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Neuroendocrine tumors secreting growth hormone-releasing hormone: Pathophysiological and clinical aspects

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Abstract

Hypothalamic GHRH is secreted into the portal system, binds to specific surface receptors of the somatotroph cell and elicits intracellular signals that modulate pituitary GH synthesis and/or secretion. Moreover, GHRH is synthesized and expressed in multiple extrapituitary tissues. Excessive peripheral production of GHRH by a tumor source would therefore be expected to cause somatotroph cell hyperstimulation, increased GH secretion and eventually pituitary acromegaly.

Immunoreactive GHRH is present in several tumors, including carcinoid tumors, pancreatic cell tumors, small cell lung cancers, endometrial tumors, adrenal adenomas, and pheochromocytomas which have been reported to secrete GHRH. Acromegaly in these patients, however, is uncommon. The distinction of pituitary vs. extrapituitary acromegaly is extremely important in planning effective management.

Regardless of the cause, GH and IGF-1 are invariably elevated and GH levels fail to suppress (<1 μg/l) after an oral glucose load in all forms of acromegaly. Dynamic pituitary tests are not helpful in distinguishing acromegalic patients with pituitary tumors from those harbouring extrapituitary tumors. Plasma GHRH levels are usually elevated in patients with peripheral GHRH-secreting tumors, and are normal or low in patients with pituitary acromegaly. Unique and unexpected clinical features in an acromegalic patient, including respiratory wheezing or dyspnea, facial flushing, peptic ulcers, or renal stones sometimes are helpful in alerting the physician to diagnosing non pituitary endocrine tumors. If no facility to measure plasma GHRH is available, and in the absence of MRI evidence of pituitary adenoma, a CT scan of the thorax and abdominal ultrasound could be performed to exclude with good approximation the possibility of an ectopic GHRH syndrome.

Surgical resection of the tumor secreting ectopic GHRH should be the logical approach to a patient with ectopic GHRH syndrome. Standard chemotherapy directed at GHRH-producing carcinoid tumors is generally unsuccessful in controlling the activated GH axis.

Somatostatin analogs provide an effective option for medical management of carcinoid patients, especially those with recurrent disease. In fact, long-acting somatostatin analogs may be able to control not only the ectopic hormonal secretion syndrome, but also, in some instances, tumor growth. Therefore, although cytotoxic chemotherapy, pituitary surgery, or irradiation still remain available therapeutic options, long-acting somatostatin analogs are now preferred as a second-line therapy in patients with carcinoid tumors and ectopic GHRH-syndrome.

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Authors and Affiliations

  1. Division of Medicine, “Carlo Poma” Hospital, Mantova

    Monica Gola, Mauro Doga & Pier Paolo Vescovi

  2. Endocrine Section, Department of Internal Medicine, University of Brescia, Brescia, Italy

    Stefania Bonadonna, Gherardo Mazziotti & Andrea Giustina

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  2. Mauro Doga
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  3. Stefania Bonadonna
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  4. Gherardo Mazziotti
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  5. Pier Paolo Vescovi
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  6. Andrea Giustina
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Correspondence to Andrea Giustina.

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Gola, M., Doga, M., Bonadonna, S. et al. Neuroendocrine tumors secreting growth hormone-releasing hormone: Pathophysiological and clinical aspects. Pituitary 9, 221–229 (2006). https://doi.org/10.1007/s11102-006-0267-0

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