The HPA axis and panic/anxiety: What you need to know

by | Sep 27, 2009

Buckle your seat belts because we’re going to zoom through the action of the HPA axis. It’s a major player in panic and anxiety, so we need to understand what it is, what it does, and how it does it. Let’s bone up…

…cortisol preps us for action by stimulating norepinephrine (noradrenaline) so it’ll flip the switch on our fight/flight response.

I love learning about the anatomy and physiology of the mood and anxiety disorders. Understanding at least a portion of why I think, feel, and behave as I do is comforting.

Is that how it is for you?

The HPA axis involves the interaction of the brain’s hypothalamus and pituitary gland, as well as the adrenal glands, located atop each kidney.

These pieces of anatomy work together to regulate vital functions and states such as stress response, mood, digestion, immune response, sexuality, and energy usage.

Physiology of the HPA axis

The only way to capture the purpose and functioning of the HPA axis is to become familiar with some physiology. Let’s take a look…

Corticotropin-releasing hormone (CRH)

Also referred to as corticotropin-releasing factor (CRF), it’s produced and secreted by the hypothalamus and deeply involved with our autonomic and behavioral responses to stress. CRH stimulates the pituitary gland to secrete adrenocorticotropic hormone (ACTH).

Scientists have suggested that the biochemical fallout of CRH hypersecretion is a major factor in depressive presentations. And though studies have yet to produce evidence showing consistent changes in CRH concentrations in the cerebrospinal fluid of those enduring panic and anxiety, preclinical research indicates such evidence may be just around the corner.

Adrenocorticotropic hormone (ACTH)

Secreted by the pituitary gland, ACTH stimulates the adrenal glands to ramp-up production of the mineralocorticoids and, of particular interest to us, the glucocorticoids.


Produced in the adrenal glands, this family of steroids is necessary for the regulation of energy metabolism, as well as immune and inflammatory responses. Cortisol is responsible for the vast majority of glucocorticoid activity.


Produced in the adrenal glands, and referred to as the “stress hormone,” this glucocorticoid is best known for sparking our physical response to stress. Motivated by stressors such as upsetting life events, trauma, excessive exercise, anxiety, and depression, cortisol preps us for action by stimulating norepinephrine (noradrenaline) so it’ll flip the switch on our fight/flight response.

Obviously, situational secretion of cortisol is natural and necessary; however, when it’s secreted in the presence of chronic stress, there may be troubling consequences, including high blood pressure, hardening of the arteries, diabetes, immune system inhibition, muscle atrophy, and osteoporosis.

Feedback loops, maintaining a balance, dysregulation

what causes panic attacks

HPA axis

The HPA axis is big on feedback loops. What are they? Most any system, biological or otherwise, has input and output capabilities. When the output of a system in some manner loops back to the system as input, and influences its functioning, a feedback loop has been established.

A positive feedback loop increases system output, a negative feedback loop decreases it.

With that under our belts, just as cortisol initiates a positive feedback loop by stimulating the activation of our fight/flight response, it creates a negative feedback loop by sending a signal to the hypothalamus and the pituitary gland to chill out.

This serves to inhibit the production of CRH in the hypothalamus and the production of ACTH in the pituitary gland, leading to stable levels of cortisol. It also reduces noradrenergic (having to do with norepinephrine) activity, making us less anxious.

Maintaining a balance

So, really, this is all about a cortisol checks and balances system. And given the negative impact of chronically hypersecreted cortisol, that’s a good thing.

But never, ever forget about the positive feedback loop created as cortisol signals norepinephrine and epinephrine (adrenaline) to get busy.

And that’s because the result will be increased production of CRH, ACTH, and yet more cortisol. Just what we need, right? Oh, our fight/flight response will be switched on as well. You think all of this may trigger a bit of panic and anxiety?

Now, in those who don’t deal with panic and anxiety, the noradrenergic system and the HPA axis work in harmony through, as we discussed, feedback loops. This maintains a sense of stress balance. When everything is operating by design, as activity in the noradrenergic system increases, activity in the HPA axis follows suit.

However, in those of us who endure panic and anxiety, this delicate balance is interrupted by chronic and/or situational overproduction of norepinephrine, which messes up the whole works.

As a result, the HPA axis is cut off from any and all noradrenergic activity, leading to an unmanaged increase in stress.


Dysregulation refers to the inability of a neural system to maintain a balance of its intended neurotransmitter activity. Well, noradrenergic activity in those dealing with panic and anxiety is theorized to be highly susceptible to dysregulation. And that’s because of the funny business in the previous paragraph.

In many cases, the selective serotonin reuptake inhibitor (SSRI) antidepressants are effective in the treatment of panic and anxiety. It may well be due to normalization of a “dysregulated” noradrenergic system by the enhancement of serotonergic (having to do with serotonin) activity.

Remember, as serotonin levels rise, levels of norepinephrine fall.

That’ll do it

No doubt, the HPA axis is a huge factor in the generation of panic and anxiety. And if you’re like me, you take comfort in understanding a portion of why you think, feel, and behave as you do.

As always, knowledge is power.

HPA axis image credit: Roberto Osti. Be sure to visit his fascinating website.

Would you like to learn more about the anatomy and physiology of the mood and anxiety disorders? Be sure to read Panic attacks, anxiety, and the limbic system: The paradox of protection.

More Chipur mood and anxiety disorder info and inspiration articles? Hit the titles.

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