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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 1 229-233
Copyright © 1997 by The Endocrine Society

Pediatric Endocrinology

Adult Height in 24 Patients Treated for Growth Hormone Deficiency and Early Puberty1

L. Adan, J. C. Souberbielle, J. M. Zucker, A. Pierre-Kahn, C. Kalifa and R. Brauner

Pediatric Endocrinology (L.A., R.B.,) and Neurosurgery (A.P.K.) Units and Physiology Laboratory (J.C.S.), Université Paris V and Hopital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Pediatric Oncology Units, Institut Curie, Paris, (J.M.Z.) and Institut Gustave Roussy (C.K.), Villejuif, France

Address all correspondence and requests for reprints to: R. Brauner, Hopital Necker-Enfants Malades, 149 rue de Sèvres 75743 Paris Cedex 15, France.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
This study evaluates the capacity of treatment with the combination of growth hormone (GH) and gonadotropin releasing hormone (GnRH) analog to preserve the height potential of 24 patients (15 girls, 9 boys) with GH deficiency and early puberty (onset at 7.8 ± 0.5 SE yr in girls and 9.0 ± 0.7 yr in boys). All but 4 were given cranial irradiation. They (group 1) were compared with 17 patients of normal pubertal age treated with GH for cranial irradiation-induced GH deficiency (group 2) and with 19 girls treated with GnRH analog for idiopathic central precocious puberty (group 3). The adult heights in groups 1, 2 and 3 were -0.5 ± 0.2, -1.3 ± 0.2, and -0.2 ± 0.2 SD, significantly lower (P < 0.01) in group 2. They were lower than the target heights in groups 1 and 2 (P < 0.001), and similar in group 3. They were similar to the predicted heights at the onset of therapy (combined, GH, or GnRH analog therapy), except in group 3 (adult height > predicted height, P < 0.0001) In group 1, as in group 3, the differences between adult and predicted heights (1.1 ± 1.3 and 6.5 ± 1.4 cm respectively) correlated positively with the difference between bone and chronological ages (P < 0.05), negatively with the predicted height (P < 0.002), and positively with the difference between the target and predicted heights (P < 0.001) at the onset of therapy.

In conclusion, treatment with the combination of GH and GnRH analog in patients with GH deficiency and early puberty leads to a normal adult height. This height is similar to the predicted height at the onset of therapy but lower than the target height.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PATIENTS TREATED with cranial irradiation are at risk of GH deficiency and early puberty (1, 2). The mean interval between the thelarche and the menarche in girls is shorter than in normal puberty (3). The early puberty may be followed by gonadotropin deficiency in patients who have received high cranial doses (4). The association of GH deficiency and early puberty raises several problems of diagnosis and therapy. First, it is difficult to recognize GH deficiency because the sex steroid secretion increases the growth rate. Second, their association decreases the growth potential by reducing the duration and amplitude of pubertal growth. And third, puberty is frequently early (onset at 8–10 yr in girls and 9–11 yr in boys) rather than precocious (onset before 8 yr in girls and 9 yr in boys) after cranial irradiation, which makes the indication of GnRH analog therapy questionable in some patients.

It has been shown that the treatment of patients with GH deficiency and early puberty with a combination of GH and GnRH analog increases the height prediction (5). This study is the first to analyze the adult height in this situation.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients

A total of 24 patients (15 girls, 9 boys) were followed for GH deficiency (GH peak after 2 stimulation tests <10 µg/L) and early puberty (onset before 10 yr in girls and 11 yr in boys). All had reached their adult height with a growth during the preceding year of less than 1 cm and a bone age (BA) of over 15 yr in girls and 16 yr in boys. All were treated with a combination of GH and GnRH analog. The initial disease was acute lymphoblastic leukemia (n = 9), optic glioma (n = 7), astrocytoma (n = 3), suprasellar arachnoid cyst (n = 3), pinealoma (n = 1), or truncus cerebrii tumor (n = 1). All but 4 patients (one with astrocytoma and 3 with suprasellar arachnoid cyst) were given cranial irradiation at 4.9 ± 0.5 yr and were prepubertal at irradiation. None of them was given spinal irradiation or therapy for early puberty other than GnRH analog. The hypothalamo-pituitary dose was 18–55 Grays (Gy), with mean doses of 32 ± 4 Gy in girls and 49 ± 2 Gy in boys (P < 0.05). They (group 1) were compared (Table 1Go) to 1) 17 patients of normal pubertal age who had been treated with GH for GH deficiency induced by 24 Gy cranial prophylactic irradiation for leukemia (group 2, ref 6); and 2) 19 girls with idiopathic central precocious puberty and normal GH peak that had been treated with GnRH analog (group 3, ref 7). The group 1 and 2 patients with leukemia were given similar chemotherapy.


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  		Table 1. Patients characteristics

 
Protocol

Informed consent for the evaluations and for therapy was obtained from the children’s parents, and assent was obtained from the children aged over 7 yr. The first evaluation included determination of height, weight, pubertal stage, BA, plasma estradiol in girls, testosterone in boys, free T4 and cortisol at 08:00 h, and GH and gonadotropin (except in 2 girls) stimulation tests performed on 2 different mornings. The interval between them was 0.7 ± 0.2 yr (0–3 yr), depending on the initial presentation. All but one underwent a second GH stimulation test, after an interval of 1.6 ± 0.2 yr (0.1–4 yr) to confirm the GH deficiency before GH therapy.

Of the 24, 15 patients were given GnRH analog alone for 1.9 ± 0.3 yr (1–4 yr) because they had a normal GH peak at the first evaluation (n = 6), or a height above the mean without significant BA advance (n = 9). Three patients were given GH alone for 1.3 ± 0.3 yr (0.9–2 yr) before the occurrence of early puberty, and 6 were given the GnRH analog plus GH simultaneously. Each GnRH analog and GH treatment was given for at least 2 yr. The GnRH analog was Decapeptyl (Ipsen/Biotech, Paris, France) (D-Trp6-GnRH) given at 3.75 mg, im, every 24–26 days. It was stopped at BA greater than 12 yr in girls and 13 yr in boys. The GH treatment was given at 0.4–0.6 U/kg/week as daily sc injection, 6 days a week. It was stopped at a BA greater than 13 yr in girls and 15 yr in boys, taking into account the growth during the preceding year. Ten patients were also given T4 replacement therapy. The patients were seen every 0.5 yr after the start of therapy for clinical evaluation and measurement of height and weight. BA and plasma free T4 were evaluated once a year. Four patients (3 girls, 1 boy) had no restoration of their pubertal activity after the end of GnRH analog therapy. They underwent a second GnRH test and evaluation of the plasma estradiol in girls and testosterone in the boy, 0.8–1.7 yr after the end of GnRH analog therapy. Sex steroid replacement therapy was then initiated.

Methods

Height was measured twice at each visit using a Harpenden stadiometer. The difference between two heights in a given patient was calculated over one year and expressed as the height change. BA was assessed by one of us (R.B., 8). Predicted height (9) was calculated at the onset of therapy (combined, GH, or GnRH analog therapy), and target height from reported midparental heights (10). The hypothalamo-pituitary-gonadal axis was investigated by measuring basal and GnRH (100 µg/m2, maximal dose 150 µg) stimulated plasma LH and FSH peaks. GH secretion was assessed first by the sequential arginine-insulin test and then by the ornithine test. Plasma insulin-like growth factor I (IGF-I) was measured without extraction. Data are expressed as means ± SE, except for height and growth rate, which are expressed as SD for chronological age (11). They were analyzed by the nonparametric Mann-Whitney U test. The height changes were analyzed by a Wilcoxon test. Correlations between variables were analyzed by Spearman’s test.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Group 1

The growth rates during the years preceding and following the onset of therapy were as follows: 7.2 ± 0.6/4.3 ± 0.4 cm (P = 0.001) in the 15 patients given GnRH analog as a first therapy, 7 ± 1.1/7.8 ± 0.2 cm (NS) in the 3 patients given GH as a first therapy, and 5.8 ± 0.8/7.4 ± 0.4 cm (P = 0.04) in the 6 patients given both GH and GnRH analog (see Protocol). The change in the mean height for each sex is shown in Fig. 1Go. The differences between adult and predicted heights (mean 1.1 ± 1.3 cm) correlated positively with the difference between bone and chronological ages (P < 0.05), negatively with the predicted height (P < 0.002), and positively with the difference between the target and predicted heights (P < 0.001) at the onset of therapy (Fig. 2Go).



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  		Figure 1. Mean height evolution in three groups of patients: group 1 (24 cases) was treated with GH and GnRH analog for GH deficiency and early puberty, group 2 (14 boys) was treated with GH for GH deficiency, and group 3 (19 girls) was treated with GnRH analog for idiopathic central precocious puberty. The ages at cranial irradiation, increase of testicular volume in boys, and breast development and first menstruation in girls are indicated by R, P, B and M, respectively.

 


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  		Figure 2. Differences between adult and predicted heights before combined or isolated GH and GnRH analog therapy (height change) in 24 patients treated for GH deficiency and early puberty. These differences were compared to the data before therapy: difference between bone and chronological ages, predicted height, and difference between target and predicted heights.

 
Comparison of groups (Table 2Go and Fig. 3Go)

The BA of the three groups at the onset of therapy were similar, but the differences between bone and chronological ages were not: 0.7 ± 0.3 yr in group 1, -1.4 ± 0.2 yr in group 2, and 3.0 ± 0.3 yr in group 3 (P < 0.0001 in each group compared to the other). The adult heights were significantly lower (P = 0.01) in group 2 than those for groups 1 and 3. They were lower than the target heights in groups 1 and 2 (P < 0.001) and similar in group 3. They were similar to the predicted heights at the onset of therapy, except in group 3 (adult height > predicted height, P < 0.0001).


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  		Table 2. Growth evolution

 


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  		Figure 3. Comparison between three groups of patients (m ± SE): group 1 (24 cases) was treated with GH and GnRH analog for GH deficiency and early puberty, group 2 (17 cases) was treated with GH for GH deficiency, and group 3 (19 cases) was treated with GnRH analog for idiopathic central precocious puberty.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In the present study, the patients treated with the combination of GH and GnRH analog had normal adult heights, similar to their predicted height at the onset of therapy, but significantly lower than their target height. The therapy prevented the height reduction induced by the GH deficiency and early puberty, but as in the group treated with GH alone for GH deficiency, it probably did not result in complete growth recovery. Untreated patients with GH deficiency and early puberty tend to have short adult heights: it was 145 cm in a girl treated with GH alone for 3 yr, 143.5 cm in an untreated girl, and 136.5 cm in a girl given craniospinal irradiation and treated with medroxyprogesterone for 3 yr (1). In 4 out of 7 girls with early puberty following 18 or 24 Gy cranial irradiation, Leiper et al. (12) reported adult height up to the third centile, but their GH state was not assessed. Bourguignon et al. (13) reported the mean adult heights of boys treated with GH for idiopathic GH deficiency. They were lower than in this study, at -2.5 SD in those with spontaneous puberty and -1.8 SD for the boys with testosterone-induced puberty. This may be the result of lower height at the onset of therapy in their study. Conversely, our group treated with GnRH analog alone for idiopathic central precocious puberty showed complete growth recovery. Among the two groups treated with GnRH analog, GH-deficient patients were older at the onset of puberty and of GnRH analog therapy than were GH-sufficient ones. The interval between the first and the second GH stimulation tests showing GH deficiency was 1.6 ± 0.2 yr. The mean growth rate of the 15 patients given GnRH analog as a first therapy decreased from 7.2 to 4.3 cm/yr, while it increased from 5.8 to 7.4 cm/yr in those given both GH and GnRH analog. These data suggest that the adult height would have been increased if patients had been treated with GH without such a delay after the evaluation showing GH deficiency, in spite of the pubertal growth rate.The lower plasma IGF-I values in the GH-deficient than in the GH-sufficient patients, in spite of similar levels of estradiol, provide additional evidence for earlier GH therapy.

Comparison with the girls with idiopathic central precocious puberty showed that the ratio of the LH/FSH peaks and the plasma estradiol levels were similar, suggesting that cranial irradiation had not decreased the activation of the hypothalamo-pituitary-gonadal axis after 4.1 ± 0.6 yr. As a ratio of LH/FSH peaks of above 0.6 in girls predicts an evolutive form of central precocious puberty (14) and is an indication for GnRH analog therapy, the present data provide additional evidence that GnRH analog therapy is indicated in patients with early puberty as a result of cranial irradiation. Four patients later suffered from gonadotropin deficiency (2 cases) or secondary amenorrhea in spite of a normal gonadotropin response to GnRH. The two patients with gonadotropin deficiency had prepubertal values for sex steroids and for the ratio of LH/FSH peaks before GnRH analog therapy, suggesting that they still had a gonadotropin deficiency and that their early puberty would not be evolutive and then would not have been treated. This is also suggested by the finding that the adult height was lower than predicted height by 1.5 SD, in spite of the 2-yr BA advance at the onset of therapy in one of them.

Our current policy for patients given cranial irradiation is to evaluate their GH secretion no later than 2 yr after cancer therapy if they have decreased growth rate before puberty, or routinely at the onset of puberty. GH therapy is given to those with low GH peaks after 2 stimulation tests and decreased growth rate that is unexplained by bone irradiation, or no increase in growth rate despite puberty. Patients with early puberty are evaluated for their BA, gonadotropins response to the GnRH stimulation test, and plasma estradiol in girls, or testosterone in boys. Those with a BA advance, pubertal response, and/or plasma estradiol of more than 73 pmol/L and testosterone of more than 3.5 nmol/L are given GnRH analog. The others are seen 0.5 yr later for reevaluation of their BA, breast development and plasma estradiol in girls, or testosterone in boys. The gonadotropin response to GnRH is reevaluated when these data do not demonstrate pubertal progression.\.


   Acknowledgments
 
We thank M.C. Perret for technical assistance, the nurses of the Pediatric Endocrinology Unit for carrying out the tests, M. Lacroix and C. Castanera for preparing the manuscript, and Dr. O. Parkes for editorial help. Growth hormone was given through France Hypophyse.


   Footnotes
 
1 This work was supported by a grant from the Association pour la Recherche sur le Cancer (ARC, No 6543). It was presented in part at the 35th Meeting of the European Society for Pediatric Endocrinology, Montpellier, France, 1996. Back

Received June 24, 1996.

Revised August 7, 1996.

Revised September 19, 1996.

Accepted September 26, 1996.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Brauner R, Rappaport R. 1985 Precocious puberty secondary to cranial irradiation for tumors distant from the hypothalamo-pituitary area. Horm Res. 22:78–82.[Medline]
  2. Ogilvy-Stuart AL, Clayton PE, Shalet SM. 1994 Cranial irradiation and early puberty. J Clin Endocrinol Metab. 78:1282–1286.[Abstract]
  3. Quigley C, Cowell C, Jimenez M, et al. 1989 Normal or early development of puberty despite gonadal damage in children treated for acute lymphoblastic leukemia. N Engl J Med. 321:143–151.[Abstract]
  4. Rappaport R, Brauner R, Czernichow P, et al. 1982 Effect of hypothalamic and pituitary irradiation on pubertal development in children with cranial tumors. J Clin Endocrinol Metab. 54:1164–1168.[Abstract]
  5. Cara JF, Kreiter ML, Rosenfield RL. 1992 Height prognosis of children with true precocious puberty and growth hormone deficiency: effect of combination therapy with gonadotropin releasing hormone agonist and growth hormone. J Pediatr. 120:709–715.[CrossRef][Medline]
  6. Adan L, Souberbielle JC, Blanche S, Leverger G, Schaison G, Brauner R. 1996 Adult height after cranial irradiation with 24 grays: factors and markers of height loss. Acta Paediatr. 85:1096–1101.[Medline]
  7. Brauner R, Adan L, Malandry F, Zantleifer D. 1994 Adult height in girls with idiopathic true precocious puberty. J Clin Endocrinol Metab. 79:415–420.[Abstract]
  8. Greulich WW, Pyle SI. 1959 Radiographic atlas of skeletal development of the hand and wrist. 2nd ed. Stanford: Stanford University Press.
  9. Bayley N, Pinneau SR. 1952 Tables for predicting adult height from skeletal age: revised for use with Greulich Pyle hand standards. J Pediatr. 50:432–441.
  10. Tanner JM, Goldstein H, Whitehouse RH. 1970 Standards for children’s height at ages 2–9 years following for height of parents. Arch Dis Child. 47:755–762.
  11. Sempe M, Pedron G, Roy-Pernot MP. 1979 Auxologie, méthode et séquences. Paris: Theraplix.
  12. Leiper AD, Stanhope R, Kitching P, Chessels JM. 1987 Precocious and premature puberty associated with treatment of acute lymphoblastic leukaemia. Arch Dis Child.62:1107–1112.
  13. Bourguignon JP, Vandeweghe M, Vanderschueren-Lodeweyckx M, et al. 1986 Pubertal growth and final height in hypopituitary boys: a minor role of bone age at onset of puberty. J Clin Endocrinol Metab.63:376–382.
  14. Pérignon F, Brauner R, Argyropoulou M, Brunelle F. 1992 Precocious puberty in girls: pituitary height as an index of hypothalamo-pituitary activation. J Clin Endocrinol Metab.75:1170–1172.



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