Mild hyperprolactinemia frequently accompanies the hypopituitarism seen in patients with pituitary macroadenomas that do not secrete PRL. We postulated that hypopituitarism in this setting, is primarily caused by compression of the portal vessels and/or pituitary stalk. If this were the case, the dynamics of PRL secretion in this instance would be similar to those in patients with stalk section, dopamine deficiency, or hypothalamic disease. Furthermore, as hypopituitarism in this setting is largely reversible, we postulate that PRL dynamics should also normalize after adenomectomy as a result of the resumption of hypothalamic regulation of pituitary hormone secretion. To test these hypotheses, we examined PRL responsiveness to TRH and the dopamine antagonist, perphenazine (PZ), in patients with pituitary macroadenomas who had hypopituitarism and others with intact pituitary function (controls). Dynamic studies were performed before and 2-3 months after total or subtotal adenomectomy, and the results were correlated with alterations in other pituitary function. In addition, plasma ACTH, cortisol, and PRL levels were measured hours to days after surgery to investigate immediate alterations in pituitary function following surgical decompression. Before surgery, hypopituitary patients had higher serum PRL level than controls (25.5 +/- 12 vs. 11 +/- 3 micrograms/L; P < 0.001). Preoperative dynamic testing of PRL secretion in hypopituitary patients demonstrated an increase in PRL levels after TRH, but not after PZ, administration. In contrast, PRL levels increased appropriately when either stimulus was given to controls. Hours after adenomectomy, PRL levels decreased by 50% in hypopituitary patients (P < 0.0001) and remained so until discharge. In contrast, controls had a transient increase in serum PRL levels after adenomectomy. After surgery, 25 of 43 previously hypopituitary patients recovered part or all pituitary function. Serum PRL levels in the latter subgroup became normal and increased appropriately after stimulation with either TRH or PZ. In contrast, patients who did not recover pituitary function had lower PRL levels that increased minimally after TRH or PZ. The mild increase in serum PRL levels in hypopituitary patients and the discordant responses to stimulation with TRH and PZ suggest dopamine deficiency as a cause of hyperprolactinemia. The drop in serum PRL levels immediately after surgery, at a time when other pituitary hormones (e.g. ACTH), were documented to rise suggests restoration of hypothalamic control over pituitary hormone secretion. The pattern of PRL responses to stimulation in patients recovering function postoperatively was similar to that in controls, although the incremental rise was subnormal.(ABSTRACT TRUNCATED AT 400 WORDS)