growth hormone-releasing hormone

**Source and structure:** GHRH is a 44-amino-acid peptide (also called somatocrinin) made by neurons of the hypothalamic arcuate nucleus. It travels through the hypophyseal portal system to the anterior pituitary.

**Mechanism:** GHRH binds the GHRH receptor on somatotrophs (acidophils). The receptor is Gs-coupled, so adenylyl cyclase is activated and cAMP and PKA rise. This increases GH gene transcription (via Pit-1/CREB) and GH release. Somatotroph proliferation also increases.

**Regulation:** - Stimulators of GHRH/GH: sleep (slow-wave, stage 3/4 NREM), exercise, hypoglycemia, fasting, amino acids (arginine), stress, estrogen/testosterone (puberty), L-dopa, clonidine, and ghrelin (acts via GHS-R on the pituitary and hypothalamus). - Inhibitors: somatostatin (GHIH, which acts via Gi and lowers cAMP), hyperglycemia/glucose load, obesity, aging, corticosteroids, and negative feedback from IGF-1 and GH itself. - GH secretion is pulsatile, and the largest pulses occur during deep sleep.

**Downstream effects of GH:** GH acts on the liver to produce IGF-1 (somatomedin C). IGF-1 acts through a tyrosine kinase receptor and promotes linear growth and protein synthesis. GH itself is diabetogenic: it causes lipolysis, gluconeogenesis, and insulin resistance (raises blood glucose).

**Clinical correlations:** - Excess GH (usually a somatotroph adenoma, not ectopic GHRH) causes gigantism in children (open growth plates) and acromegaly in adults. Findings include enlarged hands and feet, coarse facies, prognathism, glucose intolerance, and cardiomyopathy. The diagnosis is an elevated IGF-1 and GH that fails to suppress on an oral glucose tolerance test, followed by pituitary MRI. Treatment is transsphenoidal surgery. Octreotide (a somatostatin analog) and pegvisomant (a GH receptor antagonist) are medical options. - Ectopic GHRH production (e.g., from pancreatic islet tumors or bronchial carcinoids) is a rare cause of acromegaly with somatotroph hyperplasia. - GH deficiency causes short stature in children and is treated with recombinant GH. Causes include hypothalamic or pituitary lesions and Laron syndrome (GH receptor defect, with high GH and low IGF-1). Lit/GHRH receptor mutations cause isolated GH deficiency. - Diagnostic use: the GHRH-arginine stimulation test assesses GH reserve. A normal response suggests a hypothalamic cause, and a blunted response suggests a pituitary cause. - Pharmacology: tesamorelin is a GHRH analog used to reduce visceral abdominal fat in HIV-associated lipodystrophy. Sermorelin is a GHRH analog (1-29) used diagnostically.

**High-yield pearls:** - GHRH: arcuate nucleus. Somatostatin: periventricular nucleus. - GHRH acts via Gs/cAMP. Somatostatin acts via Gi. - Other GH-axis agents: octreotide (somatostatin analog), pegvisomant (GH receptor antagonist), and ghrelin (stimulates GH release). - Pit-1 mutations cause combined deficiency of GH, prolactin, and TSH.