HPA Axis Dysfunction: Cortisol and Stress

When your cortisol levels are chronically out of whack, you can feel like you’re falling apart – like things aren’t right in many different ways.

Cortisol is a hormone produced by the adrenal glands in times of stress, and it also plays many roles in your normal bodily functions. It is a multi-purpose hormone that needs to be in the right amount (not too high, not too low) and at the right time.

Your genes play a significant role in how likely you are to have problems with dysregulated cortisol levels. But this isn’t a solely genetic problem! Life stressors, diet, and environmental factors also come into play here, interacting with genetic susceptibility to mess up your cortisol regulation system. Let’s dig into the details on how the system works and how your genes can influence your susceptibility to problems here.

What is the HPA Axis?

When you are stressed, your adrenal glands produce cortisol. This applies to both physical stress, like running from a tiger, or emotional stress, such as when you screw something up at work.

Your brain controls the release of cortisol from the adrenal glands.

Specifically, a region of the brain called the hypothalamus sends a signal, called corticotrophin-releasing hormone (CRH), to the pituitary gland. The pituitary then releases adrenocorticotropic hormone (ACTH), which increases the production of cortisol in the adrenal cortex.[ref]

All of this – the Hypothalamus signaling the Pituitary which signals the Adrenals – is called the HPA axis.

image showing HPA axis - from to brain hypothalamus and pituitary to the adrenal glands releasing cortisol

Getting a little more detailed:  The hypothalamus releases corticotropin releasing hormone (CRH). The higher levels of CRH cause the pituitary gland, also located in the brain region, to release adrenocorticotropic hormone (ACTH).

When the ACTH signal reaches the adrenal glands, it stimulates the melanocortin 2 receptor, which initiates the synthesis and release of cortisol.

It takes about 3-5 minutes for all of this to happen and for cortisol levels to rise.[ref]

What is cortisol?

Your adrenal glands produce cortisol as a way to let your whole body know what is going on in your environment. It is a signal that a stressful situation is occurring. Stress can take many forms, from physical pain to mental worry to even something you might enjoy, like exercise.[ref]

At lower levels, cortisol is secreted all the time. It has a ‘diurnal’ rhythm, which means it goes up and down over a 24-hour day in a predictable pattern.

Normal cortisol levels rise quickly around the time that you wake up in the morning. CC https://doi.org/10.3390/ijerph18020676

Cortisol is a ‘steroid hormone’ which is synthesized in the adrenals from cholesterol. The signal sent by the pituitary gland for creating cortisol causes an increase in the enzyme for converting cholesterol into pregnenolone, which is the rate limiting step in creating cortisol.[ref]

Most of the time, a cortisol precursor is circulating in an inactive form, which can quickly be activated by an enzyme called hydroxysteroid dehydrogenase 1.

What does cortisol do in the body?

Cortisol has many functions:[ref]

  • mediating the stress response
  • regulating metabolism (weight gain…)
  • tamping down the immune response

I’ll go into these in more detail in just a minute…

Cortisol signals for actions to take play by binding to two different receptors: mineralocorticoid and glucocorticoid receptors.

These receptors allow for the different functions of cortisol during normal vs. stress situations:[ref]

  • Mineralocorticoid receptors (MR) – activated by low circulating levels of cortisol. The MR regulates a bunch of normal functions in the body.
  • Glucocorticoid receptors (GR) – only activated with high levels of cortisol (stress situation). GR activates the flight-or-fight response.

Let me give you an example:
When a tiger is chasing you, cortisol is elevated to a high level. It activates the GR receptors, which kick you into high gear. While you’re escaping with your life, your body doesn’t need to waste energy on things like reproduction or even most of the immune system. Those functions can be tamped down, put aside, until the crisis has passed, and your energy can be devoted to survival for the time being.

Cortisol levels can ramp up quickly (within minutes) in times of stress, but the half-life of cortisol is also pretty quick. Within 15 minutes, half of the cortisol is metabolized into a form that is excreted in the urine.

What happens when cortisol levels are too high or too low?

The problems with cortisol come when levels are chronically elevated – or – when the response to a new stress is exaggerated and out of proportion.[ref]

There are two defined diseases for extreme cortisol dysregulation:

  • Cushing’s syndrome
  • Addison’s disease

Cushing’s syndrome is due to too much cortisol, either from glucocorticoid medications or too much cortisol produced by the adrenals due to a pituitary tumor. Symptoms of Cushing’s include high blood pressure, abdominal weight gain, round face, stretch marks, thin skin, and, in women, facial hair, and menstrual irregularities.

Addison’s is due to too little cortisol production. Symptoms include weight loss, muscle weakness, nausea, and mood changes.

While Cushing’s and Addison’s show the extremes of cortisol disorders, milder manifestations plague many of us.

Symptoms of HPA axis dysfunction:

HPA axis dysfunction can mean that cortisol is chronically elevated and/or it doesn’t respond appropriately to stress. It can also be due to a disrupted circadian rhythm of cortisol production over the course of the day.

HPA axis dysfunction can mean:

  1. chronically elevated cortisol
  2. inappropriate stress response
  3. the rhythm of cortisol is out of sync

Chronically elevated cortisol can be due to repeated stress (physical or mental), genetic susceptibility (below), and traumatic childhood events (epigenetic trigger).[ref]

Chronically elevated cortisol is linked to:

  • elevated blood glucose, diabetes, insulin resistance[ref][ref]
  • immune dysfunction[ref]
  • mood disorders such as depression and anxiety[ref][ref]
  • coronary artery disease (heart disease)[ref]
  • infertility[ref]
  • weight gain[ref][ref]

Another aspect of HPA axis dysfunction is that repeated stress and high cortisol causes ‘habituation’, essentially a downregulation of the cortisol receptors and decreased acute stress response.[ref]  While this could seem like a good thing, the acute stress response is needed in times of, well, acute stress -like running from a tiger. And the downregulation can also apply to normal cortisol function during times of non-stress as well.

Let’s dig into the negative effects of HPA axis dysfunction in more detail:

1) Immune dysfunction:

Chronic stress can also lead to an increase in autoimmune diseases and to a decrease in normal immune responses.[ref][ref]

When acute stress occurs, the body cannot mount a normal stress response because of decreased GR receptors. It can lead to an increased susceptibility to infections, including colds.[ref]

2) Depression due to HPA axis dysfunction:

Reduced glucocorticoid receptor function along with altered cortisol circadian rhythm is found in women who have depression.[ref]

Several other studies show that higher basal levels of cortisol along with altered cortisol circadian rhythm is associated with major depressive disorder. It seems to be a two-way street — treating depression can reduce elevated cortisol levels.[ref][ref]

3) Metabolic syndrome, weight gain, and cortisol:

Hypertension, insulin resistance, and high cholesterol add up to metabolic syndrome. And obesity goes hand-in-hand here…All together, a problem that many of us face.

So what does research show about obesity and cortisol?

Activating the glucocorticoid receptor (GR) can increase blood glucose levels by stimulating the liver to create more glucose (gluconeogenesis).[ref]

Hair cortisol levels, which give an average cortisol reading for the past few months, were tested in a group of British adults. The cortisol levels in hair were higher in those who were obese (BMI >30) and with larger waist circumferences. Higher hair cortisol levels also correlated to being overweight for a longer period of time (>4 years).[ref]

This doesn’t mean that weight gain is due to high cortisol levels for everyone, but it could be part of the problem for many of us.

4) Infertility from stress:

Constant activation of the HPA axis can cause problems when trying to conceive. It is due to cortisol shifting the ratio of follicle stimulation hormone to luteinizing hormone (FSH:LH).

The altered hormone ratio causes decreased egg quality and an increased risk of infertility.[ref][ref] Read more details here.

Additionally, chronic and unpredictable mild stress can alter menstrual cycles and decrease estradiol levels.[ref]

5) Childhood trauma alters cortisol levels in adults:

I mentioned above that cortisol levels are controlled by three factors: genetics, chronic stress, and childhood trauma.

There is quite a bit of scientific evidence showing childhood trauma can cause persistent changes in the HPA axis. One study describes it as the brain becoming sensitized, thus allowing episodes of depression to occur more frequently.[ref]

Childhood trauma can be mental or physical – from child abuse to a parent dying to having childhood leukemia. Genetics interacts with this, and some people are more resilient to childhood trauma than others. Certain genetic variants cause a higher basal cortisol level with a blunted response to actual, acute stress. It increases the risk of depression, anxiety, and PTSD.[ref]

Is adrenal fatigue real?

I wanted to quickly address adrenal fatigue because many people may confuse it with HPA axis dysfunction. It isn’t really the same thing.

Adrenal fatigue is an idea promulgated by alternative medicine practitioners. The idea is chronic stress causes the adrenals to wear out – become exhausted – and not produce enough cortisol. It is thought to cause overall fatigue, depression, weight gain, brain fog, etc. Examples of alternative health sites writing about adrenal fatigue: Dr. Northrup’s adrenal fatigue articleDave Asprey chiming in on the adrenal fatigue idea. These are just a handful of examples, and all the big alternative health websites used to be on the adrenal fatigue band-wagon.

Most endocrinologists don’t think that ‘adrenal fatigue’ is real. And research studies back up the idea that the adrenal glands aren’t worn out, exhausted, or not producing enough cortisol.[ref][ref]

In fact, some alternative medicine practitioners seem to be revamping how they talk about adrenal fatigue and are now morphing their articles to talk about HPA axis dysfunction.[article][article]

HPA Axis Genotype Report

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Research shows that genetic variants in the HPA axis affect an individual’s response to chronic stress. The variants below impact different aspects of the HPA axis, from cortisol receptors to the corticotropin-releasing hormone receptors. Genetics is only part of the picture here, since life events will play a big part in cortisol release.

If you have symptoms of HPA axis dysfunction, understanding where your genetic susceptibility lies may help you to figure out the best solutions for you.

A recent study found that a combined genetic risk score (including some of the variants below) successfully predicts cortisol levels and the interaction with stressful life events in children. The combined genetic risk was also linked to hippocampal and amygdala volume in children. Thus, cortisol levels and stress are literally changing the developing brain in ways that vary, based on genetics.[ref]

NR3C1 genetic variants- the GR receptor

The NR3C1 gene codes for the glucocorticoid receptor (GR). This receptor receives the signal in times of higher stress and at peak circadian cortisol release. The first two variants, rs6189 and rs6190, are less common (found in around 2% of the population) and more impactful. 

Check your genetic data for rs6189 ER22 (23andMe v4, v5, AncestryDNA)

  • C/C: typical
  • C/T: glucocorticoid (cortisol) resistance
  • T/T: glucocorticoid (cortisol) resistance[ref][ref] possibly lower cardiovascular risk[ref]

Members: Your genotype for rs6189 is .

Check your genetic data for rs6190 (23andMe v4, v5, AncestryDNA) 23EK:

  • C/C: typical
  • C/T: glucocorticoid (cortisol) resistance
  • T/T: glucocorticoid (cortisol) resistance[ref]

Members: Your genotype for rs6190 is .

Check your genetic data for rs6198 (AncestryDNA only):

  • T/T: typical
  • C/T: glucocorticoid (cortisol) resistance
  • C/C: glucocorticoid (cortisol) resistance[ref][ref]

Members: Your genotype for rs6198 is .

Increased sensitivity to cortisol is linked to an increased risk of obesity, metabolic syndrome, heart disease, and insulin resistance – when coupled with stress.

Check your genetic data for rs56149945 (formerly rs6195, N363S) (23andMe v4 i4990006)

  • T/T: typical
  • C/T: increased sensitivity to glucocorticoids, increased risk of obesity, hypertension
  • C/C: increased sensitivity to glucocorticoids[ref] increased risk of obesity, hypertension[ref]

Members: Your genotype for rs56149945 is . And your genotype i4990006 is .

Check your genetic data for rs41423247 BclI (Ancestry DNA only):

  • C/C: hypersensitivity to glucocorticoids (cortisol)[ref][ref]
  • C/G: typical
  • G/G: typical

Members: Your genotype for rs41423247 is .

Check your genetic data for rs6191 (23andMe v4, Ancestry DNA):

  • A/A: increased risk of depression, increased resistance to glucocorticoids (cortisol)[ref]
  • A/C: typical risk of depression
  • C/C: typical

Members: Your genotype for rs6191 is .

Check your genetic data for rs10052957 (23andMe v4, AncestryDNA):

  • A/A: higher evening and total cortisol, increased risk of depression[ref]
  • A/G: typical
  • G/G: typical

Members: Your genotype for rs10052957 is .

 NR3C2 gene – the MR receptor

­The NR3C2 gene codes for the mineralocorticoid receptor protein (MR), which is what cortisol binds to during normal basal levels.

Check your genetic data for rs5522 (23andMe v4, v5, AncestryDNA):

  • C/C: higher plasma cortisol, depression in the elderly, increased reactivity to adversity (in children)[ref]
  • C/T: higher plasma cortisol, depression in the elderly, increased reactivity to adversity (in children)
  • T/T: typical

Members: Your genotype for rs5522 is .

CRHR1 gene:

The CRHR1 gene codes for the corticotropin-releasing hormone (CRH) receptor. It is what the corticotropin-releasing hormone binds to in the pituitary gland to signal for ACTH production.

Check your genetic data for rs110402 (23andMe v5, AncestryDNA)

  • G/G: elevated cortisol in people exposed to childhood trauma[ref]
  • A/G: slightly increased risk of depression in childhood trauma
  • A/A: typical, decreased risk of MDD in non-smokers[ref]

Members: Your genotype for rs110402 is .

Check your genetic data for rs242924 (23andMe v4, AncestryDNA):

  • G/G: elevated cortisol in people exposed to childhood trauma[ref]
  • G/T: slightly increased risk of depression in childhood trauma
  • T/T: typical

Members: Your genotype for rs242924 is .

Check your genetic data for rs242941 (23andMe v4, v5, AncestryDNA):

  • A/A: a minor increase in depression risk[ref]
  • A/C: a minor increase in the risk of depression
  • C/C: typical

Members: Your genotype for rs242941 is .

Check your genetic data for rs242939 (23andMe v4, v5, AncestryDNA):

  • T/T: typical
  • C/T: a minor increase in the risk of depression
  • C/C: increased risk of depression[ref]

Members: Your genotype for rs242939 is .

FKBP5 gene:

The FKBP5 gene codes for a chaperone protein that regulates the sensitivity of the glucocorticoid receptor (GR).  When FKBP5 binds to GR, it reduces the receptor’s affinity for cortisol and decreases its translocation to the nucleus. This protein essentially turns down the production of cortisol.

Check your genetic data for rs1360780 (23andMe v4, v5, AncestryDNA):

  • C/C: typical
  • C/T: increased risk for depression – better response to antidepressants.
  • T/T: increased risk for depression, incomplete cortisol recovery, and increased anxiety after psychosocial stress[ref][ref][ref]

Members: Your genotype for rs1360780 is .

Check your genetic data for rs3800373 (23andMe v4, v5, AncestryDNA):

  • A/A: typical
  • A/C: slightly increased risk of MDD(major depressive disorder)
  • C/C: slightly increased risk of MDD[ref]

Members: Your genotype for rs3800373 is .

 MC2R gene:

Melanocortin 2 receptor is the receptor for ACTH, located mainly in the adrenal cortex, which starts the production of cortisol.

Check your genetic data for rs1941088 (AncestryDNA only):

  • A/A: low cortisol response[ref]
  • A/G: typical
  • G/G typical

Members: Your genotype for rs1941088 is .

Check your genetic data for rs28940892 (23andMe v4, AncestryDNA):

  • T/T: typical
  • C/T: carrier of a pathogenic allele for ACTH resistance
  • C/C: ACTH resistance[ref]

Members: Your genotype for rs28940892 is .

SERPINA6 gene: transporting cortisol

This gene codes for the corticosteroid-binding globulin (also called transcortin) protein, which transports cortisol in the bloodstream.[ref]

Check your genetic data for rs11621961 (23andMe v4, v5; AncestryDNA):

  • C/C: typical cortisol binding globulin
  • C/T: somewhat less cortisol binding globulin, less plasma cortisol
  • T/T: less cortisol binding globulin, less plasma cortisol[ref]

Members: Your genotype for rs11621961 is .

Check your genetic data for rs941601 (23andMe v4, v5; AncestryDNA):

  • C/C: typical
  • C/T: more musculoskeletal pain thought to be due to blunted cortisol response
  • T/T: more musculoskeletal pain thought to be due to blunted cortisol response[ref]

Members: Your genotype for rs941601 is .

Lifehacks for HPA axis dysfunction:

Most of these ‘lifehacks’ involve reducing chronically high cortisol levels.  If you have genetic variants tied to lower cortisol, skip down to the adaptogens info.

Changing your body’s cortisol response is going to take some time. If your cortisol receptors are downregulated because of chronic high cortisol, it may take a while to see the effects of reducing cortisol levels.

Reducing Overall Stress:

It seems obvious to state that eliminating stress should help reduce cortisol levels. Sometimes, though, it is hard to see the forest for the trees when it comes to stress in your life.

Big things to look at include financial stress and relationship stress.

While it is easy to give advice such as ‘cut out cable’ or ‘stop spending too much on clothes’, making the right decisions to get out of financial or relationship stress can be hard. See, the catch-22 here is that elevated cortisol levels change the way that people make decisions. One study of stock traders given exogenous cortisol to elevate their cortisol levels showed it distorted their risk-taking decision making. Other studies show similar results, with higher cortisol levels causing poorer decision making. If you know you are not making wise decisions, try seeking advice from a coach or mentor.[ref][ref][ref]

Switching your attitude from one of being a victim (victim of divorce, social injustice, financial adversity, etc.) to one of being a problem solver may help lower cortisol levels.

There have been a couple of studies lately that looked at ‘gratitude’ interventions (such as writing a gratitude letter or journal), but the results didn’t show that gratitude journaling lowers cortisol significantly.  Instead, interventions that work on modifying expectations and distracting yourself (instead of ruminating) lead to lower cortisol levels.[ref][ref][ref][ref]

Yoga and Meditation:
Meditation decreases cortisol levels.[ref][ref]
Studies on yoga show it generally improves the HPA axis, but results are somewhat mixed.  It may depend on the type of yoga.[ref]  People doing Hatha yoga showed decreased cortisol on yoga days:[ref][ref]

Commune with the trees:
Forest bathing, popular in Japan, reduces cortisol levels.[ref]Another study shows going to a natural forest area (vs an urban park) decreased cortisol.[ref]

There are lots of studies showing the amount and quality of sleep affect cortisol levels.  Generally, short sleep raises overall cortisol the next day.  Short sleep can cause a decrease in the circadian rhythm of cortisol, flattening the overnight peak but slightly higher during the next day. Normal fluctuations in the amount of sleep don’t seem to influence cortisol much. So, for example, if one night you get seven hours of sleep vs. normally getting 8 hours, it shouldn’t affect cortisol the next day.[ref][ref][ref][ref]

Consistency is key: A recent study showed that getting more sleep the night before led to a decreased stress response during the morning and afternoon, but that effect wore off by the evening.[ref] You need good quality sleep and a good quantity of sleep every night.

Circadian rhythm:
Alongside sleep is the circadian rhythm. Your cortisol levels should exhibit a robust circadian rhythm, rising around the time you wake up in the morning.

Exposure to light in the blue wavelengths at night shuts down melatonin, affecting sleep and overall circadian rhythm.  A 2010 study also showed exposure to light in the red wavelengths also affects cortisol rhythm, indicating stress hormone function isn’t only dependent on blue light.[ref]

Decreasing overall light exposure at night by turning off overhead lights and opting for lower lamp lighting may help with cortisol circadian rhythm.

Chew Gum:
Chewing (mastication) during stressful conditions “suppresses the hyperactivity of the HPA axis via GC’s and GC receptors within the hippocampus, and ameliorates chronic stress-induced hippocampus-dependent cognitive deficits.“[ref]

It makes sense why some people are drawn to chewing gum – or chewing on a straw or pencil – when stressed. Perhaps we should all be chewing gum while driving in rush hour traffic.

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About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.