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PubMed This is a summary of 21 peer-reviewed journal articles Updated
Endocrinology

The Broken Relay: How and Why ACTH Production Fails

At a Glance

Late-onset isolated ACTH deficiency occurs when the pituitary stops sending ACTH to the adrenal glands, reducing cortisol production. Autoimmunity, immune checkpoint inhibitors, and prior moderate to severe head injury are possible causes, even when MRI looks normal.

To understand late-onset isolated ACTH deficiency (IAD), it helps to think of your hormonal system as a relay race. In a healthy body, your pituitary gland (the “control center”) produces a hormone called ACTH. This hormone travels through your blood to your adrenal glands, signaling them to produce cortisol [1][2].

In IAD, the relay is broken at the very start. For reasons we are still learning about, the pituitary stops sending the ACTH signal. Without that signal, your adrenal glands sit idle and cannot produce the cortisol your body needs to function [1][3].

The Immune System Turning Inward

In many adults, IAD is suspected to be an autoimmune condition. This means your immune system, which is supposed to protect you, mistakenly attacks the specific cells in the pituitary gland that make ACTH (called corticotrophs) [4][5].

  • Co-existing Conditions: It is very common for patients with IAD to have other autoimmune issues. Up to 31% of patients in some reviewed cohorts also have Hashimoto’s thyroiditis (an underactive thyroid caused by the immune system) [6][7].
  • Anti-POMC Antibodies: Researchers have found that some patients have “anti-POMC” antibodies. POMC is the precursor protein your body uses to make ACTH. While these antibodies have been detected in some studies, their clinical meaning is still uncertain and they are not routine diagnostic tests [5][8].

The Link to Cancer Immunotherapy

Modern cancer treatments called immune checkpoint inhibitors (ICIs) have revolutionized oncology, but they can have “off-target” effects on the pituitary gland. These drugs work by “releasing the brakes” on your immune system so it can attack cancer cells, but sometimes the immune system attacks healthy organs instead [9][10].

  • PD-1 and PD-L1 Inhibitors: Drugs like nivolumab or pembrolizumab are particularly associated with IAD [11][12].
  • The “Delayed” Effect: One of the most challenging aspects of this cause is the timing. While many side effects happen early, ACTH deficiency can develop months or even years after you have finished your cancer treatment [10][12].

Traumatic Brain Injury (TBI)

The pituitary gland is connected to the brain by a delicate stalk and sits in a bony cradle. Because of this anatomy, it is susceptible to injury during moderate to severe head impacts [13].

  • Mechanical Damage: A severe accident or fall can stretch or tear the blood vessels feeding the pituitary gland or damage the gland itself [13][14].
  • The Long Gap: Post-traumatic pituitary issues can be “silent” for a long time. A patient can develop symptoms of ACTH deficiency months or years after the original injury [14][15]. Because symptoms like fatigue and “brain fog” can mimic post-concussion syndrome, the hormonal cause is sometimes missed [16]. (Note that while established for severe injury, the link to mild concussions is less certain, and symptoms years later require evaluation for other causes).

Why Your MRI May Look Normal

One of the most confusing parts of an IAD diagnosis is that a pituitary MRI—the standard imaging scan—is often completely normal [12][17]. This can lead some doctors to incorrectly rule out a pituitary problem. Biochemical and clinical assessment determines central adrenal insufficiency, not a normal scan alone. There are a few main reasons for this “clean” scan:

  1. Microscopic Damage: The immune attack may only destroy the specific cells that make ACTH, which doesn’t change the overall shape or size of the gland [18].
  2. Timing: If the scan is taken early, the inflammation might be too subtle to see. If it is taken late, the gland may have already finished its “inflammatory phase” and returned to a normal size on imaging [19][20].
  3. Specific Triggers: For patients on immunotherapy (PD-1/PD-L1 inhibitors), a high percentage will have a completely normal-looking pituitary on their MRI, despite having severe hormone deficiencies [12][17].

Because of this, doctors must rely on specialized blood tests and your clinical history, rather than just imaging, to make the diagnosis [21][19].

Common questions in this guide

What can cause late-onset isolated ACTH deficiency?
The pituitary may stop making ACTH because the immune system attacks ACTH-producing cells, although the exact cause is not always known. Other possible causes include immune checkpoint inhibitor therapy and prior moderate to severe traumatic brain injury. These causes can lead to too little cortisol because the adrenal glands no longer receive the ACTH signal.
Can cancer immunotherapy cause ACTH deficiency after treatment ends?
Yes. Immune checkpoint inhibitors, especially PD-1 or PD-L1 inhibitors such as nivolumab and pembrolizumab, can trigger ACTH deficiency. It may appear months or even years after the last dose, so your cancer-treatment history remains important during evaluation.
Could an old head injury explain new ACTH deficiency symptoms?
A moderate to severe head injury can damage the pituitary or its blood supply, and ACTH deficiency may not become noticeable until months or years later. Fatigue and brain fog can resemble post-concussion symptoms, so clinicians need to assess other possible causes as well. The link after a mild concussion is less certain.
Can I have isolated ACTH deficiency if my pituitary MRI is normal?
Yes. A routine MRI may look normal when damage is limited to microscopic ACTH-producing cells or when inflammation has already settled; this is also common in some people affected by immunotherapy. Blood tests, symptoms, and medical history are more important than a normal scan alone when assessing ACTH deficiency.
Do autoimmune conditions or anti-POMC antibodies explain why ACTH is low?
Hashimoto's thyroiditis and other autoimmune conditions can coexist with isolated ACTH deficiency, but they do not by themselves prove why ACTH is low. Anti-POMC antibodies have been found in some patients, yet their meaning remains uncertain and they are not routine diagnostic tests. Your clinician can decide whether thyroid and other pituitary hormone testing is appropriate.

Questions For You

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Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Do I have any antibodies, such as anti-TPO or anti-corticotroph antibodies, that suggest an autoimmune cause for my condition?
  2. 2.Since my MRI was normal, could this be the 'destructive' phase where inflammation has already passed, or is it more likely to be a microscopic issue?
  3. 3.Given my history of cancer treatment, could my ACTH deficiency be a delayed side effect of immunotherapy, even though I finished treatment months ago?
  4. 4.If I had a head injury or concussion years ago, is it possible that the damage to my pituitary is just now becoming symptomatic?
  5. 5.Are we monitoring my other pituitary hormones to see if they might become deficient in the future?

References

References (21)
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    Nuclear Receptors as Regulators of Pituitary Corticotroph Pro-Opiomelanocortin Transcription.

    Zhang D, Heaney AP

    Cells 2020; (9(4)) doi:10.3390/cells9040900.

    PMID: 32272677
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    Rare clinical problem - isolated ACTH deficiency associated with chronic alcohol abuse.

    Skowrońska-Jóźwiak E, Orzechowski S, Piętak W, Lewiński A

    Endokrynologia Polska 2022; (73(4)):778-783 doi:10.5603/EP.a2022.0056.

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    Recovery of steroid induced adrenal insufficiency.

    Younes AK, Younes NK

    Translational pediatrics 2017; (6(4)):269-273 doi:10.21037/tp.2017.10.01.

    PMID: 29184808
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    Clinical Heterogeneity of Acquired Idiopathic Isolated Adrenocorticotropic Hormone Deficiency.

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    Frontiers in endocrinology 2021; (12()):578802 doi:10.3389/fendo.2021.578802.

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    Isolated adrenocorticotropic hormone deficiency as a form of paraneoplastic syndrome.

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    Idiopathic isolated adrenocorticotropic hormone deficiency: a systematic review of a heterogeneous and underreported disease.

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    Clinical features and autoimmune associations in patients presenting with Idiopathic Isolated ACTH deficiency.

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    Paraneoplastic isolated adrenocorticotropic hormone deficiency revealed after immune checkpoint inhibitors therapy: new insights into anti-corticotroph antibody.

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    Incidence of Endocrine Dysfunction Following the Use of Different Immune Checkpoint Inhibitor Regimens: A Systematic Review and Meta-analysis.

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    Immune Checkpoint Inhibitors and Associated Pituitary Dysfunctions: A Mini-Review.

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This page is for informational purposes only and does not constitute medical advice. An endocrinologist should interpret your hormone tests, medical history, and MRI when evaluating possible ACTH deficiency.