Inhibition of ACTH Response to Oral and Intravenous Metyrapone by Antiserotoninergic Treatment in Man

Abstract

Plasma ACTH levels after oral and iv metyrapone administration were studied in 7 and 5 healthy women respectively both under basal conditions and after a 4-day treatment with metergoline, a specific antiserotoninergic agent. In 3 additional women, the effects of methysergide, another antiserotoninergic drug, on the plasma ACTH rise induced by oral metyrapone, were evaluated. A significant lowering of the plasma ACTH levels attained after either oral or iv metyrapone was observed following metergoline administration: 149+/-64.3 vs 239+/-49.1 pg/ml (mean peak values), P less than 0.05 in the oral test and 331+/-19.7 vs 221+/-19.5 pg/ml, P less than 0.02 in the iv test. The fall of plasma cortisol caused by metyrapone was comparable before and after the antiserotoninergic treatment. An interference of metergoline in the ACTH radioimmunoassay was also excluded. After metergoline administration, a slight reduction in the baseline plasma ACTH values was noted: 79+/-7.7 vs 67+/-7.7 pg/ml (NS). A decrease, however not statistically significant, of the metyrapone-induced plasma ACTH elevation occured after methysergide administration: 421+/-150.7 vs 344+/-135.1 pg/ml. These results can be interpreted as indicating that antiserotoninergic treatment caused an inhibition of hypophysial ACTH release in response to metyrapone. Caution is recommended, however, before concluding, on the basis of these findings, that serotonin as such plays a physiological stimulating role on ACTH secretion.

Serotonergic Stimulation of Pituitary-Adrenal Activity in the Mouse

“…The 1st experiment attempted to potentiate the responses to 5-HTP, quipazine, and 6-MeO-THBC by pretreating animals with 3-(p-trifIuromethylphenoxy)-3-phenyl-N-methyl propylamine HC1 (Lilly 110140), a specific 5-HT uptake inhibitor [Wong et al, 1974], Lilly 110140 has already been reported to potentiate 5-HTPinduced CS elevations in rats [Fuller et al, 1976a], The 2nd experiment examined 2 putative 5-HT receptor blockers, cyproheptadine [Stone et al, 1961] and methergoline [Beretta et al, 1965], for their ability to inhibit 5-HT agonist-induced stimulation. Both of these drugs were previously found to reduce ACTH secretion following metyrapone in humans [Cavagnini et al, 1975;Plonk and F eldman, 1976]. Methysergide, another 5-HT antagonist [Gyermek, 1961], was tested only in animals given 5-HTP.…”

“…Although some experiments have failed to support a role for 5-HT in pituitary-adrenal control [Smelik, 1967;De Schaepdryver et al, 1969;D ixit and Buckley, 1969;Bhattacharya and Marks, 1970], many others have suggested participation of 5-HT in virtually every aspect of this endocrine system: circadian rhythmicity [Krieger and Rizzo, 1969;Scapagnini et al, 1971;Simon and G eorge, 1975], feedback suppression [Cavagnini et al, 1975;Plonk and F eldman, 1976], and stress responsivity Berger et al, 1974]. However, because inter pretation of these studies has been confounded by problems regarding the specificity, localization, and physiological significance of the results obtained, the regulatory function of central serotonergic pathways has remained un clear.…”

Treatment of Cushing's disease: a mechanistic update

“…In normal subjects, cyproheptadine may alter the feedback regulation of ACTH to different stimuli such as metyrapone and insulin-induced hypoglycemia (Cavagnini et al 1975). These responses are independent of the effects on basal ACTH levels, and patients treated with cyproheptadine therapy have documented normalization of low-dose dexamethasone suppression, metyrapone response, insulin tolerance test, CRH response, and diurnal cortisol patterns (Ferrari et al 1977).…”

“…Main side effects are somnolence, hyperphagia, and weight gain. Other serotonin antagonists, metergoline, ketanserine, and ritanserine, have been evaluated in very few patients with limited results (Cavagnini et al 1975, Sonino et al 1992, Miller & Crapo 1993.…”

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].…”