Steady-state regulation of whole-body thyroid hormone pool sizes and interconversion rates in hypothyroid and moderately T-3-stimulated rats

Steady-state regulation of whole-body T-3 and T-4 distribution and metabolism were directly evaluated and compared in hypothyroid, euthyroid, and in euthyroid rats moderately T-3-stimulated by continuous infusion of 0.15 mu g/day L-T-3 per 100 g BW, thereby supplementing euthyroid T-3 sources by two thirds. Our goal was to develop deeper insights into the hierarchy, quantitative adequacy, and sensitivity of this regulatory system, in response to these hormone production challenges in constant steady state. We used a novel whole-body steady-state experiment design model and data analysis approach, which entails nonexclusive whole-body homogenate extracts and blood collected after 7-day infusions of tracer T-3 (T-3*) or T-4*, quantitatively analyzed chromatographically for T-3*, T-4* and metabolite* concentrations. Hormone regulation implications across the 3 groups were assessed by comparing (per 100 g BW) total body T-4 to T-3 and T-3 from T-4 conversion rates (CR(4-3) and CR(3-4)), total body pool sizes (Q(tot)) and distribution volumes (V-D), total body production (PR), or plasma appearance rates (PAR), plasma clearance rates (PCR), and elimination rates (k). In the hypothyroid rats, absolute production of T-3 from T-4 was only a fourth of that in euthyroids: CR(3-4) = 1.55 vs. 6.77 ng/h, but the percent (efficiency) of whole-body T-4 converted to T-3 was more than double that in euthyroids: %CR(4-3) = 45.4% vs. 21.0%, reflecting an effective doubling of type I and/or type II 5'-deiodinase activity on a whole-body basis in response to severe curtailment of thyroidal production. Whole-body T-3 pools and T-3 production and clearance rates were all about 2 to 3 times lower in hypo- than in euthyroids: minimum Q(tot) = 36.8 vs. 100 ng, V-D3 = 148 vs. 236 ml, PAR(3) = 3.44 vs. 9.09 ng/h, PCR(3) = 13.8 vs. 21.3 ml/h; and nearly all T-4 pool size, production, clearance and elimination rates also were very substantially reduced: PCR(4) = 0.540 vs. 0.941 ml/h, PR(4) = 4.11 vs. 38.3 ng/h, Q(tot4) = 128 vs. 702 ng, k(4) = 0.0322 vs. 0.0530 h(-1). In moderately T-3-stimulated rats, presumed central feedback effects of the added T-3 on T-4 production and total body pool size also were quite pronounced: PR(4) = 21.4 ng/h and Q(tot4) = 346 ng were reduced to about half that in euthyroids, but T-4 elimination indices were virtually unchanged, and T-3 production and elimination were minimally affected. Thus, overall, stabilizing negative feedback regulation of TH functioning at different hierarchical levels is quite bidirectionally sensitive. We found very tight (inhibitory) control over thyroidal T-4 secretion, possibly also T-3 secretion, and probably also absolute T-3 production from T-4, in response to moderate (+68%) supplements in T-3 production; and the efficiency of total body Ta production from available T-4 was amplified substantially in the severe primary hypothyroid state, although not neatly enough to compensate for the malady. Finally, the blood to total body pool fractions (Q(b)/Q(tot)) of both T-3 and T-4, but not the plasma or blood hormone levels, remained remarkably constant in response to these oppositely directed hormone production challenges, suggesting this ratio as an actively regulated, homeostatically-maintained entity.