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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK038449-09
Application #
2701074
Study Section
Endocrinology Study Section (END)
Program Officer
Sato, Sheryl M
Project Start
1987-09-01
Project End
2000-04-30
Budget Start
1998-05-01
Budget End
2000-04-30
Support Year
9
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Racine, Michael S; Symons, Kathy V; Foster, Carol M et al. (2004) Augmentation of growth hormone secretion after testosterone treatment in boys with constitutional delay of growth and adolescence: evidence against an increase in hypothalamic secretion of growth hormone-releasing hormone. J Clin Endocrinol Metab 89:3326-31
Orrego, John J; Dimaraki, Eleni; Symons, Kathy et al. (2004) Physiological testosterone replenishment in healthy elderly men does not normalize pituitary growth hormone output: evidence against the connection between senile hypogonadism and somatopause. J Clin Endocrinol Metab 89:3255-60
Dimaraki, Eleni V; Jaffe, Craig A; Bowers, Cyril Y et al. (2003) Pulsatile and nocturnal growth hormone secretions in men do not require periodic declines of somatostatin. Am J Physiol Endocrinol Metab 285:E163-70
Dimaraki, Eleni V; Jaffe, Craig A; DeMott-Friberg, Roberta et al. (2002) Acromegaly with apparently normal GH secretion: implications for diagnosis and follow-up. J Clin Endocrinol Metab 87:3537-42
Dimaraki, E V; Jaffe, C A; Demott-Friberg, R et al. (2001) Generation of growth hormone pulsatility in women: evidence against somatostatin withdrawal as pulse initiator. Am J Physiol Endocrinol Metab 280:E489-95
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Orrego, J J; Russell-Aulet, M; Demott-Friberg, R et al. (2001) Semiquantification of hypothalamic GH-releasing hormone output in women: evidence for sexual dimorphism in the mechanism of the somatopause. J Clin Endocrinol Metab 86:5485-90
Jaffe, C A; Ocampo-Lim, B; Guo, W et al. (2000) Growth hormone secretory dynamics over the menstrual cycle. Endocr J 47:549-56
Barkan, A L; DeMott-Friberg, R; Samuels, M H (2000) Growth hormone (GH) secretion in primary adrenal insufficiency: effects of cortisol withdrawal and patterned replacement on GH pulsatility and circadian rhythmicity. Pituitary 3:175-9

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