Growth Hormone—Ready for Prime Time?

Robert Marcus M.D. and Gerald M. Reaven M.D.

Stanford University VA Medical Center Palo Alto, California

Address correspondence and requests for reprints to: Robert Marcus M.D., Geriatric Research, Education and Clinical Center, Department of Veterans Affairs Medical Center, 3801 Miranda Avenue 182-B, Palo Alto, California 94304.


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 Introduction
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Recombinant human growth hormone (rhGH) is approved in the United States to treat the consequences of GH deficiency, including childhood short stature and altered body composition in adults with pituitary disease (1). For the last decade, many laboratories have attempted to expand the clinical use of rhGH to other conditions associated with alterations in the somatotropic (GH/IGF-I) axis. Some of these attempts involved short-term administration of rhGH to patients with catabolic illness, such as respiratory failure (2) and AIDS-associated wasting (3, 4). Others involved chronic use of rhGH to counteract somatic changes of normal aging (5, 6, 7). Results of such trials have been mixed. Without doubt, short-term use of GH promotes nitrogen conservation, increases body lean mass, decreases adiposity, and stimulates bone turnover. However, measurement of lean tissue by current methods is highly confounded by changes in body water, and because GH acutely promotes sodium retention and edema (8), and subsequently increases accumulation of intracellular water (9), interpretation of changes in lean tissue remains problematic.

The most dramatic response to GH is loss of adipose mass. Reductions of several kilograms of fat tissue consistently follow GH treatment of patients with organic GH deficiency (1, 10) or healthy older women (6) and men (7). In this issue of JCEM, Johansson and colleagues (11) report on a placebo-controlled trial of rhGH in men with abdominal obesity, a condition associated with diminished activity of the somatotropic axis. Over the 9 months of this trial, rhGH decreased total body fat an average of 9%, but visceral adipose tissue showed a striking 18% decrease. Visceral adiposity has been previously shown to lead to insulin resistance (12), and the observation by Johansson et al. (11), that insulin-mediated glucose disposal improved in subjects treated with rhGH, lends additional support that this relationship exists.

On the other hand, the underlying mechanism for the relationship between visceral adiposity and insulin resistance remains unclear. For example, it has previously been stated (13) and reiterated here by the authors that visceral adiposity influences lipoprotein production and insulin resistance by increasing free fatty acid (FFA) flux, which, in turn: 1) decreases hepatic insulin catabolism; 2) increases hepatic triglyceride (TG) synthesis; and 3) inhibits insulin-mediated glucose disposal by muscle. The net effect is insulin resistance and increases in circulating FFA, insulin, and TG. By this construction, if visceral adipose mass decreases, FFA and insulin concentrations should decline, leading to improved insulin action on muscle and decreased plasma concentrations of both insulin and TG. Unfortunately for the hypothesis, neither plasma FFA nor insulin concentrations fell in response to the rhGH-mediated decrease in visceral adiposity, and the improvement in insulin-mediated glucose disposal was unrelated either to the decrease in adiposity or to FFA concentrations.

Regardless of the nature of the link between excess visceral adiposity and metabolic abnormalities, there is general agreement that they are both related to coronary heart disease risk (14). Thus, the focus on the report of Johansson et al. (11) should be whether or not favorable effects on coronary heart disease risk factors were seen in association with rhGH treatment. In this context, it should be noted that total cholesterol and TG concentrations decreased, as did diastolic blood pressure. The fact that both cholesterol and TG concentrations fell raises the interesting possibility, as commented upon by the authors (11), that rhGH upregulates the hepatic apo-B/E receptor, leading to enhanced removal of both low density and very low density lipoproteins from plasma. In this case, we would be dealing with a direct effect of rhGH, independent of any change in adiposity.

One cannot discuss rhGH today without reflecting on the fact that this agent has captured the fancy of many people who, in quest of greater muscle strength and vitality, appear to have little difficulty obtaining hormone from entrepreneurial physicians, notwithstanding the failure of the scientific literature to support these uses. It would be unfortunate if such physicians seized upon the results of Johansson et al. (11) as another profitable alternative to diet and exercise. If one were convinced of the importance of the changes in metabolic profile associated with rhGH treatment in this trial, many issues would still remain before rhGH could be embraced as clinically realistic therapy. It would be important to determine the extent to which the apparent metabolic benefits are sustained, how rapidly they dissipate on discontinuing therapy, whether similar responses are achieved in women, and most important, whether favorable changes in surrogate biochemical markers truly lead to clinical benefit. These questions are particularly important because, notwithstanding its high cost (currently about $10,000 for one year of daily treatment) sustained use of rhGH is associated with a high incidence of adverse experiences, such as peripheral edema and carpal tunnel syndrome (6).

Although the authors have contributed an interesting and carefully executed study, dramatic reductions in visceral fat and the short-term changes in metabolic indices that were observed do not satisfy the requirement for a rigorous demonstration of clinical benefit. However, to validate such benefit would require conducting sizable trials of fairly long duration, at a substantial investment of time and resources. One needs to ask whether the preliminary evidence truly warrants such an investment. In our view, although the changes observed by Johansson et al. (11) were in a favorable direction, their magnitude was, at best, small. The improvements in glucose disposal rate were nominal and might have been further diminished by appropriate corrections for lean mass. Similarly, the modest reductions achieved in circulating cholesterol and TG could be readily exceeded by other, less expensive medications. Thus, although continued physiologic studies with rhGH remain of great interest and may yet refine our understanding of this hormone to the point that large clinical trials are desirable, we find it difficult, based on current information, to justify recommending such trials for treatment of visceral obesity at the present time.

Received January 2, 1997.

Accepted January 2, 1997.


    References
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 Introduction
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  1. Bengtsson BA, Eden S, Lonn L, et al. 1993 Treatment of adults with growth hormone (GH) deficiency with recombinant human GH. J Clin Endocrinol Metab. 77:1671–1676.[Abstract]
  2. Knox JB, Wilmore DW, Demling RH, Sarraf P, Santos AA. 1996 Use of growth hormone for postoperative respiratory failure. Am J Surg. 171:576–580.[CrossRef][Medline]
  3. Schambelan M, Mulligan K, Grunfeld C, et al., and the Serostim Study Group. 1996 Recombinant human growth hormone in patients with HIV-associated wasting. A randomized, placebo-controlled trial. Ann Int Med. 125:873–882.[Abstract/Free Full Text]
  4. Waters D, Danska J, Hardy K, et al. 1996 Recombinant human growth hormone, insulin-like growth factor 1, and combination therapy in AIDS-associated wasting. A randomized, double-blind, placebo-controlled trial. Ann Int Med. 125:865–872.[Abstract/Free Full Text]
  5. Rudman D, Feller AG, Nagraj HS, et al. 1990 Effects of human growth hormone in men over 60 years old. New Engl J Med. 323:1–6.[Abstract/Free Full Text]
  6. Holloway L, Butterfield G, Hintz RL, Gesundheit N, Marcus R. 1994 Effect of recombinant human growth hormone on metabolic indices, body composition, and bone turnover in healthy elderly women. J Clin Endocrinol Metab. 79:470–479.[Abstract]
  7. Papadakis MA, Grady D, Black D, et al. 1996 Growth hormone replacement in healthy older men improves body composition but not functional ability. Ann Int Med. 124:708–716.[Abstract/Free Full Text]
  8. Marcus R, Butterfield G, Holloway L, et al. 1990 Effects of short-term administration of recombinant human growth hormone to elderly people. J Clin Endocrinol Metab. 70:519–527.[Abstract]
  9. Thompson JL, Butterfield GE, Marcus R, et al. 1995 The effects of recombinant human insulin-like growth factor-I and growth hormone on body composition in elderly women. J Clin Endocrinol Metab. 80:1845–1852.[Abstract]
  10. Baum HBA, Biller BMK, Finkelstein JS, et al. 1996 Effects of physiologic growth hormone therapy on bone density and body composition in patients with adult-onset growth hormone deficiency. A randomized, placebo-controlled trial. Ann Int Med. 125:883–890.[Abstract/Free Full Text]
  11. Johansson G, Mårin P, Lönn L, et al. 1997 Growth hormone treatment of abdominally obese men reduces abdominal fat mass, improves glucose and lipoprotein metabolism and reduces diastolic blood pressure. J Clin Endocrinol Metab. 82:727–734.[Abstract/Free Full Text]
  12. Pouliot MC, Despres JP, Nadeau A, et al. 1992 Visceral adiposity in men, associations with glucose tolerance, plasma insulin, and lipoprotein levels. Diabetes. 41:826–834.[Abstract]
  13. Kissebah AH, Peiris AN, Evans DJ. 1988 Mechanisms of association of body fat distribution to glucose intolerance and diabetes: window with a view. Acta Med Scand. 223[Suppl]:79–89.
  14. Reaven GM. 1995 Pathophysiology of insulin resistance in human disease. Physiol Rev. 75:473–486.[Abstract/Free Full Text]




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