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The Journal of Clinical Endocrinology & Metabolism
Copyright © 2000 by The Endocrine Society
Vol. 85, No. 2
Printed in U.S.A.
Adult Height in Short Normal Girls Treated with
Gonadotropin-Releasing Hormone Analogs and
Growth Hormone
ANNA MARIA PASQUINO, IDA PUCARELLI, MARIO ROGGINI,
AND
MARIA SEGNI
Pediatric Endocrinology Unit, Pediatric Radiology Unit (M.R.), Pediatric Department, University La
Sapienza, 00161 Rome, Italy
ABSTRACT
Combined treatment with GH and GnRH analogs (GnRHa) has
been proposed to improve final adult height in true precocious puberty, GH deficiency, and short normal subjects with early or normal
timing of puberty with still controversial results. We treated 12 girls
with idiopathic short stature and normal or early puberty with GH
and GnRHa and followed them to adult height; 12 girls comparable
for auxological and laboratory characteristics treated with GH alone
served to better evaluate the efficacy of addition of GnRHa. At the
start of combined treatment, the chronological age of the girls (CA;
mean ⫾ SD) was 10.2 ⫾ 0.9 yr, bone age (BA) was 10.6 ⫾ 1.9 yr, height
SD score for BA was ⫺1.81 ⫾ 0.8, PAH was 146.3 ⫾ 5.0 cm. PAH was
significantly lower than target height (TH 152.7 ⫾ 3.6 cm; P ⬍ 0.005).
GH was given at a dose of 0.3 mg/kg䡠week, sc, 6 days weekly, and
GnRHa (depot-triptorelin) was given at a dose of 100 ␮g/kg every 21
days, im. The 12 girls were treated with GH alone at the same dose;
at the start of therapy their CA was 10.7 ⫾ 1.0, BA was 10.1 ⫾ 1.4 yr,
height SD score for BA was ⫺1.65 ⫾ 0.8, PAH was 145.6 ⫾ 4.4 cm, and
TH was 155.8 ⫾ 4.6 cm. Pubertal Tanner stage in both groups was
B2P2 or B3P3. LHRH test and pelvic ultrasound showed the beginning of puberty. The GH response to standard provocative tests was
10 g/L or more. The mean period of treatment was 4.6 ⫾ 1.7 yr in the
group treated with GH plus GnRHa and 4.9 ⫾ 1.4 yr in the group
treated with GH alone; both groups discontinued treatment at comparable CA and BA. Adult height was considered to be attained when
growth during the preceding year was less than 1 cm, with a BA of
over 15 yr. Patients in the group treated with GH plus GnRHa showed
an adult height significantly higher (P ⬍ 0.001) than the pretreatment PAH (156.3 ⫾ 5.9 vs. 146.3 ⫾ 5 cm); the gain in centimeters
calculated between pretreatment PAH and adult height was 10 ⫾ 2.9
cm, and 7 of 12 girls had a gain over 10 cm. Target height was
significantly exceeded. Height SD score for BA increased from ⫺1.81 ⫾
0.8 to ⫺0.85 ⫾ 1.0. The GH alone group reached an adult height higher
than the pretreatment PAH (151.7 ⫾ 2.7 vs. 145.6 ⫾ 4.4 cm); the gain
in final height vs. pretreatment PAH was 6.1 ⫾ 4.4 cm, and 5 of 12
girls did not gain more than 4 cm. TH was even not reached. The
height SD score did not significantly change. No adverse effects were
observed in either group. All of the girls showed good compliance and
were satisfied with the results. Our experience suggests that the
combination of GH and GnRHa is significantly more effective in improving adult height than GH alone in girls with idiopathic short
stature, early or normal onset of puberty, and low PAH well below the
third percentile and TH. As the cost-benefit of such invasive treatment must be seriously considered, further studies are needed due to
the small sample of our patients as well as in other studies reported
to date. (J Clin Endocrinol Metab 85: 619 – 622, 2000)
I
Subjects and Methods
N SUBJECTS with short stature and normal GH secretion,
so-called short normal or idiopathic short stature, the
poor final growth is often the result a poor velocity during
the prepubertal age (in the low range of normality) and a
reduced spurt during the pubertal age either with a normal
tempo or with an early onset of puberty.
In idiopathic short stature, GH alone has been used in
many trials, with controversial results at least as reported
to date (1–11). GnRH analogs (GnRHa) alone have been
used in the same condition at pubertal age to induce a
delay in epiphyseal fusion and consequent prolongation of
the duration of linear growth with still controversial results (12–15).
We evaluated the effect of combined therapy with GH and
GnRHa in 12 girls with idiopathic short stature and normal
or early puberty, comparing them with a group treated with
GH alone. Adult heights are available for all of the girls in
each treatment group.
Twelve girls (group 1) with chronological age (CA; mean ⫾ sd) of
10.2 ⫾ 0.9 and bone age (BA) of 10.6 ⫾ 1.9 yr, height sd score for BA of
⫺1.81 ⫾ 0.8, predicted adult height (PAH) of 146.3 ⫾ 5.0 cm, and target
height (TH) of 152.7 ⫾ 3.6 cm were enrolled for combined treatment (GH
and GnRHa) on the basis of the low PAH (lower than the TH). Auxological data at start of GnRHa plus GH therapy are shown in Table 1.
Twelve girls (group 2) with comparable auxological and laboratory
criteria were treated with GH alone at the same dose (CA, 10.7 ⫾ 1.0; BA,
10.1 ⫾ 1.4 yr; height sd score for BA, ⫺1.65 ⫾ 0.8; PAHm 145.6 ⫾ 4.4 cm;
TH, 155.8 ⫾ 4.6 cm). Their auxological data at the start of treatment are
shown in Table 2.
In all of the girls in both groups, genetic, skeletal, systemic, and
thyroid diseases were excluded. GH secretion was normal, with a GH
peak above 10 g/L at two stimulation tests (clonidine, arginine, or
insulin), as were insulin-like growth factor I levels and biochemical and
hematological parameters. A LHRH test was performed in all patients
to assess the beginning of puberty. GH was given at a dose of 0.3
mg/kg䡠week, sc, 6 day/week, in all of the patients in both groups.
Depot-triptorelin was given at a dose of 100 ␮g/kg every 21 days, im,
in the girls treated with combined therapy.
The study was approved by the ethical committee of our institution;
written consent was obtained from parents. Both groups of patients were
evaluated at start of treatment and every 6 months either during the
course of treatment or after the withdrawal. At each evaluation, height
was measured three times with a Harpenden stadiometer. BA was
determined according to the method of Greulich and Pyle (16) by the
same observer, who was unaware of the treatment condition along the
Received June 16, 1999. Revision received October 8, 1999. Accepted
October 22, 1999.
Address all correspondence and requests for reprints to: Anna Maria
Pasquino, M.D., Pediatric Endocrinology Unit, Pediatric Department,
University La Sapienza, Viale Regina Elena 324, 00161 Rome, Italy.
619
620
TABLE 1. Auxological data of 12 short normal patients treated
with GnRHa plus GH
CA (yr)
BA (yr)
Ht (SD score
for BA)
PAH (cm)
Adult ht
TH (cm)
JCE & M • 2000
Vol 85 • No 2
PASQUINO ET AL.
At start of
GnRHa ⫹ GH
At end of
GnRHa ⫹ GH
At adult ht
10.2 ⫾ 0.9
10.6 ⫾ 1.9
⫺1.81 ⫾ 0.8
14.8 ⫾ 1.6
13.8 ⫾ 0.8
⫺0.85 ⫾ 1.0a
16.2 ⫾ 1.2
15.5 ⫾ 0.9
⫺0.91 ⫾ 1.0a
146.3 ⫾ 5.0
156.3 ⫾ 5.9a
152.7 ⫾ 3.6b
156.8 ⫾ 5.7a
Values are the mean ⫾ SD.
a
P ⬍ 0.001 vs. start of GnRHa plus GH.
b
P ⬍ 0.05 vs. adult height.
whole study, and adult height was predicted according to the Bayley and
Pinneau method (17). Pubertal stage was evaluated using the method of
Tanner and ranged between B2P2 and B3P3 in all of the girls (18).
Pelvic ultrasound was performed at the beginning of the study in both
groups to verify initial puberty and during therapy with GnRHa to
verify the suppression of gonadotropin activity. Midparental TH was
calculated from the mean height of the parents adjusted for sex, as
described by Tanner et al. (19).
Every 6 months in both groups metabolic and hematochemical analyses were assessed; a LHRH test was performed in both groups at the
beginning of treatment to confirm the initial puberty and in the GH- and
GnRHa-treated group every 6 months to verify the suppression of gonadotropins. An oral glucose tolerance test was performed in all the girls
once a year.
The duration of treatment was (mean ⫾ sd) was 4.6 ⫾ 1.7 yr in group
1 (GnRHa plus GH) and 4.9 ⫾ 1.4 in group 2 (GH alone), CA at the
discontinuation of treatment was 14.8 ⫾ 1.6 and BA was 13.8 ⫾ 0.8 in
group 1, and CA was 15.0 ⫾ 1.2 and BA was 14.4 ⫾ 1.0 in group 2.
Discontinuation of treatment was decided according to classical criteria
(i.e. growth velocity ⬍2 cm/yr and BA ⱖ14 yr), although several girls
either growing less than 2 cm/yr or satisfied with their height discontinued therapy some months before 14 yr of BA. GnRHa was discontinued at the same time as GH in group 1. Adult height was considered
to be attained when growth velocity during the last year was less than
1 cm and BA was over 15 yr or more; in two girls in group 1 no growth
was observed in the last year at a BA of less than 15 yr.
TABLE 2. Auxological data of 12 short normal patients treated
with GH alone
CA (yr)
BA (yr)
Ht (SD score for BA)
PAH (cm)
Adult ht (cm)
TH (cm)
At start of GH
At end of GH
At adult ht
10.7 ⫾ 1.0
10.1 ⫾ 1.4
⫺1.65 ⫾ 0.8
145.6 ⫾ 4.4
151.7 ⫾ 2.7a
155.8 ⫾ 4.6b
15.0 ⫾ 1.2
14.4 ⫾ 1.0
⫺1.46 ⫾ 0.4
153.5 ⫾ 2.1a
15.9 ⫾ 1.3
16.2 ⫾ 1.1
⫺1.72 ⫾ 0.4
Values are the mean ⫾ SD.
a
P ⬍ 0.001 vs. start of GH.
b
P ⬍ 0.05 vs. adult height.
Pretreatment height in sd score for BA increased significantly
from ⫺1.81 ⫾ 0.8 to ⫺0.91 ⫾ 1.0 (P ⬍ 0.001; ⌬sd score for BA,
⫹0.90 ⫾ 0.7). GnRHa treatment decelerated bone age and
arrested sexual development; pelvic ultrasound showed reduced ovarian and uterine volumes. After withdrawal of
therapy, ovarian and uterine volume increased regularly in
12 months. No ovarian cysts were observed (20). No negative
metabolic side-effects were observed, especially regarding
the oral glucose tolerance test and lipid metabolism. LH and
FSH were suppressed during treatment and resumed completely after discontinuation, followed by regular menses in
all of the girls after 6 –15 months.
In girls treated with GH alone (group 2), the height sd
score for BA changed from ⫺1.65 ⫾ 0.8 to ⫺1.46 ⫾ 0.4 (P ⫽
NS; ⌬sd score for BA, ⫹0.19 ⫾ 0.7) at discontinuation of
treatment. PAH at the beginning of treatment was 145.6 ⫾ 4.4
cm and increased to 153.5 ⫾ 2.1 cm at the discontinuation of
therapy (P ⬍ 0.001). Adult height was 151.7 ⫾ 2.7 cm, with
a gain vs. pretreatment PAH of 6.08 ⫾ 4.4 cm. TH was 155.8 ⫾
4.6 cm. Pretreatment height in sd score for BA did not significantly change from ⫺1.65 ⫾ 0.8 to ⫺1.72 ⫾ 0.45 (⌬sd score
for BA, ⫺0.26 ⫾ 0.3). No negative metabolic side-effects were
observed. The girls treated with GH alone showed a normal
pattern of puberty and no ovarian cysts.
Hormone assay
Plasma LH and FSH were measured in duplicate by immmunoradiometric assay (Maiaclone, Serono Biodata, Milan, Italy). Estradiol was
measured by RIA (Diagnostic Products, Los Angeles, CA; Bio-Rad Laboratories, Inc., Hercules, CA). GH was measured in duplicate by polyclonal RIA (Sorin Biomedica, Vercelli, Italy). Insulin was measured in
duplicate by RIA (Diagnostic Products).
Statistical analysis
Data are expressed as the mean ⫾ sd unless otherwise stated. Statistical analysis was performed using paired and unpaired Student’s t
test. P ⬍ 0.05 was considered significant.
Results
The group treated with combination treatment (GnRHa
and GH; group 1) showed an increment in height sd score for
BA from ⫺1.81 ⫾ 0.8 to ⫺0.85 ⫾ 1.0 (P ⬍ 0.001; ⌬sd score for
BA, ⫹0.96 ⫾ 0.73); the mean PAH at the start of treatment
was 146.3 ⫾ 5 cm and reached a mean of 156.8 ⫾ 5.7 cm at
discontinuation of treatment (P ⬍ 0.001). Adult height,
reached during the following year or more, was 156.3 ⫾ 5.9
cm (sd score for BA, ⫺0.91 ⫾ 1.0); TH was 152.7 ⫾ 3.6 cm.
The gain in centimeters calculated as the difference between
pretreatment PAH and final adult height was 10.0 ⫾ 2.9.
Discussion
Combined treatment with GnRHa and GH has been proposed and performed to improve adult height in true precocious puberty by several researchers (21–25); recently, we
reported data on adult height in our trial (26). GH-deficient
adolescents have also been treated with GH combined with
GnRHa to increase final height (27, 28). For idiopathic short
stature with normal or simply early puberty, combined treatment of GnRHa and GH has been performed, leading to
conflicting results for adult height (29 –33).
A loss of gain in adult height in 10 girls treated for 2–3 yr
with GH and GnRHa has been reported (31). Adult height
was reached 3 yr after the discontinuation of therapy; the
researchers themselves state that their results could have
been negatively influenced by the low dose of GH (0.6 IU/
kg䡠weekly) and the discontinuation before completion of
growth. On the other hand, a significant improvement in
adult height has been reported in 14 girls treated with
GnRHa combined with GH and with GH alone for 2 yr more
after discontinuation of GnRHa (32).
In another study, 10 subjects (7 females and 3 males) were
treated for 30 months with combined therapy (leuprolide
GnRHa AND GH TREATMENT IN SHORT NORMAL GIRLS
TABLE 3. Predicted adult height, final height, and TH of 12
short normal patients treated with GnRHa plus GH
Predicted adult Predicted adult
ht at start of
ht at end of
therapy (cm)
therapy (cm)
Patient
no.
1
2
3
4
5
6
7
8
9
10
11
12
Mean ⫾
SD
141.2
145.3
152.1
139.7
145
149.4
150.6
140.7
144.3
144.8
146
156.5
146.8
155.2
164.8
152.4
154
162
160
151.6
154.7
160.3
153.7
165.6
146.3 ⫾ 5.0
156.8 ⫾ 5.7
TABLE 4. Predicted adult height, final height, and TH of 12
short normal subjects treated with GH
Final ht
(cm)
TH
(cm)
Patient
no.
147
151
165
150
153.5
161
159
154
155.2
160
154
166
147.7
147.7
154.4
157.5
151.8
154.5
156.1
152.7
150
150
152
158.7
1
2
3
4
5
6
7
8
9
10
11
12
156.3 ⫾ 5.9 152.7 ⫾ 3.6
acetate, 300 ␮g/kg every 28 days; GH, 0.6 IU/kg weekly)
(33). Although PAH in the first year of therapy showed a
significant improvement, adult height remained significantly lower than TH. The low dose of GH, the short period
of therapy, and the evaluation of results, calculated by using
mean value PAH for males and females limits in some ways
the usefulness of this study. Our study was performed in
both groups using the same criteria, such as GH dose (0.3
mg/kg䡠week), auxological characteristics of the girls, and
time of discontinuation of treatment.
In group 1, GnRHa was given at a suppressive dose (at
least 100 ␮g/kg in 21 days, im). Furthermore, we were very
careful in adjusting the dose according to weight either for
GH in both groups or for GnRHa in group 1, and we treated
girls for longer period than in other studies (31, 33).
Girls treated with combined therapy obtained a mean gain
in adult height of 10.0 ⫾ 2.9 cm compared with pretreatment
PAH (156.3 ⫾ 5.9 vs. 146.3 ⫾ 5 cm) and similar to PAH at the
discontinuation of therapy (156.3 vs. 156.8 cm). In this group
the variability of the response (range, 5.7–15 cm) was less
striking than that in group 2; 7 of 12 subjects had a gain over
10 cm. TH was significantly exceeded (156.3 ⫾ 5.9 vs. 152.7 ⫾
3.6 cm; P ⬍ 0.05 Table 3). If we consider height in sd score
for BA at the beginning of treatment and at final adult height,
the increment is about 0.9 sd score for BA.
Girls treated with GH alone obtained a mean gain in adult
height vs. pretreatment PAH (151.7 ⫾ 2.7 vs. 145.6 ⫾ 4.4 cm)
of 6.1 ⫾ 4.4 cm, with a great variability (range, 0.1–14.1 cm).
Five of 12 patients did not gain more than 4 cm, comparing
adult height with pretreatment PAH. TH was not exceed by
adult height (155.8 ⫾ 4.6 vs. 151.7 ⫾ 2.7 cm; P ⬍ 0.05; Table
4). If we consider height sd score for BA at the beginning of
treatment and at adult height, no significant change was
obtained. All girls had good compliance, and most of them
were satisfied ith the results.
In conclusion, our experience shows that the addition of
GnRHa to GH improves adult height significantly compared
with PAH in girls with idiopathic short stature and normal
or early puberty. The advantage obtained with the combination is more significant and may be due to the deceleration
of both BA and progression of puberty compared with those
obtained in the GH alone group as to the amount of gain in
621
Mean ⫾
Predicted adult Predicted adult
ht at start of
ht at end of
therapy (cm)
therapy (cm)
SD
148.1
138.9
149.4
140.2
140.7
142.5
141.7
148.3
149.1
149.9
151.1
147.3
154.4
152.9
153.4
150.9
154.2
148.8
153.7
157.5
153.2
154
154
155.4
145.6 ⫾ 4.4
153.5 ⫾ 2.1
Final ht
(cm)
TH
(cm)
152
153
153.4
147.3
152
147
153
156.5
150
150
154
152
158.1
159.1
147.7
154
150.3
150.2
158
156.4
158.7
160.1
154.5
163
151.7 ⫾ 2.7 155.8 ⫾ 4.6
adult height (10 vs. 6 cm). The benefit of treatment remains
significant but less striking in group 1 (GH plus GnRHa) and
not significant in the GH alone group, if we compare heights
in sd score for BA as reported previously (31, 33). However,
if we consider their economical and ethical costs, these therapies should be limited to very short subjects who have a
very low PAH well below the third percentile and parental
TH, in whom even a gain of 6 cm could be considered
worthwhile. As the cost-benefit of such invasive treatment
must be seriously considered, further studies are needed.
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