Growth hormone (GH) secretion is pulsatile in nature in all species studied thus far, including man. The pulsatile mode of GH secretion is governed by the interplay of two hypothalamic peptides, GH-releasing hormone (GHRH) and somatostatin (SRIF) as well as by the negative feedback of circulating and, potentially, autocrine and paracrine effects of insulin-like growth factor-I (IGF-I). The role(s) of each of those regulatory mechanisms has been studied in animals models, but is unknown in man. Alterations in GH pulsatility have been described in many physiologic and pathologic states including puberty, aging, menstrual cycle, obesity, nutritional deprivation, diabetes, growth delay and acromegaly. Animal studies have shown that the manner of GH presentation to peripheral tissues (liver, muscle, cartilage) results in tissue- specific responses and may determine a multitude of metabolic alterations as well as the rate of somatic growth. The elucidation of the mechanisms governing GH pulsatility is essential for clear understanding of normal and pathologic processes governing growth and metabolism.
The aim of this proposal is to characterize the roles of GHRH, somatostatin and the negative feedback of IGF-I in determining GH pulsatility in healthy humans of both sexes and in patients with acromegaly as a model of GH hypersecretory state. We hypothesize that GHRH is the main determinant of GH pulsatility in normal humans and that it also maintains GH hypersecretion in acromegaly. We plan to perform detailed assessment of the discrete parameters of pulsatile GH secretion utilizing the newly developed sensitive GH chemiluminescent assay and rigorous application of statistically validated computer algorithms. Involvement of endogenous GHRH in various models of normal and altered GH secretion will be assessed with the use of a selective GHRH receptor antagonist. Patterned somatostatin infusions will be used to study the role of somatostatin. Recombinant IGF-I will be infused over prolonged periods of time to study the mechanisms of its negative feedback. These studies will provide detailed understanding of the neuroendocrine mechanisms governing GH pulsatility in normal physiology and in pathologic states.
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