The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 2 619-622
Copyright © 2000 by The Endocrine Society
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
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.
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Abstract
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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·week, sc, 6 days weekly,
and GnRHa (depot-triptorelin) was given at a dose of 100 µg/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.
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Introduction
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IN 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, 2, 3, 4, 5, 6, 7, 8, 9, 10, 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, 13, 14, 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.
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Subjects and Methods
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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·week, sc, 6 day/week, in all of the patients in both groups.
Depot-triptorelin was given at a dose of 100 µg/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
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 
14 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.
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.
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Results
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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. 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.
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Discussion
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Combined treatment with GnRHa and GH has been proposed and
performed to improve adult height in true precocious puberty by several
researchers (21, 22, 23, 24, 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, 30, 31, 32, 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·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 acetate, 300 µg/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·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 µg/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 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.
Received June 16, 1999.
Revised October 8, 1999.
Accepted October 22, 1999.
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86(1):
458 - 458.
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Abstract
Introduction
