pituitrin and Adrenal-Cortex-Neoplasms

Cushing's disease remains a difficult diagnosis in spite of new technical procedures such as pituitary MRI, selective bilateral petrosal or cavernous sampling, (111)In pentreotide scan and 18 Flurodeoxyglucose pituitary PET scan. In this article, we review biological diagnostic procedures of Cushing's disease and corticotroph adenomas. According to our experience and the literature, we summarize the approach in medical treatment of Cushing's disease.

Topics: ACTH Syndrome, Ectopic; Adenoma; Adrenal Cortex Neoplasms; Adrenocortical Hyperfunction; Adrenocorticotropic Hormone; Adult; Algorithms; Carcinoid Tumor; Child; Corticotropin-Releasing Hormone; Cushing Syndrome; Dexamethasone; Diagnosis, Differential; Diagnostic Imaging; Dopamine Agonists; Female; Humans; Hypothalamo-Hypophyseal System; Magnetic Resonance Imaging; Male; Petrosal Sinus Sampling; Pituitary Neoplasms; Pituitary-Adrenal Function Tests; Pituitary-Adrenal System; Pregnancy; Pregnancy Complications, Neoplastic; Vasopressins

We herein present the case of a 53-year-old patient with adrenocorticotropin-independent macronodular adrenocortical hyperplasia (AIMAH), which is a rare form of Cushing syndrome. He had hypercortisolemia and bilateral macronodular adrenal glands with a left side predominance. The administration of vasopressin significantly increased the plasma cortisol level (1.9-fold). Following left adrenalectomy, the patient's hypercortisolemia significantly improved and vasopressin responsiveness was lost, suggesting that the responsiveness originated from the resected left adrenal gland. The marked difference in vasopressin responsiveness between the adrenals corresponded with their asymmetrical size and function. Evaluating the differences in the vasopressin sensitivity may therefore be helpful for understanding the progression of AIMAH.

Topics: Adenoma; Adrenal Cortex; Adrenal Cortex Neoplasms; Adrenalectomy; Adrenocorticotropic Hormone; Cushing Syndrome; Deamino Arginine Vasopressin; Dexamethasone; Diabetes Mellitus, Type 2; Glucose Tolerance Test; Gonadotropin-Releasing Hormone; Humans; Hydrocortisone; Hypertriglyceridemia; Laparoscopy; Male; Middle Aged; Organ Size; Receptors, Vasopressin; Thyrotropin-Releasing Hormone; Vasopressins

Arginine vasopressin (AVP), a vasoactive peptide hormone that binds to three G-protein coupled receptors (V1R, V2R, and V3R), has long been known to activate V1R and elicit mitogenesis in several cell types, including adrenal glomerulosa cells. However, in the mouse Y1 adrenocortical malignant cell line, AVP triggers not only a canonical mitogenic response but also novel RhoA-GTP-dependent mechanisms which downregulate cyclin D1, irreversibly inhibiting K-ras oncogene-driven proliferation. In Y1 cells, AVP blocks cyclin D1 expression, induces senescence-associated beta-galactosidase (SAbeta-Gal) and inhibits proliferation. However, ectopic expression of cyclin D1 renders Y1 cells resistant to both SAbeta-Gal induction and proliferation inhibition by AVP. In addition, ectopic expression of the dominant negative RhoAN19 mutant blocks RhoA activation, yielding Y1 cell sub-lines which are no longer susceptible to cyclin D1 downregulation, SAbeta-Gal induction, or proliferation inhibition by AVP. Furthermore, inhibiting RhoA with C3 exoenzyme protects Y1 cells from AVP proliferation inhibition and SAbeta-Gal induction. On the other hand, AVP treatment does not activate caspases 3 and 7, and the caspase inhibitor Ac-DEVD-CMK does not protect Y1 cells from proliferation inhibition by AVP, implying that AVP does not trigger apoptosis. These results underline a pivotal survival activity of cyclin D1 that protects K-ras oncogene-dependent malignant cells from senescence.

Topics: Adrenal Cortex Neoplasms; Animals; Arginine Vasopressin; Caspases; Cell Transformation, Neoplastic; Cellular Senescence; Cyclin D1; Down-Regulation; Genes, ras; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Mice; Mitogen-Activated Protein Kinase 3; Phosphorylation; Proto-Oncogene Proteins c-akt; rhoA GTP-Binding Protein; Vasopressins

We studied the putative role of the vasopressin receptors in the phenotypic response of steroid-secreting adrenocortical tumors. A retrospective analysis of a series of 26 adrenocortical tumors responsible for Cushing's syndrome (19 adenomas and 7 carcinomas) showed that vasopressin (10 IU, i.m., lysine vasopressin) induced an ACTH-independent cortisol response (arbitrarily defined as a cortisol rise above baseline of 30 ng/mL or more) in 7 cases (27%). In comparison, 68 of 90 patients with Cushing's disease (76%) had a positive cortisol response. We then prospectively examined the expression of vasopressin receptor genes in adrenocortical tumors of recently operated patients (20 adenomas and 19 adrenocortical carcinomas). We used highly sensitive and specific quantitative RT-PCR techniques for each of the newly characterized human vasopressin receptors: V1, V2, and V3. The V1 messenger ribonucleic acid (mRNA) was detected in normal adrenal cortex and in all tumors. Its level varied widely between 2.0 x 10(2) and 4.4 x 10(5) copies/0.1 microgram total RNA, and adenomas had significantly higher levels than carcinomas, although there was a large overlap. Among the 6 recently operated patients who had been subjected to the vasopressin test in vivo, the tumor V1 mRNA levels were higher in the 4 responders (9.5 x 10(3) to 5.0 x 10(4)) than in the 2 nonresponders (2.0 x 10(2) and 1.8 x 10(3)). One adenoma that had a brisk cortisol response in vivo, also had in vitro cortisol responses that were inhibited by a specific V1 antagonist. In situ hybridization showed the presence of V1 mRNA in the normal human adrenal cortex where the signal predominated in the compact cells of the zona reticularis. A positive signal was also present in the tumors with high RT-PCR V1 mRNA levels; its distribution pattern was heterogeneous and showed preferential association with compact cells. RT-PCR studies for the other vasopressin receptors showed a much lower signal for V2 and no evidence for V3 mRNA. We could not establish whether the V2 mRNA signal observed in normal and tumoral specimens was present within adrenocortical cells or merely within tissue vessels. We conclude that the vasopressin V1 receptor gene is expressed in normal and tumoral adrenocortical cells. High, and not ectopic, expression occurs in a minority of tumors that become directly responsive to vasopressin stimulation tests.

Topics: Adenoma; Adrenal Cortex Hormones; Adrenal Cortex Neoplasms; Carcinoma; Cushing Syndrome; Gene Expression; Humans; Hydrocortisone; In Situ Hybridization; Lypressin; Phenotype; Polymerase Chain Reaction; Receptors, Vasopressin; Retrospective Studies; RNA-Directed DNA Polymerase; RNA, Messenger; Vasopressins

Topics: Adenoma; Adrenal Cortex Neoplasms; Animals; Humans; Hypertension; Hypertension, Malignant; Rats; Vasopressins