Cushing Syndrome Adrenal Lesion
A Cushing syndrome adrenal lesion is an adrenal gland abnormality that produces excess cortisol, leading to the clinical features and health effects of Cushing syndrome. Common adrenal causes include a cortisol-producing adenoma in one adrenal gland and specific forms of bilateral adrenal nodular disease. Adrenal cortical carcinoma is a rare but important cause. Adrenal causes account for a minority of endogenous Cushing syndrome cases. They are generally characterized by cortisol production that is independent of normal pituitary control, resulting in suppressed ACTH. Biochemical testing establishes cortisol excess and helps identify whether the condition is ACTH-dependent or ACTH-independent. Adrenal CT and, when needed, MRI are then used to characterize the adrenal glands.
What is it?
The adrenal glands are two small triangular organs located above the kidneys. Their outer portion, called the adrenal cortex, produces cortisol, aldosterone, and adrenal androgens.
Cortisol contributes to metabolism, blood pressure regulation, immune function, the response to illness and stress, and many other processes.
Under normal circumstances, cortisol production is regulated by ACTH from the pituitary gland. Cortisol follows a daily rhythm, with higher levels in the morning and lower levels around midnight.
Cushing syndrome describes prolonged exposure to excessive glucocorticoid activity from any cause.
The most common cause overall is the use of glucocorticoid medications, including oral, injected, inhaled, or topical preparations in sufficient doses or combinations. This is called exogenous or medication-induced Cushing syndrome.
Endogenous Cushing syndrome occurs when the body produces too much cortisol. It is divided into ACTH-dependent and ACTH-independent forms.
In ACTH-dependent Cushing syndrome, excessive ACTH stimulates both adrenal glands to produce cortisol. The most common cause is an ACTH-producing pituitary tumor, known as Cushing disease. Less commonly, a tumor elsewhere in the body produces ACTH.
In ACTH-independent Cushing syndrome, abnormal tissue within one or both adrenal glands produces cortisol autonomously. The resulting cortisol excess suppresses pituitary ACTH.
A cortisol-producing adrenal adenoma is a benign adrenal cortical nodule that autonomously secretes cortisol. It is the most common adrenal tumor responsible for overt adrenal Cushing syndrome.
On imaging, the affected gland generally contains a discrete nodule or mass. The opposite adrenal gland may appear smaller because prolonged ACTH suppression reduces stimulation of normal adrenal tissue.
Adrenal cortical carcinoma is a rare malignant tumor of the adrenal cortex. It may produce cortisol alone or together with androgens, estrogen precursors, or other adrenal steroids.
These cancers are often larger and more heterogeneous than benign adenomas and may contain areas of hemorrhage, necrosis, or calcification. Imaging findings can raise concern for malignancy, but definitive assessment also depends on clinical, hormonal, surgical, and pathologic findings.
Primary bilateral macronodular adrenal hyperplasia, now also called primary bilateral macronodular adrenal disease, causes enlargement of both adrenal glands with multiple nodules. Cortisol production may be partially or substantially independent of ACTH.
Some cases are associated with pathogenic variants in genes such as ARMC5. The degree of cortisol excess ranges from mild autonomous secretion to overt Cushing syndrome.
Primary pigmented nodular adrenocortical disease is a rare cause of cortisol excess involving multiple small adrenal cortical nodules. The adrenal glands may be normal-sized or even small rather than visibly enlarged.
This condition may occur sporadically or as part of Carney complex, an inherited syndrome that can also cause spotty skin pigmentation, cardiac myxomas, and other endocrine or nonendocrine tumors.
Mild autonomous cortisol secretion refers to abnormal cortisol nonsuppression after dexamethasone in a patient with an adrenal mass but without the characteristic clinical features of overt Cushing syndrome.
These patients may nevertheless have an increased prevalence of high blood pressure, type 2 diabetes, abnormal cholesterol, obesity, cardiovascular disease, or osteoporosis. The relationship between mild cortisol autonomy and these conditions varies among patients, so treatment decisions are individualized.
The clinical effects of overt Cushing syndrome result from prolonged exposure to excessive cortisol.
More characteristic findings include easy bruising, wide reddish-purple stretch marks, facial redness, weakness of the muscles around the hips and shoulders, and osteoporosis.
Other findings may include central weight gain, facial fullness, high blood pressure, diabetes, poor wound healing, increased infection risk, mood changes, sleep disturbance, menstrual irregularity, reduced fertility, reduced libido, and blood-clotting complications.
Children may experience slowed height growth while continuing to gain weight.
Adrenal cortical carcinoma may also produce androgen excess, causing hirsutism, acne, menstrual disruption, or rapid virilization. Rapid development of mixed cortisol and androgen excess can increase concern for an adrenal cortical malignancy.
Evaluation begins by reviewing all medications and supplements that may contain glucocorticoids. Exogenous glucocorticoid exposure must be considered before diagnosing endogenous Cushing syndrome.
Routine random or morning serum cortisol measurements are not sufficiently reliable to screen for Cushing syndrome.
Recommended initial biochemical tests include late-night salivary cortisol, 24-hour urinary free cortisol, and the overnight low-dose dexamethasone suppression test. The appropriate test depends on the patient’s medications, sleep schedule, kidney function, pregnancy status, and clinical circumstances.
Because cortisol production can vary, more than one measurement or more than one type of test may be needed.
An abnormal screening result does not automatically establish the diagnosis. Repeat testing or another recommended cortisol test is generally performed, and potential causes of misleading results are considered.
Severe illness, depression, alcohol use disorder, major physical stress, poorly controlled diabetes, disrupted sleep, and certain medications can produce biochemical findings that resemble Cushing syndrome without persistent autonomous cortisol production.
Once endogenous hypercortisolism has been established, ACTH is measured.
A low or suppressed ACTH level supports an adrenal source. A normal or elevated ACTH level suggests a pituitary or ectopic ACTH source and requires a different diagnostic pathway.
When ACTH is suppressed, adrenal CT is generally used to evaluate the size, density, structure, and contrast behavior of both adrenal glands.
A unilateral benign-appearing adenoma with a small opposite gland may support a cortisol-producing adenoma. Bilateral nodules or bilateral adrenal enlargement suggest a bilateral adrenal disorder.
A large, irregular, invasive, or heterogeneous mass raises concern for adrenal cortical carcinoma or another malignant lesion.
MRI can provide additional tissue characterization when CT is inconclusive, when iodinated contrast cannot be used, or when radiation avoidance is important.
Pituitary MRI is not routinely required when ACTH is clearly suppressed and an adrenal source has been established. It is mainly used when biochemical testing indicates ACTH-dependent disease.
Inferior petrosal sinus sampling may help distinguish pituitary from ectopic ACTH production when ACTH-dependent Cushing syndrome is confirmed but noninvasive testing does not identify the source. It is not used to evaluate a clearly ACTH-independent adrenal lesion.
Genetic testing may be appropriate in Carney complex, hereditary primary bilateral macronodular adrenal disease, childhood or young-adult adrenal cortical carcinoma, and other situations in which age, tumor pattern, or family history suggests an inherited syndrome.
Before an invasive procedure involving an indeterminate adrenal lesion, pheochromocytoma should be excluded when clinically appropriate because biopsy or surgical manipulation can provoke a dangerous catecholamine surge.
Adrenal biopsy is generally not used to distinguish an adrenal adenoma from adrenal cortical carcinoma and has little role in evaluating a suspected cortisol-producing adrenal lesion.
Important to Know
Treatment depends on the cause and severity of cortisol excess, the lesion’s imaging characteristics, associated health problems, and the patient’s surgical risk.
Care is best coordinated through an experienced multidisciplinary team that may include an endocrinologist, endocrine surgeon, radiologist, oncologist, cardiologist, genetic counselor, and primary care clinician.
For a unilateral cortisol-producing adrenal adenoma causing overt Cushing syndrome, unilateral adrenalectomy is generally the preferred treatment in an appropriate surgical candidate.
The operation is commonly performed laparoscopically or robotically when imaging indicates a localized benign lesion. Open surgery may be appropriate for large or suspicious tumors, particularly when adrenal cortical carcinoma is possible.
Long-standing cortisol excess suppresses ACTH and reduces cortisol production by the remaining normal adrenal tissue. Patients therefore commonly require glucocorticoid replacement immediately after removal of a cortisol-producing adrenal adenoma.
Recovery of the hypothalamic-pituitary-adrenal axis usually takes months and may take longer than a year—and occasionally several years—in some patients.
Replacement is gradually reduced only under medical supervision and after testing shows that normal cortisol production has recovered.
During this period, patients require education about increasing glucocorticoid doses during significant illness, injury, or surgery. Medical alert identification and an emergency glucocorticoid injection kit may also be recommended.
Symptoms can temporarily change after successful treatment. Some patients experience fatigue, muscle or joint discomfort, mood changes, or glucocorticoid-withdrawal symptoms even while receiving appropriate replacement.
Blood pressure, glucose, muscle strength, bone health, weight, mood, infection risk, and cardiovascular health may improve gradually rather than immediately.
Adrenal cortical carcinoma is best managed at a center experienced in adrenal cancer.
Complete surgical removal without tumor rupture offers the best chance for long-term disease control when the cancer is localized and resectable.
After surgery, mitotane may be recommended for selected patients at higher risk of recurrence based on tumor stage, surgical margins, pathologic findings, and multidisciplinary assessment.
Advanced or recurrent disease may require mitotane, combination chemotherapy, radiation for selected sites, additional surgery, local treatments, or participation in a clinical trial.
Hormonal excess must also be treated because uncontrolled cortisol production can cause serious complications independently of tumor growth.
Treatment of primary bilateral macronodular adrenal disease is individualized.
Unilateral adrenalectomy may reduce cortisol production while preserving some adrenal function in selected patients, particularly when one gland is dominant.
Bilateral adrenalectomy may be required for severe or difficult-to-control disease. Removal of both adrenal glands causes permanent primary adrenal insufficiency and requires lifelong glucocorticoid and mineralocorticoid replacement.
Cortisol-lowering medication may be used when surgery is inappropriate, while awaiting surgery, or when additional biochemical control is required.
In rare cases, abnormal adrenal receptors respond to food-related or other hormonal signals. Receptor-directed therapy may occasionally be considered in specialist centers, but it is not suitable for most patients.
PPNAD causing clinically significant Cushing syndrome is often treated with bilateral adrenalectomy. Patients with Carney complex also require long-term screening for other manifestations of the syndrome.
Management of mild autonomous cortisol secretion is individualized rather than automatic.
Surgery may be considered when cortisol autonomy is persistent, the adrenal lesion is unilateral, and the patient has relevant conditions such as difficult-to-control hypertension, diabetes, or osteoporosis that may plausibly improve after adrenalectomy.
Other patients are managed without surgery through treatment of cardiovascular and metabolic conditions and periodic endocrine reassessment when appropriate.
The benefits of adrenalectomy must be weighed against operative risk and the possibility of temporary postoperative adrenal insufficiency.
Medications that reduce cortisol synthesis include metyrapone, osilodrostat, ketoconazole or levoketoconazole, and mitotane in selected circumstances.
Mifepristone blocks the glucocorticoid receptor and may be used in selected patients, particularly those with hyperglycemia related to endogenous Cushing syndrome.
Medication selection depends on the cause of cortisol excess, speed of action required, pregnancy potential, liver and kidney function, drug interactions, electrolyte effects, and availability.
These medications require specialist monitoring because they can cause adrenal insufficiency, liver injury, electrolyte abnormalities, medication interactions, or other significant adverse effects.
Severe cortisol excess may require rapid medical treatment before definitive surgery because it increases the risks of infection, blood clots, cardiovascular events, electrolyte disturbances, and poor wound healing.
Management also includes treatment of high blood pressure, diabetes, abnormal cholesterol, osteoporosis, infection risk, blood-clot risk, depression, anxiety, and other complications.
Bone-health treatment may include adequate calcium and vitamin D intake and, when appropriate, prescription osteoporosis medication based on fracture risk and bone-density findings.
Genetic counseling and testing may be appropriate in Carney complex, hereditary forms of primary bilateral macronodular adrenal disease, young patients with adrenal cortical carcinoma, and other cases in which personal or family history suggests an inherited tumor syndrome.
Long-term follow-up remains important after successful treatment. Some complications, including cardiovascular risk, reduced bone strength, muscle weakness, and mood symptoms, may persist or take time to improve even after cortisol levels normalize.
Red-flag symptoms include severe weakness, repeated vomiting, fainting, very low blood pressure, confusion, low blood sugar, high fever, severe abdominal pain, chest pain, shortness of breath, sudden neurologic symptoms, or rapid clinical deterioration.
In a patient receiving postoperative glucocorticoid replacement, these symptoms may indicate adrenal crisis and require immediate emergency treatment.