Aromatase activity in the brain of the three-spined stickleback, Gasterosteus aculeatus. I. Distribution and effects of season and photoperiod.

Tritiated androstenedione was in vitro aromatized to estrone and estradiol by the stickleback brain. Highest aromatase activity was found in the diencephalon, particularly in the periventricular hypothalamic region containing the nucleus preopticus (NPO), in the area containing the nucleus lateralis tuberis, and in the pituitary. This localization suggests a role of aromatase in controlling the secretion of gonadotropic hormone. The activity in the area containing the NPO was higher in May than in December. The possible role of seasonal changes in aromatase activity in the control of the yearly reproductive cycle is discussed.

Identification of potential antiatherosclerotic/hypolipidemic agents by their effect on hepatic conversion of androst-4-ene-3,17-dione to etiocholanolone and androsterone.

Clinical observations have shown that hypercholesterolemia is associated with abnormal androgen metabolism, viz. an increased excretion of etiocholanolone (E) relative to androsterone (A). Substances which restore the A/E ratio to normal likewise lower serum cholesterol. Postulating that the abnormal steroid and sterol metabolism may be either causally related or dependent on the same metabolic defect, we have developed in vitro and in vivo models to select drugs which favorably effect the ratio of A to E produced from [4-14C]androst-4-ene-3,17-dione [4-14C]A-dione). The in vitro model employs a mixture of rat liver microsomal delta 4-3-ketosteroid-5 alpha-reductase and cytosolic 3 alpha-hydroxysteroid dehydrogenase and delta 4-3-ketosteroid-5 beta-reductase. Kinetic and mechanistic studies have been performed on active compounds using this in vitro assay. The in vivo model employs i.v. injection of [4-14C]A-dione followed by collection of bile in anesthetized, hypophysectomized female rats. Many compounds preselected in the in vitro assay likewise reduced the A/E ratio in vivo. One of these compounds (CGS 10614A) also lowered serum cholesterol and reduced the incidence and severity of atherosclerotic lesions in aortas of cholesterol-fed rabbits.

Identification of steroids produced by bovine chorion incubated with [14C]androstenedione.

Individual chorion taken from cows in early pregnancy (days 27, 44, 45 and 49) was incubated with [14C]androstenedione in short-term incubation in vitro. After preliminary extraction, separation and purification, metabolites were identified by recrystallization with authentic unlabelled steroids to constant specific activity. Major metabolites identified were 5 beta-androstane-3,17-dione (5 beta-androstanedione) and 5 beta-androstan-3 alpha-ol-17-one (aetiocholanolone) while minor metabolites were identified as 5 beta-androstane-3 alpha,17 beta-diol and 5 beta-androstan-17 alpha-ol-3-one. There was no 14C-labelled oestradiol or oestradiol detectable in the medium either as free oestrogens or as sulphates.

Metabolism of C 19 -steroids by homogenates of normal rat and mouse adrenal tissue and of the Snell transplantable rat adrenocortical tumour 494.

C(19)-steroid metabolism in homogenates of adrenal tissue from rats and mice has been studied. Production of these compounds from [7alpha-(3)H]cholesterol by rat adrenal tissue appeared to follow a route independent of pregnenolone. The major products of [7alpha-(3)H]-dehydroepiandrosterone metabolism by rat adrenal tissue were 5alpha-reduced steroids, principally androsterone, epiandrosterone and 5alpha-androstanedione. No differences in metabolism of [7alpha-(3)H]dehydroepiandrosterone or [4-(14)C]pregnenolone were detected between adrenal tissue from Sprague-Dawley, Wistar and Osborne-Mendel rats, but experiments with the Snell rat adrenocortical tumour 494 showed that this tissue had low 5alpha-reductase activity. In contrast, the major products of [7alpha-(3)H]dehydroepiandrosterone metabolism by mouse adrenal tissue were 5beta-reduced steroids. Differences were observed between LACA and NH strains of mice in that there was a lower metabolism of androstenedione by NH mouse adrenal and a considerable difference in the proportions of aetiocholanolone and epiaetiocholanolone produced.