Free testosterone vs. total testosterone

Description

Dr. Morgentaler starts by pointing out that one important purpose of the Androgen Society meeting is to bring together health care professionals to share and discuss various ideas and opinions. One topic in the field, for which opinions diverge, is that of free testosterone vs. total testosterone. Dr. Morgentaler presents his take by sharing his own experience of dealing with men who have symptoms suggestive of hypogonadism but normal total testosterone levels. Further laboratory testing revealed that these men had low free testosterone despite having normal total testosterone, which explained their symptoms. While it is true that aging is associated with a reduction in testosterone levels, the reduction in total testosterone is relatively small compared to the larger reduction in free testosterone. This is because with aging, there is a marked increase in SHBG levels, which will bind to serum testosterone and reduce the free testosterone fraction. However, what is relatively unknown is that there is a wide variability in SHBG levels among men of any age, even in younger men.1 In Dr. Morgentaler’s laboratory, the normal range is 20 to 60 nmol/L. When calculating free testosterone using an online calculator, for any total testosterone level, inputting 60 nmol/L vs. 20 nmol/L for SHBG will reduce free testosterone by half. Considering that it is the free testosterone fraction that is active, this can explain why among men with the same total testosterone level, some can suffer from hypogonadal symptoms while others do not.

The value of clinically available free testosterone assays remains controversial. Dr. Morgentaler presents data comparing the agreement between two free testosterone methodologies that are available in routine clinical practice - radioimmunoassay (RIA) and calculated free testosterone by the Vermeulen formula - versus equilibrium dialysis (EqD), considered the gold standard.2 A robust correlation was noted for RIA and EqD (r=0.966) and for calculated free testosterone and EqD (r=0.986). Strong correlations were observed for men receiving testosterone therapy and for men in the lowest and highest quartiles for total and free testosterone. The correlation of total testosterone with free testosterone was similar for calculated free testosterone (r=0.843), RIA (r=0.806), and EqD (r=0.809). Notably, numerical values for RIA were approximately one seventh of EqD values. These results support the clinical use of both RIA and calculated free testosterone as measures of free testosterone levels. Due to numerical differences, each test requires its own set of reference values and the numerical results from RIA and calculated free testosterone cannot be compared against each other.2

The European Male Ageing Study clearly showed that symptoms correlated significantly with free testosterone, not total testosterone.3 Low free testosterone (calculated), even in the presence of normal total testosterone, is associated with symptoms suggestive of low testosterone. This finding, coupled with the wide variability in SHBG levels, supports the utility of free testosterone assessment in men with suspected hypogonadal symptoms.3

Hence, free testosterone is a useful tool in the diagnosis and treatment monitoring of men with low testosterone. Free testosterone assays such as RIA, despite being inaccurate, may be useful in clinical practice if physicians know how to interpret the results (i.e. pay attention to different reference ranges and don’t compare numerical results from different methods). Dr. Morgentaler concludes:

  • Symptoms of testosterone deficiency correspond more closely to free testosterone than total testosterone.
  • Symptomatic men with low free testosterone have similar presentation over a broad range of total testosterone levels, including levels that typically would be considered eugonadal.
  • Measurement of free testosterone can be performed by EqD, calculation or RIA. The important thing to remember is that each method has its own reference range, and that numerical results from different tests cannot be compared against each other.
  • Free testosterone <100 pg/mL is diagnostic of hypogonadism.
  • SHBG levels vary widely and cannot be predicted.
  • Symptomatic men with reduced free t should be treated regardless of their total t

 

Speakers

Prof. Dr. med. Marija Pfeifer

Abraham Morgentaler, MD
President, the Androgen Society
Associate Clinical Professor of Urology, Harvard Medical School, Boston, Massachusetts

References

  • Krakowsky Y, Conners W, Morgentaler A. Serum Concentrations of Sex Hormone-binding Globulin Vary Widely in Younger and Older Men: Clinical Data from a Men's Health Practice. Eur Urol Focus. 2017 Jun 3. [Epub ahead of print] Return to content
  • Kacker R, Hornstein A, Morgentaler A. Free testosterone by direct and calculated measurement versus equilibrium dialysis in a clinical population. Aging Male. 2013 Dec;16(4):164-8. Return to content
  • Antonio L, Wu FC, O'Neill TW, et al. Low Free Testosterone Is Associated with Hypogonadal Signs and Symptoms in Men with Normal Total Testosterone. J Clin Endocrinol Metab. 2016 Jul;101(7):2647-57. Return to content