vasoactive-intestinal-peptide and Cushing-Syndrome

We have previously reported and confirmed that vasoactive intestinal peptide (VIP) is a significant stimulator of ACTH and cortisol secretion in at least some patients with Cushing's disease. We have also found that the hormonal responses to corticotropin-releasing hormone (CRH) in VIP-responsive patients with Cushing's disease were higher than those in VIP non-responders, which suggested a linkage between the actions of CRH and VIP in this disorder. Therefore, in the present study we examined whether this linkage also exists after glucocorticoid treatment by testing the effect of dexamethasone (DEX) pretreatment (1.0 mg, intravenous bolus, 60 min before) on ACTH and cortisol responses to CRH (100 microg, i.v. bolus) and VIP (100 microg, i.v. bolus) in 7 patients with Cushing's disease who were responsive to both neuropeptides while under no DEX pretreatment. The results were that in 5 patients, DEX was able to significantly suppress the ACTH and cortisol responses to both CRH and VIP, and in the remaining 2 patients, DEX did not significantly affect the action of either CRH or VIP. This study is the first to demonstrate the parallel inhibition by DEX of ACTH and cortisol responses to CRH and VIP in Cushing's disease. Although the possibility cannot be excluded that VIP may act on CRH receptors in corticotropinomas as a partial agonist, it seems more likely that specific receptors for CRH and VIP, respectively, may concurrently express in substantial quantity in those corticotropinomas that are responsive to both neuropeptides.

Topics: Adrenocorticotropic Hormone; Adult; Anti-Inflammatory Agents; Corticotropin-Releasing Hormone; Cushing Syndrome; Dexamethasone; Drug Interactions; Female; Humans; Hydrocortisone; Middle Aged; Vasoactive Intestinal Peptide

This study assesses the action of hypercortisolism on the hormone and peptide periadenoma region of removed ACTH-producing microadenoma. Our findings show that cortisol excess affects both ACTH and GH production, with no immunoreaction for these hormones. The remaining pituitary hormones (TSH, FSH and PRL) and POMC-derived peptides (betaEnd, alphaMSH and betaMSH) were not modified. Likewise, we observed pituitary immunoreactive cells for Neurotensin (NT), Intestinal vasoactive peptide (VIP), Substance P (SP) and Angiotensin-II (Ang-II). The colocalization demonstrated that NT was expressed in thyrotrope and gonadotrope cells, VIP in gonadotrope cells and SP in corticotrope cells. The results about Ang-II were inconclusive. On the other hand, immunoreaction for the NPY and Gal peptides were not present. In the adenomatous cells, the peptide NT is present in ACTH cells as well as SP. These results suggest a peptide regulation of pituitary cells in the pathological state that can differ between normal and tumoural cells of the same pituitary.

Topics: ACTH-Secreting Pituitary Adenoma; Adenoma; Adrenocorticotropic Hormone; Adult; Angiotensin II; Corticotrophs; Cushing Syndrome; Female; Gonadotrophs; Human Growth Hormone; Humans; Immunohistochemistry; Neuropeptides; Neurotensin; Pituitary Hormones; Substance P; Thyrotrophs; Vasoactive Intestinal Peptide

Topics: ACTH Syndrome, Ectopic; Adenoma; Adrenocorticotropic Hormone; Adult; Aged; Cushing Syndrome; Female; Humans; Male; Middle Aged; Petrosal Sinus Sampling; Pituitary Neoplasms; Prolactin; Vasoactive Intestinal Peptide

The effect of peptide histidine methionine (PHM) on ACTH and cortisol secretion was examined in 12 female patients with Cushing's disease and 8 normal women. For comparison, we examined in both groups the effects of vasoactive intestinal peptide (VIP), human (h) CRH plus PHM, and hCRH plus VIP. Each peptide was given as an i.v. bolus in a dose of 100 micrograms, and plasma levels of ACTH and cortisol were measured before and at intervals up to 120 min after the injection. In all normal subjects, hCRH induced significant rises in ACTH (> 50% above the basal) and cortisol (> 20% above the basal), but PHM and VIP were without effect. In this group, hormonal responses after hCRH plus PHM and hCRH plus VIP were statistically indistinguishable from those after hCRH alone. Of the patients with Cushing's disease, 9 (75%) were responsive to hCRH, 5 (42%) were to VIP, and 3 (25%) were to PHM, showing significant increases in both ACTH and cortisol. All the 3 PHM responders were also responsive to VIP, and all the 5 VIP responders were also responsive to hCRH. Interestingly, the responders to VIP and PHM had higher ACTH and cortisol responses to hCRH compared with the nonresponders. In addition, in the patients with Cushing's disease the coadministration of hCRH with PHM or VIP produced additive increases in both ACTH and cortisol. These results suggest that PHM may be another hypothalamic hormone capable of paradoxically stimulating ACTH secretion in at least some patients with Cushing's disease. Although the ACTH-releasing action of PHM appears less potent than those of hCRH and VIP, the possibility was suggested that a certain common mechanism may operate in inducing the ACTH response to these 3 peptides.

Topics: Adrenocorticotropic Hormone; Adult; Corticotropin-Releasing Hormone; Cushing Syndrome; Dexamethasone; Drug Interactions; Female; Humans; Hydrocortisone; Metyrapone; Middle Aged; Peptide PHI; Reference Values; Time Factors; Vasoactive Intestinal Peptide

Abnormalities in hypothalamic-pituitary adrenal axis function were demonstrated by measuring plasma adrenocorticotropin abnormal concentrations following Vasoactive Intestinal Peptide (VIP) and Corticotropin Releasing Hormone (CRH) administration during a phase of remission of Cushing's disease in a 45-year-old female patient. When observed 80 days after the first examination, the patient no longer showed cushingoid features and serum cortisol and plasma ACTH were not abnormally high. VIP infusion (75 micrograms during 12 min) induced a significant increase in serum cortisol and ACTH plasma levels with respect to the normal unresponsiveness. Exaggerated plasma ACTH response to CRH (50 micrograms iv) was also observed. We conclude that the study of ACTH and cortisol response to VIP and CRH may be useful in revealing Cushing's disease even during a remission phase of the disorder.

Topics: Adrenal Glands; Adrenocorticotropic Hormone; Corticotropin-Releasing Hormone; Cushing Syndrome; Drug Therapy, Combination; Female; Humans; Hydrocortisone; Hypothalamus; Middle Aged; Pituitary Gland; Remission, Spontaneous; Vasoactive Intestinal Peptide

Vasoactive intestinal polypeptide (VIP) was administered (75 micrograms iv over 12 min) to 14 patients with Cushing's disease, 1 patient with Nelson's syndrome, and 8 normal subjects. VIP induced a significant rise of plasma ACTH levels in 6 patients with Cushing's disease, from a baseline of 13.2 pmol/l (9.9-18.5 pmol/l) to a peak of 24.5 pmol/l (7.7-18.9 pmol/l), median and range (P less than 0.05), and in the patient with Nelson's syndrome, from a baseline of 260.9 to 461.3 pmol/l. A significant elevation of cortisol levels was also observed, from a baseline of 567 nmol/l (185-842 nmol/l) to a peak of 727 nmol/l (364-1029 nmol/l); P less than 0.05. No modifications in plasma ACTH and cortisol levels were noticed in the other 8 patients with Cushing's disease, or in the normal subjects. In the responsive patients, the median plasma ACTH level reached after VIP was found to be less than that induced by CRH administration. In 2 of the responsive patients, VIP was injected again after successful microadenomectomy and did not then cause changes in ACTH and cortisol concentration. These data demonstrate that VIP specifically stimulates ACTH release in some patients with corticotropinomas but not in normal subjects; the disappearance of such abnormal ACTH responses after successful adenomectomy suggests the presence of specific VIP receptors only on the adenomatous corticotropes.

Topics: Adenoma; Adolescent; Adrenocorticotropic Hormone; Adult; Cushing Syndrome; Female; Humans; Hydrocortisone; Male; Middle Aged; Nelson Syndrome; Pituitary Neoplasms; Radioimmunoassay; Vasoactive Intestinal Peptide

To characterize the functional aspect of prolactin (Prl) cells coexisting with corticotroph adenomas, pituitary adenoma cells obtained from a patient with Cushing's disease and a patient with Nelson's syndrome, who were associated with hyperprolactinaemia, were cultured in monolayer and their Prl responses to various secretagogues were compared with those of prolactinoma cells in culture. Immunohistochemistry performed in one of these two adenomas demonstrated the presence of Prl-containing cells in addition to ACTH cells. When ACTH-Prl adenoma cells were exposed to ovine corticotrophin-releasing factor (CRF), a dose-dependent increase in both ACTH and Prl secretion was observed, which was blocked by coincubation with hydrocortisone. In contrast, no stimulatory effect of CRF on Prl release was observed in all of the experiments using prolactinoma cells. Thyrotrophin-releasing hormone, which consistently stimulated Prl secretion in ACTH-Prl adenomas, was effective in triggering Prl release in only 25% of the prolactinomas. Exposure of the cultured cells to lysine vasopressin, growth hormone-releasing factor and vasoactive intestinal peptide resulted in an increase in ACTH and Prl secretion in one ACTH-Prl adenoma, however, none of the prolactinomas responded to these stimuli to secrete Prl. Dopamine and somatostatin, on the other hand, uniformly suppressed Prl secretion from ACTH-Prl adenomas as well as from prolactinoma cells. These results suggest that the mode of Prl secretion by mixed ACTH-Prl pituitary adenomas is not identical to that by pure prolactinomas and is, at least in part, common to that of ACTh secretion.

Topics: Adenoma; Adrenocorticotropic Hormone; Adult; Cells, Cultured; Corticotropin-Releasing Hormone; Cushing Syndrome; Dopamine; Female; Haloperidol; Humans; Lypressin; Nelson Syndrome; Pituitary Neoplasms; Prolactin; Radioimmunoassay; Somatostatin; Thyrotropin-Releasing Hormone; Vasoactive Intestinal Peptide