Adrenal Hyperplasia
Adrenal hyperplasia is enlargement of one or both adrenal glands caused by an increase in the number of adrenal cells. It is a descriptive term rather than a single disease and can result from several conditions, including inherited enzyme deficiencies such as congenital adrenal hyperplasia, long-standing stimulation by ACTH as in Cushing disease or ectopic ACTH production, and specific nodular adrenal hyperplasia syndromes. Bilateral adrenal enlargement may also occur during severe physiologic stress or systemic illness. The clinical significance depends on the underlying cause and whether the adrenal glands are producing abnormal amounts of hormones. Imaging—particularly CT and MRI—and biochemical testing are central to evaluation.
What is it?
The adrenal glands are two small triangular organs that sit on top of the kidneys. The adrenal cortex produces cortisol, aldosterone, and adrenal androgens, while the adrenal medulla produces adrenaline and noradrenaline.
Adrenal hyperplasia is a general term for enlargement of one or both adrenal glands caused by an increase in the number of cells within the gland. It is a descriptive term rather than a single disease, and identifying the underlying cause is the central goal of evaluation.
On imaging, adrenal hyperplasia may appear in several patterns. Diffuse hyperplasia describes smooth thickening or enlargement of one or both adrenal glands that generally preserves the glands’ overall shape. Nodular hyperplasia describes one or more nodules within an enlarged gland, sometimes producing a beaded or irregular appearance.
Primary bilateral macronodular adrenal hyperplasia, or PBMAH, refers to bilateral adrenal enlargement with multiple macronodules. It is most often associated with autonomous or partially autonomous cortisol production, although the degree of cortisol excess varies.
Micronodular adrenal disease includes rare entities such as primary pigmented nodular adrenocortical disease, or PPNAD, which is frequently associated with Carney complex.
Distinguishing these patterns and separating hyperplasia from adenomas, pheochromocytomas, metastases, and other adrenal lesions are important parts of imaging interpretation.
The causes of adrenal hyperplasia are diverse. Congenital adrenal hyperplasia, or CAH, is a group of inherited disorders caused by deficiencies in enzymes needed for adrenal steroid production. Deficiency of 21-hydroxylase is by far the most common cause.
Reduced cortisol production in CAH leads to increased ACTH secretion by the pituitary gland. Persistent ACTH stimulation can enlarge the adrenal glands and causes characteristic steroid-hormone abnormalities.
Classic CAH usually presents in infancy or childhood. Salt-wasting forms can cause dehydration, low sodium, high potassium, low blood pressure, and adrenal crisis. Some affected female newborns have atypical external genital development, while other children may develop early androgen effects.
Nonclassic CAH is milder and may present later with early pubic hair development, acne, hirsutism, menstrual irregularity, or fertility difficulties. Some people with nonclassic CAH have few or no symptoms.
Long-standing ACTH stimulation from other sources can also cause bilateral adrenal hyperplasia. Cushing disease, caused by an ACTH-producing pituitary tumor, commonly produces bilateral adrenal stimulation and may lead to adrenal enlargement.
Ectopic ACTH secretion by certain tumors, including some lung and neuroendocrine cancers, can produce similar adrenal changes and severe cortisol excess.
PBMAH is a distinct adrenal condition in which multiple bilateral adrenal nodules produce cortisol independently or partly independently of pituitary ACTH. Some patients carry pathogenic variants in ARMC5 or other genes.
PPNAD is a rare form of micronodular adrenal disease that produces cortisol excess. It is frequently associated with Carney complex, an inherited syndrome that may also cause spotty skin pigmentation, cardiac myxomas, and other endocrine tumors.
Bilateral adrenal enlargement may sometimes be seen during severe physiologic stress or systemic illness, although mild adrenal prominence on imaging can also represent normal variation rather than true hyperplasia.
Some hereditary forms of adrenal hyperplasia are associated with inherited conditions, including Carney complex and pathogenic variants involving genes such as ARMC5. Genetic counseling and testing may be appropriate when a hereditary form is suspected.
The clinical significance of adrenal hyperplasia depends on the cause and whether the glands are producing excessive or insufficient amounts of hormones.
Cortisol-producing hyperplasia can cause Cushing syndrome, with features such as central weight gain, muscle weakness, easy bruising, high blood pressure, high blood sugar, osteoporosis, and mood changes.
Excess aldosterone production from bilateral adrenal disease can cause primary aldosteronism, which most commonly presents with high blood pressure. Low potassium may occur but is not present in every patient.
Excess adrenal androgen production can cause acne, hirsutism, menstrual irregularity, early puberty, or virilization.
Some patients with adrenal enlargement have no hormonal abnormalities or symptoms, and the finding is discovered incidentally.
Evaluation combines clinical assessment, biochemical testing, imaging, and, in selected patients, genetic or specialized testing.
Hormonal evaluation is guided by the clinical presentation. Tests may include cortisol, ACTH, aldosterone, renin, DHEA-S, testosterone, 17-hydroxyprogesterone, electrolytes, glucose, and other adrenal steroid measurements.
Twenty-four-hour urinary free cortisol, late-night salivary cortisol, and overnight or extended dexamethasone suppression testing may be used when Cushing syndrome is suspected. No single test is appropriate for every patient, and abnormal results may need confirmation.
A baseline or ACTH-stimulated 17-hydroxyprogesterone measurement may be used when 21-hydroxylase-deficient CAH is suspected. Genetic testing may help confirm the diagnosis in selected cases.
CT provides detailed information about adrenal size, shape, density, and nodularity. MRI may provide additional tissue characterization when CT findings are indeterminate or when radiation avoidance is important.
Adrenal vein sampling may be used in patients with confirmed primary aldosteronism who are potential surgical candidates. It helps determine whether excess aldosterone production is unilateral or bilateral because CT findings alone may not reliably establish the source.
Genetic testing can play an important role in CAH, PPNAD, Carney complex, and selected cases of PBMAH.
Important to Know
Management of adrenal hyperplasia is directed at the underlying cause, the degree of hormonal abnormality, associated health effects, and the patient’s overall condition.
Care is usually coordinated by an endocrinologist. Geneticists, endocrine surgeons, cardiologists, obstetricians, pediatric endocrinologists, oncologists, and primary care clinicians may also be involved.
Classic CAH generally requires lifelong glucocorticoid replacement. Patients with salt-wasting disease also require mineralocorticoid replacement, such as fludrocortisone, and infants may require supplemental salt.
Treatment is adjusted to prevent adrenal crisis, support normal growth and development, control excessive androgen production, and minimize adverse effects from excessive glucocorticoid exposure.
Patients and caregivers receive education about increasing glucocorticoid doses during significant illness, injury, or surgery; carrying medical alert identification; and using emergency injectable glucocorticoids when indicated.
Many people with nonclassic CAH do not require treatment. For symptomatic patients, management may include hormonal therapies or, in selected cases, glucocorticoids, depending on symptoms, fertility goals, and specialist assessment.
Newer therapies that target ACTH-driven androgen production or provide more physiologic glucocorticoid delivery may be available for selected patients through specialized endocrine care.
When adrenal hyperplasia results from Cushing disease, treatment is directed at the pituitary tumor, usually with transsphenoidal surgery. Radiation therapy and medications that reduce ACTH secretion, block cortisol production, or block cortisol action may be used when surgery is unsuccessful, inappropriate, or insufficient.
Ectopic ACTH syndrome requires treatment of the underlying tumor when possible. Medications that rapidly reduce cortisol production may also be needed.
In severe or treatment-resistant ACTH-dependent Cushing syndrome, bilateral adrenalectomy may be considered. This controls adrenal cortisol production but causes permanent primary adrenal insufficiency requiring lifelong glucocorticoid and mineralocorticoid replacement.
Treatment of PBMAH depends on the degree of cortisol excess, associated medical problems, adrenal anatomy, genetic findings, and patient-specific factors.
Unilateral adrenalectomy may reduce cortisol production in selected patients while preserving some adrenal function. Bilateral adrenalectomy may be necessary in severe cases but causes permanent adrenal insufficiency. Medications that inhibit cortisol production may be used when surgery is unsuitable or as temporary treatment.
In selected PBMAH cases, cortisol production can be influenced by abnormally expressed receptors. Receptor-directed treatment may occasionally be considered in specialist centers, but it is not appropriate for every patient.
Bilateral adrenalectomy is often used to treat clinically significant cortisol excess from PPNAD. Patients with Carney complex also require ongoing screening and management for other manifestations of the syndrome.
Bilateral primary aldosteronism is generally treated with a mineralocorticoid receptor antagonist such as spironolactone or eplerenone, together with management of blood pressure and potassium.
Unilateral aldosterone-producing disease may be treated surgically. Adrenal vein sampling is commonly used to establish whether aldosterone production is unilateral or bilateral when surgery is being considered.
For nonfunctioning adrenal enlargement without suspicious imaging findings, treatment may not be necessary. Biochemical evaluation is individualized according to symptoms, imaging characteristics, and the possibility of hormone excess.
Follow-up imaging is not automatically required for every case of mild adrenal enlargement. The need for additional imaging depends on the certainty of the diagnosis, hormonal findings, imaging appearance, and whether changes over time would affect management.
Adrenal biopsy is not generally used to diagnose adrenal cortical hyperplasia. When biopsy or another invasive adrenal procedure is being considered for an indeterminate lesion, pheochromocytoma should be excluded first whenever clinically feasible because manipulation can cause a dangerous catecholamine surge.
Genetic counseling and evaluation may be important in CAH, PPNAD, Carney complex, PBMAH—particularly when an ARMC5-related form is suspected—and other hereditary adrenal conditions. Family testing may be appropriate in selected cases.
Imaging and laboratory findings must be interpreted alongside symptoms, physical examination, medications, family history, and the broader clinical context.
Patient education is especially important for people at risk of adrenal insufficiency. This includes medication adherence, stress dosing, emergency treatment planning, and recognition of adrenal crisis.
Red-flag symptoms include severe weakness, fainting, very low blood pressure, signs of shock, persistent vomiting with dehydration, confusion, low blood sugar, severe headache with palpitations and sweating, severe hypertension, marked muscle weakness associated with very low potassium, or rapid clinical deterioration.
These symptoms warrant prompt or emergency medical evaluation because they may indicate adrenal crisis, hypertensive emergency, severe cortisol excess, or a serious electrolyte disturbance.