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

Abstract

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.

Figure 1.

Serum TSH changes in response to the administration of TRH in humans. (a) WT progeny of fathers with RTH-β. (b) WT progeny of mothers with RTH-β. (c) Diagram depicting the experimental protocol with the time of TRH administration, times of blood sampling, and the substances measured. (d) The schedule of TRH testing and L-T3 administration. The same four individuals in each group, as indicated by the same color, were tested before (open symbols) and after (closed symbols) treatment with L-T₃. Results from male subjects are in blue. CK, creatinine kinase; i.v., intravenously; SHBG, sex hormone–binding globulin; TG, thyroglobulin.

Figure 2.

Mean peak responses of serum TSH to TRH after the administration of L-T₃ (a) in humans and (b) in mice without RTH-β. Open bars show data from adult controls born to fathers with RTH-β, and black bars show data from adults born to mothers with RTH-β and thus exposed to the high maternal levels of TH. (c) The schedule of TRH testing in mice. There are four human subjects and six male mice in each of the respective groups.

Figure 3.

(a) Gene expression in the anterior pituitaries of male mice born to mothers with RTH-β and thus exposed to high maternal TH levels during intrauterine life (black bars), as compared with those born to fathers with RTH-β as controls (open bars), because they were exposed to normal maternal levels of TH. (b) Gene expression in hypothalami of the same two groups of mice. (c) Gene expression in cerebral cortices of the same two groups of mice. Note the increase of D3 in anterior pituitary of progeny of mothers with RTH-β is not shared by the hypothalamus and cerebral cortex. There are six mice in each of the respective groups.