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Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School (M.M., K.K.M., J.B., A.H., A.A., J.C., A.K.); Pediatric Endocrine Unit, MassGeneral Hospital for Children and Harvard Medical School (M.M.), and Eating Disorders Unit, Massachusetts General Hospital and Harvard Medical School (D.B.H.), Boston, Massachusetts 02114; Eating Disorders Center (M.O.), Dover, New Hampshire 03820; and University of Virginia Medical School (M.L.J.), Charlottesville, Virginia 22908
Address all correspondence and requests for reprints to: Anne Klibanski, M.D., BUL 457B, Neuroendocrine Unit, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114. E-mail: aklibanski{at}partners.org.
Anorexia nervosa (AN) is a disorder that is increasing in frequency in adolescents, and the age of onset is often in the prepubertal years, potentially affecting the development of peak bone mass and linear growth. The GH-IGF-I axis plays an important role in bone formation, and alterations in GH secretory patterns have been described in adult women with AN. However, GH secretory dynamics in adolescents with AN have not been described, and the effects of alterations in GH secretory patterns and GH concentration on bone metabolism in AN are not known. We examined patterns of GH secretion by deconvolutional analysis, and GH concentration by Cluster analysis, in adolescent girls with AN (n = 22) and controls (n = 20) of comparable bone age and pubertal stage. We also examined the roles of cortisol, leptin, and estradiol in the regulation of GH secretion and concentration, and the relationship of GH secretory patterns and concentration to bone metabolism. Basal GH secretion and secretory pulse number in adolescent girls with AN were increased compared with control values (P = 0.03 and 0.007, respectively), and increased disorderliness of GH secretion (approximate entropy) was found in AN (P = 0.004). Mean and nadir GH concentrations and total area under the concentration curve were increased (P = 0.03, 0.002, and 0.03, respectively), and IGF-I levels were decreased (P = 0.0002) in girls with AN compared with healthy adolescent girls. IGF-I levels correlated negatively with nadir GH concentrations (r = -0.35; P = 0.02). Serum cortisol levels were higher in girls with AN than in controls (P < 0.0001) and correlated inversely with IGF-I (r = -0.58; P = 0.0001) and weakly with GH concentration (area under the concentration curve; r = -0.43; P = 0.05). A strong inverse relationship between markers of nutritional status (body mass index, fat mass, and leptin) and basal and pulsatile GH secretion, and mean and nadir GH concentrations was observed. GH concentration predicted levels of all markers of bone formation and a marker of bone resorption (N-telopeptide) in healthy controls, but not in AN. We demonstrate increases in basal GH secretion, number of secretory bursts, and GH concentration in adolescents with AN compared with controls, accompanied by low IGF-I levels. These data are consistent with the hypothesis that an acquired GH resistance occurs in this undernourished group. We also demonstrate that GH secretion and concentration are nutritionally regulated, and that the effects of nutrition exceed the effects of cortisol on GH concentration. Acquired GH resistance may play a role in the osteopenia and decreased peak bone mass frequently associated with AN.
This work was supported in part by NIH Grant M01-RR-01066, NIH Nutrition Training Grant DK-07703, and a fellowship grant from Eli Lilly & Co.
This work was presented in part at the 84th Annual Meeting of The Endocrine Society, San Francisco, CA, 2002; the American Pediatric Society/Society for Pediatric Research Meeting, Seattle, WA, 2003; and the 85th Annual Meeting of The Endocrine Society, Philadelphia, PA, 2003.
Abbreviations: AN, Anorexia nervosa; ApEn, approximate entropy; AUC, area under the concentration curve; BA, bone age; BMAD, bone mineral apparent density; BMD, bone mineral density; BMI, body mass index; BSAP, bone-specific alkaline phosphatase; DPD, deoxypyridinoline; DXA, dual energy x-ray absorptiometry; GCRC, General Clinical Research Center; NTX, N-telopeptide; OC, osteocalcin; PICP, C-terminal propeptide of type I procollagen; UFC, urinary free cortisol.
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