Modification of Adrenal Function by the Anti-Serotonin Agent Cyproheptadine

Abstract

The effect of the serotonin antagonist, cyproheptadine (Cypro), on metyrapone-induced stimulation of the pituitary-adrenal axis was evaluated in nine normal subjects. The subjects underwent standard oral metyrapone tests (750 mg every four h, for six doses) while taking no medications and while receiving oral Cypro (4 mg every six h). Cypro administration caused a significant reduction in: 1) baseline 17-hydroxycorticosteroid (17-OH) excretion (-31 +/- 7.2%), 2) the increase above baseline in 24 h 17-OH excretion on the day after metyrapone (-32 +/- 4.9%), 3) serum 11-deoxycortisol concentrations 8 h (-45 +/- 5.5%) and 24 h (-18 +/- 3.6%) after the first dose of metyrapone, and 4) plasma ACTH concentration 8 h (-32 +/- 8.2%) and 24 h (-22 +/- 8.0%) after the first dose of metyrapone. When compared with the control test, Cypro administration did not alter: 1) baseline 17-ketosteroid secretion, 2) the fall in serum cortisol concentration while taking metyrapone, 3) the serum free metyrapone concentration, 4) cortisol metabolism, 5) the adrenal response to ACTH, and 6) assay methods for measurement of serum and urinary corticosteroids. Our data suggest that Cypro can reduce pituitary-adrenal responsiveness by reducing plasma ACTH concentrations. If Cypro acts as a serotonin antagonist, our data lends support to the idea that serotoninergic mechanisms are important in the control of pituitary ACTH secretion in normal human subjects.

Neuroendocrine effects of quipazine in man in health state or with neurological disorders

“…Suggestions that brain serotonin is also important for augmented release of ACTH derived from the observations that 5-HT antagonists had an inhibitory effect on metyrapone- (Cavagnini et al, 1975;Plonk and Feldrnan, 1976) or insulin-hypoglycemia-induced (Plonk et al, 1974) ACTH and cortisol responses.…”

A Role for Serotonin in the Hypothalamic-Pituitary-Adrenal Response to Insulin Stress

“…In humans, the 5-HT recep tor blocker metergoline reduced ACTH levels in response to insulin stress [9], Other 5-HT antagonists in addition to me- tergoline, namely methysergide [8] and cyproheptadine [48], were effective in lowering ACTH levels following metyrapone administration. Cyproheptadine was also found to be effective in reducing symptoms of two clinical endocrino pathies, Cushing's disease, which is characterized by adre nocortical hypersecretion [34], and Nelson's syndrome, in which excessive ACTH secretion occurs as a result of bilat eral adrenalectomy in Cushing's patients [36].…”

Failure of Cyproheptadine to Inhibit Vasopressin-Stimulated Cortisol Release in a Patient with Cushing’s Disease

“…In normal subjects, cyproheptadine blunts the cortisol rise following insulininduced hypoglycemia (4) and significantly decreases morning plasma ACTH levels prior to and during oral metyrapone testing, compared with pretreatment ACTH levels (5). These data indicate that cyproheptadine either decreases ACTH secretion from the pituitary directly and/or indirectly by modifying cortico tropin-releasing factor secretion from the hypothalamus.…”

“…It has been suggested previously that cyproheptadine probably exerts its action at both the hypothalamic and pituitary levels because the mechanism for cyproheptadine action is most likely due to its anti-serotoninergic effects, and serotonin is known to exist in both the hypothalamus and pituitary (2). Cyproheptadine clearly has no direct influence on cortisol secretion from the adrenal gland (2,5).…”