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Decreased Sex Hormone-Binding Globulin Indicated Worse Biometric, Lipid, Liver, and Renal Function Parameters in Women with Polycystic Ovary Syndrome. Luo X et al. (2020) To investigate the relationships between sex hormone-binding globulin (SHBG) and comprehensive metabolic parameters including biometric, glycemic, lipid, liver, and renal functions of women with polycystic ovary syndrome (PCOS). Study Design and Methods. A total of 1000 women diagnosed as PCOS by modified Rotterdam criteria were enrolled in a randomized controlled trial. SHBG and comprehensive metabolic parameters were measured at the baseline visit. Metabolic parameters included biometric parameters, glucose and lipid panels, and liver and renal function parameters. An independent t-test and linear regression were performed to investigate the associations between SHBG and metabolic parameters. Logistic regression was used to detect the relationship between SHBG and the presence of metabolic syndrome. In comparative analyses, PCOS women with lower SHBG levels had higher body mass index, waist circumference, insulin, homeostatic model assessment-insulin resistance (HOMA-IR) index, systolic and diastolic blood pressure, triglycerides, apolipoprotein B (APOB), low-density lipoprotein (LDL), aspartate transferase (AST), alanine transferase (ALT), and blood urea nitrogen (BUN), but lower high-density lipoprotein (HDL) and apolipoprotein A1 (APOA1). In linear regression, SHBG was inversely associated with waist circumference, systolic blood pressure, triglyceride, LDL, APOB, ALT, AST, and BUN but positively associated with HDL and APOA1 after adjusting the BMI. In logistic regression, SHBG is a protective predictor for metabolic syndrome (odds ratio = 0.96; 95% confidence interval: 0.95-0.97). The area under the receiver-operator characteristic curve is 0.732 with a 95% confidence interval of 0.695-0.770. SHBG <26.75 mmol/L is the cutoff point with the best Youden index, which has a sensitivity of 0.656 and specificity of 0.698. Lower SHBG was associated with worsening biometric, lipid, liver, and renal functions but not glycemic parameters among women with PCOS. SHBG can be used as a tool to screen metabolic syndrome. This trial is registered with NCT01573858 and ChiCTR-TRC-12002081.//////////////////
The (TAAAA)n microsatellite polymorphism in the SHBG gene influences serum SHBG levels in women with polycystic ovary syndrome. Ferk P et al. BACKGROUND Hyperandrogenaemia is a common feature of polycystic ovary syndrome (PCOS). The sex hormone-binding globulin (SHBG) gene was proposed as being aPCOS candidate genes. A possible influence of the microsatellite polymorphism (TAAAA)(n) in the SHBG gene on serum SHBG levels in PCOS patients was investigated. METHODS One hundred and twenty-three PCOS patients and 110 age-matched controls were included in the study. Peripheral blood samples were obtained. Genotyping of the (TAAAA)(n) polymorphism in the SHBG gene was performed. Serum LH, FSH, SHBG and total testosterone concentrations were determined. RESULTS SHBG alleles with 6-11 TAAAA repeats were found. None of the SHBG alleles or genotypes were present at a significantly more frequent rate in PCOS patients compared with controls. Serum SHBG levels were significantly lower (P<0.001) in PCOS patients compared with controls and were found to be strongly influenced by the (TAAAA)(n) SHBG polymorphism, in both the PCOS (55.3%) and control (33.1%) groups of patients. CONCLUSIONS The (TAAAA)(n) SHBG gene polymorphism might be an important predictor for serum SHBG levels and, consequently, for hyperandrogenaemic clinical presentation of PCOS. Andersen CY et al observed higher levels of SHBG and CBP in serum compared to those in FF, and the positive relationship between serum and FF levels, suggesting that both proteins arise from the circulation. The similar levels in serum and FF indicate that neither SHBG nor CBP is responsible for maintaining the concentration gradient of estradiol and progesterone from follicle to plasma.
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Role of D327N sex hormone-binding globulin gene polymorphism in the pathogenesis of polycystic ovary syndrome. Bendlov? et al. SHBG (sex hormone-binding globulin) is a transport protein specific for dihydrotestosterone, testosterone and estradiol. The missense mutation in exon 8 (GAC-->AAC) causing the amino acid exchange Asp-->Asn in codon 327 (D327N) correlates according to the published data with increased SHBG levels. We studied possible association of this polymorphism with polycystic ovary syndrome (PCOS) and anthropometric and biochemical parameters in 248 PCOS patients and 109 healthy control women. The D327N polymorphism (wild-type and variant allele) was detected using PCR-RFLP method (restriction enzyme Bbs-I). For statistical evaluation chi(2) test, Mann-Whitney test, ANCOVA, ANOVA (NCSS 2004, Statgraphics Plus v.5.1, USA) were used. There was no significant difference in genotype distribution between PCOS and controls (chi(2)=1.03, p=0.59). Moreover, we did not find an association of the variant allele with plasma SHBG level, steroid hormones, or screened parameters of lipid and glucose metabolism. In conclusion, the D327N polymorphism of the SHBG gene does not influence susceptibility to PCOS.
Association of serum and follicular fluid SHBG levels and SHBG (TAAAA)(n) polymorphism with follicle size in women undergoing ovarian stimulation. Hatzi E et al. 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 /=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.
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Mutations |
3 mutations
Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Hogeveen KN et al 2002 reported that human sex hormone-binding globulin variants associated with
hyperandrogenism and ovarian dysfunction.
Serum SHBG levels are low in
patients with hyperandrogenism, especially in association with polycystic ovarian
syndrome (PCOS) and in individuals at risk for diabetes and heart disease. Here, the authors
identify SHBG coding region variations from a compound heterozygous patient who
presented with severe hyperandrogenism during pregnancy. Serum SHBG levels in
this patient measured 2 years after her pregnancy were exceptionally low, and her
non-protein-bound testosterone concentrations greatly exceeded the normal reference
range. A single-nucleotide polymorphism within the proband's maternally derived
SHBG allele encodes a missense mutation, P156L, which allows for normal steroid
ligand binding but causes abnormal glycosylation and inefficient secretion of SHBG.
This polymorphism was identified in four other patients with either PCOS, ioiopathic
hirsutism, or ovarian failure. The proband's paternal SHBG allele carries a
single-nucleotide deletion within exon 8, producing a reading-frame shift within the
codon for E326 and a premature termination codon. CHO cells transfected with a
SHBG cDNA carrying this mutation fail to secrete the predicted truncated form of
SHBG.
Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Polymorphisms in the Sex Hormone-Binding Globulin (SHBG) Gene Influence Serum SHBG Levels in Women with Polycystic Ovary Syndrome. Wickham EP et al. Context: Single-nucleotide polymorphisms (SNPs) in the SHBG gene are associated with type 2 diabetes mellitus. SHBG has also been proposed as a candidate gene for the polycystic ovary syndrome (PCOS). Objective: The study aims were 1) to determine whether any of four SHBG SNPs (rs1779941, rs6297, rs6259, and rs727428) are associated with PCOS and 2) to determine whether SNP genotype influences SHBG levels in PCOS women. Design: Using the transmission disequilibrium test, evidence of associations between SHBG SNPs and PCOS were analyzed. Additionally, correlations between SHBG levels and SNP genotype, body mass index, non-SHBG-bound testosterone, and insulin resistance estimated by the homeostasis model were determined. Setting: The study was conducted at academic medical centers. Patients or Other Participants: A total of 430 families having a proband with PCOS were included in the family-based study. Associations between SNP genotypes, SHBG, and metabolic parameters were determined in 758 women with PCOS including probands from the family cohort. Main Outcome Measures: Primary outcome measures included transmission frequency of SNP alleles and correlation coefficients between SHBG and allele frequency/metabolic parameters. Results: No evidence of association between SNPs of interest and PCOS was found. However, in multivariate analyses, SHBG levels varied significantly with rs1799941 and rs727428 genotype after controlling for body mass index, non-SHBG-bound testosterone, and homeostasis model for insulin resistance. Conclusions: Although SHBG SNPs associated with type 2 diabetes mellitus do not appear to be associated with PCOS status, rs1799941 and rs727428 genotypes are associated with SHBG levels independent of the effects of insulin resistance and obesity.
Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Common variants in the sex hormone-binding globulin gene (SHBG) and polycystic ovary syndrome (PCOS) in Mediterranean women. Martnez-Garca MA et al. STUDY QUESTION: Is there an association between polycystic ovary syndrome (PCOS) and the sex hormone-binding globulin (SHBG) rs1799941, rs6257, rs6259 and rs727428 variants in a large series of Mediterranean women? SUMMARY ANSWER: The rs727428 and rs6259 variants are associated with PCOS in Mediterranean women. WHAT IS KNOWN ALREADY: The level of SHBG, the primary plasma transport protein for sex steroids, which regulates the bioavailability of these hormones to target tissues, is reduced in patients with PCOS. Single-nucleotide polymorphisms in the SHBG gene influence circulating SHBG levels in American patients with PCOS and may predict the development of type 2 diabetes. STUDY DESIGN, SIZE AND DURATION: This was a genetic case-control association study including 1004 premenopausal Mediterranean women. PARTICIPANTS/MATERIALS, SETTINGAND METHODS: In an Academic setting, we genotyped a clinical cohort consisting of 281 patients with PCOS and 142 women without any evidence of androgen excess, and a population-based cohort comprised of 581 unselected female blood donors from Spain and Italy. The latter included 31 patients with PCOS and 550 controls, of whom 298 had no evidence of any androgen excess disorder and were considered hyper-normal controls. MAIN RESULTS AND THE ROLE OF CHANCE: Mutant alleles of the rs727428 variant were more frequent in patients with PCOS compared with controls and with hyper-normal controls. This association was independent of obesity. Carrying mutant alleles of rs727428 was found to be associated with a 1.29 odds ratio (OR) for PCOS, whereas carrying mutant alleles of rs6259 associated with a 0.68 OR for PCOS. The rs1799941 and rs6257 variants were not associated with PCOS. None of the SHBG variants influenced serum SHBG concentrations. LIMITATIONS AND REASONS FOR CAUTION: The associations found here were relatively weak and, arising from a case-control study, do not necessarily indicate a causative role of the SHBG variants in the development of PCOS. Also, we studied different patients and controls from different sources, making some of the interpretations difficult. Finally, the rs1799941 variant was not in Hardy-Weinberg equilibrium in the small group of patients with PCOS recruited from the general population, yet this variant was not associated with PCOS. WIDER IMPLICATIONS OF THE FINDINGS: SHBG variants that influenced circulating SHBG levels in American patients with PCOS are also associated with this syndrome in Mediterranean women, pointing to SHBG as a candidate gene for PCOS. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by grants PI080944 and PI110357 from Instituto de Investigacin Carlos III, Spanish Ministry of Economy and Competitiveness. CIBERDEM is also an initiative of Instituto de Investigacin Carlos III. The Authors have no competing interests to declare. Association between serum levels and pentanucleotide polymorphism in the sex hormone binding globulin gene and cardiovascular risk factors in females with polycystic ovary syndrome. Baldani DP et al. (2014) The objective of the present study was to evaluate the influence of TAAAA repeat allele length on the levels of serum sex hormone binding globulin (SHBG) and cardiovascular risk factors in patients with polycystic ovary syndrome (PCOS). The study included 91 females with PCOS and 99 healthy controls. Phenotypic hyperandrogenism, body mass index and waist‑to‑hip ratio (WHR) were recorded. Hormonal profiles, fasting insulin and glucose levels, lipid profiles and C‑reactive protein (CRP) levels were measured. Genotyping of TAAAA repeat polymorphisms in the SHBG gene was performed. No significant difference was found in the frequency and distribution of TAAAA repeat alleles between PCOS patients and controls (P=0.739). In PCOS patients, SHBG levels were inversely correlated with serum C‑reactive protein (CRP) levels (R=-0.489, P<0.001). PCOS patients with long TAAAA repeat alleles had significantly lower serum SHBG and free testosterone levels, yet higher CRP levels than patients with short allele repeats. A multiple linear regression model using the number of TAAAA repeats, waist‑to‑hip ratio, a homeostatic model assessment of insulin resistance and age as independent predictors explained 44.8% of the variability in serum SHBG levels. In this model, TAAAA repeat polymorphism was found to be the only reliable predictor of serum SHBG levels (P<0.001). In conclusion, the TAAAA repeat polymorphism was shown to not be a major determinant of the PCOS status, although it influenced serum SHBG levels in females with PCOS. A strong independent association existed between serum SHBG and CRP levels. CRP is an established risk factor of cardiovascular disease and a marker of low‑grade inflammation, typical of atherogenesis. This may be one of the pathways by which low SHBG levels affect cardiovascular risk.//////////////////
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