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Human Growth Hormone and Human Aging

Endocrinology Section, Francis Scott Key Medical Center and Johns Hopkins University School of Medicine Baltimore, Maryland 21224
Laboratory of Clinical Physiology, Gerontology Research Center, National Institute on Aging, National Institutes of Health, University School of Medicine, and the Departments of Medicine Francis Scott Key Medical Center and Johns Hopkins University School of Medicine Baltimore, Maryland 21224

Correspondence: Address requests for reprints to: S. Mitchell Harman, M.D., Ph.D, Gerontology Research Center, Room 2B19, 4940 Eastern Avenue, Baltimore, Maryland 21224.

Abstract

I. Introduction: UNTIL recently, there has been little scientific inquiry into the physiological significance of, and possible therapy for, GH deficiency in adulthood. This was because the lack of efficacy in humans of animal-derived (e.g.1 bovine or porcine) GH and the limited supply of human cadaveric GH restricted use of exogenous GH to treatment of GHdeficient children. The availability of recombinant human GH (rhGH) has led to a renewal of scientific and clinical interest in investigating wider indications for GH administration. It is now recognized that GH deficiency may exert adverse metabolic effects in adults with panhypopituitarism, and that these effects can be reversed or attenuated by treatment with rhGH (1, 2). Recently, it has also become apparent that, with advancing age, an increasing proportion of men and women with no clinical evidence of pituitary pathology show decreases in GH secretion and serum levels of insulin-like growth factor-I (IGF-I) (3, 4). Because GH deficiency (1, 2) and normal aging (5) are both associated with decreases in protein synthesis and percent of lean body and bone mass, and with increases in percent of body fat, it is possible that reduced GH secretion and IGF-I levels might account, at least in part, for one or more of the above effects of aging, and that some older people might benefit from treatment with rhGH. In this regard, in several recent studies, administration of rhGH for periods varying from a few weeks to 6 months has resulted in improvements in nitrogen balance, an increase in lean body mass, and a decrease in percent body fat in older persons with low IGF-I levels (3, 4, 6, 7). We review herein the published work describing the alterations in GH and IGF-I production with increasing age, and the methods, benefits, and risks of GH treatment of older persons in the light of new knowledge regarding basic physiology of GH secretion and action. We also attempt to point out areas requiring further investigations.

Footnotes

^* Recipient of Grant 89/1030 from Ministerio de Sanidad y Consumo, Fondo de Investigaciones Sanitarias and Hospital General Universitario de Guadalajara, Spain. Current address: Merck Sharpe & Dome Espafia, Josefa Valcarcel 38, 28027 Madrid-Spain.

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				P. Tollet-Egnell, A. Flores-Morales, N. Ståhlberg, R. L. Malek, N. Lee, and G. Norstedt Gene Expression Profile of the Aging Process in Rat Liver: Normalizing Effects of Growth Hormone Replacement Mol. Endocrinol., February 1, 2001; 15(2): 308 - 318. [Abstract] [Full Text]

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				E. Volpi, B. Mittendorfer, B. B. Rasmussen, and R. R. Wolfe The Response of Muscle Protein Anabolism to Combined Hyperaminoacidemia and Glucose-Induced Hyperinsulinemia Is Impaired in the Elderly J. Clin. Endocrinol. Metab., December 1, 2000; 85(12): 4481 - 4490. [Abstract] [Full Text]

				P. Sytze van Dam, H. E. C. Smid, W. R. de Vries, M. Niesink, E. Bolscher, E. J. Waasdorp, C. Dieguez, F. F. Casanueva, and H. P. F. Koppeschaar Reduction of Free Fatty Acids By Acipimox Enhances the Growth Hormone (GH) Responses to GH-Releasing Peptide 2 in Elderly Men J. Clin. Endocrinol. Metab., December 1, 2000; 85(12): 4706 - 4711. [Abstract] [Full Text]

				R. Fernholm, M. Bramnert, E. Hägg, A. Hilding, D. J. Baylink, S. Mohan, and M. Thorén Growth Hormone Replacement Therapy Improves Body Composition and Increases Bone Metabolism in Elderly Patients with Pituitary Disease J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 4104 - 4112. [Abstract] [Full Text]

				L. Gianotti, M. Maccario, F. Lanfranco, J. Ramunni, L. Di Vito, S. Grottoli, E. E. Muller, E. Ghigo, and E. Arvat Arginine Counteracts the Inhibitory Effect of Recombinant Human Insulin-Like Growth Factor I on the Somatotroph Responsiveness to Growth Hormone-Releasing Hormone in Humans J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3604 - 3608. [Abstract] [Full Text]

				A. Chrisoulidou, S. A. Beshyah, O. Rutherford, T. J. Spinks, J. Mayet, P. Kyd, V. Anyaoku, A. Haida, B. Ariff, M. Murphy, et al. Effects of 7 Years of Growth Hormone Replacement Therapy in Hypopituitary Adults J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3762 - 3769. [Abstract] [Full Text]

				E. Van Cauter, R. Leproult, and L. Plat Age-Related Changes in Slow Wave Sleep and REM Sleep and Relationship With Growth Hormone and Cortisol Levels in Healthy Men JAMA, August 16, 2000; 284(7): 861 - 868. [Abstract] [Full Text] [PDF]

				K. Dorshkind and N. D. Horseman The Roles of Prolactin, Growth Hormone, Insulin-Like Growth Factor-I, and Thyroid Hormones in Lymphocyte Development and Function: Insights from Genetic Models of Hormone and Hormone Receptor Deficiency Endocr. Rev., June 1, 2000; 21(3): 292 - 312. [Abstract] [Full Text]

				P. Tollet-Egnell, A. Flores-Morales, J. Odeberg, J. Lundeberg, and G. Norstedt Differential Cloning of Growth Hormone-Regulated Hepatic Transcripts in the Aged Rat Endocrinology, March 1, 2000; 141(3): 910 - 921. [Abstract] [Full Text] [PDF]

				M. H. Aguiar-Oliveira, M. S. Gill, E. S. de, A. Barretto, M. R. S. Alcântara, F. Miraki-Moud, C. A. Menezes, A. H. O. Souza, C. E. Martinelli, F. A. Pereira, et al. Effect of Severe Growth Hormone (GH) Deficiency due to a Mutation in the GH-Releasing Hormone Receptor on Insulin-Like Growth Factors (IGFs), IGF-Binding Proteins, and Ternary Complex Formation Throughout Life J. Clin. Endocrinol. Metab., November 1, 1999; 84(11): 4118 - 4126. [Abstract] [Full Text]

				M. Russell-Aulet, C. A. Jaffe, R. DeMott-Friberg, and A. L. Barkan In Vivo Semiquantification of Hypothalamic Growth Hormone-Releasing Hormone (GHRH) Output in Humans: Evidence for Relative GHRH Deficiency in Aging J. Clin. Endocrinol. Metab., October 1, 1999; 84(10): 3490 - 3497. [Abstract] [Full Text] [PDF]

				H. M. Perry III The Endocrinology of Aging Clin. Chem., August 1, 1999; 45(8): 1369 - 1376. [Abstract] [Full Text] [PDF]

				M. Zaccaria, M. Varnier, P. Piazza, D. Noventa, and A. Ermolao Blunted Growth Hormone Response to Maximal Exercise in Middle-Aged Versus Young Subjects and No Effect of Endurance Training J. Clin. Endocrinol. Metab., July 1, 1999; 84(7): 2303 - 2307. [Abstract] [Full Text]

				A. Hilding, K. Hall, I.-L. Wivall-Helleryd, M. Sääf, A.-L. Melin, and M. Thorén Serum Levels of Insulin-Like Growth Factor I in 152 Patients with Growth Hormone Deficiency, Aged 19-82 Years, in Relation to Those in Healthy Subjects J. Clin. Endocrinol. Metab., June 1, 1999; 84(6): 2013 - 2019. [Abstract] [Full Text]

				N. Girard, L. Boulanger, S. Denis, and P. Gaudreau Differential in Vivo Regulation of the Pituitary Growth Hormone-Releasing Hormone (GHRH) Receptor by GHRH in Young and Aged Rats Endocrinology, June 1, 1999; 140(6): 2836 - 2842. [Abstract] [Full Text]

				E. Ghigo, G. Aimaretti, M. Maccario, G. Fanciulli, E. Arvat, F. Minuto, G. Giordano, G. Delitala, and F. Camanni Dose-response study of GH effects on circulating IGF-I and IGFBP-3 levels in healthy young men and women Am J Physiol Endocrinol Metab, June 1, 1999; 276(6): E1009 - E1013. [Abstract] [Full Text] [PDF]

				P. Parini, B. Angelin, and M. Rudling Cholesterol and Lipoprotein Metabolism in Aging : Reversal of Hypercholesterolemia by Growth Hormone Treatment in Old Rats Arterioscler Thromb Vasc Biol, April 1, 1999; 19(4): 832 - 839. [Abstract] [Full Text] [PDF]

				V. G. Kaklamani, A. Linos, E. Kaklamani, I. Markaki, and C. Mantzoros Age, Sex, and Smoking Are Predictors of Circulating Insulin-Like Growth Factor 1 and Insulin-Like Growth Factor–Binding Protein 3 J. Clin. Oncol., March 1, 1999; 17(3): 813 - 813. [Abstract] [Full Text] [PDF]

				A. Aleman, H. J. J. Verhaar, E. H. F. de Haan, W. R. de Vries, M. M. Samson, M. L. Drent, E. A. van der Veen, and H. P. F. Koppeschaar Insulin-Like Growth Factor-I and Cognitive Function in Healthy Older Men J. Clin. Endocrinol. Metab., February 1, 1999; 84(2): 471 - 475. [Abstract] [Full Text]

				Y. Marmary, A. F. Parlow, C. M. Goldsmith, X. He, R. B. Wellner, K. Satomura, M. F. Kriete, P. G. Robey, L. K. Nieman, and B. J. Baum Construction and in Vivo Efficacy of a Replication-Deficient Recombinant Adenovirus Encoding Murine Growth Hormone Endocrinology, January 1, 1999; 140(1): 260 - 265. [Abstract] [Full Text]

				A. Giustina and J. D. Veldhuis Pathophysiology of the Neuroregulation of Growth Hormone Secretion in Experimental Animals and the Human Endocr. Rev., December 1, 1998; 19(6): 717 - 797. [Abstract] [Full Text]

				H. Sternbach Age-Associated Testosterone Decline in Men: Clinical Issues for Psychiatry Am J Psychiatry, October 1, 1998; 155(10): 1310 - 1318. [Abstract] [Full Text]

				E. Montecino-Rodriguez, R. Clark, and K. Dorshkind Effects of Insulin-Like Growth Factor Administration and Bone Marrow Transplantation on Thymopoiesis in Aged Mice Endocrinology, October 1, 1998; 139(10): 4120 - 4126. [Abstract] [Full Text] [PDF]

				M. S. Gill, A. A. Toogood, P. A. O’Neill, M. O. Thorner, S. M. Shalet, and P. E. Clayton Urinary Growth Hormone (GH), Insulin-Like Growth Factor I (IGF-I), and IGF-Binding Protein-3 Measurements in the Diagnosis of Adult GH Deficiency J. Clin. Endocrinol. Metab., July 1, 1998; 83(7): 2562 - 2565. [Abstract] [Full Text]

				M. E. Wilson Regulation of the Growth Hormone-Insulin-Like Growth Factor I Axis in Developing and Adult Monkeys Is Affected by Estradiol Replacement and Supplementation with Insulin-Like Growth Factor I J. Clin. Endocrinol. Metab., June 1, 1998; 83(6): 2018 - 2028. [Abstract] [Full Text]

				B. E. Engstrom, F. A. Karlsson, and L. Wide Marked gender differences in ambulatory morning growth hormone values in young adults Clin. Chem., June 1, 1998; 44(6): 1289 - 1295. [Abstract] [Full Text] [PDF]