The modulatory role of estrogens on corticotropin-releasing factor gene expression in the hypothalamic paraventricular nucleus of ovariectomized rats: role of the adrenal gland.

In vitro, estrogens stimulate corticotropin-releasing factor (CRF) gene transcription. In ovariectomized (OVX) rats, estrogens have a negative effect on CRF mRNA levels in the hypothalamic paraventricular nucleus. This suggests that the stimulatory influence of estrogens found in vitro may be masked in vivo by an inhibitory effect mediated through neural and/or humoral factors. Glucocorticoids may be involved in this phenomenon since estrogens increase circulating corticosterone levels in OVX rats. We studied the effect of 7-day 17 beta-estradiol (E2) treatment on CRF gene expression in the paraventricular nucleus of 2-week OVX mature rats after sham operation or adrenalectomy (ADX) with or without corticosterone replacement. In sham ADX animals, E2 administration increased plasma corticosterone concentrations, did not change the binding capacity or the affinity of circulating corticosteroid binding globulin, and decreased hypothalamic CRF gene expression. Following ADX, CRF mRNA levels increased and were normalized by corticosterone treatment. Estrogens induced a significant build up in CRF mRNA concentrations in both ADX or ADX corticosterone-replaced animals. Our data demonstrate that the positive effect of estrogens on CRF gene expression found in vitro or in vivo after ADX is antagonized, in vivo when the adrenal glands are intact, by a negative influence. They strongly suggest that the increased circulating corticosterone levels induced by E2 administration mediate the inhibitory effect of estrogens on CRF mRNA levels. These observations may explain the gender related differences in the basal and stress-induced hypothalamo-pituitary-adrenal activity.