Sex-steroid modulation of growth hormone (GH) secretory control: three-peptide ensemble regulation under dual feedback restraint by GH and IGF-I.
Technical, genetic, and clinical developments have unveiled a burgeoning array of novel effectors of GH secretion. The present appraisal of central neuroregulatory components of the somatotropic axis highlights a simplifying concept of ensemble control by the final common peptides, GH-releasing hormone (GHRH), GH-releasing peptide(s) (GHRP, ghrelin), and somatostatin. These potent signals act individually, antagonistically, and synergistically to direct pulsatile GH secretion. GHRH, GHRP/ghrelin, and somatostatin further adapt to autonegative feedback by GH and IGF-I. Estradiol modulates the impact of each of the primary peptidyl inputs; viz.: (i) enhances submaximally effective feedforward by discrete pulses of (injected) recombinant human GHRH-1,44-amide (as defined by increased agonistic potency and pituitary sensitivity); (ii) potentiates the submaximally stimulatory effects of GHRP-2, a hexapeptidyl mimetic of ghrelin; (iii) blunts dose-dependent inhibition of fasting GH secretion by somatostatin- 14; and (iv) relieves rhGH-enforced negative feedback on GHRP-2 (but not on basal, exercise, or GHRH)-stimulated GH secretion. The foregoing estrogenic activities collectively augment GH secretory burst mass by amplifying feedforward (via both GHRH and GHRP) and attenuating feedback (imposed by somatostatin and GH). Whether testosterone fully mimics the foregoing mechanistic actions of estradiol is not known. In conclusion, the present conceptual platform of tri-peptide-directed feedforward and GH/IGF-I-mediated feedback should aid in unraveling some of the complex regulatory dynamics targeted by sex-steroid hormones.
Veldhuis
Johannes D
JD
Division of Endocrinology and Metabolism, Department of Internal Medicine, General Clinical Research Center, Mayo Medical and Graduate School of Medicine, Mayo Clinic, Rochester, MN 55905, USA. veldhuis.johannes@mayo.edu
Bowers
Cyril Y
CY
D000818:Animals; D005246:Feedback / Q000502:physiology; D005260:Female; D054439:Ghrelin; D012739:Gonadal Steroid Hormones / Q000502:physiology*; D013006:Growth Hormone / Q000378:metabolism*; D013007:Growth Hormone-Releasing Hormone / Q000502:physiology; D019382:Human Growth Hormone / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D008297:Male; D036361:Peptide Hormones / Q000502:physiology
D054439:Ghrelin; D012739:Gonadal Steroid Hormones; D036361:Peptide Hormones; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone