RXR-selective retinoids (rexinoids) can cause central hypothyroidism in humans, and this effect has been confirmed in rodent models. In this report, we have characterized the effect of rexinoids on the HPT axis in mice and TSH regulation in a thyrotrope-derived 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 rexinoids on thyrotropes. LG 268 suppressed TSH protein secretion and TSH mRNA in TT1 thyrotropes as early as 8 h after treatment, while the RAR-selective retinoid (TTNPB) had no effect. D2 mRNA and activity were suppressed by LG 268 in TT1 cells, while only D2 mRNA was suppressed in mouse pituitaries. 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 isotype 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 HPT axis. Rexinoids directly suppress TSH secretion, TSH mRNA levels and promoter activity, and D2 mRNA levels, but have no direct effect on hypothalamic TRH levels. Rexinoids also stimulate D1 activity in the liver and pituitary.