Principle of hormonal male contraception

The testes have an endocrine and an exocrine function: the production of androgens and of male gametes. Suppression of gamete production or interference with gamete function without affecting the endocrine function is the goal of endocrine approaches to male fertility regulation. However, since the two functions ofthe testes are interdependent, it has remained impossible so far to suppress spermatogenesis exclusively and reversibly without significantly affecting androgen synthesis.

FSH and LH/testosterone are responsible for the maintenance of fully normal spermatogenesis (for review see Chapter 5, also Weinbauer and Nieschlag 1996). If only one of the two is eliminated, spermatogenesis will be reduced, but only in quantitative terms, i.e. fewer but normal sperm will be produced and azoospermia will not be achieved. This has been demonstrated in monkeys by the elimination of FSH by immunoneutralization, resulting in reduced sperm numbers but not in complete azoospermia (Srinath et al. 1983), which - at least until quite recently -was considered to be required for an effective male method. Therefore, even if new modalities for the selective suppression of FSH or FSH action should become available, it remains doubtful whether they would lead to a method for male contraception (Nieschlag 1986). However, in bonnet monkeys immunization against FSH or the FSH receptor led to an impairment of the fertilizing capacity of sperm (Moudgal et al. 1992; 1997a). To date it has remained equivocal whether similar effects can be obtained in humans (Moudgal etal. 1997b; 1997c).

Until such results become available, the concept of azoospermia remains valid as a prerequisite for effective hormonal male contraception. However, as it is very difficult to achieve azoospermia uniformly in all volunteers participating in clinical trials for hormonal contraception and the pregnancy rates appear to be acceptably low if sperm counts drop below 1 mill/ml, investigators active in the field reached a consensus that azoospermia or at least oligozoospermia <1 mill/ml sperm should be the goal for an effective hormonal method (Nieschlag 2002). To achieve this goal not only FSH must be suppressed, but also intratesticular testosterone must be drastically reduced. Since testosterone alone can maintain spermatogenesis and much lower testosterone concentrations appear to be necessary for maintenance of spermatogenesis than previously considered, intratesticular testosterone must be depleted to such an extent that peripheral serum concentrations drop into the hypogonadal range. In order to maintain androgenicity, including libido, potency, male sex characteristics, psychotropic effects, protein anabolism, bone structure and hematopoesis, testosterone levels in the general circulation have to be replaced, while the testes themselves are depleted of testosterone. However, even testes of volunteers achieving azoospermia show measurable testosterone concentrations, although reduced to 2% of normal, and volunteers developing azoospermia have low intratesticular levels similar to those suppressing only to oligozoospermia (McLachlan et al. 2002). Therefore, other factors must be of additional importance. Interestingly, the macaque monkey suppressed to azoospermia shows hardly any decrease in intratesticular testosterone and elimination of FSH action appears to be more important than intratesticular testosterone (Narula et al. 2001; Weinbauer et al. 2001). For some time it was thought that the intratesticular conversion of testosterone to DHT is of importance in the maintenance of spermatogenesis and should be interfered with. However, the application of a 5a-reductase inhibitor did not additionally effect the suppression of spermatogenesis by testosterone alone (McLachlan et al. 2000). Recently, the number of CAG repeats in exon 1 of the androgen receptor has been found to determine the suppressibility of spermatogenesis, provided FSH and LH are well suppressed (von Eckardstein etal. 2002).

This leads to the general principle of hormonal male contraception, namely the suppression of FSH and LH, resulting in depletion of intratesticular testosterone and cessation of spermatogenesis, while at the same time, peripheral testosterone is substituted with an androgen preparation. This can be achieved by testosterone alone. However, since testosterone alone does not lead to azoospermia or severe oligozoospermia (<1 mill/ml) in all individuals tested, testosterone needs to be combined with other substances suppressing pituitary gonadotropin secretion. As in female hormonal contraceptives, gestagens as pituitary-suppressing agents are being tested in men in combination with androgens. GnRH agonists, as well as antagonists are also being explored as further possible combinations with androgens.

Recommendations for Regulatory Approval for Hormonal Male Contraception

(Int J Androl 25:375 (2002)

The investigators at the 6th Summit Meeting on Hormonal Male Contraception, Petersberg, Germany, held on July 7-9th, 2002 recognized the need for standardized clinical trials to develop a hormonal male method and drafted the following recommendations: The goal of hormonal male contraception is the reversible suppression of spermatogenesis to a level compatible with infertility. In principle this can be achieved by using an androgen alone or an androgen in combination with a gestagen or a GnRH-antagonist. The success of this principle in terms of lowering sperm counts in semen to azoospermia or to very low counts has been demonstrated in a multitude of trials. Some trials demonstrated the contraceptive efficacy of this approach when couples used no other method of contraception. Investigators agree that information gained from preliminary studies on male contraception have reached a stage that hormonal contraceptive products for men should now be proposed for development for general use.

In order to bring a hormonal method to the market, larger scale clinical trials are required. As no pharmacological method for male contraception is currently available, this represents a novel effort requiring new recommendations for testing.

The investigators agreed that the following criteria should be fulfilled:

1. In phase II dose-finding studies, the suppression of spermatogenesis can be used as the main parameter.

As the surrogate parameter, sperm concentrations, measured according to WHO criteria, can be used and the goal should be < 1 million/mL.

After cessation of treatment, the return to normal values should be ascertained, i.e. > 20 million/mL.

2. In the efficacy trials, pregnancy rate will be the endpoint, using the efficacy rate of condoms as a reference. For contraceptive efficacy, two independent phase III trials for 1 year should be completed by 200 men/couples per trial. Alternatively, the number of subjects that can establish a significant improvement against condom use could be investigated.

3. For safety assurance for a new chemical entity, trials are required involving at least 300-600 men for 6 months at the intended combination and dose, 100 men exposed for 1 year and a total of 1500 men in phase I- III studies at the minimum.

4. Long-term safety will be monitored by post-marketing surveillance.

The necessary laboratory investigations, especially semen analysis, need to be made under strict quality control.

These recommendations were drafted and approved by:

Prof. Dr. Eberhard Nieschlag (Organizer of the Summit Meeting) (University ofMuenster, Germany), Dr. Richard A. Anderson (University of Edinburgh, Scotland), Dr. Dan Apter (Family Federation of Finland, Helsinki, Finland), Dr. Kiagus M. Arsyad (University of Sriwijaya, Palembang, Indonesia), Prof. Dr. David Baird (University of Edinburgh, Scotland), Prof. Dr. Hermann M. Behre (University of Halle, Germany), Prof. Dr. William J. Bremner (University of Washington, Seattle, WA, USA), Doug Colvard (CONRAD, Arlington, VA, USA), Dr. T. G. Cooper (University ofMuenster, Germany), Dr. Gu Yi-Qun (National Research Institute for Family Planning, Beijing, China), Prof. Dr. Mike Harper (CONRAD, Arlington, VA, USA), Prof. Dr. Ilpo Huhtaniemi (University of Turku, Finland), Dr. Axel Kamischke (University ofMuenster, Germany), Dr. Peter Liu (University of Sydney, Australia), Dr. Robert McLachlan (Monash University, Melbourne, Australia), Dr. M. Cristina Meriggiola (University of Bologna, Italy), Prof. Dr. Dr. Nukman Moeloek (University of Indonesia, Jakarta, Indonesia), Prof. Dr. Somnath Roy (National Institute of Health and Family Welfare, New Delhi, India), Dr. Regine Sitruk-Ware (Population Council, New York, NY, USA), Dr. Kalyan Sundaram (Population Council, New York, NY, USA), Prof. Dr. Ronald S. Swerdloff (University of California, Torrance, CA, USA), Prof. Dr. Geoffrey M. H. Waites (St. Jean de Gonville, France), Prof. Dr. Christina C. L. Wang (University of California, Torrance, CA, USA), Dr. Xing-Hai Wang (Jiangsu Family Planning Research Institute, Nanjing, China), Prof. Dr. Frederick C. W. Wu (University of Manchester, UK), Dr. Michael Zitzmann (University ofMuenster, Germany).

Present at the Summit Meeting were also representatives of Schering/Jenapharm (Dr. Ulrich Gottwald, Dr. Doris Huebler, Dr. Albert Radlmaier, Dr. Farid Saad, Dr. Rolf Schuermann) and Organon (Dr. Thom

Dieben, Dr. AJ Grootenhuis, Dr. Wendy Kersemaekers, Dr. Mirjam L. P. J. Mol-Arts, Dr. Gerrit Voortman), Dr. Robert Spirtas (National Institutes of Health, Bethesda, MD, USA), Dr. Judy Manning (USAID, Washington, DC, USA), and WHO-HRP Dr. Michael T. Mbizvo (WHO, Geneva, Switzerland), and Dr. Kirsten Vogelsong (WHO, Geneva, Switzerland).

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