Hypothesis to be tested: """"""""Serum dehydroepiandrosterone sulfate (DHEAS) of adrenal origin serves as an important precursor for ovarian steroidogenesis"""""""". If serum DHEAS is an important precursor for ovarian steroidogenesis, the hypothesis explains the need for adrenarche and for adrenal secretion of DHEAS, and it provides a rationale for a multitude of other data suggesting an undiscovered mechanism of adrenal-ovarian interaction. This hypothesis will be tested in the human using both in vivo and in vitro experiments. The in vivo experiments will include intravenous infusions of 3H-DHEAS along with either 14C-estrone or 14C-testosterone and intravenous infusions of non-isotopic DHEAS. The fractions of androstenedione, testosterone, estrone, and 17Beta-estradiol arising from serum DHEAS will be measured both in the untreated state and following pretreatment with human menopausal gonadotropins (HMG) in normal controls, women with hypothalamic amenorrhea (HA), women with polycystic ovarian disease (PCOD), and women with PCOD during dexamethasone adrenal suppression in an efficient experimental design utilizing each woman as her own control. Radioimmunoassay of DHEAS, androstenedione, testosterone, estrone, and 17Beta-estradiol will be utilized for evaluation of the results of the non-isotopic DHEAS infusions and in vitro incubations of ovarian compartments with non-isotopic DHEAS. The metabolic clearance rates (MCR) for DHEAS and testosterone will be measured simultaneously with determination of the conversion of DHEAS to testosterone for both the left and the right ovary using samples of ovarian venous blood obtained at surgery. The MCR for DHEAS and conversions of DHEAS to testosterone and estrone will be determined for the first time in non-pregnant women of reproductive age with evaluation of the effect of increases in the plasma DHEAS concentration on the MCR for DHEAS. The in vitro studies will include: 1) direct tracer assays of the conversion of DHEAS to dehydroepiandrosterone (DHEA) in cell-free preparations, and 2) analysis of the conversion of non-isotopic DHEAS to androstenedione, testosterone, estrone, and 17Beta-estradiol in cultures of ovarian compartments. One and two-way analysis of variance will be utilized for statistical analysis of the results of these investigations. This hypothesis is pertinent to understanding the medical conditions of HA and PCOD which are important causes of infertility and amenorrhea, and this information may potentially open new avenues for treating these conditions.
