Reproductive Health and Male Contraception

9th Postgraduate Course for Training in Reproductive Medicine and Reproductive Biology

Michael T. Mbizvo, Manager
Research Area for Male Fertility Regulation/Male Reproductive Health, UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, (HRP)
Department of Reproductive Health and Research, World Health Organization, CH-1211 Geneva, Switzerland

LEARNING OBJECTIVES

Have an understanding of the rationale for widening contraceptive choice by developing new methods for use by men.

Be informed on research approaches towards male contraceptive development.

Be updated on the status of hormonal male contraceptive trials conducted by WHO alone or with other agencies.

Provide information on the assessment of acceptability and sexual behaviour related to use of male contraceptive methods.

Update participants on the interest of WHO/HRP on percutaneous vas occlusion.

Be informed on WHO/HRP’s interests on ensuring safety and ethical considerations in the conduct of male contraceptive research.

Be also informed on WHO/HRP’s interest in the broad male reproductive health research agenda as defined by the International Conference on Population and Development (ICPD).

NEED FOR MALE CONTRACEPTION

Male reproductive health encompasses reproductive and sexual function and dysfunction. It entails a biomedical and behavioural process that recognises the regulation of fertility and prevention and treatment of infertility.

The development of safe, effective and reversible contraceptive methods for men is an important goal in expanding the choices available to couples to regulate their fertility. The advent of an effective and reversible systemic male contraceptive method should provide a valuable alternative to the limited options of the condom, vasectomy and withdrawal, that are currently available to men. The 1994 International Conference on Population and Development (ICPD), called for the development and promotion of male methods of contraception alongside those for the prevention of STDs and HIV/AIDS. Such methods need to be as effective as comparable female methods and acceptable to both partners. The shortcomings of currently available methods are a major barrier to the greater involvement of men in family planning. Increasing the choice of methods, which include those available to men, should go a long way in responding to the diverse individual contraceptive needs of couples. In WHO/HRP’s experience, most men who participate in male contraceptive clinical trials report that their main reason for participating was that the female partner had experienced problems with her method of contraception. As a result of increased understanding of gender issues and roles required for improved reproductive health, there is more recognition for the need for shared contraceptive responsibility. Acceptable male contraceptive methods should reduce the burden traditionally placed almost exclusively on the female partner.

Contraceptive needs of couples vary according to the type of relationship, purpose of contraception and age of users. The purpose of contraception for individual couples varies from postponing childbearing, spacing of births and limiting of family size to freedom from childbearing. Currently available methods of fertility regulation do not adequately meet the varied and changing personal needs of couples in their reproductive lives and in the widely different geographical, cultural, religious and service settings around the world. Thus, increasing the choice available to either partner will ensure the wider availability of safe and effective means for fertility regulation for each situation and at different reproductive stages.

Therefore, widening contraceptive options by including reversible methods for men should address an unmet reproductive health need.

In addition to WHO, a number of other international organizations are conducting or supporting studies which focus on the male contraceptive aspect of reproductive health. These include the Rockefeller Foundation, the Population Council, the National Institute of Child Health and Human Development (NICHD/NIH, USA), the Contraceptive Research and Development Program (CONRAD, USA), AVSC International and the United States Agency for International Development (USAID, USA).

Within WHO/HRP’s Research Area on Methods for the Regulation of Male Fertility, the research agenda on male contraception addresses the following:

male hormonal contraception;

assessment of acceptability and sexual behaviour related to male contraceptive methods;

male reproductive physiology research towards identification of new leads for fertility regulation;

improved technology for vas occlusion.

Other male reproductive health research of WHO/HRP includes the following:

assessment of semen quality, reproductive function and epidemiology, especially as they relate to the environment;

defining norms and standards in investigative andrology;

men’s role in fertility choices, preferences and behaviour;

research training workshops in andrology and semenology.

Hormonal Male Contraception

Finding an acceptable, reversible and preferably long-acting, hormonal contraceptive method for men is a research priority for WHO. Although there are currently no systemic methods of contraception for use by men, the development of a male-use equivalent of the oral, injectable and implantable female steroid hormone methods of contraception has been the subject of research for the past 30 years or more. The advent of a safe, effective and reversible systemic method should provide a valuable addition to the currently limited options of male initiated methods. A number of studies in animals and men have shown that the administration of androgens alone, combinations of gonadotrophin-releasing hormone and androgens, and progestogen and androgen combinations, can suppress gonadotrophin secretion and spermatogenesis either completely to azoospermia or to a sufficiently low level of oligozoospermia to render the treated individuals infertile.

The administration of exogenous sex steroids simulates the endogenous negative feedback mechanism that regulates the gonadotrophins. Supraphysiological doses of a testosterone ester have been shown to inhibit pituitary luteinising hormone (LH) and follicle stimulating hormone (FSH) secretion, but peripheral testosterone remains high enough to preserve libido and potency.

In a landmark, 1990, ten-centre WHO/HRP study in both developed and developing countries¹, the contraceptive efficacy of weekly injectable testosterone enanthate (TE) (200 mg) was demonstrated. However, this regimen required weekly intramuscular injections and some Caucasian men did not suppress to azoospermia.

A subsequent study in 1993 demonstrated that the combination of TE with depot-medroxyprogesterone acetate (DMPA) was more effective in suppressing spermatogenesis than using an androgen alone².

In 1996³, WHO/HRP together with CONRAD, established that the spermatogenic suppression to azoopermia or severe oligozoospermia induced by weekly TE resulted in sustained but reversible contraception with pregnancy rates of 0/230.4 person-years and 4/49.9 person-years, respectively. Observations were, however, made that sperm counts suppressed more slowly in the Asian than in the non-Asian men in the first two months of injections, although by 6 months comparable suppression was achieved⁴. In the clinical trial to investigate the efficacy of azoopermia and oligozoospermia induced by the androgen ester (TE), a high level of acceptability was found among both the users and their partners, in spite of the need for weekly injections with this particular regimen. However, many of the men indicated that a longer-acting preparation, such as testosterone buciclate (TB), which could be taken at intervals of three months, would be more attractive.

Testosterone Buciclate and Levonorgestrel Butanoate]

WHO, in collaboration with NIH, is focusing on the development of TB in combination with levonorgestrel butanoate (LNG-B) as a three-monthly injectable regimen.

The pharmacokinetic profile of TB is superior to that of TE in that it is not associated with a peak of testosterone release soon after injection and its release rate more closely approximates zero-order kinetics. In addition, the side chain is metabolized to products that are normal body constituents. During the past two years, studies have been carried out by a custom formulating facility to identify a formulation of the highest TB concentration that would be stable and easily resuspendable. Clinical trials with the new formulation should start during 1999. (See also references 5 and 6).

Testosterone Undecanoate

Testosterone undecanoate (TU) is a testosterone ester which, in its injectable formulation, has a pharmacokinetic profile that falls between that of TE (two-three weeks) and TB (three months). It offers the promise of a one-monthly or two-monthly injectable product for use alone or in combination with a progestogen. A WHO/HRP supported multicentre contraceptive efficacy study was started during 1998 in six centres in China. The suppression phase entails a 1000 mg TU loading dose, followed by 500 mg maintenance (treatment) doses given either every four or six weeks. By the end of 1998, all of the 310 men required for the study had been recruited. Acceptability studies, involving both the trial participants and their partners, are running concurrently with the efficacy studies.

In another proposed Phase II study in Indonesia, TU will be used in combination with DMPA or northisterone enanthate (NET-EN). NET-EN is marketed as a two monthly injectable contraceptive for women and offers the possibility of being used with TU as a two-month male contraceptive regimen. (See reference 7)

Cyproterone Acetate (CPA) plus TU

Because of its progestational activity, CPA is thought to synergize with testosterone at the hypothalamic-pituitary level to suppress gonadotrophins. Furthermore, because of its antiandrogenic property, it may act directly at the gonadal level to block the stimulatory effects of androgens on spermatogenesis. Because of the low intratesticular testosterone concentrations induced by hormonal suppression, CPA may be able to successfully block the residual androgen effect within the testis. On the other hand, testosterone concentrations in the peripheral circulation are maintained by exogenous injections. Therefore, in a combined regimen using CPA, the doses of testosterone and the antiandrogen could be adjusted to achieve sperm suppression while maintaining important physiological functions.

A WHO six-centre study, with co-funding from CONRAD, in both developing and developed countries proposes to test whether the combined administration of CPA and testosterone undecanoate induces adequate and consistent suppression of spermatogenesis. In this prospective, Phase II, randomized controlled study, subjects will be divided to receive either of the following arms.

- CPA 20 mg/day plus TU 1,000 mg/8 weeks

- Placebo plus TU 1,000 mg/8 weeks

Metabolic effects, sexual behaviour change and acceptability of this hormonal combination will also be evaluated. The acceptability component will include both partners.

Finasteride and testosterone implants

It is hypothesized that the low level of spermatogenesis that persists in some men who do not suppress to azoospermia following the administration of an androgen alone or a progestogen plus androgen combination, is due to a persisting, low level of production of dihydrotestosterone (DHT). To determine if this might be the case, WHO/HRP supported a project to investigate if the administration of a 5" -reductase inhibitor, finasteride, which would prevent the conversion of testosterone to DHT, would result in complete suppression of spermatogenesis. The data obtained in this project failed to show any additional effect of finasteride on the testosterone-induced suppression of spermatogenesis, although the number of men who completed the study in both the finasteride treatment and control groups was small (n=7 in both groups). It has been suggested to investigate the effects of dual inhibition of both type 1 and type 2 5" -reductase.

Acceptability and behavioural studies

The Programme considers it important to carry out acceptability studies and assessments of behavioural changes during the course of the clinical testing of male hormonal contraceptive regimens. Both qualitative and quantitative methodologies are being used to collect information on general contraceptive use acceptability, family size preferences, decision-making regarding contraceptive use; and perceptions on male contraceptive injections. Focus group discussions and some in-depth interviews have also been carried out with the partners of men taking part in the male contraceptive trials. Instruments are also being developed to assess changes in sexual behaviour, if any, among the participating men.

The Programme is also supporting a study in the U.K. to collect, develop, adapt and validate a range of psychometric tools, not previously available or applied, to quantify testosterone-associated changes in behaviour (especially aggression) in healthy adult men. A male aggression questionnaire (MAQ) and a partner aggression questionnaire (PAQ) have been developed. Preliminary results indicate that there is good correlation between the information provided on the MAQ and PAQ.

Non-Surgical Vas Occlusion

Millions of couples world-wide use vasectomy as their preferred method of fertility regulation. It is highly effective and has a low complication rate. However, its more widespread acceptability is affected by two main factors: (i) the need for a surgical intervention; and (ii) the fact that the procedure needs to be considered permanent as the success rate of reversal as determined by subsequent fertility, is low. Thus an approach is needed to vas occlusion technology which makes it easier to perform and more predictably reversible. One of the approaches that has been considered promising is percutaneous vas occlusion. This method uses liquid silicone which is injected into the vas where it rapidly hardens to form a plug which prevents the passage of sperm. This plug can be removed at a later date, through a small incision in the scrotum and vas to ensure subsequent vas patency without the need for microsurgery.

Earlier Programme-supported pilot clinical studies, carried out in China and Indonesia, provided encouraging preliminary data to indicate that the percutaneous intravasal injection of liquid silicone to form cured-in-place plugs could result in effective vas occlusion. However, a relatively high rate of rupture of the vas was observed in these studies. Another study, carried out later with male volunteers in The Netherlands by AVSC International and the manufacturers of the prototype method, yielded disappointing results in that only a few men achieved azoospermia. The incidence of vas rupture was lower in this study, which could suggest that the volume of the liquid silicone injection was less than optimal.

An expert consultative meeting convened by the Programme in 1998 concluded that further animal studies and follow-up of men in the Indonesia trials needed to be done before a decision could be made about further clinical testing.

A ten-centre study in China investigated the effectiveness, reversibility and safety of three methods: i) no scalpel vasectomy, ii) chemical vas occlusion, iii) and polyurethane plug occlusion. The efficacy rates were better for the first two methods while there were marginally fewer complications following plug occlusion. Comparative success of the reversal is still being evaluated.

Basic Science Research Leads towards Male Fertility Regulation

Mechanisms underlying triptolide’s antispermatogenic effect

The Programme has supported studies which investigate the mechanism by which triptolide, a compound isolated from the roots of the plant Tripterygium wilfordii, causes infertility in male rats. So far, the results indicate that triptolide acts on both mature and maturing germ cells⁸. The first action manifests earlier and impairs mainly epididymal sperm, whereas the second action impairs spermatogenesis. Ultrastructural studies show no changes in the epididymal epithelium.

Goal-oriented basic science research on spermatogenesis and sperm maturation

In 1998, the WHO Research Group on Methods for the Regulation of Male Fertility announced an initiative in which it would support and promote research on the molecular and cellular aspects of spermatogenesis/spermiogenesis, and the acquisition of sperm-fertilising capacity. The purpose of these studies will be to identify potential new targets for fertility regulation during the development of spermatids, acrosome and flagellar formation. Such research should identify important events in the spermatogenesis process and how they can be targeted for male contraception.

Safety Considerations with Male Contraceptive Use

Safety and ethical issues are important concerns in the design and execution of any clinical trials undertaken or supported by WHO.

The Programme has thus built into clinical trials and research proposals a rigorous evaluation process to determine the suitability of a study on scientific merit, safety and ethical issues. Studies are also conducted on the safety of existing methods of contraception in use by both women and men.

A large scale collaborative study was undertaken in China to examine if vasectomy carried any risk of cardiovascular disease. The results showed that there was no evidence for this in China and in other study populations.^8,9 Concerns that vasectomy may predispose to prostate and testicular cancer have also been shown to be unfounded.¹⁰

The Programme’s Toxicological Panel concluded that, because the toxic dose in non-human primates with gossypol was considerably less than 10 times the antifertility dose, gossypol was too toxic to be developed for human contraception. Thus, the evidence for side effects and permanent sterility induced by gossypol has led the Programme’s Scientific and Ethical Review Group (SERG) to recommend that no further clinical studies should be undertaken with gossypol as an antifertility agent.

Conclusions

Available scientific data suggest that the prospects of reversible male contraception appear plausible. There is evidence that an androgen, with or without a progestogen, can provide effective contraception and is well tolerated. The World Health Organization and other agencies continue to promote research towards acceptable contraceptive methods for use by men. Such research can focus on:

inhibition of sperm production

interference with sperm function and structure

interruption of sperm transport

interruption of sperm deposition

prevention of sperm-egg interaction.

Meanwhile, discussions are under way with some pharmaceutical companies to ensure the continued development and testing of hormonal male contraceptives and to ensure their availability at low cost to the public sector in developing countries.

1. WHO Task Force on Methods for the Regulation of Male Fertility. Contraceptive efficacy of testosterone-induced azoospermia in normal men. Lancet, 1990, 336: 955-959.

2. World Health Organization Task Force on Methods for the Regulation of Male Fertility. Comparison of two androgens plus depot-medroxyprogesterone acetate for suppression to azoospermia in Indonesian men. Fertility and sterility, 1993,60:1062-1068.

3. World Health Organization, Task Force on Methods for the Regulation of Male Fertility. Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men. Fertility and sterility, 1996, 65: 821-829.

4. World Health Organization, Task Force on Methods for the Regulation of Male Fertility. Rates of testosterone-induced suppression to severe oligozoospermia or azoospermia in two multinational clinical studies. International journal of andrology, 1995, 18:157-165.

5. Goncharov NP, Katzia GV, Butnev VU, Richkor EG, Matikainen T, Waites GMH. A non-human primate study (baboon; Papio hamadryas) to determine if a long-acting progestogen, levonorgestrel butanoate, combined with a long-acting androgen, testosterone buciclate, can suppress spermatogenesis: II. Efficacy study. International journal of andrology, 1995, 18:83-87.

6. Behre HM, Baus S, Kliesch S, Keck C, Simoni M, Nieschlag E. Potential of testosterone buciclate for male contraception: endocrinological differences between responders and nonresponders. Journal of clinical endocrinology and metabolism, 1995, 80(8):2394-2403.

7. Zhang GY, Gu YQ, Wang SH, Cui YG, Bremner, WJ. Pharmacokinetic study of injectable testosterone undecanoate in hypogonadal men. Journal of Andrology. 1998, 19:761-768

8. Tang GH, Zhang YH, Ma YM, Luo L, Gui K, Luo J. et al. Vasectomy and health: cardiovascular and other diseases following vasectomy in Sichuan Province, People's Republic of China. International journal of epidemiology. 1988, 17:608-617.

9. Pettiti DB. Epidemiological studies in vasectomy. In: Satuchni GI, Goldsmith A, Spieler JM, Sciarra JJ eds. Male contraception: advances and future prospects. Philadelphia; Harper & Row; 1986: p.24-33.

10. Farley TMM, Meirik O, Mehta S, Waites GMH. The safety of vasectomy: recent concerns. Bulletin of the World Health Organization, 1993, 71:413-419.