DIRECT INHIBITION OF OVARIAN STEROIDOGENESIS BY CORTISOL AND THE MODULATORY ROLE OF 11-BETA-HYDROXYSTEROID DEHYDROGENASE

OBJECTIVE The association of adrenal hyperactivity with ovarian dysfunction may involve direct inhibition of ovarian steroidogenesis by glucocorticoids. Therefore, the objectives of this study were to investigate the direct effects of cortisol on luteinizing hormone (LH) action in human granulosa-lutein cells and the modulation of this interaction by ovarian 11beta-hydroxysteroid dehydrogenase (11betaHSD). DESIGN AND PATIENTS Effects were investigated in cultured human granulosa-lutein cells isolated from the follicular aspirates of 14 patients undergoing oocyte collection for in-vitro fertilization and embryo transfer. MEASUREMENTS Pregnenolone production and H-3-cortisol oxidation to H-3-cortisone (11betaHSD activity) by cultured cells were measured. RESULTS In cells from nine (of 14) patients, cortisol inhibited LH-stimulated steroidogenesis in a concentration dependent manner with an ID50 of 1250 +/- SEM 377 nmol/l. In these cultures, the 11betaHSD activities were high (133 +/- SEM 23 pmol/mg protein/4h) and inhibition of the enzyme with carbenoxolone potentiated the action of cortisol. Conversely, cells from the remaining five patients lacked detectable 11betaHSD activity and exhibited an increased sensitivity to the inhibitory action of cortisol (ID50 = 158 +/- SEM 41 nmol/l in the absence of carbenoxolone). CONCLUSIONS Cortisol acts directly inhuman granulosalutein cells to inhibit the support of steroidogenesis by LH and this interaction is modulated by ovarian 11betaHSD in the majority of patients.