Androgen-receptor blockade enhances pulsatile luteinizing hormone production in late pubertal males: Evidence for a hypothalamic site of physiologic androgen feedback action

To determine potential mechanisms by which androgens alter gonadotropin secretion and elimination in the pubertal male, we administered the potent nonsteroidal androgen receptor blocking agent, flutamide, to eight males with Tanner IV or V genital development. Venous blood samples were obtained every 10 min for 24 h and assayed for LH by a sensitive and high-precision fluorimmunoassay. Subjects were studied before and after the administration of flutamide. Deconvolution analysis was used to assess specific pulsatile LH secretory characteristics and estimate LH production and metabolic clearance rates quantitatively. After antagonism of endogenous androgen action, mean 24-h serum LH concentrations increased significantly. An increased mean 24-h LH production rate, without evident changes in serum LH half-life, accounted for the increase in average serum LH levels. The increased daily secretion rate of LH was in turn due to both an augmented mass of LH released per secretory episode and increased frequency of secretory events. There was no demonstrable change in the maximal rate of LH secretion attained within each secretory event. Serum concentrations of total testosterone, free-testosterone, and 170-estradiol all increased during blockade of androgen action. Administration of the antiandrogen had no measurable effect on the pituitary response to a single maximally effective dose of exogenous gonadotropin releasing hormone (GnRH). These results indicate that, in the late pubertal male, endogenous androgen exerts negative feedback control of gonadotropin secretion primarily at a hypothalamic site reflected by regulation of the frequency of pulsatile LH secretion. Antiandrogen had no discernible effects on exogenous GnRH-stimulated pituitary LH release or on the elimination rate of LH, but amplified the mass of LH secreted in response to endogenous GnRH. Assuming that pituitary response to exogenous GnRH reflects responsivity to endogenous releasing factor, we can infer an augmentation of the endogenous GnRH stimulus when androgen negative feedback is withdrawn. Accordingly, we suggest that endogenous androgen acting via androgen receptors negatively regulates both the amount and frequency of hypothalamic GnRH release in late pubertal boys.