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

OBJECTIVE The association of adrenal hyperactivity with ovarian dysfun ction may involve direct inhibition of ovarian steroidogenesis by gluc ocorticoids. Therefore, the objectives of this study were to investiga te the direct effects of cortisol on luteinizing hormone (LH) action i n 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 undergoin g oocyte collection for in-vitro fertilization and embryo transfer. ME ASUREMENTS Pregnenolone production and H-3-cortisol oxidation to H-3-c ortisone (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 1 250 +/- SEM 377 nmol/l. In these cultures, the 11betaHSD activities we re high (133 +/- SEM 23 pmol/mg protein/4h) and inhibition of the enzy me with carbenoxolone potentiated the action of cortisol. Conversely, cells from the remaining five patients lacked detectable 11betaHSD act ivity and exhibited an increased sensitivity to the inhibitory action of cortisol (ID50 = 158 +/- SEM 41 nmol/l in the absence of carbenoxol one). 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.