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The contribution of Asian scientists to global research in andrology

Geoffrey MH WAITES

Clinic for Infertility and Gynaecological Endocrinology, University Hospital of Geneva, SWITZERLAND and Department of Medicine, University of Sydney, Sydney NSW 2006, AUSTRALIA

Asian J Androl  1999 Jun; 1: 7-12

Keywords: andrology; Asia; contraception; vas occlusion; gossypol; Tripterygium; hormonal methods; World Health Organization
Aim: To present a personal account of the involvement of the World Health Organization (WHO) in the collaborative development in Asia of those areas of andrology concerned with male contraception and reproductive health. Methods: The andrology training through workshops and institution support undertaken by the WHO Human Reproduction Programme (HRP) and how they contributed to the strengthening of andrology research in Asia are summarised. Results: The author's experience and the Asian scientific contributions to the global research in the following areas are reviewed: the safety of vasectomy and the development of new methods of vas occlusion; gossypol and its failure to become a safe, reversible male antifertility drug; Tripterygium and whether its pure extracts will pass through the appropriate toxicology and phased clinical studies to become acceptable contraceptive drugs; hormonal methods of contraception for men. Conclusion: The WHO policy of research capacity building through training and institution strengthening, together with the collaboration of Asian andrologists, has created strong National institutions now able to direct their own programmes of research in clinical and scientific andrology.

1 Introduction

This review will discuss the research to develop improved methods of fertility regulation for men. It will give a personal account of how the policy of WHO-HRP to build the capacity to do research in Asia has led to the active participation of Asian scientists in the global research in male reproductive health. It is also intended to provide literature sources for wider reading (see reviews 6,21,27,28,32,34).

The author first went to China in 1983 with Drs Henry Burger and David De Kretser (Australia) and Christina Wang (then in Hong Kong) to participate in an andrology workshop in Beijing. This was one of the thirteen workshops undertaken by WHO-HRP in the period 1980-1993. The impact of these workshops has been examined in a Supplement of the International Journal of Andrology[1]. This contains research papers submitted by workshop trainees and provides evidence for the success of the workshops. In addition, many workshop participants later became senior staff members of Research Institutes of national importance, senior academics of Universities and Medical faculties, and others established male infertility clinics. Several have served WHO and other international agencies in various advisory roles.

Another training programme selected Asian scientists to spend up to 3 years in overseas centres and who could apply for re-entry grants to enable them to continue their research at home. Other research grants were awarded in a basic science programme, co-funded by the Rockefeller Foundation (Director, Dr Mahmoud Fathalla), to support studies to underpin the contraceptive research. Many of the trained scientists became principal investigators in the clinical trials and scientific studies organized by the WHO-HRP Male Task Force. The success of their training and the associated policy of research capacity building assured the high quality of the results obtained. The WHO collaborations with Asian investigators in the following areas of research, in which the author participated in the period 1983-1994, will be discussed: safety and new techniques in vas occlusion; gossypol; drugs from Tripterygium; and hormonal methods of contraception for men.

The aim of this review, therefore, is to emphasize the importance of established Asian scientists to andrology and to encourage young Asian scientists to contribute to the exciting field of male reproductive health.

2 Materials and methods

Andrology workshops. The objectives of the workshops were: to teach standardized clinical and scientific methods in all aspects of andrology; and to encourage research in andrology. The workshops now usually have the following main features[1]: a general programme, including male infertility and contraception, involving lectures, discussions and laboratory procedures lasting 7-10 d; a parallel component to give training in vas occlusion techniques lasting 3-4 d; the development of new research protocols.

Standardization was achieved by teaching from the laboratory and clinical manuals produced by WHO-HRP: WHO Laboratory Manual for the Examination of Human Semen and Sperm-cervical Mucus Interaction[2]; and WHO Manual for the Standardized Investigation and Diagnosis of the Infertile Couple[3].

3 Results and discussion

3.1 Andrology workshops

Thirteen WHO-HRP workshops were undertaken in the period 1980-1993, of which nine were conducted in Asia: Singapore (1980, 1981); Beijing (1983); Chengdu (1984); Hong Kong (1988); Beijing/Shandong (1991); Bangkok (1992); Surabaya (1992); Hanoi (1993). Three were specialist workshops: on Sperm Function (Hong Kong); and on Techniques in Vas Occlusion (Beijing/Shandong and Surabaya), in which Chinese surgeons were the instructors. Since 1993, other andrology workshops have been supported by WHO-HRP in Lithuania, Russia, South Africa and VietNam. National governments are now organizing their own workshops, applying the experience gained in the WHO workshops.

3.2 Safety and new techniques in vas occlusion

In the period 1983-1988, one of the author's responsibilities was to manage a large scale collaborative study undertaken by the Sichuan Family Planning Institute, Chengdu, to examine if vasectomy carried any risk of cardiovascular disease. The results showed that there was no evidence for this in China, a country with a low incidence of cardiovascular disease and different patterns of cardiovascular risks factors[4], confirming the results obtained in other study populations[5]. More recently, concerns that vasectomy may predispose to other health risks, eg, prostate and testicular cancer were similarly shown to be unfounded in Western populations[6]. However, few epidemiological studies have been conducted in Asia. Although the incidence rates of fatal prostate cancer in Asia are only a fraction of those of men in the USA, the prevalence of prostate diseases is increasing in urbanized regions of China[7]. In keeping with its mandate to monitor the safety of reproductive health practices, WHO-HRP has conducted a hospital-based case-control study in China, Republic of Korea and Nepal to determine whether vasectomy is associated with a risk of prostate cancer. The results will shortly be published.

In 1987, the author, accompanied by Wu Jie-Ping and other international scientists, toured centres in China to review the many different techniques of vas occlusion and to identify those procedures offering a better chance of successful reversal. Subsequently, in collaboration with the PRC State Family Planning Commission, a 10-centre study was initiated to investigate the effectiveness, safety and reversibility of three methods: no-scalpel vasectomy[8]; chemical vas occlusion; and polyurethane plug occlusion[9]. The efficacy rates were better for the first two methods while there were marginally fewer complications following plug occlusion[10]. The comparative success of the reversal operations has yet to be fully assessed. The plug method, while promising, clearly needed further study and, since there were toxicological reservations about polyurethane, WHO-HRP supported studies with silicone as the occluding material. Such studies in Indonesia[11] and others in India using intra-vasal styrene maleic anhydride[12] are encouraging for countries where the reversal of vas occlusion may be requested.

3.3 Gossypol

Following clinical trials conducted in China in the 1970s[12-14], gossypol was proposed as a drug for male contraceptive use. Even though some investigators in China expressed concern about the incidence of side effects, e.g., hypokalaemia, in these trials[15], small-scale studies started in Austria and Brazil[16,17]. Soon after, two reviews concluded that the evidence of side effects and the permanent sterility induced in some volunteers would make gossypol unacceptable to drug regulatory agencies[18,19]. Although the interest in gossypol had stimulated much innovative research in China and elsewhere, a conference in Wuhan in 1986, involving Chinese and international scientists, took the decision to discontinue work on gossypol as a potential contraceptive drug[20]. The basis for this decision was recently fully reviewed[21] and a brief summary only is given here.

Animal toxicity tests conducted with standardized protocols in toxicology laboratories accredited to international drug regulatory standards, revealed that: the lethal toxic dose of pure gossypol acetic acid to cynomolgus monkeys (25 mgkg-1d-1) was only 2.5 the antifertility dose in the same species; the toxic dose of pure (-)gossypol, the active enantiomer, in cynomolgus monkeys was 4 mgkg-1d-1, and even the low dose of 1.5 mgkg-1d-1 produced clinical signs involving the gastrointestinal tract and reduced liver weights[22]. The HRP Toxicology Panel concluded that, because the toxic dose in non-human primates was considerably less than 10 the antifertility dose, both forms of gossypol were too toxic to be developed for human contraception.

The aetiology of gossypol-related hypokalaemia proved hard to resolve because of the lack of good animal models. However, double-blind, randomized trials carefully conducted in Chinese volunteers established that gossypol treatment directly induced hypokalaemia, possibly by impairment of kidney function[23,24]. Finally, this evidence of animal and human toxicity, together with the high incidence (20-25%) of irreversible testicular damage in both Chinese and Brazilian men, led the HRP Scientific and Ethical Review Group to recommend that no further clinical studies should be undertaken with gossypol as an antifertility agent.

3.4 Tripterygium

Alpha-chlorohydrin and the 6-chloro-6-deoxy sugars had established that there are compounds which could have reversible antifertility effects on sperm stored in the epididymis (see review in this issue by Cooper, post-testicular contraception). It was therefore of considerable interest when a multiglycoside extract of the plant Tripterygium wilfordii, long used in Chinese traditional medicine for the treatment of psoriasis, was shown to cause reduction in sperm motility and concentration in male patients[25]. A collaborative programme between Chinese, Thai and UK centres succeeded in isolating a series of diterpene epoxides from extracts of the root bark of the plant. Several were shown to be orally active in rats at exceedingly low doses. One, triptolide, was selected for further toxicological and pharmacological evaluation and was found to induce complete infertility in male rats, acting primarily on epididymal sperm with minimal effects on the testis[26]. This is encouraging but the path for triptolide to become a marketable contraceptive drug is long and expensive and would require the involvement of a pharmaceutical company.

3.5 Hormonal methods

These are the most advanced of the contraceptive methods for men. Their development owes much to the involvement of Asian centres and investigators. The suppression of sperm production by hormonal means is achieved by: the suppression of the secretion of both LH and FSH, or of FSH alone; and the maintenance of androgen levels in the physiological range. Various drugs, either alone or in combination, have been tried[27,28]. For WHO, a major consideration in the choice of drugs is their affordability for developing countrie.

The end-point of all earlier studies was the laboratory assessment of the effect of the drug on semen quality. The degree of suppression of spermatogenesis needed to ensure protection against pregnancy was unknown. Studies to establish this inevitably involved the risk of pregnancy to the female partner and had not been attempted before. Two multi-centre studies, in which men suppressed to azoospermia or severe oligozoospermia had unprotected intercourse with their partners for 12 months, were conducted by WHO to establish what was the contraceptive efficacy rate[29,30]. Weekly injections of testosterone enanthate (TE), a safe androgen in widespread use in clinical andrology, was the regimen chosen to establish the degree of sperm suppression needed for contraceptive efficacy. TE was not envisaged as a usable contraceptive drug.

Among the 16 centres in 10 countries, six centres were in Asia: 4 in China and 1 in each of Singapore and Thailand. Some 670 couples were recruited of which 205 were Asian. The principal results were: a greater proportion of men from Asian centres suppressed to consistent azoospermia compared to men from non-Asian centres; even so, over 97 % men from both population groups suppressed to severe oligozoospermia (<3106/mL); once established, escape from spermatogenic suppression was rare. Pregnancy rates were related strongly to sperm concentration during the efficacy phase (Figure 1). In the second study on 399 couples[30], no pregnancies occurred while the men were azoospermic whereas four occurred in 49.5 person-years attributable to men with sperm concentrations 0.1 to 3.0106/mL. No pregnancies occurred among the Asian couples.

Figure 1. Pregnancy rates per 100 person-years in each sperm concentration stratum (inset), and according to the cumulative sperm concentration. Bars indicate 95% confidence limits and numbers in brackets are the number of pregnancies observed. Reprinted by permission from the American Society for Reproductive Medicine (Fertility and Sterility, 1996; 65: 821-829)

For men with sperm concentrations in the range 0 to 3106/mL, the overall pregnancy rate was 1.4 (95% CI, 0.4 to 3.7) per 100 person-years. This is comparable with the failure rates of modern, reversible female methods. Complete recovery of sperm production occurred after stopping the injections and all full-term deliveries of pregnancies resulted in healthy infants of normal weight. The important conclusion for Asian investigators is that the small risk of pregnancy in the study population overall is even smaller for Asian couples because the Asian men were more readily suppressed to azoospermia.

All hormonal regimens capable of suppressing sperm production to the same degree as in the WHO studies[29,30] should achieve similar high levels of ustained and reversible contraceptive efficacy. Consequently, the encouraging results of these studies have stimulated interest in new long-acting drugs. For example, novel formulations of testosterone esters, either developed in China (testosterone undecanoate)[10] or by WHO-NIH (testosterone buciclate)[31,32]. These may be administered alone or combined with progestogens such as DMPA[33] and levonorgestrel or desogestrel[34], or with GnRH analogues[32].

4 Conclusions

4.1 Vas occlusion

WHO and NIH consultations concluded that vasectomy does not carry health risks and that there should be no change in family planning policies. The no-scalpel procedure is the preferred method of vas occlusion in family planning programmes.

4.2 Gossypol

We must learn from the lessons that gossypol research has provided. Future potential contraceptive drugs must be developed by the established routes of appropriate animal toxicology and phased clinical studies in order to define their safety, efficacy and acceptability for human use.

4.3 Tripterygium 

Triptolide, as a diterpene epoxide, has potential secondary effects of which immunosuppression is one. As for gossypol, the issue of toxicology must be resolved together with the conduct of animal studies on its efficacy, site of action and safe reversibility before clinical trials are initiated.

4.4 Hormonal methods 

The landmark WHO studies[29,30] have provided an incentive to National family planning programmes and others to explore the efficacy of safe, longer-acting, drugs for contraceptive and other reproductive health applications.

It is concluded that the WHO-HRP policy of research capacity building, through training and institution strengthening, has enabled Asian andrologists to make important contributions to the basic science and clinical research involved in the development of contraceptive agents for men and thereby to male reproductive health.

5 Acknowledgements

I thank Professor DJ Handelsman, Sydney University, and my former WHO-HRP colleagues, Drs TMM Farley (Statistician), M Mbizvo (Manager, Male Methods) and Yi-Fei Wang (Manager, Asia and the Pacific) for their helpful comments.


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Correspondence to Dr GMH Waites. Past President, International Society of Andrology; Emeritus Professor; ex-staff member WHO.
Address: 31B Roland Avenue, Wahroonga, NSW 2076, AUSTRALIA.
Tel: +61-2-9487 7240   Fax: +61-2-9487 7250 
E-mail: gmhw@mail.usyd.edu.au
Received 1999-03-12     Accepted 1999-04-20