Abstract and Introduction
Purpose: Mifepristone is a glucocorticoid and progesterone receptor blocker that can be used for patients with hyperglycemia and Cushing syndrome in whom surgery failed to achieve remission or who were ineligible for surgery. We report a case series of patients with Cushing disease (CD) and central hypothyroidism that presented with increased levothyroxine requirements during mifepristone therapy.
Methods: Retrospective longitudinal case series of patients with CD and central hypothyroidism treated with mifepristone in a retrospective database at four pituitary centers in the United States.
Results: Five patients with CD were found, all women, median age 50 (interquartile range 47 to 64.5). They received mifepristone because no adequate response or intolerance to other drugs was observed. Mifepristone initiation was associated with a decrease in free thyroxine levels, mandating a dose increase of a median 1.83 (1.71 to 3.5) times the initial dose of levothyroxine to achieve normal levels. Weight loss was seen in four of five patients, ranging from 3.2 to 42.6 kg in up to 54 months of follow-up.
Conclusions: Although the mechanism behind the decrease in thyroid hormone level is unknown, intestinal malabsorption, decreased residual thyroid function and increased inactivation of T4 via deiodinases are all potential causes. Whereas therapies for hypercortisolism aim to decrease features of hypercortisolemia such as weight gain and depression, hypothyroidism can hamper these goals. This case series raises awareness on the importance of assessment of thyroid status in patients receiving mifepristone to optimize clinical outcomes.
Hypercortisolemia is associated with impaired quality of life and increased morbidity and mortality. Clinical manifestations include weight gain, muscle atrophy, skin thinning, thromboembolic disorders, metabolic disturbances, among others.[1,2] Medical therapy for the management of surgically persistent or recurrent Cushing disease (CD) includes drugs that target the pituitary, adrenals, or glucocorticoid receptors in peripheral tissues.
Central hypothyroidism (CH) is defined by a state of thyroid hormone insufficiency that results from pituitary or hypothalamic dysfunction, causing a decrease in TSH or TRH secretion. Because pituitary thyrotropes are not able to increase thyroid stimulation, CH is diagnosed in patients with low free thyroxine levels (FT4) in association with a low or inappropriately normal TSH. Management includes the administration of levothyroxine, aiming at thyroid hormone values in the normal range, because TSH is no longer an appropriate marker of adequate replacement.
Initially used for pregnancy termination, mifepristone is a compound that acts as a progesterone receptor blocker and glucocorticoid receptor antagonist. In 2012, mifepristone was Food and Drug Administration-approved for the treatment of patients with hypercortisolemia and diabetes mellitus or glucose intolerance in whom surgery failed to achieve remission or who were not adequate surgical candidates. Weight loss was achieved in most patients, with persistence of this effect after a median of 29 months, shown in an extension study of the same cohort.
Because the glucocorticoid and progesterone receptors have a myriad of functions in all systems, some studies were dedicated to evaluating its effects in different organs. In 1983, a study showed an increase in pituitary ACTH, arginine vasopressin, and plasma cortisol levels in patients receiving the progesterone blocker, but no effect on gonadotropins or TSH. Later, it was suggested that the use of mifepristone (or RU486) could impair thyroid function by reducing iodine uptake in normal porcine thyrocytes treated previously with hydrocortisone. Also, in meningiomas, it was shown that long-term use of mifepristone could increase TSH levels within normal range with a slight decrease in FT4 levels. In 2015, an increase in the expression of critical proteins in thyroid function, such as the sodium iodide symporter, thyroglobulin, and thyroperoxidase, was shown after the administration of progesterone, an effect that was blunted by the administration of mifepristone. In other tissues, thyroid hormone receptors were shown to be downregulated in placenta and decidua after mifepristone administration and, as expected with an antiprogesterone agent, gynecological follow-up should be instituted in patients treated with mifepristone because of endometrial thickening.
Among patients with hypercortisolemia treated with mifepristone, the Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing Syndrome (SEISMIC) reported primary subclinical hypothyroidism in 8 of 50 patients within six months of administration of mifepristone. However, the mechanisms involved in these findings remain unclear. Furthermore, the effect of mifepristone on FT4 levels in patients with central hypothyroidism receiving thyroid hormone replacement has not been evaluated previously.
Because low thyroid hormone levels may lead to impaired weight loss, altered mood, and decreased energy expenditure, optimization of thyroid hormone therapy is of particular importance in patients with Cushing syndrome.
A retrospective case series study was conducted to report the effects of mifepristone on the increased requirement of levothyroxine doses in patients with CD and CH seen at four pituitary centers across the United States.
J Endo Soc. 2019;3(9):1707-1714. © 2019 Endocrine Society