Mifepristone Increases Thyroid Hormone Requirements in Patients With Central Hypothyroidism

A Multicenter Study

Francisco J. Guarda; James Findling; Kevin C.J. Yuen; Maria Fleseriu; Lisa B. Nachtigall

Disclosures

J Endo Soc. 2019;3(9):1707-1714. 

In This Article

Discussion

Few reports have discussed longitudinal outcomes in patients with Cushing syndrome receiving mifepristone and only one clinical trial and its extension report have formally assessed the efficacy in this population.[1,17] Mifepristone is associated with improvement in metabolic profile, including a decrease in plasma fasting glucose and HbA1c, persistent body weight loss in many, and lower diastolic blood pressure in some patients with hypertension.[1,7] The effects of mifepristone on thyroid function are not well known, but evidence in thyroid cell cultures have shown that mifepristone generates a reduction in iodine uptake as well as a reduced expression of several essential proteins in thyroid hormone synthesis.[9,11] These effects may explain an increased levothyroxine requirement in hypothyroid patients. This study reviewed levothyroxine requirements in patients with CH who received mifepristone. These cases provide evidence that the initiation of mifepristone can be associated with an increase in thyroid hormone requirement in patients with CH. Several concepts may be considered to explain this phenomenon, including the possibility of decreased intestinal absorption, decreased thyroid residual function, and increased deiodination of thyroid hormones (Figure 2).

Figure 2.

Proposed mechanisms.

Mifepristone may impair intestinal absorption of levothyroxine, which would lead to decreased FT4 levels and, subsequently an increased dose requirement. To determine that mifepristone causes malabsorption of thyroid hormone, compliance issues and conditions that affect gastrointestinal absorption, such as gastric acidity, bowel resection or celiac sprue, as well as concomitant use of drugs that are known to interfere in levothyroxine absorption should be excluded. Although not done routinely, nor strictly validated, T4 absorption tests could be performed to test this hypothesis.

Regarding residual thyroid function, studies have shown that hydrocortisone stimulates iodine uptake in thyroid cells, but the effect is blunted after mifepristone use.[9] FT4 levels are usually kept at steady state by the negative feedback of the hypothalamic-pituitary-thyroid axis in normal conditions, however, because these patients had central hypothyroidism, the absence of TSH increase as well as the fact that they receive exogenous T4 replacement would make thyroid production negligible. Nevertheless, it could be proposed that even in patients with long-standing central hypothyroidism, the thyroid gland may still produce a small amount of T3 and T4 to keep stable FT4 levels. As it has been shown that mifepristone can lower iodine uptake and lower thyroglobulin production and thyroperoxidase expression,[9] it could be inferred that a decrease in these factors could explain a lower hormone secretion and, therefore, a higher levothyroxine requirement to augment the thyroid supply in compensation for this putative decrease in residual endogenous function.

Thyroid hormone metabolism is complex and includes several factors that catalyze deiodination of tyrosine residues, activating or deactivating T4 and T3. Iodothyronine deiodinases type 1, 2, and 3 (DIO1, DIO2, and DIO3, respectively) are the main enzymes involved in the process and are present in different concentrations throughout the body. DIO1 and DIO2 are the primary activators of T4, converting it into T3 so that it can trigger responses via the nuclear thyroid hormone receptor. DIO2 is primarily responsible for T3 production peripherally. DIO3 inactivates T4 and T3, turning them into rT3 and diiodothyronine, which are not usually measured in clinical settings.[18,19] The increased levothyroxine requirements could be explained by an increased deactivation of T4 by DIO3, which would lead to increased concentrations of rT3 in plasma. As it is not usually performed, only two of the patients had rT3 measured and were both normal, making this theory less likely to explain this effect in mifepristone-treated hypercortisolemic patients, but still viable considering baseline values were not available and both were in the lower normal range.

In terms of clinical manifestations, four of the patients enrolled presented with substantial weight loss that ranged from 4.1 to 42.6 kg in up to 54 months of follow-up, which is concordant with the data published by the SEISMIC extension study.[7] The optimization of thyroid hormone levels could play a role in aiding in this outcome, because it has been shown that hypothyroidism may impair energy expenditure and metabolic rate.[20]

This longitudinal case series, although retrospective, reveals that mifepristone decreases FT4 in patients with CH receiving thyroid hormone replacement, even in the presence of substantial weight loss. To determine the exact causes of this increased levothyroxine requirement, more studies are needed to test the different hypotheses and confirm the existence of this entity. Limitations of this study include its retrospective design, which includes selection bias of patients who continued the treatment of a longer duration, the small number of subjects and the observational data taken from real-life clinical practice rather than a standardized protocol. Larger studies would be helpful to confirm this findings, and specific tests to determine the pathophysiology behind this phenomenon, such as thyroxine malabsorption tests and baseline and periodic rT3 levels,[21,22] would be useful.

The experience reported represents all cases with CD and CH treated with mifepristone in three of the four centers and most of such cases in the fourth. Therefore, it appears that this requirement for an increased dose of thyroid hormone commonly occurs with the administration of mifepristone. However, given the retrospective nature of this study and the small number of subjects, the exact frequency of this increased requirement cannot be definitively determined from this series. In addition, regarding published data on this topic, the SEISMIC study reported that 16% of patients developed subclinical hypothyroidism based on elevated TSH levels, but no information on free T4 levels was described on the eight patients with CH.[1]

As treatment of persistent hypercortisolemic patients aims to reduce clinical manifestations of Cushing syndrome, including weight gain or mood changes, the presence of untreated hypothyroidism can hamper these changes. We therefore recommend close monitoring of the thyroid status in all patients treated with mifepristone to optimize outcomes. In this case series, the fact that thyroid function was monitored regularly aided in maintaining normal thyroid hormone levels and, probably, may have enhanced the efficacy of mifepristone in maintaining weight loss.

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