Menstrual cycle phase differences in myofiber damage and macrophage infiltration following electrical stimulation-induced muscle injury.

The purpose of this study was to examine the effects of menstrual cycle phase on myofiber injury, regenerative events, and inflammation after electrical stimulation (ES)-induced myofiber damage. Twenty-eight premenopausal women (20.8 ± 2 yr) were randomized into early follicular (EF; n = 14) and late follicular (LF; n = 14) groups. After menstrual cycle tracking and phase confirmation, subjects underwent 200 electrically stimulated eccentric muscle contractions 1 wk after providing a muscle biopsy. Seven days post-ES, subjects provided a final biopsy. Primary outcomes included serum estradiol, indirect markers of muscle damage, direct indicators of myofiber necrosis and regeneration, satellite cell number, and macrophage infiltration. Women in the LF group had higher serum estradiol (122.1 ± 23.4 vs. 81.7 ± 30.8 pg/mL; P < 0.001) than in the EF group on the day of ES. Although the EF group recovered baseline maximal isometric strength by 4 days post-ES, the LF group did not. Only women in the LF group showed significant and consistent evidence of myofiber necrosis and regeneration pre- to post-ES. Despite showing more evidence of myofiber damage, women in the LF group also experienced reduced total and CD206+ macrophage infiltration relative to the EF group. Satellite cell quantity increased significantly post-ES in both groups, with no differences between groups. Collectively, the data suggest that the high-estrogen LF phase may be associated with increased susceptibility to myofiber injury while also limiting the subsequent intramuscular inflammatory response.NEW & NOTEWORTHY The menstrual cycle has widespread physiological effects across many systems, including skeletal muscle. In this study, we show that women in the late follicular phase of the menstrual cycle may be more susceptible to myofiber necrosis following electrical stimulation. We also show reduced evidence of inflammation in the late follicular phase. This is the first study to demonstrate a difference in the response of human skeletal muscle to a necrotic stimulus across a menstrual cycle.

Blunted Cortisol Response to Acute Psychosocial Stress in Women With Premenstrual Dysphoric Disorder.

BACKGROUND: Despite being considered a stress-related condition, it is not known whether the hypothalamic-pituitary-adrenal (HPA) axis is dysfunctional in response to acute psychosocial stress in premenstrual dysphoric disorder (PMDD). This is problematic because many women with PMDD report that they are not able to control their stress levels, and a blunted cortisol output has been identified in women with related psychiatric conditions, such as anxiety and depression. The present study is a part of the Premenstrual Hormonal and Affective State Evaluation (PHASE) project, and it aimed to characterize the cortisol trajectory in response to an acute psychosocial stress challenge. METHODS: Women with PMDD and healthy controls with confirmed ovulatory cycles underwent the Trier Social Stress Test (TSST) procedure in the mid-late luteal phase of the menstrual cycle, throughout which we collected serum samples of cortisol that we analyzed using ultra-performance liquid chromatography tandem mass spectrometry. RESULTS: The linear mixed model analysis indicated a significant time*diagnosis interaction (P = .008) such that women with PMDD displayed significantly lower serum cortisol levels at +40 through +90 minutes from the time of stress induction. CONCLUSION: This is the first study to show that women with PMDD have a blunted cortisol response to psychosocial stress. Combined with our earlier finding showing a greater parasympathetic nervous system withdrawal on heart oscillations in PMDD during acute stress, these and other results show that the dysregulated processing of stress in PMDD may be captured using objective study measures.

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.

Early versus late follicular phase ovarian stimulation: a randomized controlled trial.

RESEARCH QUESTION: Is late follicular phase stimulation as efficient as early follicular phase stimulation in a gonadotrophin-releasing hormone (GnRH) antagonist protocol in oocyte donors in terms of the number of oocytes. DESIGN: In this open label, phase 3, non-inferiority, randomized controlled trial using a two-arm design with a 1:1 allocation ratio, 84 oocyte donors were allocated to the early follicular start group (control group, n = 41) or the late follicular start group (study group, n = 43). In the control group, women followed a fixed GnRH antagonist protocol with recombinant FSH (r-FSH) 225 IU. In the study group, r-FSH 225 IU was initiated in the late follicular phase. The primary outcome was the number of oocytes. The secondary outcomes were the number of mature oocytes, consumption of gonadotrophins and GnRH antagonist, and cost of medication. RESULTS: The number of oocytes did not differ between the control group and the study group (intent-to-treat analysis 15.5 ± 11.0 versus 14.0 ± 10.7, P = 0.52; per-protocol analysis 18.2 ± 9.7 versus 18.8 ± 7.8, P = 0.62). In addition, the number of mature oocytes did not differ between the groups (14.1 ± 8.1 versus 12.7 ± 8.5, P = 0.48). The duration of stimulation was shorter in the control group (10.0 ± 1.4 versus 10.9 ± 1.5 days, P = 0.01). The total amount of r-FSH used was lower in the control group (2240.7 ± 313.9 IU versus 2453.9 ± 330.1 IU, P = 0.008). A GnRH antagonist was used for approximately 6 days in the control group, while a GnRH antagonist was only prescribed for one woman in the study group (6.0 ± 1.4 days versus 0.13±0.7 days, P < 0.001). There was a significant difference in the cost of medication per cycle between the groups (1147.9 ± 182.8€ in control group versus 979.9 ± 129.0€ in study group, P < 0.001). CONCLUSIONS: Late follicular phase stimulation is as efficient as early follicular phase stimulation in terms of the number of oocytes.

Performance of the MiniMed 780G system on mitigating menstrual cycle-dependent glycaemic variability.

AIM: To map the glycaemic variabilities and insulin requirements across different phases of the menstrual cycle and assess the efficacy and performance of the MiniMed 780G system on mitigating glycaemic variabilities during phases of the menstrual cycle. MATERIALS AND METHODS: A pilot study recruiting 15 adolescent and young adult females with type 1 diabetes was conducted. Only females with regular spontaneous menstruation were enrolled in the current study. Phases of each menstrual cycle were determined as either follicular phase or luteal phase. The study analysed continuous glucose monitoring metrics during two study periods: the open loop period (OLP) and the advanced hybrid closed-loop (AHCL) period; each period lasted 3 consecutive months. RESULTS: During the OLP, the mean time in range (TIR) significantly decreased during the luteal phase compared with the follicular phase (65.13% ± 3.07% vs. 70.73% ± 2.05%) (P < .01). The mean time above range significantly increased from 21.07% ± 2.58% during the follicular phase to 24.87% ± 2.97% during the luteal phase (P < .01). After initiating the AHCL period, TIR was comparable during both phases of the menstrual cycle (P = .72), without increasing the time spent below 70 mg/dL (P > .05). Regarding insulin delivery during the AHCL period, the percentage of Auto basal and Auto correction delivered by the algorithm increased by 13.55% and 30.6%, respectively (P < .01), during the luteal phase. CONCLUSIONS: The fully automated adaptive algorithm of the MiniMed 780G system mitigated menstrual cycle-dependent glycaemic variability, successfully attaining the recommended glycaemic outcomes with a TIR greater than 70% throughout the entire menstrual cycle.

How do phases of the menstrual cycle affect sleep? A polysomnographic study of the EPISONO database.

PURPOSE: Our study aimed to evaluate the impact of the menstrual cycle stages, especially menses, on sleep, inflammatory mediators, fatigue, anxiety, depression, and quality of life. METHODS: We used data from the EPISONO study cohort, selecting 96 women who had undergone one-night polysomnography. The women were distributed in three groups according to the time point of the menstrual cycle on the polysomnography night: menses, mid/late follicular phase, and luteal phase. The volunteers completed questionnaires related to sleep quality, daytime sleepiness, insomnia, fatigue, anxiety, depression, and quality of life. Blood samples were collected to analyze interleukin 6, tumor necrosis factor-alpha, and C-reactive protein. RESULTS: Sleep efficiency was statistically higher in women in the mid/late follicular group (89.9% ± 9.6) compared to menstrual (83.0% ± 10.8) and luteal (83.7% ± 12.7) groups. The mid/late follicular group presented a statistically significant reduction in sleep onset latency (7.1 ± 7.1 min) compared to the menstrual (22.3 ± 32.4 min) and luteal groups (15.9 ± 14.7 min). No statistical differences among the three groups were observed in other polysomnographic parameters, inflammatory mediators, daytime sleepiness, insomnia, fatigue, anxiety, depression, and quality of life. CONCLUSIONS: Our findings demonstrate that the mid/late follicular phase might be beneficial for women's sleep, although there were no statistically changes in inflammatory mediators among the groups.

Menstrual cycle status does not impact exercise-based changes in cerebral blood flow or executive function benefits.

A single bout of exercise enhances executive function (EF) and may relate to an increase in cerebral blood flow (CBF). A limitation in the current literature is that biologically female participants are underrepresented given some evidence that changes in hormone levels across the menstrual cycle impact physiological and psychological variables. Here, biologically female participants completed separate single bouts of moderate intensity exercise (80% of estimated lactate threshold) during the follicular (FOL) and luteal (LUT) phases of their menstrual cycle. In addition, biologically male participants completed a same duration/intensity exercise session. Middle cerebral artery velocity (MCAv) was used to estimate CBF and pre- and postexercise EF was assessed via the antisaccade task. Results showed that resting MCAv was larger in the LUT than FOL phase; however, the exercise-mediated increase in MCAv was equivalent between menstrual cycle phases, and between female and male participants. Antisaccade reaction times reliably decreased from pre- to postexercise and frequentist and non-frequentist statistics demonstrated that the magnitude of the decrease was equivalent across FOL and LUT phases, and between female and male participants. Thus, results evince that menstrual cycle status should not serve as a basis limiting biologically female participants' inclusion in research examining exercise and EF.

[Comparative Study of the Embryo Development and Clinical Outcomes of 3 Ovarian Stimulation Protocols in Different Age Groups]. / 不同年龄段人群三种促排卵方案胚胎发育及临床结局比较.

Objective: The main purpose of this study is to compare the embryo development and clinical outcomes of women in different age groups undergoing in vitro fertilization (IVF) processes using gonadotrophin-releasing hormone (GnRH) antagonist protocol, GnRH agonist long protocol, and early follicular phase protocol. We aim to provide reliable reference for future clinical treatments. Methods: We conducted a detailed analysis of patients who underwent treatment between January 2021 and February 2023. 1) In the overall patient population, we comprehensively compared the basic characteristics, the embryo development, and the clinical outcomes of patients treated with three different ovarian stimulation protocols, including the GnRH antagonist protocol group (n=4173), the agonist long protocol group (n=2410), and the early follicular phase long protocol group (n=341). 2) We divided the overall population into three age groups, one group for patients under 30 years old (n=2576), one for patients aged 30-35 (n=3249), and one for patients older than 35 years old (n=1099). Then, we compared the three stimulation protocols based on the group division. We separately compared the embryo development and clinical outcomes of patients using the three stimulation protocols in the under 30 years old, the 30-35 years old, and the over 35 years old age groups. With this analysis, we aimed to explore the response of different age groups to different stimulation protocols and their impact on the success rate of IVF. Results: 1) In the overall population, we found that the average number of oocytes retrieved in the GnRH agonist long protocol group was significantly higher than that in the GnRH antagonist protocol group ([13.85±7.162] vs. [13.36±7.862], P=0.0224), as well as the early follicular phase long protocol group ([13.85±7.162] vs. [11.86±6.802], P<0.0001). Patients in the GnRH antagonist protocol group not only had a significantly lower starting dose of gonadotrophin (Gn) compared to the other two groups (P<0.05) but also had a significantly lower number of days of Gn use (P<0.05). The blastocyst formation rate in the GnRH antagonist protocol group was the highest among the three groups, significantly higher compared to the GnRH agonist long protocol group (64.91% vs. 62.35%, P<0.0001) and the early follicular phase long protocol group (64.91% vs. 61.18%, P=0.0001). However, there were no significant differences in the clinical pregnancy rates or the live birth rates among the three groups treated with different ovarian stimulation protocols (P>0.05). 2) In the <30 age group, the blastocyst formation rate in the GnRH antagonist protocol group was the highest among the three groups, significantly higher compared to the GnRH agonist long protocol group (66.12% vs. 63.33%, P<0.0001) and the early follicular phase long protocol group (66.12% vs. 62.13%, P=0.0094). In the 30-35 age group, the blastocyst formation rate in the GnRH antagonist protocol group was the highest among the three groups, significantly higher compared to the GnRH agonist long protocol group (64.88% vs. 62.93%, P=0.000 9) and the early follicular phase long protocol group (64.88% vs. 60.39%, P=0.0011). In the >35 age group, the blastocyst formation rate in the GnRH antagonist protocol group was significantly higher than that in the GnRH agonist long protocol group (59.83% vs. 56.51%, P=0.0093), while there was no significant difference compared to that of the early follicular phase long protocol group (P>0.05). In the three age groups, we found that there were no significant differences in clinical pregnancy rate, live birth rate, and neonatal outcome indicators (fetal weight and Apgar score) among the three stimulation protocols (antagonist protocol, GnRH agonist long protocol, and early follicular phase long protocol) (P>0.05). The findings showed no significant differences between clinical and neonatal outcomes in patients of all ages, regardless of the ovarian stimulation protocol, suggesting that the three ovarian stimulation protocols have similar therapeutic effects in patients of different ages. The results of this study have important implications for the selection of an appropriate ovarian stimulation protocol and the prediction of treatment outcomes. Conclusion: In the younger than 30 and 30-35 age groups, the GnRH antagonist protocol showed a more significant advantage over the GnRH agonist long protocol and the early follicular phase long protocol. This suggests that for younger and middle-aged patients, the antagonist protocol may lead to better outcomes during ovarian stimulation. In the older than 35 age group, while the antagonist protocol still outperformed the GnRH agonist long protocol, there was no significant difference compared to the early follicular phase long protocol. This may imply that with increasing age, the early follicular phase long protocol may have effects similar to the antagonist protocol to some extent. The advantages of the antagonist protocol lie in its ability to reduce stimulation duration and the dosage of GnRH, while enhancing patient compliance with treatment. This means that patients may find it easier to accept and adhere to this treatment protocol, thereby improving treatment success rates. Particularly for older patients, the use of the antagonist protocol may significantly increase the blastocyst formation rate, which is crucial for improving the success rates. Although there were no significant differences in the clinical outcomes of patients treated with the three protocols in each age group, further research is still needed to validate these findings. Future multicenter studies and increased sample sizes may help comprehensively assess the efficacy of different stimulation protocols. Additionally, prospective studies are needed to further validate these findings and determine the optimal treatment strategies.

Effects of cognitive emotion regulation strategies on mood and cortisol in daily life in women with premenstrual dysphoric disorder.

BACKGROUND: The psychological risk factors of premenstrual dysphoric disorder (PMDD) are not fully understood, but initial evidence points to a potential role of unfavorable cognitive emotion regulation (ER-) strategies. Given the symptom cyclicity of PMDD, ambulatory assessment is ideally suited to capture psychological and physiological processes across the menstrual cycle. Our study examines habitual ER-strategies in women with PMDD and their predictive value for the course of mood and basal cortisol across the cycle in affected women. METHODS: Women with and without PMDD (n = 61 each) were compared regarding habitual mindfulness, reappraisal, and repetitive negative thinking (RNT). Momentary affect and cortisol output were assessed over two consecutive days per cycle phase (menstrual, follicular, ovulatory, late luteal). RESULTS: Women with PMDD reported lower mindfulness, less use of reappraisal and stronger RNT than controls (ps < 0.035). In women with PMDD, higher mindfulness and reappraisal and lower RNT predicted decreased negative and increased positive affect across the menstrual cycle (ps < 0.027). However, women using more favorable ER-strategies displayed stronger mood cyclicity, resulting in stronger mood deterioration in the late luteal phase, thereby resembling women with more unfavorable ER-strategies toward the end of the cycle. Lower mindfulness predicted lower cortisol in the menstrual phase. CONCLUSIONS: Protective ER-strategies seem to be generally linked to better momentary mood in women with PMDD, but do not appear to protect affected women from premenstrual mood deterioration. Habitual mindfulness, in turn, seems to buffer blunted cortisol activity in women with PMDD, especially in the menstrual phase.

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.

Is it necessary to monitor the serum luteinizing hormone (LH) concentration on the human chorionic gonadotropin (HCG) day among young women during the follicular-phase long protocol? A retrospective cohort study.

BACKGROUND: The normal physiological function of LH requires a certain concentration range, but because of pituitary desensitization, even on the day of HCG, endogenous levels of LH are low in the follicular-phase long protocol. Therefore, our study aimed to determine whether it is necessary to monitor serum LH concentrations on the day of HCG (LHHCG) and to determine whether there is an optimal LHHCG range to achieve the desired clinical outcome. METHODS: A retrospective cohort study included 4502 cycles of in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) from January 1, 2016, to June 30, 2019, in a single department. The main outcome measures included retrieved eggs, available embryos, and live birth rate. RESULTS: The LHHCG was divided into five groups: Group A (LH ≤ 0.5), Group B (0.5 IU/L < LH ≤ 1.2 IU/L), Group C (1.2 IU/L < LH ≤ 2.0 IU/L), Group D (2.0 IU/L < LH ≤ 5.0 IU/L), Group E (LH > 5 IU/L). In terms of the numbers of retrieved eggs (15.22 ± 5.66 vs. 13.54 ± 5.23 vs. 12.90 ± 5.05 vs. 12.30 ± 4.88 vs. 9.6 ± 4.09), diploid fertilized oocytes (9.85 ± 4.70 vs. 8.69 ± 4.41 vs. 8.39 ± 4.33 vs. 7.78 ± 3.96 vs. 5.92 ± 2.78), embryos (7.90 ± 4.48 vs. 6.83 ± 4.03 vs. 6.44 ± 3.88 vs. 6.22 ± 3.62 vs. 4.40 ± 2.55), and high-quality embryos (4.32 ± 3.71 vs. 3.97 ± 3.42 vs. 3.76 ± 3.19 vs. 3.71 ± 3.04 vs. 2.52 ± 2.27), an increase in the LHHCG level showed a trend of a gradual decrease. However, there was no significant difference in clinical outcomes among the groups (66.67% vs. 64.33% vs. 63.21% vs. 64.48% vs. 63.33%). By adjusting for confounding factors, with an increase in LHHCG, the number of retrieved eggs decreased (OR: -0.351 95%CI - 0.453-[- 0.249]). CONCLUSION: In the follicular-phase long protocol among young women, monitoring LHHCG is recommended in the clinical guidelines to obtain the ideal number of eggs.

Individual variation of follicular phase changes in endothelial function across two menstrual cycles.

NEW FINDINGS: What is the central question of this study? The purpose of this study was to determine intra-individual reproducibility of follicular phase changes in endothelial function (flow-mediated dilatation) over two menstrual cycles in healthy, premenopausal women. What is the main finding and its importance? Phase changes in endothelial function were not consistent at the individual level across two menstrual cycles, which challenges the utility of interpreting individual responses over one cycle. ABSTRACT: Evidence regarding the impact of menstrual phase on endothelial function is conflicting, and studies to date have examined responses only over a single cycle. It is unknown whether the observed inter-individual variability of phase changes in endothelial function reflects stable, inter-individual differences in responses to oestrogen (E2 ; a primary female sex hormone). The purpose of this study was to examine changes in endothelial function from the early follicular (EF; low-E2 ) phase to the late follicular (LF; high-E2 ) phase over two consecutive cycles. Fourteen healthy, regularly menstruating women [22 ± 3 years of age (mean ± SD)] participated in four visits (EFVisit 1 , LFVisit 2 , EFVisit 3 and LFVisit 4 ) over two cycles. Ovulation testing was used to determine the time between the LF visit and ovulation. During each visit, endothelial function [brachial artery flow-mediated dilatation (FMD)], E2 and progesterone were assessed. At the group level, there was no impact of phase or cycle on FMD (P = 0.48 and P = 0.65, respectively). The phase change in FMD in cycle 1 did not predict the phase change in cycle 2 (r = 0.03, P = 0.92). Using threshold-based classification (2 × typical error threshold), four of 14 participants (29%) exhibited directionally consistent phase changes in FMD across cycles. Oestrogen was not correlated between cycles, and this might have contributed to variability in the FMD response. The intra-individual variability in follicular fluctuation in FMD between menstrual cycles challenges the utility of interpreting individual responses to phase over a single menstrual cycle.

Luteal Phase Ovarian Stimulation versus Follicular Phase Ovarian Stimulation results in different Human Cumulus cell genes expression: A pilot study.

Background: Luteal-phase ovarian stimulation (LPOS) is an alternative in vitro fertilization (IVF) protocol. However, limited data showed the genes expression of cumulus cells (CCs) in LPOS. Therefore, this study aimed to investigate CC genes expression between LPOS and follicular-phase ovarian stimulation (FPOS) in poor ovarian responders (PORs) undergoing IVF cycles. Methods: This was a prospective non-randomized trial (ClinicalTrials.gov Identifier: NCT03238833). A total of 36 PORs who met the Bologna criteria and underwent IVF cycles were enrolled. Fifteen PORs were allocated to the LPOS group, and 21 PORs were allocated to the FPOS group. The levels of CC genes involved in inflammation (CXCL1, CXCL3, TNF, PTGES), oxidative phosphorylation (NDUFB7, NDUFA4L2, SLC25A27), apoptosis (DAPK3, BCL6B) and metabolism (PCK1, LDHC) were analyzed using real-time quantitative PCR and compared between the two groups. Results: The number of retrieved oocytes, metaphase II oocytes, fertilized oocytes, day-3 embryos and top-quality day-3 embryos, clinical pregnancy rates and live birth rates were similar between the two groups except for significantly high progesterone levels in the LPOS group. The mRNA expression levels of CXCL1 (0.51 vs 1.00, p < 0.001) and PTGES (0.30 vs 1.00, p < 0.01) were significantly lower in the LPOS group than in the FPOS group. The LPOS group had significantly lower mRNA expression of NDUFB7 (0.12 vs 1.00, p < 0.001) and NDUFA4L2 (0.33 vs 1.00, p < 0.01) than the FPOS group. DAPK3 (3.81 vs 1.00, p < 0.05) and BCL6B (2.59 vs 1.00, p < 0.01) mRNA expression was significantly higher in the LPOS group than in the FPOS group. Increased expression of PCK1 (3.13 vs. 1.00, p < 0.001) and decreased expression of LDHC (0.12 vs. 1.00, p < 0.001) were observed in the LPOS group compared to the FPOS group. Conclusions: Our data revealed different CC genes expression involving in inflammation, oxidative phosphorylation, apoptosis and metabolism between LPOS and FPOS in PORs. However, the results are non-conclusive; further large-scale randomized controlled trials are needed to validate the results.

DuoStim cycles potentially boost reproductive outcomes in poor prognosis patients.

AIM: To evaluate the overall performance and oocyte quality of follicular phase stimulation (FPS) vs. luteal phase stimulation (LPS) among patients undergoing double ovarian stimulation (DuoStim). MATERIALS AND METHODS: Observational retrospective two-center cohort study including 79 infertile women who underwent a total of 87 DuoStim cycles between January 2017 and May 2019. Besides assessing baseline characteristics in order to determine the patients' clinical profile, we analyzed the FPS and LPS regarding the total dose of gonadotropin received, the duration of stimulation, the number and maturity of oocytes, fertilization and blastocyst formation rates, and the number of blastocysts obtained. RESULTS: The patients' baseline characteristics were compatible with a diminished ovarian reserve and poor reproductive prognosis. While the luteal phase needed longer stimulation (12 days (5-19) vs. 11 (7-16), p < .001) and slightly higher gonadotropin doses (2946 ± 890 IU vs. 2550 ± 970 IU, p < .001), no significant differences were detected in the oocyte maturity, fertilization, and blastocyst formation rates. However, the number of oocytes retrieved (5 (0-16) vs. 4 (0-15), p = .006), mature oocytes (4 (0-15) vs. 3 (0-11), p = .032), and blastocysts obtained (70 vs. 53) were substantially greater after LPS. CONCLUSIONS: The DuoStim strategy in poor prognosis patients increases the number of oocytes and blastocysts available. Moreover, the number of oocytes and blastocysts obtained are higher after LPS when compared to FPS. Thus, it should be considered for selected patients in order to not only improve reproductive outcomes but also shorten the time to pregnancy.

Distinct follicular and luteal transcriptional profiles in engineered human ectocervical tissue dependent on menstrual cycle phase.

To investigate genomic pathways that may influence physiology and infectivity during the menstrual cycle, RNA sequence analysis was performed on patient-matched engineered ectocervical tissue after follicular and luteal phase (LP) hormone treatments. We developed distinct cellular, molecular, and biological profiles in ectocervical epithelium dependent on the menstrual cycle phase. Follicular phase hormones were associated with proliferation, transcription, and cell adhesion, while LP samples expressed genes involved in immune cell recruitment, inflammation, and protein modifications. Additionally, our analysis revealed mucins not previously reported in ectocervical tissue, which could play an important role in fertility and disease prevention. This study provides insight into the phenomenon of increased LP vulnerability to infection and identifies potential targets for future research.

CCL20-CCR6 axis directs sperm-oocyte interaction and its dysregulation correlates/associates with male infertility‡.

The interaction of sperm with the oocyte is pivotal during the process of mammalian fertilization. The limited numbers of sperm that reach the fallopian tube as well as anatomic restrictions indicate that human sperm-oocyte encounter is not a matter of chance but a directed process. Chemotaxis is the proposed mechanism for re-orientating sperm toward the source of a chemoattractant and hence to the oocyte. Chemokines represent a superfamily of small (8-11 kDa), cytokine-like proteins that have been shown to mediate chemotaxis and tissue-specific homing of leukocytes through binding to specific chemokine receptors such as CCRs. Here we show that CCR6 is abundantly expressed on human sperms and in human testes. Furthermore, radioligand-binding experiments showed that CCL20 bound human sperm in a specific manner. Conversely, granulosa cells of the oocyte-surrounding cumulus complex as well as human oocytes represent an abundant source of the CCR6-specific ligand CCL20. In human ovaries, CCL20 shows a cycle-dependent expression pattern with peak expression in the preovulatory phase and CCL20 protein induces chemotactic responses of human sperm. Neutralization of CCL20 in ovarian follicular fluid significantly impairs sperm migratory responses. Conversely, analyses in infertile men with inflammatory conditions of the reproductive organs demonstrate a significant increase of CCL20/CCR6 expression in testis and ejaculate. Taken together, findings of the present study suggest that CCR6-CCL20 interaction may represent an important factor in directing sperm-oocyte interaction.

Luteal phase stimulation versus follicular phase stimulation in poor ovarian responders: results of a randomized controlled trial.

BACKGROUND: In young women with poor ovarian response, luteal-phase ovarian stimulation (LPOS) is a potential method for collecting competent oocytes. The aim of this study was to assess the efficacy of LPOS compared with follicular phase ovarian stimulation (FPOS) in young women with poor ovarian response (POR). METHODS: This single-center, prospective, randomized pilot study compared LPOS and FPOS in women with POR fulfilling Bologna criteria who underwent in vitro fertilization at the Instituto Bernabeu. The primary outcome was the number of metaphase II (MII) oocytes obtained by follicular puncture. RESULTS: Sixty women were included in the study, with 27 women completing LPOS and 30 undergoing FPOS. There was no statistically significant difference in the number of MII oocytes obtained between the LPOS group and the FPOS group (2.1 ± 2.0 vs. 2.6 ± 2.2, p = 0.31). Length of stimulation was also similar in both groups (8.35 ± 2.8 vs. 8.15 ± 4.1 days, p = 0.69). Similarly, there was no significant difference in the follicle-stimulating hormone total dose, number of cumulus-oocyte complexes, survival rate, fertilization rate, or cancellation rate between groups. A significantly higher Ovarian Sensitivity Index was observed in the LPOS group versus the FPOS group (0.96 vs. 0.57, p = 0.037). CONCLUSION: LPOS was comparable with FPOS in terms of efficacy and may improve ovarian responsiveness in young women with POR. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02625532; EudraCT identifier: 2015-003856-31.

The best execution of the DuoStim strategy (double stimulation in the follicular and luteal phase of the same ovarian cycle) in patients who are poor ovarian responders.

BACKGROUND: Patients found to be poor ovarian responders (POR) are a challenging patient population for any assisted reproduction technology. Despite attempts at various controlled ovarian stimulation schemes, reproductive outcomes in this patient population have not improved. In recent years, the DuoStim protocol (both follicular and luteal phase stimulation during the same menstrual cycle) has shown a potential for use in patients with POR. METHODS: This retrospective study reviewed the medical records of 304 women who were diagnosed as POR and underwent the DuoStim protocol. We compared follicular phase stimulation (FPS) data and luteal phase stimulation (LPS) data of the same patients. We also compared the effects of different trigger drugs including urine human chorionic gonadotropin (uHCG; 10,000 IU), recombinant human chorionic gonadotropin (rHCG; 250 µg), and gonadotropin-releasing hormone agonist (GnRH-a; 0.2 mg) at the FPS and LPS stages. RESULTS: POR undergoing the DuoStim protocol resulted in a significantly higher number of oocytes retrieved, normal fertilised oocytes, cleaved embryos, cryopreserved embryos, and good quality embryos at the LPS stage than at the FPS stage. Trigger drugs at the FPS stage did not affect the FPS stage data. Regardless of the stage, rHCG and GnRH-a yielded significantly more cryopreserved embryos and good quality embryos than uHCG. CONCLUSION: The use of GnRH-a or rHCG as the trigger drug may be better than uHCG in both the FPS and LPS stages for POR undergoing the DuoStim protocol. This will increase the number of good quality embryos at the LPS stage. We found that the LPS stage results in more oocytes (and therefore more embryos) than the FPS stage.

No impact of acute hyperglycaemia on arterial stiffness in the early and late follicular phases of the menstrual cycle in young females.

NEW FINDINGS: • What is the central question of this study? This is the first study to examine the impact of acute hyperglycaemia on arterial stiffness across the early and late follicular phases of the menstrual cycle. • What is the main finding and its importance? Central and peripheral arterial stiffness were not impacted by acute hyperglycaemia. This indicates that premenopausal women might experience protection against deleterious effects of acute hyperglycaemia, regardless of menstrual cycle phase. This research furthers our understanding of the interaction between nutrient intake, hormonal fluctuation and vascular function in premenopausal women. ABSTRACT: Acute hyperglycaemia may result in transient increases in arterial stiffness. However, research in healthy premenopausal women is lacking, and the impact of menstrual phase [early follicular (EF; low oestrogen) and late follicular (LF; high oestrogen)] on vulnerability to acute hyperglycaemia-induced changes in arterial stiffness is unknown. We hypothesized that an acute hyperglycaemia-induced increase in arterial stiffness in the EF phase would be attenuated in the LF phase. Seventeen healthy, naturally menstruating women [21 ± 1 years of age (mean ± SD)] participated in three experimental visits. During two visits, in the EF and LF phase, arterial stiffness was assessed via central and peripheral (arm and leg) pulse wave velocity (PWV) before and 15, 45, 75 and 105 min after consuming an oral glucose challenge (75 g glucose in 300 ml of solution). Blood samples were taken to assess glucose, insulin, oestrogen and progesterone concentrations. During a third visit in the EF phase, participants ingested 300 ml of water as a time control for PWV. Despite significant increases in blood glucose and insulin (P < 0.001), both central and peripheral arm PWV remained unchanged across time and phase, indicating that neither acute hyperglycaemia nor menstrual phase had an impact on central or peripheral arm arterial stiffness. There was a small effect of phase for peripheral leg PWV, where PWV was lower in the LF phase (P = 0.04, Cohen's d = 0.39); however, and in contrast to recent results in young men, peripheral leg PWV was unaffected by hyperglycaemia. These results suggest that premenopausal women might experience protection from acute hyperglycaemia-induced increases in arterial stiffness.

The effect of follicular phase length on cycle outcomes and endometrial development in gonadotrophin ovarian stimulation/intrauterine insemination cycles.

RESEARCH QUESTION: Does a shorter follicular phase length (FPL) affect cycle outcomes and endometrial development among women undergoing gonadotrophin ovarian stimulation/intrauterine insemination (OS/IUI)? DESIGN: Retrospective cohort study of 4773 OS/IUI cycles among 2054 patients. FPL was analysed first continuously, then dichotomously using an arbitrary cut-off at the 15th percentile (8 days) to divide cycles into shorter and longer FPL groups. Receiver operating characteristic (ROC) curves were constructed to further analyse the impact of FPL on all outcomes. Primary outcomes included clinical pregnancy, spontaneous abortion, multiple pregnancy and non-viable (ectopic/biochemical) pregnancy rates (CPR, SABR, MPR and NVPR, respectively). Secondary outcomes included endometrial thickness. All analyses controlled for age, day 3 FSH and body mass index. RESULTS: When analysing FPL continuously, CPR increased by 6.0% (adjusted odds ratio [aOR] 1.06, 95% CI 1.03-1.09, P < 0.001) with each additional follicular phase day. Similarly, in the dichotomous analysis, cycles with a longer FPL resulted in higher CPR with 45% higher odds of clinical pregnancy (aOR 1.45, 95% CI 1.07-1.97, P = 0.018). No effect of FPL was noted on NVPR, SABR or MPR. Endometrial thickness increased by 0.09 mm (95% CI 0.06-0.12, P < 0.001) with each additional FPL day and was increased in the longer compared with the shorter FPL group (adjusted mean difference 1.08 mm, 95% CI 0.81-1.34, P < 0.001). CONCLUSIONS: The data suggest that in gonadotrophin OS/IUI cycles, FPL might impact both chance of clinical pregnancy and endometrial thickness, independent of maternal age and ovarian reserve.