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The molecular mechanisms leading to increased cellular proliferation rates and, thus, tumor formation in the anterior pituitary gland are poorly understood. The cyclin-dependent kinase inhibitor p27Kip1 is a key molecule regulating the G1 phase of the cell cycle in many cell types. Furthermore, it was shown that p27 knock-out mice develop pro-opiomelanocortin-positive pituitary tumors. In an effort to clarify the role of p27 in the normal and tumorous human pituitary, we studied the expression of p27 by immunohistochemistry, using a highly specific mouse monoclonal anti-human p27 antibody. Normal pituitaries and 54 pituitary adenomas (twelve somatotrope adenomas, nine prolactinomas, twelve corticotrope adenomas, three TSH-producing tumors, six gonadotrope adenomas, six null cell adenomas, and six oncocytomas) were analyzed. p27 expression was determined semiquantitatively with regard to both the percentage of positive cells and the intensity of the staining. Normal human pituitaries showed strong expression of p27 in most nuclei. In contrast, the levels of p27 were reduced in the majority of the tumors analyzed. Twenty-two tumors (six somatotrope adenomas, five prolactinomas, four corticotrope adenomas, two TSH-producing tumors, two gonadotrope adenomas, and three null cell adenomas) were completely p27-negative. In 18 tumors, p27 expression was found in Յ10% of the cells. In the other ten tumors, 11-80% of the cells were p27-positive. In summary, we were able to demonstrate reduced expression levels of the cell-cycle inhibitor p27 in tumors derived from all pituitary cell types. Our data indicate that p27 may be an important regulator of cellular proliferation in the anterior pituitary, the underexpression of which could play a role in pituitary tumorigenesis.

We investigated the effect of exogenous corticotropin-releasing factor on plasma levels of ACTH and cortisol in 13 patients with ACTH-secreting pituitary adenomas (Cushing's disease) and in 9 patients with other forms of Cushing's syndrome. In all patients with Cushing's disease, ovine corticotropin-releasing factor, given intravenously as a bolus injection (1 microgram per kilogram of body weight), caused a further increase in the already elevated levels of ACTH and cortisol. Successful transphenoidal adenomectomy was followed as early as one week after surgery by normalization or near-normalization of the ACTH and cortisol responses to corticotropin-releasing factor. On the other hand, patients with the ectopic ACTH syndrome, who also had high basal plasma concentrations of ACTH and cortisol, had no ACTH or cortisol responses to corticotropin-releasing factor. This difference in responsiveness between these two patient groups cannot be explained on the basis of different metabolic clearance rates of exogenous corticotropin-releasing factor, as shown by similar disappearance curves of immunoreactive corticotropin-releasing factor from plasma. Patients with Cushing's syndrome of adrenal origin who were hypercortisolemic during testing had undetectable plasma levels of ACTH and no ACTH or cortisol responses to corticotropin-releasing factor. We conclude that stimulation of the pituitary-adrenal axis with corticotropin-releasing factor may be useful in differentiating pituitary from ectopic causes of Cushing's syndrome.

We administered ovine corticotropin-releasing factor (CRF) as a bolus intravenous injection (1 µg/kg) at 09.00 and at 20.00 to assess the influence of circadian changes in the hypothalamic-pituitary-adrenal axis on the response to CRF. The increase in plasma ACTH levels after CRF was only slightly lower in the morning than in the evening. The plasma cortisol response to ACTH, however, was significantly greater in the evening than in the morning (p < 0.005). At both times of day CRF administration had no effect on plasma concentrations of GH, PRL, LH, AVP, insulin, PRA or glucose. No effects were observed on the hematopoietic system, kidneys or liver. In addition, CRF had no effect on heart rate, blood pressure or respiratory rate at the dose employed. Approximately 10% of the subjects complained of a transient upper body and facial hot flush. These observations indicate that the magnitude of the plasma cortisol rise after CRF depends on the time of administration.

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