In vivo studies on the mechanism of action of 6-dehydro-16-methylene-hydrocortisone (STC 407) on the hypothalamo-pituitary-adrenal axis in rats.

Abstract

The mechanism of action of a new synthetic steroid, 6-dehydro-16-methylene-hydrocortisone (STC 407), which has been found useful in the treatment of Cushing’s syndrome due to adrenal hyperplasia, was studied in the rat. After treatment of normal rats with STC 407 for 11–14 days, the CRF content of the median eminence of the hypothalamus (SME), the concentration of ACTH in the anterior pituitary, the wet weight of the adrenal glands/ 100 g b.w., the adrenal corticosterone concentration/100 mg, and the plasma corticosterone level were significantly decreased. After treatment of adrenalectomized rats with STC 407 for 4 days, the concentration of ACTH in the pituitary was increased, but there was no appreciable change in CRF activity in the SME. Plasma levels of ACTH, which were elevated after adrenalectomy, decreased to undetectable levels after 4 days’ treatment with 400 <i>µ</i>g/100 g b.w. daily. Treatment of adrenalectomized rats with this steroid for 13 days considerably reduced CRF activity in the SME, and significantly raised the pituitary ACTH content. These results indicate that STC 407 suppresses both the release and the synthesis of ACTH by the pituitary in normal rats, this effect being mediated at least in part by a reduction in hypothalamic CRF activity. In adrenalectomized rats, the predominant effect of this steroid seems to be suppression of release of ACTH by the pituitary.