THYROTROPIN REGULATION BY THYROID-HORMONE IN THYROID-HORMONE RECEPTORBETA-DEFICIENT MICE

Thyroid hormone responsive genes can be both positively and negatively regulated by thyroid hormone. TSH is down-regulated by thyroid hormon e and rises during thyroid hormone deprivation. Because both thyroid h ormone receptor (TR) alpha and beta genes are expressed in the pituita ry gland, it is unclear what the relative roles of TR alpha and TR bet a are in TSH regulation. Experiments using over expression of artifici al genes have yielded conflicting results. The TR beta knock-out mouse that lacks both TR beta 1 and TR beta 2 isoforms provides a model to examine the role of these receptors in TSH regulation. TR beta deficie nt (TR beta-/-) and wild-type (TR beta+/+) mice of the same strain wer e deprived of thyroid hormone by feeding them a low iodine diet contai ning propylthiouracil and were then treated with different doses of L- T-3 and L-T-4. Thyroid hormone deprivation rapidly increased the serum TSH level in both TR beta+/+ and TR beta-/- mice, reaching a similar level in the absence of thyroid hormone. In contrast, the decline of s erum TSH by treatment with both L-T-3 and L-T-4 was severely blunted i n TR beta-/- mice, and full suppression was not achieved with the maxi mal L-T-3 dose of 25 mu g/day.mouse. These data indicate that TR beta is not required for the up-regulation of TSH in thyroid hormone defici ency. However, although TR alpha alone can mediate thyroid hormone ind uced TSH suppression, TR beta enhances the sensitivity of TSH down-reg ulation and may be essential for the complete suppression of TSH.