Endocrine Rev, Suppl 1, June 2010, 31(3):S1201 (Endocrine Society Annual Meeting, 2010, San Diego)
`
`P2-326
`
`IT SOUTHWESTERN
`MEDICAL C E N T E R
`
`Mifepristone (RU-486) in the Treatment of Refractory Cushing’s Disease
`Erin E. Dunnigan MD, Barbara Carranza Leon MD, Michael J. McPhaul MD
`University of Texas Southwestern Medical Center Dallas, TX
`Background
`Optimal management of Cushing’s Disease (CD) consists of surgical resection with a cure
`rate estimated between 70-80% (1). Persistent hypercortisolism is associated with elevated
`mortality. For these patients, chemical adrenolytic therapy using dopamine agonists
`(cabergoline) and 17a-hydroxylase inhibitors (ketoconazole) are variably successful. Such
`tumors may also exhibit progressive growth and compromise neighboring neuroanatomy
`making further attempts at resection technically difficult. We describe a case of a woman
`with refractory CD and use of a novel agent, mifepristone.
`Presentation
`A 47 year old Hispanic female with historically well-controlled Type 2 diabetes mellitus on
`oral agents presented with two weeks of progressive weakness, fatigue and exertional
`dyspnea. She endorsed polyuria and acutely increased capillary blood glucose levels.
`Diabetic control had recently deteriorated as evidenced by a Hgb Ale of 13.3 mg/dL She
`had decreased oral intake secondary to dysphagia and odynophagia to solids and liquids
`resulting in an unintentional thirty pound weight loss. She denied fevers, chills, nausea,
`vomiting, but described pre-syncope and orthostasis without recent falls. The remainder of
`her review of systems was negative. Past medical history was notable for Type 2 Diabetes
`Mellitus for 13 years with retinopathy, no known neuropathy or nephropathy. The remainder
`of the social and family history was non-contributory. Admission medications included
`metformin, glyburide and baby aspirin.
`PE: T 35.7, HR 103, BP 144/77. General: Obese with facial plethora, appropriate and
`oriented to four spheres. HEENT: extraocular movements intact, no visual field cuts. Neck:
`no thyromegaly. CV: regular rate and rhythm. Lungs: clear bilaterally. Abdomen: central
`obesity, soft, non-tender without striae or masses. Extremities: +2 pitting edema.
`Neurologic: cranial nerves intact, reflexes normal, decreased sensation and strength in the
`lower extremities bilaterally. Skin: easy bruising, multiple subcutaneous nodules and
`superficial ulcers which cultured positive for Mucor and S. aureus.
`
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`Endocrine Rev, Suppl 1, June 2010, 31(3):S1201 (Endoerine Society Annual Meeting, 2010, San Diego)
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`A Brain MRI revealed a large enhancing macroadenoma in the sella with anterior extension
`into the sphenoid sinus and suprasellar extension into the third ventricle displacing the optic
`chiasm.
`
`«May 2009
`
`May 2009»
`
`-i-sJuly 2009
`
`July 2009»
`
`Hospital Course
`Two months after initial presentation, the patient was hospitalized for volume overload and
`bilateral pulmonary infiltrates. Infectious and cardiac evaluations were negative.
`Subsequently, the patient developed complications due to her relatively immunosuppressed
`state first E coli urosepsis then cholecystitis^—^for which she was not felt to be sufficiently
`medically stable to undergo cholecystectomy.
`For the patient’s hypercortisolism, she was started on ketoconazole and titrated to a target
`cortisol level of 30-35 iiicg/dL. Although she initially responded well, the patient developed
`hypokalemia. Ketoconazole was discontinued and the patient was started on spironolactone
`instead to continue diuresis.
`Although not originally felt to be a good surgical candidate, the
`patient’s persistently elevated cortisol and ACTH levels
`prompted Neurosurgery to perform a transsphenoidal resection.
`Because of the extensive size and involvement of this tumor,
`approximately 20% residual tumor could not be resected.
`Postoperative, repeat MRI revealed residual tumor eroding
`inferiorly into the clivus and on the left into the cavernous sinus,
`possibly into the left Meckel's cave. She was continued on
`maximal doses of ketoconazole. Cabergoline was added and
`titrated to 1 mg/d. Stress dose steroids were given immediately
`following surgery, but these were discontinued when her serum
`cortisol level continued to increase.
`
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`Rndocrinc Rev, SuppI I, June 2010, 31(3):S1201 (F.ndociine Society Annual Meeting, 2010, San Diego)
`
`Osteopenia was first noted one month prior to surgery, also attributed to hypereortisolism.
`CT imaging revealed anterior wedging of 1.2-L5 without retropulsion and diffuse
`osteopenia. I’ostoperatively she complained of hemiplegia and was found to have an
`irreversible cord compression and multiple thoraeie and lumbar vertebral compression
`fractures.
`Mifepristone was then added using compassionate use protocol. Owing to her other
`medications, a do.se of 600 mg/d was u.sed. Following initiation of treatment, the patient’s
`insulin and hypertensive medication requirements dropped dramatically and mental status
`improved markedly. Potential common side effects, particularly hypokalemia, did not
`develop. However, after several days of treatment, the patient grew despondent,
`hypotensive, and hypoglycemic, requiring short-term treatment with dexamethasone.
`
`Mean MifepristoneTrough Levels
`3000,00
`
`2500.00
`
`2000,00
`
`i 1500,00
`
`1000.00
`
`500.00
`
`0.00
`
`300
`
`600
`
`Dos« (ing/dav)
`
`900
`
`1200
`
`Time
`C-1073
`RU-42633
`RU-42698
`RU-42848
`
`7/30
`1035
`8,770
`5,770
`3,280
`820
`
`7/30
`1150
`8,520
`5,780
`3,170
`817
`
`8/17
`1350
`3,160
`2,940
`1,960
`728
`
`This development of clinical adrenal insufficiency was likely exacerbated by the P450
`(CYP3A4) -inhibiting properties of ketoeona/ole, which led to unexpectedly high levels of
`mifepristone and its metabolites.
`Notably, even following discontinuation of mifepristone administration, the patient's insulin
`and anti-hypertensive requirements remained low.
`
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`Sep-09
`
`Aug-09
`
`Jun-09 Jul-09
`
`267
`May-09
`
`338
`Apr-09
`
`Mar-09
`
`294
`Feb-09
`
`167
`Dec-08
`
`1
`
`1
`
`1
`
`1
`
`10
`
`4
`
`14
`
`51
`
`230
`
`44
`
`0
`
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`22
`
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`
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`
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`
`8
`
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`
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`12
`
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`
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`6-58 pg/mL
`Reference
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`poststimulation
`Cortisol,
`Cortisol, baseline
`Hbg AlC
`FT3
`
`FT4
`
`TSH
`
`PTH
`Renin
`HCG Quant
`Testosterone
`FSH
`LH
`Prolactin
`In$ulin-like GF-1
`
`Cortisol
`
`ACTH
`
`Endocrine Rev, Suppl 1, June 2010, 31(3):S1201 (Endocrine Society Annual Meeting, 2010, San Diego)
`
`js. S P
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`
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`
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`Day 8
`22
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`Day 7
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`Day 6
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`21
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`15
`
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`14
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`
`13
`
`Appetite
`Depression/Lethargy
`Hallucinations
`Carvedilol 3.125 mg BID
`Spironolactone
`DBF
`
`SBP
`ql2h
`Dexamethasone 4 mg
`Hypoglycemia
`(units)
`Total insulin requirement
`Cabergoline 1 mg q D
`Ketoconazole 400 tid
`RU486 600 mg daily
`July
`
`Endocrine Rev, Suppl 1, June 2010, 31 (3);S 1201 (Endocrine Society Annual Meeting, 2010, San Diego)
`
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`105
`
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`9
`
`Day 12
`
`Day 11
`
`Day 10
`
`26
`
`25
`
`24
`
`Day 9
`23
`
`Appetite
`Depression/Lethargy
`Hallucinations
`Carvedilol 3.125 mg BID
`Spironolactone
`DBF
`SBP
`ql2h
`Dexamethasone 4 mg
`Hypoglycemia
`(units)
`Total insulin requirement
`Cabergoline 1 mg q D
`Ketoconazole 400 tid
`RU486 600 mg daily
`July
`
`Endocrine Rev, Suppl 1, June 2010, 31 (3):S 1201 (Endocrine Society Annual Meeting, 2010, San Diego)
`
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`0
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`
`

`

`Endocrine Rev, Suppl 1, June 2010, 31(3):S1201 (Endocrine Society Annual Meeting, 2010, San Diego)
`
`Mifepristone
`Mifepristone, a potent glucocorticoid and progesterone receptor antagonist, also known as
`17-hydroxy-1 l-(4-dimethylaminophenyl)-17-(l-propynyl)-estra-4,9-dien-3-one, was started
`when the patient proved refractory to medications for chemical adrenalectomy. Its effects
`are largely dose-dependent and vary aeeording to the affected receptor, as shown below:
`
`Receptor
`Progesterone
`
`Glucocorticoid
`
`Androgen
`
`Daily Dose
`>5mg
`>10mg
`>50mg
`>100-200mg
`>200-400mg
`>200mg
`>200mg
`>400mg
`>200mg
`
`Potential Side Effects
`Amenorrhea
`Endometrial hyperplasia
`Increase in cortisol, ACTH and adrenal androgens
`Mild to moderate fatigue/nausea
`Adrenal Insufficiency
`Gynecomastia (due to elevated estrogen)
`Hypokalemia (due to MR activation of cortisol?)
`Hypothyroidism (isolated cases)
`Gynecomastia (decrease in libido)
`
`Known adverse effects of mifepristone include rash, hypokalemia, LFT elevation, adrenal
`insufficiency, hypoglycemia; potential effects include Nelson syndrome with loss of cortisol
`negative feedback resulting in an rapid tumor reexpansion from residual pituitary
`corticotroph growth. Glucocorticoid receptor (GR) effects occur at single doses of 4 mg/kg
`and higher, whereas antiprogestin activity is already apparent at much lower doses (2, 3).
`Since mifepristone blocks the GR in a competitive manner, the effect can be reversed by
`glucocorticoid administration; dexamethasone, in a dose of one milligram abolishes the
`effects of mifepristone 400 mg. However, the antiglucocorticoid effects of mifepristone may
`reappear one day later due to its long plasma half-life (4). As mifepristone antagonizes both
`peripheral and central GR, its administration causes disinhibition of ACTH release, resulting
`in increased levels of detectable levels of serum ACTH and cortisol. (4).
`
`7
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`Kndocriiic Rev. Siippl 1, June 2010. .3I(3):SI201 (Endocrine .Society Annual Meeting, 2010, San Diego)
`
`Hypokalemia results from mifepristone's blockade of the GR which results in a reciprocal
`increase in ACTII, and shunting to increased activation of the mincralcorticoid receptor
`(MR). This overstimulation results in hypokalemic alkalosis and hyi^crtcnsion (5).
`Thus the use of spironolactone may have reduced the potential for hypokalemia, yet it may
`have also provided additional mincralcorticoid antagonism to make signs of adrenal
`insufficiency more clinically apparent.
`In the .setting of persistent hypcrcortisolism, it was not possible to assess therapeutic effect
`of mifepristone or the potential for ovcitrcatmcnt by following biomarkers, such as scrum
`cortisol and ACTH. Thus, symptoms of adrenal insufficiency had to be monitored
`symptomatically using clinical signs of cortisol withdrawal such as the reduced need for
`insulin and anti-hypertensive medications. When the patient became despondent, anorexic
`and relatively hypotensive, mifepristone was discontinued. After short-term dexamethasonc
`treatment, her residual mifepristone levels continued to antagonize her circulating cortisol
`until surgical adrenalectomy was performed.
`Definitive Management
`After nearly a month treatment with ketoconazolc, cabcrgolinc and mifepristone, the patient
`undciAvcnt bilateral adrenalectomy {Augu.st 2009). Cortisol levels tapered and the patient
`required permanent glucocorticoid and mincralcorticoid replacement. Post operative MRI
`Brain revealed a residual pituitary adenoma grossly unchanged from prior examination with
`involvement of the clivus, invasion of the left cavernous sinus into Meckel's cave and
`greater wing of the sphenoid. The patient will be closely monitored by serial imaging for
`Nelson Syndrome.
`
`8
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`Endocrine Rev, Suppl 1, June 2010, 31(3):S1201 (Endocrine Society Annual Meeting, 2010, San Diego)
`
`2)
`
`3)
`
`4)
`
`The patient was discharged for rehabilitation from her vertebral fractures and
`glucocorticoid-induced osteoporosis. Radiotherapy is planned as soon as she recovers from
`her adrenalecctomy.
`References
`1) Johanssen S, Allolio B. Eur J Endocrinol. Mifepristone (RU 486) in Cushing's
`syndrome. 2007 Nov; 157(5):561-9.
`Stewart PM, Walker BR, Holder G, O’Halloran D, Shackleton CHE 1995. 11-
`Hydroxysteroid dehydrogenase activity in Cushing’s syndrome: explaining
`the mineralocorticoid excess state of the ectopic adrenocorticotropin
`syndrome.
`J Clin Endocrinol Metab 80:3617-3620.
`Sugihara N, Shimizu M, Kita Y, et al. 1992 Cardiac characteristics and
`postoperative courses in Cushing’s syndrome. Am J Cardiol. 69:1475-1480
`Raux-Demay MC, Pierret T, Bouvier D’yvoire M, Bertagna X, Girard F. Transient
`inhibition of RU 486 antiglucocorticoid action by dexamethasone. J Clin
`Endocrinol Metab 1990 70 230-233.
`Bertagna X, Bertagna C, Laudat MH, Husson JM, Girard F, Luton JP. Pituitary-
`adrenal response to the antiglucocorticoid action of RU 486 in Cushing’s syndrome.
`J Clin Endocrinol Metab, 63:639-643.
`Castinetti F, Fassnacht M, Johanssen S, Terzolo M, Bouchard P, Chanson P, Do Cao
`C, Morange I, Pic6 A, Ouzounian S, Young J, Hahner S, Brue T, Allolio B, Conte-
`Devolx B. Merits and pitfalls of mifepristone in Cushing's syndrome.
`Em J
`Endocrinol. 2009 Jun; 160(6): 1003-10.
`Chu JW, Matthias DF, Belanoff J, Schatzberg A, Hoffman AR, Feldman D.
`Successful long-term treatment of refractory Cushing's disease with high- dose
`mifepristone. J Clin Endocrinol Metab. 2001 Aug;86(8):3568-73.
`Dang CN, Trainer P. Pharmacological management of Cushing's syndrome: an
`update. Arq Bras Endocrinol Metabol. 2007 Nov;51(8): 1339-48.
`Orth DN, Kovacs WJ 1998 Diseases of the adrenal cortex. Tn: Wilson JD, Foster
`DW, Kronenberg HM, Larsen PR, eds. Williams textbook of endocrinology. 9* ed.
`St. Louis: Saunders; 1848.
`
`9)
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`5)
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`6)
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`7)
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`8)
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