Uremic hypogonadism is characterized in the male by low testosterone and elevated gonadotropin levels suggesting a primary testicular disturbance. It is uncertain, however, whether the magnitude of the gonadotropin increase is appropriate for the degree of depression of testicular function or is impaired by a coexisting hypothalamic - pituitary disturbance. Indeed, clomiphene, a nonsteroidal estrogen antagonist which increases hypothalamic gonadotropin releasing hormone (GnRH) secretion, results in normalization of testosterone levels in uremic men. No detailed studies of GnRH secretion are available in uremia. Zinc supplementation also reverses uremic hypogonadism. The mechanism of zinc action may involve the correction of a deficiency state and/or antagonizing the effect of toxins on the hypothalamic-pituitary-testicular axis. No direct assessment of the effect of zinc on the testes or on GnRH secretion has been reported. Finally, zinc may act by suppressing uremic hyperprolactinemia. The objectives of this proposal are: I. To evaluate the central regulation of gonadotropin secretion in uremia; II. To assess the short and long term effect of zinc on gonadal function in uremic men, the time course of such an effect and its mechanism(s); III. To compare the effects of zinc and bromocryptine mediated prolactin suppression on the gonadal axis in uremia. 40 dialysed uremic men 20 to 50 years old will undergo four sets of studies in the baseline state, after 5 days of treatment with pulsatile GnRH (20 ng/kg q 2h), after 10 days of treatment with clomiphene citrate (100 mg p.o. BID), and at 2 months intervals during and after six months of randomized administration of placebo, zinc sulfate (25 mg elemental zinc p.o. BID), clomiphene, or bromocryptine (2.5 mg p.o. BID). A testicular biopsy and NPT will be performed at the beginning and the end of the study. 20 healthy male subjects will undergo the baseline study of LH and testosterone secretion. LH and testosterone secretion will be assessed by blood sampling every 10 min for 12 hours, and LH pulsatility will be assessed using the CLUSTER program; Prolactin studies will assest the prolactin response to 100 and 500 ug of TRH and to 10 mg of metoclopramide; Testicular response to HCG will be assessed by measuring the testosterone response to 2000 U of HCG at 12, 24 and 48 hours and zinc status by measurement of plasma and hair zinc contents. Each patient will be his own control between the different phases of the study and comparisons between groups of patients on different treatments will be performed using 2-way analysis of variance after logarithmic transformation of the data.
