Joint pituitary-hypothalamic and intrahypothalamic autofeedback construct of pulsatile growth hormone secretion.
Growth hormone (GH) 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, concentration-dependent 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.
Farhy
Leon S
LS
Division of Endocrinology and Metabolism, Dept. of Internal Medicine, Mayo Medical and Graduate Schools of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, MN 55905, USA.
Veldhuis
Johannes D
JD
D000818:Animals; D025461:Feedback, Physiological / Q000502:physiology; D005260:Female; D013006:Growth Hormone / Q000378:metabolism*; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology*; D008297:Male; D008954:Models, Biological; D011673:Pulsatile Flow / Q000502:physiology; D017481:Receptors, Somatostatin / Q000378:metabolism
D017481:Receptors, Somatostatin; D013006:Growth Hormone