European Joumal of

Eur. J. Pediatr. 132, 215-219 (1979)

Pediatrics 9 by Springer-Verlag 1979


Growth Hormone Deficiency--Current Problems M. A. Preece Department of Growth and Development, Institute of Child Health, University of London, 30 Guilford Street, London, WC1 1EH, England

Following Raben's first report (1958) ever-increasing numbers of children with growth hormone deficiency ( G H D ) have been treated with human growth hormone (hGH). Many of the published reports of treatment are listed by Ranke et al. (1979) in the current issue of this Journal. Recently, the total 20 years of experience in the United Kingdom concerning diagnosis, treatment, complications and the problems of provision of h G H have been reported (Milner et al., 1979). Despite the evident world-wide experience there remain several points of uncertainty in terms of aetiology, diagnosis and optimal management. Considering the aetiology of idiopathic G H D , extensive opinion agrees on the relevance of birth trauma, and especially breech deliveries (Goodman et al., 1968; Bierich, 1972; Job et al., 1972; Francois et al., 1974; Joss, 1975; Guyda et al., 1975; Rona and Tanner, 1977). Most recently Rona and Tanner (1977) showed an increased incidence of idiopathic G H D in children with breech deliveries and a greater association with those children who had multiple pituitary hormone deficiencies (MPHD). It is noteworthy that Ranke et al. (1979) report similar high associations of difficult deliveries, especially breeches. It is especially interesting that with their greater number of children born by breech delivery they have a higher incidence of M H P D amongst their total experience of idiopathic G H D . In 1977, Preece et al. reported two children with associated G H D and congenital rubella and Ranke et al. (1979) report a third case. It is now important that this particular factor should be seriously considered, both in terms of an aetiological factor in new cases of G H D , but more importantly by awareness of the possibility of G H D in children with already diagnosed congenital rubella. This is important because of the ready acceptance that these children will be small as part of their general disease, whereas in some cases there may be a treatable cause present. It is worthwhile noting that the two cases reported by Preece et al. (1977) responded well to h G H treatment, in terms of growth, making the diagnosis worthwhile and not just an academic exercise.



M.A. Preece

Apart from aetiological considerations there are three further areas of discussion. Questions of optimal dosage including frequency, have produced many publications. Similarly the question of the prevalence of M P H D versus isolated G H D and the advisability of supplementary hormone replacements has differed greatly from one series to another. The final and most difficult consideration is the relevance of partial G H D , if it exists. Firstly we shall consider questions of dose and frequency of injection. Although comparisons of different dosage regimes between different groups must be treated with circumspection, it is still valuable to look at the different regimes used throughout the world. We must bear in mind, however, that there are also differences of h G H preparation, criteria of diagnosis and general differences in the types of patients treated, particularly in terms of their age and severity of disease. Reported regimes discuss total amounts of growth hormone from 2 IU to 30IU per week and frequencies from one to three times weekly. Most dosages have been around 8 - - 1 2 I U / w e e k usually given in two or three divided doses (Wright et al., 1965; G o o d m a n et al., 1968; Soyka et al., 1970; Tanner et al., 1971; Aceto et al., 1972, 1974; G u y d a et al., 1975; Preece et al., 1976; Fiasier et al., 1977; Milner et al., 1979). When the criterion of the greatest acceleration in growth rate during the first treatment year is used, the regime which gave the best results was that described by Aceto et al. (1974), giving 10 IU three times a week. Very similar results were obtained in the United Kingdom with 5 IU three times per week (Milner et al., 1979), but is noticable that the top five regimes were all thrice weekly. In contrast, when one considers maximum growth/IU, h G H used each year, the lower dose regimes of Frasier et al. (1977), Soyka et al. (1970) and Aceto et al. (1974) are best. The regime of Frasier et al. (1977) was a very low 0.7 IU three times each week, producing very poor growth acceleration (2.9 cm increase in growth rate over the first treatment year) albeit at a very economical usage. The regimes of Soyka et al. (1970) and Aceto et al. (1974) using 2 IU three times a week were very economical and achieved reasonable acceleration of about 6 c m / y r in the first year. The one clear message that emerges from review of this data is that whatever total dosage of growth hormone is going to be used, it would seem to be most economical and beneficial to use a thrice weekly regime. Trials of more frequent dosage have not yet been reported although a trial of 2 IU daily is at present underway in Great Britain and will be reported soon. The data discussed so far must be cautiously interpreted in view of the comparisons between different investigators and it only refers to the first treatment year. Longer-term comparison of two twice-weekly regimes was reported by Preece et al. (1976) comparing 5IU and 10IU, both given twice weekly. Even after four years a clear difference was seen between the groups, such that extrapolation (dangerous as that is) suggested a mature height difference between the groups of 10 cm in favour of the higher dose. There have been few reports of h G H given as a depot preparation. Milner et al. (1979) report that serum concentrations of h G H following injection in 16% gelatin solution were indistinguishable from those after injection in saline. In contrast Lippe et al. (1979) showed rather lower serum h G H concentrations after twice weekly injections in 15% gelatin. However, comparable growth over two

Growth Hormone Deficiency


years was obtained from this gelatin regime to that gained from a three times weekly regime using only an aqueous injection medium. A further major difference between different reports of groups of children with growth hormone deficiency is the relative incidence of M P H D and isolated GHD. Comparison between six series of G H D patients (Goodman et al., 1968; Seip et al., 1971; Aceto et al., 1972; Guyda et al., 1975; Calzada et al., 1978 and Milner et al., 1979) showed a relative frequency of acquired lesions causing G H D similar in all groups, from 17 to 31%. In contrast, the frequency of M P H D within the idiopathic group was quite different in the British study (18%) compared to the others, who mostly reported around 50%. There is no obvious explanation for this discrepancy; certainly some of the patients in the British study with so-called "isolated" G H D may manifest associated gonadotrophin deficiency as puberty fails to appear. This possibility, however, applies with equal force to other studies. Another possible explanation is the greater acceptance of the diagnosis of partial G H D in the British series, which tends to increase the apparent number of isolated G H D states. Further, Ranke et al. (1979) suggest that the relative frequency of M P H D might be greatest with higher incidences of abnormal deliveries. Earlier studies do not give this data so the hypothesis cannot be tested from the literature. An allied problem is the suggested complication in the treatment of G H D where thyroid function declines during prolonged treatment of h G H (Oliver and Ballantyne, 1968; Root et al., 1973). Rubio et al. (1976) and Milner et al. (1979) failed to demonstrate this. The latter group who continuously screened 241 patients receiving h G H , failed to demonstrate a fall in thyroxine levels in all but one child. Certainly the evidence for thyroid function declining as a result of h G H therapy seems to be scant. The question of replacement of established thyroid deficiencies should not cause controversy. Certainly, when hypothyroidism is demonstrated secondary to TSH deficiency, thyroxine should be instituted at a dosage adequate to restore a euthyroid state. More contentious is the routine use of corticosteroids when A C T H deficiency has been demonstrated. Remarkably small amount of corticosteroids will reduce the growth response to h G H (Preece, 1976); doses of hydrocortisone in excess of 10mg/day are inhibitory. On the other hand, A C T H deficiency is a potentially lethal condition and it is clearly wrong to say the children should not be steroid replaced. In general a policy of the use of 7.5--10mg of hydrocortisone in divided doses daily would seem to provide a satisfactory compromise. If facilities allow, it is sensible to adjust each patient's dose of corticosteroids so that they maintain a normal or near normal diurnal range of plasma cortisol, but I suspect this is rarely possible and in the end a clinical compromise is required. Replacement of gonadotrophins or sex steroids is in general a less important decision as withholding them will not kill. There is, however, the important consideration of the child's psychological well-being and a too long, too assiduous withholding of induction of puberty may be extremely damaging. There is also the unresolved problem as to whether it is important to give sex hormones during a critical period to get maximum synergism between h G H and the sex steroids. It is an important consideration and requires urgent resolution.


M.A. Preece

Finally, we must turn to the vexed question o f partial G H D . The most c o m m o n definition of this is the situation where children with all the clinical features of G H D show an intermediate peak o f serum h G H on testing of pituitary function. Whereas peaks below 7 m I U / 1 would in general be considered to indicate severe G H deficiency, levels between 7 and 15 mlU/1 are arbitrarily considered as suggesting partial deficiency (Preece and Tanner, 1976). I, however, believe that this rigid definition is not tenable. There appears to be a g r o u p of patients who have mild deficiency with varying combinations of a low peak plasma h G H response, low growth velocity, and moderate short stature. These patients show a less dramatic response to growth h o r m o n e treatment, although they still, by and large, benefit f r o m it. It is particularly important to exclude from this g r o u p those p a t i e n t s - - a l m o s t exclusively b o y s - - w h o show apparent G H D just before, or in the early stages o f puberty with m a r k e d growth delay, but w h o spontaneously resolve and do not require treatment (see, for example, Eastm a n et al., 1971; Preece, 1979). W h e t h e r these are all within the same spectrum of disease or whether they are quite separate entities is, at the m o m e n t , uncertain.

References Aceto, T., Frasier, S. D., Hayles, A. B., Meyer-Bahlburg, H. F. L., Parker, M. L., Munschauer, R., Di Chiro, G.: Collaborative study of the effects of human growth hormone in growth hormone deficiency. I. First year of therapy. J. Clin. Endocrinol. Metab, 35, 483 (1972) Aceto, T., Frasier, S. D., Hayles, A. B., Mayer-Bahtburg, H. F. L., Parker, M, L., Munschauer, R., DiChiro, G.: Collaborative study of the effects of human growth hormone in growth hormone deficiency. 3. First eighteen months of therapy, In Advances in Human Growth Hormone Research: A Symposium 1973, U.S. Dept. of Health, Education and Welfare, Publication No. NIH 74-612 (1974) Bierich, J. R.: On the aetiology of hypopituitary dwarfism. Growth and Growth Hormone, Proceedings of the Second International Symposium on Growth Hormone, A. Pecile, E. E, MUller (eds.). Amsterdam: Excerpta Medica 1972 Calzada, L.-D., Chaussain, J.-L., Job, J.-C.: Etiologie et associations du nanisme hypophysaire, Arch. Franc. Pediatr. 35, 144 (1978) Eastman, C. J., Lazarus, L,, Stuart, M. C., Casey, J. H.: The effect of puberty on growth hormone secretion in boys-with short stature and delayed adolescence. Aust. N. Z. J. Med. 2, 154 (1971) Francois, R., David, L., Clerget-Guarnaud, M.: Traitment des nanismes hypophysaires. Pediatrie 29, 305 (1974) Frasier, S. D., Aceto, T., Hayles, A. B., Mikity, V.: Collaborative study of the effects of human growth hormone in growth hormone deficiency: IV. Treatment with low doses of human growth hormone based on body weight. J. Clin. Endocrinol. Metab. 44, 22 (1977) Goodman, H. G., Grumbach, M. M., Kaplan, S. L.: Growth and growth hormone. II. A comparison of isolated growth hormone deficiency and multiple pituitary-hormone deficiencies in 35 patients with idiopathic hypopituitary dwarfism. New Engl. J. Med. 278, 57 (1968) Guyda, H.,.Friesen, H., Bailey, J. D., LeBoeuf, G., Beck, J. C.: Medical Research Council of Canada therapeutic trial of human growth hormone: first 5 years of therapy. Can. Med. Ass. J. 112, 1301 (1975) Job, J.-C., Lejeune, C., Canlorbe, P., Rossier, A.: Le nanisme par insuffisance hypophysaire sporadique idiopathique. Etude d'une serie de 31 cas. Arch. Franc. Pediatr. 29, 117 (1972) Joss, E. E.: Growth hormone deficiency in childhood: Evaluation of diagnostic procedures. Monographs in Pediatrics, No. 5. Basel: Karger 1975

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Milner, R. D. G., Russell-Fraser, T., Brook, C. D. G., Cotes, P. M., Farquhar, J. W., Parkin, J. M., Preece, M. A., Snodgrass, G, J. A. I., Stuart Mason, A., Tanner, J. M., Vince, F. P.: Experience with human growth hormone in Great Britain: The report of the MRC Working Party. Clin. Endocrinol. 11, 15 (1979) Oliver, L., Ballantine, J. J.: Effect of human growth hormone on thyroid secretion, radiothyroxine turnover and transport in man. J. Clin. Endocrinol. Metab. 28, 603 (1968) Preece, M. A., Tanner, J. M., Whitehouse, R. H., Cameron, N.: Dose dependence of growth response to hGH in ,,isolated" growth hormone deficiency. J. Clin. Endocrinol. Metab. 42, 477 (1976) Preece, M. A.: The effect of administered corticosteroids on the growth of children. Br. Postgr. Med. J. 52, 625 (1976) Preece, M. A.: Growth delay. Acta Paediatr. Belg. 32, 7 (1979) Preece, M. A., Tanner, J. M.: The diagnosis and management of growth hormone deficiency. Min. Endocrinol. 1, 42 (1976) Preece, M. A., Kearney, P. J., Marshall, W. C.: Growth hormone deficiency in congenital rubella. Lancet 1977II, 842 Raben, M. S.: Treatment of a pituitary dwarf with human growth hormone. J. Clin. Endocrinol. Metab. 18, 901 (1958) Ranke, M., Weber, B., Bierich, J. R.: Long-term response to human growth hormone in 36 children with idiopathic growth homone deficiency. Eur. J. Pediatr. 132, 221--238 (1979) Rona, R. J., Tanner, J. M.: Aetiology ot idiopathic growth hormone deficiency in England and Wales. Arch. Dis. Childh. 52, 197 (1977) Root, A. W., Snyder, P. J., Rezvani, I., DiGeorge, A. M., Utiger, R. D.: Inhibition of thyrotrophin-releasing hormone-mediated secretion of thyrotrophin by human growth hormone. J. Clin. Endocrinol. Metab. 36, 103 (1973) Rubio, G. R., Mellinger, R. C., Saeed Zafar, M., Wolf, C. B.: Evaluation of thyroid function during growth hormone therapy. Metabolism 25, 15 (1976) Seip, M., Trygstad, O., Aarskog, D.: Comment on pituitary dwarfism in Norway, 1961--1970. Birth Defects Original Article Series, Vol. 7, No. 6, 33 (1971) Soyka, L. F., Bode, H. H., Crawford, J. D., Flynn, F. J.: Effectiveness of long-term human growth hormone therapy for short stature in children with growth hormone deficiency. J. Clin. Endocrinol. Metab. 30, 1 (1970) Tanner, J. M., Whitehouse, R. H., Hughes, P. C. R., Vince, F. P.: The effect of human growth hormone treatment for 1 to 7 years on the growth of 100 children with growth hormone deficiency, low birthweight, inherited smallness, Tuner's syndrome and other complaints. Arch. Dis. Childh. 46, 745 (1971) Wright, J. C., Brasel, J. A., Aceto, T., Finkelstein, J. W., Kenny, F. M., Spaulding, J. S., Blizzard, R. M.: Studies with human growth hormone (hGH). An attempt to correlate metabolic response during short-term administration with linear growth during prolonged therapy. Amer. J. Med. 38, 499 (1965)

Received September 26, 1979

Growth hormone deficiency--current problems.

European Joumal of Eur. J. Pediatr. 132, 215-219 (1979) Pediatrics 9 by Springer-Verlag 1979 Annotation Growth Hormone Deficiency--Current Problem...
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