Growth hormone and protein metabolism

Clinical Nutrition

Volumn 28, Issue 6, 2009, Pages 597-603

  Moller, Niels ^a   Vendelbo, Mikkel H ^a   Kampmann, Ulla ^a   Christensen, Britt ^a   Madsen, Michael ^a   Norrelund, Helene ^a   Jorgensen, Jens O ^a  

^a AARHUS UNIVERSITY HOSPITAL   (Denmark)

Author keywords

Growth hormone; Substrate metabolism

Indexed keywords

AMINO ACID; ANABOLIC AGENT; FATTY ACID; GLUCOSE; GROWTH HORMONE; INSULIN; MUSCLE PROTEIN; PROTEIN; SOMATOMEDIN C; STAT5 PROTEIN; UREA;

BIOSYNTHESIS; BODY FAT; CATABOLISM; DIET RESTRICTION; FATTY ACID OXIDATION; GLUCOSE OXIDATION; GROWTH HORMONE DEFICIENCY; HUMAN; LIPOLYSIS; NONHUMAN; OBESITY; PHYSICAL PERFORMANCE; PROTEIN DEGRADATION; PROTEIN DEPLETION; PROTEIN METABOLISM; PROTEIN SYNTHESIS; REVIEW; SIGNAL TRANSDUCTION; STRESS;

ANIMALS; BODY COMPOSITION; FASTING; GROWTH HORMONE; HUMANS; PROTEINS; STRESS, PHYSIOLOGICAL;

EID: 71849109375     PISSN: 02615614     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.clnu.2009.08.015     Document Type: Review

References (104)

1. Davidson M.B. Effect of growth hormone on carbohydrate and lipid metabolism. Endocr Rev 8 (1987) 115-131
2. Press M. Growth hormone and metabolism. Diabetes Metab Rev 4 (1988) 391-414
3. Baumann G. Growth hormone heterogeneity: genes, isohormones, variants, and binding proteins. Endocr Rev 12 (1991) 424-449
4. Baumann G. Growth hormone binding protein. The soluble growth hormone receptor. Minerva Endocrinol 27 (2002) 265-276
5. Hartman M.L., Faria A.C., Vance M.L., Johnson M.L., Thorner M.O., and Veldhuis J.D. Temporal structure of in vivo growth hormone secretory events in humans. Am J Phys 260 (1991) E101-E110
6. Ho K.Y., Veldhuis J.D., Johnson M.L., Furlanetto R., Evans W.S., Alberti K.G., et al. Fasting enhances growth hormone secretion and amplifies the complex rhythms of growth hormone secretion in man. J Clin Invest 81 (1988) 968-975
7. Parker D.C., Sassin J.F., Mace J.W., Gotlin R.W., and Rossman L.G. Human growth hormone release during sleep: electroencephalographic correlation. J Clin Endocrinol Metab 29 (1969) 871-874
8. Takahashi Y., Kipnis D.M., and Daughaday W.H. Growth hormone secretion during sleep. J Clin Invest 47 (1968) 2079-2090
9. Roth J., Glick S.M., Yalow R.S., and Berson S.A. Secretion of human growth hormone: physiologic and experimental modification. Metabolism 12 (1963) 577-579
10. Hansen A.P. Abnormal serum growth hormone response to exercise in maturity-onset diabetics. Diabetes 22 (1973) 619-628
11. Veldhuis J.D., Roemmich J.N., Richmond E.J., and Bowers C.Y. Somatotropic and gonadotropic axes linkages in infancy, childhood, and the puberty-adult transition. Endocr Rev 27 (2006) 101-140
12. Moran A., Jacobs Jr. D.R., Steinberger J., Cohen P., Hong C.P., Prineas R., et al. Association between the insulin resistance of puberty and the insulin-like growth factor-I/growth hormone axis. J Clin Endocrinol Metab 87 (2002) 4817-4820
13. Corpas E., Harman S.M., and Blackman M.R. Human growth hormone and human aging. Endocr Rev 14 (1993) 20-39
14. Vahl N., Jorgensen J.O., Skjaerbaek C., Veldhuis J.D., Orskov H., and Christiansen J.S. Abdominal adiposity rather than age and sex predicts mass and regularity of GH secretion in healthy adults. Am J Physiol 272 (1997) E1108-E1116
15. Kawauchi H., and Sower S.A. The dawn and evolution of hormones in the adenohypophysis. Gen Comp Endocrinol 148 (2006) 3-14
16. Schindler C., Levy D.E., and Decker T. JAK-STAT signaling: from interferons to cytokines. J Biol Chem 282 (2007) 20059-20063
17. Hernandez-Sanchez C., Mansilla A., de la Rosa E.J., and de P.F. Proinsulin in development: new roles for an ancient prohormone. Diabetologia 49 (2006) 1142-1150
18. Nielsen J.H., Galsgaard E.D., Moldrup A., Friedrichsen B.N., Billestrup N., Hansen J.A., et al. Regulation of beta-cell mass by hormones and growth factors. Diabetes 50 Suppl. 1 (2001) S25-S29
19. Moller N., and Jorgensen J.O. Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. Endocr Rev 30 (2009) 152-177
20. Moller L., Dalman L., Norrelund H., Billestrup N., Frystyk J., Moller N., et al. Impact of fasting on growth hormone signaling and action in muscle and fat. J Clin Endocrinol Metab 94 (2009) 965-972
21. Moller N., Gormsen L.C., Schmitz O., Lund S., Jorgensen J.O., and Jessen N. Free fatty acids inhibit growth hormone/signal transducer and activator of transcription-5 signaling in human muscle: a potential feedback mechanism. J Clin Endocrinol Metab 94 (2009) 2204-2207
22. Nielsen C., Gormsen L.C., Jessen N., Pedersen S.B., Moller N., Lund S., et al. Growth hormone signaling in vivo in human muscle and adipose tissue: impact of insulin, substrate background, and growth hormone receptor blockade. J Clin Endocrinol Metab 93 (2008) 2842-2850
23. Neel J.V. Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress"?. Am J Hum Genet 14 (1962) 353-362
24. Randle P.J., GARLAND P.B., Hales C.N., and NEWSHOLME E.A. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1 (1963) 785-789
25. Hue L., and Taegtmeyer H. The Randle cycle revisited: a new head for an old hat. Am J Physiol Endocrinol Metab (2009)
26. Rabinowitz D ZKL 1963 A metabolic regulating device based on the actions of human growth hormone and of insulin, singly and together, on the human forearm. 199 ed.; p.913-15.
27. Freda P.U., Shen W., Heymsfield S.B., Reyes-Vidal C.M., Geer E.B., Bruce J.N., et al. Lower visceral and subcutaneous but higher intermuscular adipose tissue depots in patients with GH & IGF-I excess due to acromegaly. J Clin Endocrinol Metab (2008)
28. O'Sullivan A.J., Kelly J.J., Hoffman D.M., Freund J., and Ho K.K. Body composition and energy expenditure in acromegaly. J Clin Endocrinol Metab 78 (1994) 381-386
29. Moller N., Jorgensen J.O., Schmitz O., Moller J., Christiansen J., Alberti K.G., et al. Effects of a growth hormone pulse on total and forearm substrate fluxes in humans. Am J Physiol 258 (1990) E86-E91
30. Djurhuus C.B., Gravholt C.H., Nielsen S., Pedersen S.B., Moller N., and Schmitz O. Additive effects of cortisol and growth hormone on regional and systemic lipolysis in humans. Am J Physiol Endocrinol Metab 286 (2004) E488-E494
31. Gravholt C.H., Schmitz O., Simonsen L., Bulow J., Christiansen J.S., and Moller N. Effects of a physiological GH pulse on interstitial glycerol in abdominal and femoral adipose tissue. Am J Physiol 277 (1999) E848-E854
32. Krag M.B., Gormsen L.C., Guo Z., Christiansen J.S., Jensen M.D., Nielsen S., et al. Growth hormone-induced insulin resistance is associated with increased intramyocellular triglyceride content but unaltered VLDL-triglyceride kinetics. Am J Physiol Endocrinol Metab 292 (2007) E920-E927
33. Gormsen L.C., Jessen N., Gjedsted J., Gjedde S., Norrelund H., Lund S., et al. Dose-response effects of free fatty acids on glucose and lipid metabolism during somatostatin blockade of growth hormone and insulin in humans. J Clin Endocrinol Metab 92 (2007) 1834-1842
34. Gormsen L.C., Gjedsted J., Gjedde S., Norrelund H., Christiansen J.S., Schmitz O., et al. Dose-response effects of free fatty acids on amino acid metabolism and ureagenesis. Acta Physiol (Oxf) 192 (2008) 369-379
35. Fryburg D.A., Louard R.J., Gerow K.E., Gelfand R.A., and Barrett E.J. Growth hormone stimulates skeletal muscle protein synthesis and antagonizes insulin's antiproteolytic action in humans. Diabetes 41 (1992) 424-429
36. Fryburg D.A., Gelfand R.A., and Barrett E.J. Growth hormone acutely stimulates forearm muscle protein synthesis in normal humans. Am J Physiol 260 (1991) E499-E504
37. Copeland K.C., and Nair K.S. Acute growth hormone effects on amino acid and lipid metabolism. J Clin Endocrinol Metab 78 (1994) 1040-1047
38. Nielsen S., Jorgensen J.O., Hartmund T., Norrelund H., Nair K.S., Christiansen J.S., et al. Effects of lowering circulating free fatty acid levels on protein metabolism in adult growth hormone deficient patients. Growth Horm IGF Res 12 (2002) 425-433
39. Fryburg D.A., and Barrett E.J. Growth hormone acutely stimulates skeletal muscle but not whole-body protein synthesis in humans. Metabolism 42 (1993) 1223-1227
40. Horber F.F., and Haymond M.W. Human growth hormone prevents the protein catabolic side effects of prednisone in humans. J Clin Invest 86 (1990) 265-272
41. Yarasheski K.E., Campbell J.A., Smith K., Rennie M.J., Holloszy J.O., and Bier D.M. Effect of growth hormone and resistance exercise on muscle growth in young men. Am J Physiol 262 (1992) E261-E267
42. Garibotto G. Muscle amino acid metabolism and the control of muscle protein turnover in patients with chronic renal failure. Nutrition 15 (1999) 145-155
43. Zachwieja J.J., Bier D.M., and Yarasheski K.E. Growth hormone administration in older adults: effects on albumin synthesis. Am J Physiol 266 (1994) E840-E844
44. Hoffman D.M., Pallasser R., Duncan M., Nguyen T.V., and Ho K.K. How is whole body protein turnover perturbed in growth hormone-deficient adults?. J Clin Endocrinol Metab 83 (1998) 4344-4349
45. Beshyah S.A., Sharp P.S., Gelding S.V., Halliday D., and Johnston D.G. Whole-body leucine turnover in adults on conventional treatment for hypopituitarism. Acta Endocrinol (Copenh) 129 (1993) 158-164
46. Liu H., Bravata D.M., Olkin I., Nayak S., Roberts B., Garber A.M., et al. Systematic review: the safety and efficacy of growth hormone in the healthy elderly. Ann Intern Med 146 (2007) 104-115
47. Welbourne T., Joshi S., and McVie R. Growth hormone effects on hepatic glutamate handling in vivo. Am J Physiol 257 (1989) E959-E962
48. Wolthers T., Grofte T., Jorgensen J.O., Moller N., Vahl N., Christiansen J.S., et al. Effects of growth hormone (GH) administration on functional hepatic nitrogen clearance: studies in normal subjects and GH-deficient patients. J Clin Endocrinol Metab 78 (1994) 1220-1224
49. Wolthers T., Grofte T., Moller N., Vilstrup H., and Jorgensen J.O. Effects of long-term growth hormone (GH) and triiodothyronine (T3) administration on functional hepatic nitrogen clearance in normal man. J Hepatol 24 (1996) 313-319
50. Short K.R., Moller N., Bigelow M.L., Coenen-Schimke J., and Nair K.S. Enhancement of muscle mitochondrial function by growth hormone. J Clin Endocrinol Metab 93 (2008) 597-604
51. Cahill Jr. G.F. Starvation in man. N Engl J Med 282 (1970) 668-675
52. Jensen M.D., Haymond M.W., Gerich J.E., Cryer P.E., and Miles J.M. Lipolysis during fasting. Decreased suppression by insulin and increased stimulation by epinephrine. J Clin Invest 79 (1987) 207-213
53. Owen O.E., Felig P., Morgan A.P., Wahren J., and Cahill Jr. G.F. Liver and kidney metabolism during prolonged starvation. J Clin Invest 48 (1969) 574-583
54. Owen O.E., and Reichard Jr. G.A. Human forearm metabolism during progressive starvation. J Clin Invest 50 (1971) 1536-1545
55. Owen O.E., Smalley K.J., D'Alessio D.A., Mozzoli M.A., and Dawson E.K. Protein, fat, and carbohydrate requirements during starvation: anaplerosis and cataplerosis. Am J Clin Nutr 68 (1998) 12-34
56. Gjedsted J., Gormsen L.C., Nielsen S., Schmitz O., Djurhuus C.B., Keiding S., et al. Effects of a 3-day fast on regional lipid and glucose metabolism in human skeletal muscle and adipose tissue. Acta Physiol (Oxf) 191 (2007) 205-216
57. Beck J.C., McGarry E.E., Dyrenfurth I., and Venning E.H. The metabolic effects of human and monkey growth hormone in man. Ann Intern Med 49 (1958) 1090-1105
58. Henneman P., FORBES A.P., Moldawer M., Dempsey E.F., and CARROLL E.L. Effects of human growth hormone in man. J Clin Invest 39 (1960) 1223-1238
59. Ikkos D., Luft R., and Gemzell C.A. The effect of human growth hormone in man. Lancet 1 (1958) 720-721
60. Manson J.M., and Wilmore D.W. Positive nitrogen balance with human growth hormone and hypocaloric intravenous feeding. Surgery 100 (1986) 188-197
61. Lundeberg S., Belfrage M., Wernerman J., von der D.A., Thunell S., and Vinnars E. Growth hormone improves muscle protein metabolism and whole body nitrogen economy in man during a hyponitrogenous diet. Metabolism 40 (1991) 315-322
62. Norrelund H., Moller N., Nair K.S., Christiansen J.S., and Jorgensen J.O. Continuation of growth hormone (GH) substitution during fasting in GH-deficient patients decreases urea excretion and conserves protein synthesis. J Clin Endocrinol Metab 86 (2001) 3120-3129
63. Norrelund H., Nair K.S., Jorgensen J.O., Christiansen J.S., and Moller N. The protein-retaining effects of growth hormone during fasting involve inhibition of muscle-protein breakdown. Diabetes 50 (2001) 96-104
64. Norrelund H., Djurhuus C., Jorgensen J.O., Nielsen S., Nair K.S., Schmitz O., et al. Effects of GH on urea, glucose and lipid metabolism, and insulin sensitivity during fasting in GH-deficient patients. Am J Physiol Endocrinol Metab 285 (2003) E737-E743
65. Veldhuis J.D., Iranmanesh A., Ho K.K., Waters M.J., Johnson M.L., and Lizarralde G. Dual defects in pulsatile growth hormone secretion and clearance subserve the hyposomatotropism of obesity in man. J Clin Endocrinol Metab 72 (1991) 51-59
66. Felig P., Marliss E.B., and Cahill Jr. G.F. Metabolic response to human growth hormone during prolonged starvation. J Clin Invest 50 (1971) 411-421
67. Clemmons D.R., Snyder D.K., Williams R., and Underwood L.E. Growth hormone administration conserves lean body mass during dietary restriction in obese subjects. J Clin Endocrinol Metab 64 (1987) 878-883
68. Snyder D.K., Clemmons D.R., and Underwood L.E. Treatment of obese, diet-restricted subjects with growth hormone for 11 weeks: effects on anabolism, lipolysis, and body composition. J Clin Endocrinol Metab 67 (1988) 54-61
69. Norrelund H., Borglum J., Jorgensen J.O., Richelsen B., Moller N., Nair K.S., et al. Effects of growth hormone administration on protein dynamics and substrate metabolism during 4 weeks of dietary restriction in obese women. Clin Endocrinol (Oxf) 52 (2000) 305-312
70. Norrelund H., Nair K.S., Nielsen S., Frystyk J., Ivarsen P., Jorgensen J.O., et al. The decisive role of free fatty acids for protein conservation during fasting in humans with and without growth hormone. J Clin Endocrinol Metab 88 (2003) 4371-4378
71. Norrelund H., Nielsen S., Christiansen J.S., Jorgensen J.O., and Moller N. Modulation of basal glucose metabolism and insulin sensitivity by growth hormone and free fatty acids during short-term fasting. Eur J Endocrinol 150 (2004) 779-787
72. Sakharova A.A., Horowitz J.F., Surya S., Goldenberg N., Harber M.P., Symons K., et al. Role of growth hormone in regulating lipolysis, proteolysis, and hepatic glucose production during fasting. J Clin Endocrinol Metab (2008)
73. Nair K.S., Welle S.L., Halliday D., and Campbell R.G. Effect of beta-hydroxybutyrate on whole-body leucine kinetics and fractional mixed skeletal muscle protein synthesis in humans. J Clin Invest 82 (1988) 198-205
74. Sherwin R.S., Hendler R.G., and Felig P. Effect of ketone infusions on amino acid and nitrogen metabolism in man. J Clin Invest 55 (1975) 1382-1390
75. Tessari P., Nissen S.L., Miles J.M., and Haymond M.W. Inverse relationship of leucine flux and oxidation to free fatty acid availability in vivo. J Clin Invest 77 (1986) 575-581
76. Gibney J., Healy M.L., and Sonksen P.H. The growth hormone/insulin-like growth factor-I axis in exercise and sport. Endocr Rev 28 (2007) 603-624
77. Liu H., Bravata D.M., Olkin I., Friedlander A., Liu V., Roberts B., et al. Systematic review: the effects of growth hormone on athletic performance. Ann Intern Med (2008)
78. Christensen S.E., Jorgensen O.L., Moller N., and Orskov H. Characterization of growth hormone release in response to external heating. Comparison to exercise induced release. Acta Endocrinol (Copenh) 107 (1984) 295-301
79. Wheldon A., Savine R.L., Sonksen P.H., and Holt R.I. Exercising in the cold inhibits growth hormone secretion by reducing the rise in core body temperature. Growth Horm IGF Res 16 (2006) 125-131
80. Juul A., Hjortskov N., Jepsen L.T., Nielsen B., Halkjaer-Kristensen J., Vahl N., et al. Growth hormone deficiency and hyperthermia during exercise: a controlled study of sixteen GH-deficient patients. J Clin Endocrinol Metab 80 (1995) 3335-3340
81. Kanaley J.A., Dall R., Moller N., Nielsen S.C., Christiansen J.S., Jensen M.D., et al. Acute exposure to GH during exercise stimulates the turnover of free fatty acids in GH-deficient men. J Appl Phys 96 (2004) 747-753
82. Wee J., Charlton C., Simpson H., Jackson N.C., Shojaee-Moradie F., Stolinski M., et al. GH secretion in acute exercise may result in post-exercise lipolysis. Growth Horm IGF Res 15 (2005) 397-404
83. Lange K.H., Isaksson F., Juul A., Rasmussen M.H., Bulow J., and Kjaer M. Growth hormone enhances effects of endurance training on oxidative muscle metabolism in elderly women. Am J Physiol Endocrinol Metab 279 (2000) E989-E996
84. Healy M.L., Gibney J., Russell-Jones D.L., Pentecost C., Croos P., Sonksen P.H., et al. High dose growth hormone exerts an anabolic effect at rest and during exercise in endurance-trained athletes. J Clin Endocrinol Metab 88 (2003) 5221-5226
85. Healy M.L., Gibney J., Pentecost C., Croos P., Russell-Jones D.L., Sonksen P.H., et al. Effects of high-dose growth hormone on glucose and glycerol metabolism at rest and during exercise in endurance-trained athletes. J Clin Endocrinol Metab 91 (2006) 320-327
86. Hansen M., Morthorst R., Larsson B., Dall R., Flyvbjerg A., Rasmussen M.H., et al. No effect of growth hormone administration on substrate oxidation during exercise in young, lean men. J Physiol 567 (2005) 1035-1045
87. Lange K.H., Larsson B., Flyvbjerg A., Dall R., Bennekou M., Rasmussen M.H., et al. Acute growth hormone administration causes exaggerated increases in plasma lactate and glycerol during moderate to high intensity bicycling in trained young men. J Clin Endocrinol Metab 87 (2002) 4966-4975
88. Gibney J., Healy M.L., Stolinski M., Bowes S.B., Pentecost C., Breen L., et al. Effect of growth hormone (GH) on glycerol and free fatty acid metabolism during exhaustive exercise in GH-deficient adults. J Clin Endocrinol Metab 88 (2003) 1792-1797
89. Van den B.G., de Z.F., Veldhuis J.D., Wouters P., Awouters M., Verbruggen W., et al. The somatotropic axis in critical illness: effect of continuous growth hormone (GH)-releasing hormone and GH-releasing peptide-2 infusion. J Clin Endocrinol Metab 82 (1997) 590-599
90. Vila G., Maier C., Riedl M., Nowotny P., Ludvik B., Luger A., et al. Bacterial endotoxin induces biphasic changes in plasma ghrelin in healthy humans. J Clin Endocrinol Metab 92 (2007) 3930-3934
91. Battezzati A., Benedini S., Fattorini A., Losa M., Mortini P., Bertoli S., et al. Insulin action on protein metabolism in acromegalic patients. Am J Physiol Endocrinol Metab 284 (2003) E823-E829
92. Gibney J., Wolthers T., Burt M.G., Leung K.C., Umpleby A.M., and Ho K.K. Protein metabolism in acromegaly: differential effects of short- and long-term treatment. J Clin Endocrinol Metab 92 (2007) 1479-1484
93. Hansen T.B., Gram J., Bjerre P., Hagen C., and Bollerslev J. Body composition in active acromegaly during treatment with octreotide: a double-blind, placebo-controlled cross-over study. Clin Endocrinol (Oxf) 41 (1994) 323-329
94. Moller N., Schmitz O., Joorgensen J.O., Astrup J., Bak J.F., Christensen S.E., et al. Basal- and insulin-stimulated substrate metabolism in patients with active acromegaly before and after adenomectomy. J Clin Endocrinol Metab 74 (1992) 1012-1019
95. McNurlan M.A., Garlick P.J., Steigbigel R.T., DeCristofaro K.A., Frost R.A., Lang C.H., et al. Responsiveness of muscle protein synthesis to growth hormone administration in HIV-infected individuals declines with severity of disease. J Clin Invest 100 (1997) 2125-2132.
96. Takala J., Ruokonen E., Webster N.R., Nielsen M.S., Zandstra D.F., Vundelinckx G., et al. Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med 341 (1999) 785-792
97. Van den B.G., Wouters P., Weekers F., Verwaest C., Bruyninckx F., Schetz M., et al. Intensive insulin therapy in the critically ill patients. N Engl J Med 345 (2001) 1359-1367
98. Kojima M., Hosoda H., Date Y., Nakazato M., Matsuo H., and Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402 (1999) 656-660
99. Moller N., Nygren J., Hansen T.K., Orskov H., Frystyk J., and Nair K.S. Splanchnic release of ghrelin in humans. J Clin Endocrinol Metab 88 (2003) 850-852
100. Takaya K., Ariyasu H., Kanamoto N., Iwakura H., Yoshimoto A., Harada M., et al. Ghrelin strongly stimulates growth hormone release in humans. J Clin Endocrinol Metab 85 (2000) 4908-4911
101. Wren A.M., Seal L.J., Cohen M.A., Brynes A.E., Frost G.S., Murphy K.G., et al. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 86 (2001) 5992
102. Gormsen L.C., Gjedsted J., Gjedde S., Vestergaard E.T., Christiansen J.S., Jorgensen J.O., et al. Free fatty acids decrease circulating ghrelin concentrations in humans. Eur J Endocrinol 154 (2006) 667-673
103. Goldenberg N., and Barkan A. Factors regulating growth hormone secretion in humans. Endocrinol Metab Clin North Am 36 (2007) 37-55
104. van Vught A.J., Nieuwenhuizen A.G., Brummer R.J., and Westerterp-Plantenga M.S. Effects of oral ingestion of amino acids and proteins on the somatotropic axis. J Clin Endocrinol Metab 93 (2008) 584-590