Control of TSH secretion

Topic: Effects of acute bexarotene administration on TSH secretion in normal subjects

Title: Single-Dose Rexinoid rapidly and specifically suppresses serum thyrotropin (TSH) in normal subjects.

Authors: Golden WM, Weber KB, Hernandez TL, Sherman SI, Woodmansee WW, & Haugen BR.

Reference: Journal of Clinical Endocrinology & Metabolism 92: 124-130, 2007

Summary

Background

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.

Purpose

The objective of this study was to determine the effect of a single dose of bexarotene on levels of TSH, T 4 and T 3 in healthy subjects.

Design

This study was a randomized, double-blind, placebo-controlled, crossover trial, conducted at the General Clinical Research Center (University of Colorado Health Sciences Center, Aurora, CO).

Subjects

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

Methods

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. The main outcome was the serum TSH level at 24 hour.

Results

Single-dose bexarotene suppressed serum TSH (P<0.001) over time. Compared with placebo, levels of TSH were significantly lower by 12 hour (P=0.043); the nadir of 0.32 - 0.02 mU/L (P<0.001) was reached at 24 hour. Free T 4 index and free T 3 index were also significantly lower than with placebo over time (48 hr) (P=0.029 & P=0.004, respectively). Serum prolactin, cortisol, and triglycerides were not affected. There was no significant effect of a single-dose of bexarotene on reverse T 3 or the ratio of T 3 /rT 3 at 24 hour.

Conclusions

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

Commentary

Retinoid X receptor antagonists (rexinoids) and in particular -Bexarotene- (TARGRETIN, LG1069) are employed in the medical treatment of cutaneous T-cell lymphoma and are currently investigated for potential usage in other malignancies. It has been previously shown that cancer patients on Bexarotene therapy develop frequently symptomatic and reversible central hypothyroidism. However, the precise time-course of the TSH-lowering effect of Bexarotene and the effects of this drug on other endocrine axes has not been investigated.

In this context, Golden et al. designed a randomised, double-blind, placebo-controlled crossover trial in six healthy subjects (5 females & 1 male), aged 24-53 years, to assess serum TSH, prolactin, cortisol, free thyroid hormones and reverse T 3 before and at different time intervals (between 1 and 48 hour) after the oral administration of a single dose (400 mg/m 2 ) of Bexarotene. Glucose, insulin, free fatty acids (FFA) and triglycerides (TG) were also measured. A rapid decrease of serum TSH concentration (starting at 12 h with a nadir at 24 h) was observed reaching values <0.5 mU/L in all cases. This suppression was considered specific for TSH, since serum prolactin concentrations were unchanged and no effect was observed on the circadian cortisol rhythm. It should be noticed, however, that no other pituitary hormone was tested. The effects of Bexarotene on free T4 index, free T3 index and free T4 (by equilibrium dialysis RIA) were less clear. Using free T4 or free T3 indices, a significant decrease was observed for free T3 as early as 12 hr, whereas the suppression of free T4 was significant only at 48 h. Interestingly, changes in free T4 concentration assessed by equilibrium dialysis were not significant and serum reverse T3 as well as the ratio of T3/rT3 were unchanged. The design of the study did not allow for dissecting the potential effects of rexinoids on thyroid hormone secretion by the thyroid gland versus the peripheral metabolism of thyroid hormone (by deiodination or non-deiodinating pathways). Finally, no effect was observed on glucose, insulin, FFA and TG either in the fasting or postprandial state. These metabolic parameters were included in the study because chronic Bexarotene administration has been found to be associated with hyper-triglyceridemia. Although this study cannot give insights on the mechanism(s) involved in serum TSH suppression by Bexarotene ( in vitro and animal studies have suggested that this drug inhibits both the synthesis & secretion of TSH subunits directly at the pituitary cell level through thyroid hormone independent effects), it is an interesting pharmacological investigation providing the following new information:

  • After Bexarotene administration, TSH suppression is clearly and reproducibly obtained in normal healthy subjects (it should be noted that all previous data were obtained in patients with advanced cancer, in whom several other conditions could have concurred in lowering TSH);
  • The effect of Bexarotene is apparently specific for TSH and does not involve cortisol secretion.
  • Bexarotene acutely does not affect fasting and postprandial serum glucose, insulin, FFA and TG.

An interesting corollary of this study is that Bexarotene could have potential clinical applications in reducing TSH secretion in rare conditions such as thyroid hormone resistance and TSH-secreting tumors, but further studies particularly designed to clarify the chronic effects of this drug are needed to ascertain the actual feasibility of such therapeutic approach.

Summary and commentary prepared by Stefano Mariotti (related to Chapters 4 & 9 of TDM)

PDF available at: http://jcem.endojournals.org/cgi/reprint/92/1/124?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&author1=Golden&searchid=1 &FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCIT