Menu
Menu
Cushing’s syndrome is a rare disease resulting from chronic exposure to excessive circulating levels of cortisol produced from tumours in the pituitary or adrenal glands or from other sources.
This introductory section on Cushing’s Hub is designed for non-specialists whom may be largely unfamiliar with the disorder, such as medical students, GPs, or specialists from other fields. Here you will find an explanation of the symptoms of Cushing’s syndrome in adults together with a detailed description of the pathophysiology and its resultant impact on morbidity and mortality.
In 1912, Harvey Cushing reported an endocrinological syndrome caused by a malfunction of the pituitary gland which he termed ‘polyglandular syndrome’, and which came to be known as Cushing’s syndrome. Cushing developed many foundational techniques and practices in neurosurgery, for example, the use of X-rays to diagnose brain tumours, the use of electrical stimuli to study the human sensory cortex, and the development of the Bovie electrocautery tool with William T. Bovie, a physicist.
Cushing was also the world’s leading teacher of neurosurgeons in the early 20th century and considerably improved the survival of patients after difficult brain operations for intracranial tumours.
Cushing’s Awareness Day is celebrated on April 8th, the birthday of Harvey Cushing.
The Disease Overview section details the history of Cushing’s syndrome; its prevalence; the HPA axis – interactions between the hypothalamus, pituitary and adrenal glands; and its wide range of presentations and symptoms, such as hypertension, rounded face, thin skin and osteoporosis. The Diagnosis section provides details of several diagnostic methods, such as the 24-hour urinary free cortisol test, late-night salivary cortisol test, overnight dexamethasone suppression test and desmopressin test, as well as information on differential diagnoses to help find the cause of the disease. Treatment goals, the different comorbidities, current guidelines, transsphenoidal surgery, radiotherapy, bilateral adrenalectomy, pharmacological interventions and future treatments can be found in the Disease Management section. The section concludes with a range of helpful Patient Resources.
Cushing’s Syndrome can be challenging to detect by family medicine or primary care practitioners due to its rarity and lack of specific symptoms. However, identifying symptoms of Cushing’s syndrome is vital for diagnosis and treatment to prevent irreversible organ damage as well as malignancies. Read on to learn more about the incidence, symptoms, and pathophysiology of this condition.
Cushing’s syndrome (CS) was first described by Harvey Cushing in 1932. It is a condition where the body produces excess cortisol over a long period of time, regardless of the physiological cause;1 therefore, it is often interchangeably called hypercortisolism. Cortisol is a steroid hormone produced by the adrenal glands and is sometimes called the “stress hormone” because it helps the body cope with stressors like illness or injury through its anti-inflammatory and immune-modulating properties. Most often, CS is caused by supraphysiological doses of exogenous glucocorticoids, such as prednisone, used for inflammation or corticosteroids used for asthma. Topical and injectable steroids may also cause the condition.1, 2
CS is a rare disease with an incidence of 0.7–2.4 per million people per year.1, 3 However, its comorbidities are similar to those of more common disorders such as uncontrolled diabetes mellitus or hypertension, so the true incidence may be underestimated.3 CS is more common in women than men (ratio 3:1) and patients are typically aged ≥40 years at diagnosis.4, 5 The mortality rate is around four times higher in CS than in the general population, and even higher among women.3, 4
As its name suggests, the hypothalamic-pituitary-adrenal (HPA) axis involves a complex interplay between three glands: the hypothalamus, pituitary and adrenal glands (Figure 1). The HPA axis controls the synthesis of corticotrophin-releasing hormone in the hypothalamus, adrenocorticotrophic hormone (ACTH) in the anterior pituitary gland, and cortisol in the adrenal cortex. It functions mainly to produce basal cortisol rhythms and to respond to a wide variety of stimuli or stressors. A negative feedback system ensures that cortisol levels remain within a healthy physiological range.6
The hypercortisolism in endogenous CS is caused by either excess cortisol production or excess ACTH secretion.5, 6 The classification of CS is shown in Figure 2. Endogenous CS is typically caused by tumours of the pituitary or adrenal gland, although other causes, such as ectopic tumours, can also result in CS. While all cases of CS are characterised by excessive levels of cortisol, some forms of the disease are a consequence of increased production of ACTH, which promotes the production of cortisol.6, 7 Endogenous CS can, therefore, be defined as ACTH-dependent (70–80% of cases, typically associated with pituitary tumours or ectopic tumours) or ACTH-independent (20–30% of cases, caused by adrenal tumours or other adrenal disorders; Figure 2). Excessive ACTH production from a pituitary tumour is called as Cushing’s Disease (CD).3, 7
ACTH-independent CS is most commonly caused by adrenal cortical tumours. As many as 10% of adults over 40 years of age may have an adrenal cortical tumour, with CS manifesting itself in approximately one-third of these tumours.8 In adults, the majority of these tumours are adenomas. However, malignant neoplasms of the adrenal cortex still account for 0.05–0.2% of all cancers, with a prevalence of 2 per million people per year, and can occur at any age.8 Patients with advanced adrenal cortical carcinoma have a poor prognosis, with 5-year survival rates of <15% in patients with metastatic disease.9 Meanwhile, adrenal adenomas are increasingly being diagnosed when patients are assessed for other reasons. Around 4% of patients undergoing abdominal imaging are found to have adrenal ‘incidentalomas’, allowing for the assessment and treatment of unrecognised secretory tumours.10
CS is clinically unmistakable when it is fully developed, but the spectrum of clinical presentation is wide, and the diagnosis can be challenging in mild cases.11 Clinical signs of CS depend on a variety of factors, such as age, sex, duration of the disease, genetic predisposition and the degree of hypercortisolism.1, 12 The symptoms of CS may present in a cyclical fashion and often mimic those of other conditions (e.g. obesity, diabetes, hypertension, depression or menstrual irregularity), leading to difficulties in diagnosis.1, 11 Delayed diagnosis can result in irreversible organ damage.13 As cortisol excess is associated with chronic illnesses such as hypertension and diabetes, CS patients are at increased cardiovascular risk.1 If left untreated, CS can become life-threatening as a result of systemic complications.14 The 5-year mortality rate for untreated CS is 50%, predominantly from cardiovascular events, or overwhelming infection.13
The most common symptoms of CS are shown in Figure 3.
A few features are highly specific for CS. They include reddish-purple striae, facial plethora, proximal muscle weakness, bruising with no obvious trauma and unexplained osteoporosis.11 Children with CS usually show slow growth despite weight gain, accompanied by a drop in the height percentile and a delay in puberty.7, 11
Since diagnosis of Cushing’s syndrome (CS) can be difficult due to its non-specific and variable pattern of clinical manifestations, this section provides information on diagnosis and how to differentiate between different aetiologies.
CS is often undiagnosed for years, partly because of a lack of awareness of this condition’s subtle, progressive nature and its testing complexity.1, 2 An evidence-based clinical practice guideline was jointly published by the American Endocrine Society and the European Society of Endocrinology in 2008 for the diagnosis of CS.3
The guideline recommended obtaining a thorough drug history to exclude exogenous glucocorticoid exposure. In most of these patients, the symptoms will resolve when these agents are discontinued. As endogenous CS is progressive, reviewing old photographs of the patient can help the clinician determine whether facial changes typical of CS have occurred over time. Further, it is worth noting that many conditions other than CS are associated with hypercortisolism, such as alcoholism, poorly controlled diabetes, depression or other psychiatric disorders.3 Testing is recommended in the following groups:3
The various diagnostic tests for CS are shown in Figure 4.1
With a sensitivity of up to 98% and a specificity of up to 92%, the 24-hour UFC test is one of the first-line screening tests.4 The 24-hour UFC test gives an indication of the free cortisol (cortisol not bound to corticosteroid-binding globulin [CBG]) circulating in the blood over a 24-hour period. Unlike serum cortisol measurements, which reflect both CBG-bound and free cortisol, UFC is not affected by conditions and medications that have an impact on CBG. At least two 24-hour urine collections are advised to measure UFC to account for intra-patient variability. Since UFC results are strongly dependent on urinary volume and glomerular filtration rate, other tests might be preferred for patients with renal impairment (creatinine clearance <60 mL/min) or clinically significant polyuria (>5 L/day).1, 3
False-positive elevations of UFC may occur as various conditions are associated with increased UFC in the absence of CS.3 If the patient is suspected of having CS and the UFC result is normal, it should be repeated two to three times to confirm the diagnosis. If all three results are normal, then a diagnosis of CS is highly unlikely.3, 5
The 24-hour UFC may not detect preclinical, cyclic (urine collected when the disease is inactive) or mild CS,3, 5 so additional testing is needed.
The LNSC test is one of the most sensitive diagnostic tests for CS, with a sensitivity and specificity of 92–100%. Cortisol secretion is usually very low between 11:00 pm and midnight in healthy individuals with fixed sleep-wake cycles, but patients with CS lose this diurnal drop and have elevated cortisol levels instead. The measurement of LNSC correlates with free plasma cortisol,3 detecting the altered circadian cortisol profile shown by patients with CS.
LNSC should be performed twice for improved sensitivity and specificity.1, 3 Sampling saliva at the usual bedtime instead of at midnight could decrease false-positive results in patients with CS, as the cortisol diurnal drop is associated with sleep onset. LNSC may be just above the upper limit of normal in patients with mild CS. Multiple, periodic and sequential LNSC testing is particularly useful for the repeated and long-term monitoring required to distinguish patients with cyclic CS, as these patients have weeks to months of normal cortisol secretion interspersed with episodes of excessive cortisol secretion.1 However, LNSC should not be performed in patients whose circadian rhythm is disrupted, such as night-shift workers, patients with depressive illness and those with diabetes mellitus and hypertension.1, 3
LNSC measurement is non-invasive and samples can be easily collected at home. Samples are stable at room temperature so can be easily transported to the laboratory.3
The 1-mg DST takes advantage of the loss of glucocorticoid negative-feedback inhibition of corticotropin-releasing hormone (CRH) and adrenocorticotrophic hormone (ACTH) secretion in CS.6 Patients are given 1-mg of dexamethasone, a synthetic glucocorticoid, between 11:00 pm and midnight, and serum cortisol levels are measured between 8:00 am and 9:00 am the following morning. Normally dexamethasone suppresses ACTH and cortisol levels, but not in patients with CS. A serum cortisol reading of <1.8 µg/dL (50 nmol/L) excludes the diagnosis of CS with >95% sensitivity but 80% specificity.3 False-positive results are common, particularly in women on oral oestrogen therapy or patients taking anticonvulsants or medications that induce hepatic cytochrome P450 3A4 enzyme activity. Moreover, reduced clearance of dexamethasone, as seen in liver and renal failure, and decreased CBG concentrations in patients with concurrent nephrotic syndrome may lead to false-negative results. Therefore, some experts have advocated the simultaneous measurement of cortisol and dexamethasone for these tests to prevent false-positive and false-negative results and improve test interpretability.1, 3
In the longer low-dose DST, patients take dexamethasone in doses of 0.5 mg at 6-hour intervals for 48 hours. Serum cortisol is measured 6 hours after the last dose of dexamethasone. A final level of >1.81 µg/dL (50 nmol/L) is ~95% sensitive and specific for CS.2, 3 The longer low-dose DST is useful in patients for whom UFC measurements are less useful as an initial test, such as patients with psychiatric conditions, alcoholism, morbid obesity and poorly controlled diabetes mellitus.3
Since there is no consensus on the preferred diagnostic test for CS or when to test, these decisions are based on the clinical scenario of the patient and the physicians’ clinical judgment. The interpretation of results from any of the initial tests are influenced by clinical pre-test probability, so patients whom test positive upon initial screening and those with a normal result but high pre-test probability should be referred to an endocrinologist. No further testing for CS is required in individuals with two normal test results for 24-hour UFC, LNSC or 1-mg DST, but if there is a high index of suspicion for CS, they should be followed up in a few months to see if there is any progression in signs and symptoms.2, 3 Confirmatory tests may be another of the initial tests, or guidelines suggest either the dexamethasone-CRH test or midnight serum cortisol test.3
One of the first steps before any additional testing is to exclude any physiological causes that may be causing hypercortisolism in the absence of CS. Conditions with similar clinical features to CS include pregnancy, depression or other psychiatric conditions, glucocorticoid resistance, alcoholism, obesity and poorly controlled diabetes, whereas conditions like physical stress, malnutrition or anorexia nervosa, intense chronic exercise, hypothalamic amenorrhea and excess cortisol-binding globulin are unlikely to have any clinical features of CS.3
The dexamethasone-CRH test is useful in patients with ambiguous 24-hour UFC results. The test is done by administering dexamethasone as per the 48-hour 2 mg/d longer low-dose DST, and then CRH (1 µg/kg) is administered intravenously two hours after the last dose of dexamethasone. Cortisol is measured 15 minutes later. If the plasma cortisol value is >1.4 µg/dL, then the patient is likely to have CS.3 To exclude false-positive results, dexamethasone levels should also be measured at the time of CRH administration.3
The midnight serum cortisol test is useful in patients whom, despite a high clinical index of suspicion of CS, had normal 24-hour UFC and full suppression on dexamethasone testing. A sleeping midnight serum cortisol value >1.8 µg/dL or an awake value >7.5 µg/dL increases the probability of CS. The sleeping midnight cortisol test may not be feasible in outpatient settings. It usually requires inpatient admission for a period of 48 hours or longer to avoid false-positive responses due to the stress of hospitalisation.3
Once the diagnosis of CS has been confirmed, the cause of hypercortisolism must be identified. A combination of blood tests and imaging modalities (e.g., magnetic resonance imaging [MRI]/computed tomography [CT] scans) can be employed to determine the cause of CS and localisation of the tumour (Figure 4).1
The first step is a blood test in the morning to measure the plasma ACTH level to determine whether CS is ACTH-dependent or -independent. Values <5 pg/mL (1.1 pmol/L) suggest ACTH-independent CS, while an inappropriately normal or elevated ACTH level (>20 pg/mL, 4.4 pmol/L) is consistent with ACTH-dependent CS.6 Levels between 10 and 20 pg/mL are indeterminate, and measurement should be repeated several times. When still uncertain, a CRH test should be performed. If the values are between 1.1 and 4.4 pmol/L, further evaluation with a CRH stimulation test is required to distinguish between pituitary and ectopic sources of ACTH. However, extremely high ACTH levels (>500 pg/mL, 110 pmol/L) indicate an ectopic source of ACTH.5, 6
The CRH stimulation test is performed by intravenous injection of 1 µg/kg or 100 µg of recombinant ovine or human CRH to stimulate corticotroph tumours to secrete ACTH. In ACTH-independent and ectopic-ACTH CS, there is usually very little or no cortisol or ACTH response to CRH, whereas the response is exaggerated in patients with Cushing’s disease (CD; pituitary-dependent CS). There is generally a >34% increase in ACTH levels and/or >20% increase in cortisol levels within 45 minutes of ovine CRH administration in patients with CD (sensitivity 93%), whereas with human CRH administration, these patients have ≥14% increase in cortisol levels (sensitivity 85%, specificity 100%). However, 7–14% of patients with CD do not respond to this test.6
The desmopressin test is used to differentiate between mild CS and pseudo CS and also between pituitary and ectopic sources of ACTH due to its high specificity for CD.1, 7
After an overnight fast, patients are given an intravenous injection of 10 µg of 1-desamino-8-D-arginine vasopressin, otherwise known as desmopressin, and blood samples for plasma cortisol and ACTH measurements are taken just before and 10, 20 and 30 minutes after the injection. Plasma cortisol and ACTH levels are significantly higher in patients with CS but not in pseudo-CS patients and in those without CS.3
The high-dose DST can be used to distinguish between pituitary and ectopic tumours. Dexamethasone (either 2-mg every 6 hours for 48 hours, or 8-mg overnight) is administered and plasma cortisol levels are evaluated. The principle is that high doses of dexamethasone will suppress cortisol production in pituitary ACTH-secreting tumours, as these tumours retain some sensitivity to glucocorticoid negative feedback but will not suppress an ectopic source of ACTH because of the loss of glucocorticoid negative-feedback inhibition. The high-dose DST lacks optimal diagnostic accuracy, so many endocrinologists do not recommend it unless bilateral inferior petrosal sinus sampling (BIPSS) is not available.6
When an adrenal source is suspected in patients with low ACTH levels or when an ectopic ACTH source is suspected, CT/MRI scanning of the adrenals or the whole body, respectively, can be used to localise and identify the lesion responsible for CS.5, 6
Pituitary MRIs with gadolinium enhancement should be performed in all patients with ACTH-dependent CS; this can identify a pituitary tumour in around 50% of patients. However, the majority (80–90%) of ACTH-secreting pituitary tumours are small (<10 mm) and some may not be detected, even using more advanced MRI techniques, such as spoiled gradient-recalled acquisition or dynamic MRI sequences.5, 6 In addition, pituitary ‘incidentalomas’ are increasingly recognised in the general population, so the presence of a pituitary lesion in a patient with ACTH-dependent CS may not necessarily indicate that the lesion is the source of the CD.5, 8
In cases where the CRH-stimulation test and desmopressin test are both consistent with a pituitary origin and imaging studies identify a pituitary lesion (>6 mm), further testing may not be necessary.6 On the other hand, if clinical, biochemical and radiological (lesion <6 mm) studies are inconclusive, BIPSS with ACTH measurements before and after CRH administration should be performed.5, 6
BIPPS is an invasive procedure and can be used to distinguish between pituitary and non-pituitary sources of CS. Blood samples are taken from the inferior petrosal sinuses that drain the pituitary gland and from a peripheral vein. ACTH levels at both sites are measured before and after CRH stimulation and compared. Patients with an ectopic source of ACTH do not have a gradient between petrosal sinus samples and peripheral ACTH values, whereas a central-to-peripheral ACTH gradient of ≥2 at baseline and/or ≥3 after CRH stimulation is confirmatory of a pituitary tumour.6 This test has sensitivity and specificity of ~95%.5
Another option to localise an ectopic ACTH secreting tumour is an octreotide scan, where radiolabelled octreotide (somatostatin analogue) is injected into the bloodstream. This radiolabelled somatostatin analogue binds to the somatostatin receptors present on ACTH secreting tumours, which then become visible by X-ray imaging.6 Most often used compounds are Ga68-DOTATATE, DOTATOC and 111In-DTPA-pentetreotide.1
When performing diagnostic tests, the results and the likelihood of adverse events are related to the experience of the radiology team, and should therefore only be performed in specialist centres.
Patients with suspected adrenocortical carcinoma (ACC) may also undergo additional tests to identify excess sex steroids and steroid precursors, mineralocorticoids and glucocorticoids. Table 2 provides a summary of the tests recommended by the European Society of Endocrinology in collaboration with the European Network for the Study of Adrenal Tumors in patients with suspected ACC.10
Patients with Cushing’s syndrome (CS) have increased morbidity and mortality rates compared with the general population. Providing effective and timely management is therefore essential. Here, we discuss treatment goals, the different comorbidities, current guidelines and the various lines of treatment for CS, including transsphenoidal surgery, radiotherapy, bilateral adrenalectomy, pharmacological interventions and future treatments.
In 2015, the Endocrine Society produced a comprehensive set of guidelines for the treatment of CS.1 The guidelines were co-sponsored by the European Society of Endocrinology and participants included an Endocrine Society-appointed Task Force of experts from France, the UK and the US. The Task Force assessed the quality of the available evidence, resulting in consensus on best practice for the treatment of CS. With the development of novel screening and diagnostic techniques and new treatments gaining approval for use, the Pituitary Society critically reviewed the current literature and in 2021 provided updated recommendations for the identification and management of disease-related and treatment-related complications.2
You can access the guideline recommendations here.
In 1952, before effective treatment was available, patients with CS had a median survival of 4.6 years. While some treatments for comorbidities have been developed, standardised mortality rates for patients with active CS remain 1.7–4.8 times higher than the general population. In contrast, the standardised mortality rate improves when CS and its associated comorbidities are successfully treated, although it is unclear whether this improvement results in a mortality rate similar to that in the general population.1 Data suggest that curative therapy with pituitary surgery alone is most likely to provide a normalised standardised mortality ratio, whereas patients in remission after pituitary surgery but receiving treatment for other comorbidities are at increased risk for all-cause and circulatory mortality.3
CS is associated with a number of risk factors for comorbidities (Figure 5). Many of these strongly impact morbidity and mortality, with cardiovascular events and infections being the most common causes of death in CS.4 Treatment of comorbidities is therefore important, along with or even before (in case of severe life-threatening hypercortisolism) addressing the cause of hypercortisolaemia and during long-term follow-up post-treatment. Symptomatic treatment of comorbidities is mandatory in cases where definitive diagnosis is delayed or curative treatment is not feasible or when comorbidities persist even after treatment.4 Urgent treatment (within 24–72 hours) should be provided for hypercortisolaemia if life-threatening complications are present, such as infection, pulmonary thromboembolism, cardiovascular complications or acute psychosis.1
The guidelines suggest immunisation against influenza, shingles and pneumonia as severe hypercortisolism impairs immunity and puts the patient at risk for severe, systemic infections and/or sepsis. There is also an increased risk of venous thrombosis, so clinicians should monitor their patients for thrombosis and bleeding and administer prophylactic anticoagulants before, during and after curative surgery, as required. In addition, clinicians should monitor and treat all other cortisol-dependent comorbidities, such as psychiatric disorders, diabetes, hypertension, hypokalaemia, dyslipidaemia, osteoporosis and poor physical fitness, and also advise rehabilitation medicine.1, 2
CS treatment aims to rapidly normalise the cortisol levels, and consequently, to improve the metabolic and biochemical abnormalities associated with the disorder. Current guidelines provide advice on the surgical, radiological and medical management of CS with clear recommendations on lines of therapy and patient suitability.1, 2
Complete surgical resection of primary tumours (pituitary adenoma, non-pituitary tumour secreting adrenocorticotrophic hormone [ACTH] or adrenal tumours) is the first-line treatment for CS, unless surgery is not practicable. The success of the surgery depends on the skill and experience of the surgeon.1, 7
In Cushing’s disease (CD), transsphenoidal surgery (TSS) is used to remove the pituitary tumour. Typically, around 80% of patients with microadenomas and 60% with macroadenomas achieve remission after TSS, defined by postoperative serum cortisol concentrations of <50 nmol/L (<1.8 µg/dL).1, 2 However, this cortisol value does not exclude the possibility of tumour recurrence, even after a prolonged period of time; therefore, life-long follow-up is advised.1 After initially successful TSS, recurrence may occur in up to 66% of cases, with a higher rate in macroadenoma cases.8 The overall recurrence rate is 5–10% at 5 years and 10–20% at 10 years, although recurrence is more likely and occurs earlier in patients with macroadenomas than in those with microadenomas (mean of 16 vs 49 months).9 Patients with persistent hypocortisolism in the immediate postoperative period should be given glucocorticoid replacement until the hypothalamic-pituitary-adrenal (HPA) axis recovers, which can take up to 3 years.7 The recommended approach to post-surgical management is shown in Figure 6.
Both the Pituitary Society and the Endocrine Society suggest a shared decision-making approach to allow patients a choice in their treatment when surgery is not possible or is unsuccessful.1, 2 The factors that should be taken into account when developing a treatment plan are presented in Figure 7.
In CD, second-line therapies include repeat TSS, radiation therapy/radiosurgery, bilateral adrenalectomy and medical therapy. Patients with adrenal carcinomas may require chemotherapy, radiotherapy or mitotane therapy post-surgery, and should be managed by an adrenal cancer-specific multidisciplinary team.1
TSS should be repeated when there is evidence of incomplete resection of the pituitary adenoma or imaging shows a pituitary lesion, and especially if the first surgery was not performed by an expert team.1
Radiation therapy/radiosurgery is suitable in patients with persistent or recurrent disease and when the tumour is visible in the magnetic resonance imaging (MRI), especially, when surgery was performed despite the invasiveness of the tumour. Because the effects of radiation occur over a long time, it is important to normalise cortisol levels through medical therapy while waiting for the radiation to take effect. Radiation is delivered as either external beam therapy or as stereotactic surgery.1, 2 Radiation therapy can be very effective, but its effects can take as long as ten years to manifest, and it can lead to long-term hypopituitarism. Stereotactic radiosurgery is associated with more rapid effectiveness, but has a relapse rate of 20%.2, 7
Laparoscopic bilateral adrenalectomy is an alternative secondary approach for patients with CD unsuccessfully treated by pituitary surgery. It offers immediate control of hypercortisolism, but is generally only indicated in patients for whom medical therapy has failed or is not suitable. Additionally, as the surgery results in the permanent removal of the adrenal gland, the patient will require life-long treatment with glucocorticoid and mineralocorticoid replacement therapies.1, 7 There is also the risk of developing Nelson’s syndrome (continued growth of the pituitary releasing ACTH), so close endocrinological follow-up with ACTH evaluation and regular MRI scans are mandatory in patients whom undergo bilateral adrenalectomy. Nevertheless, this will immediately control the cortisol excess, and should be considered as a reasonable option, especially in the absence of an obvious pituitary tumour.1, 7, 10
Medical therapy may be needed while awaiting surgery or the maximal efficacy of radiation techniques or when the patient refuses adrenalectomy or has contraindications for surgery. It can be used to control excess cortisol after radiotherapy, as a bridging treatment or in fragile and high-risk patients with severe disease and acute life-threatening complications to improve the clinical picture before they undergo adrenalectomy. The most important advantage of medical therapy is that it does not induce permanent adrenal insufficiency (except for mitotane in some patients), allowing the production of adequate amounts of steroid hormones, primarily cortisol. However, it is a lifelong treatment because discontinuing treatment leads to disease recurrence.1, 11
Medical treatment falls into three categories (Figure 8):
Guidelines recommend pituitary-directed therapies in patients with CD in whom surgery is contraindicated or whom have persistent disease after TSS. These therapies directly target the corticotroph pituitary adenomas to reduce ACTH hypersecretion. Two currently available classes of medications that act centrally are dopamine type 2 receptor agonists (DAs), and somatostatin receptor ligands (SRLs).1, 2
Cabergoline is a DA indicated for the inhibition of lactation and treatment of hyperprolactinaemia disorders. It acts by directly stimulating D2-dopamine receptors on pituitary lactotrophs, thus inhibiting prolactin secretion. Cabergoline for CS is typically initiated at 0.5 mg per week, with titration to a maximal dose of 7 mg/week. It has been shown to normalise urinary free cortisol (UFC) levels in 30–40% of the patients,1, 7 improve weight, glucose levels and hypertension in 25–40% of complete responders and shrink tumours in 50% of patients.12 In a study of 30 CS patients, long-term treatment resulted in complete remission in 30% of patients, although some patients subsequently relapsed.13 In one of the largest cohort studies in patients with CD, cabergoline had acceptable tolerability and provided long-term control of hypercortisolism at relatively low doses. Among the 53 patients receiving low-dose cabergoline monotherapy (1.5 mg/week), 21 patients (40%) achieved normal UFC values and clinical improvement within 12 months of treatment, which was sustained through 32.5 months in 12 patients (23%). Among patients receiving cabergoline add-on therapy (1.0 mg/week) for 19 months, hypercortisolism was controlled in 56% of patients during the first year of treatment.14 Adverse effects with cabergoline may include headache, dizziness, gastrointestinal discomfort, asthenia and cardiac valve fibrosis at high doses.1, 7
Pasireotide is a somatostatin receptor ligand indicated for the treatment of CD. Pasireotide binds with high affinity to somatostatin receptors 1–3 and 5, i.e. four of the five human somatostatin receptors, inhibiting tumour growth and lowering ACTH production.1 A long-acting monthly formulation has been recently trialled, with slightly higher response rates compared with the subcutaneous formulation. Nevertheless, only patients with relatively mild disease responded, and the issue of hyperglycaemia and frank diabetes remains problematic.15 In a phase III trial of 150 adults with CD, long-acting pasireotide (10 mg or 30 mg), administered intramuscularly, normalized UFC in about 40% of patients after 7 months.16 Moreover, the safety profile of long-acting pasireotide was similar to that of subcutaneous pasireotide (600–900 µg twice daily).17 Pasireotide should be given for as long as clinical benefit is observed, but blood sugar levels must be carefully monitored due to an increased risk of hyperglycaemia. Other potential adverse effects are diarrhoea, nausea, cholelithiasis, transient increases in liver function tests and hypothyroidism.1, 2
These therapies control cortisol production by decreasing steroid hormone production in the adrenal gland by inhibiting one or more enzymes involved in steroid synthesis.2 Guidelines recommend steroidogenesis inhibitors under the following conditions:1, 2
Ketoconazole is an antifungal agent approved by the European Medicines Agency for the treatment of CS and has a rapid onset of action. It is an imidazole derivative that inhibits steroid synthesis through inhibition of cytochrome P450 enzymes; 17, 20-lyase; 11β-hydroxylase; 17-hydroxylase and side-chain cleavage enzymes. These effects are dose dependent and completely and rapidly reversible upon drug discontinuation. The recommended dose of ketoconazole is 400–1600 mg (the usual maximal dose being 1200 mg/day) (every 6–8 hours dosing). In a large retrospective study, ketoconazole was associated with a normalization of UFC in 50% of patients and at least a 50% reduction in UFC in 25% of patients.18 Ketoconazole requires an acidic environment to be most effective, therefore, it has reduced efficacy if used with proton pump inhibitors. Potential adverse effects include serious hepatotoxicity (requiring liver function test monitoring at treatment initiation and after each dose adjustment), gastrointestinal discomfort, decreased testosterone levels, gynaecomastia and adrenal insufficiency.7 Since ketoconazole can potentially interact with a number of drugs, clinicians should be aware of their patients’ medication list to avoid problematic interactions.2
Metyrapone is approved in a number of European countries for the treatment of CS. It inhibits 11β-hydroxylase and has a rapid onset of action, with a success rate of 50–75%. It must be administered three to four times daily (500 mg to 6 g daily) because of its short half-life of 2 hours.1 According to various prospective and retrospective studies and case reports, up to 70% of patients treated with metyrapone show a general improvement in clinical features of CS, including blood pressure, glucose metabolism, psychiatric disturbances and muscle weakness.19 Potential adverse effects include dizziness, rash, gastrointestinal discomfort, acne and hirsutism in women, worsening or new hypertension, hypokalaemia, adrenal insufficiency and neutropenia (rarely).7
In cases of severe hypercortisolaemia, a combination of metyrapone and ketoconazole may be used.1 A study involving 22 patients showed that a combination of metyrapone (median dose 2125 mg/day) and ketoconazole (median dose 900 mg/day) was well tolerated and dramatically decreased UFC within 1 week. After 1 month, UFC had normalised in 73% of patients with ectopic ACTH syndrome and 86% of patients with adrenal carcinoma.20 Similar results had been previously reported by Kamenický and colleagues.21
Mitotane inhibits several steroidogenic enzymes and has a slow-onset, long-lasting adrenolytic action in steroid-secreting adrenocortical cells. It suppresses hypercortisolism in 80% of cases. Mitotane is indicated for the symptomatic treatment of advanced (unresectable, metastatic or relapsed) ACC,1, 2 but it has also been delivered in patients with CD.22 European Society for Medical Oncology guidelines recommend a starting dose of 1.5 g/day, increasing within 4–6 days up to 6 g/day. Blood levels should be monitored and a target level of 14–20 mg/L should be sought for adrenal carcinoma (whereas target level of mitotane is 10 mg/L for CD); approximately 50% of patients achieve this target within 3 months.23 Mitotane increases cortisol-binding globulin levels, with corresponding increases in plasma cortisol; therefore, biochemical monitoring should be done with UFC or salivary cortisol measurements.1 Moreover, mitotane usually induces adrenal insufficiency requiring higher doses of hydrocortisone than in classical adrenal insufficiency (up to 40–50 mg/day because of the enzymatic inducer effect of the drug).23 It is teratogenic and not well tolerated; adverse effects may include hepatotoxicity, gastrointestinal discomfort, hypercholesterolaemia, gynaecomastia, prolonged bleeding time, dizziness, ataxia, dysarthria, memory loss and adrenal insufficiency.7
Osilodrostat is an 11β-hydroxylase and aldosterone synthase inhibitor that effectively reduces cortisol levels with a high success rate. It is approved in the US for CS patients whom have failed surgery or are contraindicated for surgery.24 It is well-tolerated and associated with improvements in bodyweight, psychiatric disturbances, blood pressure, total cholesterol, low-density lipoprotein cholesterol, fasting serum glucose and glycated haemoglobin concentrations. The most common adverse effects are nausea, anaemia, headache and adverse events related to hypocortisolism.2
Etomidate is an intravenous medication originally developed as an anaesthetic, but which rapidly normalises cortisol levels by inhibiting 11β-hydroxylase and cholesterol side-chain cleavage.2 Guidelines indicate that etomidate can be used to manage hypercortisolaemia in severely ill patients of any age whom cannot receive surgery immediately or take oral medications. It has a quick onset of action but requires monitoring in a high-dependency unit. First, a loading dose of 3–5 mg is administered followed by a maintenance dose of 0.03–0.1 mg/kg/h (2.5–3.0 mg/h) to achieve stable serum cortisol levels of 10–20 µg/dL (280–560 nmol/L). Etomidate is not sedative at these doses, but dose reduction might be needed if renal failure occurs.1
Levoketoconazole is an enantiomer of ketoconazole. Both the US Food and Drug Administration and European Medicines Agency have granted orphan drug status to levoketoconazole for treatment of endogenous CS. The recommended dose is 300–1200 mg, given orally twice a day.2 Levoketoconazole has been shown to normalise UFC levels in 31% of patients,25 with a lower rate of withdrawal compared with placebo (41% vs 96%).26 The most common adverse effects include gastrointestinal disturbances, headache, oedema, increased liver enzymes and adrenal insufficiency. There is a possibility of interaction with other drugs.2
Guidelines recommend glucocorticoid receptor antagonists in patients with diabetes or glucose intolerance whom cannot undergo surgery or whom have persistent disease after TSS.1, 2 Glucocorticoid receptor antagonists bind to the glucocorticoid receptor with higher affinity than cortisol, causing rapid systemic control of cortisol excess in patients with CS.27
Mifepristone is a glucocorticoid and progesterone-receptor antagonist. It has been approved in the US for hypercortisolism-mediated hyperglycaemia in CS patients whom have failed surgery or in whom surgery is contraindicated.1, 2, 7 However, mifepristone has not gained approval in Europe. It is important to note that cortisol and ACTH levels remain unchanged or increase with the use of mifepristone, and so these levels cannot be used to gauge treatment success or to diagnose adrenal insufficiency. Therefore, clinicians are advised to start initial dosing at 300 mg/day and titrate it slowly (up to a maximum 1200 mg/day) based on glucose levels and weight reduction. Significant improvements up to 40% and 60% in hypertension and glycaemia, respectively, in addition to improvements in clinical signs and symptoms of hypercortisolism were seen in a phase 3 study.28 Adverse effects may include hypokalaemia, worsening hypertension, adrenal insufficiency, endometrial hyperplasia and gastrointestinal discomfort.7 Thyroid function should be monitored carefully, and the dose of thyroid hormones adjusted as necessary. Given the potential for drug–drug interactions with mifepristone, all concomitant medications should be reviewed carefully.2
As no single drug has demonstrated complete efficacy and current treatments have numerous adverse effects, drug combinations offer the potential of reduced doses and fewer adverse effects.29 Combinations tested in small studies include up to three different steroidogenesis inhibitors, cabergoline and ketoconazole, and pasireotide, cabergoline and ketoconazole.29
There are also a number of novel treatments currently under investigation:4, 29
The initial management of adrenal carcinomas involves resection of the lesion, unless surgery is not possible. Since patients with ACC have a poor prognosis, complete resection should be the goal of surgery.1 Patients with ACC should undergo evaluation of tumour size and stage of development and treated accordingly. Follow-up care should be provided by an adrenal cancer-specific multidisciplinary team, and may include cytotoxic chemotherapy and adjuvant radiotherapy or medical therapy (mitotane) to achieve eucortisolism.1 Severe hypercortisolism can also be managed with a combination of steroidogenesis inhibitors.20, 21
A website for patients with adrenal disorders, their families, carers, and the healthcare practitioners they engage with, to work towards better diagnosis and care. This website has editions in Dutch, German and Danish.
The Association Surrénales is an organisation for sufferers of adrenal disease which aims to provide support, raise awareness and promote scientific research. The website is in French.
Netzwerk Glandula is a network forum for exchange between doctors and patients with pituitary and adrenal diseases. This website is in German.
A website for patients to interact with health professionals to aid management of Cushing’s Syndrome. This website is in Spanish.
An association for people diagnosed with pituitary disease, assisting with access to medical care and dedicated to protecting patients’ rights. This website is in Spanish.
AMEND is a patient group to support and inform anyone affected by or interested in multiple endocrine neoplasia disorders and their associated endocrine tumours.
The Pituitary Foundation is a national support and information organisation for pituitary patients, their families, friends and carers.
A website dedicated to providing support and medical information to adrenocortical cancer patients, their carers and families.
The Cushing’s Support and Research Foundation (CSRF) was founded in 1995 to provide information and support to Cushing’s patients and their families.
This website offers links to articles on Adrenocortical Carcinoma.
Providing diagnosis and treatment Information, articles and research news and access to a patient support services program.
