The DOI matches its Crossref record; 53 of the 53 references it cites were found in a registry or an index.
A novel spreadsheet method for calculating the free serum concentrations of testosterone, dihydrotestosterone, estradiol, estrone and cortisol: With illustrative examples from male and female populations
Abstract
In humans, testosterone (T), dihydrotestosterone (DHT), estradiol (E2), estrone (E1) and cortisol (C) bind to the serum proteins sex hormone-binding globulin (SHBG), albumin (Alb) and corticosteroid-binding globulin (CBG). Equilibrium dialysis is considered to be the "gold standard" for measuring the free concentrations of these steroids but is technically difficult and not widely available. Based on a mathematical model of the 5-ligand/3-protein binding equilibria, we developed a novel spreadsheet method for calculating the free and bioavailable (free+Alb-bound) concentrations of each steroid in terms of the total steroid and protein concentrations. The model uses 15 association constants K(SHBG-X), K(Alb-X), and K(CBG-X) (X=T, DHT, E2, E1 and C) that have been estimated from a systematic review of published binding studies. The computation of the free and bioavailable concentrations uses an iterative numerical method that can be readily programmed on a spreadsheet. The method is illustrated with six examples corresponding to young men (YM), old men (OM), obese men (Ob M), young women (YM), pregnant women in the 3rd trimester (Preg T3) and oophorectomized women on oral conjugated equine estrogens (CEE). The resulting free hormone concentrations for YM and YW fall within the normal references ranges obtained by equilibrium dialysis for all five hormones. The model also accounts for the competitive binding effects of high estrogen levels on the free T levels in Preg T3. This novel spreadsheet method provides a "user-friendly" approach for estimating the free concentrations of circulating sex hormones and cortisol in men and women.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Among steroid hormones, T has the second highest association constant (Ka), valued at 1–2 × 109 M−1 s−1, whereas DHT has the highest Ka for SHBG (2.69 × 109 M−1 s−1) [16].”
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 [16]
In the citing paper
“First, several equations were derived from the general law of mass action. Association constants for albumin and SHBG used in these formulas were obtained from in vitro experiments by linearizing data through Scatchard analysis [16, 208, 212].”
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 [16]
In the citing paper
“A wide spectrum of algorithms for free T exists, which can broadly be divided into three categories (Table 6).”
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 [16]
In the citing paper
“Circulating T is predominantly bound to sex hormone binding globulin (SHBG) and albumin, with small percentages freely circulating or associated with corticosteroid binding globulin.”
From Challenges in Testosterone Measurement, Data Interpretation, and Methodological Appraisal of Interventional Trials (2016) · cites this paper as [10]
In the citing paper
“Testosterone levels were measured by a radioimmunoassay that has been validated against liquid chromatography tandem mass spectrometry (13) and has a sensitivity of 10 ng/dL.”
From Testosterone induces erythrocytosis via increased erythropoietin and suppressed hepcidin: evidence for a new erythropoietin/hemoglobin set point (2014) · cites this paper as [13]
In the citing paper
“The Testosterone in Older Men with Mobility Limitation trial was a randomized, double-blind, placebo-controlled trial whose design and primary results have been published (13).”
From Testosterone induces erythrocytosis via increased erythropoietin and suppressed hepcidin: evidence for a new erythropoietin/hemoglobin set point (2014) · cites this paper as [13]
In the citing paper
“Eligible participants were randomized to placebo or testosterone gel based on concealed, computer-generated randomization tables, using a block size of 6. Randomization was stratified by age: (a) 65-74 and (b) 75 and older.”
From Testosterone induces erythrocytosis via increased erythropoietin and suppressed hepcidin: evidence for a new erythropoietin/hemoglobin set point (2014) · cites this paper as [13]
Citations
Cites
A Critical Evaluation of Simple Methods for the Estimation of Free Testosterone in Serum
Vermeulen, A., Verdonck, L., & Kaufman, J. M. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.84.10.6079 · Cited by 3,824
DUNN, J. F., NISULA, B. C., & RODBARD, D. (1981) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-53-1-58 · Cited by 1,238
ANDERSON, D. C. (1974) · Clinical Endocrinology · doi:10.1111/j.1365-2265.1974.tb03298.x · Cited by 1,127
Södergard, R., Bäckström, T., Shanbhag, V., & Carstensen, H. (1982) · Journal of Steroid Biochemistry · doi:10.1016/0022-4731(82)90038-3 · Cited by 1,080
The Free Hormone Hypothesis: A Physiologically Based Mathematical Model*
MENDEL, C. M. (1989) · Endocrine Reviews · doi:10.1210/edrv-10-3-232 · Cited by 961
Transdermal testosterone treatment in women with impaired sexual function after oophorectomy.
Shifren, J. L., Braunstein, G. D., Simon, J. A., Casson, P. R., Buster, J. E., Redmond, G. P., Burki, R. E., Ginsburg, E. S., Rosen, R. C., Leiblum, S. R., et al. (2000) · New England Journal of Medicine · doi:10.1056/nejm200009073431002 · Cited by 954
Self-citationKudielka, B. M., Buske-Kirschbaum, A., Hellhammer, D. H., & Kirschbaum, C. (2004) · Psychoneuroendocrinology · doi:10.1016/s0306-4530(02)00146-4 · Cited by 851
Leptin and Androgens in Male Obesity: Evidence for Leptin Contribution to Reduced Androgen Levels
Isidori, A. M., Caprio, M., Strollo, F., Moretti, C., Frajese, G., Isidori, A., & Fabbri, A. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.84.10.6082 · Cited by 562
Kenny, A. M., Prestwood, K. M., Gruman, C. A., Marcello, K. M., & Raisz, L. G. (2001) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/56.5.m266 · Cited by 456
Vermeulen, A. (1996) · Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.81.5.1821 · Cited by 455
The Apparent Free Testosterone Concentration, An Index of Androgenicity
Vermeulen, A., Stoica, T., & Verdonck, L. (1971) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-33-5-759 · Cited by 388
Vermeulen, A., Verdonck, L., Straeten, M. V. D., & ORIE, N. (1969) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-29-11-1470 · Cited by 385
Measurement of Free Hormones in Blood
Ekins, R. P. (1990) · Endocrine Reviews · doi:10.1210/edrv-11-1-5 · Cited by 308
Miller, K. K., Rosner, W., Lee, H., Hier, J., Sesmilo, G., Schoenfeld, D., Neubauer, G., & Klibanski, A. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030680 · Cited by 301
Sex hormone-binding globulin mediates steroid hormone signal transduction at the plasma membrane
Rosner, W., Hryb, D. J., Khan, M., Nakhla, A. M., & Romas, N. A. (1999) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/s0960-0760(99)00070-9 · Cited by 195
Soldin, O. P., Guo, T., Weiderpass, E., Tractenberg, R. E., Hilakivi‐Clarke, L., & Soldin, S. J. (2005) · Fertility and Sterility · doi:10.1016/j.fertnstert.2005.02.045 · Cited by 186
Ly, L. P., & Handelsman, D. J. (2005) · European Journal of Endocrinology · doi:10.1530/eje.1.01844 · Cited by 180
Rosner, W., & Smith, R. N. (1975) · Biochemistry · doi:10.1021/bi00693a006 · Cited by 154
Pétra, P. H. (1991) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/0960-0760(91)90299-k · Cited by 147
Mathematical theory of cross-reactive radioimmunoassay and ligand-binding systems at equilibrium
Feldman, H. A., Rodbard, D., & Levine, D. M. (1972) · Analytical Biochemistry · doi:10.1016/0003-2697(72)90216-3 · Cited by 143
Errors in the Measurement of Plasma Free Testosterone 1
Rosner, W. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.6.9999 · Cited by 140
The Free Hormone Hypothesis Distinction from the Free Hormone Transport Hypothesis
Mendel, C. M. (1992) · Journal of Andrology · doi:10.1002/j.1939-4640.1992.tb01639.x · Cited by 128
Morris, P., Malkin, C., Channer, K., & Jones, T. (2004) · European Journal of Endocrinology · doi:10.1530/eje.0.1510241 · Cited by 122
Zumoff, B., Miller, L. K., & Strain, G. W. (2003) · Metabolism · doi:10.1016/s0026-0495(03)00186-0 · Cited by 118
Purnell, J. Q., Kahn, S. E., Samuels, M. H., Brandon, D., Loriaux, D. L., & Brunzell, J. D. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90769.2008 · Cited by 112
de Ronde, W., van der Schouw, Y. T., Muller, M., Grobbee, D. E., Gooren, L. J., Pols, H. A. P., & de Jong, F. H. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-0422 · Cited by 97
Mickelson, K. E., Forsthoefel, J., & Westphal, U. (1981) · Biochemistry · doi:10.1021/bi00524a047 · Cited by 95
Moll, G., ROSENFIEL, R. L., & Helke, J. (1981) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-52-5-868 · Cited by 92
Klosterman, L. L., Murai, J. T., & Siiteri, P. K. (1986) · Endocrinology · doi:10.1210/endo-118-1-424 · Cited by 89
Shifren, J. L., Desindes, S., McIlwain, M., Doros, G., & Mazer, N. A. (2007) · Menopause · doi:10.1097/gme.0b013e31803867a · Cited by 89
Self-citationInterspecies variations of corticosteroid-binding globulin parameters
Gayrard, V., Alvinerie, M., & Toutain, P. (1996) · Domestic Animal Endocrinology · doi:10.1016/0739-7240(95)00042-9 · Cited by 83
Transport of protein-bound steroid hormones into liver in vivo.
Pardridge, W. M., & Mietus, L. J. (1979) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1979.237.4.e367 · Cited by 79
Plasma Cortisol Transport and Primate Evolution
Pugeat, M., Chrousos, G. P., Nisula, B. C., Loriaux, D. L., Brandon, D. D., & LIPSETT, M. B. (1984) · Endocrinology · doi:10.1210/endo-115-1-357 · Cited by 79
The Endocrine Function of the Human Testis
(1973) · Elsevier eBooks · doi:10.1016/c2013-0-10910-5 · Cited by 75
Avvakumov, G. V., Grishkovskaya, I., Muller, Y. A., & Hammond, G. L. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m106274200 · Cited by 74
Sex hormone-binding globulin/androgen-binding protein: Steroid-binding and dimerization domains
Hammond, G. L., & Bocchinfuso, W. P. (1995) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/0960-0760(95)00110-l · Cited by 71
Interaction of Estrogen Therapy and Thyroid Hormone Replacement in Postmenopausal Women
Mazer, N. A. (2004) · Thyroid · doi:10.1089/105072504323024561 · Cited by 71
Self-citationKerlan, V., Nahoul, K., Le Martelot, M., & Bercovici, J. (1994) · Clinical Endocrinology · doi:10.1111/j.1365-2265.1994.tb02478.x · Cited by 66
Maternal hormone levels among populations at high and low risk of testicular germ cell cancer
Zhang, Y., Graubard, B. I., Klebanoff, M. A., Ronckers, C. M., Stanczyk, F. Z., Longnecker, M. P., & McGlynn, K. A. (2005) · British Journal of Cancer · doi:10.1038/sj.bjc.6602545 · Cited by 45
Cherkasov, A., Ban, F., Santos-Filho, O., Thorsteinson, N., Fallahi, M., & Hammond, G. L. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm7011485 · Cited by 42
Westphal, U. (1955) · Endocrinology · doi:10.1210/endo-57-4-456 · Cited by 37
Fernández‐Real, J. M., PUGEAT, M. M., López‐Bermejo, A., Bornet, H., & Ricart, W. (2005) · Metabolism · doi:10.1016/j.metabol.2004.11.015 · Cited by 32
Interactions of steroids with human plasma proteins
Slaunwhite, W. R., Rosenthal, H. E., & Sandberg, A. A. (1963) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(63)90116-4 · Cited by 27
THE PHYSICAL STATE OF TESTOSTERONE IN PLASMA
Vermeulen, A. (1973) · Elsevier eBooks · doi:10.1016/b978-0-12-380101-2.50013-x · Cited by 26
Corticosteroid-binding globulin
Westphal, U. (1983) · Molecular and Cellular Biochemistry · doi:10.1007/bf00673709 · Cited by 25
Belgorosky, A., Escobar, M. E., & Rivarola, M. A. (1987) · Journal of Steroid Biochemistry · doi:10.1016/0022-4731(87)91061-2 · Cited by 25
Metzger, J., Schnitzbauer, A. A., Meyer, M., Söder, M., Cuilleron, C. Y., Hauptmann, H., Huber, E., & Luppa, P. B. (2003) · Biochemistry · doi:10.1021/bi035269k · Cited by 25
Shanbhag, V. P., & Södergård, R. (1986) · Journal of Steroid Biochemistry · doi:10.1016/0022-4731(86)90118-4 · Cited by 24
Circulating Progesterone and Obesity in Men
Blanchette, S., Marceau, P., Biron, S., Brochu, G., & Tchernof, A. (2006) · Hormone and Metabolic Research · doi:10.1055/s-2006-925392 · Cited by 22
BINDING OF 5α-ANDROSTANE-3α,17β-DIOL TO HUMAN PLASMA PROTEINS
CLARK, A. F., & BIRD, C. E. (1973) · Journal of Endocrinology · doi:10.1677/joe.0.0570289 · Cited by 14
Jong, D. A., & James, A. (1977) · Pro Rege · Cited by 8
Steady-state pharmacokinetics of conjugated equine estrogens in healthy, postmenopausal women.
Mayer, P. R., Tse, S. Y. H., Sendi, M., Bourg, D., & Morrison, D. (2008) · PubMed · Cited by 7
Pripp, U., Schenck-Gustafsson, K. G., Landgren, B.-M., & Carlström, K. (2004) · Scandinavian Journal of Clinical and Laboratory Investigation · doi:10.1080/00365510410002995 · Cited by 6
Cited by
Sorted by citations
Adverse Events Associated with Testosterone Administration
Basaria, S., Coviello, A. D., Travison, T. G., Storer, T. W., Farwell, W. R., Jette, A. M., Eder, R., Tennstedt, S., Ulloor, J., Zhang, A., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa1000485 · Cited by 1,494
Self-citationBachman, E., Travison, T. G., Basaria, S., Davda, M. N., Guo, W., Li, M., Connor Westfall, J., Bae, H., Gordeuk, V., & Bhasin, S. (2014) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/glt154 · Cited by 426
Lindheim, L., Bashir, M., Münzker, J., Trummer, C., Zachhuber, V., Leber, B., Horvath, A., Pieber, T. R., Gorkiewicz, G., Stadlbauer, V., et al. (2017) · PLOS ONE · doi:10.1371/journal.pone.0168390 · Cited by 416
“Free testosterone and free DHT were calculated from total testosterone/DHT and SHBG according to Mazer, assuming a blood albumin concentration of 6.2 μmol/l [28].”
InfluentialA Reappraisal of Testosterone’s Binding in Circulation: Physiological and Clinical Implications
Goldman, A. L., Bhasin, S., Wu, F. C. W., Krishna, M., Matsumoto, A. M., & Jasuja, R. (2017) · Endocrine Reviews · doi:10.1210/er.2017-00025 · Cited by 414
Androgen therapy in women: a reappraisal: an Endocrine Society Clinical Practice Guideline
Wierman, M. E., Arlt, W., Basson, R., Davis, S. R., Miller, K. K., Murad, M. H., Rosner, W., & Santoro, N. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-2260 · Cited by 363
Metadata
- Authors
- Mazer, N. A.
- Affiliations
- Boston University (US)
- Corresponding author
- Mazer, Norman A.
- ORCID
- Mazer, Norman A.
- Venue
- Steroids
- Publisher
- Elsevier BV
- Published
- 2009-06
- Volume
- 74
- Issue
- 6
- Pages
- 512-519
- ISSN
- 0039-128X (ISSN-L)
- OpenAlex
- W2003710746
- Cited by
- 189
- References
- 53
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 8 · 2023: 8 · 2022: 9 · 2021: 11 · 2020: 5 · 2019: 13 · 2018: 13 · 2017: 17 · 2016: 11 · 2015: 11 · 2014: 11 · 2013: 13 · 2012: 11
- FWCI
- 9.84
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Steroids (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p30ag031679-15)
- National Institute on Aging (U01AG014369, R01AG031206, 1 P30 AG031679, 5UO1AG14369)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Keywords
- sex hormone-binding globulin, albumin, corticosteroid-binding globulin, testosterone, dihydrotestosterone, estradiol, estrone, cortisol, competitive binding, pregnancy, oophorectomy, conjugated equine estrogens, binding constant
- MeSH terms
- Adult, Aged, Algorithms, Estradiol, Estrone, Female, Humans, Hydrocortisone, Male, Mathematical Computing, Ovariectomy, Pregnancy, Pregnancy Trimester, Third, Reference Values, Dihydrotestosterone, Testosterone, Reproducibility of Results
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 ›
Are you an author, or do you see a problem with this page? Request a review
