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Free testosterone matters more than total
Total versus free
Picture a man with a total testosterone of 900 nanograms per deciliter, around the 70th percentile on the scale used, and a free testosterone of 8. That is under 1% free, where a man should be about 2%, so his free level should be closer to 16 to 18. His SHBG, the protein that binds testosterone, is probably in the 80 to 90 range, well above a typical top near 55.
What sets SHBG
Genetics gives each person a different SHBG set point, and three hormones run it: estradiol, probably the most important, with higher estradiol meaning higher SHBG, plus insulin and thyroxine. A thyroid out of whack interferes with SHBG, and so does a lot of aromatase activity, the enzyme that converts testosterone into estradiol. Individually these are rarely enough to move the needle.
Insulin's role
Insulin suppresses SHBG, which creates an irony: helping someone get metabolically healthy can lower free testosterone in the short run. As insulin comes down, SHBG goes up, and if testosterone hasn't risen with it, the free portion drops. A very low carbohydrate diet that cuts insulin enough does the same.
Why does free testosterone matter most?
Most circulating testosterone is bound, roughly half to SHBG and the rest loosely to albumin, leaving only about 2 percent free. The free hormone hypothesis, set out by Christopher Mendel in a 1989 Endocrine Reviews paper, holds that only the unbound fraction enters cells to act. Albumin binds weakly enough that albumin-bound testosterone can release in the capillaries, so labs often report bioavailable testosterone as free plus albumin-bound.
How is free testosterone actually measured?
The reference method is equilibrium dialysis, which physically separates the free fraction across a membrane. It is slow and costly, so most labs calculate free testosterone from total testosterone, SHBG, and albumin, using the equation published by Alex Vermeulen and colleagues in 1999. The Endocrine Society's 2018 guideline advises against direct analog immunoassays for free testosterone because they are unreliable.
Why does estradiol raise SHBG?
The liver makes SHBG, and estrogen stimulates its production there. That is one reason women's SHBG levels typically run about twice those of men. Oral estrogens raise SHBG especially sharply because they reach the liver in high concentration before entering the rest of the body.
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