European Journal of Endocrinology (1999) 141 218–224 ISSN 0804-4643

CLINICAL STUDY

Final height in young women with Turner syndrome after GH

therapy: an open controlled study
Ze’ev Hochberg and Zvi Zadik1
Department of Pediatrics, Rambam Medical Center, Haifa, Israel and 1Pediatric Endocrine Unit, Kaplan Hospital, Rehovot, Israel
(Correspondence should be addressed to Z Hochberg, Faculty of Medicine, POB 9697, Haifa 31096, Israel)

Abstract
GH therapy has been applied to patients with Turner syndrome for over a decade, but small sample
size, delayed initiation of therapy into adolescent age and comparison with historical control subjects
limit the usefulness of these studies for appraisal of the effect of GH on final adult height. We report 49
young women with Turner syndrome who completed a clinical trial in an open, non-randomized, age-
matched controlled study of GH, given as daily s.c. injections at a weekly dose of 8.2 mg/m2 for 1.9–7.5
years. Final height was defined as the measurement taken 2 years or more after height velocity
declined below 2 cm/year and after a bone age of 15 ‘years’. The gain in height was evaluated in three
ways. The mean final height gain, compared with the control group, was 4.4 cm. When corrected for
the projected height at inception of therapy, the mean gained height was 5.3 cm above the control
group. Shorter girls showed better response to GH then did taller girls. After correcting for parental
height, the mean gain was 4.7 cm. The adult height of the GH-treated Turner women was significantly
correlated with the target height, whereas no such correlation was obtained for control untreated
women. Furthermore, no correlation was observed between height gain and the age or duration of GH
therapy, or the age of inception of estrogen replacement therapy. It is concluded that GH therapy
augments final height of girls with Turner syndrome by a mean 4.4–5.3 cm, depending on the method
of evaluation, and that shorter girls may be preferred candidates for such therapy. GH therapy can be
initiated after age 10 years and there is no reason to delay estrogen therapy beyond the age of 12.
Indirect evidence suggests that high-dose GH therapy may surmount a pathophysiological resistance
in the GH–IGF-I axis.

European Journal of Endocrinology 141 218–224

Introduction GH therapy, significant growth acceleration, already

observed after short-term treatment, created a bias in
Early reports of growth hormone (GH) therapy in girls favor of therapy and prevented the design of controlled
with Turner syndrome, using doses that are used in the studies (7, 9). In the leading study of Rosenfeld et al. (7),
treatment of children with GH deficiency, revealed poor the randomized control group was maintained without
growth acceleration (1, 2). After high-dose GH therapy treatment only for the initial 12–24 months, after
was instituted, therapy was estimated to be effective, as which GH therapy was initiated. As a result their final
inferred from short-term growth acceleration and final heights are compared with historical control subjects
height projections. Results of long-term growth and (7). Only later were randomized clinical trials initiated
final height after GH therapy in girls with Turner in the US and Canada, but these results are still pending.
syndrome are now available from several studies. These We report a controlled trial of GH therapy in 49
reports are mostly based on small sample sizes, variable patients with Turner syndrome. In the design of the
ages of GH initiation and historical controls, and thus, present study, a placebo control group was deemed
as might be expected, vary considerably from study to unnecessary, since placebo treatment was previously
study. Whereas some reports show only a small gain shown to have no effect on growth (1). An age-
in height (3, 4), others claim a significant improve- matched open untreated control group was followed
ment in adult height (5–7). It is quite likely that other for growth. In the present study GH therapy exerted
factors also account for these variations, including greater effects on the shorter patients, but overall,
ethnic and genetic differences (8) and differences in the there was a great disparity in final height and it
age of initiation of estrogen replacement therapy. Ever was poorly correlated with therapeutic modality and
since the availability of the currently used recombinant estrogen replacement.

q 1999 Society of the European Journal of Endocrinology Online version via http://www.eje.org
EUROPEAN JOURNAL OF ENDOCRINOLOGY (1999) 141 GH therapy in Turner syndrome 219

Patients and methods therapy, and continued for 5.1 6 1.9 years (range 1.9–
7.5 years) until commencement of a bone age of 14
The subjects of the present report are 49 young women ‘years’. Ethinyl estradiol replacement was added 2 years
with Turner syndrome who completed the clinical trial, or more after GH initiation; the actual age was decided
out of 50 who started it in two centers, each center individually by the patient and parents, but it was
treating half of its patients. This number of patients started no earlier then at 12 years old. The initial dose of
was calculated to have the statistical power for signifi- 50 ng/kg was increased 12 months later to 100 ng/kg
cant results. The karyotype distribution was: 25 women and then again to 200 ng/kg after a further 12 months.
with 45,XO, 15 with 45,XO/46,XisoXq, 4 with 45,XO/ Final height was defined as a measurement taken 2
46,XX and 5 with 45,XO/46,XY. The short-term growth years or more after height velocity declined below 2 cm/
response to GH therapy was previously reported for the year and after a bone age of 15 ‘years’ was repeated
first ten patients enrolled (10). The study protocol was (Greulich and Pyle method).
approved by the Helsinki Committees of the Rambam Heights are expressed as standard deviation scores
Medical Center, the Kaplan Hospital and the Israel (SDS) of the general population, calculated from the
Ministry of Health. This clinical trial was supported by a Tanner growth charts (12) and from the Ranke’s
pharmaceutical company only in as much as GH was Turner growth charts (11). The latter were also used
donated for the initial 1 or 2 years of therapy. for adult height projection. Results are expressed as
All the patients with Turner syndrome of these two mean 6 S.D. Student’s t-tests compared means of the
clinics, with an age limit of 7–14 years and a bone age control against treatment population, after both were
<12 ‘years’ were divided openly into a GH treatment shown to be normally distributed.
group and a control age-matched group. After a
thorough explanation of the experimental nature of
this treatment, the parents’ approval or refusal to Results
participate in a new treatment trial was the only The gain in height attributed to therapy was evaluated
criterion for selection. Though open and unrandomized, in three ways: final height; gain over projection; and
the clinical characteristics of the two groups were height deficit.
similar and statistically not different from each other, as For final height, whereas the mean initial height
shown in Table 1. and growth velocity at age 10.7 years was similar for
The treatment protocol included the following para- the GH and the control groups, being 120.6 and
meters. Recombinant GH (BioTropin, BioTechnology 121.7 cm respectively, final height was 147.3 6 4.9
General Ltd, Rehovot, Israel, and Humatrope, Eli Lilly, and 142.9 6 5.1 cm respectively. The mean gain in
MN, USA) was given as daily s.c. injections at a weekly height of the GH-treated group was 4.4 cm (P < 0.005)
dose of 8.2 mg/m2. Therapy was initiated at age (Table 1).
10.7 6 1.4 years (mean 6 S.D., range 7.9–14.1 years) To assess gain over projection, to allow for indivi-
in prepubertal girls and before estrogen replacement dual assessment of height gain, Fig. 1 shows the adult

Table 1 Clinical characteristics of the 49 young women with Turner syndrome who were the subjects of this study. Mean 6 S.D. (range). No
significant difference was observed between untreated and treated groups for the first five sets of parameters studied (P > 0.05).

Control untreated (n ¼ 24) After GH treatment (n ¼ 25)

Mother’s height (cm) 161:3 6 7:3 (147.2–174.1) 159:6 6 5:7 (151.1–170.3)

Father’s height (cm) 172:7 6 5:8 (162.1–180.2) 174:0 6 5:3 (162.2–183.1)
Target height (cm) 163:5 6 5:8 (152.5–173.5) 163:3 6 4:8 (156.5–173.0)
Study initiation age (years) 10:7 6 1:4 (8.5–14.0) 10:7 6 1:4 (7.9–14.1)
Study initiation bone age (‘years’) 9:4 6 0:9 (8.0–10.5) 9:3 6 1:0 (7.0–11.3)
Height SDS TW standards1 ¹2:2 6 1:4 (¹3.5–¹1.0) ¹2:4 6 1:1 (¹3.3–¹1.2)
Height SDS TS standards2 ¹0:2 6 1:5 (¹1.4–þ1.7) ¹0:5 6 1:3 (¹0.9–þ1.1)
Growth velocity (TW) SDS ¹2:1 6 0:5 (¹3.2–¹1.0) ¹2:1 6 0:4 (¹3.0–¹1.2)
BMI SDS ¹0:4 6 0:6 (¹1.3–þ1.1) ¹0:1 6 1:2 (¹1.8–þ3.8)
Projected height (cm) 143:5 6 4:2 (134.5–153.5) 142:6 6 5:2 (133.0–150.0)
GH therapy duration (years) – – 5:1 6 1:9 (2.6–7.5)
Estrogen replacement age (years) 13:4 6 0:8 (12.0–15.2) 13:2 6 1:0 (12.0–16.2)
Spontaneous puberty (n ) (Tanner B2 age) 3 (11.0–12.5) 5 (11.5–12.1)
Final height (cm) 142:9 6 5:1 (133.0–154.6) 147:3 6 4:9 (139.0–154.0)
Final age (years) 19:6 6 2:9 (17.0–24.0) 18:1 6 1:0 (16.9–20.0)
Gain in height3 (cm) ¹0:6 6 2:2 (¹6.0–2.2) 4:7 6 2:9 (¹0.4–10.4)
Height deficit4 (cm) 20:7 6 6:0 (7.1–36.5) 16:0 6 4:6 (8.0–25.3)
1
Tanner-Whitehouse (12). 2 Turner syndrome (11). 3 Final height ¹ projected height. 4 Target height ¹ final height.
220 Z Hochberg and Z Zadik EUROPEAN JOURNAL OF ENDOCRINOLOGY (1999) 141

height as a function of projected height in control and mothers’ (r = 0.323, P = 0.123) or with their fathers’
GH-treated girls. The gain in height was calculated for heights (r = ¹ 0.123, P = 0.554, Fig. 2B and C). On the
each subject as [final height¹projected height]. In the other hand, the adult height of treated patients
control group, projected height reached the final height correlated significantly and to a similar extent with
within 6 2.5 cm, in 21 of 24 patients and deviated both their mothers’ (r = 0.484, P < 0.02) and their
by 3.5–6.0 cm in the other three. The height gained by fathers’ heights (r = 0.488, P < 0.02, Fig. 2D–F).
the GH group averaged 5.3 cm more then that by the Grouping the patients according to their karyotype
controls (P < 0.005) (Table 1). showed a mean height gain of 5.7 cm in the 45,XO
For height deficit, adjustment for parental height patients, 3.6 cm in the 45,XO/46,XisoXq, 4.8 cm in
was made by calculation of the target height, and the 45,XO/46,XX and 2.4 cm in the 45,XO/46,XY.
height deficit was calculated as [target height¹final These differences were statistically insignificant.
height]: it was 20.7 6 6.0 cm in the control group In an attempt to determine retrospective therapeutic
(range 7.1–36.5 cm) and 16.0 6 4.6 cm in the GH factors that might have influenced the success of GH
group (range 8.0–25.3 cm, P < 0.01), and the mean treatment, we determined the correlation between the
gain was 4.7 cm (Table 1). The adult heights of the gain in height (defined above) and several treatment
women who had been treated with GH were parameters. We also determined the correlations
significantly correlated with the target height between the height deficit and these treatment para-
(r = 0.553, P < 0.005), unlike the control untreated meters, but since they were essentially identical to those
Turner women (r = 0.383, P = 0.065, Fig. 2A). Final for gain in height, they are not shown. The negative
heights of untreated patients did not correlate with their correlation of gain in height with the pretreatment
projected height was close to significance (r = 0.374,
P = 0.066, Fig. 3). As expected, correlation with pre-
treatment height SDS gave identical results. Thus,
shorter girls show better response to GH than do taller
girls. The projected height of control untreated girls did
not correlate with the deviation of final height from
projected height (Fig. 3).
We then correlated the age of treatment, its duration
and the age of estrogen initiation with the gain in
height. None of these variables bear any significant
correlation (Fig. 4). Furthermore, the degree of obesity
(calculated as body mass index (BMI) SDS for age) also
did not correlate with the gain in height after GH
therapy (P > 0.1, data not shown).
Overall, in spite of the relatively high doses adminis-
tered, GH therapy was tolerated well, with no clini-
cally apparent untoward effects. Hyperinsulinemia
with normal glucose tolerance was observed in most
patients in whom it was looked at (Z Hochberg,
unpublished observation).

Discussion
A decade or more has evolved since recombinant GH
became available on a large scale and we now can
evaluate final height results of GH therapy in Turner
syndrome. Since results of the larger American con-
trolled study are still pending, we hereby present a
controlled study of a significant size. The results show
a gain of adult height that is variable, ranging from no
gain at all to over 10 cm (average 4.4–5.3 cm,
depending on the method used) when compared with
the control group. These results are similar in magni-
tude to those in the interim report of the Canadian open
Figure 1 Final height as a function of pretreatment projected controlled study (13), where a dose of GH that was 10%
height in young women with Turner syndrome. (A) Twenty-four
untreated women, r ¼ 0:818, P < 0:0001; (B) 25 women after
higher than the one used here was administered and
GH treatment, r ¼ 0:836, P < 0:001. The diagonal line indicates there was a reported mean gain of 5 cm. These results,
the projected height as the final height. however, show a smaller effect than the Genentech
EUROPEAN JOURNAL OF ENDOCRINOLOGY (1999) 141 GH therapy in Turner syndrome 221

Figure 2 Final height as a function of target height (A and D), maternal height (B and E) and paternal height (C and F) in young
women with Turner syndrome in 24 control untreated women (A–C), and in 25 women after GH treatment (D–F). (A) r ¼ 0:383,
P ¼ 0:065; (B) r ¼ 0:323, P ¼ 0:123; (C) r ¼ ¹0:123, P ¼ 0:554; (D) r ¼ 0:553, P ¼ 0:004; (E) r ¼ 0:484, P ¼ 0:014;
(F) r ¼ 0:488, P ¼ 0:013.

uncontrolled study (7), where a dose that was 37% in final height, probably since the mean age of treat-
higher then the one used here was administered and ment initiation was high, at 12.5 years (14).
there was a reported mean gain of 7.4 cm. A Greek The study design did not include a placebo or
controlled study reported no significant improvement randomized control group for ethical and practical
222 Z Hochberg and Z Zadik EUROPEAN JOURNAL OF ENDOCRINOLOGY (1999) 141

(6, 8) but not by others (18). It cannot be excluded that

increasing the sample size might have produced a
stronger correlation. It was interesting to note that this
correlation was significantly better in women who had
been treated with GH. This implies that GH treatment
may surmount a physiological deficit or resistance in
the GH–insulin-like growth factor-I (IGF-I) axis. Indeed,
physiological doses of GH are ineffective in the treat-
ment of Turner syndrome (1, 2). The dose of GH
required to accelerate growth in Turner syndrome is
larger then that used for GH deficiency or for idio-
pathic short stature, suggesting some resistance along
the GH–IGF-I axis. Whereas serum GH and IGF-I are
generally normal in Turner syndrome, we have recently
demonstrated decreased sensitivity to GH and IGF-I of
lymphocytes and monocytes in patients with this
syndrome (19). Nevertheless, this would account for
only a small part of the mechanism underlying growth
retardation in Turner syndrome, since the final height is
only partly restored by GH therapy. Since in Turner
syndrome, 70% of patients have lost their paternal X
chromosome (20), we wanted to test the relative impact
of paternal versus maternal height. In fact, heights
correlated significantly and to a similar degree with
final height after GH therapy, but not in untreated
patients. Earlier studies have variously reported that the
patient height correlated to a similar extent (21) with
maternal and paternal height with a somewhat better
maternal correlation (22) or paternal correlation (8). It
is likely that in the study reported here the sample size
may not be large enough to expose the 70% of patients
who lose their paternal X chromosome.
Figure 3 Gain in height as a function of pretreatment projected It is of practical and economical importance that
height in young women with Turner syndrome. (A) Twenty-four
untreated women, r ¼ 0:185, P > 0:1; (B) 25 women after GH
the final height did not correlate with age at GH
treatment, r ¼ ¹0:374, P > 0:05. initiation or treatment duration, as previously sugges-
ted by some (3, 6, 13) and disputed by others (18). It
is also consistent with the well-characterized waning
reasons. However, the auxological and demographic in the effects of GH therapy during the course of GH
data for the treated and untreated groups at inception treatment. Thus, based on this prospective controlled
of therapy were comparable. In untreated controls the study of 49 women, we can see no justification for
divergence of the final heights from their projected initiation of GH therapy in young girls with Turner
height emphasizes the limitations of height prediction syndrome and for carrying it on for many years. It
methods. The validity of that conclusion is reinforced would seem more straightforward to initiate treatment
by the fact that these methods are based on only a small at the age of 10–11 years and to continue for 3–4
number of observations (15). The comparably less years. Initiation of GH treatment at a younger age, and
demanding design of the current study allowed for a its termination before final height has been attained,
study that was relatively free of industry support and may introduce catch down growth after withdrawal
completely free of its influence. This has been suggested of therapy, as shown for children with idiopathic short
to induce a bias in favor of publication of uncontrolled stature (23).
positive results, often in non-peer-reviewed articles The timing of estrogen replacement has been an
(16, 17). issue of much debate in the management of Turner
Analysis of results according to karyotype has syndrome patients. Previous recommendations for
previously shown that it has no influence on height late estrogen replacement were based either on theo-
(5, 8). The impression gained here by t-test supported retical considerations of the known role of estrogen
this contention, yet grouping the patients into such in advancing bone maturation (6) or on uncontrolled
small groups had a limited statistical power. studies where estrogen was given late and which
Parental height correlated only poorly with non- showed a better final height outcome (5, 7). In
treated final height, as previously suggested by some retrospect, the decision to base the timing of estrogen
EUROPEAN JOURNAL OF ENDOCRINOLOGY (1999) 141 GH therapy in Turner syndrome 223

Figure 4 Gain in height as a function of the age at initiation of GH therapy (A), the duration of GH therapy (B), and the age at initiation
of estrogen replacement therapy (C and D) in young women with Turner syndrome. All correlations are not significant.

replacement on the patient’s wishes seems justified, Acknowledgements

both in terms of the individual needs and in terms
of the lesson learnt from the correlation analysis. Recombinant GH was provided for some of the patients
Retrospective analysis of the present study, based on for some of the time by Eli Lilly, Israel and by Bio-
results from these 49 women, shows no correlation Technology General, Israel. We are indebted to
between height gain and the age at which estrogen Dr Ronnie Barkey for his constructive comments.
replacement was initiated, provided that this was
beyond the age of 12 years. Indeed, most patients
express the wish to develop puberty along with their References
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