If you have ever talked about stress, cortisol, energy, or fatigue, then you have likely talked about the Hypothalamic-Pituitary-Adrenal (HPA) Axis, the command center in charge of the body's stress, hormone, and immune response. When we are constantly over or under-stimulating our HPA Axis, our body responds through a cascade of hormonal fluctuations, inflammatory responses, shifts in neurotransmitter production, and alterations in energy levels. This axis impacts the optimal functioning of various glands and organs throughout the body, such as our thyroid, ovaries, testes, brain, and adrenal glands. This complex neuroendocrine pathway's primary function is maintaining physiological homeostasis (1).

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What is The Hypothalamic-Pituitary-Adrenal (HPA) Axis?

The HPA axis is seminal for homeostasis in the body and deals primarily with stress response, energy metabolism, immune function, and neuropsychiatric function. The Hypothalamic-Pituitary-Adrenal (HPA) axis is the major neuroendocrine mediator of the response to stress as well as the regulation of stress.

This homeostasis headquarters explains three vital glands' interaction and interconnected function (and dysfunction). The hypothalamus is an area of the brain that controls body temperature, heart rate, hunger, and mood. The pituitary gland regulates growth, metabolism, and reproduction through the various hormones it produces. The adrenal glands make adrenaline, regulate stress hormones and minerals, and control various functions like blood pressure, heart rate, and blood glucose levels (2).

The HPA axis is an important hormonal response system to stress. It is involved in releasing stress hormones, which are tightly regulated to ensure that the body can respond quickly to stressful events and return to a normal state just as rapidly. Exposure to stressful events increases glucocorticoid release by activating the HPA axis. Prolonged activation of the HPA axis may result in maladaptive changes in neural circuitry, leading to anxiety, poor mood, and alterations in other hormones such as cortisol, epinephrine, norepinephrine, and aldosterone (3, 4).

What Causes HPA Axis Dysfunction?

The HPA axis responds to two main types of stress, immediate (acute) stress and chronic stress. When stress becomes chronic and prolonged, the HPA axis can stop functioning optimally without lifestyle and dietary interventions to compensate. Since a variety of stressors can trigger HPA axis dysfunction, it is advantageous to begin discovering all cumulative stressors that can contribute to the HPA Axis, which can include:

Stress

Stress can be considered an umbrella term encompassing any internal or external influence that causes or leads to malfunction. This can include mental, emotional, physical, chemical, and biochemical stress. Lifestyle stressors such as inadequate sleep, disruptions to the circadian cycle, and emotional stress (think financial stress, recent breakup, moving across the country, or a major life change such as a death) can fall under the stress umbrella that impacts HPA axis functioning. Undiagnosed infections, exposure to environmental toxins (such as mold, pollutants, pesticides, and endocrine-disrupting plastics), and dysregulation of the inflammatory response may also negatively influence the HPA axis (4).

Inflammation

A maladaptive inflammatory response can lead to alterations in the HPA axis, specifically inappropriate stress response through the excessive activation of the HPA axis has been shown to increase inflammation. This can result in an unchecked stress response, subsequently leading to an inflammatory response. Inflammatory factors can stimulate the HPA axis to increase cortisol production, and prolonged inflammation can promote chronic HPA axis activation. These chronically elevated cortisols create an inflammatory response in the body, which can disrupt the normal function of the HPA axis pathway in our brain, which controls other hormones in the body (5, 6).

Nutrition

When our body is under stress, its need for nutrients is in greater demand. Key nutrients that can quickly become depleted during HPA dysregulation include B vitamins, Magnesium, Vitamin C, and Zinc, as well as digestive enzymes and HCL. Avoid eating processed refined and high-sugar foods that can negatively affect the HPA axis (7).

How Does HPA Axis Dysfunction Affect Our Health and Wellbeing?

Over time, our nervous systems gradually become strained and overloaded, overstimulated, and overextended, which can lead to dysregulation of the stress response. This can eventually lead to the overactivation of the HPA axis, which results in the activation of various inflammatory pathways and ultimately can negatively impact mood, hormones, fertility, immune function, energy levels, and metabolic function (2, 3, 4).

HPA Axis Dysfunction Symptoms

While there are many symptoms associated with HPA Axis dysfunction, some of the most common symptoms include (9, 14):

• Feeling chronically exhausted and fatigued
• Feeling tired but wired
• Unexplained weight gain or weight loss (weight gain may be seen around the hips and belly area)
• Poor quality sleep (which can include waking up feeling unrefreshed even after getting hours of sleep)
• Trouble falling asleep or staying asleep
• Poor immune response
• Brain fog, difficulty concentrating, and poor mood (including anxiety and depression)
• Increased cravings for sugar and salt
• Poor circulation, inflammation, and feeling "puffy"
• Hair loss and weak nails
• Hormone imbalances such as changes to the menstrual cycle (shorter or longer cycles, as well as completely missed periods)

Functional Medicine Labs to Test for Root Cause of HPA Axis Dysfunction

Testing for HPA axis functioning can be done through a few key labs:

The HPA Profile evaluates hormones and neurotransmitters to assess adrenal gland and nervous system function. This profile is ideal for individuals reporting quality-of-life stress-related complaints, such as poor sleep, anxiety, fatigue, mood issues, etc. It looks at DHEA-S, GABA, Epinephrine, and Norepinephrine biomarkers.

DUTCH Complete comprehensively assesses sex and adrenal hormones and their metabolites and includes the daily free cortisol pattern. While the DUTCH Plus offers an extensive assessment of sex and adrenal hormones and their metabolites. It also assesses the Cortisol Awakening Response (CAR) (13). It is best for those experiencing conditions related to less severely abnormal cortisol levels, including fatigue, depression, insomnia, fibromyalgia, anxiety, inflammation, and more.

The Adrenocortex Stress Profile measures cortisol and DHEA through carefully timed saliva samples. It can help in understanding a person's natural diurnal rhythm and the diagnosis of HPA imbalances.

The HPA-G Complete Profile can examine your hormone and neurotransmitters to assess nervous and endocrine system function.

Functional Medicine Treatment for HPA Axis Dysfunction

Nervines and adaptogens can be two of the best functional medicine treatments when it comes to supporting the HPA axis.

Adaptogens are innocuous agents which nonspecifically increase resistance against physical, chemical, biological, and psychological stressors. They can enhance stress resistance and are a unique class of healing plants that help balance, restore, and protect the body. Adaptogens such as Eleuthero, Rhodiola, Cordyceps, Ashwagandha, Schisandra, and Tulsi (Holy Basil) can be helpful long-term for the HPA axis (10).

The term nervine is a bit of a catch-all. But by definition, a nervine is a plant/herb that has a beneficial effect on the nervous system. There are stimulating nervines, calming nervines, and some that fall right in the middle. But for the most part, they work to support relaxation, stress, and the nervous system. Nervines such as Kava, Albizia, Passionflower, Milky Oats, and Skullcap can support HPA axis dysfunction (11, 12).

Complementary and Alternative Medicine

The good news is that there are many ways to support the HPA axis with lifestyle changes, including complementary and alternative medicine. One of the most impactful ways to support the HPA axis is by modulating your overall stress (the goal is to mitigate it, not eliminate it). This could look like developing a stress-reduction protocol, starting with identifying your main stressors. Can you cut out certain pro-inflammatory people from your life that are triggering? Is it possible to change jobs? Can you find more time for yourself or add more relaxation techniques such as walking, meditation, or spending time in nature? Can you work on being kinder to yourself, giving yourself more vitamin R & R (rest and relaxation)?

Try to focus on balancing blood glucose levels by getting enough quality fat, protein, and fiber. Be sure to increase your intake of folate, magnesium, and sulfur-rich veggies, such as broccoli, Brussels sprouts, kale, spinach, and cauliflower. Also, increasing your intake of Vitamin D, which acts as a pro-regulatory hormone in the body, can reduce inflammation and support immune cell production (7, 8).

You should also prioritize sleep, ideally getting to bed before 10:00 PM and aiming for 7-9 hours of sleep per night. Acupuncture, low-intensity exercise, and even nature therapy (such as grounding or forest therapy) can all effectively support the HPA axis (15).

Summary

The Hypothalamic-Pituitary-Adrenal (HPA) axis is the major neuroendocrine mediator of the stress response. It regulates stress, energy metabolism, immune function, and neuropsychiatric function. Factors such as stress, inflammation, and nutrition can all influence the HPA axis. Lifestyle factors such as stress modulation, improving sleep, and focusing on the diet can all be positive ways to support the HPA Axis. You can also consider running a few functional labs to assess your cortisol levels and overall stress response to help create a more individualized protocol.