Many people think of stress as an emotion: anxiety, tension, irritability, or a mind that keeps racing even when told to “relax”; it can also feel like a rise in body temperature that is hard to control or a heartbeat that refuses to settle. Physiologically, however, stress is not a trick that disappears with a calming phrase. It is a body-wide neuroendocrine response that begins in the brain and is driven by a complex set of physiological signals that must be detected, prioritized, and processed. Stress can change attention, heart rate, energy availability, immune activity, and sleep rhythms, temporarily reallocating resources toward “dealing with the immediate problem first.” Understanding stress—and the way the body responds to it—is a first step toward understanding our own reactions more scientifically. From a functional-medicine perspective, these changes form a systems-level response involving neuroendocrine signaling, immune and inflammatory activity, energy metabolism, and sleep–circadian rhythms.

The hypothalamic–pituitary–adrenal axis, or HPA axis, is a major regulatory pathway within this stress-response network. One of its best-known messengers is cortisol. The HPA axis is far more than a “stress pathway” that simply produces cortisol; it is an evolutionarily conserved emergency-response system built around precisely coordinated activation, amplification, feedback, and recovery. Understanding the HPA axis therefore requires more than labeling cortisol as a “good” or “bad” hormone. The more useful question is whether the body can respond when needed, gradually return toward homeostasis once the challenge has passed, and remain coordinated with its circadian rhythm.

1. First, Understand the HPA Axis: How the Body Sends a “Stress Signal” Throughout the System

A stressful event does not jump directly from experience to cortisol in the bloodstream. External and internal events are first received, evaluated, and interpreted by the brain. The trigger may be physical pain, infection, low blood glucose, or intense exercise; it may also be a work deadline, interpersonal conflict, or a constant stream of information. Multiple neural networks evaluate these different stressors and then recruit stress-response systems such as the sympathetic–adrenal–medullary system and the HPA axis.[1][2] The HPA axis is a classic master regulatory pathway of the physiological stress response and an important part of neuroendocrine feedback control. It is a hormone-regulating circuit formed sequentially by the hypothalamus, pituitary gland, and adrenal glands.

The HPA axis works through a hormonal cascade and negative-feedback regulation. It can be pictured as a three-stage relay. The first stage is the hypothalamus, which releases corticotropin-releasing hormone (CRH) and works together with signals such as arginine vasopressin. The second stage is the anterior pituitary, which responds by releasing adrenocorticotropic hormone (ACTH). The third stage is the adrenal cortex, where ACTH stimulates the release of cortisol. Once cortisol enters the circulation, it acts on multiple tissues and helps the body reorganize energy use and physiological priorities.[1][3]

This pathway is called an “axis” because it is not simply the sum of three organs working independently. It is a regulatory loop in which upstream signals, downstream hormones, and feedback information continuously travel back and forth. What the body needs is an HPA circuit with appropriate sensitivity and the ability to recover.

2. Cortisol Is Not a “Bad Hormone”: A Short-Term Rise Buys the System Time

Cortisol is often given a negative label simply because it is called a “stress hormone.” In acute stress, however, a rise in cortisol has adaptive value. It helps mobilize usable energy, supports the cardiovascular system as it responds to a challenge, and adjusts immune and inflammatory signaling at multiple levels so that resources can be temporarily redirected toward more urgent tasks.[1][2]

Sudden high-intensity exercise, a brief dangerous situation, or a task requiring intense concentration can all trigger a stress response. Consider abrupt high-intensity exercise. Once the brain determines that a rapid response is needed, the sympathetic–adrenal–medullary system acts first, increasing heart rate and blood pressure, deepening breathing, and directing more blood toward the brain and skeletal muscles. The HPA axis then joins in: cortisol promotes hepatic glucose output and helps maintain blood glucose at a level that can support energy demand. Digestion, reproduction, and long-term tissue maintenance temporarily move down the priority list, while immune and inflammatory signaling is adjusted according to the situation. In this way, the body concentrates limited resources on assessing the environment, taking action, and maintaining circulation.[1][2] Cortisol acts much like an accelerator. At this stage, the body is entering a temporary state of heightened responsiveness and alertness. Once the stressor has passed, cortisol and related signals should gradually decline, allowing resources to shift back toward digestion, sleep, tissue maintenance, and other everyday functions.

For this reason, evaluating the HPA axis requires more than asking whether cortisol is “high.” Three questions are more informative: Can cortisol rise appropriately when it is needed? Can it come back down once the stress has passed? And does a relatively clear daily rhythm remain intact? Looking at activation, response, and recovery together provides a much more realistic picture of physiology.

3. Why the Body Needs a “Brake”: Negative Feedback Allows the Stress Response to Start—and to End

A system that can accelerate but cannot brake cannot remain stable for long. One of the HPA axis’s most important design features is negative feedback. It is as if the final runner in the relay sends a message back to the starting line: this round of the stress response is moving toward completion. Elevated cortisol then acts through glucocorticoid receptors in the hypothalamus, pituitary gland, and brain regions involved in stress appraisal, suppressing upstream signals such as CRH and ACTH and helping the response gradually slow and wind down.[1][3]

This functions like an automatic brake on the stress response. If braking occurs too early, the body may not have finished dealing with the challenge. If it comes too late, a state of high responsiveness that was useful for a short period may persist and begin to interfere with sleep, appetite, attention, and recovery. The goal of stress management, therefore, is broader than eliminating every source of stress. The body also needs to preserve an appropriate response intensity and regain the ability to settle after the challenge has ended.

It is also important to distinguish between “feeling tired” and “the system being relaxed.” A person may feel physically exhausted while still remaining in a state of high arousal. Conversely, someone may not feel obviously anxious, yet circadian rhythm and recovery processes may already be disrupted. Subjective feelings, behavior, and hormone measurements do not map onto one another in a simple one-to-one way.

4. The HPA Axis Also Has a “Clock”: Cortisol Does Not Stay at the Same Level All Day

HPA-axis activity does not remain constant from morning to night. Cortisol usually follows a clear circadian rhythm: in humans it is relatively higher during the active period—the daytime—and gradually declines as night approaches, typically reaching a low level around midnight. More detailed research also shows that cortisol is not released as a smooth, continuous stream; shorter ultradian pulses are superimposed on the daily rhythm.[3][4]

This rhythm is closely coordinated with everyday life. Higher cortisol activity in the morning helps the body transition from sleep to wakefulness and action, while the nighttime decline creates a physiological environment more compatible with sleep and restoration. Light exposure, sleep schedules, meal timing, exercise, night-shift work, and ongoing stress can all influence how this internal “clock” operates.

Because the HPA axis is dynamic, a single cortisol measurement taken at one time point cannot easily represent a person’s full-day rhythm or long-term stress burden. Research often uses salivary samples collected at multiple time points, standardized stress tasks, or other methods to examine rhythm, reactivity, and recovery. Different assessment methods capture different aspects of the system.[8][9]

5. Chronic Stress Does Not Simply Mean “Cortisol Is Always High”: Dysregulated Patterns Matter More

Acute stress has a recognizable beginning and end. Chronic stress can repeatedly send the body the message that “safety has not yet returned.” Over time, the intensity of HPA-axis responses, the day–night cortisol slope, cortisol pulsatility, and the speed of recovery after stress may all change. Digestion, sleep, tissue maintenance, and other routine functions may repeatedly be asked to wait for fuller resource allocation, which can gradually disturb homeostasis. The direction of these changes is not identical across individuals, stress histories, or stages of exposure, so chronic stress cannot be summarized simply as “cortisol stays elevated.”[5][6]

When HPA-axis regulation shifts, the effects may extend into mood, immunity, and metabolism. Related changes have been studied in depression, anxiety disorders, post-traumatic stress disorder, autoimmune disease, and metabolic syndrome. In depression research, for example, a systematic review and meta-analysis of 26 studies found that higher morning cortisol in adolescents and young adults was associated with a greater subsequent risk of developing major depressive disorder. Among people who already had depression, however, changes in morning, afternoon, or stress-induced cortisol did not show a consistent pattern.[10] These findings illustrate the complex relationship between the HPA axis and depression: age, sex, disease course, and sampling time can all influence what is observed, and a single cortisol test cannot serve as a stand-alone diagnostic tool.

The popular idea of “adrenal fatigue” tends to compress these complex regulatory changes into a single malfunction. Fatigue, unstable sleep, mood fluctuations, and reduced concentration can arise from many different causes and need to be considered alongside sleep, medications, nutrition, endocrine status, and psychological factors.

A more appropriate way to think about the HPA axis is to place it back in the context of the whole system: Is the stress response excessively strong or unusually weak? Can the body gradually slow down at night? Can it activate effectively in the morning? Do daytime energy and mood remain relatively stable? And once a stressor has passed, can the body regain its previous rhythm?

6. From “Lowering Cortisol” to Restoring Regulatory Capacity

Once the HPA axis is understood, many popular ideas about stress need to be recalibrated. Lower cortisol is not automatically better, and less stress is not always the only goal. What matters is whether the system can generate an adequate response to a challenge, disengage when that response is no longer needed, and preserve a clear rhythm across the day–night cycle.

The body is a system that must switch between different states. Activation, feedback, disengagement, and the return to stability are all part of resilience.

This first article explains how stress enters the body and how the HPA axis moves through activation, amplification, and braking. The next article will continue along the same pathway: when stress keeps recurring and sleep or circadian rhythms are disrupted, how does the HPA axis affect the body’s recovery window? And where can daily routines, light exposure, exercise, meal timing, and nutritional support help rebuild physiological buffering capacity?

Conclusion: A Healthy Stress Response Is Not Permanent Calm—it Is the Ability to Return to Order

Stress is part of the body’s adaptive capacity, and the HPA axis is an important regulatory network within that capacity. It helps the body concentrate resources when needed and, through negative feedback and circadian regulation, supports a gradual return to conditions more compatible with restoration and everyday life once the challenge has passed.

From this perspective, resilience does not mean never being affected by stress. It means that after being affected, the body still has the capacity to find its rhythm again. Understanding the HPA axis is also a way of understanding how the body turns an alarm into action—and then hands control back to recovery.

References

  1. HERMAN J P, MCKLVEEN J M, GHOSAL S, et al. Regulation of the hypothalamic-pituitary-adrenocortical stress response[J]. Comprehensive Physiology, 2016, 6(2): 603-621. DOI: 10.1002/cphy.c150015.
  2. GODOY L D, ROSSIGNOLI M T, DELFINO-PEREIRA P, et al. A comprehensive overview on stress neurobiology: basic concepts and clinical implications[J]. Frontiers in Behavioral Neuroscience, 2018, 12: 127. DOI: 10.3389/fnbeh.2018.00127.
  3. SPIGA F, WALKER J J, TERRY J R, et al. HPA axis-rhythms[J]. Comprehensive Physiology, 2014, 4(3): 1273-1298. DOI: 10.1002/cphy.c140003.
  4. NICOLAIDES N C, VGONTZAS A N, KRITIKOU I, et al. HPA axis and sleep[M/OL]// FEINGOLD K R, ANAWALT B, BLACKMAN M R, et al. Endotext. South Dartmouth: MDText.com, 2020[2026-09-15].
  5. LEE J H, MEYER E J, NENKE M A, et al. Cortisol, stress, and disease—bidirectional associations; role for corticosteroid-binding globulin?[J]. Journal of Clinical Endocrinology & Metabolism, 2024, 109(9): 2161-2172. DOI: 10.1210/clinem/dgae412.
  6. KARLAMANGLA A S, ALMEIDA D M, LACHMAN M E, et al. Diurnal dynamic range as index of dysregulation of system dynamics: a cortisol exemplar using data from the Study of Midlife in the United States[J]. Psychoneuroendocrinology, 2022, 142: 105804. DOI: 10.1016/j.psyneuen.2022.105804.
  7. WESARG-MENZEL C, MARHEINECKE R, STAAKS J, et al. Associations of diurnal cortisol parameters with cortisol stress reactivity and recovery: a systematic review and meta-analysis[J]. Psychoneuroendocrinology, 2024, 163: 106976. DOI: 10.1016/j.psyneuen.2024.106976.
  8. GOLDEN S H, WAND G S, MALHOTRA S, et al. Reliability of hypothalamic-pituitary-adrenal axis assessment methods for use in population-based studies[J]. European Journal of Epidemiology, 2011, 26(7): 511-525. DOI: 10.1007/s10654-011-9585-2.
  9. CHOSHEN-HILLEL S, ISHQER A, MAHAMEED F, et al. Acute and chronic sleep deprivation in residents: cognition and stress biomarkers[J]. Medical Education, 2021, 55(2): 174-184. DOI: 10.1111/medu.14296.
  10. ZAJKOWSKA Z, GULLETT N, WALSH A, et al. Cortisol and development of depression in adolescence and young adulthood—a systematic review and meta-analysis[J]. Psychoneuroendocrinology, 2022, 136: 105625. DOI: 10.1016/j.psyneuen.2021.105625.