Effect of 17α-ethinylestradiol on the Secretion of Corticosterone in Male Rats

Export The 17α-ethinylestradiol (EE2) is a derivative of estradiol, which has been used to be the oral contraceptive pills. EE2 is an environmental hormone and influences the endocrine system in animals. In the present study, we explored the mechanism of EE2-modulatory corticosterone production in vitro and in vivo. EE2-pretreatment not only decreased the corticosterone production from rat zona fasciculata reticularis (ZFR) cells but also led to a reduction of the stimulatory effect of adrenocorticotropic hormone (ACTH) on the maximum level of plasma corticosterone in rats. Administration of EE2 (10–40 μg/ml/kg) in vivo dose dependently decreased the basal and 8-bromo-cyclic AMP (8-Br-cAMP)-induced production of corticosterone from rat ZFR cells in vitro. The in vitro corticosterone production in response to ACTH was also attenuated after in vivo administration of EE2. The steroidogenic acute regulatory (StAR) protein, a protein transports cholesterol from outer to inner mitochondria membrane, and P450scc, a steroidogenesis-limiting enzyme, were downregulated after treatment with EE2 in vivo. Other results revealed that EE2 significantly increased the basal levels of pregnenolone but decreased the pregnenolone levels in response to 25-OH-cholesterol (a biologically active derivative of cholesterol; 10−6 M) and trilostane (an inhibitor of 3 β-hydroxysteroid dehydrogenase). Moreover, EE2 affected the negative feedback regulation of hypothalamus–pituitary–adrenal (HPA) axis through downregulation of glucocorticoid receptor protein level in the anterior pituitary gland but not in rat medial basal hypothalamus. These results suggest that EE2 may affect the HPA axis to inhibit P450scc activity, basal and ACTH-induced corticosterone production from rat ZFR cells through a cAMP-dependent pathway.