|Year : 2017 | Volume
| Issue : 1 | Page : 14-20
Measurement of serum sex hormone-binding globulin as an early marker for gestational diabetes
Fatma S El Desh M.B.B.CH. 1, Gamal F El Naggar1, Manal A Eid2, Engy A Ibrahim1
1 Department of Internal Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt
|Date of Submission||25-Jan-2017|
|Date of Acceptance||14-Mar-2017|
|Date of Web Publication||28-Jun-2017|
Fatma S El Desh
Department of Internal Medicine, Faculty of Medicine, Tanta University, Alestad Street, Tanta
It is estimated that 90% of all pregnancies associated with diabetes are due to gestational diabetes mellitus (GDM). If GDM is not properly treated, there is an increased risk for adverse maternal, fetal, and neonatal complications. Therefore, early diagnosis and accurate screening of GDM are necessary to reduce maternal and fetal morbidity and to help prevent or delay the onset of type 2 diabetes in the mother and offspring. The diagnosis of GDM appears to unmask women with inadequate β-cell reserves and gives a window of time for any prevention techniques, an idea that has been used in the Diabetes Prevention Program of the National Institutes of Health.
The aim of this study was to compare serum levels of serum sex hormone-binding globulin (SHBG) in pregnant women with GDM with levels in nondiabetic pregnant women as an early marker for GDM.
Patients and methods
This was a comparative study with a total of 45 participants in their second and third trimester of pregnancy. Group I (pregnant nondiabetic) included 25 women and group II included 20 women (pregnant with GDM). Maternal serum SHBG and high-sensitivity C-reactive protein (hs-CRP) were measured and compared between the two studied groups.
SHBG concentrations were lower in the GDM group (SHBG=27.32±14.52) compared with the control group (SHBG=507.61±187.79) (P=0.0001). hs-CRP concentrations were higher in the GDM group (2964.65±315.06) than in the control group (2254.00±585.48), but with low sensitivity of 60.00% and accuracy of 77.78%.
SHBG is valuable for screening women for GDM risk, and hs-CRP as an inflammatory marker is not a dependable screening test for GDM.
Keywords: gestational diabetes mellitus, high-sensitivity C-reactive protein, screening and diagnosis of gestational diabetes mellitus, sex hormone-binding globulin
|How to cite this article:|
El Desh FS, El Naggar GF, Eid MA, Ibrahim EA. Measurement of serum sex hormone-binding globulin as an early marker for gestational diabetes. Tanta Med J 2017;45:14-20
|How to cite this URL:|
El Desh FS, El Naggar GF, Eid MA, Ibrahim EA. Measurement of serum sex hormone-binding globulin as an early marker for gestational diabetes. Tanta Med J [serial online] 2017 [cited 2017 Oct 20];45:14-20. Available from: http://www.tdj.eg.net/text.asp?2017/45/1/14/209101
| Introduction|| |
Pregnancy is characterized by endocrine and metabolic changes to ensure energy and nutrient supply to the fetus. Placental diabetogenic hormones cause insulin resistance and hyperinsulinemia, which predispose diabetes development in pregnancy. Abnormal glucose tolerance first recognized in pregnancy is defined as gestational diabetes mellitus (GDM) .
GDM is characterized by metabolic defects such as β-cell dysfunction and insulin resistance . There is a potential pathophysiological relationship between GDM and type 2 diabetes. It has been hypothesized that GDM may represent the transient phase of a latent metabolic syndrome and may become clinically apparent later in life as type 2 diabetes mellitus . The significance of GDM in pregnancy is due to adverse maternal and neonatal outcomes, including pre-eclampsia, birth trauma, macrosomia, polyhydramnios, and operative delivery . The diagnosis and appropriate treatment of GDM can decrease maternal and fetal complications .
At present, an early diagnostic test − oral glucose tolerance test (OGTT) − is performed in pregnant women with obesity, past history of GDM, glycosuria, BMI more than 30 kg/m2, previous history of a macrosomic baby (>4.5 kg), or family history of diabetes .
Limited epidemiological studies suggest that high-sensitivity C-reactive protein (hs-CRP), which is an early marker of low-grade inflammation, may be predictive of GDM. Therefore, GDM itself, as a state of subclinical inflammation, has not been directly evaluated .
Plasma serum sex hormone-binding globulin (SHBG) is secreted in the liver under hormonal and nutritional control; it is important for the transport and the regulation of distribution of sex steroids . Because of the inhibitory effects of both insulin and insulin-like growth factor-1 on SHBG secretion in vitro, it has been proposed that SHBG levels could be a marker of insulin resistance and/or hyperinsulinism in humans .
Low SHBG level is a strong predictor of risk of type 2 diabetes mellitus in women and men . The inverse association of SHBG with risk of type 2 diabetes mellitus is stronger in women than in men . Treatment for GDM includes three different therapies: dietary changes, exercise, and pharmacotherapy .
| Patients and methods|| |
This study was conducted at the Internal Medicine Department, Tanta University Hospital, during the period between November 2014 and May 2015. The present study included 50 women in their second and third trimesters of pregnancy, selected from outpatient clinics and wards of the Gynecology and Obstetrics Department of Tanta University Hospital. Patients with known diabetes mellitus and hypertension, pre-eclampsia, or gestational hypertension were excluded from the study. Pregnant women below 18 years of age (SHBG decline at puberty, with uncertain reason, partly from androgens that suppress SHBG levels) with chronic liver disorders, renal impairment, or hemolysis were also excluded.
They were divided into two groups: group I included 25 pregnant nondiabetic women, and group II included 20 pregnant women with GDM (five cases were lost to follow-up and were excluded from our study).
Both groups were subjected to complete history taking, full clinical examination, laboratory investigations including routine investigations (random blood sugar, complete blood analysis, coagulation profile, urine analysis, and renal and liver function tests), specific investigations (OGTT, SHBG, and hs-CRP), pelvic-abdominal ultrasound, prenatal follow-up, and neonatal assessment. Treatment for group II (GDM group) included diet, exercise, and insulin.
Patients undergoing the OGTT for GDM followed a carbohydrate-loading regimen for 3 days preceding the test (>150 g carbohydrates) and an overnight fast of 8–14 h the night before; patients were restricted from smoking. Two or more of the following glucose values had to be met or exceeded for the diagnosis of GDM: fasting≥105 mg/dl (5.8 mmol/l), 1 h≥190 mg/dl (10.5 mmol/l), 2 h≥165 mg/dl (9.2 mmol/l), and 3 h≥145 mg/dl (8.0 mmol/l).
Patients with a single abnormal value on a 3-h OGTT are likely to exhibit some degree of glucose intolerance. If the abnormal value on the OGTT is obtained before 26 weeks of gestation, a repeat OGTT should be performed ∼4 weeks later.
Maternal blood samples for SHBG and hs-CRP were collected from the antecubital vein into a nonheparinized tube in second and third trimester. Samples were immediately centrifuged, and serum was separated and analyzed.
The collected data were organized, tabulated, and statistically analyzed using Statistical Package for the Social Sciences software (version 16; SPSS Inc., Chicago, Illinois, USA). For quantitative data, the range, mean, and SD were calculated. For qualitative data, comparison between groups was carried out using the χ2-test with Yate’s continuity correction. For comparison between means of two groups of parametric data of independent samples, Student’s t-test was used. For comparison between means of two groups of nonparametric data of independent samples, the Z-value of the Mann–Whitney U-test was used.
| Results|| |
Our study included 45 pregnant women − 25 pregnant, nondiabetic women (group I) and 20 pregnant women with GDM (group II) ([Table 1],[Table 2],[Table 3],[Table 4],[Table 5],[Table 6],[Table 7] and [Figure 1]).
|Table 1 Basic data (Age, BMI, family history of diabetes) of the studied pregnant women in both groups (n=45)|
Click here to view
|Table 2 Oral glucose tolerance test mean values of plasma glucose (fasting and after the first, second, and third hour) among the studied pregnant women (n=45)|
Click here to view
|Table 3 Maternal outcome and complications among the studied pregnant women|
Click here to view
|Table 4 Fetal and neonatal complications among the studied pregnant women|
Click here to view
|Table 5 Mean values of serum high-sensitivity C-reactive protein among the studied pregnant women|
Click here to view
|Table 7 Degree of sensitivity from the area under the receiver operating characteristic curve for high-sensitivity C-reactive protein and serum sex hormone-binding globulin serum levels|
Click here to view
|Figure 1 Area under the receiver operating characteristic (ROC) curve for sensitivity of serum high-sensitivity C-reactive protein and serum sex hormone-binding globulin (SHBG) as a diagnostic marker of gestational diabetes mellitus among pregnant women (n=45).|
Click here to view
| Discussion|| |
In the present study, the mean age of women in the control group was 26.92±5.39 years (range 19–39), and the mean age of women in the GDM group was 27.80±4.30 years (range 24–42), but this difference was statistically nonsignificant (P=0.556). This is in agreement with a study by Caglar et al. , who found that women in the GDM group were older than those in the control group.
BMI values in our study (P=0.789) were comparable with the values obtained by Anderson and Zhiqun , who found no significant difference between both groups with respect to BMI.
Regarding family history of diabetes, we found that it was more prevalent among GDM cases − one case (4%) with positive family history was in the control group, whereas nine cases (45%) with positive family history were in the GDM group (P=0.001). These results agree with the results of Caglar et al. , where 11.1% of cases with a family history of diabetes were in the control group, whereas 66.7% with a family history of diabetes were in the GDM group (P<0.001).
Regarding 100-g OGTT, there were statistically significant differences in fetal bovine serum (mean of 82.00±6.15 for the control group and 140.35±52.65 for the GDM group) after the first hour (mean of 168.96±9.59 for the control group and 292.30±77.71 for the GDM group), after the second hour (mean of 139.76±16.41 for the control group and 215.45±74.42 for the GDM group), and after the third hour (mean of 99.28±19.88 for the control group and 153.95±56.15 for the GDM group) (P=0.0001 for all). Our findings are in agreement with Caglar et al. , who showed that plasma glucose levels determined by 100-g OGTT were statistically higher in the GDM group after the first, second, and third hour.
Regarding maternal complications, two cases (8%) from the control group and five cases (25%) from the GDM group developed pregnancy-induced hypertension (P=0.003). Similar results were obtained by Gasim  − 5.9% of cases from the control group and 18.2% of cases from the GDM group developed pregnancy-induced hypertension (P<0.0001). Considering cesarean delivery, in our study, there were 15 cases (75%) in the GDM group and 10 cases (40%) in the control group who delivered by cesarean section (P=0.041). These results are comparable with the study by Gasim , who found a cesarean section rate of 24.1% in the GDM group versus 12.3% in the control group (P<0.0019).
Regarding neonatal complications, in our study, neonates of women with GDM had a significantly higher mean birth weight than babies born of mothers from the control group − 25% of the neonates were macrosomic (birth weight≥4000 g) in the GDM group versus 4% in the control group (P=0.036). Gasim  reported 12.7% macrosomic neonates in the GDM group, whereas in the control group 5% were macrosomic (P=0.0186). We reported 15% of neonates to be small for gestational age (SGA) (≤2.6 kg) in the GDM group and 4% in control group. Gasim  reported 7.3% of SGA cases in the GDM group and 6.8% in the control group.
The percentage of poor neonatal suckling in the GDM group was 44 versus 12% in the control group (P=0.033). We found a significant difference in need for incubator among neonates in each group − 50% in the GDM group versus 16% in the control group (P=0.021). Gasim  reported that ∼16.4% of babies delivered by GDM mothers were admitted to the neonatal ICU for more than 24 h compared with 5.5% in the control group (P=0.0003).
In our study, hs-CRP concentration in the control group was 2254.00±585.48 ng/ml (range 1000–3150) with a median of 2400.00, whereas in the GDM group it was 2964.65±315.06 ng/ml (range 2000–3340) with a median of 3000.00. The difference between the two means was found to be statistically significant (P=0.0001).
The area under the receiver operating characteristic (ROC) curve in the present study was 0.123 (with 95% confidence interval ranging from 0.021 to 0.225), which reflects that serum hs-CRP (ng/ml) had no significant sensitivity in the diagnosis of GDM in pregnant women. Serum hs-CRP had sensitivity of 60%, specificity of 92%, 85.71% positive predictive value, 74.19% negative predictive value, and 77.78% accuracy for diagnosing GDM among pregnant women, depending on a cutoff value of 3000 ng/ml.
Its elevation in the GDM group supposes that GDM, in itself, is a state of subclinical inflammation (cytokines such as interleukins-6 and tumor necrosis factor-α induce insulin resistance and stimulate the acute-phase inflammatory response). It also explains the role of subclinical inflammation in the pathogenesis of insulin resistance, metabolic syndrome, and associated vascular diseases; however, hs-CRP is also elevated in other comorbidities such as infection, trauma, obesity, and pregnancy complications such as pre-eclampsia, chorioamnionitis, and preterm labor. Therefore, it can be used only in determining disease progression or effectiveness of treatments and not as a marker for GDM as it has low sensitivity and accuracy.
We agree with the results of a study by Leipold et al. , who demonstrated that women with GDM had significantly higher hs-CRP serum levels than normal pregnant women at 37–38 weeks of gestation, but during OGTT (24–28 weeks of pregnancy) there was no significant difference between the two groups. Our results are comparable with Qiu et al. , who demonstrated that elevated CRP is associated with GDM risk.
Regarding SHBG, the present study demonstrated that the mean SHBG concentration in the control group was 507.61±187.79 nmol/l (ranged 66.20–820) with a median of 546.00, whereas in the GDM group it was significantly lower with a mean of 27.32±14.52 nmol/l (ranged 1.50–51.70) and a median of 27.50. The difference between the two means was found to be statistically significant (P=0.0001).
The decline in SHBG level in GDM can be explained by insulin resistance and compensatory hyperinsulinemia. Low levels of SHBG occur in similar cases of insulin resistance such as metabolic syndrome, polycystic ovary syndrome, and nonalcoholic fatty liver disease. SHBG levels also negatively correlated with fasting glucose levels, and were markedly lower in uncontrolled fasting glucose level. The risk of developing GDM may also depend on 1alterations in free sex steroid concentrations and SHBG genotype and its specific receptor (RSHBG), implying a direct role in the regulation of intracellular signaling pathways.
We agree with Anderson and Zhiqun , who showed that the mean SHBG concentration in the control group was 71.33±30.58 nmol/l, whereas in the GDM group it was significantly lowered with a mean of 53.64±31.91 nmol/l (P=0.03).
In our study, the mean SHBG in the GDM group was lower than 60 nmol/l, and as already suggested by Ding et al.  at this concentration women are at a higher risk for type 2 diabetes mellitus.
The predictive accuracy of SHBG as a marker for GDM was determined by the ROC curve analysis (area under curve: 1.000, with 95% confidence interval ranging from 1.000 to 1.000), which reflects that serum SHBG (nmol/l) has negative significant sensitivity in the diagnosis of GDM in pregnant women. SHBG had sensitivity of 100%, specificity of 76.00%, 76.92% positive predictive value, 100% negative predictive value, and 86.67% accuracy for diagnosing GDM among pregnant women, depending on a cutoff value of 497 nmol/l.
Our study is in agreement with the study by Caglar et al. ; the predictive accuracy of SHBG early in gestation as a marker for GDM was found by the ROC curve analysis (area under curve: 0.866, 95% confidence interval: 0.773–0.959). The cutoff point of 97.47 had the best sensitivity and positive predictive value in this evaluation. An SHBG threshold for 97.47 nmol/l had a sensitivity of 80.0%, specificity of 84.6%, positive predictive value of 50.0%, and negative predictive value of 95.7% .
Similar results were obtained by Mehrabian and Rezae . These results are also nearly comparable with the results by Anderson and Zhiqun .
| Conclusion|| |
SHBG levels were significantly lower in pregnant women with GDM; therefore, SHBG can, in the future, be used as both a diagnostic marker and a monitoring tool in patients with GDM. SHBG seems to be a more practical, sensitive tool and reliable in nonfasting states. hs-CRP cannot be used as a screening test to predict development of GDM during pregnancy.
Future studies including a larger number of patients and longer duration are required to better clarify the exact role of SHBG as an early marker for gestational diabetes.
The authors thank all the participants who helped during this study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Metzger B, Lowe L, Dyer A, Trimble E, Chaovarindr U, Coustan D et al.
HAPO Study Cooperative Research Group Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 2008; 358:1991–2002.
Buchanan T. Pancreatic B-cell defects in gestational diabetes: implications for the pathogenesis and prevention of type 2 diabetes. J Clin Endocrinol Metab 2001; 86:989–993.
Clark M, Qiu C, Amerman B, Porter B, Fineberg N, Aldasouqi S et al.
Gestational diabetes: should it be added to the syndrome of insulin resistance? Diabetes Care 1997; 20:867–871.
Ferrara A, Weiss N, Hedderson M, Quesenberry C, Selby J, Ergas I et al.
Pregnancy plasma glucose levels exceeding the American Diabetes Association thresholds, but below the National Diabetes Data Group thresholds for gestational diabetes mellitus, are related to the risk of neonatal macrosomia, hypoglycemia and hyperbilirubinaemia. Diabetologia 2007; 50:298–306.
Crowther C, Hiller J, Moss J, McPhee A, Jeffries W, Robinson J. Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) Trial Group. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med 2005; 352:2477–2486.
American Diabetes Association. Classification and diagnosis of diabetes. Sec. 2. In Standards of Medical Care in Diabetes. Diabetes Care 2016; 39(Suppl 1):S13–S22.
Pendergrass M, Fazioni E, DeFronzo R. Noninsulin dependent diabetes mellitus and gestational diabetes mellitus: same disease, another name? Diab Rev 1995; 3:566–583.
Rosner W, Hryb D, Kahn S, Nakhla A, Romas N. Interactions of sex hormone-binding globulin with target cells. Mol Cell Endocrinol. 2010; 316:79–85.
Pugeat M, Nader N, Hogeveen K, Raverot G, Déchaud H, Grenot C. Sex hormone-binding globulin gene expression in the liver. Drugs and the metabolic syndrome. Mol Cell Endocrinol 2010; 316:53–59.
Ding E, Song Y, Manson J, Hunter D, Lee C, Rifai N et al.
Sex hormone-binding globulin and risk of type 2 diabetes in women and men. N Engl J Med 2009; 361:1152–1163.
Ding E, Song Y, Malik V, Liu S. Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA 2006; 295:1288–1299.
Langer O. Oral anti-hyperglycemic agents for the management of gestational diabetes mellitus. Obstet Gynecol Clin North Am 2007; 34:255–274.
Caglar G, Ozdemir E, Cengiz S, Demirtaş S. Sex-hormone-binding globulin early in pregnancy for the prediction of severe gestational diabetes mellitus and related complications. J Obstet Gynaecol Res 2012; 38:1286–1293.
Anderson S, Zhiqun Z. Sex hormone binding globulin in gestational diabetes mellitus. Med J Obstet Gynecol 2011; 3:1057.
Gasim T. Gestational diabetes mellitus: maternal and perinatal outcomes in 220 Saudi women. Oman Med J 2012; 27:140–144.
Leipold H, Worda C, Gruber C, Prikoszovich T, Wagner O, Kautzky-Willer A. Gestational diabetes mellitus is associated with increased C reactive protein concentrations in the third but not second trimester. Eur J Clin Invest 2005; 35:752–757.
Qiu C, Sorensen T, Luthy D, Williams M. A prospective study of maternal serum C reactive protein (CRP) concentrations and risk of gestational diabetes mellitus. Paediatr Perinat Epidemiol 2004; 18:377–384.
Mehrabian F, Rezae M. Sex hormone binding globulin measurement before conception as a predictor of gestational diabetes in women with polycystic ovarian syndrome. J Res Med Sci 2013; 18:637–640.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]