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Reports on Individual Drugs An androgen contraceptive for men: preliminary findings It is estimated, globally, that about one-third of couples using contraception rely upon a method involving the male partner- either withdrawal, the condom or vasectomy (1 ). The shortcomings of these long-established methods reflect subsequent failure to develop a method for men that is acceptably reliable, readily reversible and adequately safe. A new initiative has aroused optimism that this goal may now be attainable. Androgen-induced azoospermia or oligozoospermia tends to develop when exogenous testosterone or other androgenic substances are administered over extended periods (2). As circulating levels of androgens rise, secretion of the pituitary gonadotrophins which drive spermatogenesis is depressed. That this effect might provide the basis of a practicable approach to contraception was first demonstrated on a large scale in a multicentre clinical trial conducted by WHO in 1990 (3). Sustained weekly injection of 200 mg testosterone enantate - a dose some three to five times greater than that used in replacement therapy for adult hypogonadism was shown in a cohort of healthy men to be well tolerated and, in 70% of the group, to induce sustained azoospermia and to reduce fertility to a level approximating to zero. These preliminary findings have now been confirmed in a larger trial of the same regimen over a 12month period in a cohort of 400 volunteer couples drawn from 15 centres in 9 countries (Australia, China, France, Hungary, Singapore, Sweden, Thailand, the United Kingdom and the United States) (4). In this second study, as a means of assessing how risk of pregnancy is related to sperm concentration (2, 5, 6}, contraceptive efficacy was additionally studied in men whose sperm count was considerably reduced (3 x 106/ml or less) but not fully suppressed. All were healthy subjects aged between 21 and 45 years, most of whom had volunteered to participate because of their, or their partner's, dissatisfaction with other methods of contraception. Overall, some 95% of men from the Asian centres and 70% of those from other centres became consistently azoospermic within a six-month preliminary run-in period. Only 2% of the couples were withdrawn from the study at the end of this period because the man's sperm count (7) failed to fall consistently below the defined threshold for entry into the efficacy phase of the study. Serial sperm counts rose occasionally above this threshold in only 1% of men retained within the trial. No pregnancies were reported among women whose partner remained azoospermic throughout the efficacy phase. In contrast, four women became pregnant at a time when the male partner's sperm count fell within the range 0.1 to 3.0 x 106 /ml. Overall, these results translate into a pregnancy rate of 1.4 per 100 person years. This is comparable to first-year failure rates associated with reversible methods for women, including injectable and oral hormonal contraceptives (8). However, within the subgroup of oligozoospermic men, the failure rate was some sixfold higher at 8.1 per 100 person years. Information on the re-establishment of spermatogenesis following withdrawal of testosterone enantate is as yet incomplete, and results obtained after one year will be reported in due course. Some 20% of men were lost to follow-up at the end of the efficacy phase. Of the remainder, sperm concentrations had returned to normal in two-thirds of the men within some four months, but only in one-third had they attained pretreatment levels, and this in a median of some 200 days. Analysis of the sperm concentrations at one year after cessation of treatment is currently under way. The outcomes of 10 pregnancies which occurred during the suppression and efficacy phases of the study, and a further 33 which were recorded during the recovery phase provided no suggestion of any adverse drug-related effect. All iofants known to have been born at term were healthy, of normal weight, and - save for a bilateral hydrocoele that resolved spontaneously - without significant abnormalities. It is emphasized that this trial was designed to explore the feasibility of a hormonal approach to the suppression of spermatogenesis. Testosterone enantate was chosen because it has been exten-
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sively used in other clinical situations and is widely available. It was not expected to prove suitable for routine use. In the event, it seems that reliable contraception can be assured in most men, but only after a run-in period extending over some three months, and not for a minority in whom suppression of spermatogenesis remains incomplete. This creates a need for extended monitoring of sperm counts that would be impracticable in a routine setting. The possibility that spermatogenesis may be suppressed more rapidly and more reliably by combining an androgen with either a progestin or an antagonist of gonadotrophin-releasing hormone is consequently already under investigation (3, 914). The aim is to identify a regimen in which the dose of androgen is reduced to physiological levels and which can be administered at intervals of 3-4 months. As yet, information bearing upon potential drugrelated adverse effects is limited both by the small scale of the completed studies and the relatively short period of exposure and follow-up. The results consequently need to be considered in the light of accumulated knowledge regarding both legitimate therapeutic use and uncontrolled abuse of the various available androgenic preparations. The risk of an adverse effect is remote when testosterone enantate is used at physiological dosage to correct androgen deficiency in hypogonadism (15). Androgens are now rarely administered to men in a medical context at higher dosage: with the advent of recombinant erythropoietin, the supraphysiological doses once used to stimulate renal erythropoietin production (16) in anaemic patients with chronic renal failure are now rarely employed. The hazards of massive intermittent abuse of androgens as a means of increasing muscle mass in athletes and others (17) hold little relevance to therapeutic use- except, questionably, to identify organ systems susceptible to dose-related damage. In general, testosterone esters are far better tolerated than the alkylated androgens and the chemically-related anabolic steroids (18). It is abusive doses of these latter compounds which are less readily metabolized within the liver, that has associated androgens with severe liver disease. This abuse has resulted in cases of extensive hepatocellular damage and intrahepatic cholestasis that have culminated in severe hepatic failure and jaundice, and - rarely - in benign or malignant liver tumours or cyst formation which sometimes result in life-threatening intra-abdominal haemorrhage (19, 20). Testosterone ester replacement therapy has only very rarely been
associated with any hepatic disease. No impairment of liver function was reflected in tests undertaken at three-month intervals throughout the two contraception studies (3, 4, 21 ). Alkylated androgens also adversely modify plasma lipid profiles (22). The ratio of high-density (HDL} to low-density lipoprotein (LDL) cholesterol is reduced - a trend which has been associated with increased risk of cardiovascular disease (23). There is also some evidence to show that high doses of alkylated androgens promote platelet aggregation (24). However, the clinical evidence to substantiate cardiovascular risk rests essentially on a handful of case reports (18). Consistent results have now been obtained from contraceptive studies to show that sustained administration of exogenous testosterone enantate at supraphysiological dosage also induces a reversible and selective reduction in HDL cholesterol (3, 4, 11, 21 ). Moreover, in the most recent of these studies (4}, this fall was accompanied by a corresponding rise in plasma triglyceride levels. These changes presumably reflect the potential of testosterone to increase hepatic triglyceride lipase activity (25), but their clinical implications remain uncertain. This uncertainty is compounded by apparently conflicting information from cross-sectional epidemiological studies showing that endogenous testosterone levels are positively associated with HDL cholesterol levels (26). There is general recognition that further detailed studies are needed to explore the effects of exogenous androgens both on lipid metabolism and on thrombotic mechanisms (21 ). The behavioural effects of androgens have received much attention. Abuse, predominantly of alkylated androgens, has been reported to increase aggression and to cause psychotic symptoms (27, 28) and withdrawal syndromes (29, 30). Short-term administration of methyltestosterone has also been claimed to cause irritability and aggressive behaviour in normal men (31 ). However, such changes were not detected when moderate supraphysiological doses of testosterone enantate were used over several months in an experimental setting (32, 33). Within the second of the contraceptive studies (4), among 50 men who discontinued participation prematurely, 10 complained of psychological changes. In no instance, however, do these appear to have been substantial. In general, the weekly injections administered throughout this study were well accepted (34). Only 10 of 42 men who discontinued before the end of the suppression phase indicated that they had 51
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"problems" with the regimen. Within the group as a whole, other androgenic effects, including acne (which resulted in the withdrawal of 8 men from the study), and the expected increases in body weight, haemoglobin, creatinine, urea and the decrease in testicular size all subsequently returned to baseline values. However, an immediate need is acknowledged, firstly to determine whether or not sperm counts return to their former levels in the cohort of men already studied, and secondly to carry out long-term follow-up studies to determine the nature, frequency and persistence of any adverse effects. It is also conceded that more remains to be known about the effect of such regimens on bone, muscle, bone marrow, and other androgen-responsive tissue (35), and that long-term effects, particularly on the cardiovascular system and the prostate, can only be effectively investigated - as is the case with hormonal contraceptives for women - on an epidemiological basis within large cohorts of individuals. For many years, few innovative pharmaceutical companies have been engaged in contraceptive research (36). The commercial consequences of the regulatory restrictions recently imposed on combined oral contraceptive products containing third-generation progestogens as a result of their thrombogenic potential will doubtless deepen this disengagement. The hope, now expressed within WHO, is that this new avenue of research will rekindle interest within the research-based industry in extending the current options for reliable contraception. References 1. UN Department for Economic and Social Information and Policy Analysis, Population Division. World contraceptive use 1994. Unpublished document ST/ESA/SER. AI 143, United Nations, New York, 1994. 2. Wallace, E., Aitken, R., Wu, F. Residual sperm function in oligozoospermia induced by testosterone enantate administered as a potential steroid male contraceptive. International Journal of Andrology, 15: 416-424 (1992). 3. WHO Task Force on Methods for the Regulation of Male Fertility. Contraceptive efficacy of testosteroneinduced azoospermia in normal men. Lancet, 336: 955959 (1990). 4. WHO Task Force on Methods for the Regulation of Male Fertility. Contraceptive efficacy of testosteroneinduced azoospermia and oligozoospermia in normal men. Fertility and Sterility, 65: 821-829 (1996).
5. Jouannet, P., Ducat, B., Feneux, D., Spira, A. Male factors and the likelihood of pregnancy in infertile couples. 1: Study of sperm characteristics. International Journal of Andrology, 11: 379-394 (1988). 6. Barfield, A., Melo, J., Coutinho, E. et al. Pregnancies associated with sperm concentrations below 10 million/ml in clinical studies of a potential male contraceptive method, monthly depot medroxyprogesterone acetate and testosterone esters. Contraception, 20: 121-127 (1979). 7. World Health Organization. WHO laboratory manual for the examination of human semen and semen-cervical mucus interaction. 2nd ed. Cambridge University Press, Cambridge, 1987. 8. Hatcher, R., Kowal, D., Guest, F. et al. Contraceptive technology: international edition. Printed Matter, Inc., Atlanta, 1989. 9. US Department of Health, Education and Welfare. Hormonal control of male fertility, Ed. Patanelli, D. Publication No. (NIH) 78-1097. Washington DC, 1978. 10. Knuth, U., Behre, H., Belkien, L. et al. Clinical trial of 19-nortestosterone hexoxyphenylpropionate (Anadur) for male fertility regulation. Fertility and Sterility, 44: 814-821 (1985). 11. Handelsman, D., Conway, A., Boylan, L. Suppression of human spermatogenesis by testosterone implants in man. Journal of Clinical Endocrinology and Metabolism, 75: 1326-1332 (1992). 12. Pavlov, S., Brewer, K., Farley, M. et al. Combined administration of a gonadotrophin-releasing hormone antagonist and testosterone in men induces reversible azoospermia without loss of libido. Journal of Clinical Endocrinology and Metabolism, 73: 1360-1369 (1991 ). 13. Tom, L., Bhasin, S., Salameh, W. et al. Induction of azoospermia in normal men with combined Nai-Giu gonadotrophin-releasing hormone antagonist and testosterone enantate. Journal of Clinical Endocrinology and Metabolism, 75: 476-483 (1992). 14. Bebb, R., Anawall, B., Christensen, R. et al. Combined administration of levonorgestrel and testosterone induces more rapid and effective suppression of spermatogenesis than testosterone alone: a promising male contraceptive approach. Journal of Clinical Endocrinology and Metabolism, 81:757-762 (1996). 15. Bhasin, S. Androgen treatment of hypogonadal men. Journal o 1 Clinical Endocrinology and Metabolism, 74: 1221-1225 (1992). 16. Ammus, S. The role of androgens in the treatment of haemorrhagic disorders. Advances in Internal Medicine, 34: 191-208 (1989).
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17. Bhasin, S., Storet, T., Berman, N. et al. The effects of supraphysiological doses of testosterone on muscle size and strength in normal men. New England Journal of Medicine, 335: 1-7 (1996). 18. Bagatell, C., Bremner, W. Androgens in men- uses and abuses. New England Journal of Medicine, 334: 707714 (1996). 19. Ishak, K., Zimmerman, H. Hepatotoxic effects of the anabolic/androgenic steroids. Seminars on Liver Disease, 7: 230-236 (1987). 20. Soe, K., Soe, M., Gluud, C. Liver pathology associated with the use of anabolic-androgenic steroids. Liver, 12: 73-79 (1992). 21. Wu, F., Farley, T., Peregoudov, A., Waites, G. for the WHO Task Force on Methods for the Regulation of Male Fertility. Effects of testosterone enantate in normal men: experience from a multicenter contraceptive efficacy study. Fertility and Sterility, 65: 626-636 (1996). 22. Plymate, S., Swerdloff, R. Androgens, lipids and cardiovascular risk. Annals of Internal Medicine, 117: 871-872 (1992). 23. Jacobs, D., Mebane, 1., Bangdiwala, S. et al. High density lipoprotein cholesterol as a predictor of cardiovascular disease mortality in men and women: the followup study of the Lipid Research Clinics Prevalence Study. American Journal of Epidemiology, 131:32-47 (1990). 24. Ferenchick, G., Schwartz, D., Ball, M., Schwartz, K. Androgenic-anabolic steroid abuse and platelet aggregation: a pilot study in weight lifters. American Journal of Medical Sciences, 303: 78-82 (1992). 25. Sorva, R., Kuusi, T., Taskinan, M. et al. Testosterone substitution increases the activity of lipoprotein lipase and hepatic lipase in hypogonadal males. Atherosclerosis, 69: 191-197 (1988). 26. Barratt-Connor, E. Testosterone, HDL-cholesterol and cardiovascular disease in men. In: Pharmacology, biology and clinical application of androgens: current status and future prospects. Eds. Bhasin, S., Gabelnick H., Spieler, J. et al. Wyley-Liss, New York, 1996, pp. 215-223. 27. Uzych, L. Anabolic-androgenic steroids and psychiatric-related effects: a review. Canadian Journal of Psychiatry, 37: 23-28 (1992). 28. Pope, H., Katz, D. Affective and psychotic symptoms associated with anabolic steroid use. American Journal of Psychiatry, 145: 487-490 (1988). 29. Bahrke, M., Yesalis, C., Wright, J. Psychological and behavioural effects of endogenous testosterone levels and anabolic-androgenic steroids among males: a review. Sports Medicine, 10: 303-337 (1990).
30. Brower, K., Blow, F., Beresford, T., Fuelling, C. Anabolic-androgenic steroid dependence. Journal of Clinical Psychiatry, 50: 31-33 (1989). 31. Su, T-P., Pagliaro, M., Schmidt, P. et al. Neuropsychiatric effects of anabolic steroids in male normal volunteers. Journal of the American Medical Association, 269: 2760-2764 (1993). 32. Bagatelle, C., Heiman, J., Matsumoto, A. et al. Metabolic and behavioural effects of high dose, exogenous testosterone in healthy men. Journal of Clinical Endocrinology and Metabolism, 79: 561-567 (1994). 33. Anderson, R., Bancroft, J., Wu, F. The effects of exogenous testosterone on sexuality and mood of normal men. Journal of Clinical Endocrinology and Metabolism, 75: 1503-1507 (1992). 34. Ringheim, K. Evidence for the acceptability of an injectable hormonal method for men. International Family Planning Perspectives, 21: 75-80 (1995). 35. Young, N., Baker, H., Liu, G., Seeman, E. Body composition and muscle strength in healthy men receiving testosterone enantate for contraception. Journal of Clinical Endocrinology and Metabolism, 77: 1028-1032 (1993). 36. Mastrioanni, L., Donaldson, P., Kane, T. Development of contraceptives - obstacles and opportunities. New England Journal of Medicine, 322: 482-484 (1990).
Do estrogens have antidepressant activity? Puerperal psychosis of a severity requiring hospital admission is a rare complication of childbirth (1, 2), but lesser degrees of non-psychotic (or neurotic) postnatal depression are common within the first few months following delivery (2, 3). Many of these episodes remain untreated and resolve spontaneously within a matter of months (4). Others are considerably more persistent (5-7) and these may be serious enough to contribute to family disruption and maladjustment of the child (8-10). These disturbances, which often seem to be determined or influenced by social and environmental factors, have no clinical characteristics that distinguish them from other cases of depressive illness (1 ). They have consequently been treated, in general, by the orthodox approaches of supportive counselling, psychotherapy, and antidepressant drugs. The possibility that hormonal perturbations may contribute to some cases of postnatal depression
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