The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 10 3493-3497
Copyright © 1998 by The Endocrine Society
Changes in Thyroid Hormone Levels during Growth Hormone Therapy in Initially Euthyroid Patients: Lack of Need for Thyroxine Supplementation1
David T. Wyatt,
Neil Gesundheit and
Barry Sherman
Department of Pediatrics, Medical College of Wisconsin (D.T.W.),
Milwaukee, Wisconsin 53226; and the Department of Medical Affairs,
Genentech, Inc. (N.G., B.S.), South San Francisco,
California 94080
Address all correspondence and requests for reprints to: David T. Wyatt, M.D., Medical College of Wisconsin, Department of Pediatrics, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226. E-mail:
dtwyatt{at}mcw.edu
 |
Abstract
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The occurrence of central hypothyroidism in previously euthyroid
children during GH therapy has been reported with widely varying
incidence. We monitored the acute effects on the
hypothalamic-pituitary-thyroid axis in 15 euthyroid children with
classic GH deficiency during the first year of GH therapy. All were
initially euthyroid, as assessed by normal baseline TSH,
T4, free T4, and T3 levels and
negative antithyroid antibodies. A thyroid profile (T4,
free T4 index, T3, rT3, and TSH)
was performed at baseline and 1, 3, 6, 9, and 12–15 months after GH
therapy began; a TRH stimulation test was performed at baseline and
after 1, 3, and 9 months of therapy. By 1 month, there were significant
decreases in T4, free T4 index, and
rT3, and significant increases in T3 and the
T3/T4 ratio. The changes from baseline values
were greatest at 1 month, were almost universal for all thyroid values,
and showed a gradual return to baseline from 3–12 months. There were
no clinical signs of hypothyroidism and no change in baseline or
TRH-stimulated TSH levels or in cholesterol levels, and all patients
grew at velocities expected for the treatment schedule. There is little
evidence for the development of clinically significant hypothyroidism
in the great majority of initially euthyroid patients after GH therapy
is begun. T4 supplementation is seldom needed in such
patients.
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Introduction
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THE DEVELOPMENT of central hypothyroidism
has been reported during GH therapy in children initially thought to
have normal thyroid function. The actual incidence is controversial,
however, with some studies showing a rare (1, 2, 3, 4, 5, 6) and others a high
(7, 8, 9, 10, 11) occurrence. The reasons for this wide discrepancy are unclear,
but may be related to the complex interaction between GH and the
hypothalamic-pituitary-thyroid axis. The issue has important clinical
implications. A recent analysis of endocrine therapy in over 2300
patients showed that 29% of children with idiopathic GH deficiency and
61% of children with organic GH deficiency were also receiving thyroid
hormone therapy (12). To clarify this issue, we monitored the acute
effects of GH on the hypothalamic-pituitary-thyroid axis in euthyroid
children with previously untreated GH deficiency during the first year
of therapy.
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Experimental Subjects
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Fifteen naive GH-deficient patients were sequentially recruited.
GH deficiency was defined as a peak GH level of 10 ng/dL or less
(Kallestad Quantitope, Austin, TX) in response to two standard
stimulation tests (iv arginine followed by oral clonidine) in a patient
with a growth velocity of 6 cm/yr or less if younger than 5 yr or of 5
cm/yr or less if older than 5 yr. All patients were prepubertal (bone
age, 
10 yr for females and 11 yr for males), were taking no thyroid
supplementation, and had normal baseline endogenous thyroid function,
as assessed by normal TSH, T4, free T4, and
T3 levels and negative thyroid antibodies (antimicrosomal
and antithyroglobulin). No patient was taking any medication known to
interfere with thyroid metabolism (13). Eleven patients had idiopathic
GH deficiency. Four patients had organic GH deficiency, three had
received central nervous system radiation, and two had central diabetes
insipidus treated with desmopressin acetate (Rorer
Pharmaceuticals, Fort Washington, PA). Patients were
randomized for 1 yr to either daily (n = 8) or three times weekly
(n = 7) recombinant human GH therapy
(Protropin, Genentech, Inc., South San
Francisco, CA) at a standard sc dose of 0.30 mg/kg·week as part of a
multicenter treatment study. No other endocrine therapy was given
during the year of the study. This study was approved by the human
research review committee of the Medical College of Wisconsin and the
human rights review board of Childrens Hospital of Wisconsin. Written
informed consent was obtained from all families.
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Materials and Methods
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A thyroid profile [T4, free T4 index
(FT4I), T3, rT3, and TSH] was
performed before and 1, 3, 6, 9, and 12–15 months after GH therapy
began. Serum T4 and T3 were determined by RIA
(Diagnostic Products, Los Angeles, CA), with a normal
adult range of 64–154 nmol/L for T4 and 1.38–2.84 nmol/L
for T3 (14). The FT4I was calculated as the
product of T4 and the normalized T4 resin
uptake, with a normal range of 80–135 (15). Serum rT3 was
measured by RIA (Serono Laboratories, Norwell, MA), with a
normal adult range of 0.22–0.46 nmol/L (14). Standard TSH stimulation
(Protirelin, Abbot Labs, North Chicago, IL, 7
µg/kg iv; TSH drawn at 0, 10, 20, 30, 60, and 120 min) was performed
before and 1, 3, and 9 months after GH therapy. TSH was measured by an
immunoradiometric assay (Serono Laboratories), with a
normal range of 0.5–4.0 mU/L (14). The TSH area under the curve
was calculated by the trapezoidal rule. The large number of samples
required four assay runs for T4, T3, and TSH,
and two assay runs for rT3. Each run had its own standard
curve, internal control, and duplication. The interassay coefficient of
variation for T4 was 3.8% for 50–180 nmol/L; those for
T3 were 5.6%, 2.6%, and 3.2% for mean values of 0.08,
1.95, and 2.95 nmol/L, respectively; those for TSH were 22%, 3.4%,
and 2.5% for mean values of 0.5, 7.3, and 27.2 mU/L,
respectively (14). Insulin-like growth factor I (IGF-I) was measured at
baseline and 12 months (16). Fasting cholesterol was obtained at
baseline and after 6 and 12 months of therapy. At each clinic visit,
attention was given to signs or symptoms of hypothyroidism, such as
constipation, fatigue, cold intolerance, skin or hair changes, delayed
Achilles reflex relaxation phase, or poor response to GH therapy.
Statistical analysis was performed with SigmaStat for Windows (version
2.0, 1995, Jandel Scientific, San Rafael, CA). Data were analyzed for
normality (Kolmogorov-Smirnov test) and equal variance (Levine Median);
nonparametric testing was performed whenever data did not meet both
these criteria. Data from thrice weekly patients (n = 7) were
compared to those from daily patients (n = 8) by either Student’s
t test or the Mann-Whitney rank sum test. Baseline
auxological and laboratory data were compared within each group,
between groups, and as a combined group (n = 15) with end of year
data by either paired t test or Wilcoxon signed rank test.
As there were no significant differences in thyroid data between the
daily and the thrice weekly groups, all reported analyses were for the
combined group. Comparisons between the sampling points for thyroid
values were made with Friedman repeated measures ANOVA on ranks and the
Student-Newman-Keuls method for pairwise multiple comparisons
(P < 0.05 was considered significant). Exploratory
analyses with Pearson product-moment correlations were performed
between clinical variables (age; baseline and year-end height or height
age; baseline and year-end weight, ponderal index; baseline and
year-end growth velocity; and baseline and year-end height and velocity
SD score), between lab variables (all thyroid values;
baseline and year-end IGF-I), and between both clinical and lab
variables to detect possible predictive variables for the first year
growth velocity response (Vel-1 or Vel-1 SD score). To
allow for the large number of comparisons, we used a significance level
of P 0.01 for correlations. Both best subsets (for
optimum Cp and adjusted r2) and forward
stepwise regression analyses were then used to confirm significant
predictive variables with minimal multicollinearity for final models of
prediction of first year velocity (17). SD scores
(z-scores) were calculated from the National Center for Health
Statistics data (18).
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Results
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The daily group weighed less at baseline (18.3 vs. 25.4
kg; P = 0.04) and had a lower baseline (14.4
vs. 17.1; P = 0.007) and end of year
ponderal index (14.9 vs. 17.2; P = 0.04).
For all other auxological or biochemical parameters, there were no
significant differences between the daily and thrice weekly groups.
These included age; baseline or end of year height, height age, or
height SD score; baseline or end of year growth velocity
(Vel-1) or velocity SD score (Vel-1 z); baseline or end of
year IGF-I, or cholesterol; or any thyroid value at any time point.
All patients in both subgroups (daily and thrice weekly) and as a
combined group showed the expected increases in growth parameters and
IGF-I (Table 1
). These growth rates are
slightly better than those reported in the first year of therapy for
naive patients with GH deficiency by the National Cooperative Growth
Study (9.8 cm/yr for daily; 8.9 cm/yr for thrice weekly) (1, 19). There
was a significant negative correlation between the first year growth
velocity (Vel-1) and age, baseline height, baseline and year-end height
age, and baseline and year-end bone age. Thus, better treatment
velocity tended to occur in younger, shorter children who had lower
bone ages. However, there was no correlation between Vel-1 and baseline
or year-end height SD score; baseline velocity; baseline or
year-end predicted adult height or height SD score; or
baseline or year-end IGF-I values. The Vel-1 z-score did not correlate
with any auxological value or with any IGF-I level.
Individual changes in T4 are shown in Fig. 1. No patient had any clinical indication
of hypothyroidism, and all remained without T4
supplementation for the year of the study. One T4 value was
below the normal range: 57 nmol/L after 3 months of GH therapy (normal
adult range, 64–154 nmol/L). The T3 and TSH levels for the
same sample were 2.0 nmol/L (normal, 1.38–2.84 nmol/L) and 2.3 mIU/mL;
baseline T4 was 69 nmol/L, the lowest of the group; growth
velocity increased from 3.6 to 7.4 cm/yr. Although about half of the
patients showed a substantial return to baseline values by 3 months,
one half remained well below baseline until later in the treatment
year.
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Figure 1. Changes in T4 during the first
year of GH therapy. n = 15 for all months (some symbols overlap)
except month 12, where n = 13.
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Changes in mean T4, FT4I, rT3,
T3, and T3/T4 ratio are shown in
Figs. 2 and 3. The greatest change from baseline
always occurred by month 1, with a gradual recovery during months
3–12. The declines in T4, FT4I, and
rT3 were mirrored by increases in T3 and the
T3/T4 ratio. The changes were seen by month 1
in nearly all patients, occurring in the same direction in 11 of 15
patients for T4 (mean decline, -15.5%; baseline mean,
106.4 nmol/L; month 1 mean, 88.6 nmol/L), in 14 of 15 patients for
FT4I (mean decline, -17.3%), in 14 of 15 patients for
rT3 (mean decline, -21.3%; baseline mean, 0.30 nmol/L;
month 1 mean, 0.23 nmol/L), in 13 of 15 patients for T3
(mean rise, 14.0%; baseline mean, 2.37 nmol/L; month 1 mean, 2.66
nmol/L), and in all 15 patients for T3/T4 ratio
(mean rise, 35.9%). There were no significant changes in either
baseline TSH values or TRH-stimulated peak TSH or area under the curve
values during the year (Table 2).
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Figure 2. Changes in T4, FT4I,
rT3, T3, and T3/T4
ratio during the first year of GH therapy. The mean ±
[scap]sd are shown for each sampling point. n = 15 for all
months except where noted. Significant (P 0.05,
by repeated measures ANOVA) changes from baseline (marked by
downward arrow) are shown by asterisks above the
error bar. Significant changes from month 1 (marked by
upward arrow) are shown by asterisks below the
error bar. Thus, when the series of top
asterisks ends, the value is no longer significantly different
from and has essentially returned to baseline. The series of
bottom asterisks marks recovery from the point of
maximal change, which was always the month 1 point.
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The rT3 month 1 level correlated with Vel-1 (r =
0.659; P = 0.008); the T4 baseline
level correlated with Vel-1 SD score (r = 0.641;
P = 0.010). There were no correlations (at
P 0.01) between Vel-1 or Vel-1 SD score
and any other thyroid value or with the change from month 0 to month 1
for any thyroid value. There were no significant changes in cholesterol
levels (Table 1
), nor were there any correlations between any
cholesterol level at any time point and any thyroid hormone level at
any time point, including peak TSH levels or the change in thyroid
levels between baseline and month 1.
Baseline T4, FT4I, and T3
correlated with all subsequent values, respectively (except month 1 for
FT4I and T3). Thus, patients remained for the
most part in the same respective positions for all thyroid hormone
levels; each showed approximately the same percent changes. Both
T4 and FT4I correlated positively with
T3 at all time points (except month 9). Thus, patients with
higher T4 values also had higher T3
values throughout the study. T4 and FT4I also
correlated positively with rT3 at all but baseline values.
However, T3 did not correlate (even negatively) with
rT3 at any time point.
All clinical and laboratory variables selected with best subsets
regression analysis for a predictive model of Vel-1 showed high
multicollinearity; no sets could be produced with forward stepwise
regression. All models reduced to simple correlations between at most
one single independent variable and Vel-1; thus, it was not possible to
develop a multiple linear regression model to account for the variance
in Vel-1. As only the baseline T4 value correlated with the
Vel-1 SD score, no multiple regression analysis was
attempted for that dependent variable.
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Discussion
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This study shows that shifts in thyroid hormone levels are very
common during the first year of GH therapy in children who are
initially euthyroid. Clinical hypothyroidism, however, is very
uncommon. Although almost all children showed a decline in
T4 values, only one T4 value was below the
normal range, and all T3 levels were within or slightly
above the normal adult range (14). There were no clinical signs of
hypothyroidism, no change in baseline or TRH-stimulated TSH levels, and
no changes in cholesterol levels as might be seen with hypothyroidism
(20), and all patients grew at the velocities expected for the
treatment schedule.
The mechanism of these shifts remains unclear. They are of rapid onset
(16, 21, 22) and gradual resolution; they occur in children (21, 23, 24, 25) and adults with GH deficiency, even during T4
therapy (23, 26), and in normal adults (16, 22, 27). Some of these
changes may be due to a GH-induced increase in peripheral conversion of
T4 to T3 and a decrease in conversion of
T4 to rT3 (16, 23, 24, 26, 27, 28, 29). GH produces
increases in extracellular water, which could have indirect effects on
thyroid hormone kinetics. However, this study was not designed to
evaluate such kinetics. Whatever the mechanism, the increase in
T3 levels and the decreases in T4 and
rT3 levels can be seen as temporary perturbations, with the
patient remaining euthyroid as evidenced by a normal growth response to
GH and a lack of change in TSH levels.
Some have suggested that GH inhibits TSH release (16, 23, 28, 29),
perhaps via increased somatostatinergic tone or by the negative
feedback of an increased T3 level. Jorgensen found
decreased nocturnal TSH surge in GH-deficient adults treated with GH
(30), but Rose could not find such a change in children with idiopathic
short stature (6). Sato reported increased TSH release in GH-deficient
children treated with GH (24), whereas Demura reported a mixed
population, with some children showing no change in TSH and some
developing a delayed and sustained response to TRH during GH therapy
(31). Conners (32) and Porter (33) found a reversible suppression of
TRH-stimulated TSH in GH-deficient children, which returned to
pretherapy responses after several months of continuing GH therapy.
Others, like us, have found no change in either baseline or
TRH-stimulated TSH levels in GH-deficient children (3, 21, 34), in
normal adults (35), or in GH-deficient adults (26) during GH therapy.
All of these studies differ somewhat in subjects, GH dose, sample
timing, and TSH assays. None, including ours, determined whether there
were changes in relative distribution volumes, relative clearance
rates, or production rates of thyroid hormones.
In a recent survey of pediatric endocrinologists (36), we found that
86% of respondents routinely recheck thyroid hormone status during the
first year of GH therapy, with 28% retesting at 3 months,
29% at 6 months, and 22% at 12 months. Total and free
T4 and TSH are usually measured (79%, 49%, and 82%,
respectively), whereas total and free T3 are rarely
determined (14% and 4%, respectively). As we have shown, about one
half of patients will have T4 levels below baseline
with unchanged TSH levels after 3–6 months of GH therapy, a bichemical
combination that could lead to the frequent impression that a
dysfunctional hypothalamic-pituitary-thyroidal axis had been uncovered.
Supplemental thyroid hormone might then be prescribed as a prophylactic
measure regardless of the clinical status or growth response, because
the balanced rise in T3 levels would not have been
recognized. Indeed, such a policy of rechecking T4 levels 3
months after GH therapy had begun and supplementing those with
declining levels resulted in T4 treatment of almost 50% of
previously euthyroid, GH-deficient patients at our institution. At
best, such inappropriate supplementation would be an unnecessary
expense and inconvenience, but it may add some risk of excess bone age
advancement with reduction of final height (37), decreased bone mineral
density (38, 39), or cardiac conduction abnormalities (40).
In summary, a transient decrease in T4, rT3,
and FT4I and a transient increase in T3 occur
almost universally in previously euthyroid children during the first
year of GH therapy. These children remain clinically euthyroid and do
not require T4 supplementation. All thyroid values return
to pretreatment levels by 3–6 months of continued GH therapy.
T4 supplementation should be considered only if there is a
persistent decline in both T3 and T4
levels.
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Acknowledgments
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We thank Sam Refetoff, M.D., for performing the thyroid assays,
and Joyce Kuntze, R.N., for help in obtaining the data.
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Footnotes
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1 This work was supported in part by a grant from Genentech,
Inc. 
Received April 15, 1998.
Revised August 9, 1998.
Revised May 28, 1998.
Accepted July 8, 1998.
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S. Porretti, C. Giavoli, C. Ronchi, G. Lombardi, M. Zaccaria, D. Valle, M. Arosio, and P. Beck-Peccoz
Recombinant Human GH Replacement Therapy and Thyroid Function in a Large Group of Adult GH-Deficient Patients: When Does L-T4 Therapy Become Mandatory?
J. Clin. Endocrinol. Metab.,
May 1, 2002;
87(5):
2042 - 2045.
[Abstract]
[Full Text]
[PDF]
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Abstract
Introduction
