Dr. Martina Melzer, published: 22.05.2022


Deutsche Version

It is very likely that in ME/CFS a malfunctioning hypothalamic-pituitary-adrenal axis (HPA axis) plays a very important role. This has been shown in numerous studies. If this axis is out of whack, it can mess up all the hormones and endocrine glands in the body - from the thyroid to the adrenal glands.

Why? The hypothalamus contains important switching points of the autonomic nervous system, which sends data to it from the body's periphery. It is linked to the pituitary gland. Depending on the situation, the hypothalamus sends various precursor hormones to this gland. Depending on what info it has received from the hypothalamus, it in turn releases hormones that signal, for example, to the thyroid or adrenal glands whether they should ramp up or ramp down their hormone production. Hormones play an important role in how much energy we have available.

Stress hormone cortisol

The pituitary gland sends the hormone ACTH to the adrenal glands. These then produce the hormones aldosterone, DHEA and cortisol. This happens normally at different times of the day, for example, and the hormones perform their normal functions. Cortisol affects, among other things, the release of insulin and sugar metabolism, blood pressure, the immune system, inflammation, energy levels and much more.

When we are stressed, the hypothalamus responds very quickly to the appropriate signals from the autonomic nervous system and causes a lot of cortisol to be released acutely - as well as norepinephrine and epinephrine, which are also released from the adrenal glands. The body should be prepared for an acute dangerous situation so that it can fight or run for its life in an emergency. We are full of energy. These in the past really dicey events, we now call "stress". It is important that after the danger, when we are safe again, the release of cortisol, adrenaline and noradrenaline is stopped, we can rest - and replenish energy reserves. Because otherwise the hormones, especially cortisol, can do damage in the long run.

With chronic stress, to which we are all somehow exposed today, too much cortisol can permanently circulate in the organism. We are constantly „on“, unable to switch off. The HPA axis gets out of whack and functions incorrectly. We are totally tired and exhausted, but still under power ("tired but wired"). In people with ME/CFS, for example, it can happen that they have much too high cortisol levels at the beginning and much too low later, or that there is too much cortisol available at night but not in the morning when we get up. Then we feel totally flat and exhausted in the morning, despite 14 hours of (non-restorative) sleep. One study found that people with ME/CFS had 50 percent smaller adrenal glands than healthy people. Cortisol levels are also altered in other conditions, such as anxiety disorders, fibromyalgia and depression, and even in what is called post intensive care syndrome. It keeps people who are in intensive care from getting back on their feet.

Is there such a thing as adrenal insufficiency?

Whether adrenal insufficiency exists is disputed. Traditional western medicine only knows Addison's disease, in which there is a deficiency of cortisol and other adrenal hormones and the adrenal glands eventually stop functioning. In addition, conventional medicine refers to Cushing's disease, in which too much cortisol is permanently produced. In diseases such as ME/CFS, however, it is probably the interaction between the brain and the adrenal glands that is disturbed - the HPA axis. If the adrenal glands are under stress for too long, they either can no longer keep up with the production of hormones (are exhausted, adrenal fatigue). Or the brain blocks the activation of the adrenal glands as a protective mechanism by shutting down the HPA axis, in the sense of a negative feedback mechanism. Anyway, this leads to almost all typical ME/CFS symptoms.

By the way, in case you are interested: Cortisol is made in the mitochondria. These are the little energy power plants in our cells from which we get our life energy. If we have too much cortisol for too long, first of all the hormone constantly demands the mitochondria, because it wants to provide energy for stress situations. This exhausts the small organelles. Second, when they are overtaxed, they can produce less new cortisol. This not only affects energy levels, but numerous other bodily functions.

Sex hormones

The sex hormones testosterone, estradiol and progesterone are also controlled via the HPA axis. It is clear that if the axis is out of balance, this also affects these hormones and their functions. Particularly in women who have ME/CFS or a related syndrome, endometriosis or polycystic ovary syndrome (PCOS) often occurs in parallel. Female menstrual cycles and the ability to have children are also affected.

There is a good video on this on Raelan Agle's YouTube channel with Anna Marsh:


In addition to the hypothalamic-pituitary-adrenal axis, there is one that extends from the hypothalamus to the thyroid gland (HPT axis). It monitors our metabolism. If it doesn't function properly, it can trigger not only exhaustion but myriad other symptoms that are very similar to ME/CFS and fibromyalgia. The tricky thing here is: thyroid levels can be normal, but the gland is still only functioning below average. This is called non thyroidal illness syndrome (NTIS). This is a protective mechanism controlled by the hypothalamus, which shuts down the thyroid gland and thus the energy metabolism. The body does this when its survival conditions are not optimal.

In addition, there is Hashimoto's thyroiditis, an autoimmune disease in which the body attacks the thyroid gland and it eventually loses its function. This results in hypothyroidism. This disease often occurs in parallel with ME/CFS, but of course could be an alternative cause to ME/CFS.

Blood sugar

The dysregulated HPA axis also throws insulin and sugar metabolism out of balance. In people with dysautonomias like POTS and ME/CFS, blood sugar (glucose) often rides a roller coaster. It can rise way too high and then drop rapidly. Triggered by epinephrine, norepinephrine, and cortisol, it shoots up even more and is subsequently depleted. This can also happen at night, leading to hypoglycemia during sleep. Some people with dysautonomia already have insulin resistance: the body cells that are supposed to absorb sugar from the blood shut down. However, this condition does not necessarily have to be detectable in laboratory tests.

There are other hormones that may be out of balance.

What to do?

From my point of view, it is extremely important to first find out potential causes for hormone imbalances with doctors. It is important to rule out or determine diseases that can cause fatigue and other complaints. This is also part of the normal and important process when diagnosing ME/CFS, POTS, fibromyalgia or the like. Other diseases can accompany these syndromes, but they can also be the alternative cause. In terms of hormones, I would actually see an endocrinologist because they do a lot more investigation.

Personally, I would also be extremely cautious about taking nature-identical hormones on your own or the numerous supplements that are recommended. It is best to talk to your doctor about this beforehand or to see a doctor for functional medicine.

You can bring the HPA axis back into balance by bringing your autonomic nervous system and the limbic system out of their chronic states of stress. See the "Nervous System" and "Mindset" strategies for more information.

To support adrenal function, it helps to reduce stress (!!!), avoid caffeine, too much rapidly available sugar, and other stimulants, and get daylight in the morning. Also, eat enough protein and low carbs in the morning, a little more carbs at lunch, and the largest portion in the evening (I know this goes against a lot of recommendations, best make up your own mind!).

I keep reading that the so-called AIP diet (Autoimmune Paleo Diet) helps people with Hashimoto's thyroiditis. If you're taking thyroxine for it, though, I would definitely talk to your doctor about it before trying it, even if they're not familiar with it. It's just that you might mess up your thyroid if you radically change your diet, that might really have an effect and then you're adding way too much thyroid hormone.


PS: Of course, I research and check everything I write here as well as possible. Nevertheless, I am only human and make mistakes. In addition, I may draw completely different conclusions as someone else would. Simply because they fit my story. But every story is different.

Important: The content on this page is for informational purposes only and is not a substitute for talking to your doctor or other therapist. The content reflects my personal experiences, research and findings that have helped me and that I therefore want to share. However, in your personal case, completely different things may play a role and other things may help. Please talk to your doctor or therapist before making any decisions that affect your physical or mental health. Also important: I don't want to convince anyone of anything here. Rather, I want to point out possible ways that hopefully can help some people to improve or overcome their Fatigue or ME/CFS.


Dr. Rosamund Vallings: CFS/ME – Symptoms, Diagnosis, Management
Alex Howard: Decode your Fatigue

Dan Neuffer: CFS Unravelled

Fatigue Super Conference 2021

Alan Christianson: Adrenal Reset Diet

Morris G, Anderson G, Maes M. Hypothalamic-Pituitary-Adrenal Hypofunction in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) as a Consequence of Activated Immune-Inflammatory and Oxidative and Nitrosative Pathways. Mol Neurobiol. 2017

Dominic Stanculescu, Lars Larsson and Jonas Bergquist : Hypothesis: Mechanisms That Prevent Recovery in Prolonged ICU Patients Also Underlie Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Hypothesis and Theory Front Med 2021

Picard M, McEwen BS, Epel ES, Sandi C. An energetic view of stress: Focus on mitochondria. Front Neuroendocrinol. 2018