Disease relevance of GHRH

• Collectively, our findings show that the expression of SV1 confers oncogenic activity and provide further evidence that GHRH operates as a growth factor in breast cancer and probably other cancers as well [1].
• In this study, GHRH antagonist JV-1-38 (20 microgram/day per animal s.c.) inhibited the growth of orthotopic CAKI-1 human renal cell carcinoma (RCC) by 83% and inhibited the development of metastases to lung and lymph nodes [2].
• A 52-yr-old woman presented with loss of visual acuity, diabetes insipidus, and acromegaly caused by a GHRH-producing endocrine carcinoma metastasized to the pituitary [3].
• We conclude that pituitary GH-secreting adenomas have specific GHRH receptors [4].
• In three nonfunctioning pituitary adenomas, GHRH receptors were not detected [4].

Psychiatry related information on GHRH

• Alpha 2-adrenoceptor sensitivity in anorexia nervosa: GH response to clonidine or GHRH stimulation [5].
• In young normal subjects, GHRH stimulates slow-wave sleep and growth hormone secretion but inhibits cortisol release, whereas CRH has the opposite effect [6].
• After GHRH, the increase of NREMS and the decrease of wakefulness were more distinct than after placebo [7].
• The present study therefore investigated the ability of CRH to inhibit the GH response to GHRH in eight young women with anorexia nervosa (AN) and in seven young women with eating disorders which were not otherwise specified (NOS) [8].
• GH responses to GHRH were negatively correlated with the plasma insulin-like growth factor (IGF-I) concentrations and the severity of dementia [9].

High impact information on GHRH

• Since the identification of the GHRH peptide, recombinant DNA procedures have been used to characterize the corresponding cDNA and to clone GHRH receptor isoforms in rodent and human pituitaries [10].
• Growth hormone secretion was increased after pulses of growth hormone-releasing factor during the entire six-month period, and growth was accelerated [11].
• The growth hormone response to growth hormone-releasing factor was inversely correlated with the percentage of ideal body weight (P less than 0.01) and directly correlated with the growth hormone response to insulin (P less than 0.01) [12].
• The impaired responsiveness to growth hormone-releasing factor suggests that the diminished response to insulin hypoglycemia is mediated by an impaired pituitary response to endogenous growth hormone-releasing factor [12].
• Production of growth hormone-releasing factor in pheochromocytoma [13].

Chemical compound and disease context of GHRH

• Arginine but not pyridostigmine, a cholinesterase inhibitor, enhances the GHRH-induced GH rise in patients with anorexia nervosa [14].
• When acromegaly and abnormal GH responsiveness are induced by a GHRH-secreting tumor, the increases in plasma GH after TRH, glucose, and insulin administration are not mediated by GHRH [15].
• Similarly, coincubation of dopamine resulted in inhibition of GHRH-induced hormone secretion in some adenomas [16].
• Nonresectable, disseminated or reccurrent carcinoid syndrome with ectopic GHRH secretion can also be managed medically with long-acting somatostatin analogs (octreotide and lanreotide) [17].
• The distribution of GHRH receptors was investigated in 69 formalin-fixed, paraffin-embedded human tumours showing that GHRH receptors were frequently expressed in breast, ovarian and prostate carcinomas [18].

Biological context of GHRH

• In accordance with previous findings, the expression of both GHRHR and SV1 restored the sensitivity to GHRH-induced stimulation of cell proliferation, with SV1 being more potent than the GHRHR [1].
• The presence of specific receptor proteins that bind GHRH antagonists in CAKI-1 RCC supports the view that distinct binding sites that mediate the inhibitory effect of GHRH antagonists are present on various human cancers [2].
• Furthermore, MCF-7 cells transfected with SV1 proliferated more quickly than the controls, even in the absence of exogenously added GHRH, suggesting the existence of intrinsic, ligand-independent activity of SV1 after its transfection [1].
• A specific GHRH antagonist blocked both binding and second messenger response [19].
• In AN patients, GHRH administration induced a GH rise higher, though not significantly, than that in NV [delta area under the curve (AUC) 1173.6 +/- 167.6 versus 834.6 +/- 188.1 micrograms/L/h] [14].

Anatomical context of GHRH

• A splice variant (SV) of the full-length receptor for GHRH (GHRHR) is widely expressed in various primary human cancers and established cancer cell lines and appears to mediate the proliferative effects of GHRH [1].
• In addition, high-affinity, low-capacity binding sites for GHRH antagonists were found on the membranes of cancer cell lines such as MiaPaCa-2 that are negative for the vasoactive intestinal peptide/pituitary adenylate cyclase-activating polypeptide receptor (VPAC-R) or lines such as LNCaP that are positive for VPAC-R [20].
• Transient expression of this cDNA in COS cells induced saturable, high affinity, GHRH-specific binding and also stimulated intracellular cAMP accumulation in response to physiological concentrations of GHRH [19].
• GHRH is released by the hypothalamus into the portal hypophysial circulation to bind to a membrane surface receptor [GHRH receptor (GHRHR)] expressed by the somatotropic cells [21].
• The functional and morphological changes in the pituitary gland caused by a GHRH-producing pancreatic islet cell tumor that metastasized to the pituitary and caused somatotroph hyperplasia are described [3].

Associations of GHRH with chemical compounds

• Pituitary function was studied in detail during each phase of the study protocol by measuring hormone levels in basal conditions and after dynamic testing (GnRH, insulin tolerance test, GHRH plus arginine, TRH, and corticotropin-releasing factor; tests) [22].
• Pyridostigmine enhanced the first GH response to GHRH with an increase in the GH release rate; second GH responses were not augmented [23].
• Neither the responses to clonidine nor the responses to GHRH were significantly lower in depressed patients than in controls [24].
• No change in plasma immunoreactive GHRH (IR-GHRH) occurred after TRH, glucose, insulin, or SRIH administration [15].
• Plasma GH did not change after GH-releasing hormone (GHRH), LHRH, or L-dopa administration [15].

Physical interactions of GHRH

• The GHRH receptor is a seven-transmembrane G protein-coupled receptor that localizes to the surface of somatotroph cells and binds GHRH [25].
• Expression of the W250X GHRH receptor on the cell membrane was severely decreased and GHRH binding to the G294R GHRH receptor was impaired [26].
• The present results also show that Ghrelin interacts with GHRH and SS to in the release of GH from porcine adenohypophysial cells [27].
• In a single-blind placebo-controlled study, the effect of an iv bolus injection of 100 micrograms GHRH(1-29)NH2 on the response to 200 micrograms TRH was assessed in 10 untreated patients with acromegaly to determine whether GHRH interacts with TRH in acromegaly, as previously described in healthy subjects [28].
• The human growth hormone releasing factor (hGRF) derivative with acetylated N-terminus e.g. Ac-Tyr1hGRF binds to VIP receptors in both tissues with a similar affinity [29].

Enzymatic interactions of GHRH

• In the short precursor, the coding region for GHRH is deleted leaving the PACAP-coding region in a correct reading frame [30].
• We also observed that human tissue kallikrein hydrolysed growth hormone-releasing hormone at the Arg11-Lys12 bond, although this peptide contains in its structure a pair of leucines (Leu22-Leu23), in contrast with the Phe-Phe pair in somatostatin [31].

Regulatory relationships of GHRH

• When cells were coincubated with 0.1 nM somatostatin, GH and PRL secretion induced by 10 nM GHRH were completely blocked in most adenomas [16].
• The GH response to GHRH was similarly inhibited (P < 0.01) by either CST-14 or SS-14 [32].
• Galanin enhances both baseline and growth hormone-releasing hormone (GHRH)-induced GH secretion both in animals and in man [33].
• Our failure to demonstrate a difference in GH response to GHRH between schizophrenics and controls would seem to indicate that GH secretory pituitary reserve is intact in young acute male schizophrenics [34].
• These results show that antagonistic analogs of GHRH suppress the stimulatory effects of GHRH and VIP on the cAMP production of various cancer cells [35].

Other interactions of GHRH

• This indicates the essential role of GHRH in regulation of GH secretion [36].
• Omission of extracellular Ca2+ blocked the stimulatory effect of GHRH on GH and PRL secretion [16].
• Endocrine activities of cortistatin-14 and its interaction with GHRH and ghrelin in humans [32].
• These findings suggest that SSTR-specific SRIH analogs may be useful in the medical therapy of GHRH-secreting bronchial carcinoids [37].
• In group 1 (n = 7) Gal (15 micrograms/kg h i.v.) plus GHRH (1 microgram/kg i.v.) administration induced a higher GH rise (peak = 73.1 +/- 10.2 ng/mL, mean +/- SD; area under the curve (AUC) = 531.9 +/- 78.7 ng.min.mL-1) than did GHRH alone (peak = 38.9 +/- 26.5 ng/mL, p less than 0.05; AUC = 256.9 +/- 165.6 ng/mL/min-1, p less than 0.005) [38].

Analytical, diagnostic and therapeutic context of GHRH

• All 3 mutant receptors were expressed in CHO cells, and each failed to show a cAMP response after treatment of the cells with GHRH [39].
• RT-PCR analyses also revealed the expression of mRNA for GHRH in 13 of 15 (86%) prostatic carcinoma specimens examined [40].
• Immunohistochemical and in situ hybridization study revealed GHRH immunoreactivity and GHRH messenger RNA (mRNA) in the metastatic tumor cells [3].
• Gel filtration of pooled extracts from adrenal pheochromocytomas showed that the major component of the IR-CRH, IR-GHRH, IR-SRIH, and IR-PHM eluted in the position of their synthetic counterparts [41].
• Anemic patients on chronic hemodialysis had high basal GH concentrations, an exaggerated GH response to exogenous GHRH, increased levels of IGF-1, and elevated levels of IGF-1 binding protein-3 in comparison to controls [42].

References