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Factors that Impact Low/High Cortisol & the Stress Response

Written by Ana Aleksic, MSc (Pharmacy) | Last updated:
Puya Yazdi
Medically reviewed by
Puya Yazdi, MD | Written by Ana Aleksic, MSc (Pharmacy) | Last updated:

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Cortisol is widely known as a “stress hormone.” Some research suggests that it may impact blood sugar, proteins, cholesterol, and inflammatory markers. According to one hypothesis, imbalanced cortisol may create a lot of health issues that at first seem unrelated. What does the science say? Learn about factors that may trigger excessive cortisol release in this article.

Disclaimer: This post focuses on the neuroscience of the stress response in relation to cortisol. It is solely informational. Talk to your healthcare provider if you feel like you’re under too much stress or if your cortisol labs are abnormal.

What Increases and Decreases our Stress Response?

Diving into the Science

Since the stress response pathway is so critical to our health, it’s important to explore what increases and what decreases it. Modern neuroscience has come a long way in understanding the stress response [1].

According to one hypothesis, the problem comes when it’s activated too little, too much or it doesn’t have a good rhythm. In other words, HPA “dysregulation” is viewed as bad [1].

Scientists point out that this has nothing to do with the capacity of the adrenal glands (See the myth of adrenal fatigue). Rather, it’s likely related to many other factors. The consequences also seem to depend on whether the HPA axis is activated short- or long-term and to what extent [1].

We know that the HPA axis controls such vital functions as heart rate, blood pressure, and digestion [2].

The HPA axis also communicates with several regions of the brain, including the limbic system, which is implicated in motivation and mood, with the amygdala, which generates fear in response to danger, and with the hippocampus, which plays an important part in memory formation as well as in mood and motivation [2].

In addition, the HPA axis is also connected with brain regions that control body temperature, suppress appetite, and control pain [2].

Research suggests that a chronically over-activated stress response may decrease growth, reproduction, metabolism, and immunity [3].

Similarly, the HPA axis also interacts with various other glandular systems, among them those producing reproductive hormones, growth hormones, and thyroid hormones [4, 5].

Prolonged HPA activation is hypothesized to hinder the release of growth hormone and IGF-1, both of which are essential for normal growth. Cortisol also seems to cause tissues to be more resistant to IGF-1, according to animal data [6].

Researchers suspect that psychological symptoms excessive HPA activation include sleep disturbances, loss of libido, and loss of appetite, as well as an increased risk for accumulating abdominal fat. More human data are needed [7, 8].

Additionally, it’s a good idea to read our post on why stress is bad for a more detailed look.

Limitations

Note that the HPA axis is not the only system that participates in the stress response. Your sympathetic nervous system (SNS) is a different arm of the stress response. As an example, beta 2-adrenoreceptor blockers like propranolol block beta receptors in the heart that belong to the SNS [9].

Sympathetic, fight-or-flight activity can also be counteracted by parasympathetic, rest-and-digest activity. This is part of the cholinergic pathway in the body.

Lastly, the stress response can involve many other possible factors – including brain chemistry, environment, health status, and genetics – that may vary from one person to another.

Daily Cortisol Patterns

Scientists think stressors that are uncontrollable, threaten physical integrity or involve trauma tend to have a high, flat cortisol release, with lower-than-normal levels of cortisol in the morning and higher-than-normal levels in the evening. This seems to result in a high overall level of daily cortisol release [10].

On the other hand, controllable stressors tend to produce higher-than-normal morning cortisol [10].

However, there’s not enough reliable evidence to verify this cortisol release pattern. Large human studies are needed.

Cortisol Circadian Rhythm

Here’s a simple way to think about the circadian rhythm. The body has thousands of processes going on at any given moment. Many of these processes function better in concert with other processes – just like in a symphony, where different sounds work better with other sounds.

These processes have a certain rhythm or flow. Scientists suggest that the body conducts this orchestra with “clock genes.” When they get expressed, it happens all over the body, in a synchronous way [11].

Circadian rhythm disruptions have been linked with inflammation, oxidative stress, and cognitive problems [11].

Since the HPA axis (includes CRH, ACTH, Cortisol) is involved in so many bodily functions, science emphasizes the importance of its rhythm.

In humans, cortisol levels seem to peak in the early morning (approximately 8 a.m.) and reach their lowest level at about midnight-4 a.m., or three to five hours after the onset of sleep. Information about the light/dark cycle is transmitted from the retina to the suprachiasmatic nuclei in the hypothalamus [12].

While people differ in their cortisol rhythms, a given person tends to have consistent rhythms [12].

It’s also important to realize that the ratio of cortisol to DHEA may have various effects. These are still an active area of research [13].

Rhythms of the HPA axis

According to one hypothesis that has yet to be verified in humans, alterations in the circadian rhythm of the HPA axis have been linked to the severity of autoimmune diseases [14].

Researchers suggest that conditions such as autism may be linked with a dysregulated cortisol rhythm [15].

Limited studies suggest that shift workers are at increased risk of several chronic diseases [16].

Additionally, some breast and ovarian cancer patients have alterations in their cortisol rhythm [17].

Studies in humans and animal models hypothesized a loose association between cancer and the loss of a circadian rhythm. This rhythm is claimed to control energy balance, immune function, and other pathways that are controlled by the HPA axis. According to this experimental theory, these pathways could be involved in tumor suppression. Human data are lacking, though [18].

There’s still not enough evidence to draw any solid conclusions. Large, well-designed studies are needed to understand these fragmented findings.

Diseases Associated with HPA Axis Dysregulation

Limited studies suggest that people with too low or too high cortisol may be at risk of various diseases, including cognitive-related problems.

However, the majority of studies covered in this section deal with associations only, which means that a cause-and-effect relationship hasn’t been established.

For example, just because abnormal cortisol and HPA dysregulation have been linked with anxiety doesn’t mean that anxiety is caused by HPA dysregulation. Data are lacking to make such claims.

Nonetheless, chronic stress response activation (HPA) is believed to be a causal factor of:

  • Anxiety disorders
  • Eating disorders, including anorexia [19] and bulimia [20]
  • Major depression [21] (a blunted ACTH response is thought to be common)
  • Burnout, CFS [22], Fibromyalgia
  • IBS [21]
  • Bipolar [21]
  • Insomnia [21]
  • PTSD [21]
  • Borderline personality [21]
  • ADHD [21]
  • Alcoholism and many other diseases [21].
  • Rheumatoid arthritis [23] – There’s lower cortisol in RA, in some people.

Large human studies are needed to confirm these associations.

Additionally, researchers suspect that lack of the hormone CRH may result in tiredness common to people suffering from chronic fatigue syndrome. Lack of CRH is also thought to be central to seasonal affective disorder (SAD) – the feelings of fatigue and depression that plague some people during the winter months. More research is needed to verify this theory [24, 25].

Researchers suggested that, when compared to a group of people who did not have difficulty falling asleep, insomniacs had higher ACTH and cortisol levels, both in the evening and in the first half of the night. Moreover, the insomniacs with the highest cortisol levels tended to have the greatest difficulty in falling asleep. These findings have yet to be verified [26].

Diseases like diabetes have also been associated with too much HPA activation and high levels of CRH [27]. People with Alzheimer’s tend to have high levels of cortisol, but it’s believed to be a result and not a cause of the disease [28].

In PTSD, there’s a lower-than-normal cortisol release, and it is thought that a blunted hormonal response to stress may predispose a person to develop PTSD. The exact HPA axis changes that happen in PTSD are still unclear [21].

Factors that Trigger or Counteract the Stress Response

Remember that it’s natural and healthy for the stress response to be activated moderately and for a short time. Issues usually arise when activation becomes chronic [1].

If your goal is to improve extreme stress-related issues – including those of panic disorders or anxiety – it’s important to talk to your doctor, especially if stress is significantly impacting your daily life.

Major mental changes, such as excessive sadness, panic, persistent low mood, euphoria, or anxiety, are all reasons to see a doctor.

Your doctor should diagnose and treat any underlying conditions causing your symptoms.

Additionally, changes in brain and body chemistry are not something that people can change on their own with the approaches listed in this article. Instead, the factors to avoid listed here are meant to reduce daily stress and support overall mental health and well-being.

You may try avoiding the factors listed below if you and your doctor determine that this could be an appropriate approach for reducing your stress response.

Avoiding these triggers should never be done in place of what your doctor recommends or prescribes.

Lastly, clinical evidence is lacking to support avoiding some of the factors listed below as a means of stress reduction.

Stress Response Triggers to Avoid

This is a partial list of potential stress response triggers described in the scientific literature. Stress can be highly subjective and involve many factors that are not mentioned here.

In General

  • Psychological/Social stress [29], including income insecurity and other occupational stress [30].

Psychological

Some psychologists consider that the people who fall under the following emotional patterns may have an increased stress response:

  • Try to control an outcome
  • Try to change yourself
  • Try to exert your willpower
  • Try to increase your motivation
  • Do something you don’t want to
  • Make goals
  • Have ambitions or try to get somewhere
  • Have a strong attachment – to an idea, object, person, etc.
  • Think about the past or future
  • Take life too seriously
  • Feel fear
  • Feel anxiety
  • Feel anger
  • Feel frustrated
  • Feel guilt
  • Feel jealousy
  • Feel hate
  • Feel embarrassed
  • Feel rejected

Sleep-Related

  • Reduced Sleep [31, 32]
  • Bad quality sleep [32]
  • Staying up late [33] – cortisol may be increased when people are awake during normal sleep times.

See our post about keeping a circadian rhythm.

Stimulants

Inflammation-Related

Lifestyle

  • Intense prolonged exercise [12], Strenuous Breathing (IL-6, IL-1) [44]
  • Hypoxia, High altitudes [45]
  • Temperature variations, e.g. extreme cold [46] or hot [47] temperatures. Chronic cold seems to increase CRH receptors potentially via  dopamine [48].
  • Smoking [49] (even just 2 cigarettes)
  • Long commutes [50]
  • Noise [51]
  • “low power postures” [52]
  • Excess Alcohol consumption [12]. Continuous consumption of alcohol over an extended period of time has been shown to raise cortisol levels in the body [53].
  • Marijuana/Pot/THC [54] – dose-dependently raises cortisol.
  • Poisoning with toxins such as heavy metals like cadmium [55] over an extended period of time. Fish with elevated mercury, PAH, PCBs had a decreased cortisol response [56], so other toxins may impair cortisol. More research is needed.

Dietary

  • Overeating (esp. in men) [57] – mostly caused by VIP [58]
  • Lectins (subjective)
  • Protein restriction/Leucine deprivation [59]
  • Excess sodium [60]
  • Severe calorie restriction [12]
  • Excess omega-6 [12]
  • Intermittent Fasting or regular Fasting [61] – Modern Ramadan practices in Saudi Arabia are associated with excess evening cortisol (and increased insulin resistance.) Other kinds of fasting might decrease CRH. More research is needed [62].

Nutrient Deficiencies

  • Vitamin A inadequacy [63, 64]
  • Zinc inadequacy [65]
  • Magnesium inadequacy [66, 67]
  • Potassium loading [68] – increases ACTH and cortisol in humans. Scientists suspect this might be the reason why potassium deficiency causes cortisol to decline (as mentioned) and causes a decrease in the conversion of 11-deoxycortisol to cortisol. This may also have a role in rheumatoid arthritis pain; cell potassium is always low in RA [12].

Health Status

Hormonal Pathways and Neurotransmitters

The following factors are theoretical. They help scientists better understand the stress response pathway, but their impact hasn’t been tested in humans.

Be sure to discuss your hormone-related labs with your doctor and do not start or stop taking prescription hormones unless recommended by a doctor.

Hormones: CCK [71, 72], NPY [73], Estrogen (alpha, beta – CRH) [74], Pregnenolone, DHEA[75], GLP-1 [76], Leptin [77], VIP (raises CRH) [78], Sex hormones [79], Thyroid hormones [80], Vasopressin (releases CRH [81] and ACTH [82]), Ghrelin [79], AngiotensinII/ACE [83, 84], Insulin [79], Substance P (CRHR1) [84, 85], Low estrogen and melatonin supplementation increase cortisol levels in postmenopausal women [12]. MSH (prevents a fasting-induced decrease in CRH) [62]. Insulin may cause the release of vasopressin, which stimulates ACTH/cortisol [86].

Peptides: Orexins [87], NGF [37], BDNF [75]

Neurotransmitters: Noradrenaline [88], Glutamate [89], Dopamine (D1/D2) (CRH in PVN) [90] – contradictory [91], Serotonin (specifically 5-HT2CRs): Serotonin increased CRH and its neuronal activity and CRH (and corticosterone release) [92, 93]. Acetylcholine [34]. Chronic SSRI usage increases CRH, but decreases ACTH and therefore cortisol [94], but fluoxetine decreases CRH [95].

Mechanisms

Scientists suspect that chronic stress increases CRH receptors in the PVN, which might make people even more susceptible to the harmful effects of stress [96].

Everyone is affected differently by stress. Limited studies suggest that, in many conditions such as Autism, psychological stress over-activates the stress response pathway and results in too much cortisol [97]. In IBS, CRH seems to cause significantly more ACTH when compared to people without IBS [98].

Thus, with a given amount of HPA activation, some people are affected more. Larger human studies are needed to better understand these relationships.

Factors That May Counteract the Stress Response

Supplements have not been approved by the FDA for medical use and generally lack solid clinical research. Regulations set manufacturing standards for them but don’t guarantee that they’re safe or effective.

It’s important to consult your healthcare provider before making any changes to your lifestyle, diet, or supplements regime.

Lifestyle

  • Positive social encounters [35]
  • Laughing/being happy [12]
  • Meditation [99]
  • Yoga [100]
  • Being physically active (lowers cortisol in the longer term) [101]
  • Massage therapy [102]
  • Regular dancing [12]
  • Music therapy [12]

Devices & Experimental Approaches Lacking Evidence

  • Glucose restriction/fasting (careful) [103]
  • Chewing (CRH) [104] “High Power Postures” [52]
  • Vagus Nerve Stimulation [105]
  • PEMF (higher AM, lower PM) – depends on the device used [106]
  • tDCS [107]
  • rTMS (CRH production and release) [108, 109]
  • Electroacupuncture [110]

Investigational Supplements

Proper evidence is lacking to support the use of any of these supplements in people who are under high stress.

Hormonal Pathways

Oxytocin [35], Endorphins [70], GHRH (in men, but not women) [124], NPY – antagonizes CRH, even though it increases its release (Y1 receptor, lateral septum) [125, 126], Progesterone (lowers CRH), Allopregnanolone (progesterone metabolite) [127], Testosterone [128] – In people, testosterone increases ACTH and lowers cortisol in response to CRH [129]. In male animals, DHT reduces corticosterone response to stressors. So finasteride can increase the stress response by reducing DHT [130]. a-MSH lessens the stimulatory effects of IL-1b on the HPA axis [131].

GABA-related: inhibit the HPA axis. This includes GABAb [132, 133] or GABAa [134, 135]. Note that in normal situations, GABA inhibits CRH. But after stress, GABA may stimulate CRH [134].

NPY Stimulators: Eleuthero (NPY) [136], Schisandra (NPY) [136],

Prenatal/Childhood Stress and the HPA Axis

Stress Before Birth

There is evidence that prenatal stress can influence HPA regulation, though more human research is needed.

In animal experiments, exposure to prenatal stress led to a hyper-reactive HPA stress response [137].

Rats that were prenatally stressed had elevated baseline levels and abnormal circadian rhythm of corticosterone as adults [137].

Some studies have found an association between maternal depression during pregnancy and childhood cortisol levels [138].

Additionally, these children may require a longer time for their stress hormone levels to return to baseline following exposure to both acute and prolonged stressors [138].

In limited human studies, prolonged maternal stress during gestation was associated with mild impairment of intellectual activity and language development in their children, and with behavior disorders such as attention deficits, schizophrenia, anxiety, and depression; self-reported maternal stress is associated with higher irritability, emotional and attentional problems [139].

However, these findings should be cautiously interpreted. Most of the studies dealt with associations. And while we know that being relaxed during pregnancy is probably better for the future baby, we don’t know how much stress – and what type of stress – will cause significant and long-term harm.

Early Childhood

Early-life exposure to extreme or prolonged stress has been suggested to induce a hyper-reactive HPA Axis and may contribute to lifelong vulnerability to stress [140].

Mothering may enhance HPA functioning in at least two ways.

First, maternal care seems to be crucial in maintaining normal stress in a period where the HPA doesn’t activate much in childhood. The extreme stress of maternal separation may lead to permanent HPA dysregulation, according to one animal study [141].

Second, increased maternal handling (hugging, kissing) has been suggested to alter the expression of the glucocorticoid receptor gene implicated in adaptive stress response (in animals) [142].

According to one study, adult victims of childhood abuse seem to show increased ACTH concentrations in response to CRH/stress, compared to healthy controls and people with depression but not childhood abuse [143].

Irregular Cortisol Levels?

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About the Author

Ana Aleksic

Ana Aleksic

MSc (Pharmacy)
Ana received her MS in Pharmacy from the University of Belgrade.
Ana has many years of experience in clinical research and health advising. She loves communicating science and empowering people to achieve their optimal health. Ana spent years working with patients who suffer from various mental health issues and chronic health problems. She is a strong advocate of integrating scientific knowledge and holistic medicine.

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