Low dose of cyproterone acetate and testosterone enanthate for contraception in men.

Human Reproduction vol.13 no.5 pp.1225–1229, 1998 Low dose of cyproterone acetate and testosterone enanthate for contraception in men M.Cristina Meriggiola1,3, William J.Bremner2, Antonietta Costantino1, Giulio Di Cintio1 and Carlo Flamigni1 1Department of Obstetrics and Gynecology and Core Lab, S.Orsola Hospital, University of Bologna Italy and 2Department of Veterans Affairs, Puget Sound Health Care System, Population Center for Research in Reproduction and Department of Medicine, University of Washington, Seattle, WA, USA 3To whom correspondence should be addressed at: I Clinic of Obstetrics and Gynecology, S. Orsola Hospital, Via Massarenti 13, 40138 Bologna, Italy After a control phase, 10 normal men received cyproterone acetate (CPA) at a dose of 25 mg/day (CPA-25; n J 5) or 12.5 mg/day (CPA-12.5; n J 5) plus testosterone enanthate (TE) 100 mg/week, for 16 weeks. Throughout the study sperm counts were performed every 2 weeks, and luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone, biochemical and haematological tests were performed every 4 weeks. All five men in group CPA-25 and three men in group CPA-12.5 achieved azoospermia. One man in group CPA-25 was azoospermic by week 12 of hormone administration, but had a sperm count of 0.1H106/ml at week 16. Time to azoospermia was 9.0 K 1.3 and 8.7 K 0.7 weeks in groups CPA-25 and CPA-12.5 respectively. Gonadotrophins were decreased by week 4 of hormone administration, remained around the minimum detectability of the assay for the duration of hormone administration and returned to baseline after stopping hormone administration. Testosterone values did not change. No change in any biochemical parameters was found. Haematological parameters were decreased at week 16 of hormone administration and returned to baseline after stopping hormone administration. In conclusion, these results suggest that an hormonal regimen consisting of testosterone plus a progestin with anti-androgenic properties holds promise as an effective, safe and reversible male contraceptive. Key words: contraception/cyproterone acetate/gonadotrophins/ spermatogenesis/testosterone Introduction Recent studies have shown that the administration of a progestin in combination with an androgen is more effective than that of an androgen alone in suppressing spermatogenesis (Bebb et al., 1996; Meriggiola et al., 1996; Meriggiola and Bremner, 1997). The rationale for this hormonal combination is based on the additive effect of these two compounds in suppressing © European Society for Human Reproduction and Embryology gonadotrophins and therefore spermatogenesis. Because of this combined effect, the addition of a progestin allows the use of lower and more physiological doses of testosterone without reducing the suppression of gonadotrophins. This would minimize the incidence of androgen-related side-effects. Research in this field is aimed at both defining the minimum testosterone dose and at selecting the optimal progestin to be used in contraceptive regimens for men. Among all compounds tested so far, the progestin that has provided the best results both in terms of spermatogenic suppression and in terms of absence of adverse effects is cyproterone acetate (CPA) (Roy et al., 1976; Roy, 1985; Meriggiola et al., 1996). In combination with testosterone enanthate (TE), CPA at high doses induces a more profound, rapid and consistent suppression of spermatogenesis than other regimens. No adverse effects on metabolic parameters were reported except a slight decrease in body weight and in haematological parameters, which seemed to be dependent on the dose of CPA. These effects could be due in part to the fact that CPA is also an anti-androgen. In the work reported here, we studied the effects of lower doses of CPA than those administered previously in combination with the same dose of TE (100 mg/week), on spermatogenesis, gonadotrophins and metabolic and haematological parameters. Materials and methods Subjects Ten normal Caucasian men, aged 19–42 years (31.4 6 2.1; mean 6 SE) were enrolled in this study. All men were healthy by medical history, physical examination and screening laboratory tests. All of the men had basal sperm counts of .203106/ml as well as gonadotrophins and testosterone concentrations within the normal range. The study was approved by the Ethical Committee of the S.Orsola Hospital in Bologna, and each man signed an informed consent form. Clinical protocol The study protocol consisted of a control period, a 16 week treatment period and a recovery period that lasted until subjects had at least two sperm counts within their own baseline range. During the control phase, subjects provided three seminal fluid samples separated from each other by ù7 days. Three fasting blood samples separated by at ù1 week were obtained. During the treatment phase, the subjects provided seminal fluids every 2 weeks and fasting (ù10 h) blood samples every 4 weeks. Blood samples were obtained immediately before the weekly injections of TE were administered. Samples were stored at –20°C until assayed. Every 4 weeks, volunteers attended the clinic to undergo physical examination, weight and blood pressure 1225 M.C.Meriggiola et al. Figure 1. Mean 6 SE sperm concentration at baseline, throughout treatment period and during the recovery phase in the two groups of men: cyproterone acetate (CPA)-25, d; CPA-12.5, j. recording. Volunteers were also asked to complete a sexual and behavioural questionnaire each month (Bagatell et al., 1994). After the control period, subjects were randomly assigned to receive: (i) CPA 25 mg/ day orally, plus TE 100 mg/week i.m. (CPA25); or (ii) CPA 12.5 mg/ day orally, plus TE 100 mg/week (CPA12.5). TE (Test-enant; Geymonat, Frosinone, Italy) was administered in a sesame oil suspension of 1 ml i.m. weekly. CPA (Androcur, Schering, Italy) was taken orally. Measurements Semen samples were analysed according to World Health Organization (WHO, 1992) guidelines. Azoospermia was defined as no spermatozoa found in a sample after centrifugation and analysis of the pellet. Recovery of sperm count was calculated considering the first of at least two sperm counts within the baseline range of each subject. Recovery was considered complete when each subject had at least two sperm counts within his own baseline range. Estimation of testis size was performed by orchiometer. Luteinizing hormone (LH) and follicle stimulating hormone (FSH) and testosterone were measured according to previously described methodologies (Meriggiola et al., 1996). The sensitivity of the LH assay was 0.1 IU/l. The sensitivity of the FSH assay was 0.3 IU/l. Haematology (haemoglobin, haemato- 1226 Figure 2. Mean 6 SE values of luteinizing hormone (LH), follicle stimulating hormone (FSH) and testosterone levels throughout the study periods in the cyproterone acetate (CPA)-25 (d) and CPA12.5 (j) groups. crit, red blood cell), chemistry (total cholest (...truncated)