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1 Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, VA, USA
2 Department of Internal Medicine, Division of Endocrinology and Metabolism, Mayo Medical and Graduate Schools of Medicine, Rochester, MN, USA
* To whom correspondence should be addressed. E-mail: veldhuis.johannes{at}mayo.edu.
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: (i) 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 to 3.5 h); (ii) SRIF delivered to the anterior pituitary gland competitively antagonizes exocytotic release, but not synthesis, of GH during intervolley intervals; (iii) arcuate-nucleus GHRH pulses drive the synthesis and accumulation of GH in saturable somatotrope stores; and (iv) a purely intrahypothalamic mechanism sustains high-frequency GH pulses (intervals of 30 to 60 min) within a volley, assuming short-latency reciprocal coupling between (a) GHRH and SRIF neurons (stimulatory direction) and (b) SRIF and GHRH neurons (inhibitory direction). This two-oscillator formulation explicates (but does not prove): (1) the GHRH-sensitizing action of prior somatostatin exposure; (2) a three-site (intrahypothalamic, hypothalamo-pituitary and somatotrope GH store-dependent) mechanism driving rebound-like GH secretion after somatostatin 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.
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