Free Hormones and the Physiological State
Overt reduction in gland function or stimulation leads to reduced TH and FH plasma concentrations, and conversely, excess gland stimulation or ectopic hormone production leads to increased concentrations of TH and FH (Table 1). In health, the hypothalamic-pituitary-end organ axes promote homeostasis by adjusting TH and binding protein concentrations to optimize FH concentrations needed for physiological demands. Therefore, TH and FH ratios are impacted when physiological states influence binding protein concentration or affinity for the target hormone (10). Binding protein excess or deficiency, structural variants, or altered binding affinity in some cases could be compensated, to allow for normal concentrations of FHs (15). Table 1 also depicts how conditions other than those affecting primary or secondary endocrine glands, such as pregnancy, renal insufficiency, obesity, liver disease, aging, and malnourishment, influence binding protein concentration, function, and the hormone metabolism, often result in altered FH concentrations and pathologic changes.
Medication Influence on Free Hormone Concentrations
Medications may directly influence the production or suppression of hormones by their direct (i.e., on-target) influence on a specific endocrine signaling axis (Table 2). TH and FH concentrations adjust appropriately to these medications when the endocrine axis is intact as the body alters the production of binding proteins to adequately compensate (6). Medications can also have an indirect (i.e., off-target) influence on TH and FH concentrations, often by their influence on the principal binding protein, either by altering protein expression or binding affinity (70). Transient fluctuations of FH can occur in vivo based on drug dosage, drug-specific pharmacokinetics, and timing of administration. It is prudent to interpret test results considering the medications administered to the patient and time of specimen collection (71). When FH concentrations in these individuals do not correlate with clinical findings, assay specific limitations, and preanalytical factors should be considered.
*In vitro measurements of FHs provide a glimpse into the dynamic hormone equilibrium in vivo: that is, continually adapting to acute physiologic demands or disturbances due to a particular physiologic state, a binding protein abnormality, or medication use. However, FH measurements correlate with physiological hormone effects and are a standard clinical tool for the assessment of thyroxine, sex hormone, and cortisol status.