Joint pituitary-hypothalamic and intrahypothalamic autofeedback construct of pulsatile growth hormone secretion

Abstract

Farhy, Leon S., and Johannes D. Veldhuis. Joint pituitary-hypothalamic and intrahypothalamic autofeedback construct of pulsatile growth hormone secretion. Am J Physiol Regul Integr Comp Physiol 285: R1240-R1249, 2003. First published July 24, 2003 10.1152/ajpregu.00086.2003 secretion is vividly pulsatile in all mammalian species studied. In a simplified model, self-renewable GH pulsatility can be reproduced by assuming individual, reversible, time-delayed, and threshold-sensitive hypothalamic outflow of GH-releasing hormone (GHRH) and GH release-inhibiting hormone (somatostatin; SRIF). However, this basic concept fails to explicate an array of new experimental observations. Accordingly, here we formulate and implement a novel fourfold ensemble construct, wherein 1) systemic GH pulses stimulate long-latency, concentrationdependent secretion of periventricular-nuclear SRIF, thereby initially quenching and then releasing multiphasic GH volleys (recurrent every 3-3.5 h); 2) SRIF delivered to the anterior pituitary gland competitively antagonizes exocytotic release, but not synthesis, of GH during intervolley intervals; 3) arcuate-nucleus GHRH pulses drive the synthesis and accumulation of GH in saturable somatotrope stores; and 4) a purely intrahypothalamic mechanism sustains high-frequency GH pulses (intervals of 30-60 min) within a volley, assuming short-latency reciprocal coupling between GHRH and SRIF neurons (stimulatory direction) and SRIF and GHRH neurons (inhibitory direction). This two-oscillator formulation explicates (but does not prove) 1) the GHRH-sensitizing action of prior SRIF exposure; 2) a three-site (intrahypothalamic, hypothalamo-pituitary, and somatotrope GH store dependent) mechanism driving rebound-like GH secretion after SRIF withdrawal in the male; 3) an obligatory role for pituitary GH stores in representing rebound GH release in the female; 4) greater irregularity of SRIF than GH release profiles; and 5) a basis for the paradoxical GH-inhibiting action of centrally delivered GHRH. feedback; mathematical model; somatotropic axis; hormone pulsatility; somatostatin; growth hormone-releasing hormone; hypothalamus THE SECRETION OF GROWTH HORMONE (GH) is pulsatile in the human, monkey, sheep, swine, guinea pig, rat, and mouse (10,20,21,30,34,37,40,48,49). In the rodent, episodic GH release directs somatic growth, cellular gene expression, and autonegative feedback (3,20,31,34,37,42). A distinctive feature of pulsatile GH secretion is the dual representation of 1) multiburst volleys, which recur every 3-3.5 h in the adult male rat and every 1.5-2.5 h in men and women, and 2) rapid discrete GH pulses, which arise every 30-60 min within an individual volley (19-22, 30, 37, 38, 42, 48, 49). Such complex patterns of GH release are evident by high-frequency (0.5-and 5-min) sampling paradigms in the unanesthetized rat, sheep, and healthy human (19,22,23,37,38,42,49). The mechanisms that generate composite low-frequency volleys and high-frequency GH bursts are not established.Our earlier construction...

Growth hormone secretion in primary adrenal Cushing's syndrome is disorderly and inversely correlated with body mass index

“…The ApEn statistic quantitates the relative orderliness or reproducibility of subordinate (nonpulsatile) secretory patterns in neurohormone time series, which in turn mirrors feedforward and feedback adjustments driven by (patho)physiological changes in interglandular communication. The validity of ApEn to this end has been established in theoretical and experimental contexts (9,55,56). In view of the unchanged IGF-I feedback signal in the patients, decreased regularity of GH secretion could reflect impaired coordinate control of GH secretion by somatostatin, GHRH, and ghrelin and/or altered pituitary responsiveness to these peptides (9,10).…”

“…The validity of ApEn to this end has been established in theoretical and experimental contexts (9,55,56). In view of the unchanged IGF-I feedback signal in the patients, decreased regularity of GH secretion could reflect impaired coordinate control of GH secretion by somatostatin, GHRH, and ghrelin and/or altered pituitary responsiveness to these peptides (9,10). Available data do not address the reversibility of disorderly GH release due to endogenous adrenal cortisol excess with presumptively normal premorbid hypothalamo-pituitary function.…”

Short-Term Testosterone Supplementation Relieves Growth Hormone Autonegative Feedback in Men

“…6). This ensemble of actions would, in principle, limit the duration of autoinhibition and enhance GH pulse renewal (4,5,22).…”

The impact of the mother on the hypothalamic-pituit aryadrenal, hypothalamic-pituit ary-gonadal and somatotropic axes activity of offspring during postnatal ontogeny

“…Growth hormone releasing hormone released from the ARC stimulates the synthesis and release of GH in the pituitary cells. Circulating GH suppresses its own synthesis through reducing of the effectiveness of the GHRH secretion and the enhancement of the somatostatin secretion (Farhy et al 2003). Growth hormone elicits its effects directly in the cartilage or mature adipocytes or trough IGF-I (insulin-like growth hormone I) and IGF-II (insulin-like growth hormone II) which are mostly produced in the liver.…”