Counteractive effects of agonistic and antagonistic gonadotropin-releasing hormone analogs on spermatogenesis: sites of action.

Both gonadotropin-releasing hormone (GnRH) agonistic and antagonistic analogs have been shown to inhibit reproductive hormonal function. While predictable and complete suppression of spermatogenesis is the ultimate goal of a number of clinical studies aimed at developing male contraceptive agents based on GnRH analogs, neither class of analog has been shown to completely inhibit spermatogenesis in man. The potential for a synergistic interaction of submaximal doses of these two classes of GnRH analogs was investigated in the present studies. In these studies 200 ng/day of a potent agonist (D-Leu6des-Gly10GnRH ethylamide) and 100 micrograms/day of a potent antagonist (NAc-L-Ala1, pCl-D-Phe2, D-Trp3,6GnRH) were administered subcutaneously, both alone and in combination, to adult male rats for 21 days. Serum gonadotropins and testosterone, pituitary GnRH receptor content, gonadal gonadotropin receptors, and intratesticular sperm counts were quantitated in each treatment group. Despite the ability of both GnRH agonists and antagonists to inhibit reproductive function when administered as single agents in this study, combined treatment with the two classes of GnRH analogs was less effective than either agent alone at these doses in the pharmacologic suppression of spermatogenesis.