Executive Summary

  • There’s evidence against the adrenal fatigue concept.
  • The main symptoms of ‘adrenal fatigue‘ are caused by other scientifically valid concepts.
  • Inflammation and oxidative stress (OS) are the fundamental causes of what people call ‘adrenal fatigue‘.
  • The hypothalamus ‘senses’ inflammation and OS.  In their presence, the hypothalamus sends out ‘signals’ to the body to  behave in a way that makes us feel tired, sick, unmotivated, etc… (via orexin, neurotransmitters, and other hormones)
  • The active thyroid hormone (T3) is decreased by inflammation and OS, which independently causes problems of its own.
  • The tiredness you feel is mainly because of your hypothalamus (suppression of orexin) and secondarily because of low T3 and low pregnenolone.
  • In some cases, low cortisol can also contribute to tiredness, but cortisol levels are controlled by your hypothalamus.  Chronic inflammation generally increases cortisol levels.
  • Generally, there is no defect or problem with your adrenal glands themselves;  They are not ‘fatigued’.

To heal ‘adrenal fatigue‘ you need to get to the source of the problem.  You need to find out what factors are causing your inflammation and oxidative stress.  Read this post to discover the source of your ‘adrenal fatigue’.

What is Adrenal Fatigue?

The adrenals produce several hormones such as adrenaline, which is responsible for “fight or flight” response.

Adrenal Fatigue is the belief that the adrenal glands are exhausted and unable to produce adequate quantities of hormones, primarily cortisol.

What’s The History of Adrenal Fatigue?

James Wilson coined the term “adrenal fatigue” in his 1998 book of the same name. (R)

Wilson is a lone wolf in his adrenal fatigue concept.  He’s got degrees behind him, but I think he misunderstands the body.

Is There Any Scientific Support For Adrenal Fatigue?

A search of PubMed for “adrenal fatigue” brings up only eight results.

None of the results contain any substantive information or provide any markers or a sound biological basis for adrenal fatigue.  Basically, it’s as if nothing came up.

Contrast this with chronic fatigue syndrome, which has plenty of biological markers to speak of and scientific studies behind it.

The problem with the adrenal fatigue concept is that the underlying biology is false since our adrenals have a pretty good capacity to pump out enough cortisol.

When animals -and probably humans – undergo chronic stress, their adrenals get bigger. (R)  So we have a good ability to adapt and make more cortisol.

Adrenal fatigue shouldn’t be confused with Addison’s disease, which is an autoimmune disease that causes adrenal insufficiency. Also, adrenal insufficiency can be caused by a pituitary disorder that gives insufficient hormonal stimulation to the adrenals.

It could very well be the case that someone’s adrenals are not working well, but it would likely be an extremely rare condition (1 in a million maybe) and there’s no way to diagnose it.    Additionally, there’s not a shred of evidence for it.  This is opposed to Dr. Wilson’s view that most of the population has adrenal fatigue.

Nonspecific symptoms of fatigue aren’t evidence for adrenal fatigue because there are many scientifically validated causes of fatigue, and they don’t arise from adrenal dysfunction.

Low or high cortisol levels are found in many conditions, especially cognitive disorders.

Chronic stress response activation is a causal factor of a variety of health problems, including depression. See why stress is bad.

However, the adrenals themselves are not the problem.  Inflammation and other factors are.

What Endocrinologists Have to Say About Adrenal Fatigue

The public education arm of the Endocrine Society, representing 14,000 endocrinologists, recently issued the following advisory:

“Adrenal fatigue” is not a real medical condition. There are no scientific facts to support the theory that long-term mental, emotional, or physical stress drains the adrenal glands and causes many common symptoms. (R)

Now, you know I don’t take the words of any organization as true without my own research or understanding.  I look at the scientific literature and if none exists, I think about possible mechanisms based on sound biology.  But in this case, they are right.

What Are The Symptoms/Criteria of Adrenal Fatigue?

I’m bringing down the symptoms and criteria to show you that there are much better scientific explanations as to what’s going on.

Take a look at the James’ own questionnaire, at adrenalfatigue.org, to see if you have it. Do you ever experience the following?

  1. Tired for no reason?
  2. Having trouble getting up in the morning?
  3. Need coffee, cola, salty or sweet snacks to keep going?
  4. Feeling run down and stressed?
  5. Crave salty or sweet snacks?
  6. Struggling to keep up with life’s daily demands?
  7. Can’t bounce back from stress or illness?
  8. Not having fun anymore?
  9. Decreased sex drive?

If you answered yes to any of these questions, you may have adrenal fatigue.

Elsewhere, Wilson mentions:

  • One or more severely stressful events that have affected my well-being,
  • Hopelessness and despair,
  • Trouble thinking clearly or finishing your tasks,
  • Unexplained fears/anxieties,
  • Low blood pressure,
  • Frequently cold,
  • Often become hungry, confused, shaky,
  • Hands and legs get restless,
  • Lost weight without reason while feeling very tired and listless.

He also lists a variety of inflammatory conditions that coexist with adrenal fatigue (CFS, Arthritis, Asthma, Fibromyalgia, Allergies, etc..)

See his whole quiz of questions.

If you read this list with a straight face then I commend you.  I got a good laugh.  If this is the criteria of adrenal fatigue, then over 90% of the world has it.

How is Adrenal Fatigue Diagnosed?

By checking your cortisol levels in the morning and throughout the day.  This is highly problematic as a diagnostic test because many factors can influence cortisol levels.

What’s The Real Cause of Fatigue? It’s The Hypothalamus, Silly.

All of the symptoms and diagnostic criteria above can be explained in a way that has much more evidence to it.  We don’t need to rely on the adrenal explanation.

First, the hypothalamus is mainly responsible for how fatigued we are and it works principally through orexin, but also histamine neurons.  See my post on why we get tired even after we have enough sleep and why you get tired after meals.

In short, the most common reason we are fatigued is because of inflammation (IL-1, TNF) and mitochondrial dysfunction, both of which lead to the suppression of orexin neurons.  

This inflammation can be localized in the hypothalamus.  Inflammation directly leads to the suppression of orexin.

Mitochondrial dysfunction indirectly leads to the suppression of orexin by causing an increased sensitivity to orexin being suppressed by glucose. (R)

So if your mitochondria are working well, you wouldn’t get tired from a little glucose, whereas if they aren’t you will.

No disrespect to Dr. Wilson, but he created his fake disease 17 years ago.  Science only discovered that inflammation suppresses orexin in 2011 and the same for mitochondrial dysfunction.

Is Salivary Cortisol a Good Test?

I use salivary cortisol to see how bad the condition is and to get a deeper understanding of what’s going on.

Cortisol levels are also a good indicator of how someone’s circadian rhythm is doing.

When you suppress orexin neurons, that interferes with cortisol production, as Orexin A stimulates cortisol release. (R)

Since orexin is being suppressed (from mitochondrial dysfunction and inflammation), cortisol rhythms often shift and people have lower AM cortisol and higher relative PM cortisol.  (This is one possible/theoretical reason.)

When you have low cortisol, it’s not feeding back to inhibit CRH, which is causing more hypothalamic dysregulation as a result of excess CRH.

So low cortisol will tell me that somebody will likely do better with increasing cortisol in order to inhibit CRH.

On the other hand, if cortisol is high, then that means that CRH is chronically high, as it’s a good indicator of CRH (unless there’s an issue).

If cortisol is low, CRH can still be high, but other things are going on.

Hundreds or even thousands of studies speak about cortisol being too low or high in relation to various diseases, usually cognitive- based conditions.

For example, PTSD is associated with lower cortisol and higher DHEA. (R) The question is why?

Why Cortisol is Low and DHEA is High

It’s unlikely that cortisol is low from adrenal malfunction because DHEA is also produced by the adrenal gland and it’s relatively high usually.

One reason why this imbalance occurs is because of the hormone CRH (precursor to ACTH->Cortisol).

CRH directly stimulates DHEA‘s production in human adrenal cells. CRH increased the enzymes that shunt pregnenolone production to DHEA (17alpha-hydroxylase/17,20 lyase via PKC), which deprives cortisol production and causes low cortisol. (R)

The enzyme that causes cortisol to increase (3betaHSD via PKA) is stimulated by ACTH(R), but ACTH may be reduced in chronic stress as a result of glutathione depletion from oxidative stress caused by CRH (R) (just a theory). When this occurs, it usually means it’s been a problem for a while.

Low(ish) cortisol levels could also be due to HPA axis underactivity, increased negative feedback sensitivity (from cortisol) and/or changes in enzymes that metabolize it.

In PTSD, people are more sensitive to cortisol inhibiting the HPA axis because of higher glucocorticoid receptor density. (R)

There is also changes in the enzymes 11β-HSD1, 11β-HSD2, and 5α-reductase, which affect cortisol levels. (R)

Holocaust survivors show strikingly less liver 5α-reductase type 1, as well as a relative deficiency of 11β-HSD2 in the kidney, which increases cortisol levels in certain tissues, but reduces the HPA axis and lower cortisol more systemically.  These changes often happen early in life such as childhood or adolescence and the effects can be long term. (R)

What’s Really Going on in ‘Adrenal Fatigue’?

I can’t speak for everyone that has been diagnosed with adrenal fatigue because the purported symptoms can refer to any disease. Really.  It’s a brilliant marketing tactic.  List as many symptoms as possible so that everyone will think they have the disease.

But there’re some common themes.  Let’s deconstruct one symptom at a time.

1) Fatigue.  We spoke about this.  The lateral hypothalamus controls fatigue via orexin.   This has nothing to do with an inability to pump cortisol.

2) Stress.  If we are feeling stressed then that’s actually more from CRH (produced in the hypothalamus) than cortisol.  Our stress response can activate because of a number of reasons.

I’ve also spoken about how a variety of cytokines like IL-1, TNF and IL-6 can stimulate the hypothalamus to release CRH, which eventually leads to cortisol.

3) Cravings.  The ventromedial hypothalamus (VMH) is actually the part of the brain that is responsible for cravings and appetite.  It works via orexin, NPY, Leptin and other hormones.

4) Low mood and motivation.  Motivation is based on epinephrine and dopamine in the hypothalamus (R), as well as orexin and MCH (R).  Dopamine can activate orexin (R).  Read how orexin affects our mood and motivation and how to increase it.

5) Gut problems.  The hypothalamus controls two chemicals called VIP and CRH, both of which influence gut function.   CRH is known to cause IBS (R).  Various cytokines like IL-8, IL-6, IL-1b and TNF can also cause IBS and gut problems (directly and indirectly).  TNF and inflammation increase CRH (R).  Oxidative stress and inflammation are at the root of gut problems, not an inability to pump out cortisol.

6) Cold hands and feet.  The paraventricular nucleus and ventromedial hypothalamus (VMH) controls temperature regulation.(R) When you get inflammation like elevated TNF-alpha, this suppresses orexin and therefore appetite and causes you to get fatigued.  Orexin suppression also causes lower body temperature (R) and therefore you’ll feel cold.  This makes sense in order to keep the body in sync (eat less and therefore conserve energy). People who are cold are usually thin as well and have a decreased caloric intake.

7) Decreased/increased appetite.   The hypothalamus control appetite through orexin, ghrelin, NPY, T3,  leptin, norepinephrine, serotonin, MCH, FGF21+19 and GLP-1 all of which influence appetite and interact with each other (R, R2,  R3, R4). Orexin, T3, ghrelin, MCH, FGF21 and NPY increase appetite, while leptin, insulin, norepinephrine, serotonin, GLP-1, and FGF19 are appetite suppressants.  Orexin is activated by glutamate and suppressed by GABA. (R)  Low hypothalamic serotonin leads to increased carb cravings.  Low orexin leads to decreased appetite.

8) Decreased sex drive.  The ventromedial (R), arcuate and anterior nucleus are the portions of the hypothalamus that controls sex drive.   Dopamine in the hypothalamus is largely responsible for sex drive. (R) CRH, produced by the hypothalamus, also inhibits GnRH, which is largely responsible for sex drive.

9) Fear/Anxieties/Stress/OCD/Overly Emotional.   The picture below shows how the hypothalamus executes fear from the amygdala.  CRH is a very significant cause of these issues by causing glutamate to overexcite.

Specifically, the ventromedial hypothalamus (VMH) is involved in fear. (R)

FigVII30

10) Low blood pressure, Increased thirst, and urination are all from too little ADH, which is released by….you guessed it! The hypothalamus.

11) Insomnia can be from hypothalamic activation and circadian disruption, which inflammation is known to cause.  CRH inhibits GHRH, which will cause sleep problems.  Again, it’s the hypothalamus, not your adrenals.

12) Hormonal issues.  The hypothalamus is the center for hormonal control…It controls the thyroid, pituitary, and adrenal glands, for example.

13) Blood sugar swings, shaking and hypoglycemia.  The hypothalamus (paraventricular nucleus) controls glucose sensing/balance and if it’s not functioning you can get hypoglycemic, which can cause shaking. (R)

14) Attention problems. The hypothalamus is involved in attention (R) – hence why motivational and attentional issues often go to together. (R)  Orexin, melanin-concentrating hormone (R), low levels of dopamine (R) and acetylcholine (R) are also involved with attention.  Inflammation can lower these neurotransmitters.  Orexin increases acetylcholine (R) and so inflammation will lead to lower levels of this neurotransmitter.  Acetylcholine also increases orexin (R).  CRH causes glutamate excess and you feel more anxious and less grounded.

15) Losing weight.  The hypothalamus is the most important factor in controlling our weight.  Inflammation from TNF causes us to lose weight as a result of decreasing hunger.  See the TNF post.

16) OCD and an inability to let go of thoughts. The hypothalamus is responsible for attachment behaviors.  CRH causes glutamate excess and you can’t let go.  Low serotonin is also a problem.

My point isn’t to demonstrate that everyone with adrenal fatigue has a hypothalamic problem.  The issue could by thyroidal, from sleep apnea, Addison’s disease, depression, etc…

Many of the listed symptoms above could also be as a result of having low levels of T3, which is the active thyroid hormone.   Doctors generally do not check T3 even if you ask and people don’t realize that they have low T3.  Low T3 can increase your risk for heart disease by 400%.

Many of the other symptoms can be categorized into Th1, Th2 or Th17 categories.  See if you’re Th1 or Th2 dominant.

You could have excess histamine or be histamine intolerant.

Sometimes people have chronic viral infections like Epstein Barr Virus, which causes some types of inflammation and oxidative stress.

Sometimes people have CFS, which has nothing to do with the capacity of the adrenals to pump out cortisol.  An autoimmune disease like multiple sclerosis or narcolepsy can be the problem (which directly has to do with the hypothalamus).

I could keep on going, but that’s not the point of this post.  The point is to show you that you can take the symptoms of adrenal fatigue and have clear scientific evidence for an alternative explanation.

A fake diagnosis will only hold you back from really understanding what’s going on.

Why would you believe something with evidence against it when you have an alternative explanation that explains the situation much better?  And even without an alternative, “I don’t know ” is better than claiming we know when we don’t.

It’s the case that the hypothalamus is involved with all of the listed diseases (either directly or indirectly), but it’s not always (or even usually) the starting point.

The hypothalamus causes or is affected by all of the events in the picture below.  The adrenals aren’t damaged by these, but oxidative stress and inflammation usually do occur and the hypothalamus is affected.

Chronic Stress is Terrible, But Not Because Our Adrenals Are Fatigued

Most commonly, I see adrenal fatigue being used in the context of having a variety of health problems after chronic stress.

I want to be clear that there are many reasons why chronic stress is unhealthy.   However, none of them have to do with the inability to pump out more cortisol.  

The most harmful aspect of stress is because of Corticotropin Releasing Hormone (CRH), which is released by the hypothalamus and leads to the eventual production of cortisol.  The more you activate your stress pathway, the more you release CRH.  So the damage is caused without regard to the capacity of your adrenals to pump out cortisol.

Stress is bad by causing:

  • Cortisol Resistance
  • Decreased immune function – and therefore inability to handle infections
  • Inflammation (CRH causes increased Th1 dominance, TLR-4, Nf-kB, IL-1b, IL-6, TNF, MHC-II (HLA-DR) and ICAM-1.
  • Obesity – raises blood sugar, insulin, makes you hungry
  • Cognitive dysfunction – by neurotransmitter resistance, inflammation, impairing memory and lowering dopamine, acetylcholine, LTP, BDNF, neurogenesis and dendritic branching.
  • Depression – as a result of CRH, chronic HPA activation, dynorphin, lower BDNF, lower neurogenesis, lower dopamine, and GABA, serotonin and glutamate resistance.
  • Gut dysfunction – by slowing intestinal flow and causing permeability.
  • Heart damage – by increased adrenaline, oxygen demand on the body, spasm of the heart blood vessels, and electrical instability in the heart.  It also lowers heart rate variability and resting heart rate and increasing blood pressure
  • Infertility and lower libido – decreases GnRH, LH, FSH
  • Worse sleep – decreases slow wave sleep
  • Neurotransmitter resistance (Glutamate, Serotonin, GABA)
  • Lower dopamine and acetylcholine
  • Lower Pregnenolone, DHEA, Testosterone, Growth Hormone
  • Lower Thyroid Hormones (T3, T4, TSH)
  • Higher Prolactin and Estrogen
  • Oxidative stress – in your hippocampus or memory center via CRH

As you can see, stress is very harmful.  You do not want to chronically activate your stress pathway.  It also makes sense now why we start to develop all kinds of health problems after chronic stress.

All of these mechanisms that I list are based on science, whereas adrenal fatigue has not a shred of evidence.

Read my post for references and more details on why stress is harmful.

How Did This Fake Disease Get So Popular?

There’re two reasons I believe this fake disease got popular.   I’d like to mention that most people who talk about adrenal fatigue are well meaning.

1) A lack of knowledge of biology.

2) As a way to make money.

People with chronic fatigue go to doctors only to be given a blank stare or be told it’s all in their head.

By giving a name to a disease, it’s a psychological tool to give you hope and certainty, which people crave.

From the patient’s vantage, it’s a natural human tendency to not want doubt as to what condition they have and so they seek out people who will give them a concrete diagnosis.

From the practitioner’s vantage, not sounding certain is bad for business.  Putting a name on something gives people hope and with hope comes $$money$$.

Think about it.  Do you think it’s easier to sell stuff if I told you “I don’t know what you have” or if I told you “you’ve got Adrenal Fatigue.”

Keep in mind that the best and sweetest people have used this term, not for profit, but because this is what they were taught or learned from other bloggers or teachers.

If you’re such a person, no worries!  I’ve made this mistake before, too, so I’m not putting myself on a pedestal.  I’m giving you the tools to have a better idea of what’s going on and sound really cool to your patients.

How is Adrenal Fatigue Treated?

While adrenal fatigue may not exist, the same can’t be said for the treatments.

AstragalusRhodiola, EleutheroGinsengLicoriceSchisandra, and Cordyceps are just a few examples of supplements given for adrenal fatigue.

If you click on the links, you’ll see that all of them interact with the hypothalamus.  Often, they are effective if used for the right condition, but for reasons that don’t have to do with the adrenal gland.

Traditional Chinese Medicine completely misunderstood biology, yet many of their herbs were/are effective for a set of symptoms that existed in the past.

So my point isn’t that the treatments don’t work for the symptoms, it’s just that the biology is completely misunderstood.

However, I do think that by not understanding the biology, the treatments aren’t as targeted as they could be.

Most of the time, people’s immune system’s are overactive.  All of the listed supplements are mainly immune stimulants (perhaps licorice being an exception).

So not understanding our biology can have negative consequences in how we treat disease.

Conclusion

Adrenal fatigue is a misconception that arose as a result of the misunderstanding of biology, making faulty associations and a good marketing opportunity.  Many well-meaning people have been misled by this load of horse shit, including myself.

How to Deal With ‘Adrenal Fatigue’

I’ve made a post of a regimen that I recommend for ‘Adrenal Fatigue’.

Health Tools I Wish I Had When I Was Sick

At SelfHacked, it’s our goal to offer our readers all the tools possible to get optimally healthy. When I was struggling with chronic health issues I felt stuck because I didn’t have any tools to help me get better. I had to spend literally thousands of hours trying to read through studies on pubmed to figure out how the body worked and how to fix it.

That’s why I decided to create tools that will help others cut down the guesswork:

  • Lab Test Analyzer – a software tool that will analyze your labs and tell you what the optimal values are for each marker — as well as provide you with actionable tips and personalized health and lifestyle recommendations to help you get there.
  • SelfDecode – a software tool that will help you analyze your genetic data from companies such as 23andme and ancestry. You will learn how your health is being impacted by your genes, and how to use this knowledge to your advantage.
  • SelfHacked Secrets – an ebook where we examine and explain the biggest overlooked environmental factors that cause disease. This ebook is a great place to start your journey if you want to learn the essential steps to optimizing your health.
  • SelfHacked Elimination Diet course – a video course that will help you figure out which diet works best for you
  • Selfhacked Inflammation course – a video course on inflammation and how to bring it down
  • Biohacking insomnia – an ebook on how to get great sleep
  • Lectin Avoidance Cookbook – an e-cookbook for people with food sensitivities
  • BrainGauge – a device that detects subtle brain changes and allows you to test what’s working for you
  • SelfHacked VIP – an area where you can ask me (Joe) questions about health topics

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