Blunted cortisol reactivity (BCR) to stress has been linked to trauma symptoms and early life adversity (ELA). Despite evidence for sex differences in ELA's impact on cortisol reactivity, few stress reactivity studies adequately assess sex-specificity. Further, most have measured salivary cortisol response to a single regulatory probe, limiting conclusions regarding mechanisms contributing to trauma-related HPA axis dysregulation. Using measures of cortisol binding globulin (CBG), serum adrenocorticotropic hormone (ACTH), and serum and salivary cortisol across four regulatory probes, this study assessed sex-specific mechanisms of ELA-related HPA axis dysregulation. 116 adults (55 female; 61 male) completed the Trier Social Stress Test (TSST), ACTH stimulation test, and low and high dose dexamethasone suppression tests (DST), and provided serum ACTH and cortisol, salivary cortisol, and CBG samples. For women, probes were scheduled to avoid ovulatory estrogen surges. Regressions in sex-disaggregated data examined the impact of ELA on cortisol reactivity and three candidate mechanisms of BCR. We found a negative association between salivary cortisol reactivity and ELA in females (p = .037), with no relation in males. In females, neither CBG nor adrenal sensitivity explained blunting; ELA was, however, associated with enhanced feedback inhibition (p = .033). Findings imply that the relation between ELA and adult BCR may primarily be present in females. The observed patterns were more consistent with enhanced feedback inhibition as a candidate pathway to trauma-related blunting in women than altered adrenal sensitivity or blunting explained by CBG. Future sex-disaggregated approaches may clarify persistently elusive pathways between trauma, HPA axis dysregulation, and adverse health outcomes.
Early (before age 6) potentially traumatic events (PTEs) may interact with hypothalamic-pituitary-adrenal (HPA) axis functioning to shape outcomes involving externalizing problems and anxiety. However, directions of effects remain unclear. This study examined associations between aspects of HPA axis reactivity, anxiety, and externalizing problems over two years by early PTE exposure history, while statistically capturing the co-occurrence of symptom domains. Youth (N = 189; Mage = 10.96 years, SD = 2.51, Range = 8-15; 52.4% female, 47.1% male; 50.3% White, 35.4% Black/African American, 6.4% Other; 7.4% Hispanic/Latine) were included if they had early PTE exposure (n = 107) or had never experienced a PTE (n = 82). HPA axis reactivity to social stress was calculated using area under the curve with respect to ground (AUCg) and increase (AUCi). For youth with early PTE exposure, higher AUCg was concurrently associated with more externalizing symptoms and greater predominance of externalizing over anxiety. Blunted AUCi predicted increasing predominance of externalizing for the early PTE group, but elevated AUCi predicted increases in anxiety for the no PTE group. Findings highlight distinct roles of overall and reactive HPA axis functioning in shaping outcomes following early trauma.
Gretchen R. Perhamus, Rachel E. Siciliano, Tiffany Phu et al.· Development and Psychopathol...· 0 citations
PURPOSE
Examining circadian hypothalamic-pituitary-adrenal (HPA) axis activity during adolescence is vital for understanding physiological changes. Limited research explores risk and protective factors for diurnal HPA activity. This study investigates how adverse childhood experiences (ACEs) and coping are associated with changes in diurnal cortisol patterns, using a combination of physiological biomarkers (i.e., salivary cortisol), daily diaries, and longitudinal assessments spanning two years.
METHODS
The sample included 316 Chinese adolescents (33% females; T1 Mage = 10.79 years, SD = 0.84). At T1, adolescents reported ACEs, completed 7-day diaries on coping, and provided saliva samples for three consecutive days. Two years later (T2), adolescents completed a follow-up assessment on diurnal cortisol activity. Latent change score modeling was conducted to investigate changing patterns in diurnal cortisol and associations of ACEs and coping with the changing patterns.
RESULTS
From T1 to T2, waking cortisol decreased, CAR increased, and diurnal cortisol slopes became steeper. ACEs were associated with initial levels of diurnal cortisol activity but not changes in it: more ACEs were linked to higher T1 waking cortisol and a smaller T1 CAR. Higher ACEs were also associated with later wake-up times; later wake-up was associated with lower T1 CAR, more blunted T1 diurnal slopes, and flatter diurnal slopes across time. Daily coping (mean and variability) moderated the associations between ACEs and diurnal cortisol.
CONCLUSION
By observing coping as a moderator between ACEs and cortisol patterns, this study demonstrates that associations between ACEs and diurnal cortisol differ across adolescents' coping use and coping variability.
Mingjun Xie, Yijia Li, Yueqing Hu et al.· Psychoneuroendocrinology· 0 citations
This study examined whether saliva-derived DNA methylation in the glucocorticoid receptor (NR3C1) gene was linked to loneliness through dysregulation of the hypothalamic-pituitary-adrenal axis (HPA-axis) in 101 early adolescents (Mage = 11.61 years, SDage = 0.64, 55.45% girls). Using person-centered analyses to account for interindividual differences in adolescents' stress reactivity, we identified three subgroups of cortisol responders to a social evaluative stressor: A hyporesponsive subgroup (30.5%), a moderate-responsive subgroup (44.2%), and a hyperresponsive subgroup (25.3%). Exploratory analyses also identified subgroups for two markers of the autonomous nervous system (ANS), that is, heart rate (HR) and skin conductance (SC). Furthermore, the indirect effects from NR3C1 methylation to early adolescent loneliness via individual differences in stress responses were examined. Results indicated that higher NR3C1 methylation levels were associated with a lower probability of belonging to the most reactive stress response subgroups for cortisol and HR, and to the high mean-level subgroup for SC. Additionally, higher probabilities of belonging to the low mean-level SC subgroup were associated with higher levels of loneliness. However, there was no evidence that NR3C1 methylation was associated with early adolescent loneliness, either directly or indirectly via stress reactivity. These findings highlight significant individual differences in stress reactivity, emphasizing the need to explicitly consider such variability in future research. Moreover, the results suggest that NR3C1 methylation is linked to individual differences in stress responding, warranting further investigation.
Yentl Koopmans, S. Nelemans, Patricia Bijttebier et al.· Developmental Psychobiology· 0 citations
We examined whether specific maternal-perceived prenatal life stress predicted infant cortisol output at 2 or 6 months. Expectant mothers reported the occurrence and perceived impact of 47 potential prenatal life stressors. Infant cortisol was assessed across four salivary samples collected during a laboratory/home visit including stressful activities. Associations were examined between infant cortisol output and each potential life stressor, accumulation of stress within 7 distinct categories, and total stress accumulation. Although total stress was associated with higher infant cortisol output, only four specific perceived life stressors (i.e., serious accident/illness, mental health challenges, and trauma experience (self and partners')) within two categories (health/mental health and vicarious stress) predicted heightened infant cortisol output after adjusting for covariates and the false discovery rate. Findings suggest that more severe stressors related to health/mental health may be more salient for early development of the hypothalamic-pituitary-adrenal system than less severe stressors (e.g., moving). Aggregating stressors regardless of severity may obscure meaningful effects.
Yu Chen, E. Leerkes, Cheryl Buehler et al.· Infant Behavior and Developm...· 0 citations
BACKGROUND AND AIMS
Diurnal cortisol dysregulation and daily stressor severity may jointly forecast long-term alcohol use disorder (AUD) and substance use disorder (SUD) severity, yet most evidence is cross-sectional and relies on single cortisol indices. This study examined whether three cortisol indices nonlinearly interacted with daily stressor severity to predict 9-year AUD and SUD severity.
DESIGN
Longitudinal observational study with a 9-year follow-up. Analyses were not pre-registered.
SETTING
Community-based sample in the United States of America.
PARTICIPANTS
1617 community-dwelling adults aged 33-83 years at baseline.
MEASUREMENTS
Ecological momentary assessments of salivary cortisol and daily stressor severity were collected at baseline. AUD and SUD severity were self-reported at baseline and 9-year follow-up. Cortisol indices included diurnal cortisol slope, cortisol awakening response and area under the curve (AUC).
FINDINGS
Parametric hurdle Poisson models yielded null main effects and interactions (all P > 0.050). Generalized additive models with negative binomial family revealed three statistically significant nonlinear interactions: diurnal cortisol slope × stress predicting AUD severity [effective degrees of freedom (edf) = 2.09, χ2 = 12.56, P = 0.005], cortisol awakening response × stress predicting SUD severity (edf = 2.88, χ2 = 11.60, P = 0.019) and AUC × stress predicting AUD severity (edf = 4.08, χ2 = 16.34, P = 0.006). Adjusting for age, sex, education, income and race nullified all three interactions; however, AUC × stress interaction → AUD remained statistically significant after controlling for anxiety and depression.
CONCLUSIONS
Nonlinear interactions between cortisol indices and daily stressor severity appear to predict 9-year alcohol use disorder and substance use disorder severity, with cortisol area under the curve emerging as the most robust indicator. Findings are predictive rather than causal. Cognitive-behaviorally based prevention programs targeting stress and cortisol regulation may mitigate substance use risk.
N. Zainal, Natalia Van Doren· Addiction· 0 citations
Stress exposure early in life is an established risk factor for adult psychiatric illness, yet these disorders-including anxiety disorders and depression-show significant sex differences in prevalence, symptomatology, and treatment response. The biology underlying these differences remains largely unexplored and may contribute to the clinical heterogeneity in anxiety and depression. Here, we characterize the lasting impact of developmental stress on adulthood neurobiology and behavior in mice by combining analyses of multiple levels of brain function, including whole-brain c-Fos mapping, manganese-enhanced MRI, and transcriptomics with advanced behavioral phenotyping. Across levels of investigation, we find distinct and often opposite effects of developmental stress based on sex. These results together showcase the strong influence of sex on how early life adversity affects the onset of stress-related disorders. This work emphasizes the necessity of considering sex when investigating developmental and neurobiological underpinnings of stress-related disorders and displays a vast range of lasting effects of developmental stress on the brain, which provides a valuable resource for future studies aiming to improve psychiatric treatments.
S. Narayan, C. Beer, V. Kovářová et al.· Proceedings of the National...· 0 citations