Luteal phase sertraline treatment of premenstrual dysphoric disorder (PMDD): Effects on markers of hypothalamic pituitary adrenal (HPA) axis activation and inflammation.

RATIONALE: Premenstrual dysphoric disorder (PMDD) is characterized by severe affective symptoms during the luteal phase of the menstrual cycle. There is some evidence of altered interactions between the hypothalamic pituitary gonadal (HPG) and hypothalamic pituitary adrenal (HPA) axes in PMDD. There is also evidence that similar affective disorders such as major depression and perinatal depression are associated with dysregulation in immune factors, but this has not been characterized in PMDD. AIMS: The goals of this exploratory study were to identify 1) whether HPA-HPG axis interactions and immune markers differ between PMDD patients and controls across the menstrual cycle; 2) how luteal phase sertraline treatment impacts stress and inflammatory markers. METHODS: Participants were females age 18-50 with regular menstrual cycles, not using psychotropic or hormonal medications, and were assigned to a control group or PMDD group based on prospective daily symptom ratings and clinical interview. Blood was drawn in the follicular and luteal phases, during laboratory sessions involving a mildly stressful task. In a second luteal phase, PMDD participants received open-label sertraline (50 mg/d) from ovulation to menses. Serum cortisol and ACTH were measured via ELISA and operationalized as area under the curve with respect to ground (AUCg), and peak level following laboratory task. Serum TNF-α, IL-6, CXCL-8, and IL-1ß were measured using multiplex kits. Serum allopregnanolone (ALLO) was measured by gas chromatography/mass spectroscopy. To characterize HPA-HPG axis interactions across the menstrual cycle in PMDD participants and controls, multilevel linear models predicted cortisol and ACTH from the interaction of cycle phase (controlling for sertraline treatment), ALLO, and group. To determine the effects of sertraline treatment on inflammatory markers and how groups might differ in cyclical change on each marker, multilevel linear models predicted inflammatory markers from cycle phase (controlling for sertraline treatment) and group. A final set of exploratory models tested whether inflammatory markers predict premenstrual symptom score severity. RESULTS: The sample included n=77 participants (41 controls, 36 PMDD); 28 participants with PMDD completed sertraline treatment. Group x phase x ALLO interactions showed that higher ALLO levels predicted lower cortisol peak in the treated luteal phase (interaction between phase and ALLO, p=0.042), and there was a higher cortisol peak in the treated luteal phase than the untreated luteal phase (p=0.038). CXCL-8 was significantly associated with premenstrual symptom severity after controlling for group and cycle phase (p=0.011). There were no main effects of group, phase, or ALLO on cortisol AUCg, ACTH AUCg, IL-6, CXCL-8, IL-1ß, nor TNF-α (p's>0.05). CONCLUSION: Serum markers of HPA axis and immune function did not vary by menstrual cycle phase nor PMDD status. However, sertraline treatment in the luteal phase was associated with higher ALLO levels predicting lower cortisol peak in response to mild laboratory stress, suggesting that sertraline treatment may normalize HPG-HPA axis interactions among individuals with PMDD. Greater premenstrual symptomatology was associated with higher levels of the inflammatory marker CXCL-8, but further research is needed into the potential role of inflammation in PMDD.

Dimensional Affective Sensitivity to Hormones across the Menstrual Cycle (DASH-MC): A transdiagnostic framework for ovarian steroid influences on psychopathology.

Fluctuations in progesterone (P4) and estradiol (E2) across the menstrual cycle can exert direct effects on biological systems implicated in neuropsychiatric disorders and represent a key biological source of variability in affective, cognitive, and behavioral disorders. Although these cyclical symptoms may be most readily identified when they occur exclusively in relation to the menstrual cycle, as in DSM-5 premenstrual dysphoric disorder, symptom changes of similar magnitude occur in a larger proportion of people with ongoing psychiatric disorders. Studies investigating cyclical regulation of brain and behavior often produce inconsistent results, which may be attributed to a lack of focus on specific hormonal events and individual differences in related sensitivities. We propose a transdiagnostic Dimensional Affective Sensitivity to Hormones across the Menstrual Cycle (DASH-MC) framework, postulating that atypical neural responses to several key hormonal events provoke specific temporal patterns of affective and behavioral change across the menstrual cycle. We review prospective and experimental evidence providing initial support for these dimensions, which include (1) luteal-onset negative affect caused by a sensitivity to E2 or P4 surges (mediated by neuroactive metabolites such as allopregnanolone), typified by irritability and hyperarousal; (2) perimenstrual-onset negative affect caused by a sensitivity to low or falling E2, typified by low mood and cognitive dysfunction; and (3) preovulatory-onset positive affect dysregulation caused by a sensitivity to E2 surges, typified by harmful substance use and other risky reward-seeking. This multidimensional, transdiagnostic framework for hormone sensitivity can inform more precise research on ovarian steroid regulation of psychopathology, including further mechanistic research, diagnostic refinement, and precision psychiatry treatment development. Additionally, given the high rates of hormone sensitivity across affective disorders, the DASH-MC may guide broader insights into the complex neurobiological vulnerabilities driving female-biased affective risk, as well as potential triggers and mechanisms of affective state change in psychiatric disorders.

Associations of luteal phase changes in vagally mediated heart rate variability with premenstrual emotional changes.

BACKGROUND: A recent meta-analysis revealed that vagally mediated heart rate variability (vmHRV; a biomarker of emotion regulation capacity) significantly decreases in the luteal phase of the menstrual cycle. As two follow-up studies suggest, these vmHRV decreases are driven primarily by increased luteal progesterone (P4). However, analyses also revealed significant interindividual differences in vmHRV reactivity to the cycle, which is in line with longstanding evidence for interindividual differences in mood sensitivity to the cycle. The present study begins to investigate whether these interindividual differences in vmHRV cyclicity can explain who is at higher risk of showing premenstrual emotional changes. We expected a greater degree of midluteal vmHRV decrease to be predictive of a greater premenstrual increase in negative affect. METHODS: We conducted an observational study with a naturally cycling community sample (N = 31, M = 26.03 years). Over a span of six weeks, participants completed (a) daily ratings of negative affect and (b) counterbalanced lab visits in their ovulatory, midluteal, and perimenstrual phases. Lab visits were scheduled based on positive ovulation tests and included assessments of baseline vmHRV and salivary ovarian steroid levels. RESULTS: In line with previous research, multilevel models suggest that most of the sample shows ovulatory-to-midluteal vmHRV decreases which, however, were not associated with premenstrual emotional changes. Interestingly, it was only the subgroup with luteal increases in vmHRV whose negative affect markedly worsened premenstrually and improved postmenstrually. CONCLUSION: The present study begins to investigate cyclical changes in vmHRV as a potential biomarker of mood sensitivity to the menstrual cycle. The results demonstrate a higher level of complexity in these associations than initially expected, given that only atypical midluteal increases in vmHRV are associated with greater premenstrual negative affect. Potential underlying mechanisms are discussed, among those the possibility that luteal vmHRV increases index compensatory efforts to regulate emotion in those with greater premenstrual negative affect. However, future studies with larger and clinical samples and more granular vmHRV assessments should build on these findings and further explore associations between vmHRV cyclicity and menstrually related mood changes.

A novel method for quantifying affective sensitivity to endogenous ovarian hormones.

Increased sensitivity to ovarian hormone changes is implicated in the etiology of reproductive mood disorders across the female lifespan, including menstrually-related mood disorders, perinatal mood disorders, and perimenopausal depression. Developing a method to accurately quantify sensitivity to endogenous hormone fluctuations may therefore facilitate the prediction and prevention of these mental health conditions. Here, we propose one such method applying a synchrony analysis to compute time-lagged cross-correlations between repeated assessments of endogenous hormone levels and self-reported affect. We apply this method to a dataset containing frequent repeated assessments of affective symptoms and the urinary metabolites of estradiol (E2) and progesterone (P4) in 94 perimenopausal females. These preliminary findings suggest that, with further refinement and validation, the proposed method holds promise as a diagnostic tool to be used in clinical practice and to advance research investigating the etiology of reproductive mood disorders.

Smartphone keyboard dynamics predict affect in suicidal ideation.

While digital phenotyping provides opportunities for unobtrusive, real-time mental health assessments, the integration of its modalities is not trivial due to high dimensionalities and discrepancies in sampling frequencies. We provide an integrated pipeline that solves these issues by transforming all modalities to the same time unit, applying temporal independent component analysis (ICA) to high-dimensional modalities, and fusing the modalities with linear mixed-effects models. We applied our approach to integrate high-quality, daily self-report data with BiAffect keyboard dynamics derived from a clinical suicidality sample of mental health outpatients. Applying the ICA to the self-report data (104 participants, 5712 days of data) revealed components related to well-being, anhedonia, and irritability and social dysfunction. Mixed-effects models (55 participants, 1794 days) showed that less phone movement while typing was associated with more anhedonia (ß = -0.12, p = 0.00030). We consider this method to be widely applicable to dense, longitudinal digital phenotyping data.

Brain network connectivity during peer evaluation in adolescent females: Associations with age, pubertal hormones, timing, and status.

Despite copious data linking brain function with changes to social behavior and mental health, little is known about how puberty relates to brain functioning. We investigated the specificity of brain network connectivity associations with pubertal indices and age to inform neurodevelopmental models of adolescence. We examined how brain network connectivity during a peer evaluation fMRI task related to pubertal hormones (dehydroepiandrosterone and testosterone), pubertal timing and status, and age. Participants were 99 adolescents assigned female at birth aged 9-15 (M = 12.38, SD = 1.81) enriched for the presence of internalizing symptoms. Multivariate analysis revealed that within Salience, between Frontoparietal - Reward and Cinguloopercular - Reward network connectivity were associated with all measures of pubertal development and age. Specifically, Salience connectivity linked with age, pubertal hormones, and status, but not timing. In contrast, Frontoparietal - Reward connectivity was only associated with hormones. Finally, Cinguloopercular - Reward connectivity related to age and pubertal status, but not hormones or timing. These results provide evidence that the salience processing underlying peer evaluation is jointly influenced by various indices of puberty and age, while coordination between cognitive control and reward circuitry is related to pubertal hormones, pubertal status, and age in unique ways.

Is trait rumination associated with affective reactivity to the menstrual cycle? A prospective analysis.

BACKGROUND: A minority of naturally cycling individuals experience clinically significant affective changes across the menstrual cycle. However, few studies have examined cognitive and behavioral constructs that may maintain or worsen these changes. Several small studies link rumination with premenstrual negative affect, with authors concluding that a tendency to ruminate amplifies and perpetuates hormone-sensitive affective symptoms. Replication in larger samples is needed to confirm the validity of rumination as a treatment target. METHOD: 190 cycling individuals (M = 30.82 years; 61.1% Caucasian) were recruited for moderate perceived stress, a risk factor for cyclical symptoms. They completed the Rumination Response Scale at baseline, then reported daily affective and physical symptoms across 1-6 cycles. Multilevel growth models tested trait rumination as a predictor of baseline levels, luteal increases, and follicular decreases in symptoms. RESULTS: The degree of affective cyclicity was normally distributed across a substantial range, supporting feasibility of hypothesis tests and validating the concept of dimensional hormone sensitivity. Contrary to prediction, higher brooding did not predict levels or cyclical changes of any symptom. In a subsample selected for luteal increases in negative affect, brooding predicted higher baseline negative affect but still did not predict affective cyclicity. CONCLUSIONS: An individual's trait-like propensity to engage in rumination may not be a valid treatment target in premenstrual mood disorders. State-like changes in rumination should still be further explored, and well-powered prospective studies should explore other cognitive and behavioral factors to inform development of targeted psychological treatments for patients with cyclical affective symptoms.

The prevalence of premenstrual dysphoric disorder: Systematic review and meta-analysis.

BACKGROUND: Premenstrual dysphoric disorder is characterised by symptoms confined to the premenstrual phase of the menstrual cycle. Confirmed diagnosis requires prospective monitoring of symptoms over two cycles, otherwise the diagnosis is provisional. We aimed to measure the point prevalence of premenstrual dysphoric disorder. METHODS: We searched for studies of prevalence using MEDLINE, EMBASE, PsycINFO and PubMed. For each study, the total sample size and number of cases were extracted. The prevalence across studies was calculated using random effects meta-analysis with a generalised linear mixed model. Potential sources of heterogeneity were explored by meta-regression and subgroup analyses. Pre-registration was with PROSPERO (CRD42021249249). RESULTS: 44 studies with 48 independent samples met inclusion criteria, consisting of 50,659 participants. The pooled prevalence was 3.2 % (95 % confidence intervals: 1.7 %-5.9 %) for confirmed and 7.7 % (95 % confidence intervals: 5.3 %-11.0 %) for provisional diagnosis. There was high heterogeneity across all studies (I2 = 99 %). Sources of heterogeneity identified by meta-regression were continent of sample (p < 0.0001), type of sample (community-based, university, high school) (p = 0.007), risk of bias (p = 0.009), and method of diagnosis (p = 0.017). Restricting the analysis to community-based samples using confirmed diagnosis resulted in a prevalence of 1.6 % (95 % confidence intervals: 1.0 %-2.5 %), with low heterogeneity (I2 = 26 %). LIMITATIONS: A small number of included studies used full DSM criteria in community settings. CONCLUSIONS: The point prevalence of premenstrual dysphoric disorder using confirmed diagnosis is lower compared with provisional diagnosis. Studies relying on provisional diagnosis are likely to produce artificially high prevalence rates.

Attention-deficit/hyperactivity disorder and the menstrual cycle: Theory and evidence.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that exhibits striking sex differences in symptoms, prevalence, and associated problems across development. Etiological factors and mechanisms underlying these sex differences remain one of the most understudied aspects of this disorder. The current paper seeks to provide a novel theoretical framework for understanding this phenomenon by reviewing evidence that females with ADHD may experience a "double whammy" of organizational and activational pubertal hormonal effects. We propose a novel theory of activational effects of cyclical circulating ovarian hormones on ADHD with increasing risk at times of rapid declines in estrogen. These declines may decrease executive function and trait control at two points of the cycle characterized by biphasic affective risk: (1) increases in approach/risk-taking behaviors at mid-cycle (periovulatory) and (2) increases in avoidance/negative affect perimenstrually. Low estrogen and control may then interact with increases in positive and negative affect, respectively, to increase hyperactivity-impulsivity symptoms post-ovulation and inattention symptoms perimenstrually. These interactions may be exacerbated by organizational pubertal effects on relatively overdeveloped limbic circuitry and adolescent-specific social pressures magnified in females with ADHD.

Predicting Acute Changes in Suicidal Ideation and Planning: A Longitudinal Study of Symptom Mediators and the Role of the Menstrual Cycle in Female Psychiatric Outpatients With Suicidality.

OBJECTIVE: Cross-sectional and preliminary longitudinal findings suggest that cyclical ovarian hormone fluctuations influence acute suicide risk. The authors provide the first analyses in females with suicidality to investigate which daily symptoms covary with suicidal ideation and planning thoughts, the role of the menstrual cycle in daily symptom variation, how daily fluctuations in symptoms mediate the menstrual cycle-suicidality relationship, and how these associations vary across individuals. METHODS: Naturally cycling psychiatric outpatients (N=119) with past-month suicidal ideation provided daily ratings of psychiatric symptoms (depression, hopelessness, anxiety, feeling overwhelmed, agitation, anhedonia, worthlessness, rejection sensitivity, anger, perceived burdensomeness, and interpersonal conflict), suicidal ideation, and suicidal planning across at least one menstrual cycle. Symptom ratings were decomposed into trait (person-centered mean) and state (daily person-centered mean deviation) components. Five cycle phases were identified in relation to menses onset and ovulation (surge in urine luteinizing hormone level). Hypotheses were tested in multilevel structural equation models. RESULTS: Nearly all psychiatric symptoms covaried with fluctuations in daily suicidal ideation, and a limited set of symptoms (depression, hopelessness, rejection sensitivity, and perceived burdensomeness) predicted within-person increases in suicidal planning. Many patients demonstrated perimenstrual worsening of psychiatric symptoms, suicidal ideation, and suicidal planning. Depressive symptoms (depression, hopelessness, perceived burdensomeness, and anhedonia) were the most robust statistical mediators predicting perimenstrual exacerbation of suicidality. CONCLUSIONS: Research on the menstrual cycle and suicide has been limited historically by small, cross-sectional samples. This study provides the first evidence that measuring day-to-day correlates of suicidality in a large transdiagnostic sample of females with suicidal ideation can contribute to understanding the pathways by which the menstrual cycle influences acute suicide risk.

Temporal dynamics of neurobehavioral hormone sensitivity in a scaled-down experimental model of early pregnancy and parturition.

The hormonal changes of pregnancy and parturition can trigger robust changes in affective state, particularly among patients with a history of postpartum depression. However, more work is needed to elucidate the temporal dynamics of symptom emergence. The current study explored how quickly hormone-sensitive (HS+) individuals can be differentiated from hormone-insensitive (HS-) controls in the context of a tightly controlled experimental hormone manipulation, and which symptoms demonstrate the most rapid, consistent, and largest response during this protocol. Participants were female, non-pregnant, and euthymic, with a history of DSM-5 major depressive episode with peripartum onset (n = 15) or parous healthy controls with no psychiatric history (n = 15). Perinatal hormonal changes were simulated by inducing hypogonadism, adding back estradiol (E2) and progesterone (P4) to reach first-trimester levels for 8 weeks, and then subsequently withdrawing both hormones. Those reporting a 30% or greater increase during addback or withdrawal on select subscales of the Inventory of Depression and Anxiety Symptoms (IDAS) were identified as HS+. Participants provided daily ratings of symptoms throughout the study via the Daily Record of Severity of Problems. Results indicated that HS+ participants could be differentiated from HS- participants early in the hormone protocol, with many symptoms showing significantly greater change from baseline within the first week of addback. Notably, the most rapid symptom increases were observed for Anger/Irritability, Mood Swings, Overwhelm, Lethargy, Increased Appetite, Joint and Muscle Pain, and Breast Tenderness, reaching 50% of peak group contrast within the first week of hormone addback. The largest group effects were observed for Anger/Irritability, followed by Fatigue and Anxiety, and the most consistent group effects were observed for Anger/Irritability, Interpersonal Conflict, Overwhelm, and Hopelessness. Findings support the role of reproductive hormones in the onset of perinatal affective disorders. The rapid emergence of anger and irritability in HS+ participants suggests that these symptoms may be early indicators of perinatal hormone sensitivity.

Threat exposure moderates associations between neural and physiological indices of emotion reactivity in adolescent females.

Early life adversity (ELA) characterized by threat (e.g., abuse, witnessing violence) impacts neural and physiologic systems involved in emotion reactivity; however, research on how threat exposure impacts the interplay between these systems is limited. This study investigates ELA characterized by threat as a potential moderator of the association between (a) neural activity during a negative image processing fMRI task and (b) cortisol production following a modified Trier Social Stress Test (TSST). The sample is comprised of 117 young adolescent females (Mage = 11.90 years, SD = 1.69) at elevated risk for internalizing problems. Whole-brain analyses revealed a positive association between cortisol production and increased right lateral orbitofrontal cortex activity during the emotion reactivity task. In moderation models, threat exposure interacted with bilateral amygdala activation (b = -3.34, p = 0.021) and bilateral hippocampal activation (b = -4.14, p = 0.047) to predict cortisol response to the TSST. Specifically, participants with low, but not high, levels of threat exposure demonstrated a positive association between cortisol production and neural activity in these regions, while no significant association emerged for participants with high threat exposure. Findings contribute to the growing field of research connecting physiological and neural emotion processing and response systems, suggesting that dimensions of ELA may uniquely disrupt associations between neural activation and cortisol production.

Smartphone keyboard dynamics predict affect in suicidal ideation.

While digital phenotyping provides opportunities for unobtrusive, real-time mental health assessments, the integration of its modalities is not trivial due to high dimensionalities and discrepancies in sampling frequencies. We provide an integrated pipeline that solves these issues by transforming all modalities to the same time unit, applying temporal independent component analysis (ICA) to high-dimensional modalities, and fusing the modalities with linear mixed-effects models. We applied our approach to integrate high-quality, daily self-report data with BiAffect keyboard dynamics derived from a clinical suicidality sample of mental health outpatients. Applying the ICA to the self-report data (104 participants, 5712 days of data) revealed components related to well-being, anhedonia, and irritability and social dysfunction. Mixed-effects models (55 participants, 1794 days) showed that less phone movement while typing was associated with more anhedonia (ß = -0.12, p = 0.00030). We consider this method to be widely applicable to dense, longitudinal digital phenotyping data.

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.

A scoping review of hormonal clinical trials in menstrual cycle-related brain disorders: Studies in premenstrual mood disorder, menstrual migraine, and catamenial epilepsy.

Cyclic variations in hormones during the normal menstrual cycle underlie multiple central nervous system (CNS)-linked disorders, including premenstrual mood disorder (PMD), menstrual migraine (MM), and catamenial epilepsy (CE). Despite this foundational mechanistic link, these three fields operate independently of each other. In this scoping review (N = 85 studies), we survey existing human research studies in PMD, MM, and CE to outline the exogenous experimental hormone manipulation trials conducted in these fields. We examine a broad range of literature across these disorders in order to summarize existing diagnostic practices and research methods, highlight gaps in the experimental human literature, and elucidate future research opportunities within each field. While no individual treatment or study design can fit every disease, there is immense overlap in study design and established neuroendocrine-based hormone sensitivity among the menstrual cycle-related disorders PMD, MM, and CE. SCOPING REVIEW STRUCTURED SUMMARY: Background. The menstrual cycle can be a biological trigger of symptoms in certain brain disorders, leading to specific, menstrual cycle-linked phenomena such as premenstrual mood disorders (PMD), menstrual migraine (MM), and catamenial epilepsy (CE). Despite the overlap in chronicity and hormonal provocation, these fields have historically operated independently, without any systematic communication about methods or mechanisms. OBJECTIVE: Online databases were used to identify articles published between 1950 and 2021 that studied hormonal manipulations in reproductive-aged females with either PMD, MM, or CE. We selected N = 85 studies that met the following criteria: 1) included a study population of females with natural menstrual cycles (e.g., not perimenopausal, pregnant, or using hormonal medications that were not the primary study variable); 2) involved an exogenous hormone manipulation; 3) involved a repeated measurement across at least two cycle phases as the primary outcome variable. CHARTING METHODS: After exporting online database query results, authors extracted sample size, clinical diagnosis of sample population, study design, experimental hormone manipulation, cyclical outcome measure, and results from each trial. Charting was completed manually, with two authors reviewing each trial. RESULTS: Exogenous hormone manipulations have been tested as treatment options for PMD (N = 56 trials) more frequently than MM (N = 21) or CE (N = 8). Combined oral contraceptive (COC) trials, specifically those containing drospirenone as the progestin, are a well-studied area with promising results for treating both PMDD and MM. We found no trials of COCs in CE. Many trials test ovulation suppression using gonadotropin-releasing hormone agonists (GnRHa), and a meta-analysis supports their efficacy in PMD; GnRHa have been tested in two MM-related trials, and one CE open-label case series. Finally, we found that non-contraceptive hormone manipulations, including but not limited to short-term transdermal estradiol, progesterone supplementation, and progesterone antagonism, have been used across all three disorders. CONCLUSIONS: Research in PMD, MM, and CE commonly have overlapping study design and research methods, and similar effects of some interventions suggest the possibility of overlapping mechanisms contributing to their cyclical symptom presentation. Our scoping review is the first to summarize existing clinical trials in these three brain disorders, specifically focusing on hormonal treatment trials. We find that PMD has a stronger body of literature for ovulation-suppressing COC and GnRHa trials; the field of MM consists of extensive estrogen-based studies; and current consensus in CE focuses on progesterone supplementation during the luteal phase, with limited estrogen manipulations due to concerns about seizure provocation. We argue that researchers in any of these respective disciplines would benefit from greater communication regarding methods for assessment, diagnosis, subtyping, and experimental manipulation. With this scoping review, we hope to increase collaboration and communication among researchers to ultimately improve diagnosis and treatment for menstrual-cycle-linked brain disorders.

Effects of estrogen and progesterone on neuroactive steroids and cytokines in patients with suicidality.

BACKGROUND: In ovulating psychiatric patients experiencing suicidality, suicidal ideation (SI) often peaks perimenstrually. Our recent double-blind, placebo-controlled, crossover randomized clinical trial (RCT; NCT03720847) showed that perimenstrual administration of estradiol and progesterone (EP) can prevent this peak in SI and depressed mood. In this pre-registered follow-up analysis, we studied how the menstrual cycle and experimental manipulation affected two neurobiological systems associated with the menstrual cycle and suicide risk: GABAergic neuroactive steroids (NAS) and peripheral cytokines. METHODS: In 26 psychiatric outpatients with natural menstrual cycles and past-month SI, we analyzed serum samples from three blood draws (midluteal, perimenstrual, midfollicular) per experimental condition (EP vs placebo) timed to a luteinizing hormone-surge ovulation test. Using gas chromatography/mass spectrometry (GC/MS), we measured the progesterone (P4)-derived pregnane NAS (3α,5α)- 3-hydroxypregnan20-one (3α,5α-THP), (3α,5ß)- 3-hydroxypregnan-20-one (3α,5ß-THP), (3α,5α)- 3,21-dihydroxypregnan-20-one (3α,5α-THDOC), (3α,5α)- 3-hydroxyandrostan-17-one (3α,5α-A), the androstane NAS (3α,5ß)- 3-hydroxyandrostan-17-one (3α,5ß-A), (3α,5α,17ß)-androstane-3,17-diol (3α,5α-A-diol), (3α,5ß,17ß)-androstane-3,17-diol (3α,5ß-A-diol), and their precursor pregnenolone. High sensitivity multiplex assay kits quantified peripheral cytokines IL-1ß, IL-6, and TNF-α. RESULTS: P4-derived NAS fluctuated in parallel with P4 and increased with exogenous perimenstrual administration of EP. Conversely, androstane NAS either did not fluctuate or fluctuated inversely from P4, and these NAS decreased with exogenous EP. Peripheral cytokines did not show cyclical patterns, but each significantly predicted SI, depressed mood, or anxiousness. Concomitant SSRI medication use predicted lower androstane NAS. CONCLUSIONS: While preliminary and exploratory, our findings provide critical descriptive context for future studies. Further, our work presents menstrual cycle-related patterns for ten frequently-studied biomarkers, allowing for improved quality of comparisons involving naturally-cycling populations in research.

Improving rigor through gender inclusivity in reproductive psychiatric science.

Accurately defining the individuals that research involves and generalizes to is critical for rigorous and reproducible science. In reproductive psychiatry, which historically focuses on the impact of the menstrual cycle, pregnancy, and menopause on mental health, this means moving beyond characterizing samples and relevant populations as "women" in favor of language that precisely identifies the physiological characteristics pertinent to the research being conducted and accurately reflects the varied genders represented in those populations. Concrete recommendations are provided for precise use of sex and gender terminology and gender inclusivity throughout the scientific process, including study conceptualization, etiquette in research environments, recruitment, methods, and dissemination. Recommendations are discussed in depth and presented in a checklist format for ease of use by research teams. Suggested items for assessing gender and relevant sex-related physiology in the context of reproductive psychiatry are also provided.