Agatha A. van der Klaauw, Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, PO Box 9600, The Netherlands, Tel: 0031-71-5263780, Fax: 0031-71-5248136, E-mail: a.a.van_der_klaauw[at]lumc.nl

Introduction

Adult growth hormone (GH) deficiency is a clinical syndrome, consisting of altered body composition with reduced muscle strength and mass and visceral obesity. Metabolic alterations include an adverse cardiovascular lipid profile that consists of increased total and low-density lipoprotein cholesterol, decreased high-density lipoprotein (HDL) cholesterol, and increased serum triglycerides, and insulin resistance. This syndrome is also associated with increased mortality due to cardiovascular disease [1]. Adult GH deficiency can be treated with recombinant GH, introduced for the treatment of adults in the early nineties. Since then, many studies reported the short- and long-term efficacy of recombinant human GH treatment. Short term placebo-controlled studies with recombinant GH treatment documented an improvement of surrogate markers of clinical endpoints like an increase in lean body mass and a decrease in fat mass, a decrease in total cholesterol levels, an increase in HDL cholesterol levels and in diastolic blood pressure. In contrast, recombinant human GH negatively influenced plasma glucose and insulin levels [2].

Long-term studies have shown an increase in HDL cholesterol levels [3-5] and fasting glucose levels [4,6,7], and a decrease in plasma triglyceride levels [8,4], whereas diastolic blood pressure decreased only in one study [9].

The metabolic syndrome is a scoring system proposed to identify persons at high risk for cardiovascular disease [10]. It combines several cardiovascular risk factors [11-15], which are associated with increased cardiovascular morbidity and mortality [13,14]. The overall prevalence of the metabolic syndrome in non-diabetic adult Europeans is 15% [16]. The underlying risk factors that promote development of the metabolic syndrome are overweight and obesity, physical inactivity, and an atherogenic diet.

There are ssimilarities between the metabolic syndrome and untreated GH deficiency in adults, consisting of visceral obesity and dyslipidemia in both syndromes. Moreover, common in both conditions are premature atherosclerosis and increased mortality from cardiovascular disease. In the general population, obesity is indeed associated with low circulating GH concentrations [17] and GH treatment in otherwise healthy obese subjects has even been proposed to counteract the negative metabolic consequences of visceral obesity [18]. From these observation, the notion emerged that treatment with recombinant GH might benefit cardiovascular risk in GH deficient patients.

Relationship between Adult GH Deficiency and Metabolic Syndrome

The extent to which changes in body composition and lipid and glucose parameters induced by treatment with recombinant human GH will translate in a net reduction of cardiovascular risk is unknown. Recent publications in the New England Journal of Medicine have suggested that reductions in cardiovascular risk factors may not actually be translated in true reductions in cardiovascular risk, like in the case of rosiglitazone. The metabolic syndrome is defined as a cluster of metabolic abnormalities to identify persons at high risk for cardiovascular disease [13,14,19]. The aim of the current study was to characterize the baseline characteristics of the metabolic syndrome, according to the definition of the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATPIII) published in 2001 [20], in adult GH deficiency and to evaluate the effect of subsequent recombinant human GH replacement during 5 years on the prevalence of the metabolic syndrome. Compared to a large group of healthy controls, hypertriglyceridemia (46% versus 19%), hypertension (66% versus 36%), and abdominal obesity (38% versus 23%) were significantly more prevalent in patients with GH deficiency.

As a result, the prevalence of the metabolic syndrome in adult GH deficiency was almost two-fold increased (38% versus 16%) compared to controls. HDL levels increased slightly during follow-up, whereas blood pressure, waist circumference, fasting glucose, and triglyceride levels remained unchanged. The increase in HDL levels did not influence the prevalence of abnormal low HDL levels, as scored with the metabolic syndrome reference values. In conclusion, long-term treatment with recombinant human GH during 5 years did not alter the prevalence of (components of) the metabolic syndrome in adult patient with GH deficiency.

Future Research

It remains to be studied whether adult GH deficient patients with the metabolic syndrome have the same risks for cardiovascular morbidity and mortality compared with those with the metabolic syndrome in the general population without GH deficiency. GH deficiency per se results in abdominal obesity and its metabolic consequences that could induce the high prevalence of the metabolic syndrome. Once these changes have occurred, recombinant GH replacement is insufficient to reverse these changes, maybe because normal physiology (for example circadian rhythm in GH secretion) might not be restored with once-daily subcutaneous administration of GH.

On the other hand, the negative effects of recombinant human GH replacement on glucose metabolism and insulin sensitivity might influence the prevalence of the metabolic syndrome in our patients, indicating that a more narrow therapeutic range might be more beneficial for insulin sensitivity. Given the documented increased cardiovascular morbidity and mortality in these patients, it would be logical to propagate that GH-deficient adults may benefit from more aggressive antihypertensive and lipid-lowering therapy and life style intervention to reverse the metabolic abnormalities seen in the adult GH-deficiency syndrome.

Finally, these patients with pituitary tumors provide a unique model of the metabolic syndrome. These patients do not only have alterations in pituitary function, but also, due to the effects of the tumor, surgery, and/or radiotherapy, in hypothalamic function. Evidence is emerging that the hypothalamus does not only alter tissue-specific insulin sensitivity, and therefore glucoregulation, but also altered lipid metabolism, as exemplified by circumstantial evidence in the present study.

References

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