Abstract
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 low-normal 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.
BEXAROTENE, a synthetic retinoic X receptor (RXR)-selective agonist, has received approval for treatment of cutaneous T-cell lymphoma (CTCL) in Japan. However, it is known that this drug adversely induces central hypothyroidism (CH) as well as increases peripheral metabolism of thyroid hormones [1-3], for which levothyroxine (LT4) replacement is recommended during bexarotene treatment [4, 5]. Experimental findings have shown that bexarotene can cause pituitary hypothyroidism though not hypothalamic hypothyroidism via activation of RXR in the pituitary gland [6-8], whereas the mechanism of bexarotene-induced CH in humans remains to be clarified.
Following introduction of synthetic TRH in 1969, TRH stimulation testing has been used for determining CH, as pituitary hypothyroidism is expected to exhibit a blunted TSH response, while that in hypothalamic hypothyroidism cases is expected to be exaggerated and delayed following TRH stimulation [9-13]. However, to the best of our knowledge, no studies have examined the pathophysiology of bexarotene-induced CH using TRH stimulation testing in patients being treated with bexarotene. The present retrospective study examined time-course changes of TSH after TRH stimulation and also the correlation of TSH level after TRH stimulation with LT4 at the replacement dosage so as to restore to the baseline serum free T4 (F-T4) level, in order to examine whether pituitary hypothyroidism might be responsible for bexarotene-induced CH.
Materials and Methods
Study design and participants
This single-arm, confirmatory, open-labeled clinical study was performed at Osaka City University Hospital and Nagoya City University Hospital to investigate the efficacy and safety of bexarotene with phototherapy for patients with CTCL, as previously described [14]. Briefly, the records of hospitalized subjects and those with outpatient status who received bexarotene administered PO at 300 mg/m2 (body surface area) once daily, and who were then followed by phototherapy such as bath-psoralen plus ultraviolet (UV)-A or narrowband UV-B, were analyzed. To assess the efficacy and safety of bexarotene with phototherapy, physical and laboratory measurements were performed at 0, 1, 2, 3, 4, 8, 12, and 24 weeks, or the day of discontinuation, according to a previously reported protocol [14]. Among patients with CTCL who were hospitalized at Osaka City University Hospital for initiation of bexarotene with phototherapy from April 2017 to August 2019, those referred to our department for examination and treatment of CH were initially considered eligible to participate in the present study (n = 11), with one patient who discontinued bexarotene with one week after initiation of bexarotene with phototherapy excluded. As a result, 10 patients with CTCL who continued bexarotene with phototherapy for more than one week were retrospectively analyzed. The present study protocol was approved by the Ethics Committee of Osaka City University Graduate School of Medicine (approval No. 4266) and performed with an opt-out option, which was explained in instructions on the website of the hospital. Following approval of the study protocol, all data subjected to analysis were collected from relevant patient medical records. The present study was conducted in full accordance with the Declaration of Helsinki.
Physical and laboratory measurements
Information regarding height, body weight, present and past illness, and use of medication was obtained. Body mass index was calculated as weight in kilograms divided by the square of height in meters (kg/m2). Blood samples were obtained in the morning after an overnight fast at 0, 1, 2, 3, 4, 8, 12, and 24 weeks [14]. Biochemical parameters including aspartate transaminase, alanine aminotransferase, and creatinine were analyzed using a standard laboratory method at the Central Laboratory of Osaka City University Hospital. Estimated glomerular filtration rate was calculated with an equation designed for Japanese subjects, as previously described [15]. TSH was determined by an Elecsys sandwich immunoassay and F-T4 by an Elecsys competitive immunoassay with an ELECSYSTM system (Roche Diagnostics K.K., Tokyo, Japan), as previously described [16, 17]. The reference values used for TSH and F-T4 were 0.4–5.0 μIU/mL and 0.9–1.7 ng/dL, respectively.
TRH stimulation test
During the follow-up period, TRH stimulation testing was performed, with patients diagnosed with CH based on combined findings of low or low-normal F-T4 with an inappropriately low or normal TSH level [18, 19]. Serum TSH level was determined before and 15, 30, 60, 90, and 120 minutes after intravenous injection of 200 μg of TRH (Tanabe Seiyaku, Osaka, Japan). A peak TSH value <4 μIU/mL was defined as indicating a blunted response, while that >15 μIU/mL in males or >30 μIU/mL in females was defined as an exaggerated response, and peak TSH occurring at 60 minutes or later was defined as a delayed response [9, 11, 18].
Treatment of hypothyroidism with oral LT4
Serum levels of F-T4 and TSH were determined during the 24-week study period, according to a previously reported protocol [14]. LT4 dosage was adjusted so as to maintain F-T4 at the pre-bexarotene treatment level, as previously described [4, 5].
Statistical analysis
Values are expressed as number or median (range). A Wilcoxon signed-rank test was used to compare variables at the baseline and follow-up examinations. Spearman’s correlation coefficient was employed to determine correlations between variables. Data analyses were performed with JMP Pro 12 (SAS Corporation, Cary, North Carolina, USA). All reported p values are two-tailed and were considered to indicate statistical significance at p < 0.05.
Results
Baseline clinical characteristics
The baseline clinical characteristics of the present 10 patients with CTCL are shown in Table 1. None were being administered LT4 or an antithyroid drug at the beginning of the study. Basal thyroid functions for each patient were within normal ranges, with the median values for TSH and F-T4 shown to be 2.82 (range, 1.03–4.46) μIU/mL and 1.22 (0.95–1.46) ng/dL, respectively.
Table 1
Clinical characteristics of subjects
| No. of patients |
10 |
| Age, years |
73 (56–79) |
| Gender, male/female |
6/4 |
| Body mass index, kg/m2 |
20.7 (17.7–28.2) |
| Aspartate transaminase, IU/L |
17 (13–72) |
| Alanine aminotransferase, IU/L |
15 (8–78) |
| eGFR, mL/min/1.73 m2 |
66.4 (19.4–100.7) |
| TSH, μIU/mL |
2.82 (1.03–4.46) |
| F-T4, ng/dL |
1.22 (0.95–1.46) |
Values are expressed as number or median (range).
Abbreviations: eGFR, estimated glomerular filtration rate; F-T4, free T4
The dose of bexarotene in two patients was 375 mg/day, in three patients was 450 mg/day, and in five patients was 525 mg/day. After one week of administration, the median values for TSH and F-T4 were significantly decreased from 2.82 (1.03–4.46) to 0.05 (0.02–0.09) μIU/mL (p = 0.002) (Fig. 1A) and 1.22 (0.95–1.46) to 0.66 (0.51–0.96) ng/dL (p = 0.002) (Fig. 1B), respectively, and all patients were diagnosed with CH.
TSH response to TRH stimulation test one week after initiation of bexarotene treatment
Since all 10 patients were diagnosed with CH at one week after initiation of bexarotene treatment, as noted above, TRH stimulation testing was performed in each at one week after starting treatment (Fig. 2). The peak response of TSH was reached at 30 minutes and that was <4 μIU/mL in each patient, thus a blunted TSH response that was not exaggerated or delayed was demonstrated.
Correlations of thyroid function with LT4 dosage after 24 weeks of bexarotene
Two of the 10 patients discontinued bexarotene treatment one month later due to worsening of the underlying disease (n = 1) or onset of neutropenia as an adverse event of bexarotene (n = 1). Finally, eight continued bexarotene treatment for 24 weeks. The replacement dosage of LT4 was 125 (75–150) μg/day, with no significant difference observed between pre-administration and 24-week F-T4 levels (p = 0.674). The correlation of thyroid function with LT4 dosage after 24 weeks of bexarotene administration was examined in the eight patients with CTCL (Table 2). TSH level at 30 minutes (peak) as well as 15, 60, 90, and 120 minutes after the TRH stimulation test was significantly correlated with LT4 dosage (ρ = –0.913, p = 0.002), though neither TSH or F-T4 level before TRH stimulation testing showed a significant correlation with LT4 dosage.
Table 2
Correlation of thyroid function at one week after beginning bexarotene treatment with LT4 dosage after 24 weeks
|
ρ |
p |
| Basal level |
| TSH |
–0.026 |
0.951 |
| F-T4 |
0.091 |
0.830 |
| TRH stimulation test |
| TSH (15 min) |
–0.717 |
0.045 |
| TSH (30 min) peak |
–0.913 |
0.002 |
| TSH (60 min) |
–0.913 |
0.002 |
| TSH (90 min) |
–0.848 |
0.008 |
| TSH (120 min) |
–0.913 |
0.002 |
Abbreviations: LT4, levothyroxine; F-T4, free T4
Discussion
The present results showed that while TSH response to TRH stimulation was blunted, it was not exaggerated or delayed at one week after initiation of bexarotene treatment (Fig. 2). Additionally, the TSH level following TRH stimulation was significantly correlated with LT4 replacement dosage after 24 weeks of bexarotene treatment, given to restore F-T4 level up to the baseline level (Table 2). These findings support the notion that pituitary hypothyroidism is responsible for bexarotene-induced CH and also suggest that TSH level following a TRH stimulation test precisely reflects residual pituitary-thyroid function in patients with CTCL undergoing bexarotene treatment.
Although the mechanism by which RXR-selective agonists cause CH is not completely understood, experimental studies have reported that those agonists decrease TSH synthesis by suppression of TSHβ gene transcription through interaction with RXR, which is distinct from the thyroid hormone responsive element in the thyrotrope [6, 7, 20]. Furthermore, RXR-selective agonists have been shown to suppress secretion of TSH from the thyrotrope under experimental conditions [8]. Therefore, bexarotene, a synthetic RXR-selective agonist, is considered to cause pituitary rather than hypothalamic hypothyroidism by suppression of TSH synthesis and/or TSH secretion. In the present patients, TSH response to TRH stimulation testing showed a blunted response at one week after initiation of bexarotene treatment (Fig. 2), indicating that bexarotene causes pituitary hypothyroidism in humans.
Pre-treatment serum TSH level is known to predict the replacement dosage of LT4 in patients with primary hypothyroidism [21], suggesting that TSH level in serum reflects residual pituitary-thyroid function in patients with primary hypothyroidism. 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. Unfortunately, TRH stimulation testing is difficult to use in routine clinical practice, thus F-T4 level instead, as well as metabolic parameters and clinical symptoms should be examined during bexarotene treatment for adjustment of LT4 dosage.
As for the onset of suppression of synthesis and secretion of TSH, previous animal studies found that only suppression of TSH secretion and not TSH synthesis occurred within two hours, while suppression of TSH synthesis occurred at eight hours or more after initiation of RXR-selective agonist administration in rats or mice [6, 8]. Therefore, suppression of both TSH synthesis and secretion likely occurs within one week after initiation of bexarotene treatment. Additionally, TSH level following a TRH stimulation test at one week after initiation of that treatment is considered to precisely reflect residual pituitary-thyroid function associated with both suppressed synthesis and secretion of TSH in the pituitary gland caused by bexarotene.
This study has some important limitations, including the low number of subjects investigated. Furthermore, while TRH stimulation testing has been used for differentiation of pituitary and hypothalamic hypothyroidism [11-13], clear-cut criteria to differentiate between them have not been fully validated in recent studies. Finally, thyroid function was assessed by TRH stimulation testing only at one week after starting bexarotene administration. A large-scale prospective study that includes serial TRH stimulation tests is needed to clarify the role of bexarotene in development of CH in patients treated with bexarotene.
The present results showed that TSH response to TRH stimulation testing at one week after initiation of bexarotene treatment was blunted. Also, TSH level following a TRH stimulation test was found to be significantly correlated with LT4 replacement dosage in patients with CTCL undergoing bexarotene treatment. Together, our findings support the notion that bexarotene causes pituitary rather than hypothalamic hypothyroidism and suggest that TSH level obtained after a TRH stimulation test precisely reflects residual pituitary-thyroid function during bexarotene treatment.
Disclosure
This clinical research was supported by Minophagen Pharmaceutical Co., Ltd. upon implementation. C.T., D.T., and A.M. have received research grants from Minophagen Pharmaceutical Co., Ltd. The other authors have no conflicts of interest related to this study to declare.
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