Pulsatile growth hormone secretion persists in genetic growth hormone-releasing hormone resistance

Abstract

. Pulsatile growth hormone secretion persists in genetic growth hormone-releasing hormone resistance. Am J Physiol Endocrinol Metab 282: E943-E951, 2002. First published January 8, 2002 10.1152/ajpendo.00537.2001 secretion is regulated by GH-releasing hormone (GHRH), somatostatin, and possibly ghrelin, but uncertainty remains about the relative contributions of these hypophysiotropic factors to GH pulsatility. Patients with genetic GHRH receptor (GHRH-R) deficiency present an opportunity to examine GH secretory dynamics in the selective absence of GHRH input. We studied circadian GH profiles in four young men homozygous for a null mutation in the GHRH-R gene by use of an ultrasensitive GH assay. Residual GH secretion was pulsatile, with normal pulse frequency, but severely reduced amplitude (Ͻ1% normal) and greater than normal process disorder (as assessed by approximate entropy). Nocturnal GH secretion, both basal and pulsatile, was enhanced compared with daytime. We conclude that rhythmic GH secretion persists in an amplitude-miniaturized version in the absence of a GHRH-R signal. The nocturnal enhancement of GH secretion is likely mediated by decreased somatostatin tone. Pulsatility of residual GH secretion may be caused by oscillations in somatostatin and/or ghrelin; it may also reflect intrinsic oscillations in somatotropes.growth hormone-releasing hormone receptor; somatostatin; pituitary gland; short stature GROWTH HORMONE (GH) IS SECRETED in a pulsatile or episodic manner. This secretion pattern is principally governed by hypothalamic growth hormone-releasing hormone (GHRH) and somatostatin (see Ref. 23 for review). Ghrelin (39) and/or a similar endogenous ligand for the GH secretagogue (GHS) receptor may also participate in GH pulse generation, although its role in physiological GH secretion is still largely unknown. GHRH and ghrelin stimulate pituitary GH release, whereas somatostatin inhibits it. In addition to its acute GH-releasing action, GHRH also stimulates GH synthesis (3) and somatotrope proliferation during pituitary ontogeny (41, 68).The pulsatile pattern of GH secretion and its relation to GHRH and somatostatin rhythms has been evaluated extensively in a number of species (23), and a concept of GHRH-induced GH pulses, modulated by prevailing somatostatin tone and rapid somatostatin oscillations, has been formulated (65). A role of ghrelin in this interplay can be postulated but remains unproved. This model is supported by studies using immunoneutralization of GHRH and somatostatin (65, 80), GHRH, or somatostatin antagonists (5,33,34,73), as well as direct pituitary portal sampling in experimental animals (18,20,55,66). A reciprocal relationship between GHRH and somatostatin, where GHRH pulses coincide with somatostatin troughs, has been reported in rats (37,55,65), but this pattern is less clear in sheep or pigs, where more complex relationships between oscillations in GHRH, somatostatin, and GH prevail (8,15,20,66). Thus important species as well as sex differences exist in the regulation...

MECHANISMS IN ENDOCRINOLOGY: The multiple facets of GHRH/GH/IGF-I axis: lessons from lifetime, untreated, isolated GH deficiency due to a GHRH receptor gene mutation

“…Interestingly, in four patients with the E72X mutation nocturnal plasma GH levels were significantly higher than daytime, with maintained pulsatility. However, there was no correlation between GH production and height or serum IGF-I level in this small group (81). In Itabaianinha IGHD children we found a positive correlation between height SDS and one parameter of the activity of the GH-IGF-I axis, namely ALS (22).…”

Sexual Dimorphism of Growth Hormone (GH) Regulation in Humans: Endogenous GH-Releasing Hormone Maintains Basal GH in Women But Not in Men

“…Despite employing a relatively high dose of GHRH antagonist (6, 17), we could not achieve a complete elimination of the pituitary responsiveness to GHRH, as evidenced by the diminished but still present GH responses to a physiological dose of exogenous GHRH. This may explain the persistence of GH pulses in both sexes albeit at a markedly diminished amplitude, or the pulses could have been due to a non-GHRH stimulus as demonstrated in patients with genetic GHRH resistance (18). Diminished pulse amplitude was the main determinant of suppressed daily GH output in both sexes.…”

Pulsatile and nocturnal growth hormone secretions in men do not require periodic declines of somatostatin

“…However, in humans, it is still unknown whether GH pulses are the direct result of episodic hypothalamic GHRH release or whether tonically secreted GHRH is required for the occurrence of GH pulses that are initiated by another factor. In support of the latter hypothesis, in patients with inactivating mutations of the GHRH receptor there are detectable GH pulses, albeit of very low amplitude (24,33). The recently discovered peptide ghrelin might play a role in GH pulse generation (19).…”