Summary statements

• In vitro, increasing T4 levels inhibits D2 activity except in cell lines derived from the pituitary, suggesting that a high fT4/fT3 ratio may lead to a “normal” TSH while reducing T3 generation in peripheral tissues.

• In hypothalamic extracts, D2 inactivation is a much less efficient process as compared with other tissues. This would reinforce a predominant role of T4 and localized T3 production in the hypothalamus-pituitary unit to mediate the TSH feedback mechanism.

• Hypothyroid rats treated with LT4 to restore serum TSH have lower T3 levels in the serum and in some tissues than control rats, but T3 levels are restored with combination therapy that adds LT3.

• Tissue markers of TH action (serum cholesterol, T3-responsive genes) in LT4-treated thyroidectomized rats with normal serum TSH indicate residual hypothyroidism; no differences compared with control rats were observed in the thyroidectomized rats treated with LT4/LT3.

• Mice homozygous for the Thr92Ala-DIO2 polymorphism have a hypothyroid-like pattern of T3-responsive genes in certain areas of the central nervous system (CNS) when compared with wild type mice.

• Mice homozygous for the Thr92Ala-DIO2 polymorphism have a hypothyroid-like pattern of T3-responsive genes in certain areas of the central nervous system (CNS) when compared with wild type mice.

• Physical activity, sleep patterns, and short-term memory in hypothyroid Thr92Ala-DIO2 homozygous mice improve more with LT4/LT3 than with LT4 therapy alone.

• The impact of the Thr92Ala-DIO2 polymorphism on the clinical treatment benefit of combination therapy for hypothyroidism in humans is currently unclear.