Effects of Growth Hormone Replacement Therapy on Body Composition and Metabolic Indices in Patients with Growth Hormone Deficiency

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1 Clin Pediatr Endocrinol 1996; 5(Suppl 8): Copyright (C) 1996 by The Japanese Society for Pediatric Endocrinology Effects of Growth Hormone Replacement Therapy on Body Composition and Metabolic Indices in Patients with Growth Hormone Deficiency Hitoshi Kohno, Hassan Mohamed, Salama Hassan, Ryuichi Kuromaru and Nami Ueyama Department of Endocrinology and Metabolism, Fukuoka Children's Hospital, Fukuoka, Japan Abstract Growth hormone (GH) is important in the regulation of fat, carbohydrate, and protein metabolism. These metabolic effects subsequently affect health risk factors, such as body composition, atherogenic risk factors, and glucose intolerance. GH deficiency is associated with obesity which reportedly responds to GH treatment. Children and adults with GH deficiency often have hypercholesterolemia and thus might be at increased risk of having atherosclerotic diseases in later life. In fact, adults with GH deficiency have been reported to have an increased mortality rate as a result of cardiovascular disease. On the other hand, the results of GH treatment in relation to carbohydrate metabolism are inconsistent in GH-deficient children. We evaluated the changes in health risk factors during GH replacement therapy in 40 children, 31 boys and 9 girls, with GH deficiency and compared our results with those in adult patients. In conclusion, GH replacement therapy in children and adults with GH deficiency can reduce health risk factors without altering glucose metabolism. These beneficial effects are reportedly reversed after the discontinuation of GH therapy. It therefore seems prudent to continue life-long GH replacement therapy in these patients. Key words: growth hormone deficiency, growth hormone therapy, body composition, metablic indices Growth hormone role in the regulation Introduction (GH) plays an important of lipid, carbohydrate, and protein metabolism. Recent studies have indicated that these metabolic effects of GH subsequently influence body composition and Correspondence: Dr. Hitoshi Kohno, Department of Endocrinology and Metabolism, Fukuoka Children's Hospital, Tojin-machi, Chuo-ku, Fukuoka 810 Japan health risk factors in patients with GH deficiency. In fact, adults with hypopituitarism who receive routine replacement therapy with corticosteroids, thyroxine, and sex hormone with the exception of GH have been reported to have an increased mortality rate due to cadiovascular disease (1), whereas the cardiovascular effects of GH replacement therapy remain controversial. This paper focuses on health risk factors, such as changes in body composition, lipid and 45

2 Kohno et al. carbohydrate metabolism, and atherogenic factors, associated with GH replacement therapy in children with GH deficiency. In addition, we compare our results with those in adult patients. Body Composition GH deficiency is associated with adiposity, 5). Rapid decreases in upper arm and calf fat have been demonstrated radiologically after 3 months of GH therapy in children with GH deficiency (2). The skin-fold thickness also decreased during the first 6 to 10 weeks of GH treatment and remained low thereafter (3). We studied 40 children (31 boys and 9 girls, age 6 to 14 years) with GH deficiency. Their heights were 2.0 to 4.5 standard deviation (SD) below the mean height for their age according which reportedly responds to GH treatment (2- growth charts compiled by the Japanese Ministry of Education. GH deficiency was diagnosed on the basis of a peak GH level of less than 10 ng/ml on two or more standard provocative tests (6). The patients received methionine-free recombinant GH by daily subcutaneous injection (0.5 IU/kg/week) for one year. Body fat was measured by bioelectrical impedance method (BIA 101, RJL Systems, Detroit, USA) because this method has been validated for use in children (7). During GH treatment, both height and weight increased linearly. Consequently, there was no significant change in body mass index. Height SD score improved significantly to after 3 months of GH therapy in both boys and girls. Percentage of body fat, however, decreased rapidly during the first 3 months of GH treatment and remained low thereafter. In con- Fig. 1 Changes in body fat (BF) and lean body mass (LBM) during GH therapy in children with GH deficiency. trast, lean body mass increased steadily during one year of therapy in both genders (Fig. 1). In addition, exogenous GH administration in children with GH deficiency was associated with the redistribution of adipose tissue from an abdominal to more peripheral areas (8). These results indicate that GH therapy is beneficial in terms of reducing adiposity-related health risk factors, even in children with GH deficiency. In adult patients with GH deficiency, the adipose tissue volume of the thigh and subscapular skin-fold thickness, estimated by computed tomography, fell significantly, con- 46

3 GH Effects on Body Composition and Metabolic Indices current with an increase in muscle volume of the thigh during GH treatment (9). The waistto-hip ratio, however, was higher in GH-deficient adults than in a control group, indicating a trend toward central obesity. This may lead to an increased risk of cardiovascular disease. These findings were markedly improved by GH therapy (10). Dramatic reductions in both subcutaneous and visceral fat mass were associated with GH replacement therapy. In a study that assessed the changes in adipose tissue at different sites after 26 weeks of GH treatment in adults with GH deficiency, the most remarkable reduction in fat mass was seen in visceral areas (Fig. 2) (11). Available evidence, derived from our own studies and those of others, indicates that GH therapy may play a physiological role in reducing obesity in children and adults with GH deficiency, which may decrease the risk of obesity-related diseases, such as hypertension, stroke, and myocardial infarction. decrease in total cholesterol (TC), but statistical significance was not reached in either gender during one year of GH therapy. Changes in high-density lipoprotein cholesterol (HDLC), however, were gender-related (Fig. 3).In boys with GH deficiency, HDLC increased rapidly during 3 months of GH treatment and remained high thereafter, consistent with our preliminary results in twelve boy patients during nine months of GH therapy (6). In girl patients, on the other hand, there was no significant change in HDLC Lipid Metabolism and Atherogenic Index In our study, there was a trend toward a Fig. 2 Changes in different adipose tissue depots, estimated by computed tomography, after 26 weeks of GH treatment (11). Fig. 3 Effects of GH on total cholesterol (TC), highdensity lipoprotein cholesterol (HDLC), and atherogenic index (AI) in boys and girls with GH deficiency. 47

4 Kohno et al. Fig. 4 Body fat (BF) percentage and atherogenic treatment in children with GH deficiency. index (AI1, AI2) during GH during one year of GH treatment, mainly because HDLC levels were high before the initiation of therapy. Higher levels of HDLC in girls than in boys may be caused by an 8-fold higher level of estrogen in prepubertal girls than boys, as determined by an ultrasensitive recombinant cell bioassay (12). Estrogen has been reported to increase triglycerides, very low-density lipoprotein cholesterol, and HDLC, and to decrease TC, low-density lipoprotein cholesterol, and apolipoprotein B (13). We additionally evaluated the changes in atherogenic index by two equations, namely atherogenic index-1 (AI-1)(14) and AI-2 (15), which are well documented as precise indicators of atherogenic risk factors. Using TC, HDLC, apolipoprotein (Apo) B and Apo A1, AI- 1 and AI-2 are calculated as follows: AI-1 = TC/HDLC, AI-2 =[(TC-HDLC)(Apo B)]/ [(Apo A1)-(HDLC)]. Both AI-1 and AI-2 decreased significantly in association with decrease in body fat (Fig. 4) during one year of GH therapy. In adults with GH deficiency, decreases in both TC and LDL-cholesterol were demonstrated during Fig. 5 Effect of GH treatment on cholesterol metabolism in adults with GH deficiency (16). the GH treatment phase in a double-blind placebo-controlled crossover study (Fig. 5)(16)., 48

5 GH Effects on Body Composition and Metabolic Indices These results indicate that GH replacement therapy reduces the risk of atherosclerotic dis - ease in both children and adults with GH deficiency. Glucose Metabolism As for glucose tolerance during GH therapy in children with GH deficiency, we have already reported the results of oral glu - cose tolerance tests (17). Although there were several changes in the blood glucose curve after one year of GH therapy, there were no significant changes in sigma blood glucose, sigma insulin, sigma C-peptide reactivity, or delta insulin to delta blood glucose ratio. In addition, hemoglobin Alc, 1,5-anhydro-glucitol, and fructosamine did not change significantly after one year of GH therapy. In adult patients, however, sigma insulin was higher than baseline, although there were no significant changes in blood glucose curves after 18 months of GH treatment (18). In another report, no changes in glucose metabolism variables were detected during 6 months of GH treatment (19). GH treatment may therefore be lipolytic without altering glucose tolerance. assessed by measuring skin-fold thickness and by computed tomography or muscle biopsy (20). Nevertheless, no change in any variable was seen in a non-gh deficient group on retesting at the end of the study. Another study reported a rapid increase in fat mass and a decrease in lean body mass after the discontinuation of GH therapy in young adults with GH deficiency (Fig. 6)(21). GH replacement therapy may have beneficial effects by reducing health risk factors in 'true' GH-deficient children and adults. Further studies are needed to evaluate the clinical usefulness of GH therapy and the need for GH replacement after the completion of height growth in these Outcome after Discontinuation of GH Therapy Several studies examine the effects on body composition and health risk factors of terminating long-term GH replacement therapy in patients with GH deficiency. One study revealed an increase in body fat percentage and decreases in muscular strength, size and fiber area in GH-deficient patients, Fig. 6 Fat weight and lean body weight after the discontinuation of GH therapy in GH deficiency (open column) and non-gh deficiency (striped column) (21). The increase in fat weight is significant (* P<0.05) only in the GH-deficient patients with a slight decrease in lean body weight. 49

6 Kohno et al. patients. Several issues remain to be clarified. before GH replacement therapy can be recommended unequivocally after epiphyseal closure: 1) the definition of 'true' GH deficiency, 2) the optimal dose of GH for replacement therapy in young adults, middleaged adults, and elderly patients, and 3) the time of discontinuation of GH replacement therapy in elderly patients. As for 'true' GH deficiency, it has been reported that 18-20% of children in whom GH deficiency was initially diagnosed showed normal GH responses on retesting after several years of GH treatment (22). It is therefore necessary to reevaluate GH secretory dynamics after the completion of height growth. The second issue is the establishment of the optimal dose of GH for replacement therapy in young adults, middle-aged adults, and elderly patients. In children with GH deficiency, 0.5 IU/kg/week of GH is recommended in Japan, as compared with 0.7 IU/kg/week in Europe and America. We have reported that normalization of 24hour urinary GH excretion requires 0.7 IU/kg/week of GH in children with GH deficiency (23), and 1.0 IU/kg/week in patients with Turner's syndrome (24). Although a wide range of doses has been used in adult patients, IU/kg/week or less is generally recommended as the initial dose for replacement therapy (16,25). Studies of GH secretory dynamics have revealed age-related alterations, with GH levels rising during puberty, peaking at late puberty, and subsequently declining into old age (26). Perhaps age-specific dosage recommendations for GH replacement therapy should be developed. The last issue pertains to the time to discontinue replacement therapy in adults or elderly patients with GH deficiency, even though GH may be beneficial in terms of reducing health risk factors. Should GH replacement therapy be terminated at 80 or 90 years of age, or should it be continued indefinitely? Conclusion GH replacement therapy in children and adults with GH deficiency can reduce health risk factors. These beneficial effects are reversed after the discontinuation of GH therapy in these patients. It therefore seems prudent to continue life-long GH replacement therapy in patients with 'true' GH deficiency, although the consequences of continuing GH therapy on life expectancy must be objectively evaluated before firm conclusions can be made. References 1. Rosen T, Bengtsson B-A. Premature mortality due to cardiovascular disease in hypopituitarism. Lancet 1990; 336: Tanner JM, Hughes PCR, Whitehouse RH. Comparative rapidity of response of height, limb muscle and limb fat to treatment with human growth hormone in patients with and without growth hormone deficiency. Acta Endocrinol (Copenh) 1977; 84: Collipp PJ, Curti V, Thomas J, Sharma. RK, Maddaiah VT, Cohn SH. Body composition changes in children receiving human growth hormone. Metabolism 50

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