In unanesthetized, ovariectomized female sheep, the fluctuation of LH levels in peripheral veins and GnRH levels in the portal vein is coordinated. This supports the idea that the release of LH in pulses is dependent on pulsatile stimulation of the pituitary by GnRH. The regulation of FSH and LH secretion from gonadotropes is frequency-encoded. High frequency of GnRH stimulation (1 pulse per hour) preferentially stimulates LH secretion, while a lower frequency promotes FSH secretion. In serum, GH exists in different forms, with the 191-amino acid form representing about 75% of circulating GH. The GH receptor belongs to the cytokine/GH/PRL/erythropoietin receptor family and is linked to the JAK/STAT signaling pathway. Human GH can also act as an agonist of the PRL receptor. Approximately 50% of the 22-kDa form of GH in serum is bound to GH-binding protein (GHBP), derived from the N-terminal portion of the GH receptor. Individuals with Laron syndrome lack normal GH receptors but have normal GH secretion, resulting in undetectable GHBP in their serum. GHBP reduces renal clearance, increasing the biological half-life of GH. GH degradation primarily occurs in the liver and kidney. GH secretion is regulated by the hypothalamus through both positive and negative control mechanisms. GHRH stimulates GH secretion predominantly, while somatostatin inhibits pituitary GH synthesis and release. Ghrelin, produced primarily by the stomach and expressed in the hypothalamus, stimulates GH secretion through the GH secretagogue receptor. Ghrelin also increases appetite and may coordinate nutrient acquisition with growth. The primary negative feedback on the somatotrope is exerted by IGF-I.
Fig. 41.15 FluctuationofperipheralveinplasmaLHlevelsandportalveinplasmaGnRHlevelsinunanesthetized,ovariectomizedfemalesheep.EachpulseofLHiscoordinatedwithapulseofGnRH.ThissupportstheviewthatpulsatilityofLHreleaseisdependentonpulsatilestimulationofthepituitarybyGnRH.(FromLevineJetal.Endocrinology 1982;111:1449.)
Fig. 41.16 Frequency-encodedregulationofFSHandLHsecretionfromgonadotropes.AhighfrequencyofGnRH(1pulse/hr)preferentiallystimulatesLHsecretion,whereasaslowerfrequencyofGnRHpromotesFSHsecretion.(FromLarsenPRetal[eds].Williams Textbook of Endocrinology. 10th ed.Philadelphia:Saunders;2003.) are present in serum, with the 191–amino acid (22-kDa) form representing approximately 75% of circulating GH. The GH receptor is a member of the cytokine/GH/PRL/ erythropoietin receptor family and as such is linked to the JAK/STAT signaling pathway (see ). Human GH can also act as an agonist of the PRL receptor. About 50% of the 22-kDa form of GH in serum is bound to GH-binding protein (GHBP), which is derived from the N-terminal portion (the extracellular domain) of the GH receptor. Individuals with Laron syndrome, who lack normal GH receptors but have normal GH secretion, do not have detectable GHBP in their serum. GHBP reduces renal clearance and thus increases the biological half-life of GH, which is about 20 minutes. The liver and kidney are major sites of GH degradation.
GH secretion is under dual positive/negative control by the hypothalamus (see
Fig. 41.17 ). The hypothalamus predominantly stimulates GH secretion via the peptide growth •Fig. 41.17 Hypothalamic-pituitary-liveraxis.ALS,acidlabilesubunit;GHBP,growthhormone–bindingprotein;GHRH,growthhormone–releasinghormone;IGFBP,insulinlikegrowthfactor–bindingprotein;IGF-I,insulinlikegrowthfactorI;SS,somatostatin.(FromPorterfieldSP,WhiteBA.Endocrine Physiology.
3rded.Philadelphia:Mosby;2007.) hormone–releasing hormone (GHRH). This hormone is a member of the vasoactive intestinal polypeptide (VIP)/ secretin/glucagon family and is processed from a larger prohormone into a 44–amino acid peptide with an amidated C-terminus. GHRH enhances GH secretion and GH gene expression. The hypothalamus inhibits pituitary GH synthesis and release via the peptide somatostatin. In the anterior pituitary, somatostatin inhibits release of GH and TSH. GH secretion is also stimulated by ghrelin, which acts through the GH secretagogue receptor on somatotropes. Ghrelin is primarily produced by the stomach but is also expressed in the hypothalamus. Ghrelin increases appetite and may serve as a signal to coordinate nutrient acquisition with growth.
The primary negative feedback on the somatotrope is exerted by IGF-I (see