cortisol

1st January 2017

It is my hope within this article to illuminate some of the conflicting opinions about adrenal fatigue, but also to provide patients with some solid information.  Though I am going to go deep into the science, the end paragraphs will simplify this right down to the steps you need to take if you’ve been diagnosed (whether by yourself, or by a practitioner) with “Adrenal Fatigue”.

What is “Adrenal Fatigue”?

This is a bit of a trick question, because the phrase “Adrenal Fatigue” has fallen out of favour – even for those within the Functional Medicine community (at least, for those who are most up-to-date).  Once the mainstay of a lot of practitioners’ work, there is now a deep recognition that not only may the terminology be flawed here, but also that the diagnostic criteria and therefore treatments offered may be far from what we had previously promoted.

The main reason why the term “adrenal fatigue” has fallen out of favour is because it implies a tiredness of the adrenal glands themselves.  We interpret fatigue as an exhaustion that is inherent to the organ which is being described: therefore adrenal fatigue means tired-out adrenals.

The issue with this is that it is just not what happens, biologically speaking.  Our adrenal glands are pretty much able to carry on regardless.  The fact that they seemingly stop functioning and/or slow down their production of adrenal hormones (adrenaline and cortisol) is not actually a failure of the gland itself.

Therefore, the so-called ‘stages’ of adrenal fatigue may actually make sense in logic: first the adrenals rev up to cope with stresses and pump out loads more hormones, then they get so tired that one hormone starts to fall, quickly followed by the other and eventually your adrenals are flat-lining.  This is partly why the explanation is so attractive.

It leaves you hoping for some sort of adrenal defibrillator that can just restart those glands as if they were your heart when it had stopped beating.

But the problem comes when you assess the biology and realise that the adrenal glands don’t stop working because they are ‘tired’ or ‘fatigued’.  They aren’t a muscle powered by electrical impulses so cannot be restarted.  In truth, they haven’t really ‘stopped’.  There is no doubt that adrenaline, cortisol and DHEA production slows in some patients, but viewing this as the result of adrenal glands having used up all of their energy is narrow and inaccurate.

The HPA Axis

You may have heard of a more advanced understanding of adrenal health which is founded on the HPA Axis (Hypothalamic-Pituitary-Adrenal Axis) which explains that the adrenal glands are at the end of a chain of communication from the brain.  To quickly break down the physiology: all hormone production is directed by messages from the brain.  In the case of the adrenals, the signal given is ACTH (Adrenocorticotrophic Hormone) from the pituitary – and further back than this, the hypothalamus releases CRH (Corticotropin Releasing Hormone) into the pituitary, which in turn releases the ACTH.

Therefore, understanding the Hypothalamic-Pituitary-Adrenal Axis would seem to be a whole step up in appreciating the precise mechanisms behind the slowing of output from the adrenal glands, right?

Well, unfortunately, not entirely.

Interrupting these signals from the hypothalamus and pituitary seem not to have predictable effects on the adrenal glands’ production of cortisol.  In fact, in mouse models, severing the link between the hypothalamus and the pituitary actually boosts the ACTH production (i.e. the pituitary up regulates its production of ACTH even without the instruction of CRH from the hypothalamus).  And even if and there is a constant infusion of CRH (i.e there is a constant ‘on’ signal to the adrenals) they actually revert to demonstrating a diurnal rhythm to the production of cortisol.  In other words, even in the presence of a constant stimulus, the body seemingly self-regulates to restore a normal high-in-the-morning/low-at-night cycle of ACTH and hence cortisol production.

The precise mechanisms and understandings around this are, as yet, not fully understood (and certainly not by me).  However, it really rather invalidates our second theory of adrenal fatigue, or failure and suggests that this isn’t just a simple physiological messaging problem any more than it’s just an issue with overexertion.

So if “Adrenal Fatigue” isn’t anything to do with tired adrenals, and it’s also not entirely to do with brain signalling issues… What on earth is going on?

The Adrenal Glands Exist Within the Biological Whole

The problem with the old ‘four-stages of Adrenal Fatigue’ model is that it neglects to understand that the adrenals do what they are told to do through very complex and interwoven feedback systems involving brain, hypothalamus, pituitary.  The problem with the secondary understanding of the adrenals as the end-stage organ of brain signalling is that it is still a very narrow interpretation of physiology which doesn’t account for complexity.

The adrenal glands exist within the physiology of the whole body, and therefore are not only receivers of brain signals but are also impacted by other factors including nutritional status, mitochondrial health and oxidative stress.  We also cannot forget that along with the stress hormones that we all know about, the adrenals both produce and are suppressed by inflammatory cytokines.

Additionally, cortisol does many more things in the body than provide us with ‘fight or flight’ responses.  The suppression of cortisol by the HPA axis may actually be a result of inflammation.  Or indeed, cortisol suppression may be a choice, rather than a fate of overexertion, fatigue or mistake in brain signalling.

Inflammation

If we take inflammation – the adrenals have been shown to produce and have receptors for inflammatory cytokines.  In addition, the production and receiving of cortisol can be inhibited by the presence of TNFa (tumour necrosis factor alpha).

TNFa is an inflammatory cytokine given off in situations of inflammation which can occur as a result of a panoply of different biological insults: nutritional, allergenic, toxic, biochemical.  If inflammation is systemic within the body, therefore, rather than ramp up stress responses, it is highly possible that cortisol release will be suppressed due to the excessive quantity of TNFa.

Inflammation, toxicity and impaired cellular metabolism can also cause increased levels of oxidative stress.  This means that mitochondria are creating more reactive oxygen species (ROS) than normal.  I don’t want to stray into the territory of ‘excessive science’, but suffice to say that the creation of ROS and the antioxidant function of certain nutrients is just a natural part of life that occurs simply by breathing.  However, it is essentially a see-saw and too many nutrient deficiencies or biochemical imbalances can skew this balance more towards the creation of ROS, with not enough antioxidant potential on the other side of this.

In a situation where mitochondrial health is impaired (too many ROS), so is hormone production.  Why?  Well, all hormones come from cholesterol.  And cholesterol is, in varying ways, taken into and out of the mitochondria by way of making it into pregnenolone and then into various hormones – one of which is cortisol.  In a situation where mitochondrial robustness is impaired (or endoplasmic reticulum stress occurs, which is another factor regarding ROS and influencing what can travel across cellular boundaries) such as in excess toxicity, ROS production or inflammation, the whole production of cortisol is suppressed due to this impairment of cellular health.  If the mitochondria and the cell boundaries are at all impaired, so is hormone production.

All of which is powerful enough insight to understand that inflammation and ROS might play a more important role in adrenal health and cortisol production.  But there is another interesting factor which is closely linked and can provide further evidence that adrenal dysfunction is not due to “tired glands”.

Immune System

A common misstatement amongst practitioners, doctors and on the internet is that cortisol suppresses the immune system.  This isn’t entirely true.  Instead, a more correct statement would be that cortisol suppresses one branch of the immune system: the Th1 branch.  Broadly speaking, this is the branch that deals with viral infections, cancers and smaller bacteria (as opposed to the Th2 branch which broadly deals with larger molecules requiring antibody production).

Another factor of cortisol suppression could therefore arise if the body recognises that there is a viral infection present.  Rather than ramping up the production of the hormone that will suppress the Th1 branch of the immune system, in this situation the body may be naturally suppressing cortisol so that the Th1 response can be fully free to attack any viral infection.  This is an interesting thought experiment to understand post-viral fatigue syndromes.  If the adrenal response is down-regulated to handle the initial viral insult, is this something to do with the subsequent exhaustion that can occur once the viral infection is theoretically ‘gone’?

Is There A New Model of Adrenal Health?

It is clear that the immune system, inflammation, cellular health (including mitochondrial function) and generalised toxicity (including the responsive presence of inflammatory cytokines AND the responsive down regulation in times of viral stressors) all play a role in how the adrenal glands function.  However, it should now be clear that this doesn’t automatically give us a new, simple picture of adrenal health.  It doesn’t replace the old “adrenal fatigue” model with a quick, alternate understanding.  In fact, it makes the picture more complex, more individualised and more nuanced.

And all of this said, the reality is that patients do show up at my door exhausted, burnt out and, to all intents and purposes, adrenally wasted.  I can test these patients’ adrenal function and will always find dysregulation.  Those of you who have read my blog for a while will know that I am a fan of the DUTCH testing over Adrenal Stress Index saliva testing – but this is solely because it gives me a broader, more complete picture of hormonal health.  I never test adrenal health just because someone seems to have stress-related fatigue.  In fact, if cortisol production issues are indicated, I rarely test for them at all.

Why?  Precisely because, as is shown above, knowing that your adrenals are not producing adequate levels of hormones (or indeed are producing far too much cortisol) is to understand the end stage of a process that begins long before the adrenals become involved.  The adrenals are in response to a complex physiological whole – and as such, and as always within Functional Medicine, I am looking to provide resolution as high up this pathway as possible.  Starting with the adrenals is not starting at the top.

The Bedrock of Wellness

Sometimes I become frustrated with the fact that the real ‘cure’ for most conditions always comes back to similar conclusions. There really is no better therapy than removal of stressors and improving an individual’s ability to manage any and all stressors.  It should now be clear that the same approach holds true for adrenal insufficiency/deficiency symptoms – even after explaining all of the science above.

Toxicity and inflammation are fundamentally undermining to all aspects of health.  This means dietary attention to remove allergens and inflammatory foods is a natural first step.  Then liver detoxification is key, and can be supported to ensure proper removal of toxins from the body.  Digestion can be also be supported to ensure that toxins are fully carried out of the body.

Further than this, exercise is a big key to mitochondrial health and toxin removal.  Even small amounts can make massive differences, especially in those who don’t feel like expending energy this way.  And this can be supplemented with nutritional support for mitochondrial function, which means healthy fats and dietary cholesterol, including Omega 3 and fat soluble vitamin supplementation where required.

And then there is the mental and lifestyle approaches: fostering healthy sleep patterns, technology limits at night time, creating an emotional understanding of your capacity to tolerate overwhelm and/or a stressful life or job.  Psychosocial factors are also key, with healthy relationships and laughter providing foundational improvements to overall wellbeing.

In fact, the therapeutic actions that I would take after understanding all of the above about adrenal health are pretty much the same as those I would have taken if I was looking at the adrenals through the lens of the ‘four stages of fatigue’.  I have never been a huge fan of adaptogenic herbs, or shoving in extra DHEA, without properly addressing the underlying causes.  So my methodologies don’t change much when we understand adrenal glands as susceptible to and an agent within the overall toxic and inflammatory load of the body.

However, I do know that using the old lens of adrenal illnesses has given rise to some different practices within the Functional Medicine community.  If you or someone you know is trying to address ‘adrenal fatigue’ by using adaptogens or supplementing with DHEA – or even using adrenal glandulars (supplements which try to replicate adrenal hormones artificially) – perhaps this new way of understanding the adrenal glands within the complex of your physiology will encourage you that there really is no better therapy than good, wholesome nutrition, supported digestion and detoxification.

It may be boring and it is the ‘long game’, but there is no magic pill which will boost your energy, hormones and health overnight.  Yes there are countless biohacks that you can experiment with when you get the foundations dialled in.  However, there is no equivalent for stress reduction and stress management – whether cellular, physiological, biochemical or psychological/emotional.  Ensuring health practices for removing and dealing with stressors will always be the route to ensuring full wellbeing: whether for your adrenal glands, your stress hormone levels and/or for your whole body.