Symptoms, Diagnosis, and Treatment of Immunotherapy-Induced Thyroiditis and Hypophysitis: Is Hormone Deficiency Permanent, and Should Immunotherapy Be Discontinued?
In this article
When Immunotherapy Affects the Hormone Glands: Recognizing Thyroid and Pituitary Problems Early
Immune checkpoint inhibitors (immunotherapies) switch on the immune system against cancer, but at times they can also target the body's own tissues (immune-related adverse events, irAEs). Hormone-producing glands are among the organs most often affected by these side effects. Inflammation of the thyroid gland (thyroiditis) and inflammation of the pituitary gland in the brain (hypophysitis) can be missed because their symptoms resemble ordinary tiredness; yet when recognized early, they are easy to treat. In this article we explain the symptoms of these two side effects, which tests reveal them, how they are treated and whether immunotherapy can be continued. We have previously covered the side effects of immunotherapies, their kidney side effects and long-lasting skin side effects in separate articles.
- Thyroiditis: The most common endocrine side effect, especially with PD-1 inhibitors and combination therapy. Usually a temporary phase of hyperthyroidism lasting a few weeks (palpitations, sweating) comes first, followed by hypothyroidism that is usually permanent (fatigue, feeling cold, weight gain). Treatment is a thyroid hormone tablet; immunotherapy can be continued in most patients.
- Hypophysitis: Seen mostly with ipilimumab and combination therapy. It can present with headache, extreme fatigue, nausea, low blood pressure and low blood sodium. Cortisol deficiency can be life-threatening; diagnosis relies on morning cortisol, ACTH and a pituitary MRI.
- Treatment order matters: If both cortisol and thyroid hormone are deficient, cortisol (hydrocortisone) must be started first; the reverse order can trigger an adrenal crisis.
- Permanence: Unlike other immunotherapy side effects, hormone deficiencies are usually permanent and require lifelong hormone replacement. These side effects on their own are usually not a reason to stop immunotherapy.
Why does this matter?
Immunotherapies are now part of standard treatment for lung, melanoma, kidney, bladder, head and neck, stomach and many other cancers (pembrolizumab, nivolumab, ipilimumab + nivolumab). The immune-related side effects of these drugs differ from those of chemotherapy: they can appear at any point during treatment, even months after treatment has ended, and they can affect any organ.
Endocrine (hormonal) side effects occur in roughly 1 in every 10 patients receiving immunotherapy, and they differ from other side effects in three important ways: their symptoms can be vague and easily confused with cancer- or treatment-related fatigue; the damage is usually permanent; but because the missing hormones can easily be replaced with tablets, cancer treatment often does not need to be stopped. A missed hypophysitis, however, can lead to an emergency with a sudden drop in blood pressure and confusion caused by cortisol deficiency (causes of fatigue in cancer).
What are the symptoms of immunotherapy-related thyroiditis and hypophysitis?
Immunotherapy-related thyroiditis may first cause symptoms of temporary hyperthyroidism, such as palpitations, sweating, irritability and weight loss, followed by symptoms of hypothyroidism, such as fatigue, feeling cold, weight gain, constipation and dry skin; in many patients it is noticed only on a blood test. Hypophysitis presents with headache, extreme fatigue, loss of appetite, nausea, dizziness, low blood pressure and low blood sodium.
Thyroiditis: the most common endocrine side effect
The thyroid gland produces hormones that regulate the body's energy and metabolic rate. When immune cells attack the thyroid gland during immunotherapy, the hormone stored in the gland is first released into the bloodstream (temporary hyperthyroidism, or thyrotoxicosis), and then the damaged gland can no longer produce enough hormone (hypothyroidism).
Thyroid side effects by type of treatment
Percent. Same meta-analysis. Red bar: combination therapy.
With PD-1 inhibitors, the risk of hypothyroidism was about twice that with ipilimumab (OR 1.89), and the risk of hyperthyroidism about five times that with PD-L1 inhibitors (OR 5.36).
Figure 1 · The typical course of immunotherapy-related thyroiditis
Simplified diagram; not every patient goes through every phase
| Phase | Symptoms | Blood test | Treatment |
|---|---|---|---|
| Temporary hyperthyroidism (thyrotoxicosis) | Palpitations, sweating, heat intolerance, hand tremor, sleeplessness, weight loss; often no symptoms | TSH low, free T4 high | A beta blocker if there are symptoms; antithyroid drugs are usually not needed |
| Hypothyroidism | Fatigue, sleepiness, feeling cold, weight gain, constipation, dry skin, hair loss, swelling | TSH high, free T4 low | Levothyroxine (thyroid hormone); monitoring in mild cases without symptoms |
| Pituitary-related (central) hypothyroidism | Hypothyroidism symptoms + headache, extreme fatigue | Free T4 low, TSH low or normal | Cortisol must be assessed first; managed as hypophysitis |
TSH: thyroid-stimulating hormone. In hypothyroidism, a TSH that is not raised suggests the problem may lie in the pituitary rather than the thyroid; this distinction changes the order of treatment.
Thyroiditis usually appears within the first 2–3 months of immunotherapy, but it can also develop later. The hyperthyroid phase usually resolves on its own. Hypothyroidism, however, is permanent in most patients, and the thyroid hormone tablet is taken long term, often for life. The tablet should be taken in the morning on an empty stomach and separately from other medicines; the dose is adjusted with TSH and free T4 measurements every few weeks. Immunotherapy rarely needs to be stopped because of thyroid side effects; if symptoms are severe, only a short pause may be needed.
Hypophysitis: less common, but a side effect that must not be missed
The pituitary is the "master gland" at the base of the brain that controls the thyroid, the adrenal glands and the reproductive glands. The most important problem in immunotherapy-related hypophysitis is a fall in ACTH, the hormone that stimulates the adrenal glands, and the resulting cortisol deficiency. Cortisol is a vital hormone that maintains blood pressure, blood sugar and sodium balance at times of stress.
Hypophysitis rates: which immunotherapy carries the higher risk?
Percent. Meta-analysis of randomized trials (38 trials, 7,551 patients). Red bar: combination therapy.
The rate with PD-L1 inhibitors was reported as below 0.1%. These data come from a single meta-analysis; rates may differ with newer drugs and in real-world series.
Hypophysitis is seen most often with ipilimumab and ipilimumab-containing combinations, usually within the first 2–3 months of treatment (dual immunotherapy in melanoma, dual immunotherapy in mesothelioma). With PD-1 and PD-L1 inhibitors it is less common and usually appears later; with these drugs, often only ACTH deficiency develops (isolated ACTH deficiency), and the pituitary MRI may be normal.
| Hormone affected | Symptoms | Blood test | Permanence |
|---|---|---|---|
| ACTH (cortisol deficiency) | Extreme fatigue, loss of appetite, nausea, vomiting, dizziness, low blood pressure, muscle and joint pain | Morning cortisol low, ACTH low or normal, sodium low | Usually permanent |
| TSH (central hypothyroidism) | Fatigue, feeling cold, weight gain | Free T4 low, TSH low or normal | May recover in some patients |
| LH and FSH (reproductive hormones) | Reduced sex drive, erection problems in men, irregular periods in women | Testosterone or estradiol low, LH/FSH low | May recover in some patients |
| Pituitary enlargement | Headache; very rarely vision problems | Enlarged gland on pituitary MRI | Usually shrinks back within weeks |
Deficiency of the hormone that regulates water balance (diabetes insipidus, with excessive urination and thirst) is very rare in immunotherapy-related hypophysitis; if it occurs, other causes should also be investigated.
Figure 2 · Diagnosis and treatment when hypophysitis is suspected
Simplified approach
Points to watch in treatment: If a patient with cortisol deficiency is given thyroid hormone first, the body's need for cortisol rises and an adrenal crisis can develop; that is why the order is always cortisol first, then thyroid hormone. High-dose steroid treatment (such as dexamethasone) is used only briefly, if there is a severe headache or a vision problem; what the hormone deficiency itself requires is replacement therapy at physiological doses. In most patients who develop hypophysitis, immunotherapy can be continued once hormone replacement has been started and symptoms have improved.
If you are receiving immunotherapy or have received it within the past year, contact your doctor or go to the emergency department without delay if you have any of the following, and be sure to say that you are receiving immunotherapy:
- Severe or persistent headache, blurred or disturbed vision
- Dizziness on standing up, feeling faint, very low blood pressure
- Vomiting that will not stop, abdominal pain, extreme fatigue or confusion
- Extreme thirst, very frequent urination, fruity-smelling breath, rapid breathing (these may be signs of sudden immunotherapy-related diabetes and ketoacidosis)
- Marked palpitations, chest pain or shortness of breath
Other endocrine side effects
- Damage to the adrenal gland itself (primary adrenal insufficiency): Rare; in addition to cortisol, the hormone that maintains salt balance also falls. Low sodium together with high potassium and high ACTH is typical. Treatment adds a salt-retaining hormone to hydrocortisone.
- Immunotherapy-related type 1 diabetes: Seen in fewer than about 1% of patients, most often with PD-1 and PD-L1 inhibitors. The insulin-producing cells of the pancreas are damaged within a few days or weeks, and a substantial share of patients are diagnosed when they present with diabetic ketoacidosis. It is permanent and requires lifelong insulin (diabetes and insulin resistance, the link between cancer and diabetes).
- Parathyroid gland failure: Very rare; presents with numbness, muscle cramps and spasms caused by low calcium.
Which tests, and how often?
The European Society of Endocrinology and oncology guidelines recommend hormone tests before starting immunotherapy and before every treatment cycle:
- At baseline: TSH and free T4, morning cortisol (and preferably ACTH), blood sugar and electrolytes (sodium, potassium, calcium).
- Before every treatment cycle: TSH and free T4, blood sugar and electrolytes; morning cortisol, especially with ipilimumab-containing treatments and when symptoms are present.
- After treatment has ended, too: Because endocrine side effects can appear months later, symptoms should be watched for and regular check-ups should continue. Permanent hormone deficiencies matter even more for patients who receive short-term immunotherapy before or after surgery and have a high chance of cure (immunotherapy before surgery, long-term effects of cancer treatment).
Some studies have observed that immunotherapy works better in patients who develop a thyroid side effect. However, this link is observational; not developing a side effect does not mean the treatment is not working (reading research correctly).
Thyroid hormone, morning cortisol, ACTH and electrolyte tests are widely available in Turkey, and pituitary MRI can easily be done at many centers. Replacement therapies such as levothyroxine, hydrocortisone or an equivalent steroid tablet, and insulin are available on prescription with coverage from the SGK (the Turkish Social Security Institution); current availability of the drugs may vary by pharmacy. Joint follow-up of patients receiving immunotherapy by oncology and endocrinology teams makes it easier to recognize side effects early. For the reimbursement conditions of immunotherapies, see our article on SGK conditions.
Tips for patients and their families
- Write down your symptoms: Do not brush off new symptoms such as tiredness, headache, palpitations, weight change or feeling cold as "just the cancer or the treatment"; tell your doctor.
- Do not skip your blood tests: Thyroid, sugar and electrolyte tests before every treatment cycle can catch a problem before symptoms appear.
- If you are taking steroid treatment: Do not stop the medicine on your own; learn how to increase the dose on sick days such as fever, vomiting or diarrhea (sick-day dose rules), and carry an emergency steroid card.
- Take your thyroid medicine correctly: Take it in the morning on an empty stomach, about half an hour before breakfast, and separately from medicines such as iron and calcium.
- Also talk about changes in your mood: Hormone disorders can cause depressive symptoms or irritability (psychological support in oncology).
- When making decisions, do not hesitate to get a second opinion.
Frequently asked questions
- How does immunotherapy affect the thyroid gland?
- Immunotherapy can cause the immune system to attack the thyroid gland (thyroiditis). Usually a temporary phase of hyperthyroidism lasting a few weeks (palpitations, sweating) comes first, followed by hypothyroidism that is usually permanent (fatigue, feeling cold, weight gain). Hypothyroidism occurs in about 6–7% of people receiving immunotherapy; with dual immunotherapy the rate rises to 13%. Treatment is a thyroid hormone tablet.
- What is hypophysitis, and what are its symptoms?
- Hypophysitis is inflammation of the pituitary gland in the brain. It presents with headache, extreme fatigue, loss of appetite, nausea, dizziness, and low blood pressure and sodium. It is seen most often with ipilimumab-containing treatments (6.4% with the combination, 0.4% with PD-1 inhibitors). Because cortisol deficiency can be life-threatening, rapid diagnosis and treatment are needed.
- Is immunotherapy stopped if thyroiditis or hypophysitis develops?
- Usually not. Because the missing hormones can be replaced with tablets, immunotherapy is generally continued once symptoms are under control. If symptoms are severe, a short pause may be taken. The decision is made jointly by the oncologist and the endocrinologist.
- Do these hormone problems go away?
- The hyperthyroid phase of thyroiditis is temporary, but the hypothyroidism that follows and the cortisol deficiency caused by hypophysitis are usually permanent. For this reason, most patients take a thyroid hormone or steroid tablet long term, often for life.
Glossary
- Immune checkpoint inhibitor
- A drug that strengthens the immune response against cancer by releasing the immune system's "brakes" (PD-1, PD-L1, CTLA-4).
- Thyroiditis
- Inflammation of the thyroid gland.
- Thyrotoxicosis
- An excessive rise in thyroid hormones in the blood; causes palpitations, sweating and weight loss.
- Hypothyroidism
- A shortage of thyroid hormones; causes fatigue, feeling cold and weight gain.
- Hypophysitis
- Inflammation of the pituitary gland at the base of the brain.
- ACTH
- A hormone released by the pituitary that stimulates the adrenal glands to produce cortisol.
- Cortisol
- A vital hormone released by the adrenal glands that maintains blood pressure and blood sugar at times of stress.
- Adrenal crisis
- An emergency caused by a sudden lack of cortisol, with low blood pressure, vomiting and confusion.
- Levothyroxine
- A tablet that replaces thyroid hormone.
DROZDOGAN Academy Commentary
Endocrine side effects are among the most common and most lasting side effects of immunotherapy; yet with proper monitoring and simple hormone treatments they can be managed without interrupting cancer treatment.
⚡ Why it matters
Because their symptoms are vague, they can be missed; cortisol deficiency caused by hypophysitis in particular can be life-threatening if it goes unrecognized. Because they are permanent, they also affect the patient's quality of life after cancer.
✅ Strengths
They can be recognized early with simple blood tests; treatment is inexpensive, easy and effective. In most patients, immunotherapy can be continued without interruption.
⚠️ Limitations
Frequency data come mostly from clinical trials; in real-world practice, mild cases may be more common. There is not yet a reliable test that can predict in advance which patient will develop a side effect.
🩺 In practice
Before every treatment cycle we check TSH, free T4, blood sugar and electrolytes, and we check morning cortisol with ipilimumab-containing treatments and in unexplained fatigue. When hypophysitis is suspected, we do not hesitate to start steroids even while waiting for test results, and we give thyroid hormone after the steroid. We always explain sick-day rules and the emergency card to our patients.
❓ Open questions
Can markers be found that predict the development of endocrine side effects in advance? Is it possible to reduce the risk of permanent hormone deficiency with short-term immunotherapy given with curative intent?
Bottom line: Every patient receiving immunotherapy, and their family, should know the symptoms of thyroid and pituitary side effects. With early diagnosis and hormone treatment started in the right order, these side effects can be managed safely, and cancer treatment can often be continued.
- This article was prepared in October 2026.
- Frequency data are taken from a meta-analysis (2018) of 38 randomized trials; rates may differ with newer drugs and in real-world data. The diagnostic and treatment recommendations reflect the general approach of the European Society of Endocrinology (2022), ESMO and ASCO guidelines.
- Time frames for when symptoms appear are approximate and vary from patient to patient.
- Information on access to drugs and tests in Turkey reflects the general situation. This article is for general information only; it is not personal medical advice. The diagrams are derived from the text. The Academy commentary is our own.
References
- Barroso-Sousa R, Barry WT, Garrido-Castro AC et al. Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: a systematic review and meta-analysis. JAMA Oncol 2018;4:173-182. doi:10.1001/jamaoncol.2017.3064
- Endocrine-related adverse conditions in patients receiving immune checkpoint inhibition: an ESE clinical practice guideline. Eur J Endocrinol 2022. doi:10.1530/EJE-22-0689
- Haanen J et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 2022;33:1217-1238. doi:10.1016/j.annonc.2022.10.001
- Schneider BJ et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol 2021;39:4073-4126. doi:10.1200/JCO.21.01440
- Incidence of endocrine dysfunction with immune checkpoint inhibitors. The ASCO Post, 2017. ascopost.com
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