The late-follicular-phase progesterone to retrieved oocytes ratio in normal ovarian responders treated with an antagonist protocol can be used as an index for selecting an embryo transfer strategy and predicting the success rate: a retrospective large-scale study.

Objective: To determine whether the late-follicular-phase progesterone to retrieved oocytes (P/O) ratio during in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) impacts pregnancy outcomes. Design: 12,874 cycles were retrospectively categorized into four groups according to the P/O ratio percentile, with divisions at the 25th, 50th and 75th percentiles. Results: The clinical pregnancy and live birth rates of fresh cycle embryos in Group D were significantly lower than those in the other three groups (45.1% and 39.0%, 43.2% and 37.2%, 39.6% and 33.5%, 33.4% and 28.2% in Group A, B, C, D, respectively; both P < 0.008). Multivariate logistic regression analysis revealed a significant negative correlation between the P/O ratio and live birth, particularly when the P/O ratio was ≥0.22 (OR = 0.862, 95% CI [0.774-0.959], P = 0.006). Conclusions: The P/O ratio has certain predictive value for IVF/ICSI pregnancy outcomes and can be used for decision-making decision regarding fresh embryo transfer.

The prevalence of late-follicular phase progesterone elevation and impact on the ongoing pregnancy rate after fresh and frozen blastocyst transfer. Sub-study of an RCT.

The effect of late-follicular phase progesterone elevation (LFPE) during ovarian stimulation on reproductive outcomes in ART treatment remains controversial, but recent studies indicate lower pregnancy rates with rising progesterone levels. This study aims to investigate the prevalence of late-follicular phase progesterone elevation (LFPE) and possible impact on ongoing pregnancy rate after fresh or frozen blastocyst transfer in a sub-study setting of a randomised controlled trial. A total of 288 women were included (n=137 and n=151 in the fresh transfer and freeze-all group, respectively). Among these 11(3.8%) had a progesterone level ≥1.5 ng/ml, and 20(6.9%) had a progesterone level ≥1.2 ng/ml on trigger day. Spline regression analysis showed no significant effect of late follicular phase progesterone levels on ongoing pregnancy. In the multivariate regression analysis (n = 312) only age, but not progesterone level on trigger day was significantly associated with ongoing pregnancy. In conclusion, in a clinical setting with moderate gonadotrophin stimulation and well-defined trigger and fresh transfer cancellation criteria, the prevalence of women with LFPE ≥1.5 ng/ml was low and did not indicate the clinical value of routine measurement of progesterone in the late follicular phase.

High ovarian responders have the highest risk of premature progesterone rise.

OBJECTIVE: Late follicular phase progesterone elevation is a complication that affects approximately 38% of IVF cycles. There is a lack of consensus on the appropriate cut-off levels for progesterone on hCG day. Although premature progesterone rise occurs in all kinds of ovarian responses, there is a knowledge gap regarding the ovarian response with the highest risk of this phenomenon. Our study aims to assess the relative risk of each kind of ovarian response for premature progesterone rise and evaluate the prevalence of premature progesterone rise in each ovarian response. METHODS: A retrospective, cross-sectional, comparative and analytic study was performed at the Reproductive Endocrinology Department in Centro Médico Nacional 20 de Noviembre in Mexico City. All conventional-antagonist cycles were grouped according to their ovarian response and were evaluated from 2015 to 2020. Pearson's Squared-chi, Cramer's V, cross-table and the relative risk were calculated. RESULTS: The prevalence of premature progesterone rise oscillated from 20.8 to 67.9% for low and high ovarian responders, respectively. After calculating the relative risk, high ovarian responders had a 1.38 higher risk for premature progesterone rise than other groups. CONCLUSIONS: High ovarian responders have the highest risk for premature progesterone rise compared to normal and low ovarian responders. High ovarian responders have a 67.9% prevalence of premature progesterone rise.

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.

Menstrual Phase Identification Questionnaire (MPIQ): Development and validation of a cross-sectional survey to identify follicular and luteal phases.

Evidence continues to accumulate on the influence of the menstrual phase on several biobehavioral outcomes (e.g., substance misuse). Expansion of this knowledge is limited due to the burdensomeness of accurate menstrual phase assessment. Thus, we sought to create and validate a questionnaire that can be used as a stand-alone item within low-resource settings and numerous study designs (e.g., cross-sectional) to accurately identify both the follicular phase (FP) and the luteal phase (LP). Participants completed the self-administered four-item Menstrual Phase Identification Questionnaire (MPIQ) in two recently completed clinical trials. We assessed the accuracy of two MPIQ scoring criteria (less restrictive and more restrictive), as compared to self-report of onset of menses alone, with progesterone confirmation via dried blood spots. Participants (n = 59) were, on average, 33.7 (standard deviation [SD]: ± 4.3) years old and provided a total of 83 responses. Assessing FP and LP using the self-reported onset of menses alone classified 65.1% of the responses with an overall phase identification accuracy of 60.2%. While the more restrictive MPIQ scoring classified 100% of the responses, it yielded a similar accuracy (68.4%). In contrast, the less restrictive MPIQ scoring classified 100% of the responses and also significantly improved phase identification accuracy to 92.1% (p < .001). The MPIQ, as a stand-alone item, allows all cross-sectional responses to be classified with a high level of accuracy. This low-burden questionnaire can be used alone to identify FP and LP in studies that may be otherwise limited by study design, finances, and/or participant burden. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The true natural cycle frozen embryo transfer - impact of patient and follicular phase characteristics on serum progesterone levels one day prior to warmed blastocyst transfer.

BACKGROUND: In a true-natural cycle (t-NC), optimal progesterone (P4) output from the corpus luteum is crucial for establishing and maintaining an intrauterine pregnancy. In a previous retrospective study, low P4 levels (< 10 ng/mL) measured one day before warmed blastocyst transfer in t-NC were associated with significantly lower live-birth rates. In the current study, we aim to examine the relationship between patient, follicular-phase endocrine and ultrasonographic characteristics, and serum P4 levels one day prior to warmed blastocyst transfer in t-NC. METHOD: 178 consecutive women undergoing their first t-NC frozen embryo transfer (FET) between July 2017-August 2022 were included. Following serial ultrasonographic and endocrine monitoring, ovulation was documented by follicular collapse. Luteinized unruptured follicle (LUF) was diagnosed when there was no follicular collapse despite luteinizing-hormone surge (> 17 IU/L) and increased serum P4 (> 1.5 ng/mL). FET was scheduled on follicular collapse + 5 or LH surge + 6 in LUF cycles. Primary outcome was serum P4 on FET - 1. RESULTS: Among the 178 patients, 86% (n = 153) experienced follicular collapse, while 14% (n = 25) had LUF. On FET-1, the median serum luteal P4 level was 12.9 ng/mL (IQR: 9.3-17.2), ranging from 1.8 to 34.4 ng/mL. Linear stepwise regression revealed a negative correlation between body mass index (BMI) and LUF, and a positive correlation between follicular phase peak-E2 and peak-P4 levels with P4 levels on FET-1. The ROC curve analyses to predict < 9.3 ng/mL (< 25th percentile) P4 levels on FET-1 day showed AUC of 0.70 (95%CI 0.61-0.79) for BMI (cut-off: 23.85 kg/m2), 0.71 (95%CI 0.61-0.80) for follicular phase peak-P4 levels (cut-off: 0.87 ng/mL), and 0.68 (95%CI 0.59-0.77) for follicular phase peak-E2 levels (cut-off: 290.5 pg/mL). Combining all four independent parameters yielded an AUC of 0.80 (95%CI 0.72-0.88). The adjusted-odds ratio for having < 9.3 ng/mL P4 levels on FET-1 day for patients with LUF compared to those with follicle collapse was 4.97 (95%CI 1.66-14.94). CONCLUSION: The BMI, LUF, peak-E2, and peak-P4 levels are independent predictors of low serum P4 levels on FET-1 (< 25th percentile; <9.3 ng/ml) in t-NC FET cycles. Recognition of risk factors for low serum P4 on FET-1 may permit a personalized approach for LPS in t-NC FET to maximize reproductive outcomes.

Women in their mid-follicular phase outcompete hormonal contraceptive users, an effect partially explained by relatively greater progesterone and cortisol reactivity to competition.

Early evidence suggests that hormonal contraceptive (HC) use alters psychological functioning and competitive behavior. Yet, there is limited data on endocrine models for explaining how HC use affects these outcomes. In this pre-registered and open-data study, we test if HC users and naturally cycling (NC) females in their low (mid-follicular) and high (mid-luteal) progesterone phase differ in competitive persistence and whether progesterone and cortisol reactivity mediate of this effect. HC users (N = 73) in the active hormone-exposure phase and NC participants in the mid-follicular (N = 69) or mid-luteal (N = 72) phase completed two behavioral measures of competitive persistence, holding up a weight for time followed by attempting to solve an unsolvable anagram. Participants also completed measures of handgrip strength and self-reported competitiveness as well as gave saliva samples before and after the tasks for hormone assay. Results showed that NC-follicular group had greater competitive persistence in the weight-holding task compared to both NC-luteal (d = 0.38) and HC use (d = 0.43) groups independent of physical strength and self-reported competitiveness covariates. Although anagram task performance showed similar trends for group differences, analyses for this task were inconclusive. Baseline progesterone did not mediate the effect of cycle phase group on competitive persistence. HC users showed relatively blunted cortisol and progesterone reactivity, and this effect partially mediated the difference in competitive persistence between HC users and the NC-follicular group. In sum, results suggest that HC use could downregulate competitive behavior at least partly by dampening cortisol-progesterone reactivity. These findings offer a new endocrine model for understanding HC use and cycle phase effects on motivational and energetic outcomes required for optimal performance in competitive contexts.

Menstrual cycle influences on cue-induced smoking cravings and heart rate variability.

Women experience greater difficulties in quitting smoking than men, though the hormonal factors contributing to this sex difference remain to be clarified. The current study aimed to examine menstrual cycle effects on smoking cue-induced cravings as well as examine dynamic reproductive hormone change as a potential mediator underlying any cycle effects observed. Twenty-one women who smoke underwent two laboratory sessions - one in the mid-follicular phase and the other in the late luteal phase - involving an in-vivo smoking cue task, administered before and after exposure to a psychosocial laboratory stressor. Heart rate variability (HRV) and subjective smoking cravings were assessed in response to the cue task. The degree of change in the urinary metabolites of estradiol and progesterone from 2 days before to the day of each laboratory session was measured. Results revealed that both before and following exposure to psychosocial stress, highly nicotine-dependent women exhibited smaller cue-induced increases in HRV relative to the follicular phase. In contrast, less nicotine-dependent women exhibit an increase in HRV in both menstrual cycle phases. Results furthermore suggest that menstrual cycle effects seen in highly nicotine-dependent women are driven by the decline in estradiol and progesterone occurring in the late luteal phase. Though limited by a small sample size, this study suggests that withdrawal from reproductive hormones in the late luteal phase may alter highly nicotine-dependent women's physiological response to smoking cues, which may reflect greater difficulty resisting temptation. These findings may provide some insight regarding women's greater difficulty in maintaining abstinence after quitting smoking.

Effect of stress on spatial working memory and EEG signal dynamics in the follicular and luteal phases of the menstrual cycle in young single girls.

AIM: Women undergo behavioral changes during the menstrual cycle. This study aimed to investigate the effect of estradiol (Es) on stress and effect of stress on spatial working memory (WM) and also to investigate electroencephalogram (EEG) signal's dynamics in the early and late follicular (EF and LF) and luteal (LU) phases of unmarried girls' menstrual cycle. METHODS: Stress was induced by presentation of a short (3 min) movie clip. Simultaneous with a memory test and stress induction, EEG, serum Es levels, and galvanic skin response (GSR) were assessed. RESULTS: Serum Es concentrations were decreased in LF, LU, and EF phases. The mean GSR score decreased after stress induction in all three phases, but it increased in the LF and LU phases versus the EF phase. Spatial WM diminished after stress induction in all three phases, but it increased in the LF phase versus the two phases before and after stress induction. Average power spectrum density in all frequency bands increased after stress induction in the frontal and prefrontal channels in the spatial WM test. CONCLUSION: The results showed that stress led to spatial WM dysfunction; however, Es improved spatial WM performance in the LF phase versus the other two phases.

Premature progesterone elevation during the early and mid-follicular phases in fresh in vitro fertilization (IVF) cycles is associated with lower live birth, clinical pregnancy, and implantation rates.

PURPOSE: Evaluate follicular phase progesterone elevation (≥ 1.5 ng/mL) prior to trigger during IVF stimulation and its effects on live birth rate (LBR), clinical pregnancy rate (CPR), and implantation rate (IR) in fresh IVF cycles. METHODS: This was a retrospective cohort study within an academic clinic. A total of 6961 fresh IVF and IVF/ICSI cycles from October 1, 2015 to June 30, 2021 were included and grouped by progesterone (PR) prior to trigger: PR < 1.5 ng/mL (low PR group) and PR ≥ 1.5 ng/mL (high PR group). Main outcome measures included LBR, CPR, and IR. RESULTS: Among all cycle starts, 1568 (22.5%) were in the high PR group and 5393 (77.5%) were in the low PR group. Of the cycles which proceeded to an embryo transfer, 416 (11.1%) were in the high PR group and 3341 (88.9%) were in the low PR group. The high PR group had significantly lower IR (RR 0.75; 95% CI 0.64-0.88), CPR (aRR 0.74; 95% CI 0.64-0.87), and LBR (aRR 0.71; 95% CI 0.59-0.85) compared to the low PR group. When stratified by progesterone on the day of trigger (TPR), there was a clinically notable decrease in IR (16.8% vs 23.3%), CPR (28.1% vs 36.0%), and LBR (22.8% vs 28.9%) in the high PR group compared to the low PR group even when TPR < 1.5 ng/mL. CONCLUSIONS: In fresh IVF cycles in which TPR < 1.5 ng/mL, progesterone elevation ≥ 1.5 ng/mL at any point in time prior to trigger negatively impacts IR, CPR, and LBR. This data supports testing of serum progesterone in the follicular phase prior to trigger, as these patients may benefit from a freeze-all approach.

Elevated glucocorticoids during the ovarian follicular phase predict conception in wild female chacma baboons.

Mating related behavior during ovarian cycling can be energetically demanding and constitute a significant stressor, requiring physiological responses to mediate investment in reproduction. To better understand the proximate mechanisms underlying these responses, we examine hormonal and behavioral variation across the ovarian cycle during conceptive and nonconceptive cycles in wild female chacma baboons (Papio ursinus). We quantified immunoreactive fecal estradiol, progesterone, and cortisol metabolites for 21 adult females, and calculated activity budgets and rates of received aggression from over 5000 15-min behavioral samples. We found conception to be associated with higher concentrations of both estradiol and cortisol during the follicular phase, but no difference in progesterone between conceptive and nonconceptive cycles for either the follicular or luteal phase. While females spent less time feeding during the follicular compared to the luteal phase, we found no difference in time spent feeding, moving, or copulating between conceptive and nonconceptive cycles of the same phase. Rates of received aggression also were similar across the ovarian cycle, with no difference between conceptive and nonconceptive cycles. Finally, we found positive associations between cortisol and estradiol, indicating that glucocorticoids (GCs) do not suppress hypothalamic-pituitary-gonadal (HPG) activity and reproductive function in this context. Overall, our results suggest that elevated GCs may play an adaptive role in mobilizing energy during sexually receptive periods of ovarian cycling.

Application value of Early-Follicular Phase Long-Acting Gonadotropin-Releasing Hormone Agonist Long Protocol in patients with resistant ovary syndrome.

BACKGROUND: Resistant ovarian syndrome(ROS) is a rare disease. It is difficult to diagnose and treat. Most of the literature reports on assisted pregnancy treatment for ROS patients are individual case reports. In this paper, the ovulation stimulation protocol and assisted pregnancy process of ROS infertile patients in our reproductive center were summarized and analyzed to provide information and support for the clinical treatment of ROS patients. METHODS: From January 2017 to March 2022, assisted reproductive technology treatments and clinical characteristics parameters of six patients with ROS were retrospectively reviewed. Based on controlled ovarian stimulation protocols, these stimulation cycles were separated into four groups: Early-Follicular Phase Long-Acting Gonadotropin-Releasing Hormone Agonist Long Protocol (EFLL) group (n = 6), Progestin Primed Ovarian Stimulation(PPOS) protocol group (n = 5), mild-stimulation protocol group (n = 2), and Natural cycle protocol group (n = 3). RESULTS: A total of 16 cycles of ovulation stimulation were carried out in 6 patients with ROS. A total of 19 oocytes were retrieved, as well as 13 MII oocytes, 11 two pronuclear(2PN) fertilized embryos, and 8 excellent embryos. The oocytes acquisition rate was 50% and the fertilization rate of 2PN was 57.9%, and the excellent embryo rate was 72.7%. The EFLL protocol obtained 17 oocytes, 12 MII oocytes, 11 2PN fertilized embryos, and 8 excellent embryos; the mild-stimulation protocol obtained 1 oocyte; the Natural cycle protocol obtained 1 oocyte, and oocytes were not matured after in vitro maturation (IVM); the PPOS protocol obtained no oocytes. Compared with three other protocols, The fertilization rate of 2PN (64.7%) and excellent embryo rate (72.7%) in the EFLL protocol were higher than those of other protocols(0%). Two fresh cycle embryo transfers resulted in live births, while two frozen-thawed embryo transfer cycles resulted in one live birth and one clinical pregnancy using the EFLL protocol. CONCLUSION: Although the current study is based on a small sample of participants, the findings suggest that the EFLL protocol can be employed for ovarian stimulation and may result in a live birth in ROS patients.

Delta and kappa opioid receptors in human endometrium during the menstrual cycle: Expression and localization.

OBJECTIVE: Endogenous opioid peptides were reported to be involved in the regulation of reproductive physiology and their precursors and receptors were described in many of the male and female reproductive tissues. Mu opioid receptor (MOR) was described in human endometrial cells and its expression and localization changed during the menstrual cycle. However, there is no data from the distribution of the other opioid receptors: Delta (DOR) and Kappa (KOR). The objective of the present work was to analyze the dynamics of expression and localization of DOR and KOR in human endometrium throughout the menstrual cycle. STUDY DESIGN: Human endometrial samples from different menstrual cycle phases were analyzed by immunohistochemistry. RESULTS: DOR and KOR were present in all samples analyzed and the protein expression and localization changed throughout the menstrual cycle. Both receptor expression increased during the late proliferative phase and decreased during the late secretory-one, especially in the luminal epithelium. DOR expression was generally higher than KOR expression in all cell compartments. CONCLUSIONS: The presence of DOR and KOR in human endometrium and their dynamic changes during the menstrual cycle join the results previously obtained in MOR suggesting a possible role of opioids in reproduction events related to the human endometrium.

Effect modification by developmental stage of embryos on the association between late follicular phase progesterone elevation and live birth in fresh transfers.

BACKGROUND: Late follicular phase progesterone elevation (LFPE) during ovarian stimulation is associated with reduced live birth rates (LBRs) after cleavage-stage embryo transfer. However, due to better synchronization with a stimulated endometrium, prior studies shown that LFPE had no effect on transferring embryos at blastocyst stage. The study aim to exam whether the developmental stage of embryos and serum progesterone levels on the day of human chorionic gonadotropin (hCG) administration jointly affect the odds of live birth in fresh fresh IVF/intracytoplasmic sperm injection (ICSI) cycles.  METHODS: The single-center retrospective cohort study included a total of 4,471 fresh embryo transfer cycles with 2,342 at cleavage stage versus 2,129 at blastocyst stage. Patients underwent IVF/ICSI with ovarian stimulation in gonadotropin-releasing hormone antagonist protocol. The serum progesterone level was examined both as a continuous variable and as a categorical variable by quartiles. Analysis was performed using the generalized estimating equations framework and multivariate regression models. RESULTS: LBRs were inversely associated with progesterone as a continuous variable on the day of hCG in both the cleavage-stage (crude OR 0.87, 95%CI 0.73-1.03; adjusted OR 0.80, 95% CI 0.65-0.98) and the blastocyst-stage (crude OR 0.66, 95%CI 0.56-0,78; adjusted OR 0.61, 95%CI 0.50-0.73) groups. The interaction testing was highly significant (P = 0.018) indicating an effect modifying role of stage of embryos transferred on the association of pregesterone values with the LBRs in fresh cycles. A similar pattern for a greater reduction in ORs for live birth in cycles with blastocysts transfer was also observed when progesterone was analyzed by interquartile ranges. The findings remained unchanged in subgroup analysis stratified by types of ovarian response. CONCLUSIONS: In fresh cycles, detrimental effect of late follicular phase progesterone elevation on live birth was more prominent in blastocyst-stage group compared with that in clevaged-stage group.

Understanding the female athlete: molecular mechanisms underpinning menstrual phase differences in exercise metabolism.

Research should equitably reflect responses in men and women. Including women in research, however, necessitates an understanding of the ovarian hormones and menstrual phase variations in both cellular and systems physiology. This review outlines recent advances in the multiplicity of ovarian hormone molecular signaling that elucidates the mechanisms for menstrual phase variability in exercise metabolism. The prominent endogenous estrogen, 17-ß-estradiol (E2), molecular structure is bioactive in stabilizing plasma membranes and quenching free radicals and both E2 and progesterone (P4) promote the expression of antioxidant enzymes attenuating exercise-induced muscle damage in the late follicular (LF) and mid-luteal (ML) phases. E2 and P4 bind nuclear hormone receptors and membrane-bound receptors to regulate gene expression directly or indirectly, which importantly includes cross-regulated expression of their own receptors. Activation of membrane-bound receptors also regulates kinases causing rapid cellular responses. Careful analysis of these signaling pathways explains menstrual phase-specific differences. Namely, E2-promoted plasma glucose uptake during exercise, via GLUT4 expression and kinases, is nullified by E2-dominant suppression of gluconeogenic gene expression in LF and ML phases, ameliorated by carbohydrate ingestion. E2 signaling maximizes fat oxidation capacity in LF and ML phases, pending low-moderate exercise intensities, restricted nutrient availability, and high E2:P4 ratios. P4 increases protein catabolism during the luteal phase by indeterminate mechanisms. Satellite cell function supported by E2-targeted gene expression is countered by P4, explaining greater muscle strengthening from follicular phase-based training. In totality, this integrative review provides causative effects, supported by meta-analyses for quantitative actuality, highlighting research opportunities and evidence-based relevance for female athletes.

Heightened sensitivity to the disinhibiting effect of alcohol in women during the late follicular phase of the menstrual cycle.

Compared with men, women are disproportionately affected by alcohol, including greater risks of physiological damage, behavioral impairment, and relapse. One likely mechanism underlying the sexual disparity in this vulnerability is the fluctuation of ovarian hormones, particularly estradiol (E2), across phases of the menstrual cycle. Several preclinical and clinical studies have shown that higher E2 levels positively correlate with drinking, suggesting E2 may play a significant role in modulating drinking. Inhibitory control also modulates drinking; when it is reduced or compromised by alcohol, the drinker's ability to stop the self-administration of alcohol could be impaired, leading to a binge episode. The present study aimed to examine the degree to which menstrual cycle phase can influence the disinhibiting effect of alcohol. Twenty-four healthy young adult women participated in a within-subjects placebo-controlled study of the acute disinhibiting effect of 0.60 g/kg alcohol over the course of two test sessions. A cued go/no-go task measured the disinhibiting effects of alcohol and placebo beverages during the early follicular phase of the cycle when E2 levels were low and the late follicular phase (i.e., ovulation) when E2 was elevated. Results showed that the disinhibiting effect of alcohol increased nearly twofold during the late follicular phase when E2 was elevated. These findings highlight the role of alcohol-induced disinhibition as a potential behavioral mechanism by which fluctuations in ovarian hormones as a function of the menstrual cycle contribute to increased risk for excessive alcohol use in women. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Effects of Oral Delta-9-Tetrahydrocannabinol in Women During the Follicular Phase of the Menstrual Cycle.

Background: This study examined effects of oral delta-9-tetrahydrocannabinol (THC) in women at two phases of the menstrual cycle differing in circulating levels of estrogen (E). Pre-clinical findings indicate that E increases sensitivity to THC and other cannabinoids, raising the possibility that higher E may be a risk factor for adverse responses to THC in women. Methods: We examined subjective and behavioral responses to THC (7.5 and 15 mg oral) and placebo in women during the early follicular (EF) phase when E levels are low and the late follicular (LF) phase when E levels are higher. Outcome measures included self-report ratings of drug effects, cardiovascular measures, and biochemical verification of ovarian hormone levels. We hypothesized that women would exhibit greater responses to THC during the LF phase compared to the EF phase. Results: On most measures, responses to THC were similar during the two phases. However, on two self-report measures, "Wanting More" drug and anxiety, the effects occurred slightly earlier after drug administration in women who were tested during the EF phase. Conclusions: We conclude that the differences in levels of E occurring during the early and LF phase of the menstrual cycle do not strongly influence responses to THC. It remains to be determined whether responses are similarly stable across other cycle phases, or in women receiving exogenous hormone treatments.

Comparison of blastocyst euploidy rates following luteal versus follicular phase stimulation in a GnRH antagonist protocol: a prospective study with repeated ovarian stimulation cycles.

STUDY QUESTION: Is there any difference in the mean number of euploid embryos following luteal phase start (LS) and follicular phase start (FS) of ovarian stimulation? SUMMARY ANSWER: The mean number of euploid blastocysts is equivalent independent of whether the inseminated oocytes are derived from FS or LS. WHAT IS KNOWN ALREADY: Starting ovarian stimulation at any time of the cycle ('random-start') is commonly used for emergency fertility preservation in cancer patients. A few retrospective studies have been published evaluating LS in women undergoing ovarian stimulation in the context of IVF, but there is a lack of robust data on the comparative efficacy of LS versus FS.Although 'random start' is commonly used in cancer survivors, few retrospective and uncontrolled studies have been published evaluating luteal phase stimulation in women undergoing ovarian stimulation in the context of IVF. Owing to this evident lack of robust data on the efficacy of LS, guidelines typically recommend the LS approach only for medical reasons and not in the context of IVF. STUDY DESIGN, SIZE, DURATION: This is a prospective, equivalence study, with repeated stimulation cycles, conducted between May 2018 and December 2021. Overall, 44 oocyte donors underwent two identical consecutive ovarian stimulation cycles, one initiated in the FS and the other in the LS. The primary outcome of the study was to evaluate whether FS and LS in the same patient would result in equivalent numbers of euploid embryos following fertilization of oocytes with the same sperm sample. PARTICIPANTS/MATERIALS, SETTING, METHODS: Overall, 44 oocyte donors underwent two consecutive ovarian stimulation protocols with 150 µg corifollitropin alpha followed by 200 IU recombinant FSH (rFSH) in a fixed GnRH antagonist protocol. The only difference between the two cycles was the day of initiation of ovarian stimulation, which was in the early follicular phase (FS) in one cycle, and in the luteal phase (LS) in the other. Forty-four oocyte recipients participated in the study receiving a mean of six metaphase II (MII) oocytes from each stimulation cycle (FS and LS). All MIIs were inseminated with the corresponding recipient's partner sperm (which had been previously frozen) or donor sperm, in order to safeguard the use of the same sample for either the FS or LS. Following fertilization and blastocyst culture, all generated embryos underwent genetic analysis for aneuploidy screening (preimplantation genetic testing for aneuploidy). MAIN RESULTS AND THE ROLE OF CHANCE: FS resulted in a significantly shorter duration of ovarian stimulation (difference between means (DBM) -1.05 (95% CI -1.89; -0.20)) and a lower total additional dose of daily rFSH was needed (DBM -196.02 (95% CI -319.92; -72.12)) compared with LS. The donors' hormonal profile on the day of trigger was comparable between the two stimulation cycles, as well as the mean number of oocytes (23.70 ± 10.79 versus 23.70 ± 8.81) (DBM 0.00 (95% CI -3.03; 3.03)) and MII oocytes (20.27 ± 9.60 versus 20.73 ± 8.65) (DBM -0.45 (95% CI -2.82; 1.91)) between FS and LS cycles, respectively. Following fertilization, the overall blastocyst formation rate was 60.70% with a euploid rate of 57.1%. Comparisons between the two stimulation cycles did not reveal any significance differences in terms of fertilization rates (71.9% versus 71.4%), blastocyst formation rates (59.4% versus 62%) and embryo euploidy rates (56.9 versus 57.3%) for the comparison of FS versus LS, respectively. The mean number of euploid blastocysts was equivalent between the FS (1.59 ± 1.30) and the LS (1.61 ± 1.17), (DBM -0.02 (90%CI -0.48; 0.44)). LIMITATIONS, REASONS FOR CAUTION: The study was performed in young, potentially fertile oocyte donors who are patients with high blastocyst euploidy rates. Although results may be extrapolated to young infertile women with good ovarian reserve, caution is needed prior to generalizing the results to infertile women of older age. WIDER IMPLICATIONS OF THE FINDINGS: The current study provides evidence that initiation of ovarian stimulation in the luteal phase in young potentially fertile women may result in a comparable number of oocytes and comparable blastocyst euploidy rates compared with follicular phase stimulation. This may imply that in case of a freeze-all protocol in young patients with good ovarian reserve, clinicians may safely consider initiation of ovarian stimulation during the luteal phase. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by an unrestricted grant from MSD/Organon. N.P.P. has received Research grants and honoraria for lectures from: Merck Serono, MSD/Organon, Ferring Pharmaceuticals, Besins Intenational, Roche Diagnostics, IBSA, Theramex, Gedeon Richter. F.M., E.C., M.R. and S.G. declared no conflict of interests. TRIAL REGISTRATION NUMBER: The study was registered at Clinical Trials Gov (NCT03555942).

The effect of polymorphisms in FSHR gene on late follicular phase progesterone and estradiol serum levels in predicted normoresponders.

STUDY QUESTION: Does the presence of FSHR single-nucleotide polymorphisms (SNPs) affect late follicular phase progesterone and estradiol serum levels in predicted normoresponders treated with rFSH? SUMMARY ANSWER: The presence of FSHR SNPs (rs6165, rs6166, rs1394205) had no clinically significant impact on late follicular phase serum progesterone and estradiol levels in predicted normoresponders undergoing a GnRH antagonist protocol with a fixed daily dose of 150 IU rFSH. WHAT IS KNOWN ALREADY: Previous studies have shown that late follicular phase serum progesterone and estradiol levels are significantly correlated with the magnitude of ovarian response. Several authors have proposed that individual variability in the response to ovarian stimulation (OS) could be explained by variants in FSHR. However, so far, the literature is scarce on the influence of this genetic variability on late follicular phase steroidogenic response. Our aim is to determine whether genetic variants in the FSHR gene could modulate late follicular phase serum progesterone and estradiol levels. STUDY DESIGN, SIZE, DURATION: In this multicenter multinational prospective study conducted from November 2016 to June 2019, 366 patients from Vietnam, Belgium and Spain (166 from Europe and 200 from Asia) underwent OS followed by oocyte retrieval in a GnRH antagonist protocol with a fixed daily dose of 150 IU rFSH. All patients were genotyped for 3 FSHR SNPs (rs6165, rs6166, rs1394205) and had a serum progesterone and estradiol measurement on the day of trigger. PARTICIPANTS/MATERIALS, SETTING, METHODS: Included patients were predicted normal responder women <38 years old undergoing their first or second OS cycle. The prevalence of late follicular phase progesterone elevation (PE), as well as mean serum progesterone and estradiol levels on the day of trigger were compared between the different FSHR SNPs genotypes. PE was defined as >1.50 ng/ml. MAIN RESULTS AND THE ROLE OF CHANCE: The overall prevalence of PE was 15.8% (n = 58). No significant difference was found in the prevalence of PE in Caucasian and Asian patients (17.5% versus 14.5%). Estradiol levels on the day of trigger and the number of retrieved oocytes were significantly higher in patients with PE (4779 ± 6236.2 versus 3261 ± 3974.5 pg/ml, P = 0.003, and 16.1 ± 8.02 versus 13.5 ± 6.66, P = 0.011, respectively). Genetic model analysis, adjusted for patient age, body mass index, number of retrieved oocytes and continent (Asia versus Europe), revealed a similar prevalence of PE in co-dominant, dominant and recessive models for variants FSHR rs6166, rs6165 and rs1394205. No statistically significant difference was observed in the mean late follicular phase progesterone serum levels according to the genotypes of FSHR rs6166 (P = 0.941), rs6165 (P = 0.637) and rs1394205 (P = 0.114) in the bivariate analysis. Also, no difference was found in the genetic model analysis regarding mean late follicular phase progesterone levels across the different genotypes. Genetic model analysis has also revealed no statistically significant difference regarding mean estradiol levels on the day of trigger in co-dominant, dominant and recessive models for variants FSHR rs6166, rs6165 and rs1394205. Haplotype analysis revealed a statistically significant lower estradiol level on the day of trigger for rs6166/rs6165 haplotypes GA, AA and GG when compared to AG (respectively, estimated mean difference (EMD) -441.46 pg/ml (95% CI -442.47; -440.45), EMD -673.46 pg/ml (95% CI -674.26; -672.67) and EMD -582.10 pg/ml (95% CI -584.92; -579.28)). No statistically significant differences were found regarding the prevalence of PE nor late follicular phase progesterone levels according to rs6166/rs6165 haplotypes. LIMITATIONS, REASONS FOR CAUTION: Results refer to a population of predicted normal responders treated with a normal/low fixed dose of 150 IU rFSH throughout the whole OS. Consequently, caution is needed before generalizing our results to all patient categories. WIDER IMPLICATIONS OF THE FINDINGS: Based on our results, FSHR SNPs rs6165, rs6166 and rs1394205 do not have any clinically significant impact neither on late follicular phase serum progesterone nor on estradiol levels in predicted normal responders. These findings add to the controversy in the literature regarding the impact of individual genetic susceptibility in response to OS in this population. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by an unrestricted grant by Merck Sharp & Dohme (MSD, IISP56222). N.P.P. reports grants and/or personal fees from MSD, Merck Serono, Roche Diagnostics, Ferring International, Besins Healthcare, Gedeon Richter, Organon, Theramex and Institut Biochimique SA (IBSA). C.A. reports conference fees from Merck Serono, Medea and Event Planet. A.R.N., C.B., C.S., P.Q.M.M., H.T., C.B., N.L.V., M.T.H. and S.G. report no conflict of interests related to the content of this article. TRIAL REGISTRATION NUMBER: NCT03007043.

Identification of miR-34-3p as a candidate follicular phase serum marker for endometriosis: a pilot study.

OBJECTIVE: To identify early follicular phase microribonucleic acids (miRNAs) that are altered in serum of women with endometriosis. DESIGN: Case-control study. SETTING: Large university-affiliated in vitro fertilization center. PATIENT(S): Women with (n = 21) and without (n = 24) endometriosis. INTERVENTION(S): Serum samples were obtained from laparoscopy-confirmed patients with endometriosis. MAIN OUTCOME MEASURE(S): The differential expression of serum miRNAs relative to controls was measured using the NanoString nCounter technology and validated by quantitative real-time polymerase chain reaction in an independent cohort of 27 patients with endometriosis and controls (n = 24). Microribonucleic acid target signaling pathways and genes were analyzed bioinformatically. A chemically modified stable miR-34-3p oligonucleotide was used to examine the effect on proliferation of VK2E6/E7 endometrial cells in vitro. RESULT(S): Eighteen miRNAs were significantly up-regulated, and 1 miRNA (hsa-miR-34c-3p) was significantly down-regulated in the follicular phase of patients with endometriosis. The analysis of target signaling pathways using TargetScan predicted regulation of the mitogen-activated protein kinase, phosphoinositide 3-kinase/protein kinase B, Hippo, adenosine monophosphate-activated protein kinase, transforming growth factor beta, and endometrial cancer pathways, which have been implicated in the pathogenesis of endometriosis, by these miRNAs. The analysis of sequence complementarity identified prostaglandin E2 receptor 4, interleukin 6 signal transducer, and polo-like kinase 4 genes as possible direct targets of hsa-miR-34-3p. DSDI-1, a chemically modified stable miR-34-3p oligonucleotide, reduced cell proliferation in VK2E6/E7 endometrial cells in vitro. CONCLUSION(S): The follicular phase miRNA levels are altered in serum of women with endometriosis and may be useful as reproducible detection biomarkers for early diagnosis of endometriosis. hsa-miR-34-3p is significantly down-regulated in endometriosis, targets endometriosis genes, and reduces endometrial cell proliferation in vitro. These results support hsa-miR-34-3p as a potential therapeutic target in endometriosis.