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Eur. J. Pediatr. 132, 221-238 (1979)
Pediatrncs 9 by Springer-Verlag 1979
Original Investigations Long-term Response to Human Growth Hormone in 36 Children with Idiopathic Growth Hormone Deficiency M. Ranke, B. Weber, and J. R. Bierich Univ.-Kinderklinik, Rtimelinstr., D-7400 T/Jbingen, Federal Republic of Germany
Abstract. The results of long term treatment with human growth hormone (Crescormon| 12.4IU/m2/week) in 36 patients with idiopathic growth hormone deficiency are given. Birth trauma--in particular assisted breech delivery (30%)--is the major aetiological cause. Twelve patients had isolated growth hormone deficiency (IGHD), 24 had multiple pituitary hormone deficiencies (MPHD) of which 19 were treated with additional thyroid hormones. The results were judged by the criteria of height velocity, total height gain and change of height prediction (TW2, age based). It is concluded that the growth hormone dose chosen in many cases is insufficient to maintain high growth rates after the first year of treatment, when "catch-up" no longer takes place. The tendency of patients supplemented with thyroid hormone to grow better--without additional bone-age advancement--calls for careful search for hypothyroidism and suggests the use of thyroxin in cases of doubt. Key words: Idiopathic growth hormone deficiency - Diagnosis - Aetiology Treatment - Prognosis.
Introduction Almost 20 years ago, Raben [31] was the first to report successful treatment of a patient with growth hormone deficiency. By now a considerable number of reports on the effect of h G H in growth hormone deficient patients and patients with other growth disorders have been published [1,5--7, 9--12, 14--16, 19, 27, 35, 40, 42, 45]. Though there is no debate on h o w to establish the diagnosis of growth hormone deficiency and to differentiate it from other forms of small stature [15, 38], there is considerable variety in the way such patients are treated. The majority of groups prefer a regimen with continuous treatment with hGH, while others [16, 19] claim comparably good results with intermittent therapy. There is
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also s o m e u n c e r t a i n t y a b o u t the dose which is o p t i m a l for the p a t i e n t s ' needs a n d at the same time e c o n o m i c a l l y justifiable. F u r t h e r m o r e , h o w a n d whether add i t i o n a l p i t u i t a r y deficiencies s h o u l d be s u b s t i t u t e d awaits final clarification. One r e a s o n for this is the relative r a r i t y o f the d i s o r d e r with the consequence t h a t even large e n d o c r i n e centers d i a g n o s e only small n u m b e r s o f patients over long periods. I n a d d i t i o n , the g r o u p s are relatively u n h o m o g e n o u s with respect to the extent o f their p i t u i t a r y deficits, b o t h in t e r m s o f quality a n d quantity. M o s t i m p o r t a n t , however, is the fact t h a t t r e a t m e n t has to be for long p e r i o d s a n d its u l t i m a t e effect has to be j u d g e d o n the final heights achieved. I n c o m p a r i s o n to the n u m b e r o f p a t i e n t s t r e a t e d for one or t w o years, only a few have been f o l l o w e d for longer p e r i o d s or into to a d u l t life. In this r e p o r t we p r e s e n t the results o f l o n g - t e r m t r e a t m e n t in 36 patients with i d i o p a t h i c g r o w t h h o r m o n e deficiency. As in o t h e r reports, we are u n a b l e to present d a t a on the u l t i m a t e height achieved in the m a j o r i t y of the patients. In a d d i t i o n to the a n a l y t i c a l " s t a n d a r d " a p p r o a c h to the data, we have i n c l u d e d the m e t h o d o f height p r e d i c t i o n for e v a l u a t i o n o f the t h e r a p e u t i c regimen which was chosen at the initiation o f t h e r a p y several years ago.
Methods and Patients Laboratory Diagnosis The diagnosis of growth hormone deficiency was established if plasma hGH concentrations did not exceed 7ng/ml in both arginine- [26] and insulin tests [17,37], Measurements of somatomedin (porcine cartilage bioassay (SM)) in 30 patients were below the range of normal controls (SMcontr.= 0.87 • 0.22 U/ml) [32]. Additional thyroid hormone deficiency was assumed if T4-RIA values were below the lower limit of normal (in our laboratory: 4.8 gg/dl) and if the TSH-response to TRH clearly showed pathological pituitary/hypothalamic pattern of TSH secretion [23, 29]. Gonadotrophic dysfunction was assumed if clinical signs of puberty were still lacking at appropriate bone developments or if the responses of serum LH and FSH to LH-RH were subnormal [36, 39]. Normal adrenal function was assumed if cortisol responses to insulininduced hypoglycemia exceeded 151ag/dl, or if the increment above basal levels exceeded 7 gg/dl.
Anthropometrie Measurements Height. Height was measured according to the recommendations of Tanner and Whitehouse [43], applying a Harpenden stadiometer. Height measurements were usually taken every 3 months. For comparison the cross sectional standards of Tanner et al. were used [60]. The same standards were used for weight comparisons. Bone Age. Determinations of bone ages were made from X-rays of the left hand by the methods of Greulich and Pyle [14] and by Tanner et al. [44]. All films were evaluated by one investigator (M.R.). Since TW20 and RUS values were very similar, we chose to use the RUS data. TW-RUS and Greulich/Pyle bone ages were highly correlated, with a systematic retardation for the Greulich-Pyle values (N= 152; RUS = 1.0 • GP + 0.805 (years); r-0.69, P
Eur. J. Pediatr. 132, 221-238 (1979)
Pediatrncs 9 by Springer-Verlag 1979
Original Investigations Long-term Response to Human Growth Hormone in 36 Children with Idiopathic Growth Hormone Deficiency M. Ranke, B. Weber, and J. R. Bierich Univ.-Kinderklinik, Rtimelinstr., D-7400 T/Jbingen, Federal Republic of Germany
Abstract. The results of long term treatment with human growth hormone (Crescormon| 12.4IU/m2/week) in 36 patients with idiopathic growth hormone deficiency are given. Birth trauma--in particular assisted breech delivery (30%)--is the major aetiological cause. Twelve patients had isolated growth hormone deficiency (IGHD), 24 had multiple pituitary hormone deficiencies (MPHD) of which 19 were treated with additional thyroid hormones. The results were judged by the criteria of height velocity, total height gain and change of height prediction (TW2, age based). It is concluded that the growth hormone dose chosen in many cases is insufficient to maintain high growth rates after the first year of treatment, when "catch-up" no longer takes place. The tendency of patients supplemented with thyroid hormone to grow better--without additional bone-age advancement--calls for careful search for hypothyroidism and suggests the use of thyroxin in cases of doubt. Key words: Idiopathic growth hormone deficiency - Diagnosis - Aetiology Treatment - Prognosis.
Introduction Almost 20 years ago, Raben [31] was the first to report successful treatment of a patient with growth hormone deficiency. By now a considerable number of reports on the effect of h G H in growth hormone deficient patients and patients with other growth disorders have been published [1,5--7, 9--12, 14--16, 19, 27, 35, 40, 42, 45]. Though there is no debate on h o w to establish the diagnosis of growth hormone deficiency and to differentiate it from other forms of small stature [15, 38], there is considerable variety in the way such patients are treated. The majority of groups prefer a regimen with continuous treatment with hGH, while others [16, 19] claim comparably good results with intermittent therapy. There is
0340-6 ! 99/79/0132/0221/$ 03.60
222
M. Ranke et al.
also s o m e u n c e r t a i n t y a b o u t the dose which is o p t i m a l for the p a t i e n t s ' needs a n d at the same time e c o n o m i c a l l y justifiable. F u r t h e r m o r e , h o w a n d whether add i t i o n a l p i t u i t a r y deficiencies s h o u l d be s u b s t i t u t e d awaits final clarification. One r e a s o n for this is the relative r a r i t y o f the d i s o r d e r with the consequence t h a t even large e n d o c r i n e centers d i a g n o s e only small n u m b e r s o f patients over long periods. I n a d d i t i o n , the g r o u p s are relatively u n h o m o g e n o u s with respect to the extent o f their p i t u i t a r y deficits, b o t h in t e r m s o f quality a n d quantity. M o s t i m p o r t a n t , however, is the fact t h a t t r e a t m e n t has to be for long p e r i o d s a n d its u l t i m a t e effect has to be j u d g e d o n the final heights achieved. I n c o m p a r i s o n to the n u m b e r o f p a t i e n t s t r e a t e d for one or t w o years, only a few have been f o l l o w e d for longer p e r i o d s or into to a d u l t life. In this r e p o r t we p r e s e n t the results o f l o n g - t e r m t r e a t m e n t in 36 patients with i d i o p a t h i c g r o w t h h o r m o n e deficiency. As in o t h e r reports, we are u n a b l e to present d a t a on the u l t i m a t e height achieved in the m a j o r i t y of the patients. In a d d i t i o n to the a n a l y t i c a l " s t a n d a r d " a p p r o a c h to the data, we have i n c l u d e d the m e t h o d o f height p r e d i c t i o n for e v a l u a t i o n o f the t h e r a p e u t i c regimen which was chosen at the initiation o f t h e r a p y several years ago.
Methods and Patients Laboratory Diagnosis The diagnosis of growth hormone deficiency was established if plasma hGH concentrations did not exceed 7ng/ml in both arginine- [26] and insulin tests [17,37], Measurements of somatomedin (porcine cartilage bioassay (SM)) in 30 patients were below the range of normal controls (SMcontr.= 0.87 • 0.22 U/ml) [32]. Additional thyroid hormone deficiency was assumed if T4-RIA values were below the lower limit of normal (in our laboratory: 4.8 gg/dl) and if the TSH-response to TRH clearly showed pathological pituitary/hypothalamic pattern of TSH secretion [23, 29]. Gonadotrophic dysfunction was assumed if clinical signs of puberty were still lacking at appropriate bone developments or if the responses of serum LH and FSH to LH-RH were subnormal [36, 39]. Normal adrenal function was assumed if cortisol responses to insulininduced hypoglycemia exceeded 151ag/dl, or if the increment above basal levels exceeded 7 gg/dl.
Anthropometrie Measurements Height. Height was measured according to the recommendations of Tanner and Whitehouse [43], applying a Harpenden stadiometer. Height measurements were usually taken every 3 months. For comparison the cross sectional standards of Tanner et al. were used [60]. The same standards were used for weight comparisons. Bone Age. Determinations of bone ages were made from X-rays of the left hand by the methods of Greulich and Pyle [14] and by Tanner et al. [44]. All films were evaluated by one investigator (M.R.). Since TW20 and RUS values were very similar, we chose to use the RUS data. TW-RUS and Greulich/Pyle bone ages were highly correlated, with a systematic retardation for the Greulich-Pyle values (N= 152; RUS = 1.0 • GP + 0.805 (years); r-0.69, P
