Hsa-miR-483-5p/mRNA network that regulates chemotherapy resistance in locally advanced rectal cancer identified through plasma exosome transcriptomics.

BACKGROUND: Chemoresistance is the primary contributor to distant metastasis in the context of neoadjuvant chemoradiotherapy (nCRT) for rectal cancer. However, the underlying mechanisms remain elusive. AIM: To detect the differential expression profiles of plasma exosomal microRNAs (miRNAs) in poor and good responders and explore the potential mechanisms of chemoresistance. METHODS: In this study, the profiles of plasma exosomal miRNAs were compared in two dimensions according to treatment responses (poor/good responders) and treatment courses (pre/post-nCRT) using RNA sequencing. RESULTS: Exosome hsa-miR-483-5p was up-regulated in good responders post-nCRT. Bioinformatics analysis revealed that the target genes of hsa-miR-483-5p were mainly enriched in tumor-specific pathways, such as the MAPK signaling pathway, EGFR tyrosine kinase inhibitor resistance, Toll-like receptor signaling pathway, VEGF signaling pathway, and mTOR signaling pathway. Further analysis indicated that MAPK3, RAX2, and RNF165 were associated with inferior recurrence-free survival in patients with rectal cancer, and the profiles of MAPK3, TSPYL5, and ZNF417 were correlated with tumor stage. In addition, the expression profiles of MAPK3, RNF165, and ZNF417 were negatively correlated with inhibitory concentration 50 values. Accordingly, an hsa-miR-483-5p/MAPK3/RNF 165/ZNF417 network was constructed. CONCLUSION: This study provides insights into the mechanism of chemoresistance in terms of exosomal miRNAs. However, further research is required within the framework of our established miRNA-mRNA network.

Poor Response to Gonadotropin Stimulation and Perinatal Outcomes in Fresh In Vitro Fertilization Embryo Transfer Cycles-A Retrospective Cohort Study.

Objective: The objective was to examine the association between poor ovarian response to gonadotropin stimulation for in vitro fertilization (IVF) and adverse perinatal outcomes in singleton gestations in young patients. Methods: This was a retrospective cohort study including women aged 17-39 who underwent fresh embryo transfer and delivered a singleton neonate at a single center (pre-implantation genetic testing excluded) (2007-2022). Patients were classified as one of the following categories: poor responders-daily follicle-stimulating hormone (FSH) ≥ 150 IU yielding ≤ 3 retrieved oocytes; normal responders-4-15 oocytes; and high responders with ≥16 oocytes. The primary outcome was a composite of pre-eclampsia (mild or severe), small-for-gestational-age, gestational diabetes mellitus, and preterm birth (<37 weeks). We compared maternal and neonatal outcomes between the three groups. Multivariable logistic regression was used to control for confounders. Results: Overall, 507 women met the inclusion criteria. Of them, there were 44 (8.68%) poor responders, 342 (67.46%) normal responders, and 121 (23.87%) high responders. Poor responders, compared to normal and high responders, were characterized by a higher maternal age (34.64 ± 4.01 vs. 31.4 ± 5.04 vs. 30.01 ± 4.93, p < 0.001, respectively) and total FSH dosage (3028.41 ± 1792.05 IU vs. 2375.11 ± 1394.05 IU vs. 1869.31 ± 1089.63 IU, p < 0.001). The perinatal outcomes examined, including cesarean delivery (CD) rate and the composite outcome, were comparable between groups. Using multivariable logistic regression and adjusting for ovarian response group, maternal age, nulliparity, and estradiol level and endometrial thickness before ovulation triggering, poor response was not associated with CD rate or the composite outcome, with maternal age associated with CD (p = 0.005), and nulliparity with the composite outcome (p = 0.007). Similar results were obtained when comparing poor responders to each other group separately or to all other responders. Conclusions: Poor ovarian response is not associated with increased adverse maternal or neonatal outcomes.

Clinical factors associated with unexpected poor or suboptimal response in Poseidon criteria patients.

RESEARCH QUESTION: What clinical factors are associated with 'unexpected' poor or suboptimal responses to IVF ovarian stimulation per POSEIDON's criteria, and which AMH and AFC threshold values distinguish this population? DESIGN: Tri-centre retrospective cohort study (2015-2017) involving first-time IVF and ICSI cycles with conventional ovarian stimulation (≥150 IU/day of FSH). Eligibility criteria included sufficient ovarian reserve markers according to POSEIDON's classification (AMH ≥1.2 ng/ml; AFC ≥5). Ovarian response categories were poor (<4 oocytes), suboptimal (4-9 oocytes) and normal (≥9 oocytes). Primary outcomes included clinical factors associated with an unexpected poor or suboptimal response to conventional ovarian stimulation using logistic regression analyses, and the threshold values of AMH and AFC predicting increased risk of such responses using ROC curves. RESULTS: A total of 7625 patients met the inclusion criteria: 204 (9.3%) were poor and 1998 (90.7%) were suboptimal responders. Logistic regression identified significant clinical predictors for a poor or suboptimal response, including AFC, AMH, total gonadotrophin dose, gonadotrophin type and trigger type (P ≤ 0.02). The ROC curves indicated that AMH 2.87 ng/ml (AUC 0.740) and AFC 12 (AUC 0.826) were the threshold values predicting a poor or suboptimal response; AMH 2.17 ng/ml (AUC 0.741) and AFC 9 (AUC 0.835) predicted a poor response; and AMH 2.97 ng/ml (AUC 0.722) and AFC 12 (AUC 0.801) predicted a suboptimal response. CONCLUSIONS: The threshold values of AMH and AFC predicting 'unexpected' poor or suboptimal response were higher than expected. These findings have critical implications for tailoring IVF stimulation regimens and dosages.

Best Practice Recommendations for Infertility Management.

Aim: The objective of this document is to provide guidance to the infertility specialist, gynecologist, embryologist, and counselors on the management of sub-fertility and brief them with the recent advances in the field. These recommendations will aid the aforementioned healthcare professionals in everyday clinical decisions about appropriate and effective care of their patients with the best available evidence. Participants: Extensive deliberations, discussion, and brainstorming was done between different reproductive medicine (RM) specialists, to develop the recommendations. Evidence: A systematic review of the literature published up to June 2019 was carried out using PubMed and Cochrane Collaboration Library. International guidelines, cohort studies, case series, observational studies, and randomized controlled trials currently available in the literature were reviewed. Indian data whatever available was also reviewed. Process: Primary meetings were held with leading reproductive medicine specialists. Each topic was brainstormed on by a group of reproductive medicine experts, who then prepared the first draft of the recommendation. These recommendations then were reviewed by Dr. Jaideep Malhotra, Dr. Gouri Devi, and Dr. Madhuri Patil along with the chief co-ordinator of each consensus to finalize the final draft. Conclusions: From the literature and discussion of the available evidence, several topics were identified for which evidence is inconsistent, insufficient, or non-existing. For the benefit of couples undergoing several treatments, the working committee recommends that future research, where possible in well-designed RCTs, will help in establishing evidence for a particular practice. In the Indian context, one also needs to take into consideration facilities and options available, cost, lack of insurance coverage, experimental nature of some advanced techniques used.

Does dual oocyte retrieval with continuous FSH administration increase the number of mature oocytes in low responders? An open-label randomized controlled trial.

STUDY QUESTION: Is there an increase in the total number of metaphase II (MII) oocytes between a conventional ovarian stimulation (OS) and a double uninterrupted stimulation? SUMMARY ANSWER: There is no increase in the total number of MII oocytes when comparing one conventional OS to a continuous stimulation with double oocyte aspiration. WHAT IS KNOWN ALREADY: Based on the concept of multiple follicular waves, the combination of two stimulations in the same ovarian cycle has gained interest in patients with a low ovarian reserve. This so-called dual stimulation approach is usually characterized by a discontinuation of FSH administration for ∼5 days and appears to have a favourable impact on the number of retrieved oocytes without affecting the embryo quality or ploidy status. The outcomes of dual uninterrupted OS have not yet been studied. STUDY DESIGN, SIZE, DURATION: This was an open-label randomized controlled trial (RCT) with superiority design, performed in a single tertiary centre. Subjects were randomized with a 1:1 allocation into two groups between October 2019 and September 2021. All patients underwent a conventional stimulation with recombinant FSH. When two or more follicles of 17 mm were present, the final inclusion criterion was assessed; randomization occurred only in the presence of ≤9 follicles of ≥11 mm. In Group A, ovulation was triggered with hCG, and oocyte retrieval (OR) was performed 34-36 h later, followed by a fresh single or double embryo transfer (SET or DET) on Day 3/5. In Group B, ovulation was triggered with GnRH agonist, followed by another OS, without discontinuation of the FSH administration. In the presence of one or more follicles of ≥17 mm, the second stimulation was completed with hCG. A freeze-all strategy (Day 3/5) was applied for both retrievals, followed by transfer of one or two embryos in an artificially prepared frozen-thawed cycle. In the absence of one or more follicles of ≥17 mm after 13 additional days of stimulation, the second cycle was cancelled. All ORs were executed by a senior fertility specialist who was blinded for the first treatment, and all follicles >10 mm were aspirated, according to routine clinical practice. The primary outcome was the total number of MII oocytes. Patients were followed up until all embryos were transferred, or until live birth was achieved. Other secondary outcomes included the number of cumulus-oocyte complexes (COCs), the number of good quality embryos (Day 3/5), the ongoing pregnancy rate, and gonadotropin consumption. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients between 25 and 40 years old, with an anti-Müllerian hormone level of ≤1.5 ng/ml, antral follicle count of ≤6, or ≤5 oocytes after a previous stimulation, were included. At the start, 70 patients were eligible for participation in the trial, of whom 48 patients fulfilled the final inclusion criterium and were randomized. After drop-out of two patients, 23 patients were randomized to a single round of OS (Group A), and 23 patients were randomized to two uninterrupted rounds of OS (Group B). MAIN RESULTS AND THE ROLE OF CHANCE: Baseline characteristics were similar between both groups. The cumulative number of COCs and MII oocytes after completion of the second OR was similar in Group A and Group B [5.3 ± 2.7 versus 5.3 ± 3.0 (P = 0.95); 4.1 ± 2.4 versus 4.3 ± 2.7 (P = 0.77)]. Likewise, a comparable number of excellent and good quality embryos was available on Day 3 (3.0 ± 2.0 versus 2.7 ± 2.0; P = 0.63). In Group B, the cancellation rate due to insufficient response to the second round of stimulation was 39.1% (9/23). When focusing on the first stimulation in both groups, there were no significant differences regarding basal FSH, gonadotropin consumption, and the number of preovulatory follicles. After the first OR, the mean number of COC and MII oocytes was significantly higher in Group A (who had hCG triggering), compared to Group B (who had GnRH agonist triggering) [5.3 ± 2.7 versus 3.3 ± 2.2; difference 95% CI (0.54 to 3.45), P = 0.004 and 4.1 ± 2.4 versus 3.0 ± 2.2; difference 95% CI (-0.15 to 2.6), P = 0.05, respectively]. Likewise, the number of excellent and good quality embryos on Day 3 was significantly higher (3.0 ± 2.0 versus 1.9 ± 1.7; P = 0.02) in Group A. LIMITATIONS, REASONS FOR CAUTION: This study was powered to demonstrate superiority for the number of MII oocytes after dual stimulation. Investigating the impact of dual stimulation on pregnancy rates would have required a larger sample size. Furthermore, the heterogeneity in embryo vitrification and transfer policies precluded a correct comparison of embryologic outcomes between both groups. WIDER IMPLICATIONS OF THE FINDINGS: This is the first RCT investigating the role of continuous stimulation with double aspiration in low responders. Our results show no statistically significant differences in the cumulative number of MII oocytes between one conventional stimulation with fresh ET and two consecutive stimulations with a freeze-only approach. Furthermore, the observed suboptimal oocyte yield after agonist ovulation triggering in low responders in the dual uninterrupted OS group is a reason for concern and further scrutiny, given that previous RCTs have shown similar outcomes in normal and high responders after hCG and GnRH agonist triggers. STUDY FUNDING/COMPETING INTEREST(S): This work was supported in part by a research grant from Organon. H.T. received honoraria for lectures and presentations from Abbott, Cooper Surgical, Gedeon-Richter, Cook, Goodlife, and Ferring. L.B. received fees for lectures from Merck & Organon and support for attending ESHRE 2023. M.D.V. reports fees for lectures from Ferring, Merck, Organon, IBSA, Gedeon Richter, and Cooper Surgical and support for attending ASRM 2023. S.M. received honoraria for lectures and presentations from Abbott, Cooper Surgical, Gedeon-Richter, IBSA, and Merck. C.B. was on the Advisory board and received consulting fees from Theramex and received honoraria for lectures and presentations from Abbott, Ferring, Gedeon-Richter, IBSA, and Merck. TRIAL REGISTRATION NUMBER: NCT03846544. TRIAL REGISTRATION DATE: 19 February 2019. DATE OF FIRST PATIENT'S ENROLMENT: 28 October 2019.

Ultra-low-dose and very-low-dose Lupron downregulation protocols for poor responders based on POSEIDON group 3 and 4 classifications.

PURPOSE: The objective of this study was to assess if very-low-dose Lupron (VLDL) and ultra-low-dose Lupron (ULDL) protocols can have comparable cycle outcomes when compared to other "poor responder" stimulation protocols based on POSEIDON classification groups 3 (PG3) and 4 (PG4). METHODS: A retrospective cohort study at a single, large academic center was performed. Women in PG3 (age < 35, AMH < 1.2 ng/mL) or PG4 (age ≥ 35, AMH < 1.2 ng/mL) undergoing in vitro fertilization using an ULDL (Lupron 0.1 to 0.05 mg daily), VLDL (Lupron 0.2 to 0.1 mg daily), microflare (Lupron 0.05 mg twice a day), estradiol priming/antagonist, antagonist, or minimal stimulation protocols from 2012 to 2021 were included. The primary outcome was the number of mature oocytes (MII) obtained. The secondary outcome was live birth rate (LBR). RESULTS: The cohort included 3601 cycles. The mean age was 38.1 ± 3.8 years. In the PG3 group, ULDL and VLDL protocols produced a comparable number of MIIs (5.8 ± 4.3 and 5.9 ± 5.4, respectively) and live births (33.3% and 33.3%, respectively) when compared to other protocols. In the PG4 group, ULDL and VLDL protocols resulted in a higher percentage of MIIs when compared to microflare or minimal stimulation (Microflare/ULDL: adjusted relative risk (aRR) 0.78 (95% CI 0.65, 0.95); min stim/ULDL: aRR 0.47 (95% CI 0.38, 0.58); microflare/VLDL: aRR 0.77 (95% CI 0.63, 0.95); min stim/VLDL: aRR 0.47 (95% CI 0.38, 0.95)). There were no significant differences in LBR. CONCLUSION: Dilute Lupron downregulation protocols have comparable outcomes to other poor responder protocols and are reasonable to use.

Association between Leukemia Inhibitory Factor Gene Polymorphism and Clinical Outcomes among Young Women with Poor Ovarian Response to Assisted Reproductive Technology.

BACKGROUND: Does the presence of single-nucleotide polymorphisms (SNPs) in the leukemia inhibitory factor (LIF) gene affect ovarian response in infertile young women? METHODS: This was a case-control study recruiting 1744 infertile women between January 2014 to December 2015. The 1084 eligible patients were stratified into four groups using the POSEIDON criteria. The gonadotropin-releasing hormone receptor (GnRHR), follicle-stimulating hormone receptor (FSHR), anti-Müllerian hormone (AMH), and LIF SNP genotypes were compared among the groups. The distributions of LIF and FSHR among younger and older patients were compared. Clinical outcomes were also compared. RESULTS: The four groups of poor responders had different distributions of SNP in LIF. The prevalence of LIF genotypes among young poor ovarian responders differed from those of normal responders. Genetic model analyses in infertile young women revealed that the TG or GG genotype in the LIF resulted in fewer oocytes retrieved and fewer mature oocytes relative to the TT genotypes. In older women, the FSHR SNP genotype contributed to fewer numbers of mature oocytes. CONCLUSIONS: LIF and FSHR SNP genotypes were associated with a statistically significant reduction in ovarian response to controlled ovarian hyperstimulation in younger and older women with an adequate ovarian reserve, respectively.

Presence of Endometrioma Does Not Impair Embryo Quality and Assisted Reproductive Technology (ART) Cycle Outcome in Diminished Ovarian Reserve (DOR) Patients.

This study aims to assess the impact of endometrioma on embryo quality and cycle outcome in patients who undergo assisted reproductive technology (ART) treatment due to diminished ovarian reserve (DOR). Retrospective case-control study was conducted in women ≤ 40 years of age who underwent ART treatment caused by DOR, defined according to POSEIDON criteria, at a university-based infertility clinic between January 2015 and December 2020. Three groups of patients were selected: group A included patients with an idiopathic DOR, group B included patients with endometrioma(s) who underwent ovarian cystectomy, and group C included patients with endometrioma(s) without surgical treatment. A total of 351 women with DOR were included in the final analysis. Demographic characteristics, including age and AMH, were similar between the groups. Significant differences were observed among groups on mean number of MII oocytes retrieved (1.88 ± 1.59 vs. 2.84 ± 2.89 vs. 2.78 ± 2.41, respectively; p < 0.001) and mean number of embryos (1.04 ± 1.18 vs. 1.87 ± 2.01 vs. 1.66 ± 1.81, respectively; p < 0.001). However, the mean number of top-quality embryos, cycle cancellation, and live birth rates were similar between the groups. Clinical pregnancy (35 (26.5%) vs. 8 (18.2%) vs. 18 (42.9%), respectively; p = 0.038) and miscarriage rates (12 (9.1%) vs. 0 vs. 8 (19.0%), respectively; p = 0.009) were higher in endometrioma group without surgery. Women with DOR appear to have similar ART cycle outcomes regardless of the etiology, in terms of live birth rates. Infertility of endometrioma patients might be related to altered endometrium rather than to decreased oocyte quality. Cystectomy for endometrioma before IVF did not seem to affect the LBR.

A randomized, non-inferiority trial on the DuoStim strategy in PGT-A cycles.

RESEARCH QUESTION: Is the DuoStim strategy an effective alternative to two conventional ovarian stimulation cycles in poor-prognosis patients undergoing preimplantation genetic testing for aneuploidies (PGT-A) to improve euploidy rates and obtain the first euploid embryo in less time? DESIGN: This randomized controlled trial was performed at IVI Madrid between June 2017 and December 2020 and included 80 patients with a suboptimal profile aged 38 or older undergoing PGT-A cycles. Patients were blindly randomized into two groups: 39 women underwent two ovarian stimulations in consecutive cycles (control group), whereas the double stimulation strategy was applied to 41 women (DuoStim group). The main outcome was the euploidy rate in each group. The secondary outcomes were the time it took to obtain a euploid embryo and the main cycle outcomes. RESULTS: The baseline characteristics of the patients were similar. No differences were found between the control group and the DuoStim group in the mean days of stimulation (21.3 ± 1.6 versus 23.0 ± 1.4, P = 0.10), total gonadotrophins (4005 ± 450 versus 4245 ± 430, P = 0.43), metaphase II oocytes (8.7 ± 1.8 versus 6.8 ± 1.7, P = 0.15) or euploid embryos obtained (0.8 ± 0.4 versus 0.6 ± 0.4, P = 0.45). The euploid rate per randomized patient (ITT) was 16.1% in the control group versus 22.7% in the DuoStim group, with P-values of 0.371, and the euploidy rate per patient treated was 39.0% versus 45.7% in the control versus DuoStim groups. However, there was a significant difference in the average number of days it took to obtain a euploid blastocyst, favouring the DuoStim group (44.1 ± 2.0 versus 23.3 ± 2.8, P < 0.001). CONCLUSIONS: The use of the DuoStim strategy in poor-prognosis patients undergoing PGT-A cycles maintains a similar euploidy rate while reducing the time required to obtain a euploid blastocyst.

"Short agonist stop" protocol, an ovarian stimulation for poor responders in in vitro fertilization (IVF): A pilot study.

Introduction: Poor responder patients remain a challenge in assisted reproductive technologies. The "short agonist stop" (SAS) stimulation protocol uses a double stimulation (flare up effect with the gonadotropin-releasing hormone (GnRH) agonist (GnRH-a) then gonadotropins) associated with a less strenuous blockage (discontinuation of GnRH-a) to favor follicular recruitment in order to obtain a better ovarian response. This study aims to compare the number of oocytes obtained after a SAS stimulation protocol with those obtained after the previous stimulation protocol, in the same women, with poor ovarian response (POR) diagnosed according to the POSEIDON criteria. Design: This therapeutic observational retrospective cohort from 2018 to 2022, with a case-control evaluation compared with the same patients' previous performance, included women with POR undergoing IVF with SAS stimulation protocol. The primary outcome was the number of total oocytes recovered and secondary outcomes were the numbers of mature oocytes, total embryos observed at day 2 and usable cleaved embryos and blastocysts (day 5/6). Results: 63 patients with SAS and previous cycles were included. In the SAS group, the mean number of oocytes was significantly higher: 7.3 vs 5.7, p=0.018 in comparison with the previous attempt. So was the number of mature oocytes (5.8 vs 4.1, p=0.032) and the total mean number of embryos obtained at day 2 (4.1 versus 2.7, p=0.016). The SAS stimulation generated 84 usable embryos: 57 cleaved embryos and 27 blastocysts. The mean number of usable embryos was similar in both groups (1.64 vs 1.31, respectively, p=0.178). In total, out of 63 patients, after the SAS protocol, and subsequent embryo transfers (fresh and frozen, n=54), 9 patients had ongoing pregnancies and no miscarriage occurred. The cumulative ongoing pregnancy rate (cOPR) after the SAS protocol was 14.3% (9/63) per oocyte pick-up and 16.7% (9/54) per transfer. Conclusion: SAS stimulation is a short and original protocol strengthening the therapeutic arsenal of poor responders, that may offer promising results for those patients with low prognosis and previous failed IVF. Results must be confirmed with a randomized controlled trial.

The role of growth hormone in assisted reproduction.

In contemporary ART, the use of "add-ons" during ovarian stimulation has increased, especially in poor responders. Growth Hormone (GH) is an adjunctive therapy that has been studied extensively in the translational and clinical setting, with an ongoing scientific debate over its effectiveness and optimal use. In this review, we aim to provide an overview of the physiologic basis for the use of GH in ART, and to summarize the latest evidence regarding its clinical use, primarily as an adjunct to ovarian stimulation, but also in the IVF lab and with regards to its effects on the endometrium.

The effect of androgen administration on in vitro fertilization outcome in poor responders undergoing ovarian stimulation with microdose protocol: A randomized clinical trial.

OBJECTIVE(S): Patients with poor ovarian response who have reduced ovarian reserve sometimes despite the maximum dose of gonadotropins do not respond properly. Androgens have been shown to play an important role in the early follicular development and proliferation of granulosa cells. This study aimed to evaluate the effect of androgen administration on IVF outcome in poor responders. STUDY DESIGN: In this randomized clinical trial, 60 poor responder women candidate for controlled ovarian stimulation were randomly enrolled in two groups (n = 30/each). In the intervention group testosterone gel added to the interrupted microdose flare protocol. The control group received the conventional microdose flare protocol. RESULTS: The main outcome was clinical and chemical pregnancy; and the second outcomes were the number of mature oocytes, duration of cycle and total dose of gonadotropins. Basic clinical and demographic features were comparable between the groups. The total gonadotropin consumption were significantly higher in the control group than the intervention group (p = 0.047). In addition, the number of MII oocytes was higher (but not significant) in the intervention group than the control group (p = 0.16). The mean total duration of the cycle was equal in both groups. There were no significant differences in chemical and clinical pregnancy rates between the two groups (p = 0.41, p = 0.67). CONCLUSION(S): The results of the current study showed that androgen administration in poor responders in in vitro fertilization reduces the total dose of gonadotropin, but it does not improve the pregnancy outcomes.

Does the dose or type of gonadotropins affect the reproductive outcomes of poor responders undergoing modified natural cycle IVF (MNC-IVF)?

OBJECTIVE: Does the dose or type of gonadotropin affect the reproductive outcomes of poor responders undergoing IVF in a modified natural cycle (MNC-IVF)? STUDY DESIGN: This is a retrospective cohort study including patients attending a tertiary referral University Hospital from 1st January 2017 until 1st March 2020. All predicted poor responders (Poseidon groups 3 and 4) who underwent MNC-IVF in our center were included. Mild ovarian stimulation (rFSH/uFSH/hp-hMG) was started when a follicle with a mean diameter of 12-14 mm was observed on ultrasound scan; GnRH antagonist was added from the next day onwards. Mature oocytes were inseminated using ICSI. RESULTS: In total 484 patients undergoing 1398 cycles were included. Mean (SD) age and serum AMH were 38.2 (3.7) years and 0.28 (0.26) ng/ml, respectively. The daily dose of gonadotropins was either < 75 IU/d [11/1398 (0.8 %)] or 75 to < 100 IU/d [1303/1398 (93.2 %)] or ≥ 100 to 150 IU/d [84/1398 (6 %)]. Patients were stimulated with rFSH [251/1398 (18 %)], uFSH [45/1398 (3.2 %)] or hp-hMG [1102/1398 (78.8 %)]. Clinical pregnancy rate was 119/1398 (8.5 %). Live birth was achieved in 80/1398 (5.7 %) of cycles. There was no significant difference in rates of pregnancy and live birth across different types and doses of gonadotropins. The GEE multivariate regression analysis, adjusting for relevant confounders, showed that the type of treatment strategy (rFSH/uFSH/hp-hMG) and the daily dose of gonadotropins were not associated with live birth rates (LBR) (p value 0.08 and 0.8, respectively). CONCLUSIONS: The type and daily dose of gonadotropins do not affect the reproductive outcome of poor responders undergoing MNC-IVF.

Ovarian Stimulation in Assisted Reproductive Technology Cycles for Varied Patient Profiles: An Indian Perspective.

Controlled ovarian stimulation has been an integral part of in vitro fertilisation (IVF) treatment cycles. Availability of different gonadotropins for ovarian stimulation and gonadotropin releasing hormone (GnRH) analogues for prevention of premature rise of leutinising hormone during follicular phase offer an opportunity to utilise them for a successful outcome in women with different subsets of ovarian response. Further, use of GnRH agonist as an alternative for human chorionic gonadotropin improves safety of ovarian stimulation in hyper-responders. Mild ovarian stimulation protocols have emerged as an alternative to conventional protocols in the recent years. Individualisation plays an important role in improving safety of IVF in hyper-responders while efforts continue to improve efficacy in poor responders. Some of the follicular and peri-ovulatory phase interventions may be associated with negative impact on the luteal phase and segmentalisation of the treatment with frozen embryo transfer may be an effective strategy in such a clinical scenario. This narrative review looks at the available evidence on various aspects of ovarian stimulation strategies and their consequences. In addition, it provides a concise summary of the evidence that has emerged from India on various aspects of ovarian stimulation.

When is the right time to stop autologous in vitro fertilization treatment in poor responders?

Declining oocyte quality and quantity with age are the main limiting factors in female reproductive success. Age of the female partner, ovarian reserve, the patient's previous fertility treatment outcomes, and the fertility center's pregnancy success data for specific patient profiles are used to predict live birth rates with in vitro fertilization (IVF) treatment. The chance of finding a euploid blastocyst or achieving live birth after the age of 45 is close to zero. Therefore, any IVF cycle using autologous oocytes after the age of 45 can be accepted as futile and should be discouraged. The number of mature eggs retrieved and the number of embryos available for transfer are the second most important predictors of pregnancy and live birth after female age. For patients aged ≤45 years, the recommendation for attempting IVF should be given considering the patient's age and the expected ovarian response. Before the start of the IVF cycle, patients with a very poor prognosis must be fully informed of the prognosis, risks, costs, and alternatives, including using donor oocytes. Alternative treatments to improve oocyte quality and decrease aneuploidy have the potential to change how clinicians treat poor responders. However, these treatments are not yet ready for clinical use.

Effect of rLH Supplementation during Controlled Ovarian Stimulation for IVF: Evidence from a Retrospective Analysis of 1470 Poor/Suboptimal/Normal Responders Receiving Either rFSH plus rLH or rFSH Alone.

We retrospectively studied a real-life population of 1470 women undergoing IVF, with poor/suboptimal/normal ovarian responsiveness to controlled ovarian stimulation (COS), comparing the cumulative live birth rate (cLBR) when COS was performed using rFSH alone or rFSH + rLH in a 2:1 ratio. Overall, we observed significantly higher cLBR in the rFSH alone group than in the rFSH + rLH group (29.3% vs. 22.2%, p < 0.01). However, considering only suboptimal/poor responders (n = 309), we observed comparable cLBR (15.6% vs. 15.2%, p = 0.95) despite the fact that patients receiving rFSH + rLH had significantly higher ages and worse ovarian reserve markers. The equivalent effectiveness of rFSH + rLH and rFSH alone was further confirmed after stratification according to the number of oocytes retrieved: despite basal characteristics were still in favor of rFSH alone group, the cLBR always resulted comparable. Even subdividing patients according to the POSEIDON classification, irrespective of differences in the baseline clinical characteristics in favor of FSH alone group, the cLBR resulted comparable in all subgroups. Despite the retrospective, real-life analysis, our data suggest that rLH supplementation in COS may represent a reasonable option for patients with predictable or unexpected poor/suboptimal ovarian responsiveness to FSH, those matching the Bologna criteria for poor responsiveness, and those included in the POSEIDON classification.

Influence of Maternal Age and Ovarian Reserve on the Decision to Continue or to Cancel IVF Cycles in Patients with One or Two Large Follicles: a Dual Effect.

This study aimed to study whether IVF stimulation that results in one or two mature follicles should proceed to oocyte retrieval. This is a retrospective cohort study conducted at McGill University Health Center on 459 patients who underwent IVF treatment between 2011 and 2014, undergoing hormonal stimulation and monitoring of their ovarian response. The primary outcomes were pregnancy and live birth rates. Statistical modeling was used to determine individual roles of patient age and ovarian reserve on outcomes, while controlling for the other factors. Of the 459 cycles included in the study, 360 cycles (78.4%) ended in embryo transfer. Live birth rates per cycle were 15.6%, for the ≤ 34-year-olds; 6.5%, for the 35-39-year-olds; and 2.7%, for the ≥ 40-year-olds (p < 0.01). Twenty-five percent of the cycles in the ≥ 40-year-old group were canceled versus 17% and 15% in the 35-39-year-old and ≤ 34-year-old groups, respectively (p < 0.05). Testing likelihood of live birth as a function of age and antral follicular count (AFC) revealed that a 1-year increase in age reduces the likelihood of live birth by 11% (p < 0.05) and one-unit increase in AFC count leads to a 9% increase in the odds of a live birth (p < 0.05). For the youngest age group, the AFC had a most significant effect, and those with AFC > 11 had 56% live birth rate, while those with AFC ≤ 11 had only 6% of live birth rate. This study supports a shift in reasoning from age being the predictor of outcomes in women with a low response at IVF to both age and ovarian reserve needing to be taken into consideration.

A mathematical model to identify optimal combinations of drug targets for dupilumab poor responders in atopic dermatitis.

BACKGROUND: Several biologics for atopic dermatitis (AD) have demonstrated good efficacy in clinical trials, but with a substantial proportion of patients being identified as poor responders. This study aims to understand the pathophysiological backgrounds of patient variability in drug response, especially for dupilumab, and to identify promising drug targets in dupilumab poor responders. METHODS: We conducted model-based meta-analysis of recent clinical trials of AD biologics and developed a mathematical model that reproduces reported clinical efficacies for nine biological drugs (dupilumab, lebrikizumab, tralokinumab, secukinumab, fezakinumab, nemolizumab, tezepelumab, GBR 830, and recombinant interferon-gamma) by describing system-level AD pathogenesis. Using this model, we simulated the clinical efficacy of hypothetical therapies on virtual patients. RESULTS: Our model reproduced reported time courses of %improved EASI and EASI-75 of the nine drugs. The global sensitivity analysis and model simulation indicated the baseline level of IL-13 could stratify dupilumab good responders. Model simulation on the efficacies of hypothetical therapies revealed that simultaneous inhibition of IL-13 and IL-22 was effective, whereas application of the nine biologic drugs was ineffective, for dupilumab poor responders (EASI-75 at 24 weeks: 21.6% vs. max. 1.9%). CONCLUSION: Our model identified IL-13 as a potential predictive biomarker to stratify dupilumab good responders, and simultaneous inhibition of IL-13 and IL-22 as a promising drug therapy for dupilumab poor responders. This model will serve as a computational platform for model-informed drug development for precision medicine, as it allows evaluation of the effects of new potential drug targets and the mechanisms behind patient variability in drug response.

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 STATEMENTWhat 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.

Double HCG trigger improves recovery of oocytes in women with a paucifollicular response to ovarian stimulation: A pilot study.

OBJECTIVE: To examine whether adding a second HCG trigger, 12.5 h after the first (36.5 h before ovarian puncture), can facilitate recovery of oocytes in women with a paucifollicular response to ovarian stimulation. METHODS: A total of 85 women aged 35-42 years, with a paucifollicular response to ovarian stimulation and who had experienced a total failure of oocyte recovery after the standard HCG ovulation trigger 36.5 h before ovarian puncture, were subsequently treated by the same protocol but with the addition of a second HCG trigger 12.5 h later. The recovered oocytes were inseminated by intracytoplasmic sperm injection (ICSI) and all available embryos were transferred 3 days later. RESULTS: The double trigger enabled recovery of cumulus oophorus cells from most of the follicles in the women who experienced failure of total recovery of oocytes after a single trigger. Fifteen patients became pregnant, and no signs of ovarian hyperstimulation syndrome were observed. Nine women delivered a healthy child. CONCLUSION: In women aged 35-42 years with a paucifollicular response to ovarian stimulation, a double HCG trigger appears to improve the rate of oocyte recovery. The conclusion of this pilot study needs to be confirmed by larger prospective trials.