HPA axis [hypothalamic-pituitary-adrenal axis]

The HPA axis, or hypothalamic-pituitary-adrenal axis, is a complex set of interactions between the hypothalamus, pituitary gland, and adrenal glands.

It plays a critical role in regulating stress responses, mood, digestion, immune function, and energy storage and expenditure in the body.

The pathway of the axis results in the production of cortisol, the body’s main stress hormone. Cortisol keeps that energy flowing.

The stress response aims to provide energy for an extended period of time. It does not need to be fast, so it uses hormones to transmit signals.

What Is the HPA Axis?

The HPA axis is a communication network that links your brain to your adrenal glands. It includes three main parts:

• Hypothalamus: Located at the base of the brain, it detects stress and releases a hormone called corticotropin-releasing hormone (CRH).
• Pituitary Gland: Triggered by CRH, it sends out adrenocorticotropic hormone (ACTH).
• Adrenal Glands: Sitting atop your kidneys, they respond to ACTH by releasing cortisol, the primary stress hormone.

Together, these organs help regulate stress, energy levels, digestion, mood, and the immune system.

How Does the HPA Axis Work?

When your body encounters a stressor, it triggers two responses.

First, within seconds, the sympathetic nervous system triggers the adrenal medulla, the inner core of the adrenal gland, to release epinephrine and norepinephrine directly into the bloodstream. This causes immediate physical changes like increased heart rate.

About 10 seconds later, the HPA axis activates, providing a longer-term stress response.

Imagine you’re about to give a presentation. Your body prepares in two stages:

1. Immediate Response: Your sympathetic nervous system kicks in, increasing your heart rate and alertness.
2. Sustained Response: A few seconds later, the HPA axis activates, gradually releasing cortisol to maintain energy and focus.

HPA Axis and the Fight-or-Flight Response

The fight-or-flight response has two parts. The sympathetic-adrenal-medullary (SAM) system triggers the body’s immediate reaction to danger—releasing adrenaline and noradrenaline within seconds to increase heart rate and alertness.

The HPA axis, in contrast, kicks in a little later. It releases cortisol to help the body sustain energy, focus, and vigilance during prolonged stress. Together, these systems coordinate your full biological response to threats.

The HPA axis follows a cascade of hormone releases:

1. The hypothalamus releases Corticotropin-Releasing Hormone (CRH), the main regulator of the stress response.
2. CRH travels to the anterior pituitary gland, triggering it to release Adrenocorticotropic Hormone (ACTH) into the bloodstream.
3. ACTH reaches the adrenal glands and binds to the outer layer (adrenal cortex), specifically the zona fasciculata region.
4. The adrenal cortex then produces and releases cortisol into the bloodstream.

Cortisol and the Negative Feedback Loop

The HPA axis uses a negative feedback loop to maintain homeostasis—your body’s internal balance. When cortisol levels rise, receptors in the hypothalamus and hippocampus detect the increase and signal the system to stop producing more. This prevents overstimulation and helps your body return to a steady state after stress.

The hippocampus plays an outsized role in this brake. It is rich in cortisol receptors and normally helps shut the stress response down.

But the hippocampus is also vulnerable to prolonged cortisol exposure. This sets up a self-reinforcing spiral: chronic stress raises cortisol, high cortisol damages the hippocampus, and a weakened hippocampus applies a weaker brake, letting cortisol climb even further.

Selye’s General Adaptation Syndrome

Long before scientists mapped the HPA axis, physiologist Hans Selye proposed that the body meets any prolonged demand with the same coordinated pattern. His general adaptation syndrome (GAS) is the historical model that the HPA axis later explained mechanistically. It remains one of psychology’s most influential stress theories.

Selye’s Stress Study

Aim: Selye wanted to know whether the body’s response to noxious demands was specific to each stressor, or a general, stereotyped reaction common to all of them.

Method: Selye noticed that rats injected with ovarian extracts in the 1930s developed the same physical changes no matter what was injected. The trigger did not matter. He spent the next four decades testing many aversive stimuli, including extreme heat, cold, forced exercise, toxins, and surgical injury (Selye, 1956).

Results: Whatever the stressor, the same triad appeared. The adrenal glands enlarged, the thymus and lymphatic tissue shrank, and ulcers developed in the digestive tract.

Selye described three stages. An alarm reaction, where the body mobilizes its defenses, is followed by a stage of resistance, where arousal falls from its peak but stays elevated. Finally, a stage of exhaustion sets in, where prolonged resistance depletes the body’s resources.

Conclusion: Selye’s conclusion was simple. Living organisms have an innate drive to defend their internal balance against demand, and it is the wear of prolonged defense, not the stressor itself, that produces stress-related illness.

Evaluating the GAS Model

The GAS was a landmark. It established stress as a measurable physiological process and pointed research toward the pituitary-adrenal system that the HPA axis later mapped in full.

Its central weakness is the claim that the stress response is non-specific. Later research found that different stressors produce different physiological signatures: psychological challenges tend to raise adrenaline, while physical challenges raise noradrenaline.

The model also rests heavily on animal research. It says little about psychological appraisal, the process of judging whether an event counts as stressful in the first place. Later transactional models of stress were built specifically to fill that gap.

Modern accounts keep Selye’s staged, cumulative-cost insight. They replace his claim of a single non-specific response with a more differentiated, appraisal-sensitive picture.

HPA Axis Dysfunction

Sometimes, chronic stress, trauma, or certain medications can disrupt the HPA axis. This dysfunction affects how your body produces and regulates cortisol.

Common Signs of Imbalance:

• Persistent fatigue
• Difficulty coping with stress
• Mood swings or irritability
• Trouble sleeping or concentrating
• Weakened immune system

Health Conditions Linked to HPA Dysregulation:

• Cushing Syndrome: Caused by too much cortisol, often due to prolonged steroid use or tumors.
• Depression and Anxiety: Irregular cortisol levels can affect brain regions involved in mood and memory.
• PTSD: Trauma can alter how the HPA axis responds to stress.
• Alcohol Dependence: Cortisol may interact with the brain’s reward system, increasing vulnerability to addiction.

Keeping the HPA Axis Regulating Normally

Maintaining balance in your HPA axis is essential for long-term physical and mental health. Here’s how to help your body stay regulated:

Medical Treatments:

• Medications for hormone-related conditions like Cushing syndrome
• Antidepressants or anti-anxiety drugs that normalize cortisol levels

Researchers are also testing drugs that target the axis directly. Early trials of the glucocorticoid receptor blocker mifepristone eased psychotic symptoms in severe depression (Belanoff et al., 2002).

A separate trial of a CRH-receptor blocker reduced depressive and anxiety symptoms in its first patients (Zobel et al., 2000). Neither is a first-line treatment yet, but both show that each link in the cascade is a potential drug target.

Therapeutic Approaches:

• Cognitive Behavioral Therapy (CBT): Helps reframe stressful thoughts and improve resilience.
• Biofeedback: Teaches control over bodily stress responses using real-time feedback.

Lifestyle Changes That Help:

• Regular aerobic exercise
• Consistent sleep schedule
• Balanced diet to stabilize blood sugar
• Relaxation techniques like meditation, deep breathing, and yoga

Why the HPA Axis Matters

The HPA axis is more than a stress switch—it’s central to your health. When it’s working well, you feel energized, calm, and focused.

When it’s not, everyday challenges can feel overwhelming. By understanding and supporting this system, you can build resilience and improve both mental and physical well-being.

Critical Evaluation of the HPA Axis

The HPA axis is a well-mapped biological mechanism, but it is not the whole story of stress and mental health.

Strengths and Limitations

Strengths. The HPA axis gives a clear, well-mapped biological mechanism linking a psychological stressor to a measurable hormonal output. Cortisol offers a convenient, objective marker of stress that has enabled decades of research on life events, coping, and health.

The axis also ties together phenomena that once looked unrelated, from Selye’s stress physiology to the biology of depression and PTSD, under one regulatory system.

Limitations. The picture is incomplete, though. A purely HPA-focused account leaves out the psychological appraisal and social factors that also shape whether an event feels stressful. Cortisol measures are also noisy, shaped by time of day, sex, and medication, so effect sizes here are often modest.

The evidence is also mostly correlational, so cause and effect are hard to untangle without experiments or genetically informative designs like twin studies.

Contemporary Research

Modern research asks not just whether the HPA axis is disturbed in mental disorder, but how. The direction of dysregulation turns out to depend on the disorder.

Depression and PTSD: Opposite Directions

In major depression, the HPA axis tends to be over-active. A systematic review and meta-analysis of adolescents found that elevated morning cortisol predicted the later onset of depression (Zajkowska et al., 2022). That points to cause, not consequence.

Each relapse adds to the biological toll, including further cortisol dysregulation. ‘Neuroprogressive’ models argue this makes the illness progressively harder to treat over time (Moylan et al., 2013).

PTSD shows the opposite pattern: lower, not higher, cortisol, alongside enhanced negative feedback that shuts the axis down too readily. Two meta-analyses converge on this finding.

Pooled data on 24-hour urinary cortisol found lower levels in people with PTSD than in controls (Pan et al., 2020). A separate analysis of salivary cortisol likewise found lower morning cortisol in PTSD (Pan et al., 2018).

Early-Life Stress and Adult Cortisol Reactivity

A large meta-analysis pooled 30 datasets covering 4,292 people to test how early-life adversity affects the adult cortisol response to social stress (Bunea et al., 2017).

The pattern: blunted reactivity. The effect was strongest for people who experienced childhood maltreatment, and strongest in adulthood (g = -0.39), suggesting the dampening deepens over the life course. Early adversity leaves a lasting, measurable mark on the HPA axis.

Practice Questions for Exam Revision

Use these questions to test your understanding of the HPA axis:

1. Outline the role of the HPA axis in the stress response. (4 marks)
2. Explain how the negative feedback loop helps regulate cortisol levels. (4 marks)
3. Describe one physical and one psychological health consequence of HPA axis dysfunction. (6 marks)
4. Compare the roles of the HPA axis and the SAM system in the stress response. (6 marks)

References

Belanoff, J. K., Rothschild, A. J., Cassidy, F., DeBattista, C., Baulieu, E.-E., Schold, C., & Schatzberg, A. F. (2002). An open label trial of C-1073 (mifepristone) for psychotic major depression. Biological Psychiatry, 52(5), 386-392. https://doi.org/10.1016/S0006-3223(02)01432-4

Bunea, I. M., Szentagotai-Tatar, A., & Miu, A. C. (2017). Early-life adversity and cortisol response to social stress: A meta-analysis. Translational Psychiatry, 7(12), 1274. https://doi.org/10.1038/s41398-017-0032-3

Guilliams, T. G., & Edwards, L. (2010). Chronic stress and the HPA axis. The standard, 9(2), 1-12.

Mayo Clinic. (2021, April 30). Cushing syndrome. https://www.mayoclinic.org/diseases-conditions/cushing-syndrome/symptoms-causes/syc-20351310

Moylan, S., Maes, M., Wray, N. R., & Berk, M. (2013). The neuroprogressive nature of major depressive disorder: pathways to disease evolution and resistance, and therapeutic implications. Molecular psychiatry, 18(5), 595-606.

Neuroscientifically Challenged. (2014, June 4). Know Your Brain: HPA Axis. https://www.neuroscientificallychallenged.com/blog/2014/5/31/what-is-the-hpa-axis

Newcomer, J. W., Selke, G., Melson, A. K., Hershey, T., Craft, S., Richards, K., & Alderson, A. L. (1999). Decreased memory performance in healthy humans induced by stress-level cortisol treatment. Archives of general psychiatry, 56(6), 527-533.

Pan, X., Kaminga, A. C., Wen, S. W., Wang, Z., Wu, X., & Liu, A. (2020). The 24-hour urinary cortisol in post-traumatic stress disorder: A meta-analysis. PLOS ONE, 15(1), e0227560. https://doi.org/10.1371/journal.pone.0227560

Pan, X., Wang, Z., Wu, X., Wen, S. W., & Liu, A. (2018). Salivary cortisol in post-traumatic stress disorder: A systematic review and meta-analysis. BMC Psychiatry, 18(1), 324. https://doi.org/10.1186/s12888-018-1910-9

Selye, H. (1956). The stress of life. McGraw-Hill.

Smith, S. M., & Vale, W. W. (2006). The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues in clinical neuroscience, 8(4), 383.

Stephens, M. A. C., & Wand, G. (2012). Stress and the HPA axis: Role of glucocorticoids in alcohol dependence. Alcohol research: current reviews.

Zajkowska, Z., Gullett, N., Walsh, A., Zonca, V., Pedersen, G. A., Souza, L., Kieling, C., Fisher, H. L., Kohrt, B. A., & Mondelli, V. (2022). Cortisol and development of depression in adolescence and young adulthood: A systematic review and meta-analysis. Psychoneuroendocrinology, 136, 105625. https://doi.org/10.1016/j.psyneuen.2021.105625

Zobel, A. W., Nickel, T., Kunzel, H. E., Ackl, N., Sonntag, A., Ising, M., & Holsboer, F. (2000). Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: The first 20 patients treated. Journal of Psychiatric Research, 34(3), 171-181. https://doi.org/10.1016/S0022-3956(00)00016-9