Central hypothyroidism associated with retinoid X receptor-selective ligands
Abstract
BACKGROUND: The occurrence of symptomatic central hypothyroidism (characterized by low serum thyrotropin and thyroxine concentrations) in a patient with cutaneous T-cell lymphoma during therapy with the retinoid X receptor-selective ligand bexarotene led us to hypothesize that such ligands could reversibly suppress thyrotropin production by a thyroid hormone-independent mechanism and thus cause central hypothyroidism. METHODS: We evaluated thyroid function in 27 patients with cutaneous T-cell lymphoma who were enrolled in trials of high-dose oral bexarotene at one institution. In addition, we evaluated the in vitro effect of triiodothyronine, 9-cis-retinoic acid, and the retinoid X receptor-selective ligand LGD346 on the activity of the thyrotropin beta-subunit gene promoter. RESULTS: The mean serum thyrotropin concentration declined from 2.2 mU per liter at base line to 0.05 mU per liter during treatment with bexarotene (P<0.001), and the mean serum free thyroxine concentration declined from 1.0 ng per deciliter (12.9 pmol per liter) at base line to 0.45 ng per deciliter (5.8 pmol per liter) (P<0.001) during treatment. The degree of suppression of thyrotropin secretion tended to be greater in patients treated with higher doses of bexarotene (>300 mg per square meter of body-surface area per day) and in those with a history of treatment with interferon alfa. Nineteen patients had symptoms or signs of hypothyroidism, particularly fatigue and cold intolerance. The symptoms improved after the initiation of thyroxine therapy, and all patients became euthyroid after treatment with bexarotene was stopped. In vitro, LGD346 suppressed the activity of the thyrotropin beta-subunit gene promoter in thyrotrophs by as much as 50 percent, an effect similar to that of triiodothyronine and 9-cis-retinoic acid. CONCLUSIONS: Hypothyroidism may develop in patients with cutaneous T-cell lymphoma who are treated with high-dose bexarotene, most likely because the retinoid X receptor-selective ligand suppresses thyrotropin secretion.
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The retinoid bexarotene causes central hypothyroidism in almost all patients, via TSH suppression and non-deiodinase-mediated thyroid hormone increased metabolism.
“The retinoid bexarotene causes CH in almost all patients (22), via TSH suppression (93) and non-deiodinase-mediated thyroid hormone increased metabolism (94).”
From L-T4 therapy in the presence of pharmacological interferents (2020) · cites this paper as [93]
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“The retinoid bexarotene causes CH in almost all patients (22), via TSH suppression (93) and non-deiodinase-mediated thyroid hormone increased metabolism (94).”
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- Authors
- Sherman, S. I., Gopal, J., Haugen, B. R., Chiu, A. C., Whaley, K., Nowlakha, P., & Duvic, M.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- University of Colorado Health (US)
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 1999-04-08
- Volume
- 340
- Issue
- 14
- Pages
- 1075-1079
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W1998787622
- Cited by
- 315
- References
- 21
- Citations by year
- 2026: 5 · 2025: 13 · 2024: 10 · 2023: 12 · 2022: 10 · 2021: 9 · 2020: 9 · 2019: 15 · 2018: 10 · 2017: 3 · 2016: 16 · 2015: 16 · 2014: 5 · 2013: 13 · 2012: 11
- FWCI
- 11.07
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Dermatology › Cutaneous lymphoproliferative disorders research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Keywords
- central hypothyroidism, bexarotene, cutaneous T-cell lymphoma, TSH suppression, 9-cis-retinoic acid, triiodothyronine, thyrotrophs, interferon-alpha, drug-induced hypothyroidism, thyroxine therapy
- MeSH terms
- Bexarotene, Aged, Humans, Hypothyroidism, Ligands, Male, Promoter Regions, Genetic, Retinoids, Tetrahydronaphthalenes, Thyroid Function Tests, Thyroid Gland, Thyrotropin, Transcription Factors, Cohort Studies, Lymphoma, T-Cell, Cutaneous, Receptors, Retinoic Acid, Retinoid X Receptors
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