Testosterone Undecanoate Maintains Spermatogenic Suppression Induced by Cyproterone Acetate Plus Testosterone Undecanoate in Normal Men

0021-972X/03/$15.00/0 Printed in U.S.A. The Journal of Clinical Endocrinology & Metabolism 88(12):5818 –5826 Copyright © 2003 by The Endocrine Society doi: 10.1210/jc.2003-030574 Testosterone Undecanoate Maintains Spermatogenic Suppression Induced by Cyproterone Acetate Plus Testosterone Undecanoate in Normal Men M. C. MERIGGIOLA, A. COSTANTINO, S. CERPOLINI, W. J. BREMNER, D. HUEBLER, A. M. MORSELLI-LABATE, B. KIRSCH, A. BERTACCINI, C. PELUSI, AND G. PELUSI Departments of Obstetrics and Gynecology (M.C.M., A.C., S.C., G.P.), Internal Medicine (A.M.M.-L., C.P.), and Urology (A.B.), S. Orsola-Malpighi Hospital and University of Bologna, 40138 Bologna, Italy; Department of Medicine, University of Washington (W.J.B.), Seattle, Washington 98108; and Jenapharm (D.H., B.K.), D-07745 Jena, Germany In this study we evaluated whether testosterone undecanoate (TU), alone or combined with low dose cyproterone acetate (CPA), can maintain spermatogenic suppression induced by higher doses of CPA plus TU. Twenty-four men received for 12 wk 20 mg/d CPA plus 1000 mg/6 wk TU and then 1000 mg/8 wk TU plus 20 mg/d CPA (n ⴝ 8), 2 mg/d CPA (n ⴝ 8), or plus placebo (n ⴝ 8) for 32 wk. Blood samples, physical examinations, hormones, chemistry, hematology, semen analysis, and sexual/ behavioral assessments were performed throughout the study. Sperm counts decreased to less than 1 million/ml in all subjects by wk 12, and 54% of them achieved azoospermia. Suppression of sperm counts was maintained until wk 44. T HERE IS A general concern about long-term steroid intake, and in both in females and males, the aim of hormonal contraceptive research is to find the lowest hormonal dose that would allow reliable contraception and at the same time maximally reduce the incidence of complications and the likelihood of developing long-term side effects (1– 4). Most recently developed androgen-progestin combinations have been shown to be highly effective in terms of sperm suppression and fully reversible contraceptive regimens in men (5–15). In the short-term, these hormonal combinations do not induce any major changes in clinical and laboratory parameters, thus promising to also be safe for long-term use (1). Therefore, androgen-progestin regimens hold great promise to be further developed and become a real option for contraception in the male. Establishing the minimum effective combined dose of the two steroids of this contraceptive regimen would further improve its long-term safety. Among recently tested prototype androgen-progestin regimens, the combined administration of CPA plus low dose testosterone enanthate (TE) proved to induce rapid and profound sperm suppression (5, 16, 17). However, the need for weekly injections of TE would not be acceptable for contraception. Moreover, although no major changes in laboratory parameters were detected with this prototype regimen, a Abbreviations: CI, Confidence interval; CPA, cyproterone acetate; E2, estradiol; HDL, high-density lipoprotein; PRL, prolactin; PSA, prostate-specific antigen; T, testosterone; TE, testosterone enanthate; TU, testosterone undecanoate. Serum LH and FSH levels were suppressed by wk 12 of hormone administration and remained suppressed until wk 44. No significant changes in any biochemical parameters were detected at wk 44 in any group. There was a slight increase in total prostate volume to within the normal range at wk 44 that returned to baseline 1 yr after stopping hormone administration. In conclusion, TU alone or combined with lower doses of CPA maintains sperm suppression induced by higher dose CPA plus TU for 32 wk. This prototype regimen represents a promising male contraceptive regimen. (J Clin Endocrinol Metab 88: 5818 –5826, 2003) decrease in hemoglobin and hematocrit was found that seemed to be dependent on the antiandrogenic activity of CPA and that would certainly decrease the acceptability of such a regimen. The recent development of the long-acting injectable testosterone undecanoate (TU) formulation represents a major breakthrough in the andrology field and in particular will greatly improve hormonal contraceptive regimens. With this preparation, testosterone (T) levels can be maintained within the physiological range for 12 wk in hypogonadal men (18). The reduction of supraphysiological testosterone peaks that were present with previously used im T preparations will contribute to improving sperm suppression and reducing androgen-related side effects. TU has been used in male contraceptive trials alone or in combination with the progestins levonorgestrel or norethisterone enanthate (19 –21). In these studies it has proved to be at least as effective as previously tested androgens, such as TE, but is more acceptable because of the longer injection intervals at which it can be administered. Preliminary studies in nonhuman primates and in humans have suggested that sperm suppression induced with a higher hormonal load can be maintained with a lower hormonal dose (22, 23). This maneuver would allow for the use of higher hormonal doses for a short period of time needed to induce a rapid and profound sperm suppression that can be maintained by lower, and probably safer for long-term use, hormonal doses. Therefore, in the present study we tested whether the long-acting T preparation TU, alone or in combination with 5818 Meriggiola et al. • Low Hormonal Dose Maintains Sperm Suppression lower CPA doses, could maintain sperm suppression induced with higher dose CPA and TU for 12 wk. Subjects and Methods Population Twenty-four Caucasian male subjects, aged 18 – 45 yr, were enrolled in the study (Table 1). All men were healthy by medical history, clinical examination, and routine clinical chemistry. They had normal reproductive function as assessed by reproductive hormones and semen analysis. All volunteers signed the consent form to participate in the trial. The ethics committee of the S. Orsola Hospital and University of Bologna approved the study. Study design A prospective, monocentric, randomized, controlled, and singleblind design was used. The study consisted of a baseline phase lasting at least 4 wk, a treatment phase lasting 44 wk, and a recovery phase that lasted until each subject had at least two sperm counts within his own baseline range. The treatment phase was divided into a suppression phase that lasted 12 wk and a maintenance phase that lasted 32 wk. Baseline phase. During this period volunteers provided three seminal fluid samples and three fasting blood samples. They filled out a sexual and behavior questionnaire three times (wk ⫺4, ⫺2, and 0) and underwent a transrectal prostatic ultrasound. Suppression phase. During this period all 24 subjects received 20 mg/d CPA, orally, and 1000 mg TU injected every 6 wk until wk 12. Maintenance phase. At wk 12, all volunteers were randomly divided into three groups to receive 1000 mg/8 wk TU plus 20 mg/d CPA (CPA-20; n ⫽ 8 subjects), plus 2 mg/d CPA (CPA-2; n ⫽ (...truncated)