Stress and the HPA Axis: A Review for the Busy Practitioner
If you have been out of school for a while, have been too busy to pull out that textbook, or want to brush up on some Biomed analogies, terms and research concerning the Hypothalamic-Pituitary Axis, then this article is a good place to start.
Stress and the HPA Axis: A Review for the Busy Practitioner
By: Stacy Frerking, L.Ac.
If you have been out of school for a while, have been too busy to pull out that textbook, or want to brush up on some Biomed analogies, terms and research concerning the Hypothalamic-Pituitary Axis, then this article is a good place to start. Memorize a few interesting facts to add to your repertoire of “Western talk” to suffice a patient’s curiosity that you can converse in both worlds of medicine.
“Appropriate regulatory control of the hypothalamo-pituitary-adrenocortical stress axis is essential to health and survival” noted Herman and Cullinan (2003).
The HPA axis and cortisol play roles in maintaining homeostasis when the body is under stress, short or long term. Carbohydrate, protein and fat metabolism, obesity challenges, mood, reproduction, inflammation, and gender differences will be covered in this article, with regard to how they are affected by cortisol and the HPA axis.
The body is always trying to maintain homeostasis and adapt to the environmental changes around it. However, when outside or internal stressors occur, the body has to react, and it does so by way of linear reactions. Kloet, Joels, and Holsboer (2005) note that when under stress the brain stimulates the release of neuropeptides that lead to feedback on the brain via the release of corticosteroid hormones via the adrenals.
Functioning in a binary fashion, corticosteroids control the responses that allow for behavioral adaption by way of neurons. Physical, emotional or chemical stress, real or perceived, large or small, can be influenced by previous life experiences and learned personal coping mechanisms. Each individual handles their perceived or real stress in a unique way. This is similar to the way the hypothalamo-pituitary-adrenal stress response integrates the interactions received from the PVN, paraventricular nucleus, housed in the hypothalamus, and the portions of the brain wired to handle stress circuits (Herman and Cullinan, 1997).
“The main components of the stress system are the corticotropin-releasing hormone and locus ceruleus-norepinephrine/autonomic systems and their peripheral effectors, the pituitary-adrenal axis, and the limbs of the autonomic system. Activation of the stress system leads to behavioral and peripheral changes that improve the ability of the organism to adjust to homeostasis and increase its chances for survival” (Chrousos and Gold, 1992). In response to stress, the neuroendocrine system tries to balance social behavior and reproduction to allow for homeostasis; Viau, 2002, explains the link. “Basal adrenocorticotropic hormone (ACTH) release is regulated by testosterone-dependent effects on arginine vasopressin synthesis, and corticosterone-dependent effects on corticotropin-releasing hormone (CRH) synthesis in the paraventricular nucleus (PVN) of the hypothalamus. In contrast, testosterone and corticosterone interact on stress-induced ACTH release and drive to the PVN motor neurones.
Candidate structures mediating this interaction include several testosterone-sensitive afferents to the HPA axis, including the medial preoptic area, central and medial amygdala and bed nuclei of the stria terminalis. All of these relay homeostatic information and integrate reproductive and social behaviour.”
HPA axis plays a major role in the regulation of the neuroendocrine system. The brain stem and hypothalamus have neurons that control the central HPA axis.
The locus ceruleus being noradrenergic (nerve impulses are sent by norepheniphrine), in the brainstem, activates the HPA, responds to stress, and is involved in REM sleep. The dorsal rahpe has a large number of cortisol receptors and is mostly serotonergic in action, which means serotonin is involved in the stimulation of the nerves. The PVN, paraventricular nucleus, in the hypothalamus has neurons that project into the pituitary gland and help with the regulation of the HPA.
According to Lightman (2008) the neuroendocrine response is capable of altering its output based on current needs, as well as demands that the body might have to face in the future. “The release of CRH and AVP activates pro-opiomelanocortin in anterior pituitary corticotroph cells and the release of adrenocorticotrophic hormone into peripheral blood from where it targets receptors in the adrenal cortex to release glucocorticoid hormones.
These hormones (i.e. corticosterone in the rat and cortisol in man) are released in a pulsatile ultradian pattern which defines the normal circadian rhythm. The frequency of the pulses is increased under states of chronic stress, and in rats with genetically determined hyper-responsiveness of the hypothalamic-pituitary-adrenal axis” noted Lightman (2008). The article was called “The neuroendocrinology of stress: a never ending story.” That title explains so clearly how stress is a constant repetitive motion that challenges the body to alter, adapt, and survive.
One way the body does this is when blood glucose levels drop. This triggers the hypothalamus to release Corticotropic Releasing hormone (CRH). ACTH, Adrenocorticotropic hormone, is then released from the anterior pituitary, also known as the adenohypophysis. (Not only does the adenohypophysis release ACTH, but it also releases TSH, PRL, GH, FSH, LH, and beta endorphins. The posterior pituitary is responsible for secreting oxytocin and ADH. These nine hormones help the endocrine system maintain homeostasis via their connection to the hypothalamus.) The ACTH targets the adrenal cortex, which is home to cortisol and DHEA.
The resulting increase in cortisol, allows for an increase in fats and protein in the blood stream, which causes blood glucose levels to rise and allows the body to return to homeostasis. The hypothalamus, the connection between the nervous system and the endocrine system, also keeps a check on cortisol levels in the bloodstream, and if they decrease too much the same pathways are stimulated, as previously mentioned, to increase cortisol secretion from the adrenal cortex by way of the release of CRH and ACTH. To inhibit the production of too much cortisol, the negative feedback loop comes into play by relaying to the anterior pituitary to stop production of ACTH. Cortisol can also go straight to the hypothalamus and decrease production of CRH. The anterior pituitary, protected by the sella turcica in the sphenoid bone, also can decrease production of CRH.
There are three pathways for reaching the hypothalamus, and controlling the amount of circulating cortisol in the bloodstream. This is the process for the HPA axis to help with the regulation of hormones and the traditional response to stress.
“At least 95 per cent of the glucocorticoid activity of the adrenocortical secretions results from the secretion of cortisol, known also as hydrocortisone. In addition to this, a small but significant amount of glucocorticoid activity is provided by corticosterone” ( Guyton and Hall, 1996).
As stated by McPhee and Papadakis (2010) , “Cortisol is a steroid hormone that is normally secreted by the adrenal cortex in response to ACTH. It exerts its action by binding to nuclear receptors, which then act upon chromatin to regulate gene expression, producing effects throughout the body.” Guyton and Hall (1996) noted that the adrenal cortex has over 30 steroid hormones. However, the main mineralcorticoid, being aldosterone, and the chief glucocorticoid, cortisol, are the major players in steroid hormones. The chemistry of adrenocortical hormones can best be described by Guyton and Hall (1996) as the following:
“All the adrenocortical hormones are steroid compounds. They are formed mainly from cholesterol absorbed directly from the circulating blood by endocytosis through the cell membrane.
This membrane has specific receptors for the low-density lipoproteins that contain high concentrations of cholesterol, and attachment of the lipoproteins to the membrane promotes the endocytotic process. Small amounts of cholesterol are also synthesized within cortical cells from acetyl coenzyme A; this, too, can be used for forming the adrenocortical hormones.”
The adrenal cortex produces steroid hormones that are cholesterol based, making them fat soluble. They are therefore able to go into a cell’s nucleus and allow for transcription of the proteins inside the nucleus. The adrenal cortex has three layers surrounding the adrenal medulla.
The zona fasiculata makes up about 80% of the bulk of the layers and is the one responsible for cortisol production to increase glucose, this is possible by gluconeogenesis and glycogenolysis. The outermost layer, known as the zona granulosa (which is stimulated by potassium), produces mainly aldosterone, which is a mineralcorticoid, responsible for absorption of sodium and excretion of potassium and protons. Testosterone, among other androgens, are secreted from the zona reticularis, the innermost layer. When the adrenal cortex experiences imbalances, the homeostasis is disrupted and these diseases come about.
Addison’s disease is when none of the layers are working properly and a rise in potassium and metabolic acidosis occurs; this causes poor sodium absorption, a decrease in glucose from lack of cortisol, and low blood pressure.
Cushing’s disease occurs where there is too much ACTH being released from the anterior pituitary. Cushing’s syndrome could be from endogenous sources, the adrenals, pituitary, or some source outside the central nervous system. There would be a decrease in potassium and protons, while an increase in sodium causing a rise in blood pressure. Excess testosterone and cortisol also come into play, and the male characteristics that plague women with Cushing’s disease.
Guyton and Hall (2006) explain how Cushing’s disease is connected to stress:
“Stress also causes large quantities of corticotropin to be released by the anterior pituitary gland, and this in turn causes the adrenal cortex to secrete excessive quantities of glucocorticoids. Both the corticotropin and glucocorticoids activate either the same hormone-sensitive triglyceride lipase as that activated by epinephrine and norepinephrine or a similar lipase.
Therefore, this is still another mechanism for increasing the release of fatty acids from fat tissue. When corticotropin and glucocorticoids are secreted in excessive amounts for long periods, as occurs in the endocrine disease call Cushing’s disease, fats are frequently mobilized to such a great extent that ketosis results.
Corticotropin and glucocorticoids are then said to have a ketogenic effect.”
When the body is under short term stress (real or perceived), cortisol causes the following changes in the body: increases in mental focus, metabolism, blood pressure, strength, speed, blood sugar, and energy, and a decrease in the perception of pain. These are to accommodate the short term demands placed on the body when “fight or flight” occurs. These are normal responses to stress.
However, when the stress becomes chronic and does not get resolved, the body responds with symptoms that impede a healthy body. Long term stress and elevated cortisol can lead to the following: decreased thyroid function, slowed healing process, suppression of immune system, and increased blood pressure. Prolonged elevation of cortisol levels can also lead to increased bone density loss, possible depression, and an increased appetite. Weight gain, especially in the abdominal region, along with muscle loss in the limbs, is common.
Cortisol is vital for human life, but when cortisol levels are out of balance, unhealthy symptoms start to appear. Weight gain is one of the most commonly associated symptoms with imbalanced cortisol levels and stress. Cortisol levels stay elevated for as long as the adrenals have the raw materials and energy to maintain and make it.
Every person is different and once the body cannot handle the demands, cortisol levels decrease and adrenal fatigue can develop. Adrenal insufficiencies can be diagnosed by: orthostatic hypotension, cortisol levels (blood and saliva), melatonin levels, and DHEA levels.
Guyton and Hall (2006) state the reasons cortisol is released:
1. Trauma of almost any type
2. Infection 3. Intense heat or cold
4. Injection of norepinephrine and other sympathomimetic drugs
6. Injection of necrotizing substances beneath the skin
7. Restraining an animal so that it cannot move
8. Almost any debilitating disease.
These trigger the HPA axis to release CRH followed by ACTH and then cortisol from the adrenal cortex.
“When the body’s stores of carbohydrates decrease below normal, moderate quantities of glucose can be formed from amino acids and the glycerol portion of fat. This process is called gluconeogenesis.” (Guyton and Hall, 2006). Amino acids are converted to glucose in the liver cells by activation of liver cell nuclei, specifically DNA transcription from the glucocorticoids. The formation of glucose is possible when more amino acids become available in the blood stream from the extra-hepatic tissues. This is how cortisol effects the metabolism of carbohydrates. Cortisol effects protein metabolism by taking from cells everywhere in the body except basically the liver.
When cortisol levels are in excess, muscle weakness can occur because of the increase in catabolism, the breakdown of cells which gives an energy release, and the decrease in protein synthesis. Fat metabolism follows the same course as the protein did, but adipose tissue is activated instead of muscle. Then the plasma has an increase in fatty acid availability for fuel or energy by the body for use in times of stress.
Excess weight or obesity occurs when extraneous fat is deposited on the body due to an imbalance in energy input versus energy output. Pasquili (n.d.) stated that, “Excess cortisol increases lipoprotein lipase levels (a lipid storing enzyme) in adipose tissue and particularly in visceral fat.” “Despite the fact that cortisol can cause a moderate degree of fatty acid mobilization from adipose tissue, many people with excess cortisol secretion develop a peculiar type of obesity, with excess deposition of fat in the chest and head regions of the body, giving a buffalo-like torso and a rounded face, a ‘moon face.‘Although the cause is unknown, it has been suggested that this obesity results from excess stimulation of food intake, so that fat is generated in some tissues of the body more rapidly than it is mobilized or oxidized” (Guyton and Hall, 2006).
Cortisol, in excess, released from stress triggering the HPA axis, can cause the body to adapt by putting on weight. The body has to pay a price for adaptation, known as the allostatic load, and when the demand is too great the process can become diseased. One way to assess the allostatic load on the body is to measure cortisol. Cortisol measurements via saliva collections are much easier for patient compliance and ease of use. The saliva has 30-50% less cortisol than in the blood, but helps give an image of how the HPA axis is functioning (Pasquili, n.d.). Pathological changes in cortisol can be found by saliva collection because it looks at the concentrations of cortisol throughout the day. Chalew, Nagel, and Shore (1995) noted, “The hypothalamic-pituitary adrenal axis normally maintains the concentration of cortisol within a narrow range of diurnal variation characterized by higher cortisol concentrations in the morning and reduced levels in the evening.” Any variation of this, deficient cortisol in the morning or excess at night, can usually be correlated to symptoms like sleep problems, fatigue, weight imbalances, headaches, digestive abnormalities, trouble handling stresses of daily life, etc.
A study done by Peeters, Nicholson, and Berkhof (2003) focused on “Cortisol responses to daily events in major depressive disorder (MDD)”.
Trying to find out the mitigating effects the HPA axis, and consequently therefore cortisol had on individuals with MDD. MDD, according to the National Institute of Mental Health, is characterized by a combination of symptoms that interfere with a person's ability to work, sleep study, eat, and enjoy once-pleasurable activities. 47 depressed patients and 39 healthy participants were evaluated for whether cortisol response to positive and negative events differed as well as mood changes. The method for evaluation involved six consecutive days of saliva collection taken ten times daily, along with patient reports on how they perceived daily events and therefore their mood.
The results are as follows, “In contrast to healthy participants, depressed participants showed no increase in cortisol following a negative events. Responses were even more blunted in depressed participants with a family history of mood disorders...These results suggest that responses of the HPA axis to negative daily events and mood changes are blunted in MDD” (Peeters, Nicholson, and Berkhof ,2003).
Reproduction is something that is put on hold when fight or flight is activated. It is not necessary to escape the immediate danger. It returns to normal once the stress is eliminated. However if the stress is chronic, or perceived to never leave, then the body’s reproductive homeostasis is altered. Rivier and Rivest (1991) explain it as thus:
“The effects of stress on reproductive functions and the mechanisms mediating these effects depend on the type, duration, and frequency of the stimulus, as well as on the influence of the steroid milieu on adrenergic and opiate components that have an impact on the HPG axis. In particular, there is evidence that “the response of the pituitary-testicular system to aversive stimuli is potentially biphasic, with an initial stimulatory phase and, if the stress is prolonged or of sufficient magnitude, a subsequent inhibitory phase”. Though much remains to be done before we gain a better understanding of the mechanisms mediating the stress response of the HPG axis, there is strong evidence that the immediate changes in LH secretion are mediated at the level of GnRH-secreting neurons, while long-term effects also involve peripheral mechanisms such as alteration in pituitary and gonadal responsiveness. There is also little doubt that though the early effect of stress may, at least under some circumstances, be stimulatory, prolonged or severe stimuli are accompanied by both an increased activity of the HPA axis and a suppression of reproductive functions. This phenomenon may have adaptive importance, i.e., to “conserve energy during hardship”.
Cortisol can help prevent inflammation by either blocking the early stages of it or speeding up the healing process. Guyton and Hall (2006) summarize the five main stages of inflammation as such:
Chemicals (histamine, bradykinin, proteolytic enzymes, prostaglandins, leukotrienes) are released from the tissue cells that are damaged. These rev up the inflammation process.
Erythema, an increase in blood flow to the damaged area happens. Increased capillary permeability allows for leakage of plasma out of the capillaries resulting in non-pitting type edema. Leukocytes come on the scene, as a result of the immune system sending them in. After so many days or weeks, fibrous tissue starts to develop to aid in the healing process.
Cortisol responds to these phases of inflammation by stabilizing the lysosomal membrane, decreasing the permeability of capillaries, decreasing white blood cells in damaged area and phagocytosis, suppressing immune system, and decreasing fever. “That is, cortisol makes it much more difficult than is normal for the membranes of intracellular lysozymes to rupture.Therefore, most of the proteolytic enzymes that are released by damaged cells to cause inflammation, which are mainly stored in lysosomes, are released in greatly decreased quantity...Cortisol diminishes the formation of prostaglandins and leukotrienes that would otherwise increase vasodilatation, capillary permeability, and mobility of white blood cells...causing T lymphocytes reproduction to decrease markedly...reduces the release of interleukin-1 from white blood cells, which is one of the principal excitants to the hypothalamic temperature control system” (Guyton and Hall (2006).
Pasquali (n.d.) touches on the interrelation between gender differences and the HPA axis:
“Sex difference may exist in the response to chronic stress, particularly in those individuals susceptible to developing an abnormal allostatic load, which intrinsically implies a maladaptation (pathological) syndrome to chronic stress exposure, either internal or related to environmental factors. Intriguingly, these mechanisms may also imply derangements in the regulation of neuroendocrine and peripheral actions of sex hormones.”
Studies regarding the sex differences and cortisol are highly controversial and the data collected from them contradicts one another. Animal studies have also been done and consistently show higher glucocorticoid levels in females than in their male counterparts.
Genetics, psychological stress, metabolic and hormonal dynamics need to be looked at in more detail to further this area of study, and need to be in a longitudinal study.
In conclusion, the HPA axis, glucocorticoids (mainly cortisol), and stress pathways are all interrelated in their responses to the allostatic load placed on the body in response to a stimulus.
Homeostasis is the end goal, and the hypothalamic-pituitary-adrenal axis maintains this by the firing of the hypothalamus to the anterior pituitary to the adrenal cortex, to cause the adaptation needed to meet the demand placed on the body momentarily, or in the case of disease, extended periods of time.
Chalew S, Nagel H, Shore S. The hypothalamic-pituitary-adrenal axis in obesity. Obes. Res.
Chrousos G, Gold PW. The concept of stress and stress system disorders. JAMA.
De Kloet E. R., Joëls M., Holsboer F. (2005). Stress and the brain: from adaptation to disease.
Nat. Rev. Neurosci. 6, 463–475. doi: 10.1038/nrn1683.
Guyton, A. C., & Hall, J. E. (1996). Textbook of medical physiology. Philadelphia: Elsevier
Herman JP, Cullinan WE. Neurocircuitry of stress: central control of the hypothalamic-pituitary-
adrenocortical axis. Trends Neurosci. 1997;20:78–84
Herman JP, Figueiredo H, Mueller NK, et al. Central mechanisms of stress integration:
hierarchical circuitry controlling hypothalamic-pituitary-adrenocortical responsiveness. Front.
Lightman SL. The neuroendocrinology of stress: a never ending story. J. Neuroendocrinology.
McPhee, S. J., & Papadakis, M. A. (2010). Current medical diagnosis & treatment 2010. New
York: McGraw-Hill Medical.(p.1077).
National Institutes of Mental Health. (n.d.) What is Depression?. Retrieved July 28, 2013, from
Pasquali, Renato. (n.d.). The hypothalamic–pituitary–adrenal axis and sex hormones in chronic
stress and obesity: pathophysiological and clinical aspects. Blackwell Publishing Inc.
Peeters F, Nicholson N, Berkhof I. Cortisol response to daily events in major depressive
disorders. Psychosom. Med. 2003;65:836–841
Rivier C, Rivest S. Effect of stress on the activity of the hypothalamic-pituitary-gonadal axis:
peripheral and central mechanisms. Biol. Reprod. 1991;45:523–532
Viau V. Functional cross-talk between the hypothalamic-pituitary-gonadal and -adrenal axes. J.