HPA Axis Dysfunction: Genes and Environment

Stress. We all face it at times! But it doesn’t affect us all the same way.  Some people bounce back easily from a stressful situation. Others may face the effects of stress continually over their lifetime.

I’m going to dig into the science of how stress affects us by looking at how the HPA axis works, how genetic variants influence stress response, and how you can apply this knowledge to ‘hack’ the system.

The HPA Axis:

The HPA axis refers to how the hypothalamus, pituitary gland, and adrenal glands regulate of cortisol. This system does a lot!  It regulates body temperature, immune function, digestion, mood, energy levels, heart rate, and more.

The HPA axis controls your physiological reaction to stress. This includes both psychological stressors (job stress, can’t pay the bills, family life) and physical stress (injury, illness, allergies, and toxins). It also controls normal cortisol levels at times when you aren’t under stress.

Cortisol Production Pathway:

This all starts in the brain. Neurons in the paraventricular nucleus, which is part of the hypothalamus, release corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP). This stimulates the pituitary gland to produce adrenocorticotropic hormone (ACTH), which enters the blood circulation. When ACTH enters the adrenal glands, located on top of the kidneys, it induces the adrenals to synthesize cortisol.

Cortisol is the main glucocorticoid produced by the adrenals. Glucocorticoid is a more general term — glucose + cortex + steroid — and other glucocorticoids include some of the steroid medications such as prednisone.

Cortisol is essential for life and produced rhythmically over the course of the day. So CRH induces ACTH which causes a cascade of events in the adrenal cortex to produce cortisol. When cortisol levels in the body rise, this is the signal to shut off CRH production. This feedback loop keeps cortisol production at the right levels. (Except when it doesn’t…. more on that to come.)[ref]

Here is a good video if you want some pictures with your explanation: https://www.youtube.com/watch?v=QAeBKRaNri0

Creating the Cortisol in the Adrenals:

The process by which the body creates glucocorticoids (cortisol, mainly) in the adrenals is more complex than you might think. Within the adrenals, in a part called the zona fasciculata, the ACTH molecule attaches to the ACTH receptor on the surface of the cell.  This receptor then triggers a series of events that causes cholesterol to be taken into the mitochondria. Within the mitochondria, the cholesterol is transformed to pregnenolone (with the help of the CYP11A1 enzyme). Pregnenolone then through a series of four more steps (with four more different enzymes) is converted into progesterone and then cortisol. [ref]

Cortisol is transported in the bloodstream throughout the body. Most cortisol is bound to corticosteroid-binding globulin or to albumin. About 3-5% of cortisol is freely circulating.[ref]

So what does cortisol do in the body?

We often think of cortisol as the stress hormone, but it also is essential at the right levels throughout the day.  Cortisol binds to two types of receptors – mineralocorticoid receptors (MR) and glucocorticoid receptors (GR). It has a higher binding affinity for MR receptors, so it binds to that first. In times of stress, when cortisol production is increased, it will bind to the glucocorticoid receptors. This is essentially how one hormone can play an important role at a basal level (binding to MRs) and cause a different response at higher levels (binding to GRs). Cortisol binds to the GR receptors in times of stress and at the circadian peak of production.[ref][ref]

Normally, the cortisol that your body produces during the day does quite a few things including regulating blood glucose levels, digestion, memory, energy production, and more.

Blood glucose levels are intricately tied to cortisol. When your blood sugar drops too much (hypoglycemia), it triggers a cortisol release. Cortisol increases blood glucose levels through gluconeogenesis (creation of glucose from fatty acids or certain amino acids). Higher serum cortisol levels are associated with higher HOMA-IR (measure of insulin resistance) levels. [ref]

Circadian regulation of cortisol:

The normal daily rhythm of cortisol is to rise in the morning, about the time that you wake up. Your lowest cortisol levels should be during the night, about 3 hours after sleep onset. The rhythm of cortisol is intricately entwined with your core circadian rhythm, which is set by the suprachiasmatic nucleus (SCN) in the hypothalamus. Your core circadian rhythm is controlled by a molecular clock, which is reset by exposure to light and dark.  But the core circadian rhythm is only part of the picture, there is also a peripheral clock mechanism in the adrenals that acts on cortisol also. Part of the problem with dysregulation of the HPA axis comes with a mismatch of circadian control of cortisol. [ref][ref]

Stress and Cortisol:

Cortisol levels rise in stressful situations. This is what is supposed to happen! It triggers several important responses in the body that are helpful under stress — like when you are being chased by a tiger or have a traumatic injury.

When cortisol levels rise due to an acute stressor:

  • the immune system is dampened (so you aren’t overwhelmed by inflammatory cytokines)
  • blood pressure increases (more oxygen to your cells)
  • blood glucose levels increase (lots of energy to run from a  tiger)
  • ability to remember things is impaired, but memory consolidation of the stressful event is increased (remember that tigers are scary)[ref]

HPA Axis Dysfunction:

The problems with cortisol come when levels are chronically elevated – or chronically low. There are two conditions of extreme cortisol dysregulation: Cushing’s syndrome and Addison’s disease. Cushing’s 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 changes in mood.

While Cushing’s and Addison’s show the extreme’s of cortisol disorders, there are milder manifestations that plague many of us. HPA axis dysfunction can mean that cortisol is chronically elevated and/or that it doesn’t respond appropriately to stress. It can also be due to a disrupted rhythm of cortisol production over the course of a day.

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

Chronically elevated cortisol is linked to:

  • diabetes, insulin resistance [ref][ref]
  • immune dysfunction [ref]
  • depression and anxiety [ref][ref]
  • coronary artery disease [ref]
  • reproductive problems [ref]
  • weight gain [ref][ref]

Immune dysfunction: One theory is that chronically elevated cortisol leads to glucocorticoid receptor resistance, which is a downregulation of the glucocorticoid receptor. When acute stress occurs, the body then cannot mount a normal stress response. This can lead to an increased susceptibility to infections, including colds.[ref]

Depression: 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. This seems to be a two-way street — treating depression can reduce elevated cortisol levels. [ref][ref]

Metabolic syndrome: Hypertension, insulin resistance, and altered lipids add up metabolic syndrome. And obesity goes hand-in-hand here. So what do studies show on obesity and cortisol? 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]

Infertility: Constant activation of the HPA axis can cause problems with getting pregnant.  This is due to cortisol shifting the ratio of follicle stimulation hormone to luteinizing hormone (FSH:LH). This causes decreased egg quality. [ref][ref] Read more details here.

Childhood trauma

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 that shows that childhood trauma can cause persistent changes in the HPA axis. One study describes it as the brain becoming sensitized and episodes of depression can 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. The response in some people is a higher basal cortisol level with blunted response to actual, acute stress. This increases the risk of depression, anxiety, and PTSD. [ref]

Adrenal fatigue: is it real?

Adrenal fatigue is an idea promulgated by alternative medicine practitioners. The idea is that chronic stress causes the adrenals to wear out – become exhausted – and not be able to produce enough cortisol. This is thought to cause overall fatigue, depression, weight gain, brain fog, etc. [article][article][article][article]

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 re-vamping the way that they talk about adrenal fatigue and now morphing it into HPA axis dysfunction. [article][article]


Genetic Variants in the HPA Axis

More and more research is coming out on how genetic variants in the HPA axis affect an individual’s response to chronic stress.  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. This was also linked to hippocampal and amygdala volume in the children. So cortisol levels and stress are literally changing the brain in ways that vary based on genetics. [ref]

NR3C1 gene:

Codes for the glucocorticoid receptor (often abbr. GR). This is what is receiving the ACTH signal in times of higher stress (or at peak circadian cortisol levels).  The first two variants 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: normal
  • C/T: glucocorticoid (cortisol) resistance
  • T/T: glucocorticoid (cortisol) resistance [ref] [ref]

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

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

Check your genetic data for rs6198 (AncestryDNA only):

  • A/A: normal
  • A/G: glucocorticoid (cortisol) resistance
  • G/G: glucocorticoid (cortisol) resistance (not pathogenic) [ref] [ref]

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

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

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

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

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

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

 NR3C2 gene:

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

CRHR1 gene:

The CRHR1 gene codes for the corticotropin-releasing hormone receptor. This is what the corticotropin-releasing hormone binds to in the pituitary gland to signal for A/C/TH 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: normal, decreased risk of MDD in non-smokers [ref]

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: normal

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

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

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

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

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: normal
  • 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]

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

  • A/A: normal
  • A/C: slightly increased risk of MDD
  • C/C: slightly increased risk of MDD [ref]

 MC2R gene:

Melanocortin 2 receptor is the receptor for ACTH, located mainly in the adrenal cortex.

Check your genetic data for rs1941088 (AncestryDNA only):

  • A/A – low cortisol response [ref]
  • A/G – normal
  • G/G – normal

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

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

SERPINA6 gene:

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

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

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

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

  • C/C: normal pain
  • 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]

Lifehacks:

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

Reducing Overall Stress:

It seems obvious to state that eliminating stress should help reduce cortisol levels. Sometimes 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 showed that elevating their cortisol levels by giving them exogenous cortisol 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 out advice from a coach or mentor. [ref][ref][ref]

Switching your mental 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 Mediation:
Meditation decreases cortisol levels.  [ref][ref]
Studies on yoga show that 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 showing that going to a natural forest area (vs an urban park) decreased cortisol: [ref]

Sleep & Circadian rhythm:
There are lots of studies showing that 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]

A recent study showed that getting more sleep the night before lead to a decreased stress response during the morning and afternoon, but that effect wore off by evening.[ref] So you need good quality sleep and a good quantity of sleep, every single night.

Alongside sleep is circadian rhythm. Your cortisol levels should exhibit a robust circadian rhythm, rising around the time that 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 that exposure to light in the red wavelengths also affects cortisol rhythm, indicating that the 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] And now 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.

BPA:
Studies show that BPA, a substance found in many plastics, is able to bind to the glucocorticoid receptor.[ref] So increased exposure to BPA may mimic increased cortisol levels as well as affecting fat cells and androgen production.[ref]

CBD Oil, but only when under acute stress:
A recent animal study showed that cannabidiol doesn’t affect the HPA axis under baseline conditions, but when under stress conditions, low and intermediate doses of CBD blocked the HPA axis effects of stress.  [ref]

Saturated and unsaturated fats have opposite reactions:
An animal study found that saturated fats suppress ACTH and unsaturated fats increased ACTH release.[ref] A human study found that oleic and linoleic (both unsaturated fats) stimulated the adrenocortical cells. Saturated fat had no effect on cortisol production.[ref]

Taking both of these results indicates that avoiding unsaturated fats, especially in the form of fried foods, may decrease your cortisol levels. Step away from those french fries…

Supplements that may increase cortisol levels:
An animal study found that N-acetylcysteine (NA/C) and vitamin E increase corticosterone (cortisol) levels.  NA/C reduced GR and MR expression in the pituitary, which caused hyperactivity of the HPA axis.[ref] Keep in mind that this is an animal study.

Adaptagens that may decrease or moderate cortisol levels:
Adaptogens are herbs that have been used traditionally for thousands of years to moderate stress response. It seems like every region has adaptogens that are native plants that have been chewed or brewed as traditional medicine. Modern research backs up these adaptogens in their role in moderating the HPA axis.

  • Holy Basil shown in animal studies to inhibit cortisol release. You can get Holy Basil as a supplement or drink it as Tulsi tea. [ref]
  • Ashwagandha has been shown in multiple clinical trials and research studies to reduce cortisol. One study, for example, tested 300 mg/twice a day vs. placebo. After 8 weeks, cortisol was reduced by an average of 22%. Weight also went down for the Ashwagandha group. [ref]  [ref]
  • Rhodiola has been shown to reduce high cortisol levels.[ref][ref][ref]
  • Korean Ginseng reduces the increase in cortisol due to stress.[ref]

Exercise and Eating Carbs:
Prolonged heavy exercise (>1 hr) usually causes a stress response and elevates cortisol levels, but moderate exercise is good for modulating cortisol levels. Eating carbs before prolonged exercise helps to decrease the cortisol response. [ref][ref][ref]

Weight Loss:
Long term weight loss is associated with lower cortisol levels. [ref] The study doesn’t really make clear whether lowering cortisol caused weight loss or if the weight loss caused the body to have less physical stress and thus lower cortisol.

Puppies and Oxytocin:
Oxytocin, a hormone that produces good feelings of love,  reduces ACTH and cortisol.[ref]

Oxytocin is released in copious amounts after childbirth and is responsible for parent-child bonding.  But there are other (much easier) ways to increase oxytocin levels as well.

Oxytocin is intertwined with smell receptors and memory. It is what links good feelings to a certain smell. (Like smelling a baby’s head…  but I don’t think that wandering around your local park sniffing babies is necessarily a recommended ‘lifehack’ for lowering cortisol.) Instead, try using aromatherapy or essential oils to associate smells with feelings of relaxation. Lavender essential oil has recently been studied and found to ameliorate depression due to high cortisol (in animals). But if you don’t like lavender, find a scent that you do like and use it while doing something that makes you relaxed.[ref][ref]

Studies show that bonding with your dog will raise oxytocin levels. So maybe taking a break at work and looking at dog or cat videos is actually lowering your cortisol levels instead of just wasting time.[ref]

Learn more:

 

3 Comments on “HPA Axis Dysfunction: Genes and Environment

  1. Upon seeing my variant, I checked the rs4713916 of the FKBP5 gene. I seems A is the minor allele, with a MAF around 22%, G being the native variant. Yet, you listed A as normal. Can you please clarify?

    • Thanks so much for letting me know about that inconsistency. I’m going to take that SNP off for now and double check everything. SNPedia is listing A as the common allele and the sequence name indicates A>G showing A as the major allele. But you are correct that the frequency of A is 22%, so I need to re-read through the referenced studies to see which way they were interpreting it.
      Debbie

  2. You are such a wonderful writer. Somehow you take a topic like genetics and make it not only understandable but, gasp, might I say it?– palatable and humorous! Tigers, sniffing babies heads (you pegged me there as I am that person stalking wee ones for a sniff of that precious scent). Off to figure out how to meditate while sniffing a babies head….as soon as I outrun this tiger! Great article and thank you!!!

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