Physiological data and clinical outcomes demonstrate that bioidentical hormones are associated with lower risks, including the risk of breast cancer and cardiovascular disease, and are more efficacious than their synthetic and animal-derived counterparts. Until evidence is found to the contrary, bioidentical hormones remain the preferred method of HRT. Further randomized controlled trials are needed to delineate these differences more clearly.

New research is demonstrating that thyroid hormone transport across cellular membranes plays an important role in intracellular triiodothyronine (T3) levels of peripheral and pituitary tissues and is proving to have considerable clinical significance. 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. The pituitary has different transporters than every other tissue in the body. 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 widespread 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 a T3/reverse T3 ratio and the level of sex hormone binding globulin (SHBG), should be used to determine the likely overall thyroid status and if a therapeutic trail of straight T3 or a T4/T3 combination is indicated and not based solely on standard thyroid function tests.

There have been recent advances in understanding of the local control of thyroid activity and metabolism, including deiodinase activity and thyroid hormone membrane transport. The goal of this review is to increase the understanding of the clinical relevance of cellular deiodinase activity. The physiologic significance of types 1, 2 and 3 deiodinase (D1, D2 and D3, respectively) on the intracellular production of T3 are discussed along with the importance and significance of the production of reverse T3. The difference in the pituitary and peripheral activity of these deidoidinases under a wide range of common physiologic conditions results in different intracellular T3 levels in the pituitary and peripheral tissues, resulting in the inability to detect low tissue levels of thyroid hormone in peripheral tissues with TSH testing. This review demonstrates that extreme caution should be used in relying on TSH or serum thyroid levels to rule out hypothyroidism in the presence of a wide range of conditions, including physiologic and emotional stress, depression, dieting, obesity, leptin insulin resistance, diabetes, chronic fatigue syndrome, fibromyalgia, inflammation, autoimmune disease, or systemic illness, as TSH levels will often be normal despite the presence of significant hypothyroidism. The review discusses the significant clinical benefits of thyroid replacement in such conditions despite having normal TSH levels and the superiority of T3 replacement instead of standard T4 therapy.

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