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Original Studies |
Department of Pediatrics, Division of Endocrinology (T.C.J.S., S.M.P.F.d.M.K-S., S.L.S.D.) Sophia Children’s Hospital, 3015 GJ Rotterdam; Department of Epidemiology and Biostatistics (T.S.), Erasmus University Rotterdam, 3015 GJ Rotterdam; Wilhelmina Children’s Hospital (M.J.), 3584 EA Utrecht; Sint Radboud University Hospital (B.J.O.), 6525 GA Nijmegen; Free University Hospital (J.J.G.H-N.), 1081 HV Amsterdam; Emma Children’s Hospital, Academic Medical Center (T.V.), 7105 AZ Amsterdam; Medical University Center (G.G.M.), 2333 AA Leiden; Beatrix Children’s Hospital (C.W.R.), 9713 EZ Groningen; Juliana Children’s Hospital (H.M.R.), 2566 ER The Hague; Academic Hospital (W.J.G.), 6202 AZ Maastricht; Rijnland Hospital (J.J.G.), 2353 GA Leiderdorp; Canisius-Wilhelmina Hospital (C.R-W.), 6532 SZ Nijmegen, the Netherlands
Address correspondence and requests for reprints to: Theo Sas, M.D., Division of Endocrinology, Sophia Children’s Hospital, Dr. Molewaterplein 60, 3015 GJ Rotterdam, the Netherlands. E-mail: sas{at}alkg.azr.nl
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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0.045 mg/kg·day); group B, first yr 4,
thereafter 6 IU/m2·day (0.0675 mg/kg/day); group C,
first yr 4, second yr 6, thereafter 8 IU/m2·day (0.090
mg/kg·day). In the first 4 yr of GH treatment, no estrogens for
pubertal induction were given to the girls. Thereafter, girls started
with 17ß-estradiol (5 µg/kg bw·day, orally) when they had reached
the age of 12 yr. Subjects were followed up until attainment of adult
height or until cessation of treatment because of satisfaction with the
height achieved. Seven-year data of all girls were evaluated to compare the growth-promoting effects of three GH dosages during childhood. After 7 yr, 85% of the girls had reached a height within the normal range for healthy Dutch girls. The 7-yr increment in height SD-score was significantly higher in groups B and C than in group A. In addition, we evaluated the data of 32 of the 68 girls who had completed the trial after a mean duration of treatment of 7.3 yr (range, 5.0 - 8.75). Mean (SD) height was 158.8 cm (7.1), 161.0 cm (6.8), and 162.3 cm (6.1) in groups A, B, and C, respectively. The mean (SD) difference between predicted adult height before treatment and achieved height was 12.5 cm (2.1), 14.5 cm (4.0), and 16.0 cm (4.1) for groups A, B, and C, respectively, being significantly different between group A and group C. GH treatment was well tolerated in all three GH dosage groups.
In conclusion, GH treatment starting in relatively young girls with TS results in normalization of height during childhood, as well as of adult height, in most of the individuals. With this GH and estrogen treatment regimen, most girls with TS can grow and develop much more in conformity with their healthy peers.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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To optimize GH and estrogen treatment, in 1989 we started a randomized dose-response study in 68 girls with TS. Four-year results were described earlier (5). We now report 7-yr results to compare the long-term growth-promoting effect of GH in childhood between the three dosage groups. In addition, growth data of the girls who had completed the trial before the end of August 1998 have been evaluated.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Sixty-eight previously untreated girls with TS were enrolled in a multicenter GH dose-response study. The diagnosis was confirmed by lymphocyte chromosomal analysis. Three girls had a prenatal diagnosis. Inclusion criteria were a chronological age (CA) between 2 and 11 yr, height below the 50th percentile for healthy Dutch girls (13), and normal thyroid function. Exclusion criteria were: associated endocrine and/or metabolic disorders; growth failure caused by other disorders or emotional deprivation; hydrocephalus; previous use of drugs, which could interfere with GH treatment; and spontaneous puberty (14). Written informed consent was obtained from the parents or custodians, whereas a written assent was obtained in the girls more than 12 yr of age. The study protocol was approved by the ethics committee of each participating center.
Study design
After stratification for CA and height
SD-score for CA girls were randomly assigned to
one of three GH dosage groups: A, (n = 23) receiving 4
IU/m2 body surface·day (equivalent to 0.045
mg/kg); B, (n = 23) receiving 4 IU/m2·day
in the first yr, followed by 6 IU/m2·day
(0.0675 mg/kg·day); or C (n = 22) receiving 4
IU/m2·day in the first yr, 6
IU/m2·day in the second yr, and thereafter 8
IU/m2·day (0.090 mg/kg·day).
Biosynthetic human GH (Norditropin, Novo Nordisk A/S,
Bagsvaerd, Denmark) was given sc once daily at bedtime using a pen
injection system. Every 3 months, the total GH dose was adjusted to the
calculated body surface. According to the study protocol, the GH
treatment was stopped when subjects had grown less than 1 cm over 6
months. However, when girls were satisfied with their height achieved,
they elected to stop GH treatment before study criteria for the
termination of treatment had been reached. In the first 4 yr of GH
treatment, no estrogens for pubertal induction were given to the girls.
After 4 yr of GH treatment, estrogen therapy was started in the girls
who were older than 12.0 yr of age; the younger girls started estrogen
therapy at a yearly visit after reaching the age of 12 yr.
17ß-Estradiol, 5 µg/kg body weight·day, orally, were given in the
first 2 yr, 7.5 µg/kg·day in the third yr, and 10 µg/kg·day
thereafter. Cyclic progestagen therapy (Duphaston 5 mg/day in the first
14 days of the month) was added after 2 yr of estrogen therapy. If
puberty had developed spontaneously (Tanner breast stage 
2) during
the study period and before start of estrogens, no estrogens were
given.
Height was measured at baseline and subsequently every 3 months using a
Harpenden stadiometer. Four measurements per visit were made by two
trained observers (A.v.T. and, subsequently T. Sas), and the mean was
used for the analysis. For the adult height evaluation, adult height
was defined as the most recent available height after discontinuation
of GH treatment. Height was expressed as SD-score
using the references for healthy Dutch girls (13) or the references for
North European untreated girls with TS (2). At adult height, the height
SD-score for TS was calculated using the
reference data of 21 yr of age. Target height was adapted from Dutch
reference data with the addition of 3 cm for secular trend: TH =
1/2 x (Hmother +
Hfather - 12 cm) + 3 cm (13). Target range was
defined as the TH ± 8 cm (15). During GH treatment pubertal
stages were assessed according to Tanner (14). Bone age was determined
by the same two observers according to the Tanner and Whitehouse
radius, ulna, short-bones score (16). Bone maturation was expressed as
the ratio of the change in BA to the change in CA (
BA/CA).
Predicted adult height was calculated with the modified projected adult
height method, using the equation of Lyon, adapted to North European
untreated girls with TS (2, 17, 18). To assess the gain in adult
height, the attained adult height was compared with the modified
projected adult height before treatment. Blood samples were taken at
the start of the study and subsequently every yr for determination of
the glycosylated hemoglobin.
Statistical analysis
Results were expressed as mean (SD), unless indicated otherwise. Differences between the dosage groups were first tested by a linear trend test. In case of a significant result, this was followed by comparisons with Student’s t tests. Differences between points in time were tested by paired Student’s t tests.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The trial started in November 1989. During the first 3 yr, three
girls, one in each dosage group, dropped out of the study because of
noncompliance and were lost to follow-up. In October 1997, the
remaining 65 girls had been followed for 7 yr. Table 1
lists the baseline clinical data of
these girls. The three dosage groups had similar initial
characteristics.
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shows the individual heights of
the 65 girls at the start of GH treatment, as well as after 7 yr.
Twelve girls had completed the trial during the 7-yr study period.
After 7 yr of GH treatment, 55 of the 65 girls (85%) had a height
within the normal range for healthy Dutch girls, whereas only 10 girls
(15%) had a height just below the 3rd percentile. Fig. 2 shows the height
SD-score of the 65 girls using references of
healthy Dutch girls (bottom) and the height
SD-score using Turner references (top)
during the 7-yr study period. At baseline, the girls in all three
groups have a mean height that is normal for untreated North European
girls with TS. After 7 yr of GH treatment, the Turner height
SD-score in all three groups has increased
significantly (P < 0.001). The change in
SD-score was significantly higher in groups B and
C compared with group A [95% confidence interval (CI): 0.08, 0.95;
P = 0.02 and 95% CI: 0.38, 1.27; P =
0.001, respectively]. However, the difference in
SD-score between groups B and C was not
statistically significant (95% CI: -0.19, 0.81, P =
0.22). The height after 7 yr was 16.5 cm (3.5) in group A, 19.6 cm
(4.5) in group B, and 21.2 cm (4.3) in group C, greater than the
expected height assuming that these girls would follow their height
percentile when they were not treated with GH. Compared with healthy
Dutch girls, the mean baseline height of the girls was far below normal
(Fig. 2, bottom). After 7 yr, the mean height
SD-score in all three groups had increased to
values within the normal range for healthy girls.
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bone age
(yr)/CA (yr) over 7 yr of GH treatment was 1.17 (0.14), 1.24
(0.16), and 1.20 (0.14) in groups A, B, and C, respectively, being
significantly higher than 1 (P < 0.005 for all three
GH dosage groups). These data indicate an acceleration of bone
maturation compared with healthy children. However, no significant
differences in bone maturation were found between the three GH dosage
groups. After 7 yr of GH treatment, 35 girls had started estrogen therapy at a mean (SD) CA of 12.9 yr (0.8) and a bone age of 13.2 yr (0.6). Twelve of the 35 girls started estrogen therapy between the CA of 13 and 15 yr because in the first 4-yr study period no estrogens were given, even if these girls were older than 12 yr of age. The other 23 of the 35 girls started estrogen therapy after reaching the age of 12 yr. The distribution of the 35 girls over the Tanner breast stages was: 11 girls were M2, 14 girls were M3, 6 girls were M4, and 4 girls were M5 after a mean (SD) duration of estrogen therapy of 1.8 yr (0.8). Five girls did not receive estrogens because of starting spontaneous puberty during GH treatment (at the end of the 7-yr study period, one girl had Tanner breast stage M2, two girls had M3, one girl had M4, and one girl had M5).
Adult height results
At the end of August 1998, 32 of the 65 girls (groups A, B, and C,
n = 10, 10, 12, respectively) had completed the study after a mean
duration of treatment of 7.3 yr (1.1) (range, 5.0 - 8.75). Twenty
girls had discontinued GH treatment because of a height velocity less
than 1 cm over 6 months, whereas 12 girls stopped GH treatment because
they were satisfied with their attained height. Table 2 lists the clinical data of these 32
patients. Except for age, the baseline clinical data of these 32 girls
were comparable with the baseline data of the 65 girls. Mean height was
158.8 cm (SD 7.1; range, 148.3–172.4 cm) in
group A, 161.0 cm (SD 6.8; range, 152.8–176.2
cm) in group B, and 162.3 cm (SD 6.1; range,
154.3–171.2 cm) in group C, respectively. Except one girl, all girls
(31 of 32) had a height of more than 150 cm. More than half the girls
(17 of 32) had a height above 160 cm, and five of them exceeded 170 cm.
The mean difference between the target height and the attained height
was 10.9 cm (5.1) for group A, 9.5 cm (4.1) for group B, and 6.7 cm
(4.6) for group C. The target range was reached in 4 of 10 girls in
group A, 4 of 10 girls in group B, and 9 of 12 girls in group C. Fig. 3 shows the attained height of each
subject relative to each subject’s modified projected adult height.
The mean increment in height was 12.5 cm (SD 2.1;
range, 7.8–15.7 cm) for group A, 14.5 cm (SD
4.0; range, 8.1–20.3 cm) for group B, and 16.0 cm
(SD 4.1; range, 10.2–24.8 cm) for group C,
respectively, being significantly different from baseline
(P < 0.001). The linear trend test showed a
significant positive trend toward a higher gain in height (equal
attained height minus baseline modified projected adult height) in the
dosage groups receiving a higher GH dose (P = 0.027).
The gain in height was significantly higher in group C compared with
group A (P = 0.024), but without significant
differences between groups A and B and groups B and C,
respectively.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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0.045 mg/kg·day), results in a
normalization of height during childhood and a normalization of adult
height in most of the girls. The ideal study design to assess the
growth-promoting effect of GH is a randomized controlled trial with an
untreated study group until adult height. Because at the start of the
present study GH treatment in girls with TS was an accepted indication
in the Netherlands, such a trial was not possible. Therefore, a
randomized dose-response design was chosen to assess the effect of GH
treatment on growth. To determine the effect of GH on adult height, the
attained adult height was compared with the individually predicted
adult height using the modified projected adult height method based on
our own references for untreated Dutch girls with TS (2, 18).
However, in such a growth analysis, secular trend and errors in adult
height prediction have to be taken into account. Remarkably, the
growth-promoting effect of GH found in the present study exceeds the
effects of secular trend and prediction errors. After 7 yr of GH
treatment, most girls had a height within the normal range for healthy
Dutch girls. In addition, in the 32 girls who had reached adult height,
the mean height in the three dosage groups was approximately 160 cm.
Baseline predicted adult height was exceeded in all subjects, and the
mean gain in adult height was well above 10 cm, even in the group
receiving the standard GH dose of 4 IU/m2·day.
Moreover, in more than half of the 32 girls, the attained height was
within the target range. As in the study of Rosenfeld et al. (9), some girls discontinued the GH treatment earlier because they were satisfied with their attained height. Although the maximal growth-promoting effect could not be obtained in these girls, such a precocious termination of GH treatment is the consequence of the good growth response of the treatment.
The results of the present study contrast with reports stating that GH treatment in girls with TS results only in modest increments or have no positive effect at all (6, 19, 20). In these studies, the age of start of GH treatment was considerably older than in our study. In the study of Rosenfeld et al. (9), however, girls were started at a younger age (9.1 yr) and showed a mean gain in adult height (8.4 cm) being more comparable with our results. The girls who have reached adult height in our study had a mean age at baseline of 8.2 yr, being even younger than in the study of Rosenfeld et al (9). Therefore, in our opinion, the most important reason of our better results is the fact that GH treatment was started at a younger age compared to earlier studies. Because the girls of our study who are still receiving GH are even younger than the girls who have already attained their adult height, we expect at least a similar gain in adult height in these younger girls. To start GH treatment at an appropriate age to achieve a normal adult height, early diagnosis of TS is very important. Each physician should consider the diagnosis in every short girl even when Turner stigmata are absent.
In our view, it is very important for the psychosocial well-being of the girls to induce the pubertal development in conformity with their healthy peers. Therefore, in the present study, estrogen therapy was started at a pubertal age. However, when estrogen therapy is started before the end of the growth phase one runs the risk of earlier epiphysial closure, and consequently a lower gain in adult height. From the results of the present study we can state that low-dose estrogens at a pubertal age does not interfere with the capability of GH treatment to normalize adult height in most of the girls with TS. Thus, a major outcome of our study is that with these GH and estrogen treatment regimens, most girls with TS can grow and develop much more in conformity with their healthy peers.
Seven-year data demonstrated a higher increment in height in the GH dosage groups receiving 6 or 8 IU/m2·day compared with 4 IU/m2·day. In the 32 girls who had attained their adult stature, the gain in adult height over the baseline predicted adult height was higher with a GH dose of 8 compared with 4 IU/m2·day (16.0 vs. 12.5 cm). However, this difference in gain in adult height is quite small in proportion to the difference in the GH dose between these two groups. In contrast, Carel et al. (21) found an increment in adult height that was twice as high in a study group who received an increasing GH dose (dependent on the height velocity, up to 9 IU/m2·day) compared to a fixed GH dose (approximately 3.9 IU/m2·day) group (10.6 vs. 5.2 cm). However, these increments in adult height in both study groups were even lower compared to the results of our dosage group receiving 4 IU/m2·day, probably due to the higher baseline age of the girls in that study compared to our study.
In conformity with the study of Carel et al. (21) in which even higher GH dosages were used than in our study, tolerance to all three GH regimens was good. Our 4-yr results of the effects of GH treatment on lipid metabolism showed no unwanted side effects (22). As described in other studies, GH treatment had no adverse effect on glucose metabolism, but the insulin levels had increased significantly after 4 yr of GH treatment compared to baseline levels (22, 23, 24). In the present study, we showed that during 7 yr of treatment glycosylated hemoglobin levels stayed within the normal range; an extensive evaluation of the effects of long-term GH treatment on carbohydrate metabolism is described elsewhere (24A ). In a previous paper, we showed that 7 yr of GH treatment does not have adverse effects on left ventricular heart dimensions or blood pressure (25).
If higher GH dosages have proven to be safe on the very long-term and result in a clinically significant higher increment in adult height compared to lower GH dosages, cost-benefit evaluations have to be performed. Furthermore, psychological studies are required to evaluate whether the (early) normalization of height is accompanied by an improvement of the psychosocial functioning in childhood as well as in adulthood.
In conclusion, GH treatment starting in relatively young girls with TS
results in normalization of height during childhood and normalization
of adult height in most of the girls, even using the "standard" GH
dose of 4 IU/m2·day (0.045 mg/kg·day), and
without unwanted side effects. Higher GH doses may be more effective,
but the efficacy on adult height and safety in the very long-term have
still to be proven. Induction of puberty with low-dose estrogens can be
started at normal pubertal age without interference with the capability
of GH treatment to normalize adult height in most of the girls with
TS.
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Acknowledgments |
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Footnotes |
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Received August 25, 1999.
Accepted October 5, 1999.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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) and after 7 yr of GH treatment (•) in groups A, B, and C,
respectively. Twelve girls had completed the trial during the 7-yr
study period (
). Reference curves for healthy Dutch girls (3rd,
10th, 50th, 90th, and 97th percentiles) and for untreated girls with TS
(North European references; 3rd, 50th, and 97th percentiles) are given.
