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Effects of Rexinoids on Thyrotrope Function and the Hypothalamic-Pituitary-Thyroid Axis

Division of Endocrinology, Metabolism, and Diabetes (V.S., W.R.H., W.M.W., U.P., B.R.H.), Department of Medicine, University of Colorado Cancer Center, University of Colorado Health Sciences Center, Aurora, Colorado 80045; Department of Physiology (D.L.S.), Dartmouth Medical School, Lebanon, New Hampshire 03756; Thyroid Section (A.C.B.), Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, Boston, Massachusetts 02115; and Institut de Genetique et de Biologie Moleculaire et Cellulaire (W.K., P.C.), Clinique de la Souris and College de France, 67404 Illkirch Cedex, Communaute Urbaine de Strasbourg, France

Address all correspondence and requests for reprints to: Bryan R. Haugen, M.D., University of Colorado at Denver and Health Sciences Center, MS 8106, P.O. Box 6511, Aurora, Colorado 80045. E-mail: bryan.haugen{at}uchsc.edu.

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 characterized the effect of rexinoids on the hypothalamic-pituitary-thyroid 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 TSHß mRNA levels were significantly lowered, suggesting a direct effect of rexinoids on thyrotropes. LG 268 suppressed TSH protein secretion and TSHß mRNA in TT1 thyrotropes as early as 8 h after treatment, whereas the retinoic acid receptor-selective retinoid (TTNPB) had no effect. Type 2 iodothyronine deiodinase (D2) mRNA and activity were suppressed by LG 268 in TT1 cells, whereas only D2 mRNA was suppressed in mouse pituitaries. LG 268 suppressed TSHß 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 hypothalamic-pituitary-thyroid axis. Rexinoids directly suppress TSH secretion, TSHß mRNA levels and promoter activity, and D2 mRNA levels but have no direct effect on hypothalamic TRH levels. Rexinoids also stimulate type 1 iodothyronine deiodinase activity in the liver and pituitary.

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