10.1007@s40265 019 01128 7

Drugs (2019) 79:935–956
https://doi.org/10.1007/s40265-019-01128-7
REVIEW ARTICLE
Medical Management of Cushing’s Syndrome: Current and Emerging

Treatments
José Miguel Hinojosa‑Amaya1,2 · Daniel Cuevas‑Ramos3 · Maria Fleseriu1
Published online: 17 May 2019

© Springer Nature Switzerland AG 2019
Abstract
Endogenous Cushing’s syndrome is a chronic disease associated with increased morbidity and mortality if not appropri-
ately treated. Recurrence and/or persistence of hypercortisolemia after surgical treatment, especially for Cushing’s disease,
are high, and long-term medical treatment is used to decrease cortisol levels and risk of metabolic comorbidities. Medical
treatment is also often required while waiting for radiation effects to take place. In some cases, severe or life-threatening
hypercortisolism must be urgently and medically treated, via intravenous medications or with combination therapy, before
patients can undergo surgery. In the last decade, medical treatment has progressed from a few steroidogenesis inhibitors to
three novel drug groups: new inhibitors for steroidogenic enzymes with possibly fewer side effects, pituitary-directed drugs
that aim to inhibit the pathophysiological pathways of Cushing’s disease, and glucocorticoid receptor antagonists that block
cortisol’s action. Understanding the pathophysiology of Cushing’s syndrome has also led to the identification of potential
targets that may decrease adrenocorticotrophic hormone and/or cortisol excess, and/or decrease tumor cell proliferation,
and induce senescence or apoptosis. We provide here a review of current and near-future medical options to treat Cushing’s
syndrome, and discuss updates on clinical trials and the efficacy and safety of novel or in-development drugs, as well as
future potential targets.
1 Introduction
Key Points
Cushing’s syndrome (CS) is defined as the composite of
symptoms, signs and metabolic abnormalities resulting from Cushing’s syndrome leads to increased morbidity and
an inappropriate and chronic exposure to excessive levels of mortality, and severe cortisol increase may be life-threat-
glucocorticoids (GCs), either endogenous or exogenous [1]. ening if not appropriately treated.
The most common cause of endogenous hypercortisolism is Currently, available treatments for Cushing’s syndrome
Cushing’s disease (CD), which is caused by an adrenocorti- include pituitary-directed therapies (pasireotide and
cotropic hormone (ACTH)-secreting adenoma (in ~ 70–80% cabergoline), steroidogenesis inhibitors (ketoconazole,
of cases). Disease persistence is associated with increased metyrapone and mitotane), and a glucocorticoid receptor
morbidity and mortality among the affected individuals antagonist (mifepristone).
[2–5]. The primary treatment of CD is transsphenoidal
Novel medical treatments for Cushing’s syndrome
inhibit pathways that cause adrenocorticotropic hormone
* Maria Fleseriu (ACTH) and cortisol excess or prevent cortisol action
fleseriu@ohsu.edu
at the target tissue; phase III clinical trials have been
1
Departments of Medicine (Endocrinology) and Neurological recently completed and some, to determine efficacy and
Surgery, and Northwest Pituitary Center, Oregon Health safety, are ongoing.
and Science University, 3303 SW Bond Ave, Mail Code
CH8N, Portland, OR 97239, USA New molecules are under further investigation as poten-
2
Endocrinology Division, Department of Medicine, Hospital tial drugs to treat Cushing’s syndrome, hence increase
Universitario, Dr. José E. González, Universidad Autónoma the available therapeutic armamentarium.
de Nuevo León, Monterrey, Nuevo León, Mexico
3
Neuroendocrinology Clinic, Department of Endocrinology
and Metabolism, Instituto Nacional de Ciencias Médicas y
Nutrición Salvador Zubirán, Mexico City, Mexico
Vol.:(0123456789)
936 J. M. Hinojosa‑Amaya et al.
surgery (TSS), with remission rates up to 70% for com- control hypercortisolism and reduced morbidity shown.
bined micro- and macroadenomas; however, up to 30% of Benefits should be weighed against side effects, which may
patients will suffer recurrence in the long-term following be secondary to accumulation of cortisol synthesis precur-
TSS [4, 6]. Medical therapy is sometimes prescribed pre- sors (i.e., hypertension and hypokalemia due to 11-deox-
surgically in patients with severe hypercortisolism and/ ycortisol increment after 11β-hydroxylase [CYP11B1]
or significant comorbidities, and after TSS in the case of inhibition), an increase in the synthesis of non-blocked
non-remission or recurrence. Radiotherapy or stereotactic steroids (i.e., hirsutism in women due to increased dehy-
radiosurgery is also an important option for the treatment droepiandrosterone [DHEA] and androstenedione pro-
of relapsing CD, aggressive corticotroph tumors, and Nel- duction after CYP11B1 inhibition), or the consequence
son’s syndrome [7–12], but concerns about long-term side of direct drug side effects (i.e., hepatotoxicity due to keto-
effects such as hypopituitarism, cerebrovascular disease and conazole) (Table 1). Large variations in clinical and bio-
secondary intracranial tumors have been reported [13–15]. chemical responses between patients are well-known. and
Other causes of endogenous hypercortisolism are adrenal it has been reported that some polymorphisms of adrenal
Cushing’s syndrome (ACS) and ACTH-dependent ectopic enzymes may affect the response to this group of medica-
Cushing’s syndrome (ECS) (ACTH-ECS). tions [16]. All steroidogenesis inhibitors, like all medica-
Here, we review current and near-future medical treat- tions for CS, pose a risk of adrenal insufficiency (AI), and
ment options to control endogenous CS hypercortisolism if present, substitution therapy with GCs is required.
(Fig. 1). We provide an update on the efficacy and safety of
drugs in clinical trials and the current status of in-develop-
ment therapies/drugs. 2.1.1 Ketoconazole
Ketoconazole is an antifungal imidazole derivative, first

2 Adrenal‑Directed Drugs used to treat hypercortisolism in 1983 [17, 18]. Despite
efficacy in reducing cortisol levels, ketoconazole is not
2.1 Current Adrenal Steroidogenesis Inhibitors US Food and Drug Administration (FDA) approved for the
treatment of CS, and has been used off-label (Table 1). The
Inhibition of adrenal steroidogenesis targets cortisol European Medicines Agency (EMA) approved use of keto-
release in adrenal CS, and although it does not target conazole in the treatment of CS in 2014, but with strong
the primary cause of cortisol excess in non-adrenal CS, warnings of potential hepatotoxicity [19]. Ketoconazole is
steroidogenesis inhibitors reduce/normalize serum corti- a mixture of two cis-enantiomers, the dextrorotatory iso-
sol levels in both ACTH- and non-ACTH-dependent CS form consisting of (2R,4S)-(+)-KET and the levorotatory
(Table 1). Adrenal-directed drugs have been largely stud- isoform (2S,4R)-(−)-KET [20].
ied retrospectively, with short- and long-term efficacy to
Fig. 1 Main mechanism of action for the medical treatment of CS, EGFR epidermal growth factor receptor, GR glucocorticoid receptor,
including pituitary-directed therapies (green), steroidogenesis inhibi- RARretinoic acid receptor, RXR retinoic acid X receptor, SSTR soma-
tors (blue), and GR antagonists (orange). CDK2 cyclin-dependent tostatin receptor
kinase 2, CS Cushing’s syndrome, D2R dopamine type 2 receptor,
Cushing’s Syndrome: Current and Emerging Treatments 937
Ketoconazole inhibits the side-chain cleavage com- ketoconazole with cyclosporine for example can increase
plex (steroidogenic acute regulatory protein [StAR] cyclosporine levels five- to tenfold. This can then cause an
and 20,22-desmolase [CYP11A1]), CYP11B1 and increase in drug side effects such as nephro- and neurotox-
17α-hydroxylase/17,20-lyase (CYP17) in the adrenal cor- icity [26–28]. A similar effect is found in the case of some
tex [21]. After cortisol level reduction, the expected incre- statins; taking ketoconazole with some statins can increase
ment of ACTH is not always observed with ketoconazole; statin levels, and myopathy and rhabdomyolysis have been
therefore, some controversy exists as to whether ketocon- described [29, 30]. Concomitant use of benzodiazepines dur-
azole has an additional inhibitory effect in corticotroph ing ketoconazole therapy is contraindicated due to decreased
reduced ACTH secretion [22, 23]. benzodiazepine clearance, which may cause increased and
The French Retrospective Study on Ketoconazole prolonged sedation and impairment of psychomotor perfor-
Outcome (FReSKO) evaluated 200 patients treated with mance [31–33].
doses between 200 and 1200 mg (median 600 mg). Nor-
mal 24-h urinary free cortisol (UFC) was achieved in 2.1.2 Fluconazole
approximately 50% of patients in a selected population,
with improvement in glycemic control, hypertension, and Fluconazole is another antifungal imidazole that inhibits
hypokalemia. Patients may escape from the enzyme inhi- CYP17 and CYP11B1 (Fig. 1), and is not US FDA, nor
bition while on treatment with ketoconazole, and this is EMA approved. Fluconazole has decreased potency com-
probably related to an adrenal compensatory increment of pared to racemic ketoconazole, but also has a decreased risk
cortex enzymes. Such “escape phenomenon” was found in of hepatotoxicity (Table 1). Two cases treated with 100 mg
23% of cases in the FReSKO study. Therapy was stopped twice a day had normal UFC levels [34], and fluconazole
in 20% of patients as a consequence of adverse events has been used off-label with variable efficacy in a few other
(AEs). Liver enzymes significantly increased (fivefold) in cases [21, 22, 34, 35].
2.5% of patients, and a mild elevation was observed in
13%. No fatal hepatitis was reported. Other common side 2.1.3 Etomidate
effects were gastrointestinal (GI) complaints in 13% and
AI in 5.4% [19]. A more recent French prospective study Etomidate is an intravenous (IV) imidazole with sedative
reported similar hepatotoxicity results. Four ketoconazole- properties (amidate or hypnomidate). It is the only IV ther-
naïve patients (8.5%) and two treated with another keto- apy available for CS (Table 1), and its use is limited for
conazole formulation (3.3%) developed liver injury, but cases with very severe hypercortisolism (Table 2). It is a
only three of these events were related to ketoconazole fast-acting therapy when life-threatening hypercortisolism
(median dose 600 mg/ day). Other reported AEs were AI is present [36, 37]. Etomidate blocks multiple steps of ster-
in two patients, one case of alopecia, and one case of gen- oidogenesis, including CYP11B1, CYP17 and cholesterol
eralized pruritus [24]. side-chain cleavage (Fig. 1). Dose-dependent decreases of
In another series, that included nine patients with severe serum cortisol are achieved rapidly after an IV non-hypnotic
ECS, in whom liver enzymes (aspartate aminotransferase dose bolus (0.03 mg/kg) followed by a constant infusion of
[AST] and alanine aminotransferase [ALT]) were reported to 0.3 mg/kg/h (Table 1). Significant suppression can be seen
be twice the upper limit of normal (ULN), four patients with after 5 h of treatment, and maximal effect is reached after
liver metastasis were treated with ketoconazole (400–1000 11 h [38, 39]. A new validation of the etomidate infusion
mg/day; median 1000 mg) associated with metyrapone protocol in the management of severe CS in nine patients
(seven out of nine; median dose 2750 mg/day) and mito- used an initial bolus dose of 5 mg IV once over 30–60 min,
tane (one out of nine; dose 2500 mg/day). The treatment followed by an infusion rate of 0.02 mg/kg/h, titrated every
induced a sustained response (mean UFC 37.5 × ULN to 6 h by 0.01 or 0.02 mg/kg/h increments to a maximum rate
1.0 × ULN) with a concurrent reduction in AST and ALT of 0.3 mg/kg/h. Serum cortisol was measured every 6 h. A
(2.1 to 1.0 × ULN and 3.7 to 0.6 × ULN, respectively), serum cortisol target of < 20 μg/dL was achieved in seven
suggesting that moderately increased liver enzymes should of eight cases, and < 40 μg/dL was achieved in the remain-
not preclude ketoconazole therapy in severe, life-threatening ing case. Median baseline cortisol was 105 μg/dL and took
hypercortisolism [25]. a median of 38 h to achieve a median nadir of 15.8 μg/dL
Ketoconazole is a potent inhibitor of CYP450 3A4 and (median reduction of 80%). Mild sedation was the only seri-
exhibits drug-drug interactions with all medications that ous adverse event (SAE), in one case, and there were two
are metabolized via the same pathway. A total of 838 drug episodes of nausea and vomiting. Cumulative median pro-
interactions have been reported, with 248 documented as pylene glycol exposure was 90.3 g (232 mg/kg/day), without
major interactions, most frequently, with co-administra- related AEs [40].
tion of cyclosporine, statins, and benzodiazepines. Taking
938
Table 1 Medical treatment options for Cushing’s syndrome directed to adrenal glands
Drug Family Mechanism of action Dose Effectiveness Side effects Approval status/use Clinical trials
FDA EMA
Current steroidogenesis inhibitors

Ketoconazole Imidazole Inhibits StAR, 400–1200 mg daily Normal UFC in GI disturbance, liver Off-label Approved Large retrospective
CYP11A1 (BID dosage) 48.7–50%. Escape enzyme increase, FReSKO
CYP11B1, CYP17 phenomenon in AI
23%
Fluconazole Inhibits CYP17 200 mg QD No studies Liver enzyme Off-label Case reports
increase
Etomidate Inhibits StAR, Bolus 5 mg once fol- Median serum cor- Sedation/anesthe- Off-label Case reports, retro-
CYP11A1, lowed by 0.02–0.3 tisol reduction by sia, AI, propylene spective studies
CYP11B1, CYP17 mg/kg/h 80%, after median glycol toxicity
time of 38 h
Metyrapone – Potent inhibitor of 0.5–4.5 g daily in Response rate in “Pseudohyperaldo- Approved Approved Retrospective studies
(SU4885) CYP11B1 multiple doses 43–76%. Escape steronism” due to for ACTH
Weaker CYP17, (TID or QID) phenomenon in aldo precursors stimulation
CYP11B2, CYP19 19% of responders (hypertension, test
hypokalemia),
hirsutism, AI
Mitotane Insecticide derivative Inhibits StAR, 2–5 g QD Remission rates of GI disturbance, diz- Approved for adrenal Retrospective studies
CYP11A1, 72% ziness, cognitive carcinoma treatment
CYP11B1, alterations, AI
CYP11B2, 3β-HSD
Adrenolytic
Novel steroidogenesis inhibitors in phase III trials
Osilodrostat – Potent inhibitor of LINC 2: 2–50 mg Phase II: UFC nor- Nausea, diarrhea, Not approved Phase I LINC1, phase
(LCI699) CYP11B1 BID malized in 79.8% at asthenia, “pseudo- II LINC2, Ongoing
LINC 3: 2–30 mg po 22 weeks hyperaldosteron- phase III LINC3 and
BID Phase III: 66.0% ism” due to aldo LINC4
maintained normal precursors (hyper-
mUFC levels for tension, hypoka-
at least 6 months lemia), hirsutism,
after first mUFC hyperkaliemia, AI
normalization
Levoketoconazole Imidazole Inhibits StAR, 150–600 mg BID Phase III: UFC nor- Nausea, headache, Not approved Ongoing phase III
(COR-003) CYP11A1, malized in 38–48% edema, liver SONICS and LOG-
CYP21A2, enzyme increase, ICS
CYP11B1, CYP17 AI
Novel steroidogenesis inhibitors in other phases of development
Nevanimibe (ATR- ACAT1 inhibitor ACAT1 Under study Under study Under study Not approved Phase II
101) NCT03053271
J. M. Hinojosa‑Amaya et al.
“Block and replacement” therapy may be needed to pre-
3β-HSD 3β-hydroxysteroid dehydrogenase, ACAT1 acyl-coenzyme A:cholesterol O-acyltransferase 1, ACTH adrenocorticotrophic hormone, AI adrenal insufficiency, BID twice daily, CYP11A1
20,22-desmolase, CYP11B1 11β-hydroxylase, CYP11B2 aldosterone synthase (18-hydroxylase), CYP17 17α-hydroxylase/17,20-lyase, CYP19 aromatase (19-hydroxylase), CYP21A2 21-hydrox-
ylase, EMA European Medicines Agency, FDA Food and Drug Administration, GI gastrointestinal, mUFC median urinary free cortisol, po by mouth, QD once daily, QID four times daily, StAR
vent AI after 24 h of etomidate infusion [37].
NCT03145285
Clinical trials
2.1.4 Metyrapone
Phase II
Metyrapone is a fast-acting inhibitor of steroid

11-β-monooxygenase. Cortisol levels start to decrease
within 2 h of the first dose. Metyrapone has predominant
activity on CYP11B1 and a weaker inhibitory effect on
EMA
Approval status/use
CYP17, 18-hydroxylase (CYP11B2) and 19-hydroxylase

(CYP19) [41]. Due to this cortisol reduction, it has been
Not approved
suggested that ACTH release from corticotroph cells may

stimulate type 2 melanocortin receptor (MC2R) at the
FDA
adrenal glands, causing a drug “escape effect” [21, 22,

42]. Therefore, drug dose may be increased from 500
mg up to 6 g per day in divided doses [43, 44]. Even
hypokalemia), AI
though the escape effect may occur in 19% of cases, some

“Pseudohyperal-
(hypertension,
dosteronism”
studies have shown a sustained long-term response to

Side effects
metyrapone [45]. Metyrapone is approved for the treat-

ment of CS by the EMA; however, the US FDA has
only authorized drug use to perform metyrapone-ACTH
stimulation tests (Table 1). Metyrapone has several side
effects, including accumulation of mineralocorticoid
precursors (i.e., deoxycorticosterone and 11-deoxycor-
Effectiveness
Under study
tisol) as well as adrenal androgens (i.e., DHEA, DHEA-

sulfate, and androstenedione), causing hypertension and
hirsutism [42, 45–47]. A recent metyrapone treatment in
CS study of 31 patients treated with a median dose of 1
g of metyrapone for 9 months showed quick hypercorti-
250–500 mg BID
solism control, sustained by 70% of the patients at 12 and

24 months, although only 37% recovered cortisol rhythm,
steroidogenic acute regulatory protein, TID thrice daily, UFC urinary free cortisol
as assessed by late-night salivary cortisol (LNSC). Dur-

ing the study there were no severe side effects, only half
Dose
of the female patients had hirsutism, and blood pressure

was not increased. Escape phenomenon was found in
Mechanism of action
three patients (9.6%) [48]. No major drug interactions

have been described during treatment with metyrapone,
although there are 41 reported moderate interactions,
CYP21A2
CYP11B1
reported on drugs.com [49]. Use of metyrapone has

CYP17
been rarely reported during pregnancy; however, safety

in pregnancy has not been confirmed by well-designed
Androgen biosynthe-
clinical studies [50]. Availability of metyrapone is also

limited in certain countries.
sis inhibitor
2.1.5 Mitotane
Family
An analog of the insecticide dichlorodiphenyltrichlo-

roethane, mitotane {brand name Lysodren; for-
Abiraterone acetate
Table 1 (continued)
mula 1-(o-chlorophenyl)-1-(p-chlorophenyl)-2,2-dichloro-
ethane [o,p’-DDD]}, has been used to treat all causes of
hypercortisolism; mainly those caused by adrenal carcinoma
[51]. Mitotane has three different adrenal effects: (1) an
Drug
adrenolytic action caused by lipid accumulation and atrophy

Table 2 Severe hypercortisolism criteria [144] persist long after drug discontinuation, and circulating levels
of cortisol remain low [54]. Mitotane activates cytochrome
1 or more Plus recent onset of ≥ 1
P450 enzymes 3A4 (CYP3A4), which increases metabolism
Serum cortisol ≥ 41 µg/dL (1100 nmol/L) Sepsis of synthetic GCs, and supraphysiological levels of hydrocor-
24-h UFC > 4-fold ULN Opportunistic infection tisone are necessary to treat mitotane-induced AI [56]. Mito-
Severe hypokalemia (< 3.0 mmol/L) Intractable hypokalemia tane has 148 documented major drug interactions, including
Uncontrolled hypertension opioids, leading to decreased drug efficacy or withdrawal
Edema syndrome, and a potential risk of opioid overdose when
Heart failure mitotane is discontinued [57].
Intestinal hemorrhage
Acute psychosis (glucocorti- 2.2 Novel Adrenal Steroidogenesis Inhibitors
coid-induced)
in Development
Progressive debilitating
myopathy
Thromboembolism 2.2.1 Osilodrostat
Uncontrolled hyperglycemia/
ketoacidosis Osilodrostat (formerly LCI699) is a potent inhibitor of
24-h UFC 24-h urinary free cortisol, ULN upper limit of normal
CYP11B1, which catalyzes the final step of cortisol synthe-
sis [58]. Osilodrostat also inhibits aldosterone synthase and
decreases blood pressure in patients with essential hyperten-
of the fascicularis and reticularis regions of the adrenal cor- sion and primary aldosteronism [59, 60]. Enzyme inhibition
tex; zona glomerulosa affects are observed only after long- is expected to increase ACTH and levels of cortisol precur-
term therapy [22, 52, 53]; (2) inhibition of steroidogenesis sors, such as the mineralocorticoid 11-deoxycorticosterone
enzymes such as side-chain cleavage complex, CYP11B1, (DOC), with a subsequent potential risk of hypertension
CYP11B2 and 3β-hydroxysteroid dehydrogenase (3β-HDS); and hypokalemia (Table 1). Additional side effects include
and (3) increases in cortisol-binding globulin (CBG), reduc- an increment of androgens through higher CYP17 activity
ing free active cortisol (Table 1). The onset of action is very that may lead to increased testosterone levels and female
slow (3 months on average), but remission rates in patients hirsutism [58].
with pituitary irradiation are almost 100%, and potentially The phase II, proof-of-concept study {Safety and Effi-
without an escape phenomenon due to the adrenolytic action cacy of LCI699 in Cushing’s Disease Patients (LCI IN Cush-
[6]. A single-center study also reported remission rates of ing’s [LINC]); clinicaltrials.gov identifier NCT01331239}
72% at 6 months in pre- and post-surgical non-irradiated showed that LCI699 normalized cortisol levels in 11 out
CD patients [54]. of 12 patients with CD after 10 weeks, without SAEs [58].
Pediatric use of mitotane has also been reported [55]. The overall response rate was 89.5% after 10 weeks and
Low-dose mitotane (up to 2 g/daily) for at least 6 months 79% at the end of the study (22 weeks). UFC levels were
was assessed in a retrospective study of nine patients with normalized in 88% of patients who completed the study, and
CD (either pre-surgical or after TSS) before the end of decreased in two non-responders (~ 48% from baseline lev-
their growth period, and compared to 13 patients in remis- els). Changes in morning serum and LNSC correlated with
sion after surgery. Mitotane improved growth velocity and UFC values [61]. Two patients discontinued the study drug
BMI z-scores, as well as pubertal development, without at 10 weeks, and only one patient experienced an escape
significant body mass index (BMI) differences when com- phenomenon. Levels of 11-deoxycortisol increased 11-fold
pared with TSS-treated patients. Nonetheless, side effects and those of DOC increased 22-fold from ULN at week 22.
were similar to those described for adult patients (see Renin and aldosterone were decreased, but there was no sig-
below). Out of seven patients with prolonged mitotane nificant change in blood pressure levels. Testosterone levels
treatment, six had side effects; all had digestive complaints were greater than the ULN in 75% of women at the end of
(i.e., nausea, vomiting), four complained of asthenia, two the study. ACTH levels increased fourfold, but there was
reported difficulties at school, and five had severe AEs no meaningful change in the size of the evaluable pituitary
(two out of six patients with AI, two out of six with acute tumors. AEs were noted in 95% of patients; most common
hepatitis, and one out of six with severe acute hepatitis). were nausea, diarrhea, asthenia and AI (~ 30% of each).
One patient (11.1%) had progressive pituitary adenoma Only two SAEs (grade 3–4) occurred: one case of AI and
growth [55]. one case of increased testosterone level [61].
Frequent side effects are GI disturbance (50%), dizzi- A phase III clinical trial, LINC-3 (Safety and Efficacy
ness (30%), and cognitive alterations (30%) (Table 1) [53]. of LCI699 for the Treatment of Patients With Cushing’s
Mitotane has a prolonged half-life (160 days), and AEs may Disease; NCT02180217), is ongoing, with preliminary data
reported in an oral presentation in 2019 [62]. The study was no drug-related deaths (as reported in an oral presentation
an open-label phase, 26-week osilodrostat dose-adjustment in 2018) [66].
(2 mg/twice a day to 30 mg/twice a day), double-blind, pla-
cebo-controlled, randomized trial where eligible patients
2.2.3 Nevanimibe (ATR‑101)
continued osilodrostat (n = 36) versus placebo (n = 35) until
week 34. The remaining patients continued as open label
The cholesterol acyltransferase 1 (ACAT1) inhibitor neva-
until week 48 (n = 47). More patients taking osilodrostat
nimibe, initially evaluated for the treatment of congenital
maintained median UFC ≤ ULN than those in the placebo
adrenal hyperplasia, has been proposed as a potential target
group, without drug up-titration (86% vs 29%; odds ratio
for the treatment of CS. ACAT1 creates a cholesterol ester
13.7, P < 0.001). Sixty-six percent of patients had median
reservoir for steroid formation by catalyzing cholesterol ester
UFC ≤ ULN at week 48. The most common side effects
formation in the adrenal cortex. Inhibition of this enzyme
were nausea (42%), headache (34%) and fatigue (28%). AI
leads to a decrease of adrenal steroid formation, and at
was found in 51%, and increased adrenal-hormone-precur-
higher doses, causes free cholesterol accumulation that leads
sors in 42%. Only 24 patients (18%) discontinued the drug,
to adrenocortical cell stress and apoptosis. Animal studies in
mostly because of side effects.
canines have shown cortisol level reduction of 50% at a dose
of 30 mg/kg, without SAEs [67]. Currently, a phase II, ran-
2.2.2 Levoketoconazole
domized, double-blind, placebo-controlled clinical trial (A
Study of ATR-101 for the Treatment of Endogenous Cush-
Levoketoconazole, (2S,4R)-ketoconazole (formerly COR-
ing’s Syndrome; NCT03053271) to evaluate the efficacy and
003), is the single (2S,4R) enantiomer of ketoconazole [63].
safety of nevanimibe in 16 adults with a confirmed diagnosis
Levoketoconazole inhibits side-chain cleavage complex,
of endogenous CS for 16–22 weeks is underway.
CYP17, 21-hydroxylase (CYP21A2) and CYP11B1, and
thus decreases levels of circulating cortisol [64, 65].
Results of the phase III, open-label, single-arm and 2.2.4 Abiraterone Acetate (CB7630)
dose-titration SONICS study (Study of levOketocoNazole
In Cushing’s Syndrome; NCT03277690) found that 30% of Abiraterone acetate (CB7630; Zytiga), currently US FDA
patients had a maintained reduction of 24-h UFC to nor- and EMA approved for the treatment of castration-resistant
mal levels at the end of the 6-month maintenance phase of prostate carcinoma, prevents adrenal androgen production by
treatment (Table 1). Dose titration started at 150 mg and inhibiting CYP17, with secondary inhibition of serum corti-
increased up to 600 mg, which was used in the majority of sol in those patients. Additionally, abiraterone acetate is dea-
the subjects (66%). Median UFC was normalized in 38% cetylated to abiraterone, which in turn is metabolized into
of patients, and 48% had a normalized or reduced median Δ4-abiraterone (D4A) that contributes to CYP21A2 inhi-
UFC, by > 50% from baseline. Significant reductions were bition. An in vitro canine animal model for CS confirmed
also observed in mean fasting glucose, hemoglobin A1c CYP17 inhibition, with elevated progesterone precursors,
(HbA1c), and low-density lipoprotein (LDL) cholesterol, but decreased DOC [68]. This may be due to CYP21A2 and
although there were no significant changes in blood pressure CYP11B1 inhibitory activity. Side effects in prostate cancer
and there was a slight increase in high-density lipoprotein patients were AI and increased ACTH. The later may lead
(HDL) cholesterol, as well as triglycerides. At least one AE to an increase in steroids upstream of CYP17, including the
presented in 98% of patients, of which 43% were related mineralocorticoid DOC, which can lead to pseudohyperal-
to the study drug. The most common were nausea (32%), dosteronism. GC replacement prevented the rise in ACTH
headache (28%), peripheral edema (19%), fatigue (16%) and and was able to overcome the AEs of the mineralocorti-
diarrhea (15%). Treatment-emergent SAEs presented in 15% coid excess syndrome [68]. Currently, a phase II clinical
of patients. Elevation of liver enzymes less than 3 × ULN trial (Activity of Abiraterone Acetate in the Management of
was observed in 31% of patients, but increases of greater Cushing’s Syndrome in Patients With Adrenocortical Car-
than threefold and fivefold were observed in 7.4% and 3.2%, cinoma [ABACUS]; NCT03145285) is ongoing.
respectively. All abnormal liver enzymes (ALT) > 3 × ULN
occurred in the first 60 days of the maintenance phase, and in 2.2.5 Azd4017
all ten patients (11%) with ALT > 3 × ULN (including three
with ALT > 5 × ULN), the ALT elevation was reversible The 11β-hydroxysteroid dehydrogenase type 1 inhibi-
after discontinuing the drug, without any clinical sequelae. tor (AZD4017) is a new oral, fully reversible and potent
QTc prolongation of 60 ms presented in 10.2%, and QTc inhibitor of human recombinant 11β-hydroxysteroid dehy-
surpassed 500 ms in 2% of subjects. The study drug was drogenase type 1 (11β-HSD1). AZD4017 (2-[(3S)-1-[5-
discontinued in 13% of patients due to AEs, and there were (cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl]-3-pi-
peridyl]acetic acid) has been evaluated for the treatment of insulin sensitivity [72]. Medical expert recommendations
idiopathic intracranial hypertension and has been proposed have been issued regarding the treatment of hyperglycemia
as a potential treatment for CS [69]. 11β-HSD1 is a nicotina- in patients treated with pasireotide [73]. Metformin and/or
mide adenine dinucleotide (NADP) reduced form, NADPH- incretin-related therapies (dipeptidyl peptidase-4 [DPP-4]
dependent enzyme expressed in the liver, adipose tissue and inhibitors or glucagon-like peptide-1 [GLP-1] agonists) have
brain. 11β-HSD1 catalyzes the conversion of the inactive been suggested as first-line options [73].
steroid cortisone to active cortisol, playing an important An expanded analysis of the pasireotide trial (Safety and
role in the regulation of intracellular cortisol concentra- Efficacy of Different Dose Levels of Pasireotide in Patients
tions. There is a phase II clinical trial (Targeting Iatrogenic With de Novo, Persistent or Recurrent Cushing’s Disease;
Cushing’s Syndrome With 11β-hydroxysteroid Dehydroge- NCT00434148) showed continued benefit regarding the
nase Type 1 Inhibition [TICSI]; NCT03111810) aimed at clinical signs and symptoms of hypercortisolism due to
preventing the metabolic adverse features of iatrogenic CS. CD because of persistent reduction in 24-h UFC at 6 and
12 months [74]. Analysis of 40 patients who completed 24
months of treatment showed that 50% and 34.5% of patients
3 Pituitary‑directed Drugs had controlled UFC at 12 and 24 months (mean reduction
of 57% and 62%), respectively. GI symptoms continued to
3.1 Currently Available Pituitary‑Directed Drugs be the main side effects (diarrhea 55.6% and nausea 48%),
as well as hyperglycemia (39%) and cholelithiasis (35%).
3.1.1 Pasireotide New-onset DM2 was experienced in 8.6% of patients [75].
Data from an expanded-access subcutaneous pasireotide
Cell membrane expression of somatostatin receptor (SSTR) study (An Open-label, Multi-center, Expanded Access
subtype 2 decreases with hypercortisolism, while SSTR5 Study of Pasireotide s.c. in Patients With Cushing’s Disease.
subtype remains unaffected [70] or even increased [71]. [SEASCAPE]; NCT01582061) showed that 54.5%, 47.8%
Higher expression of SSTR5 over SSTR2 is observed in and 42.9% of evaluable patients had median UFC ≤ ULN at
active CS [17, 70, 71]. This could explain why octreotide weeks 12, 24 and 48, respectively. Clinical symptoms and
and lanreotide, which exhibit strong affinity to SSTR2 and signs of CD and quality of life (QoL) were improved from
weak affinity to SSTR5, remain ineffective in treating CD week 12 and sustained to week 48. AEs were similar to those
and have partial efficacy in treating Nelson’s syndrome. previously reported, and fewer than 20% of patients discon-
Previously known as SOM230, pasireotide is a multi- tinued therapy due to AEs [76].
ligand somatostatin receptor ligand (SRL) that targets four A phase III trial (Efficacy and Safety of Pasireotide
of five SSTR subtypes, with highest affinity for SSTR5, fol- Administered Monthly in Patients With Cushing’s Disease;
lowed by SSTR2, SSTR3, and SSTR1 [4] (Table 3). Pasire- NCT01374906) showed similar results with doses of 10 mg
otide is the only SRL that is currently US FDA and EMA or 30 mg. Median UFC was normalized in 40% of patients at
approved for treatment of CD. 7 months, and > 20% of tumor mass reduction was achieved
The double-blind, phase III study (Safety and Effi- in 43–47% of patients, with a similar safety profile. No sig-
cacy of Different Dose Levels of Pasireotide in Patients nificant differences were found in the 10 mg versus the 30
With de Novo, Persistent or Recurrent Cushing’s Disease; mg group [77]. In the extension trial, 81 out of 104 patients
NCT00434148) had two starting dose arms: 600 μg twice who completed the core study and had either median UFC
a day and 900 μg twice a day. At the end of the 12-months, ≤ ULN or significant clinical benefit, showed a controlled
13% of the 600 μg group and 25% of the 900 μg group had response of 51.9%, 65.5%, and 72.2% at months 12, 24,
a normal 24-h UFC. Only 20 of the 36 patients with nor- and 36, respectively. Tumor volume reduction ≥ 20% was
malized UFC at 6 months remained normal until the end of observed in 65.8% and 64.3% of patients with a pituitary
the study. Nonetheless, 50 out of 103 treated patients had a macroadenoma at 24 and 36 months, respectively. Tumor
reduction in UFC > 50% from baseline levels. Tumor vol- volume reduction of 71.4% and 100% was achieved at 24
ume decreased from baseline in 9% and 44% in the 600 μg and 36 months in patients with a pituitary macroadenoma,
and 900 μg groups, respectively. The most common AEs respectively. The safety profile was consistent with the core
were related to transient GI discomfort (diarrhea, nausea, study findings [76]. Predictors of response to pasireotide
and cholelithiasis), but hyperglycemia-related AEs (hyper- have been assessed, and while overall, 41.3% of patients had
glycemia, diabetes mellitus type 2 [DM2], and an increase in a controlled UFC at 7 months, patients in the lowest quartile
HbA1c) occurred in 73% of patients [4]. Studies in healthy basal UFC had higher response rates at that time [78].
volunteers showed that pasireotide-associated hyperglyce- The correlation between UFC or LNSC, and response
mia is related to decreases in insulin secretion and incretin to treatment remains unclear with most treatments. In the
hormone responses, without changes in hepatic/peripheral phase III, pasireotide long-acting repeatable (LAR) study, a
Table 3 Medical treatment options for Cushing’s syndrome directed to pituitary gland and glucocorticoid receptor antagonists
Drug Family Target Mechanism of Dose Effectiveness Side effects Approval status/use Clinical trials
action
FDA EMA
Current pituitary-directed therapies

Pasireotide (SOM-230) SRL SSTRs 5,2,3,1 Decreases ACTH 600-900 μg BID. Hypercortisolism Transient Approved for CD Phase III Pasire-
Agonist secretion and LAR: 10–30 improvement diarrhea and otide 2305
tumor cell mg/month in 34.5–50%. nausea; Expanded Pasire-
proliferation Tumor volume cholelithiasis; otide 2305
decrease hyperglycemia
9.1–43.8%
Cabergoline Ergot derivative DR type 2 Decreases ACTH 0.5–7 mg/week Normal UFC in Nausea and diz- Off-label for CS Retrospective study
Agonist secretion (mean 3.5 mg/ 30–40% ziness (usually Prospective study
week) transient) Large retrospective
multicenter
Cushing’s Syndrome: Current and Emerging Treatments
Temozolomide Alkylating agent DNA Metabolite MTIC 150–200 mg/m2/ Small studies: Fatigue, hearing Off-label Case reports
Alkylation causes DNA day for 5 days tumor regres- loss, phleg- Retrospective
methylation each month per sion 50%, mon, UTI, studies
cycle decreased liver enzyme Case series
ACTH by 88% increase,
and decreased hematological
UFC by 98% (cytopenia)
(MGMT (−)
MSH-6 (+)
could be a pre-
dictive factor)
Novel pituitary-directed therapies in phase II clinical trials
Retinoic acid Vitamin A RARs and RXRs Inhibits POMC RA: 10–80 mg RA: normal UFC Conjunctival irri- Not approved Prospective multi-
derivatives Agonist transcription QD 43% tation, nausea, center study
and ACTH Isotretinoin: Isotretinoin: nor- headache and Phase II prospec-
secretion. 20–80 mg QD mal LNSC and arthralgia tive open-label
Tumor cell UFC in 25%
apoptosis
R-roscovitine Purine analog CDK2 Dissociates 400 mg BID (4 Under study Asthenia, nausea Not approved Ongoing phase II
(CYC202, seliciclib) Antagonist CDK2/cyclin days/wk) and hypoka- Prospective
E complex, lemia NCT02160730
inducing cell
senescence.
Suppresses
ACTH secre-
tion and tumor
growth
Gefitinib (ZD1839) Tyrosine kinase EGFR Inhibits USP8 250 mg QD Under study Rash and diarrhea Not approved Ongoing phase II
inhibitor Antagonist mutation- prospective for
induced EGFR USP8 mutated
overexpression CD
943
Table 3 (continued)
944
Drug Family Target Mechanism of Dose Effectiveness Side effects Approval status/use Clinical trials
action
FDA EMA
Current glucocorticoid receptor antagonist

Mifepristone (RU486) Antiprogestogen PR and GR Blocks PR and 300–1200 mg Glucose improve- Nausea, fatigue, Approved for hypergly- Phase III SEISMIC
and antigluco- Antagonist GR, prevent- daily ment 60%. headache, cemia associated with
corticoid ing activation Hypertension hypokalemia, CS
despite high improvement arthralgia,
cortisol levels 38%. peripheral
edema, endo-
metrial thicken-
ing, vaginal
bleeding, AI
Novel GR antagonist
Relacorilant Antiglucocorti- GR Blocks GR, 100–400 mg QD Glucose improve- Musculoskeletal Not approved Phase I prospective
(CORT125134) coid Antagonist preventing acti- ment in 81.8%. and gastrointes- Ongoing phase II
vation despite Hypertension tinal, AI
high cortisol improvement in
levels 45.5%
ACTH adrenocorticotrophic hormone, AI adrenal insufficiency, BID twice daily, CD Cushing’s disease, CDK2 cyclin-dependent kinase type 2, CS Cushing’s syndrome, DNA deoxyribonucleic
acid, DR dopamine receptor, EGFR Epidermal growth factor receptor, EMA European Medicines Agency, FDA Food and Drug Administration, GR glucocorticoid receptor, LAR long-acting
repeatable, LNSC late-night salivary cortisol, MGMT O-6-methylguanine-DNA methyltransferase, MSH-6 DNA mismatch repair protein Msh6, MTIC 3-methyl-(triazen-1-yl)imadazole-4 car-
boxamide, POMC pro-opiomelanocortin, PR progestin receptor, QD once daily, RA retinoic acid, RAR retinoic acid receptor, RXR retinoid X receptor, SRL somatostatin receptor ligand, SSTR
somatostatin receptor, UFC urinary free cortisol, USP8 ubiquitin-specific protease 8, UTI urinary tract infection
J. M. Hinojosa‑Amaya et al.
greater proportion of patients achieved normal median UFC 3.1.3 Temozolomide

than median LNSC. Only 17.7% normalized both, and these
patients displayed the greatest changes in blood pressure and Temozolomide (TMZ; Temodar) is a chemotherapeuti-
weight. Mean LNSC basal level was 10.4 nmol/L (normal cal alkylating agent, which intracellularly metabolizes to
up to 3.2 nmol/L), with changes of −1.6 and −3.3 nmol/L 3-methyl-(triazen-1-yl)imadazole-4 carboxamide (MTIC).
at 7 and 12 months, respectively. There was a moderate cor- MTIC travels to the cell nucleus and causes DNA guanine
relation between median UFC and median LNSC when all methylation, which interferes with gene transcription. The
time points were pooled; this discrepancy may be because mechanism of action is via a mismatch with thymine during
dose titration was in reference to median UFC or due to an the cellular S-phase, resulting in DNA damage, senescence
intra-patient coefficient of variation of ~ 50% in patients or apoptosis [87, 88]. It is essential to maintain integrity
with CD [79]. of the mismatch repair (MMR) pathway, especially DNA
mismatch protein 6 (MSH-6), in addition to low expres-
3.1.2 Cabergoline sion or absence of O-6-methylguanine-DNA methyltrans-
ferase (MGMT) (see below) for TMZ to have good effect.
Dopamine D2 receptors (D2Rs) are mostly expressed in The presence of MGMT removes the methyl groups from
the anterior and intermediate lobes of the pituitary gland. guanine and repairs the DNA strands before the S-phase of
These receptors mediate tonic inhibitory control of hypo- the cellular cycle [87, 88]. TMZ has the potential to induce
thalamic dopamine on prolactin (PRL) and melanocyte- regression of corticotroph pituitary adenomas refractory
stimulating hormone (MSH) secretion. Functional D2Rs to medical, surgical and radiation therapy [89] and in the
are also present in corticotroph adenoma cells, albeit rare setting of pituitary carcinoma [90–92], in which it may
with lower expression than in prolactinoma or non- improve survival [93]. Absence of MGMT staining and
functioning pituitary adenoma (NFPA) [71], and D2R preservation of MSH-6 have been described by some, but
agonists are effective in controlling ACTH-dependent not all, as predictors of medical response to treatment with
cortisol hypersecretion [80]. Cabergoline is not US FDA TMZ [87, 88]. TMZ is US FDA approved for refractory ana-
approved for treatment of CD, but it has been used as an plastic astrocytoma, and its use for aggressive corticotroph
off-label medication (Table 3). A retrospective analysis or other pituitary adenomas and pituitary carcinoma is off-
of 30 patients treated with cabergoline (mean dose 3.5 label. Patients should be carefully selected for this therapy.
mg/week) as monotherapy for CD showed a short-term Efficacy and safety trials of TMZ in CD are lacking; how-
response of 30–40% and a long-term response of 30% ever, optimistic data have been reported in case reports [89,
[81]. A prospective, 6-week study using increasing dos- 90] and case series (either silent, CD or Nelson’s syndrome)
ages of cabergoline 0.5–5 mg/week in 20 patients with and in aggressive pituitary adenomas or carcinomas [91,
ACTH-dependent CD recruited from four academic 94]. A case series of 24 patients with aggressive pituitary
pituitary centers did not show significant reductions in adenomas or carcinomas reported three patients with CD
24-h UFC [82]. Nonetheless, a large retrospective mul- and pituitary carcinoma treated with TMZ. There was up to
ticenter study of 62 CD patients showed normal UFC in 50% regression on the tumor, ACTH decreased by 88%, and
40% within 12 months of treatment [83]. Furthermore, in UFC decreased by 98% [91]. Another case series, compris-
a prospective combination treatment study starting with ing four patients with multimodal treatment-refractory CD
either cabergoline (up to 3 mg/week) or ketoconazole, treated with TMZ and capecitabine, showed good response
33% of patients achieved UFC normalization with caber- for tumor control (ranging from stable tumor to complete
goline alone, and up to 79% with combined medications resolution of radiographic disease), cranial nerve deficits
[84]. The “escape phenomenon” is found in up to one- (improvement or resolution), and biochemical response
third of responsive patients, and tumor shrinkage is rare (ACTH decreased by > 50% to normalization) in all patients
[22]. Main AEs are mild transient nausea, dizziness, nasal (Table 3). Hematological AEs (thrombocytopenia and lym-
congestion, and depression. Cabergoline is usually well phopenia) were found in 50% [94].
tolerated, and there has not been a significant association
with valvular disease in the treatment of pituitary tumors 3.2 Novel Pituitary‑Directed Therapies in Clinical
[22, 85]; however, a new meta-analysis found an associa- Trials
tion with increased asymptomatic tricuspid regurgitation
in hyperprolactinemic patients treated even with low-dose 3.2.1 The Retinoic Acid Receptor, Retinoid X Receptor,
cabergoline [86]. As doses used in CD patients are much and Vitamin A Derivatives
higher, serially performed echocardiogram (ECHO) might
be needed. Retinoic acid receptor (RAR) and retinoid X receptor (RXR)
belong to the steroid hormone/nuclear receptor superfamily
along with other hormones and are present in the hypothala- Even though cyclin E is undetectable in normal pituitary,
mus and pituitary, where they modulate the activation of corticotroph cell adenomas are the only pituitary tumors that
the glucocorticoid receptor (GR) [95]. Retinoic acid (RA) show increased expression [101].
is the natural ligand of these receptors, which can dimerize R-roscovitine (formerly CYC202, seliciclib) is a purine
with multiple nuclear receptors (i.e., vitamin D, thyroid hor- analog with high inhibitor affinity to CDKs (Table 3).
mone, peroxisome proliferator-activated receptor [PPAR], R-roscovitine binds to CDK2 and dissociates the CDK2/
and liver X receptor [LXR]) [96]. Of these, chicken ovalbu- cyclin E complex, downregulating its activity, which in turn
min upstream promoter transcription factors (COUP-TFs), causes dephosphorylation of Rb, leading to senescence and/
present in normal pituitary cells, but rarely in adenomas [67, or apoptosis [101]. R-roscovitine has been shown to suppress
97], are inhibitors of the RA effect and are negative regu- ACTH secretion and tumor growth on transgenic POMC-
lators of RARs and RXRs (Table 3). Transcription of the pituitary tumor transforming gene (POMC-PTTG) zebrafish
target gene will be induced or inhibited depending on the embryos and murine models of ACTH-secreting pituitary
co-factors bound to RAR-RXR complexes [96]. adenomas. In vitro and in vivo analyses show a downregu-
lation of cyclin E expression and upregulation of the CDK
inhibitors p27, p21 and p57 [102]. Since ectopic POMC is
3.2.2 Retinoic Acid also suppressed by this pathway, ACTH production may be
reduced in ECS after R-roscovitine treatment [103].
RA is a product of the metabolism of retinol, and isotreti- R-roscovitine is not US FDA approved, but has been
noin is the most frequently used vitamin A isomer. In vitro tested in several phase I and II clinical trials [104, 105]. Cur-
studies using AtT20 mice pituitary ACTH-secreting tumor rently, there is an ongoing phase II trial (Treatment of Cush-
cells have shown that RA inhibits pro-opiomelanocortin ing’s Disease With R-roscovitine; NCT02160730) using oral
(POMC) transcription and ACTH secretion via transcrip- 400 mg R-roscovitine twice daily for 4 days every week for
tion factors such as activator protein 1 (AP-1) and nuclear a total of 4 weeks. The primary outcome measure is nor-
receptors Nur77/Nurr1 [67, 96, 97]. RA also decreases malization of 24-h UFC after treatment. Side effects include
adenoma cell proliferation by inducing bone morphogenic asthenia, nausea and hypokalemia, usually using higher dos-
protein 4 (BMP-4), which induces chromatin remodeling, ages of 800 mg twice daily [67, 104, 105].
and activates caspase 3, which leads to apoptosis [95–97].
In murine and canine models, RA decreased plasma ACTH 3.2.4 Gefitinib, an Epidermal Growth Factor Receptor
and cortisol in the former and also α-MSH and urinary cor- Inhibitor
tisol/creatinine ratio in the latter. A reduction in pituitary
adenoma size was observed in both models [96–98]. The Epidermal growth factor receptor (EGFR) is expressed
role of oral isotretinoin (13-cis-RA) therapy for CD trial in both the normal pituitary and in corticotroph pituitary
showed normal UFC and LNSC in 25% of the subjects with adenomas. This receptor controls POMC expression, and
a daily dose of 20 to 80 mg for 6–12 months. In addition to inhibition has been studied as a possible target for the
AEs observed previously, cheilitis and mucositis were found treatment of CD [106]. There is also evidence that EGFR
with isotretinoin [99]. induces corticotroph tumorigenesis with more aggressive
In a prospective, multicenter trial, RA was started with ACTH-secreting pituitary adenomas, including some fea-
an oral 10-mg dose once a day and titrated up to 80 mg tures of Crooke’s cell in transgenic mice, which correlates
once a day, with 43% of patients normalizing UFC at 6 and with a more aggressive subtype [107]. EGFR overexpression
12 months of treatment (Table 3). Conjunctival irritation, is associated with downregulation of p27, a CDK inhibitor
nausea, headache and arthralgia were the most common AEs that can be restored after EGFR inhibition [95, 106, 108].
[100]. Gefitinib (Iressa; ZD1839) is an oral EGFR inhibitor used
Vitamin A derivatives are US FDA approved for the treat- as the first-line treatment of metastatic non-small-cell lung
ment of acne, but use for CD is off-label [96]. cancer (NSCLC) with EGFR-specific mutations and is US
FDA approved for locally advanced or metastatic NSCLC
3.2.3 R‑Roscovitine after failure of both platinum-based and docetaxel chemo-
therapies. Studies in canine and human corticotroph tumors
Cyclin E is a regulatory subunit of cyclin-dependent and murine models showed POMC attenuation and induc-
kinase (CDK) type 2 (CDK2). The cyclin E-CDK2 com- tion of tumor-cell apoptosis after blocking EGFR (Table 3).
plex phosphorylates retinoblastoma protein (Rb), which in Although the effects of gefitinib on cell cycle proteins
turn releases E2F transcription factor and promotes G1 to S and apoptosis seem weak, there was a 80% suppression of
cell-phase progression. In corticotroph cells, this pathway POMC expression and a 75% decrease in ACTH secretion
increases cell division, causing ACTH overproduction [101]. [106]. There is an ongoing phase II, single-group, open-label
clinical trial (Targeted Therapy With Gefitinib in Patients induces phosphorylation of the transcription factors Nurr77,
With USP8-mutated Cushing’s Disease; NCT02484755) for c-jun, and c-fos, promoting POMC transcription and over-
patients treated with an oral daily dose of gefitinib (250 mg expression [114].
once daily) for a total of 4 weeks. The primary endpoint is Vemurafenib is a BRAF inhibitor marketed to treat BRAF-
change in 24-h UFC at the end of the study. mutation–positive melanoma [115, 116] and is also approved
for the treatment of BRAF V600-mutation–positive Erdheim-
3.3 Future Targets at the Pituitary Level Chester disease [115]. It is currently being studied for the
treatment of BRAF-positive thyroid cancer and other BRAF
3.3.1 Ubiquitin‑Specific Protease 8 Gene V600-positive malignancies [115]. Corticotroph tumor cell
cultures with BRAF V600E mutation show a greater reduc-
EGFR overexpression is linked to a somatic gain of function tion in ACTH secretion than the wild type after 24-h incuba-
mutation of the ubiquitin-specific protease 8 gene (USP8) tion with vemurafenib at a minimal inhibitory concentration
[109–111]. USP8 deubiquitinates multiple target proteins of 0.3 μM [114]. In vitro research data are limited.
including EGFR, protecting them from degradation, and
its activity is downregulated by phosphorylation and asso- 3.3.3 Silibinin
ciation with 14-3-3 protein. Mutant USP8 fails to bind to
14-3-3 protein, leading to a greater USP8 activity deubiq- The GR of the corticotroph cell suppresses transcription
uitinating EGFR. Deregulated EGFR increases mitogen- of POMC, a direct precursor of ACTH. Heat shock protein
activated protein kinase (MAPK) signaling, which in turn 90 (HSP90) is essential for proper folding of the ligand-
promotes POMC transcription by inducing the degrada- binding domain of GRs. However, the excessive expression
tion of regulators such as p27 (Kip1) and receptor tyrosine and continued binding of HSP90 to GRs inhibits the GR
kinases (RTKs) such as Erb3 and C-Met. USP8 mutation transcriptional activity by reducing DNA binding, resulting
also deubiquitinates smoothened (Smo), a key factor to acti- in partial corticotroph adenoma GC resistance. Corticotroph
vate hedgehog signaling, leading to ACTH secretion [111]. adenomas overexpress HSP90 as compared to the normal
Studies have shown that 35–62% of corticotroph pituitary pituitary and NFPAs [117]. Therefore, HSP90 inhibitors
adenomas harbor somatic USP8 mutations, mainly in exon may release GRs from HSP, restoring GC sensitivity [110].
14 (77.6% of these at Ser718 and Pro720), which codes Silibinin (Legalon), a compound obtained from the milk
the protein’s phosphorylation and binding sites [109, 111, thistle plant (Silybum marianum), is a C-terminal inhibitor
112]. A USP8 inhibitor (9-ehtyloxyimino-9H-indeno[1,2- of HSP90 that has been used for the treatment of amatoxin
b]pyrazine-2,3dicarbonitrile) is available, but has not been poisoning-induced hepatotoxicity, with a good safety profile
extensively studied. USP8 inhibition in mouse AtT20 pitui- [117, 118]. It also has been studied as a potential treatment
tary corticotroph cells downregulated EGFR expression, of prostate cancer, breast cancer, hepatocellular carcinoma
decreased ACTH synthesis, and induced apoptosis [109, and lymphoblastic leukemia [119]. Currently, there are no
113]. registered clinical trials of silibinin for treatment of CD.
3.3.2 Vemurafenib 3.3.4 Testicular Orphan Receptor 4
Recent whole exome sequencing revealed recurrent muta- Testicular orphan receptor 4 (TR4) is a nuclear receptor
tions in USP48 and BRAF genes in the presence of wild that lacks a specific ligand (hence the term “orphan”) with
USP8 phenotype, making the BRAF kinase inhibitor vemu- many physiological roles. Normal pituitary corticotroph
rafenib (Zelboraf) a potential option for the treatment of CD. cells express TR4 and TR4-knock out models have found
USP48 gene codes a deubiquitinating protein, which acti- decreased expression of POMC. Corticotroph tumors
vates nuclear factor kappa-light-chain-enhancer of activated have an over expression of TR4, which leads to increased
B cells (NF-κB), which directly binds the POMC promoter POMC transcription, ACTH secretion and also cell pro-
and regulates its transcription. Missense mutations cause liferation in in vitro and in murine models [120]. TR4
inhibition of NF-κB activity, inducing a gain-of-function also decreases negative feedback on POMC transcrip-
mutation, which causes overexpression of POMC messenger tion/ACTH secretion of corticotroph cells by blunting
RNA (mRNA), compared with the USP48 wild type. The the interaction of cortisol with GR and, in the latter, with
BRAF gene is a mutational hotspot gene for multiple can- the promoter region of POMC [120, 121]. TR4 may be a
cers, including melanoma and craniopharyngioma. BRAF potential therapeutic target, but there are no developed
V600E mutations cause a constitutive activation of BRAF molecules known to inhibit or antagonize this orphan
kinase and, downstream, cAMP-dependent MAPK activa- receptor activity.
tion, which in turn upregulates Erk1/2 phosphorylation. This
3.3.5 Monoclonal Antibodies Against ACTH sequences for nuclear translocation, dimerization and trans-
activation, as well as silencing sites on the receptor if the
ALD1613 is a novel long-acting monoclonal antibody that hormone is absent [127]. Ligand binding causes a confor-
controls ACTH-driven pharmacology. Preclinical in vitro mational change in the GR molecule that causes irreversible
studies with ALD1613 have shown decreased ACTH- dissociation from the HSP complex; the receptor protein
dependent cAMP production in MC2R-expressing cells. becomes hyperphosphorylated, and nuclear localization
In vivo studies have shown reduced corticosterone produc- signals are unmasked to allow translocation of the recep-
tion levels in rats and prevented ACTH-induced pheno- tor to the DNA to perform its biological activity via one of
type in a rat animal-model. ALD1613 also reduced cortisol two mechanisms (type 1 or type 2). In the type 1 or classi-
levels in an cynomolgus monkey animal-model, in which cal mechanism of action, a receptor homodimer binds GC
pharmacokinetics and pharmacodynamics were described response elements; this interaction stabilizes the initiation
[122]. To date, there are no ongoing clinical phase I stud- complex on the promoter and enhances transcription by
ies for this drug. RNA polymerase. The type 2 mechanism, on the other hand,
achieves inhibition rather than activation and involves nega-
tive transcriptional regulation by directly binding AP-1 and
3.3.6 MicroRNA Manipulation downregulating its transcriptional activity [127].
In CS, blocking GRs can prevent the deleterious effects
The endogenous non-coding RNA molecules that are of chronic uncontrolled hypercortisolism, but these ben-
cleaved from intronic or inter-genic primary RNA efits must be weighed against adverse effects and the
sequences are called microRNA (miRNA). Mature miR- need for intensive monitoring. GR antagonists block GRs
NAs can be incorporated into the RNA-induced silencing without blocking either corticotrophin releasing hormone
complex (RISC) and bind imperfectly to the 3′ region of (CRH), ACTH, cortisol syntheses or secretion; instead,
their target mRNA. The RISC contains additional endonu- absence of negative feedback by blocking the tumor’s GRs
cleases that can either repress translation or induce mRNA may increase levels of ACTH and cortisol; thus a patient
degradation. In this way miRNAs can “fine-tune” mRNA may have AI with high cortisol and ACTH circulating
levels and contribute to cellular homeostasis [123]. Corti- levels. If a GR antagonist drug cannot bind to mineralo-
costeroidogenic enzyme expression is tightly controlled at corticoid receptors (MRs), excess of cortisol may over-
transcription, but studies suggest that post-transcriptional whelm and activate the MRs (spill-over effect) and cause
modification of miRNA plays a significant role in that both hypokalemia and hypertension (Table 3). Similarly,
expression and has been proposed as a potential treatment if the GR antagonist binds to the progesterone receptors,
mechanism for CD and hyperaldosteronism [123]. In vitro this antagonism may lead to vaginal bleeding, endome-
studies have shown that a reduction in miRNA increases trial hyperplasia or carcinoma in female patients with a
all cytochrome P450 encoding mRNA of steroidogenesis uterus in the long term [128, 129]. To date there is no
enzymes, except for StAR and dehydrogenase enzymes. In biochemical marker to confirm effective GR antagonism
this same study, in vitro miR-125a-5p and miR-125b-5p and no prognostic marker of AI exists for the patients to
altered CYP11B2 expression [123]. Likewise, miRNAs be followed with. Polymerized chain reaction–measured
seem to influence various genes associated with the patho- FK506 binding protein 5 (FKBP5) mRNA levels have been
genesis of pituitary adenomas, and altered expression has proposed as a potential clinical biomarker [130]; however,
been described in a specific fashion related to clinical its usefulness is yet to be confirmed.
and therapeutic characteristics of the adenomatous tissue
[124], including ACTH-secreting tumors [125]. There are
no current ongoing clinical trials to test miRNA for the 4.1 Mifepristone
treatment of CD, but their expression in this disease and
in ACTH-ECS is being studied [126]. Mifepristone {RU486; 11β-[P-(dimethylamino)phenyl]-
17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one} is a
progestin receptor (PR) antagonist with GR antagonism
4 Glucocorticoid Receptor Antagonists at higher doses. Affinity to GR is four times higher than
dexamethasone and 18 times higher than cortisol, with
GR expression is found in every human cell. These nuclear no biological activity. It also has a weak anti-androgenic
receptors are encoded by the NR3C1 gene, located in locus effect, but does not bind to mineralocorticoid and estrogen
31 of the long arm of chromosome 5 (5q31). In addition receptors [43, 131]. It is US FDA approved for the treat-
to the binding site for the specific hormonal ligand, GRs ment of hyperglycemia associated with CS. The phase III,
bind chaperone proteins, such as HSPs, and have important 24-week, open-label after failure of multimodal treatment
trial (A Study of the Efficacy and Safety of CORLUX in relacorilant after a high-fat breakfast has been completed. A
the Treatment of Endogenous Cushing’s Syndrome [SEIS- single dose assessment of pharmacological effects with three-
MIC]; NCT00569582) evaluated 50 patients with endog- way crossover to prednisone alone/prednisone + mifepristone/
enous CS and hyperglycemia (either DM2 or impaired prednisone + relacorilant was then performed. Finally, a mul-
glucose tolerance) or hypertension [43]. The daily dose tiple ascending dose study with assessment of pharmacologi-
of mifepristone was between 300 and 1200 mg (Table 3). cal effects was also performed, with relacorilant doses of 50,
The drug produced a significant clinical and metabolic 150, 250 and 500 mg; doses of 250 and 500 mg were given
improvement, with 60% of hyperglycemic patients for 14 days, either alone or along with prednisone at day 5 and
responding favorably (decrease of HbA1c from 7.43% to day 14. Relacorilant was well tolerated up to single doses of
6.29% and fasting plasma glucose from 149 to 104 mg/dL). 500 mg and repeated doses of 250 mg. Main side effects were
Only 38% of hypertensive patients had response regard- musculoskeletal disorders such as back pain [134].
ing diastolic blood pressure. There was also a significant An open-label, phase II study in adult patients with CS with
improvement in QoL, depression and cognition. AEs were impaired glucose tolerance or type 2 diabetes and a require-
found in 88% of patients; the most common were nausea ment for medical treatment of hypercortisolism was under-
and fatigue (48%), headache (44%), hypokalemia (34%), taken in low-dose and high-dose relacorilant groups (Study
arthralgia (30%), vomiting and peripheral edema (26%), to Evaluate CORT125134 in Patients With Cushing’s Syn-
hypertension (24%), dizziness (22%), hyporexia (20%) drome; NCT02804750). The low-dose group (n = 17) received
and endometrial thickening due to PR antagonism (20%). relacorilant at dosages of 100 mg/day for 4 weeks, then 150
Severe AEs occurred in four patients (two AI, one severe mg/day for 4 weeks, then 200 mg/day for 4 weeks, while the
hypokalemia, and one vaginal bleeding) [43]. Metabolized high-dose group (n = 15) received 250 mg/day for 4 weeks,
by CYP450 3A4 and as a PR and GR antagonist, mife- then 300 mg/day for 4 weeks, then 350 mg/day for 4 weeks,
pristone has 778 known drug interactions, 362 of which then 400 mg/day for 4 weeks. Partial results from the low-dose
are listed as major (www.drugs.com). Decreased levels of group are available. At week 12, 82% of patients had signifi-
mifepristone may be caused by potent inducers of CYP450 cant improvement in glucose area under the curve and mean
3A4, which should be avoided [132]. glucose values. However, only 45.5% had met the hypertension
There are no biochemical tests to follow the treatment control endpoint. Interestingly, treatment with relacorilant led
response or predict AI, and follow-up should be based on to small increases of ACTH and non-significant increases in
close clinical evaluation. AI will require treatment with UFC. Treatment-emergent AEs occurred in 88% of patients;
high-dose dexamethasone (to overcome the GR blockade) the most common were musculoskeletal (25%) and GI (19%).
and mifepristone withdrawal or dose reduction. If severe There were no serious or life-threatening AEs and there were
hypokalemia were to occur, supplementation of potassium no discontinuations attributed to relacorilant [135].
salts and spironolactone may be required. Endometrial
hyperplasia in women may be another complication, and
mifepristone should be stopped if there is vaginal bleeding 5 Combination Therapies
and further evaluation will be necessary. This drug is also
contraindicated if pregnancy is planned [131]. 5.1 Ketoconazole and Metyrapone
4.2 Relacorilant A combination of ketoconazole (300–1200 mg/day) and

metyrapone (750–1000 mg) during 4 months of treatment
Relacorilant, {CORT125134; [(R)-(1-(4-fluorophenyl)-6- achieved a UFC normalization in 52% of 62 preoperative,
((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexa- previously untreated CS (85% CD) patients. Interestingly,
hydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl) (4-(trifluo- clinical improvement did not always follow biochemical
romethyl)pyridin-2-yl) methanone} is an oral, selective improvement [136].
anti-GC with very high affinity to GR in development [133]
(Table 3). Unlike mifepristone, relacorilant does not bind 5.2 Ketoconazole, Metyrapone and Mitotane
PR, and therefore patients will not be prone to have anti-
progestin side effects such as termination of pregnancy, Triple therapy with ketoconazole (400–1200 mg/day),
endometrial hyperplasia or vaginal bleeding [134]. metyrapone (3.0–4.5 g/day), and mitotane (3.0–5.0 g/day)
A phase I, double-blind, randomized, placebo-controlled has also been studied as an alternative to rescue bilateral
trial (Relacorilant Food Effect Study in Healthy Subjects; adrenalectomy in severe ACTH-dependent CS, leading to a
NCT03442621) in 81 healthy volunteers who received 5–500 rapid and sustained normalization of UFC and to improve-
mg of relacorilant following a single ascending dose sched- ment in signs, symptoms and biochemical parameters. A
ule, followed by a single-dose food-effect test with 150 mg of reported high AE rate (36% of patients with acute AI and
elevated liver enzymes in 82%) has limited the use of this a day) was initially given as monotherapy, then at day 28,
triple combination [46, 47]. cabergoline (0.5–1 mg once a day) was added and increased
if UFC levels were above ULN. Finally, at day 60, ketocona-
zole (200 mg three times a day) was added to the regimens
5.3 Cabergoline and Ketoconazole of all patients who did not have normalized UFC. Effective-
ness at the end of 80 days was 29% with monotherapy, which
A small case series reported normalized UFC in six patients increased to 53% after cabergoline and to 88% after addition
with partial response to 3.5 mg/week of cabergoline after of ketoconazole [138].
ketoconazole (50–200 mg once a day) was added. There
was a significant clinical improvement during the treat- 5.6 Bromocriptine and Retinoic Acid
ment, and there was no liver damage nor valvular heart dis-
ease observed [137]. A small prospective crossover study A pre-clinical, in vitro study of the effect of bromocriptine
was performed to assess the effectivity of this combina- or 9-cis retinoic acid (9-cis-RA) and combined therapy was
tion starting with one drug or the other. Six patients began performed in murine AtT20 and corticotropinoma-derived
with cabergoline (0.5–3.0 mg/week) for 4–6 months, with primary cells [139]. 9-cis-RA induced DR2 expression in
ketoconazole added, and eight patients initiated with keto- AtT20 cells and doubled bromocriptine POMC-activity
conazole (200–600 mg once a day) for the same time before inhibition (34–68%, p < 0.01). While 9-cis-RA alone,
cabergoline was added. This combination was effective in inhibited ACTH synthesis and secretion, this same effect
79% of patients after 18 months, with no difference between was 31% higher (p < 0.01) with the combined therapy. Cell
groups [84]. viability was decreased with each independent drug in a
dose-dependent manner (half maximal inhibitory concen-
tration [CI50]: 9-cis-RA 150 nM and bromocriptine 4.97
5.4 Pasireotide and Cabergoline μM), but was achieved at lower doses when drugs were
combined (CI50: 9-cis-RA 5 nM and bromocriptine 0.53
Cabergoline has been used in combination with SRLs,
μM) [139]. In vivo preclinical and clinical studies are yet
including pasireotide, when the latter cannot achieve disease
to be undertaken.
control in acromegaly. As most corticotropinomas show co-
expression of SSTR5 and DR2, the combination of pasire-
otide (100–250 µg subcutaneous, three times a day) and
cabergoline was tested versus pasireotide alone (100–250 6 Choice of Medical Therapy and Monitoring
µg subcutaneous, three times a day) in a small number of
patients (n = 17), and showed an increased response rate CS treatment goals are multiple and include reversal of clini-
with the combined treatment (53%) against monotherapy cal features, normalization of biochemical parameters, and
(29%) [138]. The ongoing prospective phase II trial (Study tumor control, all while minimizing morbidity and attempt-
of the Efficacy and Safety of Pasireotide s.c. ± Cabergoline ing to achieve long-term remission. As multiple cortisol-
in Patients With Cushing’s Disease; NCT01915303) was lowering therapies are now available, albeit with differing
designed to test this combination in a larger population (n mechanisms of action, an ideal medical agent should be
= 66) [137]. Pasireotide (600–900 µg subcutaneous, twice efficacious, cost-effective, have a favorable pharmacokinetic
a day) was started as a monotherapy for 8 weeks. If UFC profile, be safe and well tolerated, encourage high patient
remained above ULN, cabergoline 0.5 mg once a day was adherence, and improve patient satisfaction [140–142].
added for 8 weeks, and then increased to 1 mg once a day Medical treatment should be individualized based on disease
if UFC remained abnormal. Study efficacy was 38% (n = severity, the desired onset of drug action, presence of comor-
25/66) at week 35, with improved CS symptoms and a self- bidities, baseline clinical and biochemical findings, gender,
reported QoL score increase of 11.5%. Drug-combination concomitant medications, expected side effects, costs and
side effects were similar to the effects described for each regional drug availability.
individual drug, SAEs presented in 9%, and drug-attributed If the patient meets the criteria for severe or life-threat-
discontinuation was 13.6% [64]. ening hypercortisolism (Table 2), etomidate is the only IV
medication available with a quick onset of action. If hyper-
cortisolism is not life-threatening or if intensive-care unit
5.5 Cabergoline, Ketoconazole and Pasireotide (ICU) admission for etomidate administration or the medi-
cation itself is not available, metyrapone and ketoconazole
A small trial evaluated a step-wise approach to treatment,
are also fast-acting alternative drugs, and combined therapy
in which pasireotide (100–250 µg subcutaneous, three times
may be considered (if there are no contraindications), while For most drugs, the biochemical control target is UFC
awaiting stabilization after bilateral adrenalectomy. and/or LNSC normalization. Most studies to date have used
For longer term therapy, ketoconazole is preferred in UFC as a definition of biochemical control, since it is nor-
female patients due to the inhibitory activity of CYP17 that malized more frequently than LNSC, and studies that used
blocks adrenal androgen synthesis and diminishes hirsutism. just LNSC found only moderate correlation with UFC, as
Ketoconazole is less convenient for men, who may expe- described for pasireotide [79]. At least two repeated tests are
rience primary hypogonadism as a drug side effect. Fur- necessary to confirm biochemical control, as it is known that
thermore, due to frequent elevation of liver enzymes, use UFC has a within-patient variability of 52% [143].
in patients with severe liver abnormalities at baseline needs Careful education on identifying and reporting symptoms
cautious monitoring. Metyrapone, on the other hand, may of AI and the side effects of each drug should be provided to
cause hirsutism in women and may be preferred for men as all patients, as well as emergency actions to take. Further-
initial therapy. Metyrapone availability is limited to certain more, for patients taking mifepristone, they should be made
countries, and use in the USA is limited. aware that cortisol will not be an indicator of AI. Blood pres-
Mitotane is the most beneficial agent in CS secondary to sure should be monitored at all visits and serum potassium
adrenal carcinoma, but neurological side effects, adrenolysis levels assessed. If patients are taking anti-diabetic medica-
and teratogenesis may limit drug use to treat other forms of tions, doses might be reduced with CS improvement.
CS. Serum cortisol should be measured every 6 h while on an
Treatment with pituitary-directed drugs should only be etomidate infusion, and the patient should have hourly neu-
attempted in patients with CD. Pasireotide can provide rological assessments because of the hypnotic effects of the
both biochemical and tumor size shrinkage, thus should drug. If a drop in cortisol is abrupt or serum cortisol meas-
be considered as initial treatment post-surgery in the pres- urements cannot be obtained frequently, block-replacement
ence of a macroadenoma or a growing pituitary adenoma, therapy may be required. Since patients taking etomidate
regardless of size. Pasireotide use may be limited by uncon- are admitted to the ICU, supraphysiological (stress) doses
trolled hyperglycemia, liver enzyme elevation or gallblad- of steroids should be started as replacement.
der disease. Cabergoline may also achieve disease control There is no prospective data about when and how fre-
at higher doses, but does not induce adenoma shrinkage per quently laboratory tests should be performed at follow-up.
se; pre-existing psychiatric, heart valve disease or pulmo- We suggest individualized protocols, as needed, based on the
nary fibrosis are known cabergoline contraindications. TMZ, patient’s symptoms, clinical findings and baseline results.
either with or after radiotherapy, should only be used in the
case of aggressive adenomas refractory to all other treat-
ment modalities, or for a pituitary carcinoma. TMZ efficacy 7 Conclusion
should be carefully balanced with known drug side effects.
GR antagonists may be considered in cases of CS with New pathophysiological pathways to treat endogenous CS
severe hyperglycemia; women with a history of endometrial and more therapeutic targets have increased the armamen-
hyperplasia or vaginal bleeding or women desiring preg- tarium available to control hypercortisolism and prevent
nancy should not be treated with mifepristone. disease excess morbidity and mortality. These new targets
Patients with polypharmacy or high-risk CYP450 3A4 are not only limited to novel, steroidogenesis inhibitors and
metabolized drugs may benefit from medications other than prevention of steroid substrate uptake by the adrenals, but
ketoconazole, mitotane or mifepristone. Severe hyperten- have expanded to include decreased target tissue corticos-
sion or pre-existent hypokalemia may also limit the use of teroid concentrations, target tissue GR blockage, restora-
metyrapone or mifepristone. tion of negative feedback on the pituitary, decreasing POMC
There is no one test that can perfectly assess treatment transcription and ACTH secretion, inducing adenomatous
efficacy. Careful review of symptoms, hypercortisolism corticotroph cell senescence and apoptosis, as well as pre-
or AI, as well as a thorough review of side effects and a venting secreted ACTH reaching target receptors. This vis-
directed physical exam should always precede biochemical ible armamentarium growth offers unprecedented opportuni-
interpretation. Assessments for biochemical tests are based ties and hope for CS patients, in the relatively near future.
on the mechanism of action of the medication used. A base- More effective and safe individualized treatment paradigms
line laboratory workup (i.e., liver function tests, glucose, (personalized medicine) for individual CS patients are now
serum electrolytes) will screen for contraindications for a possible.
medication and also will be used for comparison during
follow-up. A baseline electrocardiogram (ECG) is also nec- Acknowledgements The authors thank Shirley McCartney, PhD, for
manuscript preparation and editorial assistance.
essary for all drugs that are known to prolong QTc.
Compliance with Ethical Standards A et al. Effectivity and side effects of LINAC stereotactic radi-
otherapy as treatment for pituitary adenomas. 2018. ENDO
2018; March 17, 2018; SAT-626-LB; Chicago, IL2018.
Funding No sources of funding were used to assist in the preparation
13. Burman P, van Beek AP, Biller BM, Camacho-Hubner
of this study.
C, Mattsson AF. Radiotherapy, especially at young age,
increases the risk for de novo brain tumors in patients
Conflict of interest José Miguel Hinojosa-Amaya and Daniel Cuevas- treated for pituitary/sellar lesions. J Clin Endocrinol Metab.
Ramos have no conflicts of interest that are directly relevant to the 2017;102(3):1051–8. https://doi.org/10.1210/jc.2016-3402.
content of this study. Maria Fleseriu is a principal investigator with 14. van Varsseveld NC, van Bunderen CC, Ubachs DH, Franken
funding from research grants to Oregon Health & Science University AA, Koppeschaar HP, van der Lely AJ, et al. Cerebrovascular
from Millendo, Novartis, and Strongbridge, and has done occasional events, secondary intracranial tumors, and mortality after radi-
scientific consulting work for Novartis and Strongbridge. otherapy for nonfunctioning pituitary adenomas: a subanalysis
from the Dutch National Registry of Growth Hormone Treat-
ment in Adults. J Clin Endocrinol Metab. 2015;100(3):1104–
12. https://doi.org/10.1210/jc.2014-3697.
15. Yamanaka R, Abe E, Sato T, Hayano A, Takashima Y. Sec-
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Drugs (2019) 79:935–956

Medical Management of Cushing’s Syndrome: Current and Emerging

Published online: 17 May 2019

Ketoconazole is an antifungal imidazole derivative, first

Current steroidogenesis inhibitors

“Block and replacement” therapy may be needed to pre-

Metyrapone is a fast-acting inhibitor of steroid

CYP17, 18-hydroxylase (CYP11B2) and 19-hydroxylase

suggested that ACTH release from corticotroph cells may

adrenal glands, causing a drug “escape effect” [21, 22,

though the escape effect may occur in 19% of cases, some

studies have shown a sustained long-term response to

metyrapone [45]. Metyrapone is approved for the treat-

tisol) as well as adrenal androgens (i.e., DHEA, DHEA-

solism control, sustained by 70% of the patients at 12 and

as assessed by late-night salivary cortisol (LNSC). Dur-

of the female patients had hirsutism, and blood pressure

three patients (9.6%) [48]. No major drug interactions

reported on drugs.com [49]. Use of metyrapone has

been rarely reported during pregnancy; however, safety

clinical studies [50]. Availability of metyrapone is also

An analog of the insecticide dichlorodiphenyltrichlo-

adrenolytic action caused by lipid accumulation and atrophy

Current pituitary-directed therapies

Current glucocorticoid receptor antagonist

greater proportion of patients achieved normal median UFC 3.1.3 Temozolomide

3.3.2 Vemurafenib 3.3.4 Testicular Orphan Receptor 4

4.2 Relacorilant A combination of ketoconazole (300–1200 mg/day) and

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greater proportion of patients achieved normal median UFC 3.1.3 Temozolomide

3.3.2 Vemurafenib 3.3.4 Testicular Orphan Receptor 4

4.2 Relacorilant A combination of ketoconazole (300–1200 mg/day) and