Periovulatory Phase Research Articles

Characterizing within-person variance in, and menstrual cycle associations with, event-related potentials associated with positive and negative valence systems: The reward positivity and the error-related negativity

Event-related potentials (ERPs) are widely employed as measures of transdiagnostic cognitive processes that are thought to underlie various clinical disorders (Hajcak et al., 2019). Despite their prevalent use as individual difference measures, the effects of within-person processes, such as the human menstrual cycle, on a broad range of ERPs are poorly understood. The present study leveraged a within-subject design to characterize between- and within-person variance in ERPs as well as effects of the menstrual cycle in two frequently studied ERPs associated with positive and negative valence systems underlying psychopathology—the Reward Positivity (RewP) and the Error- Related Negativity (ERN). Seventy-one naturally-cycling participants completed repeated EEG and ecological momentary assessments of positive and negative affect in the menstrual cycle's early follicular, periovulatory, and mid-luteal phases. We examined the mean degree of change between cycle phases in both ERPs, the between-person variability in the degree of change in both ERPs, and whether an individual’s degree of cyclical change in these ERPs show coherence with their degree of cyclical change in positive and negative affect recorded across the cycle. Results revealed no significant changes in positive and negative affect across the cycle and rather small changes in ERP amplitudes. Significant random slopes in our model revealed larger individual differences in trajectories of change in ERP amplitudes and affect, in agreement with prior evidence of heterogeneity in dimensional hormone sensitivity. Additionally, state-variance in these ERPs correlated with positive and negative affect changes across the cycle, suggesting that cycle-mediated ERP changes may have relevance for affect and behavior. Finally, exploratory latent class growth mixture modeling revealed subgroups of individuals that display disparate patterns of change in ERPs that should be further investigated.

Neural adaptation of the reward system in primary dysmenorrhea.

Introduction: The brain's reward system (RS) reacts differently to pain and its alleviation. This study examined the correlation between RS activity and behavior during both painful and pain-free periods in individuals with primary dysmenorrhea (PDM) to elucidate their varying responses throughout the menstrual cycle. Methods: Ninety-two individuals with PDM and 90 control participants underwent resting-state functional magnetic resonance imaging (rsfMRI) scans during their menstrual and peri-ovulatory phases. Regional homogeneity (ReHo) and amplitude of low-frequency fluctuation (ALFF) analyses were used to evaluate RS responses. Psychological evaluations were conducted using the McGill Pain Questionnaire and the Pain Catastrophizing Scale. Results: ReHo analysis showed higher values in the left putamen and right amygdala of the PDM group during the peri-ovulatory phase compared to the menstrual phase. ALFF analysis revealed lower values in the putamen of the PDM group compared to controls, regardless of phase. ReHo and ALFF values in the putamen, amygdala, and nucleus accumbens were positively correlated with pain scales during menstruation, while ALFF values in the ventral tegmental area inversely correlated with pain intensity. Those with severe PDM (pain intensity ≥7) displayed distinct amygdala ALFF patterns between pain and pain-free phases. PDM participants also had lower ReHo values in the left insula during menstruation, with no direct correlation to pain compared to controls. Discussion: Our study highlights the pivotal role of the RS in dysmenorrhea management, exhibiting varied responses between menstrual discomfort and non-painful periods among individuals with PDM. During menstruation, the RS triggers mechanisms for pain avoidance and cognitive coping strategies, while it transitions to processing rewards during the peri-ovulatory phase. This demonstrates the flexibility of the RS in adapting to the recurring pain experienced by those with PDM.

P-627 Does artificial hormonal therapy increase the TSH levels in frozen embryo transfer?

Abstract Study question Does administration of estradiol valerate for frozen embryo transfer (FET) increase the TSH value and the risk of miscarriage? Summary answer TSH is increased at the time of endometrial thickness and pregnancy test in HRT cycles. Women with higher TSH have an increased risk of miscarriage. What is known already Several studies describe the correlation between estradiol and TSH levels during menstrual cycles. The circulated TSH is upregulated by estradiol, in fact, TSH increases in the periovulatory phase and in women taking oral contraceptive therapy. A higher estradiol in the first trimester is correlated with an increased risk of thyroid dysfunction in offspring. TSH is also correlated to beta-Human Chorionic Gonadotropin (b-HCG) levels, many studies reported an increase of TSH values at b-HCG peak during 10-12 weeks of gestation. Study design, size, duration This is a retrospective, single-center, observational study enrolling 607 patients at IVI Roma from April 2022 to June 2023.Patients with 30-47 years old with single blastocyst transfer were included in the study. Both euploid frozen embryo transfer (FET) from autologous oocyte ICSI-PGT-A cycles and FET from ICSI cycles using donated oocytes were considered. FET performed under artificial endometrial preparation with HRT using exogenous estradiol and progesterone (vaginal, subcutaneous and intramuscular) were included in the study. Participants/materials, setting, methods TSH was evaluated before estradiol valerate administration (T0), at the control for endometrial thickness (T1), the day of embryo transfer (T2), and the day of b-HCG evaluation (T3). Accordingly, the patients were divided into two groups based on their TSH levels (low-normal group, ≤ 2.5 mIU/L; high group, > 2.5 mIU/L). The primary outcome was TSH values at different times. The secondary outcome evaluated the miscarriage rate (MR) calculated for FET. Main results and the role of chance TSH mean at T0 was 1.65 ± 0.87. The mean value of TSH after estradiol valerate administration was 1.97 ± 1.28. TSH value increased during the estradiol valerate administration with a mean increase of 0.29 mIU/L reaching statistical significance (p < 0.0001). No statistical differences were reported between T0-T2 (p = 0.64) while the statistical difference was reported in time T0-T3 with a mean increase of 0.40 mIU/L (p < 0.0001). Women with T1-TSH value > 2.5 mIU/L were 18.95%. The miscarriage rate in the group with TSH value >2.5 mIU/L was 17.81%. The univariate analysis showed that T1-TSH values >2.5 mIU/L did not affect the miscarriage rate OR 0.79 (95 CI% 0.37-1.67), p = 0.54. The multivariate analysis considering age, BMI and source of oocytes showed no statistical significance on the miscarriage rate OR 0.82 (95 CI% 0.39-1.72), p = 0.62. T2-TSH values did not affect the miscarriage rate in the univariate and multivariate analyses. Regarding T3-TSH, the univariate analysis showed that THS >2.5 mIU/L affects the miscarriage rate OR 1.97(95 CI% 1.07-3.65), p = 0.03. Multivariate analysis considering possible confounders showed that women with THS >2.5 mIU/L have a higher risk of miscarriage OR 1.96 (95 CI% 1.02-3.78), p = 0.04. Limitations, reasons for caution The retrospective design and patients with different female infertility factors for IVF were included in the study, leading to a possible biased population. The T1-TSH assessment was not scheduled at the same time for each patient. Women with TSH >2.5 mIU/L at the T1-TSH value were treated with levothyroxine. Wider implications of the findings This study emphasizes the correlation between estradiol valerate administration and TSH values and the possible relation with increasing risk of miscarriage in women with higher TSH. Patients undergoing FET with HRT should consider thyroid supplementation or increasing dosage to reduce the risk of miscarriage. Trial registration number not applicable

The use of transvaginal ultrasound alters physiologic uterine peristalsis in gynecologic participants

To study whether transvaginal ultrasound (TVUS) affected the uterine peristalsis (UP) patterns in nonpregnant participants. Institutional review board-approved, prospective observational cohort study. The noninvasive UP imaging (UPI) system uses electrode patches placed on the patient's skin just above the pubic bone and on the low back to quantify the 3-dimensional electrical activation pattern during UP by calculating peristalsis frequency, duration, magnitude, and activation ratio. A 20-minute UPI scan was completed without TVUS followed by a 10-minute UPI scan acquired simultaneously during TVUS examination as a comparison. University medical center. Twenty-eight participants with regular menstrual cycles not taking hormonal medication and with a normal uterus were included in analysis. Subjects were imaged longitudinally during the four phases of the menstrual cycle (menses, proliferative, periovulatory, and secretory) with a UPI scan followed by concurrent TVUS and UPI scan. Serum hormone levels (estradiol and progesterone) and TVUS evaluating follicular development were obtained during each visit to confirm menstrual cycle phase. Duration, frequency, magnitude, and activation ratio of the UP waves. With the use of simultaneous TVUS, UP waves had a change in at least one of the outcomes measured in all visits. The frequency, magnitude, and duration were significantly higher with TVUS use in all phases of the menstrual cycle. The activation ratio was higher with TVUS during all phases except the periovulatory phase. This study demonstrated that TVUS may inherently affect UP waves. Therefore, noninvasive technology may more accurately measure physiologic peristalsis waves.

Endometrial Proliferative Phase-Centered View of Transcriptome Dynamics across the Menstrual Cycle.

The endometrium, the inner mucosal lining of the uterus, undergoes complex molecular and cellular changes across the menstrual cycle in preparation for embryo implantation. Transcriptome-wide analyses have mainly been utilized to study endometrial receptivity, the prerequisite for successful implantation, with most studies, so far, comparing the endometrial transcriptomes between (i) secretory and proliferative endometrium or (ii) mid-secretory and early secretory endometrium. In the current study, we provide a complete transcriptome description of the endometrium across the entire menstrual cycle and, for the first time, comprehensively characterize the proliferative phase of the endometrium. Our temporal transcriptome analysis includes five time points including the mid-proliferative, late proliferative (peri-ovulatory phase), early secretory, mid-secretory, and late secretory phases. Thus, we unveil exhaustively the transitions between the consecutive proliferative and secretory phases, highlighting their unique gene expression profiles and possible distinct biological functions. The transcriptome analysis reveals many differentially expressed genes (DEGs) across the menstrual cycle, most of which are phase-specific. As an example of coordinated gene activity, the expression profile of histone-encoding genes within the HIST cluster on chromosome 6 shows an increase in cluster activity during the late proliferative and a decline during the mid-secretory phase. Moreover, numerous DEGs are shared among all phases. In conclusion, in the current study, we delineate the endometrial proliferative phase-centered view of transcriptome dynamics across the menstrual cycle. Our data analysis highlights significant transcriptomic and functional changes occurring during the late proliferative phase-an essential transition point from the proliferative phase to the secretory phase. Future studies should explore how the biology of the late proliferative phase endometrium impacts the achievement of mid-secretory endometrial receptivity or contributes to molecular aberrations leading to embryo implantation failure.

The impact of ovarian stimulation on the human endometrial microenvironment.

How does ovarian stimulation (OS), which is used to mature multiple oocytes for ART procedures, impact the principal cellular compartments and transcriptome of the human endometrium in the periovulatory and mid-secretory phases? During the mid-secretory window of implantation, OS alters the abundance of endometrial immune cells, whereas during the periovulatory period, OS substantially changes the endometrial transcriptome and impacts both endometrial glandular and immune cells. Pregnancies conceived in an OS cycle are at risk of complications reflective of abnormal placentation and placental function. OS can alter endometrial gene expression and immune cell populations. How OS impacts the glandular, stromal, immune, and vascular compartments of the endometrium, in the periovulatory period as compared to the window of implantation, is unknown. This prospective cohort study carried out between 2020 and 2022 included 25 subjects undergoing OS and 25 subjects in natural menstrual cycles. Endometrial biopsies were performed in the proliferative, periovulatory, and mid-secretory phases. Blood samples were processed to determine serum estradiol and progesterone levels. Both the endometrial transcriptome and the principal cellular compartments of the endometrium, including glands, stroma, immune, and vasculature, were evaluated by examining endometrial dating, differential gene expression, protein expression, cell populations, and the three-dimensional structure in endometrial tissue. Mann-Whitney U tests, unpaired t-tests or one-way ANOVA and pairwise multiple comparison tests were used to statistically evaluate differences. In the periovulatory period, OS induced high levels of differential gene expression, glandular-stromal dyssynchrony, and an increase in both glandular epithelial volume and the frequency of endometrial monocytes/macrophages. In the window of implantation during the mid-secretory phase, OS induced changes in endometrial immune cells, with a greater frequency of B cells and a lower frequency of CD4 effector T cells. The data underlying this article have been uploaded to the Genome Expression Omnibus/National Center for Biotechnology Information with accession number GSE220044. A limited number of subjects were included in this study, although the subjects within each group, natural cycle or OS, were homogenous in their clinical characteristics. The number of subjects utilized was sufficient to identify significant differences; however, with a larger number of subjects and additional power, we may detect additional differences. Another limitation of the study is that proliferative phase biopsies were collected in natural cycles, but not in OS cycles. Given that the OS cycle subjects did not have known endometrial factor infertility, and the comparisons involved subjects who had a similar and robust response to stimulation, the findings are generalizable to women with a normal response to OS. OS substantially altered the periovulatory phase endometrium, with fewer transcriptomic and cell type-specific changes in the mid-secretory phase. Our findings show that after OS, the endometrial microenvironment in the window of implantation possesses many more similarities to that of a natural cycle than does the periovulatory endometrium. Further investigation of the immune compartment and the functional significance of this cellular compartment under OS conditions is warranted. Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases (R01AI148695 to A.M.B. and N.C.D.), Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD109152 to R.A.), and the March of Dimes (5-FY20-209 to R.A.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or March of Dimes. All authors declare no conflict of interest.

Brain flexibility increases during the peri-ovulatory phase as compared to early follicular phase of the menstrual cycle

The brain operates in a flexible dynamic regime, generating complex patterns of activity (i.e. neuronal avalanches). This study aimed at describing how brain dynamics change according to menstrual cycle (MC) phases. Brain activation patterns were estimated from resting-state magnetoencephalography (MEG) scans, acquired from women at early follicular (T1), peri-ovulatory (T2) and mid-luteal (T3) phases of the MC. We investigated the functional repertoire (number of brain configurations based on fast high-amplitude bursts of the brain signals) and the region-specific influence on large-scale dynamics across the MC. Finally, we assessed the relationship between sex hormones and changes in brain dynamics. A significantly larger number of visited configurations in T2 as compared to T1 was specifically observed in the beta frequency band. No relationship between changes in brain dynamics and sex hormones was evident. Finally, we showed that the left posterior cingulate gyrus and the right insula were recruited more often in the functional repertoire during T2 as compared to T1, while the right pallidum was more often part of the functional repertoires during T1 as compared to T2. In summary, we showed hormone-independent increased flexibility of the brain dynamics during the ovulatory phase. Moreover, we demonstrated that several specific brain regions play a key role in determining this change.

Uterine peristalsis in women affected by adenomyosis: A step towards functional assessment.

The non-pregnant uterus shows an intrinsic contractility pattern, actively involved in early reproductive processes. Uterine contractility is characterized by endometrial waves that originate from the junctional zone and varies throughout the menstrual cycle due to fluctuations in the concentrations of hormones. The aim of this study was to compare the uterine contractility patterns in the periovulatory phase in a group of patients with isolated adenomyosis and a group of healthy women using transvaginal ultrasound (TVUS). From March 2019 to March 2021, we enrolled consecutive nulliparous patients in the periovulatory phase of the menstrual cycle, divided in patients with isolated adenomyosis (group A, n = 18) and healthy patients in the control group (group B, n = 18). Patients who met the inclusion criteria underwent TVUS for the study of uterine contractility: the uterus was scanned on sagittal plane for 3 min and all the movies were recorded. Then, static images and video were evaluated offline and the uterine contractility patterns were defined. The patients belonging to the study group had a higher incidence of painful symptoms (dysmenorrhea, 6.11 ± 2.81 vs 1.39 ± 2.17; chronic pelvic pain, 2.56 ± 3.01 vs 0.39 ± 1.04) and a larger uterine volume (137.48 ± 117.69 vs 74.50 ± 27.58 cm3; P = 0.04). Regarding the uterine contractility, a statistically significant difference was observed about the retrograde patterns (group A, 27.8% vs group B, 72.2%, P < 0.01) and opposing (group A, 38.9% vs, group B, 5.6%, P = 0.02). The study confirms the presence of altered uterine peristalsis in the periovulatory phase in patients with adenomyosis. The abnormal uterine peristalsis could lead to both structural and functional changes, which are the basis of the clinical manifestations of adenomyosis and the perpetuation of the anatomical damage.

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

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

Value of 2D ultrasonography in the diagnosis and evaluation of intrauterine adhesions – a prospective study

Research questionWhat is the value of 2D ultrasonography in the diagnosis and assessment of intrauterine adhesions (IUA)? DesignThis was a prospective study conducted at a hysteroscopy centre. ResultsOf a total of 600 subjects recruited, 41 dropped out and 559 were finally enrolled and analysed. The observed 2D ultrasonography features, in decreasing order of frequency, were ‘irregular endometrium’ (37.9%), ‘broken endometrial echo’ (23.4%), ‘thin endometrium’ (13.7%), ‘loss of endometrial echo’ (13.1%,), ‘hyperechoic focus’ (12.5%) and ‘fluid in the cavity’ (8.8%). The sensitivity of individual ultrasound features ranged from 8.8% to 37.9%, whereas the specificity of individual ultrasound features ranged from 78.9% to 100%. When all the six ultrasound features were considered together, the sensitivity and specificity were 71.7% and 66.2% respectively. The sensitivity, specificity and accuracy of ultrasound diagnosis in the mid-proliferative phase, peri-ovulatory phase and mid-luteal phase did not appear to be significantly different statistically, although the results in the mid-proliferative phase appeared to be consistently higher than those in the mid-luteal phase. In women confirmed to have IUA, the likelihood of the adhesions being severe in nature in the presence of zero, one, two or three or more ultrasound features was 8.7%, 23.0%, 40.2% and 80.5%, respectively (P < 0.001). ConclusionsThe findings in this study support the notions that ultrasonography examination in women suspected to have IUA cannot replace hysteroscopy in the diagnosis of the condition. However, it does provide useful clinical information regarding severity and could help in the planning of hysteroscopy to optimize management.

Temporal and spatial differences in the vaginal microbiome of Chinese healthy women.

Up the reproductive tract, there are large differences in the composition of vaginal microbes. Throughout the menstrual cycle, the structure of the vaginal microbiome shifts. Few studies have examined both in combination. Our study was designed to explore trends in the microbiome of different parts of the vagina in healthy women over the menstrual cycle. We performed metagenomic sequencing to characterize the microbiome differences between the cervical orifice and mid-vagina throughout the menstrual cycle. Our results showed the vaginal microbiome of healthy women in the cervical orifice and the mid-vagina was similar during the periovulatory and luteal phases, with Lactobacillus being the dominant bacteria. In the follicular phase, Acinetobacter was detected in the cervical orifice. From the follicular phase to the luteal phase, the community state types (all five community status types were defined as CSTs) in samples No. 10 and No. 11 changed from CST III to CST I. In addition, the composition of the vaginal microbiome in healthy women from different regions of China was significantly different. We also detected viruses including Human alphaherpesvirus 1 (HSV-1) during periovulatory phase. This study is valuable for understanding whether the microbial composition of the vagina is consistent in different parts of the menstrual cycle.

High Incidence of Postoperative Nausea and Vomiting in Transgender Women Undergoing Facial Feminization Procedures.

Postoperative nausea and vomiting (PONV) is a significant concern due to its impact on patient comfort, recovery time, and extended hospital stay. Previous research links higher PONV rates in women during their periovulatory phase to estrogen. This study investigates the PONV risk in transgender women after facial feminization surgery. Retrospective chart reviews of transgender women aged older than 18 undergoing facial feminization from 2014 to 2020 were undertaken. Data included demographics, hormone use history, comorbidities, and PONV history. PONV was classified as any nausea/vomiting episode before discharge. Anesthesia records were examined, and PACU notes were analyzed for PONV indicators. A cis-gender male and female cohort undergoing rhinoplasty served as controls. Of the 282 transgender women receiving facial feminization surgery, 104 experienced PONV, marking a 37% PONV rate. Compared with the 11% PONV rate among cis-gender rhinoplasty patients, this was notably higher. Hormone therapy discontinuation showed no influence on PONV incidence. Transgender women undergoing facial feminization surgery have a 38% PONV rate, surpassing the 11% rate in cis-gender rhinoplasty patients and the general 20%-30% rate for all procedures, including the 25% for oral and maxillofacial surgery. This suggests a heightened PONV risk for transgender women after facial feminization procedures.

OR09-05 GPBAR1- Understanding Its Function In The Secretory Endometrium

Abstract Disclosure: M. Saad-Naguib: None. P. Timmins: None. L. George: None. C. Samuels: None. N. Douglas: None. A.V. Babwah: None. Every successful pregnancy relies on implantation of an embryo into a receptive uterine endometrium. While implantation failure accounts for 50% of pregnancy failures, it remains the least understood aspect of pregnancy. In the mid-secretory (MS) phase of the menstrual cycle, under the influence of progesterone and cAMP, fibroblasts decidualize, a critical requirement for implantation. Decidualization involves the differentiation of stromal fibroblasts into secretory epithelioid cells that contribute to the formation of the decidua, the support of the pregnancy prior to placentation. A defective decidua can lead to implantation failure, but if implantation occurs, it could compromise placenta formation and function. Several studies have demonstrated the importance of G protein-coupled receptors (GPCRs) in mouse endometrial receptivity and decidualization. GPCRs are transmembrane signaling molecules that are ubiquitously expressed in the body and regulate almost every cellular and physiological process. They are major pharmaceutical targets, with 35% of all the drugs approved by the US FDA targeting GPCRs. To identify novel GPCR regulators of embryo implantation, we conducted bulk RNA sequencing of the human endometrium at the periovulatory (PO) and mid-secretory (MS) phase in natural menstrual cycles in healthy women of reproductive age and observed that genes encoding 11 GPCRs, not previously reported to regulate implantation, were differentially expressed between these two time points. Among these was the gene encoding the G protein-coupled bile acid receptor 1 (GPBAR1), and this was upregulated 4.6-fold in the MS vs PO phase. Single cell RNA sequence analysis showed that within the human endometrium, GPBAR1 mRNA expression is mostly and strongly localized to stromal fibroblasts. Upon activation by secondary bile acids, GPBAR1 couples to Gαs leading to an increase in intracellular cAMP levels. We hypothesize that in the MS endometrium, upon ligand binding, GPBAR1 produces cAMP and induces human endometrial stromal cell (HESC) decidualization. This hypothesis is being tested in vitro using primary HESCs. Interestingly, in the pregnant mouse, GPBAR1 mRNA is barely expressed at the implantation site on E7.5, and therefore unlikely plays a role in stromal cell decidualization in the mouse. Whether Gpbar1 is expressed in the pregnant mouse endometrium prior to implantation and plays a role in regulating endometrial receptivity is being investigated. Overall, our studies have uncovered a GPCR, that to our knowledge, has not been previously described in the human endometrium. Our data show that the expression of this GPCR is upregulated at the time of endometrial stromal cell decidualization, and therefore it might regulate decidualization and/or be required for decidual function in women. These possibilities are being examined. Presentation: Friday, June 16, 2023

OR09-04 Ovarian Stimulation Disrupts Expression Of The Retinoic Acid (RA) Signaling Pathway In The Human Endometrium

Abstract Disclosure: Q. Zhao: None. P. Timmins: None. M. Saad-Naguib: None. C. Samuels: None. R. Loia: None. T. Wu: None. A. Chemerinski: None. S.S. Morelli: None. A.V. Babwah: None. N. Douglas: None. Ovarian stimulation (OS) is employed to recruit multiple dominant follicles and mature oocytes for in vitro fertilization (IVF). OS followed by a fresh embryo transfer (ET) is associated with decreased pregnancy rates. By better understanding the processes which prepare the endometrium for implantation, we hope to improve outcomes following OS. To understand the impact of OS on the endometrium, we performed an in-depth comparative analysis of the human endometrium under natural vs OS conditions during the periovulatory (PO) and mid-secretory (MSE) phase of the menstrual cycle. Our data showed that OS, which significantly elevated serum E2 and P4 levels, was associated with dyssynchronous glandular-stromal development, increased glandular epithelial volume, and increased macrophage and B cell abundance. We then performed bulk and single-cell RNA sequencing (RNA-seq) to identify the molecular pathways and cell-type specific transcriptomes associated with these changes. We found that OS significantly changed the expression of numerous genes in the retinoic acid (RA) signaling pathway, a pathway known to be crucial for a successful pregnancy. Our data showed that OS affected the fibroblast and epithelial cell-specific expression of genes that regulate RA signaling, with increased expression of RA synthesis genes and RA target genes, suggesting that OS increases endometrial RA signaling. RA is the metabolically active form of vitamin A which regulates the transcription of over 500 genes and adversely affects pregnancy when deficient or in excess. Thus, these findings led us to hypothesize that OS disrupts normal endometrial RA signaling and thereby endometrial differentiation that is required for implantation. We investigated whether RA is required for endometrial differentiation in humans and the establishment of pregnancy in mice. Using siRNAs against the RA receptor RARA, we observed that reduced expression of RARA mRNA in human endometrial stromal cells reduced their ability to undergo decidualization, an essential requirement for successful embryo implantation. We found that administration of BMS93, a pan RAR receptor antagonist, to pregnant dams prior to implantation from E0.5 or E2.5 until E7.5 resulted in pregnancy failure. Whereas BMS493 administration to pregnant dams from E4.5 to E7.5, resulted in pregnancies with reduced decidual vascular development in the anti-mesometrial region. Together, these data suggest that RA is required for the proper preparation of the endometrium for embryo implantation and loss of RA signaling in the endometrium, not the embryo, is a cause of pregnancy failure. Importantly, OS induced disruptions of RA signaling might contribute to reduced implantation rates in fresh ET, uncovering a novel pharmacologic target for improving pregnancy outcomes in fresh ET following OS. Presentation: Friday, June 16, 2023

Analyzing the atypical – Methods for studying the menstrual cycle in adolescents

BackgroundThe 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). MethodsThirty-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. ResultsMethods 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. ConclusionsRecommendations 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.

Assessment of neurotransmitter imbalances within the anterior cingulate cortex in women with primary dysmenorrhea: An initial proton magnetic resonance spectroscopy study

PurposeThe neural pathophysiology underlying primary dysmenorrhea (PDM), which leads to poor mode and changes in central pain modulatory systems, remains largely unknown. The objective of this study was to investigate the changes in glutamate/glutamine (Glx) and gamma-aminobutyric acid (GABA+) levels within anterior cingulate cortex (ACC), and their associations with clinical indicators in PDM women. MethodsUsing 3 T proton magnetic resonance spectroscopy (1H-MRS), we acquired and compared ACC-Glx and ACC-GABA+ levels in PDMs (N = 41) and age- and education-matched healthy controls (HCs) (N = 39) during both the menstrual and periovulatory phases, and between menstrual and periovulatory phases within each group. Total creatine (Cr referencing) level was used as an endogenous reference. The correlations of ACC-neurotransmitter levels with clinical characteristics and the correlations of ACC-Glx with ACC-GABA+ levels in the two groups were analyzed. ResultsCompared to HCs or the periovulatory phase, PDMs exhibited significantly increased ACC-Glx levels (p < 0.05) during the menstrual phase. Positive correlations between GABA+ and Glx levels (r = 0.385, p = 0.025) were found in PDMs during the menstrual phase. ACC-GABA+ levels were associated with self-rating distress scale (SDS) scores (GABA+/Cr: r = 0.369, p = 0.045) and pain catastrophizing scale (PCS) scores (GABA+/Cr: r = 0.373, p = 0.042) in PDM group in only the menstrual phase. ConclusionOur study represents the first report of ACC-GABA+/Glx imbalances in PDMs during the menstrual phase, which may underlie the mechanisms mediating depression and painful catastrophic symptoms.

Cyclical exacerbation of suicidal ideation in female outpatients: Prospective evidence from daily ratings in a transdiagnostic sample.

Suicide is a leading cause of death among females of reproductive age. The menstrual cycle is a plausible yet understudied trigger for acute suicide risk. Cross-sectional studies have demonstrated a greater frequency of suicide attempts and deaths in the weeks before and after the onset of menses compared to other cycle phases. Here, using prospective daily ratings, we examine the relationship between the cycle and suicidal ideation (SI) and related symptoms known to show a cyclical change in some patients (depression, hopelessness, guilt, rejection sensitivity, interpersonal conflict, anxiety, mood swings, and anger/irritability). Thirty-eight naturally cycling outpatients recruited for past-month SI reported SI severity and other symptoms across an average of 40 days. Participants were excluded for hormone use, pregnancy, irregular cycles, serious medical illness, and body mass index > 29.9 or < 18. Intraclass correlations ranged from .29 to .46, highlighting that most symptom variance lies within-person. Cyclical worsening of symptoms was evaluated using phase contrasts in multilevel models. Most symptoms, including SI, were significantly worse in the perimenstrual phase than in all other phases. Additionally, anger/irritability was higher in the midluteal than in the midfollicular phase, and several symptoms of depression were higher in the midfollicular than in the periovulatory phase. Otherwise, symptoms did not significantly differ between the midluteal, midfollicular, and periovulatory phases. Cycle phase predictors accounted for 25% of the within-person variance in SI. Females with SI may be at risk for perimenstrual worsening of SI and related symptoms. These findings highlight the importance of assessing the cycle phase for improved prediction of suicide risk. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Emotion recognition and mood along the menstrual cycle

Previous studies have demonstrated menstrual cycle dependent changes in the recognition of facial emotional expressions, specifically the expression of fear, anger, sadness or disgust. While some studies demonstrate an improvement of emotion recognition performance during the peri-ovulatory phase, when estradiol levels peak, other studies demonstrate a deterioration of emotion recognition performance during the mid-luteal phase, when progesterone levels peak. It has been hypothesized, that these changes in emotion recognition performance mirror mood changes along the menstrual cycle. In the present study, we investigate, whether changes in emotion recognition performance along the menstrual cycle are mediated by mood changes along the menstrual cycle. In a combined cross-sectional and longitudinal study design, two large samples of women completed an emotion recognition task, as well as several mood questionnaires during their menses, peri-ovulatory or mid-luteal cycle phase. 65 women completed the task thrice, once during each cycle phase, order counterbalanced. In order to control for potential learning effects, a sample of 153 women completed the task only once in one of the three cycle phases. In both samples, results demonstrated no significant changes in emotion recognition performance along the menstrual cycle, irrespective of the performance measure investigated (accuracy, reaction time, frequency of emotion classifications) and irrespective of the emotion displayed. Bayesian statistics provided very strong evidence for the null hypothesis, that emotion recognition does not change along the menstrual cycle. There was also no moderation of emotion recognition changes along the menstrual cycle by mood changes along the menstrual cycle. Mood changes along the menstrual cycle followed the expected pattern with highest positive affect and least premenstrual symptoms around ovulation and lowest positive affect, but strongest premenstrual symptoms during menses. Interestingly, premenstrual symptoms were negatively related to estradiol, suggesting a protective effect of estrogen during the luteal cycle phase against mood worsening during the premenstrual phase.

Menstrual cycle-modulated intrinsic connectivity enhances olfactory performance during periovulatory period.

Olfactory capacity increases during the period of ovulation, perhaps as an adjunct to mate selection; however, researchers have yet to elucidate the neural underpinning of menstrual cycle-dependent variations in olfactory performance. A cohort of healthy volunteers (n = 88, grand cohort) underwent testing for gonadal hormone levels and resting-state functional magnetic resonance imaging with a focus on intrinsic functional connectivity (FC) in the olfactory network based on a priori seeds (piriform cortex and orbitofrontal cortex) during the periovulatory (POV) and menstrual (MEN) phases. A subcohort (n = 20, olfaction cohort) returned to the lab to undergo testing of olfactory performance during the POV and MEN phases of a subsequent menstrual cycle. Olfactory performance and FC were both stronger in the periovulatory phase than in the menstrual phase. Enhanced FC was observed in the network targeting the cerebellum in both the grand and olfaction cohorts, while enhanced FC was observed in the middle temporal gyrus, lingual gyrus, dorsal medial prefrontal cortex, and postcentral gyrus in the grand cohort. Periovulatory progesterone levels in the grand cohort were positively correlated with FC in the network targeting the insula and paracentral lobule. Our analysis revealed that superior olfactory function in the periovulatory period is associated with enhanced intrinsic connectivity in the olfactory network. These findings can be appreciated in the context of evolutionary biology.

PEAK EXPIRATORY FLOW RATE DURING VARIOUS PHASES OF MENSTRUAL CYCLE IN ASTHMATICS PRESENTING TO A TERTIARY CARE CENTRE

Introduction: Asthma is a chronic inflammatory lung disease characterized by airway hyper responsiveness and reversible airway obstruction. Worsening of asthma symptoms and pulmonary functions in relation to menstruation has been documented by some authors. Objectives: To determine peak expiratory flow rate during various phases of menstrual cycle among adult asthmatic women. Methods: A Prospective studyof1 year duration (July 2020 to June2021) A consecutive series of 100 patients with asthma, attending the outpatient clinic of department of chest diseases, satisfying inclusion criteria were included in the study. The socio demographic details and the relevant clinical details was collected using the socio demographic Performa prepared specifically for the study, Patients asked to record asthma symptom scores, morning Peak Expiratory Flow Rate (m-PEFR) (best out of 3 readings taken) daily during the one month screening period to identify women with and without pre-menstrual asthma Results And Discussion: From our study we found highest mean PEFR value is during post ovulatory phase. Lowest during perimenstrual phase. Fall in PEFR seen mostly during perimenstrual phase (43%). Then during preovulatory phase (34%). No such fall seen during periovulatory and postovulatory phase. Severe symptoms were present during perimenstrual phase (19%) and preovulatory phase (14%) only. Similarly, moderate symptoms also during perimenstrual (22%) and preovulatory phase (21%). Both severe and moderate symptoms were not seen during periovulatory and postovulatory phase. Conclusion: Premenstrual exacerbation of asthma occurs in a significant proportion of female adult asthmatics. Thus proper history including menstrual variation of asthma of all these patients should be taken for effective management.