The Selective Loss of the Type 2 Iodothyronine Deiodinase in Mouse Thyrotrophs Increases Basal TSH but Blunts the Thyrotropin Response to Hypothyroidism

The type 2 iodothyronine deiodinase (D2) is essential for feedback regulation of TSH by T-4. We genetically inactivated in vivo D2 in thyrotrophs using a mouse model of Cga-driven cre recombinase. Pituitary D2 activity was reduced 90% in the Cga-cre D2 knockout (KO) mice compared with control Dio2(fl/fl) mice. There was no growth or reproductive phenotype. Basal TSH levels were increased 1.5- to 1.8-fold, but serum T-4 and T-3 were not different from the controls in adult mice. In hypothyroid adult mice, suppression of TSH by T-4, but not T-3, was impaired. Despite mild basal TSH elevation, the TSH increase in response to hypothyroidism was 4-fold reduced in the Cga-cre D2KO compared with control mice despite an identical level of pituitary TSH alpha- and beta-subunit mRNAs. In neonatal Cga-cre D2KO mice, TSH was also 2-fold higher than in the controls, but serum T-4 was elevated. Despite a constant TSH, serum T-4 increased 2-3-fold between postnatal day (P) 5 and P15 in both genotypes. The pituitary, but not cerebrocortical, D2 activity was markedly elevated in P5 mice decreasing towards adult levels by P17. In conclusion, a congenital severe reduction of thyrotroph D2 causes a major impairment of the TSH response to hypothyroidism. This would be deleterious to the compensatory adaptation of the thyroid gland to iodine deficiency.