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 .
Although the functions of beta cells and insulin resistance are the basic factors for developing type2 diabetes, other parameters such as testosterone and sexhormonebindingglobulin (SHBG) may be important (8). The studies on both men and women have shown that higher level of SHBG leads lower risk of complication in diabetic patients (9).
One consistent observation we made is that the rela- tive abundance of the electrophoretic isoforms associ- ated with the SHBG P156L variant differs from that of those associated with normal SHBG, and this can be attributed to differences in the utilization of the two sites for N-glycosylation within the carboxy-terminal domain of the molecule (32). Since this amino acid sub- stitution occurs within the amino-terminal LG–like domain of SHBG, it must somehow exert a long-range effect on posttranslational modifications within the carboxy-terminal region of the molecule; this is feasible, since we have observed similar effects when other amino acids are substituted within the amino-terminus of SHBG (16). Thus, the P156L substitution appears to influence the degree of N-glycosylation of SHBG, due presumably to subtle differences in the folding and posttranslational processing of the nascent polypeptide. The P156L substitution occurs within a phylogeneti- cally conserved region of SHBG (19) adjacent to residues located within the homodimer interface (16). It also lies within an inter– β strand loop region that contains a coordination ligand (A160) for the calcium atom that plays an important role in maintaining the structural stability of the SHBG homodimer (15, 27). The substi- tution of a highly conserved proline at position 156 (19) might therefore be expected to influence the secondary structure of SHBG and might explain subtle differences in its posttranslational modification. It might also influ- ence the rate of SHBG production/secretion or clearance from the blood circulation. Our observation that the SHBG P156L variant is secreted at a much reduced rate compared with that of normal SHBG from mouse liver cells, despite the fact that the levels of transcripts encod- ing them are similar in these cells, suggests that the vari- ant protein is not processed efficiently during secretion. This is also consistent with the observation that greater amounts of immunoreactive SHBG are detected in the insoluble fraction of CHO cells expressing the SHBG P156L variant compared with the wild-type protein.
Multivariate logistic regression models were used to evalu- ate the relationship between hepatic steatosis and elevated ALT levels with the risk of low SHBG levels (Table 3). In multi- variable regression analysis model 1, adjusting for age and BMI, the OR for lower SHBG was 3.287 (95% CI 2.007–5.385) in the hepatic steatosis group with ALT ≥40, compared with the reference group. Even after progressive adjustment for several factors that were previously found to be associated with SHBG, the subjects in the hepatic steatosis group with ALT ≥40 were still more likely to have a lower SHBG level (OR: 2.729; 95% CI 1.591–4.681). Before we divided men into three groups, we conducted a logistic regression analysis to confirm if there is an interaction between hepatic steatosis and ALT and the risk of lower SHBG level. We found that there was a significant interaction between hepatic steatosis and ALT in men (p=0.014).
15. Zhao JL, Chen ZJ, Zhao YR, Zhao LX, Wang LC, Li Y, Tang R, Shi YH. Study on the (TAAAA) n repeat polymorphism in sexhormone-bindingglobulin gene and the SHBG serum levels in putative association with the glucose metabolic status of Chinese patients suffering from polycystic ovarian syndrome in Shandong province. Zhonghua Yi Xue Yi Chuan Xue Za Zhi; 22: 644 -7, 2005. 16. Ding EL, Song Y, Manson JE, Hunter DJ, Lee CC,
Earlier identification and treatment of pregnancies with, or at risk for, GDM with SHBG might present a good option to improve outcomes. Thus, SHBG might be a useful marker in predicting GDM. A prospective observational study (n=269) evaluating several biomarkers earlier than 15 weeks of gestation showed that low levels of SHBG were associated with an increased risk of GD. SHBG showed an acceptable sensitivity of 85% but a low specificity of 37%. Adding hs-CRP increases the specificity to 75.46%. 27 Present
All analyses were performed separately for men and women. Using general linear models, we evaluated the change from baseline in SHBG, testosterone (total and free), estradiol (total and free), testosterone to estradiol ratio, and DHEAs regressed on treatment group as a main effect with baseline log values of the dependent variable and age as additional covariates. Both covariates were grand mean centered to improve the interpretabil- ity of the estimates. Because SHBG and sex hormones did not follow a normal distribution, the variables were log-transformed and subsequently back-transformed to yield geometric means. Differences between caffeinated and decaffeinated coffee compared with the control group were based on linear contrasts. The adjusted geo- metric means with standard errors were reported by treatment, and 95% confidence intervals (CI) were com- puted. In addition, we calculated the difference between the treatment groups versus control for change from baseline. This yielded a ratio (or percentage when sub- tracting the value one and multiplying by 100), given the principles of logged numbers.
The clinical studies and in vitro experiments reported in this thesis provide evidence that insulin is likely to be an important regulator of circulating SHBG and IGFBPl. The results from the in-vitro experiments, while showing no significant inter experimental differences, should be interpreted with caution since the Hep G2 cells are a transformed immortal cell- line and therefore exhibit important cellular differences from normal hepatocytes. The most important of these with respect to ts thesis is the presence of IGF-1 receptors on their surface which are not present in adult hepatocytes. In addition experimental factors such as the binding of insulin to the plastic flasks, the difference in the distribution of the cells could not be quantified. The clinical studies although done on small numbers of women provide additional and supportive evidence for this finding. There is little evidence in the literature or in this thesis ,however,that the two binding proteins are truly co-regulated. The production of the binding proteins by the liver is inhibited by insulin, yet their responses to insulin-like growth factor-1 (IGF-1), growth hormone (GH), thyroxine and the sex steroids shows important differences. These are emphasised by the in vivo response to changes in insulin concentrations; SHBG concentrations change over a longer period but remain stable while IGFBPl concentrations change rapidly. In this summary I shall therefore consider the regulation of the two binding proteins separately.
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.
Objective: Increased testosterone and decreased sexhormone-bindingglobulin (SHBG) are associated with a number of adverse cardiovascular risk factors in postmenopausal women. The aim of this popula- tion-based study of women aged 25 to 50 was to as- sess the relationship between free androgen index (FAI) and cardiovascular risk factors in premeno- pausal women. Methods: A population-based survey of 396 premenopausal women with no hormonal trea- tment was undertaken as part of the Northern Swe- den MONICA study. The study involved question- naires, anthropometry and assays of testosterone and SHBG. Results: Increased FAI was associated with a number of cardiovascular risk factors in premeno- pausal women but this relationship was strongly af- fected by body mass index (BMI). After adjustment for age and BMI, FAI was significantly associated with increased systolic and diastolic blood pressures. Conclusion: Hyperandrogenism is associated with increased blood pressure and these findings empha- size the need to assess cardiovascular risk factors in women with hyperandrogenism of all ages.
GDM is a common pregnancy complication and is associated with increased maternal and neonatal morbidity. Identifying and treating women with GDM is important to improve the outcomes. The definitive diagnostic testing for GDM is an oral glucose tolerance test. Such test requires fasting of at least 8 h, needs 3 – 4 blood samplings and re- quires 2 – 3 h to be completed. SHBG is simple, inexpensive blood test that can be performed in the non-fasting state,  with no diurnal variation, . This makes SHBG a valuable marker for GDM diagnosis. The aim of this study is to compare maternal serum SHBG level between GDM and normal glucose tolerant women and to investigate the roll of SHBG in GDM diagnosis.
Methods A total of 99 patients aged 18-40 years with PCOS diagnosed by the Rotterdam consensus criteria- 2003 and a hirsutism score of 8 or more according to the Ferriman-Gallway Score (FGS) were studied. BMI, WC, fasting lipid profile, serum leptin, insulin, sexhormonebindingglobulin (SHBG), free-androgen index (FAI), fasting blood glucose (FBG) and oral glucose tolerance test (OGTT) were determined. Homeostasis model assessment (HOMA)-beta, HOMA-insulin resistance (IR) and VAI were calculated. Diameter and rate of hair growth at sideburns and chin; density of hair at sideburns were measured. Data were analyzed by SPSS-22.0.
All venous blood samples were obtained after overnight fasting. The serum was separated into several aliquots and stored at − 80 °C within 2 h. Serum glucose, triglycerides (TG), total cholesterol (TC), high-density lipoprotein chol- esterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), aspartate aminotransferase (AST), alanine ami- notransferase (ALT) and uric acid (UA) were determined enzymatically on a Hitachi 7600–010 automated analyser (Hitachi, Tokyo, Japan). Insulin resistance was evaluated using the homeostasis model assessment (HOMA) index [fasting glucose (mmol/L) × insulin (μU/mL) / 22.5]. Serum SHBG, testosterone (Testo) and dehydroepiandros- terone sulphate (DHEAS) were measured by chemilumin- escent enzyme immunometric assay (CLIA) using kits obtained from Abbott Corporation (Chicago, IL, USA) with an Abbott ARCHITECT I2000 automated analyser. The minimum detectable dose of SHBG was 2 nmol/L, and the intra- and inter-assay coefficients of variation for SHBG were 4.1% and 5.8%, respectively.
Monosaccharides decrease human SHBG production by HepG2 cells in concert with reduced cellular HNF-4 α levels. (A) Human SHBG accu- mulation in the medium of HepG2 cells treated daily with 10 mM of glucose or fructose was substantially reduced. Data points are shown as mean ± SD of triplicates; **P < 0.01 compared with no glucose/fruc- tose supplementation. (B) Human SHBG and HNF-4α mRNA levels determined by RT-PCR in HepG2 cells cultured for 5 days as in A. Cyclophilin A (CypA) mRNA was amplified as in internal control. (C) HNF-4α and cyclophilin A levels measured by Western blotting in HepG2 cells cultured for 5 days as in B. (D) Human SHBG promoter activity was measured in the context of a luciferase reporter gene assay in HepG2 cells cultured for 4 days in the presence or absence of 10 mM glucose or fructose. Data points are shown as mean ± SD of triplicates; **P < 0.01 compared with no glucose/fructose supplementation.
Insulin down-regulates hepatic SHBG production , while an inverse correlation between BMI and insulin sensitivity has been shown in various studies in obese children and adolescents [37, 38]. Our study demonstrating an inverse correlation between BMI and SHBG levels is also in accordance with previous investi- gations in children [39, 40]. Krishnasamy and colleagues demonstrated an inverse relation between SHBG levels and waist circumference, as well as body mass index percentile in children at risk for MetS . Our study partially supports the above results showing a signifi- cant inverse correlation between SHBG levels and waist circumference but only in boys. There is evidence show- ing an inverse association between SHBG, BP and TG in adults and children [40, 41]. The studies also observed a direct association of SHBG with HDL-c level. Our study supports the above results showing a significant inverse correlation between SHBG, systolic BP and TG levels and a direct relation between SHBG with HDL-c levels in the MetS group including boys and girls. The lowest tertile of SHBG level showed a higher prevalence of MetS in boys, with a uniform inverse trend than girls. The possible explanation for this trend may the corre- lation of SHBG level with more MetS components as compared to girls. The ROC analysis also supports the above trend which shows SHBG as a clearer predictor of MetS components in boys than girls.
Liver fat is recognized as a separate and important contributor to metabolic disease development. The liver is an insulin responsive tissue that contributes significantly to both whole body insulin sensitivity and availability of sex steroids through the production of sexhormonebindingglobulin (SHBG). Our objective was to describe the relationship between ectopic liver fat, insulin resistance, and hormonal profile in perimenopausal women. The Study of Women Across the Nation (SWAN) is a cross sectional multiethnic population of women recruited from multiple geographic areas during their perimenopausal years for longitudinal evaluation. A subset of women from SWAN (n=208) were evaluated from the Pittsburgh site as part of the SWAN-Heart study. Women had computed tomography scans to quantify visceral and subcutaneous adipose tissue, and liver fat. Adiposity measures, blood pressure, and menopausal stage, based on cycle irregularity, were recorded. Blood samples were collected and measured for hormonal and metabolic endpoints. We found in this overweight but healthy cohort that liver fat and SHBG were unaffected by menopausal stage or race. Both endpoints remained significantly associated with insulin after adjustment for adiposity. SHBG and liver fat had interactive effects on measured insulin concentration. Other sex hormones were not significantly associated with metabolic endpoints. Only liver fat accounted for differences in insulin across increasing SHBG quartiles, suggesting ectopic liver fat modifies SHBG. Both higher liver fat and lower SHBG have consequences for insulin sensitivity and the role of liver fat in modifying SHBG should be explored.
Our study has several strengths. First, about 95% of the participants who did not self-report diabetes under- went the 75 g oral glucose tolerance test, which mini- mized the possibility of the inclusion of undiagnosed diabetic patients in the control group. Second, we obtained detailed measures of variables, allowing us to control for a number of potential confounding factors. Third, the control participants were randomly selected from the same population that gave rise to the cases which minimized the selection bias. Nevertheless, some limitations of the present study merit consideration. First, we were unable to establish a temporal relationship between the exposure (i.e., testosterone and SHBG) and diabetes. In addition, the observed associations may vary according to the duration of diabetes. Hyperinsulinemia or insulin resistance typically associated with diabetes might have resulted in decreased testosterone and SHBG levels (i.e., reverse causality). Further controlling for fast- ing insulin levels did not materially alter the results in our study, but use of sulphonylurea or insulin among participants with diabetes might have influenced the in- sulin levels. Therefore, the adjustment for fasting insulin levels may not have adequately captured the influence of hyperinsulinemia or insulin resistance. Second, we used the FLI, a validated surrogate maker for fatty liver, to examine the impact of fatty liver on the SHBG-diabetes association. Although this measure has been validated in independent studies, the FLI is not a perfect measure of fatty liver. Thus, residual confounding due to misclassifi- cation of fatty liver cannot be ruled out. Third, we did
diabetic murine models have been reported previously [6,7]. Low testosterone and sexhormonebindingglobulin (SHBG) concentrations in elderly men have also been demonstrated to be associated with established diabetes . Other symptoms that have been documented include: testicular atrophy and hypogonadism with desquamation of the germinal epithelium [8-10]. Testicular biopsies from oligospermic or impotent men with diabetes mellitus reveal discrete ultrastructural lesions in the apical sertoli cell cytoplasm, spermatogenic disruption and morphological changes in the interstitial compartment indicating microvascular complications . In addition, altered testicular structure and functions have been observed in diabetic animal models .
A stem cell burden theory has been invoked to explain how in utero and perinatal factors might impact lifetime breast cancer risk [7-10]. The tenets of this theory include the following. Firstly, the breast cancer risk is related to the pool size of breast stem cells, which may be determined in utero or early in life. A second tenet is that individuals with relatively elevated in utero/perinatal levels of growth factors (for example, insulin- like growth factor-1 (IGF-1)) and hormones (for example, estrogens) that act as mammary epithelial cell mitogens will have relatively large and mitotically active pools of breast stem cells. This would increase the probability that oncogenic muta- tions will occur in one of these cells. Thirdly, in the presence of elevated levels of mitogens, such individuals might also have a general increase in various stem cell pools and possibly birth weights. When first proposed, this concept was highly speculative [1,7]. Since that first proposal, however, the exist- ence of stem-like, multipotential breast epithelial cells in both mice [11,12] and humans [13,14] has been established. Addi- tionally, there is evidence for malignant breast 'stem' cells with some properties of normal breast stem/progenitor cells, sug- gesting that the former may be derived from the latter . Preliminary and indirect support for this stem cell-based hypothesis came from a pilot study on 40 umbilical cord blood samples from infants delivered in the Worcester, MA, area . In that study, cord blood plasma levels of several key sex hormones, including estradiol, estriol, testosterone and pro- gesterone, the sexhormone-bindingglobulin (SHBG) and cer- tain growth factors including prolactin and IGF-1, as well as one of the major IGF-1 binding proteins, insulin-like growth factor binding protein-3 (IGFBP-3), were assayed to deter- mine whether they correlated with the density of cord blood- derived hematopoietic stem cell and progenitor cell popula- tions, serving as surrogates for overall stem cell potential. Such populations included cord blood CD34 + cells, repre-
Background and Objective: The hormonal responses are different, according to type, intensity and the duration of training. We aimed to compare the effect of endurance and resistance training in untrained men on the level sexual hormone including testosterone, estradiol, and on sexhormonebindingglobulin (SHBG).