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.

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.

Cumulative stressor exposure predicts menstrual cycle affective changes in a transdiagnostic outpatient sample with past-month suicidal ideation.

BACKGROUND: Affective responses to the menstrual cycle vary widely. Some individuals experience severe symptoms like those with premenstrual dysphoric disorder, while others have minimal changes. The reasons for these differences are unclear, but prior studies suggest stressor exposure may play a role. However, research in at-risk psychiatric samples is lacking. METHODS: In a large clinical sample, we conducted a prospective study of how lifetime stressors relate to degree of affective change across the cycle. 114 outpatients with past-month suicidal ideation (SI) provided daily ratings (n = 6187) of negative affect and SI across 1-3 menstrual cycles. Participants completed the Stress and Adversity Inventory (STRAIN), which measures different stressor exposures (i.e. interpersonal loss, physical danger) throughout the life course, including before and after menarche. Multilevel polynomial growth models tested the relationship between menstrual cycle time and symptoms, moderated by stressor exposure. RESULTS: Greater lifetime stressor exposure predicted a more pronounced perimenstrual increase in active SI, along with marginally significant similar patterns for negative affect and passive SI. Additionally, pre-menarche stressors significantly increased the cyclicity of active SI compared to post-menarche stressors. Exposure to more interpersonal loss stressors predicted greater perimenstrual symptom change of negative affect, passive SI and active SI. Exploratory item-level analyses showed that lifetime stressors moderated a more severe perimenstrual symptom trajectory for mood swings, anger/irritability, rejection sensitivity, and interpersonal conflict. CONCLUSION: These findings suggest that greater lifetime stressor exposure may lead to heightened emotional reactivity to ovarian hormone fluctuations, elevating the risk of psychopathology.

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.

The effect of visual parameters on neural activation during nonsymbolic number comparison and its relation to math competency.

Nonsymbolic numerical comparison task performance (whereby a participant judges which of two groups of objects is numerically larger) is thought to index the efficiency of neural systems supporting numerical magnitude perception, and performance on such tasks has been related to individual differences in math competency. However, a growing body of research suggests task performance is heavily influenced by visual parameters of the stimuli (e.g. surface area and dot size of object sets) such that the correlation with math is driven by performance on trials in which number is incongruent with visual cues. Almost nothing is currently known about whether the neural correlates of nonsymbolic magnitude comparison are also affected by visual congruency. To investigate this issue, we used functional magnetic resonance imaging (fMRI) to analyze neural activity during a nonsymbolic comparison task as a function of visual congruency in a sample of typically developing high school students (n = 36). Further, we investigated the relation to math competency as measured by the preliminary scholastic aptitude test (PSAT) in 10th grade. Our results indicate that neural activity was modulated by the ratio of the dot sets being compared in brain regions previously shown to exhibit an effect of ratio (i.e. left anterior cingulate, left precentral gyrus, left intraparietal sulcus, and right superior parietal lobe) when calculated from the average of congruent and incongruent trials, as it is in most studies, and that the effect of ratio within those regions did not differ as a function of congruency condition. However, there were significant differences in other regions in overall task-related activation, as opposed to the neural ratio effect, when congruent and incongruent conditions were contrasted at the whole-brain level. Math competency negatively correlated with ratio-dependent neural response in the left insula across congruency conditions and showed distinct correlations when split across conditions. There was a positive correlation between math competency in the right supramarginal gyrus during congruent trials and a negative correlation in the left angular gyrus during incongruent trials. Together, these findings support the idea that performance on the nonsymbolic comparison task relates to math competency and ratio-dependent neural activity does not differ by congruency condition. With regards to math competency, congruent and incongruent trials showed distinct relations between math competency and individual differences in ratio-dependent neural activity.

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.

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.

Effects of acute estradiol administration on perimenstrual worsening of working memory, verbal fluency, and inhibition in patients with suicidal ideation: A randomized, crossover clinical trial.

Accumulating evidence indicates that most female patients with suicidal ideation (SI) experience a dimensional worsening of depressive symptoms and SI in the perimenstrual phase of the menstrual cycle. Experimental trials demonstrate that acute perimenstrual administration of estradiol (E2; with or without progesterone/P4), can prevent these recurring episodes of increased risk. In this archival sample drawn from one of these clinical trials, we examined whether these beneficial E2 effects extend to specific types of cognition. For a double-blind, placebo-controlled experiment, we recruited transdiagnostic psychiatric outpatients with natural menstrual cycles who experienced past-month SI (N(per-protocol sample)=23; N(intent-to-treat sample)=44). In each of two counterbalanced conditions (perimenstrual administration of 0.1mg/d transdermal E2 vs. placebo), participants completed three cognitive tasks in three menstrual cycle phases (mid-luteal, perimenstrual, mid-follicular). Multilevel models revealed a significant interaction of condition and phase: E2 administration prevented mid-luteal-to-perimenstrual drops in working memory (p=.006) and verbal fluency (p=.005) observed under placebo. No effects were found for inhibitory control. In conclusion, we find perimenstrual declines in working memory and verbal fluency in patients with SI, which can be prevented by administering E2. This study contributes to our understanding of the hormone-brain pathways involved in the cyclical worsening of suicidality.

Alcohol use and motives for drinking across the menstrual cycle in a psychiatric outpatient sample.

BACKGROUND: Females who misuse alcohol experience high rates of negative physical and mental health consequences. Existing findings are inconsistent but suggest a relationship between ovarian hormones and alcohol use. We aim to clarify how alcohol use and drinking motives vary across the menstrual cycle in female psychiatric outpatients using the luteinizing hormone (LH)-confirmed cycle phase. METHODS: Daily self-reports (n = 3721) were collected from 94 naturally cycling females, recruited for past-month suicidal ideation, during the baseline phase of three parent clinical trials between February 2017 and May 2022. Multilevel logistic and linear models estimated the relationship between the cycle phase (with LH-surge confirmed ovulation) and daily alcohol use or drinking motives, moderated by the weekend. Models were adjusted for age, legal drinking status, substance use disorder, and the COVID-19 pandemic, and included random effects. RESULTS: Participants were generally more likely to drink in the midluteal (vs. perimenstrual) phase, but more likely to drink heavily on weekends in periovulatory and perimenstrual (vs. midluteal) phases. Social motives for drinking were significantly higher on weekends in the periovulatory, mid-follicular, and midluteal phases (vs. weekdays), but this finding was non-significant in the perimenstrual phase. Participants rated drinking to cope higher in the perimenstrual phase (vs. midluteal phase), regardless of the weekend. CONCLUSION: In a psychiatric sample with LH-surge-confirmed ovulation, we find an increased likelihood to drink heavily in periovulatory and perimenstrual phases on weekends. We also find that the perimenstrual phase is associated with increased drinking to cope, and relatively lower weekend social drinking. Finally, random effects across models suggest individual differences in the extent to which the cycle influences drinking. Our findings stress (1) predictable phases of increased high-risk alcohol use across the menstrual cycle, and (2) the importance of individual assessment of cyclical changes in alcohol use to predict and prevent ovulation- and menses-related surges in heavy drinking.

What's Stopping Us? Using GnRH Analogs With Stable Hormone Addback in Treatment-Resistant Premenstrual Dysphoric Disorder: Practical Guidelines and Risk-Benefit Analysis for Long-term Therapy.

Objective: Despite the documented success of gonadotropin-releasing hormone analogs (GnRHa) for the treatment of treatment-resistant premenstrual dysphoric disorder (PMDD), many patients struggle to find providers who have sufficient knowledge of PMDD and its evidence-based treatments and/or who are comfortable treating PMDD after first-line treatment options have failed. Here, we discuss the barriers to initiating GnRHa for treatment-resistant premenstrual dysphoric disorder (PMDD) and offer practical solutions to address these barriers for providers who encounter patients with treatment-resistant PMDD but may not have the necessary expertise or comfort with providing evidence-based treatments (ie, gynecologists, general psychiatrists). We have included supplementary materials including patient and provider handouts, screening tools, and treatment algorithms with the hope that this review may serve as a primer on PMDD and the use of GnRHa with hormonal addback as a treatment, as well as a guideline for clinicians delivering this treatment to patients in need.Options: In addition to offering practical treatment guidelines for first and second lines of treatment for PMDD, this review offers an in-depth discussion of GnRHa for treatment-resistant PMDD.Outcomes: The burden of illness in PMDD is estimated to be similar to that of other mood disorders, and those suffering from PMDD are at a high risk for suicide.Evidence: We present a selective review of relevant clinical trials evidence supporting the use of GnRHa with addback hormones in treatment-resistant PMDD (the most recent evidence cited was published in 2021), highlighting the rationale for addback hormones and presenting the different possible hormonal addback approaches.Values: The PMDD community has and continues to suffer from debilitating symptoms despite the known interventions. This article provides guidance for implementing GnRHa into practice among a broader scope of clinicians including general psychiatrists.Benefits, Harms, and Costs: The primary benefit of implementing this guideline is that a broad range of clinicians beyond reproductive psychiatrists who encounter patients with PMDD will have a template for assessing and treating PMDD and implementing GnRHa treatment when first-line treatments fail. Harms are expected to be minimal; however, some patients may have side effects or adverse reactions to the treatment or may not respond as they had hoped. Costs of GnRHa can be high depending on insurance coverage. We provide information within the guideline to help navigate this barrier.Recommendations: (1) Prospective symptom rating in evaluating for PMDD is necessary for diagnosis and evaluating treatment response. (2) SSRIs and oral contraceptives should be trialed as the first- and second-line treatments for PMDD. (3) When first- and second-line treatments have failed to yield symptom relief, the use of GnRHa with hormone addback should be considered. Risks and benefits of GnRHa should be weighed among clinicians and patients, and potential barriers to access should be discussed.Validation: This article adds to the available systematic reviews on the effectiveness of GnRHa in the treatment of PMDD and Royal College of Obstetrics and Gynecology's guidelines on the treatment of PMDD.

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.

How to study the menstrual cycle: Practical tools and recommendations.

Despite decades of research on the physiological and psychological effects of the menstrual cycle, studies have not sufficiently adopted consistent methods for operationalizing the menstrual cycle. This has resulted in substantial confusion in the literature and limited possibilities to conduct systematic reviews and meta-analyses. In order to facilitate more rapid accumulation of knowledge on cycle effects, the present paper offers a set of integrative guidelines and standardized tools for studying the menstrual cycle as an independent variable. We begin with (1) an overview of the menstrual cycle and (2) premenstrual disorders, followed by (3) recommendations and tools regarding data collection in cycle studies. These recommendations address selecting the appropriate study design and sampling strategy, managing demand characteristics, identifying a sample of naturally-cycling individuals, and measuring menstrual bleeding dates, ovarian hormones, and ovulation. We proceed with suggestions for (4) data preparation and coding of cycle day and phases, as well as (5) data visualization, statistical modeling, and interpretation of menstrual cycle associations. We also provide (6) recommendations for using menses start day and ovulation testing to schedule visits in laboratory studies and end with a (7) comprehensive summary and conclusion. Regardless of whether the influence of the menstrual cycle is of central interest in a study or should be controlled to accurately assess the effects of another variable, the use of these recommendations and tools will help make study results more meaningful and replicable.