Recovery of hypothalamic-pituitary-adrenal function after long term suppression by aminoglutethimide and...

Little data are available concerning recovery of adrenal function after prolonged inhibition of steroidogenesis by enzyme inhibitors. Aminoglutethimide (AG), a potent blocker of adrenal steroid biosynthesis, combined with physiological replacement doses of hydrocortisone (HC) is currently being used to treat women with metastatic breast carcinoma. We studied the time-course of recovery of hypothalamic-pituitary-adrenal function after prolonged drug therapy in 10 women. Fifteen hours after stopping AG-HC therapy, 0900 h serum cortisol levels were normal [12.9 +/- 3.4 (SEM) micrograms/100 ml], but increments observed after provocative stimulation were blunted. However, the cortisol responses to both insulin-induced hypoglycemia and cortrosyn stimulation normalized 36 and 42 h after stopping AG and HC therapy. In addition, the concentration of plasma ACTH peaked at 175 +/- 9.3 pg/ml 15 min after the nadir of hypoglycemia. Adrenal histology in two patients who died while on chronic AG and HC therapy showed hypertrophic cells with large amounts of finely vacuolated cytoplasm in the zona fasciculata but no other abnormalities. We conclude that recovery of the hypothalamic-pituitary-adrenal axis is complete within 36 h after discontinuing chronic AG and HC therapy. This is in contrast to the prolonged suppression observed after chronic therapy with pharmacological doses of glucocorticoids.