Ovarian Stimulation Group Research Articles

Cost-Effectiveness of Clomiphene Citrate-Based Minimal Stimulation Compared with Controlled Ovarian Stimulation Protocol in Women with Diminished Ovarian Reserve

Background: In Japan, where infertility treatment is now covered by insurance, appropriate protocols for patients with diminished ovarian reserve (DOR) based on treatment outcomes and cost-effectiveness must be selected. Therefore, this study aims to provide information on the outcomes and cost-effectiveness of conventional ovarian stimulation and mild stimulation for patients with DOR in Japan. Methods: Data from 66 women who underwent first oocyte retrieval at Showa University Hospital between May 2019 and November 2023 were analyzed. Results: The clomiphene citrate (CC) group used significantly fewer gonadotropins and incurred lower costs than the conventional ovarian stimulation group while achieving comparable clinical outcomes, including cumulative live birth rates. Conclusions: CC-based minimal stimulation is a cost-effective alternative to conventional ovarian stimulation for patients with low ovarian reserve without compromising clinical efficacy. Further randomized controlled trials are required to confirm these findings and optimize protocols for this population.

P-577 A randomized trial to compare the live birth rate following the progestin-primed ovarian stimulation versus the antagonist protocol in women with anticipated high ovarian responses

Abstract Study question Is there difference in the live birth rate following the progestin-primed ovarian stimulation (PPOS) versus the antagonist protocol in women with anticipated high ovarian responses? Summary answer The live birth rates of the first frozen embryo transfer following PPOS and the antagonist protocol were comparable in women with anticipated high ovarian responses. What is known already Progestin when given orally inhibits the pituitary LH surge during ovarian stimulation when taken orally i.e. progestin-primed ovarian stimulation. Two randomized trials showed similar number of oocytes for PPOS and the antagonist protocol in oocyte donation cycles. However, there is still no randomized trial to compare the live birth rate between PPOS and the antagonist protocol. Study design, size, duration This is a randomized controlled trial of 784 infertile women conducted from June 2020 and October 2021. Participants/materials, setting, methods Infertile women aged <43 years undergoing the first IVF cycle in a tertiary fertility center and having antral follicle count >15 randomly assigned in a 1:1 ratio into two groups: PPOS group and the antagonist group. Medroxyprogesterone 10 mg daily was given from the start of ovarian stimulation until the day of ovulation trigger in the PPOS group. The primary outcome was the live birth rate of the first frozen embryo transfer. Main results and the role of chance 784 women were randomly assigned into two groups: PPOS group (n = 392) and antagonist group (n = 392). Embryo transfer was either cancelled or postponed in 62 (62/392, 15.8%) women in the PPOS group and 65 (65/392, 16.6%) in the antagonist group because of no transferable embryos or no frozen embryo transfer within 6 months following randomization. The two groups were similar in demographic characteristics and number of oocytes obtained/fertilized, the number of cleaving embryos, number of good quality embryos at day 3, number of blastocysts developed and number of embryo/blastocyst frozen. There was no statistically significant difference in the live birth rate of the first frozen embryo transfer cycle between the progestin-primed ovarian stimulation and antagonist groups based on both intention to treat [37.5.0% (147/392) versus 32.7% (128/392), RR 1.148 (95% CI = 0.949–1.390), P = 0.16] and per protocol analysis [44.5% (147/330) versus 39.1.% (128/327), RR 1.138 (95%CI = 0.950–1.364), P = 0.16]. Both groups showed comparable clinical pregnancy, ongoing pregnancy, miscarriage, multiple pregnancy, ectopic pregnancy and cumulative live birth rates. Limitations, reasons for caution Women with anticipated high ovarian responses were recruited and the results may not be extrapolated to the general population seeking IVF. This is not a blind study although the live birth rate as the primary outcome is objection. The duration of the study is 6 months since randomization. Wider implications of the findings In situations in which fresh embryo transfer is not required such as oocyte/embryo freezing for fertility preservation, oocyte donation or preimplantation genetic testing, the PPOS protocol may be preferred over the antagonist protocol. Trial registration number NCT04414761

A modified flexible GnRH antagonist protocol using antagonist early cessation and a gonadotropin step-down approach improves live birth rates in fresh cycles: a randomized controlled trial.

Can pregnancy outcomes following fresh elective single embryo transfer (eSET) in gonadotropin-releasing hormone (GnRH) antagonist protocols increase using a gonadotropin (Gn) step-down approach with cessation of GnRH antagonist on the day of hCG administration (hCG day) in patients with normal ovarian response? The modified GnRH antagonist protocol using the Gn step-down approach and cessation of GnRH antagonist on the hCG day is effective in improving live birth rates (LBRs) per fresh eSET cycle. Currently, there is no consensus on optimal GnRH antagonist regimens. Studies have shown that fresh GnRH antagonist cycles result in poorer pregnancy outcomes than the long GnRH agonist (GnRHa) protocol. Endometrial receptivity is a key factor that contributes to this phenomenon. An open label randomized controlled trial (RCT) was performed between November 2021 and August 2022. There were 546 patients allocated to either the modified GnRH antagonist or the conventional antagonist protocol at a 1:1 ratio. Both IVF and ICSI cycles were included, and the sperm samples used were either fresh or frozen from the partner, or from frozen donor ejaculates. The primary outcome was the LBRs per fresh SET cycle. Secondary outcomes included rates of implantation, clinical and ongoing pregnancy, miscarriage, and ovarian hyperstimulation syndrome (OHSS), as well as clinical outcomes of ovarian stimulation. Baseline demographic features were not significantly different between the two ovarian stimulation groups. However, in the intention-to-treat (ITT) population, the LBRs in the modified antagonist group were significantly higher than in the conventional group (38.1% [104/273] vs. 27.5% [75/273], relative risk 1.39 [95% CI, 1.09-1.77], P = 0.008). Using a per-protocol (PP) analysis which included all the patients who received an embryo transfer, the LBRs in the modified antagonist group were also significantly higher than in the conventional group (48.6% [103/212] vs. 36.8% [74/201], relative risk 1.32 [95% CI, 1.05-1.66], P = 0.016). The modified antagonist group achieved significantly higher implantation rates, and clinical and ongoing pregnancy rates than the conventional group in both the ITT and PP analyses (P < 0.05). The two groups did not show significant differences between the number of oocytes retrieved or mature oocytes, two-pronuclear zygote (2PN) rates, the number of embryos obtained, blastocyst progression and good-quality embryo rates, early miscarriage rates, or OHSS incidence rates (P > 0.05). A limitation of our study was that the subjects were not blinded to the treatment allocation in the RCT trial. Only women under 40 years of age who had a good prognosis were included in the analysis. Therefore, use of the modified antagonist protocol in older patients with a low ovarian reserve remains to be investigated. In addition, the sample size for Day 5 elective SET was small, so larger trials will be required to strengthen these findings. The modified GnRH antagonist protocol using the Gn step-down approach and cessation of GnRH antagonist on hCG day improved the LBRs per fresh eSET cycle in normal responders. This project was funded by grant 2022YFC2702503 from the National Key Research & Development Program of China and grant 2021140 from the Beijing Health Promotion Association. The authors declare no conflicts of interest. The RCT was registered in the Chinese Clinical Trial Registry; Study Number: ChiCTR2100053453. 21 November 2021. 23 November 2021.

A randomized controlled trial to compare the live birth rate of the first frozen embryo transfer following the progestin-primed ovarian stimulation protocol vs. the antagonist protocol in women with an anticipated high ovarian response

ObjectiveTo compare the live birth rate of the first frozen embryo transfer following ovarian stimulation by the progestin-primed ovarian stimulation protocol versus the antagonist protocol in women with anticipated high ovarian response undergoing IVF DesignRandomized controlled trial SettingsA tertiary assisted reproduction center PatientsInfertile women aged <43 years undergoing the first IVF cycle and having antral follicle count >15 InterventionsMedroxyprogesterone 10 mg daily was given from the start of ovarian stimulation until the day of ovulation trigger in the progestin-primed ovarian stimulation protocol. In the antagonist protocol, an antagonist 0.25mg daily was given from 6th day of ovarian stimulation until the day of ovulation trigger. Blinding was not possible for women or physicians but the biostatistician was blinded to the group assignment. Main Outcome MeasuresLive birth rate of the first frozen embryo transfer cycle Results784 women were recruited from June 2020 and October 2021 and randomly assigned in a 1:1 ratio into two groups: progestin-primed ovarian stimulation group (n=392) and antagonist group (n=392). Embryo transfer was either cancelled or postponed in 62 (62/392, 15.8%) women in the progestin-primed ovarian stimulation group and 65 (65/392, 16.6%) in the antagonist group because of no transferable embryos or no frozen embryo transfer within 6 months following randomizaion. The two groups were similar in demographic characteristics and number of oocytes obtained/fertilized, the number of cleaving embryos, number of good quality embryos at day 3, number of blastocysts developed and number of embryo/blastocyst frozen. There was no statistically significant difference in the live birth rate of the first frozen embryo transfer cycle between the progestin-primed ovarian stimulation and antagonist groups based on both intention to treat [37.5.0% (147/392) versus 32.7% (128/392), RR 1.148 (95% CI=0.949–1.390), P=0.16] and per protocol analysis [44.5% (147/330) versus 39.1.% (128/327), RR 1.138 (95%CI = 0.950–1.364), P=0.16]. Both groups showed comparable clinical pregnancy, ongoing pregnancy, miscarriage, multiple pregnancy, ectopic pregnancy and cumulative live birth rates. ConclusionThe live birth rates of the first frozen embryo transfer following the progestin-primed ovarian stimulation and the antagonist protocol were comparable in women with an anticipated high ovarian response.

Ovarian Stimulation Altered Uterine Fluid Extracellular Vesicles miRNA Affecting Implantation in Rats.

Uterine fluid (UF) extracellular vesicle (EV) miRNA may affect implantation and could be the potential biomarker of endometrial receptivity (ER). Ovarian stimulation (OS) could damage the ER but its mechanism is still unclear. Here, we evaluate the affections of OS on UF EV miRNA expression and implantation. Female rats were divided into three groups: natural cycle or injection with GnRH-a following HP-HMG or u-FSH. UF was collected on the 5th day of gestation. Affinity membrane columns were utilized to isolate EVs from UF, obtained during implantation flushing. The EV miRNAs were sequenced, and five of them were validated by qRT-PCR. HTR-8/Svneo cells were transfected with miR-223-3p mimic and inhibitor, followed by conducting colony formation, invasion, migration, and adhesion assays to assess the cellular functions. In OS groups, the implantation rate decreased (p < 0.05), and the pinopode was damaged in the OS groups. The EVs were isolated from UF, and the differential expression key miRNAs were involved in several regulation pathways, such as cancer, endocrine, and cell cycles, which were correlated with ER and implantation. Among the miRNAs, miR-223-5p greatly differed and was most consistent with the sequencing results, followed by miR-223-3p and miR-98-5P. miR-223-3p promoted HTR-8/SVneo cells grow and ability of invasion, migration, and adhesion. OS altered UF EVs miRNAs affecting implantation in rats, and miR-223-3p might be the key molecule.

Exploratory cohort study into underlying mechanism of differences in estrogen metabolism between Asian and Caucasian women during assisted reproductive technology treatment

Explore whether racial differences in prevalence of CYP1A2∗1F polymorphism underlies estrogen metabolism differences among Asians and Caucasians. Prospective cohort study. University-based fertility practice. Asian or Caucasian patients who underwent ovarian stimulation (OS) or programmed cycle frozen embryo transfer (FET) between October 2019 and April2021. None. Trigger-day serum E2 per oocyte retrieved in OS cycles, and E2 on day of lining check in FET cycles. Seventy-one participants were enrolled, 55 in OS group (29 Caucasian and 26 Asian) and 16 in FET group (10 Caucasian and 6 Asian). Peak E2 per oocyte retrieved in the OS group (n = 48) differed by race, with significantly lower levels in Caucasians compared with Asians (177.5 ± 64.2 vs. 261.1 ± 139.5 pg/mL). Prevalence of CYP1A2∗1F polymorphism did not significantly differ by race. Compared using Kruskal-Wallis test, peak E2 per oocyte retrieved did not differ by CYP1A2∗1F genotype. In multivariate linear regression model, adjusting for body mass index, caffeine intake, and self-reported race, there remained no significant correlation. In FET group, serum E2 on day of lining check was also not significantly different by CYP1A2∗1F genotype. Although a consistent difference in serum E2 between Asians and Caucasians undergoing OS was noted, the CYP1A2∗1F polymorphism is unlikely the primary driver of this difference.

P-575 Follicle-stimulating hormone receptor genotype and its influence on the results of ovarian stimulation using corifollitropin alfa

Abstract Study question Does the follicle-stimulating hormone receptor (FSHR) genotype influence the results of the ovarian stimulation treatment using corifollitropin alfa? Summary answer The use of collifolitropin alfa in SS genotype patients appears to be associated with the obtention of a lower number of oocytes and MII. What is known already Previous studies suggest that FSH receptor polymorphism in position 680 influences the response to ovarian stimulation: patients with SS genotype perform better with urinary FSH and need a higher dose of FSH to obtain similar results to the SN and NN genotypes. These differences could be explained by the longer half-life of urinary gonadotropins, which might compensate for the lower affinity of the receptor in SS genotype patients. Our aim was to elucidate whether corifollitropin alfa, a long-acting recombinant FSH, has the same impact with respect to FSH receptor genotypes as recombinant FSH used habitually. Study design, size, duration One hundred and fifty-two egg donors were included in a retrospective cohort study between September 2019 and September 2020. In 80 of them, ovarian stimulation treatment was carried out using a single dose of Elonva 150 micrograms (Group 1). In 72 of them, in addition to the 150 microgram dose of Elonva, stimulation was continued with a daily dose of Puregon 225 UI from the eighth day of controlled ovarian stimulation (Group 2). Participants/materials, setting, methods To genotype the 680 position of the FSH receptor, a real-time PCR for allelic discrimination was carried out using StepOnePlus™ Real-Time PCR System (Applied Biosystems™). Linear regression analysis was performed to study the differences between the groups doing a correction for the variables anti-müllerian hormone, age and BMI. The statistical analysis was made with Software Statistical Product and Service Solutions, version 20.0 (SPSS, Chicago, IL, EE.UU.). Main results and the role of chance Regarding the whole set of patients, the results of ovarian stimulation using corifollitropin alfa are better in egg donors with SN and NN genotypes compared to those with SS genotype. Statistically significant differences were found in the number of retrieved oocytes (15.78 versus 10.83; p = 0.007) and retrieved MII (12.34 versus 9.00; p = 0.026). There were no statistically significant differences between both groups of genotypes (SN-NN versus SS) in terms of age (24.04 versus 26.44; p = 0.514), BMI (22.22 versus 22.83; p = 0.781), anti-müllerian hormone levels (26.40 versus, 23.58; p = 0.495), antral follicle count (15.57 versus 14.97; p = 0.567) and the number of previous ovarian stimulations (2.71 versus 2.53; p = 0.812). Studying both treatment groups separately, in Group 2, we find significant differences in the number of retrieved oocytes (17.55 versus 13.06, p = 0.012) and retrieved MII (14.25 versus 11.39; p = 0.031), between SN-NN versus SS, respectively. On the other hand, in Group 1, we observe a trend towards statistical significance in the number of retrieved oocytes (13.83 versus 7.50, p = 0.089) and retrieved MII (10.24 versus 5.42; p = 0.120) comparing the same groups of genotypes. Limitations, reasons for caution The group of egg donors with the SS genotype barely represents 20% of the donors included in the study. This percentage is similar to its prevalence in the general population, so it is necessary to have a large sample size to be able to carry out studies regarding this genotype. Wider implications of the findings Despite the fact that corifollitropin alfa has a longer half-life, the results of SS patients do not match the rest of genotypes, so other factors must influence. Therefore, it would be advisable to genotype patients for 680 position of FSHR in order not to treat SS patients with this gonadotropin. Trial registration number -

Risks of Placenta Previa and Hypertensive Disorders of Pregnancy Are Associated With Endometrial Preparation Methods in Frozen-Thawed Embryo Transfers.

Background: Endometrial preparation is essential in frozen-thawed embryo transfer (FET) cycles. Recent studies suggested that different endometrial preparation methods may influence obstetrical complications. However, the association between hormone replacement therapy (HRT) and ovarian stimulation (OS) FET endometrial preparation and obstetrical complications remains unknown.Methods: This retrospective cohort study included a total of 79,662 confirmed embryo transfer cycles during the period from January 2003 to December 2019. After exclusion, the remaining cases were categorized into an ovarian stimulation FET group (OS FET group, n = 29,121) and a hormone replacement therapy FET group (HRT FET group, n = 26,776) and subjected to the analyses. The primary outcome was the rate of obstetrical complications included placenta previa, placenta abruption, hypertensive disorders of pregnancy (HDP), placenta accreta, gestational diabetes mellitus (GDM), preterm premature rupture of the membrane (pPROM). The secondary outcome was pregnancy outcomes such as live birth rate, birth weight, pre-term and post-term delivery and cesarean sections. In order to minimize the bias, 10 pregnancy-related factors were adjusted in multiple logistic regression analysis.Results: Placenta previa (0.6 vs. 1.2%, P < 0.001) and HDP (3.5 vs. 5.3%, P < 0.001) were found lower in the OS FET than HRT FET group. Cesarean section was observed lower in the OS than HRT group (76.3 vs. 84.3%, P < 0.001). After adjustment for 10 important pregnancy-related confounding factors, we found that the risk of placenta previa (aOR 0.54, 95% CI 0.39–0.73) and HDP (aOR 0.65, 95% CI 0.57–0.75) and cesarean section (aOR 0.61, 95% CI 0.57–0.66) were still significantly reduced in the OS than HRT group. Furthermore, live birth rates were higher (80.0 vs. 76.0%, P < 0.001), and the miscarriage rate was lower (17.7 vs. 21.3%, P < 0.001) for pregnancies conceived with OS FET than with HRT FET. And the average birth weight was lower in the OS group compared to HRT group (2982.3 ± 636.4 vs. 3025.0 ± 659.0, P < 0.001), as well as the small-for-gestational age (SGA) was higher (8.7 vs. 7.2%, P < 0.001) and the large-for-gestational age (LGA) was lower (7.2 vs. 8.6%, P < 0.001) in the OS group than in the HRT group.Conclusions: The risks of placenta previa and HDP were lower in patients conceiving after OS FET than in those after HRT FET. Further prospective studies are required to further clarify the mechanism underlying the association between endometrium preparation and obstetrical complications.

Ovulation Induction Changes Epigenetic Marks of Imprinting Genes in Mice Fetus Organs.

Objective Genomic imprinting is an epigenetic phenomenon that plays a critical role in normal development of embryo. Using exogenous hormones during assisted reproductive technology (ART) can change an organism hormonal profile and subsequently affect epigenetic events. Ovarian stimulation changes gene expression and epigenetic pattern of imprinted genes in the organs of mouse fetus. Materials and Methods For this experimental study, expression of three imprinted genes H19, Igf2 (Insulin-like growth factor 2) and Cdkn1c (Cyclin-dependent kinase inhibitor 1C), which have important roles in development of placenta and embryo, and the epigenetic profile of their regulatory region in some tissues of 19-days-old female fetuses, from female mice subjected to ovarian stimulation, were evaluated by quantitative reverse-transcription PCR (qRT-PCR) and Chromatin immunoprecipitation (ChIP) methods. Results H19 gene was significantly lower in heart (P<0.05), liver (P<0.05), lung (P<0.01), placenta (P<0.01) and ovary (P<0.01). It was significantly higher in kidney of ovarian stimulation group compared to control fetuses (P<0.05). Igf2 expression was significantly higher in brain (P<0.05) and kidney (P<0.05), while it was significantly lower in lung of experimental group fetuses in comparison with control fetuses (P<0.05). Cdkn1c expression was significantly higher in lung (P<0.05). It was significantly decreased in placenta of experimental group fetuses rather than the control fetuses (P<0.05). Histone modification data and DNA methylation data were in accordance to the gene expression profiles. ConclusionResults showed altered gene expressions in line with changes in epigenetic pattern of their promoters in the ovarian stimulation group, compared to normal cycle.

Duration of stimulation in patients with polycystic ovarian syndrome undergoing ICSI: Does it affect the outcome?

Back ground: Oocyte and embryo quality are affected by the duration of ovarian stimulation in differentcategories of patients undergoing ICSI specially forthose having polycystic ovarian syndrome as theyundergo ovarian stimulation usinglow dose step up antagonist protocol.Methods: Retrospective analysis of 139 patient underwent ovarian stimulatiaon using antagonist protocol and freeze all policyResults: Patients were divided into 3 groups according to the duration of ovarian stimulation (group A≤ 8 days, group B 9-10 days, group C ≥ 11 days).We found that in spite of having no statistically significant difference in the total number of retrievedoocytes, there was statistically significant differencein the median number of germinal vesicle oocytesbetween group A and group C (3 (1-13) & 1(0-5) Pvalue= 0.01). Also this difference is present betweengroup B and group C (3 (1-11) & 1(0-5) P value=0.01). For metaphase II oocytes there was a statistically significant difference in the median numberbetween group A and group B (3 (0-8) & 5 (1-14)P value= 0.001). Also this difference is present between group A and group C (3 (0-8) & 3 (3-12) Pvalue= 0.001).There was no statistically significantdifference in the total number of embryos in betweenthe 3 groups.Conclusion: We found that it seems to be safe toextend the duration of stimulation more than 8 dayswhen treating patients with polycystic ovarian syndrome undergoing IVF/ICSI, as it was associatedwith more increase in mature oocytes (MII)

Early pregnancy loss in patients with polycystic ovary syndrome after IVM versus standard ovarian stimulation for IVF/ICSI.

Is the incidence of early pregnancy loss (EPL) in patients with polycystic ovary syndrome (PCOS) higher after IVM of oocytes than after ovarian stimulation (OS) for IVF/ICSI? Women with PCOS who are pregnant after fresh embryo transfer have a higher probability of EPL following IVM, but after frozen embryo transfer (FET), no significant difference in the incidence of EPL was observed following IVM compared to OS. There is conflicting evidence in the current literature with regard to the risk of EPL after IVM of oocytes when compared with OS. Because of the limited sample size in previous studies, the use of different IVM systems and the possible bias introduced by patient characteristics and treatment type, firm conclusions cannot be drawn. This was a retrospective cohort study evaluating 800 women, with a diagnosis of infertility and PCOS as defined by Rotterdam criteria, who had a first positive pregnancy test after fresh or FET following IVM or OS between January 2010 and December 2017 in a tertiary care academic medical centre. Pregnancies after non-hCG triggered IVM following a short course of highly purified human menopausal gonadotropin were compared with those after conventional OS. The primary outcome was EPL, defined as a spontaneous pregnancy loss before 10 weeks of gestation. In total, 329 patients with a positive pregnancy test after IVM and 471 patients with a positive pregnancy test after OS were included. Women who were pregnant after IVM were younger (28.6 ± 3.4 years vs 29.3 ± 3.6 years, P = 0.005) and had higher serum anti-Mullerian hormone levels (11.5 ± 8.1 ng/ml vs 7.2 ± 4.1 ng/ml, P < 0.001) compared to those who were pregnant after OS. The distribution of PCOS phenotypes was significantly different among women in the IVM group compared to those in the OS group and women who were pregnant after OS had previously suffered EPL more often (28% vs 17.6%, P = 0.003). EPL was significantly higher after fresh embryo transfer following IVM compared to OS (57/122 (46.7%) vs 53/305 (17.4%), P < 0.001), while the results were comparable after FET (63/207 (30.4%) vs 60/166 (36.1%), respectively, P = 0.24). In the multivariate logistic regression analysis evaluating fresh embryo transfer cycles, IVM was the only independent factor (adjusted odds ratio (aOR) 4.24, 95% CI 2.44-7.37, P < 0.001)) significantly associated with increased odds of EPL. On the other hand, when the same model was applied to FET cycles, the type of treatment (IVM vs OS) was not significantly associated with EPL (aOR 0.73, 95% CI 0.43-1.25, P = 0.25). The current data are limited by the retrospective nature of the study and the potential of bias due to unmeasured confounders. The increased risk of EPL after fresh embryo transfer following IVM may point towards inadequate endometrial development in IVM cycles. Adopting a freeze-all strategy after IVM seems more appropriate. Future studies are needed to ascertain the underlying cause of this observation. The Clinical IVM research has been supported by research grants from Cook Medical and Besins Healthcare. All authors declared no conflict of interest. N/A.

Mild stimulation protocol vs conventional controlled ovarian stimulation protocol in poor ovarian response patients: a prospective randomized controlled trial

To compare the efficacy of mild ovarian stimulation protocol and conventional controlled ovarian stimulation (COS) protocol for poor ovarian response (POR) patients undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). This single-center prospective randomized controlled trial conducted from September 2013 to September 2015, including 191 patients who met the Bologna criteria of POR. Ninety-seven patients allocated to the mild ovarian stimulation group (MS group) were stimulated according to the letrozole/antagonist protocol, while 94 patients in the controlled ovarian stimulation group (COS group) were stimulated according to a high dose of gonadotropin (Gn) combined with gonadotropin-releasing hormone agonist (GnRH-a) stop protocol. The cumulative live birth rate was the primary outcome. Chinese clinical trial number ChiCTR-TRC-13003454. Comparing with the COS group, both the stimulation duration and the total gonadotropin dose were significantly shorter and lower in the MS group (P < 0.001). A higher number of retrieved oocytes (P = 0.003) and transferrable embryos (P = 0.029) were obtained in the COS group. The cumulative live birth rates (OR 1.103; 95% CI 0.53 to 2.28; P = 0.791) were comparable between the two groups. The increase of Gn dose during ovulation stimulation was associated with a higher number of transferrable embryos for POR patients, but this increase did not lead to a concomitant improvement of reproductive outcome, especially in terms of the cumulative live birth rate. Using a mild stimulation protocol was economically preferential while it was as effective as higher doses of Gn stimulation protocol in reproductive outcome for POR patients.

Progestin vs. Gonadotropin-Releasing Hormone Antagonist for the Prevention of Premature Luteinizing Hormone Surges in Poor Responders Undergoing in vitro Fertilization Treatment: A Randomized Controlled Trial.

Objective: Progestin was recently used as an alternative of gonadotropin-releasing hormone (GnRH) analog for preventing premature luteinizing hormone (LH) surge with the aid of vitrification techniques, however, limited data were available about the potential of progestin in poor responders undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment. We performed a randomized parallel controlled trial to investigate the difference of progestin and GnRH antagonist in poor responders.Methods: A total of 340 poor responders who met with Bologna criteria were randomly allocated into the progestin-primed ovarian stimulation (PPOS) group and GnRH antagonist group. Fresh embryo transfer was preferred in the GnRH antagonist group and freeze-all was performed in the PPOS group. The primary outcome was the incidence of premature LH surge, secondary outcomes were the number of retrieved oocytes, the number of viable embryos and the pregnancy outcomes.Results: The results showed that the incidence of premature LH surge in PPOS group was lower than that in antagonist group (0 vs. 5.88%, P < 0.05). In PPOS group, the average numbers of oocytes and viable embryos were comparable to those in GnRH antagonist group (3.7 ± 2.6 vs. 3.4 ± 2.4; 1.6 ± 1.7 vs. 1.4 ± 1.3, P > 0.05), the live birth rate was similar between the two groups (21.8 vs. 18.2%, RR 1.25 (95% confidence interval 0.73, 2.13), P > 0.05).Conclusions: The study demonstrated that PPOS had a more robust control for preventing premature LH rise than GnRH antagonist in poor responders, but PPOS in combination with freeze-all did not significantly increase the probability of pregnancy than GnRH antagonist protocol for poor responders.

Higher live birth rate with stimulated rather than artificial cycle for frozen-thawed embryo transfer

ObjectiveTo study which endometrial preparation allows a better ongoing pregnancy rates (OPR) and live birth rate (LBR) after frozen-thawed embryo transfer (FET) between mild gonadotropin ovarian stimulation (OS) and artificial cycles (AC). Study designRetrospective follow-up study including all FET performed in one fertility center from 2013 to 2016. In the OS group, gonadotropins were followed by r-hCG triggering. Vaginal micronized progesterone (200 mg/day) was given systematically. In the AC group, estradiol (E2) was started on Day 1. Vaginal micronized progesterone (600 mg/d) was added to E2 for 12 weeks. Data were analyzed using a multiple regression model. ResultsAmong 1021 FETs, 35% underwent OS preparation, 65% had an AC. As expected, patients in the AC group suffered more from endometriosis (18.5% vs. 12.9%; p = .021) and polycystic ovarian syndrome (21.7% vs. 10.9%; p < .0001) than patients in the OS group. There was no difference between groups with respect to endometrial thickness, number of embryos transferred, development stage at FET, cryopreservation technique. Despite a similar clinical pregnancy rate (CPR) (24.4% vs. 20.8%; p = .189), the OPR was significantly higher in the OS than in the AC group (17.9% vs. 11%; p = .002), leading to an increased LBR (17.1% vs. 9.8%; p < .001). After adjusting for parameters usually linked to early pregnancy losses or potential bias (patient age at freezing, smoking status, PCOS, endometriosis, rank of transfer and previous miscarriages), the results remained significant. ConclusionDespite a similar CPR, LBR was significantly higher with mild OS than with the AC preparation, even after adjusting for potential confounders. In light of these results, the first-line endometrial preparation could be OS instead of an AC. In an AC, a potential defect of the luteal phase may exist, treatment could be optimized to avoid pregnancy losses. A randomized controlled trial should be undertaken to assess the role of OS and ACs in FET.

Stimulation of the ovaries in women with breast cancer undergoing fertility preservation: alternative versus standard stimulation protocols

to evaluate the effectiveness of ovarian stimulation with tamoxifen or letrozole compared to standard ovarian stimulation on the number of oocytes retrieved in women with breast cancer in the course of fertility preservation. Multi-center randomized open-label trial in the Netherlands and Belgium. Women between 18 and 43 years with breast cancer who opted for banking of oocytes or embryos in the course of fertility preservation were included. We randomly assigned them to one of the three study groups; group 1 ovarian stimulation plus tamoxifen (60 mg per day), group 2 ovarian stimulation plus letrozole (5 mg per day) or group 3 standard ovarian stimulation without additional medication. Primary outcome was the number of oocytes retrieved at follicle aspiration. Secondary outcomes were number of mature oocytes retrieved, number of oocytes or embryos banked and peak E2 levels during ovarian stimulation. Between January 2014 and December 2018, we randomised 162 women with breast cancer. We analysed the primary outcome for 148 (91%) women of which 142 women (88%) underwent ovum pick up. Mean age of the women was 32 years.51 women underwent ovarian stimulation plus tamoxifen, 51 plus letrozole and 46 standard ovarian stimulation without additional medication. The mean number of oocytes retrieved at follicle aspiration was 12.6 (group 1), versus 14.2 (group 2) versus 13.3 (group 3) (mean difference in number of oocytes: group 1 vs. group 3 -0.675 ;95% CI, -5.6 to 4.3; group 2 vs. group 3 0.871; 95% CI, -4.1 to 5.9). The mean number of oocytes banked was 10.4 (group 1) versus 10.5 (group 2) versus 10.2 (group 3) (mean difference in number of oocytes banked: group 1 vs. group 3 0.243; 95% CI,-4.2 to 4.7; group 2 vs. group 3 0.297; 95% CI, -4.2 to 4.8). Mean number of embryos banked was 5.9 (group 1) versus 4.9 (group 2) versus 5.0 (group 3) (mean difference in number of embryos banked: group 1 vs. group 3 0.857; 95% CI, -3.0 to 4.7; group 2 vs. group 3 -1.33; 95% CI, -4.0 to 3.7). These results show that the addition of tamoxifen or letrozole to standard ovarian stimulation did not effect the number of oocytes or embryos banked in the course of fertility preservation for women with breast cancer. Whether the addition of tamoxifen or letrozole to standard ovarian stimulation affects the long-term follow up in terms of safety in women with breast cancer, remains to be seen.

Dual oocyte retrieval and embryo transfer in the same cycle for women with premature ovarian insufficiency

To compare dual oocyte retrieval with minimal ovarian stimulation and embryo transfer in the same menstrual cycle versus conventional ovarian stimulation among women with premature ovarian insufficiency (POI). A retrospective study of 51 women with POI attending a reproductive center in Turkey between 2013 and 2015. Women with an ovarian follicle of 12mm or larger early in the follicular phase who underwent oocyte retrieval followed by an immediate cycle of ovarian stimulation (group 1, n=14) were compared with those who received conventional ovarian stimulation (group 2, n=37). Both groups underwent subsequent ovarian stimulation cycles to obtain optimally two embryos for transfer. The groups had similar baseline parameters. Serum estradiol was higher in group 1 (P<0.001); total number of oocyte retrievals was higher in group 2 (P<0.001); and total number of oocytes retrieved was similar (P=0.192). Group 1 had more higher-quality embryos (P=0.031). There was a non-significant trend toward higher live birth rates in the dual trigger group (28% vs 8%, P=0.08). Rescuing growing follicles early in the follicular phase combined with subsequent ovarian stimulation and embryo transfer in the same cycle resulted in fewer oocyte retrieval cycles and might potentially improve reproductive outcomes.

Calcitonin administration improves endometrial receptivity via regulation of LIF, Muc-1 and microRNA Let-7a in mice.

Calcitonin (CT) is one of the factors affecting the embryo implantation, but its effects on the implantation window have not been fully investigated. The current study investigated the effects of CT on the endometrium receptivity by morphological study and evaluation of leukemia inhibitory factor (LIF), mucin 1 (Muc-1), and microRNA (miRNA) Let-7a in the ovarian stimulation and the normal ovarian cycle. Then the mechanism of the CT effects through the mammalian target of rapamycin (mTOR) signaling pathway was studied by using PP242. A total of 64 BALB/c mice were divided into the normal ovarian cycle and ovarian stimulation groups. Each group consisted of four subgroups: control, calcitonin, PP242, and calcitonin+PP242. CT and PP242 were injected on the fourth of pregnancy into the mice and 24 hr later all the mice were killed. The uterine tissue samples were used for morphological analysis, and endometrial cells were mechanically isolated for evaluation of gene and protein expression. The results showed that ovarian stimulation induced mTOR phosphorylation as well as increased expression of the Let-7a miRNA. In addition, CT injection increased the expression of LIF and miRNA Let-7a in ovarian stimulation similar to that in normal ovarian cycles. However, injection of PP242 reduced expression of miRNA Let-7a and increased Muc-1 expression in ovarian stimulation group. In conclusion, the administration of CT improved endometrial receptivity in mice. This phenomenon occurred by upregulation of LIF, miRNA Let-7a and downregulation of Muc-1 via mTOR signaling pathway.

Delayed Start Protocol with Gonadotropin-releasing Hormone Antagonist in Poor Responders Undergoing In Vitro Fertilization: A Randomized, Double-blinded, Clinical Trial.

We sought to determine the effects of the delayed start protocol with gonadotropin-releasing hormone (GnRH) antagonists in poor responders undergoing in vitro fertilization (IVF). This randomized clinical trial was conducted during a 15-month period from April 2014 to July 2015 in clinics in Shiraz, Iran. A total of 42 poor responders with primary infertility were randomly assigned to the controlled ovarian stimulation group utilizing the delayed start protocol (n = 21) or the traditional group (n = 21) using GnRH antagonist, Cetrotide. The primary endpoint was the number of patients undergoing oocyte pick-up, implantation, and the rate of pregnancy. The baseline characteristics of the two study groups were comparable including age, infertility duration, and body mass index. The number of follicles measuring > 13 mm in diameter (p = 0.057), retrieved oocytes (p = 0.564), mature metaphase II oocytes (p = 0.366), embryos (p = 0.709), and transferred embryos (p = 0.060) were comparable between the two groups. The number of patients undergoing oocyte pick-up (p = 0.311), the rates of implantation (p = 0.407), and pregnancy (p = 0.596) were also comparable between the two groups. The delayed start protocol was not associated with better conception results or cycle outcomes in poor responders with primary infertility undergoing IVF cycles.

Effects of endometrial preparations and transferred embryo types on pregnancy outcome from patients with advanced maternal age

ABSTRACTWe explored the strategy of frozen-thawed embryo transfer (FET) in the women with advanced maternal age (AMA). We first determined the age cut-off point of AMA by retrospective analysis of pregnancy outcomes in the patients undergoing FET. The patients with AMA were divided into 3 groups including natural cycle (NC) group, controlled ovarian stimulation (COS) group, and hormone replacement therapy (HRT) group, and simultaneously were divided into 2 groups including cleavage-stage embryo transfer (CET) group and blastocyst-stage embryo transfer (BET) group. The clinical pregnancy, embryo implantation, abortion and live birth rates were compared between the 3 groups and the 2 groups, respectively. We found that in the women aged 38 years or over, the clinical pregnancy rate and live birth rate were all significantly decreased as compared with the younger than 38-year-old women (all P < 0.05), so the women aged 38 years or over were regarded as the patients with AMA in this study. In the patients with AMA, the clinical pregnancy rate and live birth rate were 22.95% and 18.03% in NC group, 23.68% and 15.79% % in COS group as well as 24.58% and 15.92% in HRT group, and there were no significant differences in the clinical pregnancy rate and live birth rate between the 3 groups. However, the clinical pregnancy rate (42.96% vs 15.87%) and embryo implantation rate (32.26% vs 9.67%) were all significantly higher in the BET group than in the CET group (all P < 0.01). We conclude that in the women aged 38 years or over, the choice of endometrial preparation protocols may depend on the individual specific conditions because the endometrial preparation protocols do not affect FET outcome, but BET can obtain better FET outcomes as compared with CET.Abbreviations: AMA: advanced maternal age; FET: frozen-thawed embryo transfer; NC: natural cycle; COS: controlled ovarian stimulation; HRT: hormone replacement therapy; CET: cleavage-stage embryo transfer; BET: blastocyst-stage embryo transfer; LH: luteinizing hormone; HCG: human chorionic gonadotropin; HMG: human menopausal gonadotropin; FSH: follicle-stimulating hormone; BMI: body mass index

Luteal phase ovarian stimulation for poor ovarian responders.

ObjectiveTo compare the clinical outcomes of follicular versus luteal phase ovarian stimulation in women with poor ovarian response (Bologna criteria) undergoing IVF.MethodsThis retrospective study investigated 446 patients submitted to 507 cycles in three groups. First, the two larger cohorts were examined: 154 patients treated with luteal phase ovarian stimulation (Group Lu); and 231 patients administered follicular phase ovarian stimulation (Group Fo). Then the clinical outcomes of 61 patients submitted to double ovarian stimulation were analyzed. Clinical outcomes included number of retrieved oocytes, fertilization rate, cleavage rate, top-quality embryo rate, clinical pregnancy rate (CPR), and live birth rate (LBR).ResultsLonger stimulation, higher dosages of HMG, and higher MII oocyte rates were achieved in Group Lu (p<0.001). There were no significant differences in CPR and LBR between the two groups offered frozen-thawed embryo transfer (28.4% vs. 33.0%, p=0.484; 22.9% vs. 25.5%, p=0.666). In the double ovarian stimulation group, the number of oocytes retrieved in the luteal phase stimulation protocol was higher (p=0.035), although luteal phase stimulation yielded a lower rate of MII oocytes (p=0.031). CPR and LBR were not statistically different (13.8% vs. 21.4%, p=0.525; 10.3% vs. 14.3%, p=0.706).ConclusionLuteal phase ovarian stimulation may be a promising protocol to treat women with POR, particularly for patients unable to yield enough viable embryos through follicular phase ovarian stimulation or other protocols.