Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat.

Abstract

We have recently shown that it is not possible to restore euthyroidism completely in all tissues of thyroidectomized rats infused with T4 alone. The present study was undertaken to determine whether this is achieved when T3 is added to the continuous sc infusion of T4. Thyroidectomized rats were infused with placebo or T4 (0.80 and 0.90 microgram/100 g BW.day), alone or in combination with T3 (0.10, 0.15, or 0.20 microgram/100 g BW.day). Placebo-infused intact rats served as euthyroid controls. Plasma and 12 tissues were obtained after 12 days of infusion. Plasma TSH and plasma and tissue T4 and T3 were determined by RIA. Iodothyronine deiodinase activities were assayed using cerebral cortex, pituitary, brown adipose tissue, liver, and lung. Circulating and tissue T4 levels were normal in all the groups infused with thyroid hormones. On the contrary, T3 in plasma and most tissues and plasma TSH only reached normal levels when T3 was added to the T4 infusion. The combination of 0.9 microgram T4 and 0.15 microgram T3/100 g BW.day resulted in normal T4 and T3 concentrations in plasma and all tissues as well as normal circulating TSH and normal or near-normal 5'-deiodinase activities. Combined replacement therapy with T4 and T3 (in proportions similar to those secreted by the normal rat thyroid) completely restored euthyroidism in thyroidectomized rats at much lower doses of T4 than those needed to normalize T3 in most tissues when T4 alone was used. If pertinent to man, these results might well justify a change in the current therapy for hypothyroidism.

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

“…However, in rats L-T 4 monotherapy cannot simultaneously normalize serum T 3 , T 4 , and TSH, presumably because of the higher thyroidal T 3 production in rodents (243,244). Thus to normalize T 3 and TSH, the serum T 4 must be higher than normal in rats, and the same applies to tissue T 3 and T 4 content.…”

“…However, because of the substantial direct thyroidal secretion of T 3 in rodents, the ideal thyroid hormone replacement regimen would feature a mixture of T 4 and T 3 . Some studies have established the optimal dosing for combination therapy in rodents (244). When T 4 is used alone for replacement, tissue T 3 content can vary across a large number of tissues because of the role played by the deiodinases as a local source of tissue T 3 (via conversion from T 4 ) (243,244).…”

“…Notably, a slightly lower dose of T 3 , 2.0 ng/g BW, has been shown to restore growth and the activity of liver a-GPD in previously rendered hypothyroid rats (202). However, administration of T 3 alone is not sufficient to restore euthyroidism in all tissues, particularly in those with a significant contribution of the D2 pathway (243,244).…”

“…While food-and water-based drug delivery methods are subject to feeding variability, this may not be critical for studies of chronic thyrotoxicosis; for example, powdered rodent diet containing 3 mg of T 4 and 1 mg of T 3 per kilogram has been used successfully to induce chronic thyrotoxicosis (205). Consideration should be given to more consistent methods such as subcutaneous pumps or pellets (243,244).…”

Modulation of adult hippocampal neurogenesis by thyroid hormones: implications in depressive-like behavior

“…This procedure was based on previous data. 33 The solution was prepared daily in sterile 0.01% bovine serum albumin and kept in the dark to avoid hormone degradation. The hormonal concentration in the drinking water was calculated, on the basis of fluid intake, to provide 2.4 mg T4 and 0.4 mg T3 /100 g BW/ day.…”