Cushing’s Syndrome (CS) refers to the clinical manifestations induced by chronic exposure to excess glucocorticoids and may have exogenous causes (e.g., excess glucocorticoid intake for the treatment of inflammatory conditions) or endogenous. There are three pathological conditions that can result in the chronic overproduction of endogenous cortisol. The most common condition is Cushing’s Disease (CD), where pituitary corticotroph adenoma overproduces ACTH. Secondly, and more rare, a non-pituitary tumor can produce ACTH in an “ectopic” manner. Finally, one or (rarely) both two adrenals that have tumors (benign or malignant) can directly over-secrete cortisol. Adrenocortical or exogenous adenomas and carcinomas cause primary hypercortisolism, which accounts for 20% of endogenous CS cases.5,53,54 Chronic hyperproduction of ACTH causes secondary hypercortisolism, which accounts for roughly 80% of endogenous CS,54 and ACTH-secreting pituitary or exogenous adenomas causes CD, which is the most common form of secondary hypercortisolism. CD accounts for 70% of CS cases.55
CS may follow over administration of prednisone, dexamethasone, or prednisolone. CS manifestations typically are nonspecific, which complicates the initial diagnosis.4
Commonly recommended initial testing are urinary free cortisol, late-night salivary cortisol, and 1-mg overnight dexamethasone suppression test (DST). Imaging is the key to diagnosis. CS continues to pose diagnostic and therapeutic challenges; life-long follow-up is mandatory.56
Untreated, it has significant morbidity and mortality. The syndrome remains a challenge to diagnose and manage.57,58
CS is a rare condition that, according to one estimate, affects fewer than five in 10,000 individuals.59 Table 6 summarizes data on the prevalence and incidence of CS and CD.
|Population||Data Source||Prevalence (cases per million)||Incidence rates (cases per million per year)||Reference|
|US, aged ≤ 65 from 2007 to 2010*||Commercial database of patients||N/A||
CS, 48.6 in 2009 and 39.5 in 2010**
CD, 7.6 in 2009 and 6.2 in 2010***
|Broder et al. 201460|
|Medline database, 2000-2005||Systematic review||CS, 20,000-50,000 in patients with diabetes||CS, 0.7 to 2.4 (researchers acknowledged that this estimate probably was too low)||Newell et al. 200657|
|166 Danish patients diagnosed with CS, 1985-1995||Data from the National Patient Register of the Danish National Board of Health||N/A||CD, 1.2-1.7||Lindholm et al. 200161|
|49 CD patients in Vizcaya (Spain) between 1975 and 1992||Epidemiological study||CD, 39.1||CD, 2.4 (15 times more frequent in women vs. men)||Extabe et al. 199462|
Initial diagnosis of CD typically is made in adults—mostly women—aged 30-50, and pediatric cases are rare.63 Table 7 shows the age distribution among CD patients. Endogenous CS has been divided into corticotropin-dependent and corticotropin-independent types; the former may account for 80-85% of instances, of which an estimated 80% are caused by pituitary adenomas.57
|Age (years)||Number (%)|
|≤ 17||29 (4.2)|
|≥ 65||8 (1.2)|
Source: Broder et al. 201517
CS is rare and is associated with increased mortality in patients with no concurrent malignancy; also, the excess mortality usually occurs during the first year of disease. However, data on mortality associated with CD and CS are scarce, and the impaired quality of health in long-term survivors of CD is not fully explained.61,64 Table 8 presents mortality data related to CD and CS.
|166 Danish patients diagnosed with CS from 1985-1995.||Data from the National Patient Register of the Danish National Board of Health||
Of 139 patients with nonmalignant disease, SMR=3.68.
In 45 patients with CD who had been cured through transsphenoidal neurosurgery, SMR=0.31.
Of 20 patients with persistent hypercortisolism after initial neurosurgery, SMR=5.06.
In patients with adrenal adenoma, SMR=3.95.
|Lindholm et al. 200161|
|N/A||Systematic review and meta-analysis of mortality studies in patients with CD and CS secondary to a benign adrenal adenoma||
In patients with CD, SMR=1.84.
In CD patients with persistent disease after initial surgery, SMR=3.73.
In CD patients with initial remission, SMR=1.23.
In patients with a benign adrenal adenoma, SMR=1.90.*
|Graversen et al. 201264|
|Spain, N=49, 1975-1992||Epidemiological study||
In patients with vascular disease, SMR=5.**
|Extabe et al. 199462|
|UK 1967-2009, Greece 1962-2009, N=418, all with endogenous CS (311 with CD, 74 with adrenal CS and 33 with ectopic CS)||Systematic analysis of a large series with prolonged follow-up||
In CD overall, SMR=9.3. In adrenal CS, SMR=5.3. ***
In ectopic CS, SMR=68.5.
|Ntali et al. 201365|
|N=33, CS patients||Columbia Presbyterian Medical Center Records, 1932-1951||5-year survival rate was 50%; life expectancy generally was limited by cardiovascular events, but over time mortality rates have decreased.||Plotz et al. 195266|
|N=60, UK, 51 female, median age 36-46 years, median follow-up 15 years||SMR for 60 CD patients was compared with general UK. A meta-analysis of SMRs from seven studies (including this study) was performed for overall mortality in CD.||
For vascular disease, SMR=13.8.
For persistent disease (n = 6), SMR=16 vs. remission (n = 54) SMR=3.3. After adjustment for age and sex, relative risk of death for persistent disease was 10.7. Hypertension and diabetes mellitus were associated with significantly worse survival.
|Clayton et al. 201167|
|N=248 Dutch patients with pituitary adenomas treated by transsphenoidal surgery for NFMAs (N = 174) and ACTH-producing adenomas (N = 74).||Clinical study.||
For the entire cohort, SMR=1.41.
For NFMA patients, SMR=1.24 vs. 2.39 in CD.
In patients with CD vs. NFMAs, the age-adjusted mortality was significantly increased.
|Dekkers et al. 200768|
Clinical presentation can be highly variable, and establishing the diagnosis can often be difficult.58
A positive diagnosis of CS requires that chronic hypercortisolism is unequivocally demonstrated biologically using tests such as the 24-hour urinary cortisol, late-evening plasma or salivary cortisol, diurnal cortisol test, midnight 1-mg, or the classic 48-hour-low-dose DST. All of which have essentially the same diagnosis potencies. The search for the responsible cause then relies on the assessment of corticotroph function and imaging. Suppressed ACTH plasma levels indicate adrenal CS, and the responsible unilateral adrenocortical tumor is always visible on computed tomography scans. However, its benign or malignant nature may be difficult to diagnose before surgery. Imaging can suspect bilateral adrenal CS, when the two adrenals are small, as in the primary pigmented nodular adrenal dysplasia associated with Carney complex, or enlarged, as in the ACTH-independent macronodular adrenocortical hyperplasia (or primary macronodular adrenal hyperplasia). Measurable or increased ACTH plasma levels indicate either CD or the ectopic ACTH syndrome. When the dynamics of the corticotroph function (high-dose DST, the CRH test) are equivocal, and/or the imaging is non-contributive, it may be difficult to distinguish between the two. This is a situation where sampling ACTH plasma levels in the inferior petrosal sinus may be necessary.53
Biochemical diagnosis of CS is complicated by the cyclical nature of cortisol secretions. First-line biochemical tests include late-night salivary cortisol and urinary free cortisol tests.57 Researchers have compared these two diagnostic approaches in a group of patients who presented with CS, CD, or obesity; each patient provided three samples for both tests.69 The two approaches had similar variability, but late-night salivary cortisol testing demonstrated better diagnostic performance.69
Dexamethasone extinction testing is another approach to confirm a CS diagnosis, but it requires careful controls and may not provide sufficient diagnostic accuracy to be used alone.57 Thus, a differential CS diagnosis often relies on biochemical assays.70 The dexamethasone extinction test followed by the CRH extinction test71,72 has provided a single measurement of cortisol from late-night serum or saliva samples. The desmopressin test may facilitate a rapid diagnosis of cyclical CD.73 Researchers are studying tests and strategies that may enable more accurate and more convenient diagnosis of CS and CD.74,75
Imaging studies for the diagnosis of CS and CD have been challenging: MRI has been estimated to detect only 60-70% of CD adenomas.76-78 Moreover, positive MRI results may be confounding because incidental pituitary adenomas may exist in 10% of the population.79 Further, microadenomas may be difficult to image, and full-body scans have been used for differential diagnosis.53
Bilateral intrapetrosal sinus sampling may help physicians to distinguish between pituitary and ectopic sources of increased ACTH levels,80,81 but the procedure has been termed invasive and elaborate.77,78,81,82
Authors of a later study suggested that because adrenal lesions are relatively common place and are easily detected by advanced imaging technologies, clinicians may be tempted to test all patients with such lesions for excess cortisol secretion that is indicative of CS.83 However, since most such lesions rarely lead to frank disease, one author suggested that routine screening in unselected populations is clinically ineffective and potentially deleterious if unaffected patients undergo invasive surgery.83
One report suggested that the probability of finding an adrenal incidentaloma in a patient 20-29 years old was 0.2%, but the probability of such a finding in a patient > 70 years was 6.9%.84
Some authors suggested that CS should be included in the differential diagnoses of certain high-risk patient populations, including patients who present with diabetes mellitus, hypertension, and early-onset osteoporosis.85
Quality of Life
CS of any etiology (adrenal, pituitary, or ectopic) impacts negatively on health-related QOL, especially in active hypercortisolism but also after an endocrine cure. Generic questionnaires (e.g., the short-form 36 health survey SF-36, the derived SF-12, and the Hospital Anxiety and Depression Scale), as well as disease-specific measures (e.g., the Cushing QOL and the Tuebingen CD-25 questionnaires) have provided information on the impact of CS on patients perceived health.86 Patients may experience severe fatigue, physical changes, emotional instability, depression, and cognitive impairment.87
Treating CS improves patient-perceived QOL, but it often takes many months and often never normalizes. In addition to persistent decreased QOL in cured CS patients, brain and cerebellar volume are also reduced. Depression, anxiety, and cognitive dysfunction are common. Pediatric patients with CS also have worse QOL than normal children, and they have delayed growth and pubertal development and sub-normal body composition and psychological and cognitive maturation. Fluoxetine has been suggested as a neuroprotectant and antidepressant for patients with CS, although no prospective studies are yet available.86
The initial onset of CD is insidious and can involve nonspecific, highly variable, and often cyclical presentations of clinical signs (Table 9). Reports about the time required for CD diagnosis vary widely. A study that included 19 patients with ACTH-secreting tumors reported an average of 4.3 years from initial presentation to diagnosis.88 A study that included 49 patients reported an average time from symptom onset to diagnosis of 45.8 ± 2.7 months (range 6-144 months).62 The European Registry on CS identified 481 CS patients (66% of whom presented with CD) and reported a median diagnostic delay of 2 years.89
|Symptom||Prevalence in All CS patients|
Source: Feelders et al. 201287
The therapeutic goal is to normalize tissue exposure to cortisol to reverse increased morbidity and mortality. Optimum treatment consisting of selective and complete resection of the causative tumor is necessary to allow eventual normalization of the hypothalamic-pituitary-adrenal axis, maintenance of pituitary function, and avoidance of tumor recurrence. The development of new drugs offers clinicians several choices to treat patients with residual cortisol excess. However, for patients affected by this challenging syndrome, the long-term effects and comorbidities associated with hypercortisolism require ongoing care.90
Surgery (resection of the pituitary or ectopic source of ACTH, or unilateral or bilateral adrenalectomy) remains the optimal treatment in all forms of CS, but may not always lead to remission. Bilateral adrenalectomy is reserved for recurrent cases of CD and can be performed laparoscopically.91
The best treatment option of CD is total removal of the responsible corticotroph adenoma using a transsphenoidal approach, while preserving the normal anterior pituitary function. If this fails, all other options directed towards the pituitary (radiation therapies) or the adrenals (medications or surgery) have numerous side effects. There is at present no recognized efficient medical treatment for corticotroph adenomas.53
Medical therapy (steroidogenesis inhibitors, agents that decrease ACTH levels, or glucocorticoid receptor antagonists) and pituitary radiotherapy may be needed as an adjunct. A multidisciplinary approach, long-term follow-up, and treatment modalities customized to each individual are essential for controlling hypercortisolemia and managing comorbidities.58
A study that examined two US claims databases between 2008 and 2010 and reported that among 228 newly treated CD patients, 180 (78.9%) underwent surgery, 42 (18.4%) received pharmacotherapy, and 6 (2.6%) were administered radiotherapy.92
Table 10 presents outcomes data of surgical/radiation treatments for CD and CS.
|Transsphenoidal surgery||Remission rates were between 60-80% (< 15% for microadenomas), but relapse rates were as high as 20%.||Newell-Price et al. 200657
|Remission rates were between 65-90% (65% for macroadenomas > 1 cm).||Aghi et al. 200893|
|Transsphenoidal surgery||Remission occurred in 60-90% of CD patients with microadenomas and slightly fewer (50-70%) in cases with macroadenomas.||Hofman et al. 200894; Hoybye et al. 200495; Shimon et al. 200296|
|Transsphenoidal surgery||Experienced neurosurgeons reportedly have achieved perioperative mortality rates between 0-1.5% with low overall complication rates.||Barker et al. 200397|
|Transsphenoidal surgery||Recurrence was as high as 25% at 45 months.||Patil et al. 2008 98|
|Transsphenoidal surgery||Recurrence occurred in 20-25% of patients.||Barbetta et al. 200199; Sonino et al. 1996100; Patil et al. 200898|
|Repeat transsphenoidal surgery
|Treatment resulted in remission in 50-60% of patients, along with corresponding increases in the incidence of complications.||Biller et al., 2008101; Tritos et al., 2011102|
|Laparoscopic surgery||Prognosis was good except for adrenocortical carcinomas.||Newell-Price et al. 200657|
|Conventional fractionated radiotherapy||Treatment was effective but was associated with long-term hypopituitarism.||Newell-Price et al. 200657|
|Proton stereotactic radiation therapy||Treatment led to remission in 17 cases (52%).||Petot et al. 2008103|
|Laparoscopic adrenalectomy||All patients resolved signs/symptoms of CS, maintained weight, improved glucose tolerance and blood pressure control, and had no residual cortisol secretion.||Vella et al. 2001104|
|50% of patients experienced tumor progression within 3 years.||Assie et al. 2007105|
Abbreviations: CD, Cushing’s disease; CS, Cushing’s syndrome
Pharmaceutical therapies for CD can be divided into two groups: steroidogenesis inhibitors (drugs that act on the corticotrophic cells of the adenoma) and glucocorticoid receptor antagonists.106
Steroidogenesis inhibitors currently used for the treatment of CD include ketoconazole, metyrapone, mitotane, and etomidate.106
Ketoconazole and metyrapone are enzyme inhibitors that have a rapid onset but diminished control following corticotropin oversecretion in CD.57 Both these agents are used off-label to treat CS.107 The long-term use of ketoconazole may be limited by liver toxicity.108,109
Mitotane has been used to treat relatively benign CD, and etomidate, which is the only drug approved for intravenous treatment of CD, rapidly reduces cortisol levels.108,110
In 2012, the FDA approved pasireotide and mifepristone as pharmacological alternatives for treating CD patients who are not eligible for surgery.106,111-113 Pasireotide targets the somatostatin receptor subtype 5, which is overexpressed in corticotrophic adenomas.114 Ongoing phase III trials are further investigating pasireotide’s safety and efficacy in new, persistent, or recurring cases of CD, and another clinical trial is evaluating an extended-release formulation of pasireotide for once-a-month dosing.113 Pasireotide’s safety profile is similar to that of other somatostatin analogs but has been associated with elevated incidences of hyperglycemia.108,114
Mifepristone is a glucorticoid receptor antagonist that reportedly improved glucose tolerance with patients and showed long-term safety.115
A proof-of-concept study is currently underway for the treatment of CD with LCI699, a potent 11b-hydroxylase inhibitor.110,116,117 Table 11 summarizes outcome data on a variety of drug therapies for CD and CS.
|Mifepristone (Phase 3)||Treatment improved glycemic control in 60% and reduced hypertension in some subgroups; the overall clinical status of 87% of patients improved.||Fleseriu et al. 2012118|
|LCI699 (phase 2)||Treatment reduced plasma aldosterone and ACTH-stimulated cortisol response at all doses administered with no increased side effects compared with placebo.||Wang et al. 2015119|
|Ketoconazole||One study reported that 50% of patients taking ketoconazole achieved biochemical control and clinical improvement, but 20% of the patients discontinued the drug because of poor tolerability.||Fleseriu et al. 2015110|
|Cabergoline||Treatment has been reported to suppress cortisol production in 50-70% of patients over a 12-month period, but only 30-40% of patients remain in remission after 2 to 3 years.||Pivonello et al. 1999120; Pivonello et al. 2009121; Godbout et al. 2010122|
|Cabergoline||Treatment was well tolerated, but normalized cortisol levels in only one-third of patients.||Molitch et al. 2014108|
|Pasireotide||Treatment decreased cortisol levels in 88% of patients in a recent phase 3 study.||Colao et al. 2012123|
|Pasireotide||Treatment normalized cortisol levels in 25% of patients who received the drug and worsened glucose tolerance in most patients.||Molitch et al. 2014108|
Abbreviations: CS, Cushing’s syndrome; ACTH, adrenocorticotropic hormone
Studies are examining genetics-based approaches for treating CD. One author reasoned that disruptions of cell signaling were associated with ACTH-producing adenomas and suggested investigating epithelial growth factor receptors, cyclins, and cyclin-dependent kinases.124
Subclinical Cushing’s Syndrome
Abstract clinically unapparent adrenal masses have become a common in everyday practice. These are usually incidentally detected, mostly due to the routine use of imaging techniques, such as ultrasound and computed tomography. A substantial percentage of these incidentalomas are hormonally active, with 5-20% of the tumors producing glucocorticoids. Autonomous glucocorticoid production without specific signs and symptoms of CS is termed subclinical CS.125,126
With an estimated prevalence of 79 cases per 100,000 persons, subclinical CS is much more common than classic CS. Depending on the amounts of glucocorticoids secreted by the tumor, the clinical spectrum ranges from slightly attenuated diurnal cortisol rhythm to complete atrophy of the contralateral adrenal gland with lasting AI after unilateral adrenalectomy.125
Patients with subclinical CS lack the classical stigmata of hypercortisolism but have a high prevalence of obesity, hypertension, type 2 diabetes and cardiovascular complications. All patients with incidentally detected adrenal masses scheduled for surgery must undergo testing for subclinical CS to avoid postoperative adrenal crisis.125
The diagnosis of subclinical CS is based on biochemical evaluation; however, there is still no consensus regarding diagnostic criteria. Many experts agree that an abnormal 1mg DST initial screening test in combination with at least one other abnormal test of the hypothalamic-pituitary-adrenal axis is sufficient to diagnose subclinical CS. Although some recommend a higher dexamethasone dose (3 mg instead of 1 mg) to reduce false-positive results.125
The optimal management of patients with subclinical CS is not yet defined. The conservative approach of observation and medical treatment of morbidities is appropriate for the majority of these patients; however, the duration of follow-up and the frequency of periodical evaluation still remain open issues. Surgical resection may be beneficial for patients with hypertension, diabetes mellitus type 2, or abnormal glucose tolerance and obesity.126 Some researchers also recommend surgery in patients < 50 years and those with suppressed plasma ACTH.125