Structure-activity relationship of various corticosteroids on the feedback control of corticotrophin secretion

Several steroids occurring in the pathway of corticosteroid biosynthesis were investigated for their ability to exert a fast or delayed feedback inhibition of stress-induced release of corticotrophin. Rats were injected subcutaneously with vehicle or a steroid either 10 min (fast feedback) or 4 h (delayed feedback) before they were subjected to stress which consisted of a 2 min exposure to ether vapour. 2 Changes in plasma corticosterone concentration and in vitro corticosterone production by excised adrenal glands were used as indices of corticotrophin release. 3 Among the steroids tested only 11beta, 21-dihydroxypregn-4-ene-3, 20-dione (corticosterone) and 11beta, 17alpha, 21-trihydroxypregn-4-ene-3, 20-dione (cortisol) inhibited the stress response 10 min after their administration. Therefore, it appears that the fast feedback mechanism is limited to steroids with a 21-hydroxyl and a 11beta-hydroxyl group. 4 In contrast, many steroids caused inhibition of the stress response 4 h after their administration. These steroids were corticosterone, cortisol, 21-hydroxypregn-4-ene-3, 20-dione (11-deoxycorticosterone), 17alpha, 21-dihydroxypregn-4-ene-3, 20-dione (11-deoxycortisol), 11beta-hydroxypregn-4-ene-3, 20-dione (11beta-hydroxyprogesterone) and 11beta, 17alpha-dihydroxypregn-4-ene-3, 20-dione (11beta, 17alpha-dihydroxyprogesterone). Thus, either the 21-hydroxyl group (e.g. 11-deoxycorticosterone) or the 11beta-hydroxyl group (e.g. 11beta-hydroxyprogesterone) is sufficient for delayed feedback activity. The 11alpha-hydroxyl group, e.g. 11alpha, 17alpha, 21-trihydroxypregn-4-ene-3, 20-dione (11-epicortisol) renders the steroid inactive on both feedback mechanisms. 5 18,21-Dihydroxypregn-4-ene-3, 20-dione (18-hydroxydeoxycorticosterone) was found to be the only steroid that is secreted by the adrenal gland of the rat in quantities sufficient to cause exaggeration of the stress-induced release of corticotrophin. This steroid has been implicated as a possible hypertensive agent, and its role in the control of corticotrophin secretion is discussed here.