Depot testosterone with etonogestrel implants result in induction of azoospermia in all men for long-term contraception

doi:10.1093/humrep/deh491 Human Reproduction Vol.19, No.11 pp. 2658–2667, 2004 Advance Access publication August 27, 2004 Depot testosterone with etonogestrel implants result in induction of azoospermia in all men for long-term contraception B.M.Brady1, M.Walton1, N.Hollow1, A.T.Kicman3, D.T.Baird1 and R.A.Anderson2,4 1 Contraceptive Development Network and 2MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, University of Edinburgh, Edinburgh and 3Drug Control Centre, King’s College London, UK 4 To whom correspondence should be addressed at: MRC Human Reproductive Sciences Unit, The Chancellors Building, 49 Little France Crescent, Edinburgh EH16 4SB, UK. E-mail: BACKGROUND: Combined testosterone and progestogen preparations are a promising approach to male hormonal contraception. We investigated the effect of s.c. etonogestrel with depot testosterone on spermatogenesis in normal men over a period of 48 weeks. METHODS: Fifteen healthy men received three s.c. 68 mg etonogestrel implants. Testosterone pellets (400 mg) were administered at 12 weekly intervals. RESULTS: Nine men completed 48 weeks of treatment. Four subjects chose to discontinue after 6 months, one man withdrew from the study early for personal reasons and one was withdrawn due to illness. Sperm concentrations of <13106/ml were achieved in all men by 16 weeks of treatment. All men became azoospermic, although the time to achieve this varied from 8 to 28 weeks. Azoospermia was maintained in eight of the nine men treated for 48 weeks, one subject showing partial recovery from 40 weeks. Testosterone levels remained in the physiological range throughout. Treatment did not result in weight gain, change in body composition or decline in high-density lipoprotein cholesterol concentrations. CONCLUSIONS: The combination of three etonogestrel implants with depot testosterone results in rapid and consistent suppression of spermatogenesis. This can be maintained for up to 1 year and may therefore be a suitable approach for a long-acting male hormonal contraceptive. Key words: etonogestrel/male contraception/progestogen/spermatogenesis/testosterone Introduction Current approaches to male hormonal contraception are based on the withdrawal of the gonadotrophin support to the testis resulting in suppression of spermatogenesis and intratesticular testosterone (Anderson and Baird, 2002; Nieschlag et al., 2003). Two large international studies sponsored by the World Health Organization (WHO) administering high dose testosterone enanthate demonstrated that hormonal suppression of spermatogenesis sufficient for contraceptive efficacy is a possibility (World Health Organization Task Force on Methods for the Regulation of Male Fertility, 1990, 1996). However, such regimes resulted in metabolic side effects such as a fall in high-density lipoprotein cholesterol (HDL-C) concentration, acne and weight gain due to supraphysiological testosterone levels (Wu et al., 1996), and revealed ethnic polymorphism in spermatogenic response, with a lesser suppression among Caucasians than in Asians. Progestogens are effective suppressors of gonadotrophin secretion, but the concomitant fall in testosterone production by the testis necessitates the co-administration of androgen. The introduction of a progestogen acting synergistically with testosterone allows a lowering of the total testosterone dose 2658 avoiding unwanted metabolic effects, and may also enhance the degree of spermatogenic suppression, potentially by direct intra-testicular effects (Bebb et al., 1996; Meriggiola et al., 1996; McLachlan et al., 2002; Zhang et al., 2003). Several progestogens have been investigated in this context, including medroxyprogesterone acetate (Knuth et al., 1989; World Health Organization Task Force on Methods for the Regulation of Male Fertility, 1993; Handelsman et al., 1996; Turner et al., 2003), levonorgestrel (Bebb et al., 1996), cyproterone acetate (Meriggiola et al., 1996, 1998) and norethisterone enanthate (Kamischke et al., 2001). Promising results have been obtained using oral desogestrel, with high rates of azoospermia achieved in men from several ethnic backgrounds (Wu et al., 1999; Anawalt et al., 2000; Kinniburgh et al., 2002) Compared with oral administration, a long-acting drug delivery system has advantages, including dose-sparing and the avoidance of hepatic exposure to high doses, both of which may contribute to the reduction of unwanted adverse effects. Moreover, it may be preferred by some individuals because of ease of compliance (Martin et al., 2000a). Etonogestrel, the active metabolite of oral desogestrel, has Human Reproduction vol. 19 no. 11 q European Society of Human Reproduction and Embryology 2004; all rights reserved Azoospermia with testosterone and etonogestrel implants been marketed recently in many countries as a long-acting implant (Implanonw, NV Organon, Oss, The Netherlands) providing 3 years of contraceptive efficacy in women. We have reported previously our experience with one or two etonogestrel implants in combination with depot testosterone pellets (Anderson et al., 2002). Although profound suppression of spermatogenesis with minimal non-reproductive side effects was induced, azoospermia was achieved in only 64 and 75% of the one and two implant groups, respectively. Etonogestrel implants release , 50 mg/day, thus even with two implants the daily dose is markedly lower than the optimally effective dose of 300 mg desogestrel, which has , 80% oral bioavailability (Hasenack et al., 1986). There was therefore evidence for significant dose-sparing with the implant preparation but, as spermatogenic suppression was not complete in all men, we hypothesized that the addition of a third etonogestrel implant may enhance this spermatogenic suppression. In this study, we additionally have extended the duration of treatment to 48 weeks to investigate whether the steady decline in etonogestrel release from the implants will maintain suppression of gonadotrophins and thus spermatogenesis for that length of time, using the same testosterone regimen we have used previously in the investigation of both oral desogestrel and etonogestrel implants. Methods Subjects Fifteen healthy men (mean age 31.6 years, range 18 –37) were recruited from the same general population as previous studies (Anderson et al., 2002; Kinniburgh et al., 2002). Inclusion criteria included age (18 – 45), mentally and physically healthy, body mass index (BMI) between 18 and 32 kg/m2, normal pre-treatment FSH, LH and testosterone concentrations, routine haematological and biochemical analyses, two normal semen analyses according to WHO criteria at least 2 weeks apart, and a normal physical and andrological examination. Pre-treatment sperm concentrations were . 20 £ 106/ml in all men, and motility and morphology were within normal ranges for the local population. Subjects provided written informed consent and the study had ethica (...truncated)