Ectopic Secretion of Corticotropin-Releasing Factor as a Cause of Cushing’s Syndrome

Carey, Robert M.; Varma, Shalendra K.; Drake, Charles R.; Thorner, Michael O.; Kovács, Kálmán; Rivier, Jean; Vale, Wylie

doi:10.1056/nejm198407053110103

Cited by 270 publications

(65 citation statements)

References 24 publications

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“…Tumor markers ACE, CA 15-3, CA 19-9, NSE and a-fetoprotein were all in the normal range except b-LPH at 366 pg/ml (normal range 85G39). Tomography emission positron imaging showed increased uptake of 18 F-fluoride in the liver, while no uptake of 111In-pentetreotide was observed on liver scintigraphy. The patient rapidly underwent left hepatectomy with apparent complete removal of the tumor.…”

Section: Patientmentioning

confidence: 89%

“…This hypothesis of the tumoral source of circulating plasma ACTH is reinforced by the finding that 2 months after tumor resection, the pituitary ACTH secretion was low, suggesting the suppression of pituitary ACTH secretion during the active phase of the disease rather than its stimulation by circulating CRH. The low level of ACTH immunoreactivity in the tumor tissue may thus be explained by reduced ACTH storage (18).…”

Section: Discussionmentioning

confidence: 99%

“…RT was performed at 37 8C for 60 min in presence of 1 mg of total RNA, using 50 pmol oligodT [12][13][14][15][16][17][18] , 0.2 mM of each deoxynucleotide triphosphate, 10 mM dithiothreitol, 5 U of RNasin and 200 U Moloney murine leukemia virus-RT (Invitrogen) in a final volume of 40 ml. The reaction was terminated by the inactivating enzyme at 95 8C for 5 min.…”

Section: Quantitative Pcr For Pomc 11b-hsd1 and Crh Mrnamentioning

confidence: 99%

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Cushing's syndrome associated with a nested stromal epithelial tumor of the liver: hormonal, immunohistochemical, and molecular studies

Rod

Voicu²,

Chiche³

et al. 2009

European Journal of Endocrinology

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Context: Ectopic ACTH syndrome (EAS) is principally associated with aggressive malignant tumors but also with neuroendocrine tumors of good prognosis. Recently, rare nonhepatocytic nested stromal and epithelial tumors (NSET) were characterized by their possible association with Cushing's syndrome of which biochemical and physiopathological features were still incompletely studied. Objective: To describe the clinical and hormonal characteristics of an EAS originating from a liver NSET and further understand the mechanism of cortisol overproduction. Design and setting: This is a clinical case report from the Endocrinology Department of Caen University Hospital, France. Patient and intervention: A 17-year-old female patient was found to have a large liver NSET with mild Cushingoid clinical features and intense biological hypercortisolism but moderate ACTH secretion. Resection of the tumor was curative with a 30-month follow-up. Results: The epithelial component of the tumor coexpressed ACTH mildly, corticotropin-releasing hormone (CRH) strongly, and 11b-hydroxysteroid dehydrogenase at a level comparable with normal human hepatocytes. Conclusions: Liver NSET is a new cause of EAS, which may evoke hypercortisolism by multiple biochemical pathways.

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Section: Patientmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Quantitative Pcr For Pomc 11b-hsd1 and Crh Mrnamentioning

confidence: 99%

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Cushing's syndrome associated with a nested stromal epithelial tumor of the liver: hormonal, immunohistochemical, and molecular studies

Rod

Voicu²,

Chiche³

et al. 2009

European Journal of Endocrinology

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“…Animal and clinical studies have demonstrated that HPA axis activation by corticotropinreleasing hormone (CRH) or by stress leads to an increase in the number and size of corticotropes in the pituitary gland (Asa et al, 1992;Carey et al, 1984;Gertz et al, 1987;Westlund et al, 1985). This increase in the size and numbers of corticotropes can increase pituitary volume in humans as Figure 3 Individual measures of pituitary volumes in first-episode patients (n ¼ 77; one subject on which we had no medication history was excluded from this analysis) divided by antipsychotic treatment (free, n ¼ 18; atypicals, n ¼ 26; typicals, n ¼ 33).…”

Section: Discussionmentioning

confidence: 99%

Increased Pituitary Volume in Antipsychotic-Free and Antipsychotic-Treated Patients of the Æsop First-Onset Psychosis Study

Pariante

Dazzan

Danese

et al. 2005

Neuropsychopharmacol

142

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Subjects at their first psychotic episode show an enlarged volume of the pituitary gland, but whether this is due to hypothalamicpituitary-adrenal (HPA) axis hyperactivity, or to stimulation of the prolactin-secreting cells by antipsychotic treatment, is unclear. We measured pituitary volume, using 1.5-mm, coronal, 1.5 T, high-resolution MRI images, in 78 patients at the first psychotic episode and 78 age-and gender-matched healthy controls. In all, 18 patients were antipsychotic-free (12 of these were antipsychotic-naïve), 26 were receiving atypical antipsychotics, and 33 were receiving typical antipsychotics. As hypothesized, patients had a larger pituitary volume than controls ( þ 22%, po0.001). When divided by antipsychotic treatment, and compared to controls, the pituitary volume was 15% larger in antipsychotic-free patients (p ¼ 0.028), 17% larger in patients receiving atypicals (p ¼ 0.01), and 30% larger in patients receiving typicals (po0.001). Patients receiving typicals not only had the largest pituitary volume compared to controls but also showed a trend for a larger pituitary volume compared to the other patients grouped together ( þ 11%, p ¼ 0.08). When divided by diagnosis, and compared to controls, the pituitary volume was 24% larger in patients with schizophrenia/schizophreniform disorder (n ¼ 40, po0.001), 19% larger in depressed patients (n ¼ 13, p ¼ 0.022), 16% larger in bipolar patients (n ¼ 16, p ¼ 0.037), and 12% larger in those with other psychoses (n ¼ 9, p ¼ 0.2). In conclusion, the first-episode of a psychotic disorder is associated with a larger pituitary independently of the presence of antipsychotic treatment, and this could be due to activation of the HPA axis. Typical antipsychotics exert an additional enlarging effect on pituitary volume, likely to be related to activation of prolactin-secreting cells. This activation of the hormonal stress response could participate to the important metabolic abnormalities observed in patients with psychosis.

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“…Analysis of the GRF receptor in dwarf mouse strains, snell (dw), and little (lit) indicated that in addition to regulating growth hormone secretion, GRF plays a crucial role in the ontogeny and proliferation of somatotropes (24,37). CRF has also been implicated in regulating cell growth, both in corti- Biochemistry: Kishimoto et aL cotrope hyperplasia (38) and in human small cell lung cancer cells, where CRF stimulates clonal cell growth that is reversed by ahel CRF-(9-41) (39). It is tempting to speculate that CRF or a mammalian sauvagine homolog is involved in the autocrine or paracrine regulation of myocyte growth and hypertrophy.…”

Section: E-qe--neekkskv--h--v-i-mentioning

confidence: 99%

A sauvagine/corticotropin-releasing factor receptor expressed in heart and skeletal muscle

1995

Proc. Natl. Acad. Sci. U.S.A.

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Corticotropin-releasing factor (CRF) mediates many critical aspects of the physiological response to stress. These effects are elicited by binding to specific highaffinity receptors, which are coupled to guanine nucleotide stimulatory factor (Gs)-response pathways. Recently, a gene encoding a receptor for CRF, expressed in pituitary and the central nervous system (PC-CRF receptor), was isolated and characterized. Here we report the identification and characterization of a second, distinct CRF receptor that is expressed primarily in heart and skeletal muscle and exhibits a specific ligand preference and antagonist sensitivity compared with the PC-CRF receptor. We refer to this second receptor as the heart/muscle (HM)-CRF receptor.Corticotropin-releasing factor (CRF) (1) is a member of a family of peptides from different species that act as agonists of the CRF receptor. These peptides include the frog skin peptide, sauvagine (2), and the teleost fish urophysis peptide, urotensin I (3). CRF is a 41-amino acid hypothalamic neuropeptide that plays a central role in coordinating the communications between endocrine, nervous, and immune systems to achieve homeostasis in response to environmental adversities (4, 5). The peptide was originally characterized in the hypothalamo-hypophyseal system but was later found to be widely distributed throughout the central nervous system (CNS), where it appeared to function as a neurotransmitter or neuromodulator (6). In the CNS, CRF initiates the hypothalamic-pituitary-adrenal axis by stimulating the release of adrenocorticotropin (ACTH) and ,B-endorphin from the anterior pituitary. ACTH stimulates adrenal cortex to secrete corticosteroids that, in turn, elicit a wide range of biological responses and exert negative feedback on the hypothalamus and pituitary (4, 5, 7). Both sauvagine and urotensin I have been shown to stimulate the hypothalamic-pituitary-adrenal axis after i.v. administration (8). Intracerebroventricular administration of CRF provokes stress-like responses including activation of the sympathetic nervous system, resulting in an elevation of plasma epinephrine, norepinephrine, and glucose, which results in increased heart rate and mean arterial blood pressure (9, 10). Outside the CNS, CRF immunoreactivity is detectable in multiple peripheral organs, including placenta, adrenal medulla, pancreas, lung, stomach, duodenum, and liver (4, 5). i.v. administration of CRF, sauvagine, and urotensin I has been shown to elicit peripheral systemic responses, including vasodilation (11).CRF functions by binding to a membrane-bound receptor that is coupled to the guanine nucleotide stimulatory factor (G,) signaling protein, resulting in increased intracellular cAMP levels (12,13 (23), and growth hormonereleasing factor ]. The PC-CRF receptor mRNA was found to be most highly expressed in the cerebellum and pituitary and found at lower levels in other brain areas, intestine, and testes. This receptor is undetectable in other tissues examined, including heart and skeletal mus...

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Ectopic Secretion of Corticotropin-Releasing Factor as a Cause of Cushing’s Syndrome

Cited by 270 publications

References 24 publications

Cushing's syndrome associated with a nested stromal epithelial tumor of the liver: hormonal, immunohistochemical, and molecular studies

Cushing's syndrome associated with a nested stromal epithelial tumor of the liver: hormonal, immunohistochemical, and molecular studies

Increased Pituitary Volume in Antipsychotic-Free and Antipsychotic-Treated Patients of the Æsop First-Onset Psychosis Study

A sauvagine/corticotropin-releasing factor receptor expressed in heart and skeletal muscle

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