Intramuscular Testosterone Undecanoate and Norethisterone Enanthate in a Clinical Trial for Male Contraception

0021-972X/00/$03.00/0 The Journal of Clinical Endocrinology & Metabolism Copyright © 2000 by The Endocrine Society Vol. 86, No. 1 Printed in U.S.A. Intramuscular Testosterone Undecanoate and Norethisterone Enanthate in a Clinical Trial for Male Contraception* AXEL KAMISCHKE, STEFAN VENHERM, DANIELA PLÖGER, SIGRID VON ECKARDSTEIN, AND EBERHARD NIESCHLAG Institute of Reproductive Medicine, University of Münster, D-48129 Münster, Germany ABSTRACT Recent trials for hormonal male contraception are based on gestagens or GnRH antagonists combined with oral or injectable testosterone substitution. However, the efficacy of most trials remained disappointing. Norethisterone enanthate (NETE) has been used as a long-acting injectable female contraceptive and has shown sustained suppression of spermatogenesis in male monkeys and prolonged suppression of gonadotropins in men. This study was designed to prove the efficacy of the long-acting testosterone undecanoate ester (TU) alone or in combination with NETE in a phase II clinical trial. Fourteen healthy men received injections of 1000 mg TU in combination with injections of 200 mg NETE every 6 weeks over a period of 24 weeks, followed by a control period of 28 weeks. Another 14 volunteers received TU alone. During the study semen variables, reproductive hormones, clinical chemistry and lipid parameters, well-being, and sexual function were monitored. Scrotal content and prostates were checked sonographically. During the entire treatment period mean testosterone serum concentrations remained within the normal limits. Marked suppression of gonadotropins in both treatment groups resulted in azoospermia in 7 of 14 and 13 of 14 volunteers and in oligozoospermia in 7 of 14 and 1 of 14 in the groups given TU only or TU/NETE, respectively. However, the highest azoospermia rate in the TU/NETE group was achieved 8 weeks after the end of the treatment period, and 1 volunteer with very high initial sperm counts (mean, 190 million/mL at baseline) remained oligozoospermic (10.2 million/mL). From week 20 to week 24 there was a significant, fully reversible maximum weight gain of 3.7 kg, on the average, in the NETE group. In the NETE and TU alone groups there were significant 26.6% and 11.5% maximum decreases in high density lipoprotein cholesterol compared with baseline values during the treatment period. A significant elevation of low density lipoprotein and a decrease in lipoprotein(a) were detected in the TU/NETE group. In conclusion, combination treatment with NETE showed suppression of spermatogenesis comparable with results using testosterone esters in combination with GnRH antagonists or cyproterone acetate, but had more favorable injection intervals and better efficacy. Because of its long-lasting, profound suppression of spermatogenesis and the absence of serious side-effects, the combination of TU and NETE can be considered a first choice for further studies of hormonal male contraception. (J Clin Endocrinol Metab 86: 303–309, 2000) T HE GOAL OF hormonal male contraception is the suppression of spermatogenesis to azoospermia. Initial studies were based on weekly injections of testosterone enanthate, and they achieved suppression of spermatogenesis in about two thirds of Caucasian and almost all Chinese volunteers (1, 2). For better efficacy, testosterone was combined with different gestagens (for a review, see Ref. 3). However, despite better gonadotropin suppression, suppression of spermatogenesis remained unsatisfactory in most of these studies (4 – 6) or, as in the case of cyproterone acetate, produced an unwanted decline of red blood cell production (7, 8). Therefore, the search for more appropriate gestagens continues. In addition, most regimens tested to date are based on impractical weekly or biweekly im injections of testosterone enanthate, as injection-free approaches, such as oral or transdermal testosterone application, were not successful (6, 9, 10). Apart from testosterone implants (11), to date only the injectable testosterone esters, testosterone undecanoate (TU) (12–17) and testosterone buciclate (18), have half-lives long enough to warrant long injection intervals and, hence, long-term acceptance. In a phase II clinical trial for hormonal male contraception we evaluated injectable TU in combination with norethisterone enanthate (NETE). NETE has proven useful in female contraception and showed rapid and sustained suppression of serum FSH and testosterone levels in males (19, 20). NETE was also chosen because it produces partial androgenic effects in women, which might be of advantage in male contraception. Subjects and Methods Subjects The study consisted of 3 arms, each comprising 14 volunteers. All volunteers received im injections of TU. In addition, 1 group received oral levonorgestrel, the second was given oral placebo, and the third group received im NETE injections. While results from the first 2 groups have been published previously (17), we report here the results from the NETE group and again include the placebo group for comparison. The study was approved by the ethics committee of the University and the State Medical Board (Münster, Germany). All volunteers gave written informed consent to participate in the study. Caucasian men, aged 18 – 45 yr, were recruited by local press advertisement and were examined for normal general medical history; normal physical condition; normal blood values for routine clinical chemistry, lipids, hematology, and reproductive hormones; and normal semen Received February 15, 2000. Revision received June 23, 2000. Rerevision received August 25, 2000. Accepted September 12, 2000. Address all correspondence and requests for reprints to: Prof. Dr. Eberhard Nieschlag, Institute of Reproductive Medicine, University of Münster, Domagkstrasse 11, D-48129 Münster, Germany. E-mail: . * This work was supported in part by the Bundesministerium für Gesundheit; the Deutsche Forschungsgemeinschaft Confocal Research Group, “The Male Gamete: Production, Maturation, Function” (Ni 130/ 15); and the Medical Faculty Münster (IZKF, Project A3). 303 304 JCE & M • 2000 Vol. 86 • No. 1 KAMISCHKE ET AL. parameters. Volunteers with clinically relevant abnormalities of the above-mentioned parameters were excluded, and the remaining volunteers were again screened for fulfillment of the inclusion criteria. All 28 volunteers finished the study. Study design After the 2 screening visits, all volunteers received im injections of 1000 mg TU dissolved in 4 mL castor oil in study weeks 0, 6, 12, and 18. In addition, at the same intervals 14 volunteers received 200-mg NETE (dissolved in 1 mL castor oil) injections or daily oral placebo treatment over 24 weeks. Examinations consisting of general and genital examination; evaluation of adverse events; measurements of blood biochemistry, lipid profile, hematology, sex hormone-binding globulin (SHBG), prostate-specific antigen (PSA), and reproduct (...truncated)