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The Physiology of ‘Adrenal Fatigue’, pt II: The Adrenal-Endotoxemia Cycle and How Symptoms are Mediated by Inflammation

This is Part Two of a two-part series. For the first part, “What Does the Science Say”, click here. This first part covers the introduction of ‘Adrenal Fatigue’ into medical vocabulary, the impact it had on many patients who undertook the suggested protocols and why doctors rejected the concept. It also noted the flaws in the physiological mechanisms that were proposed.


The Hypothalamic-Pituitary-Adrenal Axis: Basic Physiology

So what’s really going on in ‘adrenal fatigue’? Let’s take a whistle-stop tour of the HPA axis…

The hypothalamus sits in the back of your head. This is the ‘director’ of the body’s hormonal responses and it is constantly assessing the conditions in the body and, when called to do so, releases chemicals to maintain balance. There are many ways that the body can be stressed;  this can be inflammatory, energetic or oxidative stress, as well as the emotional stress we face in everyday life. In any case, whenever the body is subject to stress, the hypothalamus releases CRH (Corticotrophin Releasing Hormone) within seconds.

CRH does two things:

  1. invokes the nervous response (“fight or flight”) This response occurs begins in milliseconds and normally lasts for just a few minutes. It sees increased firing of the sympathetic nerves, which innervate various areas:
    1. key structures in the brain, which dutifully release a load of noradrenaline. This promotes arousal/vigilance/threat perception/aggression and defensiveness.
    2. the adrenal medulla, which releases a load of adrenaline. This empties glucose/fatty acids from storage sites in the muscles and the liver, making them available for use in the upcoming physical challenge.
    3. activates SGLT proteins in the gut lining (ref), which opens up the cells enough to allow glucose from the gut to enter the circulation. This is rarely discussed but very important.


  1. invokes a hormonal response (“stress recovery”). This is a response that alters the hormonal balance of the body to handle the challenge, highly focused on the recovery phase. It takes several minutes to get going and can last for hours. It sees CRH travel through the brain to the pituitary, which sits toward the front of the head (just behind the eyebrows) and acts as the ‘middle manager’ of the adrenal system. When CRH rises, the pituitary launches into action. It reduces the stimulation of the thyroid system and to the testes/ovaries (reduces TSH, FSH and LH) and increases the release of ACTH (AdrenoCorticoTrophic Hormone). ACTH then activates the adrenals into producing more hormones, such as cortisol.

The key things to take from this is that the nervous response is hard-wired and drives the ‘fight or flight’ response. It is the cortisol that helps the body recover. Cortisol promotes the movement of fatty acids/glucose back into muscles and, crucially, provides negative feedback to the hypothalamus (tells the hypothalamus ‘to relax’ (ref). As a consequence, CRH levels drop. This is crucial because this key hormone is the de facto ‘switch’ for the stress response (ref) which means that, if you turn off CRH, you turn off the stress response.  There are some downsides to having high cortisol – if this is sustained, it can compromise thyroid function, compromise the immune response, lower serotonin signalling and compromise insulin sensitivity  – but there is a key pattern to recognise; the higher the cortisol response, the quicker we turn off the stress response. If you do not produce enough cortisol, the stress response remains stuck in the ‘on’ mode. Yes, there are major consequences if you cannot produce enough cortisol.

Cortisol is produced in the adrenal cortex. More accurately, it is formed from precursor hormones (of which Pregnenolone is the ‘mother steroid’); the conversion from base hormones into the effector hormones, such as cortisol, is depending on enzymes. These enzymes operate in membrane structures of the cell (called the endoplasmic reticulum) and need Vitamin C and B1-dependant cofactors (called NADPH) (ref). These enzymes also need an ongoing supply of heme, a protein that is formed by a the eight-step pathway, that is notoriously disturbed should someone have poor B6/zinc/copper/iron status or be subject to mercury/lead/arsenic exposure (ref).

The takeway? Compromised membrane health, due to poor phospholipid supply, a lack of Vitamin C/B1 or disrupted heme formation can therefore compromise the ability to produce cortisol. It’s ironic that endotoxemia, a consequence of poor adrenal response, is known to compromise phospholipid status (ref). Equally, nitric oxide, homocysteine and excessive calcium (both common in chronic inflammation) can also hinder enzyme function. Viral infection also releases a cytokine called interferon which downregulates adrenal activity (ref). The cruel irony here? There are multiple ways that chronic health complaints can increase the need for cortisol, while compromising the ability to produce cortisol.

From the above, you can see how there are a number of ways that the adrenal response can be compromised. Too much coffee, mould exposure or a chronic dysbiosis with B1-degrading bacteria? You may run low on this key nutrient. Evoking the stress response too regularly? Expect poor digestive absorption of key nutrients (such as B12, which supports methylation) and poor insulin sensitivity. Subject to ongoing chronic dysbiosis? The oxidative stress can heavily hit your Vitamin C stores and drive up inflammation. Any sustained inflammation can easily compromise methylation, allowing homocysteine to rise and interfere with enzyme function. The inflammation can also trigger the release of nitric oxide and its metabolites, further interfering with function of adrenal enzymes.  It is not a case that your adrenals ‘break down’, more that one of the above issues emerges and stops the enzymes from being able to response effectively to demand.

And if your adrenal enzymes cannot respond to the demand, the stress response remains switched on… It could be a normal demand and limited adrenal output, or could be excessive demand with normal adrenal output. Often, it will be excessive demand and limited adrenal output. But the only thing that matters here is that the stress response remains switched on.


  • the stress response is all about readiness
  • readiness means two things: 1. liberating stored sugars from muscle/liver and salvaging sugars that may be in the gut, and 2. Increasing arousal/vigilance
  • adrenaline activates this ‘fight or flight’ response, cortisol helps recovery from this response
  • if you don’t produce enough cortisol, you cannot switch off the stress response
  • there are a number of factors that can stop you from producing cortisol, and many of these factors are promoted by chronic activation of the stress response
  • your adrenals do not ‘blow a fuse’, they simply run out of co-factors to maintain optimal response to ACTH stimulation and, crucially, lose the ability to ‘switch off’ your stress response



Endotoxemia: What’s Really Going On

If the stress response remains switched on, then the SGLT (Sodium and Glucose Linked Transporter) proteins in the gut remain activated. This opens up channels in the cells in an attempt to bring in sugars from the gut. But there is one huge problem with this: this is a form of increased intestinal permeability (“leaky gut”), and does more than just allow sugars into the circulation; it also allows lipopolysaccharides to make the same journey.

Lipopolysaccharides, sometimes referred to as LPS or endotoxins, are fragments of the cellular wall and are found on gram-negative bacteria. These will be found in large numbers in all healthy guts. There may be more lipopolysaccharides in an unhealthy gut, but the only two things that are important here are a) the amount that end up in the bloodstream and b) the way the body responds to this exposure.

Inflammation and oxidative stress can increase permeability between gut cells (ref). However, overactivation of the stress response activates the SGLT proteins and this increases permeability through the cells themselves (ref). Any increase in permeability will increase movement of lipopolysaccharides into the bloodstream.

These lipopolysaccharides, which are fat-soluble fragments of the bacterial membrane, are now in the bloodstream. Liposaccharides in the bloodstream = endotoxemia. Here is a over-simplified version of what happens whenever we are faced with endotoxemia:

  • Cholesterol lipoproteins (especially HDL lipoproteins) ‘mop up’ the lipopolysaccharides. They do this by deactivating them, via a process that blends their own phospholipids with the phospholipid-like section of the lipopolysaccharides. It then transports this new complex back to the liver to be removed via the bile
  • If these cannot get mopped up sufficiently, then these lipopolysaccharides now ‘spill over’ into the general circulation. Here they activate immune cells into mounting an inflammatory response

Once this inflammatory response has been activated, it can easily get out of hand. The problem is that lipopolysaccharides are much more irritating to the immune system than bacteria themselves (ref), meaning anyone subject to endotoxemia is likely to suffer inflammatory symptoms and fever. However, if there is any dysregulation of your inflammatory response, then we are looking at low-grade sepsis. This is where a ‘cytokine storm’ takes place and the body responds by initiating a shut down of the system; this is conducted by a deliberate ‘shutdown’ of many of the normal pathways in the brain (ref), a desperate attempt to shut down energy usage so that the body’s resources can be diverted towards fighting off the suspected infection (it also avoids the drop in oxygen delivery to the gut, which happens when we use large muscles in exercise). We see alterations in blood flow, distortions in receptor function and disturbances in adrenaline, dopamine, serotonin and GABA signalling (ref).

So you’re now subject to a cytokine storm and a potent shutdown of the brain… what does this feel like? The inflammation triggers local symptoms (which can vary from one person to the next, but often include headaches or skin flare-ups), neural agitation (this can manifest as anxiety or insomnia) and a general fever. The shutdown means weakness/shakiness, lack of motivation, brain fog and a crushing, unbearable fatigue. Depending on the force of the reaction, we may see some delirium. Within these, we will find the classic adrenal symptoms, especially the ‘tired but wired’ signature response, and a pattern where increased stress can reliably bring on these symptoms.



  • Inflammation and oxidative stress can predispose you to increased intestinal permeability, but stress will normally be the factor that makes this a big deal
  • Lipopolysaccharides are always in the gut, but they only become a problem when they are in the bloodstream (this is ‘endotoxemia’)
  • Your response to endotoxemia is determined by your HDL status, and the regulation of your inflammatory cascade
  • If HDL status and inflammatory regulation is poor, low-grade sepsis occurs whenever stress is increased
  • While there are impacts on energy metabolism, thyroid, testosterone/estrogen and on electrolyte balance, ‘adrenal fatigue’ symptoms are mainly caused by low-grade sepsis


Options in Treatment

Once we understand the pathways that are involved in the adrenal-toxemia pattern, we can determine where we have leverage in controlling this response. Our options are:

  • Reduce nervous activation of SGLT proteins
    • Switch off the chronic stress response at it’s root. This is by far away the most effective change we can make, although it can be a tangled web of both reducing metabolic stressors and delving into subconscious activation of the stress responses
    • Avoid unnecessary acute stressors, whether this is intense cardiovascular exercise or coffee-fuelled all-nighters
    • Switch off the stress response through increased cortisol (eg. supporting the enzyme pathway involved in hormonal production, boosting serum levels with Licorice Root). This is often a key move, but works best after basic steps to take someone out of fight-or-flight mode (replacing an adrenaline-dominant state with a cortisol-dominant state is the aim, not creating a state where both are high)
    • Using adaptogens that lower CRH release, such as Rhodiola, Ginseng or Ashwaganda. Although the anti-stress effect is reliable, the overall effect of these is hit or miss (mainly depending on whether the individual can tolerate their NRF2 impact)
    • Addition of calming supplements, such as CBD, Valerian or Theanine. These occasionally induce a great response, but rarely work alone


  • Reduce transcellular permeability
    • The new generation of diabetes drugs inhibit SGLT proteins, and it will be interesting to see if they will have an ‘off-label’ benefit in endotoxemia. There are herbs, such as Ku Shen, that inhibit SGLT, but I have not seen much of a benefit here
  • Reduce paracellular permeability
    • Avoidance of agents that trigger permeabilty, such as gluten, NSAIDS (like aspirin, etc) and alcohol
    • Reducing histamine (through improved methylation, supporting copper status, treating dysbiosis (parasite issues are especially relevant)). Based on the improvements I have seen, parasite issues and bacterial dysbiosis are major contributing factors here
    • Supporting antioxidant status of key junction proteins with Vitamin C and Glutathione… (yes, Vitamin C may not be a reliable way to boost cortisol levels but it can definitely reduce ‘adrenal fatigue’ symptoms through this mechanism)
    • Chlorella, Gamma Oryzanol, Fish oils and Nucleotides may also reduce permeability
  • Increase HDL production and bile movement
    • Activation of the stress response also shuts down acid production at the stomach and bile release. What’s interesting is that we need acidity (from the stomach) in order to trigger the release of bile. Adding in Betaine HCL to support digestion is a good first step, but the addition of Ox Bile may also required. Other options include Burdock Root and Dandelion to encourage the gall bladder into contraction
    • HDL production can be produced by coconut oil, plant sterols and exercise (not always an easy option for those suffering from adrenal-toxemia issues). Improvements in HDL levels are tough to achieve, as inflammation has such a reliable and strong impact on lowering HDL
  • Use endotoxin binders
    • If HDL cannot be increased, then it may be useful adding some external support to achieve more ‘binding’. Sarsaparilla is an effective binder of lipopolysaccharides, although it has multiple effects that may be challenging in sensitive people
  • Regulate inflammatory response
    • Vagus nerve activation (cold showers, laughing, deep breathing)… my experience has seen cold showers as especially effective
    • Vitamin D signalling (checking the whole pathway, not just calcidiol levels)
    • Glutathione status
    • Red light
    • Methylation




  • There are many options to reduce/eliminate endotoxemia symptoms and the effectiveness will vary in one person to the next
  • Most of these interventions are commonly recommended by practitioners who are treating ‘adrenal fatigue’
  • Because of this, the adrenal fatigue model works a lot of the time… but, if it doesn’t work, it can leave the individual lost as there is no accurate explanation
  • Removing the adrenal-tinted spectacles allows us to appreciate the key role the adrenals play, without losing sight of the bigger picture (and the treatment options that come with it)

Leave a comment

  1. Hey Marek,

    thank you for the great article. You write checking the whole pathway of Vitamin D signalling. What would yout recommend to test besides the calcidiol levels?

    Kind Regards from Germany

    1. Danke 🙂 For the full panel, I’d suggest getting Calcidiol (25OHD), Calcitriol (1-25OHD), and Parathyroid Hormone. This gives us a great idea if there are any issues here (eg. high Calcitriol and high Parathyroid Hormone would indicate downregulation of the receptor).

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