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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-0696
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 1 124-130
Copyright © 2007 by The Endocrine Society

Single-Dose Rexinoid Rapidly and Specifically Suppresses Serum Thyrotropin in Normal Subjects

Wendy M. Golden, Katie B. Weber, Teri L. Hernandez, Steven I. Sherman, Whitney W. Woodmansee and Bryan R. Haugen

Division of Endocrinology, Metabolism, and Diabetes (W.M.G., K.B.W., T.L.H., W.W.W., B.R.H.), University of Colorado at Denver and Health Sciences Center, Aurora, Colorado 80045; University of Texas, M.D. Anderson Cancer Center (S.I.S.), Houston, Texas 77230-1402; and University of Colorado Cancer Center (B.R.H.), Aurora, Colorado 80045

Address all correspondence and requests for reprints to: Bryan R. Haugen, M.D., Associate Professor of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado at Denver and Health Sciences Center, Building RC-1 South Tower, MS 8106; 12801 East 17th Avenue, P.O. Box 6511, Aurora, Colorado 80045. E-mail: bryan.haugen{at}uchsc.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Retinoid X receptor agonists (rexinoids) have demonstrated benefit in patients with certain malignancies but appear to cause central hypothyroidism in some patients with advanced cancer. The influence of rexinoids on thyroid function in healthy subjects is not clear.

Objective: The objective of this study was to determine the effect of a single dose of bexarotene on levels of TSH, T4, and T3 in healthy subjects.

Design: This study was a randomized, double-blind, placebo-controlled, crossover trial.

Setting: This study was conducted at the General Clinical Research Center (University of Colorado Health Sciences Center, Aurora, CO).

Subjects: Six healthy adults (>18 yr old) were studied.

Intervention: Single-dose rexinoid (bexarotene, 400 mg/m2) or placebo, with TSH measurements at 0, 1, 2, 4, 8, 12, 24, and 48 h, were used.

Main Outcome Measure: The main outcome was the serum TSH level at 24 h.

Results: Single-dose bexarotene suppressed serum TSH (P < 0.001) over time. Compared with placebo, levels of TSH were significantly lower by 12 h (P = 0.043); the nadir of 0.32 ± 0.02 mU/liter (P < 0.001) was seen at 24 h. Free T4 index and free T3 index were also significantly lower than placebo over time (48 h) (P = 0.029; P = 0.004, respectively). Serum prolactin, cortisol, and triglycerides were not affected (P > 0.05 for all). There was no significant effect of single-dose bexarotene on rT3 or T3/rT3 ratio at 24 h.

Conclusion: A single dose of a rexinoid can rapidly and specifically suppress serum TSH levels in healthy subjects. These data provide insight into the mechanisms by which rexinoids cause central hypothyroidism and potential ways this effect can be used for treatment of disorders such as thyroid hormone resistance and TSH-secreting pituitary tumors.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
BEXAROTENE (TARGRETIN, LG1069) is a retinoid X receptor-selective retinoid (rexinoid) that is Food and Drug Administration-approved for the treatment of cutaneous T cell lymphoma (CTCL) and is under investigation for its possible treatment role in other malignancies, including lung (1, 2), breast (3), and thyroid cancer (4, 5). Rexinoids are also being evaluated as a potential therapy in diabetes (6, 7) and may influence appetite regulation (8), suggesting a future potential of use in a growing number of patients with malignancy and metabolic disorders.

Bexarotene has previously been shown to induce reversible central hypothyroidism. In rats, a single dose of oral rexinoid (LG100268) resulted in a significant decrease in serum TSH in as early as 30 min and a significant decrease in T4 and T3 at 24 h (9). Twenty-six of 27 CTCL patients who received daily high-dose bexarotene had suppressed TSH concentrations, 19 of whom had symptomatic hypothyroidism (10). Laboratory abnormalities and clinical symptoms of hypothyroidism were apparent in some patients as early as 2 wk after treatment initiation, at the first follow-up evaluation.

The mechanism by which bexarotene can cause symptomatic, reversible central hypothyroidism is not completely understood but is postulated to be secondary to direct suppression of TSH subunit synthesis and/or secretion in pituitary thyrotropes (11, 12, 13, 14). Rexinoids may also affect the peripheral metabolism of T4 and T3 (11, 15). The kinetics of the effect of rexinoids on the human hypothalamic-pituitary-thyroid axis have not been previously examined. Moreover, it is not known how rapidly rexinoids affect thyrotrope function in humans. To further explore these questions, we studied the effect of single-dose bexarotene on the hypothalamic-pituitary-thyroid axis in six healthy subjects.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study population

The Colorado Multiple Institutional Review Board at the University of Colorado at Denver and Health Sciences Center approved this protocol. A convenience sample of 10 healthy adult participants was recruited; each granted their written informed consent. Six participants were enrolled in and completed the study (Table 1Go). Two participants withdrew before enrollment, and two did not meet the inclusion criteria (one had positive thyroid autoantibodies, and the other had a low white blood cell count). Inclusion criteria were age more than 18 yr and a baseline TSH between 0.5 and 3.0 mU/liter. Exclusion criteria included: pregnancy or breastfeeding; current attempt at pregnancy (including women trying to become pregnant or men whose female partners were trying to become pregnant); known hypothalamic, pituitary, or thyroid disease; impaired immunity; liver disease (defined as aspartate aminotransferase or alanine aminotransferase > 1.5 times normal value); kidney disease (creatinine > 1.5 mg/dl); diabetes; cataracts; fasting total cholesterol more than 240 mg/dl; fasting triglycerides (TGs) greater than 250 mg/dl; the presence of serum thyroid autoantibodies; or the use of medications including thyroid medication, lipid-lowering medication, those that interfere with the CYP3A4 enzyme system, or those that induce photosensitivity.


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  		TABLE 1. Characteristics at screening and bexarotene dosing in normal subjects (n = 6, numbered accordingly across top row to show individual values; mean ± SD)

 
Study design

This study was a randomized double-blind placebo-controlled crossover trial in which each participant served as his/her own control. Each participant was admitted to the General Clinical Research Center (GCRC) for two separate 24-h visits, with a minimum 4-wk washout period in between. The random order of bexarotene and placebo administration was computer-generated in the pharmacy. After an overnight fast, baseline labs were drawn on admission [serum TSH, free T4, total T4, total T3, T3 resin uptake (T3RU), rT3, prolactin, cortisol, TGs, glucose, insulin, and free fatty acids (FFAs)]. Participants were then randomly assigned to a single dose of 400 mg/m2 bexarotene or placebo. Serum TSH, free T4, total T4, total T3, and TGs were measured again at 30 min after medication or placebo administration and at 1, 2, 4, 8, 12, 24, and 48 h. FFAs and cortisol were measured at the same time points between 0 and 24 h. rT3 and prolactin were measured at baseline and 24 h.

Participants were fasting (>12 h) at baseline and were fed standardized meals (55% carbohydrate, 30% fat, 15% protein, <10% saturated fat, <300 mg cholesterol) over the first 12 h of the study. The subjects had lunch (40% of calories) after the 4-h blood draw, dinner (40% of calories) at 9 h, and a snack (20% of calories) after the 12-h blood draw. Participants were discharged from the GCRC after 24 h but were asked to return for the 48-h blood draw. Their oral intake was not monitored between 24 and 48 h, but they were asked to fast between 36 and 48 h.

The study drug dose of 400 mg/m2 was chosen to increase the likelihood of suppressing thyroid function and to minimize any adverse effects. Chronic doses of greater than 300 mg/m2 per day have caused hypothyroidism in 53–96% of patients, whereas doses less than 300 mg/m2 have caused hypothyroidism in 29% or less of patients (3, 10, 16). The initial treatment dose for CTCL is usually 300 mg/m2 each evening, but doses can be titrated from 100 up to 1000 mg/m2 per day. The exact dose for each subject was approximated closest to 400 mg/m2 using commercially available 75-mg capsules (Table 1Go). Bexarotene and placebo were given in the morning on an empty stomach.

Laboratory analysis

Serum was kept frozen at –80 C until analysis. Paired samples for each subject (bexarotene and placebo) were analyzed at the same time. The TSH assay was performed using the Advantage Chemiluminescence Immunoassay (Nichols Institute Diagnostics, San Juan Capistrano, CA). The TSH reference range was 0.5–5.0 mIU/liter. The analytical measurement range (AMR) was 0.01–50 mIU/liter. Total T3 and total T4 were performed using the Access Immunoassay System (Beckman Coulter, Fullerton, CA). The reference range was 90–190 ng/dl for total T3 and 4–12 µg/dl for total T4. The AMR was 20–800 ng/dl for total T3 and 1–28 µg/dl for total T4. The T3RU method was performed by chemiluminescence magnetic particle capture as run on the Beckman Coulter Access instrumentation. Free T4 index and free T3 index were calculated by multiplication of each total T4 (or T3) and the corresponding T3RU.

Free T4 by was performed using the Equilibrium Dialysis RIA free T4 assay (Nichols Institute Diagnostics). It is a direct dialysis method that separates Free T4 from protein-bound T4 before measuring free T4 directly in the protein-free dialysate. The dialysate thyroxine (free T4) was measured by a sensitive, solid-phase RIA for T4. The free T4 reference range was 0.6–2.0 ng/dl. The AMR was 0.3–10.0 ng/dl. Thyroglobulin autoantibodies and thyroid peroxidase autoantibodies were performed on the Nichols Institute Diagnostics Advantage chemiluminescence immunoassay system. The reference range for both autoantibodies was less than 2.0 IU/ml, and the AMR was 2.0–90 IU/ml. rT3 was measured at ARUP Laboratories (Salt Lake City, UT; reference range, 90–350 pg/ml).

Prolactin and serum cortisol were performed using the Beckman Coulter Access Immunoassay System. The prolactin reference range was 2–15 ng/ml for females and 2–10 ng/ml for males; the AMR was 1–200 ng/ml. The reference range for serum cortisol was: morning, fasting, 5–25 µg/dl; and evening, fasting, 2–16 µg/dl. The AMR was 1–60 µg/dl. FFAs and TGs were measured in the Cobas Mira Plus Chemistry Analyzer. The reference range for FFA was 100–600 µEq/liter, and the AMR was 50–2600 µEq/liter. The reference range for TG was less than 250 mg/dl, and the AMR was 25–1000 mg/dl. Glucose was measured using a hexokinase methodology (Roche Diagnostic Systems, Indianapolis, IN), and serum insulin was measured by RIA (Diagnostic Systems Laboratories, Inc., Webster, TX).

Statistical analysis

The primary endpoint of this study was serum TSH change at 24 h. The sample size of six subjects in each arm for the single-dose study was powered to have more than 95% power to detect a reduction in TSH from 2 to 1 mU/liter (50% reduction). The power calculation was based on a published, within-subject SD of 0.3 U and a two-sided {alpha}-level of 0.05 (17).

Differences in levels of TSH, free T4 index, free T3 index, dialysis free T4, cortisol, TG, glucose, insulin, and FFA were each analyzed using two-way, repeated-measures ANOVA with factors treatment (placebo vs. bexarotene) and time (baseline, 30 min, 1, 2, 4, 8, 12, 24, and 48 h for TSH, free T4 index, free T3 index, dialysis free T4, and cortisol; baseline, 4 and 8 h for TG, glucose, insulin, and FFA). The assumption of equality of variances was satisfied in all analyses where ANOVA was used with the exception of one variable (glucose). To explore differences between bexarotene and placebo at individual time points, a Tukey test was used to account for repeated measures on subjects. Differences in levels of rT3 and prolactin at 0 and 24 h were analyzed using a paired Student’s t test, and the equality of variance assumption was met. All cases were n = 6 with the following exceptions: n = 5 for TG, glucose, insulin, and FFA because one subject was not fasting; and n = 4 for dialysis free T4, 48-h time point only.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Six subjects (five females, one male; age, 24–53 yr) completed the study. Table 1Go shows individual values for screening TSH, height, weight, body surface area, and bexarotene dosing for each of these subjects.

The average baseline TSH (±SEM) was 1.47 ± 0.11 and 1.43 ± 0.08 mU/liter for the placebo and bexarotene arms of the study, respectively. There was no effect of bexarotene alone on serum TSH (F = 4.4; P = 0.089). However, there was an interaction effect of bexarotene and time; single-dose bexarotene (400 mg/m2) significantly suppressed serum TSH (F = 6.9; P < 0.001). Compared with placebo, levels of TSH were significantly lowered at 12 h (P = 0.043); the nadir of 0.32 ± 0.02 mU/liter was seen at 24 h (P < 0.001), and levels remained lower at 48 h (P < 0.001) (Fig. 1Go). Individual subject TSH values at baseline and 24 h are shown in Fig. 2Go. All six subjects had lower serum TSH levels after bexarotene administration; five of six subjects had TSH below the lower reference range (<0.5 mU/liter). Serum prolactin levels were not significantly affected by bexarotene at 24 h (Fig. 3Go). Mean prolactin concentrations before and 24 h after bexarotene administration were 10.3 ± 0.6 and 9.3 ± 0.6 ng/ml, whereas prolactin levels before and 24 h after placebo were 10.0 ± 0.6 and 13.7 ± 1.1 ng/ml. One study suggested that the circadian variation in endogenous cortisol secretion may affect TSH levels (18). Treatment with bexarotene had no significant effect of serum cortisol levels in these subjects (Fig. 4Go).


Figure 1
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  		FIG. 1. Serum TSH levels measured over 48 h after placebo or bexarotene (400 mg/m2). Six healthy subjects (normal TSH, negative thyroid antibodies, no medications) were given a single dose of 400 mg/m2 oral bexarotene or placebo, and serum TSH was measured at 0.5, 1, 2, 4, 8, 12, 24, and 48 h. Mean TSH values and SEM are given. *, Significant differences between bexarotene and placebo (P < 0.05) in a two-way repeated measures ANOVA.

 

Figure 2
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  		FIG. 2. Individual TSH levels after bexarotene or placebo. Serum TSH levels for each subject measured at baseline and bexarotene nadir at 24 h are shown. A, Bexarotene (400 mg/m2); B, placebo.

 

Figure 3
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  		FIG. 3. Individual prolactin levels after bexarotene or placebo. Serum prolactin levels for each subject measured at baseline and 24 h are shown. A, Bexarotene (400 mg/m2); B, placebo.

 

Figure 4
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  		FIG. 4. Serum cortisol levels measured over 24 h after placebo or bexarotene (400 mg/m2). Six healthy subjects were given a single dose of 400 mg/m2 oral bexarotene or placebo, and serum cortisol was measured at 0.5, 1, 2, 4, 8, 12, and 24 h. Mean cortisol values and SEM are given.

 
Single-dose bexarotene significantly affected free T4 index (Fig. 5AGo; F = 2.4; P = 0.029 for drug/time interaction) and free T3 index (Fig. 5BGo, F = 3.4; P = 0.004) over time (48 h). The drug effect was significant at 48 h for free T4 index (P = 0.027), and at 12 (P = 0.002), 24 (P < 0.001), and 48 (P < 0.001) h for free T3 index. There was a trend toward a lower dialysis free T4 (Fig. 5CGo, P = 0.067), but the effect was not statistically significant. Serum rT3 was measured at baseline and 24 h (Fig. 5DGo). There was no significant effect of single-dose bexarotene on rT3 or T3/rT3 ratio at 24 h (P = 0.934 and 0.296, respectively).


Figure 5
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  		FIG. 5. Serum total T4, total T3, free T4, and rT3 levels measured over 24–48 h after placebo or bexarotene (400 mg/m2). Six healthy subjects were given a single dose 400 mg/m2 of oral bexarotene or placebo and serum free T4 index (A), free T3 index (B), and free T4 (dialysis method) (C) were measured at 0.5, 1, 2, 4, 8, 12, 24, and 48 h. Mean hormone values and SEM are given. *, Significant differences between bexarotene and placebo (P < 0.05) in a two-way repeated measures ANOVA. Serum rT3 (D) was measured at baseline and 24 h.

 
Bexarotene is known to increase serum TG levels over time, and hypertriglyceridemia is seen in up to 80% of patients treated with high-dose bexarotene for 2–4 wk. Subjects in the present study were fasted for the first 4 h and were given a standard meal after the 4-h serum collection. Serum TG levels were not significantly affected by the single dose of bexarotene in the fasting or postprandial state. Glucose, insulin, FFA, and TG levels were measured at baseline, before the standardized meal at 4 h, and 8 h postprandial in both treatment arms (Table 2Go). As expected after eating a meal, insulin and TGs significantly increased (P = 0.001 and 0.015, respectively), and FFA significantly decreased (P = 0.03). Bexarotene alone had no significant effect on glucose, insulin, FFA, or TG levels at 0, 4, or 8 h.


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  		TABLE 2. Serum glucose, insulin, FFA, and TG levels in five normal subjects treated with single-dose bexarotene (400 mg/m2) or placebo

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this study, we have shown that a single dose of a rexinoid (bexarotene) caused a decrease in TSH as early as 4–8 h after administration, and TSH was significantly lowered by 12 h. This effect occurred in all six healthy subjects and appears to be specific for TSH because prolactin levels were not significantly changed.

In patients treated with bexarotene for CTCL or breast cancer, data show that 28–96% demonstrated suppressed serum TSH, and 10–70% experienced clinical hypothyroidism (3, 10, 16). Only one of these studies was designed to specifically examine the effect of a rexinoid on thyroid function in humans (10). Moreover, many patients in these studies had advanced cancer and had been treated with different types of chemotherapy, which could confound the results. The current study demonstrated that a single dose of bexarotene can rapidly suppress serum TSH levels in healthy subjects. Interestingly, the single dose of bexarotene had no significant effect on serum TG levels or other metabolic parameters (glucose, insulin, FFA) before or after a meal. It has been shown that chronic rexinoid therapy can increase TG levels through, at least in part, alterations in lipoprotein lipase activity (19). Furthermore, rexinoids have been shown to decrease glucose and insulin levels in animals with diabetes (20, 21). Although we observed a rapid and significant effect of single-dose bexarotene on serum TSH levels in healthy subjects, we did not see any significant effect on metabolic parameters (glucose, insulin, TG, FFA), suggesting that the hypothalamic-pituitary-thyroid axis is more sensitive to a single dose of rexinoid compared with metabolic pathways.

The mechanism by which rexinoids, including bexarotene, cause suppression of TSH is not completely understood. Potential mechanisms include TSH subunit synthesis, TSH secretion, and TSH clearance. Our group and others have used in vitro models to show that retinoids and rexinoids decrease TSH subunit mRNA levels and that rexinoids suppress {alpha}-subunit and TSHß promoter activity (10, 11, 12, 13, 14, 22). These studies would suggest that rexinoids decrease TSH, at least in part, through direct suppression of TSH subunit synthesis in the thyrotrope. Conversely, animal models show a more complex effect of rexinoids on the hypothalamic-pituitary-thyroid axis. Liu et al. (9) showed that a single dose of rexinoid (LG100268) rapidly suppressed serum TSH in rats by 30 min after administration. They also showed that TSHß mRNA levels from the pituitaries of these rats were unchanged at 2 h after rexinoid treatment. From these data, they postulated that rexinoids may have an early effect on TSH secretion from the thyrotropes. We recently treated mice with LG100268 for 3 d and observed that both serum TSH and TSHß mRNA from the pituitary were significantly lower in the rexinoid-treated animals compared with vehicle-treated controls (11). We also showed that pre-pro-TRH mRNA from hypothalami were unaffected by treatment, suggesting that rexinoids acted directly on the pituitary and not through hypothalamic TRH. These studies, however, used total hypothalami and may have missed subtle effects of rexinoids on TRH levels in the paraventricular nucleus. To explore direct, early effects of rexinoids on TSH secretion from the thyrotrope, we treated T{alpha}T1 thyrotropes with rexinoid (LG100268) and measured TSH levels in the media as well as TSHß mRNA in the cells (11). We observed no effect of rexinoid until 8 h of treatment, and the effect on TSHß mRNA preceded the effect on TSH levels in the media. Taken together with the studies from Liu, these data would suggest that very early effects (before 2–8 h) of rexinoids on serum TSH levels in rats and humans may be due to effects on clearance of TSH and not a direct effect on secretion.

The effect of rexinoids to suppress TSH may be independent of the effects of thyroid hormone. We have shown that rexinoids affect TSHß promoter activity through the –200 to –149 region, which is different from the effect of T3 near the transcriptional start site (12). Maccia et al. (23) have further shown that rexinoids can suppress TSH in a mouse model lacking TRß, which is the primary thyroid hormone receptor mediating the effects of thyroid hormone on the thyrotrope. Taken together, these data suggest that rexinoids have a T3-independent effect on the thyrotrope that may have therapeutic implications for patients with TSH-secreting tumors and the syndrome of thyroid hormone resistance.

TSH can be suppressed by cortisol, and the circadian rhythm of TSH is closely linked with that of cortisol (18). We did not observe any effect of rexinoids on serum cortisol levels, which excludes cortisol as an indirect mechanism of TSH suppression by rexinoids. We also observed that serum prolactin was not significantly affected by bexarotene at 24 h (9.7% lower than baseline). Because serum TSH was significantly suppressed at 24 h (79% lower than baseline), this suggests that the effect on the pituitary is thyrotrope-specific. Other pituitary hormones have not been tested.

In the current study, a single dose of the rexinoid bexarotene resulted in lower levels of T4 and T3 measured by free hormone index. The effect of bexarotene on T3 levels was seen as early as 12 h, whereas suppression of T4 was significant only at 48 h, which could be from T3 production (thyroid secretion, peripheral metabolism of T4) or T3 metabolism. Studies in rodents show that single-dose and 3-d treatment with a rexinoid rapidly suppresses serum T4 and T3 levels (9, 11). These differences may be related to the shorter half-life of T4 in rodents (t1/2, 2–3 d) compared with humans (t1/2, 7–8 d). We have shown recently that a rexinoid increased liver type 1 deiodinase mRNA and enzyme activity in mice, which would affect serum levels of T4 and T3 (11). In contrast, Macchia et al. (23) described a decrease in liver type 1 deiodinase by treatment with another rexinoid, AGN194204. Mice in this study had diabetes (db/db), which may explain the differences observed in these two studies. Esfandiari et al. (15) demonstrated that all-trans retinoic acid and 9-cis retinoic acid can significantly stimulate type 3 deiodinase in astroglia cells in culture. Because type 3 deiodinase catalyzes the degradation of both T4 and T3, this may be yet another mechanism of clearance of thyroid hormone stimulated by retinoic acid. It is unclear from these data if this is through a retinoic acid receptor-mediated effect, a retinoid X receptor-mediated effect, or both receptor types. Other investigators have shown that rexinoids significantly increase hepatic cytochrome P450 metabolic enzymes (CYP3A, CYP4A, CYP2B1/2), which may be a nondeiodinase mechanism of thyroid hormone metabolism (24). Studies in athyreotic animals or humans are needed to dissect the roles of rexinoids on T4 and T3 secretion from the thyroid vs. peripheral metabolism through mechanisms such as altered deiodinase or P450 enzyme function.

Conclusion

In summary, we have shown that single-dose bexarotene rapidly and specifically suppressed serum TSH in normal subjects. This effect did not occur through a secondary consequence of cortisol on the hypothalamic-pituitary-thyroid axis. Bexarotene also suppressed serum T3, but not total T4 or free T4 levels, after a single dose. Serum glucose, TG, insulin, and FFA levels before and after a meal were not acutely affected by rexinoid treatment with bexarotene. Because bexarotene and other rexinoids promise more therapeutic benefit in multiple disease processes, these data provide more insight into the mechanisms by which rexinoids cause central hypothyroidism and potential ways this effect can be used for treatment of other related disorders, such as thyroid hormone resistance and TSH-secreting pituitary tumors.


   Footnotes
 
This work was supported by National Institutes of Health Grant DK54383 (to B.R.H.). Studies were performed on the Adult GCRC at the University of Colorado Health Sciences Center, which is supported by National Institutes of Health Grant M01 RR00051.

The authors have no other disclosures.

First Published Online October 24, 2006

Abbreviations: AMR, Analytical measurement range; CTCL, cutaneous T cell lymphoma; FFA, free fatty acid; GCRC, General Clinical Research Center; TG, triglyceride; T3RU, T3 resin uptake.

Received March 30, 2006.

Accepted October 12, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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J. W. A. Smit, M. P. M. Stokkel, A. M. Pereira, J. A. Romijn, and T. J. Visser
Bexarotene-Induced Hypothyroidism: Bexarotene Stimulates the Peripheral Metabolism of Thyroid Hormones
J. Clin. Endocrinol. Metab., July 1, 2007; 92(7): 2496 - 2499.
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