Fetal Exposure to High Maternal Thyroid Hormone Levels Causes Central Resistance to Thyroid Hormone in Adult Humans and Mice

Context Fetuses exposed to the high thyroid hormone (TH) levels of mothers with resistance to thyroid hormone beta (RTH-β), due to mutations in the THRB gene, have low birth weight and suppressed TSH. Objective Determine if such exposure to high TH levels in embryonic life has a long-term effect into adulthood. Design Observations in humans with a parallel design on animals to obtain a preliminary information regarding mechanism. Setting University research centers. Patients or other participants Humans and mice with no RTH-β exposed during intrauterine life to high TH levels from mothers who were euthyroid due to RTH-β. Controls were humans and mice of the same genotype but born to fathers with RTH-β and mothers without RTH-β and thus, with normal serum TH levels. Interventions TSH responses to stimulation with thyrotropin-releasing hormone (TRH) during adult life in humans and male mice before and after treatment with triiodothyronine (T3). We also measured gene expression in anterior pituitaries, hypothalami, and cerebral cortices of mice. Results Adult humans and mice without RTH-β, exposed to high maternal TH in utero, showed persistent central resistance to TH, as evidenced by reduced responses of serum TSH to TRH when treated with T3. In mice, anterior pituitary TSH-β and deiodinase 3 (D3) mRNAs, but not hypothalamic and cerebral cortex D3, were increased. Conclusions Adult humans and mice without RTH-β exposed in utero to high maternal TH levels have persistent central resistance to TH. This is likely mediated by the increased expression of D3 in the anterior pituitary, enhancing local T3 degradation.