17. Veltman-Verhulst SM, van Haeften TW, Eijkemans MJ, de Valk HW, Fauser BC, Goverde AJ. Sexhormone-bindingglobulin concentrations before conception as a predictor for gestational diabetes in women with polycystic ovary syndrome. Human Reprod (Oxford, England). 2010;25(12):3123 – 8. Epub 2010/10/15. eng.
Thus a relationship between hyperinsulinemia and decreased serum sexhormonebindingglobulin has been described in adults. Felix Gascon et al 54 evaluated usefulness of SHBG as an index of hypertsulinemia and/or insulin resistance in obese children (aged 6-9 yrs) of both sexes. They carried out a cross-sectional study of cases and controls. The obese group presented significantly elevated levels of insulin, and insulin / glucose ratio compared with control group. SHBG and testosterone levels were significantly lower than those in the non- obese group. Fasting insulin, BMI and testosterone were inversely correlated with SHBG concentration. Multivariate analysis revealed insulin was the only independent predicting factor for serum SHBG concentration in obese group. They concluded that there is strong relationship between insulin and SHBG. Their data supported the role of insulin in the regulation of serum SHBG level.
Several studies documented the association of hyper- androgenemia with RPL [2, 9], often with inconclusive findings. This was attributed to the wide variation in an- drogen levels, the time of sampling (i.e. within 7 days of the cycle), and the testosterone pool examined. The latter was attributed to the lipophilic nature of steroid sex hormones, in which circulating androgens and estro- gens bind albumin and sexhormonebindingglobulin (SHBG), resulting in limited amounts of non-bound sex hormones, and hence reduced bioavailability [9, 10]. Ac- curate assessment of biochemical hyperandrogenemia requires measurement of either free testosterone, or free androgen index, which require determination of the serum levels SHBG, a 373-amino acid glycoprotein pro- duced mainly by the liver, and binding the testosterone, dihydrotestosterone, and estradiol [11, 12], thus limiting their target tissue availability .
The liver produces plasma sexhormone–bindingglobulin (SHBG), which transports sex steroids and regu- lates their access to tissues. In overweight children and adults, low plasma SHBG levels are a biomarker of the metabolic syndrome and its associated pathologies. Here, we showed in transgenic mice and HepG2 hepato- blastoma cells that monosaccharides (glucose and fructose) reduce human SHBG production by hepatocytes. This occurred via a downregulation of hepatocyte nuclear factor–4α (HNF-4α) and replacement of HNF-4α by the chicken OVA upstream promoter–transcription factor 1 at a cis-element within the human SHBG promoter, coincident with repression of its transcriptional activity. The dose-dependent reduction of HNF-4α levels in HepG2 cells after treatment with glucose or fructose occurred in concert with parallel increases in cellular palmitate levels and could be mimicked by treatment with palmitoyl-CoA. Moreover, inhibition of lipogenesis prevented monosaccharide-induced downregulation of HNF-4α and reduced SHBG expression in HepG2 cells. Thus, monosaccharide-induced lipogenesis reduced hepatic HNF-4α levels, which in turn attenuated SHBG expression. This provides a biological explanation for why SHBG is a sensitive biomarker of the metabolic syndrome and the metabolic disturbances associated with increased fructose consumption.
This is the first randomized controlled trial investigat- ing the effects of caffeinated and decaffeinated coffee on SHBG and sex hormones. Attrition was low among par- ticipants and non-fasting blood samples measured for caffeine and its major metabolites at the 6-week visit indicated that compliance was high. Our study also had several limitations that need to be considered. Most not- ably, our study has a small sample size which may have limited our ability to detect modest effects on SHBG and sexhormone levels. Thus, findings should be inter- preted with caution and require confirmation in larger trials. In addition, given the small sample size, stratifying analyses by menopausal status was not appropriate. In- clusion of age in the analysis of covariance models was Table 2 Sexhormone-bindingglobulin and endogenous sex hormones by treatment group at week 4 and week 8 in men
Purpose: Sexhormone-bindingglobulin (SHBG) is a serum glycoprotein produced predominantly in hepatocytes. As such, the synthesis of SHBG could be associated with liver function and metabolic syndrome. Alanine aminotransferase (ALT) levels could reflect hepatocellular injury and insulin resistance; however, the relationship between hepatic steatosis and ALT with SHBG has not been investigated in humans. The objective of this study was to investigate the associations between SHBG and hepatocyte damage among Korean male patients with hepatic steatosis enrolled in a health examination program.
Conditions of hypoandrogenism in men have been linked to insulin resistance, suggesting that alterations in normal sex steroid physiology could play a role in the pathogenesis of type 2 diabetes (T2DM). Sexhormonebindingglobulin gene polymorphisms may be the cause of sex steroid alteration The aim of this work to study effect of sexhormonebindingglobulin (SHBG) gene polymorphisms on type 2 diabetes mellitus risk through its impact on testosterone and estradiol level in Egyptian men. In 185 diabetic men and 120 matched healthy controls, two polymorphisms (rs6257 and rs6259) of the gene encoding sexhormone–bindingglobulin were genotyped and serum levels of sexhormone–bindingglobulin, testosterone and estradiol were measured by ELISA; Our results showed significant decrease in sexhormonebinding globulins in type 2 diabetic patients compared with the control group. Carrier of variant allele of SHBG single nucleotide polymorphism (SNP) rs6259 had a higher level of SHBG in serum (p=0.000) While carrier of SHBG rs6257 SNP had a lower level of SHBG level in serum SHBG gene polymorphisms are associated with risk of type 2 diabetes in Egyptian men, through lowering circulating levels of sexhormone–bindingglobulin and consequently lowering testosterone and elevating estradiol level. SHBG rs6257 genotype may have a predictive value of developing type II diabetes mellitus
Human sexhormone–bindingglobulin (SHBG) trans- ports testosterone and estradiol in the blood (1, 2). Blood concentrations of SHBG are a major determi- nant of the metabolic clearance of these sex steroids and their access to target tissues (3), and their meas- urements provide a means of estimating the amounts of circulating non–protein-bound, or “free,” sex steroids (4). Abnormally low serum SHBG levels are fre- quently found in women with polycystic ovarian syn- drome (PCOS) and contribute to hyperandrogenic symptoms such as hirsutism and acne (1). Serum SHBG levels are also reduced in patients with type 2 diabetes and coronary heart disease (5, 6). The reason that SHBG levels are low in serum samples from many of these individuals is unclear, but it has been reported that SHBG deficiencies are inherited (7, 8).
Objectives: in case of Polycystic Ovary Syndrome (SOPK), predicting ovarian response before un- dertaking risky in vitro fertilization (IVF) proceeds is crucial. SexHormoneBindingGlobulin (SHBG) is introduced in literature as an interesting indicator of follicle’s maturation and quality. The aim of this study was to investigate whether serum SHBG levels are related to fertilization outcomes in SOPK women undergoing IVF procedures. Methods: in a prospective cohort study, we enrolled 61 SOPK women and 91 matched group of infertile women. All of them were undergoing FIV/ICSI proceeds. SHBG levels were performed in peripheral blood samples as well as others hormones determination. Results: we noted significant differences between our study group of SOPK patients and the Control group concerning the characteristics of the ovarian response to gonadotrophins administration and concerning the profile of biological proceeds’ outcomes. But no significant correlation between SHBG and FIV/ICSI outcomes was found either in SOPK or in Control group. Conclusions: our study provides evidence that SHBG can’t be considered as a pre- dictor of IVF outcomes because production of this steroid-binding protein depends on many pa- rameters such as metabolic disorders frequently associated with SOPK.
Abstract: This study aims to investigate the relationship between single nucleotide polymorphisms (SNPs) of sexhormonebindingglobulin (SHBG) and type 2 diabetes mellitus (T2DM) in an Uighur population. One hundred and fourteen T2DM male patients (with a history of diabetes or diagnosed as diabetic by the oral glucose tolerance test) and 173 healthy males from the Uighur ethnic group were included in the study to test the following SNPs of SHBG: rs727428, rs1799941, rs6259, rs6257, rs858521, rs858518, rs3760213, and rs11078701. The body mass index (BMI), blood pressure, and waist circumference, and lipid, glucose, HbA1c, insulin, HOMA-IR, testosterone, and SHBG levels of enrolled individuals were measured. We used the t-test or rank sum test and Chi-square test to ana- lyze the difference and compare numeration data, respectively, between the case and control groups. Comparisons among multiple groups were carried out using analysis of variance, and the correlation between variables was de- termined by nonparametric Spearman rank correlation analysis; multivariate logistic regression analysis was used to assess the risk of abnormal glucose in the two groups. There was a significant difference (P < 0.05) in BMI, blood pressure, and waist circumference, and lipid, glucose, HbA1c, insulin, and HOMA-IR levels between the case and control groups. The risk factors for diabetes included testosterone (P = 0.042) and SHBG (P = 0.001). The distribu- tion of rs858521 (P = 0.001), rs1799941 (2.3%, P = 0.032), rs6259 (2.5%, P = 0.040), and rs727428 (3.4%, P = 0.016) was significantly different between the case and control groups (P < 0.05). In the control group, there was linkage disequilibrium (LD) between rs727428 and rs6259, while in the case group LD was found among rs858518, rs3760213, rs1799941, and rs6257. The frequency of rs858518-rs3760213-rs1799941-rs6257 haplotype TCGC was significantly different between the two groups (P = 0.033). Both testosterone and SHBGwere found to be risk factors of diabetes in the Uighur population, and SNPs of SHBG may contribute to T2DM.
BACKGROUND: Epidemiological studies have shown that both the estrogen dose and progestogen type of oral contraceptives contribute to the increased risk of thrombosis in oral contraceptive users. Thrombin generation- based activated protein C (APC) sensitivity is a global test for the net prothrombotic effect of oral contraceptives and predicts the thrombotic risk. Our objective was to test the usefulness of sexhormone-bindingglobulin (SHBG) as a marker for the thrombotic risk of an oral contraceptive. METHODS: We measured SHBG and APC resist- ance in 156 healthy users of various types of oral contraceptives. RESULTS: Users of oral contraceptives with a moderately increased risk of thrombosis (gestodene and desogestrel pills) had higher SHBG levels than users of low-risk oral contraceptives containing levonorgestrel. Similarly, for higher doses of estrogen in oral contraceptives we found higher SHBG levels. Women using oral contraceptives with the highest thrombotic risk (cyproterone acetate pills) rendered the highest SHBG levels. Users of oral contraceptives containing gestodene, desogestrel or cyproterone acetate were more resistant to APC than users of levonorgestrel pills. SHBG levels were positively associated with the increased APC resistance. CONCLUSIONS: Our findings support the hypothesis that the effect of an oral contraceptive on SHBG levels might be a marker for the thrombotic risk.
predominant in boys . Moreover, in a cross-sec- tional study performed by Garces and colleagues includ- ing pubertal children (age: 12–15 years), a significantly higher SHBG level was demonstrated in girls than boys, reinforcing that the sex and growth hormone variations during puberty manifests earlier in girls than boys of the same age. In addition, a significant inverse relation between testosterone and SHBG level was shown in boys, with a gradual increase with age, while this effect was not uniform in girls with SHBG levels not showing significant differences based on age groups . This study includes boys and girls with advancing age and puberty and sup- ports the above results, showing significantly lower SHBG levels in boys than girls in MetS.
Nuclear receptor hepatocyte nuclear factor 4-α (HNF4α) activates the promoters of multiple genes expressed in he- patocytes that play a role in lipoprotein metabolism . The proximal promoter of the SHBG gene contains an HNF4α binding site, and overexpression of transcription factor HNF4α in HepG2 cells can stimulate transcription of the SHBG promoter . Several studies found that monosaccharide and lipid, as well as other factors, could regulate the SHBG expression via changes in HNF4 α gene expression [26–28]. Among them, liver lipids were consid- ered to be a crucial factor in regulating HNF4α-SHBG. Adiponectin treatment of HepG2 cells activated AMPK, which decreased the hepatic lipid content, then increased HNF4α levels and upregulated SHBG expression . SHBG mRNA is not naturally expressed in rodent liver; therefore, to date, research on SHBG gene expression using in vivo models is limited, and studies concerning SHBG expression in humans are rarely found.
In contrast, after multivariable adjustment for known risk factors, total testosterone levels were inversely asso- ciated with diabetes among men (OR, 0.44 [95% CI, 0.23–0.84]), whereas a strong positive relation was sug- gested among women, although the estimates were very imprecise (Table 3; Model 2). Spline curves suggested a moderate inverse association between total testosterone and diabetes in men, but not in women (Figure 1A and 1B), suggesting that the total testosterone-diabetes rela- tion observed among women (Table 3) was a statistically unstable estimate. The P-value for interaction by sex was 0.29, indicating insufficient evidence to support a sex- difference in the total testosterone and type 2 diabetes relation. Further adjustment for FLI (Table 3; Model 3), and SHBG and insulin levels (Table 3; Model 4) did not
Introduction Other sites of synthesis include many cell types; endothelial cells (Bar et al 1987) fibroblasts (Conover 1990a), decidual and secretory endometrium (Rutanen et al. 1985, 1986), amniotic fluid (Povoa et al. 1984, Baxter et al. 1987, Busby et al. 1988) and human preovulatoiy follicles (Seppala et al. 1984). The amino-acid sequence of IGFBPl, a non- glycoslated protein, has been determined (Lee et al. 1988, Brewer et al. 1988, Brinkman et al. 1988a, Julkunen et al. 1988). This sequence indicates thatpre-IGFBPl consists of 259 aminoacids. The putative signal peptide is 25 residues long and the mature protein thus contains 234 amino acids and has a molecular mass o f25,293 Da. The sequence is cysteine rich at the N-terminus. While the cysteines at the N-terminus are necessary for IGF binding (Hardouin et al. 1991) the cysteine at residue 226 also seems to be essential for maintaining the intact tertiary structure of the protein since a deletion or frameshift results in the loss of IGF binding (Brinkman et al. 1991). Human IGFBPl has an Arg-Gly-Asp (RGD) sequence near the C-terminus. These sequences allow binding of the protein to the cell surface and this may enable IGFBPl to facilitate the transport of IGF-1 to its receptors. In addition there are regions of clustered Proline, Glutamine, Serine and Threonine residues (PEST) at position 89-114 . These regions are associated with proteins which have a short half-life.
SHBG is a predictor of mortality by a mechanism that is unclear. Serum levels of the peptide are regulated by sex hormones and influenced by other hormonal and non- hormonal factors including drugs such as statins [Rosner et al. 2010, Tint et al. 2016]. Indeed, the wide range of serum values in reference groups (eg. 10-57 nmol/l) and our study (7.9-185.5 nmol/l) seem to us to argue against this protein having a simple, direct causative effect on mortality. Thus, we interpret the analysis of associations between mortality and dichotomised combinations of SHBG and TT (Table 6) as showing the influence of the peptide is mediated by its ability to bind the hormone thereby reducing its free concentration. Thus, the reference category (SHBG>35 nmol/l, TT<12 nmol/l) describes the combination likely to result in the lowest levels of free hormone and the one most positively associated with mortality.
March 2019 Volume 8 Issue 3 Page 967 International Journal of Reproduction, Contraception, Obstetrics and Gynecology Sujatha MS et al Int J Reprod Contracept Obstet Gynecol 2019 Mar;8(3) 967 973 www i[.]
endometrial cell proliferation and inhibit apoptosis, partially by stimulating the local synthesis of IGF1 in endometrial tissue. Among premenopausal women, the lack of progesterone, because of ovarian androgen production and continuous anovulation, leads to reduced production of IGFBP1 by the endometrium. After menopause (and in the absence of exogenous estrogen production), when ovarian progesterone synthesis has ceased altogether, the more central risk factor seems to be obesity-related increases in bioavailable estrogen levels. In addition to estrogens and progesterone, insulin itself could also promote endometrial cancer development by reducing concentrations of sex- hormone-bindingglobulin (SHBG) in the blood, which would increase the levels of bioavailable estrogens that can diffuse into endometrial tissue.
Abstract: Gestational diabetes mellitus (GDM) occurs in approximately 7% of all pregnant women. In order to mini- mize the risk of GDM-associated complications, it is still very important to identify novel biomarkers for early predic- tion of GDM, particularly in the first trimester. In this study, we conducted a meta-analysis to assess the clinical im- plications of first-trimester biomarkers, including sexhormone-bindingglobulin (SHBG), adiponectin and C-reactive protein (CRP), in predicting the risk of GDM. Electronic databases, including Medline, Embase, Scopus, Google Scholar, and Cochrane Library, were searched and fourteen studies including 2479 patients were identified for this meta-analysis. The random-effects model was employed to pool the data from the included studies to determine the difference in the first-trimester serum levels of SHBG, adiponectin, or CRP between patients with GDM and normal pregnancies. Our meta-analysis reveals that GDM patients exhibit significantly lower levels of SHBG (SMD=-0.48; 95% CI=-0.67, -0.28; Z=-4.77, P<0.0001) or adiponectin (SMD=-2.36; 95% CI=-3.39, -1.32; Z=-4.47, P<0.0001) and significantly higher concentrations of CRP (SMD=1.67; 95% CI=0.44, 2.90; Z=2.66, P=0.0079) in the first tri- mester than those women with normal pregnancies. These findings suggest that SHBG, adiponectin, and CRP may serve as first-trimester biomarkers for predicting the risk of developing GDM in pregnant women.
RESULTS. At the time of PP diagnosis, age, bone age, and BMI were similar across birth weight subgroups; circulating sexhormone– bindingglobulin and body height were reduced in PP girls with lower birth weight, and these remained so throughout pubertal development. Onset of puberty occurred earlier in PP girls with lower birth weight; so did menarche. Adult height differed by an average of 6.5 cm ( ⬃ 1 SD) between the upper and lower birth weight subgroups; this difference was essentially achieved before puberty and even before PP. Menarche before age 12.0 years was twofold more prevalent in PP girls than in control subjects. Among PP girls, age at menarche was advanced by 8 to 10 months in lower versus higher birth weight girls. Menarche before age 12.0 years was threefold more prevalent among LBW-PP girls than in control subjects ( ⬃ 75% vs ⬃ 25%).