Neurophysiological regulation and target-tissue impact of the pulsatile mode of growth hormone secretion in the human

Johannes D. Veldhuis, Stacey M. Anderson, Nikhita Shah, Megan Bray, Tara Vick, Angela Gentili, Thomas Mulligan, Michael L. Johnson, Arthur Weltman, William S. Evans, Ali Iranmanesh

Research output: Contribution to journalReview articlepeer-review

61 Scopus citations


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 (CMS) 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 CMS reactions that jointly maintain health and homeostasis.

Original languageEnglish (US)
Pages (from-to)S25-S37
JournalGrowth Hormone and IGF Research
Issue numberSUPPL. 1
StatePublished - 2001


  • Growth hormone
  • Insulin-like growth factor I
  • Obesity
  • Pulse
  • Sex steroids
  • Somatostatin
  • Somatotropin

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology


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