© 1990 S. Karger AG. Basel 0301-0163/90/3310-0102S2.75/0

Horm Res 1990;33(suppl 4): 102-105

Relationships between Puberty and Growth at Adolescence in Growth-Hormone-Deficient Males: Effect of Growth Hormone and of Associated Gonadal Suppression Therapy Toshiaki Tanakaa , Atsuko Yoshizawaa , Ayako Tanaeb, ltsuro Hibi*~c, Kazuo Shizumec a Endocrine Research Laboratory, National Children’s Medical Research Center; bDivision of Endocrinology and Metabolism, National Children’s Hospital; cCommittee for the Treatment of Growth-Hormone-Deficient Children, Foundation for Growth Science, Tokyo, Japan

Key Words. Growth hormone deficiency • Final height • Gonadal suppression Abstract. 125 boys with idiopathic GH deficiency who received GH treatment were followed until they reached their final height. In 85 patients who had spontaneous puberty (group I), the mean final height was 151.5 ± 6.6 cm. In 23 patients with combined GH and gonadotropin deficiency (group II) whose pubertal development was induced artificially at age 19.4 ± 2.1 years, the mean final height was 163.7 ± 3.9 cm (p < 0.01 vs. group I). Final height was strongly related to height at the onset of pubertal development in combined groups I and II when the time of gonadal replacement treatment was taken as the onset of pubertal development in group II. In 17 patients (group III) who developed spontaneous puberty, gonadal suppression treatment was started at their early stage of puberty and was continued for a mean duration of 4.3 ± 1.1 years. The mean final height in group III was 157.9 ± 3.0 cm (p < 0.01 vs. group I, group II). Longitudinal growth pattern analysis demonstrated that this beneficial effect on final height by gonadal suppression treatment was attributed to the elongation of pubertal growth spurt and pubertal height gain.

Subjects and Methods 125 boys with idiopathic GHD, who were the same subjects pre­ viously described [3, 4], were divided into three groups. Group I consisted of 85 patients who had spontaneous puberty. The data on the patients of this group were collected throughout Japan in a nationwide survey by the Foundation of Growth Science in 1984. Group II consisted of 23 patients who had GND in addition to GHD and were treated with sex hormones or gonadotropins, ini­ tiated when their growth velocity decreased below 2 cm/year during GH therapy. Group III consisted of 17 patients who had early signs of spontaneous puberty and were treated with a gonadal suppressive agent. Cyproterone acetate in a mean dosage of 150.4 mg/m2 and/or medroxyprogesterone acetate in a mean dosage of 22.0 mg/m2 was given to the patients in group III. The children in groups II and III were followed at the national Children’s Hospital. All patients were treated with pituitary-derived human GH twice or three times in a dosage ranging from 0.15 to 0.53 IU/kg/week i.m. The age at which testis volume increased > 6 ml was judged to be the onset of pubertal development; the time at which growth

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It is well known that in children with eunuchoidism the final height is taller, and that children with precocious puberty are shorter. Therefore, it can be speculated that the development of puberty can influence the final height. It seems that the situation is the same in children with GH deficiency (GHD), since Burns et al. [1] and Bourguignon et al. [2] reported that the average final height of children with isolated GHD was significantly shorter compared to that of children with GHD and gonadotropin deficiency (GND). We also have confirmed such an influence of preserved gonadal function on the final height in GH-deficient children treated with GH [3]. In this study, we further analyzed the influence of puberty and elucidated the importance of the height at onset of puberty on the final height. We also confirmed the effect of gonadal suppression treatment [4] on the final height in GH-deficient children who underwent spontaneous puberty.

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Gonadal Suppression Treatment in GH Deficiency

Table 1. Different variables related to GH therapy, puberty and final height Group I

Group II

Group III

Significance1

Start of GH therapy Chronological age, years Height, cm Height SD score

12.3 ±2.3 121.3+11.3 —4.12 ± 1.30

12.3 ±3.4 121.0 ± 13.9 -4.02+ 1.12

10.2 ± 2.5 112.9 ± 11.6 -3.95 ±0.54

p < 0.01 p < 0.05 NS

Onset of pubertal development2 Chronological age, years Height, cm Height SD score

14.4 ± 1.7 136.5 + 8.7 —3.58 ± 1.58

19.4 ±2.1 156.5 ±8.1 -2 .3 4 ± 1.22

12.9 ± 1.3 129.8 ±5.4 —3.10 ± 1.12

p < 0.01 p < 0.01 p < 0.01

15.2 + 6.9

7.2 ±6.0

28.1 ±5.8

p < 0.01

Duration from the onset of pubertal development until final height, years

3.5± 1.4

3.2 ±1.9

5.6±0.7

p < 0.01

Duration of GH therapy, years

5.6± 1.8

7.6 ± 3.1

8.1 ±2.2

p < 0.01

0.70± 1.29

2.90 ±0.88

1.74 ± 0.67

p < 0.01

151.5 ± 6.6 3.42+1.25

163.7 ± 3.9 1.12 + 0.74

157.9 ± 3.0 -2.21 ±0.56

p < 0.01 p < 0.01

Height gain from the onset of pubertal development, cm

Increase in SD score from the start of GH therapy until final height age Final height, cm Final height SD score

ANOVA. At the time of spontaneous pubertal development in groups I and III or at the time of induction of puberty in group II.

velocity was lowest before the pubertal growth spurt (PGS) was judged to be the onset of PGS. The onset of PGS was estimated from the individual growth velocity curve derived from the growth curve drawn by the eye-fit method.

Results Different variables related to GH therapy, pubertal development and final height in the three groups are summarized in table 1 [3, 4], There was no significant difference between groups I and II in chronological age, height and SD score of height at the start of GH therapy. The patients in group III were younger and shorter at the start of therapy and the onset of pubertal development than those in groups I and II, but there were no signifi­ cant differences in SD score of height for these parame­ ters. Figure 1 shows a significant positive correlation between age at the start of GH therapy and onset of pubertal development in combined groups I and III. GH therapy was significantly longer in group II than in group I. The final height or its SD score differed sig­ nificantly between the two groups. In group I, the mean SD score of final height was -3.4 SD, which was only 0.7 SD higher than that at the start of GH therapy. In group I, testicular enlargement was noticed at a chrono­

logical age of 14.4 years on the average, when the mean height was 136.5 cm. In group II, sex hormone replace­ ment therapy was initiated at a mean age of 19.4 years, when the mean height was 156.5 cm. When the age at the induction of sex hormone replacement therapy in group II was taken as the onset of puberty, the difference in height at the onset of pubertal development was greater than the difference in pubertal height gain between group I and II. Therefore, the final height was taller in group II. The mean duration of pubertal development in group III was longer and the height gain from the onset of pubertal development was taller than in group I, which was attributed to the gonadal suppression treatment. The final height in group III was significantly taller, by 6.4 cm, than that in group I. The final height in group II was 5.8 cm taller than that in group III. Correlations between final height and different vari­ ables related to the start of GH therapy and the onset of pubertal development in combined groups I and II are summarized in table 2, taking the time of induction of sex hormone replacement therapy as the onset of puber­ tal development. Height at the onset of puberty was most positively correlated with final height (fig. 2). Multiple regression analysis by stepwise selection showed height

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' 2

Tanaka/Yoshizawa/Tanae/Hibi/Shizume

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1

Table 2. Correlation coefficient (r) between final height and other variables Group I + Group II Start of GH therapy Chronological age, years Height, cm Height SD score

-0.052 0.215* 0.404****

Onset of spontaneous puberty (I) or time of induction of puberty (II) Chronological age, years Height, cm Height SD score Duration of GH therapy, years

*p < 0.05; **p < 0.01; **** p < 0.0001.

0.486**** 0.780**** 0.606**** 0.284**

at the onset of pubertal development, SD score of height at the start of GH therapy and duration of GH therapy as significant variables. Longitudinal growth records were obtained for 5 boys in group I, 17 boys in group II and 23 boys in group III. Their growth patterns were analyzed and compared with that of normal boys. Figure 3 shows the mean growth curves and the mean growth velocity curves of the three groups and normal boys. There was no difference in age at the onset of PGS between groups I and III, when the mean height of both groups was approximately 12 cm shorter than that of normal boys. The mean duration of pubertal growth from the onset of PGS was 7.3 ± 1.4 years in group III, which was significantly longer than that in group I (6.0 ± 0.6 years). Pubertal height gains from the onset of PGS in groups I and III were 28.1 ± 6.6 cm and 33.7 ± 7.7 cm. respectively, i.e. not signifi­ cantly different from that of normal boys (30.8 ± 4.5 cm).

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Fig. 1. Correlation between age at the start of GH therapy and age at the onset of puberty in combined groups I and III. Fig. 2. Correlation between height at the onset of puberty and final height in combined groups I and II. Fig. 3. Longitudinal average growth of groups I, II and III, and of normal boys.

Gonadal Suppression Treatment in GH Deficiency

We have demonstrated that the final height in GHdeficient boys with spontaneous puberty was signifi­ cantly shorter than that of GH-deficient boys without spontaneous puberty (additional GND) [3]. The present study shows that the final height in GH-deficient boys is strongly related to the height at the onset of pubertal development, when the time of gonadal replacement treatment is taken as the onset of pubertal development in GH-deficient boys with GND (group II). The SD score of height at the start of GH therapy and the duration of GH therapy were the other significant variables related to final height. The longer the duration of GH therapy, and the higher the SD score of height at the start of GH therapy, the taller the patients were when they reached their final height. The unsatisfactory final height in group I was attrib­ uted to the short stature at the onset of PGS, since the mean pubertal height gain from the onset of PGS in group I was not significantly different from that of nor­ mal boys. The situation that shorter height at the onset of pubertal development is related to shorter final height is similar to precocious puberty. Therefore, the effect of gonadal suppression therapy in combination with GH therapy was evaluated in group III. The final height in group III was significantly taller than that in group I. The better prognosis in group III was attributed to the elon­ gation of PGS and pubertal height gain by gonadal sup­ pression treatment. The earlier start of GH therapy was not related to better prognosis, since the age at the start of GH therapy was not related to final height at all. The significant pos­ itive correlation between the age at the start of GH ther­ apy and the onset of pubertal development in combined groups I and III demonstrates that the earlier the GH

therapy was started, the earlier puberty developed. Ear­ lier pubertal development was closely associated with shorter height at the onset of pubertal development, which elucidated that the earlier start of GH therapy was not related to taller final height. Since the youngest chro­ nological age at the start of GH therapy was 6.0 years, it remains to be demonstrated whether it is possible to obtain a better prognosis by starting GH therapy in early infancy.

References 1 Bums EC, Tanner JM, Preece MA, Cameron N: Final height and pubertal development in 55 children with idiopathic growth hor­ mone deficiency, treated for between 2 and 15 years with human growth hormone. Eur J Pediatr 1981;134:155-164. 2 Bourguignon JP, Vandeweghe M, Vanderschueren-Lodeweyck M. Malvaux P. Wolter R. Du Caju M, Emould C: Pubertal growth and final height in hypopituitary boys: A minor role of bone age at onset of puberty. J Clin Endocrinol Metab 1986;63: 376-382. 3 Hibi I, Tanaka T, Committee for the Treatment of GrowthHormone-Deficient Children of the Growth Science Founda­ tion: Final height of patienls with idiopathic growth hormone deficiency after long-term growth hormone treatment. Acta En­ docrinol (Copenh) 1989;120:409-415. 4 Hibi I, Tanaka T, Tanae A, Kagawa J, Hashimoto N, Yoshizawa A, Shizume K: The influence of gonadal function and the effect of gonadal suppression treatment on final height in growth hor­ mone-treated GH-deficient children. J Clin Endocrinol Metab 1989;69:221-226.

Toshiaki Tanaka, MD Endocrine Research Laboratory National Children’s Medical Research Center 3-35-31 Taishidoh, Setagaya-ku Tokyo 154 (Japan)

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Discussion

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Relationships between puberty and growth at adolescence in growth-hormone-deficient males: effect of growth hormone and of associated gonadal suppression therapy.

125 boys with idiopathic GH deficiency who received GH treatment were followed until they reached their final height. In 85 patients who had spontaneo...
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