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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 6 1879-1884
Copyright © 1997 by The Endocrine Society

Pediatric Endocrinology

Growth Hormone-Binding Protein in Normal and Pathologic Gestation: Correlations with Maternal Diabetes and Fetal Growth1

Ross Barnard, Fung-yee Chan and H. David McIntyre

Co-operative Research Center for Diagnostic Technologies, Queensland University of Technology (R.B.), Brisbane, Queensland 4001; and Mater Mothers’ Hospital, South Brisbane, Queensland 4101, Australia

Address all correspondence and requests for reprints to: Dr. Ross Barnard, Co-operative Research Center for Diagnostic Technologies, Queensland University of Technology, Gardens Point, Brisbane, Queensland 4001, Australia; or Dr. David McIntyre, Mater Mothers’ Hospital, Raymond Terrace, South Brisbane, Queensland 4101, Australia.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
To date, measurements of GH-binding protein (GHBP) during human pregnancy have been carried out using assays susceptible to interference by the elevated levels of human placental GH typical of late gestation. We recruited a large cohort of pregnant women (n = 140) for serial measurements of GHBP and used the ligand immunofunctional assay for GHBP. For normal gravidas, GHBP levels fell throughout gestation. Mean levels were 1.07 nmol/L (SE = 0.18) in the first trimester, 0.90 nmol/L (SE = 0.08) at 18–20 weeks, 0.73 nmol/L (SE = 0.05) at 28–30 weeks, and 0.62 nmol/L (SE = 0.06) at 36–38 weeks. GHBP levels in the first trimester correlated significantly with maternal body mass index (r = 0.58; P < 0.01). GHBP levels in pregnancies complicated by noninsulin-dependent diabetes mellitus (NIDDM) were substantially elevated at all gestational ages. The mean value in the first quarter (2.29 nmol/L) was more than double the normal mean (P < 0.01). In contrast, patients with insulin-dependent diabetes mellitus (IDDM) showed reduced GHBP concentrations at 36–38 weeks. The correlation between body mass index and GHBP is consistent with a metabolic role for GHBP during pregnancy, as is the dramatic elevation in GHBP observed in cases of NIDDM. At 36 weeks gestation, GHBP was significantly elevated (P < 0.01) in those women whose neonates had low birth weight (<10th percentile). In early gestation (<14 weeks), GHBP tended to be higher in women whose fetuses were designated to be at risk of intrauterine growth retardation (1.39 nmol/L; n = 4; compared with 1.07 nmol/L in normals), but this did not reach statistical significance.

Although both NIDDM and IDDM pregnancies are at risk of fetal macrosomia, their GHBP concentrations are markedly divergent. This paradox and the roles of glucose and insulin in the regulation of GHBP during gestation warrant further investigation.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
EARLY PREGNANCY is an anabolic phase, a period of fat and protein storage while the fetus is small. In contrast, late pregnancy is a catabolic phase, with redistribution of maternal nutrients to support fetal growth (1). The underlying biochemical and hormonal mechanisms influencing these changes are not well understood. Human placental GH (hGH-v) is a regulator of maternal insulin-like growth factor I (IGF-I) (2, 3) and has a spectrum of metabolic activities comparable to that of pituitary growth hormone (hGH-N) (4). The high levels of GH-v measured from midgestation in human pregnancy (3) are likely to impact on maternal metabolism, placental metabolism, and substrate supply to the fetus, either directly or as mediated by IGF-I (5). Furthermore, it has been observed that maternal concentrations of GH-v and IGF-I are decreased in cases of intrauterine growth retardation (6).

Any effects of GH-v on fetal growth and maternal metabolism could be modulated by the high affinity GH-binding protein (GHBP) (7, 8) in the maternal circulation. For more complete understanding of the GH axis during pregnancy, it is necessary to make accurate measurements of the gestational profile of GHBP in normal and pathological pregnancy. Such measurements may have prognostic value in relation to maternal metabolic disorders and fetal growth outcome.

Previous studies of GHBP during human pregnancy have used assays that are potentially susceptible to interference by the high concentrations of GH-v that are present in late gestation. In the present study we employed a modification of the ligand immunofunctional assay developed by Carlsson and colleagues (9) and since tested extensively by others (10, 11, 12). This assay has been shown not to be susceptible to interference by hGH (11).

The aims of this study were 1) to document maternal serum concentrations of GHBP in normal and diabetic pregnancies, 2) to define reference ranges for GHBP at different gestational ages, 3) to detect possible pathological changes in this carrier protein in diabetic gestation or in pregnancies with a risk of fetal growth abnormality, and 4) to detect any correlation between maternal GHBP concentration, previous intrauterine growth retardation (IUGR), or macrosomia and outcome of the pregnancy in terms of neonatal size.


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

Consent forms and the study protocols were approved by the Mater Mothers’ Hospital and the Queensland University of Technology ethics committees. Patients gave formal written consent to participate in the study after receiving information from a member of the study staff.

Because clinical abnormalities of fetal growth such as macrosomia or IUGR are generally only detected late in the second trimester, an attempt was made to recruit women who were at risk of such growth abnormalities on the basis of previous obstetric history or associated conditions. Thus, the subjects were recruited into the following groups, based on maternal characteristics: 1) normal pregnancy; 2) preexisting insulin-dependent diabetes (IDDM); 3) preexisting noninsulin-dependent diabetes (NIDDM); 4) IUGR risk (within this group, 65% had had previous pregnancies complicated by IUGR, 26% were hypertensive, and 9% were heavy smokers); 5) risk of macrosomia (within this group, 80% had had previous pregnancies complicated by macrosomia, 4% were markedly obese, and 16% had had previous gestational diabetes); and 6) IUGR detected antenatally on ultrasonography.

Nondiabetic women underwent a 50-g oral glucose challenge test at 28 weeks gestation to exclude gestational diabetes. The cut-off value for this screening test was a venous plasma glucose level of 7.8 mmol 1 h after the 50-g load.

Separate nonheparinized blood samples were collected for the study. Serum was separated and stored at -20 C. The samples for GHBP assay were taken at the following gestational ages: less than 14 weeks (K<14), 18–20 weeks (K18), 28–30 weeks (K28), and 36–38 weeks (K36). Serial ultrasound measurements were performed at the latter three gestational ages to confirm estimates of gestational age and to assess fetal growth. Ultrasonographically detected IUGR was generally noted after 28 weeks. Thus, the majority of women in group 6, described above, had only one data point contributing to the study.

Fetal outcome data collected at delivery included weeks of gestation at delivery, gender, birth weight, head circumference, and crown-heel length. Percentile measurements for birth weight and head circumference, corrected for weeks of gestation at delivery, were calculated for each infant. The z (SD) scores for birth weight, corrected for gestational age and gender [(z = birth weight - mean birth weight)/SD (birth weight)] were calculated for each infant to allow comparison of relative fetal sizes across a range of gestational ages.

The following definitions were used for categorizing fetal growth: IUGR, birth weight below the 10th percentile (normal range, >10th and <90th percentile); and macrosomia, birth weight above the 90th percentile. The birth weight data used for these comparisons were derived from a contemporary cohort of 21,221 singleton births at the Mater Mothers’ Hospital.

Ligand immunofunctional assay for GHBP

All GHBP measurements were performed using the ligand immunofunctional assay for GHBP (9) as modified by Rajkovic et al. (11). The assay was carried out as described by Rajkovic et al. (11). In brief, a standard curve was prepared by serial dilution of recombinant hGHBP in modified phosphate-buffered saline (11). Serum samples were incubated overnight with an excess of human GH (1 µg/mL), which displaces endogenous hGH or hGH-v and saturates unoccupied GHBP. This allows determination of the total GHBP content in human serum and eliminates interference by elevated GH concentrations, which are characteristic of late pregnancy. The serum and standards were added to a 96-well microtiter plates coated with monoclonal antibody 263 at a concentration of 10 µg/mL. After incubation for 120 min at room temperature, plates were washed, and rabbit anti-hGH antiserum was added at an appropriate dilution in phosphate-buffered saline containing 0.1% BSA and 10% normal mouse serum. Incubation continued for an additional 60 min at room temperature. After washing, this was followed by incubation for 45 min at 37 C with donkey antirabbit IgG conjugated to horseradish peroxidase (Jackson Laboratories, Bar Harbor, ME). Plates were washed 5 times with buffer, after which peroxidase substrate was added, and incubation was performed in the dark. After sufficient color development, absorbance was read at 405 nm, and the concentration of GHBP in serum standards was determined from the standard curve using the Bio-Rad microplate manager software (Bio-Rad, Hercules, CA). Monoclonal antibody 263 (anti-GHBP) was provided by Agen (Acacia Ridge, Australia). Recombinant hGHBP was provided by Dr. M. J. Waters (Department of Physiology and Pharmacology, University of Queensland, Brisbane, Australia). Polyclonal anti-hGH antiserum was provided by Dr. Ken Ho, Garvan Institute of Medical Research (Darlinghurst, Australia).

Statistical analysis

Differences between GHBP concentrations and other continuous variables at various weeks of gestation and between differing groups at recruitment were analyzed using ANOVA and analysis of covariance (ANCOVA). Significant overall differences detected on ANCOVA were analyzed further using the LSD (least significant difference) test. Fisher’s exact test was used to compare categorical variables. All tests were two tailed, and significance was accepted at the 5% level. Linear correlation analysis was used to explore the relationships between continuous variables. The r values quoted represent Pearson’s correlation coefficients. Multiple regression analysis was also undertaken, but offered no additional insights and is not reported. All statistical analyses were computed using Statistica for Windows (StatSoft, Tulsa, OK).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
A total of 140 women with singleton pregnancies were recruited into the study. Many women presented after the first trimester, so the number of samples at K<14 was limited (n = 33) compared to 97 at K18, 101 at K28, and 99 at K36. An additional 79 normal women consented to a first trimester blood sample, but did not participate in the full study protocol. Of the latter group, prepregnant weight was available for 65 and body mass index (BMI) for 56. The 56 BMI measurements plus BMI measurements for 32 women of the original K<14 group constitute the measurements used in Fig. 1Go. Their results have been used in the correlation analyses performed with first trimester samples, but do not form part of the repeated measures comparisons for GHBP or other parameters in late pregnancy.



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  		Figure 1. Gestational profile for maternal GHBP in normal pregnancies. Columns with a different letter differ significantly (K<14 vs. K28; P < 0.03; other comparisons, P < 0.01; by two-way ANOVA followed by LSD). Error bars represent SEs.

 
Maternal characteristics classified according to recruitment indication are shown in Table 1Go. Women with IUGR detected antenatally were significantly younger than those in the normal control, IUGR risk, and macrosomia risk groups. Women with IDDM, NIDDM, or at risk of macrosomia were significantly heavier than the normal controls, and the diabetic groups also demonstrated significant elevation in body mass index. As a result, age, weight, and BMI were included as covariates in the ANOVA of GHBP levels between recruitment groups. Their inclusion did not alter the results of this analysis (see below).


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  		Table 1. Mean maternal characteristics

 
The characteristics of the babies delivered from these pregnancies are shown in Table 2Go. Babies in the IDDM, NIDDM, IUGR risk, and IUGR groups were delivered at significantly earlier gestational ages than the normal cohort. The mean birth weight was significantly lower in the NIDDM, IUGR risk, and IUGR groups due in part to premature delivery and was significantly greater in the macrosomia risk group. The birth weight z score was significantly elevated in IDDM patients and in the macrosomia risk group. The z scores were significantly lower in the IUGR risk group and in those with IUGR detected antenatally. Compared to that in normal subjects, the incidence of IUGR was significantly higher in the IUGR risk group (11% vs. 26%; P < 0.05), and the incidence of macrosomia significantly greater in the macrosomia risk group (11% vs. 44%; P < 0.05). Crown-heel length and head circumference were significantly decreased in the group with NIDDM or antenatally detected IUGR (P < 0.01).


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  		Table 2. Fetal characteristics

 
Thus, we were able to correctly identify patients as being at risk of abnormal growth at the time of recruitment. However, by no means were all of these pregnancies in fact complicated by growth anomalies. Also, as shown in Table 2Go, two babies born to mothers in the normal control group showed evidence of IUGR, and four showed evidence of macrosomia using the definitions outlined above. As a result, the data were compared not only by recruitment indication (Table 3Go), but also post-hoc, by classifying pregnancies according to fetal growth at delivery into IUGR, normal, and macrosomic groups (see Fig. 4Go).


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  		Table 3. GHBP during pregnancy by recruitment indication

 


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  		Figure 4. Comparison of GHBP concentration (mean ± SEM) at differing gestational ages in 140 gravidas classified by neonate’s birth weight percentile. The groups were: less than the 10th percentile (n = 22), 10–90th percentile (n = 92), and greater than the 90th percentile (n = 26). Columns with a different letter differ significantly (P < 0.02) from other columns for the same gestational age.

 
GHBP measurements

GHBP levels tended to fall throughout gestation. For normal gravidas, mean levels were 1.07 nmol/L (SE = 0.18) in the first quarter, 0.90 nmol/L (SE = 0.08) at 18–20 weeks, 0.73 nmol/L (SE = 0.05) at 28–30 weeks, and 0.62 nmol/L (SE = 0.06) at 36–38 weeks (by ANOVA, P < 0.01; Table 3Go).

In the first trimester, the GHBP concentration correlated significantly with maternal BMI (Fig. 2Go). This correlation was maintained either when data from all patients were pooled (r = 0.58; P < 0.01; n = 88) or when normal patients were considered separately (r = 0.64; P < 0.01). Table 4Go shows the correlations between maternal BMI or maternal weight and GHBP in the normal group for all stages of gestation.



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  		Figure 2. Correlation between maternal BMI and maternal GHBP concentration in early gestation. Eighty-eight BMI measurements were available for K<14 (P < 0.01). See Results for additional explanation.

 

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  		Table 4. Correlations between maternal BMI or maternal weight and GHBP

 
In pregnancies complicated by NIDDM, GHBP concentrations were significantly elevated at all gestational stages (Fig. 3Go). This elevation was most dramatic in the first quarter of gestation (normal, 1.07 nmol/L; NIDDM, 2.29 nmol/L; P < 0.01; Fig. 3Go). This effect remained significant (P < 0.01) after inclusion of maternal BMI and age as covariates in the ANCOVA (see Materials and Methods). In contrast, IDDM patients showed markedly reduced GHBP concentrations in the first trimester (P < 0.01) and at 36–38 weeks (P < 0.01; Fig. 3Go). GHBP in the first 14 weeks tended to be elevated in those women prospectively identified as at risk of IUGR (1.39 vs. 1.07 nmol/L in the normal group), but this trend did not reach statistical significance. However, at 36–38 weeks gestation, GHBP was significantly elevated in those women whose babies showed low birth weight [<10th percentile; 0.90 nmol/L (n = 20) vs. 0.60 nmol/L (n = 66); P < 0.0103; Fig. 4Go]. At gestational ages younger than 36 weeks in women whose neonates were small, the GHBP concentration did not differ from normal and did not correlate with the final birth weight.



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  		Figure 3. Comparison of GHBP concentration (mean ± SEM) at differing gestational ages in normal gravidas (n = 37) and patients with IDDM (n = 21) and NIDDM (n = 8). Columns with a different letter differ significantly (P < 0.01) from other columns for the same gestational age.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Much of the pathology of pregnancy is related to failure of fetal growth (13). Moreover, it is now increasingly recognized that IUGR has long term adverse consequences for childhood growth (14) and adult health (15), so it is important to understand the hormonal factors involved. Although many of the environmental and nutritional factors affecting fetal growth are known, information on the biochemical and hormonal mechanisms by which maternal nutritional status and pathology affect the growth of the fetus is still very limited.

In the human fetal circulation, GHBP is known to be present at low levels relative to that in the newborn infant (16, 17). In previous studies it was reported that the cord serum GHBP concentration correlated with gestational age and ponderal index (weight/length3), and, in agreement with earlier ontogeny studies, increased rapidly after birth (16), presumably paralleling increased GH receptor expression. The present study focused on maternal serum GHBP, as it would be likely to respond to metabolic changes or pathology in the mother that influence fetal growth. If this were the case, maternal serum GHBP measurements could provide a convenient means of monitoring fetal growth with possible prognostic utility.

Indeed, in the last 4 weeks of gestation, maternal GHBP was significantly elevated in those women who subsequently delivered babies with low birth weight. We also observed that the GHBP concentration tended to be elevated in the first quarter of gestation in women whose babies’ birth weights were less than the 10th percentile, although this did not reach significance.

Our finding of a steady decrease in the maternal concentration of GHBP during pregnancy is slightly different from the serial observations by Blumenfeld et al. (18). The latter group found an initial increase followed by a decline. However, in that study the subjects had been treated with gonadotropins, and such treatment could have resulted in an initial elevation of the GHBP concentration caused by increased estrogen levels (12). The reduction in GHBP seen with advancing gestation in human pregnancy contrasts with that in the rodent, in which GHBP increases throughout pregnancy (19, 20), reducing the concentration of unbound GH in the circulation (19).

An indicator of a possible metabolic role for GHBP in pregnancy is the observation that GHBP is markedly elevated across all stages of gestation in mothers with NIDDM. In IDDM, by contrast, the GHBP concentration is reduced at all stages of pregnancy. Although both NIDDM and IDDM pregnancies are at risk of fetal macrosomia, their GHBP concentrations are markedly divergent. This suggests the operation of divergent mechanisms of GHBP regulation in these different types of diabetes. The results contrast with observations by Mercado et al. (21) in nonpregnant subjects, who found GHBP to be reduced in IDDM and unchanged in NIDDM. Different regulatory mechanisms may be operating during pregnancy, or serum GHBP may be synthesized and released from different tissues. Indeed, GHBP is known to be synthesized by murine placental cells in vitro (22), but it remains to be established whether placental GHBP is actually released into the circulation in vivo.

Consistent with our findings, Luthman et al. (23) studied women with gestational diabetes mellitus at 35 ± 3 weeks gestation and found GHBP to be elevated. It is pertinent that Bjarnason and colleagues (24) have recently shown a correlation between peak insulin levels and GHBP in children, so a causal relationship between insulin levels and GHBP concentration is worth considering. However, the regulation of GHBP by insulin is likely to be different in nonpregnant and pregnant states, particularly in light of the contrast between our findings and those of Mercado and colleagues (21). Another plausible hypothesis is that glucose has a direct effect on the serum concentration of GHBP. Glucose is known to directly up-regulate GH receptor expression in vitro (25). The work of Harrison et al. (26) and Mullis et al. (27) suggests that such an up-regulation would be paralleled by an increased release of GHBP. It is relevant to note that glucose down-regulates hGH-v secretion by the human trophoblast in vitro (28). It remains to be seen whether down-regulation of hGH-v secretion and up-regulation of GHBP are consistent in vivo responses to elevated glucose concentrations.

It is well established that maternal glycemic status has a significant impact on fetal size. Wang and Chard (29) proposed an endocrine model to explain these effects, in which maternal glucose, insulin, and IGF-I are the key elements. The roles of maternal hGH-v and GHBP in this system remain to be determined (i.e. does GHBP respond to changes in maternal hGH-v and/or glucose concentrations, or does it drive these changes?). In conclusion, the striking finding of the present study is the substantial elevation of GHBP across all stages of gestation in women with NIDDM, which contrasts with the reduction in GHBP concentrations in IDDM patients. The existence of divergent GHBP concentrations in these different forms of diabetes has prompted further studies to clarify the relationship between acute changes in insulin concentration, glucose concentration, and hGH-v and changes in GHBP during pregnancy. An independent mechanism is likely to be involved in near-term elevations of GHBP associated with low birth weight.


   Footnotes
 
1 This work was supported by grants from Novo-Nordisk Australia and the Mater Hospital J. P. Kelly Foundation. A preliminary report of this work was presented at the 10th International Congress of Endocrinology, San Francisco, CA, June 1996. Back

Received November 21, 1996.

Revised February 20, 1997.

Accepted March 6, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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