Growth Hormone Treatment in Non-Growth Hormone-Deficient Children: Effects of Stopping Treatment F.M. ACKLAND, J. JONES, J.M.H. BUCKLER. D.B. DUNGER, P.H.W. RAYNER and M.A. PREECE From rhe Department of Growth and Developmenr. lnstirute of Child Healrh. London, the General InJirmary, Leeds. the John Radcliffe Hospital, Oxford and the Childrens Hospiral, Birmingham, UK
ABSTRACT. Ackland. F.M., Jones, J., Buckler, J.M.H.. Dunger, D.B.. Rayner. P.H.W. and Preece. M.A. (Department o f Growth and Development. Institute o f Child Health. London. the General Infirmary, Leeds, the John Radcliffe Hospital, Oxford and the Childrens Hospital. Birmingham, UK).Growth hormone treatment in non-growth hormonedeficient children: effects o f stopping treatment. Acta Paediatr .%and [Suppl] 366:32. 1990. Overnight physiological growth hormone (CH) secretion was evaluated in 95 short, prepubertal children (73 boys, 22 girls). A l l the children were below the 3 r d centile for height and achieved CH levels greater than 15 mU/I following pharmacological stimulation. The mean average CH level waq 7.1 m(J/l and the mean sum o f pulse amplitudes 80.4 mU11. No relationship was found between age. height o r height velocity and any o f the parameters o f G H secretion. The group was randomized to receive placebo, G H or remain under observation for the first 6 months and then all patients received G H treatment for a further 6 months. Those treated with GH, 0.27 I t i / k g (0.1 mglkg) three times weekly, in the first phase. demonstrated a mean increase in height velocity SDS o f 3.24. There was no difference in growth response between the placebo o r observation groups. In the second 6-month period. all children received GH according to the same dose regimen: they were then observed for a further 6 months following its discoiltinuation. In the 6 months following withdrawal o f GH. all groups showed a significant fall in height velocity SDS, which returned to pretreatment levels, without demonstrating 'catch-down' growth. Repeat sampling of overnight G H secretion within 3 days o f discontinuing G H showed normal secretory patterns with a small redurtion in mean peak amplitude. These results suggest that short children without classic G H insufficiency respond well to exogenous GH in the short term and return to pretreatment height velocities afterwards. Consequently. it may be possible to increase final adult height in such children by GH treatment. Key W O ~ S :Shun stature. growrh hormone teeretion, growth hormone treatment.
The ready availability of biosynthetic human growth hormone i hGH) has made it possible t o investigate applications for GH other than tor severe GH deficiency tGHD). One of the main areas of interest has been children whose heights lie below the 3rd centile. but who are otien growing at a velocity sufficient to maintain their heights parallel with the 3rd centile. These children are commonly. though not necessarily accurately. referred to as short, normal children. Conventionally. children have been classed as either GH deficient or normai. but a comparison of G H secretion in response to insuiin hypoglycaemia with &hour endogenous GH secretion has shown that G H secretion is a continuum. and there are not two discrete populations of GH-deficient and normal children ( 1 ). Thus. heparation of GH-deficient children from normal children a n the basis of an arbitrarily chosen GH response to provocative testing (,far example) is inappropriate. Furthermore. this finding suggests that additional GH may accelerate the growth of children who produce only moderate amounts of the hormone. Much work has been done to assess predictors o f t h e growth response to GH, but there has been no agreement on any particular parameter ( 2 - 5 ) . Rudman et d.assessed a group of children with so-called normal variant short stature. and showed that they could be divided into four subgroups with respect to their short-term metabolic response to GH (6). Unfortunately. these short-term changes are not good predictors of the long-term growth response. There has been some interest in the outcome of GH treatment in non-GH-deficient children
Acta Paediatr Scand [Supplj 366
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after treatment is stopped. Chalew et al. (7) and Raiti et ul. (8) studied groups of poorly growing children treated with GH for between 6 and 8 months. Chalew et al. observed ‘catchdown’ growth in 5 out of 11 patients when GH was stopped and Raiti et al. reported a reduction in height velocity after treatment was stopped in 38 out of 45 responders. but notably in 22 patients the velocity did not fall below pretreatment levels. As psychosocial deprivation is known to have an adverse effect on growth, it has been suggested that there may be a placebo effect when GH is administered to non-GH-deficient short children. Buchanan et al., on behalf of the UK Health Services Human Growth Hormone Committee, studied a small group of short, slowly growing children who were treated for 6 months with either GH or placebo (9). They found a significant growth response to GH and no placebo effect. Unfortunately, the study was discontinued in May 1985. following reports of Creutzfeld-Jakob disease in recipients of pituitary GH. The aim of the present study was to expand this work and, in particular. to examine the use of GH in children of near normal height, growing at normal velocities, rather than restricting GH treatment to slowly growing children.
PATIENTS A N D METHODS futienfs. A group of 95 short children (73 boys, 22 girls) was studied. At entry into the study, all children had a height on or below the 3rd centile by Tanner and Whitehouse standards (10). were over 5 years of age and prepubertal. All were of normal birth weight for gestational age, free from chronic disease or dysmorphic syndromes. and had a GH response to pharmacological testing of at least 15 mUII, demonstrated over the preceding year. Turner’s syndrome was excluded by chromosomal studies on peripheral lymphocytes. The mean age was 9.73 years (range 5-14.? years). the mean height SDS -2.7 (range -4.2 to - 1.6) and the mean height velocity SDS measured Over the preceding year - 1.2 (range -3.0 to + 1.1). lnuesrigarions qf GH secretion. Nocturnal physiological GH secretion was estimated in all children on entry into the study. Discrete samples were taken at 15-minute intervals for 12 hours (II ) . GH levels were measured hy immunoradiometric assay (Sucrosep, Celltech Diagnosticsj, calibrated against the 1RP66/2 17 standard (WHO). All samples from an overnight series were assayed i n the same batch. The lower limit of detection of the GH assay was 0.5 mUII. The intra-assay coefficient of variation was 1.3% at 1.9 mU/I and 2.5% at 29 mUil. and the inter-assay coefficient of variation was 2.2% at 3.6 mU/I and 3.6% at 27 mU/l. GH pulsatility was assessed visually and by using the Pulsar program ( 12) modified for use with GH. Treurmenf. After initial assessment, the children were randomly assigned to one of three groups for the first 6 months of the study; group A received placebo and group B received natural sequence biosynthetic GH (Humatrope. Eli Lilly). 0.27 IUlkg 10.I rng/kg) three times a week. Vials of the placebo preparation were identical to those containing GH: the powder was reconstituted in the same manner and the dose was given subcutaneously three times a week. on a double-blind basis. Group C were measured and observed. but received no treatment. There was no significant difference oetween the groups for age, height SDS and height velocity SDS. During the second 6-month period. dl three groups received GH at the sanie dose. GH treatment was then ,toaped and all children remained under observation for a further h months. After this third phase of the rtudy. ireatment was recommenced at the same dose in those who had shown a significant response to GH.Nocturnal GH secretion was reassessed in six children 24-72 hours after discontinuation of GH treatment. Growih was assessed by standard anthroportietric techniques ( 13) at 3-month intervats and compared with ihe standards of Tanner and Whitehouse I 10). Bone age was assessed by a single trained auxologist using the TWI-RUS methtd (14). Sturisritr. Statistical analysis was carried out using Pearson product-moment correlation coefficients and Students’s [-tests (paired and unpaired) for comparisons within and between groups. The repeat profiles were dssessed using the Wilcoxon signed rank test.
RESULTS Phvsiological GH secretion. The nocturnal GH profiles were all broadly similar, each having
two or three peaks of 20-40 mU/I. In all cases, the GH levels returned to baseline between peaks. However, there was a wide variation in the level of GH secretion. The mean GH level was 7.1 mU/I (range 1.6-16.8 mUII), the mean maximum level 35.1 mU/1 (range 10-109 mU/I) and the mean sum of pulse amplitudes 80.4 mU/I (range 12.6-177.5 mu/]).
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Fig. 1. Height velocity SDS for the three groups: at entry into the study. after 6 months on placebo treatment (group A), GH treatment (group B) or observation without treatment (group C) (0-6 months), after a Further 6 months when all groups received GH (6-12 months), and for 6 months after the cessation of GH treatment (12-18 months). Data are shown as mean SEM.
*
The median number of pulses was six and the median number of pulses greater than 15 mU/1 was two. There was no significant correlation between age, height or height velocity and any of the parameters of GH secretion. Placebo-controlled trial. The growth response in each group during the different phases of the trial is shown in Fig. 1. In the first 6 months, the mean height velocity SDS of the placebotreated patients (group A; n = 28) increased from - 1.29 to -0.63 ( p = 0.03),the mean height velocity SDS of the GH-treated patients (group B; n = 30) increased from - 1.26 to +1.98 ( p < O.OOOl), and that of the patients under observation only (group C; n = 31) increased from -1.09 to -0.87 ( p > 0.05). There was no significant difference in the change in height velocity SDS between the placebo and the observation groups, but the marked response to GH was highly significant ( p < 0.O001). During the second 6-month period, when all patients received GH treatment, the height velocity SDS increased significantly for both group A (-0.63 to +2.03;p < O.OOOl), and group C (-0.87 to +1.81;p < 0.OOOl).Group B showed a significant decrease (1.98to 1.09;p = O.OOO5).However, the growth rates of the three groups did not differ significantly during this period. #en treatment was stopped, all patient groups showed a significant fall in height velocity SDS: group A, from 2.03 to -0.71;group B, from 1.09to - 1.16;and group C, from 1.81 to -0.34 ( p < 0.OOOl).In most children, the height velocity SDS remained at or above pretreatment levels (Fig. 1)so no ‘catch-down’ growth was seen. ‘Catch down’ refers to the growth rate seen following a period of accelerated growth, when the height velocity falls to levels below those seen prior to the acceleration, so that height returns to its previous centile. More specifically, it is used to describe growth following the withdrawal of GH when height velocity falls below pretreatment levels (15). No relationship between pretreatment GH secretion and the growth response to GH treatment or the magnitude of the fall in height velocity after treatment could be demonstrated. However, the authors’ impression was that children with greater spontaneous GH secretion showed less response to exogenous GH. When post-treatment GH profiles were compared with pretreatment profiles a remarkable similarity in pulsatility was evident (Fig. 2), although there was a small, but significant, reduction in mean peak amplitude from 17.0 mU/1 to 10.6 mU/1 ( p = 0.04). It was
GH therapy in non-GH-deJicientchildren
Acta Paediatr Scand [Suppi] 366
" 1 1900
I
I
2300
I
t
0300
I
I
0700
,
Clock time
Fig. 2. Overnight profiles of serum GH before treatment (0)and 48 hours after the last dose of GH a patient representative of the group.
(0) in
interesting that the child with the highest pretreatment GH levels had a repeat profile which no longer distinctly differed from the others. Epiphyseal maturation. The mean delay in bone age at entry into the study was 1.12 1.2 1 years. After 18 months, the ratio of increase in bone age to increase in chronological age was not significantly different from 1.O (n = 31). There was no difference between the treatment groups.
*
DISCUSSION In the present study there was no significant correlation between height, height velocity and GH secretion. This contrasts with the results of other studies which have demonstrated relationships between height SDS and the area under the GH secretion curve (16), and height velocity and the number of GH peaks (17). The asymptotic relationship between height velocity SDS and sum of GH pulse amplitudes described by Hindmarsh et a / . (1) was not shown in this study. However, Hindmarsh et al. evaluated 24-hour secretion instead of 12-hour secretion, and they did not exclude children with poor GH secretion following pharmacological stimulation. The authors' have re-examined this data, and have found that the asymptotic relationship is still present when only 12-hour overnight GH secretion is assessed, but is no longer seen when all children who failed to achieve levels above 15 mU/1 after pharmacological stimulation are excluded. This presumably explains the apparent discrepancy between the sets of data. The children demonstrated a good growth response to GH treatment over 6-12 months, with a mean increment in velocity over 6 months of 2.95 cm/year. During the first 6-month study period, there was a small, but significant, increase in height velocity SDS in the placebo group, and a small but significant increase in the height velocity SDS of the observation group, with no significant difference in the height velocity SDS between the two groups at the end of this phase. It is suggested that the increase in height velocity was not due to the placebo injections themselves, but to increased professional involvement with the child and his family, which affected both placebo and observation groups. This highlights the value of
35
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Acta Paediatr Scand [Suppll 3W
the observation group in demonstrating that placebo injections have no greater effect o n growth than observation alone. After GH treatment, most children returned to their pretreatment height velocity without the ‘catch-down’ growth that might have been expected from studies on GH-deficient children (18). No useful predictor of growth response was found, though analysis of serum insulin-like growth factor I levels from this study has not yet been performed. It would have been preferable to treat these children with a daily regimen of GH. but it was felt unreasonable to ask patients and their parents to accept daily injections where placebo was being given. There was also concern that daily injections would discourage recruitment into the study, whereas no real objection to thrice-weekly placebo injections was found. Treatment periods were limited to 6 months, though 12-month periods would have been more desirable for reliable auxological data; it was considered unethical to give placebo injections for longer than 6 months. There was concern that exogenous GH would diminish the secretion of endogenous GH for a prolonged period of time. It was reassuring that 24-72 hours after the last injection, GH pulsatility was already present, even though the pulse amplitudes were diminished. These children were all treated with a thrice-weekly regimen-which gave more time for the pituitary gland to recover between doses than a daily regimen. Further studies should be performed to assess endogenous GH production during daily treatment. As there was no inappropriate advancement in epiphysed maturation. during the study period and since no ‘catch-down’ growth was seen, the results of the present study suggest that it may be possible to improve final adult height with GH treatment. .However, since height velocity in the second 6 months of treatment was significantly less than that during the first 6 months, it is possible that the response to GH may become imperceptible in the long term. It is also possible that advancement in epiphyseal-maturation is a late effect and that this may yet be seen. Therefore, the responders among this group of children will be treated until final height is attained. Rapid advancement through puberty in GH-deficient children on GH treatment has been described (personal communication). If this proves to be related to GH treatment per se rather than to GHD, then it may have an adverse effect on final height. Clearly, cohorts of children such as these must be followed until final height is achieved before many of these issues can be resolved.
ACKNOWLEDGEMENTS The authors would like to thank Dr Peter Hindmarsh for kindly allowing examination of his data. This work was funded by Eli Lilly, who also supplied the growth hormone. FMA was supported by a grant from Ell Lilly and JJ was supported by the Adint Trust.
REFERENCES 1. Hindmarsh P, Smith PJ, Brook CGD, Matthews DR. The relationship between height velocity and growth hormone secretion in short prepubertal children. Clin Endocrinol 1987; 27: 581-91. 2. Gertner JM, Gene1 M, Gianfredi SP el al. Prospective clinical trial of human growth hormone in short children without growth hormone deficiency. J Pediatr 1984; 104: 172-6. 3. Plotnick LP, Van Meter QL, Kowarski AA. Human growth hormone treatment of children with growth failure and normal growth hormone levels by immunoassay: lack ot’ correlation with somatomedin generation. Pediatrics 1983; 71: 324-7. 4. Van Vliet G. Stync DM, Kaplan SL, Grumbach MM.Growth hormone treatment for short stature. N Enpl J Med 1983; u)9: 1016-22. 5 . Albertsson-Wikland K. Growth hormone treatment.in short children. Acta Paediatr Scand (Suppl] 1986. 325: 64-70. 6. Rudman D, Kutner MH. Blackston RD. Jansen RD, Patterson JH. Normal variant short stature. subclassification based on responses to exogenous human growth hormone. J Clin Endocrinol Metab 1979; 49: 92-9.
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7 Chalew SA. Raiti S, Armour KM, Kowarski AA. Therapy of short children with subnormal integrated concentrations of growth hormone. .4m J Dis Child 1987; 141: 1195-8. 8 Raiti S. Kaplan SL. Van Vliet G. Moore WV. Short-term treatment of short stature and subnormal growth rate with human growth hormone. J Pediatr 1987; 110: 357-61. 9 Buchanan CR, Law CM. Milner RDG. Growth hormone in short slowly growing children and those with Turner's syndrome. Arch Dis Child 1987: 62: 912-6. 10. Tanner JM. Whitehouse RH. Takaishi M. Standards from birth to maturity for height, weight, height velocity. and weight velocity: British children. 1965. Part I. Arch Dis Child 1966: 41: 454-71. 1 I . Ackland FM. Stanhope R. Eyre C, Hamill G, Jones J. Preece MA. Physiological growth hormone .secretion in children with short stature and intra-uterine growth retardation. Horm Res 1988: 30: 241-5. 12. Merriam GR, Wachter KW. Algorithms for the study of episodic hormone secretion. Am J Physiol 1982: 143: E310-8. 13. Tanner JM. Normal growth and techniques of growth assessment. Clin Endocrinol Metab 1986; 15: 411-51.
14. Tanner JM. Whitehouse RH. Cameron N. Marshall WA. Healy MJR, Goldstein H. Assessment of skeletal maturity and prediction of adult height (TW2 method). 2nd ed. London: Academic Press, 1983: 106. 15. Ackland FM. Preece MA. Catch-up growth. Pediatrician 1987; 14: 226-33. 16. Albertsson-Wikland K. Rosberg S. Analyses of 24-hour growth hormone profiles in children: relation to growth. J Clin Endocrinol Metab 1988; 67: 493-500. 17. Rochiccioli P. Messina A. Tauber iMT, Enjaume C. Correlation of the parameters of 24-hour growth hormone secretion with growth velocity in 93 children of varying height. Honn Res 1989; 31: 115-8. 18. Tanner JM. Whitehouse RH. Hughes PCR. Vince FP. Effect of human growth hormone treatment for 1 to 7 years on the growth of 100 children with growth hormone deficiency. low binhweight, inherited smallness. Turner's syndrome. and other complaints. Arch Dis Child 1971; 46:745-82. (F.M.A.) Department of Grouih and Development Institute of Child Health 30 Guildford Street London WClN IEH UK
37
ABSTRACT. Ackland. F.M., Jones, J., Buckler, J.M.H.. Dunger, D.B.. Rayner. P.H.W. and Preece. M.A. (Department o f Growth and Development. Institute o f Child Health. London. the General Infirmary, Leeds, the John Radcliffe Hospital, Oxford and the Childrens Hospital. Birmingham, UK).Growth hormone treatment in non-growth hormonedeficient children: effects o f stopping treatment. Acta Paediatr .%and [Suppl] 366:32. 1990. Overnight physiological growth hormone (CH) secretion was evaluated in 95 short, prepubertal children (73 boys, 22 girls). A l l the children were below the 3 r d centile for height and achieved CH levels greater than 15 mU/I following pharmacological stimulation. The mean average CH level waq 7.1 m(J/l and the mean sum o f pulse amplitudes 80.4 mU11. No relationship was found between age. height o r height velocity and any o f the parameters o f G H secretion. The group was randomized to receive placebo, G H or remain under observation for the first 6 months and then all patients received G H treatment for a further 6 months. Those treated with GH, 0.27 I t i / k g (0.1 mglkg) three times weekly, in the first phase. demonstrated a mean increase in height velocity SDS o f 3.24. There was no difference in growth response between the placebo o r observation groups. In the second 6-month period. all children received GH according to the same dose regimen: they were then observed for a further 6 months following its discoiltinuation. In the 6 months following withdrawal o f GH. all groups showed a significant fall in height velocity SDS, which returned to pretreatment levels, without demonstrating 'catch-down' growth. Repeat sampling of overnight G H secretion within 3 days o f discontinuing G H showed normal secretory patterns with a small redurtion in mean peak amplitude. These results suggest that short children without classic G H insufficiency respond well to exogenous GH in the short term and return to pretreatment height velocities afterwards. Consequently. it may be possible to increase final adult height in such children by GH treatment. Key W O ~ S :Shun stature. growrh hormone teeretion, growth hormone treatment.
The ready availability of biosynthetic human growth hormone i hGH) has made it possible t o investigate applications for GH other than tor severe GH deficiency tGHD). One of the main areas of interest has been children whose heights lie below the 3rd centile. but who are otien growing at a velocity sufficient to maintain their heights parallel with the 3rd centile. These children are commonly. though not necessarily accurately. referred to as short, normal children. Conventionally. children have been classed as either GH deficient or normai. but a comparison of G H secretion in response to insuiin hypoglycaemia with &hour endogenous GH secretion has shown that G H secretion is a continuum. and there are not two discrete populations of GH-deficient and normal children ( 1 ). Thus. heparation of GH-deficient children from normal children a n the basis of an arbitrarily chosen GH response to provocative testing (,far example) is inappropriate. Furthermore. this finding suggests that additional GH may accelerate the growth of children who produce only moderate amounts of the hormone. Much work has been done to assess predictors o f t h e growth response to GH, but there has been no agreement on any particular parameter ( 2 - 5 ) . Rudman et d.assessed a group of children with so-called normal variant short stature. and showed that they could be divided into four subgroups with respect to their short-term metabolic response to GH (6). Unfortunately. these short-term changes are not good predictors of the long-term growth response. There has been some interest in the outcome of GH treatment in non-GH-deficient children
Acta Paediatr Scand [Supplj 366
GH therapy in non-GH-deficient children
after treatment is stopped. Chalew et al. (7) and Raiti et ul. (8) studied groups of poorly growing children treated with GH for between 6 and 8 months. Chalew et al. observed ‘catchdown’ growth in 5 out of 11 patients when GH was stopped and Raiti et al. reported a reduction in height velocity after treatment was stopped in 38 out of 45 responders. but notably in 22 patients the velocity did not fall below pretreatment levels. As psychosocial deprivation is known to have an adverse effect on growth, it has been suggested that there may be a placebo effect when GH is administered to non-GH-deficient short children. Buchanan et al., on behalf of the UK Health Services Human Growth Hormone Committee, studied a small group of short, slowly growing children who were treated for 6 months with either GH or placebo (9). They found a significant growth response to GH and no placebo effect. Unfortunately, the study was discontinued in May 1985. following reports of Creutzfeld-Jakob disease in recipients of pituitary GH. The aim of the present study was to expand this work and, in particular. to examine the use of GH in children of near normal height, growing at normal velocities, rather than restricting GH treatment to slowly growing children.
PATIENTS A N D METHODS futienfs. A group of 95 short children (73 boys, 22 girls) was studied. At entry into the study, all children had a height on or below the 3rd centile by Tanner and Whitehouse standards (10). were over 5 years of age and prepubertal. All were of normal birth weight for gestational age, free from chronic disease or dysmorphic syndromes. and had a GH response to pharmacological testing of at least 15 mUII, demonstrated over the preceding year. Turner’s syndrome was excluded by chromosomal studies on peripheral lymphocytes. The mean age was 9.73 years (range 5-14.? years). the mean height SDS -2.7 (range -4.2 to - 1.6) and the mean height velocity SDS measured Over the preceding year - 1.2 (range -3.0 to + 1.1). lnuesrigarions qf GH secretion. Nocturnal physiological GH secretion was estimated in all children on entry into the study. Discrete samples were taken at 15-minute intervals for 12 hours (II ) . GH levels were measured hy immunoradiometric assay (Sucrosep, Celltech Diagnosticsj, calibrated against the 1RP66/2 17 standard (WHO). All samples from an overnight series were assayed i n the same batch. The lower limit of detection of the GH assay was 0.5 mUII. The intra-assay coefficient of variation was 1.3% at 1.9 mU/I and 2.5% at 29 mUil. and the inter-assay coefficient of variation was 2.2% at 3.6 mU/I and 3.6% at 27 mU/l. GH pulsatility was assessed visually and by using the Pulsar program ( 12) modified for use with GH. Treurmenf. After initial assessment, the children were randomly assigned to one of three groups for the first 6 months of the study; group A received placebo and group B received natural sequence biosynthetic GH (Humatrope. Eli Lilly). 0.27 IUlkg 10.I rng/kg) three times a week. Vials of the placebo preparation were identical to those containing GH: the powder was reconstituted in the same manner and the dose was given subcutaneously three times a week. on a double-blind basis. Group C were measured and observed. but received no treatment. There was no significant difference oetween the groups for age, height SDS and height velocity SDS. During the second 6-month period. dl three groups received GH at the sanie dose. GH treatment was then ,toaped and all children remained under observation for a further h months. After this third phase of the rtudy. ireatment was recommenced at the same dose in those who had shown a significant response to GH.Nocturnal GH secretion was reassessed in six children 24-72 hours after discontinuation of GH treatment. Growih was assessed by standard anthroportietric techniques ( 13) at 3-month intervats and compared with ihe standards of Tanner and Whitehouse I 10). Bone age was assessed by a single trained auxologist using the TWI-RUS methtd (14). Sturisritr. Statistical analysis was carried out using Pearson product-moment correlation coefficients and Students’s [-tests (paired and unpaired) for comparisons within and between groups. The repeat profiles were dssessed using the Wilcoxon signed rank test.
RESULTS Phvsiological GH secretion. The nocturnal GH profiles were all broadly similar, each having
two or three peaks of 20-40 mU/I. In all cases, the GH levels returned to baseline between peaks. However, there was a wide variation in the level of GH secretion. The mean GH level was 7.1 mU/I (range 1.6-16.8 mUII), the mean maximum level 35.1 mU/1 (range 10-109 mU/I) and the mean sum of pulse amplitudes 80.4 mU/I (range 12.6-177.5 mu/]).
33
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Paediatr Scand ISuooll 366
Fig. 1. Height velocity SDS for the three groups: at entry into the study. after 6 months on placebo treatment (group A), GH treatment (group B) or observation without treatment (group C) (0-6 months), after a Further 6 months when all groups received GH (6-12 months), and for 6 months after the cessation of GH treatment (12-18 months). Data are shown as mean SEM.
*
The median number of pulses was six and the median number of pulses greater than 15 mU/1 was two. There was no significant correlation between age, height or height velocity and any of the parameters of GH secretion. Placebo-controlled trial. The growth response in each group during the different phases of the trial is shown in Fig. 1. In the first 6 months, the mean height velocity SDS of the placebotreated patients (group A; n = 28) increased from - 1.29 to -0.63 ( p = 0.03),the mean height velocity SDS of the GH-treated patients (group B; n = 30) increased from - 1.26 to +1.98 ( p < O.OOOl), and that of the patients under observation only (group C; n = 31) increased from -1.09 to -0.87 ( p > 0.05). There was no significant difference in the change in height velocity SDS between the placebo and the observation groups, but the marked response to GH was highly significant ( p < 0.O001). During the second 6-month period, when all patients received GH treatment, the height velocity SDS increased significantly for both group A (-0.63 to +2.03;p < O.OOOl), and group C (-0.87 to +1.81;p < 0.OOOl).Group B showed a significant decrease (1.98to 1.09;p = O.OOO5).However, the growth rates of the three groups did not differ significantly during this period. #en treatment was stopped, all patient groups showed a significant fall in height velocity SDS: group A, from 2.03 to -0.71;group B, from 1.09to - 1.16;and group C, from 1.81 to -0.34 ( p < 0.OOOl).In most children, the height velocity SDS remained at or above pretreatment levels (Fig. 1)so no ‘catch-down’ growth was seen. ‘Catch down’ refers to the growth rate seen following a period of accelerated growth, when the height velocity falls to levels below those seen prior to the acceleration, so that height returns to its previous centile. More specifically, it is used to describe growth following the withdrawal of GH when height velocity falls below pretreatment levels (15). No relationship between pretreatment GH secretion and the growth response to GH treatment or the magnitude of the fall in height velocity after treatment could be demonstrated. However, the authors’ impression was that children with greater spontaneous GH secretion showed less response to exogenous GH. When post-treatment GH profiles were compared with pretreatment profiles a remarkable similarity in pulsatility was evident (Fig. 2), although there was a small, but significant, reduction in mean peak amplitude from 17.0 mU/1 to 10.6 mU/1 ( p = 0.04). It was
GH therapy in non-GH-deJicientchildren
Acta Paediatr Scand [Suppi] 366
" 1 1900
I
I
2300
I
t
0300
I
I
0700
,
Clock time
Fig. 2. Overnight profiles of serum GH before treatment (0)and 48 hours after the last dose of GH a patient representative of the group.
(0) in
interesting that the child with the highest pretreatment GH levels had a repeat profile which no longer distinctly differed from the others. Epiphyseal maturation. The mean delay in bone age at entry into the study was 1.12 1.2 1 years. After 18 months, the ratio of increase in bone age to increase in chronological age was not significantly different from 1.O (n = 31). There was no difference between the treatment groups.
*
DISCUSSION In the present study there was no significant correlation between height, height velocity and GH secretion. This contrasts with the results of other studies which have demonstrated relationships between height SDS and the area under the GH secretion curve (16), and height velocity and the number of GH peaks (17). The asymptotic relationship between height velocity SDS and sum of GH pulse amplitudes described by Hindmarsh et a / . (1) was not shown in this study. However, Hindmarsh et al. evaluated 24-hour secretion instead of 12-hour secretion, and they did not exclude children with poor GH secretion following pharmacological stimulation. The authors' have re-examined this data, and have found that the asymptotic relationship is still present when only 12-hour overnight GH secretion is assessed, but is no longer seen when all children who failed to achieve levels above 15 mU/1 after pharmacological stimulation are excluded. This presumably explains the apparent discrepancy between the sets of data. The children demonstrated a good growth response to GH treatment over 6-12 months, with a mean increment in velocity over 6 months of 2.95 cm/year. During the first 6-month study period, there was a small, but significant, increase in height velocity SDS in the placebo group, and a small but significant increase in the height velocity SDS of the observation group, with no significant difference in the height velocity SDS between the two groups at the end of this phase. It is suggested that the increase in height velocity was not due to the placebo injections themselves, but to increased professional involvement with the child and his family, which affected both placebo and observation groups. This highlights the value of
35
36
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Acta Paediatr Scand [Suppll 3W
the observation group in demonstrating that placebo injections have no greater effect o n growth than observation alone. After GH treatment, most children returned to their pretreatment height velocity without the ‘catch-down’ growth that might have been expected from studies on GH-deficient children (18). No useful predictor of growth response was found, though analysis of serum insulin-like growth factor I levels from this study has not yet been performed. It would have been preferable to treat these children with a daily regimen of GH. but it was felt unreasonable to ask patients and their parents to accept daily injections where placebo was being given. There was also concern that daily injections would discourage recruitment into the study, whereas no real objection to thrice-weekly placebo injections was found. Treatment periods were limited to 6 months, though 12-month periods would have been more desirable for reliable auxological data; it was considered unethical to give placebo injections for longer than 6 months. There was concern that exogenous GH would diminish the secretion of endogenous GH for a prolonged period of time. It was reassuring that 24-72 hours after the last injection, GH pulsatility was already present, even though the pulse amplitudes were diminished. These children were all treated with a thrice-weekly regimen-which gave more time for the pituitary gland to recover between doses than a daily regimen. Further studies should be performed to assess endogenous GH production during daily treatment. As there was no inappropriate advancement in epiphysed maturation. during the study period and since no ‘catch-down’ growth was seen, the results of the present study suggest that it may be possible to improve final adult height with GH treatment. .However, since height velocity in the second 6 months of treatment was significantly less than that during the first 6 months, it is possible that the response to GH may become imperceptible in the long term. It is also possible that advancement in epiphyseal-maturation is a late effect and that this may yet be seen. Therefore, the responders among this group of children will be treated until final height is attained. Rapid advancement through puberty in GH-deficient children on GH treatment has been described (personal communication). If this proves to be related to GH treatment per se rather than to GHD, then it may have an adverse effect on final height. Clearly, cohorts of children such as these must be followed until final height is achieved before many of these issues can be resolved.
ACKNOWLEDGEMENTS The authors would like to thank Dr Peter Hindmarsh for kindly allowing examination of his data. This work was funded by Eli Lilly, who also supplied the growth hormone. FMA was supported by a grant from Ell Lilly and JJ was supported by the Adint Trust.
REFERENCES 1. Hindmarsh P, Smith PJ, Brook CGD, Matthews DR. The relationship between height velocity and growth hormone secretion in short prepubertal children. Clin Endocrinol 1987; 27: 581-91. 2. Gertner JM, Gene1 M, Gianfredi SP el al. Prospective clinical trial of human growth hormone in short children without growth hormone deficiency. J Pediatr 1984; 104: 172-6. 3. Plotnick LP, Van Meter QL, Kowarski AA. Human growth hormone treatment of children with growth failure and normal growth hormone levels by immunoassay: lack ot’ correlation with somatomedin generation. Pediatrics 1983; 71: 324-7. 4. Van Vliet G. Stync DM, Kaplan SL, Grumbach MM.Growth hormone treatment for short stature. N Enpl J Med 1983; u)9: 1016-22. 5 . Albertsson-Wikland K. Growth hormone treatment.in short children. Acta Paediatr Scand (Suppl] 1986. 325: 64-70. 6. Rudman D, Kutner MH. Blackston RD. Jansen RD, Patterson JH. Normal variant short stature. subclassification based on responses to exogenous human growth hormone. J Clin Endocrinol Metab 1979; 49: 92-9.
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7 Chalew SA. Raiti S, Armour KM, Kowarski AA. Therapy of short children with subnormal integrated concentrations of growth hormone. .4m J Dis Child 1987; 141: 1195-8. 8 Raiti S. Kaplan SL. Van Vliet G. Moore WV. Short-term treatment of short stature and subnormal growth rate with human growth hormone. J Pediatr 1987; 110: 357-61. 9 Buchanan CR, Law CM. Milner RDG. Growth hormone in short slowly growing children and those with Turner's syndrome. Arch Dis Child 1987: 62: 912-6. 10. Tanner JM. Whitehouse RH. Takaishi M. Standards from birth to maturity for height, weight, height velocity. and weight velocity: British children. 1965. Part I. Arch Dis Child 1966: 41: 454-71. 1 I . Ackland FM. Stanhope R. Eyre C, Hamill G, Jones J. Preece MA. Physiological growth hormone .secretion in children with short stature and intra-uterine growth retardation. Horm Res 1988: 30: 241-5. 12. Merriam GR, Wachter KW. Algorithms for the study of episodic hormone secretion. Am J Physiol 1982: 143: E310-8. 13. Tanner JM. Normal growth and techniques of growth assessment. Clin Endocrinol Metab 1986; 15: 411-51.
14. Tanner JM. Whitehouse RH. Cameron N. Marshall WA. Healy MJR, Goldstein H. Assessment of skeletal maturity and prediction of adult height (TW2 method). 2nd ed. London: Academic Press, 1983: 106. 15. Ackland FM. Preece MA. Catch-up growth. Pediatrician 1987; 14: 226-33. 16. Albertsson-Wikland K. Rosberg S. Analyses of 24-hour growth hormone profiles in children: relation to growth. J Clin Endocrinol Metab 1988; 67: 493-500. 17. Rochiccioli P. Messina A. Tauber iMT, Enjaume C. Correlation of the parameters of 24-hour growth hormone secretion with growth velocity in 93 children of varying height. Honn Res 1989; 31: 115-8. 18. Tanner JM. Whitehouse RH. Hughes PCR. Vince FP. Effect of human growth hormone treatment for 1 to 7 years on the growth of 100 children with growth hormone deficiency. low binhweight, inherited smallness. Turner's syndrome. and other complaints. Arch Dis Child 1971; 46:745-82. (F.M.A.) Department of Grouih and Development Institute of Child Health 30 Guildford Street London WClN IEH UK
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