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1. Many aspects of the social environment affect hypothalamic-pituitary-adrenal (HPA) axis function and increase circulating glucocorticoid concentrations. In this review, we examine the relationships between the social environment and the function of the HPA axis in vertebrates. 2. First, we explore the effects of the social environment on glucocorticoid secretion in territorial (primarily non-social) species, with an emphasis on the effects of variation in population density, as modified by environmental factors such as predation risk and food availability. In general, high population density or frequent territorial intrusions are associated with increased glucocorticoid secretion in a wide range of taxa, including mammals, birds, fish and reptiles, although there is considerable variability across species. 3. Second, we consider the effects of social interactions and dominance rank on glucocorticoid secretion in social species, mostly in birds and mammals. We review studies that have detected an association between social status and glucocorticoid levels — sometimes with higher glucocorticoid levels in low-ranking individuals, and sometimes with higher glucocorticoid levels in dominant individuals. The relationship between dominance and glucocorticoid levels varies among species, populations and years, in a manner that depends on the stability of the social hierarchy, environmental conditions, the type of breeding system, and the manner in which high rank is obtained and maintained. 4. Finally, we discuss the concept of allostasis and consider interactions between social effects and other environmental factors, noting that there is relatively little research on these interactions to date. For both non-social and social species, we identify priorities of future research. These priorities include more complete descriptions of HPA function that move beyond measurements of basal glucocorticoid concentrations (which will generally require field experiments), to studies that examine organizational effects of social stressors, that directly test the relationship between HPA function and fitness, and that examine how glucocorticoid responses affect population dynamics. 5. Although several lines of evidence suggest that glucocorticoid responses can affect the fitness of individuals and therefore can alter the dynamics of populations, the effect of glucocorticoid responses on population dynamics remains essentially unstudied.

Cortisol, a critical glucocorticoid hormone produced by the adrenal glands, plays a pivotal role in various physiological processes. Its release is finely orchestrated by the suprachiasmatic nucleus, governing the circadian rhythm and activating the intricate hypothalamic–pituitary–adrenal (HPA) axis, a vital neuroendocrine system responsible for stress response and maintaining homeostasis. Disruptions in cortisol regulation due to chronic stress, disease, and aging have profound implications for multiple bodily systems. Animal models have been instrumental in elucidating these complex cortisol dynamics during stress, shedding light on the interplay between physiological, neuroendocrine, and immune factors in the stress response. These models have also revealed the impact of various stressors, including social hierarchies, highlighting the role of social factors in cortisol regulation. Moreover, chronic stress is closely linked to the progression of neurodegenerative diseases, like Alzheimer’s and Parkinson’s, driven by excessive cortisol production and HPA axis dysregulation, along with neuroinflammation in the central nervous system. The relationship between cortisol dysregulation and major depressive disorder is complex, characterized by HPA axis hyperactivity and chronic inflammation. Lastly, chronic pain is associated with abnormal cortisol patterns that heighten pain sensitivity and susceptibility. Understanding these multifaceted mechanisms and their effects is essential, as they offer insights into potential interventions to mitigate the detrimental consequences of chronic stress and cortisol dysregulation in these conditions.

The hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-gonadal (HPG) axis systems are inversely related in humans and animals. Although livestock animals, such as sheep (Ovis aries), tend to be well adapted to their environment, it is known that the livestock production processes subject animals to a multitude of physical and psychological stressful stimuli that have the potential to elevate the HPA axis activity. Chronic stress is one of the major challenges in sheep production, as it is difficult to detect and can result in prolonged dysfunction of the HPA axis, causing downstream negative physiological effects such as immunosuppression, increased susceptibility to disease and reproductive dysfunction. The elevation of HPA axis activity during chronic stress has been suggested as the primary neuroendocrine mechanism underlying the aetiology of reproductive dysfunction in sheep. Research in sheep has demonstrated that glucocorticoids act on the HPG axis at the level of the hypothalamus and hypophyseal portal system to decrease gonadotrophin secretion and at the level of the pituitary gland to reduce responsiveness and sensitivity of gonadotroph cells and their receptors to GnRH. Sheep farming enterprises rely on the breeding efficacy of ewes to optimise lambing percentage and reproductive success in order to ensure a profitable business. This review discusses the influences of the HPA axis on the HPG axis and defines any significant reproductive function consequences caused by stress in ewes and places them into perspective for sheep management and productivity.

Central nervous system injuries may lead to the disorders of the hypothalamic‐pituitary‐adrenal axis, autonomic nervous system, and enteric nervous system. These effects then cause the changes in the intestinal microenvironment, such as a disordered intestinal immune system as well as alterations of intestinal bacteria. Ultimately, this leads to an increase in intestinal permeability. Inflammatory factors produced by the interactions between intestinal neurons and immune cells as well as the secretions and metabolites of intestinal flora can then migrate through the intestinal barrier, which will aggravate any peripheral inflammation and the central nervous system injury. The brain‐gut‐microbiota axis is a complex system that plays a crucial role in the occurrence and development of central nervous system diseases. It may also increase the consequences of preventative treatment. In this context, here we have summarized the factors that can lead to the increased intestinal permeability and some of the possible outcomes.

Stress and Hypothalamic–Pituitary–Adrenal (HPA) axis dysregulation play a major role in various pathophysiological processes associated with both mood disorders and suicidal behavior. We conducted a systematic review with the primary aim of clarifying the nature and extent of HPA axis activity and suicidal behavior. The second aim of this review was to investigate whether potential biomarkers related to HPA axis abnormalities act as individual susceptibility factors for suicide. The PRISMA statement for reporting systematic reviews was used. Only articles published in English peer-reviewed journals were considered for possible inclusion; we excluded case reports, meta-analyses, and systematic reviews, and studies that did not clearly report statistical analysis, diagnostic criteria, or the number of patients included. Overall, 36 articles on HPA axis and suicide risk met inclusion criteria and were reviewed. Studies that investigated tests detecting biomarkers and the role of early life stressors in suicide risk were also included. We found that HPA axis activity is involved in suicide risk, regardless of the presence or absence of psychiatric conditions. The HPA axis abnormalities, mainly characterized by hyperactivity of the HPA axis, may exert an important modulatory influence on suicide risk. Impaired stress response mechanisms contribute to suicide risk. Targeting HPA axis dysregulation might represent a fruitful strategy for identifying new treatment targets and improving suicide risk prediction.

Depression is a multifactorial psychiatric condition with complex pathophysiology, increasingly linked to neuroinflammatory processes. The present review explores the role of neuroinflammation in depression, focusing on glial cell activation, cytokine signaling, blood–brain barrier dysfunction, and disruptions in neurotransmitter systems. The article highlights how inflammatory mediators influence brain regions implicated in mood regulation, such as the hippocampus, amygdala, and prefrontal cortex. The review further discusses the involvement of the hypothalamic–pituitary–adrenal (HPA) axis, oxidative stress, and the kynurenine pathway, providing mechanistic insights into how chronic inflammation may underlie emotional and cognitive symptoms of depression. The bidirectional relationship between inflammation and depressive symptoms is emphasized, along with the role of peripheral immune responses and systemic stress. By integrating molecular, cellular, and neuroendocrine perspectives, this review supports the growing field of immunopsychiatry and lays the foundation for novel diagnostic biomarkers and anti-inflammatory treatment approaches in depression. Further research in this field holds promise for developing more effective and personalized interventions for individuals suffering from depression.

Abstract Context Perturbations to the hypothalamic-pituitary-adrenal (HPA) axis have been hypothesized to increase postmenopausal cardiometabolic risk. Although sleep disturbance, a known risk factor for cardiometabolic disease, is prevalent during the menopause transition, it is unknown whether menopause-related sleep disturbance and estradiol decline disturb the HPA axis. Objective We examined the effect of experimental fragmentation of sleep and suppression of estradiol as a model of menopause on cortisol levels in healthy young women. Methods Twenty-two women completed a 5-night inpatient study during the mid-to-late follicular phase (estrogenized). A subset (n = 14) repeated the protocol after gonadotropin-releasing hormone agonist-induced estradiol suppression. Each inpatient study included 2 unfragmented sleep nights followed by 3 experimental sleep fragmentation nights. This study took place with premenopausal women at an academic medical center. Interventions included sleep fragmentation and pharmacological hypoestrogenism, and main outcome measures were serum bedtime cortisol levels and cortisol awakening response (CAR). Results Bedtime cortisol increased 27% (P = .03) and CAR decreased 57% (P = .01) following sleep fragmentation compared to unfragmented sleep. Polysomnographic-derived wake after sleep-onset (WASO) was positively associated with bedtime cortisol levels (P = .047) and negatively associated with CAR (P < .01). Bedtime cortisol levels were 22% lower in the hypoestrogenized state compared to the estrogenized state (P = .02), while CAR was similar in both estradiol conditions (P = .38). Conclusion Estradiol suppression and modifiable menopause-related sleep fragmentation both independently perturb HPA axis activity. Sleep fragmentation, commonly seen in menopausal women, may disrupt the HPA axis, which in turn may lead to adverse health effects as women age.

Objective In major depressive disorder (MDD) patients, higher morning cortisol levels due to a hyperactive hypothalamic–pituitary–adrenal (HPA) axis have been reported. The aim of the present study was to evaluate the relationship between cortical thinning and the serum cortisol levels during the first depressive episode in drug‐naïve MDD patients using an automated surface‐based morphometry (SBM) method. Methods The institutional review board approved this prospective study. MR imaging data were obtained using a 3T scanner by a three‐dimensional fast‐spoiled gradient recalled acquisition with steady state (3D‐FSPGR). Thirty drug‐naïve patients with MDD and 41 age‐ and gender‐matched healthy subjects (controls) were enrolled. We then used the SBM method (Freesurfer) to generate cortical thickness maps, and measured the cortical thickness in each subject. Morning blood samples were drawn from all participants for cortisol measurements. Results We found the serum cortisol levels were significantly higher in the MDD patients than in the controls. The MDD patients manifested significant thinning of the left lateral orbitofrontal cortex compared with the controls. There was a significant negative linear correlation between the thickness of the left lateral orbitofrontal cortex and the serum cortisol levels in the MDD patients. Conclusions In the early stage of MDD, the thickness of the lateral orbitofrontal cortex was significantly reduced, and also showed a significant inverse correlation with the serum cortisol levels. Since the lateral orbitofrontal cortex contains a high concentration of glucocorticoid receptor, glucocorticoid receptor‐mediated signaling transductions could contribute to neurotoxicity, which might occur when there are high cortisol levels in patients with MDD.

Abstract Background. This study investigates the impact of childhood maltreatment (CM) on hypothalamic- pituitary-adrenal (HPA)-axis functioning and on anxiety perception. Moreover, the influence of CM severity and frequency was also explored. Methods. In total, 187 participants aged 7-17 were assessed for CM history using validated questionnaires and ad hoc interviews to be classified according to the criteria of the Tool for Assessing the Severity of Situations in which Children are Vulnerable (TASSCV). Psychopathology was ascertained using the K-SADS-PL5. To assess HPA-axis functioning, salivary cortisol samples were collected throughout a normal day and during an acute psychosocial stressor, the Trier Social Stress Test for children (TSST-C). Subjective anxiety was evaluated using STAI/-C. Results. Youth with a CM history had higher overall diurnal cortisol levels ( p = 0.001), blunted cortisol response to acute psychosocial stress ( p = 0.002) and greater perceived anxiety ( p = 0.003), than those without CM. Specifically, participants exposed to moderate/severe or often/frequent CM showed the greater diurnal cortisol output ( pseverity = 0.002; pfrequency = 0.003), and blunted cortisol response during the TSST-C ( pseverity = 0.006; pfrequency = 0.008). Meanwhile, youth with low CM severity/frequency exhibited a similar cortisol response to those without CM. However, perceived anxiety was higher in those exposed to CM ( p < 0.001), regardless of its severity/frequency. Conclusions. Disturbances in HPA-axis functioning are already evident early after CM exposure, while psychological and physiological responses to an acute stressor are dissociated in youth exposed to CM. The dose-response relationship described in this paper highlights the need to comprehensively evaluate CM so that vulnerable children can be identified and assigned to proper interventions.

Children and mothers' cortisol production in response to family psychosocial conditions, including parenting demands, family resource availability and parental conflict, has been extensively studied in the United States and Europe. Less is known about how such family dynamics relate to family members' cortisol in societies with a strong cultural emphasis on cooperative caregiving. We studied a cumulative indicator of cortisol production, measured from fingernails, among BaYaka forager children (77 samples, n = 48 individuals) and their parents (78 samples, n = 49) in the Congo Basin. Men ranked one another according to locally valued roles for fathers, including providing resources for the family, sharing resources in the community and engaging in less marital conflict. Children had higher cortisol if their parents were ranked as having greater parental conflict, and their fathers were seen as less effective providers and less generous sharers of resources in the community. Children with lower triceps skinfold thickness (an indicator of energetic condition) also had higher cortisol. Parental cortisol was not significantly correlated to men's fathering rankings, including parental conflict. Our results indicate that even in a society in which caregiving is highly cooperative, children's cortisol production was nonetheless correlated to parental conflict as well as variation in locally defined fathering quality. This article is part of the theme issue 'Multidisciplinary perspectives on social support and maternal–child health'.