Bridging the Gap: Integrating Awareness of Polycystic Ovary Syndrome Into Mental Health Practice.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age. Individuals with PCOS report reduced quality of life compared with those without PCOS, with possible contributing factors including infertility, hirsutism, irregular menses, and weight gain. Recent literature also supports increased associations between PCOS and co-occurring psychiatric conditions, particularly depression, anxiety, bipolar disorder, and eating disorders. It is concerning that a higher prevalence of suicidal ideation has been observed in individuals with PCOS. Given the high rates of psychiatric burden among those with PCOS, psychiatric care providers are well suited to be on the front lines of screening for psychiatric symptoms as well as initiating treatment. Current interventions include lifestyle changes (improving exercise and nutrition), pharmacological treatments (e.g., insulin-sensitizing agents, oral contraceptives, and psychotropic drugs), and psychotherapeutic interventions (e.g., cognitive-behavioral therapy and mindfulness-based therapy). This review provides an overview of recent research on the prevalence of comorbid psychiatric conditions, a foundation in PCOS-specific symptom screening and diagnosis, and an overview of treatments for psychiatric symptoms among individuals with PCOS.

Efficacy of the Flo App in Improving Health Literacy, Menstrual and General Health, and Well-Being in Women: Pilot Randomized Controlled Trial.

BACKGROUND: Reproductive health literacy and menstrual health awareness play a crucial role in ensuring the health and well-being of women and people who menstruate. Further, awareness of one's own menstrual cycle patterns and associated symptoms can help individuals identify and manage conditions of the menstrual cycle such as premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD). Digital health products, and specifically menstrual health apps, have the potential to effect positive change due to their scalability and ease of access. OBJECTIVE: The primary aim of this study was to measure the efficacy of a menstrual and reproductive health app, Flo, in improving health literacy and health and well-being outcomes in menstruating individuals with and without PMS and PMDD. Further, we explored the possibility that the use of the Flo app could positively influence feelings around reproductive health management and communication about health, menstrual cycle stigma, unplanned pregnancies, quality of life, work productivity, absenteeism, and body image. METHODS: We conducted 2 pilot, 3-month, unblinded, 2-armed, remote randomized controlled trials on the effects of using the Flo app in a sample of US-based (1) individuals who track their cycles (n=321) or (2) individuals who track their cycles and are affected by PMS or PMDD (n=117). RESULTS: The findings revealed significant improvements at the end of the study period compared to baseline for our primary outcomes of health literacy (cycle tracking: D̄=1.11; t311=5.73, P<.001; PMS or PMDD: D̄=1.20; t115=3.76, P<.001) and menstrual health awareness (D̄=3.97; t311=7.71, P<.001), health and well-being (D̄=3.44; t311=5.94, P<.001), and PMS or PMDD symptoms burden (D̄=-7.08; t115=-5.44, P<.001). Improvements were also observed for our secondary outcomes of feelings of control and management over health (D̄=1.01; t311=5.08, P<.001), communication about health (D̄=0.93; t311=2.41, P=.002), menstrual cycle stigma (D̄=-0.61; t311=-2.73, P=.007), and fear of unplanned pregnancies (D̄=-0.22; t311=-2.11, P=.04) for those who track their cycles, as well as absenteeism from work and education due to PMS or PMDD (D̄=-1.67; t144=-2.49, P=.01). CONCLUSIONS: These pilot randomized controlled trials demonstrate that the use of the Flo app improves menstrual health literacy and awareness, general health and well-being, and PMS or PMDD symptom burden. Considering the widespread use and affordability of the Flo app, these findings show promise for filling important gaps in current health care provisioning such as improving menstrual knowledge and health. TRIAL REGISTRATION: OSF Registries osf.io/pcgw7; https://osf.io/pcgw7 ; OSF Registries osf.io/ry8vq; https://osf.io/ry8vq.

GABAergic neuroactive steroid response to sertraline in premenstrual dysphoric disorder.

RATIONALE: Premenstrual dysphoric disorder (PMDD) affects approximately 5% of menstruating individuals, with significant negative mood symptoms in the luteal phase of the menstrual cycle. PMDD's pathophysiology and treatment mechanisms are poorly characterized, but may involve altered neuroactive steroid function in the brain. Selective serotonin reuptake inhibitors (SSRIs), a first-line PMDD treatment, reportedly alter gamma-aminobutyric acid (GABA)ergic neuroactive steroid levels in PMDD. AIMS: The aims of this study were to determine whether the SSRI sertraline increased serum levels of neuroactive steroids that modulate the effect of GABA at GABA-A receptors (GABAAR) and if so, whether an increase was associated with improvement in PMDD symptoms. METHODS: Participants included controls and individuals with PMDD. Serum levels of 9 neuroactive steroids were measured (3α,5α-THP; 3α5ß-THP; pregnenolone; 3α,5α-androsterone; 3α,5ß-androsterone; 3α,5α-A-diol; 3α5ß-A-diol; 3α,5α-THDOC; 3α5ß-THDOC) in the follicular and luteal phases. In the subsequent luteal phase, neuroactive steroids were measured during sertraline treatment (50 mg sertraline from approximate ovulation to menses onset) in the PMDD group. Mixed models assessed associations among diagnostic group, menstrual cycle phase, and sertraline treatment. RESULTS: Participants included 38 controls and 32 women with PMDD. There were no significant differences in neuroactive steroid levels between controls and participants with PMDD in the luteal phase (p > 0.05). Within the PMDD group, sertraline treatment significantly increased serum pregnanolone levels and the pregnanolone:progesterone ratio, and decreased 3α,5α-androsterone. CONCLUSIONS: This was the first study to assess the impact of SSRI treatment on peripheral levels of GABAergic neuroactive steroids in PMDD. Within the PMDD group, sertraline treatment was associated with a significant increase in luteal phase serum pregnanolone levels and a significantly increased pregnanolone:progesterone ratio, a novel finding. Future research should examine alterations in the metabolic pathways among GABAergic neuroactive steroids in individuals with PMDD, in a placebo-controlled design.

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.

Towards understanding the biology of premenstrual dysphoric disorder: From genes to GABA.

Premenstrual dysphoric disorder (PMDD) is a severe mood disorder, with affective symptoms that rise and fall in concert with the hormonal fluctuations of the menstrual cycle. PMDD's pathophysiology is poorly understood. This review describes recent research on potential biological contributors to PMDD, with a focus on neuroactive steroids, genetics, neuroimaging and cellular studies. Studies suggest that a key contributor is abnormal central nervous system (CNS) response to fluctuations in neuroactive steroid hormones. Imaging studies are limited but support alterations in serotonergic and GABA transmission. Genetic studies suggest heritability, yet specific genetic contributors have not been characterized. Finally, recent cutting-edge cellular studies indicate an underlying vulnerability to the effect of sex hormones at a cellular level. Overall the findings across studies do not yet fit together into a complete description of the underlying biology of PMDD. It is possible that PMDD consists of biological subtypes, and future research may benefit from a subtyping approach.

Maternal adverse childhood experiences impact fetal adrenal volume in a sex-specific manner.

BACKGROUND: The mechanisms by which parental early life stress can be transmitted to the next generation, in some cases in a sex-specific manner, are unclear. Maternal preconception stress may increase susceptibility to suboptimal health outcomes via in utero programming of the fetal hypothalamic-pituitary-adrenal (HPA) axis. METHODS: We recruited healthy pregnant women (N = 147), dichotomized into low (0 or 1) and high (2+) adverse childhood experience (ACE) groups based on the ACE Questionnaire, to test the hypothesis that maternal ACE history influences fetal adrenal development in a sex-specific manner. At a mean (standard deviation) of 21.5 (1.4) and 29.5 (1.4) weeks gestation, participants underwent three-dimensional ultrasounds to measure fetal adrenal volume, adjusting for fetal body weight (waFAV). RESULTS: At ultrasound 1, waFAV was smaller in high versus low ACE males (b = - 0.17; z = - 3.75; p < .001), but females did not differ significantly by maternal ACE group (b = 0.09; z = 1.72; p = .086). Compared to low ACE males, waFAV was smaller for low (b = - 0.20; z = - 4.10; p < .001) and high ACE females (b = - 0.11; z = 2.16; p = .031); however, high ACE males did not differ from low (b = 0.03; z = .57; p = .570) or high ACE females (b = - 0.06; z = - 1.29; p = .196). At ultrasound 2, waFAV did not differ significantly between any maternal ACE/offspring sex subgroups (ps ≥ .055). Perceived stress did not differ between maternal ACE groups at baseline, ultrasound 1, or ultrasound 2 (ps ≥ .148). CONCLUSIONS: We observed a significant impact of high maternal ACE history on waFAV, a proxy for fetal adrenal development, but only in males. Our observation that the waFAV in males of mothers with a high ACE history did not differ from the waFAV of females extends preclinical research demonstrating a dysmasculinizing effect of gestational stress on a range of offspring outcomes. Future studies investigating intergenerational transmission of stress should consider the influence of maternal preconception stress on offspring outcomes.

Enduring impact of childhood adversity: Affective modulation of acoustic startle response during pregnancy and postpartum.

BACKGROUND: Women with a history of adverse childhood experiences (ACEs) enter pregnancy and the postpartum with a physiologic system programmed by early life stress, potentially reflected in psychophysiologic reactivity. METHODS: We enrolled pregnant, psychiatrically healthy women ≥18 years old. Using the ACE Questionnaire, women were categorized as high (≥2 ACEs; n = 77) or low ACE (<2 ACEs; n = 72). Participants completed an affective modulation of acoustic startle response (ASR) task during pregnancy and postpartum, in which ASR magnitude was measured while participants viewed pleasant, unpleasant, and neutral pictures. Two types of control trials were included (habituation trials presented at baseline and intertrial interval trials presented when no picture was present). RESULTS: Among high ACE women, ASR was significantly higher postpartum compared with pregnancy in the unpleasant (p = 0.002, ß = 0.46, 95% CI [0.18, 0.74], χ2 = 10.12, z = 3.18) and intertrial interval trials (p = 0.002, ß = 0.44, 95% CI [0.16, 0.73], χ2 = 9.25, z = 3.04), accounting for multiple comparisons using a Bonferroni correction at p < 0.005. Among low ACE women, ASR was similar in pregnancy and postpartum. CONCLUSIONS: Physiological reactivity increased in high ACE women from pregnancy to postpartum, but no change was observed in low ACE women.

Premenstrual symptoms across the lifespan in an international sample: data from a mobile application.

Premenstrual symptoms, including physical and mood symptoms, affect a large proportion of women worldwide. Data on premenstrual symptoms across nations and age groups is limited. In the present study, we leveraged a large international dataset to explore patterns in premenstrual symptom frequency with age. A survey was administered to users of the Flo mobile application (app), aged 18 to 55. The survey queried app users about a range of premenstrual symptoms. Respondents were asked whether they experienced each symptom every menstrual cycle, some cycles, or never. Age was also captured and categorized as 18-27, 28-37, 38-47, 48-55. Data was summarized and Pearson's chi square test for count data assessed differences in symptom frequency by age group. A sample of 238,114 app users from 140 countries responded to the survey. The most common symptoms reported were food cravings (85.28%), mood swings or anxiety (64.18%), and fatigue (57.3%). Absentmindedness, low libido, sleep changes, gastrointestinal symptoms, weight gain, headaches, sweating or hot flashes, fatigue, hair changes, rashes, and swelling were significantly more frequent with increasing age (p's < 0.001). Mood swings and anxiety did not vary by age group. Of the respondents, 28.61% reported that premenstrual symptoms interfered with their everyday life each menstrual cycle. In a large international sample, the majority of women reported premenstrual food cravings, mood changes, and fatigue every menstrual cycle. Mood symptoms did not vary by age group, suggesting that premenstrual mood changes are a persistent issue among women of reproductive age.

Engagement in and Benefits of a Short-Term, Brief Psychotherapy Intervention for PTSD During Pregnancy.

Trauma-related symptoms and post-traumatic stress disorder (PTSD) are common during pregnancy and have adverse effects on pregnancy and birth outcomes, post-partum maternal mental health, and child development. The arousal symptoms associated with PTSD, including heightened or dysregulated physiology, may contribute to these adverse outcomes. Low-income minoritized women may be at highest risk given more lifetime exposure to trauma and limited access to mental health care. While evidence-based psychotherapies for PTSD exist, none are targeted to non-treatment seeking individuals nor specifically integrated with prenatal care. Thus, we developed and tested the efficacy of a short-term (four sessions) brief (30-45 min) psychotherapeutic intervention designed to address PTSD symptoms in pregnant women receiving prenatal care at two urban medical centers. Participants were 32 pregnant women with an average gestational age of 18.5 weeks at the time of enrollment. The sample was overwhelmingly non-Caucasian, single, and reported very low income. Participants completed measures of trauma-related symptoms (Post-traumatic Stress Disorder Checklist, PCL), and depression (Edinburgh post-natal Depression Scale, EPDS) at baseline, twice during treatment, post-treatment, and at 10-14 weeks post-partum. The intervention was successful at significantly decreasing symptoms of PTSD (PCL score = -20.27, 95% CI: -25.62, -14.92, P < 0.001, W = -7.43) and depression (EPDS score = -4.81, 95% CI: -7.55, -2.06, P = 0.001, W = -3.23) by the final session. These benefits were sustained at post-treatment and post-partum follow ups. Future research should further explore the effectiveness of this treatment in a randomized controlled trial.

Allopregnanolone and depression and anxiety symptoms across the peripartum: an exploratory study.

Recent research has implicated allopregnanolone (ALLO), a neuroactive steroid and metabolite of progesterone, in perinatal mood and anxiety symptoms. We sought to add to the limited literature examining ALLO and mood and anxiety at multiple time points across the peripartum. We measured mood and anxiety symptoms and ALLO levels by ELISA at the second and third trimester (T2 and T3) and week 6 postpartum (W6) in N = 73 women with prior histories of mood and/or anxiety disorders and N = 38 healthy controls. Analytic methods included multivariate and logistic regressions with linear mixed effect models. Among all participants (N = 111), higher ALLO levels at W6 were associated with higher depression and anxiety scores: each one unit increase in log ALLO at W6 was associated with a 2.54 point increase on the Edinburgh Postnatal Depression Scale (EPDS) (95% CI: 0.73 to 4.33) and an 8.0 point increase on the Perinatal Anxiety Screening Scale (PASS) (95% CI: 3.82 to 12.6). In addition, the nature of the relationship between log ALLO level and psychological measures changed across time; from T2 to W6 for EPDS, ß = 3.73 (95% CI:1.16, 6.30), p = 0.0045; for PASS ß = 9.78 (95% CI:3.77, 15.79), p = 0.0014); from T3 to W6, for (EPDS, ß = 2.52 (95% CI:0.08, 4.96), p = 0.043; for PASS ß = 7.33 (95% CI:1.63, 13.02), p = 0.018). The relationship of log ALLO to mood and anxiety symptoms was the same among women with and without psychiatric histories. Our exploratory findings indicate that the relationship between ALLO and mood and anxiety symptoms may change across the peripartum.

Patient Experiences of Health Care Providers in Premenstrual Dysphoric Disorder: Examining the Role of Provider Specialty.

Background: Premenstrual dysphoric disorder (PMDD) is a severe mood disorder that affects ∼5% of menstruating individuals. Although symptoms are limited to the luteal phase of the menstrual cycle, PMDD causes significant distress and impairment across a range of activities. PMDD is under-recognized by health care providers, can be difficult to diagnose, and lies at the intersection of gynecology and psychiatry. Thus, many patients are misdiagnosed, or encounter challenges in seeking care. The aim of this study was to examine patients' experiences with different health care specialties when seeking care for PMDD symptoms. Methods: We examined data from the 2018 Global Survey of Premenstrual Disorders conducted by the International Association for Premenstrual Disorders (IAPMD). Patients rated their health care providers (general practitioners, psychiatrists, gynecologists, psychotherapists) in three key areas related to treatment of premenstrual mood complaints: interpersonal factors, awareness and knowledge of PMDD, and whether the patient was asked to track symptoms daily. Intraclass correlations examined between- and within-person variance. Multilevel regression models predicted ratings on each provider competency item, with ratings nested within individuals to examine the within-patient effect of provider type on outcomes. Results: The sample included 2,512 patients who reported seeking care for PMDD symptoms. Regarding interpersonal factors, psychotherapists were generally rated the highest. On awareness and knowledge of PMDD, gynecologists and psychiatrists were generally rated the highest. Gynecologists were more likely than other providers to ask patients to track symptoms daily. Conclusions: These findings suggest that different providers have different strengths in assessing and treating PMDD. Further, graduate and medical training programs may benefit from increased curricular development regarding evidence-based evaluation and treatment of PMDD.

Symptom profiles of women at risk of mood disorders: A latent class analysis.

BACKGROUND: Depression is the leading cause of disease burden among women worldwide. However, an understanding of symptom profiles among women at risk of mood disorders is limited. We determined distinct profiles of affective symptoms among high risk women, along with their distinguishing characteristics. METHODS: Women were recruited from 17 clinical sites affiliated with the National Network of Depression Centers. They completed measures of depression (Patient Health Questionnaire - 9) and anxiety (Generalized Anxiety Disorder - 7) as well as questions regarding demographics, reproductive status, behavioral/mental health history, and life stress/adversity. Latent class analysis and multinomial logistic regression were used to identify and characterize symptom profiles. RESULTS: 5792 women participated, ages 18 to 90 (M = 38). Three latent classes were identified: generally asymptomatic (48%), elevated symptoms of comorbid anxiety and depression (16%), and somatic symptoms (36%). Financial security and greater social support were protective factors that distinguished asymptomatic women. The profile of the class with elevated anxiety/depressive symptoms constituted a complex mix of adverse social determinants and potentially heritable clinical features, including a diagnosis of Bipolar Disorder. Women in the 3rd latent class were characterized by menstrual irregularity and a stronger expression of neurovegetative symptoms, especially sleep disturbance and fatigue. LIMITATIONS: Limitations included less than optimal racial diversity of our sample and reliance on self-report. CONCLUSIONS: Different symptom profiles may reflect distinct subtypes of women at risk of mood disorders. Understanding the etiology and mechanisms underlying clinical and psychosocial features of these profiles can inform more precisely targeted interventions to address women's diverse needs.

High worry in pregnancy predicts postpartum depression.

BACKGROUND: Anxiety in pregnancy is one of the strongest risk factors for postpartum depression (PPD), and high worry is a hallmark of many anxiety disorders. We sought to determine whether the Penn State Worry Questionnaire (PSWQ), designed for the general population, could identify high worry in pregnancy and predict the development of PPD symptoms (PPDS). METHODS: We followed women (N = 295) with and without mood and anxiety disorders across pregnancy and up to 6 months postpartum. Diagnoses were confirmed by SCID and by an experienced perinatal psychiatrist, and we administered the PSWQ and the Edinburgh Postnatal Depression Scale (EPDS) at up to 6 time points. We determined the trajectory of worry across time and its relationship to PPDS. RESULTS: Women with a history or current diagnosis of major depressive disorder (MDD) or generalized anxiety disorder (GAD) were more likely to experience high antenatal worry (defined as PSWQ >60), p < .004 for MDD and <0.001 for all others. High antenatal worry was the only significant predictor of PPDS, with an OR of 3.91 (95% CI 1.44-10.65); neither psychiatric diagnosis nor elevated antenatal depressive symptoms was significantly associated with PPDS in a multivariate model. LIMITATIONS: Our study used self-report measures in a largely homogeneous population, which may limit the generalizability of our results. CONCLUSIONS: The PSWQ may be a useful clinical tool in pregnancy. High worry is a strong predictor of PPDS, and is a better predictor of PPDS than psychiatric diagnosis or elevated antenatal depressive symptoms in this population.

Response to sertraline is associated with reduction in anxiety-potentiated startle in premenstrual dysphoric disorder.

RATIONALE: Women with premenstrual dysphoric disorder (PMDD) appear to have altered central nervous system sensitivity to neuroactive steroid hormones, manifesting as affective symptoms and heightened arousal in the luteal phase of the menstrual cycle. In particular, women with PMDD appear less sensitive to allopregnanolone, a positive allosteric GABA-A receptor (GABA-A-R) modulator. OBJECTIVES: This study evaluated psychophysiologic reactivity in women with PMDD in the follicular and luteal phases of the menstrual cycle, utilizing anxiety-potentiated startle (APS), a potential translational marker of GABA-A-R sensitivity. The study also assessed APS response to low-dose sertraline treatment in women with PMDD. METHODS: Participants' APS and fear-potentiated startle (FPS) were assessed in the follicular and luteal phases. Women with PMDD received 50 mg sertraline in the following luteal phase to examine impact on APS and FPS. RESULTS: There were no significant differences between controls (n = 41) and PMDD participants (n = 36) in change from follicular to luteal phases in baseline startle, APS nor FPS. However, among participants who responded to sertraline, APS was higher in the untreated luteal phase than the follicular phase, but lower in the treated luteal phase than the follicular phase. CONCLUSION: These data demonstrate elevated psychophysiologic arousal in the luteal phase among some women with PMDD, suggesting impaired ability to modulate arousal reactivity. Specifically, alterations in APS suggest potential GABA-A-R changes across the menstrual cycle and in response to sertraline among treatment responders.

Stress gets into the belly: Early life stress and the gut microbiome.

Research has established that stress "gets under the skin," impacting neuroendocrine and neuroimmune pathways to influence risk for physical and mental health outcomes. These effects can be particularly significant for early life stress (ELS), or adverse childhood experiences (ACEs). In this review, we explore whether stress gets "into the belly," that is, whether psychosocial stress affects the gut microbiome. We review animal and human research utilizing a variety of stress paradigms (acute laboratory stressors, chronic stress, stressful life events, perceived stress, ELS, in utero stress) and their impacts on the gut microbiota, with a particular focus on ELS. We also review data on dietary interventions to moderate impact of stress on the gut microbiome. Our review suggests strong evidence that acute laboratory stress, chronic stress, and ELS affect the gut microbiota in rodents, and growing evidence that perceived stress and ELS may impact the gut microbiota in humans. Emerging data also suggests, particularly in rodents, that dietary interventions such as omega-3 fatty acids and pre- and pro-biotics may buffer against the effects of stress on the gut microbiome, but more research is needed. In sum, growing evidence suggests that stress impacts not only the neuroendocrine and neuroimmune axes, but also the microbiota-gut-brain-axis, providing a pathway by which stress may get "into the belly" to influence health risk.

Polycystic Ovary Syndrome, Affective Symptoms, and Neuroactive Steroids: a Focus on Allopregnanolone.

PURPOSE OF REVIEW: To provide an overview of existing studies on alterations in gonadal and neuroactive steroids (NASs) and mood symptoms among women with polycystic ovary syndrome (PCOS). RECENT FINDINGS: Recent studies have demonstrated a previously underappreciated association between PCOS and comorbid depression and anxiety. However, most studies on affective symptoms among women with PCOS have been cross-sectional, limiting our knowledge about fluctuations in symptoms over the menstrual cycle and reproductive lifespan for women with PCOS, as well as the potential interplay between NAS alterations and mood symptoms. Changes in the NAS allopregnanolone (ALLO) have been implicated in several reproductive-related psychiatric disorders (e.g., premenstrual dysphoric disorder (PMDD) and postpartum depression (PPD)) as well as in normal reproductive functioning, warranting further investigation for its potential role in the psychiatric symptoms observed in women with PCOS. Prospective studies evaluating associations between psychiatric symptoms and NAS are needed to elucidate the biological causes of the increased rates of psychiatric symptoms among women with PCOS and inform clinical treatment. ALLO, with its role in normal reproductive function, menstrual dysregulation among women with PCOS, and reproductive-related psychiatric conditions, makes it a particularly intriguing candidate for future investigation.

Allopregnanolone in premenstrual dysphoric disorder (PMDD): Evidence for dysregulated sensitivity to GABA-A receptor modulating neuroactive steroids across the menstrual cycle.

Premenstrual dysphoric disorder (PMDD) is a severe mood disorder with core symptoms (affective lability, irritability, depressed mood, anxiety) and increased sensitivity to stress occurring in the luteal phase of the menstrual cycle. PMDD can be conceptualized as a disorder of suboptimal sensitivity to neuroactive steroid hormones (NASs). In this review, we describe the role of the NAS allopregnanolone (ALLO), a positive allosteric modulator of the GABAA receptor (GABAA-R), in PMDD's pathophysiology. We review evidence of impaired interaction between ALLO and GABAA-Rs in terms of affective symptom expression, with evidence from rodent and human studies. We discuss evidence of increased luteal phase stress sensitivity as a result of poor ALLO-GABA control of the HPA axis. Finally, we describe how treatments such as selective serotonin reuptake inhibitors (SSRIs) and new drugs targeting GABAA-Rs provide evidence for impaired ALLO-GABA function in PMDD. In sum, the literature supports the hypothesis that PMDD pathophysiology is rooted in impaired GABAA-R response to dynamic ALLO fluctuations across the menstrual cycle, manifesting in affective symptoms and poor regulation of physiologic stress response.

Glucocorticoid-immune response to acute stress in women and men living with HIV.

Despite high risk for serious non-AIDS events (SNAEs) and accelerated age-related increases in inflammatory markers relative to HIV+ men, HIV+ women have been understudied, particularly in terms of stress impacts on immune parameters. The purpose of this study was to examine sex differences in glucocorticoid-immune stress response in mid-life HIV+ individuals, as poor glucocorticoid control of stress-induced inflammation may contribute to health risk in HIV+ women. Male and female participants completed a threat of shock laboratory stressor. Serum cortisol and cytokines [interleukin (IL)-6, IL-8, IL-10, IL-1ß, C-reactive protein (CRP), tumor necrosis factor (TNF)-α, interferon (IFN)-γ] were assessed at six timepoints prior to and in response to the stressor. Participants included 8 HIV- controls (n = 5 female) and 9 HIV+ (n = 5 female) who were virally suppressed. Repeated measures mixed models revealed a significant sex by HIV status by time interaction for IL-10, IL-1ß, TNF-α, and cortisol. IL-10 response, an anti-inflammatory cytokine, was larger in males than females, regardless of HIV status. TNF-α response was blunted in HIV+ individuals compared with HIV-, and specifically in HIV+ women, IL-1ß and cortisol response were blunted. Individuals living with HIV may have impaired coordination between the immune system and hypothalamic pituitary adrenal (HPA) axis. HIV+ women in particular exhibited dysregulated IL-1ß and cortisol response to acute stress. Future work should focus on relationships among proinflammatory cytokines, stress, and SNAEs in HIV, with attention to sex as a biological variable.

Inflammation: A Proposed Intermediary Between Maternal Stress and Offspring Neuropsychiatric Risk.

During pregnancy, programming of the fetal central nervous system establishes vulnerabilities for emergence of neuropsychiatric phenotypes later in life. Psychosocial influences during pregnancy, such as stressful life events and chronic stress, correlate with offspring neuropsychiatric disorders and inflammation, respectively. Stress promotes inflammation, but the role of inflammation as a mediator between maternal psychosocial stress and offspring neuropsychiatric outcomes has not been extensively studied in humans. This review summarizes clinical evidence linking specific types of stress to maternal inflammatory load during pregnancy. We propose that inflammation is a mediator in the relationship between psychosocial stress and offspring neuropsychiatric outcomes, potentially influenced by poor maternal glucocorticoid-immune coordination. We present relevant experimental animal research supporting this hypothesis. We conclude that clinical and preclinical research supports the premise that stress-induced maternal immune activation contributes in part to prenatal programming of risk. Programming of risk is likely due to a combination of vulnerabilities, including multiple or repeated inflammatory events; timing of such events; poor maternal regulation of inflammation; genetic vulnerability; and lifestyle contributors.

Childhood adversity impact on gut microbiota and inflammatory response to stress during pregnancy.

BACKGROUND: Adverse childhood experiences (ACEs), such as abuse or chronic stress, program an exaggerated adult inflammatory response to stress. Emerging rodent research suggests that the gut microbiome may be a key mediator in the association between early life stress and dysregulated glucocorticoid-immune response. However, ACE impact on inflammatory response to stress, or on the gut microbiome, have not been studied in human pregnancy, when inflammation increases risk of poor outcomes. The aim of this study was to assess the relationships among ACE, the gut microbiome, and cytokine response to stress in pregnant women. METHODS: Physically and psychiatrically healthy adult pregnant women completed the Adverse Childhood Experiences Questionnaire (ACE-Q) and gave a single stool sample between 20 and 26 weeks gestation. Stool DNA was isolated and 16S sequencing was performed. Three 24-hour food recalls were administered to assess dietary nutrient intake. A subset of women completed the Trier Social Stress Test (TSST) at 22-34 weeks gestation; plasma interleukin-6 (IL-6), interleukin-1ß (IL-1ß), high sensitivity C-reactive protein (hsCRP), tumor necrosis factor α (TNF-α), and cortisol were measured at four timepoints pre and post stressor, and area under the curve (AUC) was calculated. RESULTS: Forty-eight women completed the ACE-Q and provided stool; 19 women completed the TSST. Women reporting 2 or more ACEs (high ACE) had greater differential abundance of gut Prevotella than low ACE participants (q = 5.7 × 10^-13). Abundance of several gut taxa were significantly associated with cortisol, IL-6, TNF-α and CRP AUCs regardless of ACE status. IL-6 response to stress was buffered among high ACE women with high intake of docosahexaenoic acid (DHA) (p = 0.03) and eicosapentaenoic acid (EPA) (p = 0.05). DISCUSSION: Our findings suggest that multiple childhood adversities are associated with changes in gut microbiota composition during pregnancy, and such changes may contribute to altered inflammatory and glucocorticoid response to stress. While preliminary, this is the first study to demonstrate an association between gut microbiota and acute glucocorticoid-immune response to stress in a clinical sample. Finally, exploratory analyses suggested that high ACE women with high dietary intake of ω-3 polyunsaturated fatty acids (PUFAs) had a dampened inflammatory response to acute stress, suggesting potentially protective effects of ω-3s in this high-risk population. Given the adverse effects of inflammation on pregnancy and the developing fetus, mechanisms by which childhood adversity influence the gut-brain axis and potential protective factors such as diet should be further explored.