Retinoid X receptor (RXR)-selective retinoids (rexinoids) can cause central hypothyroidism in humans, and this effect has been confirmed in rodent models. In this report, we charac- terized the effect of rexinoids on the hypothalamic-pituitary- thyroid axis in mice and TSH regulation in a thyrotrope-de- rived cell line. The synthetic rexinoid (LG 268) suppressed TSH and T4 levels in mice. Hypothalamic TRH mRNA was unaffected, but steady-state pituitary TSH mRNA levels were significantly lowered, suggesting a direct effect of rexi- noids on thyrotropes. LG 268 suppressed TSH protein secre- tion and TSH mRNA in T T1 thyrotropes as early as 8 h after treatment, whereas the retinoic acid receptor-selective reti- noid (TTNPB) had no effect. Type 2 iodothyronine deiodinase (D2) mRNA and activity were suppressed by LG 268 in T T1 cells, whereas only D2 mRNA was suppressed in mouse pitu- itaries. LG 268 suppressed TSH promoter activity by 42% and the 200 to 149 region accounted for a majority of the LG 268-mediated suppression of promoter activity. The RXR iso- type is expressed in thyrotropes. In vitro transfection and in vivo transgenic studies indicate that any RXR isotype can mediate TSH suppression by rexinoids, but the RXR isotype is most efficient at mediating this response. RXR -deficient mice lacked pituitary D2 mRNA suppression by LG 268, but D2 activity remained intact. In summary, RXR-selective retinoids (rexinoids) have multiple effects on the hypothalamic-pitu- itary-thyroid axis. Rexinoids directly suppress TSH secretion, TSH mRNA levels and promoter activity, and D2 mRNA lev- els but have no direct effect on hypothalamic TRH levels. Rexinoids also stimulate type 1 iodothyronine deiodinase ac- tivity in the liver and pituitary.
Effects of Rexinoids on Thyrotrope Function and the Hypothalamic-Pituitary-Thyroid Axis.
Vibha Sharma, William R. Hays, William M. Wood, Umarani Pugazhenthi, Donald L. St. Germain, Antonio C. Bianco, Wojciech Krezel, Pierre Chambon, and Bryan R. Haugen. Endocrinology. June 27, 2007. doi: 10.1210/en.2005-0706