What medications can cause adrenal insufficiency?: An in-depth pharmacological review

October 8, 2025 •

5 min read

According to the Endocrine Society, suppression of the hypothalamic-pituitary-adrenal (HPA) axis is an inevitable effect of chronic exogenous glucocorticoid therapy. Understanding what medications can cause adrenal insufficiency is critical for patient safety, as it involves a variety of drug classes that can disrupt the body's delicate hormonal balance.

Quick Summary

This article explores the different types of medications that can lead to adrenal insufficiency, detailing the mechanisms by which they suppress cortisol production. Key drug classes discussed include glucocorticoids, opioids, and immune checkpoint inhibitors, with an emphasis on clinical presentation and risk management.

Key Points

Glucocorticoid Side Effect: Long-term use of corticosteroids is the most common cause of drug-induced adrenal insufficiency, suppressing the HPA axis.
Abrupt Withdrawal Risk: Stopping systemic glucocorticoids suddenly can trigger a life-threatening adrenal crisis, necessitating a gradual tapering process.
Opioid Impact: Chronic, high-dose opioid therapy can cause secondary adrenal insufficiency by suppressing the HPA axis centrally.
ICI Autoimmunity: Immune checkpoint inhibitors, used in cancer therapy, can cause AI as an immune-related adverse event by damaging endocrine glands.
Enzyme Inhibition: Medications like ketoconazole and metyrapone directly block the enzymes required for cortisol production, leading to primary AI.
Megestrol Acetate Effects: This appetite stimulant has glucocorticoid-like properties and can cause HPA axis suppression and adrenal insufficiency with chronic use.
Patient Awareness: Because symptoms can be subtle and nonspecific, patient awareness and physician vigilance are essential for early diagnosis and prevention of adrenal crisis.

Understanding the Adrenal Gland and the HPA Axis

To comprehend how medications can cause adrenal insufficiency (AI), it is essential to first understand the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is a complex neuroendocrine pathway that controls the body's stress response. It works via a negative feedback loop: the hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to release adrenocorticotropic hormone (ACTH). ACTH then signals the adrenal glands to produce cortisol. When external factors, such as medications, interfere with this process, it can suppress the HPA axis, leading to secondary AI. If the adrenal glands themselves are directly affected, this can lead to primary AI.

Glucocorticoids: The Most Common Culprit

By far the most prevalent cause of drug-induced adrenal insufficiency is the use of exogenous glucocorticoids, which are synthetic steroids that mimic cortisol. When administered, these drugs provide a form of external cortisol, causing the HPA axis to detect high levels and subsequently reduce its own production of ACTH and endogenous cortisol. This prolonged suppression can lead to adrenal atrophy, where the adrenal glands shrink and lose the ability to produce cortisol on their own. The risk is particularly high with long-term, high-dose therapy, but can occur even with shorter courses or non-oral routes of administration.

Key risk factors for glucocorticoid-induced AI:

Dosage and duration: Higher doses and longer treatment periods significantly increase the risk. Some studies show that as little as 5 mg of prednisone daily for three weeks can cause suppression.
Abrupt withdrawal: The most dangerous time for a patient is during or after withdrawal. If the medication is stopped too quickly, the atrophied adrenal glands cannot produce enough cortisol to meet the body’s needs, which can trigger a life-threatening adrenal crisis. Tapering the dose slowly allows the HPA axis time to recover.
Route of administration: While oral and intravenous steroids are most commonly associated with AI, non-systemic forms are also a risk. Inhaled steroids for asthma, intra-articular injections for joint pain, and topical steroids for skin conditions have all been reported to cause HPA axis suppression.
Drug interactions: Concomitant use of drugs that inhibit the CYP3A4 enzyme, such as certain antifungals (itraconazole) or protease inhibitors (ritonavir), can increase glucocorticoid levels and potentiate their suppressive effects.

Opioid-Induced Adrenal Insufficiency (OIAI)

In recent years, long-term opioid use has been increasingly recognized as a cause of secondary adrenal insufficiency. The mechanism involves the suppression of the HPA axis at the central level, affecting the hypothalamus and pituitary glands. This leads to decreased CRH and ACTH, ultimately reducing cortisol production.

Characteristics of OIAI:

Linked to long-term use: Studies indicate that OIAI is a risk for patients on chronic opioid therapy, with prevalence rates estimated to be between 9% and 29%.
Nonspecific symptoms: The symptoms of OIAI, such as fatigue, weight loss, nausea, and dizziness, can be easily mistaken for other issues related to chronic pain or the underlying condition, making diagnosis challenging.
Reversible upon withdrawal: In many cases, HPA axis function can recover after the opioid is tapered and discontinued, although this process can take months.

Immune Checkpoint Inhibitors (ICIs)

Used in modern cancer treatment, ICIs are a class of monoclonal antibodies that can cause a range of immune-related adverse events (irAEs), including adrenal insufficiency. The mechanism typically involves the immune system mistakenly attacking healthy endocrine tissue.

Types of ICI-induced AI:

Primary AI: This results from autoimmune adrenalitis, where the immune system destroys the adrenal glands. This is less common but can be severe.
Secondary AI: This is more common and arises from hypophysitis, an inflammation of the pituitary gland.

Medications That Directly Inhibit Steroidogenesis

Some drugs cause AI by directly blocking the enzymes necessary for cortisol synthesis within the adrenal glands, leading to primary AI. These medications are sometimes used specifically to treat conditions like Cushing's syndrome, where excess cortisol is produced, but can lead to overt adrenal insufficiency.

Examples of steroidogenesis inhibitors:

Ketoconazole: An antifungal agent that inhibits multiple CYP enzymes in the adrenal glands, including 17α-hydroxylase and 11β-hydroxylase, thereby blocking cortisol production.
Metyrapone and Aminoglutethimide: These drugs also inhibit adrenal enzyme function and are used to manage high cortisol levels.
Mitotane: An antineoplastic agent that causes selective destruction of the adrenal cortex, leading to decreased hormone production.

Other Notable Medications

Megestrol Acetate (MA): This synthetic progestin, often used as an appetite stimulant, has significant glucocorticoid-like activity. Chronic use can suppress the HPA axis and cause secondary AI, a complication that is frequently under-recognized.
Phenytoin, Rifampin, and Phenobarbital: These drugs can increase the metabolism of cortisol, potentially leading to relative AI, though this mechanism is less direct.

Comparison of Medications Causing Adrenal Insufficiency


Medication Class	Mechanism of Action	Type of AI Caused	Key Risk Factors	Management/Considerations
Glucocorticoids	Suppresses HPA axis via negative feedback, leading to reduced ACTH and adrenal atrophy.	Secondary/Tertiary AI.	High dose, long duration, abrupt cessation; also with inhaled, topical, intra-articular use.	Slow tapering, stress-dose steroids during illness, patient education.
Opioids	Suppresses HPA axis centrally at the hypothalamus and pituitary.	Secondary AI.	Chronic, high-dose therapy (>3-6 months).	Consider tapering opioids, glucocorticoid replacement.
Immune Checkpoint Inhibitors	Autoimmune-mediated damage to adrenal or pituitary glands.	Primary AI (adrenalitis) or Secondary AI (hypophysitis).	Use of ICIs for cancer therapy, especially combinations.	Lifelong hormone replacement may be necessary; monitor for symptoms.
Steroid Synthesis Inhibitors (e.g., Ketoconazole)	Directly inhibits enzymes required for cortisol production in adrenal glands.	Primary AI.	Used to treat Cushing's, so AI is an intended effect but can be excessive; requires careful monitoring.	Hormone replacement as needed, monitoring of cortisol levels.
Megestrol Acetate	Synthetic progestin with glucocorticoid-like activity, suppresses HPA axis.	Secondary AI.	Chronic use for appetite stimulation.	Slow tapering, vigilance for symptoms, glucocorticoid replacement.

Conclusion

Medication-induced adrenal insufficiency is a significant and often underappreciated clinical concern. From the widespread use of glucocorticoids to newer cancer immunotherapies and chronic pain medications, a variety of pharmacological agents can interfere with the body's hormonal balance. The risk factors, mechanisms, and presentation vary, but the potential for life-threatening adrenal crisis is a common thread. Patient education, careful monitoring, and a high index of suspicion are crucial for the timely diagnosis and management of this condition. Clinicians must be vigilant when prescribing or withdrawing these medications, and patients should be aware of the signs and symptoms. For individuals on long-term steroid therapy, carrying a medical alert card is a vital safety measure.

For additional information on diagnosis and management, authoritative guidelines such as those from the Endocrine Society are invaluable.

Frequently Asked Questions

Yes, although oral and intravenous steroids are the most common culprits, non-systemic forms such as inhaled steroids for asthma or topical creams and ointments used for prolonged periods can also be potent enough to suppress the HPA axis and cause adrenal insufficiency.

During prolonged steroid use, the body's HPA axis is suppressed and the adrenal glands become atrophied and inactive. If the medication is stopped suddenly, the body is left without enough cortisol to handle daily functions or stress, leading to a potentially fatal adrenal crisis. Gradual tapering allows the glands to slowly regain function.

Early symptoms are often nonspecific and can include persistent fatigue, muscle weakness, decreased appetite, weight loss, nausea, and abdominal pain. As the condition worsens, symptoms like low blood pressure, dizziness, and confusion may appear.

OIAI is estimated to affect approximately 9% to 29% of patients on chronic opioid therapy, especially those on high doses for at least three to six months. However, the prevalence and risk factors can vary, and the condition is often under-recognized.

The potential for reversal depends on the cause and duration of the suppression. In cases of glucocorticoid-induced AI, slow tapering can often lead to eventual recovery of the HPA axis, though it can take months or longer. For AI caused by immune checkpoint inhibitors, the damage may be permanent.

Diagnosis typically involves a thorough medication history and blood tests to measure cortisol and ACTH levels, often in the morning when cortisol is highest. A cosyntropin (ACTH) stimulation test may be used to confirm the diagnosis and assess adrenal gland function.

An adrenal crisis is a medical emergency that requires immediate treatment. It is triggered by severe stress or illness in a patient with AI. Treatment includes administering intravenous fluids and high-dose glucocorticoids, such as hydrocortisone, to stabilize the patient.