Sex and gender differences in risk factors for posttraumatic stress disorder: A systematic review and meta-analysis of prospective studies.

Women are at higher risk than men for developing posttraumatic stress disorder (PTSD), but underlying mechanisms are still unclear. Comprehensive knowledge about these mechanisms is necessary to develop tailored, sex- and gender-sensitive preventive interventions. This systematic review and meta-analysis examined sex-/gender-dependent risk factors, that is, risk factors with sex/gender differences in (a) vulnerability or (b) prevalence/severity, as well as sex-/gender-specific risk factors, that is, and (c) risk factors present in one sex/gender only. We searched PubMed, Web of Science, PsycINFO, PsycArticles, and PSYNDEX for articles published until October 16, 2022. We included prospective studies that assessed risk factors to predict subsequent PTSD symptom severity, as measured with the Clinician-Administered PTSD scale. The primary outcomes were sex/gender stratified pooled for sex-/gender-dependent vulnerability and sex-/gender-specific risk factors and pooled odds ratio (OR) or standardized mean difference (SMD) for sex-/gender-dependent risk factor prevalence/severity. We screened 17,270 records and included 117 reports from 45 studies (N = 13,752) in the systematic review. Seventeen studies (N = 4,257; 1,827 women, 2,430 men) were included in the meta-analysis. Regarding risk factor vulnerability, analyses revealed no significant sex/gender differences except for acute stress symptoms, with stronger associations for men (b = 0.11, SE = 0.06, p < .05). Regarding risk factor prevalence/severity, women reported more severe immediate psychological stress responses (range SMD = 0.23-0.56) and more commonly had a history of mental illness (OR = 1.81, 1.27-2.58). Men showed higher trauma load (SMD = -0.15, -0.29 to 0.01). Few women-specific and no men-specific factors were identified. Results suggest that women's heightened immediate psychological stress response drives sex/gender disparities in PTSD symptom severity. Preventive interventions should thus target women early after trauma. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Higher risk-less data: A systematic review and meta-analysis on the role of sex and gender in trauma research.

Women and men are at different risk for posttraumatic stress disorder (PTSD). It is unclear, however, how studies on PTSD risk factors integrate this knowledge into their research. Moreover, the temporal development of women's higher PTSD risk is unknown. In this systematic review and meta-analysis, we examine how prospective studies on PTSD development (k = 47) consider sex and gender across four domains (samples, terminology, analyses, and reporting). Further, we differentially analyze sex/gender differences within five time intervals from 1 month to 5 years posttrauma. PTSD prevalence (OR = 1.72 [1.27-2.34]) and severity (g = 0.31 [0.09, 0.53]) were increased for women relative to men at 1 month posttrauma already, that is, at the first timepoint of a possible PTSD diagnosis. PTSD severity was elevated for women compared to men across all time intervals, but evidence for increased PTSD prevalence for women relative to men was less stable with longer follow-ups. Despite women's higher PTSD burdens, they were clearly underrepresented in samples (68.3% male, 31.7% female participants). Only 5.0% of studies explained or described their understanding of sex and gender, and only 2.6% used sex as discovery variable, that is, investigating sex-dependent risk mechanisms. Sex and gender aspects in design, data, and discussion were considered by only one-third of studies each. Trauma research falls short of its potential to adequately consider sex and gender. Sex- and gender-sensitive practices can advance rigor, innovation, and equity in psychopathology research. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Higher Depressive Symptoms in Irregular Menstrual Cycles: Converging Evidence from Cross-Sectional and Prospective Assessments.

BACKGROUND: Menstrual cycle regularity is an important marker of reproductive health and associated with physiological and psychological illnesses, as well as experiencing stress. We hypothesized that individuals with irregular menstrual cycles report higher depressive symptom severity, after controlling for stress occurrence. METHODS: The hypothesis was examined through two measurement approaches: a cross-sectional and a prospective, longitudinal study. In the cross-sectional study, participants (n = 394) reported depressive symptoms and their overall menstrual cycle regularity. In the longitudinal study, participants (n = 77) completed questionnaires on depressive symptoms and stress during the mid-follicular and periovulatory phase of one menstrual cycle. Depressive symptoms were compared between participants with regular and irregular cycles through a Welch t test and an ANCOVA. RESULTS: Participants with irregular menstrual cycles reported more depressive symptoms in the cross-sectional analysis. Similarly, in the longitudinal analysis, the group with a current irregular menstrual cycle reported more depressive symptoms after controlling for stress occurrence. When including only complete data sets without multiple imputation (n = 52), the direction of the effects remained but did not reach statistical significance. CONCLUSIONS: The results indicate an association between depressive symptoms and menstrual cycle irregularity. Limitations were that although we investigated the menstrual cycle prospectively, it would have been more precise to include two or more cycles and daily sex hormone measurements. Further limitations were the suboptimal statistical power and the data collection during the COVID pandemic. We give recommendations on how to incorporate the association of depressive symptoms and cycle irregularity in future study designs on women's mental health.

Analyzing the atypical - Methods for studying the menstrual cycle in adolescents.

BACKGROUND: The female pubertal transition is characterized by a rapidly changing hormone milieu, which is heavily influenced by the first menstrual cycle - menarche. The first year following menarche is associated with menstrual cycles that are irregular and anovulatory. Peripuberty also marks the beginning of a female-biased risk for suicidality and depression, suggesting some influence by the menstrual cycle and ovarian hormone fluctuations. However, there are limited methods and guidelines for studying the menstrual cycle and related affective symptoms in this developmental window. Thus, this study's objective was to identify the most accurate methods for detecting ovulation in irregular cycles (Part 1) and develop guidelines based on these methods for determining menstrual cycle phases. These methods were applied to investigate hormones and affective symptoms based on cycle phase and ovulation status in a sample of peripubertal females (Part 2). METHODS: Thirty-two peripubertal females (ages 11-14) provided daily urine samples of estrogen (E1G) and progesterone (PdG) metabolites and luteinizing hormone (LH), and ratings of affective symptoms for one menstrual cycle. Ten literature-derived methods for determining the presence of an LH-peak or PdG rise were compared, focusing on their feasibility for psychological research. RESULTS: Methods by Sun et al. (2019) and Park et al. (2007) most accurately detected PdG rises and LH peaks in this sample, identifying 40.6% of cycles as ovulatory. As expected, ovulatory participants showed greater LH in the periovulatory phase (p = .001), greater PdG in the mid-luteal phase (p < .0001), and greater E1G in the periovulatory phase (p = .001) compared with anovulatory participants. Exemplary methods to compare psychological symptoms between both groups are provided. CONCLUSIONS: Recommendations and guidelines for studying the menstrual cycle in irregular cycling adolescents are offered. Novel methods for ovulation detection identified phase-specific hormonal patterns in anovulatory and ovulatory adolescent cycles.

Cortisol response to traumatic stress to predict PTSD symptom development - a systematic review and meta-analysis of experimental studies.

Background: Pre-and post-traumatic hypothalamic-pituitary-adrenal (HPA) axis markers have been studied to predict posttraumatic stress disorder (PTSD) risk, but its acute reactivity cannot be measured in real-life settings. Experimental paradigms can depict the cortisol response to stimuli that simulate traumatic events.Objective: To review experimental studies on the cortisol response to traumatic stimuli and the correlation between cortisol and PTSD symptoms.Method: Experimental, (un-)published studies in German or English from any year were eligible if they confronted non-traumatized humans with traumatic stimuli, assessed cortisol before, during or after stimulus presentation and subsequent PTSD symptoms. The literature was searched via PubMed, PubPsych, PsychINFO, PsycArticle, Web of Science, EMBASE, ProQuest and ClinicalTrials.gov up to 16th February 2021. Risk of bias was assessed with the Cortisol Assessment List. Multilevel-meta-analyses were conducted under the random effects model. The standardized mean change (dSMC) indicated the cortisol response. Coefficient r indicated the correlations between cortisol and PTSD symptoms.Results: 14 studies, investigating 1004 individuals, were included. A cortisol response was successfully induced between 21 and 40 min post-presentation onset (kobservations = 25, dSMC = 0.15 [.03; .26]). Cortisol was not associated with overall or cluster-level PTSD symptoms. On a symptom-level, higher pre-presentation onset cortisol was correlated with lower state tension (k = 8, r = -.18 [-.35; -.01]), higher state happiness (k = 8, r = -.34 [-.59; -.03], variable inverted) and lower state anger (k = 9, r = -.14 [-.26; -.01]). Higher post-presentation onset cortisol was correlated with higher state happiness (k = 16, r = -.20 [-.33; -.06]) and lower state sadness (k = 17, r = -.16 [-.25; -.05]), whereas cortisol response was positively correlated with state anxiety (k = 9, r = .16 [0.04; 0.27]).Conclusions: Experimental paradigms effectively induce a cortisol response. Higher basal cortisol, higher cortisol, as measured after traumatic stimulus presentation, and a lower cortisol response were associated with more adaptive emotional reactions. These markers did not predict longer-term PTSD symptoms.

Experimental trauma paradigms successfully induced a cortisol response.Cortisol was predictive for single state, emotion-related symptoms, but not overall PTSD symptoms.Trauma paradigms shed light into the immediate post-trauma period that is hard to capture in real life, but the gap between experimental and naturalistic settings is difficult to overcome.

Menstrual cycle-related changes in HPA axis reactivity to acute psychosocial and physiological stressors - A systematic review and meta-analysis of longitudinal studies.

Sex disparities are evident in the biological response to acute stressors, with a suggested influence of ovarian hormones on hypothalamic-pituitary-adrenal (HPA) axis functioning. This systematic review and meta-analysis investigates differences in HPA axis reactivity to acute psychosocial or physiological stressors between menstrual cycle phases. A systematic literature search of six databases resulted in 12 longitudinal studies (n = 182) examining HPA axis reactivity in healthy, naturally-cycling, non-breastfeeding participants aged between 18 and 45 years in at least two cycle phases. The quality of cortisol and menstrual cycle assessment was rated and a descriptive synthesis and meta-analysis of HPA axis reactivity between two broader and five more precise cycle phases was conducted. Three studies provided sufficient data for the meta-analysis and showed a significant, small-sized effect, indicating higher cortisol reactivity in the luteal than in the follicular cycle phase. More primary studies with high-quality menstrual cycle and cortisol assessment are needed. The review did not receive funding and was pre-registered (PROSPERO; CRD42020181632).

Life stress influences the relationship between sex hormone fluctuation and affective symptoms in peripubertal female adolescents.

Female adolescents have a greatly increased risk of depression starting at puberty, which continues throughout the reproductive lifespan. Sex hormone fluctuation has been highlighted as a key proximal precipitating factor in the development of mood disorders tied to reproductive events; however, hormone-induced affective state change is poorly understood in the pubertal transition. The present study investigated the impact of recent stressful life events on the relationship between sex hormone change and affective symptoms in peripubertal female participants. Thirty-five peripubertal participants (ages 11-14, premenarchal, or within 1 year of menarche) completed an assessment of stressful life events, and provided weekly salivary hormone collections [estrone, testosterone, dehydroepiandrosterone (DHEA)] and mood assessments for 8 weeks. Linear mixed models tested whether stressful life events provided a context in which within-person changes in hormones predicted weekly affective symptoms. Results indicated that exposure to stressful life events proximal to the pubertal transition influenced the directional effects of hormone change on affective symptoms. Specifically, greater affective symptoms were associated with increases in hormones in a high stress context and decreases in hormones in a low stress context. These findings provide support for stress-related hormone sensitivity as a diathesis for precipitating affective symptoms in the presence of pronounced peripubertal hormone flux.

The effect of an internet-based intervention for depression on cortisol and alpha-amylase.

INTRODUCTION: Psychotherapeutic interventions for major depressive disorder (MDD) have been suggested to be associated with a normalization of biological stress system (i.e., the hypothalamic-pituitary-adrenal axis and the autonomic nervous system) dysregulation. Furthermore, pre-intervention cortisol parameters have been identified as prescriptive biological markers of treatment success. However, evidence of treatment effects on the biological stress systems is still sparse, and results are heterogeneous. The current study examined the effect of an internet-based intervention for MDD on salivary cortisol and alpha-amylase as well as hair cortisol concentrations. Moreover, the prescriptive capacity of pre-intervention cortisol and alpha-amylase concentrations on treatment response was explored. METHODS: Thirty-eight participants suffering from mild to moderate MDD collected saliva and hair samples throughout the intervention. Biological outcome parameters were salivary cortisol and alpha-amylase (awakening response, total diurnal output, diurnal slope) and hair cortisol concentrations. Treatment response was indicated by change in depression severity and perceived chronic stress. RESULTS: Treatment response on depression scores or chronic stress was not associated with changes in any of the cortisol or alpha-amylase parameters. Exploratory analysis indicated that non-responders showed a steeper alpha-amylase slope pre-intervention. DISCUSSION: The results indicate that changes in depressive symptoms did not correspond to changes of the biological stress systems, contradicting the suggested normalization of dysregulated hypothalamic-pituitary-adrenal axis or autonomic nervous system activity through a psychotherapeutic intervention. However, the results point to a potential role of pre-intervention alpha-amylase slope as a prescriptive marker of treatment response for depression.

Biological markers in clinical psychological research - A systematic framework applied to HPA axis regulation in PTSD.

Biological markers, particularly endocrine measurements, are increasingly being integrated into clinical psychological research. We introduce a systematic framework that classifies different functions of such biomarkers. The framework distinguishes between diagnostic biomarkers which add a biological perspective to conventional clinical assessments, prognostic biomarkers that inform about an individual's risk to develop or maintain a mental health disorder, and intervention-related biomarkers. Regarding interventions, including prevention and treatment, it further distinguishes between prescriptive biomarkers which predict an individual's response to an intervention, outcome biomarkers which evaluate intervention-related changes on a biological level and indicators of change mechanisms. We demonstrate how to apply the framework by exemplarily classifying and describing previously published systematic reviews and primary empirical studies on endogenous, peripheral cortisol concentrations as a biomarker for posttraumatic stress disorder (PTSD). The evidence on cortisol's diagnostic and prognostic value is heterogeneous and still sparse regarding parameters based on multiple cortisol measurements, such as the cortisol awakening response. With regard to interventions, most research focused on trauma-focused psychotherapy and cortisol reactivity to trauma reminders. This field of research appears to be growing and very promising due to its potential to optimize PTSD-related interventions. The proposed framework can help in gaining a systematic overview of existing research. It can assist in structuring, comparing, summarizing and evaluating empirical studies, and in identifying research gaps.

HPA axis activity across the menstrual cycle - a systematic review and meta-analysis of longitudinal studies.

Differential HPA axis function has been proposed to underlie sex-differences in mental disorders; however, the impact of fluctuating sex hormones across the menstrual cycle on HPA axis activity is still unclear. This meta-analysis investigated basal cortisol concentrations as a marker for HPA axis activity across the menstrual cycle. Through a systematic literature search of five databases, 121 longitudinal studies were included, summarizing data of 2641 healthy, cycling participants between the ages of 18 and 45. The meta-analysis showed higher cortisol concentrations in the follicular vs. luteal phase (dSMC = 0.12, p =.004, [0.04 - 0.20]). Comparisons between more precise cycle phases were mostly insignificant, aside from higher concentrations in the menstrual vs. premenstrual phase (dSMC = 0.17, [0.02 - 0.33], p =.03). In all included studies, nine samples used established cortisol parameters to indicate HPA axis function, specifically diurnal profiles (k = 4) and the cortisol awakening response (CAR) (k = 5). Therefore, the meta-analysis highlights the need for more rigorous investigation of HPA axis activity and menstrual cycle phase.

Trauma-related but not PTSD-related increases in hair cortisol concentrations in military personnel.

Dysregulated hypothalamic-pituitary-adrenal (HPA) axis functioning has been associated with posttraumatic stress disorder (PTSD). The current literature is inconsistent regarding this association, possibly due to confounding influences. Hair cortisol concentrations (HCC) allow for retrospective assessment of cumulative HPA axis secretion over several weeks and are considered a trait-like marker of HPA axis activity. Three groups of active and former German Armed Forces service members, comprising PTSD patients (n = 19), healthy controls with deployment-related trauma exposure (n = 10), and non-deployed healthy controls (n = 10) provided samples for HCC analysis. We observed significantly higher HCC in the PTSD and the deployed compared to the non-deployed group. HCC was neither significantly correlated with perceived chronic stress, nor with PTSD severity within patients. The results suggest a differential impact of trauma exposure on HPA axis activity and highlight the notion of cumulative, retrospective cortisol secretion as a psychobiological indicator of trauma exposure. TRIAL REGISTRATION: Australian Clinical Trials Registry (ACTRN12616000956404).

Associations between oxytocin and vasopressin concentrations, traumatic event exposure and posttraumatic stress disorder symptoms: group comparisons, correlations, and courses during an internet-based cognitive-behavioural treatment.

Background: Posttraumatic stress disorder (PTSD) is characterized by impairments in extinction learning and social behaviour, which are targeted by trauma-focused cognitive behavioural treatment (TF-CBT). The biological underpinnings of TF-CBT can be better understood by adding biomarkers to the clinical evaluation of interventions. Due to their involvement in social functioning and fear processing, oxytocin and arginine vasopressin might be informative biomarkers for TF-CBT, but to date, this has never been tested. Objective: To differentiate the impact of traumatic event exposure and PTSD symptoms on blood oxytocin and vasopressin concentrations. Further, to describe courses of PTSD symptoms, oxytocin and vasopressin during an internet-based TF-CBT and explore interactions between these parameters. Method: We compared oxytocin and vasopressin between three groups of active and former male service members of the German Armed Forces (n = 100): PTSD patients (n = 39), deployed healthy controls who experienced a deployment-related traumatic event (n = 33) and non-deployed healthy controls who never experienced a traumatic event (n = 28). PTSD patients underwent a 5-week internet-based TF-CBT. We correlated PTSD symptoms with oxytocin and vasopressin before treatment onset. Further, we analysed courses of PTSD symptoms, oxytocin and vasopressin from pre- to post-treatment and 3 months follow-up, as well as interactions between the three parameters. Results: Oxytocin and vasopressin did not differ between the groups and were unrelated to PTSD symptoms. PTSD symptoms were highly stable over time, whereas the endocrine parameters were not, and they also did not change in mean. Oxytocin and vasopressin were not associated with PTSD symptoms longitudinally. Conclusions: Mainly due to their insufficient intraindividual stability, single measurements of endogenous oxytocin and vasopressin concentrations are not informative biomarkers for TF-CBT. We discuss how the stability of these biomarkers might be increased and how they could be better related to the specific impairments targeted by TF-CBT.

Antecedentes: El trastorno de estrés postraumático (TEPT) se caracteriza por deficiencias en el aprendizaje de extinción y el comportamiento social, que son el objetivo del tratamiento cognitivo conductual centrado en el trauma (TF-CBT). Los fundamentos biológicos de TF-CBT se pueden entender mejor agregando biomarcadores a la evaluación clínica de las intervenciones. Debido a su participación en el funcionamiento social y el procesamiento del miedo, la oxitocina y la arginina vasopresina podrían ser biomarcadores informativos para la TF-CBT, pero hasta la fecha, esto nunca se ha probado.Objetivo: Diferenciar el impacto de la exposición a un evento traumático y los síntomas del TEPT en las concentraciones de oxitocina y vasopresina en la sangre. Además, para describir la evolución de los síntomas del TEPT, la oxitocina y la vasopresina durante una TF-CBT basada en Internet y explorar las interacciones entre estos parámetros.Método: Comparamos la oxitocina y la vasopresina entre tres grupos de militares activos y ex militares de las Fuerzas Armadas Alemanas (n = 100): pacientes con TEPT (n = 39), controles sanos desplegados que experimentaron un evento traumático relacionado con el despliegue (n = 33) y controles sanos no desplegados que nunca experimentaron un evento traumático (n = 28). Los pacientes con TEPT se sometieron a una TF-CBT basada en Internet durante 5 semanas. Correlacionamos los síntomas del TEPT con la oxitocina y la vasopresina antes del inicio del tratamiento. Además, analizamos la evolución de los síntomas del TEPT, la oxitocina y la vasopresina antes y después del tratamiento y el seguimiento de 3 meses, así como las interacciones entre los tres parámetros.Resultados: La oxitocina y la vasopresina no difirieron entre los grupos y no se relacionaron con los síntomas del TEPT. Los síntomas del TEPT fueron muy estables en el tiempo, mientras que los parámetros endocrinos no lo fueron, y tampoco cambiaron en la media. La oxitocina y la vasopresina no se asociaron con los síntomas del TEPT de forma longitudinal.Conclusiones: Principalmente debido a su estabilidad intraindividual insuficiente, las mediciones únicas de las concentraciones de oxitocina y vasopresina endógenas no son biomarcadores informativos para TF-CBT. Discutimos cómo podría aumentarse la estabilidad de estos biomarcadores y cómo podrían relacionarse mejor con las deficiencias específicas a las que se dirige TF-CBT.

Trauma exposure, posttraumatic stress disorder and oxytocin: A meta-analytic investigation of endogenous concentrations and receptor genotype.

Oxytocin's stress-reducing and social functions suggest an involvement in trauma processing and posttraumatic stress disorder (PTSD). We searched PubMed, PubPsych, PsycINFO, PsycARTICLES, Web of Science, ProQuest and ClinicalTrials.gov for studies assessing endogenous oxytocin, oxytocin receptor genotype or methylation in traumatized humans. Eligible studies (k = 66) were systematically described. We meta-analytically compared oxytocin parameters between traumatized and non-traumatized individuals (k = 17) and individuals with and without PTSD (k = 8), and correlated oxytocin with trauma exposure (k = 16) and PTSD symptoms (k = 8). Endogenous oxytocin concentrations did not differ between PTSD patients and healthy individuals. The remaining effects on endogenous oxytocin were heterogeneous. Subgroup analyses identified sampling-related, trauma-related and demographic moderators, resulting in inconsistent or non-significant effects. Methylation data were insufficient for meta-analyses, and meta-analytic genotype results were inconsistent. Unstimulated endogenous oxytocin was not a biomarker for trauma exposure or PTSD. Given the impact of methodology, more basic research on endogenous oxytocin measurements is needed. Future studies might consider the oxytocin stress response and investigate oxytocin longitudinally.

HPA axis regulation in posttraumatic stress disorder: A meta-analysis focusing on potential moderators.

Posttraumatic stress disorder (PTSD) is often associated with alterations in the hypothalamic-pituitary-adrenal (HPA) axis. Previous findings are inconsistent, possibly due to trauma exposure of controls or different hormone measurement methods. We investigated cortisol, dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) in adults with clinical PTSD under basal or challenged conditions (Prospero registration no. CRD42016041690). A search of PubMed, Scopus, Medline, PsycINFO, Pilots/ProQuest, and Web of Science resulted in 108 included studies (N = 6484). Morning and 24 h cortisol were significantly lower in PTSD than in controls (g = -0.21; 95% CI: -0.42-(-0.01); g = -0.31; CI: -0.60-(-0.03)). Significant cortisol increases occurred after awakening in PTSD (g = 0.40; CI: 0.13-0.67) and in non-exposed controls (g = 0.96; CI: 0.59-1.33). Evening DHEA was significantly higher in PTSD than in non-exposed controls (g = 0.58; CI: 0.17-0.99). All groups showed large cortisol suppression effects after dexamethasone administration. Overall, the potential moderators investigated did not reveal a consistent pattern of HPA alterations.

Menstrual cycle-related fluctuations in oxytocin concentrations: A systematic review and meta-analysis.

Oxytocin affects physiological and psychological functions that are often expressed sex-specifically, suggesting interactions between oxytocin and sex hormones. As female sex hormone concentrations change during the menstrual cycle, oxytocin might fluctuate, too. This systematic review and meta-analysis investigated endogenous oxytocin concentrations across menstrual cycle phases in healthy women. Data from 13 studies (120 women) showed a significant increase of oxytocin concentrations from the early follicular phase to ovulation (g = 0.39 [0.25; 0.53], p < .001) and a significant decrease from ovulation to the mid-luteal phase (g = -0.50 [-0.81; -0.18], p < .001). There were no significant differences between the early follicular and mid-luteal phase (g = -0.19 [-0.70; -0.32], p = .471). These findings contribute to a deeper understanding of differences in normal and abnormal psychobiological processes in women. They highlight the necessity to consider the menstrual cycle phase in studies on oxytocin in women.