Endocrinology · Primary Bilateral Macronodular Adrenal Hyperplasia

The Biology of Your Adrenal Glands: Genetics and Mechanisms

At a Glance

PBMAH causes both adrenal glands to develop large nodules and make too much cortisol. Changes in ARMC5 or KDM1A and abnormal responses to hormones such as those released after eating can explain the disease and help distinguish it from pituitary Cushing’s disease.

Understanding the “how” and “why” behind a diagnosis of Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) or Bilateral Macronodular Adrenal Disease (BMAD) requires looking deep into the biology of your adrenal glands.

In a healthy system, ACTH from the brain regulates cortisol production, though the adrenal glands also produce other normal hormones like aldosterone and androgens and respond to other natural signals. In your case, the adrenal glands have essentially “rewired” themselves to respond to the wrong signals or to grow autonomously ^[1]^[2].

Misplaced “On Switches”: Aberrant Receptors

One of the most fascinating aspects of PBMAH is the development of aberrant receptors—which you can think of as “misplaced on-switches.”

Normally, adrenal cells rely heavily on ACTH for cortisol regulation. However, in PBMAH, the cells may start expressing receptors for hormones they aren’t supposed to listen to ^[3]. When these other hormones float by, they accidentally flip the switch, telling your adrenal glands to pump out cortisol ^[4].

Common “misplaced” switches include:

GIP (Gastric Inhibitory Polypeptide): A hormone released by your gut after you eat.
Vasopressin: A hormone that regulates water and blood pressure.
Catecholamines: “Fight or flight” hormones like adrenaline.

Because these receptors are active, your cortisol levels might spike at unusual times—such as right after a meal or when you stand up—rather than following the body’s natural daily rhythm ^[5]^[6].

The Genetic Code: ARMC5 and KDM1A

Scientists have identified two major genetic players that can cause this rewiring and growth.

The ARMC5 Mutation

A significant genetic cause of PBMAH is a mutation in the ARMC5 gene, found in about 20% to 25% of cases that seem to occur randomly and up to 80% of cases that run in families ^[7]^[8].

How it works: ARMC5 is a tumor-suppressor gene, meaning its job is to stop cells from growing too fast. When it’s broken, the adrenal cells multiply, forming the “macronodules” (large lumps) seen on your scans ^[1].
The “Two-Hit” Model: Many patients have a “germline” mutation (one they were born with in every cell) and a “somatic” mutation (a second “hit” that happens only in the adrenal nodules) ^[9]. This explains why the disease often takes decades to develop, typically appearing in the 50s or 60s ^[10].

The KDM1A Mutation (Food-Dependent Cortisol)

A rarer, highly specialized mutation involves the KDM1A gene. This is specifically linked to food-dependent Cushing syndrome ^[11]. When this gene is inactivated, it causes a massive increase in the GIP receptors mentioned above ^[12]. For these patients, eating a meal triggers a surge of cortisol, while their cortisol levels might look completely normal or even low if they are fasting ^[13]^[5]. Mixed-meal testing and KDM1A testing are specialist investigations used only in highly selected cases.

Distinguishing Look-Alikes: PBMAH vs. PPNAD

It is easy to confuse PBMAH with another rare condition called PPNAD (Primary Pigmented Nodular Adrenocortical Disease), but they are biologically very different. These are useful clinical patterns, but not absolute diagnostic rules.

Feature	PBMAH / BMAD	PPNAD
Nodule Size	Large (macronodules), usually >1 cm ^[3]	Tiny (micronodules), often <1 cm ^[10]
Typical Age	50s and 60s ^[14]	Children and young adults ^[15]
Genetic Link	Often ARMC5 or KDM1A ^[8]	Often PRKAR1A ^[10]
Associated Syndrome	Usually occurs alone ^[10]	Often part of Carney Complex ^[16]

Carney Complex is a hereditary syndrome that involves PPNAD along with other symptoms like unusual dark spots on the skin (lentiginosis), heart tumors (myxomas), and issues with the pituitary or thyroid glands ^[16]^[17].

Why It’s Not the Pituitary

Your doctor’s first priority was likely to make sure your high cortisol isn’t coming from the brain. In “classic” Cushing’s Disease, a small tumor on the pituitary gland pumps out too much ACTH, which then forces the adrenal glands to work overtime.

While low ACTH, low DHEAS, and bilateral nodules strongly point to PBMAH, specialists integrate these with repeated testing to completely rule out pituitary disease:

ACTH Levels: In PBMAH, your ACTH is usually very low or “suppressed” because your brain is trying to shut down cortisol production ^[1].
DHEAS Levels: DHEAS is another hormone made by the adrenal glands. It is typically low in PBMAH but high in pituitary-dependent Cushing’s disease ^[18]. DHEAS is age- and medication-dependent.
Imaging: In PBMAH, the “problem” is clearly visible on both adrenal glands as large nodules, whereas in pituitary disease, the adrenal glands may look normal or only slightly enlarged ^[3].

Common questions in this guide

Which genes are linked to PBMAH?

ARMC5 is the most established genetic cause described for PBMAH and is found in a subset of sporadic cases and many familial cases. A rarer change in KDM1A is associated with food-dependent Cushing syndrome, in which eating can trigger cortisol release. Many people with PBMAH do not have an identified change in either gene.

How can an ARMC5 change lead to adrenal nodules?

ARMC5 normally helps limit cell growth. In some patients, one altered copy is present throughout the body and a second change develops in adrenal tissue, allowing cells to grow into large nodules and produce excess cortisol. This two-step pattern may help explain why familial disease can appear decades later.

What does food-dependent Cushing syndrome mean?

It means cortisol rises unusually after a meal instead of following the usual daily pattern. In KDM1A-related disease, adrenal cells can have many extra receptors for GIP, a gut hormone released after eating, so meals may trigger a cortisol surge while fasting levels are normal or low. Specialists may use mixed-meal testing and selected genetic testing to investigate this pattern.

How is PBMAH different from PPNAD?

PBMAH usually causes large adrenal nodules, often bigger than 1 cm, and is more often recognized in adults in their 50s or 60s. PPNAD causes tiny nodules, often occurs in children or young adults, and is commonly linked with PRKAR1A and Carney complex. These are useful patterns, but doctors use the full clinical, laboratory, genetic, and imaging picture.

How do doctors tell PBMAH apart from pituitary Cushing disease?

Doctors combine repeated hormone tests with imaging rather than relying on one result. PBMAH usually has very low ACTH, often low DHEAS, and nodules in both adrenal glands, whereas pituitary Cushing disease is driven by an ACTH-producing pituitary tumor. DHEAS can vary with age and medicines, so results need specialist interpretation.

Can hormones other than ACTH trigger cortisol in PBMAH?

Yes. Some adrenal cells develop abnormal receptors that respond to hormones such as GIP after eating, vasopressin, or catecholamines, the body's fight-or-flight hormones. This can cause cortisol changes at unusual times, such as after a meal or with changes in posture.

What could an ARMC5 finding mean for my family?

A germline ARMC5 variant is present throughout the body and may be inherited, so it can have implications for blood relatives. A genetic counselor can confirm whether the variant is disease-causing, discuss who might benefit from testing, and help plan how to share the results.

Get notified when new evidence is published on Cushing syndrome due to bilateral macronodular adrenocortical disease.

We monitor PubMed for new peer-reviewed studies on this topic and email a short summary when something meaningful changes.

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This page is for informational purposes only and does not constitute medical advice about PBMAH. Your endocrinologist and genetic counselor should interpret your test results and discuss any family implications.