Hormonal Effects of Gonadotropin-Releasing Hormone (GnRH) Agonist in the Human Male. III. Effects of Long Term Combined Treatment with GnRH Agonist and Androgen*

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Abstract
Chronic treatment with agonist analogs of GnRH results in reversible oligospermia i man, but leads to impotence and decreased libido due to a concomitant fall in serum testosterone(T) concentrations. We, therefore, assessed the effects of combined treatment with a potent GnRH agonist and T on gonadotropins and spermatogenesis in normal men, anticipating that addition of androgen would prevent agonistinduced changes in libido. Seven normal men were treated with 200 fig of the GnRH agonist D-(Nal2)6GnRH (GnRH-A), sc, daily for 16 weeks. In addition, 200 mg T enanthate were administered every 2 weeks for the entire 16-week treatment period. Basal LH, FSH, and T concentrations were measured every week during a 5-week control period, daily on treatment days 0, 1-10, 14, 18, 22, 26, and 28, every week thereafter until day 56, and every 2 weeks thereafter for the remainder of the treatment and recovery phases. Detailed analysis of LH and FSH over the 24-h period was performed by multiple blood sampling on days 0, 1, 10, 28, 56, 84, and 112. Semen analyses were performed every week during the controlphase and every 2 weeks during the treatment and recovery phases. The mean sperm count declined by 83‰, to a nadir of 16.6 ± 6.2 (±SEM) million⁄ml. One subject hadno significant decrease in sperm count. Azoospermia was not achieved in any subject. Basal serum LH concentrations, after an early phase of stimulation, declined to near baseline by day 14. However, basal, 24- h integrated serum LH concentrations, and 24-h urinary LHexcretion were not significantly lowered by combined treatment. Bioassayable serum LH concentrations, however, declined significantly from 20.4 ± 6.3 to 4.5 ± 0.5 mlU⁄ml, and the bioassayableto immunoassayable LH ratio decreased from 2.1 ± 1.0 to 0.7 ± 0.1after 16 weeks ofGnRH-A treatment. Basal and 24- h integrated FSH concentrations, after an initial period of stimulation, declined progressively to baseline by days 5-6 and were significantly below baseline by day 112. Serum T concentrations did not fall into the hypogonadal (<250 ng⁄dl) rangein any subject at any time during the treatment period. After discontinuation of treatment, LH, FSH, and sperm counts returned to normal in all subjects. Thus, single daily injection of GnRH-A and T failed to predictably induce azoospermia in normal men over the 16-week treatment period. GnRH-A treatment led to marked decreases in bioassayable LHconcentrations, but little or no change in immunoassayable LH concentrations, suggesting secretion of molecularly altered LH species with diminished biological activity.