Mild hyperprolactinemia frequently accompanies the hypopituitarism associated with pituitary macroadenomas not secreting PRL. Because of this association, hypopituitarism was postulated to be due to compression of portal vessels. We postulate that resumption of hypothalamic control over pituitary function occurs immediately after adenomectomy. To test this hypothesis, we examined pituitary function before and after transsphenoidal adenomectomy in 26 ACTH-deficient patients and 23 subjects with normal adrenal and thyroidal functions (control group). Glucocorticoids, given only to ACTH-deficient subjects, were withdrawn 36 h after surgery. ACTH, cortisol, and PRL levels were measured twice daily in all patients. Both ACTH and PRL levels increased hours after surgery in controls and returned to baseline over 4 days. In all hypopituitary subjects, PRL levels decreased by 50% within hours of adenomectomy and remained so until discharge. ACTH levels, measured simultaneously, increased within hours in 17 of 26 hypopituitary patients, all of whom recovered normal adrenal function before discharge. Nine additional patients had low ACTH levels and required cortisol replacement. The reciprocal changes in PRL and ACTH levels measured simultaneously, hours after surgery, support the hypothesis that hypopituitarism is reversible and largely caused by compression of the protal vessels and the resulting interruption of delivery of hypothalamic hormones. The persistence of hypopituitarism in some patients suggests that ischemic necrosis of the anterior pituitary could limit recovery.