Hormonal contraception in the male R A Anderson MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, University of Edinburgh, Edinburgh, UK

The hormonal approach to male contraception is based on the suppression of gonadotrophin secretion with secondary suppression of spermatogenesis. This can be achieved by administration of testosterone or other androgen alone, but combined administration with a progestogen or GnRH analogue allows the dose of testosterone to be reduced to physiological replacement doses. This approach has been investigated for many years but without identification of a regimen which results in sufficient suppression of spermatogenesis to provide ensured contraception in all men, safely and conveniently. The reasons for this are discussed, and recent developments towards a regimen that fulfils all these criteria are described. Crucial to development of any new product is that it will be used: surveys of both men and women indicate firmly positive attitudes towards a 'male pill'. There are, therefore, grounds for cautious optimism that the next decade may see the introduction of the first novel male contraceptive for several hundred years.

Correspondence to Dr RA Anderson, MRC Human Reproductive Sciences Unit Centre for Reproductive Biology, University of Edinburgh, 37 Chalmers Street Edinburgh EH3 9ET, UK

Access to a wide range of effective methods of contraception is an important element of reproductive health. Female-dependent methods have been the subject of considerable scientific advance, offering effective and male-independent contraception, but there is an emerging emphasis that men should be more involved in family planning1. The supremacy of modern, female methods in the industrialised world obscures the fact that one-third of all couples world-wide rely on a maledependent method of contraception, mostly the condom or withdrawal, methods that have been used since antiquity. The basis of the hormonal approach to male contraception is that spermatogenesis is dependent on gonadotrophin secretion, directly in the case of follicle stimulating hormone (FSH) and indirectly, secondary to the production of testosterone, in the case of luteinizing hormone (LH). Suppression of gonadotrophin secretion, therefore, results in loss of both endocrine and spermatogenic activity in the testis (Fig. 1). This can be achieved by over-riding the physiological negative feedback control mechanisms at the hypothalamus and pituitary gland by administration of high doses of an androgen or progestogen, by preventing the stimulatory effect of gonadotrophin hormone releasing

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EXOGENOUS Androgen Progestogen GnRH analogue Peripheral effects

+ Testosterone

f

Peripheral effects

Leydig cell

Seminiferous tubule

Normal

Contraception

Fig. 1 Representation of the basic principles of hormonal male contraception. The left-hand diagram reflects the physiological relationships between the hypothalamus, anterior pituitary and testis resulting in the production of spermatozoa and of testosterone with both intratesticular and peripheral effects. During exogenous administration of androgen, progestogen or GnRH analogue, gonadotrophic support of the testis is withdrawn resulting in loss of sperm and testosterone production, the latter requiring the administration of testosterone to prevent hypogonadal symptoms.

hormone (GnRH) on the gonadotroph, or by a combination of such agents. Spermatogenic suppression following testosterone administration has been investigated for over 50 years, but a hormonal male contraceptive remains stubbornly absent from the pharmacist's shelves. There have, however, been significant developments in the field in recent years, amongst which is the increasing interest of the pharmaceutical industry. While this may partly reflect the rapid growth of research into androgen supplementation in the ageing male, the benefit to contraceptive research will be improved methods of androgen administration, common to all clinical indications. An ideal hormonal male contraceptive method might induce universal azoospermia while being devoid of adverse metabolic effects, in a practical and acceptable formulation. The need for azoospermia is based on the results of two landmark multicentre studies by the World Health Organization (WHO) investigating the contraceptive efficacy of sex steroidinduced azoospermia and oligozoospermia, using a testosterone-only regimen. Incomplete suppression of spermatogenesis was associated with a 718

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significant risk of pregnancy, with a pregnancy rate of 8.1 per 100 personyears for sperm concentrations between 0.1-3 x lOVml, but no pregnancies in 230 person-years with azoospermia1-3. While these results may not seem surprising, they should be seen as proof of the concept that wide-spread hormonal male contraception is a real possibility and greatly facilitate present and future contraceptive efficacy studies. These data also supported the results of laboratory studies indicating the presence of residual fertilising potential of spermatozoa from men with testosteroneinduced severe oligozoospermia4, negating the possibility of development of a contraceptive method that did not result in azoospermia. A supraphysiological dose of testosterone enanthate (TE, 200 mg/week) was used to ensure adequate suppression of gonadotrophins: this also induced significant effects on lipid metabolism, skin, liver and haematopoiesis5, but not behaviour6. While this testosterone-based regimen was a prototype to investigate contraceptive efficacy, these WHO studies illustrate the major current problems, i.e. (i) incomplete suppression of spermatogenesis; (ii) lack of a long-duration androgen preparation; and (iii) the metabolic consequences of androgen administration.

Incomplete suppression of spermatogenesis A consistent finding of the great majority of studies has been that significant proportions of men maintain a low rate of spermatogenesis despite prolonged treatment. In the WHO efficacy studies, azoospermia was achieved in 77% of men within 6 months of treatment. Similar percentages are achieved using a variety of other sex-steroid based regimens7. Even allowing for the necessity of demonstrating azoospermia in men intending to use a method for contraception, a 'failure rate' of over 20% is clearly unacceptable; thus, a major objective of current protocols is to produce azoospermia more consistently and rapidly. The proportion of men achieving azoospermia has been reported to be higher using two different combinations of sex steroids, although TE by weekly injection was the androgen preparation in both. Firstly, all men treated with the potent progestogen and anti-androgen cyproterone acetate (CPA) with TE became azoospermic. Subsequent dose-finding studies confirmed that doses of CPA of 25 mg/day or more induced complete azoospermia in all men8 (although the number of men treated was low; Fig. 2). In a second study, men were treated with oral desogestrel with TE; both drugs given in two doses in a total of 3 combinations9. All 8 men in the group receiving 300 mg desogestrel daily p.o. with 50 mg TE weekly became azoospermic, whereas not all became azoospermic when either the dose of desogestrel was reduced to 150 mg or the dose of testosterone increased to 100 mg/week. These British Medical Bulletin 2000, 56 (No 3)

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a)

120

100 -

b) 128 CPA+TE

m-

"*"*

(0

to I

40 -

20 -

-2 -1 0 2 4 • 8 1012141« 2 4 1 8 101214181120 TME(w**fc»)

- 2 - 1 0 2 4 8 8 10121416 2 4 8 8

101214181820

Fig. 2 Suppression of spermatogenesis during administration of oral cyproterone acetate with i m. testosterone enanthate. Sperm concentration in individuals before, during, and following administration of (a) 25 mg (b) 12.5 mg CPA daily, both with 100 mg TE weekly to 5 men in each group. The inserts show sperm concentrations during drug administration on a log scale From Menggiola et al1, with permission.

results require to be confirmed in larger groups of men, and the basis for the increased efficacy is unclear. Possible mechanisms include inhibition by progestogens of the effect of testosterone or its metabolites within the testis10. The high efficacy of CPA-based regimens also provides indirect evidence of the importance of intratesticular testosterone in the maintenance of low rates of spermatogenesis, supporting the need to avoid regimens which results m supraphysiological concentrations. Our own studies confirm the efficacy of oral desogestrel in combination with testosterone given as subcutaneous pellets11. The prevalence of azoospermia also varies in different ethnic populations; men in Chinese and Asian centres showmg more consistent suppression to azoospermia. This is seen both with testosterone-only treatment and combinations of testosterone with progestogens. While differences in pre-treatment FSH concentrations and speed of spermatogenic suppression between men who suppress to azoospermia and those who do not have been identified12, these did not account for the differences between Chinese and non-Chinese centres. 5a-reductase converts testosterone to the more potent androgen dihydrotestosterone, thus amplifying the androgen signal. Physiological intratesticular testosterone concentrations are very high, but during conditions of suppressed testosterone production, i.e. during contraceptive administration, conversion to dihydrotestosterone may become more important. Differences in 5a-reductase activity between men becoming azoospermic and those remaining oligozoospermic have also been suggested13: while there are parallel differences in 5ot-reductase 720

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activity between populations14-15 and intratesticular 5a-reductase has been demonstrated in animal experiments to amplify the effect of testosterone on spermatogenesis16, direct evidence of the importance of 5a-reductase in spermatogenesis in humans has not been obtained. In addition to 5areduction, testosterone is metabolised to oestradiol by aromatase. This is of physiological importance in mediating the negative feedback effects of testosterone on gonadotrophin secretion; thus co-administration of an oestrogen might be expected to increase the degree of suppression of spermatogenesis during administration of exogenous testosterone. This effect has been clearly demonstrated in both rodents and non-human primates17, and in a preliminary study m men18. Adverse effects of oestrogen administration, such as gynaecomastia and the possibility of increased risk of thrombosis, however, may limit the practical use of this effect19. The inhibition of gonadotrophin secretion by interference with the action of gonadotrophin hormone releasing hormone (GnRH) on the gonadotroph has potential advantages over the use of sex steroids for this effect. These include a reduction in the total dose of steroid required, as only physiological replacement of testosterone is required. Other potential advantages include the availability of GnRH analogues with a variety of routes of administration and duration of action. Currently available analogues, however, have agomstic effects on the GnRH receptor subsequently resultmg in inhibition of the effect of GnRH by downregulation, and their effects on human spermatogenesis have been disappointing (reviewed by Nieschlag et aV). The development of GnRH antagonists has been problematical with histamine-like side-effects and a necessity for frequent administration, although the results obtained with one prototype agent, Nal-Glu, were encouraging. Azoospermia was achieved in 7 out of 8 subjects in each of two studies using a protocol in which the antagonist was administered followed by either a low dose of TE after 2 weeks20 or by replacement at physiological levels21. Novel GnRH antagonists such as Cetrorelix result in effective suppression of gonadotrophins. When given with androgen, a high prevalence of azoospermia is achieved, but this was not maintained by the androgen alone22. This may reflect the dosage interval of androgen used in that study (19-nortestosterone, 200 mg, 3 weekly), as a recent study using Nal-Glu with TE demonstrated that suppression of spermatogenesis was maintained for a further 20 weeks in 10 out of 14 men by TE alone following discontinuation of Nal-Glu23. In summary, the great majority of preparations using steroids alone or in combination do not result in universal azoospermia. Two possible exceptions to this are the combinations of either CPA or desogestrel with TE. The studies with desogestrel demonstrate a narrow effective dose range for both the gestogen and the androgen which may be wider when British Medical Bulletin 2000; 56 (No 3)

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CPA is used: this may reflect its anti-androgenic activity within the testis, but the numbers of men treated with either preparation are very limited. Both combinations, however, have metabolic effects which may limit their widespread application, and are discussed more fully below.

Androgen replacement Suppression of gonadotrophin secretion results in a decline in testosterone secretion by the testis. As testosterone is needed to maintain nonreproductive physiological systems, such as bone and muscle metabolism as well as sexual behaviour, any hormonal method that results in gonadotrophin suppression needs to include replacement of testosterone. The physiological production rate of testosterone in young men has been recently re-investigated, giving a mean value of 3.7 mg/day24. Replacement should, therefore, provide a similar dose, with concentrations fluctuating little from day-to-day. The importance of the diurnal variation in testosterone concentrations is unknown and is not regarded as important in replacement. The most commonly used testosterone preparations in clinical use are the injectable 17p-hydroxyl esters. These have unfavourable pharmacokinetics, resulting initially in supraphysiological concentrations followed by a rapid decline over the succeeding days. Nevertheless, these preparations (usually as TE) have been the most widely investigated in male contraception, with a dose of 100 mg/week (equivalent to 19.3 mg testosterone/day) regarded as providing physiological replacement25. The recent study by Wu et aP, however, confirms the supraphysiological concentrations of testosterone achieved with this dose. Fused, fully biodegradable testosterone pellets have been in clinical use since the 1950s. A dose of 800 mg (given as 4 x 200 mg pellets) provides physiological replacement for 4—6 months with approximately zeroorder release of 6 mg testosterone/day. Testosterone concentrations are dose-dependent and highly reproducible, and, despite the need for a minor surgical procedure for insertion, are acceptable to patients. Adverse effects are rare, but pellet extrusion occurs in approximately 7% of insertions. Testosterone pellets have been used in male contraceptive studies both alone26 and in combination with a progestogen27. Repeated administration of pellets has not been investigated in a male contraceptive study, where there is the need to balance avoidance of over-frequent administration to avoid build-up of the effective dose with too infrequent administration resulting in escape of gonadotrophin suppression and thus spermatogenesis, and possibly adverse effects from inadequate replacement. The major disadvantage of the pellets is the need for a minor surgical procedure for insertion. A longer-acting injectable testosterone ester, 722

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testosterone buciclate, has been developed by the NIH and WHO and used for male contraception (Fig. 3)28, but is unavailable for further study at present. An alternative preparation is an injectable form of testosterone undecanoate. The undecanoate ester is used for oral administration as it is absorbed directly into the lymphatics thus avoiding first-pass metabolism in the liver, but it has a short duration of action and results in variable plasma testosterone concentrations. When dissolved in oil, it has improved pharmacokinetics compared to TE providing testosterone replacement for 6-8 weeks29. This preparation is also being investigated by the WHO in male contraceptive studies. While there have been other developments in testosterone administration, such as buccal absorption of cyclodextrintestosterone and non-scrotal transdermal patches, advantages for male contraception are unclear30. All the above preparations are based on testosterone itself. Synthetic androgens have the potential advantages of increased potency and tissue selectivity. Increased potency would also require a smaller quantity of drug, which might allow improved transdermal administration. The possibility of tissue selectivity is based on the differential metabolism of testosterone in different tissues: aromatisation is important in bone,

Testosterone buciclate

7a-methyl-19-nortestosterone Fig. 3 The structure of testosterone buciclate and MENT, illustrating the different approaches to androgen administration. The lipophilic side-chain of the buciclate results in slow release from the site of injection, prolonging the duration of action. Conversely, MENT is a more potent androgen than testosterone and is not Set-reduced, resulting in a lower dosage requirement and potential tissue selectivity.

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whereas 5a-reduction is important in the prostate and testosterone itself appears to act on skeletal muscle. 7a-methyl-19-nortestosterone (MENT; Fig. 3) is a synthetic androgen that is approximately 10 times more potent than testosterone in anabolic bioassays and as a suppresser of gonadotrophin secretion, but it is resistant to 5a-reduction31. It thus has relatively low potency in bioassays such as stimulation of prostate size in castrate animals. MENT can be converted by aromatase to an active oestrogen, thus it may be effective in the maintenance of bone mass. Although this androgen was initially developed many years ago, detailed human data remain limited to pharmacokinetic and pharmacodynamic studies. MENT is not bound by sex hormone binding globulin (SHBG) and is cleared rapidly from the circulation. MENT acetate (MENT Ac) can, however, be prepared in the form of implants for subdermal insertion, thus giving the potential for long-term replacement therapy or treatment. These have recently been demonstrated to support mood and sexual behaviour in hypogonadal men similarly to conventional testosterone replacement32. MENT also has progestogenic activity, which might be advantageous in the context of male contraception. The currently available testosterone preparations are thus a major limiting factor in the development of a male contraceptive. The short acting injectable forms such as TE are now regarded as obsolete in this context, and while testosterone pellets offer many advantages, the need for surgical insertion and the occasional extrusion remain drawbacks. Longer acting preparations are, however, becoming available, and the application of 'selective' synthetic androgens offers opportunities for a more complex but potentially beneficial replacement therapy.

Metabolic consequences of androgen administration The WHO studies described above illustrate the metabolic effects of mildly supraphysiological administration of testosterone to normal men. These include increases in acne, weight, haemoglobin concentration and haematocrit, and decreases in HDL-C with little change in total cholesterol or LDL-C5, although the changes in HDL-C were not observed Ln the Chinese men. All changes were reversible by 90 days after discontinuing TE. HDL-C is important in removal of cholesterol from peripheral tissues to the liver and is regulated by physiological concentrations of sex steroids via modulation of hepatic triglyceride lipase activity. Such changes have been reported in most9, but not all27, male contraceptive studies and may reflect the route of administration being reduced or absent if supraphysiological testosterone concentrations are avoided. Low concentrations of HDL-C are associated in epidemiological studies with coronary artery disease, although no clear association has 724

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been found between testosterone concentrations and cardiovascular disease (reviewed by Barrett-Connor33). The significance of androgeninduced changes in a single marker on the pathogenesis of a disease with a complex array of risk factors is thus uncertain and will require epidemiological studies following introduction of a hormonal male contraceptive. Nevertheless, the consistently observed changes in HDL-C during testosterone administration may be a useful marker of an androgenic effect. This may be of particular importance during administration of synthetic androgens where monitoring of plasma testosterone concentrations cannot guide dose requirements. SHBG also changes during administration of sex steroids, with a decline during administration of testosterone or progestins, either oral or parenteral. SHBG has, therefore, been proposed as a convenient marker of excessive hepatic steroidal effects27. Desogestrel (as its active metabolite, 3ketodesogestrel or etonogestrel) shows greater relative selectivity for the progesterone receptor over the androgen receptor than other gestogens and, when administered alone, has less on SHBG in women than levonorgestrel. Oral desogestrel, however, resulted in a significant fall in SHBG in men, despite a concomitant fall in testosterone concentrations9. Stimulation of erythropoiesis is a well-recognised effect of androgens. Haemoglobin concentrations and haematocrit rise during TE administration5. Conversely, the administration of CPA with TE results in a fall in these variables8. This effect is dose-dependent, and may reflect the anti-androgemc effect of CPA despite the relatively large dose of TE used. The administration of desogestrel alone did not, however, result in any change in haemoglobin or haematocrit despite a marked fall in testosterone concentrations9; thus it may be a specific effect of CPA. It is noteworthy that, while the combination of CPA and TE resulted in a fall in haemoglobin concentration and haematocrit, it had no effect on HDL-C8. These results illustrate the complexity of devising a steroidbased regimen without significant metabolic impact. The uncertainty of the importance of these changes must also be recognised, particularly as they are likely to differ in different populations.

Is there a market? Popular discussion of the possibility of the introduction of a hormonal male contraceptive frequently revolves around the issues of whether men would use it, and whether women would trust them to. These questions remain unanswerable until such a time as a real product is launched, but attempts to assess potential usage have been made through the use of surveys that have generally elicited very positive responses from men. The attitudes of women have been less frequently sought. We have British Medical Bulletin 2000, 5fi (No 3)

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recently completed two questionnaire-based surveys addressing the attitudes of both men and women to male contraceptive methods, in 4 cities with very different social and economic situations: Edinburgh, Cape Town, Hong Kong and Shanghai34'35. The major finding of the male study was that the majority of men surveyed welcomed new hormonal methods of contraception even though they were mostly happy with their current method. Indeed, 44-83% said they would definitely or probably use a male pill. Attitudes to existing and novel methods, however, differed greatly between centres. Hong Kong was the only centre where a male-directed method (condom) was the main method currently used, and men in that centre were least keen on novel methods. Women were also generally positive; over 84% of women in all centres thought that the availability of a hormonal method for men would allow greater sharing of responsibility for contraception. While it would be naive to expect such high percentages to use hormonal male methods in reality, it should be borne in mind that one-third of couples world-wide currently use a male method.

Conclusion Some would argue that the search for a hormonal male contraceptive is an example of hope over experience, and that the funds and research effort should be redirected elsewhere36. The alternative view, illustrated here, is that the last few years have seen a clearer definition of where the major problems he and significant advances in all of them. The increased involvement and interest of the pharmaceutical industry has yet to translate into the large-scale clinical research which will be needed to translate small pilot studies into an actual product. However, this positive change in what is otherwise the flight of industry from contraception, together with the progress described here and the wide-spread media coverage of developments in this field provide grounds for optimism that not only is a product possible but that it will secure a place in the market. References Cairo Programme of Action. International Conference on Population and Development. Cairo, Egypt: 1994 World Health Organization Task Force on Methods for the Regulation of Male Fertility. Contraceptive efficacy of testosterone-induced azoospermia in normal men. Lancet 1990; 336: 955-9 World Health Organization Task Force on Methods for the Regulation of Male Fertility. Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men. Fertil Stenl 1996; 65: 821-9

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23

Wallace EM, Aitken RJ, Wu FCW. Residual sperm function in ohgozoospermia induced by testosterone enanthate administered as a potential male contraceptive. Int ] Androl 1992; 15: 416-24 Wu FCW, Farley TMM, Peregoudov A, Wanes GMH, WHO Task Force on Methods for the Regulation of Male Fertility. Effects of testosterone enanthate m normal men: experience from a multicenter contraceptive efficacy study Ferttl Stenl 1996; 65 626-36 Anderson RA, Bancroft J, Wu FCW The effects of exogenous testosterone on sexuality and mood of normal men / Clm Endocrtnol Metab 1992; 75: 1503—7 Nieschlag E, Behre HM, Weinbauer GF. Hormonal male contraception a real chance? In: Nieschlag E, Behre HM, Weinbauer GF (Eds) Spermatogemsis-Fertilization-Contraception. Molecular, Cellular and Endocrine Events in Male Reproduction. Berlin: Springer, 1992; 477-501 Menggiola MC, Bremner WJ, Costantino A, Di Cintio G, Flamigni C. Low dose of cyproterone acetate and testosterone enanthate for contraception in men. Hum Reprod 1998; 13: 1225-9 Wu FCW, Balasubramaruan R, Mulders TMT, Ceohngh-Bennink HJT. Oral progestogen combined with testosterone as a potential male contraceptive: additive effects between desogestrel and testosterone enanthate in suppression of spermatogenesis, pituitary-testicular axis, and lipid metabolism. / Clm Endocnnol Metab 1999; 84: 112—22 Menggiola MC, Bremner WJ. Progestin-androgen combination regimens for male contraception. / Androl 1997; 18: 240-4 Martin CW, Riley SC, Evenngton D, Groome NP, Riemersma RA, Baird DT, Anderson RA. Dose-finding study of oral desogestrel with testosterone pellets for suppression of pituitarytesticular axis in normal men. Hum Reprod 2000; 15 101-10 Handelsman DJ, Farley TMM, Peregoudov A, Wanes GMH, WHO Task Force on Methods for the Regulation of Male Fertility Factors in nonuniform induction of azoospermia by testosterone enanthate in normal men. Fertil Stenl 1995; 63' 125-33 Anderson RA, Wallace AM, Wu FCW. Comparison between testosterone enanthate-induced azoospermia and ohgozoospermia in a male contraceptive study. HI. Higher 5a-reductase activity in ohgozoospermic men administered supraphysiological doses of testosterone / Clm Endocrmol Metab 1996; 81: 902-8 Lookingbill DP, Demers LM, Wang C et al Clinical and biochemical parameters of androgen action m normal healthy Caucasian versus Chinese subjects. / Clm Endocnnol Metab 1991; 72: 1242-8 Ross RK, Bernstein L, Lobo RA et al. 5-alpha-reductase activity and the risk of prostatic cancer among Japanese and US white and black males Lancet 1992; 339 887-9 O'Donnell L, Stanton P, Wreford NG, Robertson DM, McLachlan RI. Inhibition of 5areductase activity impairs the testosterone-dependent restoration of spermiogenesis in adult rats. Endocrinology 1996; 137: 2703-10 Lobl TJ, Kirton KT, Forbes AD et al. Contraceptive efficacy of testosterone-estradiol implants in male Rhesus monkeys. Contraception 1983; 27: 383-9 Bnggs M, Bnggs M. Oral contraception for men. Nature 1974; 252: 585-6 The Coronary Drug Project Research Group. The coronary drug project. Findings leading to discontinuation of the 2.5-mg/day estrogen group. JAMA 1973; 226: 652—7 Pavlou SN, Brewer K, Farley MG et al. Combined administration of a gonadotropin-releasing hormone antagonist and testosterone in men induces reversible azoospermia without loss of libido. / Clm Endocnnol Metab 1991, 73: 1360-9 Tom L, Bhasin S, Salameh W et al. Induction of azoospermia in normal men with combined Nal-Glu gonadotrophin releasing hormone antagonist and testosterone enanthate. / Clm Endocnnol Metab 1992; 75: 476-83 Behre HM, Kleisch S, Lemcke B, Nieschlag E. Suppression of spermatogenesis to azoospermia by combined administration of GnRH antagonist and 19-nortestosterone cannot be maintained by 19-nortestosterone alone. In: Proceedings 77tb Annual Meeting of The Endocrine Society. Washington DC: 1995 Swerdloff RS, Bagatell CJ, Wang C et al. Suppression of spermatogenesis in man induced by Nal-Glu gonadotrophin releasing hormone antagonist and testosterone enanthate (TE) is maintained by TE alone. / Clm Endocnnol Metab 1998; 83: 3527-33

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24 Vierhapper H, Nowotny P, Waldhausl W. Determination of testosterone production rates in men and women using stable isotope/dilution and mass spectrometry J Clin Endocrmol Metab 1997, 82: 1492-6 25 Bebb RA, Anawalt BD, Chnstensen RB et al Combined administration of levonorgestrel and testosterone induces more rapid and effective suppression of spermatogenesis than testosterone alone: a promising male contraceptive approach. / Clm Endocrmol Metab 1996, 81 757-62 26 Handelsman DJ, Conway AJ, Boylan LM. Suppression of human spermatogenesis by testosterone implants. / Clin Endocrmol Metab 1992; 75: 1326-32 27 Handelsman DJ, Conway AJ, Howe CJ, Turner L, Maclcey M-A. Establishing the minimum effective dose and additive effects of depot progestin in suppression of human spermatogenesis by a testosterone depot. / Clm Endocrmol Metab 1996; 81 4113-21 28 Behre HM, Baus S, Kleisch S et al. Potential of testosterone buciclate for male contraception: endocrine differences between responders and nonresponders / Clm Endocrmol Metab 1995, 80: 2394-403 29 Zhang GY, Gu YQ, Wang XH, Cui YG, Bremner WJ. A pharmacokinetic study of in)ectable testosterone undecanoate in hypogonadal men J Androl 1998; 19 761-8 30 Buchter D, von Eckardstein S, von Eckardstein A et al. Clinical trial of transdermal testosterone and oral levonorgestrel for male contraception. / Clin Endocrmol Metab 1999; 84: 1244-9 31 Sundaram K, Kumar N, Bardin CW 7a-methyl-nortestosterone (MENT): the optimal androgen for male contraception Ann Med 1993; 25 199-205 32 Anderson RA, Martin CW, Kung AWC, Evenngton D, Pun TC, Tan KCB et al 7oc-Methyl-19nortestosterone (MENT) maintains sexual behavior and mood in hypogonadal men. / Clin Endocrmol Metab 1999, 84 3556-62 33 Barrett-Connor E. Testosterone, HDL-cholesterol, and cardiovascular disease in men In Bhasin S, Gabelnick HL, Speiler JM, Swerdloff RS, Wang C, Kelly C (Eds) Pharmacology, Biology and Clinical Applications of Androgens: Current Status and Future Prospects. New York: Wiley-Liss, 1996; 215-23 34 Martin CW, Anderson RA, Cheng L, Ho PC, vander Spuy Z, Smith KB et al. Potential impact of hormonal male contraception: cross-cultural implications for development of novel preparations. Human Reprod 2000; 15: 637-45 35 Glasier A, Anakwe R, Evenngton D, Martin CW, van der Spuy Z, Cheng L et al. Would women otrust their partners to use a male pill? Hum Reprod 2000; 15: 646-9 36 Potts M. The myth of a male pill. Nat Med 1996, 2: 398-9

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