Arch Dis Child: first published as 10.1136/adc.42.223.225 on 1 June 1967. Downloaded from Annotation

Arch. Dis. Childh., 1967, 42, 225. Dwarfism, Hypopituitarism, and Growth Hormone

Small stature or growth retardation is a frequent Stimmler, and Lines; and Clayton, Tanner, Newns, problem in children, often leading to serious Whitehouse, and Renwick. Most workers in this psychological repercussions. In some patients, as discipline agree that on clinical grounds alone the for instance in those with achondroplasia, severe diagnosis of GH deficiency can only be suspected, hypothyroidism, or classical Turner's syndrome, the and that the impressive battery of available diagnos- underlying disorder can easily be recognized. More tic tests solves many but not all diagnostic problems. often the growth retarded child presents no other Some of the tests are, as Hubble points out, time symptoms, and the cause of dwarfism remains consuming and painful, and need a great deal of obscure in spite of a good history and a careful co-operation from the patient. Some require a physical examination. A few years ago, many of highly specialized laboratory. The results are these children were treated with anabolic steroids influenced by the presence or absence of the other without further investigation. Most of them anterior pituitary hormones TSH and ACTH. respond to anabolic steroids with an impressive They further depend on the degree ofGH deficiency, spurt of growth, but bone maturation is likely to be and on whether the primary disturbance is in the more accelerated than growth, resulting in a decrease hypothalamus or in the pituitary. These variables rather than the intended increase in the final height explain the discrepancies of results from different attained. Now hope has turned from the anabolic centres, and the search for new and better diagnostic steroids to growth hormone (GH) which in contrast tests. copyright. to anabolic steroids stimulates growth rather than The best simple guide to the diagnosis of GH bone maturation. deficiency is the growth curve, as Hubble, and GH shows a remarkable species specificity in Clayton and her co-workers have concluded. It chemical structure and biological activity. In man begins to flatten at the age of 3 months to 2 years. only human GH (HGH) is effective. The structure During the following years it shows an increasing of HGH has recently been elucidated (Li, Liu, and distance from the normal 3rd centile. The bone Dixon, 1966). It is a polypeptide chain with a age is much delayed, but there are no or only molecular weight of 21,500 consisting of 188 amino questionable clinical symptoms of hypothyroidism. acids of known sequence. The synthesis of such a All other clinical findings, such as the mild obesity, http://adc.bmj.com/ large molecule is not yet possible, but it may soon be the doll-like appearance, the normal body propor- possible to synthesize a smaller, biologically active tions, and sexual infantilism, have little diagnostic part ofthe original molecule, as has been successfully value in children. In the absence of neurological done with ACTH. At the moment we still depend and radiological signs of a craniopharyngioma, one on HGH extracted from pituitary glands obtained has therefore to rely on laboratory tests. at necropsy. The supply of this material is scarce, Many but not all patients have a deficiency of and experience with its therapeutic use still limited. TSH and/or ACTH, which is usually only recogniz- on October 1, 2021 by guest. Protected So far it seems that dwarfs with supposed deficiency ed by appropriate functional studies. TSH func- of GH respond with a marked growth acceleration, tion is evaluated mainly by PBI and radio-iodine whereas dwarfs without GH deficiency show only a uptake. ACTH deficiency can be recognized with small or dubious response (Soyka, Ziskind, and the help of the metyrapone test, the plasma cortisol Crawford, 1964; Mason and Tanner, 1967). It is, response to insulin-induced hypoglycaemia, and the therefore, important to reserve the available HGH water loading test (delay of water excretion, for treatment of children with hypopituitarism, and correctable by ACTH). Of these tests the water to refuse it to children with dwarfism of other origin. loading test is the most simple, and the metyrapone This raises the question of how to diagnose GH test probably the most sensitive. The response of deficiency in children, and this difficult problem is plasma and urine corticoids to a prolonged ACTH discussed in this issue of the Archives by several test and to vasopressin (vasopressin acting like the authors, Hubble; Stimmler and Brown; Brown, corticotrophin releasing factor, CRF) may be normal 225 Arch Dis Child: first published as 10.1136/adc.42.223.225 on 1 June 1967. Downloaded from 226 A. Prader in the presence of ACTH deficiency, indicating a tests for distinguishing hypopituitary from non- normal pituitary-adrenal axis and pointing to a hypopituitary dwarfs. This cannot be said for the hypothalamic origin of the pituitary insufficiency insulin tolerance test: in hypopituitarisiufthis test (Landon, James, and Stoker, 1965; Landon, frequently but not always reveals increased sensitiv- Greenwood, Stamp, and Wynn, 1966). ity of plasma glucose to insulin, or more strictly, a The best way to demonstrate GH deficiency is decreased responsiveness of plasma glucose to probably by the plasma GH response to insulin- insulin-induced hypoglycaemia, i.e. a retarded induced hypoglycaemia (Roth, Glick, Yalow, and return of plasma glucose towards fasting values Berson, 1963) as discussed in this issue by Hubble (Fraser, Albright, and Smith, 1941). Since insulin and by Stimmler and Brown. There are, however, should be given intravenously, there is some danger only a few laboratories which have mastered the of severe hypoglycaemia, requiring close observa- delicate radioimmunological GH assay, and the tion of the patient and intravenous glucose if serious results occasionally contradict those from other symptoms develop. In the hands of some investi- tests. Hubble feels that this test does not separate gators this test, or a modification of it, has proved a hypopituitary from non-hypopituitary children as useful screening test for recognizing GH deficiency well as the N-retention test. Furthermore, Zim- (Prader et al., 1964a; Trygstad, 1965), while others merman, White, Daughaday, and Goetz (1967) have find mostly normal results in patients with GH recently reported two male patients with TSH, deficiency (Hubble, 1967; Stinmler and Brown, ACTH, and gonadotrophin deficiency, with no 1967; Clayton et al., 1967). It may be that hypo- plasma GH response to insulin-induced hypoglycae- glycaemia unresponsiveness is only found when GH mia, yet with normal stature. and cortisol are lacking simultaneously. This hypo- N-retention during a short HGH treatment period thesis is supported by the normal results obtained on is higher in hypopituitary dwarfs than in control applying this test to patients with isolated ACTH children (Prader, Illig, Szeky, and Wagner, 1964a). deficiency (Odell, 1966), to patients with Addison's The test is time consuming and tedious but has disease that are DOC treated and are well nourished diagnostic value (Hubble, 1966, 1967; Brown et al., (Fajans, 1961), and to patients with GH deficiency 1967). In theory it should tell us whether those but with normal or increased cortisol response to copyright. patients with normal stature but without GH insulin-induced hypoglycaemia (Stinumler and response to hypoglycaemia really lack GH, and Brown, 1967). In hypopituitary dwarfs, non- whether the intriguing type of dwarfism with responsiveness to hypoglycaemia can be corrected increased plasma levels of GH (Laron, Pertzelan, by one injection of HGH Raben 2 mg./m.2, a and Mannheimer, 1966) is due to unresponsiveness presumably physiological dose (Prader et al., 1967b). to normal HGH, or to the production ofan abnormal Another diagnostic test proposed is the growth and inactive form of HGH. It gives occasionally response to long-term treament with HGH. In misleading values (Prader et al., 1964a; Joss, Rossi, hypopituitary dwarfs there is a sharp increase in http://adc.bmj.com/ Zahnd, and Zuppinger, 1966), as do the other tests. growth velocity from pretreatment values of 1-4 cm. An interesting point is the observation that N- per year to values of 5-12 cm. during the first year of retention with 10 mg. HGH Raben (Hubble, 1966, treatment (Raben, 1962, 1965; Soyka et al., 1964; 1967; Brown et al., 1967) is the same as with 2 mg. Prader et al., 1964a; Wright, Brasel, Aceto, HGH Raben (Prader et al., 1964a). This confirms Finkelstein, Kenny, Spaulding, and Blizzard, 1965; the assumption that the dose response curve is Seip and Trygstad, 1966; Prader, Zachmann, Poley, asymptotic, and that 2 mg. are in or near the Illig, and SzEky, 1967c; Mason and Tanner, 1967), physiological range. In an extension of this short- whereas no such acceleration has been observed in on October 1, 2021 by guest. Protected term metabolic HGH test, Prader, Zachmann, non-hypopituitary dwarfs. This test is unfortu- Poley, and Illig (1967a) have recently shown that the nately unreliable because of the frequent develop- serumt--amino-N increases and the ot-amino-N- ment of HGH antibodies (Trafford, Lillicrap, and clearance decreases in hypopituitary dwarfs but not Lessof, 1963; Prader, Wagner, Szeky, Illig, Touber, in control children. These results reflect in part an and Maingay, 1964b; Parker, Mariz, and Daughaday, increased transport of amino acids through the cell 1964). The development of antibodies during the membranes. Other parameters, like the decrease of first months of treatment in sufficient concentration serum urea, the increase of serum phosphorus, and to block the effect of supposedly physiological the increase of urinary calcium, are not significantly amounts of HGH has been observed in 8 out of 19 different in the two groups. patients (Prader et al., 1967c) treated with HGH The GH response to hypoglycaemia and the N Raben, and in at least one patient treated with HGH response to GH are generally regarded as fairly good Li (Frasier and Smith, 1966). The antibodies have Arch Dis Child: first published as 10.1136/adc.42.223.225 on 1 June 1967. Downloaded from Annotation 227 always appeared during the first 6-9 months of Mason, A. S., and Tanner, J. M. (1967). Human growth hormone in the treatment of dwarfism. In Modern Trends of Endo- treatment and never later. Since normal HGH crinology. Butterworths, London. should not stimulate the development of antibodies Odell, W. D. (1966). Isolated deficiencies of anterior pituitary hormones. Symptoms and diagnosis. J. Amer. med. Ass., 197, in man, it seems likely that certain extraction and 1006. lyophylization procedures alter the HGH molecule, Parker, M. L., Mariz, I. K., and Daughaday, W. H. (1964). Resis- making it antigenic without affecting its biological tance to human growth hormone in pituitary dwarfism: clinical and immunologic studies. J. clin. Endocr., 24, 997. activity. In this connexion it is interesting to note Prader, A., Illig, R., Szeky, J., and Wagner, H. (1964a). The effect that growth resistance suggesting GH suppressing of human growth hormone in hypopituitary dwarfism. Arch. Dis. Childh., 39, 535. antibodies has not been observed in the 12 patients -, Wagner, H., Szeky, J., Illig, R., Touber, J. L., and Maingay, treated with HGH Roos (Seip and Trygstad, 1966). D. (1964b). Acquired resistance to human growth hormone caused by specific antibodies. Lancet, 2, 378. A. PRADER -, Zachmann, M., Poley, J. R., and Illig, R. (1967a). The Department of Paediatrics metabolic effect of a small uniform dose of human growth hormone in hypopituitary dwarfs and in control children. University of Ziirich Submitted for publication. Kinderspital , , and - (1967b). The effect of a small uniform dose of human growth hormone on the blood glucose response Ziirich, Switzerland to insulin induced hypoglycemia in hypopituitary dwarfs and in control children. Submitted for publication. REFERENCES -, and Szeky, J. (1967c). Therapy with human Brown, G. A., Stimmler, L., and Lines, J. G. (1967). Growth growth hormone (Raben) in small doses. Helv. paediat. Acta. hormone-induced nitrogen retention in children of short stature. In the press. Arch. Dis. Childh., 42, 239. Raben, M. S. (1962). Medical progress: growth hormone, 2. Clayton, B. E., Tanner, J. M., Newns, G. H., Whitehouse, R. H., Clinical use of human growth hormone. New Engl. J. Med., and Renwick, A. G. L. (1967). Differential diagnosis of 266, 82. children with short stature not associated with metabolic, - (1965). Effect of human growth hormone on dwarfed children. chromosomal, or gross nervous system defects. ibid., 42, 245. Proc. 2nd Int. Congr. Endocr. (London 1964), Internat. Congr. Fajans, S. S. (1961). Some metabolic actions of corticosteroids. Series No. 83, 989. Excerpta Medica Foundation. Metabolism, 10, 951. Roth, J., Glick, S. M., Yalow, R. S., and Berson, S. A. (1963). Fraser, R., Albright, F., and Smith, P. H. (1941). Carbohydrate Secretion of human growth hormone: physiologic and experi- metabolism. 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Endocr., copyright. Frasier, S. -D., and Smith, F. G. (1966). Antibodies to human Seip, M., and Trygstad, 0. (1966). Experiences with human growth hormone. Amer. J. Dis. Child., 112, 383. growth hormone in pituitary dwarfism. Actapaediat. (Uppsala), Hubble, D. (1966). Studies with human growth hormone. Arch. 55, 287. Dis. Childh., 41, 17. Soyka, L. F., Ziskind, A., and Crawford, N. (1964). Treatment of - (1967). Diagnosis of hypopituitarism in childhood. ibid., 42, short stature in children and adolescents with human pituitary 228. growth hormone (Raben). New Engl. J. Med., 271, 75. Joss, E., Rossi, E., Zahnd, G., and Zuppinger, K. (1966). Diagnosi Stimmler, L., and Brown, G. A. (1967). Growth hormone secretion biologica del nanismo ipofisario. Minerva pediat., 18, 1811. provoked by insulin-induced hypoglycaemia in children of short Landon, J., Greenwood, F. C., Stamp, T. C. B., and Wynn, V. stature. Arch. Dis. Childh., 42, 232. (1966). The plasma sugar, free fatty acid, cortisol, and growth Trafford, J. A. P., Lillicrap, D. A., and Lessof, M. H. (1963). hormone response to insulin, and the comparison of this Human growth hormone in pituitary infantilism. Lancet, 1, 1128.

procedure with other tests of pituitary and adrenal function. http://adc.bmj.com/ II. In patients with hypothalamic or pituitary dysfunction or Trygstad, 0. (1965). The insulin-glucose tolerance test in pituitary anorexia nervosa. J. clin. Invest., 45, 437. growth retardation. ibid., 40, 508. -, James, V. H. T., and Stoker, D. J. (1965). Plasma-cortisol Wright, J. C., Brasel, J. A., Aceto, T., Finkelstein, J. W., Kenny, response to lysine-vasopressin. Comparison with other tests of F. M., Spaulding, J. S., and Blizzard, R. M. (1965). Studies human pituitary-adrenocortical function. Lancet, 2, 1156. with human growth hormone (HGH). An attempt to correlate Laron, Z., Pertzelan, A., and Mannheimer, S. (1966). Genetic metabolic response during short-term administration with pituitary dwarfism with high serum concentration of growth linear growth during prolonged therapy. Amer. J. Med., 38, hormone: a new inborn error of metabolism? Israel J. med. 499. Sci., 2, 152. Zimmerman, T. S., White, M. G., Daughaday, W. H., and Goetz, Li, C. H., Liu, W. K., and Dixon, J. S. (1966). Human pituitary F. C. (1967). Hypopituitarism with normal or increased height.

growth hormone. XII. The amino acid sequence of the Report of two cases, with measurement of plasma growth on October 1, 2021 by guest. Protected hormone. J. Amer. chem. Soc., 88, 2050. hormone levels. ibid., 42, 146.