Stress, HPA axis, Cortisol & Immune System

HPA Axis = Hypothalamus, Pituitary, Adrenal Axis.

ACTH = adrenocorticotropic hormone (released by the Pituitary gland)

CRH = corticotropin releasing hormone (released by the Hypothalamus)

GR = glucocorticoid receptor (Cortisol receptor in the Pituitary gland cells, also present in all cells in the body)

Cortisol = stress hormone (released by the Adrenaline gland)

The above are the main endocrine components and hormones involved in the detection and management of stress. The final product of the HPA axis is the release of Cortisol. Other systems in the body including the Immune system receive cortisol as the primary stress hormonal input. 

There are several sources of stress. You have the everyday stress of doing chores in the home, crossing the road, dodging traffic, phone not working, etc . This type of stress is acute and only stays for a short period of time. Then you have long term stress such as stress at work, studying for board exams, worrying about money etc. You also have involuntary stress from within our body such as being diabetic, having hypertension or even having a headache. All of these are stresses, many are acute (short term) some are chronic (long term).

Stress is perceived first in the neuronal cells of the hypothalamus in the brain as a response to increased neurotransmitter (particularly dopamine) activity. The hypothalamus releases CRH into the pituitary gland. The pituitary gland responds with releasing ACTH into the blood. The adrenaline gland downstream detects the increase in ACTH and responds by secreting cortisol. Cortisol then flows in the blood to the pituitary and binds to the GR in the pituitary. Cortisol also binds to GR in all the other body cells as well. Binding of cortisol to GR regulates ACTH production. So, a negative feedback loop is established between the GR in the pituitary and the cortisol secretion in the adrenaline. ACTH and cortisol modulate the secretion of each other until the stress is alleviated and the hypothalamus decreases its CRH secretion. The binding of cortisol to receptors (GR) in the rest of the organs, glands and tissues activates a host of systems to cope with the stress. One of these systems is the immune system.

This is the mechanism by which cortisol gets elevated and then dissipates in the blood in response to a stress. This is called ultradian cortisol rhythm in the sense that rhythm comes and goes with stress.

There is another cortisol rhythm which is a 24 hour circadian rhythm. This goes on and on every day. In the morning, the pituitary releases ACTH and the adrenaline responds by releasing cortisol and slowly but steadily cortisol keep rising during the day. In fact we won’t wake up if the stress hormone cortisol doesn’t rise in the morning. During the evening ACTH goes down and so does cortisol and then we are able to go to sleep. This is called the circadian cortisol rhythm. When there is a stressor, the ultradian rhythm is superimposed on top of the circadian rhythm.

What I have described is a simplified system model of how the HPA axis works. I have left out the details of how various receptors work both in the adrenal glands and in the pituitary. This would require a more detailed understanding of cell structure and functions such as cell membranes, cell receptors, enzyme production, cytosol, endocytosis, exocytosis, channels and so on. The important thing to note is that a lot of enzymes and other proteins are involved in the production of hormones. The hormones themselves are derived from cholesterol. The enzymes act as catalysts in the biochemical reactions that produce these hormones from base cholesterol. If you thought cholesterol was always bad, think again. Cholesterol is the precursor to most hormones including testosterone, progesterone, estrogen and cortisol. These enzymes and proteins are the products of gene expression, whereby genes are translated into proteins (amino acid chains) in the ribosomes of the cells. In the case of ACTH and cortisol the necessary enzymes are produced in the cells of the pituitary and adrenal glands.

So what happens to this system when there is long term stress? Cortisol will remain elevated. This over time desensitizes the GR in the pituitary and the feedback loop between ACTH and Cortisol is no longer effective. The HPA axis feedback systems become dysregulated. The long term effect will be a reduction in base cortisol levels. Disease conditions can manifest when cortisol remains high for a prolonged period or when cortisol remains low due to dysregulation of the HPA axis. Disorders such as chronic fatigue syndrome, anxiety disorders, depressive disorders, digestive system disorders, and even autoimmune disorders can develop. The circadian cortisol rhythm can get out of regulation and can result in sleep disorders.

The HPA system can be mathematically modeled with linear and nonlinear differential equations. Such modeling can provide quantitative analysis of a functioning or nonfunctioning HPA axis. But the difficulty in mathematical modeling is in the calculation of the coefficients of these equations. These coefficients are mostly determined by enzyme activity and in turn by gene expression. So they vary from person to person. It is not important to understand the detailed mathematics or the details of all the biochemical reactions. Suffice to say that it helps scientists understand the stability of the HPA axis.

Mathematically speaking the HPA system is a bistable system with an unstable trajectory between the two stable regions. The good stability region is the solution space where cortisol responds normally to increase or decrease of ACTH and vice versa. The bad stability region is where cortisol remains low due to the reduction in GR activity. In the unstable region in between, the HPA axis behavior is that of a chaotic nonlinear system. Bistable behavior of the HPA axis has been confirmed in rodents by measurement of serum cortisol and ACTH measurements over a period of time. CRH levels in the serum are not indicative of the CRH directly dumped into the pituitary from the hypothalamus. 

When cortisol remains low, and does not respond to stress, the immune system will malfunction. Cortisol is a basic input for the normal functioning of the immune system. Long term stress desensitizes the production of cortisol by the adrenaline and thus impairs the immune system.

Short term stress is quite normal and we all experience such stress several times a day. Some acute stresses can come from an unexpected life crisis. Short term stress can be a lifesaver. It helps you be prepared for the daily tasks and navigate them successfully such as crossing the road, driving in traffic or cooking in the kitchen. Short term stress also aids athletes perform at their best levels.  During competition athletes produce a lot of cortisol that helps them improve their performance. But it is important that athletes like all of us relax and take rest to restore the cortisol to normal levels.

Prolonged long term chronic stress first elevates cortisol. Then after a prolonged period the HPA axis becomes desensitized and dysregulated. This reduces the level of cortisol. Chronic stress has a profound effect on the immune system. The level of long term stress that can be tolerated varies from person to person. 

The biochemical pathways by which cortisol gets involved in the immune system is a topic for a different blog. One biochemical pathway results in the modulation of gene expression including the gene responsible for inflammation. Long term stress resulting in bistable cortisol levels can result in alteration of gene expression that can be hard to reverse. 

The most recent recent research on dysregulation of the HPA axis due to prolonged stress can be found in the following paper from biologists at the Weizmann Institute of Science in Israel. As you can see the HPA axis is modeled using differential equations.The simulation of the equations shows how the axis can become dysregulated and lose functionality.

https://www.biorxiv.org/content/10.1101/2020.01.01.892596v1.full.pdf