Consideration of GH feedback is relevant for understanding physiology in children. From a practical therapeutic point of view, exogenous GH readily increases growth velocity. GH is directly and indirectly involved in the feedback control of its own secretion as the hypothalamic neurons that generate the GH pulse are sensitive to the pattern of GH secretion they generate (93). Administration of exogenous GH results in a blunted GH response to clonidine and GHRH in short normal boys (94) and to insulin and GHRH in healthy adult men (95,96). GH acutely inhibits its own secretion through a direct effect on the hypothalamus (97), and through increases in IGF-1, which indirectly inhibits GH release at the level of the pituitary and hypothalamus (7).
SRIF release modulates the negative feedback of GH on its own secretion independent of adrenergic and cholinergic mechanisms (97). A single injection of recombinant hGH to adult male rats acutely attenuates GH responsiveness to GHRH and subsequently enhances somatotrope sensitivity to GHRH administration owing in part to increased somatostatin tone (98). Intraventricular injection of GH in anesthetized rats increases SRIF levels in hypothalamic-hypophyseal portal blood, whereas hypophysectomy decreases hypothalamic SRIF-like immunoreactivity in rats (7). Using a double-label in vitro hybridization technique to identify neurons that co-express SRIF mRNA and GH receptor mRNA, populations of these SRIF/GH receptor mRNA-neurons were identified in the periventricular and paraventricular nuclei of the Sprague-Dawley rat, providing additional support for the direct effects of GH on hypothalamic SRIF neurons in the regulation of its own secretion (99).
GH treatment of GH-deficient children has been associated with hypothyroidism thought to be related to increased SRIF tone and its inhibitory effect on thyroid-stimulating hormone (TSH) secretion. TRH stimulation testing of TSH secretion during formal assessment of the hypothalamic-pituitary GH axis frequently identifies subjects with hypothalamic or pituitary hypothyroidism prior to initiation of GH replacement therapy (B. Bercu, unpublished data). Thus, a direct effect of GH replacement and thyroid dysfunction is unlikely. Along with increases in SRIF, in vitro studies suggest GH inhibits GHRH release in a dose-dependent fashion (7) indicating GH autofeedback is under dual control of both hypothalamic peptides.
GH excess, or pituitary gigantism, is an uncommon disorder of childhood, most often associated with isolated pituitary somatotroph adenoma (100-102), McCune Albright syndrome (103,104) or less commonly as part of the multiple endocrine neoplasia-type 1 syndrome (105,106). Acromegaly, the adult form has occurred from pancreatic tumors secreting GHRH (107,108). Hormonal secretion from tumor explants in culture obtained from a large mammosomatotroph adenoma in an 8-yr-old boy demonstrated increased adenylate cyclase activity and high levels of adenylate cyclase-stimulatory G protein alpha subunit (Gs alpha). Bromocriptine therapy resulted in reduced adenylate cyclase activity and Pit-1 mRNA expression; Gs alpha levels paradoxically increased, suggesting a beneficial effect of bromocritpine to short circuit Gs alpha-stimulated adenylate cyclase activity via reduction in Pit-1 (109). Gigantism in a 7-yr-old male, and histologic evidence of somatotroph, lactotroph, and mammosomatotroph hyperplasia was associated with hypersecretion of GHRH expands the spectrum of GH hypersecretion (110).
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