Intramuscular testosterone undecanoate with or without oral levonorgestrel: a randomized placebo‐controlled feasability study for male contraception

Abstract

Approaches to hormonal male contraception are based on injectable testosterone esters alone or in combination with gestagens or GnRH analogs but the short half-life of clinically used testosterone esters have long hindered further development. This study was designed to prove the efficacy of the long-acting testosterone undecanoate ester (TU) alone or in combination with oral levonorgestrel (LNG) in a phase II clinical trial. Twenty-eight healthy men were randomized to receive injections of 1000 mg TU every 6 weeks in combination with daily oral LNG (250 μg) or daily oral placebo treatment over a period of 24 weeks, followed by a control period of 28 weeks. During the course of the study semen analysis, reproductive hormone analysis, analysis of clinical chemistry and lipid parameters, well-being and sexual function, sonography of scrotal contents and prostate were performed. Marked suppression of gonadotrophins in both treatment groups resulted in azoospermia in 8/14 and 7/14 volunteers and severe oligozoospermia (< 3 × 10¹²/l) in 4/14 and 7/14 in the placebo and gestagen treated groups, respectively. Time to induction of azoospermia (mean ± SEM) was not significantly different between the placebo (week 19.5 ± 2.2) and LNG groups (week 15.4 ± 2.2). During the whole treatment period mean testosterone serum concentrations remained within normal limits. Although not significant, it was evident that volunteers who became azoospermic had a better suppression of gonadotrophins and lower SHBG levels during treatment compared to non-azoospermic volunteers. Despite better gonadotrophin suppression in the LNG group no significant differences compared to placebo could be observed in the extent and kinetics of suppression of spermatogenesis, thus not demonstrating a major beneficial effect of LNG in the combination with injectable TU. Treatment led in both groups to a decrease of HDL and Lp(a) which was more pronounced in the LNG group (P > 0.05). Treatment with 1000 mg testosterone undecanoate injected at 6 weekly intervals or in combination with levonorgestrel showed suppression of spermatogenesis comparable to weekly injections of 200 mg testosterone enanthate. Because of its long half-life and in the absence of severe side-effects, testosterone undecanoate can be considered as first choice testosterone ester in further studies of hormonal male contraception.