Bexarotene‐induced hypothyroidism: Characteristics and therapeutic strategies

Makita, Noriko; Manaka, Katsunori; Sato, Junichiro; Mitani, Koji; Nangaku, Masaomi; Iiri, Taroh

doi:10.1111/cen.13975

Cited by 18 publications

(9 citation statements)

References 27 publications

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“…However, no study has explored correlations of thyroid function with replacement dosage of LT4 in subjects with CH caused by bexarotene. In the present patients, TSH levels prior to starting TRH stimulation testing as well as F-T4 levels after one week showed no significant correlations with LT4 dosage following 24 weeks of bexarotene administration (Table 2), which are findings consistent with those of a previous study in which there was no significant correlation noted between TSH levels at one week with occurrence of hypothyroidism at one month [22]. On the other hand, the level of TSH after TRH stimulation testing was significantly correlated with LT4 dosage following 24 weeks of bexarotene administration in the present cohort (Table 2), suggesting that TSH level after TRH stimulation reflects residual pituitary-thyroid function in patients receiving bexarotene treatment.…”

Section: Discussionsupporting

confidence: 92%

Bexarotene-induced central hypothyroidism assessed by TRH stimulation test in cutaneous T-cell lymphoma patients

et al. 2022

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Bexarotene-induced central hypothyroidism (CH), for which levothyroxine (LT4) replacement is recommended, has been shown to be caused by pituitary but not hypothalamic disorder experimentally, though the underlying mechanism in humans remains unclear. Here, the pathophysiology of bexarotene-induced CH was examined using a TRH stimulation test in cutaneous T-cell lymphoma (CTCL) patients. In this retrospective longitudinal observational study, serum TSH and free T4 (F-T4) levels were measured in 10 euthyroid patients with CTCL during 24 weeks of bexarotene treatment. TRH stimulation testing was performed following CH diagnosis, with LT4 replacement dosage adjusted to maintain F-T4 at the pre-treatment level. After one week of bexarotene administration, all 10 patients developed CH, based on combined findings of low or lownormal F-T4 with low or normal TSH levels. TSH peak response after a stimulation test at one week was reached at 30 minutes. However, that was <4 μIU/mL in all patients, indicating a blunted though not exaggerated and delayed TSH response. In eight who continued bexarotene for 24 weeks, median LT4 replacement dosage was 125 (range, 75-150) μg/day. TSH level at 30 as well as 15, 60, 90, and 120 minutes after TRH stimulation was significantly correlated with LT4 replacement dosage (ρ = -0.913, p = 0.002), whereas TSH and F-T4 basal levels at one week were not. These results suggest that pituitary hypothyroidism is responsible for bexarotene-induced CH, while TSH levels after TRH stimulation precisely reflect residual pituitary-thyroid function in patients receiving bexarotene.

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Section: Discussionsupporting

confidence: 92%

Bexarotene-induced central hypothyroidism assessed by TRH stimulation test in cutaneous T-cell lymphoma patients

et al. 2022

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“…However, bexarotene increased the levels of TSH and reduced the levels of T4 in TS mice when compared to their vehicle-treated TS littermates, indicating that bexarotene was inducing primary hypothyroidism in these animals. In contrast to this data, the vast majority of studies in the literature had associated chronic administration of bexarotene with central hypothyroidism (Makita et al, 2019). In this regard, in the case of CO mice, bexarotene reduced the levels of both hormones, which suggests that these animals might be suffering from secondary hypothyroidism.…”

Section: Discussionmentioning

confidence: 59%

Bexarotene Impairs Cognition and Produces Hypothyroidism in a Mouse Model of Down Syndrome and Alzheimer’s Disease

et al. 2021

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All individuals with Down syndrome (DS) eventually develop Alzheimer’s disease (AD) neuropathology, including neurodegeneration, increases in β-amyloid (Aβ) expression, and aggregation and neurofibrillary tangles, between the third and fourth decade of their lives. There is currently no effective treatment to prevent AD neuropathology and the associated cognitive degeneration in DS patients. Due to evidence that the accumulation of Aβ aggregates in the brain produces the neurodegenerative cascade characteristic of AD, many strategies which promote the clearance of Aβ peptides have been assessed as potential therapeutics for this disease. Bexarotene, a member of a subclass of retinoids that selectively activates retinoid receptors, modulates several pathways essential for cognitive performance and Aβ clearance. Consequently, bexarotene might be a good candidate to treat AD-associated neuropathology. However, the effects of bexarotene treatment in AD remain controversial. In the present study, we aimed to elucidate whether chronic bexarotene treatment administered to the most commonly used murine model of DS, the Ts65Dn (TS) mouse could reduce Aβ expression in their brains and improve their cognitive abilities. Chronic administration of bexarotene to aged TS mice and their CO littermates for 9 weeks diminished the reference, working, and spatial learning and memory of TS mice, and the spatial memory of CO mice in the Morris water maze. This treatment also produced marked hypoactivity in the plus maze, open field, and hole board tests in TS mice, and in the open field and hole board tests in CO mice. Administration of bexarotene reduced the expression of Aβ1-40, but not of Aβ1-42, in the hippocampi of TS mice. Finally, bexarotene increased Thyroid-stimulating hormone levels in TS mice and reduced Thyroid-stimulating hormone levels in CO mice, while animals of both karyotypes displayed reduced thyroxine levels after bexarotene administration. The bexarotene-induced hypothyroidism could be responsible for the hypoactivity of TS and CO mice and their diminished performance in the Morris water maze. Together, these results do not provide support for the use of bexarotene as a potential treatment of AD neuropathology in the DS population.

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“…The data regarding the dose-dependent drop in TSH and fT 4 are not consistent. Makita et al (2019) studied 66 Japanese patients with CTCL on bexarotene [8]. They did not find any dose-dependent effects on TSH and fT 4 in the dose range of 96-320 mg/m 2 /day.…”

Section: Discussionmentioning

confidence: 99%

Bexarotene: A Rare Cause of Misleading Thyroid Function Tests

Pattan

Schaab

Sundaresh

2020

Cureus

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Bexarotene is a very rare cause of central hypothyroidism (CH) and its effects have been reported to be dosedependent; however, the available data in the literature on dose-dependent effects are variable. The standard practice of monitoring thyroid function using thyroid-stimulating hormone (TSH) to adjust levothyroxine (LT4) dose does not apply to bexarotene since it causes CH. In CH, TSH is not reliable. Hence free tetraiodothyronine (fT 4) level is used to monitor and adjust the LT4 dose. We report a case of an 81year-old Caucasian male with cutaneous T-cell lymphoma (CTCL) who was treated with bexarotene. His pretreatment TSH was normal at 1.6 µIU/mL (reference range: 0.46-4.68 µIU/mL). Post-bexarotene, the total tetraiodothyronine (T 4) level was within the reference range, but a downward trend was noted. Eventually, total triiodothyronine (T 3) dropped to a low level of 0.61 ng/mL (reference range: 0.97-1.69 ng/mL), and LT4 was initiated. Bexarotene dose was increased, but LT4 was not increased by the primary physician who relied on TSH level, which was low, and hence the existing LT4 dose was maintained. The patient had persistent symptoms of hypothyroidism and, eventually, a diagnosis of CH was made. The symptoms of hypothyroidism improved after normalizing fT 4 , with an increase in the LT4 dose. This case represents an example of missed CH due to bexarotene, which led to suboptimal LT4 replacement impacting the quality of life for the patient.

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Bexarotene‐induced hypothyroidism: Characteristics and therapeutic strategies

Cited by 18 publications

References 27 publications

Bexarotene-induced central hypothyroidism assessed by TRH stimulation test in cutaneous T-cell lymphoma patients

Bexarotene-induced central hypothyroidism assessed by TRH stimulation test in cutaneous T-cell lymphoma patients

Bexarotene Impairs Cognition and Produces Hypothyroidism in a Mouse Model of Down Syndrome and Alzheimer’s Disease

Bexarotene: A Rare Cause of Misleading Thyroid Function Tests

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