Poor Ovarian Responders Research Articles

Squeeze and Freeze, A Periodic Consecutive Oocyte Retrieval Method for Poor Ovarian Responders, Increases the Chance of Childbearing

Purpose: To assess if consecutive oocyte retrieval (OR) of more than three times for poor ovarian responders could be an effective method to obtain competent embryos becoming babies.

Effect of dehydroepiandrosterone administration before in vitro fertilization on the live birth rate in poor ovarian responders according to the Bologna criteria: A randomised controlled trial

AbstractObjectiveTo evaluate the effect of dehydroepiandrosterone (DHEA) pre‐treatment before in vitro fertilization and embryo transfer (IVF‐ET) on the live birth rate in infertile women with poor ovarian response (POR) defined according to the Bologna criteria.DesignA randomized, double‐blind, placebo‐controlled trial.SettingNine reproductive medical centers in China.PopulationA total of 821 participants with POR defined according to the Bologna criteria were enrolled in the study between April 2016 and December 2018.MethodsEligible participants were randomly assigned to receive either DHEA (n = 410) or placebo (n = 411) treatments for 4–12 weeks prior to IVF‐ET, in a 1:1 ratio.Main outcome measuresLive birth rate after the first embryo transfer.ResultsThirty‐six (8.8%) of 410 women in the DHEA group and 37 (9.0%) of 411 women in the placebo group had a live birth, with no significant difference observed between groups (relative risk, 0.98, 95% CI, 0.63–1.51; p = 0.911). There were no significant differences in the number of retrieved oocytes, and the rates of clinical pregnancy, pregnancy loss, and cumulative live births between the two groups.ConclusionsDHEA administration prior to IVF‐ET had no beneficial effect on the live birth rate relative to placebo in women with POR defined according to the Bologna criteria.Tweetable AbstractNo benefit was found in poor ovarian responders who received DHEA administration prior to IVF.

Efficacy of the depot gonadotropin-releasing hormone agonist protocol on in vitro fertilization outcomes in young poor ovarian responders from POSEIDON group 3.

To investigate whether the depot gonadotropin-releasing hormone (GnRH) agonist protocol could improve in vitro fertilization (IVF) outcomes for young poor responders from POSEIDON group 3. This retrospective cohort study was carried out from June 2017 to June 2020. A total of 451 patients were assigned to three groups depending on the ovarian stimulation protocols. The outcome parameters of IVF were compared in each group. Patients who received the depot GnRH agonist had significantly higher cumulative clinical pregnancy rates (50.88%, 32.02%, and 31.88%, respectively; P=0.009 and P=0.007) and cumulative live birth rate (48.25%, 26.97%, and 28.99%, respectively; P=0.004 and P=0.009) compared with mild ovarian stimulation protocol and GnRH antagonist protocol. They also had higher live birth rate per fresh embryo transfer cycle (47.78%, 32.35%, and 36.62%, respectively), but these differences were not statistically significant. Moreover, duration of stimulation, total dose of gonadotropins and endometrial thickness were significantly higher among women who received the depot GnRH agonist (P<0.001). However, they had lower embryo transfer cancellation rate, and abnormal endometrium rate (P<0.001). The depot GnRH agonist protocol may improve cumulative clinical pregnancy rate and cumulative live birth rate for young women with poor ovarian response from POSEIDON group 3.

Dual trigger with the combination of gonadotropin-releasing hormone agonist and standard dose of human chorionic gonadotropin improves in vitro fertilisation outcomes in poor ovarian responders

The study aimed to evaluate the impact of the dual trigger with the combination of GnRH agonist and standard dose of recombinant hCG on IVF outcomes in poor ovarian responders with GnRH antagonist protocol. 1283 cycles of 1010 poor responder patients according to Bologna criteria were retrospectively analysed in terms of final oocyte maturation: dual trigger group (250 μg hCG + 0.2 mg triptorelin) or standard group (250 μg hCG). Primary outcome measures were the number of retrieved and mature oocytes. The secondary outcome measures were clinical pregnancy rates and live birth rates. The number of retrieved oocytes, mature oocytes, and the top-quality embryos transferred were significantly higher in the dual trigger group (p < .001). Fertilisation rates (73.6% vs 69.6%, p = .009), implantation rates (18.7% vs 14.6, p = .039), clinical pregnancy rate per embryo transfer (27.5% vs. 19.9%, p = .010) and live birth rate per embryo transfer (21.6% vs. 14.9%, p = .011) were also significantly higher in the dual trigger group as compared to the hCG trigger group. The usage of dual trigger with a GnRH agonist and a standard dosage of hCG could improve clinical pregnancy rates and live birth rates in poor ovarian responders undergoing GnRH antagonist IVF/ICSI cycles. IMPACT STATEMENT What is already known on this subject? Dual trigger with standard dose of hCG has been the subject of trials in normal responders to optimise IVF outcomes. The results of these studies showed significant improvements in implantation and pregnancy rates with an increase in the number of mature oocytes retrieved. As a result, dual trigger has become a popular ovulation trigger option in GnRH antagonist cycles. What do the results of this study add? There is limited data about the use of dual trigger in poor ovarian responders (PORs). According to our study, increasing the number of retrieved oocytes, mature oocytes, the number of fertilised oocytes, the number of transferred embryos and top quality embryos transferred by using dual trigger in patients with PORs have a positive impact on pregnancy outcomes. What are the implications of these findings for clinical practice and/or further research? These findings implies potential advantages of dual trigger usage for improving IVF outcomes in PORs. With large sample sized prospective randomised trials, dual trigger with combination of GnRHa and a standard dose of hCG might replace the traditional ovulation trigger with hCG in PORs.

PROSTAGLANDIN D2 ASSOCIATION WITH POOR OVARIAN RESPONDER IN FEMALE INFERTILITY

Regulation factors and biomarkers in the follicular phases can be targeted to overcome poor ovarian responders (POR) remain poorly identified. All patients underwent conventional COS protocols. Follicular fluid was harvested during ovum pick-up from POR and normal patients. We analyzed the level of and PGD2 in the follicular fluid of patients with a normal ovarian response and patients with a POR using ELISA. The PGD2 concentration was significantly lower in the follicular fluid of patients with POR than in the follicular fluid of younger and older patients with a normal ovarian response. We measured the concentrations of prostaglandins in human follicular fluid and found that PGD2 supports ovarian functions and female fertility. It plays an important role and modulates the proliferation and differentiation of granulosa cells and steroidogenic activity in these cells. Our data demonstrated that PGD2 levels were lower in the follicular fluid of patients with POR than in the follicular fluid of patients with a normal ovarian response. We suggest that PGD2 is a potential regulator and biomarker to enhance and diagnose POR. This data shows a possibility in developing a therapeutic factor for PORs which promotes follicular development that can be used to develop new COS protocols for personalized induction in women with POR.

CLINICAL APPLICATION OF LETROZOLE COMBINED WITH PROGESTIN-PRIMED OVARIAN STIMULATION PROTOCOL IN POOR OVARIAN RESPONDERS AT ADVANCED AGE

To investigate the clinical application value of Letrozole as co-treatment agent in progestin-primed ovarian stimulation（PPOS） protocol on poor ovarian responders at advanced age undergoing in vitro controlled ovarian hyperstimulation(COH).

Development and Validation of a Clinical Pregnancy Failure Prediction Model for Poor Ovarian Responders During IVF/ICSI.

BackgroundsDespite the great advances in assisted reproductive technology (ART), poor ovarian response (POR) is still one of the most challenging tasks in reproductive medicine. This predictive model we developed aims to predict the individual probability of clinical pregnancy failure for poor ovarian responders (PORs) under in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI).MethodsThe nomogram was developed in 281 patients with POR according to the Bologna criteria from January 2016 to December 2019, with 179 in the training group and 102 in the validation group. Univariate and multivariate logistic regression analyses were used to identify characteristics that were associated with clinical pregnancy failure. The nomogram was constructed based on regression coefficients. Performance was evaluated using both calibration and discrimination.ResultsAge >35 years, body mass index (BMI) >24 kg/m2, basic follicle-stimulating hormone (FSH) >10 mIU/ml, basic E2 >60 pg/ml, type B or C of endometrium on human chorionic gonadotropin (hCG) day, and the number of high-quality embryos <2 were associated with pregnancy failure of POR patients. The area under the receiver operating characteristic curve (AUC) of the training set is 0.786 (95% confidence interval (CI): 0.710–0.861), and AUC in the validation set is 0.748 (95% CI: 0.668–0.827), showing a satisfactory goodness of fit and discrimination ability in this nomogram.ConclusionOur nomogram can predict the probability of clinical pregnancy failure in PORs before embryo transfer in IVF/ICSI procedure, to help practitioners make appropriate clinical decisions and to help infertile couples manage their expectations.

P–657 Prostaglandin D2 is correlated with follicles development and a reliable marker of ovarian reserve of poor ovarian responder patients

Abstract Study question Is the prostaglandin D2 (PGD2) associated with growing follicles and ovarian reserve of poor ovarian responders? Summary answer PGD2 is correlated with ovarian stimulation activity and follicle growth. Especially, poor ovarian responders show a significant decrease in the level of follicular fluid. What is known already Prostaglandins (PGs) are involved in the female reproductive process, mainly ovulation, fertilization, and implantation. Study design, size, duration We investigated the PGD2 level in the follicular fluid of poor ovarian responders. The collection of human follicular fluid was approved by the Institutional Research and Ethical Committees of CHA University (approval number: 1044308–201611-BR–027–04) from January to December 2019. Follicular fluid was collected from patients with normal ovarian response and patients with POR. Participants/materials, setting, methods We studied whether prostaglandin has related to POR in the clinical key factor by measuring human follicular fluid. Follicular fluid was collected from patients with normal ovarian response and patients with POR. The concentration of PGD2 in follicular fluid was determined with ELISA kits following the manufacturer’s protocol. Main results and the role of chance We analyzed the level of PGD2 in the follicular fluid of patients with normal ovarian response and patients with POR using an ELISA. The PGD2 concentration was significantly lower in the follicular fluid of patients with POR than in the follicular fluid of young and old patients with normal ovarian response. Limitations, reasons for caution This study has an identification of biomarker of the clinical samples as POR criteria patients. Therefore, further investigations aimed at specific recovery of low PGD2 metabolic activity in the CCs during control ovarian stimulation. Wider implications of the findings: Until now there is no specific biomarker of POR. AMH is just an ovary reserve marker for an indication of ovary function. PGD2 is one of the metabolites in steroid metabolism in the ovary. Therefore, we can find some cure through further study for improved PGD2 production to POR patients. Trial registration number none

P–789 Obstetric and perinatal outcomes in poor ovarian responders and normal responders flowing fresh embryo transfer: a prospective, monocentric, observational study

Abstract Study question Whether women pregnant after a poor response in IVF have obstetric and perinatal complications more frequently than women with pregnancies after a normal response in IVF? Summary answer There were no statistically significant differences in obstetric and perinatal complications rate between poor responders and normal responders in Chinese women. What is known already Poor ovarian response usually indicates a reduction in follicular response, resulting in a reduced number of retrieved oocytes. Patients are less likely to conceive and have a higher risk of cycle cancellation and low clinical pregnancy rate. Whether poor ovarian response is associated with obstetric and perinatal complications is however debated. Study design, size, duration Design: Prospective, monocentric, observational study. Size: 1664 women with poor ovarian response and 1061 women with normal ovarian response duration : July 1, 2017 to Aug 15, 2019.Participants/materials, setting, methods: 1664 women with poor ovarian response and 1061 women with normal ovarian response undergoing IVF or ICSI were enrolled in this study. The primary outcome was obstetric and perinatal complications rate. Main results and the role of chance 1664 women with POR and 1061 women with NOR were enrolled in this study.Poor and normal responders did not have significantly different incidences in obstetric and perinatal complications(25.42% vs 25.45%), nor were there a significant difference in preeclampsia, gestational diabetes mellitus, postpartum hemorrhage or abruptio placentae. But POR group have a lower frequency of twin pregnancies(8.47% vs 28.66%,P&amp;lt;0.01),low birth weight(5.08% vs 14.23%,P&amp;lt;0.01)and prematurity (9.32% vs 17.03%,P&amp;lt;0.01). Limitations, reasons for caution Despite its size, an observational study such as this has a number of inherent limitations, and the best way to confirm its findings will be to compare obstetric and perinatal outcomes in different subgroup of pregnancies following ART in an adequately powered randomized, controlled trial. Wider implications of the findings: This prospective, monocentric, observational study suggests that women with poor ovarian response did not have higher perinatal complication rate than women with normal ovarian response. Oocyte quality and quantity may not affect the rate of perinatal complications. Trial registration number Not applicable

Monopronucleated (1PN) and tripronuclear (3PN) zygotes formation during assisted reproduction in POSEIDON group 4 patients: Emphasizing on polar bodies.

Abnormal fertilization (1PN/3PN) and its accompanying polar body (PB) conditions have been less discussed in poor ovarian responders. By observing the PBs, we analyzed the mechanisms of abnormal fertilization and aimed to explore the role of intracytoplasmic sperm injection/in vitro fertilization (ICSI/IVF) in POSEIDON group 4 patients. An observational study. All fresh IVF/ICSI cycles from January 2018 to December 2019 were evaluated. The inclusion criteria were POSEIDON group 4. Fertilization and PB conditions were assessed 16-18 h post-insemination. Primary observation endpoints including normal fertilization, abnormal fertilization, and total fertilization failure rate. A total of 351 cycles involving 180 patients met the inclusion criteria. Of these, 15 cycles reported no retrieved oocytes. Finally, 336 cycles (IVF, n=267; ICSI, n=69) were included. A total of 1005 oocytes and 939 embryos were assessed. The mean female age was 40.8 years, and the mean AMH level was 0.6 ng/mL. The normal fertilization rate was 69.7%. The zygote distribution was 18.7% 0PN, 3.9% 1PN, 66.9% 2PN, 9.5% 3PN, and 1.0% ≥4PN. For 1PN zygotes, 59% were denoted as 1PN2PB. The mean 3PN rate was 8.9%. In POSEIDON group 4, most of the monopronucleated zygotes were 1PN2PB. Digyny (3PN1PB), due to failure to extrude the second PB, was the major cause of triploidy in which ICSI could not circumvent. The distribution of abnormally fertilized zygotes was similar in IVF and ICSI. To investigate the mechanisms of abnormal fertilization and assess whether ICSI is necessary, analysis of PB will provide important clues.

The Role of Traditional Chinese Formula Ding-Kun Pill (DKP) in Expected Poor Ovarian Response Women (POSEIDON Group 4) Undergoing In Vitro Fertilization-Embryo Transfer: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

ObjectiveThe primary objective of the study was to assess traditional Chinese formula DKP supplementation in terms of efficacy and safety on reproductive outcomes of expected poor ovarian responder (POR, POSEIDON Group 4) undergoing in vitro fertilization-embryo transfer (IVF-ET).Design, Setting, and ParticipantsWomen eligible for IVF-ET were invited to participate in this randomized, double-blind, placebo-controlled, superiority trial at academic fertility centers of ten public hospitals in Chinese Mainland. A total of 462 patients (35–44 years) equally divided between DKP and placebo groups with antral follicle count (AFC) <5 or anti-müllerian hormone (AMH) <1.2 ng/ml were randomized.InterventionsAll participants were given DKP or 7 g placebo twice daily on the previous menstrual cycle day 5 until oocyte retrieval, which took approximately 5 to 6 weeks.Main Outcome MeasureThe primary outcome was the ongoing pregnancy defined as more than 20 gestational weeks of an intrauterine living fetus confirmed by pelvic ultrasonography.ResultsDemographic characteristics were equally distributed between the study populations. Intention-to-treat (ITT) analysis revealed that ongoing pregnancy rate (OPR) was not significantly different between DKP and placebo groups [26.4% (61/231) versus 24.2% (56/231); relative risk (RR) 1.09, 95% confidence interval (CI) 0.80 to 1.49, P = 0.593]. No significant differences between groups were observed for the secondary outcomes. The additional per protocol (PP) analysis was in line with ITT results: OPR in DKP group was 27.2% (61/224) versus 24.1% (55/228) in placebo group [RR 1.13, 95%CI (0.82 to 1.55), P = 0.449]. After subgroup analysis the findings concluded that POR population of 35–37 years had a significantly higher OPR after 5–6 weeks of oral DKP (41.8%, 33/79) versus placebo (25.4%, 18/71) [RR 1.65, 95% CI (1.02 to 2.65), P = 0.034, P for interaction = 0.028].ConclusionThis well-designed randomized controlled trial (RCT) offers new high-quality evidence to supplement existing retrospective literature concerning DKP performance in expected PORs. DKP could be recommended as a safe and natural remedy for expected PORs (aged 35–37 years) who fulfill the POSEIDON group 4 criteria. However, additional interventional clinical studies are undoubtedly required to be conducted in the future to validate this hypothesis.Clinical Trial Registration www.chictr.org.cn, identifier ChiCTR1900026614.

Live birth rate with double ovarian stimulation is superior to follicular phase ovarian stimulation per started cycle in poor ovarian responders.

To compare the outcome of double ovarian stimulation (DOS) with follicular phase ovarian stimulation (FPS) per started cycle in poor ovarian responders (PORs). A total of 204 PORs who underwent ovulation induction for in vitro fertilization, cryopreservation of all embryos available, and frozen embryo transfer cycle were retrospectively analyzed. Of those, 146 received single FPS, and 58 received DOS. All viable embryos were cryopreserved and subsequently transferred within 1-6months. The number of oocytes collected and the number of mature oocytes per started cycle were higher in the DOS group compared to the FPS group (6.0 ± 1.9 vs. 2.8 ± 1.3 and 4.3 ± 1.3 vs. 2.2 ± 1.2, respectively, p=0.001). Clinical pregnancy rate and live birth rate per started cycle were also significantly higher in the DOS group than the FPS group (41.4% vs. 16.4% and 36.2% vs. 15.1%, respectively, p < 0.001). The cancellation rate of embryo transfer due to no viable embryo was significantly lower in the DOS group (10.3%) than the FPS group (40.4%) (p=0.001). In the DOS group, numbers of oocytes (3.2 ± 1.2 vs. 2.7 ± 1.1, p=0.006), MII oocytes (2.6 ± 1.0 vs. 2.1 ± 0.8, p=0.001), and cryopreserved blastocysts (1.5 ± 0.8 vs. 1.1 ± 0.7, p=0.002) were significantly higher in the luteal ovarian stimulation compared to follicular ovarian stimulation. Live birth per started cycle with DOS is superior to FPS in PORs. Luteal phase stimulation contributes to improving pregnancy rates in these patients.

Live birth rates in different subgroups of poor ovarian responders according to Bologna and POSEIDON group classification criteria

PurposeThe present study was designed to compare the live birth rates (LBRs) according to Bologna criteria or Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number (POSEIDON) group classifications to determine the important predictive factors for LBR in patients with POR. Basic proceduresIn this cross-sectional study, the database of Royan Institute (Tehran, Iran) from December 2015 to December 2017 was evaluated and the fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles outcomes for all the patients with at least one POR after standard controlled ovarian stimulation were collected. The patients divided into five subgroups according to Bologna criteria and four groups on the basis of POSEIDON group classification. Main finding812 patients with POR diagnosis were assessed which 517 (63.6%) of them were underwent embryo transfer (ET) during the last treatment cycle. According to Bologna criteria, 41 patients were not included in any subgroup and the patients in Bologna group II had highest LBR (19.8%). In terms of POSEIDON classification, all of the patients were classified into subgroups and the women in POSEIDON group III had the highest LBR (27%). According to multivariable regression analysis, the significant independent predictive factors for LBR were the number and morphology (good and excellent) of the embryos transferred, and POSEIDON group III classification. Principal conclusionThe results indicated that the POSEIDON group classification could be more comprehensive and practical than Bologna criteria for categorizing POR patients and predicting their outcome. Moreover, the number and morphology of transferred embryos were the most important prognostic factors for live births in these patients.

Does LH supplementation in poor responders affect granulosa cells apoptosis rate in ART? A prospective randomised controlled trial

The aim was to compare granulosa cell's (GCs) apoptosis rate with (group A) or without (group B) luteinising hormone (LH) supplementation in poor ovarian responders (PORs) during controlled ovarian stimulation (COS). After oocyte retrieval, the follicular fluid was analysed by cytoflowmetry. Primary outcomes were GCs apoptosis rate in terms of viability, early apoptosis, late apoptosis and necrosis. Secondary outcome was clinical pregnancy rate. The viability was 96.7{IQR: 8} and 83.5{IQR: 20} for groups A and B, respectively (p < .001). Late apoptosis rates were significantly lower in group A (median 1.5, {IQR: 3.1}) than group B (median 9.5, {IQR: 20.6}) (p < .001). Median early apoptosis rates were 1.4 {IQR: 2.9} and 5.2 {IQR: 6.5} for group A and B respectively (p = .04). No significant difference was observed in the clinical pregnancy rate. Although LH seems necessary in PORs to decrease late granulosa apoptosis rates, this does not improve clinical pregnancy rates. IMPACT STATEMENT What is already known on this subject? LH supplementation during COS has long been an issue in PORs to overcome the rFSH responsiveness due to the LH polymorphism. LH receptors have also been on GCs and their expression increases in preovulatory follicles. GCs apoptosis rates may show the oocyte quality and reproductive potential of oocyte retrieved and the requirement for LH supplementation. What do the results of this study add? The present study shows that LH supplementation during COS for PORs promotes the GC viability and reduces early/late apoptosis rates. Similarly, the number of MII oocytes was significantly higher in the LH regimen group. However, there was no significant difference in terms of clinical pregnancy rates. What are the implications of these findings for clinical practice and/or further research? The oocyte quality parameters such as higher GC viability and lower GC early/late apoptosis rates verify the LH supplementation in PORs during COS. However, the limited size of this study requires further multi-centre research in a larger cohort of patients. Results obtained with a sensitive and validated method will help clinicians to make better decisions in patient care.

The effect of Myo-inositol on fertility rates in poor ovarian responder in women undergoing assisted reproductive\xa0technique: a randomized clinical trial

BackgroundPoor ovarian response to gonadotropin is a significant challenge in assisted reproductive technique (ART) and affect 9–24% of ART cycles. This study aimed to evaluate the effect of Myo-inositol on fertility rates in poor ovarian responder women undergoing assisted reproductive technique.MethodsThis study is a double-blinded randomized controlled study that involved 60 poor ovarian responders included in an ICSI program and divided into two groups; intervention group: 30 patients who have been assuming Inofolic (4 g myo-inositol + 400 μg folic acid) for the before the enrollment day; control group: 30 patients assuming folic acid (400 μg) for the same period. Controlled ovarian stimulation was performed in the same manner in the two groups. The main outcomeswere the assessment of oocytes retrievednumber and quality, ovarian sensitivity index,required dose of Gonadotropinsunits × 1000), fertilization rate, biochemical, and clinical pregnancy rate.ResultThere is no significant difference in clinical characteristics between study groups. The number of oocytes retrieved, number of MII oocytes, number of embryos transferred, chemical, and clinical pregnancy were higher in the intervention group. However, they are not statistically significant in comparison to the control group. The ovarian sensitivity index and fertilization rate were significantly higher in the intervention group than the control group (P > 0.05). The required dose of gonadotropin significantly lower in the intervention group than the control group.ConclusionOur results suggest that the supplementation myo-inositol in poor ovarian responders significantly improved the ART outcomes such as fertilization rate gonadotropin, ovarian sensitivity index (OSI) and significantly reduced the required unities of gonadotropin. Additionally, more extensive randomized controlled studies are needed.Trial registrationIranian Registry of Clinical Trials, IRCT20180515039668N1, retrospectively registered since 2020-03-16.

A large observational data study supporting the PROsPeR score classification in poor ovarian responders according to live birth outcome.

Can the Poor Responder Outcome Prediction (PROsPeR) score identify live birth outcomes in subpopulations of patients with poor ovarian response (POR) defined according to the ESHRE Bologna criteria (female age, anti-Müllerian hormone (AMH), number of oocytes retrieved during the previous cycle (PNO) after treatment with originator recombinant human follitropin alfa? The PROsPeR score discriminated the probability of live birth in patients with POR using observational data with fair discrimination (AUC ≅ 70%) and calibration, and the AUC losing less than 5% precision compared with a model developed using the observational data. Although scoring systems for the likelihood of live birth after ART have been developed, their accuracy may be insufficient, as they have generally been developed in the general population with infertility and were not validated for patients with POR. The PROsPeR score was developed using data from the follitropin alfa (GONAL-f; Merck KGaA, Darmstadt, Germany) arm of the Efficacy and Safety of Pergoveris in Assisted Reproductive Technology (ESPART) randomized controlled trial (RCT) and classifies women with POR as mild, moderate or severe, based upon three variables: female age, serum AMH level and number of oocytes retrieved during the previous cycle (PNO). The external validation of the PROsPeR score was completed using data derived from eight different centres in France. In addition, the follitropin alfa data from the ESPART RCT, originally used to develop the PROsPeR score, were used as reference cohort. The external validation of the PROsPeR score l was assessed using AUC. A predetermined non-inferiority limit of 0.10 compared with a reference sample and calibration (Hosmer-Lemeshow test) were the two conditions required for evaluation. The observational cohort included data from 8085 ART treatment cycles performed with follitropin alfa in patients with POR defined according to the ESHRE Bologna criteria (17.6% of the initial data set). The ESPART cohort included 477 ART treatment cycles with ovarian stimulation performed with follitropin alfa in patients with POR. The external validation of the PROsPeR score to identify subpopulations of women with POR with different live birth outcomes was shown in the observational cohort (AUC = 0.688; 95% CI: 0.662, 0.714) compared with the ESPART cohort (AUC = 0.695; 95% CI: 0.623, 0.767). The AUC difference was -0.0074 (95% CI: -0.083, 0.0689). This provided evidence, with 97.5% one-sided confidence, that there was a maximum estimated loss of 8.4% in discrimination between the observational cohort and the ESPART cohort, which was below the predetermined margin of 10%. The Hosmer-Lemeshow test did not reject the calibration when comparing observed and predicted data (Hosmer-Lemeshow test = 1.266688; P = 0.260). The study was based on secondary use of data that had not been collected specifically for the analysis reported here and the number of characteristics used to classify women with POR was limited to the available data. The data were from a limited number of ART centres in a single country, which may present a bias risk; however, baseline patient data were similar to other POR studies. This evaluation of the PROsPeR score using observational data supports the notion that the likelihood of live birth may be calculated with reasonable precision using three readily available pieces of data (female age, serum AMH and PNO). The PROsPeR score has potential to be used to discriminate expected probability of live birth according to the degree of POR (mild, moderate, severe) after treatment with follitropin alfa, enabling comparison of performance at one centre over time and the comparison between centres. This analysis was funded by Merck KGaA, Darmstadt, Germany. P.L. received grants from Merck KGaA, outside of the submitted work. N.M. reports grants, personal fees and non-financial support from Merck KGaA outside the submitted work. T.D.H. is Vice President and Head of Global Medical Affairs Fertility, Research and Development at Merck KGaA, Darmstadt, Germany. P.A. has received personal fees from Merck KGaA, Darmstadt, Germany, outside the submitted work. C.R. has received grants and personal fees from Gedeon Richter and Merck Serono S.A.S., France, an affiliate of Merck KGaA, Darmstadt, Germany, outside the submitted work. P.S. reports congress support from Merck Serono S.A.S., France (an affiliate of Merck KGaA, Darmstadt, Germany), Gedeon Richter, TEVA and MDS outside the submitted work. C.A., J.P., G.P. and R.W. declare no conflict of interest. N/A.

Retrospective outcome in women aged 45 years and older undergoing natural cycle IVF treatment

Research questionIs natural cycle IVF treatment beneficial to middle-aged women with poor ovarian response? DesignRetrospective investigation of outcomes in women aged 45 years and older, who underwent natural cycle IVF treatment between 2009 and 2018 in a single assisted reproduction clinic with the aim of reporting several successful outcomes. ResultsIn total, 2408 IVF retrievals in women aged 45 years and older were included in this study. Mean serum FSH level on day 3 was 21.4 ± 12.5 (range: 0.3–93.7) IU/ml. One fresh cleavage-stage embryo was transferred in 37.4% (900/2408) of the initiated cycles. The overall clinical pregnancy rate and live birth rate per fresh embryo transfer were 2.8% (25/900) and 0.8% (7/900), respectively. Natural cycle IVF treatment led to seven successful deliveries during the period. All seven women who successfully delivered were poor ovarian responders who met the diagnostic Bologna criteria and, among them, three had elevated serum FSH levels on day 3 (range: 39.0–47.1 mIU/ml). All seven had full-term delivery, and no congenital abnormalities were observed in their infants. No significant difference was found in serum FSH level on day 3 between those with and without positive beta-HCG test results. ConclusionsThese findings suggest that natural cycle IVF treatment could be an option for older poor responders in countries that do not permit egg donation. Careful counselling is required, however, because of the low probability of live births after IVF in middle-aged women.

A Novel Stimulation Protocol for Poor-Responder Patients: Combining the Stop GnRH-ag Protocol with Letrozole Priming and Multiple-Dose GnRH-ant: A Proof of Concept

Objective: The objective of this study was to examine whether the combined Stop GnRH-agonist (GnRH-ag), letrozole priming, and multiple-dose GnRH-antagonist (GnRH-ant) protocol may improve in vitro fertilization/intracytoplasmic sperm injection cycle in poor ovarian responders (PORs). Design: This was a historical cohort, proof of concept study under tertiary setting at University affiliated Medical Center. Patients: Five PORs fulfilling the POSEIDON Group 4 criteria were included. Main Outcome Measures: Number of oocytes retrieved, number of top-quality embryos (TQEs), and controlled ovarian hyperstimulation (COH) variables were the main outcome measures. Results: The combined Stop GnRH-ag, letrozole priming, and multiple-dose GnRH-ant COH protocol revealed significantly higher number of follicles >13 mm on the day of hCG administration and higher number of oocytes retrieved, with non-significantly more TQEs and a reasonable clinical pregnancy rate. Conclusions: The combined Stop GnRH-ag, letrozole priming, and multiple-dose GnRH-ant COH protocol is a valuable tool in the armamentarium for treating POSEIDON Group 4 patients. Further large prospective studies are needed to elucidate its role in POR and to identify the specific characteristics of women (before initiating ovarian stimulation) that will aid both fertility specialists’ counseling and their patients in adjusting the appropriate COH protocol.

Do we trust scientific evidence? A multicentre retrospective analysis of first IVF/ICSI cycles before and after the OPTIMIST trial.

Has the practice of individualizing the recombinant-FSH starting dose been superseded after the largest randomized controlled trial (RCT) in assisted reproduction technology (ART), the OPTIMIST trial? The OPTIMIST trial has influenced our ART daily practice to a limited degree, but adherence is still generally poor. Although the 'one size fits all' approach has been discouraged for decades by most authors, the OPTIMIST study group demonstrated in a large prospective RCT that, in general, dosage individualization does not improve the prospects for live birth, although it may decrease ovarian hyperstimulation syndrome (OHSS) risk in expected high responders. Retrospective analysis of all first in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles from 1st January 2017 to 31st December 2018, before and after the OPTIMIST publication on November 2017. Two thousand six hundred and seventy-seven patients, between 18 and 42 years old, undergoing their first IVF-ICSI cycle in seven Italian fertility centres, were included. Patients were allocated to three groups according to their ovarian reserve markers: predicted poor ovarian responders (POR), predicted normo-responders (NR) and expected hyper-responders (HRs). Between 2017 and 2018, there was an overall increase in prescription of the standard 150 IU dose proposed by the OPTIMIST trial and a reduction in the use of a starting dose >300 IU. After subgroup analysis, the decrease in doses >300 IU remained significant in the POR and NR sub-groups. The retrospective nature of the study. Physicians need time to adapt to new scientific evidence and a comparison between 2017 and 2019 may have found a greater impact of the Optimist trial, although other changes over the longer time span might have increased confounding. We cannot be sure that the observed changes can be attributed to knowledge of the OPTIMIST trial. Clinicians may be slow to adopt recommendations based on RCTs; more attention should be given to how these are disseminated and promoted. No external funding was used for this study. E.P. reports grants and personal fees from MSD, grants from Ferring, from IBSA, grants and personal fees from Merck, grants from TEVA, grants from Gedeon Richter, outside the submitted work. E.S. reports grants from Ferring, grants and personal fees from Merck-Serono, grants and personal fees from Theramex, outside the submitted work. All other authors do not have conflicts of interest to declare. Not applicable.

Ovarian Fragmentation and AKT Stimulation for Expansion of Fertile Lifespan.

Since the first baby was born after in vitro fertilization, the female infertility treatment has been well-developed, yielding successful outcomes. However, successful pregnancies for patients with premature ovarian insufficiency and diminished ovarian reserve are still difficult and diverse therapies have been suggested to improve the chances to have their genetically linked offspring. Recent studies demonstrated that the activation Akt pathway by using a phosphatase and tensin homolog enzyme inhibitor and a phosphatidylinositol-3 kinase stimulator can activate dormant primordial follicles in both mice and human ovaries. Subsequent researches suggested that the disruption of Hippo signaling pathway by ovarian fragmentation increased the expression of downstream growth factors and secondary follicle growth. Based on the combination of ovarian fragmentation and Akt stimulation, the in vitro activation (IVA) approach has resulted in successful follicle growth and live births in premature ovarian insufficiency patients. The approach with disruption of Hippo signaling only was also shown to be effective for treating poor ovarian responders with diminishing ovarian reserve, including advanced age women and cancer patients undergoing sterilizing treatments. This review aims to summarize the effectiveness of ovarian fragmentation and Akt stimulation on follicle growth and the potential of IVA in extending female fertile lifespan.