Vitamin A has a well recognized, but poorly understood effect on the pituitary-thyroid axis. Vitamin A excess causes central hypothyroidism with suppressed levels of serum TSH and T4. The effects of vitamin A are mediated through two nuclear hormone receptors, the retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Many synthetic derivatives of vitamin A, or retinoids, have been developed, and these retinoids exhibit unique chemotherapeutic and chemopreventive properties in many different cancers. An RXR-selective retinoid (Targretin, LG 1069) caused a reversible central hypothyroidism in patients, suggesting that the vitamin A effect on this axis is mediated, at least in part, through an RXR-liganded mechanism. The principal investigator's laboratory has utilized molecular techniques to show that retinoids directly suppress activity of thyrotrope-specific TSHbeta gene promoter. This mechanism appears to require the RXRgamma isoform, which has expression limited to the thyrotropes within the anterior pituitary gland. The goals of this proposal are to define the specific mechanisms governing the effect of retinoids on TSH regulation, to use the TSHbeta promotor as a model of negative gene regulation by retinoids, and to further define the role of RXR and the unique role of the RXR isoform.
