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Low Free Testosterone Is Associated with Hypogonadal Signs and Symptoms in Men with Normal Total Testosterone
Open accessAbstract
CONTEXT: During aging, total testosterone (TT) declines and SHBG increases, resulting in a greater decrease in calculated free T (cFT). Currently, guidelines suggest using TT to diagnose androgen deficiency and to reserve cFT only for men with borderline TT. OBJECTIVE: Our objective was to investigate if either low cFT or low TT is more strongly associated with androgen-related clinical endpoints. METHODS: A total of 3334 community-dwelling men, aged 40-79 years, were included in this study. Differences in clinical variables between the referent group of men with both normal TT (≥10.5 nmol/liter) and normal cFT (≥220 pmol/liter) with those who had normal TT/low cFT, low TT/normal cFT, and low TT/low cFT were assessed by regression models adjusted for age, center, body mass index, and comorbidities. RESULTS: A total of 2641 men had normal TT (18.4 ± 5.5 [mean ± SD] nmol/liter)/normal cFT (326 ± 74 pmol/liter), 277 men had normal TT (14.2 ± 3.7)/low cFT (194 ± 23), 96 men had low TT (9.6 ± 0.7)/normal cFT (247 ± 20), and 320 men had low TT (7.8 ± 2.5)/low cFT (160 ± 55). Men with normal TT/low cFT were older and in poorer health. They had higher SHBG and LH and reported more sexual and physical symptoms, whereas hemoglobin and bone ultrasound parameters were lower compared to the referent group. Men with low TT/normal cFT were younger and more obese. They had lower SHBG, but LH was normal, whereas features of androgen deficiency were lacking. CONCLUSIONS: Low cFT, even in the presence of normal TT, is associated with androgen deficiency-related symptoms. Normal cFT, despite low TT, is not associated with cognate symptoms; therefore, cFT levels should be assessed in men with suspected hypogonadal symptoms.
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“In our study, despite men having normal total T levels, a low calculated free T serum level was associated with androgen deficiency-related symptoms (sexual, physical and psychological functioning, biochemical measurements, body composition and bone measurements).”
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 [182]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In contrast to obese men, in whom SHBG and total T concentrations decrease but free T remains stable, obesity in women causes, next to a decrease in SHBG, a higher free T [182, 239].”
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 [182]
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“Moreover, cases of low total T in combination with normal calculated free T were not associated with hypogonadal signs.”
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 [182]
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“While we agree that measurement of total T is and should remain the first step in diagnosing male hypogonadism, results of an observational study conducted by our research group confirmed the potential added value of free T in this context [182].”
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 [182]
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“The other combination of variables, low total T, normal calculated free T, low SHBG and normal LH, without clinical symptoms suggestive for hypogonadism, are most probably obesity-related hormonal changes [182].”
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 [182]
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“Discrepant results between total and free T were also observed in our analyses of the EMAS cohort of 3334 community-dwelling men aged 40–79 years [182].”
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 [182]
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“Furthermore, symptoms of male hypogonadism were most prominent in men with low total T and low calculated free T.”
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 [182]
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“Compared to men with normal concentrations of total T and calculated free T, men with normal total T and low calculated free T, and not men with low total T and normal calculated free T, also showed signs compatible with androgen deficiency.”
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 [182]
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“Additionally, in normal total T/low calculated free T men, concentrations of SHBG and LH were higher whereas low total T/normal calculated free T men had lower SHBG but unchanged LH levels [182].”
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 [182]
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“When only total T, as opposed to the total T calculated free T combination, is used in the biochemical identification of male hypogonadal patients, there is chance of false positive and negative findings of 23.1 and 9.5%, respectively, [182].”
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 [182]
In the citing paper
“This concept is also highlighted in a recent study demonstrating high correlation of hypogonadal symptoms between TT and fT when select cutpoints were used: TT 235 ng/dl (10.5 nmol/L), fT 98 pg/ml (220 pmol/L).133”
From Challenges in Testosterone Measurement, Data Interpretation, and Methodological Appraisal of Interventional Trials (2016) · cites this paper as [133]
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Citations
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“Currently, the physiological significance as well as the applicability of FT in clinical practice remain unclear (2).”
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Metadata
- Authors
- Antonio, L., Wu, F. C. W., O'Neill, T. W., Pye, S. R., Ahern, T. B., Laurent, M. R., Huhtaniemi, I. T., Lean, M. E. J., Keevil, B. G., Rastrelli, G., Forti, G., Bartfai, G., Casanueva, F. F., Kula, K., Punab, M., Giwercman, A., Claessens, F., Decallonne, B., Vanderschueren, D., & the European Male Ageing Study Study Group
- Affiliations
- Universitair Ziekenhuis Leuven (BE)
- Manchester Academic Health Science Centre (GB)
- Manchester Royal Infirmary (GB)
- University of Turku (FI)
- Lund University (SE)
- Corresponding author
- Vanderschueren, Dirk
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2016-07
- Volume
- 101
- Issue
- 7
- Pages
- 2647-2657
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2285855758
- Cited by
- 174
- References
- 46
- Citations by year
- 2026: 11 · 2025: 18 · 2024: 9 · 2023: 13 · 2022: 23 · 2021: 14 · 2020: 26 · 2019: 16 · 2018: 15 · 2017: 19 · 2016: 9
- FWCI
- 19.80
- Type
- journal article
- Language
- en
- Open access
- green
- lirias.kuleuven.be
- Licence
- other-oa
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- Florence Research (University of Florence) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Fonds Wetenschappelijk Onderzoek (G085413N)
- Vlaamse regering
- Versus Arthritis
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- free testosterone, total testosterone, androgen deficiency, hypogonadism, sex hormone-binding globulin, luteinizing hormone, older men, bone mineral density, hemoglobin
- MeSH terms
- Adult, Aged, Cardiovascular Diseases, Cause of Death, Humans, Hypogonadism, Male, Middle Aged, Sex Hormone-Binding Globulin, Testosterone, Cohort Studies, Metabolic Syndrome, Asymptomatic Diseases
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