Poor Responders Research Articles

Melatonin levels in the follicular fluids and its correlation with ICSI Outcomes

Background: Melatonin is a hormone mainly synthesized and secreted from the pineal gland. The daily rhythm of circulatory melatonin is released in very low concentrations during the day and high levels at night. Melatonin has many functions beside regulation of circadian rhythm including immune system and autonomic cardiovascular regulation but the main melatonin function is antioxidant action and detoxification of free radicals. Patients and method: This cross sectional study was conducted during the period starting from November 2018 to May 2019. Eighty infertile female aged range 18–46 years were enrolled in the present study, the patients were undergoing controlled ovarian induction for IVF /ICSI treatment. All patents were divided into 3 groups according to age, FSH, E2, AMH and ovarian respond to controlled ovarian stimulation (COS) protocols. The follicular fluid melatonin measured at oocyte retrieval day using enzyme linked immunosorbent assay (ELISA). Results: There was significant difference in follicular fluid melatonin level between the three studied groups (p=0.031). There was also a positive significant correlation between follicular fluid melatonin with MII oocytes (r=0.343; p= 0.024), grade I embryo (r=0.375; p= 0.003) and AMH (r = 0.279; p= 0.027), on the other hand there was a negative significant correlation between follicular fluid melatonin and serum FSH (r = - 0.331; p= 0.016). There was also no significant difference of follicular fluid melatonin levels between pregnant and non-pregnant females (p=0.083). Conclusion: Melatonin levels in follicular fluid improve the oocytes and embryo qualities but have no effect in positive pregnancy rate.

FSHB and FSHR genes variants in combination with hormones levels predict low and high ovarian response to controlled ovarian stimulation: a logistic regressive model

BackgroundPredicting the number of follicles obtained after controlled ovarian stimulation (COS) is challenging, especially considering individual variability. Since FSH is a fundamental hormone that controls growing follicle activity, genetic variants are predicted to affect ovarian response to stimulation.The aim of the studyThe purpose of this study was to analyze whether FSHB rs10835638 and FSHR rs6166 genetic variants in combination with clinical parameters might be considered as potential precise predictors of ovarian response during COS.Materials and methodsThe present study included 144 women from infertile couples who underwent assisted reproductive technologies. Women with reduced FSH and/or AMH serum levels were excluded from the study. Genotyping was carried out applying restriction fragment length polymorphism analysis.ResultsGenotypes frequencies for FSHB rs10835638 and FSHR rs6166 were GG (73%), GT (24%), TT (3%) and AA (42%), AG (39%), GG (19%), respectively. FSHR rs6166 GG genotype was shown as associated with higher early follicular phase serum FSH, LH and progesterone levels, compared to AA and AG genotypes. Logistic regressive models that simultaneously use the patient’s genetic and clinical characteristics to calculate the probability of low or high ovarian response have been developed.ConclusionThe present study suggests that rs10835638 and rs6166 genetic variants affect hypothalamic-pituitary–gonadal hormones serum levels, and together may provide an improved model for predicting an ovarian response during COS.

Impact of progesterone concentration on hCG trigger day on clinical outcomes with cleavage-stage embryo transfer in in vitro fertilization cycles with an antagonist protocol

Objective: To investigate the impact of the progesterone concentration on human chorionic gonadotropin (hCG) trigger day in fresh cycles versus thawed transfer cycles (the freeze-all strategy) with an antagonist protocol, and to compare the differences in clinical outcomes. Methods: This retrospective cohort study included a total of 2 165 cycles conducted at Henan Provincial People's Hospital with cleavage-stage embryo (at least one top-quality) transfer between January 2017 and December 2023, with serum progesterone levels on hCG trigger day all≤6.34 nmol/L (i.e. 2 ng/ml). Multivariate logsitic regression analysis and curve fitting were performed based on different serum progesterone levels on hCG trigger day [≤3.17 nmol/L (i.e. 1 ng/ml) or 1-2 ng/ml]. Results: Multivariate regression analysis, by using cycle type (either fresh or frozen-thawed cycle) as the exposure variable, showed that the clinical pregnancy rate (≤1 ng/ml: OR=0.93, 95%CI: 0.75-1.14; 1-2 ng/ml: OR=1.05, 95%CI: 0.58-1.87) and live birth rate (≤1 ng/ml: OR=0.90, 95%CI: 0.71-1.13; 1-2 ng/ml: OR=1.53, 95%CI: 0.79-3.00) had no statistically significant differences in group of progesterone concentration ≤1 ng/ml or in group of 1-2 ng/ml. Using serum progesterone levels on hCG trigger day as a continuous variable for curve fitting analysis, the clinical pregnancy rate in fresh or thawed cycles showed no significant changes with increasing progesterone levels. Conclusions: In the antagonist protocol with cleavage-stage embryo transfer (at least one top-quality), when the serum progesterone level on hCG day is ≤2 ng/ml, there are no significant differences in clinical outcomes between thawed cycles and fresh cycles, including clinical pregnancy rate and live birth rate. Transferred in fresh cycles or choosing the freeze-all strategy could be selected based on the actual situation of the patients.

Inter-cycle variability of anti-Müllerian hormone: implications for predicting controlled ovarian stimulation cycle outcomes

BackgroundAnti-Müllerian hormone (AMH) is a widely used marker for estimating ovarian reserve, and it may predict response to ovarian stimulation. While AMH is considered a stable, cycle-independent marker, studies have shown it can exhibit significant fluctuations based on factors like age, reproductive stage, and menstrual cycle phase. The fluctuations in AMH levels can make it challenging to predict individual responses accurately, particularly when the AMH is not measured in the COS cycle. The aim of this study was to assess the inter-cycle variability of serum AMH levels in two consecutive menstrual cycles and their correlation with response to controlled ovarian stimulation outcome in the latter.MethodsIn this single-centre retrospective cohort study, data of normal and low responder patients who underwent intracytoplasmic sperm injection following a GnRH antagonist cycle at a university hospital infertility clinic between January 2022 and December 2023 were reviewed. Serum AMH levels were measured in the early follicular phase of two consecutive menstrual cycles with Elecsys-AMH Roche® system (Roche Diagnostics, Meylan, France). Correlations between AMH levels and controlled ovarian stimulation outcomes, including total oocyte and mature oocyte (MII) counts, were assessed. The study included normal and poor responder women to maintain data integrity.ResultsA total of 79 patients were included in the final analyses. Significant cycle-to-cycle variation in serum AMH levels was observed, with a median variation of 44.3%. Normal responders exhibited a mean change of 0.60 ± 0.46 ng/ml, while poor responders had a mean change of 0.28 ± 0.28 ng/ml. Approximately 20% of patients were reclassified between normal and poor responder categories based on the second AMH measurement. The controlled ovarian stimulation cycle AMH levels showed a stronger correlation with both total oocyte count (r = 0.871, P < 0.001) and MII oocyte count (r = 0.820, P < 0.001) compared to preceding cycle AMH levels.ConclusionAMH levels can exhibit significant variations between consecutive cycles, potentially leading to misclassification of patients. Measuring AMH in the early follicular phase of the COS cycle provides a more accurate prediction of the numbers of total and MII oocytes collected. Consistent and repeated AMH measurements can help clinical decision-making.

Correlation of T Regulatory Cells, Cytotoxic T-lymphocyte-associated Antigen 4, and Transforming Growth Factor-β1 with Treatment Response in Patients with Chronic Myeloid Leukemia Receiving Dasatinib Therapy.

Tyrosine kinase inhibitors improve chronic myeloid leukemia (CML) outcomes. Dasatinib inhibits breakpoint cluster region-Abelson 1 proto-oncogene tyrosine kinase better than imatinib in CML. T-regulatory cells prevent autoimmune diseases and aberrant immune responses by reducing oncoprotein antigen reactivity. They also reduce self-antigen-induced immune responses to maintain peripheral tolerance. In this study, T-regulatory cells in peripheral blood of chronic myeloid leukemia-chronic phase patients were measured, together with serum levels of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and transforming growth factor (TGF)-β1 at diagnosis and 3 months postdasatinib therapy. The Pathology and Clinical Haematology Departments at King George's Medical University, Lucknow, India, conducted this prospective analytical study. Forty CML-chronic patients and 10 healthy controls were analyzed. Flow cytometry was used to determine T-regulatory cell percentage in peripheral blood mononuclear cells of newly diagnosed CML patients before and after 3 months of dasatinib treatment; ELISA was used to measure serum levels of CTLA-4 and TGF-β1. T-regulatory cells, CTLA-4, and TGF-β1 significantly decreased in CML-chronic phase patients after 3 months of dasatinib therapy compared to the initial diagnosis. No significant change in T-regulatory cell, CTLA-4, or TGF-β1 percentages were seen between responders and poor responders. However, responders had a lower percentage of T-regulatory cells than suboptimal responders. The study concluded that dasatinib treatment improved response in CML patients with decreased Treg cells. Dasatinib reduces Treg-mediated immunological suppression, reducing CTLA-4 and TGF-β1 levels.

Prognostic Impact of Microbiome Dysbiosis: A Prospective Study.

To determine the relationship between microbiome dysbiosis indices and biofilm immunogenicity and their prognostic implications on periodontal treatment response. Thirty periodontally healthy controls and 30 periodontitis cases (stage III) were recruited. Cases received non-surgical periodontal therapy (NSPT), and their treatment response at 6 months was evaluated using a treat-to-target endpoint (≤ 4 sites with probing depths ≥ 5 mm). Pooled subgingival biofilm samples were obtained from controls and cases. The V3-4 hypervariable region of the 16S rRNA gene was sequenced and two compositional indices (subgingival microbiome dysbiosis index, SMDI, and dysbiosis ratio, DR) were calculated. Nuclear factor kappa-B (NF-κB) activation elicited by biofilm samples in monocytic reporter cells was quantified to assess biofilm immunogenicity. SMDI, DR and biofilm immunogenicity were highly diagnostic for periodontitis (area under curves [AUC] > 0.90, p < 0.001). Among periodontitis cases, all three microbial parameters were significantly reduced after NSPT (p < 0.001). Cases achieving the treat-to-target endpoint had lower pre-treatment SMDI and biofilm immunogenicity (p < 0.05) and different microbial recolonization patterns from poor responders. Both measures predicted treatment response (AUC of 0.767 and 0.835, respectively, p < 0.05). Subgingival biofilm dysbiosis quantified using SMDI and biofilm immunogenicity was diagnostic of periodontitis and predictive of NSPT outcomes.

Progestin-primed ovarian stimulation outcomes in in-vitro fertilization (IVF) – A systematic review of the literature

Background: Progestin-primed ovarian stimulation (PPOS) stimulates ovaries to block the premature surge of luteinizing hormone (LH) by using micronized progesterone or a progestin during the follicular phase instead of the conventional gonadotropin-releasing hormone (GnRH) analogues or GnRH antagonists downregulating LH to obtain multi-follicle engagement. Current work aims to assess the influence of progestogen treatment on ovarian stimulation and the ability to control LH surge, its efficacy and suitability in retrieving oocytes, without affecting the embryo quality and its benefit among infertile women long-term outcomes on children compared to standard stimulation protocols. Materials and Methods: The literature review used the randomized control trials published in the Pubmed database from January 2015 to April 2021. To generate the citation list, the following keywords were used: ‘progestin-primed ovarian stimulation’, ‘PPOS’, ‘micronized progesterone’, ‘medroxyprogesterone’, and/or ‘dydrogesterone’. The selected articles analyzed the cohort, intervention, and scheme of the progestin-primed ovarian stimulation protocol in controlled ovarian stimulation (COS) for in-vitro fertilization (IVF)/intra cytoplasmic sperm injection (ICSI) used in Assisted Reproductive Technologies (ART). Results: Overall we concluded that PPOS for IVF/ICSI in ART results in a higher number of obtained embryos, lower incidence of OHSS, equal duration of stimulation, number of retrieved oocytes, and number of MII oocytes. It is also suggested that long-term safety in children shows no significant difference between the study and control groups. Conclusions: Despite the outcomes of progestin stimulation cycles among all cohorts, we concluded that poor ovarian responders, patients with PCOS, women of advanced age and oocyte donors benefit the most from using PPOS.

Impact of letrozole co-treatment in an antagonist protocol for IVF/ICSI: a retrospective study

ObjectiveThe present study aimed to investigate the impact of combined use of letrozole in an antagonist protocol during IVF on live birth outcomes and to assess the safety of letrozole in terms of maternal and neonatal complications.MethodsThis retrospective cohort study included women undergoing IVF/ICSI and fresh embryo transfer (ET) treatment with and without letrozole co-treatment from 2007 to 2021 at Shanghai Ninth People’s Hospital (Shanghai, China). The primary outcome was the live birth rate, while the incidences of maternal and neonatal complications were secondary outcomes. Logistic regression models were used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for the analyzed outcomes. Sensitivity analysis was performed using a propensity score-based patient-matching (PSM) model, an inverse probability weighting (IPW) model, logistic regression models with women undergoing their first IVF-ET cycle, and subgroup analysis.ResultsOf the 4780 women enrolled in the study, 3887 underwent an antagonist protocol for ovarian stimulation, while 893 received letrozole co-treatment. In this cohort, letrozole co-treatment demonstrated comparable live birth rates to the use of antagonist protocol alone (logistic regression: aOR, 0.88; 95% CI, 0.71–1.08; PSM: aOR, 0.97; 95% CI, 0.77–1.22; IPW: aOR, 0.88; 95% CI, 0.71–1.10). Notably, individuals with a body mass index (BMI) exceeding 24 and those with high ovarian response experienced higher live birth rates under the letrozole co-treatment regimen (BMI ≥ 24: aOR, 1.85; 95% CI, 1.14-3.00; high response: aOR, 1.60; 95% CI, 1.02–2.50). Letrozole co-treatment was also associated with decreased risks of gestational diabetes (aOR, 0.34; 95% CI, 0.15–0.69) and small for gestational age (SGA) fetuses (aOR, 0.42; 95% CI, 0.22–0.75) in fresh ET cycles. These finding were robust in both PSM and IPW models.ConclusionsOur findings suggested that letrozole co-treatment in antagonist protocol for IVF/ICSI was associated with a comparable live birth rate following fresh ET. Further prospective randomized studies are needed to verify our results.

Futile recanalization after endovascular treatment in acute ischemic stroke with large ischemic core

BackgroundEndovascular therapy (EVT) is the treatment of choice for acute ischemic stroke (AIS) with large vessel occlusion. However, in many patients, successful EVT recanalization does not correspond to a clinical improvement, called futile recanalization (FR). We aimed to identify stroke risk factors and patient characteristics associated with FR in AIS with large core infarct (LCI).MethodsA total of 137 patients with AIS with LCI treated by EVT at a single stroke center were retrospectively included from January 2016 to June 2023. LCI was defined by Diffusion-Weighted Imaging-Alberta Stroke Program Early Computed Tomography Score (DWI-ASPECT) < 6. Patient age, sex, modified Rankin Scale (mRS), National Institutes of Health Stroke Scale (NIHSS), time to treatment, risk factors, and radiologic findings were collected, and potential associations with FR were analyzed. FR was defined as successful reperfusion with modified Thrombolysis in Cerebral Infarction (mTICI) ≥ 2b but without functional independence at 90 days (mRS ≥ 3). A multivariate logistic regression analysis was conducted on the clinical characteristics of patients, based on the presence or absence of FR, and the factors influencing FR.ResultsOf 137 patients, 120 showed successful recanalization (mTICI ≥ 2b). All patients were divided into FR (n = 80) and no FR (n = 40) groups. Older age (odds ratio [OR] 1.052, 95% confidence interval [CI] 1.002–1.105; p = 0.041), the higher the initial NIHSS score (OR 1.181, 95% CI 1.037–1.344; p = 0.012), and prior intravenous plasminogen activator (OR 0.310, 95% CI 0.118–0.813, p = 0.017) were independent influencing factors of FR.ConclusionsThe older age, the higher the initial NIHSS, and not receiving intravenous plasminogen activator were independently associated with FR in AIS with LCI. These factors could identify poor responders to EVT recanalization.

The PPOS protocol mitigates the detrimental effects of high BMI on embryo and clinical pregnancy outcomes

BackgroundThe impact of high body mass index (BMI) on embryo and pregnancy outcomes in women using the PPOS (progestin-primed ovarian stimulation) protocol during their first frozen embryo transfer (FET) cycles is not clear. This study is to investigate the impact of BMI on oocyte, embryo, and pregnancy outcomes in patients who underwent the PPOS protocol.MethodsThis retrospective study included the first FET cycle of 22,392 patients following the PPOS protocol. The impact of BMI on oocyte and pregnancy outcomes was assessed across different BMI groups, using direct acyclic graph to determine covariates, followed by the application of multiple linear and logistic regressions to further validate this influence.ResultsThe high BMI groups exhibited a higher number of oocytes; however, no significant differences were observed in good-quality embryos, clinical pregnancy rate, and implantation rate. Nevertheless, the high BMI groups demonstrated a significantly elevated miscarriage rate (9.9% vs. 12.2% vs. 15.7% vs. 18.3%, P < 0.001), particularly in late miscarriages, resulting in lower live birth rates (LBR, 41.1% vs. 40.2% vs. 37.3% vs. 36.2%, P = 0.001). These findings were further confirmed through multiple liner and logistic regression analyses. Additionally, several maternal factors showed significant associations with adjusted odds ratios for early miscarriage. However, women with a BMI ≥ 24 who underwent hormone replacement cycle or hMG late stimulation protocol for endometrial preparation experienced an increased risk of late miscarriage.ConclusionsBy utilizing the PPOS protocol, women with a high BMI exhibit comparable outcomes in terms of embryo and clinical pregnancies. However, an elevated BMI is associated with an increased risk of miscarriage, leading to a lower LBR. Adopting appropriate endometrial preparation protocols such as natural cycles and letrozole stimulation cycles may potentially offer benefits in reducing miscarriages.

Autophagy and inflammasome activation are associated with poor response to FLT3 inhibitors in patients with FLT3-ITD acute myeloid leukemia

Beyond its clinical diversity and severity, acute myeloid leukemia (AML) is known for its complex molecular background and for rewiring biological processes to aid disease onset and maintenance. FLT3 mutations are among the most recurring molecular entities that cooperatively drive AML, and their inhibition is a critical molecularly oriented therapeutic strategy. Despite being a promising avenue, it still faces challenges such as intrinsic and acquired drug resistance, which led us to investigate whether and how autophagy and inflammasome interact and whether this interaction could be leveraged to enhance FLT3 inhibition as a therapeutic strategy. We observed a strong and positive correlation between the expression of key genes associated with autophagy and the inflammasome. Gene set enrichment analysis of the FLT3-ITD samples and their ex vivo response to five different FLT3 inhibitors revealed a common molecular signature compatible with autophagy and inflammasome activation across all poor responders. Inflammasome activation was also shown to strongly increase the likelihood of a poor ex vivo response to the FLT3 inhibitors quizartinib and sorafenib. These findings reveal a distinct molecular pattern within FLT3-ITD AML samples that underscores the necessity for further exploration into how approaching these supportive parallel yet altered pathways could improve therapeutic strategies.

The association between structural connectivity and anti-seizure medication response in patients with temporal lobe epilepsy.

This study aimed to investigate the differences in structural connectivity and glymphatic system function between patients with temporal lobe epilepsy (TLE) and hippocampal sclerosis (HS) and healthy controls. Additionally, we analyzed the association between structural connectivity, glymphatic system function, and antiseizure medication (ASM) response. We retrospectively enrolled patients with TLE and HS and healthy controls who underwent diffusion tensor imaging at our hospital. We assessed structural connectivity in patients with TLE and HS and healthy controls by calculating network measures using graph theory and evaluated glymphatic system function using the diffusion tensor image analysis along the perivascular space (DTI-ALPS) index. Patients with TLE and HS were categorized into two groups: ASM poor and good responders. We enrolled 55 patients with TLE and HS and 53 healthy controls. Of the 55 patients with TLE and HS, 39 were ASM poor responders, and 16 were ASM good responders. The assortativity coefficient in patients with TLE and HS was higher than that in healthy controls (0.004 vs. -0.007, p = 0.004), and the assortativity coefficient in ASM poor responders was lower than that in ASM good responders (-0.001 vs. -0.197, p = 0.003). The DTI-ALPS index in patients with TLE and HS was lower than that in healthy controls (1.403 vs. 1.709, p < 0.001); however, the DTI-ALPS index did not differ between ASM poor and good responders (1.411 vs. 1.385, p = 0.628). The DTI-ALPS index had a significant negative correlation with age in patients with TLE and HS (r = -0.267, p = 0.049). We confirmed increased assortativity coefficient in structural connectivity and decreased DTI-ALPS index in patients with TLE and HS compared with healthy controls. Additionally, we demonstrated an association between decreased assortativity coefficient in structural connectivity and ASM poor response in patients with TLE patients and HS. This study investigates the relationship between brain connectivity changes and glymphatic system function with antiseizure medication response in patients with temporal lobe epilepsy and hippocampal sclerosis. The research reveals that these patients show altered brain connectivity and glymphatic function compared to healthy individuals. A key finding is the strong link between a specific connectivity measure (assortativity coefficient) and antiseizure medication response, providing valuable insights that could influence epilepsy treatment and future research directions.

Is Our Limited Understanding of the Effects of Nerve Stimulation Resulting in Poor Outcomes and the Need for Better "Rescue Programming" in SNM and PTNS, and Lost Opportunities for New Sites of Stimulation? ICI-RS 2024.

Sacral neuromodulation (SNM) and percutaneous tibial nerve stimulation (PTNS) are strongly recommended by international guidelines bodies for complex lower urinary tract dysfunctions. However, treatment failure and the need for rescue programming still represent a significant need for long-term follow-up. This review aimed to describe current strategies and future directions in patients undergoing such therapies. This is a consensus report of a Think Tank discussed at the Annual Meeting of the International Consultation on Incontinence - Research Society (ICI-RS), June 6-8, 2024 (Bristol, UK): "Is our limited understanding of the effects of nerve stimulation resulting in poor outcomes and the need for better 'rescue programming' in SNM and PTNS, and lost opportunities for new sites of stimulation?" Rescue programming is important from two different perspectives: to improve patient outcomes and to enhance device longevity (for implantable devices). Standard SNM parameters have remained unchanged since its inception for the treatment of OAB, nonobstructive urinary retention, and voiding dysfunction. SNM rescue programming includes intermittent stimulation (cycling on), increased frequency and changes in pulse width (PW). The effect of PW setting on SNM outcomes remains unclear. Monopolar configurations stimulate more motor nerve fibers at lower stimulation voltage; hence, this could be an option in patients who failed bipolar stimulation in the long term. Unfortunately, there is little evidence for rescue programming for PTNS. However, the development of implantable devices for intermittent stimulation of the tibial nerve may increase long-term adherence to therapy and increase interest in alternative programming. There has been recent promising neurostimulation targeting the pudendal nerve (PNS), especially in BPS/IC. More recently, preliminary data addressed the benefits of high-frequency bilateral pudendal nerve block for DESD and adaptive PNS on both urgency and stress UI in women. The exploration of rescue programming and new stimulation sites remains underutilized, and there are opportunities that could potentially expand the therapeutic applications of nerve stimulation. By broadening the range of target sites, clinicians may be able to tailor treatments according to individual patient needs and underlying conditions, thereby improving overall outcomes. However, further studies are still needed to increase the level of evidence, potentially allowing for an individualized treatment both in patients who are candidates for electrostimulation and in those who have already received surgical implants but seek a better outcome.

Fixed versus flexible gonadotropin releasing hormone antagonist protocol in women with polycystic ovary syndrome undergoing in vitro fertilization: An RCT

Background: Despite the extensive use of the gonadotropin-releasing hormone (GnRH) antagonist protocol in treating infertile women, particularly those with polycystic ovary syndrome (PCOS), there have not been sufficient evidence to compare the flexible and fixed variants in in vitro fertilization (IVF) cycles. Objective: This study aims to assess the treatment outcomes of flexible and fixed types of GnRH-antagonist protocol for IVF in women with PCOS. Materials and Methods: In this randomized clinical trial, 150 infertile women with PCOS, who were candidates for IVF, and referred to the Yazd Research and Clinical Center for Infertility, Yazd, Iran between October 2023 and February 2024 were included. Participants were divided into 2 groups (n = 75/ each) based on the type of antagonist protocol (fixed or flexible). GnRH antagonist administration started on the 5th day of gonadotropin treatment in the fixed group. In the flexible group when there was at least one follicle 12–14 mm, GnRH antagonist was started. Finally, the number of metaphase II oocyte, the quality of embryos, the duration of the stimulation cycle, the dose of gonadotropin, the number of GnRH-antagonist, and the rate of ovarian hyperstimulation syndrome were evaluated. Results: No statistically significant difference was observed in terms of cycle length and the total dose of gonadotropin between groups. Nevertheless, a notable distinction was observed in the total number of oocytes (17.84 vs. 15.5, p = 0.023) and mature oocytes (13.64 vs. 11.83, p = 0.019) in the flexible group compared to the fixed group. Conclusion: In conclusion, the IVF outcomes are more favorable in women with PCOS undergoing the flexible GnRH-antagonist protocol compared to the fixed protocol. Key words: Gonadotropin-releasing hormone, Polycystic ovary syndrome, Fertilization in vitro, Oocytes.

Effect of progesterone concentration on hCG trigger day on clinical outcomes after high-quality single blastocyst transfer in GnRH antagonist cycles.

To investigate whether progesterone levels on the human chorionic gonadotropin (hCG) trigger day are associated with clinical outcomes in fresh cycles and the first frozen-thawed cycles (the freeze-all strategy) following the transfer of a high-quality single blastocyst. This single-center retrospective analysis was conducted on patients undergoing in vitro fertilization with the gonadotropin-releasing hormone (GnRH) antagonist protocol from January 2017 to December 2023. The study included the first and second oocyte retrieval cycles with progesterone levels ≤2 ng/ml on hCG trigger day. Clinical pregnancy rates and early miscarriage rates were compared among groups using curve fitting, threshold effect analysis, and multivariable regression. When progesterone levels were between 1 and 2 ng/ml, the pregnancy rate in fresh cycles was only 51% of that in cycles with progesterone levels ≤1 ng/ml (95% CI: 0.33, 0.79, p = 0.0028). And the pregnancy rate decreased by 25% (95% CI: 0.51, 1.09) for frozen cycles, although there was no statistically significant (p = 0.1273). When cycle types were used as a binary variable in multivariate regression analysis, it was found that the clinical pregnancy rate in frozen cycles was 1.84 times higher than in fresh cycles (OR = 1.84, 95% CI: 1.38-2.47). For progesterone levels between 1 and 2 ng/ml, the clinical pregnancy rate in frozen cycles was 2.90 times that of fresh cycles (OR = 2.90, 95% CI: 1.59, 5.29, p = 0.0015). Progesterone levels on hCG day had no impact on the clinical pregnancy rate in thaw cycles, nor did they affect miscarriage rates in fresh or thaw cycles (p > 0.05). When progesterone levels on hCG trigger day were between 1 and 2 ng/ml, the clinical pregnancy rate for frozen-thawed cycles of high-quality single blastocyst transfer using an GnRH antagonist protocol significantly surpasses that of fresh cycles, thus elective frozen embryo transfer after the freeze-all strategy is recommended.

Comparative effectiveness of sildenafil citrate and estradiol valerate as adjuvants during clomiphene citrate-assisted ovarian stimulation cycles in patients with unexplained infertility: a double-blind randomized controlled trial

ObjectiveThis study aimed to assess the effect of sildenafil citrate and estradiol valerate as adjuvant therapy during ovarian stimulation cycles with clomiphene citrate in patients with unexplained infertility in Kisangani.MethodA double-blind, randomized controlled trial was conducted for two years at two specialized health facilities in Kisangani (University Clinics of Kisangani and “Clinique des Anges Kisangani”). The population included 148 patients, 74 of whom were on clomiphene citrate + sildenafil citrate (CCSC) regimens and 74 of whom were on clomiphene citrate + estradiol valerate (CCEV) regimens for three months. The primary indicator was the conception rate, with secondary outcomes encompassing endometrial thickness, appearance and vascularity, the number of mature follicles and ovulation rate.ResultsThe two groups were comparable in terms of sociodemographic and clinical characteristics. The mean duration of attempting to conceive was 4.39 years versus 4.36 years (P = 0.839), while the mean AFC was 11.51 versus 11.46 (P = 0.831), in the CCSC group versus CCEV group respectively. Secondary infertility was the most frequent diagnosis in each of the two groups. The biochemical pregnancy rate was comparable between the two groups (P = 0.385), while the clinical pregnancy rate was significantly higher in the CCSC group versus CCEV group (P = 0.04). Both perifollicular flow and the ovulation rate were significantly higher in the CCSC group versus the CCEV group (P = 0.006 and P = 0.002 respectively). However, endometrial vascularity/thickness, and the number of Graafian follicles were not significantly different between the two groups.ConclusionAs an adjuvant, sildenafil increases the rate of clinical pregnancy more than does estradiol in patients with unexplained infertility undergoing ovarian stimulation with clomiphene citrate.Study registrationPACTR 202,310,849,449,401 (Pan African Clinical Trials Registry).

The Effect of the Gonadotropin Dose Increment During Controlled Ovarian Hyperstimulation on Live Birth Rates of POSEIDON Group 3-4 Patients

This retrospective study seeks to explore whether modifying the gonadotropin dose in cases of poor ovarian response during controlled ovarian hyperstimulation contributes to improved live birth rates in Poseidon Group 3-4 patients. The study took place at a tertiary level university. The electronic database spanning 2012-2021 was scrutinized to identify patients with diminished ovarian reserve (DOR) who underwent intra-cytoplasmic sperm injection – embryo transfer (ICSI-ET). Diminished ovarian reserve was determined using the POSEIDON criteria. Patients were categorized into two groups based on whether dose adjustment was implemented during the initial ultrasound assessment in controlled ovarian hyperstimulation (COH). There were 188 patients in the dose adjustment (DA) group and 310 patients in the fixed-dose (FD) group. The demographic parameters were similar between the groups. The started gonadotropin dose was similar in both groups (300 IU). The median dose adjustment on the first control was +75 IU in the DA group. The follicle output rates, follicle to oocyte indexes, and the embryology parameters were comparable between the groups. The positive pregnancy rate was 19.7% (36/188) in the DA group vs. 19.1% (61/310) in the FD Group (p=0.4). The primary outcome of the study; live birth rates were 12% in the DA group vs. 9% in the FD group, and the results were statistically similar (p=0.3). Our research revealed that adjusting the gonadotropin dose in cases of inadequate ovarian response during COH results in comparable live birth rates to those observed in the fixed-dose group. For patients exhibiting an inadequate response, dose adjustment may be deemed necessary.

Association of specific PM2.5 chemical constituents and ozone exposure with pregnancy outcomes in women undergoing assisted reproductive technology treatment in central China

The associations of air pollutants exposure with assisted reproductive technology (ART) pregnancy outcomes are mixed, and the effects of specific components of fine particulate matter (PM2.5) and ozone (O3) are not well understood. We conducted a retrospective longitudinal study to explore the association of PM2.5 constituents and O3 exposure with three ART outcomes among women undergoing ART treatment. The exposure window was segmented into five periods corresponding to the cycle of ovarian stimulation and oocyte retrieval procedure. Generalized linear mixed model (GLMM) was applied to explore the relationships between PM2.5 constituents, O3, Normalized Vegetation Index (NDVI) exposure and three ART outcomes. The combined effect of PM2.5 constituents was evaluated by the quantile g (qg)-computation. We also explored the modifying effect of different covariate. Elevated exposure level of PM2.5 (OR = 0.915, 95% CI: 0.859, 0.974) and its constituents (BC: 0.905, 95% CI: 0.840, 0.975; OM: 0.910, 95% CI: 0.848, 0.976; NO3−: 0.909, 95% CI: 0.850, 0.972, SO42−: 0.905, 95% CI: 0.846, 0.968, and NH4+: 0.902, 95% CI: 0.842, 0.966) exposure throughout the year before oocyte retrieval (period 1) was correlated with a reduced odds ratio (OR) of live birth with statistical significance. Similarly, for each interquartile range (IQR) increase in O3 exposure during periods 2 (85 days prior to oocyte retrieval), 3 (30 days prior to oocyte retrieval), 4 (oocyte retrieval to embryo transfer) and 5 (embryo transfer to hCG test) was significantly related to a decreased OR of live birth. Especially, participants who underwent fresh embryo transfer cycles and received two cleavage-stage embryo transfer, and were younger than 30 years old, showed a higher susceptibility to particulate matter. Findings from this study suggest that PM2.5 constituents and O3 exposure may have adverse effects on the ART outcomes, highlighting the importance of identifying critical exposure periods for various air pollutants and the need for meticulous management of particulate matter.

Impact of GnRH antagonist pretreatment on oocyte yield after ovarian stimulation: A retrospective analysis.

The study investigates whether a 3-day pretreatment course with a GnRH antagonist in the early follicular phase has an impact on the number of retrieved COCs in a GnRH antagonist stimulation protocol. This is a retrospective single center crossover study involving women who did not conceive after one GnRH antagonist stimulation cycle ("standard cycle") and proceeded with another GnRH antagonist stimulation cycle preceded by early administration of GnRH antagonist for 3 days ("pretreatment cycle") with fresh embryo transfer or frozen embryo transfer. 430 patients undergoing 860 cycles were included. The mean female age was 34.4 ± 4.8 years. Indications for fertility treatment included unexplained infertility (34.3%), male-factor infertility (33.3%), age (16.9%), PCOS (8.2%), tubal (4.7) and endometriosis (2.6%). All cycles were divided into two groups: group 1 (standard, 430 cycles) and group 2 (pretreatment, 430 cycles). The mean duration of stimulation was similar in both groups (10.3 vs 10.3 days, p = 0.28). The starting dose of gonadotropin (234.9 vs 196.8 IU, p<0.001), total amount of gonadotropin used (2419 vs 2020 IU, p<0.001), the total number of retrieved COCs (10 vs 7.8 p<0.001) and the number of mature oocytes (8 vs 5.8 p<0.001) were significantly higher in group 2 than in group 1. The Generalized estimating equation (GEE) regression analysis showed that the pretreatment strategy had a significant positive effect on the number of COCs (coefficient 2.4, p <0.001 after adjusting for known confounders (age, indication, stimulation dose, type, and duration of stimulation). In conclusion, A 3-day course of GnRH antagonist pretreatment increases the number of COCs obtained after ovarian stimulation.

High androgen level during controlled ovarian stimulation cycle impairs endometrial receptivity in PCOS patients

PCOS is one of the most common endocrine disorders among women of reproductive age. While the mechanism involved is not yet fully characterized. Our study aims to examine the pregnancy outcomes of embryo transfers in women with PCOS after pretreatment, and to explore the possible effect of high androgen levels on endometrial receptivity. Retrospective cohort study was conducted to analyze pregnancy outcomes among 2714 infertile women with tubal factor and 452 PCOS women. Endometrium samples were collected from 6 controls and 6 PCOS patients to detect the expression of endometrial receptivity marks. The implantation rate, clinical and ongoing pregnancy rates and live birth rate in women with PCOS followed fresh embryo transfers were obviously decreased even after the pretreatment. Similar pregnancy outcomes were found in frozen-thawed embryo transfer cycles between women with or without PCOS. Strikingly, serum total testosterone (TT) levels on trigger day were significantly higher in PCOS women. Women with high TT levels presented significantly lower clinical and ongoing pregnancy rates, and the expression of insulin-like growth factor binding protein 1 (IGFBP-1), and leukemia inhibitory factor (LIF) in the endometria decreased significantly as well. High doses of testosterone significantly down-regulated the expression of IGFBP-1 and LIF in Ishikawa cells. Although endocrine abnormalities had been improved before the controlled ovarian stimulation (COS) cycle started, higher serum TT levels were detected on the trigger day of the COS cycle in PCOS patients, which may contribute to the decreased fresh embryo implantation by impairing endometrial receptivity.