title: Neurophysiological regulation and target-tissue impact of the pulsatile mode of growth hormone secretion in the human.
abstract: Neuroendocrine axes function as an ensemble of regulatory loci which communicate and maintain homeostasis via time-delayed blood-borne signals. The growth hormone (GH)-insulin-like growth factor I (IGF-I) feedback axis sustains a vividly pulsatile mode of interglandular signalling. Pulsatility is driven jointly by hypothalamic GH-releasing hormone (GHRH) and GH-releasing peptide (GHRP), and modulated by somatostatinergic restraint. Paradoxically, intermittent somatostatin inputs also facilitate somatotrope-cell responses to recurrent secretagogue stimuli, thereby amplifying pulsatile GH secretion. A concurrent low basal (8-12% of normal total) rate of GH release is controlled positively by GHRH and GHRP and negatively by somatostatin. Sex-steroid hormones (such as oestradiol and aromatizable androgen) and normal female and male puberty augment GH secretory-burst mass 1.8- to 3.5-fold, whereas ageing, relative obesity, physical inactivity, hypogonadism, and hypopituitarism mute the amplitude/mass of pulsatile GH output. An abrupt rise in circulating GH concentration stimulates rapid internalization of the GH receptor in peripheral target tissues, and evokes second-messenger nuclear signalling via the STAT 5b pathway. Discrete GH peaks stimulate linear (skeletal) growth and drive muscle IGF-I gene expression more effectually than basal (time-invariant) GH exposure. A brief pulse of GH can saturate the plasma GH-binding protein system and achieve prolonged plasma GH concentrations by convolution with peripheral distribution and clearance mechanisms. A single burst of GH secretion also feeds back after a short latency on central nervous system (CNS) regulatory centres via specific brain GH receptors to activate somatostatinergic and reciprocally subdue GHRH outflow. This autoregulatory loop probably contributes to the time-dependent physiologically pulsatile dynamics of the GH axis. More slowly varying systemic IGF-I concentrations may also damp GH secretory pulse amplitude by delayed negative-feedback actions. According to this simplified construct, GH pulsatility emerges due to time-ordered multivalent interfaces among GHRH/GHRP feedforward and somatostatin, GH and IGF-I feedback signals. Resultant GH pulses trigger tissue-specific gene expression, thereby promoting skeletal and muscular growth, metabolic and body compositional adaptations, and CNS reactions that jointly maintain health and homeostasis.
authors.affiliation: Department of Internal Medicine, General Clinical Research Center, University of Virginia School of Medicine, Charlottesville 22908-0202, USA. JDV@Virginia.Edu
authors.forename: J D
authors.initials: JD
authors.lastname: Veldhuis
authors.forename: S M
authors.initials: SM
authors.lastname: Anderson
authors.forename: N
authors.initials: N
authors.lastname: Shah
authors.forename: M
authors.initials: M
authors.lastname: Bray
authors.forename: T
authors.initials: T
authors.lastname: Vick
authors.forename: A
authors.initials: A
authors.lastname: Gentili
authors.forename: T
authors.initials: T
authors.lastname: Mulligan
authors.forename: M L
authors.initials: ML
authors.lastname: Johnson
authors.forename: A
authors.initials: A
authors.lastname: Weltman
authors.forename: W S
authors.initials: WS
authors.lastname: Evans
authors.forename: A
authors.initials: A
authors.lastname: Iranmanesh
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D025461:Feedback, Physiological; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D019382:Human Growth Hormone / Q000097:blood / Q000378:metabolism*; D006801:Humans; D009482:Neurophysiology; D009765:Obesity / Q000378:metabolism; D011627:Puberty; D013256:Steroids / Q000378:metabolism
chemical_list: D012739:Gonadal Steroid Hormones; D013256:Steroids; D019382:Human Growth Hormone