Role Of Sex Hormone-binding Globulin Research Articles

Association between levels of sex hormones and risk of multiple sclerosis: a mendelian randomization study.

This research aimed to examine the causal connections between multiple sclerosis (MS) and a range of sex hormone-related traits, such as bioavailable testosterone (BT), sex hormone-binding globulin (SHBG), testosterone, and estradiol (E2). A bidirectional two-sample Mendelian randomization (MR) analysis using summary statistics from genome-wide association studies (GWAS) was conducted to investigate the relationship between sex hormone-related traits and MS. Moreover, the Inverse-variance weighted (IVW) method was employed as the primary analysis approach. The MR analysis, using the IVW method, found a significant correlation between genetically determined SHBG levels and MS (OR = 1.634, 95% CI: 1.029-2.599, p = 0.038). Similarly, the reverse MR analysis suggested a causal link between MS and SHBG (OR = 1.005, 95% CI: 1.001-1.009, P = 0.003). However, no association was observed between MS risk and E2, testosterone, or BT levels. Our MR analysis demonstrated that genetically predicted higher SHBG may be positively correlated with the risk of MS. Moreover, the role of SHBG in MS could be further investigated.

A protective role of genetically predicted sex hormone-binding globulin on stroke

IntroductionThe role of sex hormone-binding globulin (SHBG) on stroke has been investigated in several observational studies. To provide the causal estimates of SHBG on stroke and its subtypes, bi-directional and multivariable Mendelian randomization (MR) analyses are performed. MethodsThe genetic instruments of SHBG were obtained from the UK Biobank. Outcome datasets for stroke and its subtypes were taken from the MEGASTROKE Consortium. The main analysis used in this study is the inverse variance weighting, complemented by other sensitivity approaches to verify the conformity of findings. ResultsWe found that the risk of stroke grew by 13% (odd ratio [OR] = 0.87, 95% confidence interval [CI] = 0.79–0.95, P = 0.0041) and the risk of ischemic stroke grew by 15% (OR = 0.85, 95%CI = 0.77–0.95, P = 0.0038) caused by genetically predicted SHBG. The causal association remains robust in the reverse MR and multivariable MR analyses for stroke (reverse MR: all P > 0.01 for the IVW method; MVMR: OR = 0.72, 95%CI = 0.59–0.87, P = 0.0011) and ischemic stroke (reverse MR: all P > 0.01 for IVW; MVMR: OR = 0.70, 95%CI = 0.56–0.86, P = 0.0007). ConclusionOur MR study provides novel evidence that SHBG has an inverse association with stroke and ischemic stroke, exerting protective effects on stroke.

Sex Hormone-Binding Globulin and Risk of Coronary Heart Disease in Men and Women.

The role of sex hormone-binding globulin (SHBG) levels in clinical risk stratification and intervention for coronary heart disease (CHD) remains uncertain. We aimed to examine whether circulating levels of SHBG are predictive of CHD risk in men and women. We investigated the association between SHBG and the risk of incident CHD in 128 322 men and 135 103 women free of CHD at baseline in the prospective United Kingdom Biobank (UKB) cohort. The unconfounded associations were estimated using Mendelian randomization (MR) analysis. We further conducted a meta-analysis to integrate currently available prospective evidence. CHD events included nonfatal and fatal myocardial infarction and coronary revascularization. In the UKB, during a median of 11.7 follow-up years, 10 405 men and 4512 women developed CHD. Serum levels of SHBG were monotonically associated with a decreased risk of CHD in both men (adjusted hazard ratio [HR] per log nmol/L increase in SHBG: 0.88 [0.83-0.94]) and women (HR: 0.89 [0.83-0.96]). MR-based analyses suggested causality and a dose-response relationship of SHBG with CHD risk. A cumulative meta-analysis including 216 417 men and 138 282 women from 11 studies showed that higher levels of SHBG were prospectively associated with decreased CHD risk in men comparing the highest with the lowest quartile: pooled relative risk (RR) 0.81 (0.74-0.89) and women (pooled RR: 0.86 [0.78-0.94]). Higher circulating SHBG levels were directly and independently predictive of lower CHD risk in both men and women. The utility of SHBG for CHD risk stratification and prediction warrants further study.

Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology.

According to the free hormone hypothesis, biological activity of a certain hormone is best reflected by free rather than total hormone concentrations. A crucial element in this theory is the presence of binding proteins, which function as gatekeepers for steroid action. For testosterone, tissue exposure is governed by a delicate equilibrium between free and total testosterone which is determined through interaction with the binding proteins sex hormone-binding globulin and albumin. Ageing, genetics and various pathological conditions influence this equilibrium, hereby possibly modulating hormonal exposure to the target tissues. Despite ongoing controversy on the subject, strong evidence from recent in vitro, in vivo and human experiments emphasizes the relevance of free testosterone. Currently, however, clinical possibilities for free hormone diagnostics are limited. Direct immunoassays are inaccurate, while gold standard liquid chromatography with tandem mass spectrometry (LC-MS/MS) coupled equilibrium dialysis is not available for clinical routine. Calculation models for free testosterone, despite intrinsic limitations, provide a suitable alternative, of which the Vermeulen calculator is currently the preferred method. Calculated free testosterone is indeed associated with bone health, frailty and other clinical endpoints. Moreover, the added value of free testosterone in the clinical diagnosis of male hypogonadism is clearly evident. In suspected hypogonadal men in whom borderline low total testosterone and/or altered sex hormone-binding globulin levels are detected, the determination of free testosterone avoids under- and overdiagnosis, facilitating adequate prescription of hormonal replacement therapy. As such, free testosterone should be integrated as a standard biochemical parameter, on top of total testosterone, in the diagnostic workflow of male hypogonadism.

Serum sex hormone-binding globulin is a mediator of the association between intrahepatic lipid content and type 2 diabetes: the Maastricht Study

Aims/hypothesisSerum sex hormone-binding globulin (SHBG) has been proposed to act as a hepatokine that contributes to the extrahepatic complications observed in non-alcoholic fatty liver disease (NAFLD). However, it remains uncertain whether serum SHBG mediates the association between intrahepatic lipids (IHL) and type 2 diabetes. Therefore, we studied whether, and to what extent, serum SHBG mediates the association between IHL content and type 2 diabetes.MethodsWe used cross-sectional data from the Maastricht Study (n=1554), a population-based cohort study with oversampling of individuals with type 2 diabetes. Type 2 diabetes status was assessed by oral glucose tolerance test, and IHL content was measured using 3T Dixon MRI. Mediation analyses were performed to assess the role of serum SHBG in mediating the association between IHL content and type 2 diabetes.ResultsIHL content was significantly associated with type 2 diabetes in women and men (OR 1.08 [95% CI 1.04, 1.14] and OR 1.12 [95% CI 1.08, 1.17], respectively). Serum SHBG significantly mediated the association between IHL content and type 2 diabetes. The contribution of serum SHBG was higher in women (OR 1.04 [95% CI 1.02, 1.07]; proportion mediated 50.9% [95% CI 26.7, 81.3]) than in men (OR 1.02 [95% CI 1.01, 1.03]; proportion mediated 17.2% [95% CI 9.6, 27.6]). Repeat analyses with proxies of type 2 diabetes and adjustment for covariates did not substantially affect the results.Conclusions/interpretationIn this large-scale population-based cohort study, serum SHBG was found to be a mediator of the association between IHL content and type 2 diabetes. These findings extend our understanding of the potential mechanisms by which NAFLD is a risk factor for type 2 diabetes, and further elaborate on the role of SHBG as a hepatokine.Graphical abstract

A 4-hour Profile of 17-hydroxyprogesterone in Salt-wasting Congenital Adrenal Hyperplasia: Is the Serial Monitoring Strategy Worth the Effort?

Objective:Since there is no gold standard laboratory variable for adjustment of treatment in congenital adrenal hyperplasia (CAH), the aim was to assess the use of a 4-hour profile of serum 17-hydroxyprogesterone (17-OHP) to determine the most appropriate sample time and level of 17-OHP in predicting the metabolic control and evaluate the role of sex hormone-binding globulin (SHBG) in hyperandrogenemia.Methods:This study included children with salt-wasting CAH. Measurements for 17-OHP and cortisol were made from samples obtained before and 1, 2, and 4 hours after the morning dose of hydrocortisone. Patients were designated to have poor metabolic control when androstenedione levels according to age and sex-specific reference intervals were high and annual height standard deviation score (SDS) changes were ≥0.5.Results:The study cohort was 16 children (9 girls) with a median age of 7-years old. Premedication 17-OHP levels were strongly correlated with 17-OHP levels 1, 2, and 4 hours after the morning dose (rs=0.929, p<0.01; rs=0.943, p<0.01; rs=0.835, p<0.01, respectively). 17-OHP profiles (0, 1, 2, 4 hours) of poor (n=6) and good (n=10) metabolically controlled cases were similar. Among the patients with poor metabolic control, two cases had 17-OHP levels <2 ng/mL at all times. The remaining patients with poor metabolic control had median 17-OHP levels above 104 ng/mL, 82 ng/mL, 14 ng/mL, and 4 ng/mL, for baseline and 1, 2, and 4 hours, respectively. Differences between the poor and well-controlled group were androstenedione levels with respect to upper limit of normal [1.8 (1.5) and 0.5 (1.5) ng/mL, respectively p=0.03], annual change in height SDS [0.7 (0.2) and -0.03 (0.8) SDS, respectively, p=0.001], and daily hydrocortisone doses [7 (6) and 16 (8) mg/m2/day, respectively, p=0.02]. Androstenedione and SHBG levels were negatively correlated in the pubertal children (rs=-0.7, p=0.04).Conclusion:We conclude that: (i) a 4-hour 17-OHP profile is not useful in predicting hyperandrogenemia; (ii) suppressed levels of 17-OHP do not always indicate overtreatment; (iii) reference intervals of 17-OHP for different time periods might be of importance; (iv) low hydrocortisone doses should be avoided; and (v) SHBG could be used in pubertal children as an indicator of hyperandrogenemia.

Genetically predicted sex hormone binding globulin and ischemic heart disease in men and women: a univariable and multivariable Mendelian randomization study

Men are more vulnerable to ischemic heart disease (IHD) than women, possibly due to testosterone. Correspondingly, sex hormone binding globulin (SHBG) which lowers circulating testosterone might protect men against IHD. SHBG may also affect IHD independent of testosterone, which has not previously been examined. To assess the sex-specific role of SHBG in IHD, in univariable Mendelian randomization (MR), we used sex-specific, genome-wide significant genetic variants to predict SHBG, and examined their association with IHD in the UK Biobank. We also replicated using genetic instruments from Japanese men and applied to Biobank Japan. To assess the role of SHGB independent of testosterone in men, we used multivariable MR controlling for testosterone. Genetically predicted SHBG was associated with lower IHD risk in men [odds ratio (OR) 0.78 per standard deviation, 95% confidence interval (CI) 0.70 to 0.87], and the association was less clear in women. The estimates were similar in Japanese. The inverse association remained after controlling for testosterone in men (OR 0.79, 95% CI 0.71 to 0.88). SHBG might lower the risk of IHD in men, with a role independent of testosterone. Exploring intervention strategies that increase SHBG is important for targeting IHD treatments.

The relationships of sex hormone‐binding globulin, total testosterone, androstenedione and free testosterone with metabolic and reproductive features of polycystic ovary syndrome

ObjectiveA recent Mendelian randomization study has suggested a causal role for sex hormone‐binding globulin (SHBG), total testosterone and free testosterone in the pathogenesis of polycystic ovary syndrome (PCOS). The aim of this study was to assess the relationships of SHBG, androstenedione, total and free testosterone with the individual metabolic and reproductive features of PCOS.DesignCross‐sectional data in PCOS patients (n=96) prospectively collected in a secondary/tertiary clinic for menstrual cycle disorders.MethodsMultivariable regression analyses were conducted to study the associations between SHBG, androstenedione, total and free testosterone with metabolic (BMI, waist circumference, systolic and diastolic blood pressure, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides and homeostatic model assessment for insulin resistance [HOMA2‐IR]) and reproductive features (menstrual cycle length, antral follicle count, anti‐Müllerian hormone, luteinizing hormone, follicle‐stimulating hormone and Ferriman‐Gallwey score) of PCOS.ResultsSerum SHBG and free testosterone, but not total testosterone or androstenedione, were significantly associated with BMI, waist circumference, serum triglycerides, HDL cholesterol, LDL cholesterol and HOMA2‐IR. The strength of the associations with serum lipids was reduced after adjustment for BMI, but not for HOMA2‐IR. Total testosterone was significantly associated with antral follicle count. SHBG, total testosterone and androstenedione were significantly associated with serum AMH. Only the strength of the association for SHBG was reduced after adjustment for BMI.ConclusionsSerum SHBG is associated with primarily metabolic features, whereas total testosterone and androstenedione are associated with reproductive features of PCOS. These results suggest a differential underlying pathophysiology for the metabolic and reproductive features of PCOS.

Genetically Predicted Sex Hormone-Binding Globulin and Bone Mineral Density: A Mendelian Randomization Study.

Previous observational studies have identified various risk factors associated with the development of osteoporosis, including sex hormone-binding globulin (SHBG). The aim of this study was to determine the potential causal effects of circulating SHBG concentrations on bone mineral density (BMD). Two-sample Mendelian randomization (MR) approach was applied in analyses. From summary-level data of genome-wide association studies (GWAS), we selected 11 single-nucleotide polymorphisms (SNPs) associated with SHBG levels as instrumental variable, and used summary statistics for BMD at forearm (FA) (n = 8143), femoral neck (FN) (n = 32,735), lumbar spine (LS) (n = 28,498) and heel (HL) (n = 394,929), and total-body BMD of different age-stages (15 or less, 15-30, 30-45, 45-60, 60 or more years old) (n = 67,358). Inverse causal associations was observed between SHBG levels and FA BMD (Effect = - 0.26; 95% CI - 0.49 to - 0.04; P = 0.022), HL eBMD (Effect = - 0.09; 95% CI - 0.12 to - 0.06; P = 3.19 × 10-9), and total-body BMD in people aged 45-60years (Effect = - 0.16; 95% CI - 0.31 to - 2.4 × 10-3; P = 0.047) and over 60years (Effect = - 0.19; 95% CI - 0.33 to - 0.05; P = 0.006). Our study demonstrates that circulating SHBG concentrations are inversely associated with FA and HL eBMD, and total-body BMD in people aged over 45years, suggesting that the role of SHBG in the development of osteoporosis might be affected by chronological age of patients and skeletal sites.

The role of sex hormone-binding globulin (SHBG), testosterone, and other sex steroids, on the development of type 2 diabetes in a cohort of community-dwelling middle-aged to elderly men

Contrasting findings exist regarding the association between circulating sex hormone-binding globulin (SHBG) and testosterone levels and type 2 diabetes (T2D) in men. We examined prospective associations of SHBG and sex steroids with incident T2D in a cohort of community-dwelling men. Participants were from a cohort study of community-dwelling (n = 2563), middle-aged to elderly men (35-80years) from Adelaide, Australia (the Men Androgen Inflammation Lifestyle Environment and Stress (MAILES) study). The current study included men who were followed for 5years and with complete SHBG and sex steroid levels (total testosterone (TT), dihydrotestosterone (DHT) and oestradiol (E2)), but without T2D at baseline (n = 1597). T2D was identified by either self-report, fasting glucose (≥ 7.0mmol/L), HbA1c (≥ 6.5%/48.0mmol/mol), and/or prescriptions for diabetes medications. Logistic binomial regression was used to assess associations between SHBG, sex steroids and incident T2D, adjusting for confounders including age, smoking status, physical activity, adiposity, glucose, triglycerides, symptomatic depression, SHBG and sex steroid levels. During an average follow-up of 4.95years, 14.5% (n = 232) of men developed new T2D. Multi-adjusted models revealed an inverse association between baseline SHBG, TT, and DHT levels, and incident T2D (odds ratio (OR) = 0.77, 95% CI [0.62, 0.95], p = 0.02; OR 0.70 [0.57, 0.85], p < 0.001 and OR 0.78 [0.63, 0.96], p = 0.02), respectively. However, SHBG was no longer associated with incident T2D after additional adjustment for TT (OR 0.92 [0.71, 1.17], p = 0.48; TT in incident T2D: OR 0.73 [0.57, 0.92], p = 0.01) and after separate adjustment for DHT (OR 0.83 [0.64, 1.08], p = 0.16; DHT in incident T2D: OR 0.83 [0.65, 1.05], p = 0.13). There was no observed effect of E2 in all models of incident T2D. In men, low TT, but not SHBG and other sex steroids, best predicts the development of T2D after adjustment for confounders.

Common genetic variants in the sex hormone-binding globulin (SHBG) gene in idiopathic recurrent pregnancy loss: a case control study

BackgroundA role for sex hormone-binding globulin (SHBG) in determining the pregnancy outcome was evidenced by the rise in SHBG levels during pregnancy linked with favorable pregnancy, while reduction in SHBG levels and hyperandrogenemia were linked with poor pregnancy outcome. Since SHBG production is genetically determined, this study investigated the association of SHBG polymorphisms with the susceptibility to recurrent pregnancy loss (RPL).MethodsRetrospective case-control study, involving 308 women with RPL, and 310 control women RPL, defined as ≥3 consecutive miscarriages, and with the same partner, was the main outcome measure. SHBG genotyping was done by allelic exclusion method (real-time PCR).ResultsOf the seven tested SHBG SNP, lower MAF of rs6257 was seen in RPL cases than in control women, which was linked with lower risk of RPL, after controlling for key covariates. At the genotype level, significantly higher frequencies of heterozygous rs858521 and rs6259, and homozygous rs858521 genotype carriers, and reduced frequency of heterozygous rs6257 and homozygous rs6257 and rs6259 genotype carriers were seen in RPL cases vs. control women, respectively. Univariate regression analysis confirmed the positive association of rs858521 and rs6259 with RPL. Multivariate regression analysis confirmed the positive association of rs858521 heterozygote and homozygote genotypes with RPL; only heterozygous rs6259 remained associated with RPL. Haploview analysis demonstrated marked linkage disequilibrium among 6 of the 7 tested SHBG SNP. Of the possible 6-locus haplotypes, 12 were common, and were included in subsequent analysis. Within these haplotypes, only increased frequency of CCGTGA haplotypes was seen in RPL cases, thus conferring RPL susceptibility.ConclusionsSpecific SHBG variants, and SHBG haplotypes are associated with altered risk of RPL, suggesting role for SHBG as RPL candidate gene.

Lower SHBG level is associated with higher leptin and lower adiponectin levels as well as metabolic syndrome, independent of testosterone

In addition to testosterone (T), the emerging role of sex hormone-binding globulin (SHBG) in pathogenesis of metabolic syndrome (MetS) has been noted recently. However, reports of associations with serum adipocytokine levels are still limited. Therefore, we conducted this study to evaluate whether serum T and SHBG levels are independent predictors for the risk of MetS that are associated with adiponectin and leptin levels in 614 Taiwanese men over 40 years old collected from a free health screening. Subjects in the lowest quartile of TT and SHBG levels are exposed to a 1.58 and 3.22 times risk of developing MetS, as compared to those in the highest quartile of TT and SHBG levels. However, SHBG retains its significance independent of TT as a MetS risk predictor, but not vice versa. In addition, SHBG was significantly correlated with both adiponectin and leptin levels even after adjusting for TT levels. In conclusion, SHBG served as a major predictor for the risk of MetS and was correlated with serum adiponectin and leptin levels that are independent of T. Further studies are needed to elucidate the true role of SHBG in the pathogenesis of MetS and possible mechanisms associated with serum adiponectin and leptin levels.

Sex difference determined the role of sex hormone-binding globulin in obese children during short-term weight reduction program.

The relationship between hyperinsulinemia and decreased sex hormone-binding globulin (SHBG) levels has been observed in obese adults and children. Weight reduction not only increased insulin sensitivity but also elevated serum SHBG levels in obese adults and children. However, the correlation between the changes in insulin resistance indices and serum SHBG concentration during weight reduction program (WRP) is not fully understood, particularly in obese children. This study is to evaluate whether SHBG level is a potential biomarker that can be used to assess insulin resistance in obese children during a short-term WRP. Forty-eight obese Taiwanese children (11.7 ± 2.2 years; 25 boys and 23 girls) participating in 8-week WRP were studied. Anthropometric measurements, lipid profiles, insulin resistance indices, and serum SHBG concentration were recorded at baseline and at the end of the WRP. The results showed body weight (BW), body mass index (BMI), body fat percentage (BF%), body fat weight (BFW), and insulin resistance indices such as fasting insulin, fasting insulin to glucose ratio, homeostasis model assessment (HOMA) of insulin resistance, log (HOMA) all significantly decreased after the 8-week WRP. With respect to lipid profiles, only high-density lipoprotein cholesterol (HDL-C) levels increased in both sexes. At baseline, insulin resistance indices were inversely correlated with SHBG concentrations in girls, but not in boys. The difference in SHBG after WRP was 2.58 nmol/L (95% confidence interval [CI]: −3.51, 8.66) in boys and 0.58 nmol/L (95% CI: −5.23, 6.39) in girls. There was a trend toward increased serum SHBG levels in boys (P = .39) and girls (P = .84) after weight loss, but a significantly negative correlation between the change in SHBG and in each of the insulin resistance indices only in the girls after adjusting age and ΔBFW during WRP.In conclusion, short-term WRP has the potential effects of decreased BW, BMI, BF%, and BFW, as well as increased serum HDL-C levels and insulin sensitivity in obese Taiwanese children. Although serum SHBG levels moderately increased in both sexes during short-term WRP, measuring the change in SHBG concentrations might be a potential biomarker to evaluate improvement in insulin resistance in girls only, and not in boys.

The Utility of Sex Hormone-Binding Globulin in Hypogonadism and Infertile Males

We sought to determine the role of sex hormone-binding globulin in patients with male infertility. We retrospectively reviewed the records of 168 males seen at a fertility clinic from 2012 to 2014 to investigate the accuracy of total testosterone in the biochemical diagnosis of hypogonadism using calculated bioavailable testosterone as the reference value. We used multivariable analysis to assess sex hormone-binding globulin as an independent predictor of infertility. Computations using calculated bioavailable testosterone as a standard in the measurement of definitive biochemical hypogonadism (less than 156 ng/dl) revealed 81% sensitivity, 83% specificity, 81% positive predictive value and 82% negative predictive value for diagnosing hypogonadism with total testosterone alone. Of the 90 men with total testosterone greater than 300 ng/dl, 20% had low bioavailable testosterone less than 156 ng/dl, 52% had borderline low bioavailable testosterone less than 210 ng/dl and only 48% could be considered biochemically eugonadal according to calculated bioavailable testosterone. Of the 80 patients with total testosterone less than 300 ng/dl, 19% had free testosterone levels greater than 6.5 ng/dl and, thus, could be considered to be eugonadal. By a magnitude similar to that of follicle-stimulating hormone, sex hormone-binding globulin independently predicted decreased sperm concentration (p = 0.0027) and motility (p = 0.0447). After excluding men with azoospermia, only sex hormone-binding globulin levels differed significantly in classically hypogonadal men (group 1-total testosterone less than 300 ng/dl) and those missed but hypogonadal (group 2-calculated bioavailable testosterone less than 210 ng/dl) (p = 0.0001). At a more stringent cutoff of calculated bioavailable testosterone less than 156 ng/dl, sperm motility was significantly different for groups 1 and 2 (p = 0.014). Adding sex hormone-binding globulin to total testosterone serum testing facilitates more accurate diagnosis with free testosterone and calculated bioavailable testosterone, and clinical implications of decreased semen parameters to a magnitude similar to that of follicle-stimulating hormone. This warrants further study of the role of sex hormone-binding globulin in male infertility.

Is Immunohistochemical Sex Hormone Binding Globulin Expression Important in the Differential Diagnosis of Adenocarcinomas?

Adenocarcinomas (AC) are the most frequently encountered carcinomas. It may be quite challenging to detect the primary origin when those carcinomas metastasize and the first finding is a metastatic tumor. This study evaluated the role of sex hormone binding globulin (SHBG) positivity in tumor cells in the subclassification and detection of the original organ of adenocarcinomas. Between 1994 and 2008, 64 sections of normal tissue belonging to ten organs, and 116 cases diagnosed as adenoid cystic carcinoma and mucoepidermoid carcinoma of the salivary gland, lung adenocarcinoma, invasive ductal carcinoma of the breast, adenocarcinoma of stomach, colon, gallbladder, pancreas and prostate, endometrial adenocarcinoma and serous adenocarcinoma and mucinous adenocarcinoma of the ovary, were sent to the laboratory at the Department of Pathology at the Yuzuncu Yil University School of Medicine, where they were stained immunohistochemically, using antibodies against SHBG. The SHBG immunoreactivity in both the tumor cells and normal cells, together with the type, diffuseness and intensity of the staining were then evaluated. In the differential diagnosis of the adenocarcinomas of the organs, including the glandular structures, impressively valuable results are encountered in the tumor cells, whether the SHBG immunopositivity is evaluated alone or together with other IHC markers. Further extensive research with a larger number of cases, including instances of cholangiocarcinoma and cervix uteri AC [which we could not include in the study for technical reasons] should be performed, in order to appropriately evaluate the role of SHBG in the differential diagnosis of AC.

Genetic variants determining body fat distribution and sex hormone-binding globulin among Chinese female young adults 遗传因素决定了中国青少年女性体脂分布和血清性激素结合球蛋白水平

Measures of body fat distribution (i.e. waist : hip ratio [WHR]) are major risk factors for diabetes, independent of overall adiposity. The genetic variants related to body fat distribution show sexual dimorphism and particularly affect females. Substantial literature supports a role for sex hormone-binding globulin (SHBG) in the maintenance of glucose homeostasis. The aim of the present study was to examine the association of the genetic risk score of body fat distribution with SHBG levels and insulin resistance in young (14-30 years) Chinese females. In all, 675 young Chinese females were evaluated in the present study. A genetic risk score (GRS) was calculated on the basis of 12 established variants associated with body fat distribution. The main outcome variable was serum SHBG levels and homeostasis model assessment of insulin resistance (HOMA-IR). The GRS of body fat distribution was significantly associated with decreasing serum SHBG levels (P = 0.018), independent of body mass index and WHR. In addition, the GRS and SHBG showed additive effects on HOMA-IR (P = 0.004). The GRS of body fat distribution reflects serum SHBG levels, and the GRS and SHBG jointly influence the risk of insulin resistance.

The role of sex hormone-binding globulin and testosterone in the risk of incident metabolic syndrome

The aim of this study was to further evaluate the suggested independent association of sex hormone-binding globulin (SHBG) with incident metabolic syndrome (MetS) in men. We used data from 1906 men aged 20-79 years from the population-based Study of Health in Pomerania (SHIP). Multivariable logistic regression models were implemented to analyse cross-sectional and longitudinal associations of total testosterone (TT), SHBG, and free testosterone (free T) concentrations with MetS. Furthermore, we associated changes between baseline and follow-up concentrations of TT, SHBG, and free T with incident MetS. Cross-sectional logistic regression models revealed a significant inverse association of TT (odds ratio [OR] per standard deviation [SD] decrease: 1.28; 95% confidence interval (CI): 1.10-1.50), and free T (OR per SD decrease: 1.29; 95% CI: 1.11-1.51), but not SHBG (OR per SD decrease: 1.13; 95% CI: 0.98-1.30) with prevalent MetS. At the 5-year follow-up 1435 men were repeatedly examined and of the 956 men without baseline MetS, 328 men (34.3%) had incident MetS. Longitudinal analyses showed, after adjustment for the respective sex hormone, that lower baseline SHBG (OR per SD decrease: 1.30; 95% CI: 1.03-1.65), but not TT (OR per SD decrease: 1.14; 95% CI: 0.93-1.39) was associated with incident MetS. Change analyses revealed an inverse association between TT change and incident MetS (OR per SD decrease between baseline and follow-up: 1.19; 95% CI: 1.01-1.39), independent of SHBG; whereas SHBG change was not associated with incident MetS until adjustment for TT. Although baseline SHBG predicts incident MetS independent of testosterone, change analyses suggest the testosterone decline as the main driver of the association between sex hormones and MetS.

Abstract 011: Sex Hormone-Binding Globulin (SHBG) and Risk of Clinical Diabetes in American Black, Hispanic, and Asian/Pacific Islander Postmenopausal Women.

BACKGROUND: Recent prospective studies have shown a strong inverse association between sex hormone-binding globulin (SHBG) levels and risk of clinical diabetes in Whites. However, it remains unknown whether this relation extends to other racial/ethnic populations. METHODS: We evaluated the association between baseline levels of SHBG and risk of clinical diabetes in the Women’s Health Initiative Observational Study. Over a median follow-up of 5.9 years, 542 postmenopausal women developed clinical diabetes (338 Blacks, 128 Hispanics, 76 Asians) and were matched to 1,110 controls (707 Blacks, 249 Hispanics, 154 Asians). To complement our protein-level findings, we also genotyped 5 SHBG polymorphisms. We performed Mendelian randomization analysis to assess the potential causal relation between SHBG levels and risk of clinical diabetes. RESULTS: Overall, higher levels of SHBG at baseline were associated with a significantly lower risk of clinical diabetes (Relative risk [RR]=0.24, 95% confidence interval [CI]=0.15-0.39 for highest versus lowest quartile of SHBG, adjusted for BMI and other known diabetes risk factors). The associations remained consistent across ethnic groups (p-for-heterogeneity=0.72): RR=0.29 (95%CI=0.16-0.54) for Blacks, RR=0.26 (95%CI=0.09-0.74) for Hispanics, and RR=0.32 (95%CI=0.06-1.73) for Asians, comparing highest to lowest quartiles of SHBG. In addition, SHBG polymorphisms affected diabetes risk proportional to serum SHBG levels. Mendelian randomization analysis confirmed the significant direct effect of SHBG on diabetes development (p=0.03). CONCLUSIONS: In this prospective cohort of postmenopausal women, we observed a robust, inverse relation between serum levels of SHBG and clinical diabetes risk in American Blacks, Hispanics, and Asian/Pacific Islanders. Genetic variants associated with SHBG levels demonstrated a similar relationship, providing support for a causal role of SHBG in the pathogenesis of type 2 diabetes.

Association of serum and follicular fluid SHBG levels and SHBG (TAAAA)n polymorphism with follicle size in women undergoing ovarian stimulation

Objective. Sex hormone-binding globulin (SHBG) is the main transport protein of sex steroids. Recently, it has been found to be produced by granulosa lutein cells, suggesting a local role of SHBG in the ovary. The aim of this study was to investigate whether serum and follicular fluid SHBG levels and SHBG (TAAAA)n polymorphism are related to follicle size and pregnancy rate in women undergoing in vitro fertilisation.Methods. The study population consisted of 154 women with tubal and/or male-factor infertility undergoing IVF/ICSI and follicular fluid with oocytes from small (diameter ≤12 mm) and large (diameter ≥18 mm) follicles were studied. Genotyping of SHBG (TAAAA)n polymorphism was performed in peripheral blood samples. Serum and follicular fluids were used for hormones determination.Results. Women with short allele genotypes (with less than 8 TAAAA repeats) had higher number of small follicles compared to women with long allele genotypes (5.6 ± 3.9 vs. 3.5 ± 3.2 small follicles, p < 0.003). Follicular fluid SHBG levels correlated positively with serum SHBG levels (p < 0.001) and with the total number of follicles (p < 0.02). Furthermore, small follicles had higher follicular fluid SHBG concentration compared to large follicles (102.9 ± 35.0 nmol/l vs. 85.85 ± 34.88 nmol/l, p < 0.028).Conclusion. SHBG levels and the SHBG (TAAAA)n polymorphism are associated with follicle size.

Effect of Sex Hormone Binding Globulin on the Development of Ovarian Cancer in a Mouse Model

Sex hormone-binding globulin (SHBG) is the major carrier protein of testosterone and estradiol in the blood. Although studies on the role of SHBG in ovarian cancer are inconclusive, substantial evidence indicates that SHBG- steroid complexes can play a direct role in the intracellular transport of steroids to cancer cells. SHBG is synthesized in the adult liver of many species, excluding rodents. Adult mouse and rat livers do not produce SHBG, and yet most experimental models of ovarian cancer employ these species. Data reported here indicate that SHBG has a major stimulatory effect on the growth of human ovarian cancer in athymic mice. The effect is observed in subcutaneous and intraperitoneal OVCAR-3 xenografts. Tumor doubling times were 9.98±0.14 days and 17.20±0.64 days when OVCAR-3 cells were implanted with and without SHBG, respectively (P = 0.023). The magnitude of SHBG effect depended on the age of mice and it was most prominent in the development of intraperitoneal solid tumor deposits. Levels of circulating CA-125 were also age- and tumor size-dependent. Biodistribution studies of 125 I-SHBG indicated a prolonged retention of the protein in solid tumor deposits. Estimated half-lives of 125 I-SHBG were 2.3� longer in solid tumors as compared to nonadherent cancer cells in the peritoneal lavage. The normal tissue distribution of 125 I-SHBG was similar in control and OVCAR-3-bearing mice. These data suggest that currently used models of ovarian cancer in mice, including carcinogenesis and drug evaluation studies, are imperfect because of the lack of SHBG production in these species.