Mechanism Of Action Of Retinoic Acid And Retinol On Lh Receptor Induction And Progesterone Synthesis In Granulosa And Luteal Cells.

Abstract

This thesis investigates the mechanisms by which retinol (ROH) and retinoic acid (RA) enhance the induction of luteinizing hormone (LH)/human chorionic gonadotropin (hCG) receptors and the production of progesterone in granulosa and luteal cells. It was found that ROH and RA each increased the number of LH/hCG receptors in the presence of follicle stimulating hormone (FSH). The effect on receptor-induction was found to be biphasic since low concentrations of both retinoids enhanced receptor-induction by FSH whereas at high concentration (1(mu)M) they inhibited the induction. RA was much more potent than ROH in induction as well as inhibition. Enhancement and inhibition of induction were each accompanied by respective increases and decreases in concentrations by cyclic adenosine monophosphate (cAMP). Since RA was more potent in both respects, it appears that RA itself or its metabolites may be the actual mediators of these responses. Preincubation of luteal cells with either RA or ROH for two days not only increased the subsequent basal accumulation of progesterone by these cells, but also resulted in an increased accumulation of progesterone in response to both 25-hydroxy cholesterol (25-OH) and pregnenolone. Since 25-OH and pregnenolone are substrates for side chain cleavage (SCC) and 3(beta)-hydroxysteroid dehydrogenase (3(beta)-HSD) enzymes respectively, the increased synthesis of progesterone in the presence of these compounds is attributed to retinoid-induced stimulation of SCC and 3(beta)-HSD. Contrary to the present dogma that progesterone synthesis is decreased in the presence of RA, these results suggest that RA stimulates progesterone synthesis by activation of key steroidogenic enzymes and by the induction of LH/hCG receptor.