. Castration has been employed since ancient times to destroy enemies by abolishing their ability to reproduce and transmit their genes. Until the end of the imperial period in China (1912), men were willing to sacrifice their testicles (and often with them their lives) in return for high-ranking positions and political influence at the emperor’s court. Meanwhile, in the West, up until almost the same time, some promising boys were forced to give up their manhood for the sake of preserving their prepubertal voice and achieving fame as singers, often without success. Abstinence is a less bloody means of eliminating procreation, but few men are willing to give up both sex and procreation for extended periods of time, let alone their entire lives (fig. 2).  Fig. 2. Approaches to male contraception. Eliminating procreation together with sexuality or sexuality alone is considered unacceptable. Surgical vasectomy has to be considered irreversible for all practical purposes. Of the pharmacological possibilities, only hormones have reached clinical trials. [Background painting: ‘Adam and Eve’ by Lucas Cranach (1533), Museum of Fine Arts, Leipzig].
Existing methods Traditional male methods of contraception such as periodic abstinence or coitus interruptus are associated with a relatively high rate of unwanted pregnancy and also cause a disturbance in sexual activity. Condoms are the oldest barrier method available. However, conception rates when using condoms are relatively high, with 12 out of 100 couples conceiving during the first year of use (Pearl index = 12). Condom use has increased since the beginning of the AIDS epidemic, but more for protection from HIV infection and other sexually transmitted diseases than for contraceptive purposes. Vasectomy is a safe and surgically relatively simple method for male contraception. The rate of unwanted pregnancies after vasectomy is less than 1%. The drawback to vasectomy is that it is not easily reversible. Achieving fatherhood after vasectomy requires either surgical reversion or sperm extraction from a testicular biopsy and intracytoplasmic sperm injection into the ovum. Only about 50% of these men will become fathers in the end. Given the disadvantages of these mechanical male methods, what then are the prerequisites for an ideal male contraceptive? It should · be applied independently of the sexual act · be acceptable for both partners · not interfere with libido, potency, or sexual activity · have neither short- nor long-term toxic side effects · have no impact on eventual offspring · be rapidly effective and fully reversible · be as effective as comparable female methods New approaches Despite attempts to improve existing methods, e.g., vas occlusion instead of surgical dissection, or the introduction of new materials (e.g., polyurethane) for condoms, the inherent disadvantages of these mechanical methods preventing sperm transport into the female tract persist, and must be replaced and/or supplemented by pharmacological methods. Posttesticular approaches to male contraception are still in the preclinical phase. By investigating the molecular physiology of sperm maturation and epididymal function, the aim is to identify processes that might be blocked by specific pharmacological agents with a rapid onset of action. However, all substances investigated so far have shown toxic side effects when interfering effectively with sperm function. At the moment then, only hormonal methods fulfill most of the requirements for a male contraceptive and are currently under clinical development. Principle of hormonal male contraception The general goal of hormonal male contraception is to suppress sperm production in the testes without impairing testicular function. As in female oral contraception, the principle of hormonal suppression of spermatogenesis is based on influencing the endocrine feedback mechanism between hypothalamus, pituitary, and testes (fig. 3). Women have physiologically infertile periods and contraceptive methods are designed to eliminate cyclically occurring fertility peaks. Men, however, produce sperm and are fertile continuously. A safe, reversible, and acceptable contraceptive method interrupting this state must achieve either azoospermia or severe oligozoospermia with dysfunction of any remaining sperm.  Fig. 3.
Hormonal regulation of testicular function and effects of androgens. Key hormones are luteinizing hormone (LH) and follicle-stimulating hormone (FSH), synthesized and secreted under hypothalamic control of gonadotropin-releasing hormone (GnRH). Leydig cells are located between the seminiferous tubules and synthesize and secrete testosterone under the control of LH. Testosterone stimulates the maturation of germ cells in seminiferous tubules. FSH acts directly on the seminiferous tubules. In the germinal epithelium, only Sertoli cells possess receptors for testosterone and FSH. The trophic effects of testosterone/FSH on
gametogenesis are therefore believed to be mediated via somatic Sertoli cells. The testis and the hypo-thalamo-pituitary system communicate through steroids and protein hormones. Testosterone inhibits the secretion of GnRH and gonadotropins. Inhibin B and follistatin selectively suppress the release of FSH from the pituitary gland, while activin stimulates this process. Beside the effects on gametogenesis, testosterone plays an important role in hair growth, bone metabolism, muscle mass and distribution, secondary sexual characteristics and function of the male reproductive organs. (Adapted from Nieschlag E et al. in: Deetjen & Speckmann (ed): Physiologie. München, Urban & Fischer, 1999.)
To reach this goal, the pituitary gonadotropins luteinizing hormone and follicle-stimulating hormone (FSH) must be completely suppressed, because residual FSH and intratesticular testosterone activity would suffice to maintain spermatogenesis. However, testosterone must be available in sufficient amounts outside the testes to maintain the many other functions dependent on that hormone, e.g., erythropoiesis, protein, mineral and bone metabolism, as well as libido and potency, cognitive functions, and male personality (see box).
Modalities of hormonal male contraception All these effects can be achieved with testosterone itself. The effectiveness of exogenous testosterone for contraception was first shown in clinical multicenter studies performed under the aegis of WHO using injections of testosterone enanthate. However, reactions to testosterone vary among ethnic groups: whereas almost 100% of East Asian men respond to testosterone with azoospermia, only 60% of Caucasian men reach this goal. The causes of this variable response to hormonal suppression of spermatogenesis have not been fully clarified, but there is evidence that genetic polymorphism of the hormone receptors, especially the androgen receptor, influences individual responses to the contraceptive steroid dose. So, the first hormonal male contraceptive may be marketed in China, following the recent resolution of another problem associated with testosterone enanthate. Testosterone enanthate requires weekly injections, rendering it impractical for general use. A search for longer-acting testosterone preparations identified several modalities of which testosterone undecanoate, testosterone pellets, and subdermal silastic implants with 7α-methyl-19-nortestosterone appear to be the most promising. Nevertheless, these testosterone preparations used as single entities may only be effective in East Asian men; Caucasians will require an additional substance to achieve contraceptive protection. Among the promising additives to testosterone are gonadotropin-releasing hormone (GnRH) antagonists. They block pituitary GnRH receptors so that the pituitary can no longer produce gonadotropins under the influence of hypothalamic GnRH. GnRH antagonists in combination with testosterone lead to rapid and complete suppression of sperm, but the preparations currently available require daily or weekly injections and are expensive. However, new depot preparations are being developed for the treatment of prostate carcinoma, and the antagonists may only be required during an induction phase. Studies in monkeys and humans suggest that testosterone alone may then maintain sperm suppression. The GnRH antagonist/testosterone combination could well become a feasible approach to male contraception. Another option to enhance the effectiveness of testosterone is the addition of progestins. Progestins, derivatives of natural progesterone, have been mainly developed for female contraception and have been tested only unsystematically as possible male contraceptives. Depot medroxyprogesterone acetate has the longest history in male contraceptive trials and has recently been shown to be highly effective in combination with subdermal testosterone pellets. Levonorgestrel and etonorgestrel (both used in implants for female contraception) are further options and appear to be most effective when used as silastic implants. In research at my institute, a combination of testosterone undecanoate with noresthisterone enanthate was most effective and both substances can be combined in one injection given at 8-week intervals. An alternative to injections would be long-acting implants, effective for one year or longer. The combination of an implant with an injection might be less desirable, since the use of two modalities would be impractical. Attempts to create a self-administered contraceptive such as an oral or transdermal steroid have not yet been successful. The steroids show fluctuating pharmacokinetics when administered orally or transdermally, while constant serum levels seem to be an absolute prerequisite for effectiveness. It therefore looks as if ‘the male pill’ will be an injection or an implant, at least for the time being. Side effects such as moderate weight gain, mild gynecomastia or acne were mainly observed during the early phases in the development of hormonal male contraception. In newer studies steroid levels in the circulation have been lower, their medium-range kinetics have been more constant, and side effects are less pronounced. Effects on libido, potency and psychological variables are very rare. In studies with progestins, increased sweating was encountered as an undesirable side effect, probably caused by the thermogenetic effect of progestins, which also occurs in women. In all volunteers participating in clinical trials for hormonal male contraception to date, suppression of spermatogenesis was fully reversible. Outlook Although the scientific basis of hormonal male contraception had been established and practical modalities developed, drug companies were hesitant to engage in clinical development. Leading scientists in the field of male contraception therefore met in 1997 and issued the ‘Weimar Manifesto on Male Contraception,’ challenging the drug industry to become more actively involved in this field (fig. 4). The pharmaceutical companies did respond, initiated programs for male contraception, and a healthy competition between firms has finally emerged. In addition, the Population Council (New York), WHO’s Department of Reproductive Health and Research and a few philanthropic organizations are also devoting part of their activities to male contraception. The pharmaceutical companies have finally discovered male contraception as a potentially profitable area, while governmental and philanthropic organizers believe that male contraception will help contribute to a reduction in world population growth.  Fig. 4. Location of centers worldwide active in research on hormonal male contraception.
The field has now progressed to the point that strategies for the approval of male hormonal contraceptives are being considered. At the Sixth Summit Meeting on Hormonal Male Contraception in 2002, guidelines were drafted for consideration and discussion with the regulatory authorities, preparing the path toward registration of the first hormonal male contraceptive. Although it has taken 30 years to get this far and there is still no male contraceptive on the market, one should remember that hormonal female contraceptives also required many years to develop, and regulatory agencies are more stringent today than 40 years ago when the first hormonal female contraceptives were registered for general use. Nevertheless, the first hormonal male contraceptive may be available for general use in 2006, in China, and a few years later in the West.  Eberhard Nieschlag is director of the Institute of Reproductive Medicine at the University of Muenster, Germany, which has become one of the pioneering research centers for the development of male hormonal contraception. He also conducts research on male infertility, assisted reproduction, hypogonadism, and the aging male. Professor Nieschlag was president of the International Society of Andrology and the European Academy of Andrology and is currently president of the German Societies for Reproductive Medicine and for Andrology. He has published about 600 original papers and several textbooks on andrology. Prof. Dr. Eberhard Nieschlag Insitut für Reproduktionsmedizin der Universität Münster Domagkstrasse 11 D - 48149 Münster Phone: +49 251 83 56097 Email: nieschl@uni-muenster.de Homepage: www.nieschlag.de |
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