Induction of azoospermia in normal men with combined Nal-Glu gonadotropin-releasing hormone antagonist and testosterone enanthate.

Abstract

The effects of a combined GnRH antagonist and testosterone (T) replacement regimen on gonadotropins and spermatogenesis were examined to assess its potential as a male contraceptive regimen. The potent Nal-Glu GnRH antagonist ([Ac-D2-Nal1,D4-Cl-Phe2,D3-Pal3,Arg5, D4-p-methoxybenzoyl-2-amino butyric acid6,D-Ala10]GnRH) was administered daily (7.5 mg, sc) to eight normal men for 16 weeks. T enanthate was given im starting at week 2 and every 2 weeks thereafter through week 14 of the treatment phase. Serum LH, FSH, T, and estradiol concentrations were measured frequently during the 5-week control period, the 16-week treatment phase, and the 14-week recovery phase. Semen analyses were performed every week during the control phase and every 2 weeks during the treatment and recovery phases. Seven of eight subjects became azoospermic by 6-10 weeks of treatment; the eighth subject, who failed to achieve azoospermia, suppressed his sperm count to 7 million/mL by week 14 (from a mean baseline of 42 million/mL) before treatment was prematurely terminated because of localized swelling at each of his injection sites. Sperm counts returned to baseline 10-14 weeks after the end of Nal-Glu administration. Seven of the eight subjects showed suppression of LH to the limit of assay detection (less than 0.2 U/L), whereas the eighth subject showed incomplete suppression. Serum bioactive and immunoreactive LH concentrations showed concordant responses. Mean serum FSH concentrations were also markedly suppressed. Serum T and estradiol concentrations declined dramatically during the first 2 weeks of Nal-Glu GnRH treatment, but returned to the normal physiological range after T enanthate replacement was initiated. Libido and sexual potency were maintained. No systemic side-effects, other than erythema and induration at injection sites, were observed. These data demonstrate that combined GnRH antagonist plus T treatment can predictably and reversibly induce azoospermia in most men and has potential as a male contraceptive regimen.

High Loading and Low Maintenance Doses of a Gonadotropin-Releasing Hormone Antagonist Effectively Suppress Serum Luteinizing Hormone, Follicle-Stimulating Hormone, and Testosterone in Normal Men1

“…Previously, it was believed that the development of the GnRH antagonist depot preparation is impracticable, as only GnRH antagonist doses of 7.5-20 mg/day effectively suppressed gonadotropins as well as sex hormones, whereas lower doses were ineffective (3)(4)(5)9). However, this study demonstrates that after an effective loading dose period, much smaller doses of the GnRH antagonist are sufficient.…”

“…However, we could show that GnRH agonists are not suited for male contraception because they do not cause a prolonged and effective FSH decrease and thus fail to suppress spermatogenesis in male volunteers (2). In contrast, the GnRH antagonist Nal-Glu given at relatively high doses of 7.5-20 mg/day caused a significant suppression of both gonadotropins and spermatogenesis (3)(4)(5). However, high daily doses of the GnRH antagonist Nal-Glu, which can result in local adverse side-effects, are impractical and too expensive for long term use.…”

Advances in Male Contraception

“…Initial very small trials investigated the GnRH antagonist Nal-Glu, administered by daily sc injection, in combination with testosterone to maintain peripheral androgenicity. In the first two trials, 14 of 16 subjects achieved azoospermia by 6 -10 wk of treatment (258,259). But a third small, randomized trial demonstrated no difference in azoospermia with TE plus Nal-Glu compared with TE alone, at least at the doses given (260).…”

Update on Male Hormonal Contraception: Is the Vasectomy in Jeopardy?

“…Several studies dating back to the early 1990s [88][89][90][91][92] suggest a rapid onset of suppression of spermatogenesis to azoospermia. This group of studies, each with small populations, suggested a good response to this combined therapy.…”