Inverse relationship between hSHBG affinity for testosterone and hSHBG concentration revealed by surface plasmon resonance

Heinrich-Balard, Laurence; Zeinyeh, Waël; Déchaud, H.; Rivory, Pascaline; Roux, Amandine Le; Pugeat, Michel; Cohen, Richard A.

doi:10.1016/j.mce.2014.10.002

Cited by 12 publications

(3 citation statements)

References 33 publications

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“…The variations in the apparent K d with varying estradiol concentrations and estradiol to SHBG ratios and the heterogeneity in binding isotherms were also noted in some previous investigations of testosterone and dihydrotestosterone binding to SHBG [ Heinrich-Balard et al., 2014 ; Zakharov et al., 2015 ; Metzger et al., 2003 ]. However, these divergences in the apparent K d and the nonlinearities in the binding isotherms were ignored in favor of the simplistic homogeneous interaction model.…”

Section: Discussionsupporting

confidence: 65%

Estradiol induces allosteric coupling and partitioning of sex-hormone-binding globulin monomers among conformational states

et al. 2021

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Summary Sex-hormone-binding globulin (SHBG) regulates the transport and bioavailability of estradiol. The dynamics of estradiol's binding to SHBG are incompletely understood, although it is believed that estradiol binds to each monomer of SHBG dimer with identical affinity (K d ∼2 nM). Contrary to the prevalent view, we show that estradiol's binding to SHBG is nonlinear, and the "apparent" K d changes with varying estradiol and SHBG concentrations. Estradiol's binding to each SHBG monomer influences residues in the ligand-binding pocket of both monomers and differentially alters the conformational and energy landscapes of both monomers. Monomers are not energetically or conformationally equivalent even in fully bound state. Estradiol's binding to SHBG involves bidirectional, inter-monomeric allostery that changes the distribution of both monomers among various energy and conformational states. Inter-monomeric allostery offers a mechanism to extend the binding range of SHBG and regulate hormone bioavailability as estradiol concentrations vary widely during life.

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Section: Discussionsupporting

confidence: 65%

Estradiol induces allosteric coupling and partitioning of sex-hormone-binding globulin monomers among conformational states

et al. 2021

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“…( 80 ) Thus, the ratio of testosterone to SHBG can alter the apparent affinity of these sites. ( 81 ) Moreover, such interactions in binding sites may also apply to the binding of testosterone to albumin. ( 82 ) Furthermore, there are numerous polymorphisms in SHBG that influence its affinity for sex steroids (reviewed in Hammond ( 74 ) ).…”

Section: Sex Hormone‐binding Globulin and Free Testosteronementioning

confidence: 99%

The Free Hormone Hypothesis: When, Why, and How to Measure the Free Hormone Levels to Assess Vitamin D, Thyroid, Sex Hormone, and Cortisol Status

Bikle

2020

JBMR Plus

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The free hormone hypothesis postulates that only the nonbound fraction (the free fraction) of hormones that otherwise circulate in blood bound to their carrier proteins is able to enter cells and exert biologic effects. In this review, I will examine four hormone groups-vitamin D metabolites (especially 25OHD), thyroid hormones (especially thyroxine [T4]), sex steroids (especially testosterone), and glucocorticoids (especially cortisol)-that are bound to various degrees to their respective binding proteins-vitamin D-binding protein (DBP), thyroid-binding globulin (TBG), sex hormone-binding globulin (SHBG), and cortisol-binding globulin (CBG)-for which a strong case can be made that measurement of the free hormone level provides a better assessment of hormonal status than the measurement of total hormonal levels under conditions in which the binding proteins are affected in levels or affinities for the hormones to which they bind. I will discuss the rationale for this argument based on the free hormone hypothesis, discuss potential exceptions to the free hormone hypothesis, and review functions of the binding proteins that may be independent of their transport role. I will then review the complications involved with measuring the free hormone levels and the efforts to calculate those levels based on estimates of binding constants and levels of both total hormone and total binding protein. In this review, the major focus will be on DBP and free 25OHD, but the parallels and differences with the other binding proteins and hormones will be highlighted. Vitamin D and its metabolites, thyroid hormones, sex steroids, and glucocorticoids are transported in blood bound to serum proteins. The tightness of binding varies depending on the hormone and the binding protein such that the percent free varies from 0.03% for T4 and 25OHD to 4% for cortisol with testosterone at 2%. Although the major function of the primary carrier proteins (DBP, TBG, SHBG, and CBG) may be to transport their respective lipophilic hormones within the aqueous media that is plasma, these proteins may have other functions independent of their transport function. For most tissues, these hormones enter the cell as the free hormone presumably by diffusion (the free hormone hypothesis), although a few tissues such as the kidney and reproductive tissues express megalin/cubilin enabling by endocytosis protein-bound hormone to enter the cell. Measuring the free levels of these proteinbound hormones is likely to provide a better measure of the true hormone status than measuring the total levels in situations where the levels and/or affinities of the binding proteins are altered. Methods to measure free hormone levels are problematic as the free levels can be quite low, the methods require separation of bound and free that could disturb the steady state, and the means of separating bound and free are prone to error. Calculation of free levels using existing data for association constants between the hormone and its binding protein are likewise prone to error beca...

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“…The concentration of SHBG increased from 5 to 10-fold during mid to late pregnancy, which changed the affinity of SHBG for T and DHT 43 . Heinrich-Balard et al 44 revealed an inverse relationship between SHBG affinity for T. In addition, the increase in estrogen in late pregnancy was much higher than the increases in T and DHT, and estrogen may compete with T and DHT for the available binding sites of SHBG 45 .…”

Section: Discussionmentioning

confidence: 98%

Association between prenatal androgens and cord blood androgens, a path analysis

Wang²,

Li³

et al. 2023

Sci Rep

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To determine association paths between prenatal androgens and cord blood androgens. The concentrations of T, FT, DHT, DHEA and SHBG in prenatal venous blood and cord blood were measured in 342 pregnant women and their neonates. The association paths between these hormones in prenatal and cord blood were revealed using Pearson correlation, multiple linear regression and path analysis. CB-T, CB-FT and CB-DHT in male neonates were higher than those in female neonates. In male and female neonates, P-FT was lower than CB-FT; however, P-DHT and P-SHBG were higher than CB-DHT and CB-SHBG, respectively. P-DHEA was lower than CB-DHEA in female newborns. In male neonates, there were association paths of P-T → CB-T → CB-FT → CB-DHT, P-T → CB-FT → CB-DHT, P-T → P-FT → CB-FT → CB-DHT, P-T → P-DHT, CB-DHEA → CB-DHT, CB-DHEA → P-DHT, and CB-DHEA → P-DHEA. In female neonates, there were association paths of P-T → CB-T → CB-FT → CB-DHT, P-T → P-FT → CB-FT → CB-DHT, P-T → P-FT → P-DHT, P-T → P-DHT, P-DHEA → P-DHT, CB-DHEA → P-DHEA, and CB-DHEA → CB-FT. There were differences in the T, FT and DHT concentrations in cord blood between male and female neonates and in the FT, DHT, DHEA, and SHBG concentrations between prenatal and cord blood. P-T and P-FT concentrations were positively associated with CB-T and CB-FT concentrations, while CB-DHEA concentration was positively associated with P-DHEA concentration.

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Inverse relationship between hSHBG affinity for testosterone and hSHBG concentration revealed by surface plasmon resonance

Cited by 12 publications

References 33 publications

Estradiol induces allosteric coupling and partitioning of sex-hormone-binding globulin monomers among conformational states

Estradiol induces allosteric coupling and partitioning of sex-hormone-binding globulin monomers among conformational states

The Free Hormone Hypothesis: When, Why, and How to Measure the Free Hormone Levels to Assess Vitamin D, Thyroid, Sex Hormone, and Cortisol Status

Association between prenatal androgens and cord blood androgens, a path analysis

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