Review
doi: 10.1111/joim.12975
Current management of Cushing’s disease
N. A. Tritos & B. M. K. Biller
From the Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
Abstract. Tritos NA, Biller BMK (Neuroendocrine
Unit, Massachusetts General Hospital and
Harvard Medical School, Boston, MA, USA).
Current management of Cushing’s disease. J
Intern Med 2019; 286: 526–541.
Cushing’s disease (CD) is caused by a pituitary
tumour that secretes adrenocorticotropin (ACTH)
autonomously, leading to excess cortisol secretion
from the adrenal glands. The condition is associ-
ated with increased morbidity and mortality that
can be mitigated by treatments that result in
sustained endocrine remission. Transsphenoidal
pituitary surgery (TSS) remains the mainstay of
treatment for CD but requires considerable neuro-
surgical expertise and experience in order to opti-
mize patient outcomes. Up to 90% of patients with
microadenomas (tumour below 1 cm in largest
diameter) and 65% of patients with macroadeno-
mas (tumour at or above 1 cm in greatest diameter)
achieve endocrine remission after TSS by an
Introduction
Cushing’s disease (CD) is caused by a pituitary
tumour, generally benign (adenoma) but rarely
malignant (carcinoma), which secretes adrenocor-
ticotropin (ACTH) autonomously, leading to
hypercortisolism (Figure 1) [1–3]. It accounts for
approximately 70% of patients with endogenous
Cushing’s syndrome (CS); the ectopic ACTH syn-
drome and adrenal tumours or hyperplasia
account for 10% and 20% of patients with CS,
respectively [3]. Of note, CD is estimated to occur
in 1.2-1.8 persons per million population per
year and is associated with increased morbidity
and mortality, primarily as a consequence of
increased risk of cardiovascular disease and
secondarily infection [4–6]. The diagnosis and
differential diagnosis of CD are complex and have
been the subject of Endocrine Society guidelines
[3] and a recent review article [7]. Patients who
achieve endocrine remission generally have a
more favourable prognosis, underscoring the
526 ª 2019 The Association for the Publication of the Journal of Internal Medicine
experienced surgeon. Patients who are not in
remission postoperatively or those who relapse
may benefit from undergoing a second pituitary
operation. Alternatively, radiation therapy to the
sella with interim medical therapy, or bilateral
adrenalectomy, can be effective as definitive treat-
ments of CD. Medical therapy is currently adjunc-
tive in most patients with CD and is generally
prescribed to patients who are about to receive
radiation therapy and will be awaiting its salutary
effects to occur. Available treatment options
include steroidogenesis inhibitors, centrally acting
agents and glucocorticoid receptor antagonists.
Several novel agents are in clinical trials and may
eventually constitute additional treatment options
for this serious condition.
Keywords: Cushing’s disease, medical therapy, pitu-
itary adenoma, radiotherapy, transsphenoidal
pituitary surgery.
importance of prompt diagnosis and timely man-
agement of CD [3, 8, 9].
The goals of treatment in patients with CD are to
abolish cortisol excess and restore normal cortisol
secretion, maintain normal pituitary function and
achieve tumour control. At present, transsphe-
noidal pituitary surgery (TSS), performed by an
experienced pituitary neurosurgeon, is the treat-
ment of choice for the vast majority of patients with
CD and comes closest to fulfilling the above-men-
tioned goals [8–12]. Radiation therapy (RT) to the
sella with interim medical therapy and bilateral
adrenalectomy constitute additional treatment
options and are generally second- and third-line
therapies as outlined in Figure 2 [8, 11].
The aims of the present manuscript include dis-
cussing the role, outcomes, risks and benefits of
diverse treatment options currently available for
patients with CD and highlighting emerging ther-
apies. To identify pertinent articles from the
 Treatment of Cushing’s disease / N. A. Tritos & B. M. K. Biller

Fig. 1 Coronal T1-weighted, gadolinium-enhanced, magnetic resonance imaging (MRI) of a 35-year-old woman, obtained
before (left panel) and 12 months after (right panel) transsphenoidal pituitary surgery (TSS). This patient had presented
with weight gain in a central distribution, oligomenorrhoea, acne and proximal myopathy of recent onset. Laboratory tests
showed elevated 24-h urine free cortisol and late-night salivary cortisol on several occasions (3–4 times above the upper
limit of normal). A pituitary MRI examination showed a 5 mm by 4 mm right-sided sellar hypodensity, consistent with
microadenoma (left panel). Additional tests were consistent with Cushing’s disease. She underwent TSS, leading to
resection of a pituitary adenoma (positive for ACTH on immunohistochemistry), which was followed by clinical and
endocrine remission. A follow-up MRI examination (right panel) showed no evidence of a sellar mass.

primary literature, electronic searches were con-
ducted using the keywords ‘Cushing’s syndrome’,
‘Cushing’s disease’, ‘treatment’, ‘transsphenoidal
pituitary surgery’, ‘radiation therapy’, ‘medical
therapy’, ‘bilateral adrenalectomy’. Articles were
included in the present bibliography at the
authors’ discretion.
(such as fluoroscopy and MRI), operating micro-
scopes, endoscopes and intraoperative neuronavi-
gation were not available. It is the advent of these
technological advances that have made the
transsphenoidal route increasingly safer for pitu-
itary surgery, thus leading to its widespread adop-
tion amongst neurosurgeons [13, 14].

The large majority (90%) of pituitary adenomas

Pituitary surgery
Transsphenoidal pituitary surgery is currently
first-line treatment for almost all patients with
CD, the exception being the occasional patients
with contraindications to surgery, such as the
requirement for uninterrupted anticoagulation
therapy, or those rare patients who decline sur-
gery. Patients whose condition is not immediately
stable enough for TSS, such as those with active
sinusitis or psychosis, can temporize with medical
therapy until they are well enough to undergo
surgery (as will be subsequently discussed).
Although Harvey Cushing had initially used the
transsphenoidal route for pituitary surgery, he
later abandoned it in favour of craniotomy, recog-
nizing the technical difficulties associated with the
former approach [1, 2]. At that time, however, high-
resolution cross-sectional pituitary imaging [in-
cluding magnetic resonance imaging (MRI)], mod-
ern surgical instruments, intraoperative imaging
causing CD are microadenomas, measuring less
than 10 mm in largest diameter, and are detectable
on MRI only in ~60% of patients [3, 7]. Here lies one
of the challenges for the pituitary neurosurgeon,
who may often have to meticulously examine the
pituitary gland for evidence of an adenoma by
obtaining intraoperative biopsies from suspicious
areas for cytological and frozen section pathologi-
cal analysis [15], if the tumour has not been
visualized preoperatively. It is therefore not sur-
prising that the outcome of TSS is significantly
influenced by the experience and expertise of the
pituitary neurosurgeon [16]. In expert hands,
postoperative remission of hypercortisolism, usu-
ally defined as very low morning serum cortisol
levels in the early postoperative period [17, 18] [and
in some centres, supported by very low 24-hour
urine free cortisol (UFC) and late-night salivary
cortisol (LNSC) during that time [19, 20]], is
achieved in up to ~90% of patients with microade-
nomas and ~65% of patients with macroadenomas

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Journal of Internal Medicine, 2019, 286; 526–541
 Treatment of Cushing’s disease / N. A. Tritos & B. M. K. Biller
Fig. 2 Management of patients with Cushing’s disease.
(Table 1) [9, 18, 21–64]. Other predictors of post-
operative remission include preoperative or intra-
operative tumour visualization and pathological
confirmation of the diagnosis [65–67]. Use of the
endoscope (versus operating microscope) is not
associated with higher remission rates in patients
with CD who have microadenomas but may be
associated with higher likelihood of remission in
those with macroadenomas [68].
Experienced pituitary neurosurgeons perform TSS
with very low mortality (approaching zero in some
case series) and low morbidity [9, 14, 16]. However,
complications may still occur, including epistaxis
(0.4-6.0%), tumour bed haemorrhage (1-6%), cere-
brospinal fluid leak (up to 8%), meningitis (up to
3%) and venous thromboembolism (up to 4%) [16].
Endocrine complications include transient or per-
sistent central diabetes insipidus (3-9%), hypona-
traemia (10-25%, often caused by the syndrome of
the inappropriate antidiuretic hormone secretion)
and anterior hypopituitarism (2-40%) [16].
Patients who are in endocrine remission after TSS
require glucocorticoid replacement until their pitu-
itary–adrenal axis recovers, which generally takes
many months. Some patients initially require
528 ª 2019 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2019, 286; 526–541
supraphysiologic doses of glucocorticoids in order
to alleviate glucocorticoid withdrawal symptoms.
Once shown to have recovered normal function of
the hypothalamic–pituitary–adrenal axis and no
longer need glucocorticoid replacement, patients
with CD require lifelong periodic surveillance to
detect recurrence of hypercortisolism. Recurrent
CD occurs at a rate of approximately 2% of patients
per year and peaks in the first 5 years after tumour
resection, but may also develop a decade or longer
after endocrine remission was achieved, the cumu-
lative risk approaching 30% on long-term follow-up
[69]. Patients with macroadenomas and those
requiring glucocorticoid replacement for shorter
intervals (less than 12 months) after TSS are at
higher risk for recurrence [21, 66, 70]. Patients
with ‘normal’ rather than low morning serum
cortisol levels in the early postoperative period are
also at higher risk of recurrence [29].
Patients with persistent or recurrent CD after
initial TSS may undergo a second surgical proce-
dure by an experienced pituitary neurosurgeon
(Figure 2). Of note, endocrine remission is achieved
in 55–70% of patients with CD after repeat TSS and
the risk of surgical complications appears to be
higher [71, 72]. Other treatment options for
 Treatment of Cushing’s disease / N. A. Tritos & B. M. K. Biller

Table 1. Outcomes of pituitary surgery in patients with Cushing’s disease

Number of Follow-up (mean,

Study (first author, year) patients median or range, months) Remission rate (%) Recurrence rate (%)
Pikkarainen et al. (1999) [22] 43 89 83.7 41.7
Swearingen et al. (1999) [9] 154 104 87 7.5
Kurosaki et al. (2000) [23] 51 6-36 94.1 4.2
Vallette-Kasic et al. (2000) [24] 53 139 81.1 11.6
Barbetta et al. (2001) [25] 68 58 89.7 21.3
Chee et al. (2001) [26] 61 88 78.7 14.6
Imaki et al. (2001) [27] 49 88 95.9 14.9
Shimon et al. (2002) [28] 74 50 78.4 5.2
Yap et al. (2002) [29] 97 92 62.9 11.5
Chen et al. (2003) [30] 174 NA 81.6 15.5
Flitsch et al. (2003) [31] 147 61 93.2 5.8
Hammer et al. (2004) [32] 227 133 83.2 NA
Mortini et al. (2005) [33] 262 NA 77.5 5.9
Esposito et al. (2006) [18] 40 34 77.5 3.2
Frank et al. (2006) [34] 56 54 67.8 NA
Shah et al. (2006) [35] 65 NA 61.5 12.5
Acebes et al. (2007) [36] 44 49 88.6 7.7
Rollin et al. (2007) [37] 103 72 85.4 4.5
Hofmann et al. (2008) [38] 426 72 65.7 15
Jehle et al. (2008) [39] 193 62 80.8 13.5
Patil et al. (2008) [40] 215 46 85.6 17.4
Jagannathan et al. (2009) [41] 483 84 93.8 1.3
Alwani et al. (2010) [42] 79 84 64.6 19.6
Ammini et al. (2011) [43] 81 18-132 66.7 18.5
Ciric et al. (2012) [44] 121 0-396 83.5 8.9
Honegger et al. (2012) [45] 83 38 84.3 7.1
Alexandraki et al. (2013) [46] 124 185 67.7 23.8
Barbot et al. (2013) [47] 57 77 68.4 38.4
Berker et al. (2013) [48] 69 32 95.6 6
Burkhardt et al. (2013) [49] 42 NA 95.2 NA
Starke et al. (2013) [50] 61 28 95.1 8.6
Wagenmakers et al. (2013) [51] 86 71 72.1 16.1
Huan et al. (2014) [52] 84 46 70.2 28.8
Potts et al. (2014) [53] 91 12 58.2 NA
Kuo et al. (2015) [54] 40 41 80 9.4
Chandler et al. (2016) [56] 275 80 79.6 16.9
Sarkar et al. (2016) [58] 64 20 73.4 8.5
Shirvani et al. (2016) [59] 96 44 94.8 23.1
Witek et al. (2016) [60] 40 29 80 NA
Cebula et al. (2017) [61] 230 22 79.1 9.9
Donofrio et al. (2017) [57] 142 NA 80.3 NA

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Table 1 (Continued )
Study (first author, year)
Masopust et al. (2017) [62]
Shin et al. (2017) [55]
Feng et al. (2018) [63]
Saini et al. (2019) [64]
NA, not available.
Studies include case series of ≥ 40 patients, published between 1999 and 2019, and are listed chronologically.
patients with persistent or recurrent CD will be
subsequently discussed and include radiation
therapy to the sella, generally administered in
conjunction with medical therapy and bilateral
adrenalectomy.
Radiation therapy
Radiation therapy to the sella is often considered to
be second-line treatment in patients who have
either failed TSS (i.e. those with persistent or
recurrent hypercortisolism postoperatively) or,
rarely, those who are not candidates for pituitary
surgery [73].
Radiation therapy can be delivered as conventional
fractionated photon-based RT, typically adminis-
tered 5 days a week over 5–6 weeks, to a total dose
of 45–54 Gy [73]. However, RT is increasingly being
administered as one of several stereotactic treat-
ment modalities, including photon-based (includ-
ing Gamma knifeTM or linear accelerator-based,
such as ‘CyberknifeTM’) or proton beam RT options.
Using computer-assisted techniques and precise,
positioning frames or helmets, stereotactic RT is
accurately focused on the treatment target, whilst
minimizing radiation exposure of normal tissues
[74]. It can be delivered in a single fraction
(‘radiosurgery’) to patients with smaller tumours
that are distant from the optic apparatus at a
(margin) dose ranging between 12 and 35 Gy [73].
Based on historical comparisons, it appears that
radiosurgery may lead to endocrine remission
sooner than conventional fractionated radiation
therapy [75]. However, regardless of the treatment
modality, RT leads to tumour control in 83–100%
of patients (Table 2) [76–90]. In contrast, endocrine
remission occurs in 28–84% of treated patients
after a variable time interval, which may extend to
many years. These patients require medical ther-
apy to control hypercortisolism until the salutary
effects of RT occur. It is advisable to initiate
530 ª 2019 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2019, 286; 526–541
Number of Follow-up (mean,
patients median or range, months) Remission rate (%) Recurrence rate (%)
41 6-34 87.8 NA
50 37 80 22.5
341 12-36 78.9 2.4
60 40 72 18
medical therapy before RT to ensure that hyper-
cortisolism can be medically controlled before RT is
administered [8].
Adverse effects of RT include anterior hypopitu-
itarism (affecting 20-60% of patients at 5 years and
~85% of patients at 15 years after RT), optic
neuropathy (1–2%) and other cranial neuropathies
(1%) [75, 90, 91]. Rare complications include the
development of secondary tumours (including
meningiomas or sarcomas), stroke and temporal
lobe necrosis, all of which have been observed in
patients who underwent conventional fractionated
RT [92]. Whilst it is anticipated that stereotactic RT
may be safer with regard to the risk of these rare
complications, this remains to be demonstrated.
Medical therapy
The role of medical therapy is generally adjunctive
in the management of CD. Medical therapy is
currently not considered as definitive treatment
[8]. Most commonly, medications are used to
control hypercortisolism in patients who have
failed TSS and have opted for RT as definitive
treatment. In these patients, it is advisable to begin
medical therapy before RT is administered in order
to assure the effectiveness of medical strategy in
controlling hypercortisolism whilst awaiting the
salutary effects of RT [8]. In some cases, medical
therapy is administered to patients who have
severe manifestations of CD and/or severe hyper-
cortisolism in anticipation of definitive therapy (e.g.
patients with sepsis, sinusitis or psychosis, who
will be undergoing TSS as soon as they are med-
ically stable). In a minority of cases, medical
therapy is used in patients whose tumour location
is uncertain or those who decline surgery, as may
rarely be the case.
There are currently three groups of medications
used in patients with CD (Table 3), which are
 Treatment of Cushing’s disease / N. A. Tritos & B. M. K. Biller

Table 2. Outcomes of radiation therapy in patients with Cushing’s disease

Follow-up
(mean or Endocrine Endocrine Tumour
Number of median, Treatment (Margin) remission recurrence control
Study (first author, year) patients months) modality dose (Gy) rate (%) rate (%) (%)
Sheehan et al. (2000) [77] 43 39.1 Gamma knife 20 63 6.9 100
Jane et al. (2003) [78] 45 NA Gamma knife 15 73 4 NA
Devin et al. (2004) [79] 35 7.5 Linear 14.7 49 11 91
accelerator
Minniti et al. (2007) [76] 40 108 Fractionated 45 84 0 93
conventional
RT
Jagannathan et al. (2007) [80] 90 41.3 Gamma knife 23 54 20 95
Castinetti et al. (2007) [81] 40 94 Gamma knife 29.5 42.5 NA NA
Petit et al. (2008) [82] 33 62 Proton beam 20 55 0 NA
Aghi et al. (2008) [84] 31 43 Proton beam 20 58 3 NA
Wan et al. (2009) [83] 68 67.3 Gamma knife 21.9 27.9 NA 89.7
Losa et al. (2010) [85] 49 48 Gamma knife 25 53 NA NA
Sheehan et al. (2011) [86] 82 31 Gamma knife 24 54 NA NA
Sheehan et al. (2013) [87] 96 48 Gamma knife 22 78 15.6 98
Wattson et al. (2014) [88] 79 47 Proton beam 20 67 1 99
Wilson et al. (2014) [89] 36 66 Linear 20 36.1 3 83
accelerator
Mehta et al. (2017) [90] 278 67 Gamma knife 23.7 80 18 NA

NA, not available; RT, radiation therapy.

Studies include case series of ≥ 30 patients, published between 1999 and 2019, and are listed chronologically.

conveniently categorized depending on their site of
action, including steroidogenesis inhibitors (in-
hibiting adrenal steroidogenesis), centrally acting
agents (controlling excessive ACTH secretion) and
glucocorticoid receptor (GR) antagonists (inhibiting
cortisol action) [93].
Steroidogenesis inhibitors
Steroidogenesis inhibitors act on one or several
enzymes involved in adrenal steroidogenesis to
inhibit cortisol synthesis [8]. Ketoconazole and
metyrapone are currently used for this purpose,
though they are prescribed ‘off label’ in the treat-
ment of CD in the United States. Both agents are
licensed by the European Medicines Agency (EMA)
for the treatment of hypercortisolism. Mitotane is
primarily administered to patients with adrenocor-
tical carcinoma but has been also used to treat CD
in some countries; it is seldom prescribed to
patients with CD in the United States. Etomidate
is the only agent available for intravenous use and
has been administered ‘off label’ to control serious
hypercortisolism rapidly in severely ill patients.
Several other agents are at different stages of
development, as will be discussed.
Steroidogenesis inhibitors are generally titrated
towards normalizing 24-h urine free cortisol
(UFC) levels; however, escape from their salutary
effects may occur over time. In addition, hypoad-
renalism may result as an extension of their
pharmacologic action, which is treatable with
temporary interruption of the medication and/or
dose reduction. As an alternative, a ‘block and
replace’ strategy can be employed, whereby
endogenous glucocorticoid secretion is completely
blocked with a steroidogenesis inhibitor, whilst the
patient receives glucocorticoid replacement. This
latter strategy can be particularly helpful in
patients with cyclic (intermittent) CD. However,
particular caution is required if a ‘block and

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 532
Table 3. Currently available medical therapies for patients with Cushing’s disease

Mechanism Effectiveness
Agent of action Typical dose range (% cases) Adverse effects Comments
Ketoconazole Steroidogenesis 200-600 mg po bid-tid 49%a (escape Nausea, headache, skin rash, Regular monitoring of liver
inhibitor may occur) pruritus, transaminitis, liver failure chemistries is advised;
potential for drug–drug
interactions; gastric acid
required for absorption
Metyrapone Steroidogenesis 250-1000 mg po qid 76%b/ 43%a Nausea, dizziness, hypertension, Successfully used during

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inhibitor (escape may oedema, hypokalaemia, hirsutism, pregnancy
occur) acne
Mitotane Steroidogenesis 0.5-3.0 g po tid Up to 85%a Gastrointestinal, genitourinary, Used primarily in
inhibitor haematologic, metabolic, adrenocortical carcinoma;
neurologic, ophthalmic and skin delayed onset of action;
toxicities teratogenic

ª 2019 The Association for the Publication of the Journal of Internal Medicine
1 b
Etomidate Steroidogenesis 0.03 mg kg iv (bolus), Up to 100% Sedation, vomiting, myoclonus, Monitoring in intensive care
inhibitor followed by (short term) dystonia unit is advised
1 1
0.1–0.3 mg kg h
Cabergoline Centrally acting 0.5–7.0 mg po weekly 30–40%a Nausea, vomiting, orthostasis, Effective in doses that are
(escape may headache, vivid dreams, psychiatric generally higher than those
occur) manifestations used in hyperprolactinaemia
Pasireotide Centrally acting 0.3-0.9 mg sc bid 21%a Diarrhoea, dyspepsia, nausea, Glucose monitoring is advised
cholelithiasis,
Treatment of Cushing’s disease / N. A. Tritos & B. M. K. Biller

hyperglycaemia/diabetes mellitus,
hypoadrenalism, bradycardia
Pasireotide LAR Centrally acting 10–30 mg im 40%a Same as pasireotide Same as pasireotide
every 4 weeks
Mifepristone Glucocorticoid 300-1200 mg po daily 60%c/ 38%d/ Hypoadrenalism, hypokalaemia, Dose titration based on clinical
receptor 87%e elevated blood pressure, end-points only; potential for
antagonist endometrial thickening/vaginal drug–drug interactions;
bleeding abortifacient

bid: twice daily; im: intramuscularly; LAR: long-acting release; po: by mouth; qid: four times daily; sc: subcutaneously; tid: three times daily; iv:
intravenously.
a
Based on normalization of 24-h urine free cortisol. bBased on normalization of serum cortisol. cBased on improvement in glycaemia. dBased on
improvement in blood pressure. eBased on improvement in global clinical status.
 Treatment of Cushing’s disease / N. A. Tritos & B. M. K. Biller
replace’ regimen is used in order to avoid hyper-
cortisolism as a consequence of inadequate sup-
pression of endogenous cortisol secretion and/or
overreplacement with exogenous glucocorticoid.
Ketoconazole is an imidazole with antifungal prop-
erties that inhibits several enzymes involved in
adrenal steroidogenesis, thus inhibiting cortisol
synthesis. Ketoconazole administration has been
reported to result in 24-h UFC normalization in up
to 75% of patients [94, 95]. In a more recent study
of 200 patients, ketoconazole therapy led to 24-h
UFC normalization in 49% of patients [96]. There
were improvements in blood pressure, potassium
and glucose levels in patients receiving ketocona-
zole. Its oral absorption requires gastric acid.
Consequently, oral bioavailability is lower in
patients with hypochlorhydria or those receiving
proton pump inhibitors or H2 receptor antagonists.
Adverse effects associated with ketoconazole ther-
apy include dyspepsia, transaminitis, headache,
pruritus and skin rash. Hypogonadism and gynae-
comastia may occur in men as a result of inhibition
of testosterone biosynthesis. Ketoconazole may
interfere with the masculinization of a male foetus
and should be avoided during pregnancy.
Asymptomatic transaminitis may occur in about
18% of patients and is generally reversible with
ketoconazole dose reduction but may require treat-
ment discontinuation (if severe or symptomatic). Of
particular concern, fulminant hepatic failure has
been reported and has estimated to occur in about
1 out of 15 000 treated patients [97]. The Food and
Drug Administration (FDA) has inserted a ‘black
box warning’ into the ketoconazole label, informing
prescribers of the risk of severe hepatotoxicity and
recommending regular monitoring of liver enzymes
in patients treated with ketoconazole. This medi-
cation has substantial potential for drug–drug
interactions with agents metabolized by the cyto-
chrome P450 3A4 system, necessitating caution in
reviewing all the medications that patients receive
in order to avoid significant interactions.
Metyrapone primarily inhibits 11 beta-hydroxy-
lase, the terminal enzyme involved in cortisol
synthesis. It is rapidly effective after oral adminis-
tration, which is helpful when prompt control of
hypercortisolism is especially desirable in an out-
patient setting. It has been reported to control
hypercortisolism in up to 75% of patients [98]. In a
recent study of 195 patients with CS (including 115
with CD), metyrapone therapy led to 24-h UFC
normalization in 43% of cases and control of serum
cortisol levels in 76% of treated patients [99]. As a
result of the enzymatic blockade, metyrapone
administration leads to increased ACTH secretion
by the pituitary when given to patients with CD. It
also produces an accumulation of steroid precur-
sors, some of which have mineralocorticoid or
androgenic activity, thus accounting for several of
its adverse effects, including hypertension, oedema
and hypokalaemia, or hirsutism and acne, respec-
tively. Blood pressure, serum potassium and
testosterone (the latter in women) levels ought to
be monitored in treated patients. Additional possi-
ble adverse events include nausea, dyspepsia and
dizziness. Metyrapone has been used to control
hypercortisolism during pregnancy [100, 101];
however, it is not specifically labelled for use
during gestation.
Mitotane (o, p’ – DDD) is chemically related to an
older insecticide and inhibits several enzymes
involved in adrenal steroidogenesis. It is also
adrenolytic in higher doses administered long term
and may lead to permanent hypoadrenalism. Mito-
tane has a slow onset of action as a consequence of
its gradual accumulation over several weeks.
Hydrocortisone replacement is advisable in patients
treated with mitotane; higher than usual glucocor-
ticoid replacement doses are recommended since
the drug leads to elevated cortisol-binding globulin
(CBG) levels and accelerates glucocorticoid clear-
ance [102]. Mitotane is primarily used in patients
with adrenocortical carcinoma [103, 104]. In addi-
tion, it has been administered to patients with CD in
some countries. In this latter context, it can control
hypercortisolism in up to ~85% of patients [105,
106]. Mitotane therapy has been associated with
gastrointestinal, hepatic, genitourinary, haemato-
logic, metabolic, skin, ophthalmic and neurologic
toxicities. It is extensively stored in adipose tissue
and is a potent teratogen. Owing to its prolonged
half-life, it can take several years for the drug to
completely dissipate after its discontinuation. As a
corollary, it is advisable to defer pregnancy for up to
5 years after the medication is stopped.
Etomidate is a parenterally administered anaes-
thetic agent, which additionally inhibits 11 beta-
hydroxylase, even in subhypnotic doses. It has been
used to control severe, life-threatening hypercorti-
solism and is particularly helpful as ‘bridge therapy’
to a definitive intervention [107, 108]. Careful
monitoring is required to avoid excessive sedation
in patients on etomidate therapy. Additional
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 Treatment of Cushing’s disease / N. A. Tritos & B. M. K. Biller
adverse events associated with etomidate use
include vomiting, dystonia and myoclonus.
Combination therapy has been reported in case
series, including ketoconazole plus metyrapone
with or without mitotane [109]. Such combinations
can be particularly helpful in patients with severe
hypercortisolism.
Several agents are in development, including osilo-
drostat, levoketoconazole, ATR-101 and abi-
raterone acetate, all of which act as
steroidogenesis inhibitors. Osilodrostat inhibits
11 beta-hydroxylase and aldosterone synthase.
Osilodrostat administration led to 24-h UFC nor-
malization in approximately 80% of patients in
phase II extension studies [110]. Phase 3 studies of
osilodrostat are either in progress or completed
(but the results have not been published yet).
Hypoadrenalism, headache, nausea, diarrhoea,
dizziness, mineralocorticoid (oedema, hyperten-
sion, hypokalaemia) and hyperandrogenic (hir-
sutism, acne) adverse events have been reported.
Levoketoconazole is an enantiomer (2S, 4R) of
ketoconazole that is more potent in inhibiting
several steroidogenic enzymes than its enantiomer
(2R, 4S) [111, 112]. Based on theoretical consider-
ations, it has been proposed that levoketoconazole
may be less likely to result in hepatotoxicity than
ketoconazole. A phase 3 study of levoketoconazole
has been completed but the results have not been
published yet. ATR-101 inhibits acyl coenzyme A:
cholesterol acyltransferase 1 (ACAT1) and is being
studied as potential therapy in CD [113]. Abi-
raterone acetate inhibits 17 alpha-hydroxylase and
17, 20 lyase. It has been shown to have antitumour
activity in patients with disseminated prostate
carcinoma [114, 115]. A case report of a patient
with adrenocortical carcinoma who showed a bio-
chemical response to abiraterone acetate has been
published [116]. A study of abiraterone acetate in
adrenocortical carcinoma is under way; however,
there are currently no published data on the
efficacy of abiraterone acetate in CD. Other agents
in early stages of development include a mono-
clonal antibody (ALD1613) that neutralizes ACTH
and peptides acting as antagonists of the melano-
cortin 2 receptor, which aim at inhibiting ACTH
action [111, 117].
Centrally acting agents
Centrally acting agents inhibit ACTH secretion
from tumorous corticotrophs, leading to a decrease
534 ª 2019 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2019, 286; 526–541
in cortisol secretion. These agents may also afford
tumour control in some cases. Cabergoline, pasir-
eotide and pasireotide long-acting release (LAR) are
currently the only agents available for use in CD; of
these, cabergoline is prescribed ‘off label’ to
patients with CD. There are also several drugs in
development as will be subsequently detailed.
Cabergoline is a dopamine agonist with relative
selectivity for the D2 receptor isoform [118]. This
agent is licensed for use in patients with hyper-
prolactinaemia and prolactin-secreting adenomas.
Its effectiveness in CD is predicated by the pres-
ence of dopamine receptors on tumorous corti-
cotrophs in most tumours. Cabergoline
administration leads to 24-h UFC normalization
in approximately 30-40% of patients with CD [119–
122]. However, escape from its beneficial effects
may occur over time [122]. Of note, the effective
dose range in patients with CD (1.0–
7.0 mg week 1) is generally higher than the typical
dose range prescribed to patients with hyperpro-
lactinaemia (0.5–2.0 mg week 1). Common
adverse events associated with cabergoline use
include nausea, vomiting and orthostatic dizzi-
ness, which often improve over time and can be
minimized (in some cases) by taking the medication
at bedtime with a snack. Other possible adverse
events include headache, nasal congestion, consti-
pation, digital vasospasm, vivid dreams, night-
mares, anxiety and depression. It is advisable to
avoid cabergoline administration in patients with
psychosis and use caution when prescribing it to
patients with depression. Impulse control disor-
ders have been reported in some hyperprolacti-
naemic patients treated with cabergoline [123–
126]. In addition, high-dose cabergoline therapy
used to treat Parkinson’s disease has been associ-
ated with cardiac valvulopathy [127, 128]. This
phenomenon is likely a consequence of serotonin
(5HT2B) receptor activation in the endocardium,
leading to valvular fibrosis. However, most studies
suggest that cabergoline therapy (at least in typical
doses used to treat hyperprolactinaemia) does not
appear to be associated with significant cardiac
valvulopathy [129].
Pasireotide and pasireotide LAR activate multiple
somatostatin receptor (SSTR) isoforms, including
SSTR1, SSTR2, SSTR3 and SSTR5. It is thought
that their effectiveness is dependent on activation
of SSTR2 and SSTR5, which are expressed in the
majority of corticotroph adenomas. Pasireotide
therapy led to 24-hr UFC normalization in
 Treatment of Cushing’s disease / N. A. Tritos & B. M. K. Biller
approximately 21% of 162 patients with CD [130,
131]. Pasireotide may also control nadir cortisol
levels, as measured by late-night salivary cortisol
[132]. In another study of 150 patients with CD,
pasireotide LAR administration normalized 24-h
UFC in about 40% of treated patients [133].
Improvement in clinical status, including body
weight, blood pressure and lipids, has been
reported in patients treated with these agents. A
decrease in tumour size may also occur in response
to pasireotide therapy [131]. Both agents have been
approved by the FDA and the EMA for use in
patients with CD who have hypercortisolism per-
sisting or recurring after TSS or are not candidates
for pituitary surgery. Both pasireotide and pasireo-
tide LAR share several adverse effects with first-
generation somatostatin receptor agonists (oc-
treotide and lanreotide), including diarrhoea, dys-
pepsia, nausea, cholelithiasis and transaminitis.
Hypoadrenalism, hair loss, vitamin B12 deficiency
and asymptomatic sinus bradycardia may also
develop. Hyperglycaemia and diabetes mellitus
occur frequently amongst patients treated with
pasireotide or pasireotide LAR (70–80% of cases).
In these patients, insulin secretion is inhibited
both directly and indirectly (via inhibition of
incretin peptides that are expressed in the gas-
trointestinal tract and normally stimulate food-
dependent insulin secretion) [134]. Metformin,
incretin-based therapies and insulin have been
proposed as treatments of hyperglycaemia and
diabetes mellitus in patients treated with pasireo-
tide or pasireotide LAR.
Combination therapy can be effective in patients
with severe hypercortisolism, including pasireotide
in combination with cabergoline and ketoconazole
[135], but more data are needed to fully establish
the role, risks and benefits of such therapy.
Several agents that are centrally acting to suppress
ACTH secretion or others that aim at decreasing
ACTH action are in development, including gefi-
tinib, retinoic acid, silibinin and r-roscovitine.
Gefitinib is a tyrosine kinase inhibitor that pre-
vents signalling mediated through the epidermal
growth factor receptor (EGFR) and is being studied
as a potential therapy in CD [136]. Recent studies
have identified the presence of somatic, activating
mutations of the ubiquitin-specific protease 8
(USP8) gene in 30-60% of corticotroph adenomas
[137, 138]. These mutations lead to increased
deubiquitination of proteins targeted for protea-
some-mediated degradation, thus allowing for
increased recycling of several signalling molecules,
including the EGFR, to the plasma membrane. In
turn, EGFR has been shown to stimulate ACTH
secretion. Whether gefitinib is particularly effective
in tumours harbouring USP8 gene mutations
remains to be established. A phase 2 study of
gefitinib in patients with CD and somatic USP8
mutations is under way. Retinoic acid inhibits
ACTH secretion and tumour growth in preclinical
studies [139]. In small studies, isotretinoin, a 13
cis retinoic acid isomer, controlled hypercorti-
solism in about 25% of patients [140, 141]. R-
roscovitine inhibits cyclin-dependent kinase 2 and
cyclin E and has decreased ACTH secretion and
tumour growth in animal studies [142, 143]. A
phase 2 study of r-roscovitine in CD is in progress.
Silibinin binds to heat shock protein 90, leading to
its dissociation from the GR [144]. Both in vitro and
animal studies are promising [144], but pertinent
data in humans are currently not available.
Glucocorticoid receptor antagonists
Glucocorticoid receptor antagonists inhibit cortisol
actions mediated through its cognate receptor but
have no effects on mineralocorticoid receptor (MR)
activation by cortisol. Mifepristone is currently the
only agent available for use in CD [145]. Mifepri-
stone is approved by the FDA and the EMA for use
in hyperglycaemic patients with CS (regardless of
aetiology) who have failed surgery or are not
surgical candidates. In a study of 50 patients with
CS, most of whom had CD, mifepristone therapy
led to an improvement in glycaemia amongst 60%
of 29 patients who had diabetes mellitus or hyper-
glycaemia at study entry, and a significant
decrease in blood pressure amongst 38% of 21
patients with hypertension at baseline [146]. An
improvement in global clinical status was observed
in 87% of subjects [146]. Cortisol and ACTH levels
significantly increase in patients with CD under-
going mifepristone therapy in the absence of clear-
cut evidence of tumour progression [147]. There-
fore, monitoring of serum cortisol, 24-h UFC and
LNSC levels is of no therapeutic value in treated
patients, who require close clinical monitoring to
establish effectiveness and detect the possible
emergence of hypoadrenalism. Of note, patients
who develop adrenal insufficiency on mifepristone
therapy do not have low serum cortisol levels; the
diagnosis must be made clinically. Symptomatic
patients with hypoadrenalism may require at least
temporary interruption of treatment and can be
rescued by dexamethasone administration in
ª 2019 The Association for the Publication of the Journal of Internal Medicine 535
Journal of Internal Medicine, 2019, 286; 526–541
 Treatment of Cushing’s disease / N. A. Tritos & B. M. K. Biller
higher doses over several days. Adverse effects
associated with mifepristone therapy include those
arising from unopposed activation of the MR by
endogenous cortisol, including hypertension and
hypokalaemia. Potassium levels require careful
monitoring in treated patients, who may require
large doses of potassium supplementation and/or
spironolactone in order to maintain normokalae-
mia. Mifepristone also serves as a progesterone
receptor antagonist and may therefore cause
endometrial thickening, metrorrhagia and will ter-
minate pregnancy [146]. However, precancerous
endometria hyperplasia has not been reported in
patients on mifepristone therapy. Fatigue, head-
ache, nausea and reversible abnormalities in
serum lipids and thyrotropin levels have been also
reported [146]. Mifepristone inhibits several hep-
atic enzymes, accounting for its significant poten-
tial for drug–drug interactions with other agents
metabolized through the same enzymatic path-
ways, so it is important to review all medications
taken by patients before using mifepristone.
Relacorilant is an investigational GR antagonist
that does not interact with the progesterone recep-
tor and is therefore anticipated to lack adverse
effects on the endometrium [148]. Relacorilant is
currently being studied as a potential therapy in
CS/CD. In a phase 2 study of 32 patients with CS
(including CD), improvements in blood pressure
and glucose levels were reported [148, 149]. A
phase 3 study of relacorilant is in progress.
Bilateral adrenalectomy
Bilateral adrenalectomy (BA) is currently consid-
ered as a treatment option for patients who have
had persistent or recurrent hypercortisolism after
TSS. Of note, BA leads to rapid control of hyper-
cortisolism and can be particularly helpful in
patients with severe, symptomatic hypercorti-
solism who do not respond adequately to medical
therapy. It should be also noted that BA may be
elected upon by patients eager for prompt resolu-
tion of hypercortisolism or those who are con-
cerned about potential adverse events associated
with RT, including women who are planning to
conceive.
Currently, BA is almost always performed laparo-
scopically with low morbidity [150–153]. It leads to
permanent resolution of hypercortisolism in the
vast majority of cases, the exception being the rare
patients with ectopic adrenal rest tissue. However,
536 ª 2019 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2019, 286; 526–541
BA also leads to permanent primary adrenal insuf-
ficiency and the consequent requirement for lifelong
glucocorticoid and mineralocorticoid replacement.
In addition, BA has been associated with the sub-
sequent development of corticotroph tumour pro-
gression (in about 50% of patients undergoing BA),
which may progress to Nelson’s syndrome (in 8-20%
of patients undergoing BA) [154, 155]. In these
cases, tumour growth may cause mass effect and
progressive elevation in ACTH levels, leading to skin
hyperpigmentation [12, 155]. Pituitary surgery and
RT are treatment options in patients who develop
Nelson’s syndrome [151, 156, 157]. In addition,
pasireotide LAR and cabergoline have been reported
to decrease plasma ACTH levels and tumour size in
isolated cases with Nelson’s syndrome [158, 159].
Summary
The management of patients with CD can be
complex and often requires careful coordination
between experts from neurosurgery, endocrinol-
ogy, radiation oncology and neuro-oncology. Whilst
TSS is the mainstay of treatment for CD, radiation
therapy with interim medical therapy and bilateral
adrenalectomy are important treatment options in
patients with persistent or recurrent CD after TSS.
The prognosis of patients with CD has improved
over time and is more favourable in patients who
achieve remission [7–9, 160]. However, some stud-
ies suggest that the mortality risk of patients with
CD remains elevated above that of the general
population, even if they are in remission [6, 161]. It
is anticipated that further progress in our under-
standing of the molecular pathogenesis of corti-
cotroph pituitary tumours may culminate in the
development of novel, more efficacious therapies
for this potentially serious condition.
Conflict of interest statement
NAT has received institution-directed research
support from Novartis and Ipsen. BMKB has
received institution-directed research support from
Millendo Therapeutics, Novartis and Strongbridge
Biopharma and served as an occasional consultant
to Novartis and Strongbridge Biopharma.
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Correspondence: Nicholas A. Tritos MD, DSc, Neuroendocrine and
Pituitary Tumor Clinical Center and Neuroendocrine Unit, Mas-
sachusetts General Hospital, 100 Blossom Street # 140, Boston,
MA 02114, USA. (fax: + 1 617 726 1241; e-mail: ntritos@mgh.har-
vard.edu).
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