The adrenal glands are small, triangular-shaped organs situated atop the kidneys, forming a vital part of the endocrine system. Their primary function is to synthesize and release hormones, such as cortisol and aldosterone, that regulate metabolism, blood pressure, and the body’s response to stress. Hyperplasia refers to the enlargement of an organ or tissue caused by an increase in cell reproduction. Bilateral Adrenal Hyperplasia (BAH) is the abnormal, non-cancerous enlargement of tissue in both adrenal glands, leading to the excessive production of these hormones.
Defining Bilateral Adrenal Hyperplasia
Bilateral Adrenal Hyperplasia is classified based on the underlying trigger for adrenal gland growth and hyperactivity.
ACTH-Dependent BAH
This category involves enlargement caused by chronic overstimulation from Adrenocorticotropic Hormone (ACTH). ACTH typically originates from a tumor in the pituitary gland or, less commonly, an ectopic source elsewhere in the body.
Primary Bilateral Adrenal Hyperplasia
This ACTH-independent form involves glands that grow and produce hormones autonomously, regardless of circulating ACTH levels. It is further divided based on the size and appearance of the nodules within the enlarged glands. Both primary forms result in hypercortisolism (excess cortisol), leading to Cushing’s syndrome.
##### Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH)
PBMAH is characterized by multiple large nodules, often exceeding one centimeter in diameter. This form is sometimes linked to inherited genetic mutations, such as those in the ARMC5 gene. It can also involve the aberrant expression of hormone receptors on adrenal cells, causing them to overreact to non-ACTH signals, like those from GIP or LH.
##### Primary Pigmented Nodular Adrenocortical Disease (PPNAD)
PPNAD represents the micronodular form, featuring multiple small, pigmented nodules generally less than one centimeter in size. PPNAD is frequently associated with the Carney complex, a rare genetic disorder characterized by various tumors and skin pigmentation abnormalities, often involving a mutation in the PRKAR1A gene.
Recognizing the Signs and Symptoms
The clinical presentation of Bilateral Adrenal Hyperplasia results directly from chronic overexposure to excess cortisol. Patients often develop central weight gain, characterized by fat accumulation in the trunk, face, and neck, while the limbs remain relatively thin. This contributes to the appearance of a rounded, “moon-shaped” face and a dorsal fat pad, sometimes called a buffalo hump.
Excess cortisol weakens connective tissues, leading to skin changes such as easy bruising and the development of wide, purplish stretch marks (striae), particularly over the abdomen and thighs. Muscle strength is diminished, resulting in generalized fatigue and difficulty performing physical tasks. High cortisol levels can also disrupt psychological balance, manifesting as anxiety, depression, or mood swings.
If the hyperplasia leads to significant overproduction of aldosterone, patients experience severe hypertension (high blood pressure). Aldosterone regulates salt and water balance; its excess causes the body to retain sodium and excrete potassium, potentially leading to hypokalemia. Chronic hypertension and electrolyte imbalance increase the risk for cardiovascular complications, including stroke and heart failure.
Confirming the Diagnosis
The diagnostic process for Bilateral Adrenal Hyperplasia confirms hormonal excess and pinpoints the cause. Initial biochemical testing confirms hypercortisolism, typically using a 24-hour urinary free cortisol measurement or late-night salivary cortisol samples, which reveal a loss of the normal circadian rhythm. A low-dose dexamethasone suppression test is also employed; the failure of cortisol levels to suppress indicates autonomous adrenal function.
Once hypercortisolism is confirmed, blood tests measure Adrenocorticotropic Hormone (ACTH) levels. A suppressed or very low ACTH level confirms the adrenal glands are acting independently, pointing toward a primary BAH. Imaging studies, such as a computed tomography (CT) scan or magnetic resonance imaging (MRI) of the abdomen, visualize the adrenal glands. These scans confirm bilateral enlargement and characterize the hyperplasia, distinguishing between the larger nodules of PBMAH and the smaller ones of PPNAD.
Additional dynamic testing, such as the high-dose dexamethasone suppression test, may help differentiate between primary adrenal causes and pituitary-driven conditions. For cases suggestive of a familial cause, specific genetic testing for mutations in genes such as PRKAR1A or ARMC5 can provide molecular confirmation.
Treatment Approaches
Management of Bilateral Adrenal Hyperplasia is individualized based on the specific cause, hormonal excess severity, and clinical manifestations. For PBMAH linked to aberrant hormone receptors, medical treatment may involve using antagonists or inhibitors to block the specific receptor responsible for abnormal steroid production. Steroidogenesis inhibitors, such as ketoconazole or metyrapone, can also block enzymes involved in cortisol synthesis, lowering hormone levels and alleviating Cushing’s syndrome symptoms.
If BAH is ACTH-dependent, the primary goal is addressing the source of excessive ACTH, often involving surgical removal of a pituitary tumor. Definitive treatment for primary BAH resistant to medical therapy is surgical removal of both adrenal glands (bilateral adrenalectomy). This procedure immediately resolves hormonal overproduction but requires the patient to be permanently dependent on lifelong hormone replacement therapy for lost cortisol and aldosterone.
In select PBMAH cases, a unilateral adrenalectomy (removing only the most affected gland) might be considered to control hypercortisolism while preserving some adrenal function. Treatment choice balances normalizing hormone levels with minimizing long-term complications. Regular monitoring of hormone levels is necessary for long-term care.