The treatment of idiopathic oligospermia and infertility is unsatisfactory; there is no successful therapy. A recent controlled study of the use of testolactone, an inhibitor of peripheral aromatization of androgen to estrogen, suggests that sperm count improves with administration of this drug. Testolactone increases serum testosterone, decreases serum estradiol and may increase gonadotropin levels in human males. There is controversy over whether testosterone acts in the negative feedback of LH and FSH secretion in its native form, after reduction to dihydrotestosterone or after aromatization to estradiol. Animal studies of the effects of testolactone on the hypothalamic-pituitary-gonadal axis have not been undertaken. I plan to study the effects of long term inhibition (nine months) of aromatization of androgen to estrogen on spermatogenesis and fertility and on pulsatile gonadotropin secretion in 60 oligospermic men. As there are no dose-response studies of testolactone in this population, the study will compare placebo treatment with two different dosages of testolactone in three groups of 20 patients. Additionally human studies will consist of comparing pulsatile secretion of LH and FSH and gonadotropin responses to GnRH stimulation in normal men and in men with odiopathic oligospermia, both before and after two weeks of testolactone therapy. Animal studies of the regulation of gonadotropin secretion by gonadal steroids will be performed in both in vivo and in vitro experiments. Specifically, castrated male rats will be given testolactone alone, testolactone and testosterone, or testosternone and estradiol with subsequent measurement of gonadal steroids and gonadotropins. Control for each experimental group will also be evaluated. Pituitary responsiveness to exogenous GnRH will also be determined in castrated male rats treated in the above manner. In vitro studies are designed to measure the effects of chronic inhibition of peripheral conversion of testosterone to estradiol on LH and FSH production and responsiveness to exogenous GnRH. The method of column perifusion of dispered pituitary cells will be used in these studies.
