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Hypercortisolism
Hypercortisolism results from prolonged exposure to excess cortisol, causing potentially serious metabolic, cardiovascular, musculoskeletal, and neuropsychiatric complications
Prevalence
3-6 / 1 000 000
1,000–2,100
US Estimated
2,250–4,500
EUROPE ESTIMATED
Age of Onset
Typically during the fourth to fifth decades of life.
ICD-10
E24. – Cushing's syndrome (hypercortisolism)
Inheritance Pattern
Autosomal dominant
Most cases of endogenous hypercortisolism/Cushing syndrome are sporadic. Rare cases occur as part of inherited tumor-predisposition syndromes, such as MEN1, MEN2, Carney complex, or familial isolated pituitary adenoma.
5 Facts you should know
FACT
Cortisol excess affects multiple organ systems
Chronic hypercortisolism can produce metabolic, cardiovascular, musculoskeletal, dermatologic, reproductive, immune, and neuropsychiatric manifestations
FACT
Hypercortisolism may occur without classic Cushingoid features
Patients with mild or early cortisol excess may lack the characteristic physical findings associated with overt Cushing syndrome
FACT
No single symptom confirms the diagnosis
Obesity, hypertension, diabetes, and depression are common in the general population. The development of multiple progressive features increases suspicion for hypercortisolism
FACT
Biochemical testing comes before localization
Recommended initial tests include late-night salivary cortisol, urinary free cortisol, and dexamethasone suppression testing. Once cortisol excess is established, ACTH testing helps guide evaluation of the underlying source
FACT
5
Treatment extends beyond cortisol control
Managing hypertension, diabetes, osteoporosis, cardiovascular risk, infection risk, and other complications is an essential component of care
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Common signs & symptoms
Central weight gain
Fat accumulation commonly affects the trunk and face, often with relatively thinner extremities.
Easy bruising & skin changes
Patients may develop thin skin, easy bruising, facial plethora, and wide violaceous striae.
Proximal muscle weakness
Cortisol's catabolic effects can cause progressive muscle wasting and weakness, particularly involving the proximal muscles.
Hypertension
Elevated blood pressure is a frequent cardiometabolic manifestation of chronic cortisol excess.
Glucose intolerance or diabetes
Excess cortisol promotes insulin resistance and can contribute to new or worsening hyperglycemia.
Current treatments
Treatment depends on the source of cortisol excess
Surgery
Surgical removal of the underlying cortisol- or ACTH-secreting tumor is generally the preferred first-line treatment for endogenous hypercortisolism when feasible.
Cortisol Synthesis Inhibitors
Osilodrostat (Isturisa)
Oral cortisol synthesis inhibitor approved for adults with endogenous hypercortisolemia associated with Cushing syndrome when surgery is not an option or has not been curative.
Levoketoconazole (Recorlev)
Oral cortisol synthesis inhibitor used to reduce cortisol production in adults with endogenous Cushing syndrome when surgery is not an option or has not been curative.
Metyrapone
Inhibits adrenal cortisol synthesis and may be used to achieve rapid control of cortisol excess.
Ketoconazole
Reduces cortisol synthesis through inhibition of adrenal steroidogenic enzymes and is used off-label in the United States.
Glucocorticoid Receptor Antagonism
Mifepristone (Korlym)
Blocks cortisol activity at the glucocorticoid receptor rather than lowering cortisol concentrations. It is indicated for controlling hyperglycemia secondary to endogenous Cushing syndrome in appropriate patients.
Pituitary-Directed Therapy
Pasireotide (Signifor)
A somatostatin analog that reduces ACTH secretion and is used specifically for patients with Cushing disease when pituitary surgery is unsuccessful or not an option.
Cabergoline
A dopamine agonist sometimes used off-label in Cushing disease to suppress ACTH secretion.
Bilateral Adrenalectomy
Removal of both adrenal glands provides definitive control of cortisol production and may be considered in severe or refractory cases, but requires lifelong glucocorticoid and mineralocorticoid replacement.