Presence of somatostatin receptors negatively coupled to adenylate cyclase in ectopic growth hormone-releasing hormone- and alpha-subunit-secreting tumors from acromegalic patients responsive to octreotide.

Abstract

The functional study of SRIH receptors was performed in ectopic GHRH-secreting tumors from two patients with acromegaly; patient 1 presented with multiple endocrine neoplasia type 1 with GHRH- and insulin-secreting pancreatic tumors, and patient 2 presented with a multihormone-secreting carcinoid tumor (including GHRH and alpha-subunit secretion, as demonstrated by clinical and immunohistochemical studies). In both cases, plasma GH levels were responsive to octreotide. In patient 2, plasma GHRH and alpha-subunit levels were responsive to octreotide. In vitro perifusion studies of a tumor fragment from patient 1 also showed inhibition of GHRH secretion by SRIH. A high density of specific SRIH-binding sites was visualized by autoradiography in GHRH tumors from both patients. SRIH specific binding was much higher in the GHRH tumors (6.6-8.4 fmol/surface unit) than in the insulinoma (1.9 fmol/surface unit). The binding inhibition constant (IC50) was in the nanomolar range (0.9-3 nmol/L) in the GHRH tumors. SRIH-14 inhibited forskolin-stimulated adenylate cyclase in the GHRH tumors from both patients, but not in the insulinoma. The functional SRIH receptors negatively coupled to adenylate cyclase present in ectopic GHRH-secreting tumors mediate the inhibitory effect of octreotide on GHRH secretion and on previously underrecognized ectopic alpha-subunit secretion from carcinoid tumors.

Hormonal and Volumetric Long Term Control of a Growth Hormone-Releasing Hormone-Producing Carcinoid Tumor

“…A very high density of somatostatin receptors in the liver tumor could be confirmed by somatostatin receptor autoradiography. This case therefore adds to the two cases reported by Bertherat, who documented the presence of somatostatin receptors negatively coupled to adenylate cyclase in ectopic GHRH-secreting tumors from acromegalic patients responsive to octreotide (3).…”

Nuclear Effects of the cAMP Pathway Activation in Somatotrophs

“…GHRH was first purified from a pancreatic tumor responsible for acromegaly [10,11], Acromegalic patients with GHRH-secreting tumors usually exhibit somato troph hyperplasia, although documented somatotroph ad enoma has been reported [12][13][14], GHRH is also ex pressed in somatotroph adenomas and could play an auto crine role in these tumors [15,16]. GHRH induces soma totroph proliferation by a cAMP-dependent mechanism which can be inhibited by SRIH in primary culture of the rat anterior pituitary [17], The proliferative effects of GHRH could be mediated by the proto-oncogene c-fos which is stimulated at the transcriptional level by GHRH [18], In transgenic mice, overexpression of GHRH, or pituitary targeted expression of the adenylate cyclase acti vator, cholera toxin, induces pituitary hyperplasia with GH hypersecretion and gigantism [19,20], A somatic point mutation of the Gs-protein a-subunit gene (which is coupled to the GHRH receptor) is present in about 40% of the somatotroph adenomas [21,22], The Gas mutation (termed Gsp) leads to constitutive adenylate cyclase acti vation with an increased intracellular level of cAMP [21,22].…”

Ectopic growth hormone‐releasing hormone secretion by thymic carcinoid tumour

“…However, experience in treating ectopic GHRH secretion is limited, with only 18 patients reported to date. While clinical improvement of acromegalic features was documented in most of the patients, less than 50% normalized GH and IGF‐I levels, and two patients did not respond at all (Bertherat et al ., 1994; Ezzat et al ., 1994). GH decreased by 40–90% and was accompanied by a reduction of GHRH by 54–70%.…”