Growth hormone and cardiovascular disease: an area in rapid growth.

The association between GH and premature cardiovascular disease has been in focus for a considerable amount of time (1, 2). Until recently, however, research in this area were largely confined to epidemiological studies. Before the availability of recombinant GH, the use of GH replacement in GH-deficient subjects was limited primarily to the period of linear growth. This restricted possibilities to study effects of GH replacement in adult GH-deficient subjects. The first placebo-controlled trials of GH replacement in GH-deficient adults were reported about 10 yr ago. Recently, however, this area has received considerable attention. A Medline search for “GH and cardiovascular disease” resulted in 1200 titles, among which about 300 were published since 1995. Studies in both GH-deficient and normal subjects have focused on various aspects of cardiovascular disease, including lipid levels, cardiac function and mass, and, more recently, inflammatory markers. The availability of recombinant GH makes the urgency to study effects of GH more compelling, and an excellent and comprehensive review of the effect of GH replacement in GH-deficient adults was recently published (3). In 1990, a comprehensive, retrospective study of 333 Swedish patients over 31 yr evaluating mortality in patients with hypopituitarism was reported (2). There was a statistically significant increased mortality in patients with hypopituitarism compared with ageand sex-matched population controls. In addition, death due to cardiovascular disease (myocardial infarction, cardiac failure, cerebrovascular disease, pulmonary embolism, and arterial embolus) was more common among patients than controls. Overall, there was a doubling of mortality due to vascular causes among the patients compared with that of the general population. The authors hypothesized that GH deficiency could account for this increase in mortality (2). Of note, these patients also had lower rates of malignancies, which could argue against an increased mortality due to this cause. In another retrospective study of 172 patients over 27 yr with complete or partial hypopituitarism, mortality due to all causes was higher than for ageand sex-matched control populations (4). The authors noted an increase in the number of vascular deaths. This did not reach statistical significance, however, possibly due to the lower number of patients in this study, and the authors concluded that the cause of the poor outcome in hypopituitarism may be multifactorial. However, further support for an increased cardiovascular morbidity and mortality in GH deficiency has been provided by other, more recent studies (3). Thus, altogether, available evidence indicates an association between cardiovascular risk and GH deficiency. GH has wide-ranging effects, influencing a number of key metabolic processes, body composition, muscle strength, exercise performance, as well as the immune system. All of these factors, alone or in combination, could potentially contribute to the increased cardiovascular morbidity associated with GH deficiency. With the increasing evidence that subjects with insulin resistance are at increased risk for cardiovascular disease, it is of interest that GH deficiency results in a similar phenotype. Thus, GH-deficient adults commonly have more central obesity and increased fasting insulin levels. In several studies using the hyperinsulinemic euglycemic clamp technique, results were indicative of insulin resistance (3, 5). Because GH acts contradictory to insulin in several key metabolic pathways, these findings might be perceived as being opposite to what would be expected. Interestingly, however, during short-term GH administration insulin resistance is further impaired, although long-term studies over 6 months generally report a normalized carbohydrate metabolism (3). It is likely that adaptive mechanisms may modulate a change in response over time. Changes in body composition, mediated by GH, for example, could contribute to these findings. Thus, although the interaction between GH and insulin may be complex, the existence of insulin resistance and its associated phenotype during GH deficiency is well established. It is quite feasible that prolongation of such a state over time could contribute to an increased cardiovascular risk. A substantial number of studies have addressed plasma lipid levels during both GH deficiency and in response to GH replacement (3). The most common pattern found during GH deficiency is an increase in total and low-density lipoprotein (LDL) cholesterol and apolipoprotein B (apoB) levels, an increase in triglycerides, and a decrease in high-density lipoprotein (HDL) cholesterol levels. In many ways, this profile has the features of combined hyperlipidemia. It is also similar to the lipid profile associated with insulin resistance (where hypertriglyceridemia, low HDL cholesterol, and a qualitative rather than a quantitative change in the LDL fraction with presence of small, dense LDL particles commonly is seen). The quantitative increase in total and LDL cholesterol during GH deficiency might be explained by a decrease in LDL receptor activity, as GH treatment has been found to result in an increase of the receptor activity (6). In view of the lipid and lipoprotein profile observed during GH deficiency, the decrease in total and LDL cholesterol and apoB levels observed in the majority of studies during administration of GH is compatible with an increase in LDL receptor activity (6). In most studies, GH administration has also been associated with a modest increase in HDL cholesterol, but generally no effects on triglyceride levels have been Received March 14, 2001. Accepted March 18, 2001. Address correspondence and requests for reprints to: Lars Berglund, M.D., Department of Medicine, Room PH 10-305, Columbia University, 630 West 168th Street, New York, New York 10032. E-mail: lfb9@columbia.edu. 0021-972X/01/$03.00/0 Vol. 86, No. 5 The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright © 2001 by The Endocrine Society