Hormonal effects of gonadotropin-releasing hormone (GnRH) agonist in men: effects of long term treatment with GnRH agonist infusion and androgen.
Constant infusion of GnRH agonist (GnRH-A) leads to far greater suppression of spermatogenesis and gonadotropins in the monkey than its intermittent administration. We assessed if greater suppression of gonadotropins and spermatogenesis could also be achieved in man by continuous GnRH-A administration. Seven normal men were given 400 micrograms GnRH-A daily by constant sc infusion using a mechanical pump device and bimonthly injections of 200 mg testosterone (T) enanthate for 16 weeks. Basal serum LH, FSH, T, and estradiol concentrations were measured every week during a 5-week control period, daily on treatment days 0, 1-11, 14, 18, 22, 26, 28, and every week thereafter until day 56, and every 2 weeks thereafter during the remainder of the treatment phase and during the 14-week recovery phase. Detailed analysis of LH and FSH secretion during 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 control phase and every 2 weeks during the treatment and recovery phases. The mean sperm count declined by 93% to a nadir of 6 +/- 3 (+/- SE) million/mL between weeks 14-16. Four men had sperm counts less than 1 million/mL, and three subjects were azoospermic during treatment. Basal serum immunoreactive LH concentrations, after an early increase, declined to near baseline by day 14. The basal and 24-h integrated serum LH concentrations and 24-h urinary LH excretion were not significantly lowered by treatment. Bioassayable serum LH concentrations, however, after an early rise, declined significantly below baseline by day 28 and remained low thereafter. The frequency and amplitude of LH pulses were reduced by GnRH agonist infusion. Basal and 24-h integrated serum FSH concentrations, after a brief initial increase, declined to baseline by day 10, but were not significantly below baseline by day 112. Serum T concentrations did not fall into the hypogonadal range at any time during the treatment period. After discontinuation of treatment, serum LH and FSH and sperm counts returned to normal in all men. Thus, this regimen, employing constant infusion of 400 micrograms GnRH agonist daily plus T led to a greater suppression of spermatogenesis than the previous regimen employing single daily injections of 200 micrograms of the same agonist plus T. Whether the higher dose or the constant infusion was responsible for the greater inhibition of spermatogenesis is not clear. It is conceivable that a still higher dose of the agonist, given by constant infusion, might induce azoospermia in all men.