Should You Discontinue Immunotherapy for a Low Cortisol Level?

A low cortisol level during immunotherapy usually does not mean the treatment has to stop permanently. In most cases, the standard approach is to pause immunotherapy temporarily, start hormone replacement to get cortisol levels back to a safe range, and then resume the cancer treatment once the patient is stable. Adrenal insufficiency caused by immune checkpoint inhibitors is a recognized side effect that, while potentially dangerous if missed, is manageable with the right replacement therapy. The distinction between a temporary hold and a permanent stop matters enormously here, and the answer depends on how severe the cortisol drop is, what is causing it, and how the patient responds to treatment.

Why Immunotherapy Can Cause Low Cortisol

Immune checkpoint inhibitors work by releasing the brakes on the immune system so it can attack cancer cells more effectively. The problem is that an unleashed immune system sometimes attacks healthy tissue too, including the glands responsible for producing cortisol. This can happen in two main ways. The immune system can inflame the pituitary gland in the brain, a condition called hypophysitis, which disrupts the hormonal signals telling the adrenal glands to make cortisol. Or it can directly damage the adrenal glands themselves. The first scenario, secondary adrenal insufficiency, is more common. In one study tracking over 800 patients, all those who developed pituitary dysfunction after checkpoint inhibitor treatment had impaired cortisol-producing hormone secretion.¹

Primary adrenal insufficiency, where the adrenal glands themselves are the target, is rarer and tends to present more acutely. French expert consensus has noted that primary adrenal insufficiency during immunotherapy should be treated as a medical emergency requiring immediate hydrocortisone replacement.² The distinction between these two types matters for diagnosis, because knowing whether the problem is in the pituitary or the adrenal glands affects which hormones need replacing and how aggressively to treat.

How Severity Determines Whether Immunotherapy Pauses or Stops

The American Society of Clinical Oncology has published detailed guidelines grading immunotherapy-related adrenal insufficiency by severity, and the grading directly shapes the decision about continuing treatment. For mild cases, the guidelines say clinicians may hold the checkpoint inhibitor while getting the patient stabilized on replacement hormones. The language is “may hold,” not “must stop.” Replacement therapy typically involves a physiological dose of hydrocortisone or a small dose of prednisone, and once the patient is on a stable regimen, immunotherapy can resume.³

For moderate cases, the approach is similar but with higher initial steroid doses to manage acute symptoms, followed by a taper down to maintenance levels over about a week. The checkpoint inhibitor is again held, not permanently discontinued. Severe or life-threatening cases require emergency treatment with intravenous fluids and high-dose steroids, but even here the ASCO guidelines say to hold immunotherapy until the patient is stabilized on replacement, not to abandon it entirely.³ The key word throughout the guidelines is “hold,” paired with endocrinology consultation and careful dose management. Permanent discontinuation is reserved for situations where the adrenal crisis cannot be adequately controlled or where other severe immune-related side effects compound the picture.

Endocrine Side Effects May Actually Signal Better Cancer Outcomes

One of the more counterintuitive findings in recent immunotherapy research is that patients who develop endocrine side effects, including adrenal insufficiency, tend to have better cancer outcomes than patients who sail through treatment without any immune-related complications. A study comparing survival across groups found that patients who developed endocrine immune-related adverse events had significantly improved overall survival compared with patients who had no such events. Those who developed both endocrine and non-endocrine immune side effects had the largest survival advantage of all.⁴

This pattern makes intuitive sense: if the immune system is activated enough to attack the pituitary or adrenal glands, it is probably activated enough to attack the tumor more aggressively too. A separate study looking specifically at patients receiving combination checkpoint blockade found that those on replacement steroid therapy for adrenal insufficiency had improved overall survival compared to those not on replacement steroids, suggesting the adrenal insufficiency itself was a marker of robust immune activation rather than a reason to stop treatment.⁵ This is an important context for the decision about continuing immunotherapy: discontinuing a treatment that is clearly engaging the immune system, at a time when the side effect is treatable with replacement hormones, could mean walking away from a meaningful survival benefit.

Which Immunotherapy Drugs Carry the Highest Risk

Not all checkpoint inhibitors are equally likely to cause cortisol problems. The risk is highest with combination regimens, particularly those that pair a PD-1 inhibitor with a CTLA-4 inhibitor. Overall, adrenal insufficiency occurs in roughly one to two percent of patients on single-agent therapy and in a higher range when checkpoint inhibitors are combined.⁶

A prospective study that followed patients on combination PD-1/CTLA-4 blockade versus PD-1 alone found that pituitary dysfunction developed in about one in five patients receiving the combination, compared with roughly one in thirty receiving PD-1 monotherapy. The combination group was also far more likely to develop multiple hormone deficiencies at once rather than isolated cortisol problems.¹ A separate analysis of hospitalized patients found that use of ipilimumab, a CTLA-4 inhibitor, carried a substantially elevated risk of adrenal insufficiency, and the risk was also significantly higher when CTLA-4 and PD-1 agents were combined.⁷

This matters for the discontinuation question because patients on combination regimens are precisely those who are often getting the most aggressive cancer treatment for the most serious disease. Stopping their immunotherapy entirely over a manageable hormone deficiency could be a disproportionate response. It is better, when possible, to manage the endocrine side effect and preserve the cancer treatment.

How Adrenal Insufficiency Gets Missed

One of the real dangers with immunotherapy-induced adrenal insufficiency is not that it forces a treatment stop, but that it goes unrecognized. The symptoms of low cortisol, such as fatigue, nausea, low blood pressure, and general malaise, overlap heavily with how cancer patients often feel from the disease itself or from other treatment side effects. Delayed diagnosis is common because these nonspecific symptoms get attributed to the malignancy or other toxicities. Such delays can result in preventable complications, including longer hospital stays and higher rates of readmission.⁸

One case report documented a patient on pembrolizumab whose morning cortisol level was found to be extremely low, well below the normal range, with a correspondingly low cortisol-stimulating hormone level consistent with secondary adrenal insufficiency. The presentation was persistent low blood pressure that had not responded to standard interventions.⁹ The word “underdiagnosed” in the title of that report captures the broader concern: the question should not just be whether to stop immunotherapy for low cortisol, but whether clinicians are catching low cortisol in the first place.

French expert opinion has recommended that primary adrenal insufficiency does not warrant routine screening during immunotherapy, but should be actively suspected when patients present with unexplained decline in general health or low sodium levels.² The threshold for checking a cortisol level should be low in patients who are not feeling right, because catching the problem early makes it much easier to manage without interrupting cancer treatment for long.

Rechallenge After Stabilization

The published evidence supports the idea that immunotherapy can be successfully restarted after cortisol-related adverse events are controlled. In a recently reported case, a patient who developed grade three adrenal insufficiency from a bispecific checkpoint inhibitor had immunotherapy temporarily suspended, started on hydrocortisone replacement, and experienced symptom improvement. After stabilization, the same immunotherapy agent was rechallenged successfully.¹⁰ This is consistent with the ASCO guideline framework, which treats adrenal insufficiency differently from some other severe immune-related adverse events like myocarditis, where permanent discontinuation is more often recommended. The pituitary or adrenal damage from immunotherapy is usually irreversible, meaning patients will need lifelong hormone replacement. But the need for replacement hormones does not in itself prevent ongoing cancer treatment. The two therapies run in parallel.

An important caveat applies to patients who develop multiple severe immune-related side effects simultaneously. A single organ system affected by immune toxicity is typically manageable; when several organ systems are failing at once, the calculus can shift. But for isolated adrenal insufficiency, even at a severe grade, the pattern in the literature is hold, replace, stabilize, and resume.

Choosing the Right Replacement Steroid

Once adrenal insufficiency is diagnosed, the choice of replacement steroid may matter more than clinicians have traditionally appreciated. A retrospective study of melanoma patients with secondary adrenal insufficiency found a striking difference in five-year survival depending on which glucocorticoid was used for maintenance. Patients maintained on hydrocortisone had a roughly one-in-three mortality rate over five years, while those on prednisone had a mortality rate above fifty percent. The median survival for the hydrocortisone group was 55 months compared with 38 months for the prednisone group.¹¹

This is a retrospective finding and should not be treated as conclusive on its own, but the difference is large enough to be clinically meaningful. The likely explanation involves the pharmacology of the two drugs: hydrocortisone more closely mimics the body’s natural cortisol rhythm and has a shorter duration of action, while prednisone is a synthetic glucocorticoid with a longer half-life and greater potency that may have more immunosuppressive effects at typical replacement doses. Since the whole point of immunotherapy is to activate the immune system, using a replacement steroid that dampens immune function more than necessary could blunt the treatment’s effectiveness. The ASCO guidelines list both hydrocortisone and prednisone as options, but this newer evidence tilts the balance toward hydrocortisone for patients who are continuing checkpoint inhibitor therapy.³

The distinction between replacement-dose steroids and the high-dose steroids sometimes used to manage other immune side effects is worth understanding. Replacement doses replace what the body can no longer make on its own and are not immunosuppressive in the way that pharmacological doses are. When a patient with adrenal insufficiency takes hydrocortisone at maintenance levels, they are simply restoring normal physiology. Research has confirmed that patients on replacement steroid therapy for adrenal insufficiency actually had improved overall survival, which suggests these low doses do not interfere with immunotherapy’s anti-cancer effects.⁵

Living With Adrenal Insufficiency During and After Treatment

If immunotherapy damages the pituitary or adrenal glands enough to cause cortisol deficiency, that damage is almost always permanent. Patients will need to take replacement hormones indefinitely, even after cancer treatment ends. This means learning to manage a chronic condition on top of everything else.

Practical management includes understanding sick-day rules. Any illness, injury, or significant physical stress increases the body’s cortisol demand, and patients who cannot make their own cortisol need to increase their replacement dose temporarily. Guidance published during the pandemic emphasized several key points for patients with immunotherapy-induced adrenal insufficiency:¹²

Sick-day dosing: Patients need clear instructions from their endocrinologist on when to double or triple their usual steroid dose during illness, and how to taper back down as they recover.
Emergency identification: Wearing a medical alert bracelet or carrying a card that identifies them as having adrenal insufficiency can be lifesaving, especially in emergency situations where the patient cannot communicate.
Emergency injection kit: Having injectable hydrocortisone or dexamethasone available at home, along with training on how to use it, provides a safety net for situations where oral medication cannot be taken.
Hydration: Maintaining adequate fluid intake is more important for people with adrenal insufficiency, especially during illness or hot weather.

Ongoing follow-up with an endocrinologist is valuable both during and after immunotherapy. Dose adjustments may be needed as overall health changes, and monitoring other pituitary hormones is important because immunotherapy can damage multiple hormone axes at once, particularly with combination regimens. In the prospective study comparing combination and single-agent therapy, patients on combination regimens who developed pituitary problems frequently had deficiencies in thyroid-stimulating hormone, sex hormones, and cortisol-producing hormones simultaneously.¹ Managing cortisol alone is not sufficient if thyroid or sex hormone deficiencies go untreated.

When the Timing of Detection Changes the Equation

One study tracking patients who developed hypophysitis found that the median time to onset was about seven months after starting immunotherapy.¹³ This means that a low cortisol level can appear well into a treatment course, often at a point where the patient has already had several cycles of immunotherapy and may be responding well. Stopping treatment at that point is a particularly difficult decision, and the evidence strongly favors managing the adrenal insufficiency while continuing the checkpoint inhibitor.

Early in treatment, the calculus can be slightly different. If a patient develops severe adrenal insufficiency after just one or two cycles, it raises the question of whether their immune system is hyperreactive in ways that could produce more dangerous side effects down the road. Even so, the standard of care remains to stabilize and rechallenge rather than to abandon immunotherapy preemptively. The endocrine side effects of checkpoint inhibitors are among the most manageable immune-related adverse events precisely because hormone replacement is well understood and effective. Unlike immune-related colitis or hepatitis, which may require high-dose immunosuppression that could interfere with the cancer treatment, adrenal insufficiency just needs the body’s missing hormone put back at physiological levels.

The broader picture here is reassuring for patients who are understandably alarmed by a cortisol lab result that comes back near zero. That number can look terrifying on paper. But it represents a problem that endocrinologists manage routinely in non-cancer settings, and the tools to manage it during immunotherapy are the same ones that work for patients with adrenal insufficiency from any other cause. The real risk lies in not detecting it, not in detecting it and having to make a difficult treatment decision.