Effects of rexinoids on thyrotrope function and the hypothalamic-pituitary-thyroid axis

Area of Science:

• Endocrinology
• Molecular Biology
• Pharmacology

Background:

• Retinoid X receptor (RXR)-selective retinoids (rexinoids) are known to induce central hypothyroidism in humans and rodents.
• Understanding the precise mechanisms of rexinoid action on the thyroid axis is crucial for managing potential side effects.

Purpose of the Study:

• To characterize the effects of rexinoids on the hypothalamic-pituitary-thyroid (HPT) axis in mice.
• To investigate the regulation of thyroid-stimulating hormone (TSH) by rexinoids in a thyrotrope-derived cell line.

Main Methods:

• Administration of synthetic rexinoid LG 268 and retinoic acid receptor-selective retinoid TTNPB to mice and TalphaT1 thyrotrope cells.
• Measurement of TSH, T4, TRH mRNA, TSHbeta mRNA, and type 2 iodothyronine deiodinase (D2) mRNA and activity.
• Analysis of TSHbeta promoter activity and studies using RXRgamma-deficient mice.

Main Results:

• LG 268 suppressed TSH and T4 levels in mice, with no effect on hypothalamic TRH mRNA but lowered pituitary TSHbeta mRNA.
• Rexinoids directly suppressed TSH protein secretion and TSHbeta mRNA in TalphaT1 cells, and suppressed D2 mRNA and activity.
• LG 268 suppressed TSHbeta promoter activity, with RXRgamma identified as the most efficient isotype for mediating TSH suppression.

Conclusions:

• RXR-selective retinoids (rexinoids) directly suppress TSH secretion, TSHbeta mRNA, and D2 mRNA levels.
• Rexinoids do not directly affect hypothalamic TRH levels but stimulate type 1 iodothyronine deiodinase activity.
• The RXRgamma isotype plays a key role in mediating rexinoid-induced TSH suppression.