Reference Ranges and Determinants of Testosterone, Dihydrotestosterone, and Estradiol Levels Measured using Liquid Chromatography-Tandem Mass Spectrometry in a Population-Based Cohort of Older Men
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Context: Testosterone (T) levels decline with increasing age. Controversy exists over the threshold for classifying T as low vs. normal in older men. The relevance of assessing dihydrotestosterone (DHT) and estradiol (E2) remains unclear. Objective: We assessed the associations of T, DHT, and E2 in men aged 70 yr or older and established reference ranges for these in healthy older men. Participants: Community-dwelling men aged 70–89 yr residing in Perth, Western Australia, Australia, participated in the study. Main Outcome Measures: Plasma T, DHT, and E2 were assayed using liquid chromatography-tandem mass spectrometry in early morning samples from 3690 men. Results: Increasing age, higher body mass index and waist to hip ratio, dyslipidemia, diabetes, and higher LH were independently associated with lower levels of T and DHT. Increasing age, diabetes, and higher LH were associated with lower E2. In a reference group of 394 men aged 76.1 ± 3.2 yr reporting excellent or very good health with no history of smoking, diabetes, cardiovascular disease, cancer, depression, or dementia, the 2.5th percentile for T was 6.4 nmol/liter (184 ng/dl); DHT, 0.49 nmol/liter; and E2, 28 pmol/liter. Applying these cutoffs to all 3690 men, those with low T or DHT had an increased odds ratio for frailty, diabetes, and cardiovascular disease. Men with both low T and DHT had a higher odds ratio for these outcomes. Conclusions: The 2.5th percentile in a reference group of healthy older men provides age-appropriate thresholds for defining low T, DHT, and E2. Additional studies are needed to test their potential applicability and clinical utility in older men.
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The Massachusetts Male Aging Study found a persistent age-related decrease in testosterone even after controlling for obesity, chronic illness, medication use, and excessive alcohol consumption, although healthier males had attenuation of decline and 10-15% higher testosterone levels.
“Data from the Massachusetts Male Aging Study similarly demonstrated a persistent age-related decrease in T levels even after controlling for obesity, chronic illness, medication use, and excessive alcohol consumption, although an attenuation of rate of decline and 10–15% overall higher T levels were observed among healthier males.”
From Challenges in Testosterone Measurement, Data Interpretation, and Methodological Appraisal of Interventional Trials (2016) · cites this paper as [37]
Numerous studies have consistently found age-dependent decreases in testosterone.
“Numerous studies have consistently identified age-dependent decreases in T.”
From Challenges in Testosterone Measurement, Data Interpretation, and Methodological Appraisal of Interventional Trials (2016) · cites this paper as [37]
A longitudinal cohort of men aged 40-70 reported an estimated total testosterone decrease of 0.8% per year and free testosterone decrease of 2% per year due to increases in SHBG.
“Data from a longitudinal cohort of men aged 40–70 years reported an estimated TT decrease of 0.8%/year, with fT decreasing by 2%/year (due to concomitant increases in SHBG).”
From Challenges in Testosterone Measurement, Data Interpretation, and Methodological Appraisal of Interventional Trials (2016) · cites this paper as [37]
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Self-citationTemporal Trend in Androgen Status and Androgen-Sensitive Outcomes in Older Men
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Self-citationYeap, B. B., & Wu, F. C. W. (2018) · Clinical Endocrinology · doi:10.1111/cen.13888 · Cited by 44 · see citing works
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Lecce, L., Lam, Y. T., Lindsay, L. A., Yuen, S. C. G., Simpson, P. J. L., Handelsman, D. J., & Ng, M. (2014) · Molecular Endocrinology · doi:10.1210/me.2013-1405 · Cited by 41 · see citing works
Self-citationHigher Dihydrotestosterone Is Associated with the Incidence of Lung Cancer in Older Men
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Yeap, B. B., Marriott, R. J., Antonio, L., Bhasin, S., Dobs, A. S., Dwivedi, G., Flicker, L. A., Matsumoto, A. M., Ohlsson, C., ORWOLL, E. S., et al. (2020) · Clinical Endocrinology · doi:10.1111/cen.14342 · Cited by 35 · see citing works
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Quantification of the relative contribution of estrogen to bone mineral density in men and women
Ho-Pham, L. T., Nguyen, N. D., & Nguyen, T. V. (2013) · BMC Musculoskeletal Disorders · doi:10.1186/1471-2474-14-366 · Cited by 35 · see citing works
Keevil, B. G., Clifton, S., Tanton, C., Macdowall, W. G., Copas, A. J., Lee, D. M., Field, N. M., Mitchell, K. R., Sonnenberg, P., Bancroft, J., et al. (2017) · Journal of the Endocrine Society · doi:10.1210/js.2016-1029 · Cited by 34 · see citing works
Age-related changes in estradiol and longitudinal associations with fat mass in men
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Revisiting hyper- and hypo-androgenism by tandem mass spectrometry
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Serum Estradiol Associates With Blood Hemoglobin in Elderly Men: The MrOS Sweden Study
Lewerin, C., Nilsson‐Ehle, H., Jacobsson, S., Johansson, H., Sundh, V., Karlsson, M. K., Lorentzon, M., Barrett-Connor, E. L., Vandenput, L., Ohlsson, C., et al. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-4111 · Cited by 30 · see citing works
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Androgen deficiency and type 2 diabetes mellitus
Gibb, F. W., & Strachan, M. W. J. (2014) · Clinical Biochemistry · doi:10.1016/j.clinbiochem.2014.04.004 · Cited by 29 · see citing works
Yeap, B. B., Alfonso, H. S., Chubb, S. A. P., Handelsman, D. J., Hankey, G. J., Golledge, J., Flicker, L. A., & Norman, P. E. (2013) · Clinical Endocrinology · doi:10.1111/cen.12208 · Cited by 25 · see citing works
Self-citationYeap, B. B., Alfonso, H. S., Chubb, S. A. P., Beilin, J., Hankey, G. J., Almeida, O. P., Golledge, J., Norman, P. E., & Flicker, L. A. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa115 · Cited by 23 · see citing works
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Self-citationHsu, B., Cumming, R. G., Blyth, F., Naganathan, V., Waite, L. M., Couteur, D. G. L., Seibel, M. J., & Handelsman, D. J. (2017) · The Journals of Gerontology Series A · doi:10.1093/gerona/glx170 · Cited by 24 · see citing works
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Finkelstein, J. S., Lee, H., Burnett‐Bowie, S. M., Darakananda, K., Gentile, E. C., Goldstein, D. W., Prizand, S. H., Krivicich, L. M., Taylor, A. P., Wulczyn, K. E., et al. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa318 · Cited by 23 · see citing works
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Testosterone, frailty and physical function in older men
Hsu, B., Cumming, R. G., & Handelsman, D. J. (2018) · Expert Review of Endocrinology & Metabolism · doi:10.1080/17446651.2018.1475227 · Cited by 22 · see citing works
Self-citationCarruthers, M. E., Cathcart, P. J., & Feneley, M. R. (2015) · The Aging Male · doi:10.3109/13685538.2015.1048218 · Cited by 21 · see citing works
The Cardiovascular Safety of Dutasteride
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Sex steroids and cardiovascular disease
Yeap, B. B. (2014) · Asian Journal of Andrology · doi:10.4103/1008-682x.122357 · Cited by 20 · see citing works
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Testosterone Therapy in Older Men: Present and Future Considerations
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Serum testosterone levels in type 2 diabetes mellitus
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- Authors
- Yeap, B. B., Alfonso, H., Chubb, S. A. P., Handelsman, D. J., Hankey, G. J., Norman, P. E., & Flicker, L.
- Affiliations
- The University of Western Australia (AU)
- Western Australian Centre for Health and Ageing (H.A., L.F.), Western Australia 6009, Australia
- The University of Sydney (AU)
- Corresponding author
- Yeap, Bu B.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2012-11-01
- Volume
- 97
- Issue
- 11
- Pages
- 4030-4039
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2145924182
- Cited by
- 155
- References
- 45
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 7 · 2023: 7 · 2022: 10 · 2021: 8 · 2020: 11 · 2019: 7 · 2018: 16 · 2017: 12 · 2016: 14 · 2015: 16 · 2014: 29 · 2013: 10
- FWCI
- 14.09
- Type
- journal article
- Language
- en
- Open access
- Licence
- other-oa
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion, other-oa)
- eSpace (Curtin University) (submittedVersion, cc-by)
- 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
- testosterone, dihydrotestosterone, estradiol, reference values, older men, frailty, diabetes mellitus, cardiovascular disease, luteinizing hormone, body mass index, waist-to-hip ratio, dyslipidemia
- MeSH terms
- Aged, Aged, 80 and over, Chromatography, Liquid, Estradiol, Health Status, Humans, Male, Reference Values, Dihydrotestosterone, Testosterone, Western Australia, Cohort Studies, Tandem Mass Spectrometry
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