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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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.
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References |
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