Hypothalamic-pituitary-adrenal Axis Function Research Articles

Blunted Cortisol Awakening Response Is Associated with External Attribution Bias Among Individuals with Personality Disorders.

The dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been associated with various mental disorders. One of the most commonly described parameters of HPA axis functioning is the cortisol awakening response (CAR). To date, few studies have been conducted on the relationship between personality disorders and CAR. The present study aimed to compare the CAR between individuals with personality disorders and healthy controls. Moreover, the study aimed to assess the association of CAR with cognitive biases and psychopathological symptoms in people with personality disorders. A total of 43 individuals with personality disorders and 45 healthy controls were enrolled. Participants completed questionnaires measuring the severity of depressive symptoms, anxiety, cognitive biases, and psychotic-like experiences. Cortisol levels were measured in four morning saliva samples: immediately after awakening, and after 15, 30, and 45 min. A significantly lower CAR was found among individuals with personality disorders, even after adjustment for age, sex, and the level of education. However, the receiver operating characteristic (ROC) curve analysis showed a relatively low area under the curve (AUC = 0.362). Furthermore, a significant negative correlation was observed between the CAR and the level of external attribution bias among individuals with personality disorders. No significant associations of the CAR with psychopathological symptoms and other cognitive biases were observed. Findings from this study indicate that the HPA axis activity might be altered in personality disorders. However, the clinical utility of this observation needs further studies in larger samples. External attribution might be related to the HPA axis alterations in this population.

Long-term, Dynamic Remodelling of the Corticotroph Transcriptome and Excitability After a Period of Chronic Stress.

Chronic stress results in long-term dynamic changes at multiple levels of the hypothalamic-pituitary-adrenal (HPA) axis resulting in stress axis dysregulation with long-term impacts on human and animal health. However, the underlying mechanisms and dynamics of altered of HPA axis function, in particular at the level of pituitary corticotrophs, during a period of chronic stress and in the weeks after its cessation (defined as "recovery") are very poorly understood. Here, we address the fundamental question of how a period of chronic stress results in altered anterior pituitary corticotroph function and whether this persists in recovery, as well as the transcriptomic changes underlying this. We demonstrate that, in mice, spontaneous and corticotrophin-releasing hormone-stimulated electrical excitability of corticotrophs, essential for ACTH secretion, is suppressed for weeks to months of recovery following a period of chronic stress. Surprisingly, there are only modest changes in the corticotroph transcriptome during the period of stress, but major alterations occur in recovery. Importantly, although transcriptional changes for a large proportion of mRNAs follow the time course suppression of corticotroph excitability, many other genes display highly dynamic transcriptional changes with distinct time courses throughout recovery. Taken together, this suggests that chronic stress results in complex dynamic transcriptional and functional changes in corticotroph physiology, which are highly dynamic for weeks following cessation of chronic stress. These insights provide a fundamental new framework to further understand underlying molecular mechanisms as well approaches to both diagnosis and treatment of stress-related dysfunction of the HPA axis.

Regulation of 11β-HSD1 reductase and the HPA axis by long-snake moxibustion in kidney-yang deficiency rats

BackgroundLong-snake moxibustion can improve hypothalamic-pituitary-adrenal (HPA) axis function in patients with kidney-yang deficiency (KYDS). 11β-HSD1 controls the HPA axis by boosting CORT production via reductase activity. However, the interaction and mechanism of long snake moxibustion and 11β-HSD1 remain unknown. This study examined the impact of lengthy snake moxibustion on the hypothalamus-pituitary-adrenal axis in KYDS rats. The potential significance of 11β-HSD1 in this process was explored. MethodsRats were randomly divided into two groups: the blank group and the experimental group. The KYDS model was established with an intramuscular injection of hydrocortisone. Rats were randomly assigned to four groups: model, sham intervention, long snake moxibustion, and long snake moxibustion plus 11β-HSD1 inhibitor. Physical indicators included body weight, toe temperature, rectal temperature, and spontaneous movement. The serum levels of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and CORT were measured. Immunohistochemical examination reveals 11β-HSD1 protein expression in the liver. Western blotting (WB) detected the levels of 11β-HSD1, H6PDH and NADPH/NADP + protein in the liver. ResultsThe experimental rats' body weight, toe temperature, rectal temperature, time and frequency of spontaneous activity all dropped, as did their serum ACTH, CORT, and CRH levels. The protein expressions of 11β-HSD1, H6PDH, and NADPH/NADP+ in the liver decreased significantly. Long-snake moxibustion improved HPA axis function in rats, boosting expression of 11β-HSD1, H6PDH, and NADPH/NADP+. Adding an 11β-HSD1 inhibitor to Long-snake moxibustion decreased its effect on the HPA axis. ConclusionLong-snake moxibustion improves KYDS symptoms in rats by increasing 11β-HSD1 expression and reductase activity, which regulates the HPA axis.

Early life stress influences epilepsy outcomes in mice.

Stress is a common seizure trigger that has been implicated in worsening epilepsy outcomes. The neuroendocrine response to stress is mediated by the hypothalamic-pituitary-adrenal (HPA) axis and HPA axis dysfunction worsens epilepsy outcomes, increasing seizure burden, behavioral comorbidities, and risk for sudden unexpected death in epilepsy (SUDEP) in mice. Early life stress (ELS) reprograms the HPA axis into adulthood, impacting both the basal and stress-induced activity. Thus, we propose that ELS may influence epilepsy outcomes by influencing the function of the HPA axis. To test this hypothesis, we utilized the maternal separation paradigm and examined the impact on seizure susceptibility. We show that ELS exerts a sex dependent effect on seizure susceptibility in response to acute administration of the chemoconvulsant, kainic acid, which is associated with an altered relationship between seizure activity and HPA axis function. To further examine the impact of ELS on epilepsy outcomes, we utilized the intrahippocampal kainic acid model of chronic epilepsy in mice previously exposed to maternal separation. We find that the relationship between corticosterone levels and the extent of epileptiform activity is altered in mice subjected to ELS. We demonstrate that ELS impacts behavioral outcomes associated with chronic epilepsy in a sex-dependent manner, with females being more affected. We also observe reduced mortality (presumed SUDEP) in female mice subjected to ELS, consistent with previous findings suggesting a role for HPA axis dysfunction in SUDEP risk. These data demonstrate for the first time that ELS influences epilepsy outcomes and suggest that previous life experiences may impact the trajectory of epilepsy.

Luteal phase sertraline treatment of premenstrual dysphoric disorder (PMDD): Effects on markers of hypothalamic pituitary adrenal (HPA) axis activation and inflammation

RationalePremenstrual dysphoric disorder (PMDD) is characterized by severe affective symptoms during the luteal phase of the menstrual cycle. There is some evidence of altered interactions between the hypothalamic pituitary gonadal (HPG) and hypothalamic pituitary adrenal (HPA) axes in PMDD. There is also evidence that similar affective disorders such as major depression and perinatal depression are associated with dysregulation in immune factors, but this has not been characterized in PMDD. AimsThe goals of this exploratory study were to identify 1) whether HPA-HPG axis interactions and immune markers differ between PMDD patients and controls across the menstrual cycle; 2) how luteal phase sertraline treatment impacts stress and inflammatory markers. MethodsParticipants were females age 18–50 with regular menstrual cycles, not using psychotropic or hormonal medications, and were assigned to a control group or PMDD group based on prospective daily symptom ratings and clinical interview. Blood was drawn in the follicular and luteal phases, during laboratory sessions involving a mildly stressful task. In a second luteal phase, PMDD participants received open-label sertraline (50 mg/d) from ovulation to menses. Serum cortisol and ACTH were measured via ELISA and operationalized as area under the curve with respect to ground (AUCg), and peak level following laboratory task. Serum TNF-α, IL-6, CXCL-8, and IL-1β were measured using multiplex kits. Serum allopregnanolone (ALLO) was measured by gas chromatography/mass spectroscopy. To characterize HPA-HPG axis interactions across the menstrual cycle in PMDD participants and controls, multilevel linear models predicted cortisol and ACTH from the interaction of cycle phase (controlling for sertraline treatment), ALLO, and group. To determine the effects of sertraline treatment on inflammatory markers and how groups might differ in cyclical change on each marker, multilevel linear models predicted inflammatory markers from cycle phase (controlling for sertraline treatment) and group. A final set of exploratory models tested whether inflammatory markers predict premenstrual symptom score severity. ResultsThe sample included n=77 participants (41 controls, 36 PMDD); 28 participants with PMDD completed sertraline treatment. Group x phase x ALLO interactions showed that higher ALLO levels predicted lower cortisol peak in the treated luteal phase (interaction between phase and ALLO, p=0.042), and there was a higher cortisol peak in the treated luteal phase than the untreated luteal phase (p=0.038). CXCL-8 was significantly associated with premenstrual symptom severity after controlling for group and cycle phase (p=0.011). There were no main effects of group, phase, or ALLO on cortisol AUCg, ACTH AUCg, IL-6, CXCL-8, IL-1β, nor TNF-α (p’s>0.05). ConclusionSerum markers of HPA axis and immune function did not vary by menstrual cycle phase nor PMDD status. However, sertraline treatment in the luteal phase was associated with higher ALLO levels predicting lower cortisol peak in response to mild laboratory stress, suggesting that sertraline treatment may normalize HPG-HPA axis interactions among individuals with PMDD. Greater premenstrual symptomatology was associated with higher levels of the inflammatory marker CXCL-8, but further research is needed into the potential role of inflammation in PMDD.

Longitudinal analysis of cortisol changes during pubertal development in indigenous Qom girls.

Pubertal research has primarily focused on hypothalamic-pituitary-gonadal axis (HPG) regulation of puberty, though the hypothalamic-pituitary-adrenal axis (HPA) is increasingly considered critical. Heightened HPA function proxied by increasing cortisol levels may play a role in accelerated pubertal timing. However, the extent to which cortisol varies across ages and its relation to pubertal changes in linear growth are less well substantiated. We explored relationships between age, linear growth, adiposity, C-peptide (proxy for insulin), and cortisol across puberty, and we tested whether higher cortisol levels are associated with earlier ages at menarche and peak height velocity. We utilize longitudinal data (n = 777 urine samples) from Qom females ages 7-14 (n = 46) and test our pre-registered analysis using Bayesian longitudinal mixed effects models and joint modeling techniques. We find limited evidence supporting the overarching hypothesis that HPA upregulation is associated with pubertal maturation or timing. We find some evidence that HPA upregulation, as proxied by cortisol, may be more clearly related to differences in relative linear growth at early-mid puberty, as measured by height-for-age z-scores. Transdisciplinary perspectives on puberty, including the assumption that stressors acting via cortisol accelerate pubertal development, are discussed.

Association of perinatal characteristics with biomarkers of stress and inflammation in young adults: An exploratory study

General peri- and postnatal characteristics may serve as markers linking pre- or early postnatal events to later health outcomes, which in turn are associated with altered stress- and immune system activity. Our exploratory study investigated whether A) the common perinatal measures “birth weight” and “birth mode” and B) the postnatal characteristics “breastfeeding” and “vaccination status” are associated with markers of stress systems – the hypothalamic-pituitary-adrenal (HPA) axis and autonomous nervous system (ANS) – and inflammation in healthy young adults (n = 68, females: 70.6 %, mean age: 24.21 years, SD = 4.38) exposed to psychosocial challenge, the ‘Trier Social Stress Test’ (TSST). Salivary cortisol, alpha-amylase (sAA) and plasma interleukin-6 (IL-6) were assessed before, during and after the TSST. Participants provided information on peri- and postnatal characteristics. Linear regressions were performed to determine whether peri-/postnatal variables predict basal and stress-response-related biomarker levels. Controlling for sex and sex hormone use as relevant confounders, we found a significant association between birth weight and cortisol recovery (p = 0.032), with higher birth weight predicting higher cortisol recovery values. There were no other significant associations between predictor and outcome variables. Our results show that, in healthy young adults of mixed gender, normal-ranged birth weight is related to the cortisol response to psychosocial stress, indicating a long-term association of this perinatal marker with HPA axis function. In contrast, birth weight was not associated with markers of the ANS stress response or inflammation in adulthood. Our results further suggest that the measures birth mode, duration of breastfeeding, and vaccination status at 4 months of age do not relate to markers of the inflammatory and stress systems in adulthood.

The Glucocorticoid Taper: A Primer for the Clinicians.

Glucocorticoid (GC) therapy can ameliorate debilitating and life-threatening symptoms in several inflammatory/immunological disorders. However, it can also cause significant side effects, especially with higher doses and longer duration of use. Therefore, GCs should be used at the lowest effective dose for the shortest possible time to minimise adverse effects. GC therapy may cause suppression of the endogenous hypothalamic-pituitary-adrenal (HPA) axis and abrupt discontinuation predisposes patients to features of GC-induced adrenal insufficiency. The practice of tapering GC therapy allows for recovery of the HPA axis while minimising the risk of a disease flare-up or symptoms of AI. Moderate-to-high dose GC therapy may be tapered rapidly to near-physiological doses while watching for features of disease reactivation. Once close to the physiological dose, tapering is slower and at longer intervals to allow for recovery of the HPA axis. It is important to use short- or intermediate-acting GC preparations such as hydrocortisone or prednisolone in physiological doses, administered in the morning to mimic the endogenous cortisol rhythm. A general principle to follow is that HPA axis recovery takes longer if the period of suppression has been long. In such cases, tapering should be slower over a few months to even a year. In select cases at high risk of AI or if symptoms appear during tapering, the decision to further taper and discontinue steroids may be based on testing of HPA axis function using basal and/or stimulated serum cortisol. All patients on exogenous steroids should be advised about the need for an appropriate increase in GC doses during acute medical or surgical illness and should carry a steroid alert card to avoid adrenal crisis.

A Review of Fetal Development in Pregnancies with Maternal Type 2 Diabetes Mellitus (T2DM)-Associated Hypothalamic-Pituitary-Adrenal (HPA) Axis Dysregulation: Possible Links to Pregestational Prediabetes.

Research has identified fetal risk factors for adult diseases, forming the basis for the Developmental Origins of Health and Disease (DOHaD) hypothesis. DOHaD suggests that maternal insults during pregnancy cause structural and functional changes in fetal organs, increasing the risk of chronic diseases like type 2 diabetes mellitus (T2DM) in adulthood. It is proposed that altered maternal physiology, such as increased glucocorticoid (GC) levels associated with a dysregulated hypothalamic-pituitary-adrenal (HPA) axis in maternal stress and T2DM during pregnancy, exposes the fetus to excess GC. Prenatal glucocorticoid exposure reduces fetal growth and programs the fetal HPA axis, permanently altering its activity into adulthood. This programmed HPA axis is linked to increased risks of hypertension, cardiovascular diseases, and mental disorders in adulthood. With the global rise in T2DM, particularly among young adults of reproductive age, it is crucial to prevent its onset. T2DM is often preceded by a prediabetic state, a condition that does not show any symptoms, causing many to unknowingly progress to T2DM. Studying prediabetes is essential, as it is a reversible stage that may help prevent T2DM-related pregnancy complications. The existing literature focuses on HPA axis dysregulation in T2DM pregnancies and its link to fetal programming. However, the effects of prediabetes on HPA axis function, specifically glucocorticoid in pregnancy and fetal outcomes, are not well understood. This review consolidates research on T2DM during pregnancy, its impact on fetal programming via the HPA axis, and possible links with pregestational prediabetes.

Pregestational Prediabetes Induces Maternal Hypothalamic-Pituitary-Adrenal (HPA) Axis Dysregulation and Results in Adverse Foetal Outcomes.

Maternal type 2 diabetes mellitus (T2DM) has been shown to result in foetal programming of the hypothalamic-pituitary-adrenal (HPA) axis, leading to adverse foetal outcomes. T2DM is preceded by prediabetes and shares similar pathophysiological complications. However, no studies have investigated the effects of maternal prediabetes on foetal HPA axis function and postnatal offspring development. Hence, this study investigated the effects of pregestational prediabetes on maternal HPA axis function and postnatal offspring development. Pre-diabetic (PD) and non-pre-diabetic (NPD) female Sprague Dawley rats were mated with non-prediabetic males. After gestation, male pups born from the PD and NPD groups were collected. Markers of HPA axis function, adrenocorticotropin hormone (ACTH) and corticosterone, were measured in all dams and pups. Glucose tolerance, insulin and gene expressions of mineralocorticoid (MR) and glucocorticoid (GR) receptors were further measured in all pups at birth and their developmental milestones. The results demonstrated increased basal concentrations of ACTH and corticosterone in the dams from the PD group by comparison to NPD. Furthermore, the results show an increase basal ACTH and corticosterone concentrations, disturbed MR and GR gene expression, glucose intolerance and insulin resistance assessed via the Homeostasis Model Assessment (HOMA) indices in the pups born from the PD group compared to NPD group at all developmental milestones. These observations reveal that pregestational prediabetes is associated with maternal dysregulation of the HPA axis, impacting offspring HPA axis development along with impaired glucose handling.

Cortisol awakening response in bipolar patients with comorbid type 2 diabetes mellitus

IntroductionBipolar Disorder (BD) is a severely debilitating psychiatric disorder with high rates of morbidity and mortality, and patients with BD have a 10-year reduction in their life expectancy. Bipolar disorder (BD) is frequently associated with type 2 diabetes mellitus (T2DM). BD patients with comorbid T2DM have been shown to have three times higher odds of a chronic course and rapid cycling and are more likely to present worse outcomes to treatment with lithium and/or other mood stabilisers when compared to BD patients without IGM (impaired glucose metabolism).ObjectivesThe functioning of the hypothalamic-pituitary-adrenal (HPA) axis has been never investigated in BD with respect to the glucose metabolic status. Therefore, we assessed the cortisol awakening response (CAR) in bipolar patients with or without comorbid T2DM.MethodsTwenty euglycemic bipolar patients [12 males and eight females; mean age (±SD): 47.4 ± 14.4 years; mean (±SD) duration of illness: 18.3 ± 12.1 years], 16 BD patients with T2DM [11 males and five females; mean age (±SD): 63.6 ± 12.8 years; mean (±SD) duration of bipolar illness: 17.1 ± 10.8 years; mean (±SD) duration of T2DM: 5.2 ± 5.3 years], 18 healthy subjects [seven males and 11 females; mean age (±SD): 45.0 ± 12.1 years] and 12 non-psychiatric subjects with T2DM [eight males and four females; mean age (±SD): 56.7 ± 11.2 years; mean (±SD) duration of T2DM: 5.2 ± 3.5 years] were recruited. Saliva cortisol was measured at awakening and after 15, 30, and 60 min.ResultsWith respect to both healthy controls and controls with T2DM, euglycemic and diabetic BD patients exhibited a CAR occurring at significantly lower levels. No significant difference emerged in the CAR between the two groups of bipolar patients. Controls with T2DM had an overall post-awakening cortisol production significantly higher than healthy controls.ConclusionsOur results show that the CAR of patients with BD is reduced in terms of overall cortisol production but normal in terms of cortisolo reactivity independently from the occurrence of comorbid T2DM. The dampened CAR points to a tuning down of the functioning of the HPA axis in both euglycemic and diabetic BD patients, which may be a factor of vulnerability, since a preserved HPA axis functioning is essential to deal with stressors, which may precipitate affective episodesDisclosure of InterestNone Declared

Hair cortisol and changes in cortisol dynamics in chronic kidney disease.

We compared hair cortisol (HC) with classic tests of the hypothalamic-pituitary-adrenal (HPA) axis in chronic kidney disease (CKD) and assessed its association with kidney and cardiometabolic status. A cross-sectional study of 48 patients with CKD stages I-IV, matched by age, sex, and BMI with 24 healthy controls (CTR) was performed. Metabolic comorbidities, body composition, and HPA axis function were studied. A total of 72 subjects (age 52.9 ± 12.2 years, 50% women, BMI 26.2 ± 4.1 kg/m2) were included. Metabolic syndrome features (hypertension, dyslipidaemia, glucose, HOMA-IR, triglycerides, waist circumference) and 24-h urinary proteins increased progressively with worsening kidney function (p < 0.05 for all). Reduced cortisol suppression after 1-mg dexamethasone suppression (DST) (p < 0.001), a higher noon (12:00 h pm) salivary cortisol (p = 0.042), and salivary cortisol AUC (p = 0.008) were seen in CKD. 24-h urinary-free cortisol (24-h UFC) decreased in CKD stages III-IV compared with I-II (p < 0.001); higher midnight salivary cortisol (p = 0.015) and lower suppressibility after 1-mg DST were observed with declining kidney function (p < 0.001). Cortisol-after-DST cortisol was >2 mcg/dL in 23% of CKD patients (12.5% in stage III and 56.3% in stage IV); 45% of them had cortisol >2 mcg/dL after low-dose 2-day DST, all in stage IV (p < 0.001 for all). Cortisol-after-DST was lineally inversely correlated with eGFR (p < 0.001). Cortisol-after-DST (OR 14.9, 95% CI 1.7-103, p = 0.015) and glucose (OR 1.3, 95% CI 1.1-1.5, p = 0.003) were independently associated with eGFR <30 mL/min/m2). HC was independently correlated with visceral adipose tissue (VAT) (p = 0.016). Cortisol-after-DST (p = 0.032) and VAT (p < 0.001) were independently correlated with BMI. Cortisol-after-DST and salivary cortisol rhythm present progressive alterations in CKD patients. Changes in cortisol excretion and HPA dynamics in CKD are not accompanied by significant changes in long-term exposure to cortisol evaluated by HC. The clinical significance and pathophysiological mechanisms explaining the associations between HPA parameters, body composition, and kidney damage warrant further study.

Relationships between cortisol levels across early childhood and processing speed at age 4.5 years in children born very preterm

ABSTRACT Children born very low gestational age (VLGA, 29–32 weeks gestational age [GA]) display slower processing speed and altered hypothalamic pituitary adrenal (HPA) axis function, with greater effects in those born extremely low gestational age (ELGA; 24–28 weeks GA). We investigated trajectories of HPA axis activity as indexed by cortisol output and patterns across cognitive assessment at ages 1.5, 3 and 4.5 years, comparing children born ELGA and VLGA and associations with 4.5-year processing speed. In a prospective longitudinal cohort study, infants born very preterm (<33 weeks gestation) returned for developmental assessment at ages 1.5, 3, and 4.5 years. At each age, children completed standardized cognitive testing and saliva samples collected before (Pretest), during (During) and after (End) challenging cognitive tasks were assayed for cortisol. For the total group (n = 188), cortisol area under the curve with respect to ground (AUCg) decreased, while cortisol reactivity to challenge (Pre-test to During) increased from 1.5 to 3 years, remaining stable to 4.5 years. This longitudinal pattern was related to higher Processing Speed (WPPSI-IV) scores at 4.5 years. Children born ELGA displayed higher AUCg than VLGA, particularly at age 3, driven by higher Pre-test cortisol levels. Overall, relative to those born VLGA, children born ELGA displayed greater cortisol responsivity to cognitive challenge. A higher setpoint of cortisol levels at age 3-years in children born ELGA may reflect altered HPA axis regulation more broadly and may contribute to difficulties with information processing in this population, critical for academic and social success.

Two Adverse Early Life Events Induce Differential Changes in Brain CRH and Serotonin Systems in Rats along with Hyperphagia and Depression.

Different types of stress inflicted in early stages of life elevate the risk, among adult animals and humans, to develop disturbed emotional-associated behaviors, such as hyperphagia or depression. Early-life stressed (ELS) adults present hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis, which is a risk factor associated with mood disorders. However, the prevalence of hyperphagia (17%) and depression (50%) is variable among adults that experienced ELS, suggesting that the nature, intensity, and chronicity of the stress determines the specific behavioral alteration that those individuals develop. We analyzed corticosterone serum levels, Crh, GR, Crhr1 genes expression in the hypothalamic paraventricular nucleus, amygdala, and hippocampus due to their regulatory role on HPA axis in adult rats that experienced maternal separation (MS) or limited nesting material (LNM) stress; as well as the serotonergic system activity in the same regions given its association with the corticotropin-releasing hormone (CRH) pathway functioning and with the hyperphagia and depression development. Alterations in dams' maternal care provoked an unresponsive or hyper-responsive HPA axis function to an acute stress in MS and LNM adults, respectively. The differential changes in amygdala and hippocampal CRH system seemed compensating alterations to the hypothalamic desensitized glucocorticoids receptor (GR) in MS or hypersensitive in LNM. However, both adult animals developed hyperphagia and depression-like behavior when subjected to the forced-swimming test, which helps to understand that both hypo and hypercortisolemic patients present those disorders. Different ELS types induce neuroendocrine, brain CRH and 5-hydroxytriptamine (5-HT) systems' alterations that may interact converging to develop similar maladaptive behaviors.

Vagus nerve damage increases alcohol intake and preference in a nonpreferring rat line: Relationship to vagal regulation of the hypothalamic-pituitary-adrenal axis.

Clinical and preclinical research indicates that gastric weight loss surgeries, such as Roux-en-Y gastric bypass surgery, can induce alcohol use disorder (AUD). While numerous mechanisms have been proposed for these effects, one relatively unexplored potential mechanism is physical damage to the gastric branch of the vagus nerve, which can occur during bypass surgery. Therefore, we hypothesized that direct damage to the gastric branch of the vagus nerve, without altering other aspects of gastric anatomy, could result in increased alcohol intake. To test this hypothesis, we compared alcohol intake and preference in multiple models in male Sprague-Dawley rats that received selective gastric branch vagotomy (VX) with rats who underwent sham surgery. Because the vagus nerve regulates hypothalamic-pituitary-adrenal (HPA) axis function, and alterations to HPA function are critical to the escalation of non-dependent alcohol intake, we also tested the hypothesis that gastric VX increases HPA function. We found that VX increases alcohol intake and preference in the every-other-day, two-bottle choice test and increases preference for 1 g/kg alcohol in the conditioned place preference test. The effects were selective for alcohol, as sucrose intake and preference were not altered by VX. We also found that VX increases corticotropin releasing factor (CRF) mRNA in the paraventricular nucleus of the hypothalamus (PVN), increases putative PVN CRF neuronal action potential firing, and increases corticosterone levels. Overall, these findings suggest that the vagus nerve may play a critical role in regulating HPA axis function via modulation of PVN CRF mRNA expression and putative PVN CRF neuronal activity. Furthermore, disruptions to vagal regulation of HPA axis function may increase alcohol intake and preference.

A Retrospective Study on Weaning Glucocorticoids and Recovery of the Hypothalamic-Pituitary-Adrenal Axis.

Glucocorticoids suppress the hypothalamic-pituitary-adrenal (HPA) axis, resulting in tertiary adrenal insufficiency (AI). When weaning patients off glucocorticoids there is no consensus on whether to maintain patients on prednisolone or convert to hydrocortisone. To investigate HPA axis recovery in patients on long-term prednisolone and assess outcome after hydrocortisone conversion. This was a retrospective cohort study at an outpatient endocrine steroid clinic. Patients were on long-term prednisolone and referred for HPA axis testing between 2015 and 2022. The main outcomes measured were (1) HPA axis recovery rate in patients on prednisolone demonstrated by a normal adrenocorticotrophic hormone (ACTH) stimulation test (AST) and (2) HPA axis recovery rate subanalysis of dose-matched patients with confirmed tertiary AI on prednisolone or hydrocortisone were measured. In total, 206 patients on prednisolone were tested for tertiary AI. Of these, 176 remained on prednisolone while 30 were converted to hydrocortisone. The overall HPA axis recovery rate for patients on prednisolone after interval testing was 137/206 (66.5%). The HPA axis recovery rate in dose-matched prednisolone and hydrocortisone conversion groups was 7/10 (70%) and 2/13 (15%) (P = .008), respectively. There was no difference in mean (SD) age (67.1 [12.2] vs 63.4 [11.1] years; P = .464) and baseline cortisol (5.3 [4.2] vs 4.6 [3.1] µg/dL; P = .648) and median [interquartile, IQR] glucocorticoid duration (1213 [1114] vs 2316 [4808] days; P = .693) and baseline ACTH (20.5 [29.0] vs 16.3 [14.8] ng/L; P = .905) between dose-matched prednisolone and hydrocortisone groups. Follow-up duration in the prednisolone group was significantly lower (median [IQR] 348 [975] vs 667 [884] days; P = .012). Patients with glucocorticoid-induced AI maintained on once-daily prednisolone can recover HPA axis function when weaning. There is no apparent advantage to recover HPA axis function in converting to multiple-dosing hydrocortisone.

Imaging a putative marker of brain cortisol regulation in alcohol use disorder

BackgroundStress is a potent activator of the hypothalamic-pituitary-adrenal (HPA) axis, initiating the release of glucocorticoid hormones, such as cortisol. Alcohol consumption can lead to HPA axis dysfunction, including altered cortisol levels. Until recently, research has only been able to examine peripheral cortisol associated with alcohol use disorder (AUD) in humans. We used positron emission tomography (PET) brain imaging with the radiotracer [18F]AS2471907 to measure 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a cortisol-regenerating enzyme, in people with AUD compared to healthy controls. MethodsWe imaged 9 individuals with moderate to severe AUD (5 men, 4 women; mean age = 38 years) and 12 healthy controls (8 men, 4 women; mean age = 29 years). Participants received 93.5 ± 15.6 MBq of the 11β-HSD1 inhibitor radiotracer [18F]AS2471907 as a bolus injection and were imaged for 150–180 min on the High-Resolution Research Tomograph. 11β-HSD1 availability was quantified by [18F]AS2471907 volume of distribution (VT; mL/cm3). A priori regions of interest included amygdala, anterior cingulate cortex (ACC), hippocampus, ventromedial PFC (vmPFC) and caudate. ResultsIndividuals with AUD consumed 52.4 drinks/week with 5.8 drinking days/week. Healthy controls consumed 2.8 drinks/week with 1.3 drinking days/week. Preliminary findings suggest that [18F]AS2471907 VT was higher in amygdala, ACC, hippocampus, vmPFC, and caudate of those with AUD compared to healthy controls (p < 0.05). In AUD, vmPFC [18F]AS2471907 VT was associated with drinks per week (r = 0.81, p = 0.01) and quantity per drinking episode (r = 0.75, p = 0.02). ConclusionsThis is the first in vivo examination of 11β-HSD1 availability in individuals with AUD. Our data suggest higher brain availability of the cortisol-regenerating enzyme 11β-HSD1 in people with AUD (vs. controls), and that higher vmPFC 11β-HSD1 availability is related to greater alcohol consumption. Thus, in addition to the literature suggesting that people with AUD have elevated peripheral cortisol, our findings suggest there may also be heightened central HPA activity. These findings set the foundation for future hypotheses on mechanisms related to HPA axis function in this population.

Examining Reactivity and Recovery Patterns of Pain-Evoked Cortisol and Alpha-Amylase Trajectories: Relations Between Psychological Markers of Risk and Resilience

Chronic low back pain (cLBP) is one of the leading causes of disability globally and represents an enormous burden to aging adults. While numerous factors contribute to cLBP, dysregulation in the hypothalamic-pituitary-adrenal axis and autonomic nervous system functioning have been implicated in its pathogenesis. It is well documented that negative psychological states can modulate biological stress responsivity in chronic pain; however, little is known regarding the influence of positive psychological factors in this relationship. The aim of this study was to examine the association between psychological risk and resilience factors with patterns of physiological stress reactivity and recovery in 60 older adults with cLBP. Participants completed measures of hope, optimism, pain catastrophizing, and perceived stress, and underwent psychophysical pain testing assessing responses to painful pressure, heat, and cold stimuli. Salivary samples were obtained prior to pain induction and at 7 time points spanning 90 minutes after pain testing terminated. To examine reactivity and recovery profiles in hypothalamic-pituitary-adrenal axis and autonomic nervous system function, samples were assayed for cortisol and alpha-amylase, respectively. Results revealed higher levels of hope and optimism were associated with increased cortisol reactivity (p’s < .003) and more rapid recovery (p’s = .001). Further, pain catastrophizing and perceived stress were associated with cortisol reactivity, with lower levels of these factors predicting larger increases in cortisol from baseline to peak levels (p’s < .04). No significant differences in reactivity or recovery patterns emerged for alpha-amylase. Overall, findings highlight the role of psychological risk and resilience factors in modulating physiological stress reactivity. PerspectiveThis article investigated whether psychosocial risk and resilience factors were associated with stress reactivity and recovery in response to laboratory-based pain testing in older adults with chronic low back pain. Results indicate that high resilience factors may be protective by modulating adrenocortical reactivity and recovery profiles.

Blood mRNA expression levels of glucocorticoid receptors and FKBP5 are associated with depressive disorder and altered HPA axis

BackgroundWhile depression has been associated with alterations in the hypothalamic-pituitary adrenal (HPA) axis function, there is still controversy regarding the nature and extent of the dysfunction, such as in the debate about hypercortisolism vs. hypocortisolism. It may therefore be necessary to understand whether and how HPA axis function in depression is linked to mRNA expression of key genes regulating this system. MethodsWe studied 163 depressed outpatients, most of whom were chronically ill, and 181 healthy controls. Blood mRNA expression levels of NR3C1 (including GRα, GRβ, and GR-P isoforms), FKBP4, and FKBP5 were measured at baseline. HPA axis feedback sensitivity was measured by the dexamethasone (Dex)/corticotropin-releasing hormone (CRH) test. The association between mRNA expression levels and HPA axis feedback sensitivity was examined. ResultsCompared to controls, patients showed significantly higher expression of GRα and lower expression of FKBP5, and higher post-Dex cortisol levels, even after controlling for age and sex. FKBP5 expression was significantly positively correlated with cortisol levels in patients, while GRα expression was significantly negatively correlated with cortisol levels in controls. LimitationsMost patients were taking psychotropic medications. The large number of correlation tests may have caused type I errors. ConclusionsThe tripartite relationship between depression, mRNA expression of GR and FKBP5, and HPA axis function suggests that the altered gene expression affects HPA axis dysregulation and, as a result, impacts the development and/or illness course of depressive disorder. The combination of increased GRα expression and decreased FKBP5 expression may serve as a biomarker for chronic depression.

The role of the hypothalamic-pituitary-adrenal axis in depression across the female reproductive lifecycle: current knowledge and future directions.

The aim of this narrative review is to consolidate knowledge on the role of the hypothalamic-pituitary-adrenal (HPA) axis in depression pathophysiology at different reproductive stages across the female lifespan. Despite growing evidence about the impact of gonadal hormones on mood disorders, no previous review has examined the interaction between such hormonal changes and the HPA axis within the context of depressive disorders in women. We will focus on HPA axis function in depressive disorders at different reproductive stages including the menstrual cycle (e.g., premenstrual dysphoric disorder [PMDD]), perinatally (e.g., postpartum depression), and in perimenopausal depression. Each of these reproductive stages is characterized by vast physiological changes and presents major neuroendocrine reorganization. The HPA axis is one of the main targets of such functional alterations, and with its key role in stress response, it is an etiological factor in vulnerable windows for depression across the female lifespan. We begin with an overview of the HPA axis and a brief summary of techniques for measuring HPA axis parameters. We then describe the hormonal milieu of each of these key reproductive stages, and integrate information about HPA axis function in depression across these reproductive stages, describing similarities and differences. The role of a history of stress and trauma exposure as a contributor to female depression in the context of HPA axis involvement across the reproductive stages is also presented. This review advances the pursuit of understanding common biological mechanisms across depressive disorders among women. Our overarching goal is to identify unmet needs in characterizing stress-related markers of depression in women in the context of hormonal changes across the lifespan, and to support future research in women's mental health as it pertains to pathophysiology, early diagnosis, and treatment targets.