Interrelationship between excessive levels of circulating androgens in blood and ovulatory failure.

The association of excessive circulating androgens in blood and ovulatory failure in women is well documented in a variety of clinical conditions. The restoration of ovulatory function by wedge resection of the polycystic ovary, by the administration of glucocorticoids or removal of tumors of the adrenal or ovary--measures that also reduce the level of circulating androgens--is also well documented. In view of the many hypotheses of adrenal and ovarian abnormalities and disorders of the hypothalamic-pituitary axis in the human, resulting in hirsutism and ovulatory failure, a normal intact rat model was developed to study the effect of androgens on ovulation. The administration of a weak androgen, dehydroepiandrosterone (DHA), to immature rats resulted in a single precocious ovulation followed by ovulatory failure. The conversion of DHA to estrogens appeared to be the principle mechanism for the precocious ovulation. The steps appeared to be an elevation in blood estradiol, followed by the depletion of cytoplasmic estradiol receptors of the hypothalamus and pituitary and the gonadotropin surge leading to ovulation. These events appeared to be similar to those occuring in the adult cycling rat, in precocious puberty induced by the administration of pregnant mare serum gonadotropins and during the onset of natural puberty. The role of estrogens in inducing the precocious ovulation was further supported by the absence of precocious ovulation in animals in which the conversion of DHA to estrogens was blocked or by administering androgens that could not be converted to estrogens. In contrast, the subsequent ovulatory failure could not be explained entirely by the conversion of DHA to estrogens. There was a considerable time lag between the withdrawal of DHA treatment and the replenishment of pituitary and hypothalamic cytoplasmic estradiol receptors. Unlike those of the cycling animal, the receptors were not replenished when the levels of circulating estradiol in blood receded. The replenishment occurred only after the circulating levels of androstenedione, DNA and progesterone were reduced. Receptor replenishment in the hypothalamus and pituitary was followed by increases in the levels of circulating gonadotropins, particularly LH, with subsequent restoration of cyclic ovulatory function. The ovaries in the acyclic androgen-treated rat were responsive to gonadotropins. The pituitary responded to LH-RH administration, but the sensitivity was reduced. In the adult rat, ovulatory failure and the formation of polycystic ovaries took place with doses of DHA as low as 7.5 mg per kg of body weight. Attempts are being made to obtain further insights into the mechanism of androgen-induced ovulatory failure by studying the effect of androgens and progesterone on the steroid receptors and their function in the hypothalamus and the pituitary. Furthermore, a direct effect of DHA on the ovary, causing follicular atresia and cystic changes, is also being explored.