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Journal of Clinical Endocrinology and Metabolism
Copyright © 1997 by The Endocrine Society
Vol. 82, No. 2
Printed in U.S.A.
Growth Hormone (GH) Retesting and Auxological Data
in 131 GH-Deficient Patients after Completion of
Treatment
MAÏTHÉ TAUBER, PIERRE MOULIN, CATHERINE PIENKOWSKI,
BÉATRICE JOURET, AND PIERRE ROCHICCIOLI
Service de Pédiatrie Endocrinologie, Centre, Hospitalier Universitoine, Purpan, F-31059 Toulouse
Cedex, France
ABSTRACT
GH state and auxological data after completion of GH therapy are
reported in 131 patients (79 males, 52 females). They were treated
from 1980 –1994 for partial (n ⫽ 98) or complete (n ⫽ 33) GH deficiency (GHD), either idiopathic (n ⫽ 121) or organic (n ⫽ 10). A single
stimulation test (clonidine ⫹ betaxolol) was used, and only 50 patients
(38%) maintained a blunted response (GH peak below 10 ␮g/L). Although 9 of the 10 patients with organic GHD had an abnormal low
GH peak, 67% of patients with idiopathic GHD normalized their GH
secretion. This was particularly true of partial GHD patients (71% vs.
36% of complete GH-deficient patients). Based on a retest GH peak
below 5 ␮g/L, only 23% of the patients were considered to be GH
deficient and therefore candidates for GH treatment during adulthood. We found no significant difference between hormonal state at
completion of treatment and initial GH deficiency, pubertal state, or
sex, although we did find a significantly lower GH peak value before
and after treatment in patients with elevated body mass index. Of the
14 obese children who were treated, 50% had an abnormally low
serum insulin-like growth factor-I level, arguing for true GHD, and
only two children remained obese at cessation of treatment. Auxological data showed that with a mean duration of treatment of 3.6 ⫾
2.0 yr, patients classified as having complete GHD before treatment
had significantly greater catch-up growth as expressed in SDS for
height than patients with partial GHD (0.6 ⫾ 1.1 vs. 1.1 ⫾ 0.7 SDS, P ⬍
0.05), and that boys grew better than girls (1.4 ⫾ 0.8 vs. 1.6 ⫾ 0.6 SDS)
for height, P ⬍ 0.01). That catch-up growth was not correlated with
the result of GH peak after cessation of treatment. (J Clin Endocrinol
Metab 82: 352–356, 1997)
A
LMOST 40 yr since GH was first used in therapy (1),
there is still no consensus on what is the best means
to study GH secretion and diagnose GH deficiency (GHD)
(2–5). The use of pharmacological or physiological GH tests
and the study of spontaneous GH secretion, urinary GH
secretion, or indirect data with evaluation of serum insulinlike growth factor-I (IGF-I) and serum IGF-binding protein
3 (IGFBP-3) has been widely discussed. The results of pharmacological and physiological studies of GH secretion appear widely variable on repeated testing (6).
The problem of diagnosing GHD now extends to adulthood, because GHD in adults with childhood or late-onset
deficiency has been shown to significantly increase mortality
and morbidity (7–11). In the absence of GH, body mass index
(BMI) increased, body composition was modified with an
elevated waist/hip ratio, metabolic disorders such as syndrome X were reported, and muscle strength, myocardial
efficiency, and bone mineral density were altered. All the
abnormal parameters are corrected by GH after either shortor long-term treatment (11–15).
The incidence and prevalence of adult-onset GHD can be
easily evaluated because the majority of cases (about 85%)
occur after pituitary surgery. However, the proportion of
adults with childhood-onset GHD (those patients who
should continue GH treatment after the end of somatic
growth) is not known. It thus appears very important to
clarify this point. There is little data in the literature on GH
state together with auxological data in GHD patients just
after completion of GH treatment. For these reasons, we
decided to systematically retest patients at the end of GH
treatment, and we report here the data of 131 patients treated
with GH in our department during the last 14 yr.
Subjects and Methods
The cohort was composed of 131 patients (79 males and 52 females)
who had received GH treatment from 1980 –1994 for complete (n ⫽ 33)
or partial (n ⫽ 98) GHD. Treatment was discontinued between 1992 and
1994. Most patients presented with idiopathic GHD (n ⫽ 121) and 10
patients presented with organic GHD caused by neurofibromatosis
without glioma (n ⫽ 1), central nervous system irradiation (n ⫽ 2), spina
bifida with myelomeningocele (n ⫽ 1), medulloblastoma (n ⫽ 2),
astrocytoma (n ⫽ 2), medullar hypoplasia (n ⫽ 1), and so-called empty
sella turcica (n ⫽ 1).
The mean dose of GH was that given in France by France Hypophyse
during the last 15 yr and ranged from 0.4 – 0.6 IU/kg per week.
Table 1 summarizes auxological data: mean chronological age was
16.7 ⫾ 1.7 yr (17.6 ⫾ 1.4 yr for boys and 15.3 ⫾ 1.3 yr for girls), mean
bone age 14.8 ⫾ 2.0 yr (15.3 ⫾ 2.0 for boys and 14.2 ⫾ 3.0 for girls), mean
BMI was 20 ⫾ 2. Mean duration of treatment was 3.7 ⫾ 2.1 yr, and mean
sds for height increased from ⫺2.7 ⫾ 1.0 sds before treatment to ⫺1.5 ⫾
1.0 sds at the end of treatment.
Boys started treatment at a mean age of 13.7 ⫾ 2.8 yr, were treated
for 3.8 ⫾ 2.2 yr, and had a mean sds for height after completion of GH
treatment of ⫺3 ⫾ 1.0 sds. Girls started treatment earlier, at 11.7 ⫾ 2.3
yr, were treated for a shorter period, 3.6 ⫾ 2 yr, and showed less
improvement in sds for height at the end of treatment: ⫺1.7 ⫾ 1.0 sds.
Before treatment, 33 children (11 girls, 22 boys) were classified as
complete GHD because they had two abnormal GH peaks below 5 ␮g/L
after two different stimulation tests. Ninety-eight children (41 girls, 57
Received July 23, 1996. Revision received September 17, 1996. Rerevision received October 16, 1996. Accepted October 16, 1996.
Address all correspondence and requests for reprints to: Maı̈thé
Tauber, Service de Pédiatrie Endocrinologie, CHU Purpan, Place Baylac,
F-31059 Toulouse Cedex, France.
352
3.8 ⫾ 2.2
14.7/1.25
3.6 ⫾ 2.0
11.0/1.0
3.7 ⫾ 2.1
14.7/1.0
15.3 ⫾ 2.0
17.0/14.5
14.2 ⫾ 3.0
16.5/14.0
14.8 ⫾ 2.0
17.0/14.0
164.6 ⫾ 6.0
176.0/148.0
150.3 ⫾ 7.0
163.0/142.0
159 ⫾ 9.0
176.0/142.0
17.6 ⫾ 1.4
23.0/14.0
15.3 ⫾ 1.3
17.5/13.9
16.7 ⫾ 1.7
23.0/13.9
Hormonal dosages
⫺2.7 ⫾ 1.2
⫺1.0/⫺5.0
⫺2.7 ⫾ 1.0
⫺1.0/⫺6.0
⫺2.7 ⫾ 1.0
⫺1.0/⫺6.0
18 ⫾ 2
27/14
17 ⫾ 2
30/14
18 ⫾ 2
30/14
mean ⫾ SD
max/min
mean ⫾ SD
max/min
mean ⫾ SD
max/min
⫺1.3 ⫾ 1.0
⫺0.8/⫺4.8
⫺1.7 ⫾ 1.0
0/⫺4.2
⫺1.5 ⫾ 1.0
0.8/⫺4.8
GH dosage. Kits were purchased from Cis Oris (Cis BioInternational,
Gif-sur-Yvette, France) throughout the study. The method changed in
1987 from RIA to immunoradiometric assay. The laboratory compared
the values obtained with both methods at this time, and the results were
satisfactory. With RIA, the intraassay coefficient of variation (CV)
ranged from 7.6 –9.2%, and the interassay CV ranged from 11.0 –13.7%.
With the immunoradiometric assay, the intraassay CV ranged from
2.3–2.8%, and interassay CV ranged from 3.2– 4.4%. All the GH dosages
at retesting were performed with the same method.
IGF-I dosage. Kits were purchased from the same manufacturer
(Mallinckrodt, Medica, Evry, France), and the same method was used for
all sera at retesting.
Statistical analysis
We used Pearson’s ␹2 and Yates or Fisher tests for qualitative variables. For quantitative variables, means were compared using covariance analysis to control confounding factors.
Results
GH peak at retesting after completion of treatment
SDS,
Total (n ⫽ 131)
Girls (n ⫽ 52)
Standard deviation score.
139.7 ⫾ 15.0
166.0/80.0
130.6 ⫾ 13.0
146.0/80.0
136.0 ⫾ 15.0
166.0/80.0
11.1 ⫾ 2.8
15.0/2.0
9.8 ⫾ 2.6
13.0/1.0
10.6 ⫾ 2.8
15.0/1.0
13.7 ⫾ 2.8
22.0/3.0
11.7 ⫾ 2.3
15.3/3.2
12.9 ⫾ 2.8
22.0/3.0
Boys (n ⫽ 79)
353
boys) were classified as partial GHD because they had either two low
GH peaks between 5 and 10 ␮g/L after stimulation tests (n ⫽ 74) or one
abnormal test below 10 ␮g/L and low 24-h GH secretion with an integrated concentration below 2.5 ␮g/L/min (n ⫽ 24). Ten percent of
organic GHD patients had partial GHD and 90% had complete GHD.
Eighty percent of idiopathic GHD patients had partial GHD and 20% had
complete GHD. The ratio between complete and partial GHD did not
significantly differ between prepubertal (n ⫽ 58) and pubertal (n ⫽ 73)
patients at the start of treatment. Various stimulation tests were performed either with a single stimulus: ornithine (n ⫽ 17), l-dopa (n ⫽ 40,
clonidine (n ⫽ 3), arginine (n ⫽ 45), or glucagon (n ⫽ 1) or with combined
stimuli: clonidine and betaxolol (n ⫽ 99), insulin and arginine (n ⫽ 13),
glucagon and propanolol (n ⫽ 10), or glucagon and betaxolol (n ⫽ 8).
Only a small number of patients were primed with sex steroids before
therapy.
During the first year following the discontinuation of therapy and at
least 15 days after the last GH injection, each patient came to the day
hospital unit for a single GH stimulation test that used clonidine and
betaxolol as pharmacological stimuli. This test was the most commonly
used test in our department for practical reasons, and most patients had
been tested with it before treatment (n ⫽ 99).
20 ⫾ 2
31/14
19 ⫾ 2
27/15
20 ⫾ 2
31/4
Bone age
(yr)
Height (cm)
Bone age
(yr)
Age (yr)
Before treatment
TABLE 1. Auxological data of the patients before and after GH treatment
SDS
Height
Body
mass
index
(kg/m2)
After
treatment
Height
SDS
Body
mass
index
(kg/m2)
Height (cm)
Age (yr)
Duration
GH
therapy
(yr)
GH RETESTING AFTER COMPLETION OF GH
Mean value for the group was 14.4 ⫾ 10.0 ␮g/L (range
0.2– 49.5 ␮g/L). Thirty patients had a blunted response below 5 ␮g/L (23%), 19 patients had a partially blunted response between 5 and 10 ␮g/L (15%), and 82 patients had a
normal GH peak above 10 ␮g/L (62%).
Of the 10 patients with organic GHD, only 1 (10%) had a
normal GH peak, and 9 still had a low GH peak below 5
␮g/L. Conversely, a large majority (67%) of idiopathic GHD
patients had a peak above 10 ␮g/L, 16% had a peak between
5 and 10 ␮g/L, and 17% had a peak less than 5 ␮g/L. Data
are presented in Fig. 1.
Complete and partial GHD patients. Of the 33 patients with
complete GHD, 21 (64%) still had an abnormal GH peak, 16
(49%) had a peak below 5 ␮g/L, and 5 (15%) had a peak
between 5 and 10 ␮g/L, whereas 12 (36%) had a normal GH
peak. Of the 98 patients with partial GHD, 28 (29%) still had
an abnormal GH peak, 14 (14%) had a peak below 5 ␮g/L,
and 14 (15%) had a peak between 5 and 10 ␮g/L. The majority, 70 (71%), had a normal GH peak. Data are presented
in Fig. 2.
354
JCE & M • 1997
Vol 82 • No 2
TAUBER ET AL.
TABLE 2. Mean SDS gain for height in patients according to the
results of GH test after treatment, type of GHD, complete or
partial, before treatment and sex
GH ⬍ 10 ␮g/L
at retesting
GH ⬎10 ␮g/L
at retesting
Complete GHD
Partial GHD
Boys
Girls
Number
Mean SDS gain
height
Duration of GH
therapy (yr)
49
1.4 ⫾ 0.8 (NS)
3.9 ⫾ 2.1
82
1.2 ⫾ 1 (NS)
3.6 ⫾ 1.2
33
98
79
52
1.6 ⫾ 1.1a
1.1 ⫾ 0.7a
1.4 ⫾ 0.8b
1.1 ⫾ 0.7b
4.3 ⫾ 3.1
3.6 ⫾ 1.7
3.8 ⫾ 2.2
3.6 ⫾ 2.0
SDS,
a
b
FIG. 1. Results of GH test in percentages of low, intermediate (between 5 and 10 mg/L), and normal values of GH peak a end of treatment in patients with organic and idiopathic GHD.
FIG. 2. Results of GH test expressed percentages of low, intermediate
(between 5 and 10 mg/L), and normal values of GH peak at end of
treatment in patients with complete and partial GHD.
Sex ratio. Of the 11 girls with complete GHD, 6 (55%) had a
low GH peak and 5 (45%) normalized their test. Of the 41 girls
with partial GHD, 12 (28%) had a low GH peak and 29 (72%)
a normal test. Therefore 64% of the girls (n ⫽ 33) had a normal
GH peak.
Of the 22 boys with complete GHD, 15 (68%) had a low GH
peak and 7 (32%) had a normal test. In the 57 boys with partial
GHD, 16 (28%) had a low GH peak and 41 (72%) had a normal
test. Therefore 60% of the boys (n ⫽ 48) had a normal GH
peak, which was not statistically different from the results
obtained in girls (64%) and in the group as a whole (62%).
Pubertal stage. Of the 58 children who were prepubertal when
starting treatment, 14 (24%) had complete GHD, of whom 10
(72%) still had a low GH peak. In the 44 partial GHD patients,
12 (27%) still had a low GH peak. Therefore 36 (60%) of the
58 children who were prepubertal before treatment had a
normal GH test. Of the 73 children who were pubertal at the
start of treatment, 19 (26%) had complete GHD, 11 of whom
(58%) still had a low GH peak. In the 54 with partial GHD,
16 (30%) still had a low GH peak. Therefore, 63% of the 73
pubertal children had a normal GH test after treatment,
which is not statistically different from the result obtained in
the group of prepubertal children.
BMI state. When starting treatment, only 14 patients were
obese, with a BMI above the 97th percentile, and 8 of those
Standard deviation score; NS, Not significant.
P ⬍ 0.01.
P ⬍ 0.05.
(57%) had complete GHD and 6 (75%) had a low GH peak
after completion of treatment. Of the 6 patients with partial
GHD, 4 (67%) still had a GH-deficient test. Therefore, at the
end of treatment 4/14 (29%) normalized their GH test, which
was significantly lower than the result of the whole group
(P ⬍ 0.001). Only 2/14 remained obese, and these two patients had a GH peak below 5 ␮g/L. Before treatment, GH
peak was also significantly lower (P ⬍ 0.001) in the group of
obese children than in the nonobese children. Moreover,
serum IGF-I levels were obtained in 12 of the 14 patients
before treatment and 7 had low values, suggesting that the
blunted GH response was not caused by their obesity but
related to GHD.
IGF-I plasma levels. We measured IGF-I levels in 119 patients
at retesting. The mean value was 358 ⫾ 193 ng/mL and
ranged from 37–1149 ng/mL. GH peak at retesting was positively correlated with IGF-I levels (P ⬍ 0.02). IGF-I levels
were lower in patients with persistent GHD than in those
who normalized their GH peak. The difference was more
marked in patients with complete GHD (P ⬍ 0.001) than in
patients with partial GHD (P ⬍ 0.004). Conversely, there was
no significant difference in IGF-I values between patients
with persistent complete GHD and those with partial GHD.
Auxological data
In the 33 patients with complete GHD, mean sds gain for
height was ⫹1.6 ⫾ 1.1 sds for a mean duration of therapy of
4.3 ⫾ 3.1 yr. We did not find a significant difference in sds
gain between those who normalized their test (n ⫽ 12) and
those who did not (n ⫽ 21) (1.6 ⫾ 0.6 vs. 1.7 ⫾ 1.3 sds).
In the 98 patients with partial GHD, mean sds gain for
height was 1.1 ⫾ 0.7 sds for a mean duration of therapy of
3.6 ⫾ 1.7 yr. Again, we did not find a significant difference
in sds gain between those who had a normal test (n ⫽ 70) and
those who did not (n ⫽ 28) (1.1 ⫾ 0.8 vs. 1.2 ⫾ 0.9).
However, patients with complete GHD grew significantly
better (P ⬍ 0.01) than patients with partial GHD. Boys grew
significantly better than girls (P ⬍ 0.05): 1.4 ⫾ 0.8 sds for a
duration of 3.8 ⫾ 2.2 yr vs. 1.1 ⫾ 0.7 SDS for a duration of
3.6 ⫾ 2.0 yr. Data are summarized in Table 2.
Discussion
These data show that the great majority (62%) of GHD
patients have a normal GH test at the end of GH therapy.
GH RETESTING AFTER COMPLETION OF GH
Normalization of the GH test was twice as frequent in patients with partial GHD (71%) as in patients with complete
GHD (36%) and occurred in 10% of organic vs. 67% of idiopathic GHD. In idiopathic GHD, the main question is: Do
the data merely reflect the lack of reproducibility of GH
testing, or does transient GHD really exist? Concerning the
latter point, we did not find a higher incidence of transient
GHD during puberty, as previously has been reported (6). As
for the lack of reproducibility of GH tests, a recent report on
retesting children with GHD throughout the course of treatment (6) using pharmacological tests and spontaneous GH
secretion showed that 58.1% of subjects changed from the
initial diagnostic group after the first retesting (1.1 ⫾ 5.0 yr
after starting GH therapy) and 48.5% at the second retesting
(1.5 ⫾ 0.4 yr after the first retesting). Previous studies also
reported the lack of reproducibility of GH testing, with pharmacological tests (16, 17) being significantly more variable
than spontaneous secretion studies (18). Moreover, the level
of reproducibility varied with the type of test used, and
clonidine was reported to be the most reproducible test (19).
These studies again point out the difficulty of finding a
reliable test to diagnose GHD, probably because of the wide
variation of GH secretion in short children. We cannot completely exclude transient GHD in some cases, or the decreased capacity to increase GH secretion in some circumstances, such as puberty.
Other criteria of GHD such as plasma IGF-I or IGFBP-3
evaluation could be of interest. It has been documented in
adults that serum IGF-I and IGFBP-3 are useful diagnostic
tests in identifying young adults with severe GH deficiency
if there is a sufficiently large number of age and sex-matched
controls (20, 21).
The correlation we found between GH peak and IGF-I
levels and the significant difference between the patients
who had persistent GHD and those who normalized their
test is an argument in favor of transient GHD. Unfortunately,
we do not have IGF-I values before treatment or any IGFBP-3
data. Nevertheless, our study helps to predict approximately
the number of patients who should continue GH treatment
in adulthood. In France, it has been decided that patients
should continue treatment if the GH peak is lower than 3
␮g/L at retesting. In our series, 23% had complete GHD with
a GH peak below 5 ␮g/L at the end of GH treatment and 14%
had a GH peak lower than 3 ␮g/L. Half of the patients with
complete GHD when starting treatment would need to continue GH therapy compared with 14% of partial GHD
patients.
This point has been poorly documented in the literature.
In one study of 34 patients (22), 19 patients with postirradiation GHD continued to have complete GHD with a GH peak
lower than 3.5 ␮g/L, whereas of 15 idiopathic GH patients,
only 26% remained GH deficient. A recent study (23) of 69
adult patients diagnosed as GH deficient in childhood (54
idiopathic GHD, 15 organic), retested by using GHRH ⫹
pyridostigmine, found that 57% had persistent GHD with a
GH peak below 10 ␮g/L, of whom 52% had a GH peak below
5 ␮g/L. In most studies, however, the percentage of patients
with complete or partial GHD before treatment is not stated,
and this could account for the difference observed. Another
study (16) of 50 men (17 with isolated GH deficiency, 33 with
355
multiple pituitary hormone deficiencies) 1.0 –15.5 yr after
discontinuation of GH therapy for childhood-onset GHD
found 100% persistent GHD (GH peak below 7 ␮g/L) using
GHRH or the insulin tolerance test (24).
The auxological data in our study are also interesting,
reflecting our strategy of diagnosis and treatment of GHD
during the last 14 yr. The sex ratio was 79 boys/52 girls, age
at start of treatment was too high, and the mean duration of
treatment was significantly different in boys as compared
with girls, probably because of the poorer results obtained in
the girls. There was no difference in response to GH therapy
related to peak GH response after therapy, except for those
with GHD before treatment, who grew significantly better
than patients with partial GHD.
In conclusion, it is important to retest GHD patients after
completion of GH treatment because retesting shows that
approximately one-quarter of these patients will need GH
treatment in adulthood. This result has to be explained to the
families and the patients. It will be of interest to retest all
these patients after 1 yr when they return to the department
to check their adult height.
Acknowledgments
The authors thank Mlle. Patricia Zanchetta for typing the manuscript,
Mme. Nina Crowte for correcting it, and Dr. Charlet for statistical
analysis.
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