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Joann E Manson - One of the best experts on this subject based on the ideXlab platform.

  • abstract 73 Sex hormone binding Globulin a novel hormonal biomarker for ischemic stroke risk
    Stroke, 2020
    Co-Authors: Tracy E Madsen, Joann E Manson, Xi Luo, Mengna Huang, Ki Park, Marcia L Stefanick, Simin Liu
    Abstract:

    Introduction: Sex hormone binding Globulin (SHBG) is a Sex-steroid transporter previously linked to cardiometabolic outcomes such as diabetes (DM) and coronary heart disease and their risk factors....

  • circulating shbg Sex hormone binding Globulin and risk of ischemic stroke findings from the whi
    Stroke, 2020
    Co-Authors: Tracy E Madsen, Mengna Huang, Ki Park, Marcia L Stefanick, Joann E Manson
    Abstract:

    Background and Purpose— Circulating levels of SHBG (Sex Hormone-Binding Globulin) have been inversely linked to obesity, diabetes mellitus, and other cardiometabolic disorders. It remains uncertain...

  • abstract p047 circulating testosterone and Sex hormone binding Globulin concentrations and risk of type 2 diabetes cardiovascular disease and all cause mortality in us women
    Circulation, 2019
    Co-Authors: Tianyi Huang, Joann E Manson, Kathryn M Rexrode, Susan E Hankinson, Shelley S Tworoger
    Abstract:

    Introduction: It remains unclear whether circulating testosterone and Sex Hormone-Binding Globulin (SHBG) are associated with cardiometabolic disease risk and mortality. Hypothesis: Higher SHBG and...

  • Sex hormone binding Globulin and risk of type 2 diabetes in women and men
    The New England Journal of Medicine, 2009
    Co-Authors: Eric L Ding, Yiqing Song, Joann E Manson, David J Hunter, Nader Rifai, Julie E Buring, Michael J Gaziano
    Abstract:

    Background Circulating Sex hormone–binding Globulin levels are inversely associated with insulin resistance, but whether these levels can predict the risk of developing type 2 diabetes is uncertain. Methods We performed a nested case–control study of postmenopausal women in the Women’s Health Study who were not using hormone therapy (359 with newly diagnosed type 2 diabetes and 359 controls). Plasma levels of Sex hormone–binding Globulin were measured; two polymorphisms of the gene encoding Sex hormone–binding Globulin, SHBG, that were robustly associated with the protein levels were genotyped and applied in mendelian randomization analyses. We then conducted a replication study in an independent cohort of men from the Physicians’ Health Study II (170 with newly diagnosed type 2 diabetes and 170 controls). Results Among women, higher plasma levels of Sex hormone–binding Globulin were prospectively associated with a lower risk of type 2 diabetes: multivariable odds ratios were 1.00 for the first (lowest) quartile of plasma levels, 0.16 (95% confidence interval [CI], 0.08 to 0.33) for the second quartile, 0.04 (95% CI, 0.01 to 0.12) for the third quartile, and 0.09 (95% CI, 0.03 to 0.21) for the fourth (highest) quartile (P<0.001 for trend). These prospective associations were replicated among men (odds ratio for the highest quartile of plasma levels vs. the lowest quartile, 0.10; 95% CI, 0.03 to 0.36; P<0.001 for trend). As compared with homozygotes of the respective wild-type allele, carriers of a variant allele of the SHBG single-nucleotide polymorphism (SNP) rs6259 had 10% higher Sex hormone–binding Globulin levels (P = 0.005), and carriers of an rs6257 variant had 10% lower plasma levels (P = 0.004); variants of both SNPs were also associated with a risk of type 2 diabetes in directions corresponding to their associated Sex hormone–binding Globulin levels. In mendelian randomization analyses, the predicted odds ratio of type 2 diabetes per standard-deviation increase in the plasma level of Sex hormone–binding Globulin was 0.28 (95% CI, 0.13 to 0.58) among women and 0.29 (95% CI, 0.15 to 0.58) among men, a finding that suggests that Sex hormone–binding Globulin may have a causal role in the risk of type 2 diabetes. Conclusions Low circulating levels of Sex hormone–binding Globulin are a strong predictor of the risk of type 2 diabetes in women and men. The clinical usefulness of both SHBG genotypes and plasma levels in stratification and intervention for the risk of type 2 diabetes warrants further examination.

  • low Sex hormone binding Globulin is associated with the metabolic syndrome in postmenopausal women
    Metabolism-clinical and Experimental, 2006
    Co-Authors: Melissa E Weinberg, Joann E Manson, Julie E Buring, Nancy R Cook, Ellen W Seely, Paul M Ridker, Kathryn M Rexrode
    Abstract:

    Abstract Although an association between the metabolic syndrome and hyperandrogenism has been suggested in women with polycystic ovarian syndrome, few studies have investigated this relationship in postmenopausal women. We measured estradiol, testosterone, and Sex hormone–binding Globulin (SHBG) and calculated the free androgen index (FAI) in 212 postmenopausal women not using hormone therapy in the Women's Health Study. A modified definition of the metabolic syndrome (3 or more of the following: abdominal obesity, hypertriglyceridemia, low high-density lipoprotein, elevated blood pressure, and abnormal glucose metabolism) from the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults was used. Women with the metabolic syndrome had higher mean levels of estradiol, testosterone, and FAI values and lower SHBG levels. Higher FAI and lower SHBG were associated with all components of the metabolic syndrome. After adjustment for BMI and other factors, women in the highest tertile of FAI had an odds ratio of 12.6 (95% confidence interval, 3.8-41.6) for the metabolic syndrome, whereas those in the lowest SHBG tertile had an odds ratio of 7.3 (95% confidence interval, 2.7-19.8). When stratified by body mass index, the associations with high FAI and low SHBG remained significant even in women with body mass index less than 26.7 kg/m 2 . An androgenic hormone profile is associated with both the individual components of the metabolic syndrome and clustering of metabolic abnormalities in postmenopausal women.

Geoffrey L. Hammond - One of the best experts on this subject based on the ideXlab platform.

  • GL: Diverse roles for Sex Hormone-Binding Globulin in reproduction
    2016
    Co-Authors: Geoffrey L. Hammond
    Abstract:

    Sex Hormone-Binding Globulin (SHBG) transports androgens and estrogens in blood and regulates their access to target tissues. Hepatic production of SHBG fluctuates throughout the life cycle and is influenced primarily by metabolic and hormonal factors. Genetic differences also contribute to interindividual variations in plasma SHBG levels. In addition to controlling the plasma distribution, metabolic clearance, and bioavailability of Sex steroids, SHBG accumulates in the extravascular compart-ments of some tissues and in the cytoplasm of specific epithelial cells, where it exerts novel effects on androgen and estrogen action. In mammals, the gene-encoding SHBG is expressed primarily in the liver but also at low levels in other tissues, including the testis. In subprimate species, Shbg expression in Sertoli cells is under the control of follicle-stimulating hormone and produces the androgen-binding protein that influences androgen actions in the seminiferous tubules and epididymis. In humans, the SHBG gene is not expressed in Sertoli cells, but its expression in germ cells produces an SHBG isoform that accumulates in the acrosome. In fish, Shbg is produced by the liver but has a unique function in the gill as a portal for natural steroids and xenobiotics, including synthetic steroids. However, salmon have retained a second, poorly conserved Shbg gene that is expressed only in ovary, muscle, and gill and that likely exerts specialized functions in these tissues. The present review compares the production and functions of SHBG in different species and its diverse effects on reproduction. male reproductive tract, mechanisms of hormone action, sperm, steroid hormones/steroid hormone receptors, testi

  • Diverse Roles for Sex Hormone-Binding Globulin in Reproduction
    Biology of Reproduction, 2011
    Co-Authors: Geoffrey L. Hammond
    Abstract:

    Sex Hormone-Binding Globulin (SHBG) transports androgens and estrogens in blood and regulates their access to target tissues. Hepatic production of SHBG fluctuates throughout the life cycle and is influenced primarily by metabolic and hormonal factors. Genetic differences also contribute to interindividual variations in plasma SHBG levels. In addition to controlling the plasma distribution, metabolic clearance, and bioavailability of Sex steroids, SHBG accumulates in the extravascular compartments of some tissues and in the cytoplasm of specific epithelial cells, where it exerts novel effects on androgen and estrogen action. In mammals, the gene-encoding SHBG is expressed primarily in the liver but also at low levels in other tissues, including the testis. In subprimate species, Shbg expression in Sertoli cells is under the control of follicle-stimulating hormone and produces the androgen-binding protein that influences androgen actions in the seminiferous tubules and epididymis. In humans, the SHBG gene is not expressed in Sertoli cells, but its expression in germ cells produces an SHBG isoform that accumulates in the acrosome. In fish, Shbg is produced by the liver but has a unique function in the gill as a portal for natural steroids and xenobiotics, including synthetic steroids. However, salmon have retained a second, poorly conserved Shbg gene that is expressed only in ovary, muscle, and gill and that likely exerts specialized functions in these tissues. The present review compares the production and functions of SHBG in different species and its diverse effects on reproduction.

  • Sex hormone binding Globulin in fish gills is a portal for Sex steroids breached by xenobiotics
    Endocrinology, 2008
    Co-Authors: Solange Miguelqueralt, Geoffrey L. Hammond
    Abstract:

    As in most vertebrates, plasma Sex Hormone-Binding Globulin (SHBG) is produced in fish liver and regulates Sex steroid access to target tissues. Low levels of SHBG mRNA are present in zebra fish gills but are unlikely to account for the high amounts of immunoreactive SHBG in filaments and lamellae. Although the uptake of steroids by fish from water has been reported to correlate with their affinity for SHBG, it is not known how this occurs. Our studies of zebra fish SHBG have revealed its preference for biological active androgen (testosterone), as well as for androstenedione, a Sex steroid precursor that also acts as a pheromone in some fish. In addition to natural steroids, zebra fish SHBG has a high affinity for synthetic steroids, such as ethinylestradiol and progestins (levonorgestrel and norethindrone), that are present in waste water systems. Because steroids can pass across fish gills, we examined whether SHBG serves as a portal for natural and synthetic steroids controlling their flux between the...

  • an updated steroid benchmark set and its application in the discovery of novel nanomolar ligands of Sex hormone binding Globulin
    Journal of Medicinal Chemistry, 2008
    Co-Authors: Artem Cherkasov, Fuqiang Ban, Osvaldo A Santosfilho, Nels Thorsteinson, Magid Fallahi, Geoffrey L. Hammond
    Abstract:

    A benchmark data set of steroids with known affinity for Sex Hormone-Binding Globulin (SHBG) has been widely used to validate popular molecular field-based QSAR techniques. We have expanded the data set by adding a number of nonsteroidal SHBG ligands identified both from the literature and in our previous experimental studies. This updated molecular set has been used herein to develop 4D QSAR models based on "inductive" descriptors and to gain insight into the molecular basis of protein-ligand interactions. Molecular alignment was generated by means of docking active compounds into the active site of the SHBG. Surprisingly, the alignment of the benchmark steroids contradicted the classical ligand-based alignment utilized in previous CoMFA and CoMSIA models yet afforded models with higher statistical significance and predictive power. The resulting QSAR models combined with CoMFA and CoMSiA models as well as structure-based virtual screening allowed discovering several low-micromolar to nanomolar nonsteroidal inhibitors for human SHBG.

  • estetrol does not bind Sex hormone binding Globulin or increase its production by human hepg2 cells
    Climacteric, 2008
    Co-Authors: Geoffrey L. Hammond, M Visser, K N Hogeveen, H Coelingh J T Bennink
    Abstract:

    Objectives To determine whether human Sex hormone binding Globulin (SHBG) binds estetrol (E4), and to assess whether E4 stimulates the production of SHBG by human hepatocytes.Methods Competitive ligand binding assays have been used to assess the relative binding affinity of E4 to human SHBG using either [3H]5α-dihydrotestosterone or [3H]estradiol as labeled ligands. The effect of E4 on the production of SHBG has been assessed by a fluoroimmunometric assay in wild-type human HepG2 cells and in human Hep89 cells that over-express the human estrogen receptor (ER) α, and compared to the effect of ethinylestradiol, estradiol and estriol.Results There was no detectable binding of E4 to the human SHBG steroid-binding sites. By contrast, testosterone and estradiol were bound with high affinity and the synthetic estrogen ethinylestradiol was found to bind SHBG with low affinity. Estetrol does not stimulate ERα-mediated increases in SHBG production by HepG2 or Hep89 cells, in contrast to ethinylestradiol, estradiol...

Kathryn M Rexrode - One of the best experts on this subject based on the ideXlab platform.

Julie E Buring - One of the best experts on this subject based on the ideXlab platform.

  • Sex hormone binding Globulin and risk of type 2 diabetes in women and men
    The New England Journal of Medicine, 2009
    Co-Authors: Eric L Ding, Yiqing Song, Joann E Manson, David J Hunter, Nader Rifai, Julie E Buring, Michael J Gaziano
    Abstract:

    Background Circulating Sex hormone–binding Globulin levels are inversely associated with insulin resistance, but whether these levels can predict the risk of developing type 2 diabetes is uncertain. Methods We performed a nested case–control study of postmenopausal women in the Women’s Health Study who were not using hormone therapy (359 with newly diagnosed type 2 diabetes and 359 controls). Plasma levels of Sex hormone–binding Globulin were measured; two polymorphisms of the gene encoding Sex hormone–binding Globulin, SHBG, that were robustly associated with the protein levels were genotyped and applied in mendelian randomization analyses. We then conducted a replication study in an independent cohort of men from the Physicians’ Health Study II (170 with newly diagnosed type 2 diabetes and 170 controls). Results Among women, higher plasma levels of Sex hormone–binding Globulin were prospectively associated with a lower risk of type 2 diabetes: multivariable odds ratios were 1.00 for the first (lowest) quartile of plasma levels, 0.16 (95% confidence interval [CI], 0.08 to 0.33) for the second quartile, 0.04 (95% CI, 0.01 to 0.12) for the third quartile, and 0.09 (95% CI, 0.03 to 0.21) for the fourth (highest) quartile (P<0.001 for trend). These prospective associations were replicated among men (odds ratio for the highest quartile of plasma levels vs. the lowest quartile, 0.10; 95% CI, 0.03 to 0.36; P<0.001 for trend). As compared with homozygotes of the respective wild-type allele, carriers of a variant allele of the SHBG single-nucleotide polymorphism (SNP) rs6259 had 10% higher Sex hormone–binding Globulin levels (P = 0.005), and carriers of an rs6257 variant had 10% lower plasma levels (P = 0.004); variants of both SNPs were also associated with a risk of type 2 diabetes in directions corresponding to their associated Sex hormone–binding Globulin levels. In mendelian randomization analyses, the predicted odds ratio of type 2 diabetes per standard-deviation increase in the plasma level of Sex hormone–binding Globulin was 0.28 (95% CI, 0.13 to 0.58) among women and 0.29 (95% CI, 0.15 to 0.58) among men, a finding that suggests that Sex hormone–binding Globulin may have a causal role in the risk of type 2 diabetes. Conclusions Low circulating levels of Sex hormone–binding Globulin are a strong predictor of the risk of type 2 diabetes in women and men. The clinical usefulness of both SHBG genotypes and plasma levels in stratification and intervention for the risk of type 2 diabetes warrants further examination.

  • low Sex hormone binding Globulin is associated with the metabolic syndrome in postmenopausal women
    Metabolism-clinical and Experimental, 2006
    Co-Authors: Melissa E Weinberg, Joann E Manson, Julie E Buring, Nancy R Cook, Ellen W Seely, Paul M Ridker, Kathryn M Rexrode
    Abstract:

    Abstract Although an association between the metabolic syndrome and hyperandrogenism has been suggested in women with polycystic ovarian syndrome, few studies have investigated this relationship in postmenopausal women. We measured estradiol, testosterone, and Sex hormone–binding Globulin (SHBG) and calculated the free androgen index (FAI) in 212 postmenopausal women not using hormone therapy in the Women's Health Study. A modified definition of the metabolic syndrome (3 or more of the following: abdominal obesity, hypertriglyceridemia, low high-density lipoprotein, elevated blood pressure, and abnormal glucose metabolism) from the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults was used. Women with the metabolic syndrome had higher mean levels of estradiol, testosterone, and FAI values and lower SHBG levels. Higher FAI and lower SHBG were associated with all components of the metabolic syndrome. After adjustment for BMI and other factors, women in the highest tertile of FAI had an odds ratio of 12.6 (95% confidence interval, 3.8-41.6) for the metabolic syndrome, whereas those in the lowest SHBG tertile had an odds ratio of 7.3 (95% confidence interval, 2.7-19.8). When stratified by body mass index, the associations with high FAI and low SHBG remained significant even in women with body mass index less than 26.7 kg/m 2 . An androgenic hormone profile is associated with both the individual components of the metabolic syndrome and clustering of metabolic abnormalities in postmenopausal women.

John F. Randolph - One of the best experts on this subject based on the ideXlab platform.

  • testosterone Sex hormone binding Globulin and free androgen index among adult women chronological and ovarian aging
    Human Reproduction, 2009
    Co-Authors: Maryfran Sowers, Huiyong Zheng, Carrie A Karvonengutierrez, Dan Mcconnell, John F. Randolph
    Abstract:

    BACKGROUND: In this study, levels and rates of change in total testosterone (T), Sex Hormone-Binding Globulin (SHBG) and free androgen index (FAI) were related to chronological age and to the final menstrual period (FMP) as an indicator of ovarian aging. METHODS: Data were annually acquired over a 15-year period in 629 women of the Michigan Bone Health and Metabolism Study cohort. Data were censored for hormone therapy use. Endogenous androgen patterns over time were described with stochastic processes and bootstrapping. RESULTS: With ovarian aging, T levels rose from a mean of 18 ng/dl commencing 10 years prior to the FMP to 27 ng/dl at the FMP. Over the 20-year period encompassing the FMP, modeled mean SHBG levels changed from 58 to 34 nM and the FAI ratio increased from 1.6 to 2.9 in a non-linear manner. With chronological aging, total T levels increased (P < 0.0001) from 43 to 50 years, but not thereafter. SHBG declined steadily with age with a modestly greater rate of change between 49 and 54 years. The FAI increased from 1.3 to 2.5 from 34 to 58 years. CONCLUSIONS: T increased from approximately age 40 until the FMP whereas SHBG had rate of change patterns reflecting both chronological and ovarian aging components. These data provide new insight into the endogenous androgen patterns at mid-life.