US) than might otherwise have been anticipated. But before considering this issue, let us exRmine the validity of the free hormone hypothesis itself, this having also emerged as a subject of controversy. Observation of a broad correlation between endocrine status and the free hormone concentrations measured in serum formed the basis of the free hormone hypothesis (other evidence, such as the low permeation rates of binding proteins across capillary membranes, has been adduced in its support). A corollary of the hypothesis is that the protein-bound concentration is physiologically irrelevant, a view supported by substantial experimen-tal evidence. For example, subjects lacking thyroxine-binding globulin (TBG) because of genetic abnormality suffer no obvious physiological disadvantage, despite possessing greatly decreased serum concentrations of TH.