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The theory that chronic stress contributes to the long-term, overall health of the human body was first publicly elucidated by Hans Selye in a 1950 British Medical Journal paper. Selye had observed a predictable pattern in the human biological response to stress, one that was focused on restoration of homeostasis.

He theorized that the amount of adaptive energy a body can devote to this process is limited in supply, and that exposure to the “fight or flight” initial hormonal reaction could, if continuous, cause a decline in that supply, leading to a variety of health concerns. (“Hans Selye’s general adaptation syndrome,” n.d.).

Note: It is imperative that individual responses to stress are identified prior to beginning a regimen of support for stress management and HPAT homeostasis. While all bodies do exhibit the same general hormonal cascade, the impact of our reactions varies widely and should be determined based on practitioner analysis of the individual patient.


  • An overview of the HPAT axis glands and their functions
  • A summary of the relationship between cortisol and DHEA
  • An explanation of how each stage of stress resistance (GAS stages) may present
  • An overview of how to support normal HPAT homeostasis with clinical nutrition



Fill out a downloadable PDF version of the guide you can reference later.


The HPAT axis is not a location, nor is it the compilation of the hypothalamus, pituitary, adrenal and thyroid glands. Instead, the axis is the complex set of reactions and interactions that occurs between these four glands. It is the compilation of all relevant relationships and signals. Because these interactions form a good portion of the neuroendocrine system, which also regulates digestion, immune function, emotional responses, sexual health and energy balance, the HPAT axis and its healthy function is incredibly important to overall feelings of wellbeing.

The axis influences glucose regulation, hormones, cytokines and more. Cortisol is often the primary focus of conversations about the HPAT axis, though other metabolic factors and contributions of the central nervous system and individual environment are also important. Continued cortisol release, a result of stress, affects the hypothalamic and pituitary feedback loops such that the axis may remain persistently activated. Cortisol is also the end product of activation. We know, then, that the nature of the relationship between cortisol and the axis is cyclical.



The adrenal functions regulate our responses to stress. The two main sections of the adrenal glands, the adrenal cortex and the inner adrenal medulla, have different actions. The adrenal cortex is comprised of three layers that include the sites of mineralcorticoid, glucocorticoid and sex hormone production. The inner medulla actually has a direct connection to the brain, a rarity among the hormone-producing glands, the others of which send messages about secretion through a chemical messenger in the bloodstream. (Walsh, 2009). The inner medulla produces the hormones that dictate our fight or flight response. The adrenal glands and the hormones they secrete have multiple effects on our bodies’ healthy functions.

An overactive or underactive set of adrenal glands will produce either excess or insufficient amounts of hormones respectively, especially cortisol. The health of the adrenal cascade depends on various nutrients, including the B vitamin complex. While larger (in proportion) quantities of vitamins B3, B5 and B6 are used in the adrenal hormone production process, B vitamins are known to work in concert, meaning a full complex is recommended for healthy function. Each of the eight vitamins in the complex is valuable during the adrenal cascade.

The adrenal gland boasts the highest concentration of vitamin C in the body. Interestingly, both the adrenal cortex and the medulla accumulate high levels of ascorbate. Ascorbic acid is a cofactor required both in catecholamine biosynthesis and in adrenal steroidogenesis.

With a decreased level of ascorbic acid available for the adrenal cortex and medulla, signs of depletion of catecholamine storage vesicles, signs of apoptosis, and increased glycogen storage have been observed. Further, decreased plasma levels of corticosterone and altered morphology of mitochondrial membranes were found. This underscores the critical nature of adequate vitamin C levels for optimal function of the adrenal gland (Patak, Willenberg, & Bornstein, 2004).



NOTE: The thyroid gland is not always included in the HPA axis. Historically, the HPT axis, where the T represents the thyroid gland, has been considered a separate set of complex interactions (between the hypothalamus, pituitary and thyroid glands) which regulates metabolic health. For the purpose of understanding how the neuroendocrine system responds to stress, we have chosen to include it in our understanding of the HPA axis. Just like the other components of the neuroendocrine system outlined in this paper, the thyroid gland affects our health and demands nutritional support for homeostasis. It’s also been suggested that the end product of the HPA axis activation, corticosterone, may play a role
in the regulation of the HPT axis.

The hypothalamus’ relationship to thyroid hormones is incredibly relevant to the the body’s ability to maintain hormone balance. The hypothalamus senses low circulating levels of thyroid hormones T3 and T4, and responds by releasing thyrotropin-releasing hormone (TRH). The release of TRH tells the anterior pituitary gland to produce TSH, or thyroid stimulating hormone.

TSH is the stimulating factor for the thyroid’s production of T3 and T4 (the thyroid hormones), causing blood levels to be restored. T3 and T4 then exert negative feedback over both the hypothalamus and the pituitary, thereby controlling the releases of TRH and subsequently, TSH. There are three areas of concern when we discuss the thyroid. The first is the health of the gland itself. The second is the nutritional support it demands. The third is the impact of stress hormones, which can cause increased reverse T3 and under conversion of T4 to T3, either due to liver function impairment or to a need for selenium in the diet.

The T4 the body produces is converted to reverse T3 in the liver, in order to rid the body of excess T4 (which is normally produced in about an 4:1 ratio.) The percentage of T4 that is converted to RT3 may increase when the body uses its energy for other functions, while T3 may decline.

Biological stress is one such use of energy. Excess cortisol, in fact, is known to inhibit conversion to T3, instead elevating RT3 production. (Its hypothalamic precursor, cortico-tropin releasing hormone, or CTRH, can also suppress TSH.) In this event, T3 and T4 levels can appear normal on a blood test, but the adrenal glands may still be experiencing both slowed function and increased stress (which can further slow function) due to low thyroid function. Low thyroid function also leads to an increase in cortisol-binding globulin, thereby making the cortisol inaccessible for use. So the cycle goes: low thyroid function leads to low adrenal function leads to low thyroid function. (Simpson, 2011, p. 83).

On the other hand, ongoing stress can also cause eventual depletion of cortisol production from the adrenals, meaning cortisol is low. Without that production, thyroid hormone blood levels are increased, demanding that the body respond. It does respond: with conversion, from T4 to excess RT3. So we see that excess cortisol production, which causes a high percentage of thyroid hormone to be converted to RT3, can also eventually cause depletion of cortisol production, which then causes the body to respond with elevated conversion of T4 to RT3.



Why is excess RT3 a Big Deal?


T3 is necessary for the body’s healthy metabolic function. RT3 is inactive but binds to T3 receptors, thereby blocking them from T3’s binding and resulting metabolic effects.

There are a few key nutrients that support healthy thyroid function that should be part of any successful HPAT support regimen.

The most well-known of these nutrients is iodine. It is necessary for our bodies to produce thyroid hormone.* Pregnancy in particular demands higher daily requirements for iodine intake, due to the fact that T4 production doubles in the gestation period.

It is important to bear in mind, though, that both diets high and low in iodine are associated with low thyroid function. That tells us that a diet high in iodine may only be useful when a deficiency is present.

Another mineral that affects thyroid function: selenium. Without selenium’s contribution to the enzymes that remove iodine molecules from T4, converting to T3, the thyroid hormone would never activate.* Some of the most important features of the mineral’s relationship to thyroid function

  • • Research has revealed that patients with varied thyroid concerns tend to exhibit lower
    selenium levels. Further, selenium plays a role in free radical scavenging, which is
    fortunate because thyroid cells generation hydrogen peroxide, a free radical, as part
    of their normal function, in order to make thyroid hormones.*
  • Selenium acts a balance to high iodine levels. It also supports normal efficacy of
    glutathione peroxidase, an enzyme whose inefficiency is linked to low thyroid function.*
  • A low thyroid state may be induced when, levels of T4, T3, TSH and selenium all decrease.
Zinc is important to thyroid function due to its relationship with conversion from T4 to T3.* In animal studies, researchers found that zinc deficiency significantly lowered T3 and free T4 concentrations, though total T4 levels remained unaffected (Kralik, Eder, & Kirchgessner, 1996). Though zinc deficiency is rare in the united states, though about 20-25% of adults have inadequate zinc intake (National Institutes of Health, 2019).
Zinc, though, just like iodine, could suppress function of the thyroid if the amount of zinc in the body is too high. (Taneja & Mandal, 2008). Taking copper and zinc in concert is advised, as high zinc doses can disrupt copper absorption.
Copper deficiency depletes the hypothalamus’s ability to regulate thyroid hormone. In one rat study, mothers who were copper deficient produced infant rats who produced 48% less T3 than rats from mothers without such a deficiency (Bastian, Prohaska, Georgieff, & Anderson, 2010). Copper
deficiency is very rare in the United States.
Elements aside, some vitamins also have important supportive actions for thyroid function. Vitamin E acts as a free radical scavenger.* Oxidative stress is an effect of low thyroid function, so it’s important to support oxidative balance.*
Vitamin B12 may also be considered a key nutrient to support the thyroid’s healthy function. The link between B12 deficiency and lowered thyroid function has not been fully elucidated.


A deficiency in iron also interferes with hormone production through reduced thyroid peroxidase activity. And while the etiologies of iron deficiency are many, one of the more common presently involved gluten. The prevalence of iron deficiency in the United States is around seven percent (Looker et al., 1997).


T3 and T4 have other important connections in the body, such as their influence on gut health through their protection of gut mucosal lining, which has been proven in conditions of stress-induced ulcer formation.(Koyuncu et al., 2002). Further, TSH and TRH both influence the development of a large portion of the immune system contained in the gut, called GALT (Kresser, n.d.).

Yet another thyroid-gut connection exists in the gut bacteria’s relationship with T4 and T3. Gut bacteria assist in the conversion from T4 to T3, which makes sense because about 20% of that conversion occurs in the GI tract, in T3 sulfate (T3S) and triidothyroacetic acid (T3AC) forms. Their conversion to active T3 is dependent on an enzyme called intestinal sulfatase. That enzyme comes from the presence of healthy gut bacteria. An imbalance in the gut can reduce the conversion of T3S and T3AC to active (Stratakis & Chrousos, 1995), a possible explanation for why people with unhealthy guts may have thyroid symptoms despite normal lab results.

Finally, gut inflammation contributes to reduced active T3 through increasing cortisol (Braverman & Stockigt, 1997).

All of this means that to support healthy gut function and healthy thyroid function, the two should be addressed in concert.(Kresser, n.d.).


Cortisol has one main role: release glucose into the bloodstream to effect the fight or flight response. It also has many other roles, in suppression and modulation of the digestive, reproductive and immune systems. (“hypothalamic-pituitary-adrenal (HPA) axis,” n.d.).

Simply knowing that excess cortisol eventually may lead to low cortisol tells us just how important balance is. But cortisol doesn’t stand alone in the body. In fact, maintaining its proper ratio with DHEA is considered one of the major balancing acts of human biology.

DHEA and cortisol are both synthesized from the master steroid hormone, pregnenelone (derived from cholesterol). DHEA is a testosterone and estrogen precursor produced in the adrenals. It acts antagonistically to cortisol, meaning maintenance of the ratio between the two is an obvious health goal.* If adrenal function is low (perhaps due to stress/elevated cortisol), a resulting imbalance is likely. Writes Kathleen McCormick for Connections, a publication of Women’s International Pharmacy: “The link between cortisol production and DHEA is an important one because, with high cortisol levels, the ability to produce DHEA diminishes. One of the most significant effects of restoring DHEA seems to be the restoration of the normal balance between DHEA and cortisol. As DHEA levels increase, the propensity to overproduce cortisol is dampened.” (McCormick, 2012).

From a clinical perspective, we may find that if cortisol levels are elevated at night, the body will exist in a catabolic state (the mechanism behind this lies in the fact that nighttime cortisol levels will impair the body’s ability to release adequate growth hormone levels necessary for repair and rebuilding body tissues).

The brain may also fall victim to elevated cortisol levels. A recent series of studies was published by Daniela Kaufer, UC Berkeley associate professor of integrative biology, and the findings suggested that chronic stress and elevated levels of cortisol can generate more overproduction of  ligodendrocytes and fewer neurons than is necessary for optimal function. This was specific to the hippocampus, a part of the brain which ‘regulates memory and emotions, and whose size and functionality has been known to affected under extended periods of acute stress’. Long-term, chronic stress, however, also resulted in a potentially damaging overproduction of the myelin while decreasing the number of stem cells that mature into neurons (Chetty et al., 2014).

The immune system can also be affected by altered cortisol/DHEA levels, in particular the surface of the mucosal lining, which acts as a first-line immune defense. This barrier function, specifically the modulation of the production and turnover of immunocytes (plasmacytes) which produce antibodies (secretory IgA or sIgA), is dictated by the both cortisol and DHEA. When cortisol is elevated and DHEA is low, sIgA output is suppressed. This was demonstrated in a study in 2009 in Stress & Health Journal.

It was found that the sIgA decrease significantly correlated with the cortisol rise during the 20 min after the stress induction. (Stress and Health HYPERLINK “http://onlinelibrary.wiley.com/doi/10.1002/smi. v25:2/issuetoc” Volume 25, Issue 2, pages 189–194, April 2009)

When observing patients physical traits, one may theorize a cortisol/DHEA imbalance based on excess adiposity around the hips, thighs and/or waist. This pattern presents in the absence of overt obesity and should be considered along with symptomology and appropriate diagnostic testing. However, when patients complain of exhibiting abnormal energy levels and referring to themselves as ‘wired and tired’ and display this pattern of weight gain, there is a strong likelihood of a need to balance cortisol and DHEA levels.*

Understanding cortisol and its many effects on health is crucial to the HPAT axis conversation, as HPA axis activation results, ultimately, in increased blood levels of cortisol at times of stress.





In his 1950 paper, Hans Selye theorized that the body’s continuous stress response could cause major health concerns. He coined the body’s response to prolonged stress “GAS,” or General Adaptation Syndrome, and identified three stages of stress resistance associated with this response: alarm, resistance and exhaustion.


When your older brother jumps out from behind a door to scare you, your reaction occurs in the alarm stage. Do you punch him? Do you run? Do you scream? The fight/flight/freeze reactions occur as axis activation occurs. Cortisol, adrenaline and noradrenaline are released, giving you the energy to address the threat. Too much of this energy, without expenditure through physical activity, can be harmful. Symptoms of early stage stress include anxiousness, a high pulse, and a “tired but wired” feeling.

Important nutrients:
Ashwagandha - Active constituents are withanolides which serve as important hormone precursors
that can convert into human physiologic hormones as needed*
L-Theanine - Supports GABA levels through its action as an excitatory neurotransmitter antagonist*
Magnolia - Supports the inhibitory neurotransmitter effect at the level of the GABA receptor site*
Phosphatidylserine - Supports metabolism and stimulation of acetylcholine production*



When the source of the stress is potentially resolved, the body moves into the resistance phase. While stress hormone levels may have returned to normal values, the amount of adaptive energy the body has to use may leave the body with diminished defenses. Should the condition of stress persist, the body will remain aroused. Without proper recovery (for example, if the body is inaccurately perceiving constant threats), the body moves into the exhaustion phase.

Important Nutrients:
Rhodiola - Restores the normal sensitivity of cortisol receptors by modulation of stress activated
protein Kinase which ultimately supports healthy cortisol levels*
ETAS™ (Proprietary extract of Asparagus officinalis) - Increases the production of HSP70, which
supports cell structure and repair and the balance of excitatory and inhibitory cytokines*
Ashwagandha - See above



The supply of adaptive energy has depleted and the body cannot resist, causing what we commonly
refer to as “burnout.” Because the late stage of GAS is the stage in which stress levels will stay
increased, the resistance stage is often considered the best point of nutritional intervention. Latestage
symptoms include low pulse, fatigue, impaired thinking and anxiousness.

Important Nutrients:
Eleuthero - Possibly supports the enzyme catechol-O-methyltransferase, which ultimately impacts the
body’s supply of catecholamines* (Braun & Cohen, 2015).
Vitamin B5 - B5 helps to produce co-enzyme A, which contributes to cellular respiration and the
breakdown of macronutrients for energy*
Vitamin B12 - B12 supports energy production, cell repair and the maintenance of our red blood cells*
Vitamin C - Directly involved in the production of cortisol in your adrenals*


A diet and lifestyle regimen that includes appropriate physical activity, nutritional factors and supplementation is the first step to supporting HPAT axis health and homeostasis.* DaVinci’s Thyroid, Adrenal and Estrogen Metabolism protocols are designed to support your patients as they work
toward balance.* The protocols include ingredients to promote restorative sleep, the health of energy recovery processes and cortisol/DHEA balance.*

Read our Clinical Protocol Guide to learn more about each ingredient and how to start your patients on the path to a healthy HPAT axis and stress response. 



Adrenal Benefits™ is a dietary supplement to support adrenal function, energy levels and endocrine balance.*This botanical and glandular combination product is geared toward supporting adrenal function by supporting healthy energy levels, HPA axis and endocrine balance, as well as by nourishing the adrenal glands themselves.