The importance of androgens in establishing and maintaining sexual function in males of most species is well recognized. Estrogens also stimulate male sexual function in some species. In men, most studies of androgen effects on behavior have used hypogonadal men as an experimental model; much less is known about the role of endogenous testosterone (T) or estradiol (E(2)) in the regulation of behavior in healthy, eugonadal men. In a randomized, double-blind study, we used a GnRH antagonist, Nal-Glu, without T replacement, to induce acute, profound, reversible gonadal steroid deficiency in 9 normal men for 6 weeks (Nal-Glu alone). We also studied the effects of partial androgen replacement by administering Nal-Glu together with T enanthate, 50 mg im weekly, to 10 other men. A third group of 10 men received Nal-Glu plus T, 100 mg im weekly. We studied the role of endogenous E(2) by administering Nal-Glu plus T, 100 mg im weekly, plus an aromatase inhibitor, testolactone (Teslac), 250 mg po qid, to 10 additional men (Nal-Glu+T+Teslac). Nine men received placebo injections and tablets. All subjects completed a behavioral questionnaire during the pretreatment period, at weeks 2, 4, and 6 of treatment, and at 3 weeks posttreatment. Men who received Nal-Glu alone became profoundly hypogonadal within 1 week after treatment began. Serum T levels did not change significantly in the controls and in the men who received full T replacement but decreased to approximately half the baseline level in men who received partial T replacement. E(2) levels decreased profoundly in men who received Nal-Glu alone or Nal-Glu+T+Teslac and to a lesser degree in men who received partial T replacement. In men who received Nal-Glu alone, there were clinically and statistically significant decreases in the frequency of sexual desire, sexual fantasies, and intercourse at 4-6 weeks. These men also showed a strong trend (P = 0.55) towards decreased spontaneous erections after 4 and 6 weeks of treatment. A significant decrease in the frequency of masturbation was evident after 6 weeks. All measures returned to normal by posttreatment week 3. There was a trend toward increased aggression in the hypogonadal men, but this did not reach statistical significance. No changes in satisfaction or happiness with their partners were observed. There were no significant changes in any behavioral parameter during the study in men who received any of the other regimens. Our data confirm the importance of physiological levels of T in maintaining sexual behavior in normal men. They also demonstrate that the effects of acute hypogonadism are not manifested immediately, but they become clinically and statistically significant after 4-6 weeks of androgen deficiency. Sexual function is restored at approximately the same time that serum T returns to normal levels. Our data also show that in experimentally hypogonadal men, replacement of androgens at a dose of 50 mg/week is adequate to maintain normal sexual function and behavior, and that circulating levels of E(2) have a limited role in the regulation of sexual behavior in normal men. The model of acute, reversible hypogonadism induced by GnRH antagonists plus varying amounts of androgen replacement offers an excellent in vivo bioassay for assessing androgen effects in men.
