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Endocrine Care |
Department of Internal Medicine (J.P.T.S., G.F.F.M.P., A.R.M.M.H., A.G.H.S.), Division of Endocrinology, and Department of Chemical Endocrinology (F.G.J.S.), University Medical Centre Nijmegen, Geert Grooteplein 8, The Netherlands
Address all correspondence and requests for reprints to: J. P. T. Span, M.D., University Medical Centre St. Radboud, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: j.span{at}aig.azn.nl
Abstract
In GH-deficient adults, rhGH has pronounced effects on total body
water, fat free mass, and fat mass. Recently, we observed a gender
difference in IGF-I responsivity to rhGH that was sex steroid
dependent. The aim of the present study was to assess the effect of
rhGH therapy on body composition parameters with due attention to the
gender differences in biological responsiveness to rhGH. Forty-four
women [36.9 ± 11.9 yr (mean ± SD)] and 33 men
(37.2 ± 13.8 yr) with GH deficiency were studied every 6 months
during 2 yr. The treatment goal was to achieve IGF-I levels within the
age-adjusted normal range. Total body water, fat free mass, and fat
mass were measured by bioimpedantiometry. To reach the treatment goal,
the daily rhGH dose (IU/kg/d) had to be significantly higher in women
than in men at all time intervals. During rhGH therapy, total body
water and fat free mass increased significantly in both men and women
(P 
0.01 by ANOVA), but changes were more
pronounced in men. Fat mass decreased during rhGH treatment and reached
its nadir at 6 months, which was more pronounced in men than in women
(P = 0.02 by ANOVA). After the initial decrease,
fat mass increased again and reached baseline values after 2 yr of
treatment. In both men and women, the total body water and fat free
mass increases were closely related to the IGF-I increments
(P < 0.001 by Pearson’s correlation test). The
decrease in fat mass correlated significantly with the increase in
IGF-I in men (r = -0.89, P < 0.001), not in
women. Confirming our earlier data, IGF-I responsivity to rhGH was
significantly higher in men than in women at all time intervals
(P < 0.01 by ANOVA). Total body water and fat free
mass responsivities were also higher in men than in women
(P < 0.01 by ANOVA). In conclusion, gender
differences in IGF-I responsivities to rhGH are accompanied by gender
differences in the extent of body composition changes to rhGH. Probably
because of these gender differences in IGF-I responsivity, the
increases of total body water and fat free mass to rhGH replacement
were greater in men than in women. Remarkably, however, in men, only
total body water and fat free mass responses relative to changes in
IGF-I increased during the 2 yr of rhGH therapy (P
= 0.02 and 0.01, respectively, by ANOVA). In our opinion, this
phenomenon might be explained by the increasing target organ
sensitivity to IGF-I over time.
SOON AFTER THE introduction in 1957 of GH therapy in children, it appeared that GH administration not only influenced skeletal growth but also had significant effects on body composition (1, 2). In GH-deficient adults, the first short-term controlled studies of the effect of GH also reported pronounced effects on muscle and fat mass (3, 4) as well as on body fluid (5). Recently, we (6, 7) and others (8, 9, 10) observed a gender difference in rhGH dose requirement and IGF-I responsivity to rhGH in GH-deficient adults treated for 24 months. Men appeared more sensitive to rhGH than women. Furthermore, we demonstrated that oral estrogens significantly increased rhGH requirement in women, whereas androgens decreased rhGH requirement in men. Very recently, Cook et al. (11) and Janssen and colleagues (12) confirmed the estrogen effect.
Until now, only a few rather short-term studies (9–12 months) have been published dealing with a gender difference in rhGH-induced changes in body composition. Johansson et al. (9) found a greater loss of total body fat in adult GH-deficient men treated for 9 months with rhGH than in women. Cuneo et al. (10) reported greater fat free mass (FFM) increments in GH-deficient men treated with rhGH for 12 months than in women. Very recently, Hayes et al. (13) reported a beneficial effect of rhGH treatment in 12 GH-deficient adults for 12 months only in men, not only with respect to the increase in total body water (TBW) and lean body mass but also with respect to the decrease in fat mass (FM). In a very large study dealing with 665 GH-deficient adults treated for 1 yr with rhGH, Bengtsson et al. (14) reported a greater decrease in waist/hip ratio, but not in FM, in men than in women.
These data prompted us to study the effects of rhGH therapy for a longer period (2 yr) on body composition parameters with due attention to gender and IGF-I responsivity to rhGH.
Subjects and Methods
Patients
Seventy-seven patients [44 women, age 36.9 ± 11.9 yr; 33
men, age 37.2 ± 13.8 yr (mean ± SD)] with GH
deficiency were included in this analysis. Patients were on GH
substitution for at least 1 yr. GH deficiency was diagnosed when an
arginine test revealed a peak GH concentration < 10 mU/liter
(13). Only patients with hypothalamic-pituitary pathology
or patients treated with GH in childhood were exposed to an arginine
test. Thirty-three women and 23 men received sex hormone substitution
therapy (Table 1
). Three of these women,
all older than 50 yr, received transdermal estrogen replacement; the
remaining 30 women had oral estrogen substitution. Nineteen men
received parenteral androgen substitution, whereas only 4 had oral
replacement therapy. None of the men had transdermal substitution.
Twenty-one patients (11 premenopausal women and 10 men) were eugonadal.
Fifty-seven patients received corticosteroid replacement therapy (Table 1). Sixty-nine patients needed thyroid hormone substitution (Table 1).
Hormone replacement was considered adequate when the patients were
euthyroidal (serum T4 between 54 and 154
nmol/liter), euadrenal (morning plasma cortisol between 0.19 and 0.55
µmol/liter), and eugonadal (men, testosterone between 11 and 45
nmol/liter; women, midcycle estradiol of 350-1800 pmol/liter).
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Patients were treated with rhGH (Genotropin, Pharmacia & Upjohn, Inc., Stockholm, Sweden; or Humatrope, Eli Lilly & Co., Indianapolis, IN) in varying doses. The treatment goal was to achieve an IGF-I concentration within the age-corrected—not gender-corrected—normal range (mean ± 2 SD) for our laboratory (15). All patients started with 1 IU/d, and rhGH dose was adjusted each visit if necessary. The visits were monthly during the first 6 months and twice a year thereafter. Data for up to 24 months were included in this analysis. Serum IGF-I concentration and TBW, FM, and FFM were measured every 6 months. Not all patients had a complete data set, because we included all patients with at least 1 yr of GH substitution. For the within-subject time x gender effect, a subset of 44 patients (24 women, age 36.3 ± 12.7 yr; 20 men, age 37.5 ± 13.1 yr) was used. This subgroup of patients had a complete data set. Serum IGF-I was determined by RIA as described previously (15). Body composition parameters were measured using bioimpedance analysis with the Akern 101 device (Equip Medikey, Gouda, The Netherlands). Apparatus-specific conversions as determined by the manufacturer were used.
TBW responsivity was defined as 
TBW (liters)/rhGH dose (IU/kg/d); FM
responsivity was defined as FM (kg)/rhGH dose (IU/kg/d); and FFM
responsivity was defined as FFM (kg)/rhGH dose (IU/kg/d).
Statistical methods
Data are given as means ± SEM, except for age, for which means ± SD are used. Statistical significance of the differences between genders at baseline was calculated using Student’s t test (significance denoted by P). Treatment effects over time and between genders during treatment were assessed using ANOVA (significance denoted by P*). Correlations between responsivities of IGF-I, FM, FFM, and TBW to rhGH were calculated using Pearson’s correlation test (significance denoted by P**). Statistics were calculated using SPSS 9.0 for Windows (SPSS, Inc., Chicago, IL).
To exclude major bias, the results of the 77 patients, including some with an incomplete data set, were compared with a subset of patients (n = 44) with a complete data set.
Results
Baseline body proportions, rhGH dose, and IGF-I values
Baseline weight did not differ significantly between the genders at the start of GH therapy (women, 72.9 ± 2.9 vs. men, 77.1 ± 3.1 kg; P > 0.10). The mean TBW (31.8 ± 0.8 vs. 41.2 ± 1.3 liters) and FFM (44.6 ± 1.5 vs. 56.9 ± 2.1 kg) were both significantly lower in women than in men (P < 0.001); the hip to waist ratio (1.13 ± 0.01 vs. 1.06 ± 0.01) and the FM (25.8 ± 1.5 vs. 21.6 ± 1.6 kg) were higher (P < 0.01) in women. Baseline serum IGF-I (8.8 ± 0.1 vs. 12.2 ± 1.0 nmol/liter) was significantly lower in GH-deficient women than in men (P < 0.05). Baseline IGF-I SDS was -1.9 ± 0.9 for women and -1.4 ± 0.8 for men.
Influence of gender on rhGH dose and IGF-I responsiveness
Confirming earlier data, men needed significantly lower rhGH doses (with and without correction for weight) than women. Yet, higher serum IGF-I levels were achieved in men, which is in line with their higher rhGH responsivity (data not shown).
Effects of gender on rhGH-induced changes in body composition
No statistically significant changes in weight (Fig. 1) or hip to waist ratio (data not shown)
were observed during rhGH therapy in women or men (P* >
0.10).
|
).
FM decreased significantly (P* < 0.01 for the first 6
months) in both men and women, but the maximum decrease in FM during
rhGH substitution was more pronounced in men (4.6 ± 0.9
vs. 1.4 ± 0.5 kg, respectively; P* = 0.02)
(Fig. 1). At 24 months, FM values had returned to baseline in both men
and women.
During the first 6 months of treatment, FFM increased significantly
during rhGH therapy in both men and women (P* 0.01). From
6 months on, a tendency to further increase was observed only in men.
The sex difference was statistically significant (P* = 0.05)
(Fig. 1).
Responsivity of body composition parameters related to the weight-corrected rhGH dose
TBW responsivity [i.e. TBW (liters)/rhGH dose
(IU/kg/d)] showed a statistically significant increase over time only
in men (P* < 0.01) (Fig. 2).
TBW responsivity was more pronounced in men than in women
(P* < 0.01).
|
).
FFM responsivity increased significantly during rhGH therapy
(P* 0.01) only in men, again not in women (P*
> 0.10) (Fig. 2). FFM responsivity was more pronounced in men than in
women (P* < 0.01).
Changes of body composition during rhGH therapy relative to changes in IGF-I
At all time points, there was a statistically significant
correlation between baseline IGF-I levels and the changes in TBW
(r = +0.37, P** < 0.05) and FM (r = -0.38,
P** < 0.05) but not in FFM (r = +0.26, P**
> 0.10) in the group as a whole. For women, there was a significant
correlation between baseline IGF-I levels and FM (r = -0.52,
P** < 0.01) but not TBW (r = +0.28, P**
> 0.10) or FFM (r = +0.11, P** > 0.10). For men,
no statistically significant correlation between baseline IGF-I and
TBW, FM, or FFM could be demonstrated.
There was a statistically significant increase of TBW responsivity
relative to IGF-I [i.e. TBW (liters)/IGF-I
(nmol/liter)] only in men (P* < 0.02) (Fig. 3). In both men and women, the increase
in TBW during rhGH therapy was directly correlated to the increases in
IGF-I, although the correlation coefficient was lower in women than in
men (women, r = +0.81, P** < 0.005; men, r =
+0.95, P** < 0.005).
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IGF-I remained virtually unchanged
during the 24 months of rhGH therapy in both genders. Remarkably, the
decrease in FM seen during the first 6 months of rhGH substitution
was statistically significantly correlated with the IGF-I increase only
in men (r = -0.89, P** < 0.001), not in women
(r = -0.65, P** > 0.10).
FFM responsivity related to IGF-I increased significantly during
rhGH therapy (P* < 0.01) in men, but again not in women.
There were no statistically significant differences between the
relative FFM responsivities in men and women at any time. The changes
in FFM correlated directly with the IGF-I increases in both men and
women, although again the correlation coefficient was lower in women
(r = +0.80, P** < 0.001) than in men (r = +0.95,
P** < 0.001).
Bias estimation
The incompleteness of the data sets of some patients could have introduced a confounding factor that could give rise to some bias. To get an idea of the extent of the bias introduced by the different subjects participating in different comparisons at different times, a subgroup of 44 patients with a complete data set was analyzed. The baseline characteristics of the subgroup were not different from those of the complete group. Therefore, the subgroup of 44 patients can be considered a random sample of the complete group of 77 patients. Calculations of the time effect in this subgroup resulted in comparable statistical significance with the exception of TBW in men during the last 18 months of treatment, for which P* changed from 0.02 in the complete group to <0.01 in the subgroup. The gender effect was the same in both populations. With respect to the ratios used, all statistical significances were the same in both populations. This indicates that the bias introduced by the incompleteness of the data set is marginal compared with the effects and does not interfere with the conclusions drawn from the complete population.
Discussion
This study demonstrated that TBW and FFM increased significantly during 2 yr of rhGH therapy, confirming short-term data from others (8, 9, 11, 13, 14). The hip to waist ratio, however, did not change during the rhGH replacement, which is at variance with the results of Bengtsson et al. (14), but confirms the data of others (8, 9). Remarkably the increases in TBW and FFM were more pronounced in men than in women, reflecting the higher IGF-I responsivity in men, which was confirmed in this study. The FM decrease was also more pronounced in men than in women at 6 months. After this period, the changes in FM leveled off and were no longer statistically significantly different between the genders. These data are partially in line with the findings reported in short-term studies after administration of fixed doses of GH (10, 13, 14). The dose used in those studies was conventional (i.e. 0.25 IU/kg·wk), which gives rise to supraphysiologic IGF-I concentrations, especially in men (10). In the present study, comparable results were obtained using lower doses of GH (0.167 ± 0.015 IU/kg·wk), indicating that rhGH titration using IGF-I levels is as effective as a higher fixed dose when body composition parameters are taken into account. During treatment, TBW and FFM responsivities increased in men but not in women. FM responsivity remained stable during the rhGH replacement in both men and women. Our data partially confirm the findings of Johansson et al. (9), who found a gender difference in loss of body fat after 9 months of treatment with a fixed rhGH dose (0.25 IU/kg·wk). Cuneo et al. (10), in a 1-yr multicenter study, reported a sex difference in FFM in favor of men after 6 and 12 months of substitution with rhGH (fixed dose of 0.25 IU/kg/d); however, no gender difference was observed in FM decrease. Our data confirmed the finding of Hayes et al. (13), who, in a short-term study of 9 months, observed a statistically significant increase in TBW and FFM only in men and a decrease in FM, again only in men. In our study, which lasted 2 yr, we demonstrated that using IGF-I-titrated rhGH substitution, the relative responsivity of FM was not influenced by gender if there was an equal IGF-I concentration.
The absolute TBW and FFM changes in response to rhGH were directly
correlated to the increase in IGF-I; the correlation coefficients,
however, were higher in men than in women. Unlike in men, FM and
IGF-I were not statistically significantly correlated in women.
These latter data are in line with the data of Johansson et
al. (9), who also observed a significant negative
relation between the decrease in total body fat and the increase in
serum IGF-I only in men. Other authors did not mention such a
relationship (13, 14).
One may assume that the more pronounced changes in body composition
parameters in men can be explained by the greater changes in IGF-I
found. This, however, appears not to be the only reason, because in our
study the TBW and FFM increments in men relative to the IGF-I
actually increased during the 2 yr of rhGH treatment. In our opinion,
this phenomenon might be explained by increasing target organ
sensitivity to IGF-I over time. For FM, no such time-related change was
found for men or for women.
Previously, we demonstrated increasing responsivity of IGF-I to rhGH in androgen-treated men (7, 8) with the risk of overtreatment. Unfortunately, in the present study, it was not possible to unravel the modulating role, if any, of androgen replacement on the relative responsivity of body composition parameters, because almost all men already received androgen substitution before the start of rhGH replacement. Similarly, oral estrogen replacement may have attenuated the beneficial effect of rhGH-induced changes in body composition in GH-deficient women. Because the majority of the women had oral estrogen substitution, this may have led to relative resistance to rhGH (12). Further studies are necessary to assess the role of oral estrogens on the relative responsiveness to rhGH-induced IGF-I increase.
In summary, the present study demonstrates that the greater IGF-I responsivity to rhGH in GH-deficient men than in women is accompanied by more pronounced changes in TBW and FFM in the former. FM initially decreased, but after 24 months of treatment, baseline values were reached, indicating only a temporary effect of rhGH on FM in both men and women. Remarkably, in men only, TBW and FFM responses relative to IGF-I increased during the 2-yr treatment period, which in our opinion suggests increasing target organ sensitivity to IGF-I over time. The permissive role, if any, of androgens in facilitating this response remains to be elucidated.
Acknowledgments
Footnotes
Abbreviations: FFM, Fat free mass; FM, fat mass; TBW, total body water.
Received May 8, 2000.
Accepted May 1, 2001.
References
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