Systems-Level Analysis of Physiological Regulatory Interactions Controlling Complex Secretory Dynamics of the Growth Hormone Axis: A Dynamical Network Model

This chapter presents systems-level analysis of physiological regulatory interactions controlling complex secretory dynamics of the growth hormone axis. Time-series data of growth hormone (GH) concentrations in the circulation of humans and of other animal models clearly demonstrate pulsatile patterns indicative of both rhythmic and episodic release from the pituitary gland. Understanding the physiological mechanisms that control the complex secretory dynamics exhibited by the GH neuroendocrine axis requires detailed appreciation of a highly regulated phenomenon—that is, dependent on functional interactions among a large number of processes comprising an exceedingly complex network of stimulatory and inhibitory feedback. The primary regulatory species responsible for mediating pituitary GH release are two hypothalamic peptides, a stimulatory factor, GH-releasing hormone (GHRH), and an inhibitory tetradecapeptide, somatostatin (SRIH). GHRH and SRIH are secreted from the median eminence of the hypothalamus into the hypophysial portal blood to be transported to the pituitary gland, where their influence on GH production and secretion is exerted. Growth hormone, after being released into the systemic circulation, stimulates production of insulin-like growth factor-I (IGF-I) in numerous peripheral tissues, including liver, bone, and muscle. It is IGF-I that serves the role of primary mediator of GHs peripheral effects. The GH neuroendocrine axis is a closed-loop system because both GH and IGF-I exert regulatory feedback on the hypothalamus in the form of decreasing GHRH and increasing SRIH signaling.