Hormone Biomarkers: Free Testosterone in Men

Optimal Takeaways

Measurement of free testosterone reflects the unbound physiologically active hormone in circulation. The concentration of free testosterone depends on the production, clearance, and binding of proteins.

For example, levels decrease as sex-hormone binding globulin increases. Low free testosterone may have detrimental effects even if total testosterone is optimal. Low levels are seen with late-onset hypogonadism and may be associated with high blood pressure, reduced muscle mass, anemia, diabetes, and inflammation. High levels of free testosterone may be seen with testosterone therapy.

Standard Range: Male 46 - 224 pg/mL (159.62 - 777.28 pmol/L)

The ODX Range: Male 150 - 224 pg/mL (520.50 - 777.28 pmol/L)

Low free testosterone is associated with late onset hypogonadism, chronic opioid use, anemia (Bain 2007), type 2 diabetes (Roden 2005), metabolic syndrome (Laaksonen 2004), and CVD mortality (Hyde 2012). Low levels are also associated with hypertension, lower bioavailable testosterone, increased SHBG (Yang 2019), reduced muscle mass (Yuki 2013), reduced lower extremity function, and reduced subjective health assessment (Krasnoff 2010). The %FT may be lower in those with high-grade versus low-intermediate grade prostate cancer (Bayar 2017).

High free testosterone levels may be seen with testosterone therapy.

Overview

Free testosterone (FT) represents the amount of hormone that is active and completely unbound in circulation. It is dependent on the rate of production and clearance of testosterone as well as the presence and concentration of SHBG (Davis 2015). 

Calculation of free testosterone is the preferred method of assessment though accuracy depends on the accuracy of testosterone and SHBG measurements (Shea 2014). Assessment of FT levels in men would be prudent when total testosterone is below 400 ng/dL (13.9 nmol/L), or in conditions of altered sex hormone binding globulin (Bhasin 2018).

Decreased FT is observed in late onset hypogonadism (LOH) and its measurement may be more reliable for diagnostic purposes than total testosterone. Lower FT as associated with worsening symptoms of LOH, especially at a level of 77.2 pg/mL (268 pmol/L) or below (Liu 2017).

An estimated 1 out of 3 men with type 2 diabetes have low testosterone. Research suggests this group is at increased risk for anemia and systemic inflammation. One study of 70 men with type 2 diabetes found that a calculated FT below 65 pg/mL (225.6 pmol/L) was associated with a significantly decreased hemoglobin and hematocrit and significantly increased C-reactive protein (Bhatia 2006).

In another study of 253 men undergoing routine health checkups, FT levels were inversely correlated with blood pressure. Those with a FT below 52 pg/mL (179 pmol/L) had the greatest risk of hypertension while those with a FT above 81 pg/mL (282 pmol/L) had the lowest risk of hypertension (Yang 2019).

Low free testosterone may be associated with decreased muscle mass in men. Those with a calculated FT below 46.3 pg/mL (161 pmol/L) had a 2.1-2.7 times increased risk of muscle loss than those maintaining a level of 46.3 pg/mL or above (Yuki 2013).

In men diagnosed with prostate cancer, free testosterone was lower in those with high-grade versus low or intermediate grade cancer. A free testosterone of 52 pg/mL (180 pmol/L) or lower was associated with a significantly increased risk of high-grade versus low-intermediate grade prostate cancer. The prospective study was conducted in 405 men with a PSA above 2.5 ng/mL who had undergone prostate biopsy. A lower bioavailable testosterone of 125 ng/dL (4.3 nmol/L) was also associated with high-grade prostate cancer in the study (Bayar 2017). The study confirmed earlier research suggesting that lower free testosterone may be an independent marker for more aggressive prostate cancer (Hoffman 2000).

References

Bain, Jerald. “The many faces of testosterone.” Clinical interventions in aging vol. 2,4 (2007): 567-76. doi:10.2147/cia.s1417

Bayar, Göksel et al. “Low free and bioavailable testosterone levels may predict pathologically-proven high-risk prostate cancer: a prospective, clinical trial.” Turkish journal of urology vol. 43,3 (2017): 289-296. doi:10.5152/tud.2017.35467

Bhasin, Shalender et al. “Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline.” The Journal of clinical endocrinology and metabolism vol. 103,5 (2018): 1715-1744. doi:10.1210/jc.2018-00229

Bhatia, Vishal et al. “Low testosterone and high C-reactive protein concentrations predict low hematocrit in type 2 diabetes.” Diabetes care vol. 29,10 (2006): 2289-94. doi:10.2337/dc06-0637

Davis, Susan R., and Sarah Wahlin-Jacobsen. "Testosterone in women—the clinical significance." The Lancet Diabetes & Endocrinology 3.12 (2015): 980-992.

Hoffman, M A et al. “Is low serum free testosterone a marker for high grade prostate cancer?.” The Journal of urology vol. 163,3 (2000): 824-7.

Hyde, Zoë et al. “Low free testosterone predicts mortality from cardiovascular disease but not other causes: the Health in Men Study.” The Journal of clinical endocrinology and metabolism vol. 97,1 (2012): 179-89. doi:10.1210/jc.2011-1617

Krasnoff, Joanne B et al. “Free testosterone levels are associated with mobility limitation and physical performance in community-dwelling men: the Framingham Offspring Study.” The Journal of clinical endocrinology and metabolism vol. 95,6 (2010): 2790-9. doi:10.1210/jc.2009-2680

Laaksonen, David E et al. “Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men.” Diabetes care vol. 27,5 (2004): 1036-41. doi:10.2337/diacare.27.5.1036

Liu, Zhangshun et al. “Comparing calculated free testosterone with total testosterone for screening and diagnosing late-onset hypogonadism in aged males: A cross-sectional study.” Journal of clinical laboratory analysis vol. 31,5 (2017): e22073. doi:10.1002/jcla.22073

Rhoden, Ernani L et al. “Diabetes mellitus is associated with subnormal serum levels of free testosterone in men.” BJU international vol. 96,6 (2005): 867-70. doi:10.1111/j.1464-410X.2005.05728.x

Shea, Jennifer L et al. “Free testosterone: clinical utility and important analytical aspects of measurement.” Advances in clinical chemistry vol. 63 (2014): 59-84. doi:10.1016/b978-0-12-800094-6.00002-9

Yang, Qingtao et al. “Association of total testosterone, free testosterone, bioavailable testosterone, sex hormone-binding globulin, and hypertension.” Medicine vol. 98,20 (2019): e15628. doi:10.1097/MD.0000000000015628

Yuki, Atsumu et al. “Relationship between low free testosterone levels and loss of muscle mass.” Scientific reports vol. 3 (2013): 1818. doi:10.1038/srep01818