Molecular and Cellular Endocrinology 408 (2015) 185–189
`
`Contents lists available at ScienceDirect
`
`Molecular and Cellular Endocrinology
`
`journal homepage: www.elsevier.com/locate/mce
`
`Review
`Current approaches to the pharmacological management of Cushing’s
`disease
`Mark E. Molitch *
`Martha Leland Sherwin Professor of Endocrinology, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg
`School of Medicine, Chicago, IL, USA
`
`A R T I C L E
`
`I N F O
`
`A B S T R A C T
`
`Article history:
`Received 22 July 2014
`Received in revised form 18 September
`2014
`Accepted 19 September 2014
`Available online 29 October 2014
`
`Keywords:
`Cushing’s
`Pituitary adenoma
`Adrenal
`Mifepristone
`Cabergoline
`Pasireotide
`
`Contents
`
`If treatment of Cushing’s disease (CD) by surgery is not successful, medical therapy is often required.
`Long-term use of metyrapone is limited by hirsutism and hypertension and escape because of in-
`creased ACTH levels. Although ketoconazole can normalize cortisol levels in 50%, liver toxicity limits its
`use. Mitotane, an adrenolytic agent, has had minimal use for benign disease. Etomidate is useful when
`rapid reduction in cortisol levels is needed. Cabergoline can normalize cortisol levels in CD in about one-
`third of patients and is well tolerated. Pasireotide can normalize cortisol levels in CD in about 25% but
`causes worsening of glucose tolerance in most patients. Mifepristone, a blocker of cortisol receptors, im-
`proves clinical aspects of CD in most patients but cortisol and ACTH measurements do not reflect clinical
`activity and adrenal insufficiency, hypokalemia, and endometrial hyperplasia can occur. Combinations
`of drugs can be tried in patients resistant to monotherapy.
`© 2014 Elsevier Ireland Ltd. All rights reserved.
`
`1.
`
`Introduction ........................................................................................................................................................................................................................................................ 185
`1.1.
`Case description ................................................................................................................................................................................................................................... 186
`2. Medical therapy ................................................................................................................................................................................................................................................. 186
`2.1.
`General nature of medical therapy ............................................................................................................................................................................................... 186
`2.2. Mitotane ................................................................................................................................................................................................................................................. 186
`2.3. Metyrapone ........................................................................................................................................................................................................................................... 186
`2.4.
`Ketoconazole ......................................................................................................................................................................................................................................... 187
`2.5.
`Etomidate ............................................................................................................................................................................................................................................... 187
`2.6.
`Thiazolidinediones .............................................................................................................................................................................................................................. 187
`2.7.
`Cabergoline ............................................................................................................................................................................................................................................ 187
`2.8.
`Pasireotide ............................................................................................................................................................................................................................................. 187
`2.9. Mifepristone .......................................................................................................................................................................................................................................... 187
`2.10.
`LCI699 ................................................................................................................................................................................................................................................... 188
`2.11.
`Combination therapy ....................................................................................................................................................................................................................... 188
`Conclusions ......................................................................................................................................................................................................................................................... 188
`Acknowledgements .......................................................................................................................................................................................................................................... 188
`References ............................................................................................................................................................................................................................................................ 188
`
`3.
`
`Abbreviations: CD, Cushing’s disease; CS, Cushing’s syndrome; ACTH, adreno-
`corticotropic hormone; UFC, urinary free cortisol; MRI, magnetic resonance imaging.
`* Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern
`University Feinberg School of Medicine, 645 N. Michigan Ave., Suite 530, Chicago,
`IL 60611. Tel. +312 503 4130; fax +312 926 8693.
`E-mail address: molitch@northwestern.edu.
`
`http://dx.doi.org/10.1016/j.mce.2014.09.021
`0303-7207/© 2014 Elsevier Ireland Ltd. All rights reserved.
`
`1. Introduction
`
`Cushing’s syndrome is associated with a two- to fivefold in-
`crease in mortality (Clayton et al., 2011; Dekkers et al., 2013).
`Curative treatment results in a reduction in that mortality to normal
`but substantial morbidity persists (Clayton et al., 2011; Feelders et al.,
`
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`
`2012). Transsphenoidal surgery is generally considered to be the
`initial preferred treatment for patients with Cushing’s disease with
`cure rates in the 80–90% range in the hands of experienced pitu-
`itary surgeons (Biller et al., 2008; Clayton et al., 2011; Feelders et al.,
`2012; Lambert et al., 2013; Patil et al., 2008). The following case
`illustrates the problem, however, in the patient who is not cured
`by surgery.
`
`1.1. Case description
`
`This 30 year old woman initially presented with a 3 year history
`of increasing facial hair, facial rounding, abdominal obesity, hyper-
`tension, diabetes, and oligomenorrhea. She had no muscle weakness
`or pigmented striae. Initial laboratory testing showed a basal 8 AM
`cortisol level of 30.2 μg/dL with an ACTH level 77 pg/mL (normal
`5–27 pg/mL). An overnight 1 mg dexamethasone suppression test
`showed an 8 AM cortisol level of 17.7 μg/dL. Her 24 h urinary free
`cortisol (UFC) was 305 μg (normal 4.0–50 μg). Her hemoglobin A1c
`was 8.4%. An MRI showed a 7 mm hypodense area consistent with
`a pituitary adenoma. Unfortunately, insurance issues dictated that
`she have transsphenoidal surgery at a hospital with an inexperi-
`enced pituitary surgeon. The pathology report read “Cellular debris
`with tiny fragment of adenoma.” Postoperatively, she felt the same
`with no improvement and still required large doses of insulin. Post-
`operative laboratory testing showed an 8 AM cortisol level of 18 μg/
`dL with an ACTH level of 47 pg/mL (6–50 pg/mL) and a 24 h UFC
`of 398 μg (4.0–50 μg).
`Thus, this patient has had unsuccessful pituitary surgery. Options
`now include repeat surgery by an experienced pituitary surgeon
`(Ram et al., 1994), irradiation (usually stereotactic) (Starke et al.,
`2010), or medical therapy (Bertagna and Guignat, 2013; Feelders
`and Hofland, 2013). If irradiation is chosen as the primary treat-
`ment, it takes years for this to be effective (Starke et al., 2010) and
`medical therapy would be required to bring the hypercortisolemic
`state under control so as to improve her morbidity and mortality.
`The various types of medical therapy for hypercortisolism will be
`briefly reviewed here.
`
`2. Medical therapy
`
`2.1. General nature of medical therapy
`
`The medical therapy for hypercortisolism dates back to 1975,
`when Krieger and colleagues first reported the successful use of cy-
`proheptadine, an anti-serotonin agent, for the treatment of Cushing’s
`disease, based on the concept of
`increased hypothalamic
`serontoninergic activity as being contributory to the development
`of the condition (Krieger et al., 1975). Although subsequent studies
`showed much lower response rates and further trials were not done,
`the potential for successful medical treatment had now been dem-
`onstrated and this stimulated the development of many other
`medications over the years. Drug therapy has been directed at the
`pituitary to decrease ACTH secretion by corticotroph tumors, at the
`adrenal to block multiple steps involved in cortisol synthesis, and
`at the cortisol receptor to block cortisol action (Fig. 1). These ad-
`ditional agents will be discussed in approximate order of their
`historical use, focusing on the results of relatively large series and
`not discussing the results from individual case reports and small
`series.
`
`2.2. Mitotane
`
`Mitotane (o,p′-DDD) is an adrenolytic agent that also inhibits 11β
`hydroxylase and cholesterol side chain cleavage and has been used
`as the mainstay for the treatment of adrenal cancer. However, it has
`been used at lower doses, in the range of 2–4 g/day, for the treat-
`
`Fig. 1. This schematic outlines the sites of action for the various medications used
`for the treatment of Cushing’s syndrome. Abbreviations used: CRH – corticotropin
`releasing hormone; ACTH – adrenocorticotropic hormone; GR – glucocorticoid
`receptor.
`
`ment of Cushing’s disease. In 1979, Luton et al. reported the results
`of treatment with mitotane alone in 46 patients (16 patients pre-
`viously irradiated) with Cushing’s disease, finding that 38 achieved
`remission of disease with a course of treatment. However, 60% re-
`lapsed and needed additional courses of drug or irradiation and 63%
`ultimately did not need adrenalectomy with 40/62 off medication
`(Luton et al., 1979). A new series reported from the same institu-
`tion included 49 patients treated de novo and 27 after surgery
`(Baudry et al., 2012). Of the 67 treated chronically 48 (72%) ob-
`tained a normal UFC after a median of 6.7 months, 10 (15%)
`withdrew due to lack of efficacy after a median of 7.9 months and
`19 (28%) withdrew due to intolerance (10 with normal UFC). Thus,
`38/67 (57%) had long term normal UFC; 17/24 with normal UFC who
`stopped treatment later had a recurrence. Overall, 7/76 (11%) of pa-
`tients attained permanent remission off treatment. Dose-related
`adverse gastrointestinal and neurologic symptoms are common and
`limit its use; abnormal liver function tests and gynecomastia are
`also common adverse effects. A pituitary adenoma appeared during
`follow-up in 12/48 with no visible tumor on initial MRI scans (Baudry
`et al., 2012). Furthermore, as a potent inducer of CYP3A4, drug in-
`teractions also may limit its use (van Erp et al., 2011).
`
`2.3. Metyrapone
`
`Metyrapone blocks the 11-hydroxylase enzyme that converts 11-
`deoxycortisol to cortisol. It had been used for years diagnostically
`for the evaluation of hypoadrenalism and in small series of pa-
`tients with Cushing’s syndrome. A large series reported in 1991
`showed that with short-term treatment of 2–3 months, cortisol nor-
`malized in 40/53 (75%) patients (Verhelst et al., 1991). However, with
`long-term treatment three patients were controlled for 9, 60, and
`173 months and then went into remission. However, treatment
`became ineffective in three other patients after 7–17 months. They
`noted that the decrease in negative feedback of cortisol resulted in
`increased ACTH levels which then overcame the block causing in-
`creased cortisol levels again. In addition, the increased ACTH
`stimulated other pathways resulting in increased androgen pro-
`duction with hirsutism in women and hypertension from the
`increased 11-deoxycortisol levels. In a more recent series, 23 pa-
`tients were treated for 4 months preoperatively, with cortisol levels
`being normalized in 6 (26%) and controlled in 7 (30%) (Valassi et al.,
`2012). One problem has recently been found in that the high levels
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`187
`
`of 11-deoxycortisol that occur with metyrapone treatment cross-
`react in the standard immunoassay for cortisol, so that treatment
`must be monitored using a method not affected by such interfer-
`ence, such as liquid chromatography with tandem mass spectrometry
`(Monaghan et al., 2011).
`
`2.4. Ketoconazole
`
`Ketoconazole is an imidazole derivative that has been the main-
`stay of medical treatment for Cushing’s syndrome for many years.
`It blocks several steps in cortisol synthesis, including side chain cleav-
`age, 17-hydroxylase, 17,20 lyase, 11β-hydroxylase, and aldosterone
`synthase (Feelders and Hofland, 2013). Early studies suggested a nor-
`malization rate of UFC of over 90% (Sonino et al., 1991; Tabarin et al.,
`1991). A recent series reported data on 200 patients (78% females,
`106 microadenomas, 36 macroadenomas, 58 with no tumor visible)
`treated with ketoconazole in doses ranging from 200 to 1200 mg/
`day, most receiving 600 and 800 mg/day (Castinetti et al., 2014). Of
`39 patients treated prior to surgery for 4 months, 19 pts (48.7%)
`achieved a normal UFC. In 158 patients treated postoperatively or
`primarily (surgery contraindicated), 78 (49.3%) achieved normal UFC,
`37 (23.4%) had a >50% decrease in UFC and 43 (27.2%) had an un-
`changed UFC. The drug was stopped in 26.8% due to lack of efficacy
`and in 25.6% due to adverse effects. In this series, liver enzyme el-
`evations were found as follows: <5× increase in 30 (15.8%), a 5–10×
`increase in 4 and a 40× increase in 1. These increases occurred within
`4 weeks of starting or with dose increments and all increases re-
`turned to normal with drug withdrawal. Other side effects of
`ketoconazole include rash, gastrointestinal symptoms and hypo-
`gonadism in men. Ketoconazole is a strong CYP3A4 inhibitor
`(substrates include amiodarone, carbamazepine, amitriptyline, SSRIs,
`benzodiazepines, calcium channel blockers, statins, colchicine) and
`therefore may affect dosing of these and other drugs.
`In 2013, the U.S. Food and Drug Administration (FDA) specified
`a “black box warning” regarding liver toxicity with ketoconazole use;
`ketoconazole had never had U.S. FDA approval for use in Cushing’s
`syndrome (U.S. FDA, 2013). The European Medicines Agency rec-
`ommended against prescribing ketoconazole in 2013 as well
`(European Medicines Agency, 2013). Ketoconazole is no longer avail-
`able for use in many countries at present.
`
`sient responses in a small number of patients and such use has been
`abandoned.
`
`2.7. Cabergoline
`
`Dopamine D2 receptors have been found in 80% of corticotroph
`tumors (Pivonello et al., 2004). In studies of these tumors with D2
`receptors, 100% had significant inhibition of ACTH secretion in vitro
`with cabergoline and 60% of the patients harboring these tumors
`had significant reduction of cortisol levels and 40% had normaliza-
`tion of cortisol levels with 1–3 mg cabergoline per week in vivo.
`Therefore, 80% × 40% = 32% of all patients (since measurement of D2
`receptors not routine) can expect control of hypercortisolism with
`cabergoline (Pivonello et al., 2004). In five series totaling 83 pa-
`tients, 31 (37%) achieved normal cortisol levels (Godbout et al., 2010;
`Illouz et al., 2006; Lila et al., 2010; Pivonello et al., 2009; Vilar et al.,
`2010).
`
`2.8. Pasireotide
`
`Corticotroph adenomas express substantial amounts of soma-
`tostatin receptor subtype 5 in addition to subtypes 1, 2, and 3
`(Hofland and Lamberts, 2003). Unlike octreotide and lanreotide,
`pasireotide has substantial action at subtype 5 (Hofland and
`Lamberts, 2003). In a recent prospective, randomized study of 162
`patients with Cushing’s disease, pasireotide given in daily subcu-
`taneous injections was able to normalize UFC at 12 months in 19.1%
`of patients, although many more had falls in UFC that did not reach
`normal (Colao et al., 2012). Patients had substantial improve-
`ments in body weight, blood pressure, and quality of life. However,
`a worsening of glucose tolerance occurred in 73%. Of 67 patients
`normoglycemic at baseline, 14 (21%) remained normal, 29 (43%)
`became pre-diabetic and 23 (34%) became diabetic during treat-
`ment. In a study in healthy volunteers, it was found that pasireotide
`reduced incretin (glucagon-like peptide 1 [GLP-1] and glucose
`insulinotropic peptide [GIP]) and insulin secretion, without affect-
`ing insulin sensitivity (Henry et al., 2013). In another study, treatment
`with the incretin-based antihyperglycemic agents liraglutide and
`vildagliptin significantly reduced pasireotide-induced hyperglyce-
`mia (Breitschaft et al., 2014). Therefore, these would be reasonable
`medications to initiate in patients being treated with pasireotide.
`
`2.5. Etomidate
`
`2.9. Mifepristone
`
`Etomidate is another imidazole that inhibits 11β-hydroxylase,
`aldosterone synthase, and side chain cleavage. It was originally used
`as an anesthetic agent but was found to cause adrenal insufficien-
`cy. Subsequently, it has been used for the treatment of severe
`hypercortisolemia in the critically ill patient, usually preopera-
`tively to improve surgical risk (infection, wound dehiscence,
`hypercoagulability, hypertension, hyperglycemia). It must be given
`IV – in the intensive care unit (ICU) in subhypnotic doses of 0.04–
`0.05 mg/kg/h. It has a rapid onset of action, cortisol levels falling
`in 12–24 h. There is a need to monitor serum cortisol and potas-
`sium levels closely. It is often used in a “block and replace” strategy
`with higher doses and concomitant IV hydrocortisone (0.5–1 mg/
`h). Thus, it has a very limited but specific use (Preda et al., 2012).
`
`2.6. Thiazolidinediones
`
`Great excitement followed the discovery of peroxisome
`proliferator-activated receptors-γ (PPAR-γ) in human normal and tu-
`morous corticotroph cells and that PPAR-γ ligands inhibited
`corticotroph tumor cell proliferation and ACTH secretion. Unfortu-
`nately, multiple clinical trials of these agents, rosiglitazone and
`pioglitazone, in patients with Cushing’s disease showed only tran-
`
`Mifepristone was initially developed as a progesterone recep-
`tor antagonist and has been used widely as an abortifacient (RU486).
`Mifepristone is also a glucocorticoid receptor antagonist with greater
`affinity for the receptor than either cortisol or dexamethasone.
`Between 1985 and 2010, 66 Cushing’s syndrome patients treated
`with mifepristone had been reported (Castinetti et al., 2010) prior
`to the large, multicenter SEISMIC trial, in which mifepristone was
`used in 43 patients with Cushing’s disease, 4 with ectopic ACTH syn-
`drome and 3 with adrenal cancer (Fleseriu et al., 2012). Because of
`its mechanism of action, during treatment cortisol and ACTH levels
`rise rather than fall, and treatment dosing is based on improve-
`ment in clinical outcomes (glucose tolerance, blood pressure, weight,
`waist circumference, quality of life) as well as adverse effects. Fifteen
`of 25 (60%) had a >25% fall in glucose area under the curve during
`oral glucose tolerance tests (Fleseriu et al., 2012). However, similar
`to pasireotide, there were also substantial improvements in weight
`and quality of life. Blood pressure improvement was variable because
`in many patients the high cortisol levels overwhelmed the type 2
`11-beta-hydroxysteroid dehydrogenase activity (which normally con-
`verts cortisol to cortisone) at the mineralocorticoid receptor, thereby
`activating the mineralocorticoid receptor with worsening salt re-
`tention, increase blood pressure, edema, and hypokalemia.
`
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`
`Table 1
`Drugs used to treat Cushing’s syndromea.
`
`Drug
`
`Metyrapone
`Mitotane
`Ketoconazole
`Etomidate
`Cabergoline
`Mifepristone
`Pasireotide
`LCI699
`
`Cushing’s
`disease only?
`
`Percent of patients
`achieving normal
`urinary free cortisol
`
`Adverse effects
`
`N
`N
`N
`N
`Y
`N
`Y
`N
`
`26%
`57%
`49%
`100%
`37%
`NAb
`26%
`80%
`
`Nausea, hirsutism, ↑BP
`GI, neurologic
`↑Liver function tests, liver failure
`IV only, ICU needed, sedation
`Nausea
`Adrenal insufficiency, hypokalemia, menorrhagia
`Hyperglycemia, other somatostatin receptor ligand adverse effects
`Hypokalemia
`
`a Note – only mifepristone and pasireotide are approved by the U.S. Food and Drug Administration for the treatment of Cushing’s syndrome.
`b Because of glucocorticoid receptor blockade, UFC increases rather than decreases with effective therapy and therefore UFC cannot be used to judge efficacy.
`
`Subsequent experience has shown that early addition of a miner-
`alocorticoid blocker, such as spironolactone or eplerenone (preferred
`in men as it does not cause blockade of the androgen receptor), is
`beneficial in this regard (Fleseriu et al., 2013). Another adverse effect
`was endometrial hyperplasia which is a specific progesterone re-
`ceptor modulator-associated endometrial change (PAEC) consisting
`of a thickened endometrium that is not thought to be a premalig-
`nant state (Fleseriu et al., 2012, 2013). However, this can be
`associated with severe menorrhagia. Monitoring of treatment can
`be difficult because of the lack of biochemical parameters to follow
`and overdosing causing adrenal insufficiency can occur. If severe
`adrenal insufficiency occurs, large doses of dexamethasone (10 mg)
`may be necessary because of the receptor blockade (Fleseriu et al.,
`2013).
`
`2.10. LCI699
`
`LCI699 is an 11β-hydroxylase and aldosterone synthase inhib-
`itor that is now completing phase 2 studies. In a 22 week study,
`LCI699 normalized UFC in 15 of 19 patients (78%) (Bertagna et al.,
`2014). Phase 3 trials are just now beginning. Because of the build-
`up of the 11-deoxycortisol levels with this drug, cortisol levels also
`have to be measured with liquid chromatography–tandem mass
`spectrometry (Trainer, 2014).
`
`2.11. Combination therapy
`
`Because many of these agents act by different mechanisms, it
`could be expected that using them in combination might be more
`effective that using them singly. However, because of the relative
`rarity of these patients, such combination therapy studies have only
`been done in small numbers of patients and in an uncontrolled
`manner. Two-drug treatment regimens were reported in two studies.
`Valassi et al. (2012) used metyrapone alone in 23 patients,
`ketoconazole alone in 17 patients and a combination of ketoconazole
`and metyrapone in 22 patients but how patients were chosen for
`each type of treatment was not clear. Control of Cushing’s syn-
`drome was achieved in 30%, 45% and 25% of those treated with
`metyrapone alone, ketoconazole alone and with the combination,
`respectively (Valassi et al., 2012). In a study of the combination of
`cabergoline with ketoconazole, Vilar et al. (2010) reported that 3
`of 12 patients with persistent Cushing’s disease following surgery
`were controlled with cabergoline alone and that an additional 6 pa-
`tients were controlled when ketoconazole was added to cabergoline.
`Three drug regimens were reported in two studies. Feelders et al.
`(2010) reported substantial benefit by the sequential addition of
`cabergoline to pasireotide and then ketoconazole if normalization
`of UFC was not achieved with the first two drugs. Normalization
`of UFC was achieved with pasireotide alone in 5/17 (29%), and the
`addition of cabergoline caused a normalization in an additional 4
`patients. With the further addition of ketoconazole normal UFC levels
`
`were obtained in six of the eight remaining patients (Feelders et al.,
`2010). In another study, 7 of 11 patients with severe, Cushing’s
`disease treated with therapy combining mitotane (3.0–5.0 g/
`24 h), metyrapone (3.0–4.5 g/24 h), and ketoconazole (400–1200 mg/
`24 h) concomitantly achieved normalization of UFC; substantial falls
`in UFC in the other 4 were found as well (Kamenicky et al., 2011).
`
`3. Conclusions
`
`Ketoconazole and cabergoline have had varying degrees of success
`in patients with Cushing’s disease, although the recent “black box”
`warning regarding ketoconazole hepatotoxicity makes that drug less
`desirable and less available (Table 1). Other earlier therapies, such
`as metyrapone and mitotane, are less successful but mitotane still
`seems to be popular in France. Mifepristone offers high success clin-
`ically and metabolically but can be difficult to use because of
`difficulty in titrating dose and adverse effects of adrenal insuffi-
`ciency and menorrhagia. Pasireotide will be helpful in a small
`percentage of patients with Cushing’s disease but has a major adverse
`effect of hyperglycemia. LCI 699 may end up being a better me-
`tyrapone but studies are still very preliminary. Combination therapy
`may have a role in difficult to manage cases.
`Some particular situations may influence the choice of treat-
`ment. For example, the pregnant patient cannot be treated with
`mifepristone or mitotane and safety aspects of pasireotide in this
`condition have not been established; therefore, only cabergoline,
`metyrapone and ketoconazole would be indicated but none of these
`have extensive experience recorded in pregnancy. The uncommon
`patient with a large pituitary adenoma might best be treated with
`agents with direct pituitary effects, such as cabergoline and
`pasireotide. The rare patients with very severe hypercortisolism who
`are too ill for surgery can have an initial short-term treatment with
`etomidate or longer term treatment with the combination of
`mitotane, metyrapone or ketoconazole described earlier.
`Now, 39 years following Dorothy Krieger’s first report of the
`medical therapy of Cushing’s disease, we have many choices for the
`medical therapy of patients with Cushing’s syndrome. It is now pos-
`sible to tailor treatment to the individual patient.
`
`Acknowledgements
`
`There is no funding for this paper. I acknowledge funding from
`Corcept for carrying out the SEISMIC study, for which I was an
`investigator.
`
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