The mechanism of action of mifepristone and its clinical application in the management of Cushing’s disease will be reviewed.
Physiology
Glucocorticoid receptor physiology : There are two isoforms of the glucocorticoid receptor (GR), namely the GRα and GRβ glucocorticoid receptor subtypes. The GRα isoform is the proverbial “classic glucocorticoid receptor” present in the cytosol, while the GRβ isoform resides in the nucleus. The GRβ receptor exerts mainly a modulatory role by inhibiting the function of GRα(1).
Fig. 1.0 Glucocorticoid receptor physiology. Cortisol (glucocorticoid), a steroid hormone, diffuses through the plasma membrane to bind to the ligand-binding domain (LBD) of the cytosolic glucocorticoid receptor (step 1). The hormone-receptor complex undergoes a conformational change and is then translocated from the cytosol into the nucleus to exert its genomic effects (step 2). The glucocorticoid receptor’s DNA binding domain (DBD) binds to its assigned hormone response sequence, the Glucocorticoid Response Element (GRE), to exert its intranuclear effects. This leads to the activation of transcription factors, which may either activate or inactivate gene expression(1,2). Glucocorticoids may also exert non-genomic effects through various kinases (step 3). This typically occurs within minutes after ligand-receptor interaction in the cytosol(1). The non-genomic effects of glucocorticoids include inflammatory and non-inflammatory (calcium mobilization and muscle function) processes(3). GRβ inhibits the intranuclear effects of GRα(1). Redrawn and modified from Oakley RH, Cidlowski JA (2013) The Biology of the Glucocorticoid Receptor: New Signaling Mechanisms in Health and Disease. J Allergy Clin Immunol 132:1033–1044
Mechanism of action
Mifepristone, also known as RU486 (Roussel-Uclaf 38486), has both anti-glucocorticoid and anti-progesterone effects. RU486 binds to the ligand-binding domain of the cytosolic glucocorticoid receptor without directly promoting its downstream effects, such as the activation of hormone response elements and transcription factors involved in glucocorticoid-mediated gene function(4).
Practice Guide
- Patients on mifepristone (Korlym) may develop significant hypercortisolemia (with elevated ACTH levels), which can increase their risk for hypokalemia and hypertension (cortisol activating the renal MCR) (5). The anti-progestin effects predispose female patients to endometrial hyperplasia (unopposed estrogen action)
- Monitor patients for symptoms and signs of adrenal insufficiency. It is worthy to note that cortisol levels are unreliable in patients on mifepristone. Indeed, patients may be “adrenally insufficient” despite high cortisol levels (blockade of the glucocorticoid receptor)(6).
- Mifepristone is approved by the United States (Food and Drug Administration) FDA for the management of endogenous hypercortisolemia associated with hyperglycemia(7). Glycemic control improves in up to 60% of patients treated with mifepristone. Thus, doses of antihyperglycemic agents may need to be adjusted(8).
- It is also an abortifacient due to its antiprogesterone effects.
Clinical Trial Evidence
The Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing’s Syndrome (SEISMIC) and its extension sub-study assessed the effects of long-term mifepristone on neuroimaging findings in patients with Cushing’s disease(9).
Key Message
Although mifepristone causes an increase in ACTH amongst patients with Cushing’s disease, it does not significantly increase pituitary tumor size.
The SEISMIC trial was an open-label, multicenter, prospective study that evaluated the effects of mifepristone on tumor size and ACTH levels in Cushing’s disease over a 24-week period. Subjects received a starting dose of oral mifepristone (300mg) once daily, which was steadily uptitrated to a maximum total daily dose of 1200mg. The primary outcome was defined as a change in ACTH (compared to baseline) and MRI changes (volumetric changes in tumor size). 72% of subjects had a ≥ two-fold increase in ACTH compared to baseline. ACTH returned to baseline after discontinuation of RU486. Tumor progression and regression occurred in two and three subjects, respectively. This was not statistically significant. Indeed, there was no evidence that mifepristone predisposes patients to accelerated pituitary tumor growth(9).
In conclusion, there are novel therapies for Cushing’s disease which are currently in development. These include cyclin-dependent kinase 2 (CDK2) modulators (Roscovitine), epidermal growth factor receptor (EGFR) inhibitors (Gefitinib), and glucocorticoid receptor antagonists (Relacorilant), to mention a few(10).
Table 1.0 Summary of therapeutic targets in Cushing’s disease
| Therapy | The primary site of action |
| Pasireotide | Anterior pituitary gland (SSR1, SSR2, SSR3, and SSR5 receptors) |
| Retinoic acid | Anterior pituitary gland (Retinoic acid receptors) |
| Cabergoline | Anterior pituitary gland (Dopaminergic receptors) |
| Ketoconazole | Adrenal steroidogenesis inhibitor |
| Metyrapone | Adrenal steroidogenesis inhibitor |
| Mitotane | Adrenal steroidogenesis inhibitor |
| Mifepristone | Glucocorticoid receptor antagonist |
Adapted from Hinojosa-Amaya JM et al. (2019) Medical Management of Cushing’s Syndrome: Current and Emerging Treatments. Drugs 79:935–956
References
- Oakley RH, Cidlowski JA. The Biology of the Glucocorticoid Receptor: New Signaling Mechanisms in Health and Disease. J Allergy Clin Immunol. 2013 Nov;132(5):1033–44.
- Weikum ER, Knuesel MT, Ortlund EA, Yamamoto KR. Glucocorticoid receptor control of transcription: precision and plasticity via allostery. Nat Rev Mol Cell Biol. 2017;18(3):159–74.
- Panettieri RA, Schaafsma D, Amrani Y, Koziol-White C, Ostrom R, Tliba O. Non-genomic Effects of Glucocorticoids: An Updated View. Trends Pharmacol Sci. 2019 Jan 1;40(1):38–49.
- Cadepond F, Ulmann A, Baulieu EE. RU486 (mifepristone): mechanisms of action and clinical uses. Annu Rev Med. 1997;48:129–56.
- Cohan P. Pasireotide and Mifepristone: New Options in the Medical Management of Cushing’s Disease. Endocr Pract. 2013 Oct 14;20(1):84–93.
- Yuen KCJ, Moraitis A, Nguyen D. Evaluation of Evidence of Adrenal Insufficiency in Trials of Normocortisolemic Patients Treated With Mifepristone. J Endocr Soc. 2017 Feb 21;1(4):237–46.
- Carmichael JD, Fleseriu M. Mifepristone: is there a place in the treatment of Cushing’s disease? Endocrine. 2013 Aug;44(1):20–32.
- Fleseriu M, Biller BMK, Findling JW, Molitch ME, Schteingart DE, Gross C, et al. Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing’s syndrome. J Clin Endocrinol Metab. 2012 Jun;97(6):2039–49.
- Fleseriu M, Findling JW, Koch CA, Schlaffer SM, Buchfelder M, Gross C. Changes in plasma ACTH levels and corticotroph tumor size in patients with Cushing’s disease during long-term treatment with the glucocorticoid receptor antagonist mifepristone. J Clin Endocrinol Metab. 2014 Oct;99(10):3718–27.
- Hinojosa-Amaya JM, Cuevas-Ramos D, Fleseriu M. Medical Management of Cushing’s Syndrome: Current and Emerging Treatments. Drugs. 2019 Jun;79(9):935–56.
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