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Cited by 114Vitamin D Research StudiesHormonal and reproductive studiesThyroid Disorders and Treatments

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

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Bikle, Daniel D·2021·JBMR Plus
DOI 10.1002/jbm4.10418PMC PMC7839820
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Abstract

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 protein‐bound 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 because of assumptions of linear binding models and invariant association constants, both of which are invalid. © 2020 The Author. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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Authors
Bikle, D. D.
Affiliations
San Francisco VA Medical Center (US)
Corresponding author
Bikle, Daniel D
ORCID
Bikle, Daniel D
Venue
JBMR Plus
Publisher
Oxford University Press (OUP)
Published
2020-11-02
Volume
5
Issue
1
Pages
e10418-e10418
ISSN
2473-4039 (ISSN-L)
DOI
10.1002/jbm4.10418
PMC
PMC7839820
OpenAlex
W3091609628
Cited by
114
References
105
Citations by year
2026: 19 · 2025: 26 · 2024: 19 · 2023: 27 · 2022: 12 · 2021: 11
FWCI
1.92
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journal article
Language
en
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Funders
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (RO1 AR055924)
  • U.S. Department of Veterans Affairs (I01 BX003814)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Vitamin D Research Studies
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
Keywords
free hormone hypothesis, hormone binding proteins, vitamin D binding protein, 25-hydroxyvitamin D, thyroxine-binding globulin, sex hormone-binding globulin, corticosteroid-binding globulin, cortisol, thyroxine, testosterone, hormone transport, binding constant, endocrine assessment

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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