Latest research has shown that the thyroid hormone transport across cellular membranes plays an important role in intracellular triiodothyronine (T3) levels of peripheral and pituitary tissues.

Reduced T4 and T3 transport into the cells in peripheral tissues is seen with a wide range of common conditions, including insulin resistance, diabetes, depression, bipolar disorder, hyperlipidemia, chronic fatigue syndrome, fibromyalgia, neurodegenerative diseases, migraines, stress, anxiety, chronic dieting and aging, while the intracellular T3 level in the pituitary often remains unaffected. Furthermore, the thyroid transporters in the body are very energy dependent and are affected by numerous conditions, including low energy states, toxins and mitochondrial dysfunction, while the pituitary remains unaffected.

Because the pituitary remains largely unaffected and is able to maintain intracellular T3 levels while the rest of the body suffers from significantly reduced intracellular T3 levels, there is no elevation in thyroid-stimulating hormone (TSH) despite the presence of wide-spread tissue hypothyroidism, making the TSH and other standard blood tests a poor marker to determine the presence or absence of hypothyroidism. Because the T4 transporter is more energy dependent than the transporter for T3, it is also not surprising that T4 preparations are generally ineffective in the presence of such conditions, while T3 replacement is shown to be beneficial. Thus, if a patient with a normal TSH presents with signs or symptoms consistent with hypothyroidism, which may include low basal body temperature, fatigue, weight gain, depression, cold extremities, muscle aches, headaches, decreased libido, weakness, cold intolerance, water retention, slow reflex relaxation phase or PMS, a combination of both clinical and laboratory assessment, which may include reverse T3  and the level of sex hormone binding globulin (SHBG), should be used to determine the likely overall thyroid status.