Different Dosages of Progesterone in Luteal Phase Support Reflect Varying Endometrial microRNA Expression in Frozen Embryo Transfer Cycles.

Despite serum progesterone being a widely accepted method for luteal phase support during embryo transfer cycles, debates persist regarding the optimal strategy for guiding clinical decisions on progesterone dosages to maximize reproductive outcomes. This retrospective study explored the utility of microRNA (miRNA) biomarkers in guiding personalized progesterone dosage adjustments for frozen embryo transfer (FET) cycles in 22 in vitro fertilization (IVF) patients undergoing hormone replacement therapy. Utilizing MIRA, an miRNA-based endometrial receptivity test, we analyzed patients' miRNA expression profiles before and after progesterone dosage adjustments to determine suitable dosages and assess endometrial status. Despite patients receiving identical progesterone dosages, variations in miRNA profiles were observed in the initial cycle, and all patients presented a displaced window of implantation. Following dosage adjustments based on their miRNA profiles, 91% of patients successfully transitioned their endometrium towards the receptive stages. However, two patients continued to exhibit persistent displaced receptivity despite the adjustments. Given the evident variation in endometrial status and serum progesterone levels among individuals, analyzing miRNA expression profiles may address the challenge of inter-personal variation in serum progesterone levels, to deliver more personalized dosage adjustments and facilitate personalized luteal phase support in IVF.

Cortical morphology variations during the menstrual cycle in individuals with and without premenstrual dysphoric disorder.

BACKGROUND: Premenstrual dysphoric disorder (PMDD) is hypothesized to stem from maladaptive neural sensitivity to ovarian steroid hormone fluctuations. Recently, we found thinner cortices in individuals with PMDD, compared to healthy controls, during the symptomatic phase. Here, we aimed at investigating whether such differences illustrate state-like characteristics specific to the symptomatic phase, or trait-like features defining PMDD. METHODS: Patients and controls were scanned using structural magnetic resonance imaging during the mid-follicular and late-luteal phase of the menstrual cycle. Group-by-phase interaction effects on cortical architecture metrics (cortical thickness, gyrification index, cortical complexity, and sulcal depth) were assessed using surface-based morphometry. RESULTS: Independently of menstrual cycle phase, a main effect of diagnostic group on surface metrics was found, primarily illustrating thinner cortices (0.3 < Cohen's d > 1.1) and lower gyrification indices (0.4 < Cohen's d > 1.0) in patients compared to controls. Furthermore, menstrual cycle-specific effects were detected across all participants, depicting a decrease in cortical thickness (0.4 < Cohen's d > 1.7) and region-dependent changes in cortical folding metrics (0.4 < Cohen's d > 2.2) from the mid-follicular to the late luteal phase. LIMITATIONS: Small effects (d = 0.3) require a larger sample size to be accurately characterized. CONCLUSIONS: These findings provide initial evidence of trait-like cortical characteristics of the brain of individuals with premenstrual dysphoric disorder, together with indications of menstrual cycle-related variations in cortical architecture in patients and controls. Further investigations exploring whether these differences constitute stable vulnerability markers or develop over the years may help understand PMDD etiology.

Comparison of luteal phase and follicular phase in-vitro maturation in women with oocyte maturation abnormalities.

RESEARCH QUESTION: Are there differences in immature oocyte retrieval following luteal phase in-vitro maturation (IVM) compared with follicular phase IVM in women with oocyte maturation abnormalities (OMAs). DESIGN: From January 2019 to May 2023, a retrospective cohort study at a private IVF centre included 36 women with 53 IVM cycles in Group 1 (follicular phase) and 24 women with 32 IVM cycles in Group 2 (luteal phase). Additionally, nine women had both follicular and luteal phase IVM cycles for intracycle variability analysis. RESULTS: There were no differences in oocyte maturation stages between the groups at collection. Group 1 and Group 2 exhibited comparable median metaphase II oocyte rates per patient at 48 h after collection [40.0%, interquartile range (IQR) 0.0-66.7% versus 22.5%, IQR 0.0-52.9%] (P = 0.53). The median fertilization rate in Group 1 (66.7%, IQR 50.0-66.7%) was found to be comparable with that in Group 2 (66.7%, IQR 50.0-66.7%). There were no significant differences in the yielded embryo grades and pregnancy rates between the groups. Comparing follicular and luteal phase IVM within the same menstrual cycle in nine patients, no differences were observed in metaphase II oocyte maturation rates (P > 0.05). CONCLUSIONS: This study found no significant differences in oocyte maturation, fertilization rate, embryo quality or pregnancy outcomes between luteal phase and follicular phase IVM in women with OMAs. These findings suggest that luteal phase IVM can be used similarly to follicular phase IVM, offering a potential avenue to enhance embryo yield for women with OMAs.

Selective attention towards infants in nulliparous women across the menstrual cycle.

Research in women showed that testosterone is associated with decreased selective attention towards infant stimuli, which can be compensated for by oxytocin administration. In theory, caregiving behavior is thought to be mediated by oxytocin. Oxytocin binds to dopaminergic neurons and thus supposedly motivates aspects of caregiving through its influence on dopaminergic transmission. Most previous studies on caregiving behaviors were thereby performed in women under hormonal contraception to avoid hormonal fluctuations. However, recent studies repeatedly demonstrated decisive influences of the hormonal changes across the female menstrual cycle on dopamine-mediated behaviors, suggesting that estradiol acts as dopamine agonist in the follicular phase and progesterone as dopamine antagonist in the luteal phase. In the present study, we investigated selective attention towards infants as one central aspect of caregiving behavior over the natural menstrual cycle and in relation to interindividual differences of estradiol and progesterone. As expected, we found that women with higher estradiol in the follicular phase also showed higher selective attention towards infant faces among adult distractors, whereas the correlation disappeared in the luteal phase. In contrast, progesterone did not correlate with selective attention towards infants. The present findings collectively support the assumption that estradiol may act as dopamine agonist in the follicular phase, thereby supposedly promoting an important aspect of caretaking behavior.

Changes in Psychotropic Drug Concentrations Across the Menstrual Cycle: A Pilot Study.

BACKGROUND: The escalating prescription of psychopharmacological medications to women of reproductive age underscores the growing significance of sex-specific variations in pharmacotherapy. Despite this, clinical trials have largely overlooked these differences. Preliminary data indicate sex-specific variations in the neurobiology of affective disorders and in the metabolism, pharmacodynamics, and kinetics of therapeutic drugs. This underscores the imperative for a more nuanced exploration of menstrual cycle-dependent fluctuations in psychotropic drugs. This pilot study aimed to investigate drug and hormone fluctuations in female patients with affective disorders, aiming to enhance comprehension of the interplay between cycle-related hormone fluctuations and pharmacokinetics. The ultimate goal is to facilitate more effective and safer pharmacological therapy in the future. METHODS: Blood samples were collected from 27 patients and 27 age-matched control participants at 3 distinct time points (early follicular phase, ovulation, and late luteal phase) during each menstrual cycle. Depressive and manic symptoms were assessed, and hormone concentrations were measured in the entire sample, while drug concentrations were assessed solely in the affective disorder sample using mass spectrometry. RESULTS: Significant variations in drug concentration were observed throughout the menstrual cycle for bupropion, with a trend toward altered concentration for venlafaxine. Moreover, notable differences in hormone concentrations were identified between patients and controls, even after accounting for the impact of contraceptive use, diagnoses, and medication. CONCLUSIONS: This pilot study reinforces previously reported data, underscoring the significance of sex-specific pharmacological therapy approaches. It provides further evidence supporting the interaction among sex hormones, drugs, and symptoms of affective disorders.

Luteal Phase Defects and Progesterone Supplementation.

Importance: Luteal phase defects (LPDs), or an insufficiency of progesterone production during the luteal phase of the menstrual cycle, have been identified as a potential cause of recurrent pregnancy loss (RPL), but its exact contribution to RPL is not well-defined. In addition, the role of exogenous progesterone supplementation during pregnancy remains controversial. Objective: The goal of this review is to provide an updated, evidence-based summary of LPD, including prevalence and potential pathophysiologic mechanisms, and to explore the current controversies regarding progesterone supplementation for management and treatment of RPL. Evidence Acquisition: A literature review identified relevant research using a PubMed search, Cochrane summaries, review articles, textbook chapters, databases, and society guidelines. Results: Endogenous progesterone plays a crucial role in the first trimester of pregnancy, and therefore, insufficiency may contribute to RPL. However, the precise relationship between LPD and RPL remains unclear. Luteal phase defect is primarily a clinical diagnosis based on a luteal phase less than 10 days. Although there may be a possibility of incorporating a combined clinical and biochemical approach in defining LPD, the current lack of validated diagnostic criteria creates a challenge for its routine incorporation in the workup of infertility. Moreover, no treatment modality has demonstrated efficacy in improving fertility outcomes for LPD patients, including progesterone supplementation, whose inconsistent data do not sufficiently support its routine use, despite its minimal risk. It is imperative that women diagnosed with LPD should be worked up for other potential conditions that may contribute to a shortened luteal phase. Future work needs to focus on identifying a reproducible diagnostic test for LPD to guide treatment. Conclusions and Relevance: Currently, the perceived relationship between LPD and RPL is challenged by conflicting data. Therefore, patients with an abnormal luteal phase should undergo a thorough workup to address any other potential etiologies. Although supplemental progesterone is commonly utilized for treatment of LPD and RPL, inconsistent supporting data call for exogenous hormone therapy to be only used in a research setting or after a thorough discussion of its shortcomings.

Social Stress during the Estrus or Luteal Phase in Sheep.

In mammals, progesterone and estrogens affect the stress response. The study aimed to compare the physiological and behavioral responses to the social isolation of ewes during the estrus or luteal phase. Estrous and diestrous ewes (n = 10 and 8 respectively) were individually isolated in a novel place for 10 min. Ewes' behavior was recorded during the test. Cortisol, blood proteins and glucose concentrations, and the skin surface temperature were determined before and after the test. Cortisol increased immediately after the test ended (P = 0.02). Serum total protein (P = 0.02), globulin (P < 0.0001), and plasma glucose (P = 0.006) concentrations were greater in estrus than in the luteal phase. The abdominal skin surface temperature was greater during estrus than during the luteal phase (P = 0.02). Ewes in estrus spent more time standing up immobile than ewes in the luteal phase (P = 0.05). In conclusion, the physiological and behavioral responses changed according to the phase of the estrous cycle. These results highlight the need for future studies focusing on how reproductive status influences the stress response to different management practices in sheep.

Premenstrual disorders and PMDD - a review.

Defining, diagnosing and managing premenstrual disorders (PMDs) remains a challenge both for general practitioners and specialists. Yet these disorders are common and can have an enormous impact on women. PMDD (premenstrual dysphoric disorder), one severe form of PMD, has a functional impact similar to major depression yet remains under-recognised and poorly treated. The aim of this chapter is to give some clarity to this area, provide a framework for non-specialists to work towards, and to stress the importance of MDT care for severe PMDs, including PMDD.

Demystifying the landscape of endometrial immune microenvironment in luteal-phase from cuprotosis: Implications for the mechanism and treatment of RPL.

BACKGROUND: Adaptive changes in the endometrial immune microenvironment during the luteal phase are essential for pregnancy, and their abnormalities are associated with recurrent pregnancy loss (RPL). Nevertheless, the specific mechanism is still unknown. Cuprotosis, an innovatively discovered type of programmed cell death, provides us with a pioneering perspective to decipher the landscape of luteal-phase endometrial immune microenvironment in RPL. This study aimed to analyze the immune landscape of luteal-phase endometrial microenvironment in RPL and explore the association of cuprotosis with it through integrative bioinformatics analysis. METHODS: The microarrays involving the luteal phase endometrial tissue of RPL were obtained from the GEO database. Differentially expressed genes (DEGs) of RPL were screened and key modules were detected by WGCNA. GO, KEGG, and GSEA immune enrichment analyses were performed on the DEGs in the most relevant modules to RPL. Then, the endometrial immune microenvironment landscape of RPL was analyzed, including immune infiltration analysis and correlation analysis between immune cells or immune functions. The interaction of cuprotosis-related genes (CRGs), the expression level between groups, the immune localization and their correlation with immune cells and immune function were analyzed. LASSO regression and Nomogram evaluated the diagnostic value of immune-related CRGS in RPL. Functional enrichment analysis was performed on the RPL signature CRGs. And RPL samples were grouped according to the expression of 7 RPL signature CRGs through unsupervised clustering analysis. After that, we analyzed the expression level of CRGs and immune infiltration, as well as performed immune function enrichment analysis in subtypes. In addition, we also screened potential drugs that might act on CRGs to improve the pathological mechanism of RPL. RESULTS: In this study, we uncovered that DEGs and genes in key modules derived from weighted gene co-expression network analysis (WGCNA) were involved in immune regulation. And the immune infiltration landscape of RPL was significantly different from healthy controls. Furthermore, six hub genes were screened from CRGs based on Cytohubba, and their expression profilings were verified in RPL and normal mouse samples. Besides, seven CRGs closely associated with the immune regulation of RPL were identified by Spearman correlation analysis, including SLC31A1, LIAS, DLD, DLAT, DBT, ATP7B, and ATP7A, named as immune-related CRGs. Furthermore, three subgroups clustered according to these seven genes showed significant differences in immune landscape, suggesting a remarkable effect of CRGs on immune regulation. Last but not least, we analyzed the regulation network of transcription factors, miRNAs, and CRGs, and screened potential compounds for the treatment of RPL by targeting CRGs. CONCLUSIONS: The abnormal endometrial immune microenvironment in the luteal phase was associated with the pathomechanism of RPL, and cuprotosis was closely involved in the immune microenvironment in the luteal phase endometrium of RPL. Collectively, this study revealed the potential contribution of CRGs to the pathogenesis of RPL, providing a novel breakthroughs in insights into the pathogenesis, diagnosis, and treatment of RPL.

Investigation of postural sensory organization in women with and without primary dysmenorrhea in three phases of the menstrual cycle.

BACKGROUND: The effects of the menstrual cycle in women with and without primary dysmenorrhea on phase-related postural sensory organization are controversial. RESEARCH QUESTION: This study was carried out to examine postural sensory organization in three phases of the menstrual cycle in women with and without primary dysmenorrhea and to evaluate whether there is a difference between women with/without primary dysmenorrhea in this regard. METHODS: Women aged 18-30 years were divided into two groups as primary dysmenorrhea group (PDG, n = 14) and control group (CG, n = 15). Computerized dynamic posturography were applied to the participants on the follicular, ovulation, and luteal phases of the menstrual cycle. Outcome measures were antero-posterior and medio-lateral Sensory Organization Test (SOT-somatosensory, vestibular and visual scores) and Limits of Stability test (LoS). The findings obtained were analyzed with the two-factor ANOVA, paired samples t test, and independent samples t test. RESULTS: In the PDG, follicular phase antero-posterior somatosensory scores were lower compared to luteal phase (p = 0.002). Follicular phase antero-posterior and medio-lateral vestibular scores were lower than ovulation (p = 0.003, p = 0.004, respectively) and luteal (p = 0.005, p = 0.001, respectively) phases. Follicular phase LoS scores were lower than ovulation (p = 0.001) and luteal (p = 0.002) phases. In the CG, ovulation phase antero-posterior somatosensory scores were lower than follicular phase (p = 0.003). Follicular phase LoS scores were lower than ovulation phase (p = 0.002). The PDG had lower follicular phase antero-posterior somatosensory (p = 0.019), vestibular (p = 0.031), and medio-lateral somatosensory (p = 0.019) scores than those of the CG. The PDG had lower luteal phase antero-posterior somatosensory scores than those of the CG (p = 0.029). The PDG showed lower follicular phase LoS scores than those of the CG (p = 0.009). SIGNIFICANCE: This study revealed that primary dysmenorrhea impairs postural sensory organization. Decreased sensory organization may predispose women to injury. The risk of injury should be investigated and necessary precautions should be taken.

Impact of Menstrual cycle-based Periodized training on Aerobic performance, a Clinical Trial study protocol-the IMPACT study.

BACKGROUND: The menstrual cycle and its impact on training and performance are of growing interest. However, evidence is lacking whether periodized exercise based on the menstrual cycle is beneficial. The primary purpose of this proposed randomized, controlled trial, the IMPACT study, is to evaluate the effect of exercise periodization during different phases of the menstrual cycle, i.e., comparing follicular phase-based and luteal phase-based training with regular training during the menstrual cycle on physical performance in well-trained women. METHODS: Healthy, well-trained, eumenorrheic women between 18 and 35 years (n = 120) will be recruited and first assessed for physical performance during a run-in menstrual cycle at different cycle phases and then randomized to three different interventions: follicular phase-based training, luteal phase-based training, or regular training during three menstrual cycles. The training intervention will consist of high-intensity spinning classes followed by strength training. The menstrual cycle phases will be determined by serum hormone analysis throughout the intervention period. Assessment of aerobic performance (primary outcome) and muscle strength, body composition, and blood markers will be performed at baseline and at the end of the intervention. DISCUSSION: With a robust methodology, this study has the potential to provide evidence of the differential effects of exercise periodization during different phases of the menstrual cycle in female athletes. TRIAL REGISTRATION: ClinicalTrials.gov NCT05697263 . Registered on 25 January 2023.

Relationship Between Steroid Hormone Profile and Premenstrual Syndrome in Women Consulting for Infertility or Recurrent Miscarriage.

To determine the relationships between luteal-phase steroidal hormonal profile and PMS for a large number of women attending a dedicated fertility clinic. This was a retrospective cross-sectional study on women attending a hospital-based clinic for fertility concerns and/or recurrent miscarriage. All participants were assessed with a women's health questionnaire which also included evaluation of premenstrual symptoms. Day of ovulation was identified based on the peak mucus symptom assessed by the woman after instruction in a fertility awareness-based method (FABM). This enabled reliable timing of luteal-phase serum hormone levels to be taken and analysed. Between 2011 and 2021, 894 of the 2666 women undertaking the women's health assessment had at least one evaluable serum luteal hormone test. Serum progesterone levels were up to 10 nmol/L lower for symptomatic women compared with asymptomatic women. This difference was statistically significant (p < 0.05) for the majority of PMS symptoms at ≥ 9 days after the peak mucus symptom. A similar trend was observed for oestradiol but differences were generally not statistically significant. ROC curves demonstrated that steroid levels during the luteal phase were not discriminating in identifying the presence of PMS symptoms. Blood levels for progesterone were lower throughout the luteal phase in women with PMS, with the greatest effect seen late in the luteal phase.

Fatigue Resistance Is Altered during the High-Hormone Phase of Eumenorrheic Females but Not Oral Contraceptive Users.

PURPOSE: This study aimed to examine the effect of ovarian hormones and their synthetic equivalents on substrate utilization and fatigue resistance during a race-specific cycling protocol. METHODS: Seventeen well-trained female cyclists (nine eumenorrheic females, eight oral contraceptive users) completed two experimental trials, in a randomized order, in their low- (follicular/sugar pill) and high-hormone (luteal/active pill) phases. Each 91-min trial consisted of a 45-min moderate-intensity component (submaximal cycling, or SMC) followed by 6 min of high-intensity (HIT) and then a fatigue resistance test (FRT): 6 × 1-min all-out efforts with 1-min active recovery. Meals, comprising carbohydrate (CHO) intake of 8 g·kg -1 body mass, were standardized 24-h pretrial. An electrolyte-only solution was provided ad libitum during each trial. RESULTS: In eumenorrheic females, a large reduction in average power during FRT was observed in the luteal phase (277 ± 31 vs 287 ± 33 W; P = 0.032). Greater CHO ox (~ 4%, P = 0.020) during SMC and ventilatory inefficiencies during SMC and HIT (~7%, P < 0.001) were also observed in the luteal phase. In contraceptive users, despite some phasal changes in cardiorespiratory and metabolic data in SMC (~6% higher blood glucose and ~2% higher minute ventilation in active pill phase), none of the performance parameters in the FRT were different. CONCLUSIONS: Fatigue resistance was compromised only in high-hormone phase of the menstrual cycle, with eumenorrheic females likely susceptible because of increased CHO utilization during SMC. Hormone-induced ventilatory inefficiencies may also have increased metabolic demand. These findings emphasize the need to maintain CHO availability for power production, particularly in high-hormone phases.

Role of Dydrogesterone for Luteal Phase Support in Assisted Reproduction.

Clinical outcomes of in vitro fertilization (IVF) have significantly improved over the years with the advent of the frozen-thawed embryo transfer (FET) technique. Ovarian hyperstimulation during IVF cycles causes luteal phase deficiency, a condition of insufficient progesterone. Intramuscular or vaginal progesterone and dydrogesterone are commonly used for luteal phase support in FET. Oral dydrogesterone has a higher bioavailability than progesterone and has high specificity for progesterone receptors. Though micronized vaginal progesterone has been the preferred option, recent data suggest that oral dydrogesterone might be an alternative therapeutic option for luteal phase support to improve clinical outcomes of IVF cycles. Dydrogesterone has a good safety profile and is well tolerated. Its efficacy has been evaluated in several clinical studies and demonstrated to be non-inferior to micronized vaginal progesterone in large-scale clinical trials. Oral dydrogesterone may potentially become a preferred drug for luteal phase support in millions of women undergoing IVF.

Estrogen, progesterone, cortisol, brain-derived neurotrophic factor, and vascular endothelial growth factor during the luteal phase of the menstrual cycle in women with premenstrual dysphoric disorder.

The interplay between ovarian hormones, stress, and inflammatory markers in developing premenstrual dysphoric disorder (PMDD) remains inadequately understood. This study investigated the associations of dynamic changes in the levels of estrogen, progesterone, cortisol, brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF) with PMDD during the luteal phase of the menstrual cycle. A total of 58 women with PMDD and 50 healthy women were recruited in this study. These women's estrogen, progesterone, cortisol, BDNF, and VEGF levels were evaluated during the preovulation (PO), mid-luteal (ML), and late-luteal (LL) phases. Furthermore, the severity of P MDD symptoms, depressive symptoms, perceived stress, inattention, craving for sweet foods, and fatigue was assessed. The findings revealed that women with PMDD with higher levels of progesterone during the ML or LL phase or a greater increase (ML-PO) or higher sum (ML + LL) of luteal progesterone level exhibited a greater increase in PMDD symptoms during the luteal phase than did the healthy controls. Furthermore, women with PMDD exhibited higher cortisol levels during the LL phase than did the controls. The BDNF level was negatively correlated with PMDD severity. Furthermore, BDNF and VEGF levels were negatively correlated with inattention and craving for sweet foods among women with PMDD. These results suggest an association between progesterone and the exacerbation of PMDD symptoms during the LL phase. Women with PMDD have relatively high cortisol levels during the LL phase. Future investigations with experimental designs or larger sample sizes are warranted to verify the roles of progesterone and cortisol in the development of PMDD.

Luteal phase support in assisted reproductive technology.

Infertility affects one in six couples, with in vitro fertilization (IVF) offering many the chance of conception. Compared to the solitary oocyte produced during the natural menstrual cycle, the supraphysiological ovarian stimulation needed to produce multiple oocytes during IVF results in a dysfunctional luteal phase that can be insufficient to support implantation and maintain pregnancy. Consequently, hormonal supplementation with luteal phase support, principally exogenous progesterone, is used to optimize pregnancy rates; however, luteal phase support remains largely 'black-box' with insufficient clarity regarding the optimal timing, dosing, route and duration of treatment. Herein, we review the evidence on luteal phase support and highlight remaining uncertainties and future research directions. Specifically, we outline the physiological luteal phase, which is regulated by progesterone from the corpus luteum, and evaluate how it is altered by the supraphysiological ovarian stimulation used during IVF. Additionally, we describe the effects of the hormonal triggers used to mature oocytes on the degree of luteal phase support required. We explain the histological transformation of the endometrium during the luteal phase and evaluate markers of endometrial receptivity that attempt to identify the 'window of implantation'. We also cover progesterone receptor signalling, circulating progesterone levels associated with implantation, and the pharmacokinetics of available progesterone formulations to inform the design of luteal phase support regimens.

Oral dydrogesterone versus micronized vaginal progesterone for luteal phase support: a double-blind crossover study investigating pharmacokinetics and impact on the endometrium.

STUDY QUESTION: How do plasma progesterone (P) and dydrogesterone (D) concentrations together with endometrial histology, transcriptomic signatures, and immune cell composition differ when oral dydrogesterone (O-DYD) or micronized vaginal progesterone (MVP) is used for luteal phase support (LPS)? SUMMARY ANSWER: Although after O-DYD intake, even at steady-state, plasma D and 20αdihydrodydrogesterone (DHD) concentrations spiked in comparison to P concentrations, a similar endometrial signature was observed by histological and transcriptomic analysis of the endometrium. WHAT IS KNOWN ALREADY: O-DYD for LPS has been proven to be noninferior compared to MVP in two phase III randomized controlled trials. Additionally, a combined individual participant data and aggregate data meta-analysis indicated that a higher pregnancy rate and live birth rate may be obtained in women receiving O-DYD versus MVP for LPS in fresh IVF/ICSI cycles. Little data are available on the pharmacokinetic (PK) profiles of O-DYD versus MVP and their potential molecular differences at the level of the reproductive organs, particularly at the endometrial level. STUDY DESIGN, SIZE, DURATION: Thirty oocyte donors were planned to undergo two ovarian stimulation (OS) cycles with dual triggering (1.000 IU hCG + 0.2 mg triptorelin), each followed by 1 week of LPS: O-DYD or MVP, in a randomized, cross-over, double-blind, double-dummy fashion. On both the first and eighth days of LPS, serial blood samples upon first dosing were harvested for plasma D, DHD, and P concentration analyses. On Day 8 of LPS, an endometrial biopsy was collected for histologic examination, transcriptomics, and immune cell analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: All oocyte donors were <35 years old, had regular menstrual cycles, no intrauterine contraceptive device, anti-Müllerian hormone within normal range and a BMI ≤29 kg/m2. OS was performed on a GnRH antagonist protocol followed by dual triggering (1.000 IU hCG + 0.2 mg triptorelin) as soon as ≥3 follicles of 20 mm were present. Following oocyte retrieval, subjects initiated LPS consisting of MVP 200 mg or O-DYD 10 mg, both three times daily. D, DHD, and P plasma levels were measured using liquid chromatography-tandem mass spectrometry. Histological assessment was carried out using the Noyes criteria. Endometrial RNA-sequencing was performed for individual biopsies and differential gene expression was analyzed. Endometrial single-cell suspensions were created followed by flow cytometry for immune cell typing. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 21 women completed the entire study protocol. Subjects and stimulation characteristics were found to be similar between groups. Following the first dose of O-DYD, the average observed maximal plasma concentrations (Cmax) for D and DHD were 2.9 and 77 ng/ml, respectively. The Cmax for D and DHD was reached after 1.5 and 1.6 h (=Tmax), respectively. On the eighth day of LPS, the first administration of that day gave rise to a Cmax of 3.6 and 88 ng/ml for D and DHD, respectively. For both, the observed Tmax was 1.5 h. Following the first dose of MVP, the Cmax for P was 16 ng/ml with a Tmax of 4.2 h. On the eighth day of LPS, the first administration of that day showed a Cmax for P of 21 ng/ml with a Tmax of 7.3 h. All 42 biopsies showed endometrium in the secretory phase. The mean cycle day was 23.9 (±1.2) in the O-DYD group versus 24.0 (±1.3) in the MVP group. RNA-sequencing did not reveal significantly differentially expressed genes between samples of both study groups. The average Euclidean distance between samples following O-DYD was significantly lower than following MVP (respectively 12.1 versus 18.8, Mann-Whitney P = 6.98e-14). Immune cell profiling showed a decrease of CD3 T-cell, γδ T-cell, and B-cell frequencies after MVP treatment compared to O-DYD, while the frequency of natural killer (NK) cells was significantly increased. LIMITATIONS, REASONS FOR CAUTION: The main reason for caution is the small sample size, given the basic research nature of the project. The plasma concentrations are best estimates as this was not a formal PK study. Whole tissue bulk RNA-sequencing has been performed not correcting for bias caused by different tissue compositions across biopsies. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study comparing O-DYD/MVP, head-to-head, in a randomized design on a molecular level in IVF/ICSI. Plasma serum concentrations suggest that administration frequency is important, in addition to dose, specifically for O-DYD showing a rapid clearance. The molecular endometrial data are overall comparable and thus support the previously reported noninferior reproductive outcomes for O-DYD as compared to MVP. Further research is needed to explore the smaller intersample distance following O-DYD and the subtle changes detected in endometrial immune cells. STUDY FUNDING/COMPETING INTEREST(S): Not related to this work, C.Bl. has received honoraria for lectures, presentations, manuscript writing, educational events, or scientific advice from Abbott, Ferring, Organon, Cooper Surgical, Gedeon-Richter, IBSA, and Merck. H.T. has received honoraria for lectures, presentations, manuscript writing, educational events, or scientific advice from Abbott, Ferring, Cooper Surgical, Gedeon-Richter, Cook, and Goodlife. S.M. has received honoraria for lectures, presentations, educational events, or scientific advice from Abbott, Cooper Surgical, Gedeon-Richter, IBSA, and Merck and Oxolife. G.G. has received honoraria for lectures, presentations, educational events, or scientific advice from Merck, MSD, Organon, Ferring, Theramex, Gedeon-Richter, Abbott, Biosilu, ReprodWissen, Obseva, PregLem, Guerbet, Cooper, Igyxos, and OxoLife. S.V.-S. is listed as inventor on two patents (WO2019115755A1 and WO2022073973A1), which are not related to this work. TRIAL REGISTRATION NUMBER: EUDRACT 2018-000105-23.

Expression profiles of oviductal mRNAs and lncRNAs in the follicular phase and luteal phase of sheep (Ovis aries) with 2 fecundity gene (FecB) genotypes.

FecB (also known as BMPR1B) is a crucial gene in sheep reproduction, which has a mutation (A746G) that was found to increase the ovulation rate and litter size. The FecB mutation is associated with reproductive endocrinology, such mutation can control external estrous characteristics and affect follicle-stimulating hormone during the estrous cycle. Previous researches showed that the FecB mutation can regulate the transcriptomic profiles in the reproductive-related tissues including hypothalamus, pituitary, and ovary during the estrous cycle of small-tailed Han (STH) sheep. However, little research has been reported on the correlation between FecB mutation and the estrous cycle in STH sheep oviduct. To investigate the coding and noncoding transcriptomic profiles involved in the estrous cycle and FecB in the sheep oviduct, RNA sequencing was performed to analyze the transcriptomic profiles of mRNAs and long noncoding RNAs (lncRNAs) in the oviduct during the estrous cycle of STH sheep with mutant (FecBBB) and wild-type (FecB++) genotypes. In total, 21,863 lncRNAs and 43,674 mRNAs were screened, the results showed that mRNAs had significantly higher expression levels than the lncRNAs, and the expression levels of these screened transcripts were lower in the follicular phase than they were in the luteal phase. Among them, the oviductal glycoprotein gene (OVGP1) had the highest expression level. In the comparison between the follicular and luteal phases, 57 differentially expressed (DE) lncRNAs and 637 DE mRNAs were detected, including FSTL5 mRNA and LNC_016628 lncRNA. In the comparison between the FecBBB and FecB++ genotypes, 26 DE lncRNAs and 421 DE mRNAs were detected, including EEF1D mRNA and LNC_006270 lncRNA. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment analysis indicated that the DE mRNAs were enriched mainly in terms related to reproduction such as the tight junction, SAGA complex, ATP-binding cassette, nestin, and Hippo signaling pathway. The interaction network between DE lncRNAs and DE mRNAs indicated that LNC_018420 may be the key regulator in sheep oviduct. Together, our results can provide novel insights into the oviductal transcriptomic function against a FecB mutation background in sheep reproduction.

A new method for endometrial dating using computerized virtual pathology.

Endometrial dating (ED) is the process by which the menstrual cycle day is estimated and is an important tool for the evaluation of uterine status. To date, ED methods remain inaccurate and controversial. We demonstrate how the rise of computerized virtual histology changes the state of affairs and introduce a new ED method. We present the results of a clinical trial where magnified images of ex-vivo endometrial tissue samples were captured at different cycle days, together with measurements of serum hormone levels on the same day. Patient testimonies about their cycle day were also collected. Computerized image analysis, followed by statistical representation of the tissue features, allowed mathematical representation of the cycle day. The samples underwent ED histological assessment, which is currently the ED gold standard. We compared dating results from patient reports, serum hormone levels, and histology to establish their concordance level. We then compared histology-based ED with the new method ED in the secretory phase (i.e. post ovulation). The correlation coefficient between the two resulted in an R = 0.89 with a P-value of P < 10-4. The new method, Virtual Pathology Endometrial Dating (VPED), has the benefit of being a real time, in-vivo method that can be repeatedly applied without tissue damage, using a dedicated hysteroscope. One practical use of this method may be the determination of accurate real-time embryo transfer timing in IVF treatments.

Comparison of Functional Vestibulo-Ocular Reflex in Follicular and Luteal Phase in Young Girls.

BACKGROUND: The aim of this study is to compare the possible functional involvement of the vestibulo-ocular reflex in the follicular and luteal phases. METHODS: The research was carried out at a university located in eastern Turkey. The study included 37 healthy female volunteering students aged 18-25 years. The functional head impulse test was applied twice in the follicular phase and in the luteal phase, and the results in both phases were compared. RESULTS: In the functional head impulse test, statistically significant differences were obtained between the follicular phase and the luteal phase at the stimulus to the lateral semicircular canal direction total and 6000°/s2 acceleration percentage of correct answers values, the posterior semicircular canal direction stimulations at 3000°/s2 and 5000°/s2 acceleration percentage of correct answers values, and the anterior semicircular canal direction stimulations at 5000°/s2 acceleration percentage of correct answers values. CONCLUSION: In the luteal phase, which corresponds to the period before menstruation, the vestibulo-ocular reflex is functionally negatively affected.