Testosterone in the bloodstream is mostly not free. It circulates largely bound to carrier proteins — principally sex hormone-binding globulin — and bound testosterone is, for practical purposes, not available to tissue.
The detail of how that binding works was revised in 2017. A reappraisal in Endocrine Reviews re-examined testosterone's binding in circulation and set out the physiological and clinical implications of the revised model.[1] The practical upshot for anyone reading a lab report is unchanged and simple: total and free testosterone can tell different stories about the same man.
Why this is a metabolism story
Because the things that move SHBG are metabolic. Age raises it. Thyroid disease, liver disease, obesity and diabetes all alter it, as do several medications.
So a man's metabolic state changes the relationship between his total testosterone and the fraction his tissue can use. That is not a measurement artefact — it is real physiology with a real clinical consequence.
What the guideline does with this
It builds it into the diagnostic pathway. Free testosterone should be obtained when total testosterone is near the lower limit of normal, or when the man has a condition that alters SHBG — using equilibrium dialysis or an accurate formula.[3]
That second trigger is broad. Age, obesity, thyroid and liver disease and diabetes are common, which means the free-testosterone question comes up often rather than rarely.
The estimation methods themselves have been evaluated critically — a 1999 paper in JCEM assessed the simple methods for estimating free testosterone against dialysis and identified which hold up.[4] "Free testosterone" on a report is not one standardised measurement, and asking which method produced yours is a reasonable question.
The clinical failure mode
A man with rising SHBG has a total testosterone that looks better than his situation. He is reassured by a number that is measuring the wrong thing for him.
This is the single most common way a testosterone result is misread — as reassurance, when the fraction that matters was never measured. Practical guidance is in reading your testosterone results and free vs total testosterone.
Frequently asked questions
What should my SHBG be? It is interpreted alongside total and free testosterone rather than against a target of its own.
My total is normal but free is low — which counts? Both are real; they answer different questions. Free tracks what tissue can access, which is why the guideline asks for it specifically when SHBG is likely distorting the total.[3]
Does treatment change SHBG? Testosterone therapy affects the whole system, which is part of why monitoring measures serum testosterone rather than assuming a dose produces a predictable level.[3]
Why isn't free testosterone on every panel? It should be when indicated.[3] Basic panels frequently omit it, which is worth asking about if any SHBG-altering condition applies to you.
Next in this series
Adiposity lowers testosterone. Lower testosterone favours adiposity. Working out which drives which is the hard part.
Continue with the bidirectional trap.
References
4 sources
- Goldman AL, Bhasin S, Wu FCW, et al. A Reappraisal of Testosterone's Binding in Circulation: Physiological and Clinical Implications. Endocr Rev. 2017;38(4):302–324. doi:10.1210/er.2017-00025 · PMID 28673039
- Wu FC, Tajar A, Pye SR, et al. Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study. J Clin Endocrinol Metab. 2008;93(7):2737–2745. doi:10.1210/jc.2007-1972 · PMID 18270261
- Bhasin S, Brito JP, Cunningham GR, et al. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(5):1715–1744. doi:10.1210/jc.2018-00229 · PMID 29562364
- Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999;84(10):3666–3672. doi:10.1210/jcem.84.10.6079 · PMID 10523012
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