An Effective Hormonal Male Contraceptive Using Testosterone Undecanoate with Oral or Injectable Norethisterone Preparations

Abstract

Suppression of spermatogenesis to azoospermia is the goal of hormonal male contraception based on T combined with gestagens. The combination of the long-acting T, ester testosterone undecanoate (TU), with norethisterone (NET) enanthate (E) showed high efficacy. In the present study, we tested the validity of this approach by varying the NET dose and mode of application. The aim of the study was to achieve high rates of suppression of spermatogenesis as reflected by sperm counts, monitor gonadotropins as well as other hormones, and evaluate any possible side effects. In a phase II clinical trial, groups of normal volunteers received: 1000 mg TU im at wk 2, 6, 12, and 18 combined with 200 mg NETE im at wk 0, 6, 12, and 18 (group I); 1000 mg TU im and 400 mg NETE im at wk 0, 6, 12, and 18 (group II); and 1000 mg TU im at wk 0, 6, 12, and 18 with daily oral NET acetate (NETA) from wk 0 to 24 (group III). In all groups marked suppression of gonadotropins resulted in a significant decrease of spermatogenesis and azoospermia in 13/14, 11/12, and 12/14 men in groups I to III, respectively. The remaining men all had less than 1 million sperm/ml. Reversible side effects included increase in body weight, erythrocytes, hemoglobin, and hematocrit and decrease in high-density lipoprotein cholesterol and alkaline phosphatase in all groups and increase in liver enzymes in the oral NETA group. This study documents the high efficacy of TU in combination with NET and confirms that this dose and mode of application (1000 mg TU im every 6 wk plus 400 mg NETE im every 6 wk or plus 10 mg daily oral NETA) is as effective as the previously reported regimen containing 1000 mg TU + 200 mg NETE im every 6 wk. The contraceptive efficacy of this combination of TU and NETE should be evaluated in further clinical trials.

Hormonal male contraception in men with normal and subnormal semen parameters

“…Before the study was initiated, TU had been shown to be well suited for male contraception. In the first hormonal male contraceptive trial applying TU, this ester was given alone or in combination with NETE or LNG and resulted in an azoospermia rate of 7/14, 13/14 and 8/14, respectively (Kamischke et al. , 2001, 2002).…”

“…Sonographic measurements of testes and prostate volumes were performed by applying a high frequency 7.5‐MHz sector scanner as published previously (Kamischke et al. , 2002; Behre & Zitzmann, 2010).…”

“…Gonadotropins, prolactin, testosterone, estradiol, SHBG and Prostate specific antigen (PSA) were determined at the IRM hormone laboratory by commercial highly specific time‐resolved fluoroimmunoassays and ELISA methods as chosen previously. Intra‐ and interassay coefficients of variations were below 5 and 10%, respectively (Kamischke et al. , 2002).…”

“…in the severely oligozoospermic range – may induce pregnancies at an unacceptably high rate (WHO Task Force, 1996). To achieve azoospermia uniformly in Caucasian men as well, testosterone has to be combined with other hormonal agents of which gestagens are currently favoured over effective GnRH antagonists, as they are easily available in depot preparations and exert few side effects (Kamischke et al. , 2001, 2002; Anderson & Baird, 2002; Nieschlag, 2010; Nieschlag & Behre, 2010).…”

Hormonal Contraception in Men

“…There appeared to be no increase in spermatogenic suppression in these two extra study groups, but these subjects did experience a higher degree of possible gestogenic-related side effects from the higher NET doses, including increased nocturnal sweating. All three groups were also subject to apparent androgenrelated side effects of raised haemoglobin, haematocrit and weight [71].…”