Interactions of sex hormone-binding globulin with target cells

Rosner, William; Hryb, Daniel J.; Kahn, Scott M.; Nakhla, Atif M.; Romas, Nicholas A.

doi:10.1016/j.mce.2009.08.009

Cited by 147 publications

(131 citation statements)

References 57 publications

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“…For risk factors of interest, such as SHBG, cFT and TT, crude and adjusted hazards ratios are reported to ascertain their significance independently of covariates. Candidate covariates for hazard models were chosen a priori to cover covariates affecting competing diabetes-related mortality risk markers, including i) in multivariable model 1 Cause-specific hazards models were censored for competing risks. The significance of an added factor on improving model prediction was assessed in nested models with the likelihood ratio test.…”

Section: Discussionmentioning

confidence: 99%

“…Only unliganded, but not sex steroid-bound SHBG binds to the SHBG receptor, suggesting that SHBG may have biological actions that are independent of sex steroids (1,17).…”

Section: Discussionmentioning

confidence: 99%

“…Sex hormone binding globulin (SHBG) has traditionally been considered to be a passive carrier for circulating sex steroids such as testosterone, determining their bioavailability and metabolic clearance (1). In men, 40% of serum testosterone is tightly bound to SHBG, 58% loosely to albumin, and the remaining 0.5-2% circulates as the free form.…”

Section: Introductionmentioning

confidence: 99%

“…In men, 40% of serum testosterone is tightly bound to SHBG, 58% loosely to albumin, and the remaining 0.5-2% circulates as the free form. More recent evidence suggests that SHBG is not just a passive carrier, but actively regulates the cellular uptake of testosterone and cellular proliferation via a specific receptor (1,2). SHBG gene polymorphisms influence the risk of developing type 2 diabetes mellitus (T2DM) (3), and SHBG has been implicated in the development of the metabolic syndrome independent of testosterone levels (4).…”

Section: Introductionmentioning

confidence: 99%

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Association of sex hormone-binding globulin and free testosterone with mortality in men with type 2 diabetes mellitus

Tint

Hoermann

Wong

et al. 2016

European Journal of Endocrinology

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Objective: Low circulating testosterone levels have been associated with increased mortality in men. We hypothesized that the prognostic role of testosterone in men with type 2 diabetes mellitus (T2DM) is influenced by its carrier protein sex hormone-binding globulin (SHBG). Design: We conducted a prospective cohort study at a tertiary referral centre. Methods: In total, 531 men with T2DM presenting to a diabetes clinic in 2004-2005 were followed prospectively until death, or July 31, 2014, and a survival analysis was performed. The main outcome measure was all cause mortality. Results: Over a mean (S.D.) follow up of 7.6 years (2.6) 175 men (33%) died. In Cox proportional hazard models both higher SHBG (Hazard Ratio (HR) 1.012 (95% CI 1.002-1.022), PZ0.02) and lower calculated free testosterone (cFT) (HR 0.995 (95% CI 0.993-0.998), PZ0.001) were risk factors for all cause mortality independently of age, BMI, presence of macro-and microvascular disease, duration of T2DM, hemoglobin, renal function, insulin use, C-reactive protein and homeostatic model of insulin resistance. By contrast, the inverse association of total testosterone (TT) with mortality weakened after these adjustments (PZ0.11). SHBG remained associated with mortality (P!0.001) both if substituted for or added to TT in the multivariable model. In the fully adjusted model, an increase of SHBG by 17.3 nmol/l (1 S.D.) increased mortality by 22% and a decrease in cFT by 81 pmol/l (1 S.D.) increased mortality by 45%. Conclusions: The association of SHBG with mortality in men with T2DM is novel. Whether SHBG acts via regulation of testosterone, has intrinsic biological roles, or is a marker of poor health requires further study.

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Section: Discussionmentioning

confidence: 99%

“…Only unliganded, but not sex steroid-bound SHBG binds to the SHBG receptor, suggesting that SHBG may have biological actions that are independent of sex steroids (1,17).…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Association of sex hormone-binding globulin and free testosterone with mortality in men with type 2 diabetes mellitus

Tint

Hoermann

Wong

et al. 2016

European Journal of Endocrinology

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“…Simplistically, as long as bound to SHBG, steroid hormones are inactive and serve as a reservoir for future use. In terms of molecular biology, the multiple interactions between SHBG and its putative receptors in various target tissues (breast, prostate, liver, epididymis) suggest involvement of SHBG in physiology that is more complex than the simple transport of sex steroids in serum [1,2]. SHBG has actually emerged as one of the manifold factors that contribute to the type 2 diabetes mellitus (T2DM) pathophysiology.…”

Section: Introductionmentioning

confidence: 99%

SHBG Genetic Variability and Glucose Tolerance in T2DM Patients, Gestational Diabetics, and Women with PCOS in Comparison with the Control Czech Population Sample

Vejražková¹

2013

J Steroids Horm Sci

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IntroductionSex hormone-binding globulin (SHBG) is the primary plasma transport protein for sex steroid hormones. The SHBG gene is located on the short arm of chromosome 17 and the major transcript is encoded by 8 exons, spanning approximately 3.2 Kb. The gene product is a 373 amino acid glycoprotein produced mainly by liver. It regulates the bioavailability of sex steroids to target tissues and its biological half-life is 7 days. Simplistically, as long as bound to SHBG, steroid hormones are inactive and serve as a reservoir for future use. In terms of molecular biology, the multiple interactions between SHBG and its putative receptors in various target tissues (breast, prostate, liver, epididymis) suggest involvement of SHBG in physiology that is more complex than the simple transport of sex steroids in serum [1,2]. SHBG has actually emerged as one of the manifold factors that contribute to the type 2 diabetes mellitus (T2DM) pathophysiology. In addition to epidemiological studies, which demonstrate a consistent relationship between lower levels of SHBG in serum and T2DM [3][4][5], also genetic studies reveal that specific SHBG gene polymorphisms can causally affect insulin sensitivity and T2DM risk [3,4]. The exact mechanism underlying these findings is not known. Besides the contribution of genetic studies, there is also clinical evidence that the associations between insulin sensitivity and steroids may be causal. Hyper-androgenic disorders characterized by low SHBG levels such as polycystic ovary syndrome (PCOS) in women result in an increased risk of T2DM and are very strongly associated with insulin resistance [6][7][8][9]. Second, insulin lowering interventions lead to increased SHBG levels, suggesting that insulin can causally influence sex steroid dynamics [10,11]. Third, during pregnancy, in both first and second trimester SHBG appears to be lower among women who subsequently developed gestational diabetes mellitus. Furthermore, lower levels of SHBG were observed in those patients who developed severe gestational AbstractBackground: Sex hormone-binding globulin (SHBG) belongs to the factors contributing to the pathophysiology of type 2 diabetes mellitus (T2DM). We determined genotypic frequencies of the single nucleotide polymorphisms (SNPs) rs6259 and rs6257 in T2DM patients, offspring of T2DM patients, gestational diabetics, patients suffering from polycystic ovary syndrome (PCOS), and in healthy adult Czechs. 1687 volunteers entered the study. The aim was to compare genetic constellation between the groups and to study the possible association of the SNPs with biochemical and anthropometric markers of insulin sensitivity.

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Characterization and comparison of recombinant full‐length ursine and human sex hormone‐binding globulin

et al. 2021

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Sex hormone-binding globulin (SHBG) regulates the bioavailability of sex steroid hormones in the blood. Levels of SHBG increase markedly in brown bears (Ursus arctos) during hibernation, suggesting that a key regulatory role of this protein is to quench sex steroid bioavailability in hibernation physiology. To enable characterization of ursine SHBG and a cross species comparison, we established an insect cell-based expression system for recombinant full-length ursine and human SHBG. Compared with human SHBG, we observed markedly lower secretion levels of ursine SHBG, resulting in a 10-fold difference in purified protein yield. Both human and ursine recombinant SHBG appeared as dimeric proteins in solution, with a single unfolding temperature of ~58 °C. The thermal stability of ursine and human SHBG increased 5.4 and 9.5 °C, respectively, in the presence of dihydrotestosterone (DHT), suggesting a difference in affinity. The dissociation constants for [ 3 H]DHT were determined to 0.21 AE 0.04 nM for human and 1.32 AE 0.10 nM for ursine SHBG, confirming a lower affinity of ursine SHBG. A similarly reduced affinity, determined from competitive steroid binding, was observed for most steroids. Overall, we found that ursine SHBG had similar characteristics to human SHBG, specifically, being a homodimeric glycoprotein capable of binding steroids with high affinity. Therefore, ursine SHBG likely has similar biological functions to those known for human SHBG. The determined properties of ursine SHBG will contribute to elucidating its potential regulatory role in hibernation physiology.Sex hormone-binding globulin (SHBG) is a plasma protein that transports and regulates the bioavailability of sex steroids in the blood by adjusting the equilibrium between free and protein-bound steroid [1]. Steroids are lipophilic with low solubility in water and are therefore bound to various binding proteins when transported in the circulation [2]. Sex steroids, including androgens and estrogens, are important regulatory molecules that control sexual maturation and reproduction as well as regulate other sexually dimorphic Abbreviations AEX, anion exchange chromatography; DCC, dextran-coated charcoal; DHT, 5α-dihydrotestosterone; MALDI-ToF MS, matrix-assisted laser desorption ionization-time of flight mass spectrometry; pFBD, pFastBac TM Dual; RBA, relative binding affinity; SEC-MALS, size exclusion chromatography-multi-angle light scattering; SHBG, sex hormone-binding globulin.

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Interactions of sex hormone-binding globulin with target cells

Cited by 147 publications

References 57 publications

Association of sex hormone-binding globulin and free testosterone with mortality in men with type 2 diabetes mellitus

Association of sex hormone-binding globulin and free testosterone with mortality in men with type 2 diabetes mellitus

SHBG Genetic Variability and Glucose Tolerance in T2DM Patients, Gestational Diabetics, and Women with PCOS in Comparison with the Control Czech Population Sample

Characterization and comparison of recombinant full‐length ursine and human sex hormone‐binding globulin

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