Endocrine Abstracts

Introduction

Retinoids are a class of molecules, structurally related to Vitamin A, used in various disorders of keratinization (acne, psoriasis, ichthyosis, etc.). these molecules bind two families of Retinoid Nuclear Receptors (RNR): the RA receptors (RAR), which natural ligand is retinoic acid, and the Retinoid X Receptors (RXR), which natural ligand is 9-cis-retinoic acid. Among synthetic retinoids, isotretinoin, acitretin, tazarotene and adapalene are ligands of the RAR, bexarotene is the first 3^rd generation retinoid (ligand of the RXR), known for the treatment of cutaneous T cell lymphomas. It is the only medication that cause central hypothyroidism in 30% of patients.

Case report

A 61-year-old man, with a history of mycosis fungoides cutaneous T-cell lymphoma (T2 N1 M0) treated with different chemotherapy drugs (methotrexate, puvatherapy, INF alpha, Gemcitabine) without any improvement. Due to the several treatments failures, the Bexarotene 75 mg was introduced: 4 capsules per day the first month associated with fenofibrate 200 mg per day after a pre-therapeutic thyroid assessment: TSH = 0.981 u/ml, T3 = 3.28 pg/ml, T4 = 0.98 ng/dl, with a normal level of HDL, LDL, and TG.1 month later the dose of bexarotene was increased to 6 capsules per day. 25 days later we noticed an elevation of lipid parameters with a disruption of the thyroid function HDL = 0.20 g/l, LDL = 1.71 g/l, TG = 1.69 g/l, cholesterol = 2.25 g/l, T3 = 1.79 pg/ml, T4 = 0.70 ng/dl, TSH = 0.023 iu /ml), we decided to stop bexarotene, introduce l-thyroxine 50 µg for 4 days and increase the doses up to 75 µg for 4 days. After one week, the thyroid function was normal.

Discussion

Bexarotene is a 3rd generation synthetic selective retinoid X receptor (RXRc) agonist. Once activated, these receptors regulate cell differentiation and proliferation. Central hypothyroidism and elevated blood lipid levels are the main side effects. The exploration of the pituitary axis by MRI and hormonal assay confirms the integrity of the anterior pituitary gland, concluding in a specific impairment of the Thyrotropic axis by Bexarotene (only thyrotropic cells of the antehypohysis express RXRc). This hypothyroidism is a transient and reversible condition when the treatment is stopped or when l-thyroxine is added. Euthyroidism is usually achieved with an average dose of l thyroxine 1.6 µg/kg/day.

Conclusion

Retinoid-induced central hypothyroidism is a condition that should be known by endocrinologists and dermatologists. Monitoring the thyroid function is essential in patients with substituted central hypothyroidism in order to adjust the dosage of l-thyroxine, once a week the first month, then monthly.