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How a dysfunctional HPA axis might be causing post-infectious ME/CFS and Long COVID, and how to correct it.
A recent review of the scientific literature paints a compelling picture of how post-infectious ME/CFS and Long COVID might be initiated in a subset of patients. Here, we explain how the pituitary gland is involved in the hypothalamic-pituitary-adrenal (HPA) axis, why it might be dysregulated in both conditions, and how you might address it.
The Hypothesis: A Gland in Flames
Imagine a tiny gland in your brain, the pituitary gland, suddenly engulfed in the ‘flames’ of inflammation. Could this be driving much of the overlapping disease pathology observed in both ME/CFS and Long COVID?
This hypothesis was recently explored in a review of the scientific literature. They propose that inflammation of the pituitary gland could be the culprit behind ME/CFS and Long COVID in some patients. The pituitary gland is a crucial part of the hypothalamic-pituitary-adrenal axis, a system that helps regulate our stress response.
When this gland is inflamed, it disrupts the entire HPA axis, leading to a cascade of problems. But first, let’s learn about the HPA axis and how it functions to ensure that stress does not trigger inflammation severe enough to cause disease.
HPA Axis Malfunction: The Broken Stress Response
The HPA axis is like the body’s command center for handling stress. It orchestrates a series of responses that help us cope with stressful situations.
Patient surveys and clinical data suggest that individuals with ME/CFS or Long COVID do not respond to stress properly. It’s as if their HPA axis is broken, unable to perform its vital functions.
But why is the HPA axis so important?
HPA Axis and Stress: The Inflammation Connection
When we experience stress, our bodies quickly produce pro-inflammatory cytokines in the blood. This rapid response takes only minutes and is essential for addressing immediate threats. However, inflammation must be turned off to prevent damage, even if the stressor persists.
This is where the HPA axis comes into play. It acts as a switch, reducing inflammation even if the stress continues.
Imagine you’re in a jungle about to be attacked by a jaguar. Your fight-or-flight response kicks into overdrive, causing your heart to race in your throat and heightening your alertness. Something else happens. Your white blood cells start making pro-inflammatory cytokines. Your liver also quickly begins producing more fibrinogen, the precursor of blood clots. Here is why.
Assuming you are not the jaguar’s lunch, a bite or scratch alone could be life-threatening, either from bleeding out or succumbing to a lethal bacterial infection days later. This is why the fight-or-flight branch of your nervous system causes a spike in the blood concentration of fibrinogen and pro-inflammatory cytokines, to protect you from bleeding out and from an infection, respectively.
Thus, the stress response can save your life. However, there must be a way to turn it off because chronic stress would lead to the overproduction of pro-inflammatory cytokines.
Let’s learn how it’s turned off.
How the HPA Axis Works: A Step-by-Step Guide
Let’s take a closer look at how the HPA axis functions. When stress hits (1), the hypothalamus releases corticotropin-releasing hormone (CRH) (2). This hormone signals the pituitary gland to release adrenocorticotropic hormone (ACTH) (3). ACTH enters the blood and travels to the adrenal glands above the kidneys, prompting them to produce cortisol (4). Cortisol, in turn, signals to immune cells to stop producing pro-inflammatory cytokines (5). This is how the inflammation is turned off. By producing cortisol. This intricate process helps keep inflammation in check and prevents the development of autoimmunity and chronic inflammatory diseases.
Cortisol Is More Than An Immunosuppressant
Cortisol does more than simply dampen inflammation; it is often called the body’s “stress and energy manager” because it plays a central role in helping us adapt to challenges such as physical threats, emotional strain, or daily demands. The roles of cortisol include the following:
- Mobilizing Energy. Cortisol raises blood sugar (glucose) levels to provide quick fuel to muscles and the brain during stressful periods. Cortisol naturally peaks in the morning, helping us start the day alert and energized. It also supports the breakdown of fats (lipolysis) and proteins (proteolysis) to provide additional energy substrates when needed.
- Enhancing Alertness. Cortisol helps maintain heightened awareness, sharpens attention, and supports quick decision-making and behavioral adaptation during acute stress.
- Regulating Inflammation. As mentioned, cortisol is a potent anti-inflammatory hormone that can inhibit pro-inflammatory cytokines and immune cell activity. In short bursts, this prevents the acute inflammation from causing tissue damage, while allowing the body to prioritize survival needs.
- Brain Functions: It affects mood, motivation, memory formation, and emotional processing by activating brain regions such as the hippocampus and prefrontal cortex. Balanced levels support cognitive performance, but dysregulation (too high or too low chronically) can impair these processes.
In essence, cortisol isn’t just a “stress hormone”; it’s essential for energy homeostasis, metabolic flexibility, immune balance, cardiovascular tone (e.g., helping maintain blood pressure), and overall adaptation to life’s demands. Acute rises are protective and adaptive, but chronic imbalances (as seen in conditions like ME/CFS or Long COVID) can contribute to fatigue, inflammation, mood issues, and other symptoms.
Cortisol and Stress: The Double-Edged Sword
When you or your children are sick with a viral infection, what does the physician prescribe? Assuming there is no antiviral for the particular virus, they likely prescribe a corticosteroid because the symptoms are caused by acute inflammation. The corticosteroid is similar in function to the natural steroid your body makes every day, cortisol.
Cortisol is a powerful hormone that plays a crucial role in managing stress and inflammation. However, too much cortisol from chronic stress can weaken the immune system, making us more vulnerable to infections (image below). Hence, the common phrase “worrying yourself sick.”
On the flip side, too little cortisol, a condition known as hypocortisolism, is associated with chronic inflammatory diseases and autoimmunity, such as Long COVID and ME/CFS (image below).
HPA Axis and Infection From Intracellular Invaders
How might the HPA axis become broken following infection? One possible explanation for the HPA axis dysfunction in post-infectious ME/CFS and Long COVID patients is infection with intracellular pathogens. These Long COVID and ME/CFS pathogen triggers include Epstein-Barr virus (EBV), Borrelia burgdorferi (Lyme disease), Herpes Simplex Viruses, and SARS-CoV-2 (and more), can cause direct damage to the hypothalamus and pituitary gland.
How could the HPA axis become damaged after an infection? One leading hypothesis for HPA dysfunction in post-infectious ME/CFS and Long COVID involves intracellular pathogens—viruses and bacteria that invade cells directly. Common triggers include:
- Epstein-Barr virus (EBV)
- Borrelia burgdorferi (Lyme disease)
- Herpes simplex viruses
- SARS-CoV-2 (and others)
These pathogens, or the inflammation they trigger, may directly harm the hypothalamus and pituitary gland, reducing their normal function and leading to chronically low cortisol levels (hypocortisolism).
Why Might The Pituitary Gland Be Vulnerable to Damage?
Unlike most brain structures, the pituitary gland secretes chemicals directly into the bloodstream. Therefore, the blood vessels that innervate the pituitary gland have pores (fenestrations) that allow the pituitary gland-derived messages to directly enter the bloodstream. This is in stark contrast to other brain regions, where blood vessels are zipped tight, preventing noxious chemicals from entering and damaging the brain, a phenomenon known as the blood-brain barrier (BBB).
Although rare, intracellular pathogens can enter the circulation, travel to the pituitary gland, and invade pituitary gland cells, disrupting HPA axis function. This vulnerability can also trigger localized inflammation (hypophysitis) and impair its function. Chronic inflammation and autoimmune responses can also disrupt the function of the pituitary gland and the hypothalamus, weakening signals to the adrenal glands. This reduces cortisol output, allowing unchecked chronic inflammation in the body and brain.
It’s hypothesized that this reduces communication between the pituitary gland and the adrenal glands, thereby lowering cortisol production lead to chronic inflammation in the body and brain. But is there any evidence for this?
The blood-brain barrier describes the barrier-like properties of the brain’s endothelial cells, the cells that line blood vessels. These cells are tightly ‘stitched’ together, preventing certain molecules from exiting the brain vasculature and entering the brain, such as toxins or pathogens.
Evidence of HPA Axis Dysregulation: The Clues
Research has uncovered several lines of evidence indicating HPA axis dysregulation in ME/CFS patients. For instance, some individuals with ME/CFS have:
- Autoantibodies targeting the pituitary gland and the hypothalamus
- Lower ACTH levels six months after EBV infection
- Reduced ACTH response to insulin
- Loss of the morning ACTH peak
While there is less evidence of HPA axis insufficiency in Long COVID than in ME/CFS, a subset of patients with severe COVID-19 have autoantibodies targeting the hormone ACTH. This is proposed to prevent ACTH from binding to its receptor on the adrenal glands, leading to a dysregulated HPA axis and chronically low cortisol levels.
Hypoactive HPA Axis Treatment
Medical Disclaimer: The following is not intended to be medical advice. It is information you can present to your physician, who can then guide you toward the most beneficial path to recovery (or symptom improvement) based on your unique clinical status. The symptoms of ME/CFS, Long COVID, and other neuroimmune axis disorders are caused by diverse environmental and/or genetic factors. What works for one patient might make another patient’s symptoms worse. All the information presented below can be found in this review article with the appropriate peer-reviewed references (Section 7, titled ‘Treatment’).
1. Corticosteroids
Cortisol is a steroid your body produces in response to inflammation. Therefore, if you are experiencing pituitary gland inflammation that reduces cortisol production, prescription corticosteroid supplementation may be necessary (as reviewed here).
2. Ginseng
Ginseng might help by blocking an intracellular (inside the cell) signaling pathway called the NF-kB pathway. In short, this pathway is activated after pieces of a pathogen are detected inside cells or on the cell surface. The result of NF-κB activation is the production of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1, all of which have been reported to inhibit ACTH and cortisol release from the adrenal glands (as reviewed here).
3. Dehydroepiandrosterone (DHEA)
Like cortisol, DHEA (dehydroepiandrosterone) is a hormone produced by your body’s adrenal glands. It serves as a precursor to male and female sex hormones, including testosterone and estrogen.
When using corticosteroids, it’s important to consider supplementing with DHEA. This is because cortisol released into the blood travels to the pituitary gland, telling it to stop producing ACTH. Corticosteroids can also inhibit ACTH secretion, which in turn reduces the production of DHEA and DHEA-S. Therefore, DHEA supplementation is recommended when corticosteroids are used (as reviewed here).
4. Antioxidants
Antioxidants are suggested to enhance conventional treatments with antivirals and corticosteroids/ginseng by supplementing with compounds that reduce oxidative stress and replenish precursors lost due to inflammation or malabsorption. These supplements include antioxidants such as vitamin C, as well as compounds that help restore glutathione levels in the body, including N-acetylcysteine (NAC), alpha-lipoic acid (ALA), S-adenosylmethionine (SAM-e), selenium, and B-complex vitamins.
Using antioxidants such as NAC also helps prevent mitochondrial oxidative stress during prolonged T-cell activation and restores function in exhausted T cells. Additionally, replenishing B-complex vitamins, such as B-12, B-6, and folic acid, is recommended to prevent homocysteine buildup and increase methyl group availability. Homocysteine is important to avoid as it can cause artery damage, blood clots, and heart disease (as reviewed here).
5. Glutamine
The immune system may need more glutamine during inflammation or infection, especially in active T cells. These cells use more glucose and glutamine because they are working harder and multiplying. So, taking glutamine supplements might help. Additionally, taking nicotinamide mononucleotide (NMN) can help restore NAD levels, which are important for both brain and immune cells. Keeping NAD levels up is crucial for maintaining the body’s antiviral defenses (as reviewed here).
6. Astragalus
Astragalus, known for boosting the immune system, can help reduce harmful molecules and improve the response of CD4 T cells, thereby improving the body’s ability to control chronic infections. It can also prevent Epstein-Barr virus (EBV) reactivation, so it might be useful alongside antiviral treatments to prevent EBV from returning. (as reviewed here).
7. Protein + Creatine
Protein supplements can help maintain protein production during chronic inflammation and boost the immune response. Additionally, creatine supplements may help prevent protein breakdown (as reviewed here).
8. Vitamin D
Taking vitamin D supplements can help calm overactive T-cells, reducing inflammation. Additionally, vitamin D may improve how the body handles insulin, which could benefit people with inflammatory diseases and insulin resistance (as reviewed here).
9. Melatonin
Melatonin not only helps with sleep but also protects the central nervous system. It can reduce neuron death, lower brain inflammation, and calm overactive brain cells. Additionally, melatonin boosts a protein that reduces harmful pathway activation and improves mitochondrial function in neurons. It also decreases oxidative stress by enhancing antioxidant enzymes and neutralizing harmful molecules (as reviewed here).
Conclusion: A Path to Understanding and Treatment
The journey to understanding ME/CFS and Long COVID is far from over, but the hypothesis of pituitary gland inflammation offers a promising path forward. Researchers are exploring a combination of supplements and medications to help restore HPA axis function. By continuing to investigate these conditions, we can ensure that the physical and psychological symptoms of ME/CFS and Long COVID are promptly diagnosed, widely understood, and effectively treated.
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Written By
Matthew Menendez, Ph.D.
Director of Science Communication, Brain Inflammation Collaborative
Dr. Menendez has a passion for empowering patients navigating complex chronic diseases. Through innovative educational strategies, he bridges the gap between cutting-edge research and real-world understanding, helping individuals advocate for better care, access timely treatments, and reclaim their quality of life.
