- Email: [email protected]
Safety of growth hormone
108
LETTERS to the EDITOR
Safety of growth hormone SIR,-Dr Walker and colleagues (Dec 1, p 1331) describe profound changes in body composition which may be a "stress" in short, but otherwise healthy, children treated with recombinant growth hormone (rhGH). Since this therapy is being increasingly considered for the treatment of children with chronic renal failure, a group who are not growth hormone deficient, I wish to report the unexpected rapid onset of end-stage renal failure (ESRF) in such a child treated with rhGH. The child has the clinical and radiological features of Jeune’s syndrome (asphyxiating thoracic dystrophy). At 2 years of age his height was 75-5 cm, which was below the 3rd centile (height SD score —3 15). When he was 24 years old he was referred by his general practitioner to a paediatric endocrinologist in another centre after his parents had learnt of GH therapy from a television programme. Normal levels of GH were confirmed on an insulintolerance test and the plasma creatinine was 90 tmol/I. He was put on daily subcutaneous injections of 2 units rhGH (’Genotropin’; KabiVitrum) via an auto-injector device. Three months later the rhGH treatment was suspended because of the endocrinologist’s concern about the possible effects on renal function. His plasma creatinine was 105 umol/1 and glomerular filtration rate (99mTc-DTPA method) was reduced at 53 ml/min per 1 73 m2. After he had been off treatment for a futher three months his plasma creatinine was 142 (imol/1. The advice of a nephrologist had been sought by the endocrinologist, and two months later rhGH therapy was started again. After eight weeks’ further treatment the parents were increasingly concerned about their child’s breathing pattern and ill-health. The child was transferred to our unit when his plasma creatinine was found to be 336 mol/1 (urea 54 mmol/1, bicarbonate 12 mmol/1, potassium 5-4 mmol/1, phosphate 2-9 mmol/1). His haemoglobin was 6-9 g/dl and blood pressure was 136/90 mm Hg. Acute peritoneal dialysis was instigated along with antihypertensive therapy. A percutaneous renal biopsy, done at the time of insertion of a Tenckhoff catheter for chronic peritoneal dialysis ten days later, revealed histological features compatible with nephronophthisis with areas of advanced glomerulosclerosis. The child is now stable on continuous cycling peritoneal dialysis, enalapril, and supplementary feeding overnight by means of a gastrostomy button. He is awaiting a renal transplant. His height at 33 years, when the rhGH was suspended, was 82-7 cm (SD score - 3-52). Since the child received only short-term and intermittent rhGH treatment, it was hard to discern any effect on his growth velocity. Of more importance is the question whether the treatment harmed his renal function. There is a strong association between Jeune’s syndrome and juvenile nephronophthisis.1 This is usually a slowly progressive renal condition with a median age of renal replacement therapy for males of about 13 years.2 The parents had been counselled to expect renal replacement therapy for their child at the end of the first decade. In addition they were told that the advantage of the height gain with rhGH outweighed any possible deleterious effects on renal function. The rapid progression in ESRF was traumatic for all concerned. Experience to date suggests little deleterious effect of rhGH treatment in children with chronic renal failure.3 However, Rees et al’have reported deterioration of renal function in two children with renal disease treated with rhGH, one of whom had chronic renal failure while the other was prepubertal with a functioning renal transplant. It was not possible to ascribe the effect to GH, but the transplant recipient’s blood pressure control had also deteriorated
patient was on rhGH. Our patient was significantly hypertensive at the time of his transfer to our unit. Among other effects, GH may produce hyperfiltration by increasing glomerular filtration rate and renal plasma flow.s Children with chronic renal failure are a very heterogeneous group. Our patient’s progress emphasises the need for caution and proper monitoring in the use of this potentially "stressful" therapy until further experience has accumulated. while the
City Hospital, Hucknall Road,
Nottingham NG5 1PB, UK
ALAN R. WATSON
1 Donaldson
MDC, Wamer AA, Trompeter RS, Haycock GB, Chantler C. Familial juvenile nephronophthisis, Jeune’s syndrome and associated disorders. Arch Dis Child 1985, 60: 426-34.
Gretz N, Scharer K, Waldherr R, Strauch M. Rate of deterioration of renal function in juvenile nephronophthisis Pediatr Nephrol 1989; 3: 56-60 3. Johannson G, Sietnicks A, Janssens F, et al Recombinant human growth hormone treatment in short children with chronic renal disease, before transplantation or with functioning renal transplants. an interim report on five European studies. Acta Paediatr Scand 1990; (suppl 370): 36-12. 4. Rees L, Rigden SPA, Ward G, Preece MA. Treatment of short stature in renal disease with recombinant human growth hormone Arch Dis Child 1990, 65: 856-60 5 Hirschberg R, Rabb H, Bergamo R, Kopple JD The delayed effect of growth hormone on renal function in humans Kidney Int 1989; 35: 865-70.
2
SiR,—The sensational title to an article which reiterates something well known since the 1960s has caused the parents of thousands of children who require GH replacement needless anxiety. My department has been inundated with telephone calls asking about the "cautionary tale" published in your Dec 1 issue and picked up by the newspapers. Dr Walker and colleagues are well aware that they have described nothing new. "We have no evidence that this is adverse or that the changes in body composition are not reversible with time", they say. Extensive published work over the past 20 years indicates that the changes are indeed reversible and do reverse, even if GH is continued. Unfortunately, the newspapers will not quote this letter, but I hope that your readers will be reassured-and perhaps read the paper more carefully for the non-event it is. Department of Medicine, UCMSM, Cobbold Laboratories, Middlesex Hospital. London W1 N 8AA, UK
C. G. D. BROOK
SIR,-Dr Walker and her colleagues provide some new information the metabolic effects of growth hormone (GH), but I take issue with their speculation that these effects may be adverse or undesirable. This unwarranted extrapolation has, via the lay press, alarmed many children and their parents. This is not the first time that short, slowly growing children without classical GH deficiency have been treated with GH. One study referred to, that of Hindmarsh and Brook,’ is now in its 6th year of treatment. To my knowledge no child has had any adverse clinical effects, let alone any that could be related to metabolic stress. Walker et al quantify in metabolic terms what every paediatrician has observed since children began to be treated with GH. They all lose fat: GH is lipolytic. Most GH-deficient children tend towards obesity and, usually, the first observed effect of GH therapy is the loss of much of this fat. Nobody has ever reported adverse metabolic effects from this fat loss, and Walker et al stress this point for their study in their final paragraph. What they do report is a mean loss of on
109
body fat of 0.68 kg. Over the 6 months this averaged around 4 g a day, or the burning-up of about 36 kcal per day. Is this really an adverse metabolic stress when there is an opposite, even greater, effect on lean body mass? Many people on weight-loss diets or undergoing strenuous athletic training after a winter lay-off would be very disappointed at such a rate of fat loss. Salomon et alwhen they treated GH-deficient adults with GH, recorded, over a similar 6-month period, an average loss of 5kg of body fat, which was replaced gram for gram by lean body mass. No adverse metabolic or related clinical events were reported. Admittedly these were patients receiving physiological replacement doses of GH, but one could argue that since they all had panhypopituitarism and were on fixed replacement doses of other hormones, they were less well able to cope with adverse metabolic That was not the case. Caution should always be a guiding force in research and treatment, but I do not think that Walker et al revealed anything to justify a title including "a cautionary tale". stress.
Kabi Pharmacia, Milton Keynes MK5
8PH, UK
RICHARD WILD
1 Hindmarsh PC, Brook CGD. Effect of growth hormone on short normal children. Br Med J 1987; 295: 573-78 2 Salomon F, Cuneo RC, Hesp R, Sonksen PH. The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N Engl J Med 1989; 321: 1797-803.
SIR,-Dr Walker and her colleagues show that the administration of GH to short normal children increases lean body mass (LBM), reduces body fat and increases resting energy expenditure (REE). After adjusting for LBM, they find that REE is unrelated to age, height, and weight, showing that the increase in REE is explained by the increase in LBM. They also consider REE expressed in units of kj/kg LBM and find, paradoxically, that this index is negatively correlated with height. A great deal of their discussion is given over to explaining their finding in terms of physiological changes in body composition induced by GH. There is a much simpler explanation-namely, that their index of REE is inappropriate. The purpose of adjusting REE for LBM is to remove the effect of LBM on REE-ie, to provide an index which is essentially uncorrelated with LBM. However, there is no reason a priori why dividing REE by LBM should remove the correlation between REE and LBM. One might equally divide by the square root of LBM, or the square of LBM, or some other power, and the best index would be the one that was uncorrelated with LBM. In the present instance, it is clear that dividing REE by LBM overadjusts. Normally the overadjustment would show itself as a negative correlation between the REE/LBM index and LBM. However, no further adjustment was made for LBM, and height (which is highly correlated with LBM) acted as its proxy in the regression. This is an example of a fallacy seen often in medical research. Expressing quantity A (be it, say, energy expenditure or energy intake or glomerular filtration rate) per unit of quantity B (eg, body weight or LBM or surface area) may or may not be a useful exercise, but it is incorrect to assume that the resulting index A/B will automatically be uncorrelated with B, and even more incorrect to assume that it should be. of Cambridge and Medical Research Council. Dunn Nutritional Laboratory, Cambridge CR4 1XJ, UK
Relation between REE and FFM in 88 children Bioelectrical impedance and indirect
calorimetry
aged 8-11.
were
used. In these
children, height was strongly correlated to FFM (r=0 86, p<0 0001)
so
short children will have higher REE than tall children when REE is expressed in kJ/24 h.kg FFM despite the fact that both have a "normal" REE (ie, they lie on the regression line for the group). REE=1757+151 x FFM therefore REE/FFM=1751/FFM+151.
increase in skeletal muscle tissue relative to visceral tissue during linear growth. However, a likely alternative explanation is related to the way the REE data are normalised in children of different body size and body composition. REE is best correlated to fat-free body mass (FFM).1 However, in adults and children, the regression line between REE and FFM does not pass through the origin (figure), so dividing REE by FFM mass introduces a bias3-S which results in higher REE in those with lower FFM (figure). Since FFM is positively correlated to height (r=0 86 in 88 children aged 8-11, unpublished), REE/FFM is also higher in those who are shorter. The correct way to analyse the data is to include other co-variates such as height or age in a multivariate analysis. When they did that, Walker et al did not find any extra variance in REE explained by height. Thus their data do not support the conclusion that "short children expend more energy fulfilling their basic metabolic requirements than tall children do". Clinical Diabetes and Nutrition Section, National Institutes of Health, Phoenix, Arizona 85016, USA
ERIC RAVUSSIN
1 Bogardus C, Lillioja S, Ravussin E, et al. Familial dependence of the resting metabolic rate N Engl J Med 1986; 315: 96-100. 2 Ravussin E, Lillioja S, Anderson TE, Chnstin L, Bogardus C. Determinants of 24-hour expenditure in man. methods and results using a respiratory chamber. J Clin Invest 1986; 78: 1568-78. 3 Ravussin E, Bogardus C. Relationship of genetics, age, and physical fitness to daily energy expenditure and fuel utilization. Am J Clin Nutr 1989, 49: 968-75. 4. Tanner J M Fallacy of per-weight and per-surface area standards, and their relation to spurious correlation. J Appl Physiol 1949; 2: 1-15. 5 Lillioja S, Bogardus C. Obesity and insulin resistance: lessons learned from the Pima Indians Metab Rev 1988; 4: 517-60.
University
T. J. COLE P. S. W. DAVIES
SIR,-Dr Walker and her colleagues describe the effect of daily injections of growth hormone on growth, body composition, and resting energy expenditure (REE) in short children. We agree with their caution on the use of high doses of GH but their conclusion that shorter children expend more energy than taller children is not supported by the data. REE is found to be higher in short children when compared with tall children only when REE is divided by lean body mass but not when height is a co-variate. Walker et al suggest that part of this difference in REE might be attributable to the disproportionate
SjR,—Dr Walker and her colleagues suggest caution in the use of rhGH for short children without classic GH deficiency because of the possibility of stressful metabolic changes. There may be another reason for caution. Large prospective studies confirm that taller western women are at higher risk for breast cancer; 10 cm additional height increases the risk by 20%.1-5 Tallness in adults is associated with higher circulating levels of GH in childhood, and there is evidence that insulin-like growth factor (IGF-1), a GH-dependent peptide, stimulates cellular replication in the mammary epithelium and stroma.6 Receptors for IGF-1 have been found in mammary ductal epitheliumand administration of rhGH to prepubertal girls with isolated GH deficiency can accelerate breast development.8 While IGF-1 is probably not the mediator of oestrogen-regulated
110
in the breastinteraction between GH, IGF-1, and oestrogen is likely to be involved in stimulating pubertal breast development, just as it is in stimulating the adolescent linear growth spurt. Low-dose oestrogen therapy is widely used to initiate both linear growth and sexual maturation in girls showing constitutional delay of growth and puberty, and sex steroids are known to be involved in stimulating the pubertal surge in GH levels. Mammary epithelium is most susceptible to carcinogenesis at the time of puberty, when proliferative activity is greatest,9 and the critical importance of cancer promotion at that period is shown by the observation that a first pregnancy within a few years of puberty can reduce the risk of subsequent breast cancer by over 50%. Thus, although it is speculative to suggest that high levels of IGF-1 may increase the individual risk of developing breast cancer, 10 there is no doubt that the use of rhGH in short children will accelerate proliferative activity in developing breast tissue. This will increase breast cancer risk because factors which accelerate proliferative activity will also increase the potential for atypical hyperplasia.
growth
Department of Oncology, St Thomas’ Hospital, London SE1 7EH, UK
BASIL A. STOLL
Holm LE, Carstensen JM. Breast cancer risk in relation to serum cholesterol, serum beta lipoprotein, height, weight and blood pressure Acta Oncol 1988; 27: 31-37 2. Swanson CA, Jones DY, Schatzkin A, et al. Breast cancer nsk assessed by anthropometry in the NHANES. epidemiologic follow up study. Cancer Res 1988; 1
Tomberg SA,
48: 5363-67 3. London SJ, Colditz GA, Stampfer MJ. Prospective study of relative weight, height and risk of breast cancer. JAMA 1989; 262: 2853-58 4. Tretli S. Height and weight in relation to breast cancer morbidity and mortality; a prospective survey of 570 000 women in Norway. Int J Cancer 1989; 44: 23-30. 5. Vatten LJ, Kvinnsland S. Body height and risk of breast cancer. a prospective study of 23 831 Norwegian women. Br J Cancer 1990; 61: 881-85. 6. Arteaga CL, Osbome CK. Growth inhibition of human breast cancer cells in vitro with an antibody against the type 1 somatomedin receptor Cancer Res 1989; 49: 6237-41. 7. Pollak M, Tremblay G. Immunocytochemical localisation of IGF-1 receptors in primary human breast cancers. Breast Cancer Res Treat 1989; 14: 174-79 8. Darendeliler F, Hindmarsh PC, Preece MA, et al. Growth hormone increases rate of pubertal maturation. Acta Endocrinol 1990; 122: 414-16 9 Russo JH, Calaf G, Russo J. Hormones and proliferative activity m breast tissue. In: Stoll BA, ed. Approaches to breast cancer prevention. Dordrecht Kluwer, 1991. 35-52. 10. Pollak M, Costantino J, Polychronakos C, et al. Effect of tamoxifen on serum insulin-like growth factor 1 levels in stage 1 breast cancer patients. J Natl Cancer Inst 1990; 82: 1693-97.
*** These letters have been shown follows.-ED. L.
to
Dr
Walker, and her reply
SIR,-Both Professor Brook and Dr Wild fail to distinguish between children with growth hormone (GH) deficiency and those children, as in our study, given rhGH for essentially social reasons. The work Brook cites relates almost exclusively to children with GH deficiency or other pathological causes of short stature. Many of these children were treated with dosage regimens that would today be considered inappropriate. GH was not available for trials in short normal children until rhGH was introduced in 1985. It was never our intention to worry needlessly parents of children requiring rhGH replacement for deficiency. The title of our paper and the opening words of the summary contain the words "short normal children", a clear statement of the population studied. Wild also compares our results with those adults and children receiving "physiological replacement doses of rhGH". Our children were normal and healthy. They had no evidence of the relative obesity of children with GH deficiency, which we might have expected had their hGH secretion levels below those of taller children been anything but physiological. Indeed, they started out thinner than the tall controls, although this was not significant. Hence we are not discussing the reversal of the abnormal body composition of GH deficiency but the effects of rhGH on an already normal fat and muscle mass. Coupled with a huge increase in growth velocity, a mean fat loss of 30% and a mean gain in lean body mass of 16% might be a considerable metabolic stress. However, we did not "speculate" that these effects might be "adverse or
undesirable" (Wild’s words, not ours). Nevertheless the letters of Dr Watson and Dr Stoll suggest that our "cautionary tale?" was not such a "sensational" title after all. The theoretical point made by Dr Davies and Dr Cole is well taken, but in practice either weight or lean body mass is used as the base for expressing energy expenditure. Predictive equations, widely recommended for calculating energy expenditure from weight or weight and age,1 do not allow for any possible influence of height. Dr Ravussin shows that there is a general relation between height and fat free (or lean body) mass and for a limited range this approximates to linearity. There is no reason to presume that the same relation holds beyond this range. Since each of the individual components that contribute to fat free mass has its own relation with height which is not necessarily linear, the general pattern must be an averaging of a more complex pattern of change. We have insufficient information to characterise this pattern more precisely. The media and some colleagues have misinterpreted our paper. The findings are a simple reminder to those who, in the pursuit of height, seem to forget that the effects of rhGH are not confined to linear growth. This fact should be considered by all clinicians when contemplating the use of this agent for the perceived social disadvantage of short stature as opposed to the clinical abnormality of GH deficiency. Such use should be strictly limited until the results of prospective, randomised longitudinal clinical trials, such as the Wessex Growth Study, are available. Department of Paediatrics, School of Clinical Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK 1
JOANNA M. WALKER
FAO/WHO/UNU Expert Consultation. Energy Tech Rep Ser 1985, no 724
and protein requirements. WHO
SIR,-Dr Walker and colleagues report that normal short children energy per kg lean body mass for resting metabolism than taller children. We have shown that poor Jamaican children, aged 9-24 months, who were stunted (height less than -2 standard deviations of the National Child Health Statistics reference) had significantly greater energy intakes per kg bodyweight than non-stunted children (height more than -11 SD) matched for age, sex, and neighbourhood.’ We suggested that this surprising finding could be explained by greater basal metabolic rates per kg
use more
(BMR/kg) in the stunted children compared with the non-stunted children. The decline in BMR/kg that is seen with normal growth is associated with the decrease in the relative mass of the organs, compared with skeletal muscle mass, that have high resting metabolic rates.2We also propose that the higher metabolic rate in stunted children was due to a greater proportion of visceral tissue relative to skeletal muscle. Stunting, or low height-for-age, is common in developing countries.3 The causes are thought to include increased morbidity and poor dietary intakes. The higher resting metabolic rates found in short children may be especially important for those who are short for environmental reasons. Stunting is often viewed as an adaptation that takes place when nutritional intake fails to meet demand and leads to smaller children with reduced energy needs. However, if stunted children have higher BMRJkg then their overall basal requirements may not be substantially lower than those of non-stunted children. This possibility has important implications for the formulation of recommended intakes for undernourished children. Tropical Metabolism Research Unit, University of the West Indies, Kingston 7, Jamaica
SUSAN WALKER SALLY GRANTHAM-MCGREGOR CHRISTINE POWELL
1. Walker SP, Powell CA, Grantham-McGregor SM. Dietary intakes and activity levels of stunted and non-stunted children in Kingston, Jamaica, part 1. dietary intakes. Eur J Clin Nutr 1990; 44: 527-34. 2. Holliday MA. Metabolic rate and organ size during growth from infancy to maturity Pediatrics 1971; 47: 169-79. 3. Keller W, Fillmore CM. Prevalence of protein energy malnutrition. World Health Stat Q 1983; 36: 129-67.
LETTERS to the EDITOR
Safety of growth hormone SIR,-Dr Walker and colleagues (Dec 1, p 1331) describe profound changes in body composition which may be a "stress" in short, but otherwise healthy, children treated with recombinant growth hormone (rhGH). Since this therapy is being increasingly considered for the treatment of children with chronic renal failure, a group who are not growth hormone deficient, I wish to report the unexpected rapid onset of end-stage renal failure (ESRF) in such a child treated with rhGH. The child has the clinical and radiological features of Jeune’s syndrome (asphyxiating thoracic dystrophy). At 2 years of age his height was 75-5 cm, which was below the 3rd centile (height SD score —3 15). When he was 24 years old he was referred by his general practitioner to a paediatric endocrinologist in another centre after his parents had learnt of GH therapy from a television programme. Normal levels of GH were confirmed on an insulintolerance test and the plasma creatinine was 90 tmol/I. He was put on daily subcutaneous injections of 2 units rhGH (’Genotropin’; KabiVitrum) via an auto-injector device. Three months later the rhGH treatment was suspended because of the endocrinologist’s concern about the possible effects on renal function. His plasma creatinine was 105 umol/1 and glomerular filtration rate (99mTc-DTPA method) was reduced at 53 ml/min per 1 73 m2. After he had been off treatment for a futher three months his plasma creatinine was 142 (imol/1. The advice of a nephrologist had been sought by the endocrinologist, and two months later rhGH therapy was started again. After eight weeks’ further treatment the parents were increasingly concerned about their child’s breathing pattern and ill-health. The child was transferred to our unit when his plasma creatinine was found to be 336 mol/1 (urea 54 mmol/1, bicarbonate 12 mmol/1, potassium 5-4 mmol/1, phosphate 2-9 mmol/1). His haemoglobin was 6-9 g/dl and blood pressure was 136/90 mm Hg. Acute peritoneal dialysis was instigated along with antihypertensive therapy. A percutaneous renal biopsy, done at the time of insertion of a Tenckhoff catheter for chronic peritoneal dialysis ten days later, revealed histological features compatible with nephronophthisis with areas of advanced glomerulosclerosis. The child is now stable on continuous cycling peritoneal dialysis, enalapril, and supplementary feeding overnight by means of a gastrostomy button. He is awaiting a renal transplant. His height at 33 years, when the rhGH was suspended, was 82-7 cm (SD score - 3-52). Since the child received only short-term and intermittent rhGH treatment, it was hard to discern any effect on his growth velocity. Of more importance is the question whether the treatment harmed his renal function. There is a strong association between Jeune’s syndrome and juvenile nephronophthisis.1 This is usually a slowly progressive renal condition with a median age of renal replacement therapy for males of about 13 years.2 The parents had been counselled to expect renal replacement therapy for their child at the end of the first decade. In addition they were told that the advantage of the height gain with rhGH outweighed any possible deleterious effects on renal function. The rapid progression in ESRF was traumatic for all concerned. Experience to date suggests little deleterious effect of rhGH treatment in children with chronic renal failure.3 However, Rees et al’have reported deterioration of renal function in two children with renal disease treated with rhGH, one of whom had chronic renal failure while the other was prepubertal with a functioning renal transplant. It was not possible to ascribe the effect to GH, but the transplant recipient’s blood pressure control had also deteriorated
patient was on rhGH. Our patient was significantly hypertensive at the time of his transfer to our unit. Among other effects, GH may produce hyperfiltration by increasing glomerular filtration rate and renal plasma flow.s Children with chronic renal failure are a very heterogeneous group. Our patient’s progress emphasises the need for caution and proper monitoring in the use of this potentially "stressful" therapy until further experience has accumulated. while the
City Hospital, Hucknall Road,
Nottingham NG5 1PB, UK
ALAN R. WATSON
1 Donaldson
MDC, Wamer AA, Trompeter RS, Haycock GB, Chantler C. Familial juvenile nephronophthisis, Jeune’s syndrome and associated disorders. Arch Dis Child 1985, 60: 426-34.
Gretz N, Scharer K, Waldherr R, Strauch M. Rate of deterioration of renal function in juvenile nephronophthisis Pediatr Nephrol 1989; 3: 56-60 3. Johannson G, Sietnicks A, Janssens F, et al Recombinant human growth hormone treatment in short children with chronic renal disease, before transplantation or with functioning renal transplants. an interim report on five European studies. Acta Paediatr Scand 1990; (suppl 370): 36-12. 4. Rees L, Rigden SPA, Ward G, Preece MA. Treatment of short stature in renal disease with recombinant human growth hormone Arch Dis Child 1990, 65: 856-60 5 Hirschberg R, Rabb H, Bergamo R, Kopple JD The delayed effect of growth hormone on renal function in humans Kidney Int 1989; 35: 865-70.
2
SiR,—The sensational title to an article which reiterates something well known since the 1960s has caused the parents of thousands of children who require GH replacement needless anxiety. My department has been inundated with telephone calls asking about the "cautionary tale" published in your Dec 1 issue and picked up by the newspapers. Dr Walker and colleagues are well aware that they have described nothing new. "We have no evidence that this is adverse or that the changes in body composition are not reversible with time", they say. Extensive published work over the past 20 years indicates that the changes are indeed reversible and do reverse, even if GH is continued. Unfortunately, the newspapers will not quote this letter, but I hope that your readers will be reassured-and perhaps read the paper more carefully for the non-event it is. Department of Medicine, UCMSM, Cobbold Laboratories, Middlesex Hospital. London W1 N 8AA, UK
C. G. D. BROOK
SIR,-Dr Walker and her colleagues provide some new information the metabolic effects of growth hormone (GH), but I take issue with their speculation that these effects may be adverse or undesirable. This unwarranted extrapolation has, via the lay press, alarmed many children and their parents. This is not the first time that short, slowly growing children without classical GH deficiency have been treated with GH. One study referred to, that of Hindmarsh and Brook,’ is now in its 6th year of treatment. To my knowledge no child has had any adverse clinical effects, let alone any that could be related to metabolic stress. Walker et al quantify in metabolic terms what every paediatrician has observed since children began to be treated with GH. They all lose fat: GH is lipolytic. Most GH-deficient children tend towards obesity and, usually, the first observed effect of GH therapy is the loss of much of this fat. Nobody has ever reported adverse metabolic effects from this fat loss, and Walker et al stress this point for their study in their final paragraph. What they do report is a mean loss of on
109
body fat of 0.68 kg. Over the 6 months this averaged around 4 g a day, or the burning-up of about 36 kcal per day. Is this really an adverse metabolic stress when there is an opposite, even greater, effect on lean body mass? Many people on weight-loss diets or undergoing strenuous athletic training after a winter lay-off would be very disappointed at such a rate of fat loss. Salomon et alwhen they treated GH-deficient adults with GH, recorded, over a similar 6-month period, an average loss of 5kg of body fat, which was replaced gram for gram by lean body mass. No adverse metabolic or related clinical events were reported. Admittedly these were patients receiving physiological replacement doses of GH, but one could argue that since they all had panhypopituitarism and were on fixed replacement doses of other hormones, they were less well able to cope with adverse metabolic That was not the case. Caution should always be a guiding force in research and treatment, but I do not think that Walker et al revealed anything to justify a title including "a cautionary tale". stress.
Kabi Pharmacia, Milton Keynes MK5
8PH, UK
RICHARD WILD
1 Hindmarsh PC, Brook CGD. Effect of growth hormone on short normal children. Br Med J 1987; 295: 573-78 2 Salomon F, Cuneo RC, Hesp R, Sonksen PH. The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N Engl J Med 1989; 321: 1797-803.
SIR,-Dr Walker and her colleagues show that the administration of GH to short normal children increases lean body mass (LBM), reduces body fat and increases resting energy expenditure (REE). After adjusting for LBM, they find that REE is unrelated to age, height, and weight, showing that the increase in REE is explained by the increase in LBM. They also consider REE expressed in units of kj/kg LBM and find, paradoxically, that this index is negatively correlated with height. A great deal of their discussion is given over to explaining their finding in terms of physiological changes in body composition induced by GH. There is a much simpler explanation-namely, that their index of REE is inappropriate. The purpose of adjusting REE for LBM is to remove the effect of LBM on REE-ie, to provide an index which is essentially uncorrelated with LBM. However, there is no reason a priori why dividing REE by LBM should remove the correlation between REE and LBM. One might equally divide by the square root of LBM, or the square of LBM, or some other power, and the best index would be the one that was uncorrelated with LBM. In the present instance, it is clear that dividing REE by LBM overadjusts. Normally the overadjustment would show itself as a negative correlation between the REE/LBM index and LBM. However, no further adjustment was made for LBM, and height (which is highly correlated with LBM) acted as its proxy in the regression. This is an example of a fallacy seen often in medical research. Expressing quantity A (be it, say, energy expenditure or energy intake or glomerular filtration rate) per unit of quantity B (eg, body weight or LBM or surface area) may or may not be a useful exercise, but it is incorrect to assume that the resulting index A/B will automatically be uncorrelated with B, and even more incorrect to assume that it should be. of Cambridge and Medical Research Council. Dunn Nutritional Laboratory, Cambridge CR4 1XJ, UK
Relation between REE and FFM in 88 children Bioelectrical impedance and indirect
calorimetry
aged 8-11.
were
used. In these
children, height was strongly correlated to FFM (r=0 86, p<0 0001)
so
short children will have higher REE than tall children when REE is expressed in kJ/24 h.kg FFM despite the fact that both have a "normal" REE (ie, they lie on the regression line for the group). REE=1757+151 x FFM therefore REE/FFM=1751/FFM+151.
increase in skeletal muscle tissue relative to visceral tissue during linear growth. However, a likely alternative explanation is related to the way the REE data are normalised in children of different body size and body composition. REE is best correlated to fat-free body mass (FFM).1 However, in adults and children, the regression line between REE and FFM does not pass through the origin (figure), so dividing REE by FFM mass introduces a bias3-S which results in higher REE in those with lower FFM (figure). Since FFM is positively correlated to height (r=0 86 in 88 children aged 8-11, unpublished), REE/FFM is also higher in those who are shorter. The correct way to analyse the data is to include other co-variates such as height or age in a multivariate analysis. When they did that, Walker et al did not find any extra variance in REE explained by height. Thus their data do not support the conclusion that "short children expend more energy fulfilling their basic metabolic requirements than tall children do". Clinical Diabetes and Nutrition Section, National Institutes of Health, Phoenix, Arizona 85016, USA
ERIC RAVUSSIN
1 Bogardus C, Lillioja S, Ravussin E, et al. Familial dependence of the resting metabolic rate N Engl J Med 1986; 315: 96-100. 2 Ravussin E, Lillioja S, Anderson TE, Chnstin L, Bogardus C. Determinants of 24-hour expenditure in man. methods and results using a respiratory chamber. J Clin Invest 1986; 78: 1568-78. 3 Ravussin E, Bogardus C. Relationship of genetics, age, and physical fitness to daily energy expenditure and fuel utilization. Am J Clin Nutr 1989, 49: 968-75. 4. Tanner J M Fallacy of per-weight and per-surface area standards, and their relation to spurious correlation. J Appl Physiol 1949; 2: 1-15. 5 Lillioja S, Bogardus C. Obesity and insulin resistance: lessons learned from the Pima Indians Metab Rev 1988; 4: 517-60.
University
T. J. COLE P. S. W. DAVIES
SIR,-Dr Walker and her colleagues describe the effect of daily injections of growth hormone on growth, body composition, and resting energy expenditure (REE) in short children. We agree with their caution on the use of high doses of GH but their conclusion that shorter children expend more energy than taller children is not supported by the data. REE is found to be higher in short children when compared with tall children only when REE is divided by lean body mass but not when height is a co-variate. Walker et al suggest that part of this difference in REE might be attributable to the disproportionate
SjR,—Dr Walker and her colleagues suggest caution in the use of rhGH for short children without classic GH deficiency because of the possibility of stressful metabolic changes. There may be another reason for caution. Large prospective studies confirm that taller western women are at higher risk for breast cancer; 10 cm additional height increases the risk by 20%.1-5 Tallness in adults is associated with higher circulating levels of GH in childhood, and there is evidence that insulin-like growth factor (IGF-1), a GH-dependent peptide, stimulates cellular replication in the mammary epithelium and stroma.6 Receptors for IGF-1 have been found in mammary ductal epitheliumand administration of rhGH to prepubertal girls with isolated GH deficiency can accelerate breast development.8 While IGF-1 is probably not the mediator of oestrogen-regulated
110
in the breastinteraction between GH, IGF-1, and oestrogen is likely to be involved in stimulating pubertal breast development, just as it is in stimulating the adolescent linear growth spurt. Low-dose oestrogen therapy is widely used to initiate both linear growth and sexual maturation in girls showing constitutional delay of growth and puberty, and sex steroids are known to be involved in stimulating the pubertal surge in GH levels. Mammary epithelium is most susceptible to carcinogenesis at the time of puberty, when proliferative activity is greatest,9 and the critical importance of cancer promotion at that period is shown by the observation that a first pregnancy within a few years of puberty can reduce the risk of subsequent breast cancer by over 50%. Thus, although it is speculative to suggest that high levels of IGF-1 may increase the individual risk of developing breast cancer, 10 there is no doubt that the use of rhGH in short children will accelerate proliferative activity in developing breast tissue. This will increase breast cancer risk because factors which accelerate proliferative activity will also increase the potential for atypical hyperplasia.
growth
Department of Oncology, St Thomas’ Hospital, London SE1 7EH, UK
BASIL A. STOLL
Holm LE, Carstensen JM. Breast cancer risk in relation to serum cholesterol, serum beta lipoprotein, height, weight and blood pressure Acta Oncol 1988; 27: 31-37 2. Swanson CA, Jones DY, Schatzkin A, et al. Breast cancer nsk assessed by anthropometry in the NHANES. epidemiologic follow up study. Cancer Res 1988; 1
Tomberg SA,
48: 5363-67 3. London SJ, Colditz GA, Stampfer MJ. Prospective study of relative weight, height and risk of breast cancer. JAMA 1989; 262: 2853-58 4. Tretli S. Height and weight in relation to breast cancer morbidity and mortality; a prospective survey of 570 000 women in Norway. Int J Cancer 1989; 44: 23-30. 5. Vatten LJ, Kvinnsland S. Body height and risk of breast cancer. a prospective study of 23 831 Norwegian women. Br J Cancer 1990; 61: 881-85. 6. Arteaga CL, Osbome CK. Growth inhibition of human breast cancer cells in vitro with an antibody against the type 1 somatomedin receptor Cancer Res 1989; 49: 6237-41. 7. Pollak M, Tremblay G. Immunocytochemical localisation of IGF-1 receptors in primary human breast cancers. Breast Cancer Res Treat 1989; 14: 174-79 8. Darendeliler F, Hindmarsh PC, Preece MA, et al. Growth hormone increases rate of pubertal maturation. Acta Endocrinol 1990; 122: 414-16 9 Russo JH, Calaf G, Russo J. Hormones and proliferative activity m breast tissue. In: Stoll BA, ed. Approaches to breast cancer prevention. Dordrecht Kluwer, 1991. 35-52. 10. Pollak M, Costantino J, Polychronakos C, et al. Effect of tamoxifen on serum insulin-like growth factor 1 levels in stage 1 breast cancer patients. J Natl Cancer Inst 1990; 82: 1693-97.
*** These letters have been shown follows.-ED. L.
to
Dr
Walker, and her reply
SIR,-Both Professor Brook and Dr Wild fail to distinguish between children with growth hormone (GH) deficiency and those children, as in our study, given rhGH for essentially social reasons. The work Brook cites relates almost exclusively to children with GH deficiency or other pathological causes of short stature. Many of these children were treated with dosage regimens that would today be considered inappropriate. GH was not available for trials in short normal children until rhGH was introduced in 1985. It was never our intention to worry needlessly parents of children requiring rhGH replacement for deficiency. The title of our paper and the opening words of the summary contain the words "short normal children", a clear statement of the population studied. Wild also compares our results with those adults and children receiving "physiological replacement doses of rhGH". Our children were normal and healthy. They had no evidence of the relative obesity of children with GH deficiency, which we might have expected had their hGH secretion levels below those of taller children been anything but physiological. Indeed, they started out thinner than the tall controls, although this was not significant. Hence we are not discussing the reversal of the abnormal body composition of GH deficiency but the effects of rhGH on an already normal fat and muscle mass. Coupled with a huge increase in growth velocity, a mean fat loss of 30% and a mean gain in lean body mass of 16% might be a considerable metabolic stress. However, we did not "speculate" that these effects might be "adverse or
undesirable" (Wild’s words, not ours). Nevertheless the letters of Dr Watson and Dr Stoll suggest that our "cautionary tale?" was not such a "sensational" title after all. The theoretical point made by Dr Davies and Dr Cole is well taken, but in practice either weight or lean body mass is used as the base for expressing energy expenditure. Predictive equations, widely recommended for calculating energy expenditure from weight or weight and age,1 do not allow for any possible influence of height. Dr Ravussin shows that there is a general relation between height and fat free (or lean body) mass and for a limited range this approximates to linearity. There is no reason to presume that the same relation holds beyond this range. Since each of the individual components that contribute to fat free mass has its own relation with height which is not necessarily linear, the general pattern must be an averaging of a more complex pattern of change. We have insufficient information to characterise this pattern more precisely. The media and some colleagues have misinterpreted our paper. The findings are a simple reminder to those who, in the pursuit of height, seem to forget that the effects of rhGH are not confined to linear growth. This fact should be considered by all clinicians when contemplating the use of this agent for the perceived social disadvantage of short stature as opposed to the clinical abnormality of GH deficiency. Such use should be strictly limited until the results of prospective, randomised longitudinal clinical trials, such as the Wessex Growth Study, are available. Department of Paediatrics, School of Clinical Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK 1
JOANNA M. WALKER
FAO/WHO/UNU Expert Consultation. Energy Tech Rep Ser 1985, no 724
and protein requirements. WHO
SIR,-Dr Walker and colleagues report that normal short children energy per kg lean body mass for resting metabolism than taller children. We have shown that poor Jamaican children, aged 9-24 months, who were stunted (height less than -2 standard deviations of the National Child Health Statistics reference) had significantly greater energy intakes per kg bodyweight than non-stunted children (height more than -11 SD) matched for age, sex, and neighbourhood.’ We suggested that this surprising finding could be explained by greater basal metabolic rates per kg
use more
(BMR/kg) in the stunted children compared with the non-stunted children. The decline in BMR/kg that is seen with normal growth is associated with the decrease in the relative mass of the organs, compared with skeletal muscle mass, that have high resting metabolic rates.2We also propose that the higher metabolic rate in stunted children was due to a greater proportion of visceral tissue relative to skeletal muscle. Stunting, or low height-for-age, is common in developing countries.3 The causes are thought to include increased morbidity and poor dietary intakes. The higher resting metabolic rates found in short children may be especially important for those who are short for environmental reasons. Stunting is often viewed as an adaptation that takes place when nutritional intake fails to meet demand and leads to smaller children with reduced energy needs. However, if stunted children have higher BMRJkg then their overall basal requirements may not be substantially lower than those of non-stunted children. This possibility has important implications for the formulation of recommended intakes for undernourished children. Tropical Metabolism Research Unit, University of the West Indies, Kingston 7, Jamaica
SUSAN WALKER SALLY GRANTHAM-MCGREGOR CHRISTINE POWELL
1. Walker SP, Powell CA, Grantham-McGregor SM. Dietary intakes and activity levels of stunted and non-stunted children in Kingston, Jamaica, part 1. dietary intakes. Eur J Clin Nutr 1990; 44: 527-34. 2. Holliday MA. Metabolic rate and organ size during growth from infancy to maturity Pediatrics 1971; 47: 169-79. 3. Keller W, Fillmore CM. Prevalence of protein energy malnutrition. World Health Stat Q 1983; 36: 129-67.