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Primary macronodular adrenal hyperplasia
Reviewed by Medicinsk Expert•Last updated: 2026-10-22•Condition

Primary macronodular adrenal hyperplasia

Primary macronodular adrenal hyperplasia is a rare genetic disorder characterized by multiple nodules in the adrenal glands, which cause overproduction of the hormone cortisol and can lead to Cushing syndrome.

Overview

Primary macronodular adrenal hyperplasia (PMAH) is a disorder characterized by multiple lumps (nodules) in the adrenal glands, which are small hormone-producing glands located on top of each kidney. These nodules, which usually are found in both adrenal glands (bilateral) and vary in size, cause adrenal gland enlargement (hyperplasia) and result in the production of higher-than-normal levels of the hormone cortisol. Cortisol is an important hormone that suppresses inflammation and protects the body from physical stress such as infection or trauma through several mechanisms including raising levels of blood glucose, also called blood sugar.

PMAH typically becomes evident in a person's forties or fifties. It is considered a form of Cushing syndrome, which is characterized by increased levels of cortisol resulting from one of many possible causes. These increased cortisol levels lead to weight gain in the face and upper body, fragile skin, bone loss, fatigue, and other health problems. However, some people with PMAH do not experience these signs and symptoms and are said to have subclinical Cushing syndrome.

Frequency

PMAH is a rare disorder. It is present in less than 1 percent of cases of endogenous Cushing syndrome, which describes forms of Cushing syndrome caused by factors internal to the body rather than by external factors such as long-term use of certain medicines called corticosteroids. The prevalence of endogenous Cushing syndrome is about 1 in 26,000 people.

Causes

In about half of individuals with PMAH, the condition is caused by mutations in the ARMC5 gene. This gene provides instructions for making a protein that is thought to act as a tumor suppressor, which means that it helps to prevent cells from growing and dividing too rapidly or in an uncontrolled way. ARMC5 gene mutations are believed to impair the protein's tumor-suppressor function, which allows the overgrowth of certain cells. It is unclear why this overgrowth is limited to the formation of adrenal gland nodules in people with PMAH.

PMAH can also be caused by mutations in the GNAS gene. This gene provides instructions for making one component, the stimulatory alpha subunit, of a protein complex called a guanine nucleotide-binding protein (G protein). The G protein produced from the GNAS gene helps stimulate the activity of an enzyme called adenylate cyclase. This enzyme is involved in controlling the production of several hormones that help regulate the activity of certain endocrine glands, including the adrenal glands. The GNAS gene mutations that cause PMAH are believed to result in an overactive G protein. Research suggests that the overactive G protein may increase levels of adenylate cyclase and result in the overproduction of another compound called cyclic AMP (cAMP). An excess of cAMP may trigger abnormal cell growth and lead to the adrenal nodules characteristic of PMAH.

Mutations in other genes, some of which are unknown, can also cause PMAH.

Genes Associated with Primary Macronodular Adrenal Hyperplasia

  • APC
  • ARMC5
  • FH
  • GNAS
  • MC2R
  • MEN1
  • PDE11A

Inheritance

People with PMAH caused by ARMC5 gene mutations inherit one copy of the mutated gene in each cell. The inheritance is considered such that one copy of the mutated gene is sufficient to make an individual susceptible to PMAH. However, the condition develops only when affected individuals acquire another mutation in the other copy of the ARMC5 gene in certain cells of the adrenal glands. This second mutation is described as somatic. Instead of being passed from parent to child, somatic mutations are acquired during a person's lifetime and are present only in certain cells. Because somatic mutations are also required for PMAH to occur, some people who have inherited the altered ARMC5 gene never develop the condition, a situation known as reduced penetrance.

When PMAH is caused by GNAS gene mutations, the condition is not inherited. The GNAS gene mutations that cause PMAH are somatic mutations. In PMAH, the gene mutation is believed to occur early in embryonic development. Cells with the mutated GNAS gene can be found in both adrenal glands.

Other Names for This Condition

  • ACTH-independent macronodular adrenal hyperplasia
  • ACTH-independent macronodular adrenocortical hyperplasia
  • Adrenal Cushing syndrome due to AIMAH
  • Adrenocorticotropic hormone-independent macronodular adrenal hyperplasia
  • AIMAH
  • Corticotropin-independent macronodular adrenal hyperplasia
  • PMAH
  • Primary bilateral macronodular adrenal hyperplasia

Frequently Asked Questions

Diagnosing PMAH involves several steps to confirm cortisol overproduction and identify its source. Initial tests often include blood and urine tests to measure cortisol levels, such as a 24-hour urinary free cortisol test or a late-night salivary cortisol test. A low-dose dexamethasone suppression test may also be used. Once excess cortisol is confirmed, imaging studies like a CT scan or MRI of the adrenal glands are performed to visualize the nodules and enlargement characteristic of PMAH. In some cases, genetic testing may be done to look for specific mutations associated with the condition.
Subclinical Cushing syndrome in the context of PMAH means that while there is biochemical evidence of cortisol overproduction (e.g., abnormal lab tests), the individual does not exhibit the classic, obvious signs and symptoms of Cushing syndrome. Management for subclinical Cushing syndrome is individualized. Some individuals may be monitored closely without immediate intervention, especially if they have no or minimal symptoms. However, if there are underlying health issues like uncontrolled hypertension, diabetes, or osteoporosis that could be related to even mild cortisol excess, treatment (surgical or medical) might be considered to prevent future complications. The decision depends on the severity of biochemical abnormalities and the presence of associated health risks.
Treatment for PMAH primarily aims to reduce cortisol overproduction and alleviate symptoms. Surgical removal of one or both adrenal glands (adrenalectomy) is a common and effective treatment, especially if symptoms are severe or if the nodules are unilateral. For individuals who are not surgical candidates or prefer other options, medical therapies can help block cortisol production or its effects. These medications include steroidogenesis inhibitors or glucocorticoid receptor antagonists. Regular monitoring of cortisol levels and symptoms is crucial regardless of the chosen treatment.
Primary macronodular adrenal hyperplasia (PMAH) often leads to symptoms of Cushing syndrome due to excess cortisol. Key symptoms to watch for include unexplained weight gain, particularly in the face (moon face) and upper body, easy bruising, thin and fragile skin, new or worsening stretch marks (striae), muscle weakness, fatigue, and bone loss. Some individuals may also experience high blood pressure, high blood sugar, or changes in mood. If you notice a combination of these symptoms, especially if they are progressive, it's advisable to consult a doctor.
Source: MedlinePlus, National Library of Medicine

MedlinePlus brings together authoritative health information from the National Library of Medicine (NLM), the National Institutes of Health (NIH), and other government agencies and health-related organizations.

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