Free vs Total Hormone

The free hormone hypothesis holds that only the unbound fraction of a circulating hormone can leave the capillary and reach its receptor, so a total concentration means something only alongside the binding protein present. The proportions are extreme: testosterone is roughly half carried on sex hormone-binding globulin with high affinity and most of the rest on albumin with low affinity but enormous capacity, leaving a few percent free, while thyroxine is more than 99.9 percent bound. Bioavailable hormone means free plus the loosely albumin-bound portion.

Equilibrium dialysis and ultrafiltration are the reference methods for free steroid, but are slow and not widely offered, so free testosterone calculated from total testosterone, SHBG and albumin is the common substitute. Direct analog immunoassays for free testosterone correlate poorly with dialysis and are discouraged in Endocrine Society guidance. Free thyroxine immunoassays face the same class of problem, becoming least reliable where they matter most, in pregnancy and critical illness.

The distinction matters whenever binding protein is abnormal. Obesity, insulin resistance and exogenous androgen lower SHBG; ageing, hyperthyroidism, hepatic disease and oral estrogen raise it. A young man with obesity can present with a low-normal total testosterone and a normal free concentration, and a woman on oral contraception a high total thyroxine with normal thyroid function.

The error is not usually ignoring free hormone, it is over-trusting it. Calculated values depend on which equation and albumin assumption were used, and laboratories produce systematically different numbers, so free testosterone results are not interchangeable between reports even when units match. Quoting two decimal places and then arguing about a change smaller than the method's own uncertainty outruns what the measurement can support.