Peripheral Blood Mononuclear Cell Expression of Cation-Chloride Cotransporter (CCC) Genes in Premenstrual Dysphoric Disorder (PMDD) across the Menstrual Cycle-A Preliminary Study.

Premenstrual Dysphoric Disorder (PMDD) is a psychiatric condition characterized by debilitating affective symptomatology in the luteal phase of the menstrual cycle. Based on the previous reports that PMDD may be related to GABAergic cellular dysfunction(s), we assessed whether cation-chloride cotransporter (CCC) gene expression across the menstrual cycle is altered in PMDD. As there are limitations in accessing the human CNS to study CCC-encoding genes, we utilized peripheral blood mononuclear cells (PBMCs) as an alternative model. We first sought to replicate previous reports characterizing CCC gene expression patterns in PBMCs of reproductive age women. We subsequently investigated potential distinct CCC mRNA expression patterns in women with PMDD. We collected blood samples across 8 menstrual cycle visits for PBMC separation/RNA extraction to study mRNA expression of four KCCs (KCC1, KCC2, KCC3, KCC4) and two NKCCs (NKCC1, NKCC2) cotransporters. We mostly replicated the earlier gene expression pattern findings, and found that the expression levels of KCC1 were significantly downregulated during the mid-follicular and periovulatory subphases of the menstrual cycle in women with PMDD. The present study shows that PBMCs is a valid model for studying GABAergic mechanisms underlying PMDD.

Visuospatial Function in Women with Premenstrual Dysphoric Disorder.

Background/Objectives: Premenstrual dysphoric disorder (PMDD) is an understudied psychiatric condition affecting reproductive-age women who experience negative mood in the luteal phase of the menstrual cycle. Cognitive functions in PMDD are not well understood as patients have been tested in the luteal phase. This may confound study results due to noted emotional interferences, as well as the potential opposing effects of the sex hormones estradiol and progesterone. In the present study, we evaluated visuospatial function in the follicular phase in women with PMDD and healthy controls, and further examined the effect of estradiol as research into the hormonal mediation of visuospatial function in reproductive-age women has produced mixed results. Methods: To this end, we analyzed estradiol concentrations using the gold standard mass spectrometry. Serum samples were collected in the early follicular and mid/late follicular subphases when estradiol is low and high, respectively, while progesterone is low and steady. We assessed visuospatial function using the classic mental rotation task. Results: Women with PMDD had a higher mental rotation total score (t = 2.17; p < 0.05). The addition of six demographic, biological, and anthropomorphic variables in a hierarchical fashion accounted for 45.3% of the total variance in the final model with diagnosis remaining statistically significant (t = 4.36; p < 0.001). Estradiol did not mediate the group difference and was not significantly associated with visuospatial function. Conclusions: The present results provide support for new research directions into the potential biological mechanisms that underlie the pathophysiology of PMDD, represented as enhanced visuospatial ability in women with PMDD in the follicular phase. We review the theory that PMDD is a disorder of the enhanced excitation-to-inhibition ratio, with a focus on findings to date from brain imaging research.

Neuroactive steroid hormone trajectories across the menstrual cycle in premenstrual dysphoric disorder (PMDD): the PHASE study.

It is presently not known whether endogenous neuroactive steroid hormone trajectories across the menstrual cycle are distinguishable in women with premenstrual dysphoric disorder (PMDD). To improve the rigor in this area of research, we implemented a validated study methodology, involving blood sample collection at 8 key menstrual cycle timepoints, following which the study data is realigned so that all women are compared at the same biological window (i.e., menstrual cycle subphase). Using liquid chromatography-mass spectrometry (LC-MS), we analyzed serum levels of nine steroid hormones previously implicated in the etiology of PMDD, including allopregnanolone. Other than progesterone (p ≤ 0.001), none of the steroid hormones displayed significant changes across menstrual cycle subphases when comparing participants with PMDD to the healthy controls. A thorough investigation of the progesterone trajectory showed that its left shift in the luteal phase (e.g., earlier rise in progesterone) exposes women with PMDD to a higher periovulatory progesterone and a more acute withdrawal in the late luteal subphase. Results of the present study indicate that the largely overlooked brief periovulatory subphase should be thoroughly examined in PMDD and agree with prior conclusions that rapid progesterone withdrawal associates with the development of negative affect.

Positive association between dehydroepiandrosterone (DHEA) and gene expression of the gamma-aminobutyric acid (GABA-A) receptor δ subunit.

Gamma-aminobutyric acid A (GABA-A) receptors in the cells of the immune system enhance anti-inflammatory responses by regulating cytokine secretion, cytotoxic responses, and cell activation. In the CNS, the formation of GABA-A subunits into a pentameric structure has been extensively studied; however, no such study has been conducted in the immune system. The objective of the present study was to examine associations between the levels of steroid hormones and GABA-A receptor δ subunit expression in the immune system. We focused on this subunit because GABA-A receptors that contain it become significantly more sensitive to steroid hormones. We collected 80 blood samples from reproductive age women for the purpose of analyzing dehydroepiandrosterone (DHEA), 17ß-estradiol, progesterone, and allopregnanolone using liquid chromatography-mass spectrometry (LC-MS). Furthermore, we extracted peripheral blood mononuclear cells (PBMCs) for determining mRNA expression levels of GABA-A receptor genes encoding the δ and ε subunits. We constructed linear mixed effect models for each GABA-A receptor subunit with all 4 steroid hormones, age, and age of menarche as predictors. Whereas DHEA was significantly associated with δ subunit expression (t-value = 2.981; p = 0.003), in line with our hypothesis, none of the steroid hormones were significantly associated with the expression of the ε subunit. Results of this study indicate that significant interactions between hormones from the steroid hormone biosynthesis pathway and GABAergic machinery from the immune cells may be utilized to expand models examining the molecular basis of inflammatory conditions.

Blunted Cortisol Response to Acute Psychosocial Stress in Women With Premenstrual Dysphoric Disorder.

BACKGROUND: Despite being considered a stress-related condition, it is not known whether the hypothalamic-pituitary-adrenal (HPA) axis is dysfunctional in response to acute psychosocial stress in premenstrual dysphoric disorder (PMDD). This is problematic because many women with PMDD report that they are not able to control their stress levels, and a blunted cortisol output has been identified in women with related psychiatric conditions, such as anxiety and depression. The present study is a part of the Premenstrual Hormonal and Affective State Evaluation (PHASE) project, and it aimed to characterize the cortisol trajectory in response to an acute psychosocial stress challenge. METHODS: Women with PMDD and healthy controls with confirmed ovulatory cycles underwent the Trier Social Stress Test (TSST) procedure in the mid-late luteal phase of the menstrual cycle, throughout which we collected serum samples of cortisol that we analyzed using ultra-performance liquid chromatography tandem mass spectrometry. RESULTS: The linear mixed model analysis indicated a significant time*diagnosis interaction (P = .008) such that women with PMDD displayed significantly lower serum cortisol levels at +40 through +90 minutes from the time of stress induction. CONCLUSION: This is the first study to show that women with PMDD have a blunted cortisol response to psychosocial stress. Combined with our earlier finding showing a greater parasympathetic nervous system withdrawal on heart oscillations in PMDD during acute stress, these and other results show that the dysregulated processing of stress in PMDD may be captured using objective study measures.

Late Luteal Subphase Food Craving Is Enhanced in Women with Obesity and Premenstrual Dysphoric Disorder (PMDD).

Dysregulated food craving is a complex weight-related behavior. To identify novel targets for enhancing the efficacy of weight loss interventions, we examined whether food craving varies across the menstrual cycle according to the abdominal obesity type and premenstrual dysphoric disorder (PMDD) diagnosis, and, if so, whether it is related to affective symptomatology. Reproductive-age women were classified into one of the four study groups according to whether they have abdominal obesity (AO) or are abdominally lean (AL), and the presence of PMDD: (1) AO:PMDD+ (n = 13), (2) AL:PMDD+ (n = 14), (3) AO:PMDD- (n = 15), and (4) AL:PMDD- (n = 16). Self-report measures as well as urinary luteinizing hormone (LH) tests were provided by the participants across 2-3 menstrual cycles. The ratings of food cravings were similar across the menstrual cycle, except the last, late luteal subphase as the AO:PMDD+ participants had the highest food craving rating. Irritability and depression were correlated with food cravings, but not in a distinctive manner across the menstrual cycle by group. Our study found that women with abdominal obesity and PMDD display a temporal vulnerability to a food-related behavior. The possibility of shared neurobiology between the two conditions is discussed and should be examined in future studies.

Periovulatory Subphase of the Menstrual Cycle Is Marked by a Significant Decrease in Heart Rate Variability.

(1) Background: High-frequency heart rate variability (HF-HRV) is an essential ultradian rhythm that reflects the activity of the PNS to decelerate the heart. It is unknown how HF-HRV varies across the menstrual cycle (MC), and whether progesterone mediates this potential variation. (2) Methods: We enrolled 33 women in the study to attend eight clinic visits across the MC, during which we measured their resting HF-HRV and collected samples for the analysis of luteinizing hormone (LH) and progesterone. We realigned the study data according to the serum LH surge to the early follicular, mid-follicular, periovulatory, early luteal, mid-luteal and late luteal subphases. (3) Results: Pairwise comparisons between all the subphases showed significant differences between the early follicular and periovulatory subphases (ß = 0.9302; p ≤ 0.001) and between the periovulatory and early luteal subphases (ß = -0.6955; p ≤ 0.05). Progesterone was positively associated with HF-HRV in the early follicular subphase but not the periovulatory subphase (p ≤ 0.05). (4) Conclusions: The present study shows a significant drop in HF-HRV in the anticipation of ovulation. Further research in this area is critical given the marked cardiovascular disease mortality in women.

Trajectories of Allopregnanolone and Allopregnanolone to Progesterone Ratio across the Six Subphases of Menstrual Cycle.

Background: Allopregnanolone is one of the most studied neuroactive steroids; yet, despite its relevance to neuropsychiatric research, it is not known how it, as well as its ratio to progesterone, varies across all six subphases of the menstrual cycle. Two enzymes-5α-dihydroprogesterone and 5α-reductase-convert progesterone to allopregnanolone, and, based on immunohistochemical studies in rodents, the activity of 5α-reductase is considered the rate-limiting step in the formation of allopregnanolone. It is not clear, however, whether the same phenomenon is observed across to the menstrual cycle, and, if so, at what point this takes place. Methods: Thirty-seven women completed the study during which they attended eight clinic visits across one menstrual cycle. We analyzed their allopregnanolone and progesterone serum concentrations using ultraperformance liquid chromatography-tandem mass spectrometry, and we implemented a validated method to realign the data from the original eight clinic study visits, following which we imputed the missing data. Hence, we characterized allopregnanolone concentrations, and the ratio of allopregnanolone:progesterone at six menstrual cycle subphases: (1) early follicular, (2) mid-follicular, (3) periovulatory, (4) early luteal, (5) mid-luteal, and (6) late luteal. Results: There were significant differences in allopregnanolone levels between (1) early follicular and early luteal, (2) early follicular and mid-luteal, (3) mid-follicular and mid-luteal, (4) periovulatory and mid-luteal, and (5) mid-luteal and late luteal. We detected a sharp drop in allopregnanolone:progesterone ratio in the early luteal subphase. Within the luteal subphase, the ratio was the lowest in the mid-luteal subphase. Conclusions: Allopregnanolone concentrations are the most distinct, relative to the other subphases, in the mid-luteal subphase. The shape of the allopregnanolone trajectory across the cycle is similar to that of progesterone; however, the proportion of the two neuroactive steroid hormones is drastically different due to enzymatic saturation, which takes place at the start of the early luteal subphase, but continuing through, and peaking, in the mid-luteal subphase. Hence, the estimated activity of 5α-reductase decreases, but does not cease, at any point across the menstrual cycle.

Mid-Luteal Progesterone Is Inversely Associated with Premenstrual Food Cravings.

It is not clear whether progesterone and estradiol associate with premenstrual food cravings, which significantly contribute to cardiometabolic adverse effects associated with obesity. We sought to investigate this question in the present study based on the prior literature showing a protective effect of progesterone on drug craving and extensive neurobiological overlaps between food and drug cravings. We enrolled 37 non-illicit drug- or medication-using women in the study to provide daily ratings of premenstrual food cravings and other symptoms across two-three menstrual cycles, based on which we classified them as premenstrual dysphoric disorder (PMDD) or control participants. In addition, the participants provided blood samples at eight clinic visits across the menstrual cycle. We aligned their mid-luteal progesterone and estradiol using a validated method which relies upon the peak serum luteinizing hormone and analyzed estradiol and progesterone using ultraperformance liquid chromatography tandem mass spectrometry. Hierarchical modeling, adjusted for BMI, showed a significant inverse effect of progesterone (p = 0.038) but no effect of estradiol on premenstrual food cravings. The association was not unique to PMDD or control participants. Results of research to date in humans and rodents showing that progesterone has dampening effects on the salience of the reinforcer translate to premenstrual food cravings.

Allopregnanolone Is Associated with a Stress-Induced Reduction of Heart Rate Variability in Premenstrual Dysphoric Disorder.

Human survival and wellbeing require appropriate responses to stress, including a highly coordinated and efficient nervous system control of the heart rhythm. During stress, a greater disinhibition of the vagal nerve is reflective of poor stress adaptability, which may be relevant in premenstrual dysphoric disorder (PMDD)-a debilitating affective condition thought to be marked by dysregulated stress processing and sensitivity to allopregnanolone. In the present study, women with PMDD (n = 17) and healthy controls (n = 18), who did not take medication, smoke, or consume illicit drugs, and who were free of other psychiatric conditions, participated in the Trier Social Stress Test, during which we measured the high frequency of the heart rate (HF-HRV) and allopregnanolone using ultra-performance liquid chromatography tandem mass spectrometry. Relative to their baseline, women who have PMDD, but not the healthy controls, experienced a reduction in HF-HRV during stress anticipation (p ≤ 0.05) and stress (p ≤ 0.01). Their recovery from stress was significantly delayed (p ≤ 0.05). Absolute peak HF-HRV change from baseline was significantly predicted by baseline allopregnanolone only in the PMDD group (p ≤ 0.01). The present study shows how an interaction between stress and allopregnanolone-which have both been separately implicated in PMDD-underlies PMDD expression.

Association between Neuroticism and Premenstrual Affective/Psychological Symptomatology.

Neuroticism and premenstrual conditions share pleiotropic loci and are strongly associated. It is presently not known which DSM-5 symptoms of premenstrual syndrome/premenstrual mood disorder are associated with neuroticism. We enrolled 45 study participants to provide prospective daily ratings of affective ("depression", "anxiety, "anger", "mood swings") and psychological ("low interest", "feeling overwhelmed", and "difficulty concentrating") symptoms across two-three menstrual cycles (128 total cycles). Generalized additive modeling (gam function in R) was implemented to model the relationships between neuroticism and the premenstrual increase in symptomatology. Significance level was adjusted using the False Discovery Rate method and models were adjusted for current age and age of menarche. Results of the association analysis revealed that "low interest" (p ≤ 0.05) and "difficulty concentrating" (p ≤ 0.001) were significantly associated with neuroticism. None of the remaining symptoms reached statistical significance. The late luteal phase of the menstrual cycle is characterized by complex symptomatology, reflecting a physiological milieu of numerous biological processes. By identifying co-expression between neuroticism and specific premenstrual symptomatology, the present study improves our understanding of the premenstrual conditions and provides a platform for individualized treatment developments.

Reduced Dehydroepiandrosterone-Sulfate Levels in the Mid-Luteal Subphase of the Menstrual Cycle: Implications to Women's Health Research.

The regulation of DHEA-sulfate by steroid sulfotransferase (SULT) and steryl-sulfatase (STS) enzymes is a vital process for the downstream formation of many steroid hormones. DHEA-sulfate is the most abundant steroid hormone in the human body; thus, DHEA-sulfate and its hydrolyzed form, DHEA, continue to be evaluated in numerous studies, given their importance to human health. Yet, a basic question of relevance to the reproductive-age female population-whether the two steroid hormones vary across the menstrual cycle-has not been addressed. We applied a validated, multi-step protocol, involving realignment and imputation of study data to early follicular, mid-late follicular, periovulatory, and early, mid-, and late luteal subphases of the menstrual cycle, and analyzed DHEA-sulfate and DHEA serum concentrations using ultraperformance liquid chromatography tandem mass spectrometry. DHEA-sulfate levels started to decrease in the early luteal, significantly dropped in the mid-luteal, and returned to basal levels by the late luteal subphase. DHEA, however, did not vary across the menstrual cycle. The present study deep-mapped trajectories of DHEA and DHEA-sulfate across the entire menstrual cycle, demonstrating a significant decrease in DHEA-sulfate in the mid-luteal subphase. These findings are relevant to the active area of research examining associations between DHEA-sulfate levels and various disease states.

Behavioral Symptomatology in the Premenstruum.

OBJECTIVE: Sleep and eating behaviors are disturbed during the premenstrual phase of the menstrual cycle in a significant number of reproductive-age women. Despite their impact on the development and control of chronic health conditions, these behaviors are poorly understood. In the present study, we sought to identify affective and psychological factors which associate with premenstrual changes in sleeping and eating behaviors and assess how they impact functionality. METHODS: Fifty-seven women provided daily ratings of premenstrual symptomatology and functionality across two-three menstrual cycles (156 cycles total). For each participant and symptom, we subtracted the mean day +5 to +10 ("post-menstruum") ratings from mean day -6 to -1 ("pre-menstruum") ratings and divided this value by participant- and symptom-specific variance. We completed the statistical analysis using multivariate linear regression. RESULTS: Low interest was associated with a premenstrual increase in insomnia (p ≤ 0.05) and appetite/eating (p ≤ 0.05). Furthermore, insomnia was associated with occupational (p ≤ 0.001), recreational (p ≤ 0.001), and relational (p ≤ 0.01) impairment. CONCLUSIONS: Results of the present analysis highlight the importance of apathy (i.e., low interest) on the expression of behavioral symptomatology, as well as premenstrual insomnia on impairment. These findings can inform treatment approaches, thereby improving care for patients suffering from premenstrual symptomatology linked to chronic disease conditions.

Waist Circumference and Its Association With Premenstrual Food Craving: The PHASE Longitudinal Study.

Visceral adiposity is a significant marker of all-cause mortality. Reproductive age women are at a considerable risk for developing visceral adiposity; however, the associated factors are poorly understood. The proposed study evaluated whether food craving experienced during the premenstrual period is associated with waist circumference. Forty-six women (mean BMI = 24.36) prospectively provided daily ratings of food craving across two-three menstrual cycles (122 cycles total). Their premenstrual rating of food craving was contrasted against food craving in the follicular phase to derive a corrected summary score of the premenstrual food craving increase. Study groups were divided into normal (n = 26) and obese (n = 20) based on the 80 cm waist circumference cutoff signifying an increase in risk. Waist circumference category was significantly associated with premenstrual food cravings [F (1,44) = 5.12, p = 0.028]. Post hoc comparisons using the Tukey HSD test (95% family-wise confidence level) showed that the mean score for the food craving effect size was 0.35 higher for the abdominally obese vs. normal study groups (95% CI: 0.039 to 0.67). The result was statistically significant even following inclusion of BMI in the model, pointing to a particularly dangerous process of central fat accumulation. The present study establishes an association between temporal vulnerability to an increased food-related behavior and a marker of metabolic abnormality risk (i.e., waist circumference), thereby forming a basis for integrating the premenstruum as a viable intervention target for this at-risk sex and age group.

Dual Orexin Receptor Antagonists (DORAs) as an Adjunct Treatment for Smoking Cessation.

Smoking is recognized as the most avoidable cause for multiplicity of chronic diseases. However, smoking cessation rates remain low, in part due to the limited target engagement of the currently approved medications for smoking cessation. Sleep is a promising focus for increasing smoking cessation rates because smokers' sleep problems are exacerbated during the first week of smoking abstinence and are associated with poor smoking cessation outcomes. Furthermore, the currently approved smoking cessation pharmacological agents varenicline and nicotine replacement treatment exacerbate sleep problems beyond what would be observed as a consequence of natural nicotine withdrawal. Addressing sleep problems with dual orexin receptor antagonists (DORAs) is positioned to remedy the shortcoming of overlooking sleep as a viable smoking cessation intervention target. Based on previous animal literature, DORA agents suvorexant and lemborexant may accomplish this by diminishing withdrawal difficulty and reducing nicotine cravings. The pharmacologic focus is the orexin system, not only because orexin peptides mediate the sleep-wake cycle, but also because DORA agents have a milder adverse event profile over previous treatments for insomnia. A novel adjunct DORA treatment to a currently approved smoking cessation pharmacotherapy holds a potential to reduce morbidity and mortality caused by smoking.

E-Cigarette Dependence and Weight-Related Attitudes/Behaviors Associated With Eating Disorders in Adolescent Girls.

Background: Although numerous motivations for vaping have been identified in adolescents, no study to date has examined a possible link between vaping and attitudes/behaviors that are associated with eating disorders in adolescent females. Examining this question in adolescent females is especially relevant given the higher prevalence of eating disorders in adolescent girls and women compared to adolescent boys and men. Methods: We recruited 299 girls (between 13 to 17 years old) via Facebook advertisement to complete a REDCap survey, which included the Electronic Cigarette Dependence Index (ECDI), Minnesota Eating Behavior Survey (MEBS), and demographic questions. Data were analyzed using nonparametric Spearman rank correlation test in R. Results: Electronic Cigarette Dependence Index (ECDI) scores were correlated with weight preoccupation (WP), binge eating (BE) and compensatory behavior (CB), but not body dissatisfaction (BD). The following were the results of Spearman correlation tests: (1) WP: rho = 0.13, p = 0.02; (2) BD: rho = 0.06, p = 0.28; (3) BE: rho = 0.15, p = 0.0095; (4) CB: rho = 0.021, p = 0.00027. Conclusion: The present study adds to the current literature examining motivations for e-cigarette use in adolescent girls. As eating disorders and e-cigarette dependence are significant public health concerns, our results highlight the need for intervention development.

Association Between Smoking and Premenstrual Syndrome: A Meta-Analysis.

Results of basic science studies demonstrate shared actions of endogenous neuroactive steroid hormones and drugs of abuse on neurotransmission. As such, premenstrual syndrome (PMS) may be associated with smoking, however, results from studies examining this relationship have been mixed. Following PRISMA guidelines, we extracted unique studies examining the relationship between smoking and PMS. We used the escalc () function in R to compute the log odds ratios and corresponding sampling variance for each study. We based quality assessment on the nature of PMS diagnosis and smoking estimation, confounding adjustment, participation rate, and a priori specification of target population. Our final sample included 13 studies, involving 25,828 study participants. Smoking was associated with an increased risk for PMS [OR = 1.56 (95% CI: 1.25-1.93), p < 0.0001]. Stratified by diagnosis, the effect size estimate was higher for Premenstrual Dysphoric Disorder (PMDD) [OR = 3.15 (95% CI: 2.20-4.52), p < 0.0001] than for PMS [OR = 1.27 (95% CI: 1.16-1.39), p < 0.0001]. We review some of the basic mechanisms for the observed association between smoking and PMS. Given nicotine's rewarding effects, increased smoking behavior may be a mechanism to alleviate affective symptoms of PMS. However, smoking may lead to worsening of PMS symptoms because nicotine has effects on neurocircuitry that increases susceptibility to environmental stressors. Indeed, prior evidence shows that the hypothalamic-pituitary-adrenal (HPA) axis is already sub-optimal in PMS, hence, smoking likely further deteriorates it. Combined, this complicates the clinical course for the treatment of both PMS and Tobacco Use Disorder in this population.

Higher Circulating Cortisol in the Follicular vs. Luteal Phase of the Menstrual Cycle: A Meta-Analysis.

Although results of animal research show that interactions between stress and sex hormones are implicated in the development of affective disorders in women, translation of these findings to patients has been scarce. As a basic step toward advancing this field of research, we analyzed findings of studies which reported circulating cortisol levels in healthy women in the follicular vs. luteal phase of the menstrual cycle. We deemed this analysis critical not only to advance our understanding of basic physiology, but also as an important contrast to the findings of future studies evaluating stress and sex hormones in women with affective disorders. We hypothesized that cortisol levels would be lower in the follicular phase based on the proposition that changes in levels of potent GABAergic neurosteroids, including allopregnanolone, during the menstrual cycle dynamically change in the opposite direction relative to cortisol levels. Implementing strict inclusion criteria, we compiled results of high-quality studies involving 778 study participants to derive a standardized mean difference between circulating cortisol levels in the follicular vs. luteal phase of the menstrual cycle. In line with our hypothesis, our meta-analysis found that women in the follicular phase had higher cortisol levels than women in the luteal phase, with an overall Hedges' g of 0.13 (p < 0.01) for the random effects model. No significant between-study difference was detected, with the level of heterogeneity in the small range. Furthermore, there was no evidence of publication bias. As cortisol regulation is a delicate process, we review some of the basic mechanisms by which progesterone, its potent metabolites, and estradiol regulate cortisol output and circulation to contribute to the net effect of higher cortisol in the follicular phase.

Quantitative meta-analysis of heart rate variability finds reduced parasympathetic cardiac tone in women compared to men during laboratory-based social stress.

Heart rate variability (HRV) is the inter-beat interval variation between consecutive heartbeats and an autonomic reflection of emotional regulatory abilities to flexibly respond to challenges, such as psychosocial stress. Whereas there are known sex differences in stress-induced hormonal and emotional responses, we identified a gap in our understanding of sex-specific autonomic cardiac control during stress. Thus, we assessed HRV prior to, during and after administration of a public speech task in healthy participants (n = 929) according to sex. Our meta-analysis found that during stress, women had lower HRV than men, with an overall Hedges' g of 0.29 (p < 0.0001) and 0.29 (p = 0.0003) for fixed and random effects models, respectively. We did not find significant heterogeneity or evidence of publication bias. Analyses of additional timepoints showed no baseline difference and marginally lower HRV in women during anticipation and recovery. Findings of the present meta-analysis confirm sex differences in stress-induced hyperarousal and form a justification for implementation of mechanistic studies evaluating gonadal hormones, their potent metabolites and pro-inflammatory cytokines as mediators of this relationship.

The P300 in alcohol use disorder: A meta-analysis and meta-regression.

OBJECTIVE: The P300 ERP component is a marker of reduced capacity in alcohol use disorder (AUD) to engage attentional mechanisms and update memory representations. No meta-analysis to date has been completed comparing effect size estimates of auditory vs. visual stimuli in AUD. In addition, there is a lack of consensus on whether the P3b in women is reduced, or whether the P3a - an earlier, more frontally distributed component - is reduced in AUD. METHODS: Strict inclusion criteria and data-analysis plans were implemented. Eligible studies needed to diagnose AUD using DSM or ICD-10 and exclude patients with any psychiatric co-morbidities. Data analysis was completed using a refined variance estimator of the random effects model. RESULTS: Effect size estimates were large for both auditory (Hedges' g = 1.01, p = .056) and visual (Hedges' g = 0.77, p = .040) P300 amplitudes, but only marginally significant for the auditory modality. Auditory P300 latency was significantly increased in AUD patients (Hedges' g = 0.73, p = .027). The moderator analysis did not show significant sex differences for either auditory (p = .97) or visual (p = .45) P3b. Finally, the P3a was not reduced in patients with AUD (Hedges' g = 1.01; p = .59). CONCLUSION: This meta-analysis clarifies important questions related to P300 in AUD. By resolving inconsistencies, it is hoped that this information will facilitate the design of futurestudies.