The Free Hormone Hypothesis: A Physiologically Based Mathematical Model*
Abstract
The free hormone hypothesis states that the biological activity of a given hormone is affected by its unbound (free) rather than protein-bound concentration in the plasma. The fundamental mathematical and physiological principles relating to this hypothesis are reviewed, along with experimental data that shed light on its validity. It is shown that whether or not this hypothesis is likely to be valid for any given hormone will depend largely on which step in the tissue uptake process (plasma flow, dissociation from plasma binding proteins, influx, or intracellular elimination) is rate-limiting to the net tissue uptake of that hormone. It is further shown that the free hormone hypothesis could hold even if tissue uptake of hormone occurred by a mechanism that acted directly on one or more circulating protein-bound pools of hormone. Indeed, many of the data previously interpreted as being inconsistent with the free hormone hypothesis are in fact readily consistent with it when its predictions are fully understood. Nevertheless, the free hormone hypothesis is not likely to be valid for all hormones with respect to all tissues. It is likely to be valid with respect to all tissues for the thyroid hormones, for cortisol, and for the hydroxylated metabolites of vitamin D. For many of the other steroid hormones, however, it is likely to be valid with respect to some tissues, but not with respect to others (in particular, the liver). And for some of the steroid hormones (in particular, progesterone) it may not hold at all.
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Serum fT4 should be measured in preference to TT4 despite its very low fraction of TT4 (0.03%).
“This is now widely accepted, at least for serum TH measurements, and serum fT4 should be measured in preference to TT4 despite its very low fraction of TT4 (0.03%).”
The free hormone hypothesis states that biological activity of a hormone is best reflected by free rather than total hormone concentrations.
“According to the free hormone hypothesis, biological activity of a certain hormone is best reflected by free rather than total hormone concentrations.”
From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [27]
The free hormone hypothesis is not expected to be valid under all possible sets of conditions; a single steroid hormone can be subjected to different models depending on the tissue type.
“In summary, these findings highlight that the free hormone hypothesis is not expected to be valid under all possible sets of conditions. A single steroid hormone can be subjected to different models depending on the tissue type [27].”
From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [27]
In case of rate-limitation by influx, the free hormone hypothesis may be either valid (influx via the free hormone pool) or invalid (influx via the protein-bound hormone pool).
“In case of rate-limitation by influx, the free hormone hypothesis may be either valid (influx via the free hormone pool) or invalid (influx via the protein-bound hormone pool).”
From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [27]
Mendel's mathematical models characterize cellular steroid hormone uptake through four parameters: plasma flow rate, hormone dissociation rate from its binding protein, tissue influx rate, and intracellular elimination rate.
“These models characterize the process of cellular steroid hormone uptake through four parameters: plasma flow rate, hormone dissociation rate from its BP, tissue influx rate and intracellular elimination rate.”
From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [27]
In the free hormone hypothesis, the free fraction, and by extension the free hormone concentration, accounts for the biological activity of hormone action.
“In the free hormone hypothesis, it is mostly this free fraction, and by extension the free hormone concentration, that accounts for the biological activity of hormone action.”
From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [27]
The free hormone hypothesis is invalid when flow or dissociation from the binding protein is rate-limiting.
“The hypothesis is, however, invalid when flow or dissociation from the BP is rate-limiting.”
From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [27]
Mendel introduced a sound mathematical and physiological model for the free hormone hypothesis in 1989.
“Although many insights were achieved in terms of free serum hormones, it was not until 1989 that a sound mathematical and physiological model for the hypothesis was introduced by Mendel, referring to the hypothesis now generally accepted as the free hormone hypothesis [27].”
From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [27]
In human blood, nearly 99.97% of T4 and 99.70% of T3 are bound to specific THBPs.
“nearly 99.97% of T4 and 99.70% of T3 are bound to specific THBPs (22)”
From Intrathyroidal feedforward and feedback network regulating thyroid hormone synthesis and secretion (2022) · cites this paper as [22]
SHBG binds sex steroids (including active androgens and estrogens) with high affinity (nanomolar ranges) and specificity.
“SHBG binds sex steroids (including active androgens and estrogens) with high affinity (nanomolar ranges) and specificity [[285], [286], [287]].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [286]
Like with androgens, the majority of unconjugated estrogen circulates bound to SHBG with high affinity and albumin with low affinity.
“Like with androgens, the majority of unconjugated estrogen circulates bound to SHBG with high affinity and albumin with low affinity [[285], [286], [287]].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [286]
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- Authors
- MENDEL, C. M.
- Corresponding author
- MENDEL, CARL M.
- Venue
- Endocrine Reviews
- Publisher
- The Endocrine Society
- Published
- 1989-08
- Volume
- 10
- Issue
- 3
- Pages
- 232-274
- ISSN
- 0163-769X (ISSN-L)
- 1945-7189
- OpenAlex
- W2108958077
- Cited by
- 961
- References
- 0
- Citations by year
- 2026: 19 · 2025: 25 · 2024: 33 · 2023: 28 · 2022: 42 · 2021: 34 · 2020: 37 · 2019: 38 · 2018: 39 · 2017: 40 · 2016: 49 · 2015: 29 · 2014: 36 · 2013: 37 · 2012: 28
- FWCI
- 8.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrine Reviews (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Interaction Studies and Fluorescence Analysis
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Keywords
- free hormone hypothesis, hormone binding proteins, plasma protein binding, rate-determining step, mathematical model, thyroid hormones, cortisol, vitamin D metabolites, steroid hormones, progesterone, liver
- MeSH terms
- Animals, Biological Transport, Blood Proteins, Hormones, Humans, Mathematics, Models, Biological
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