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Since the inception of in vitro fertilization (IVF), monitoring of controlled ovarian stimulation (COS) has traditionally involved numerous appointments for ultrasound and laboratory testing to guide medication use and dosing, determine trigger timing, and allow for measures to reduce the risk of ovarian hyperstimulation syndrome (OHSS). Recent advances in the field of assisted reproductive technology (ART) have called into question the timing and frequency of COS monitoring appointments, as discussed in this commentary. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether serum LH levels on hCG trigger day are associated with live birth rate (LBR) after fresh embryo transfer with GnRH antagonist regimen in different populations. Methods: This study was a retrospective study. A total of 3059 fresh embryo transfers were divided into three populations: predicted normal ovarian responders (NOR) (n=2049), patients with PCOS (n=533), and predicted poor ovarian responders (POR) (n=477). Each population was stratified into three groups based on LH levels: < 25th percentile, 25-75th percentile, and > 75th percentile. The primary outcome of the study was LBR, and secondary outcomes included implantation, clinical pregnancy, and early pregnancy loss rates. Univariable and multivariable regression analyses were performed to adjust for potential confounders. Results: In NOR, compared to the reference group (>75th percentile), LBR was significantly lower in the < 25th percentile group (adjusted OR=0.662; 95%CI, 0.508-0.863) and 25-75th percentile group (adjusted OR=0.791; 95%CI, 0.633-0.988). In PCOS patients, LBR decreased significantly in the < 25th percentile group (41.4%) compared to the 25-75th percentile group (53.7%) and > 75th percentile group (56.1%). In addition, the LBR was lower in the < 25th percentile group (33.6%) compared with the 25-75th percentile group (43.4%) and the>75th percentile group (42.0%) in POR, but this was not statistically significant. Conclusions: High serum LH levels are associated with increased LBR after fresh embryo transfer in GnRH antagonist cycles, which may be attributable to higher implantation rate. LH may be a predictor of whether to schedule fresh embryo transfer in IVF cycles for better clinical outcomes. [ABSTRACT FROM AUTHOR]

A significant number of single-nucleotide polymorphisms (SNPs) of the follicle-stimulating hormone receptor (FSHr) can modify the response to exogenous FSH administration. A significant diversity in response to controlled ovarian stimulation (COS) in assisted reproductive technologies (ART) according to the type of allelic has been reported. We aimed to evaluate the relation between the Asn680Ser allelics and COS. A total of 4 electronic databases were searched for articles published up to August 2021. Prospective and retrospective comparative studies which reported outcomes after COS in patients who underwent genotyping for the detection of FSHr polymorphisms were considered eligible. A total of 11 studies including 4343 patients with Asn680Ser polymorphisms of the FSHr were included. Patients carrying the Asn/Asn allelic provide elevated E2 on the day of human chorionic gonadotropin (hCG) administration (1549 patients MD 262.39 pg/ml, p = 0.0007), but less transferrable embryos as compared with Ser/Ser genotype (283 patients MD − 0.11 embryos, p = 0.04). Ans/Ser versus Ser/Ser genotypes showed a higher E2 on the day of hCG administration (1799 patients, MD 207.86 pg/ml, p = 0.02). Pregnancy rates were similar in all combination of genotypes. There is currently no strong evidence suggesting that the examination of one gene in relation to genotypes can be effectively used as single tool to improve COS. However, polygenic analysis of different polymorphisms by analyzing the genetic profile of each individual could be useful. Further research is warranted to develop an algorithm that will enable simultaneous analysis of many genes, which combined with hormonal profile could promote treatment individualization. [ABSTRACT FROM AUTHOR]

Purpose: To explore another choice for a controlled ovarian stimulation (COS) protocol that does not increase severe ovarian hyperstimulation syndrome (OHSS) risk among polycystic ovarian syndrome (PCOS) patients with specific clinical features. Methods: A retrospective study was performed. Two hundred and fifty-nine participants were divided into two groups, group 1 (fixed GnRH antagonist protocol, n = 295) and group 2 (follicular-phase GnRH agonist protocol, n = 69) according to COS protocols. The basic characteristics and laboratory indicators between these two groups were compared. The severe OHSS rate and clinical pregnancy rate were selected as indicators to evaluate the risks and benefits of the two COS protocols. Subgroup analyses for the severe OHSS rate and clinical pregnancy rate were performed based on baseline luteinizing hormone/follicle-stimulating hormone (bLH/FSH) and anti-Mullerian hormone (AMH) levels. Results: The severe OHSS rate was statistically higher in group 2 than in group 1 (11.6% vs. 3.7%, p = 0.008), but the biochemical pregnancy rate and clinical pregnancy rate showed no statistical difference between the groups (71.9% vs. 60.3% and 62.5% vs. 54.3%). In the higher bLH/FSH subgroup (≥1.33) and the higher serum AMH level subgroup (>3.4 ng/ml), severe OHSS incidence was statistically higher in group 2 compared to group 1, but this incidence was lower in the bLH/FSH subgroup (<1.33) and the subgroup with lower serum AMH levels (≤3.4 ng/ml); a difference in severe OHSS risk was not observed. There was no statistical difference between the two groups regarding clinical pregnancy rate in any subgroup. Conclusion: The limited evidence from this study indicates that in PCOS patients with lower bLH/FSH levels (<1.33) and lower serum AMH levels (≤3.4 ng/ml), a follicular-phase GnRH agonist protocol may be another choice that does not increase the risk of severe OHSS. [ABSTRACT FROM AUTHOR]

PurposeTo explore another choice for a controlled ovarian stimulation (COS) protocol that does not increase severe ovarian hyperstimulation syndrome (OHSS) risk among polycystic ovarian syndrome (PCOS) patients with specific clinical features.MethodsA retrospective study was performed. Two hundred and fifty-nine participants were divided into two groups, group 1 (fixed GnRH antagonist protocol, n = 295) and group 2 (follicular-phase GnRH agonist protocol, n = 69) according to COS protocols. The basic characteristics and laboratory indicators between these two groups were compared. The severe OHSS rate and clinical pregnancy rate were selected as indicators to evaluate the risks and benefits of the two COS protocols. Subgroup analyses for the severe OHSS rate and clinical pregnancy rate were performed based on baseline luteinizing hormone/follicle-stimulating hormone (bLH/FSH) and anti-Mullerian hormone (AMH) levels.ResultsThe severe OHSS rate was statistically higher in group 2 than in group 1 (11.6% vs. 3.7%, p = 0.008), but the biochemical pregnancy rate and clinical pregnancy rate showed no statistical difference between the groups (71.9% vs. 60.3% and 62.5% vs. 54.3%). In the higher bLH/FSH subgroup (≥1.33) and the higher serum AMH level subgroup (>3.4 ng/ml), severe OHSS incidence was statistically higher in group 2 compared to group 1, but this incidence was lower in the bLH/FSH subgroup (

Abstract Background Individualization of the follicle-stimulating hormone (FSH) starting dose is considered standard clinical practice during controlled ovarian stimulation (COS) in patients undergoing assisted reproductive technology (ART) treatment. Furthermore, the gonadotropin dose is regularly adjusted during COS to avoid hyper- or hypo-ovarian response, but limited data are currently available to characterize such adjustments. This review describes the frequency and direction (increase/decrease) of recombinant-human FSH (r-hFSH) dose adjustment reported in clinical trials. Methods We evaluated the proportion of patients undergoing ART treatment who received ≥ 1 r-hFSH dose adjustments. The inclusion criteria included studies (published Sept 2007 to Sept 2017) in women receiving ART treatment that allowed dose adjustment within the study protocol and that reported ≥ 1 dose adjustments of r-hFSH; studies not allowing/reporting dose adjustment were excluded. Data on study design, dose adjustment and patient characteristics were extracted. Point-incidence estimates were calculated per study and overall based on pooled number of cycles with dose adjustment across studies. The Clopper–Pearson method was used to calculate 95% confidence intervals (CI) for incidence where adjustment occurred in

This study aimed to investigate the usability of blood markers for predicting controlled ovarian stimulation (COS) outcomes in patients with breast cancer undergoing fertility preservation (FP). In total, 91 patients with breast cancer who had undergone COS using a letrozole-combined gonadotropin-releasing hormone (GnRH) antagonist protocol before chemotherapy were enrolled retrospectively in a single tertiary hospital. FP outcomes were compared in terms of the mean platelet volume (MPV), MPV/platelet count (PC), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR). The cutoff values for obtaining 10 or more mature oocytes as favorable prognoses were obtained for each parameter, and the COS outcomes were compared based on the cutoff values. The optimal cutoff levels for MPV and MPV/PC were 10.15 [sensitivity: 90.0%; specificity: 45.1%; AUC: 0.687; 95% CI (0.563, 0.810)] and 0.41 [sensitivity: 65.0%; specificity: 67.6%; AUC: 0.682; 95% CI (0.568, 0.796)], respectively. The oocyte numbers did not significantly differ with respect to the cutoff values of NLR, PLR, and LMR (p > 0.05). However, the total number of acquired and mature oocytes were significantly lower in the group with MPV<10.15 than in that with MPV≥10.15 (8.0 ± 5.1 vs. 12.6 ± 9.1, p=0.003; 4.0 ± 3.7 vs. 7.3 ± 6.3, p=0.002, respectively). Similarly, considering the cutoff of MPV/PC as 0.41, the low-MPV/PC group showed a significantly lower total oocyte yield than the high-MPV/PC group (9.5 ± 7.1 vs. 13.1 ± 9.1, p=0.048), whereas the number of mature oocytes showed similar patterns with no statistical significance (5.3 ± 5.4 vs. 7.3 ± 6.1, p=0.092). From logistic regression analysis, age, anti-Müllerian hormone (AMH) level, MPV, and MPV/PC≥0.41 were found to be significant factors for the acquisition of 10 or more MII oocytes (p=0.049, OR: 0.850; p<0.001, OR: 1.622; p=0.018, OR: 3.184; p=0.013, OR: 9.251, respectively). MPV or MPV/PC can be a reliable marker for predicting FP outcome in patients with breast cancer. Protocols to acquire more mature oocytes, such as the dual-trigger approach, could be recommended for patients with breast cancer with MPV<10.15. Furthermore, a higher dose of gonadotropins was considered to obtain more oocytes in patients with MPV/PC<0.41. [ABSTRACT FROM AUTHOR]

Abstract Background Ovarian hyperstimulation syndrome is normally induced by ovarian stimulation drugs. Severe cases of ovarian hyperstimulation syndrome involve complications such as renal failure and thrombosis. Evidence has recently been developed for a method to prevent ovarian hyperstimulation syndrome. Most cases of ovarian hyperstimulation syndrome are of an early-onset type, which occurs shortly after injection of human chorionic gonadotropin. However, late-onset ovarian hyperstimulation syndrome, which occurs in a pregnancy cycle, also requires caution. We report our experience in treating a woman who was transported to our hospital with a severe case of ovarian hyperstimulation syndrome occurring during ovarian stimulation and who was determined to have an ectopic pregnancy. Case presentation Assisted reproductive technology was planned for a 29-year-old nulligravida Japanese woman diagnosed with bilateral fallopian tube obstruction and right-sided hydrosalpinx. On day 1 of controlled ovarian stimulation, the result of her human chorionic gonadotropin urine test was negative, and her serum levels of luteinizing hormone, estradiol, and progesterone were normal. On day 11 of controlled ovarian stimulation, the levels of estradiol and progesterone had risen to 9679 pg/ml and 16 ng/ml, respectively, prompting suspension of controlled ovarian stimulation. Eleven days after controlled ovarian stimulation was suspended, the patient demonstrated ascites that did not improve despite administration of cabergoline, and she was transported to our hospital 2 days after. Late-onset ovarian hyperstimulation syndrome suggested that she was pregnant, and her serum human chorionic gonadotropin level was 27,778 IU/ml. She underwent laparoscopic bilateral salpingectomy and was diagnosed with right tubal pregnancy. Conclusion In an ectopic pregnancy, human chorionic gonadotropin sometimes increases later than in an intrauterine pregnancy. In our patient’s case, endogenous human chorionic gonadotropin following the start of controlled ovarian stimulation may have caused late-onset ovarian hyperstimulation syndrome. The key to early detection of similar cases may be to suspect pregnancy in the event of unexpectedly high progesterone levels during ovarian stimulation.

Background: The ‘freeze-all’ practice refers to the cryopreservation of all mature oocytes or viable embryos after ovarian stimulation. The development of the vitrification technique has been crucial to make this approach a reality, since it increases the post-thaw survival rates and permits comparable implantation rates with fresh embryos. Nonetheless, as implantation probabilities are comparable to fresh embryo transfer in normo-responder patients, the freeze- all strategy has demonstrated no benefits overall. Method: Narrative review in which we give an overview of this approach, discuss recent advances in the field, as well as for whom, when and how it is recommended to emply the freeze-all technique. Results: However, there is some clinical evidence that shows its feasibility. Thus, it has been demonstrated that elevation of progesterone at the end of ovarian stimulation decreases the implantation rates after the transfer of day 6 blastocysts in fresh and some uterine pathologies; freeze-all is also the preferred option for patients undergoing pre-implantation genetic testing, since there is an improvement of the results and it allows for inclusion of all blastocysts of the cohort. In high responders, the freeze-all strategy optimizes the response whilst also minimizing the risk of ovarian hyperstimulation syndrome. Conclusion: Due to the different cases that a reproductive expert might encounter, it is essential to highlight benefits and drawbacks of this practice.

This study aimed to investigate the usability of blood markers for predicting controlled ovarian stimulation (COS) outcomes in patients with breast cancer undergoing fertility preservation (FP). In total, 91 patients with breast cancer who had undergone COS using a letrozole-combined gonadotropin-releasing hormone (GnRH) antagonist protocol before chemotherapy were enrolled retrospectively in a single tertiary hospital. FP outcomes were compared in terms of the mean platelet volume (MPV), MPV/platelet count (PC), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR). The cutoff values for obtaining 10 or more mature oocytes as favorable prognoses were obtained for each parameter, and the COS outcomes were compared based on the cutoff values. The optimal cutoff levels for MPV and MPV/PC were 10.15 [sensitivity: 90.0%; specificity: 45.1%; AUC: 0.687; 95% CI (0.563, 0.810)] and 0.41 [sensitivity: 65.0%; specificity: 67.6%; AUC: 0.682; 95% CI (0.568, 0.796)], respectively. The oocyte numbers did not significantly differ with respect to the cutoff values of NLR, PLR, and LMR (p > 0.05). However, the total number of acquired and mature oocytes were significantly lower in the group with MPV

Background: Individualization of the follicle-stimulating hormone (FSH) starting dose is considered standard clinical practice during controlled ovarian stimulation (COS) in patients undergoing assisted reproductive technology (ART) treatment. Furthermore, the gonadotropin dose is regularly adjusted during COS to avoid hyper- or hypo-ovarian response, but limited data are currently available to characterize such adjustments. This review describes the frequency and direction (increase/decrease) of recombinant-human FSH (r-hFSH) dose adjustment reported in clinical trials. Methods: We evaluated the proportion of patients undergoing ART treatment who received ≥ 1 r-hFSH dose adjustments. The inclusion criteria included studies (published Sept 2007 to Sept 2017) in women receiving ART treatment that allowed dose adjustment within the study protocol and that reported ≥ 1 dose adjustments of r-hFSH; studies not allowing/reporting dose adjustment were excluded. Data on study design, dose adjustment and patient characteristics were extracted. Point-incidence estimates were calculated per study and overall based on pooled number of cycles with dose adjustment across studies. The Clopper–Pearson method was used to calculate 95% confidence intervals (CI) for incidence where adjustment occurred in < 10% of patients; otherwise, a normal approximation method was used. Results: Initially, 1409 publications were identified, of which 318 were excluded during initial screening and 1073 were excluded after full text review for not meeting the inclusion criteria. Eighteen studies (6630 cycles) reported dose adjustment: 5/18 studies (1359 cycles) reported data for an unspecified dose adjustment (direction not defined), in 10/18 studies (3952 cycles) dose increases were reported, and in 11/18 studies (5123 cycles) dose decreases were reported. The studies were performed in women with poor, normal and high response, with one study reporting in oocyte donors and one in obese women. The median day that dose adjustment was permitted was Day 6 after the start of treatment. The point estimates for incidence (95% CI) for unspecified dose adjustment, dose increases, and dose decreases were 45.3% (42.7, 48.0), 19.2% (18.0, 20.5), and 9.5% (8.7, 10.3), respectively. Conclusions: This systematic review highlights that, in studies in which dose adjustment was allowed and reported, the estimated incidence of r-hFSH dose adjustments during ovarian stimulation was up to 45%. [ABSTRACT FROM AUTHOR]

The conception rates among women with premature ovarian insufficiency (POI) remain extremely low. To achieve a successful pregnancy, most of these women have to receive donor oocytes through IVF treatment. Ovarian administration of platelet-rich plasma (PRP) has been recently applied to enhance the ovulatory function in women with poor ovarian response. However, no live birth has been reported for this application in patients with POI. In this study, we present a 37-year-old woman with POI who had secondary amenorrhea for 6 months. The clinical manifestations and evaluation of this women with a diminished ovarian function were an undetectable serum level of AMH (

Background: Clinically during ICSI, controlled ovarian stimulation (COS) is a famous way to increase the number of mature oocytes picked up. This method must be asseeed with a substantial danger of ovarian hyper stimulation syndrome (OHSS), which occurred if follicular induction is very strong. Along with multifollicular growth, COS is also resulting in increased serum concentration of estradiol (E2) that in turn may has effect on the receptivity of the endometrium. The high serum E2 concentration through COS may resulting either with an increased chance of pregnancy or an impaired reproductive score secondary to change in endometrial receptivity. Aim of the study: to assess the impact of thickness of the endometrium at the day of hCG administration on the winning of intracytoplasmic sperm injection (ICSI) cycles. Patients and method: A retrospective study in which 235 women who were undergo one time of ICSI cycle were evaluated in this retrospective study, All patients were treated with gonadotrophin agonist either short or long protocol. The patients were according to endometrial thickness they were categorized into three groups I (<7mm), II (7-14mm), and group III (>14mm). Results: the rate of clinical pregnancy was increased ingroup II (7-14mm) than other two groups depending on endometrial thickness measurement. Conclusion: endometrial thickness 7-14mm is associated with higher rate of clinical pregnancy. [ABSTRACT FROM AUTHOR]

Background: Ovarian hyperstimulation syndrome is normally induced by ovarian stimulation drugs. Severe cases of ovarian hyperstimulation syndrome involve complications such as renal failure and thrombosis. Evidence has recently been developed for a method to prevent ovarian hyperstimulation syndrome. Most cases of ovarian hyperstimulation syndrome are of an early-onset type, which occurs shortly after injection of human chorionic gonadotropin. However, late-onset ovarian hyperstimulation syndrome, which occurs in a pregnancy cycle, also requires caution. We report our experience in treating a woman who was transported to our hospital with a severe case of ovarian hyperstimulation syndrome occurring during ovarian stimulation and who was determined to have an ectopic pregnancy.Case Presentation: Assisted reproductive technology was planned for a 29-year-old nulligravida Japanese woman diagnosed with bilateral fallopian tube obstruction and right-sided hydrosalpinx. On day 1 of controlled ovarian stimulation, the result of her human chorionic gonadotropin urine test was negative, and her serum levels of luteinizing hormone, estradiol, and progesterone were normal. On day 11 of controlled ovarian stimulation, the levels of estradiol and progesterone had risen to 9679 pg/ml and 16 ng/ml, respectively, prompting suspension of controlled ovarian stimulation. Eleven days after controlled ovarian stimulation was suspended, the patient demonstrated ascites that did not improve despite administration of cabergoline, and she was transported to our hospital 2 days after. Late-onset ovarian hyperstimulation syndrome suggested that she was pregnant, and her serum human chorionic gonadotropin level was 27,778 IU/ml. She underwent laparoscopic bilateral salpingectomy and was diagnosed with right tubal pregnancy.Conclusion: In an ectopic pregnancy, human chorionic gonadotropin sometimes increases later than in an intrauterine pregnancy. In our patient's case, endogenous human chorionic gonadotropin following the start of controlled ovarian stimulation may have caused late-onset ovarian hyperstimulation syndrome. The key to early detection of similar cases may be to suspect pregnancy in the event of unexpectedly high progesterone levels during ovarian stimulation. [ABSTRACT FROM AUTHOR]

Background: The 'freeze-all' practice refers to the cryopreservation of all mature oocytes or viable embryos after ovarian stimulation. The development of the vitrification technique has been crucial to make this approach a reality, since it increases the post-thaw survival rates and permits comparable implantation rates with fresh embryos. Nonetheless, as implantation probabilities are comparable to fresh embryo transfer in normo-responder patients, the freeze- all strategy has demonstrated no benefits overall. Method: Narrative review in which we give an overview of this approach, discuss recent advances in the field, as well as for whom, when and how it is recommended to emply the freeze-all technique. Results: However, there is some clinical evidence that shows its feasibility. Thus, it has been demonstrated that elevation of progesterone at the end of ovarian stimulation decreases the implantation rates after the transfer of day 6 blastocysts in fresh and some uterine pathologies; freeze-all is also the preferred option for patients undergoing pre-implantation genetic testing, since there is an improvement of the results and it allows for inclusion of all blastocysts of the cohort. In high responders, the freeze-all strategy optimizes the response whilst also minimizing the risk of ovarian hyperstimulation syndrome. Conclusion: Due to the different cases that a reproductive expert might encounter, it is essential to highlight benefits and drawbacks of this practice. [ABSTRACT FROM AUTHOR]

The conception rates among women with premature ovarian insufficiency (POI) remain extremely low. To achieve a successful pregnancy, most of these women have to receive donor oocytes through IVF treatment. Ovarian administration of platelet-rich plasma (PRP) has been recently applied to enhance the ovulatory function in women with poor ovarian response. However, no live birth has been reported for this application in patients with POI. In this study, we present a 37-year-old woman with POI who had secondary amenorrhea for 6 months. The clinical manifestations and evaluation of this women with a diminished ovarian function were an undetectable serum level of AMH (<0.02 ng/mL) and an elevated serum level of FSH (63.65 mIU/mL). A single dose of autologous PRP (extracted from 40 mL of peripheral blood) in combination with gonadotropin (150IU rFSH/75 IU rLH) was directly injected into the stroma of bilateral ovaries via vaginal sonographic guidance. Following the treatment, this patient received controlled ovarian stimulation and IVF during the successive months. Following embryo culture, three cleavage-stage embryos were transferred, leading to a successful pregnancy, which later resulted in the live birth of twins. This case report provides one example of alternative therapy that allows POI patients to use autologous oocytes in IVF treatment. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether serum LH levels on hCG trigger day are associated with live birth rate (LBR) after fresh embryo transfer with GnRH antagonist regimen in different populations., Methods: This study was a retrospective study. A total of 3059 fresh embryo transfers were divided into three populations: predicted normal ovarian responders (NOR) (n=2049), patients with PCOS (n=533), and predicted poor ovarian responders (POR) (n=477). Each population was stratified into three groups based on LH levels: < 25th percentile, 25-75th percentile, and > 75th percentile. The primary outcome of the study was LBR, and secondary outcomes included implantation, clinical pregnancy, and early pregnancy loss rates. Univariable and multivariable regression analyses were performed to adjust for potential confounders., Results: In NOR, compared to the reference group (>75th percentile), LBR was significantly lower in the < 25th percentile group (adjusted OR=0.662; 95%CI, 0.508-0.863) and 25-75th percentile group (adjusted OR=0.791; 95%CI, 0.633-0.988). In PCOS patients, LBR decreased significantly in the < 25th percentile group (41.4%) compared to the 25-75th percentile group (53.7%) and > 75th percentile group (56.1%). In addition, the LBR was lower in the < 25th percentile group (33.6%) compared with the 25-75th percentile group (43.4%) and the>75th percentile group (42.0%) in POR, but this was not statistically significant., Conclusions: High serum LH levels are associated with increased LBR after fresh embryo transfer in GnRH antagonist cycles, which may be attributable to higher implantation rate. LH may be a predictor of whether to schedule fresh embryo transfer in IVF cycles for better clinical outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhou, Dong, Huang, Zhu, Wei, Zhang, Liu, Zhang and Liu.)

Controlled ovarian stimulation plays an integral role in assisted reproduction technology, but individual patients have different responses to exogenous gonadotropins. In order to determine whether microRNAs (miRNAs) have a regulatory role in ovarian response, we profiled the expression of microRNAs in isolated ovarian granulosa cells collected from ovarian hyperresponders and normal responders using microarrays and validated the expression of selected miRNAs using quantitative polymerase chain reaction (PCR). There were 81 miRNAs differentially expressed between the 2 groups, with 45 increased and 36 decreased in the high response group. Bioinformatics analysis of these altered miRNAs and their target genes revealed some significantly enriched pathways, including regulation of the cell cycle, transcription, cell proliferation, and gonadotrophin releasing hormone signaling pathway. The expression of hsa-miR-513a-5p, hsa-miR-27b-3p, hsa-miR-19b-3p, hsa-miR-3201, hsa-miR-423-5p, hsa-miR-193b-5p, and hsa-miR-202-3p was validated by real-time PCR. Hsa-miR-423-5p, predicted to target anti-Mullerian hormone, cytochrome P450, family 19, subfamily A, polypeptide 1, methylenetetrahydrofolate reductase, progesterone receptor, and follicle stimulating hormone, β-polypeptide was found to have significantly decreased expression in the hyperresponders (P = .023). Hsa-miR-193b-5p also showed a tendency to be significantly decreased in the hyperresponders (P = .093). In conclusion, our findings provide evidence for altered miRNA expression in granulosa cells of women with ovarian hyperresponse, suggesting a role of miRNAs in regulating ovarian response to gonadotropins. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the relationship between transforming growth factor (TGF)-β1 and its receptor, soluble endoglin (sENG), in the serum and follicular fluid of women with polycystic ovarian syndrome (PCOS) compared with that of non-PCOS normal ovulating women during controlled ovarian stimulation (COS). Design: Prospective case-control study. Setting: Academic-affiliated assisted reproductive technology unit. Patient(s): Fourteen PCOS and 14 matched non-PCOS control women undergoing COS. Intervention(s): Serum was collected on day 3 (baseline), day of hCG, and day of retrieval. Follicular fluid (FF) was collected on day of oocyte retrieval. ELISA was performed to determine TGF-β1 and sENG protein levels. Main Outcome Measure(s): Serum and FF levels of TGF-β1 and sENG. Result(s): Serum TGF-β1 did not change significantly during COS but was increased in PCOS compared with non-PCOS women on day 3 and days of hCG administration and oocyte retrieval. Serum sENG increased after hCG administration only in the non-PCOS control group. In addition, serum sENG was decreased in PCOS compared with non-PCOS control women on the days of hCG and retrieval. Accordingly, the bioavailability of TGF-β1 (TGF-β1/sENG ratio) was increased in women with PCOS compared with non-PCOS controls at all three time points. No differences in either factor were noted in FF between groups. Conclusion(s): The increased TGF-β1 bioavailability in PCOS is not only due to increased TGF-β1 levels but also to decreased levels of its receptor, sENG. These data suggest that increased TGF-β1 bioavailability may contribute to the pathogenesis of PCOS and its increased risk for ovarian hyperstimulation. [ABSTRACT FROM AUTHOR]

Controlled ovarian stimulation (COS) using recombinant follicle-stimulating hormone (rFSH) is the main treatment in assisted reproduction. We performed a pharmacogenetic analysis of bone morphogenetic protein 15 (BMP15) gene using single nucleotide polymorphisms (SNPs) in COS. We also investigated the role of the BMP15 gene in ovarian hyperstimulation syndrome (OHSS).We analysed different intragenic SNPs located within the BMP15 gene in 307 women treated with rFSH, evaluating its involvement in COS outcome.First, we analysed two polymorphisms, by applying different tests for genetic association, and we found a minimum P-value in patients producing ≥12 follicles in COS (high responders) in both polymorphisms of the BMP15 gene. Using bi-directional DNA sequencing, we identified two additional single nucleotide DNA variants. Second, we conducted association studies with all polymorphisms together, and noticed that none of them seemed to fully explain the association of the BMP15 gene with over-response to rFSH. However, N103S missense mutation is predicted to disrupt the secondary structure of human BMP15 protein and is weakly associated with OHSS. This coding mutation of the BMP15 gene may partially explain the results obtained during our research. Using Thesias software, we reconstructed haplotypes with the four intragenic variants and calculated their frequencies in normal and over-responders to rFSH. The haplotype TGGA was over-represented in high responders when compared with the rest of patients. Moreover, this association was higher in patients with OHSS, with a significant global haplotypic effect of the BMP15 gene.Our results suggest a direct relationship between increased follicle production during COS and BMP15 alleles in response to rFSH in humans. The use of BMP15 markers to prevent OHSS is also a possibility that requires thorough evaluation. [ABSTRACT FROM AUTHOR]

Background: Non-elective freeze-all policy has been increasingly utilized in assisted reproductive treatment, but the optimal timing of frozen-thawed embryo transfer (FET) after controlled ovarian stimulation (COS) remains to be investigated., Methods: This retrospective cohort study included 2,998 patients who underwent their first FETs after the first COS cycles using the non-elective freeze-all strategy from Jan 2013 to Dec 2016 at a tertiary-care academic medical center. Patients were divided into the "immediate" group in which FET took place within the first menstrual cycle after oocyte retrieval, and the "delayed" group where FET started after one or more menstrual cycles following COS., Results: The mean interval between oocyte retrieval and FET was 33.3±5.8 days in the immediate group (n=280; 9.3%) and 91.3±19.4 days in the delayed group (n=2,718; 90.7%). Cycles with delayed FET had a significantly lower live birth rate than those with immediate FET before [1,246/2,718 (45.8%) vs. 156/280 (55.7%); P=0.002] and after propensity score matching (PSM) [123/280 (43.9%) vs. 156/280 (55.7%); P=0.005]. When controlling for a number of confounding factors by multivariable logistic regression analysis, the risk remained significant with the adjusted odds ratio (aOR) [95% confidence interval (CI)] of 0.69 (0.53-0.90) and 0.60 (0.42-0.85) before and after matching, respectively., Conclusions: Performing FET immediately within the first menstrual cycle following COS was associated with a higher chance to achieve live birth compared with delaying FET to subsequent cycles in a non-elective freeze-all policy. However, further randomized controlled trials are still needed to confirm this conclusion., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2019 Annals of Translational Medicine. All rights reserved.)