📄 systems biology

A Mechanistic Model for the HPA Axis Cortisol Paradox in PTSD

This paper proposes a systems-level mathematical model demonstrating that enhanced glucocorticoid receptor sensitivity, combined with dynamic changes in gland functional mass, resolves the PTSD cortisol paradox by explaining how individuals can exhibit low basal cortisol and blunted stress responses while simultaneously experiencing elevated glucocorticoid signaling.

Original authors: Danan, D., Grosskopf, Y., Hayut, Y., Toledano, Y., Doenyas-Barak, K., Mayo, A., Alon, U.

Published 2026-09-28

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CC BY 4.0

Original authors: Danan, D., Grosskopf, Y., Hayut, Y., Toledano, Y., Doenyas-Barak, K., Mayo, A., Alon, U.

Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). ⚕️ This is an AI-generated explanation of a preprint that has not been peer-reviewed. It is not medical advice. Do not make health decisions based on this content. Read full disclaimer

The human body maintains a delicate internal balance, constantly adjusting to keep vital systems running smoothly. One of the most critical of these systems is the stress response, a chain reaction that begins in the brain and ends at the adrenal glands, small organs sitting atop the kidneys. When a person faces danger or pressure, the brain sends a signal to the pituitary gland, which in turn releases a hormone called ACTH. This hormone travels through the blood to the adrenal glands, instructing them to pump out cortisol, the body's primary stress hormone. In a healthy system, these components work in a tight loop: cortisol eventually signals the brain to stop the process, preventing the body from staying in a state of high alert for too long. This feedback mechanism is essential for survival, but for decades, scientists have struggled to explain a puzzling observation in people with post-traumatic stress disorder, or PTSD.

People with PTSD often show a strange contradiction in their blood tests. Their levels of cortisol are lower than average, yet the level of ACTH, the hormone that tells the adrenal glands to make cortisol, remains completely normal. Under normal circumstances, if the adrenal glands were failing to produce enough cortisol, the brain would sense the drop and crank up the ACTH signal to compensate, causing both levels to rise together. The fact that cortisol is low while ACTH stays steady has defied simple explanation, leading researchers to wonder if the body's stress system is broken in a way they could not yet see.

A new study from the Weizmann Institute of Science offers a resolution to this decades-old mystery by looking at the physical size of the glands themselves. The researchers proposed that the adrenal glands and the pituitary gland are not static machines with a fixed capacity; rather, they are living tissues that can grow or shrink over weeks and months in response to their workload. Just as a muscle grows when exercised and shrinks when unused, these glands adjust their functional mass based on the signals they receive. The team built a computer model that included this slow adaptation of gland size alongside the rapid chemical signals of the stress response. They found that when the body's sensitivity to cortisol changes, the glands slowly resize themselves to compensate, effectively hiding the true cause of the imbalance from standard blood tests.

The study suggests that in PTSD, the body's receptors for cortisol become significantly more sensitive—about twice as sensitive as in people without the disorder. Because these receptors are so efficient at detecting cortisol, the brain perceives the existing amount of hormone as being too high, even if the actual amount in the blood is low. In response, the brain reduces its signal to the adrenal glands. Over time, this reduced signal causes the adrenal glands to shrink slightly, while the pituitary gland, which receives the initial signal, grows slightly larger. This physical reshaping acts as a perfect counterbalance: the smaller adrenal glands produce less cortisol, but the larger pituitary gland pushes out more ACTH to keep the signal steady. The result is the paradoxical state observed in patients: low cortisol levels paired with normal ACTH levels.

To test this idea, the researchers turned to a massive database of medical records from Clalit Health Services, Israel's largest health provider. They analyzed morning cortisol tests from over 180,000 individuals, comparing those with a PTSD diagnosis to those without. The data confirmed the model's prediction: people with PTSD had morning cortisol levels that were approximately 4.5% lower than the control group. More importantly, the researchers looked at nine other common blood markers that are known to change when the body is exposed to high levels of glucocorticoids, the class of hormones that includes cortisol. If the low cortisol were simply due to a lack of stress hormones, these markers would move in one direction. Instead, eight of the nine markers shifted in the direction expected if the body were actually experiencing an excess of glucocorticoid activity. This suggests that the receptors in the body are so sensitive that they are reacting to the lower amount of cortisol as if it were a much higher dose.

The study also simulated how the system behaves during acute stress and after taking specific drugs used to test the stress response. In these simulations, the model with sensitive receptors and adapting glands accurately reproduced the blunted responses seen in real patients, such as a smaller spike in cortisol during a stressful event and a stronger-than-expected drop in cortisol after taking a synthetic steroid. The researchers noted that this sensitivity might not be a result of the trauma itself, but could be a pre-existing trait that makes some individuals more vulnerable to developing PTSD. Evidence from other studies suggests that people who later develop the disorder often show signs of heightened receptor sensitivity before the traumatic event occurs.

By focusing on the slow, physical changes in gland size, the researchers were able to explain why the stress system appears broken in blood tests while actually functioning in a highly adapted, albeit altered, state. The findings suggest that the problem in PTSD is not that the body is producing too little cortisol, but that the body's sensors are tuned so finely that the normal amount of hormone feels like too much. This insight shifts the focus from the quantity of the hormone to the sensitivity of the system reading it, offering a clearer picture of how the body adapts to the lasting effects of trauma. The work does not claim to have solved every aspect of the disorder, but it provides a unified explanation for a wide range of conflicting observations, from blood test results to drug responses, by treating the stress system as a dynamic, self-adjusting biological machine.

Technical Summary: Gland-Mass Adaptation Explains the Cortisol Paradox in PTSD

Problem Statement
Post-traumatic stress disorder (PTSD) presents a persistent endocrine paradox: patients exhibit low basal cortisol levels despite normal levels of adrenocorticotropic hormone (ACTH), its upstream driver. Standard hormone kinetics dictate that ACTH and cortisol should rise and fall together at steady state; therefore, low cortisol with normal ACTH cannot be explained by secretion rates or clearance alone. While enhanced glucocorticoid receptor (GR) sensitivity is a leading hypothesis, existing models fail to reconcile this sensitivity with the observed normal ACTH levels, as stronger negative feedback typically suppresses both hormones. Furthermore, previous models treating gland secretory capacity as fixed cannot generate this specific phenotype without violating physiological constraints.

Methodology
The authors employ a previously calibrated mathematical model of the hypothalamic-pituitary-adrenal (HPA) axis that incorporates the slow adaptation of gland functional mass (pituitary corticotrophs and adrenal cortex) over weeks.

Model Dynamics: The model tracks CRH, ACTH, cortisol, and the functional masses of the pituitary ( $P$ ) and adrenal gland ( $A$ ). Gland masses grow in proportion to their trophic inputs (CRH for $P$ , ACTH for $A$ ) and turnover at fixed rates. This creates integral feedback loops where gland mass adjusts to maintain the trophic input at a specific threshold.
PTSD Simulation: PTSD is modeled as a twofold increase in GR sensitivity (decreasing the half-maximal parameter $K_{GR}$ from 5 to 2.5 in normalized units), consistent with in-vivo feedback tests.
Parameter Constraints: The model is constrained by population-level morning serum cortisol data from Israel's largest health provider (Clalit), involving over 180,000 tests. This data sets the absolute operating point of the axis.
Validation: The model's predictions are tested against:
1. Dynamic Challenges: Trier Social Stress Test (TSST) and dexamethasone-CRH challenge data.
2. Population Data: Morning cortisol levels in PTSD vs. controls.
3. Peripheral Markers: A "signed test" using nine routine blood analytes (e.g., CRP, glucose, white blood cells) known to respond to glucocorticoid excess. The direction of change in these markers distinguishes between reduced central drive (lower peripheral action) and increased GR sensitivity (higher peripheral action).

Key Contributions and Results

Resolution of the Cortisol Paradox via Integral Feedback:
The study demonstrates that gland-mass adaptation acts as an integral feedback mechanism that "pins" ACTH to its set point. When GR sensitivity increases, the adrenal gland shrinks (reducing cortisol output per unit ACTH) and the pituitary expands slightly. The system reaches a new steady state where cortisol is lower, but ACTH remains unchanged because the gland masses have adapted to absorb the change in secretory efficiency. This explains the low cortisol/normal ACTH phenotype as a generic property of an adaptive endocrine axis, not an unusual perturbation.
Identification of Two Observable Changes:
The model proves that in an axis with adaptive gland masses, basal hormone levels are insensitive to most parameters (secretory rates, clearance). Only two parameter combinations can alter basal cortisol: reduced central drive or increased GR sensitivity. Crucially, these two mechanisms move GR occupancy in opposite directions. Reduced drive lowers occupancy, while increased sensitivity raises it.
Quantitative Reproduction of Phenotypes:
- Basal State: A twofold increase in GR sensitivity reproduces the observed ~4.4% reduction in basal cortisol with unchanged ACTH.
- Dynamic Challenges: The same single parameter change reproduces the blunted cortisol response during acute stress (TSST) and the hypersuppression of cortisol and ACTH following dexamethasone administration, without refitting feedback parameters.
- Transient Dynamics: The model predicts that ACTH would initially drop after a sensitivity shift but returns to baseline within ~60 days as glands re-adapt, explaining why chronic PTSD shows normal ACTH.
Empirical Validation via Peripheral Markers:
Analysis of 40,240 PTSD cases and 311,362 controls revealed that eight of nine glucocorticoid-responsive markers shifted in the direction of glucocorticoid excess (e.g., lower CRP, higher glucose/white blood cells) despite lower circulating cortisol. This "signed test" confirms that peripheral tissues experience higher glucocorticoid action, ruling out reduced central drive and confirming body-wide GR sensitization.
- Pre-diagnosis Shift: The glucocorticoid-action index was elevated a decade before diagnosis, suggesting sensitization may precede the disorder.
- Magnitude: The increase in GR occupancy is estimated at ~4.4 percentage points (from 0.78% to 5.2%), roughly a quarter of the rise seen in moderate Cushing's syndrome, explaining the lack of overt Cushingoid symptoms.

Significance and Claims
The paper claims to resolve a three-decade-old mechanistic puzzle in PTSD by shifting the focus from hormone concentration to receptor sensitivity and glandular adaptation.

Mechanistic Insight: It establishes that the "low cortisol" of PTSD is not a deficiency but a state where cortisol is "too high for the receptors that read it."
Diagnostic Implication: The study argues that routine clinical records (peripheral markers) provide a decisive test for HPA axis status, distinguishing between drive reduction and receptor sensitization.
Therapeutic Context: The findings suggest that the failure of HPA-targeted drugs in chronic stress may be due to the axis's ability to adapt gland mass, absorbing changes in secretory capacity. It implies that interventions targeting GR sensitivity or gland mass dynamics, rather than just hormone levels, may be necessary.
Limitations: The authors note that the model assumes a single sensitization parameter for both hypothalamic and pituitary arms and that the observed effects represent population shifts rather than clinical syndromes. The model does not account for circadian dynamics or receptor-level compensation, meaning the calculated occupancy figures are upper bounds.

In conclusion, the paper posits that the endocrine phenotype of PTSD is a stable, adapted state of a sensitized HPA axis, where integral feedback from gland mass adaptation maintains ACTH homeostasis while allowing cortisol to fall, resulting in elevated tissue-level glucocorticoid action.

Technical Summary: Gland-Mass Adaptation Explains the Cortisol Paradox in PTSD

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