Genesis of the Ultradian Rhythm of GH Secretion: a New Model Unifying Experimental Observations in Rats

Growth hormone (GH) induces growth in animals and humans and also has important metabolic functions. The GH neuroendocrine axis consists of a signaling cascade from the hypothalamus to the pituitary, the liver, and peripheral tissues, including two major feedback mechanisms. GH is secreted from the pituitary into the circulating blood according to the effect on the somatotrophs of two hypothalamic peptides, GH-releasing hormone (GHRH) and its antagonist, somatostatin (SRIF). The typical GH profile in the male rat shows secretory episodes every 3.3 h, which are subdivided into two peaks. Focusing on the mechanisms for generation of this ultradian GH rhythm, we simulated the time course of GH secretion under a variety of conditions. The model that we propose is based on feedback of GH on its own release mediated both by GH receptors on SRIF neurons in the brain and by a delayed SRIF release into both the brain and portal blood. SRIF, with a resultant periodicity of 3.3 h, affects both the somatotroph cells in the pituitary and the GHRH neurons in the hypothalamus. The secretion of GHRH is postulated to occur in an approximately 1-h rhythm modulated by the level of SRIF in the hypothalamus. The model predicts a possible mechanism for the feminization of the male GH rhythm by sex steroids and vice versa, and suggests experiments that might reveal the proposed intrinsic 1-h GHRH rhythm.