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.
References
[1]
Waites GMH, Kasonde J, editors. Studies in male fertility. Int J Androl
1995; 18 Suppl 1: 1-74.
[2] World Health Organization. Laboratory manual for the examination
of human semen and sperm-cervical mucus interaction. 3rd ed.
Cambridge: Cambridge University Press, 1992. (4th ed to be
published in 1999).
[3] World Health Organization. Manual for the standardized investigation,
diagnosis and management of the infertile couple. Cambridge:
Cambridge University Press, 1993. (2nd ed in preparation).
[4] Tang GH, Zhong YH, Ma YM, Luo L, Cui K, Luo J, et al. Vasectomy
and health: cardiovascular and other diseases following vasectomy
in Sichuan Province, People's Republic of China. Int J Epidemiol
1988; 17: 608-17.
[5] Pettiti DB. Epidemiological studies in vasectomy. In: Zatuchni GI, Goldsmith A, Spieler
JM, Sciarra JJ, editors. Male contraception: advances and future
prospects. Philadelphia; Harper & Row; 1986. p 24-33.
[6] Farley TMM, Meirik O, Mehta S, Waites GMH. The safety of vasectomy:
recent concerns.
WHO Bulletin 1993; 71: 413-9.
[7] Gu FL, Xia TL, Kong XT. Preliminary study of the frequency of
benign prostatic hyperplasia and prostate cancer in China.
Urology 1994; 44: 688-911.
[8] Li SQ, Goldstein M, Zhu J, Huber D. The no-scalpel vasectomy.
J Urol 1991; 145: 341-4.
[9] Zhao SC. Vas deferens occlusion by percutaneous injection of
polyurethane elastomer plugs:clinical experience and reversibility.
Contraception 1990; 41: 453-9.
[10] Zhang GY, Wang XH, Chen ZW, Cui YG. Research on male contraception
in China. In: Waites GMH, Frick J, Baker HWG, editors. Current
advances in andrology. Bologna: Monduzzi Editore; 1997. p 233-9.
[11] Soebadi DM, Gardjito W, Mensink HJA. Intravasal injection of formed-in-place medical grade silicone rubber for
vas occlusion. Int J Androl 1995; 18 Suppl 1: 45-52.
[12] Qian SZ, Hu JH, Ho LX, Sun MX, Huang YZ, Fang JH. The first clinical
trial of gossypol on male. In: Turner P. editor. Clinical pharmacology
and therapeutics. Proceedings of the First World Congress on
Clinical Pharmacology & Therapeutics. London: Macmillan;
1980. p 489-92.
[13] Liu ZQ, Liu GZ, Hei LS, Zhang RA, Yu CZ. Clinical trial of gossypol
as an antifertility agent. In: Chang CF, Griffin PD, Woolman
A, editors. Recent Advances in Fertility Regulation. Geneva:
Atar SA; 1981. p 160-3.
[14] Prasad MRN, Diczfalusy E. Gossypol. Int J Androl 1982; 5 Suppl:
53-70.
[15] Qian SZ, Jing GW, Wu XY, Xu Y, Li YQ, Zhou ZH. Gossypol related hypokalaemia,
clinicopharmacologic studies. Chin Med J 1980; 93: 477-82.
[16] Frick J, Danner C, Kohle R, Kumit G. Male fertility regulation. In:
Cortes-Prieto J, Compos-da-Paz A, Neves-e-Castro M, editors.
Research on Fertility and Sterility. Lancaster: MTP Press;
1981. p 300-2.
[17] Coutinho EM. Clinical studies with gossypol. Arch Androl 1982;
3: 37-8.
[18] Morris ID. Gossypol: male contraceptive with potential? IRCS Med Sci 1986; 14: 1177-80.
[19] Waller DP, Niu XY, Kim I. Toxicology and mechanism of action of gossypol. In: Zatuchni
GI, Goldsmith A, Spieler JM, Sciarra JJ, editors. Male Contraception: Advances
and Future Prospects. Philadelphia: Harper & Row; 1986. p 183-200.
[20] Waites GMH. Introduction. Contraception 1988; 37 (2): IV.
[21] Waites GMH, Wang C, Griffin PD. Gossypol: reasons for its failure
to be accepted as a safe, reversible male antifertility drug.
Int J Androl 1998; 21: 8-12.
[22] Heywood R. The toxicology of gossypol acetic acid and (-) gossypol.
Contraception 1988; 37: 185-90.
[23] Liu GZ, Lyle KC, Cao J, Zhu C, Li B. Effects of K salt or a potassium
blocker on gossypol-related hypokalaemia. Contraception 1988;
37: 111-7.
[24] Michael AE. 11 HSD (11-hydroxysteroid dehydrogenase)
and the mechanism of gossypol-induced hypokalaemia. Int J Androl
1998; 21: 313.
[25] Qian SZ. Tripterygium wilfordii: a Chinese herb effective in male fertility regulation.
Contraception 1987; 36: 247-63.
[26] Lue Y, Sinha Hikim AP,Wang C, Leung A, Baravarian S, Reutrakul V,
et al. Triptolide: a potential male contraceptive.
J Androl 1998; 19: 479-86.
[27] Waites GMH. Male fertility regulation: the challenges for the year
2000. Brit Med Bull 1993; 49: 210-21.
[28] Cummings DE, Bremner WJ. Prospects for new hormonal male contraceptives.
Endocrinol Metab Clin North Am 1994; 22: 893-922.
[29] WHO Task Force on Methods for the Regulation of Male Fertility. Contraceptive
efficacy of testosterone-induced azoospermia in normal men. Lancet 1990;
336: 955-9.
[30] WHO Task Force on Methods for the Regulation of Male Fertility. Contraceptive
efficacy of testosterone-induced azoospermia and oligozoospermia in normal
men. Fertil Steril 1996; 65: 821-9.
[31] Behre HM, Baus S, Kliesch S, Keck C, Simoni M, Nieschlag E. Potential
of testosterone buciclate for male contraception: endocrine
differences between responders and nonresponders. J Clin Endocrinol
Metab 1995; 80: 2394-403.
[32] Behre HM, Nieschlag E. New androgen esters alone and in combination
with GnRH analogs for male contraception. In: Waites GMH, Frick
J, Baker HWG, editors. Current advances in andrology. Bologna:
Monduzzi Editore; 1997. p 227-32.
[33] WHO 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. Fertil Steril
1993; 60: 1062-8.
[34] Wu FCW. Androgen/progestin combinations in male contraception: efficacy and safety. In: Waites GMH, Frick J,
Baker HWG, editors. Current advances in andrology. Bologna:
Monduzzi Editore; 1997. p 221-6.
