Integration of Peripheral and Glandular Regulation of Triiodothyronine Production by Thyrotropin in Untreated and Thyroxine-Treated Subjects

Objective: We evaluated the roles of central and peripheral T3 regulation. Design and Methods: In a prospective study involving 1796 patients the equilibria between FT3 and TSH were compared in untreated and L-T4-treated patients with varying functional states, residual thyroid secretory capacities and magnitudes of TSH stimulation. Results: T3 concentrations were stable over wide variations in TSH levels (from 0.2 to 7 mU/l) and endogenous T4 production in untreated patients, but unbalanced in L-T4-treated athyreotic patients where T3 correlated with exogenous T4 supply. T3 stability was related to TSH-stimulated deiodinase activity by clinical observation, as predicted by theoretical modelling. Deiodinase activity in treated patients was reduced due to both diminished responsiveness to TSH and lack of thyroidal capacity. Deiodinase activity was increased in high thyroid volume, compared to lower volumes in euthyroid patients (< 5 ml, p<0.001). While deiodinase differed between euthyroid and subclinically hypothyroid patients in high volume, 26.7 nmol/s (23.6, 29.2), n=214 vs 28.9 nmol/s (26.7, 31.5), n=20, p=0.02, it was equivalent between the two functional groups in low volume, 23.3 nmol/s (21.3, 26.1), n=117 vs 24.6 nmol/s (22.2, 27.5), n=38, p=0.22. Conclusions: The findings suggest that the thyroid gland and peripheral tissues are integrated in the physiological process of T3 homeostasis in humans via a feed-forward TSH motif, which coordinates peripheral and central regulatory mechanisms. Regulatory and capacity deficiencies collectively impair T3 homeostasis in L-T4-treated patients.