Ectopic secretion of growth hormone-releasing hormone (GHRH) in neuroendocrine tumors: Relevant clinical aspects

Abstract

The aim of this article is to briefly review the physiology of growth hormone-releasing hormone (GHRH) and the diagnosis and treatment of GHRH-mediated acromegaly. Moreover, the role of GHRH and its antagonists in the pathogenesis and treatment of cancer will be reviewed. 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. GHRH-producing neurons have been well characterized in the hypothalamus by immunostaining techniques. Hypothalamic tumors, including hamartomas. choristomas, gliomas. and gangliocitomas. may produce excessive GHRH with subsequent GH hypersecretion and resultant acromegaly. 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 and increased GH secretion. The structure of hypothalamic GHRH was infact elucidated from material extracted from pancreatic GHRH-secreting tumors in two patients with acromegaly. Immunoreactive GHRH is present in several tumors, including carcinoid tumors, pancreatic cell tumors, small-cell lung cancers, adrenal adenomas, and pheochromocitomas which have been reported to secrete GHRH. Acromegaly in these patients. however, is uncommon. In a retrospective survey of 177 acromegalic patients only a single patient was identified with elevated plasma GHRH levels. Measuring GHRH plasma levels therefore provides a precise and cost-effective test for the diagnosis of ectopic acromegaly. Peripheral GHRH levels are not elevated in patients with hypothalamic GHRH- secreting tumors, supporting the notion that excess eutopic hypothalamic GHRH secretion into the hypophyseal portal system does not appreciably enter the systemic circulation. Elevated circulating GHRH levels, a normal or small-size pituitary gland, or clinical and biochemical features of other tumors known to be associated with extrapituitary acromegaly, are all indications for extrapituitary imaging. An enlarged pituitary is, however, often found on MRI of patients with peripheral GHRH-secreting tumors, and the radiologic diagnosis of a pituitary adenoma may be difficult to exclude. Surgical resection of the tumor secreting ectopic GHRH should reverse the hypersecretion of GH, and pituitary surgery should not be necessary in these patients. Nonresectable, disseminated or reccurrent carcinoid syndrome with ectopic GHRH secretion can also be managed medically with long-acting somatostatin analogs (octreotide and lanreotide). The presence of GHRH and its receptors in several extrahypothalamic tissues, including ovary, testis and the digestive tract, suggests that GHRH may have a regulatory role in these tissues. As previously mentioned, biologically or immunologically active GHRH and mRNA encoding GHRH have been found in several human malignant tumors. including cancers of the breast, endometrium and ovary and their cell lines. The s...

Hormones, hormonal agents, and neuropeptides involved in the neuroendocrine regulation of sleep in humans

“…29 On the other hand, various types of benign tumours may lead to ectopic, peripheral GHRH hypersecretion, causing GHRH-associated acromegaly. 30 In these patients, feedback inhibition of GHRH may contribute to the decrease of SWS.…”

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

“…Although the presence of immunoreactive GHRH in tumor tissue does not necessarily imply hypersecretion of the peptide, over half of patients with carcinoid do in fact exhibit abnormal GH secretory dynamics including increased 24-h GH secretion, failure to suppress GH level after glucose ingestion [81] and inappropriate GH response after TRH administration [78]. The observed high incidence of GHRH expression and low incidence of true acromegaly in these patients may be due to disordered tissue processing of GHRH by some tumors, or to impaired bioactivity of circulating GHRH [82]. In fact, posttranslational processing and proteolytic degradation of GHRH is tissue and tumor-specific.…”

“…However, acromegalic patients with no evidence of pituitary tumor and extrasellar masses may be suspected of having the ectopic GHRH syndrome. The logical approach to such patients is to exclude the diagnosis of ectopic GHRH secretion by measuring the plasma level of the peptide or, if a tumor specimen is available, assessing the presence of immunostainable GHRH in the tumor cells [82].…”

Effect of GHRH and GHRP-2 treatment in vitro on GH secretion and levels of GH, pituitary transcription factor-1, GHRH-receptor, GH-secretagogue-receptor and somatostatin receptor mRNAs in ovine pituitary cells

“…GHRH and GHRP administration potently increases GH secretion and this is not altered by gender, adiposity or age (9). However, peripheral circulating GHRH levels are not usually linked to an increase in GH levels as evidenced in patients with hypothalamic GHRH-secreting tumors (33). The key cell type in the regulation of GH levels is the pituitary somatotrope, which determines the amount of GH secreted in response to hypothalamic GHRH stimulation.…”