A multicentre study investigating subcutaneous etonogestrel implants with injectable testosterone decanoate as a potential long-acting male contraceptive

Human Reproduction Vol.21, No.1 pp. 285–294, 2006 doi:10.1093/humrep/dei300 Advance Access publication September 19, 2005. A multicentre study investigating subcutaneous etonogestrel implants with injectable testosterone decanoate as a potential long-acting male contraceptive B.M.Brady1,8, J.K.Amory2, A.Perheentupa3, M.Zitzmann4, C.J.Hay5, D.Apter6, R.A.Anderson1, W.J.Bremner2, P.Pollanen3, E.Nieschlag4, F.C.W.Wu5 and W.M.Kersemaekers7 1 Centre for Reproductive Biology, University of Edinburgh, Edinburgh EH16 4TJ, UK, 2Department of Medicine, Centre for Research in Reproduction and Contraception, University of Washington, Seattle, WA, USA, 3Department of Physiology and Obstetrics and Gynaecology, Institute of Biomedicine, University of Turku, Turku, Finland, 4Institute of Reproductive Medicine of the University of Muenster, Muenster, Germany, 5Department of Endocrinology, Manchester Royal Infirmary, University of Manchester, Manchester, UK, 6 The Sexual Health Clinic, Family Federation of Finland, Helsinki, Finland and 7Clinical Development Department, N.V. Organon, Oss, The Netherlands 8 To whom correspondence should be addressed. E-mail: BACKGROUND: The combination of etonogestrel implants with injectable testosterone decanoate was investigated as a potential male contraceptive. METHODS: One hundred and thirty subjects were randomly assigned to three treatment groups, all receiving two etonogestrel rods (204 mg etonogestrel) and 400 mg testosterone decanoate either every 4 weeks (group I, n = 42), or every 6 weeks (group II, n = 51) or 600 mg testosterone decanoate every 6 weeks (group III, n = 37) for a treatment period of 48 weeks. RESULTS: One hundred and ten men completed 48 weeks of treatment. Sperm concentrations of <1 ⴛ 106/ml were achieved in 90% (group I), 82% (group II) and 89% (group III) of subjects by week 24. Suppression was slower in group II, which also demonstrated more frequent escape from gonadotrophin suppression than groups I and III. Peak testosterone concentrations remained in the normal range throughout in all groups. Mean trough testosterone concentrations were initially subphysiological but increased into the normal range during treatment. Mean haemoglobin levels increased in group I, and a non-significant increase in weight and decline in high-density lipoprotein cholesterol was observed in all groups. Fourteen subjects discontinued treatment due to adverse events. CONCLUSIONS: Subcutaneous etonogestrel implants in combination with injectable testosterone decanoate resulted in profound suppression of spermatogenesis that could be maintained for up to 1 year. Efficacy of suppression was less in group II, probably due to inadequate testosterone dosage. This combination has potential as a long-acting male hormonal contraceptive. Key words: etonogestrel/gestogen/male contraceptive/spermatogenesis/testosterone decanoate Introduction The concept of hormonal male contraception is based upon the administration of exogenous steroid to suppress pituitary gonadotrophins, with the subsequent suppression of spermatogenesis (Anderson and Baird, 2002; Nieschlag et al., 2003; Kamischke and Nieschlag, 2004; Wang and Swerdloff, 2004). Earlier approaches involved the administration of androgen alone (World Health Organization Task Force on Methods for the Regulation of Male Fertility, 1990, 1996). However, low rates of spermatogenesis were maintained in approximately one third of Caucasians, with the resulting risk of pregnancy. Furthermore, supraphysiological androgen levels resulted in significant side-effects on skin, haematopoiesis and serum lipoproteins (Wu et al., 1996). The administration of a second agent, such as a progestogen, improves the degree of spermatogenic suppression and permits lowering of the dose of testosterone to nearer physiological replacement (Bebb et al., 1996; Handelsman et al., 1996; Meriggiola et al., 1996, 2002). Several progestogens have been investigated, including levonorgestrel (Bebb et al., 1996), cyproterone acetate (Meriggiola et al., 1996, 1998), 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), norethisterone (Kamischke et al., 2001, 2002) and desogestrel (Wu et al., 1999; Anawalt et al., 2000; Kinniburgh et al., 2002). Results with desogestrel have been promising, with near universal suppression of spermatogenesis. Etonogestrel, the active metabolite of desogestrel, is now licensed as a long-acting implant preparation for use as a female contraceptive (Implanon®). In addition to convenience and © The Author 2005. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: 285 B.M.Brady et al. optimum levels of compliance, administration as an implant may confer advantages over an oral preparation, allowing dose-sparing and avoiding liver exposure by bypassing firstpass metabolism, thus minimising adverse metabolic effects. This has indeed been demonstrated in a recent study using two 68 mg etonogestrel implants with depot testosterone (Anderson et al., 2002a). Despite using lower exposure to etonogestrel in comparison with oral desogestrel, similar efficacy in suppression of spermatogenesis was observed with reduced non-reproductive effects (Kinniburgh et al., 2002). In that study, suppression of spermatogenesis was greater with two implants than with one (75 versus 64% azoospermia). We therefore hypothesized that suppression of spermatogenesis may be improved by further increasing this dose by 50%, and two larger implants (each containing 102 mg etonogestrel) were administered in the present study. The lack of availability of a convenient long-acting injectable testosterone preparation has been a major obstacle to the development of hormonal male contraception. Previous studies with testosterone enanthate relied on weekly injection intervals. Not only may this be unacceptable to volunteers, but supraphysiological testosterone peaks were observed as well. Testosterone decanoate (TD) is one of the testosterone esters contained in Sustanon®, which has been used for several years in the treatment of hypogonadism. Preliminary data demonstrated that 400 mg administered every 4 weeks with etonogestrel implants resulted in good spermatogenic suppression (Anderson et al., 2002b). We therefore further explored the optimal dose of this androgen in three administration regimens: 400 mg every 4 weeks (group I), 400 mg every 6 weeks (group II) and 600 mg every 6 weeks (group III). This combination of TD with etonogestrel implants was investigated in a Phase IIb multicentre trial. The primary objective was to assess its effects on the suppression of spermatogenesis in the three treatment groups. Secondary objectives included evaluation of the suppression of gonadotrophins, the phar (...truncated)