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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 5 1973-1980
Copyright © 2001 by The Endocrine Society

Original Studies

Blood Growth Hormone-Binding Protein Levels in Premenopausal and Postmenopausal Women: Roles of Body Weight and Estrogen Levels1

Marta Bondanelli, Angelo Margutti, Maria Rosaria Ambrosio, Lorenzo Plaino, Luigi Cobellis, Felice Petraglia and Ettore C. degli Uberti

Department of Biomedical Sciences and Advances Therapies, Section of Endocrinology, University of Ferrara (M.B., A.M., M.R.A., E.C.D.U.), 44100 Ferrara, Italy; and Department of Obstetrics and Gynecology, University of Siena (L.P., L.C., F.P.), 53100 Siena, Italy

Address all correspondence and requests for reprints to: Ettore C. degli Uberti, M.D., Department of Biomedical Sciences and Advanced Therapies, Section of Endocrinology, University of Ferrara, Via Savonarola 9, 44100 Ferrara, Italy. E-mail: ti8{at}dns.unife.it


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
A substantial proportion of GH circulates bound to high affinity GH-binding protein (GHBP), which corresponds to the extracellular domain of the GH receptor. Current evidence indicates that nutritional status has an important role in regulating plasma GHBP levels in humans. In the present study the relationship among plasma GHBP levels, body composition [by bioelectrical impedance analysis (BIA) and dual energy x-ray absorptiometry (DEXA)] and serum estradiol (E2) was evaluated in premenopausal (n = 92) and postmenopausal (n = 118) healthy women with different body weight [three groups according to body mass index (BMI): normal, 18.5–24.99; overweight, 25–29.99; obese, 30–39.99 kg/m2]. Plasma GHBP levels were measured by high pressure liquid chromatography gel filtration. GH and insulin-like growth factor I levels were determined by immunoradiometric assay and RIA, respectively.

GHBP levels were significantly higher in premenopausal women with BMI above 25 kg/m2 (overweight, 3.789 ± 0.306 nmol/L; obese, 4.372 ± 0.431 nmol/L) than those observed in postmenopausal women (overweight, 1.425 ± 0.09 nmol/L; obese, 1.506 ± 0.177 nmol/L). No significant differences were found between normal weight premenopausal (1.741 ± 0.104 nmol/L) and postmenopausal (1.524 ± 0.202 nmol/L) women. In premenopausal women GHBP levels correlated positively with BMI (r = 0.675; P < 0.001), fat mass (FM; r = 0.782; P < 0.001; by BIA; r = 0.776; P < 0.001; by DEXA), truncal fat (TF; r = 0.682; P < 0.001), waist to hip circumference ratio (WHR; r = 0.551; P < 0.001), and E2 (r = 0.298; P < 0.05), whereas no significant correlation was found in postmenopausal women between GHBP levels and BMI, FM, TF, WHR, or E2. In normal weight pre- and postmenopausal women GHBP levels did not change between the ages of 20 and 69 yr. No statistically significant correlation was found between GHBP and age for all groups studied. Moreover, in two distinct subgroups of pre- and postmenopausal women, aged 40–49 yr, the direct relationship between GHBP levels and all indexes of adiposity were only observed in premenopausal women [BMI: r = 0.836; P < 0.001; FM: r = 0.745 (BIA) and r = 0.832 (DEXA); P < 0.001; TF: r = 0.782; P < 0.001; WHR: r = 0.551; P < 0.05], but not in postmenopausal women.

In conclusion, the present data indicate a strong direct correlation between GHBP and body fat in premenopausal, but not in postmenopausal women, whereas they failed to detect a relationship between GHBP and age. Therefore, these results suggest that endogenous estrogen status may be an important determinant of the changes in GHBP levels in women with different body weights.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
UNDER PHYSIOLOGICAL conditions, an estimated 40–50% of circulating GH in humans is carried by a high affinity GH-binding protein (GHBP), the structure of which corresponds to the extracellular domain of the GH receptor (GHR) (1, 2, 3, 4). It has been proposed that serum GHBP activity may provide an indirect measure of GHR status and an index of tissue responsivity to GH (2, 3, 4). Although the exact biological role of GHBP has not yet been determined, it has been shown to protect GH from degradation (5) and elimination (6) and to increase the half-life of GH in the circulation (7). This suggests that GHBP might potentiate GH action by prolonging the availability of GH to target tissues (8).

Current evidence indicates that nutritional status has a major role in regulating plasma GHBP levels in humans (9, 10, 11, 12, 13, 14). Plasma GHBP concentrations have been reported to increase in obese subjects (9, 10, 11, 12, 13) and to return to normal after diet-induced weight loss (14). On the contrary, plasma GHBP levels are decreased in patients with malnutrition, insulin-dependent diabetes mellitus, renal failure, liver cirrhosis, hypothyroidism, and critical illness (2, 9, 10). Moreover, GHBP levels have been reported to correlate positively with body mass index (BMI) and several measures of adiposity (9, 11, 13, 14, 15, 16). However, neither the precise mechanisms nor physiological significance of the serum GHBP changes associated with alterations in nutritional status and/or body composition are fully understood. There are several lines of evidence for estrogen as a positive regulator of GH axis in women (for review, see Refs. 17 and 18). Reduced activity of the somatotropic axis in menopause may indeed be secondary to estrogen deficiency (19, 20). At present, there is limited information about the influence of estrogen status on serum GHBP in women. In postmenopausal women, oral estrogen treatment has been found to increase GHBP levels (21, 22) which is believed to reflect hepatic GHR expression (23). Treatment of infertile women with human menopausal gonadotropin (hMG) and hCG also raises GHBP levels (24). The above observations highlight the importance of considering sex steroid milieu as an additional factor that may be involved in the control of GHBP activity. To assess whether estrogen status may influence the body composition-related alterations in plasma GHBP levels, we evaluated GHBP levels in a large group of pre- and postmenopausal women with different body weight.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

A group of 118 healthy postmenopausal women [age range, 40–69 yr (mean, 53.45 ± 0.56); BMI range, 19.1–39.1 kg/m2 (mean, 25.32 ± 0.35)] and a group of 92 premenopausal women [age range, 20–48 yr (mean, 28.30 ± 1.61); BMI range, 18.5–39.5 kg/m2 (mean, 26.9 ± 1.28)], with a history of regular menstrual cycles (25–35 days) were recruited to participate in the study. Menopausal status was previously determined by plasma FSH (>30 IU/L) and estradiol (E2; <92 pmol/L) concentrations. Women with a history of hepatic, renal, gastrointestinal, and endocrine disorders; anorexia nervosa; or other medical illness were excluded from the study. Physical examination, biochemical assays, and thyroid function tests were normal. No subjects were taking medications. The postmenopausal women had never received hormonal replacement therapy, whereas the premenopausal women had not received hormonal treatment for at least 6 months before the study. No subject exercised excessively (i.e. no more than 1 h of aerobic exercise five times weekly). The women were informed in detail about the nature and purpose of the experiments before consenting to participate in the study, the protocol of which had previously been approved by the local ethical committees.

Methods

Subjects were admitted at 0800 h after an overnight fast (10–12 h). An indwelling iv cannula was inserted in the forearm for blood sampling. After initial bed rest of at least 45 min, three baseline venous blood samples were drawn at 15-min intervals for GH determination. A blood sample for GHBP activity, insulin-like growth factor I (IGF-I), and E2 measurements was also taken. BMI was calculated as weight (kilograms) divided by height (meters) squared. The waist (W) to hip (H) circumference ratio (WHR) was determined measuring W as the minimum value between the iliac crest and the lowest rib margin, whereas H was determined as the maximum values over the buttocks.

Each group was divided into 3 subgroups depending on BMI: group I (BMI, 18.5–24.99 kg/m2) consisted of 40 premenopausal women of normal weight, group II (BMI, 25–29.99 kg/m2) consisted of 34 overweight premenopausal women, group III (BMI, 30–39.99 kg/m2) consisted of 20 obese premenopausal women; group IA (BMI, 18.5–24.99 kg/m2) consisted of 66 postmenopausal women of normal weight, group IIA (BMI, 25–29.99 kg/m2) consisted of 37 overweight postmenopausal women, and group IIIA (BMI, 30–39.99 kg/m2) consisted of 15 obese postmenopausal women. Furthermore, the relationship between GHBP levels and body composition was evaluated in 2 distinct groups of pre- and postmenopausal women, aged 40–49 yr.

Body composition

Body composition was determined by bioelectrical impedance analysis (BIA) and dual energy x-ray absorptiometry (DEXA).

BIA was performed by a multifrequency analyzer (HUMAN-IM SCAN, Dietosystem s.r.l., Milan, Italy) analyzing the bioelectrical response of the body over more than 250 frequency values, ranging from 300 Hz to 100 kHz. Resistance and reactance were measured in the supine position with electrodes placed in the middle of the dorsal surface of the right hand and food. The BIA measurements had a day to day coefficient of variation of 1.9%.

DEXA was performed with a total body scanner (QDR-1000/W Hologic, Inc., Waltham, MA), which uses an x-ray tube producing a collimated beam at two different photon energies (70 and 140 kVp) and a soft tissue calibration phantom containing three different thicknessess of fatty tissue equivalent material and three different thicknessess of lean tissue equivalent material. The measurements of total body fat mass (FM), total lean body mass (LBM), and truncal body fat (TF) were determined by the ratio of attenuation of the two effective energies of the beam. The trunk region was delineated by an upper and horizontal border below the chin, vertical borders lateral to the ribs, and a lower border formed by the oblique lines passing through the hip joints. This region included the upper body segment fat (abdominal fat) and excluded most of the fat from the hips and thighs. The coefficients of variation were 2.5% and 1.5% for FM and LBM, respectively.

Biochemical analytical methods

Blood samples were drawn into glass tubes containing 1 mg/mL ethylenediamine tetraacetate-2Na and were promptly centrifuged at 3000 x g for 15 min at 4 C. The plasma was frozen at -80 C until assay.

Plasma GH levels were measured by immunoradiometric assay with reagents supplied by Nichols Institute Diagnostics (San Juan Capistrano, CA). All samples were processed in duplicate in the same assay. The limit of detection was 0.05 µg/L. The intra- and interassay coefficients of variation were 3.3% and 6.1%, respectively. No abnormal human (h) GH concentrations (>10 µg/L) were found in the specimens analyzed.

Plasma IGF-I was determined by RIA using a commercially available kit (Medgenics Diagnostic S.A., Fleurus, Belgium), after acid-ethanol extraction from ethylenediamine tetraacetate plasma. All samples were processed in duplicate in the same assay. The intra- and interassay coefficients of variation were 9.6% and 6.1%, respectively.

GHBP activity was measured by the high performance liquid chromatography (HPLC)-gel filtration. Recombinant human (rh) GH (Saizen, Serono, Rome, Italy) was used to evaluate binding activity in serum after it was radiolabeled by the chloramine-T oxidation method, as described by Lesniak et al. (25), and subsequently separated from free 125I by Sephadex G-25M (Pharmacia, Uppsala, Sweden). The specific activity after iodination ranged from 100–150 µCi/µg. The [125I]rhGH was stored in aliquots of 200 µL at -20 C until use. Plasma samples (100 µL) were incubated for 16–18 h at 4 C with 100 µL potassium phosphate (0.1 mol/L, pH 7.0) and 0.1% BSA containing a fixed amount of [125I]hGH (2 x 105 cpm) in the absence and presence of different concentrations of unlabeled rhGH (0, 4, 10, 30, and 80 µg/L and 5 mg/L) to avoid binding data being affected by the endogenous levels of GH in the sample. The concentrations of radioinert ligand were verified by immunoradiometric assay. After filtration through a 0.45-µm pore size minifilter (Millipore Corp., Bedford, MA), the entire incubation mixtures were injected into a high performance liquid chromatograph (Pharmacia LKB, HPLC pump 2248), using a Protein Pack 300sw column (Waters, Millipore Corp., Milford, MA; 0.75 x 30 cm) to separate bound and free [125I]rhGH. Elution was performed autocratically using a degassed buffer (0.1 mol/L Na2SO4 and 0.1 mol/L potassium phosphate, pH 7.0) pumped at a rate of 0.5 mL/min, and radioactivity was recorded on line by an automatic {gamma}-detector (Radiomatic Flo-one, Packard, A Canberra Co., Downers Grove, IL). The bound and free [125I]rhGH concentrations were calculated by integrating the corresponding peaks of the Protein Pack 300sw elution pattern. The concentration of GHBP was obtained by a six-point Scatchard analysis of the binding data, performed with the program Ligand (26). The maximal binding capacity, obtained from the Scatchard plot, was accepted as a measure of the GHBP concentration when Spearman’s correlation coefficient between the Scatchard plot points was more than 0.95. If correlation coefficients were below 0.95, the GH binding analysis was repeated. The GHBP assay had intra- and interassay coefficients of variation of 4% and 11%, respectively.

E2 was determined by a commercially available RIA kit (Diagnostic Products, Los Angeles, CA). The intra- and interassay coefficients of variation were 4.3% and 5.5%, respectively.

Statistical analysis

Preliminary analysis of data confirmed the acceptability of the assumption of normal distribution and homogeneous variance using Bartlett’s test. ANOVA for repeated measures was used to compare the mean values within each group and between groups. If the F values were significant (P < 0.05), Student’s paired or unpaired t test was also used. Relationships between variables were analyzed by linear regression analysis. The basal levels of GH were obtained from the mean of the three values determined for each subject. Unless otherwise indicated the results are expressed as the mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The clinical and anthropometric characteristics of the women are shown in Table 1Go. As expected, postmenopausal women were significantly (P < 0.001) older than premenopausal women, and they showed lower E2 concentrations. No significant difference was found between the BMI of each subgroup, comparing premenopausal and postmenopausal women. However, in postmenopausal women, FM and TF for each subgroup were significantly (P < 0.05) higher than those in premenopausal women.


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  		Table 1. Clinical and anthropometric characteristics of 92 premenopausal and 118 postmenopausal women

 
The mean (±SEM) GHBP concentrations in all group studied are depicted in Fig. 1Go. In premenopausal women, GHBP levels were significantly (P < 0.001) increased in overweight (group II, 3.789 ± 0.306 nmol/L) and obese (group III, 4.372 ± 0.431 nmol/L) subjects compared with those in normal weight subjects (group I, 1.741 ± 0.104 nmol/L). In postmenopausal women, GHBP levels in overweight (group IIA, 1.425 ± 0.100 nmol/L) and obese (group IIIA, 1.506 ± 0.177 nmol/L) subjects did not significantly differ from those in women of normal weight (group IA 1.524 ± 0.202 nmol/L). Moreover, ANOVA showed significantly decreased GHBP levels in the postmenopausal women with BMI above 25 kg/m2 (groups IIA and IIIA) compared with those in premenopausal women (groups II and III), whereas no differences were observed between the two groups of normal weight subjects (groups I and IA).



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  		Figure 1. Plasma GHBP levels in pre- and postmenopausal women divided into subgroups with regard to BMI. Data are expressed as the mean ± SEM. **, P < 0.001 vs. normal weight subjects; ++, P < 0.001 vs. premenopausal women.

 
Figure 2Go shows plasma GHBP levels a function of age in normal weight, pre- and postmenopausal women. No age-related changes in GHBP levels were demonstrated between the ages of 20 and 69 yr. During the third decade, there were no differences in GHBP levels between premenopausal and postmenopausal women.



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  		Figure 2. GHBP levels in normal weight premenopausal ({blacksquare}) and postmenopausal ({square}) women as a function of age. The columns indicate the mean ± SEM in each decade, with the number of subjects in brackets.

 
The mean (±SEM) GH levels in all groups studied are depicted in Fig. 3Go. In premenopausal women, GH levels in obese subjects (group III, 1.06 ± 0.16 µg/L) were significantly (P < 0.001) lower than those in normal weight (group I, 2.59 ± 0.43 µg/L) and overweight (group II, 2.20 ± 0.27 µg/L) subjects. No significant difference was found between normal weight (group I) and overweight (group II) subjects. In postmenopausal women, no significant difference in plasma GH levels was observed among the three subgroups (IA, IIA, and IIIA). Moreover, ANOVA showed significantly (P < 0.002) decreased GH levels in postmenopausal women with normal BMI (groups IA, 1.38 ± 0.13 µg/L) compared with those in premenopausal women (group I, 2.59 ± 0.43 µg/L), whereas no significant difference was observed among the groups with BMI above 25 kg/m2 (groups II, III, IIA, and IIIA).



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  		Figure 3. Plasma GH levels in pre- and postmenopausal women divided into subgroups with regard to BMI. Data are expressed as the mean ± SEM. **, P < 0.001 vs. normal weight subjects; ++, P < 0.001 vs. premenopausal women.

 
The mean (±SEM) IGF-I levels in all groups studied are depicted in Fig. 4Go. In premenopausal women, IGF-I levels in overweight (group II, 17.69 ± 1.03 nmol/L) and obese (group III, 16.94 ± 1.14 nmol/L) subjects were significantly (P < 0.05) lower than those in normal weight subjects (group I, 20.70 ± 0.84 nmol/L). No significant difference was found between overweight (group II) and obese (group III) subjects. In postmenopausal women, no significant difference in plasma IGF-I levels was observed among the three subgroups (IA, IIA, and IIIA). Moreover, ANOVA showed significantly (P < 0.001) decreased IGF-I levels in each group of postmenopausal women compared with those in the corresponding group of premenopausal women.



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  		Figure 4. Plasma IGF-I levels in pre- and postmenopausal women divided into subgroups with regard to BMI. Data are expressed as the mean ± SEM. *, P < 0.05 vs. normal weight subjects; ++, P < 0.001 vs. premenopausal women.

 
In all premenopausal women (Table 2Go), a positive correlation was shown between GHBP and BMI (r = 0.675; P < 0.001) and between GHBP and FM as determined both by BIA (r = 0.782; P < 0.001) and by DEXA (r = 0.776; P < 0.001), whereas a negative correlation was detected between GHBP and LBM (DEXA: r = -0.780; P < 0.001) or fat-free mass (FFM; BIA: r = -0.775; P < 0.001). A positive relationship was also found between GHBP levels and TF (r = 0.682; P < 0.001) or WHR (r = 0.551; P < 0.001). In all postmenopausal women, no statistically significant correlation was found either between GHBP and BMI or between GHBP and FM (BIA and DEXA) or TF or WHR. Moreover, GHBP showed a positive relationship (r = 0.298; P < 0.05) with concentrations of E2 in premenopausal women, but not in postmenopausal women.


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  		Table 2. Linear regression analysis of plasma GHBP, GH, and IGF-I vs. body fat measures, age, and E2

 
No statistically significant correlation was observed between GHBP and age for all groups studied.

Linear regression analysis (Table 2Go) failed to detect any statistically significant correlation between GH levels and all parameters studied in the two groups of pre- or postmenopausal women.

In premenopausal women IGF-I levels showed a negative relationship with BMI (r = -311; P < 0.02) and TF (r = -294; P < 0.05), but not with FM and WHR, whereas in postmenopausal women no statistically significant correlation was found between IGF-I and the indexes of adiposity. In both groups, IGF-I concentrations were inversely related to age and positively related to E2 concentrations.

To analyze whether estrogen status might be a factor linking nutritional status with plasma GHBP level independently of age, we evaluated the relationship between GHBP levels and body composition in two distinct groups of pre- and postmenopausal women, aged 40–49 yr). The clinical and anthropometric characteristics of the women are depicted in Table 3Go.


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  		Table 3. Clinical and anthropometric characteristics of 14 premenopausal and 33 postmenopausal women, aged 40–49 yr

 
There was no significant difference in BMI between premenopausal and postmenopausal women. However, TF was significantly (P < 0.05) higher in postmenopausal compared with premenopausal women, whereas no significant difference was found in total FM, as determined by DEXA or BIA.

In this group of individuals aged 40–49 yr (Fig. 5Go), a correlation between GHBP levels and BMI (r = 0.836; P < 0.001), FM (BIA: r = 0.745; P < 0.001; DEXA: r = 0.832; P < 0.001), TF (r = 0.782; P < 0.001), and WHR (r = 0.551; P < 0.05) and a negative correlation between GHBP and LBM (r = -0.746; P < 0.001) or FFM (r = -0.830; P < 0.001) were detected in premenopausal women. No significant correlation between GHBP levels and BMI, FM, LBM, FFM, TF, or WHR was found in postmenopausal women.



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  		Figure 5. Correlation between GHBP and body fat measurements in pre- and postmenopausal women, aged 40–49 yr.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study was designed to elucidate the relationship among body composition, estrogen status, and plasma GHBP levels in two groups of healthy pre- and postmenopausal women, testing the hypothesis that estrogen status may be an important determinant of GHBP generation. The data presented in the paper indicate that a strong direct relationship between GHBP and FM is apparent in premenopausal, but not postmenopausal, women.

These results combined with the observation that aging is not associated with substantial changes in GHBP levels in normal weight women suggest that endogenous estrogen status may be an important determinant of the close relationship between GHBP and body FM in women regardless of age. To our knowledge, the demonstration that estrogen deficiency in postmenopausal women is associated with the disappearance of the positive relationship between GHBP and FM has not been previously reported.

Circulating levels of GHBP in overweight and obese premenopausal women are higher than those in normal weight women and are positively correlated with FM and TF. These results are in line with previous studies indicating that nutritional status influences GHBP levels in humans (9, 10, 11, 12, 13, 14), with a direct close relationship between GHBP and BMI and body fat (15, 16). GHBP levels have been reported to be elevated in obesity and restored to normal after a diet-induced massive weight loss (14), supporting the view that adipose tissue may be an important source of GHBP (27, 28). It is well known, however, that GHRs are most abundant in the liver. Therefore, an alternative explanation could be that an increase in free fatty acids and insulin associated with visceral obesity would promote the generation of GHBP from hepatic GRHs, contributing to the increase in circulating levels of GHBP in obese subjects (11). The physiological significance of elevated GHBP in obesity is still unknown. There is evidence that adiposity, and particularly visceral fat, negatively modulates GH/IGF-I axis function by reducing GH and IGF-I release and increasing GH clearance (18). This is supported by the finding of a significant decrease in GH and IGF-I levels in overweight and obese women compared with normal weight premenopausal women. Assuming that circulating levels of GH may reflect the extracellular domain of the GHR and provide an index of the GHR status of target tissues, an increase in GHBP levels in overweight and obese premenopausal women may imply an up-regulation of the GHRs to compensate for the decrease in GH and IGF-I levels associated with augmented BMI.

We did not find any significant correlation between the parameters studied and GH levels (mean of three morning values). However, we cannot exclude that more frequent sampling of GH levels might lead to different correlations between GH levels and GHBP activity and/or between GH levels and body composition, estrogen status, and age.

In postmenopausal, normal weight women, GHBP levels are not significantly different from those in premenopausal women of comparable weight, whereas in the group of overweight and obese postmenopausal women, the increase in BMI is not associated with an augmentation in GHBP similar to that observed in premenopausal women. These results demonstrate that there is no significant relationship between GHBP and any of the various measures of body fat (BMI, FM, TF, and WHR). These data indicate that the positive correlation between fatness and GHBP level documented in premenopause disappears in postmenopause. Our observation that GHBP levels remain relatively stable between the ages of 20 and 69 yr suggests that a possible influence of aging on GHBP generation does not provide a satisfactory explanation for the facts that we did not find any further increase in GHBP levels in postmenopausal women despite the increment in BMI and that no correlation was detected between changes in body composition and GHBP level. Accordingly, data from cross-sectional studies show that GHBP levels do not change significantly during adult life (for review, see Ref. 7) and progressively decline between 60 and 98 yr of age in both genders (29). The present data indicate that the age-related decline in GH secretion is not associated with changes in GHBP levels between the 20 and 69 yr of age, but further longitudinal studies are required to address the question of alterations in serum GHBP levels during aging.

An additional possible explanation could be that endogenous estrogen status may influence GHBP/GHR levels and interfere with the mechanisms underlying the changes in GHBP/GHRs induced by different body weights. Accordingly, the demonstration that a close positive relationship persists between GHBP and FM and TF in middle-aged premenopausal women, but not in E2-deficient age-matched postmenopausal women, is consistent with a role for estrogen status in obesity-related alterations of GHBP production.

The concentration of GHBP in serum has been reported to be higher in females than in males in both humans (13, 30) and animals (31). However, the interaction between GHBP and gonadal steroids is complex, and the role of estrogen in the regulation of GHBP in humans has not yet been fully characterized. Oral estrogen administration has been reported to increase GHBP levels in postmenopausal women (21, 22) and in young women with Turner’s syndrome (32). Moreover, treatment of infertile women with hMG and hCG increases GHBP levels (24). On the contrary, other studies have shown a negative relationship between estrogen and GHBP level in girls (13) and premenopausal women (33). There is evidence in humans that proteolytic cleavage of the membrane-anchored receptor [either the full-length GHR or the recently described truncated GHR form (34, 35)] releases the GHR extracellular domain, which thereby becomes the GHBP (4, 36). The possibility that estrogen could be involved in a direct manner in GHR/GHBP production cannot be dismissed. However, studies on the effect of estrogen on GHR/GHBP generation have yielded conflicting results, probably due to differences in tissue or species. In fact, although in castrated rabbits E2 has been reported to decrease the liver expression of GHR messenger ribonucleic acid (37), in rats (38) and steers (39) E2 has been found to stimulate GHR expression.

Therefore, we speculate that the GHBP level remains unchanged in overweight and obese postmenopausal women compared with premenopausal women as a result of an alteration in body composition-related GHBP production due to estrogen deficiency during menopause. To date the mechanisms underlying the obesity-induced alterations in GHBP/GHR production remain unknown. Our data, however, emphasize the importance of considering estrogen status in the study of factors regulating GHBP production and the relationship between GHBP and body composition. Further studies are required to clarify these relationships.


   Footnotes
 
1 This work was supported by grants from the Italian Ministry of University and Scientific and Technological Research (Project 9906153187-004, 40% in 1999 and 60% in 1999) and Azienda Ospedaliera di Ferrara-Arcispedale S. Anna. Back

Received October 18, 2000.

Revised January 10, 2001.

Accepted January 18, 2001.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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