A Mechanistic Model for the HPA Axis Cortisol Paradox in PTSD

A Mechanistic Model for the HPA Axis Cortisol Paradox in PTSD | bioRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-M677548'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search New Results A Mechanistic Model for the HPA Axis Cortisol Paradox in PTSD Dor Danan , View ORCID Profile Yaniv Grosskopf , Yoav Hayut , Yoel Toledano , Keren Doenyas-Barak , Avi Mayo , View ORCID Profile Uri Alon doi: https://doi.org/10.1101/2025.10.13.681561 Dor Danan 1 Department of Molecular Cell Biology, Weizmann Institute of Science , Rehovot 76100, Israel Find this author on Google Scholar Find this author on PubMed Search for this author on this site Yaniv Grosskopf 1 Department of Molecular Cell Biology, Weizmann Institute of Science , Rehovot 76100, Israel Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Yaniv Grosskopf Yoav Hayut 1 Department of Molecular Cell Biology, Weizmann Institute of Science , Rehovot 76100, Israel Find this author on Google Scholar Find this author on PubMed Search for this author on this site Yoel Toledano 2 Division of Maternal Fetal Medicine, Helen Schneider Women’s Hospital, Rabin Medical Center , Petah Tikva 4941492, Israel Find this author on Google Scholar Find this author on PubMed Search for this author on this site Keren Doenyas-Barak 3 Sagol Center for Hyperbaric Medicine and Research , Shamir MC, Israel 4 Tel Aviv School of Medicine, Tel-Aviv University , Israel Find this author on Google Scholar Find this author on PubMed Search for this author on this site Avi Mayo 1 Department of Molecular Cell Biology, Weizmann Institute of Science , Rehovot 76100, Israel Find this author on Google Scholar Find this author on PubMed Search for this author on this site Uri Alon 1 Department of Molecular Cell Biology, Weizmann Institute of Science , Rehovot 76100, Israel Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Uri Alon For correspondence: uri.alon{at}weizmann.ac.il Abstract Full Text Info/History Metrics Data/Code Preview PDF Abstract Post-traumatic Stress Disorder (PTSD) is a debilitating psychiatric condition characterized by intrusive memories, hyperarousal, avoidance, and cognitive and mood disturbances. A longstanding biological paradox in PTSD is the observation of low basal cortisol levels, despite the expectation of elevated cortisol under chronic stress. This “low cortisol paradox” challenges traditional hypothalamic-pituitary-adrenal (HPA) axis regulation models. Individuals with PTSD also exhibit normal or near-normal adrenocorticotropic hormone (ACTH) levels despite reduced cortisol and blunted hormonal responses to acute stress. In this paper, we provide further evidence of reduced cortisol levels using a large medical database from thousands of individuals diagnosed with PTSD. To understand this dysregulation, we apply a systems-level mathematical model of HPA axis regulation that incorporates dynamic changes in gland functional mass, the pituitary corticotrophs and adrenal cortex, over weeks to months. Using this model, we demonstrate that enhanced glucocorticoid receptor (GR) sensitivity, a known risk factor for PTSD, can lead to a steady state with low cortisol and normal ACTH, reconciling key clinical observations. The model also recapitulates the blunted cortisol and ACTH responses to acute stress and the dexamethasone/ corticotropin-releasing hormone (DEX/CRH) test, reported in PTSD cohorts. Importantly, despite low cortisol levels, basal glucocorticoid receptor (GR) activity is higher than normal due to the reduced receptor affinity. Thus, individuals with PTSD effectively experience elevated cortisol signaling relative to their GR sensitivity. These findings provide a unified mechanistic explanation for HPA axis dysregulation in PTSD, grounded in the slow time scale of changes in gland functional mass and supported by literature and clinical data. Introduction Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition that emerges in the aftermath of traumatic experiences 1 . It is characterized by persistent re-experiencing, avoidance, hyperarousal, and negative alterations in mood and cognition 1 . Despite recent progress 2 – 6 , improved treatment of PTSD remains an unmet need in many cases 7 , 8 . One of the earliest and most surprising biological findings in PTSD research was the observation of relative hypocortisolemia, lower-than-expected levels of circulating cortisol, in contrast to the elevated cortisol typically associated with acute and chronic stress. First systematically described in the 1990’s 9 , low cortisol in PTSD was confirmed by meta-analysis of several dozen studies on plasma, urine, and salivary basal cortisol. Conflicting studies exist, which may be due to the dynamic nature of cortisol to stress, study conditions, and comorbid disorders 10 – 12 . The counterintuitive finding of low cortisol challenged the prevailing understanding of stress physiology, which posited that chronic or acute stress states would be marked by elevated hypothalamic-pituitary-adrenal (HPA) axis activation. Adding to this complexity, individuals with PTSD exhibit normal levels of adrenocorticotropic hormone (ACTH), the upstream regulator of cortisol. In the HPA axis, ACTH from the pituitary induces cortisol secretion from the adrenal cortex. Thus, one would expect that in the absence of adrenal insufficiency, low cortisol would be associated with low ACTH. However, despite consistent findings of low cortisol in PTSD, ACTH levels are found to be normal 13 – 16 , rather than low as would be expected. This dissociation suggests that the HPA axis, where normal ACTH should lead to normal cortisol, is not functioning as predicted by traditional textbook understanding. Subsequent studies showed that individuals with PTSD often exhibit heightened glucocorticoid receptor (GR) sensitivity 17 – 19 , increased GR expression 20 – 22 , and enhanced negative feedback 13 , 23 – 28 , PTSD patients and animal models also show blunted cortisol response to awakening 29 – 33 and acute stress 34 , 35 . This suggests an altered set point of the HPA axis. The implications of this so-called “low cortisol paradox” are important for understanding both the pathophysiology of PTSD and its treatment. This relative hypocortisolemia might lead to a heightened amygdala engagement and altered encoding of intrusive and emotionally charged memories. Such a mechanism has been proposed as a vulnerability factor for the development of PTSD, especially in individuals with a pre-existing sensitivity of the HPA axis 36 – 38 . Indeed, lower cortisol responses shortly after trauma exposure may predict later PTSD development 27 , 39 – 41 marking it as a potential significant risk factor. This paradox has spurred interest in therapeutic strategies that target the HPA axis, such as low-dose hydrocortisone in the acute post-trauma phase 42 – 46 . Additionally, it highlights the importance of considering biological heterogeneity within PTSD, with potential subtypes defined by distinct neuroendocrine profiles 47 , 48 . Understanding this paradox is important for refining diagnostic tools, preventative strategies, and personalized interventions for trauma-related disorders. One partial explanation involves enhanced GR sensitivity, particularly in the pituitary and hypothalamus, leading to suppression of ACTH despite low cortisol 38 , 49 , 50 , but this does not explain how normal ACTH leads to low cortisol in PTSD. Alternatively, trauma may induce a long-lasting recalibration of neuroendocrine set points, altering the system’s sensitivity and baseline activity. These observations call for a more nuanced, systems-level model of HPA axis function. Here, we address the dysregulation of the HPA axis using a recent mathematical model that includes changes in gland functional mass. These mass changes are due to the trophic (growth factor) effects of corticotropin-releasing hormone (CRH) and ACTH on the pituitary corticotrophs and adrenal cortex, respectively. This model thus adds a slow timescale of changes in gland functional mass over weeks, resulting in compensation, which can explain a wide range of HPA phenomena. These include withdrawal from long-term glucocorticoid steroid treatment, during which the adrenal cortex mass is reduced and takes months to recover 51 ; months-scale hormonal imbalance in ACTH/beta-endorphins and cortisol following prolonged stress or addiction 52 and seasonal changes in these hormones 53 . The gland mass model also explains why many HPA-targeted drugs fail to show effectiveness in chronic stress or depression, despite their efficacy in hypercortisolemia associated with Cushing’s syndrome: the adrenal glands adapt by changing their functional mass, compensating for most interventions targeting the HPA axis 54 . Here, we provide further evidence of low cortisol from thousands of PTSD patients, and apply the HPA gland mass model to PTSD. We employ the well-established risk factor of high GR sensitivity (low K GR ) in people susceptible to PTSD. We show that high GR sensitivity leads to normal ACTH but reduced cortisol. Despite the lower cortisol concentration, its signaling effect through the GR is higher than normal, due to low K GR . The model also explains the blunted HPA response to acute stress and dex-crh tests observed in PTSD. We use this model to explore interventions and to offer a unifying explanation of HPA dysregulation in PTSD. Results A large medical dataset shows cortisol is 10% and 12% lower in males and females with PTSD First, to confirm the surprising finding of low cortisol in PTSD patients, we employed the Clalit HMO dataset, which comprises the largest health maintenance organization (HMO) in Israel, with over 5 million members as of 2024, with broad socioeconomic and ethnic demographics 55 – 57 . We excluded all patients with a diagnosis code of HPA abnormalities (ICD-9 codes: 253, 255 and their subcodes), other affective disorders (ICD-9 codes: 296 and its subcodes) and prescribed medications that might interfere with HPA hormone levels,, and compared blood cortisol lab tests of individuals with a PTSD diagnosis (ICD-9 code 309.81 or ICD-10-F43.1) to individuals without a PTSD diagnosis ( Table 1 ). View this table: View inline View popup Download powerpoint Table 1. Age and sex of the study population. Because of privacy concerns, other demographics were not available. Statistics are shown per sample taken. View this table: View inline View popup Table 2. Definitions of the HPA mathematical model variables and parameters View this table: View inline View popup Download powerpoint Table 3: HPA model parameters. K GR is set to K GR =2nM/L to model PTSD and K GR =6nM/L for control. Hormone secretion parameters are b1, b2, b3, and the hormone removal rates are a1, a2, a3. Hormone removal rates are given by the half-lives of hormones, t½ are 4 minutes for x1, 20 minutes for x2, and 10 minutes for x3 when considering free cortisol half-life according to the four-compartment model (Dorin et al, 2022 145 ). We find that cortisol is 10% lower in males and 12% lower in females on average in those with a PTSD ICD-9 code compared to those without ( Fig. 1 ) (p<e-10; d= - 0.2) Download figure Open in new tab Figure 1: Blood cortisol lab tests in males and females comparing those with a PTSD ICD-9 code to those without. The blood cortisol lab test values are stratified by sex. Individuals with a PTSD diagnosis (ICD-9: 309.81 or ICD-10: F43.1) exhibit, on average, 10% (p=9.7e-5, d=-0.2) lower cortisol in males and 12% (p=1.38e-12, d=0.23) lower cortisol in females compared to matched controls. These findings are based on a large sample from the Clalit HMO dataset (n ≈ 210,000 females and 80,000 males in the control group; n ≈ 1,000 females and 600 males in the PTSD group). Error bars represent SEM. The gland-mass model explains HPA dysregulation in PTSD To explain the HPA axis abnormalities observed in PTSD and corroborated by our findings, we applied the Karin et al. model 51 , which captures changes in endocrine cell functional mass. The functional mass is regulated by the HPA hormones, which act as growth factors. CRH is the growth factor for pituitary corticotrophs that secrete ACTH. ACTH, in turn, is the growth factor for the adrenal cortex cells that produce cortisol. The model describes sensing of cortisol by two receptors, the mineralocorticoid receptor (MR) and GR. MR, active at the level of the hypothalamus, has high affinity and is nearly saturated at baseline levels. In contrast, GR is activated at high cortisol levels according to its effective halfway induction point, K GR . The GR receptor plays an important role in HPA feedback regulation, in which cortisol inhibits CRH and ACTH production ( Fig. 2 ). Download figure Open in new tab Figure 2: The HPA circuit diagram and corresponding equations. The hypothalamus H secretes corticotropin-releasing hormone (CRH) at a rate b 1 in response to a stressor input u . CRH causes the pituitary (P) to secrete adrenocorticotropic hormone (ACTH) at a rate b 2 and to grow in functional mass at a rate b P . ACTH signals the adrenal gland (A) to secrete cortisol at rate b 3 and to grow in functional mass at rate b A . Cortisol inhibits ACTH at the pituitary level through glucocorticoid receptors (GR) and at the level of the hypothalamus through both GR and mineralocorticoid receptors (MR). The hormone removal rates are a 1 , a 2, and a 3 for CRH, ACTH, and cortisol. Thick arrows indicate the interactions added in the Karin et al model that affect gland sizes on the scale of months. A corresponding equation is presented on the left of each interaction. We model individuals susceptible to PTSD using a low value of K GR , the effective halfway induction point of the cortisol receptor GR. Low K GR is known to be a risk factor for PTSD, whereas normal K GR characterizes resilience. Based on data extrapolated from the literature, we use K GR =2nM/L for PTSD and K GR =6nM/L for controls 58 , 59 . At steady state, the gland mass model predicts that low K GR results in mildly low cortisol and unchanged ACTH, as observed. At K GR =2nM/L, cortisol is lower by 9% than in K GR =6nM/L ( Fig. 3A ). Download figure Open in new tab Download figure Open in new tab Fig 3: HPA model with gland mass changes shows the PTSD dysregulation pattern of low cortisol and normal ACTH when GR sensitivity is high (low K GR ), together with elevated GR activity. A) Steady-state of HPA hormones, gland masses, and Average GR activation as a function of K GR . The yellow dashed line denotes the changes without the gland mass model, and the blue solid line denotes the changes with the addition of gland mass. B) Average GR activation as a function of K GR . Despite lower cortisol, GR activity is ∼20-fold higher at lower K GR . The intuitive reason for low cortisol is that at low K GR, a low cortisol level is sufficient to activate the negative feedback loops. Importantly, despite reduced cortisol, the activity of the GR receptor is higher in PTSD than in controls. Low cortisol is offset by even lower K GR ( Fig. 3B ). Based on experimental measurements, we model GR activity using a Hill function with cooperativity n=3. For K GR =2, the steady state GR receptor activity is about 20 times higher than in controls with K GR =6. The gland mass model also predicts a low adrenal cortex functional mass (by 9% at K GR =2nM/L). This is the reason for the unchanged ACTH at low K GR -the smaller adrenal cortex provides low cortisol at normal ACTH levels. Lower adrenal mass was documented in PTSD models in rats 60 , 61 . The model also predicts an enlarged pituitary corticotroph mass (by 9% at K GR =2nM/L). Human imaging studies found conflicting results on pituitary volume in PTSD 15 , 62 , 63 . However, the predicted enlargement in corticotroph mass size is below the detection ability of current imaging unless very large cohorts are tested (see Discussion) We note that the gland mass changes are essential to understanding the hormone changes when K GR is low. A model without gland mass changes shows low cortisol but also low ACTH ( Fig. 3A , dashed line). The mathematical reason for normal ACTH irrespective of K GR is the integral feedback loop on adrenal cortex mass growth that locks ACTH concentration (Karin et al. 2020 51 , Methods). The gland-mass model explains the blunted response to acute stressors in PTSD To validate our model dynamics, we explore the cortisol response to acute stress, which is known to be blunted in PTSD patients ( Fig. 4A ). For this purpose, we simulated a brief stress input pulse of twenty minutes, inspired by a Trier stress test. The HPA axis becomes stimulated and then declines to baseline after about two hours. Low K GR results in a blunted response of cortisol and ACTH compared with normal K GR ( Fig. 4B ). The gland masses show negligible change over this timescale. Download figure Open in new tab Figure 4. Blunted cortisol response to acute stress in PTSD patients is found in the HPA model when K GR is low. A) Empirical cortisol levels showing a blunted cortisol response in PTSD compared to control participants during the Trier Social Stress Test (TSST), replotted from Von Majewski et al., 2023 34 B) Simulated cortisol response in the HPA model after a 20-minute stress input. Low K GR =2 nM/L (PTSD-like) produces a blunted response compared to control K GR =6 nM/L. TSST was modeled by a 20-minute increase in input u by a factor of 6⅔. Download figure Open in new tab Fig 5. Reduced ACTH response in the Dex-CRH test in PTSD patients is captured by the model A) Clinical ACTH response data from Ströhle et al., 2008 64 . Participants received 1.5 mg oral dexamethasone at 11:00 PM. On the following day, blood samples were drawn at 2:00, 2:30, and 3:00 PM, followed by a bolus injection of 1 μg/kg ovine CRH at 3:00 PM (t = 0). B) Simulated ACTH dynamics from the gland-mass model. Dexamethasone is modeled as an exogenous GR agonist introduced at t = –14 h; CRH is introduced at t = 0. The PTSD group has K GR =2nM/L; the control group, K GR =6nM/L. The model reproduces the lower ACTH baseline and reduced peak response in PTSD. Download figure Open in new tab Fig.6 Parametric plot of cortisol steady-state levels and GR sensitivity. We analytically solved the fast-timescale version of the gland-mass model to express cortisol concentration x3 as a function of the GR dissociation constant K GR . The plot shows that cortisol levels rise rapidly and saturate as GR sensitivity decreases (i.e., K GR increases). This result reflects how enhanced GR sensitivity (low K GR ) reduces cortisol due to stronger negative feedback. Dex-CRH test shows lower ACTH in PTSD due to low K GR To further test the validity of our model dynamics, we explore the Dexamethasone-CRH (Dex-CRH) test, an endocrine challenge used to assess the function of the HPA axis. In this test, patients receive a low dose of dexamethasone the evening before testing, followed by an intravenous CRH injection the next day. Blood samples are then collected to measure ACTH and cortisol responses. Dexamethasone is a potent agonist of GR (but not MR) and has a long lifetime in the body. We model this test by adding to the equations an exogenous ligand that activates GR and then, 14h later, exogenous CRH. The dex ligand reduces ACTH to a concentration about 2-fold lower in PTSD than in controls. Exogenous CRH then causes a rise in ACTH that plateaus after an hour-the plateau is about 2-fold lower in PTSD than in controls. These dynamics match the experiments by Ströhle et al 2008 64 . We conclude that low K GR , together with the HPA axis, with functional gland mass changes, can explain the observed HPA regulation in PTSD. GR growth inhibition of corticotrophs can provide elevated CRH Although elevated CRH levels are observed in PTSD, they likely arise, at least in part, from sources outside the HPA axis (see Discussion). Nevertheless, we explored whether an interaction could account for elevated CRH, normal ACTH, and reduced cortisol in the context of low KGR. Among all tested mechanisms, only one reproduced this profile: GR-mediated growth inhibition of pituitary corticotrophs. While evidence for this interaction exists in corticotroph tumor cells and animal models, it has yet to be validated in humans in vivo 65 – 69 Discussion We provide evidence for low cortisol in PTSD from a large medical dataset, and show how a systems model of the HPA axis explains the low cortisol paradox in PTSD using gland mass changes together with low K GR . This provides a mechanistic explanation for the observed dysregulation: low cortisol, normal ACTH, and blunted stress responses. Importantly, despite hypocortisolemia, GR activity is higher in PTSD due to low K GR . The model explains how normal ACTH can result in low cortisol, due to a reduced adrenal cortex mass in PTSD. Blunted responses to acute stress are explained by the model as well, and they are in agreement with observation. We conclude that the current understanding of the HPA axis with gland mass changes can account for the dysregulation observed in PTSD. The present analysis turns the cortisol paradox on its head. Instead of saying that cortisol is too low in PTSD, we see that cortisol is not low enough-as the ratio of cortisol/K GR is higher in PTSD. Thus, GR activity is predicted to be elevated in PTSD by a factor of 20. The model links the two most robust and well-replicated biological risk factors for PTSD: hypersensitivity of GR 22,36,70–75 and reduced hippocampal volume 76 – 82 . It demonstrates that low K GR leads to sustained GR activation, which is associated with hippocampal atrophy, including dendritic retraction, impaired neurogenesis, and overall volume loss 83 – 88 . Chronic elevation of GR activity has many other negative consequences. In the CNS it is associated with impairing learning, memory, and emotional regulation 84 , 88 – 90 inhibition of beta-endorphins, as observed in PTSD 91 , 92 , and downregulates neurotrophic factors and prefrontal cortex dysfunction 93 – 95 . Together, this may contribute to altered regulation of the hippocampus-amygdala-prefrontal circuitry 96 – 98 . Elevated GR activity is also associated with sleep disturbances, hypertension, metabolic dysregulation, cardiovascular disease, and vulnerability to depression and anxiety. Many of these pathologies are prevalent in PTSD patients 99 – 102 . The model also explains the dynamics in the Dex-CRH test. This test has proven useful in psychiatric research, including studies of PTSD. Unlike major depression, which is often associated with blunted dexamethasone suppression and elevated cortisol, PTSD is characterized by exaggerated dexamethasone suppression and reduced cortisol. This blunted response likely reflects increased glucocorticoid receptor (GR) sensitivity in the pituitary and hypothalamus. Several studies have demonstrated that PTSD patients exhibit greater cortisol suppression after dexamethasone, and a more pronounced ACTH and cortisol response to subsequent CRH administration 13 , 23 , 27 , 64 . In the model, the tonic changes in pituitary functional mass temper this effect, and the model provides a quantitative agreement with measurements. The HPA axis, like other endocrine axes, has traditionally been modeled without taking changes of gland masses into account, because models have focused on the timescale of a day or a few hours. We find that gland masses are essential to understand dysregulation on the timescale of months. Without such gland-mass changes, the present model would not produce the dissociation of ACTH and cortisol levels seen in PTSD. Our model predicts a ∼ 9% increase in corticotroph functional mass when K GR is low. Corticotrophs constitute roughly 20% of the pituitary 103 , which has a total average volume of 405 ± 118 mm 3 in men and 494 ± 138 mm 3 in women 104 . The absolute change we therefore expect is only about 7-9 mm 3 on average, a shift that lies well below normal inter-individual variance and. Detecting such subtle enlargement remains an open challenge, as it would require large cohorts and high-resolution pituitary imaging, which, to our knowledge, has not yet been systematically attempted. Measurements of CRH are more challenging. Two studies found higher CRH in the CSF of PTSD patients compared to controls 105 , 106 with about 1.3 fold change. While studies of plasma CRH showed conflicting results 107 , 108 . Understanding CRH levels with the present model is complicated by the presence of other CRH sources that are abundant in the CNS outside of the HPA axis, such as the amygdala and BNST 109 – 113 , both hyperactive in PTSD and implicated in its pathophysiology 114 – 118 . These CNS sources of CRH are beyond the present scope. Interestingly, CRH is anxiogenic and its central administration or overexpression mimics the effects of acute stress and anxiety in rodents 119 – 123 . Elevated CRH in the brain may thus enhance or predispose PTSD symptoms. The present approach suggests putative targets for restoring normal HPA function in PTSD patients. The goal would be to normalize GR receptor activity rather than cortisol itself, by lowering cortisol further beyond its lowered baseline in PTSD. To do so, we can utilize an in-silico analysis of HPA drugs using the gland mass model, presented by Milo et al 2025 54 . That study showed that most interventions, such as GR receptor antagonists or hormone synthesis blockers, would not affect cortisol levels on the timescale of weeks or more because the gland masses adjust to compensate fully for the drugs. The only effective targets to lower cortisol involve CRH, such as anti-CRH antibodies. These interventions are expected to lower cortisol further in individuals with low K GR until GR activity returns to normal. According to the model, such treatment would leave CRH and ACTH levels unchanged (due to compensation by gland masses). Preclinical studies have shown that CRF1 receptor antagonists are effective under conditions of elevated CRH tone, suggesting a potential therapeutic window with minimized side effects 124 – 131 . Thus, CRH-directed therapies, including CRF1 antagonism and anti-CRH antibodies, represent mechanistically grounded strategies that align with both the biological and dynamical systems understanding of HPA dysregulation in PTSD. One concern is that excessive cortisol lowering could reduce the activity of its high-affinity receptor, the MR receptor, which is almost fully saturated at baseline cortisol levels 132 . Due to MRs tenfold higher affinity, a putative drug that lowers cortisol mildly to restore normal GR activity would not substantially impact MR signalling. If it does, a selective MR agonist is one way to restore GR/MR balance if cortisol is lowered to an extent that hampers MR signalling 133 . Limitations of this study include its reliance on evidence of HPA dysregulation in PTSD, which is supported by most but not all studies. Whereas most studies report normal ACTH, two found disrupted ACTH levels 134 , 135 . Whereas most studies report low cortisol, several found normal and even high cortisol 10 , 136 , 137 . The present data from the Clalit HMO bolsters the evidence for low cortisol in PTSD. Whereas most studies show blunted HPA responses to acute stress and dexamethasone tests, several studies did not 25 , 138 , 139 . This indicates that experimental conditions and sample heterogeneity may be necessary, and that the model may apply to only a subset of individuals. Another limitation is that the model lumps together GR receptor number and sensitivity into one parameter, K GR, for the sake of simplicity. A more complete model can address the pharmacokinetics and intracellular signaling circuitry of GR 140 , 141 . The model also focuses on long timescales and does not address factors such as HPA circadian and ultradian dynamics, which may be important 35 , 142 , 143 . In summary, we show that the paradox of low cortisol and normal ACTH in PTSD patients can be explained based on a well-established risk factor for PTSD, high GR sensitivity (low K GR ), together with gland-mass changes. The gland mass changes provide a decoupling between ACTH and cortisol that produces the observed pattern-smaller adrenal cortex mass can display low cortisol with normal ACTH. We also find that despite low cortisol, GR activity is elevated in PTSD because the cortisol/K GR ratio is higher, indicating that cortisol is not too low but rather too high relative to K GR sensitivity in PTSD. This study contributes to the physiological understanding of PTSD, which may guide future HPA-based treatments. Methods Clalit cortisol We analyzed cortisol tests in those aged 20-60. Table: Demographics age+/-, BMI +/-. The HPA gland mass model To investigate the influence of glucocorticoid receptor affinity (K GR ) on hypothalamic-pituitary-adrenal (HPA) axis dynamics, we employed the gland-mass model developed by Karin et al. (2020) 51 . This model captures the short- and long-term regulation of the HPA axis by coupling hormone secretion with dynamic changes in the functional masses of the pituitary and adrenal glands. The system is defined by five coupled ordinary differential equations (ODEs) representing hormone concentrations and gland masses. The model is thus of the following form: Where , . In response to an input stressor, u , the hypothalamus secretes CRH, x 1 , at a rate b 1 . CRH stimulates the corticotrophs at the pituitary, P , to secrete ACTH, x 2 , at a rate b 2 . ACTH signals the adrenal cortex, whose total functional mass is A , to secrete cortisol, x 3 , at a rate b 3 . Cortisol inhibits the production of CRH and ACTH by activating both mineralocorticoid (MR) and glucocorticoid (GR) receptors. GR has two parameters: K GR which represents the concentration of cortisol required to achieve half-maximal activation of the receptor, and n , the Hill coefficient, which reflects the cooperativity of cortisol binding. CRH, ACTH, and cortisol degrade at rates a 1 , a 2 and a 3 respectively. The gland-mass model includes the effects of CRH on the pituitary functional mass ( b P x 1 ) and of ACTH on the adrenal cortex functional mass ( b A x 2 ). Analytical solutions of the HPA model steady state Fast Dynamics (Minutes – Hours) In this timescale, glandular mass remains effectively static, as growth and atrophy occur over weeks to months. To analyze the fast-timescale responses, we focused on the hormonal dynamics by considering only the first three equations of the model, Eq.(1) - (3) . Solving for the steady state yields . These results imply that steady-state ACTH levels depend on cortisol steady state. However, this does not align with clinical findings in PTSD, where ACTH remains normal despite low cortisol levels 13 – 16 . This discrepancy suggests the necessity of explicitly considering glandular adaptation and steady-state gland masses to capture accurately the dynamics observed clinically. We can also derive the explicit relation between cortisol concentration x 3 and the dissociation constant K GR . Starting from the steady-state condition, we have: Solving explicitly for K GR gives a closed-form expression as a function of x 3 : To better understand this relationship, we set the combined parameter to 1, simplifying the expression to K . This allows us to plot a parametric plot of x 3 as a function of K GR . Notably, the dependence of cortisol on K GR is highly nonlinear. When K GR is large (above ∼3), indicating weak feedback, the cortisol level asymptotically approaches 1. In this regime, changes in GR sensitivity have little effect on cortisol output. However, as K GR decreases below this threshold, the system exhibits a steep decline in cortisol levels. In the regime of high GR sensitivity (very low K GR ), cortisol approaches extremely low levels, indicating strong negative feedback that effectively suppresses hormonal activity. Slow Dynamics (Weeks – Months) When considering the HPA axis on longer timescales of weeks to months, the pituitary and adrenal cortex gland masses cannot be assumed constant. Instead, they evolve dynamically through trophic interactions with upstream hormones. On this timescale, changes in gland functional mass dominate system behavior, and the hormonal concentrations gradually adapt to reflect glandular remodeling. At steady state, the gland-mass equations provide constraints that effectively pin the hormone levels of x 1 and x 2 to fixed values .The model predicts that at steady state, the adrenal cortex gland mass ( A * ) is positively correlated with cortisol concentration ( x 3 ), whereas the pituitary gland mass ( P * ) shows a negative correlation with cortisol. The steady-state gland masses are explicitly given by: , . Finally, the relation between K GR and x3 is , this relation is similar to the one in the fast timescale, and when we set the combined parameter to 1, we get , which is the same relation as from the fast time scale. Numerical simulations Trier Social Stress Test (TSST) simulation To simulate the Trier Social Stress Test (TSST), we modeled a transient increase in the external stress input u. Specifically, u were elevated by a factor of , for 20 minutes, representing the acute psychosocial challenge imposed during the TSST protocol. The simulation was run for 120 minutes, mirroring the duration tracked in Von Majewski et al. (2023). To better fit the model to empirical data, we used a baseline stress u=3, assuming that participants may have experienced elevated anticipatory stress due to their awareness of the upcoming task. PTSD patients were modeled with a growth rate constant K GR =2, whereas control participants were assigned K GR =6. DEX-CRH Dex-crh simulation We simulated the Dexamethasone-Corticotropin-Releasing Hormone (Dex-CRH) test by introducing exogenous CRH and modifying the dynamics of the HPA axis accordingly. The equation for CRH dynamics was defined as: To capture the suppressive effect of dexamethasone on ACTH secretion, we modified the glucocorticoid receptor (GR) feedback term as: This altered the ACTH dynamics, which were modeled as: Dexamethasone was excluded from the CRH production dynamics, as it crosses the blood-brain barrier minimally due to active efflux pumps. It was administered at time t=-14h, prior to the injection of exogenous CRH. The simulation was run for 75 minutes, matching the measured time in Ströhle et al. (2008) for direct comparison. Data and materials availability The source code for the simulation is available at the GitHub repository. The repository is open for public use: https://github.com/AlonLabWIS/hpa-dysregulation-ptsd Acknowledgements We thank all members of our lab, Amos Tanay, Neta Mendelsohn and Rami Jaschek for discussions. We thank Gabi Barabash and Ran Balicer for the Clalit−Weizmann collaboration. Data acquisition was approved by the Clalit Helsinki Committee RMC-1059-20. Footnotes https://github.com/AlonLabWIS/hpa-dysregulation-ptsd References 1. ↵ Diagnostic and Statistical Manual of Mental Disorders: DSM-5-TR TM . ( American Psychiatric Association Publishing , Washington, DC , 2022 ). 2. ↵ Doenyas-Barak , K. et al. Hyperbaric Oxygen Therapy for Veterans With Combat-Associated Posttraumatic Stress Disorder: A Randomized, Sham-Controlled Clinical Trial . J. Clin. Psychiatry 85 , ( 2024 ). 3. Mitchell , J. M. et al. MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial . Nat. Med . 29 , 2473 – 2480 ( 2023 ). OpenUrl CrossRef PubMed 4. Blakey , S. M. et al. 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Share A Mechanistic Model for the HPA Axis Cortisol Paradox in PTSD Dor Danan , Yaniv Grosskopf , Yoav Hayut , Yoel Toledano , Keren Doenyas-Barak , Avi Mayo , Uri Alon bioRxiv 2025.10.13.681561; doi: https://doi.org/10.1101/2025.10.13.681561 Share This Article: Copy Citation Tools A Mechanistic Model for the HPA Axis Cortisol Paradox in PTSD Dor Danan , Yaniv Grosskopf , Yoav Hayut , Yoel Toledano , Keren Doenyas-Barak , Avi Mayo , Uri Alon bioRxiv 2025.10.13.681561; doi: https://doi.org/10.1101/2025.10.13.681561 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Systems Biology Subject Areas All Articles Animal Behavior and Cognition (7635) Biochemistry (17691) Bioengineering (13892) Bioinformatics (41937) Biophysics (21452) Cancer Biology (18588) Cell Biology (25504) Clinical Trials (138) Developmental Biology (13378) Ecology (19899) Epidemiology (2067) Evolutionary Biology (24320) Genetics (15609) Genomics (22506) Immunology (17736) Microbiology (40394) Molecular Biology (17181) Neuroscience (88605) Paleontology (666) Pathology (2832) Pharmacology and Toxicology (4824) Physiology (7641) Plant Biology (15156) Scientific Communication and Education (2045) Synthetic Biology (4294) Systems Biology (9825) Zoology (2271)