Adrenal insufficiency happens when your adrenal glands can’t produce enough cortisol, the hormone that regulates blood pressure, blood sugar, metabolism, and your body’s response to stress. The causes fall into three categories: problems with the adrenal glands themselves (primary), problems with the pituitary gland that controls them (secondary), and suppression from long-term steroid medications. Each has distinct triggers and risk factors.
Primary Adrenal Insufficiency (Addison’s Disease)
Primary adrenal insufficiency means the adrenal glands themselves are damaged. In developed countries, autoimmune destruction is the most common cause. Your immune system mistakenly attacks the outer layer of the adrenal glands, gradually destroying the tissue that produces cortisol and aldosterone (a hormone that controls sodium and potassium balance). Blood tests can detect antibodies against an enzyme called 21-hydroxylase, which is essential for cortisol production. These antibodies serve as a marker confirming the autoimmune origin.
Autoimmune Addison’s disease sometimes appears alongside other autoimmune conditions, including thyroid disease, type 1 diabetes, or vitiligo. If you have one autoimmune condition, the risk of developing another is higher.
Infections That Damage the Adrenal Glands
Globally, tuberculosis remains the most common infectious cause of adrenal destruction. The bacteria can colonize the adrenal glands, slowly replacing functional tissue with scar tissue. This is still a significant cause in regions where TB is prevalent. Fungal infections can also damage the adrenals. Histoplasma is the most common fungal culprit, though Cryptococcus, Coccidioides, and several others can do the same.
In people with advanced HIV/AIDS, cytomegalovirus (CMV) is the most common virus to infect the adrenals. Other viral infections from the herpes family, Epstein-Barr virus, and others can contribute as well, though this is less common outside of severely immunocompromised patients.
Adrenal Hemorrhage
Sudden bleeding into both adrenal glands can cause rapid adrenal failure. This is rare but potentially life-threatening. Triggers include severe bacterial infections (especially meningococcal sepsis, known as Waterhouse-Friderichsen syndrome), anticoagulation therapy, abdominal trauma, antiphospholipid syndrome, and major surgery. The bleeding destroys enough tissue that the glands can no longer produce adequate hormones, sometimes within hours.
Genetic Causes
Congenital adrenal hyperplasia (CAH) is a group of inherited conditions where enzyme deficiencies block normal cortisol production. The most common form involves a deficiency of 21-hydroxylase, the same enzyme targeted in autoimmune Addison’s disease, but in this case, the problem is genetic rather than immune-mediated. Without this enzyme, the adrenal glands can’t complete the final steps of cortisol synthesis. The glands enlarge as the pituitary sends stronger and stronger signals to produce cortisol, but the enzymatic roadblock means they can’t comply.
Rarer genetic forms involve defects at even earlier stages of hormone production. Some block the transport of cholesterol into the cellular machinery where all steroid hormones begin, shutting down production of cortisol, aldosterone, and sex hormones simultaneously. These severe forms typically present in infancy. Other enzyme deficiencies produce more variable patterns, sometimes causing cortisol deficiency alongside excess of other hormones like mineralocorticoids, which can lead to high blood pressure even as cortisol remains low.
Other genetic conditions, including adrenoleukodystrophy (a disorder of fat metabolism that damages the adrenal glands and nervous system), can also cause primary adrenal insufficiency, particularly in boys and young men.
Secondary Adrenal Insufficiency
Secondary adrenal insufficiency originates not in the adrenal glands but in the pituitary gland, a pea-sized structure at the base of the brain. The pituitary produces ACTH, a signaling hormone that tells the adrenals to make cortisol. When ACTH production drops, the adrenal glands receive no signal, gradually shrink, and stop producing cortisol even though they’re structurally intact.
Several conditions disrupt ACTH production:
- Pituitary tumors: Both the tumor itself and surgical removal of the tumor can damage ACTH-producing cells.
- Autoimmune inflammation of the pituitary: The immune system can target the pituitary just as it can target the adrenal glands.
- Bleeding in the pituitary: Sudden hemorrhage can destroy hormone-producing tissue. Sheehan’s syndrome, caused by severe blood loss during childbirth, is a classic example.
- Traumatic brain injury: Head trauma can damage the pituitary or the stalk connecting it to the brain.
- Genetic conditions: Rare disorders can affect how the pituitary develops or functions.
- Radiation therapy: Treatment for brain tumors near the pituitary can cause gradual hormone loss over months or years.
Because the pituitary produces multiple hormones, ACTH deficiency from pituitary damage often comes alongside deficiencies in thyroid hormone, growth hormone, or reproductive hormones. This distinguishes it from primary adrenal insufficiency, where only adrenal hormones are affected.
Steroid-Induced Adrenal Insufficiency
This is the single most common cause of adrenal insufficiency overall. When you take corticosteroid medications (like prednisone, prednisolone, or dexamethasone) for an extended period, the external supply of cortisol-like hormones signals your pituitary to stop making ACTH. Without ACTH stimulation, your adrenal glands gradually shrink and lose the ability to produce cortisol on their own. If you then stop the medication abruptly, your body has no way to make cortisol and you can go into adrenal crisis.
The Endocrine Society identifies any dose above roughly 4 to 6 mg of prednisone daily (or its equivalent in other steroids) as posing risk for this suppression. Duration matters significantly: courses shorter than 3 to 4 weeks carry low risk regardless of dose, and glucocorticoids can generally be stopped without tapering in those cases. Beyond that window, the risk rises with both dose and duration, and a gradual taper is typically needed to give the adrenal glands time to wake back up.
This doesn’t only apply to pills. Inhaled steroids for asthma, steroid creams used over large areas of skin, and repeated steroid injections into joints can all suppress adrenal function if exposure is high enough and sustained long enough. Many people taking these forms don’t realize they’re at risk.
How Adrenal Insufficiency Is Diagnosed
The standard diagnostic test measures how your adrenal glands respond to a synthetic version of ACTH. After an injection, your cortisol level is checked at 30 and 60 minutes. A peak cortisol level below 18 micrograms per deciliter (500 nmol/L) at either time point is consistent with adrenal insufficiency, though exact thresholds vary slightly depending on the lab method used. Newer, more precise assays use somewhat lower cutoffs.
Once the diagnosis is confirmed, additional testing distinguishes between primary and secondary causes. In primary adrenal insufficiency, ACTH levels are high because the pituitary is working overtime trying to stimulate unresponsive adrenal glands. In secondary adrenal insufficiency, ACTH is low or inappropriately normal because the pituitary itself is the problem. Antibody testing for 21-hydroxylase can confirm autoimmune Addison’s disease, while imaging of the pituitary or adrenal glands helps identify tumors, hemorrhage, or other structural causes.
Why the Cause Matters for Treatment
All forms of adrenal insufficiency require cortisol replacement, but the specifics differ. Primary adrenal insufficiency often requires replacement of both cortisol and aldosterone, since the adrenal glands produce both. Secondary adrenal insufficiency typically needs only cortisol replacement because aldosterone production is regulated through a separate system that doesn’t depend on ACTH.
Steroid-induced adrenal insufficiency is often reversible. Once the medication is tapered slowly enough, the pituitary-adrenal communication system can recover, though this sometimes takes months or even over a year. Autoimmune destruction and most genetic causes are permanent, requiring lifelong hormone replacement. Infectious causes may or may not be reversible depending on how much tissue was destroyed before treatment began.
Regardless of the cause, people with adrenal insufficiency need to increase their cortisol replacement dose during illness, injury, or surgery, when the body’s cortisol demand spikes. Failing to do so can trigger adrenal crisis, a medical emergency marked by dangerously low blood pressure, severe dehydration, and loss of consciousness.