Reply of the authors: "Impact of bilateral intraovarian platelet-rich plasma in women with poor ovarian response or primary ovarian insufficiency: a retrospective study".

Study question To investigate if the anti-ovarian antibody (AOA) is associated with poor ovarian response (POR) and pro-inflammatory immune responses in women undergoing assisted reproductive technology (ART) cycles. Summary answer The POR patients have a higher prevalence of AOAs. Women with autoimmune POR (POR(+)/AOA(+)) have dysregulated pro-inflammatory immune responses and metabolic factors. What is known already It has been proved that AOAs play important role in diseases that related to human reproduction such as premature ovarian failure (POF) which also termed as premature ovarian insufficiency (POI), infertility, polycystic ovary syndrome (PCOS), in vitro fertilization (IVF) implantation failure, and in poor ovarian response in IVF stimulation. The POR women had elevated inflammatory immune responses: increased NK cell count and cytotoxicity, B cell counts, Th1/Th2 ratio and elevated metabolic factors such as higher homocysteine and plasminogen activator inhibitor–1 (PAI–1) level. Study design, size, duration This study is a retrospective cohort study between December 2015 and February 2019. 248 women who underwent ART cycles were included. Study patients were divided into four groups based on AOA test and POR diagnose defined by the European Society of Human Reproduction and Embryology consensus: POR(-)/AOA (-) group (N = 148), POR(+)/AOA(-) group (N = 34), POR (-)/AOA (+) group (N = 44), POR(+)/AOA(+) group (N = 22). Peripheral blood was collected during the early follicular phase when they enter the program. Participants/materials, setting, methods The natural killer (NK) cell levels and cytotoxicity, T helper (Th) 1/Th2 cell ratios were measured by flowcytometry. Anti-phospholipid Antibodies (APA) was tested by enzyme linked immunosorbent assay (ELISA). AOA, 25 (OH) vitamin D level, homocysteine, PAI–1 level was tested by Immunofluorescence Assay.One way ANOVA was applied to compare the continuous variables among study groups. Chi-squared analysis or Fisher’s exact test were performed to compare the categorical variables. Main results and the role of chance The POR patients have a significantly higher prevalence of AOA than non-POR patients (39.3% vs. 22.9%, P = 0.017, OR 2.176 95% CI 1.156–4.099). Peripheral blood CD56+ NK cell level (%), NK cytotoxicity, CD19+CD5+ B–1 cell level (%) and IFN-g/IL–10 producing Th1/Th2 cell ratios were significantly higher in POR(+)/AOA(+) group than those of other groups (P < 0.05, P < 0.05, P < 0.05, P < 0.05, respectively). TNF-a/IL–10 producing Th1/Th2 cell ratio of POR(+)/AOA (+) group was significantly higher than those of POR(+)/AOA(-) and POR(-)/AOA(-) groups (P < 0.05, respectively). Peripheral blood homocysteine and vitamin D levels of the POR(+)/AOA (+) group were significantly lower than those of other groups (P < 0.005, respectively). Peripheral blood PAI–1 level of POR(+)/AOA(+) group was significantly higher than that of POR(-)/AOA(-) group (P < 0.05). In POR(+)/AOA(+) group, the prevalence of antiphospholipid antibody was significantly higher than that of POR(+)/AOA(-) group (54.5% vs 20.5%, P = 0.005, OR 4.667, 95% CI 1.532–14.216). Limitations, reasons for caution This was a single center study, results need to be validated across different center and study population. Wider implications of the findings: The diagnostic and therapeutic approaches for AOA (+) autoimmune POR patients should be differentiated from those for non-autoimmune POR. Trial registration number Not applicable

Drug-free in vitro activation of ovarian follicles and fresh tissue autotransplantation in patients with poor ovarian response and premature ovarian insufficiency.

In vitro fertilization (IVF) with egg donation often stands as the sole treatment option for women with premature ovarian insufficiency (POI) or poor ovarian response (POR); for this reason, alternative techniques are being developed, among which stand surgical techniques for ovarian activation. The aim of the present study was to evaluate the effectiveness of surgical techniques for ovarian activation in patients affected by POI or POR. In this systematic review study, a comprehensive search of the literature was carried out on the principal databases. Only original studies reporting the treatment of POI or POR using surgical techniques for ovarian activation in human subjects were deemed eligible for inclusion in this qualitative analysis. Overall, 187 patients with POI and 65 patients with POR were treated with experimental surgical techniques. Among the POI patients, 10 pregnancies and 8 live births were achieved. In the POR group, 18 pregnancies were reported with 14 live births. Ovarian fragmentation (OF) appears to be a promising method for treating POI, although large sample randomized controlled trials (RCTs) are necessary to confirm this hypothesis. Regarding POR, surgical techniques do not improve IVF outcomes, and thus should not be proposed, although they may lead to a slight increase in ovarian reserve markers as compared with before treatment. Both clinical and basic science studies are highly demanded to better understand the molecular mechanisms underlying some partially promising results, with the aim of improving currently available techniques.

The aim. To conduct a comparative analysis of clinical and anamnestic data in women of reproductive age after ovarian cyst surgery and with occult premature ovarian insufficiency (POI) to predict a poor ovarian response to stimulation.Materials and methods. We conducted a retrospective study of medical records of women (aged 18–40 years) with infertility at the Assisted Reproductive Technology Center of Siberian State Medical University from 2017 to 2020. The main group consisted of 84 patients who underwent ovarian cyst surgery. The comparison group consisted of 33 patients with biochemical signs of POI (follicle stimulating hormone (FSH) 10–12 mMU / ml) who did not undergo ovarian cyst surgery. Anti-Mullerian hormone (AMH), FSH, estradiol, the antral follicle count (AFC), and the ovarian response to stimulation were compared.Results. A correlation was established between AFC and a poor ovarian response both in the main group (r = –0.7; p = 0.004) and in the comparison group (r = –0.620; p = 0.000) in women under 35 years of age. A correlation was found between the concentration of estradiol and a poor ovarian response in the comparison group in women over 35 years of age (r = –0.707; p = 0.001). A moderate negative correlation between AMH and a poor ovarian response was revealed only in the main group of women under the age of 35 years (r = –0.589; p = 0.021). A moderate negative correlation between AMH and a poor ovarian response was revealed in the comparison group in women under the age of 35 years (r = –0.648; p = 0.000), a weak negative correlation was found for women at the age of 35 years (r = –0.500; p = 0.004). In both groups, the level of FSH did not determine the ovarian response to stimulation.Conclusion. The determination of AFC and AMH is more significant in predicting a poor ovarian response in women after ovarian surgery and in women with occult signs of POI under the age of 35 years, compared with FSH. In the group of women over 35 years with occult signs of POI, the concentration of estradiol may matter in predicting a poor ovarian response, which requires further research.

Background and Aims: For non-severe male factor infertility patients with poor and sub-optimal ovarian response, are there any differences in reproduction outcomes between IVF (in vitro fertilization) and ICSI (intracytoplasmic sperm injection) methods? Methods: Retrospective cohort study. Patients with non-severe male infertility and poor ovarian response who underwent in vitro fertilization or intracytoplasmic sperm injection at the Center for Reproductive Medicine, Peking University Third Hospital between 2009 and 2019 were included in this study (n = 30,352). Results: In all groups, intracytoplasmic sperm injection cycles involved older patients and a longer duration of infertility, while body mass index, AMH, and bFSH levels were similar. Independent of the number of oocytes retrieved, intracytoplasmic sperm injection significantly increased the fertilization rate, while in vitro fertilization cycles showed a higher implantation rate, clinical pregnancy rate, and live birth rate. No differences were observed in most obstetric outcomes, including abortion, early abortion, multiple fetus, cesarean delivery, gestational age, and congenital malformations rates. However, in vitro fertilization cycles showed higher preterm delivery rates and lower birth weights in groups with 4-6, and 7-9 oocytes retrieved. A higher female/male infant ratio was observed in intracytoplasmic sperm injection cycles when 4-6 oocytes were retrieved. Conclusions: In patients with non-severe male infertility and poor or suboptimal ovarian response, even if intracytoplasmic sperm injection increased the fertilization rate, in vitro fertilization exhibited significant advantages in implantation, clinical pregnancy, and live birth rates. Our study indicates that poor ovarian response is not an indication for intracytoplasmic sperm injection in couples with non-severe male infertility.

BackgroundPOR or POI poses a significant challenge to fertility treatment with different ovarian stimulation strategies. Intra-ovarian injection of platelet-rich plasma (PRP) has been hypothesised to improve ovarian reserve and pregnancies in POI or POR. However, its effectiveness on pregnancy, embryology and ovarian reserve outcomes need to be established. Therefore, we systematically searched databases based on PRISMA guidelines that reported on the effects of intra-ovarian autologous PRP injections in sub-fertile women with POI and POR. The following outcome effects were analysed by random model and included in the meta-analysis in pre- and post-PRP injection groups of POI & POR: (a) pregnancy rates, rate of oocyte & embryo formation (b) ovarian reserve markers (Antral follicular count, Anti-Mullerian Hormone, Follicle Stimulating Hormone). A separate analysis of pregnancies, AFC and AMH was done in POI and POR groups and in age groups < 35 years and > 35 years. A total of 12 studies were included. The estimated overall effects size of the log odds ratio (log OR = 2.03; 95% CI = 0.13 to 3.92; P = 0.04; I2 = 0.42) favoured post-PRP with a moderate level of evidence. There are no significant differences in POI/POR and those with < 35 years or > 35 years.The pooled standard difference of means favoured the post-PRP injection group significantly with regards to rates of embryo formation (1.39; 95% CI = 0.56 to 2.21; P = 0.02; I2 = 46%.), Oocyte (0.84; 95% CI = -1.3 to 3.0; P = 0.24; I 2 93%), Antral follicle count (1.78; 95% CI = 0.73 to 2.84; P = 0.01. I2 = 97%) with a low level of evidence and Anti-Mullerian Hormone (1.11; 95% CI = 0.16 to 2.05; P = 0.03; I2 = 96%) with low level of evidence.ConclusionOur study shows that intraovarian PRP injection was associated with no significant increase in the rates of pregnancy, in the rates of pregnancy, oocyte, embryo formation, Anti-Mullerian Hormone and antral follicle count. Live birth rates were not calculated. There was no statistical difference between POR/POI and those with < 35 years or > 35 years. Further randomized studies are warranted to confirm our findings.

Does intraovarian platelet-rich plasma (PRP) injection increase the number of mature oocytes obtained after controlled ovarian stimulation (COS) in young women with poor ovarian response (POR) undergoing IVF? Intraovarian PRP injection procedure does not improve mature oocyte yield after COS in women less than 38 years old with an established IVF history of POR. POR is frequently encountered among the infertile population and the number of women seeking infertility treatment related to POR is increasing. Effective treatment options for this patient population to conceive with autologous oocytes are lacking. Case series and cohort studies suggest that intraovarian PRP injection may improve follicular recruitment in women with premature ovarian insufficiency (POI) and POR, yet robust randomized studies have not been performed to date to determine the clinical utility of this intervention. This was a multi-center randomized controlled trial (RCT) conducted at university-affiliated reproductive centers in the USA and Turkey, between January 2020 and November 2022. Patients who met inclusion criteria (<38 years old, two or more prior cycles with <3 oocytes retrieved; and without single gene disorders, prior ovarian surgery, endometriomas, BMI >35 kg/m2, or severe male factor infertility) were randomized to either the PRP or control group. Patients in both groups subsequently underwent COS, oocyte retrieval, ICSI, preimplantation genetic testing for aneuploidy (PGT-A), and single euploid embryo transfer. Number of metaphase II (MII) oocytes obtained was the primary outcome. Secondary outcomes included ovarian reserve tests (antral follicle count [AFC] and anti-Müllerian hormone [AMH]), blastocyst and euploid blastocyst yields, and sustained implantation. The study was powered to detect a difference of one mature oocyte obtained at oocyte retrieval. In total, 83 patients met inclusion criteria and were randomized to receive autologous intraovarian PRP injection (n = 41) or to no intervention (n = 42). No significant differences were observed in number of MII oocytes retrieved per cycle (2.8 ± 2.4 vs 3.1 ± 3.3 in PRP vs control, respectively; P = 0.9), blastocysts (1.0 ± 1.3 vs 1.3 ± 2.1, P = 0.8), or euploid blastocysts (0.8 ± 1.1 vs 0.9 ± 1.6; P = 0.5). Similarly, no differences were observed in the likelihood of obtaining at least one euploid blastocyst (45% vs 37%, P = 0.4; relative risk [RR], 95% CI = 0.9, 0.6-1.2) or the rate of sustained implantation (31% vs 29%, P = 0.9; RR 1.0, 0.7-1.3). Posttreatment AFC (7.9 ± 4.5 vs 6.8 ± 4.8, P = 0.3) and AMH (0.99 ± 0.98 vs 0.7 ± 0.6, P = 0.2) were also not different between the groups. Results from this RCT may not be generalizable to other PRP preparations owing to heterogeneity and lack of standardization. The control groups did not undergo a sham ovarian injection, which would have been relevant had the results shown benefit of PRP injection. Only patients with POR were included in this study, and these results may not be generalizable to more severe diminution of ovarian reserve, as seen with POI. The intraovarian PRP injection procedure does not improve mature oocyte yield or other parameters of IVF outcome in women less than 38 years old with an established IVF history of POR. The results from this study do not support the use of intraovarian PRP injection in this population. Departmental funds were used and no external funding was requested for this study. ES is a consultant for and receives grant funding from the Foundation for Embryonic Competence. All other authors have no conflict of interest to declare. Clinicaltrials.gov Registry Identifier: NCT04163640. 15 November 2019. 24 February 2020.

ObjectiveThe objective of this study was to evaluate the effect of the intraovarian injection of platelet-rich plasma (PRP) on ovarian reserve and reproductive outcomes in patients with premature ovarian insufficiency (POI) and poor ovarian response (POR).Methods and data sourcesThe study registered in the PROSPERO database adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. PubMed, Web of Science, Scopus, Google Scholar, and ClinicalTrials.gov databases were searched from inception to June 2024—23 studies included in the meta-analysis. A total of 1853 participants aged 29.8–45 years old were included in the meta-analysis. The human studies reporting the effect of intraovarian PRP injection on ovarian reserve indicators were included in the meta-analysis. The quality of the included studies was assessed using the Cochrane Handbook or the Newcastle–Ottawa scale. The primary outcomes were serum levels of anti-Mullerian hormone (AMH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), Estradiol, and antral follicle count (AFC), number of retrieved oocytes, metaphase II (M2) oocytes, and pregnancy and live birth rates.Result(s)The pooled analysis of the included studies showed that intraovarian PRP injection significantly increased oocyte number (WMD: 0.97, 95% CI 0.58, 1.35, P < 0.001), M2 oocyte number (WMD: 0.80, 95% CI 0.33, 1.27, P < 0.001), AFC (WMD: 1.64, 95% CI 0.90, 2.38, P < 0.001), and AMH levels (WMD: 0.12 ng/mL, 95% CI 0.07, 0.17, P < 0.001) in women with POR. Besides, in women with POI, PRP injection significantly improved AFC (WMD: 1.33, 95% CI 1.19, 1.47, P < 0.001) and serum levels of FSH (WMD: − 15.68 IU/mL, 95% CI − 24.12, − 7.24, P < 0.001), AMH (WMD: 0.29 ng/mL, 95% CI 0.08, 0.49, P = 0.006), and LH (WMD: − 9.87 IU/mL, 95% CI − 15.23, − 4.51, P < 0.001). The meta-analysis revealed a pregnancy ratio of 0.21 and a live birth ratio of 0.18 in women with poor ovarian reserve after PRP injection. In women with POI, the figures were marginally lower, recorded as 0.138 for pregnancy and 0.10 for live birth, respectively.ConclusionPRP may serve as an alternative therapy for POI and POR; however, further investigation is required to validate its efficacy and determine suitable candidates.

Poor ovarian response in assisted reproductive technology cycles is associated with anti-ovarian antibody and pro-inflammatory immune responses

Intraovarian injection of platelet rich plasma (PRP) is a novel treatment for patients with poor ovarian response (POR) and primary ovarian insufficiency (POI). This article reviews the latest literature on the effect of PRP on markers of ovarian reserve, oocyte and embryo yield, and live birth for these poor prognosis patients. Several case series and one prospective trial have demonstrated improvements in markers of ovarian reserve in patients with POI and POR and improved oocyte and embryo yields in patients with POR. These studies report multiple live births in patients who had previously failed treatment. The positive effects of PRP persist throughout the literature despite the fact that multiple protocols for preparing and injecting PRP exist, with no consensus on the optimal protocol. Intra-ovarian injection of PRP is a promising new technology for poor prognosis patients. Rigorous and appropriately controlled clinical trials are warranted to confirm the utility of this treatment for improving patients' ability to successfully conceive.

The effect of platelet-rich plasma (PRP) on ovarian reserve markers in poor ovarian response (POR) is challenging. This systematic review and meta-analysis was, therefore, designed to evaluate the effectiveness of intra-ovarian injection of autologous PRP on improving ovarian reserve markers and assisted reproductive technology (ART) outcomes in infertile women with POR. A systematic search was conducted for the efficacy of intra-ovarian injection of autologous PRP on the improvement of ovarian reserve markers and ART outcomes in infertile women with POR. The methodological quality of the included studies was checked and eligible studies were included in the meta-analysis to find pooled results. Keywords were primary ovarian insufficiency, premature menopause, poor responder, poor ovarian response, diminished/decreased ovarian reserve, platelet-rich plasma, and intra-ovarian or a combination of them. The effect of PRP on fertility indices was evaluated using the standardized mean difference (SMD). The analysis was performed through STATA version 13. 13 studies containing 1289 patients were included. Mean age, body mass index (BMI) and duration of infertility was 37.63 ± 2.66years, 24 ± 1.23kg/m2 and 4.79 ± 1.64years, respectively. Most of the studies measured the outcomes 2-3/3months after intra-ovarian injection of autologous PRP. The antral follicular count (AFC) after treatment by PRP is higher with an SMD of 0.95 compared to before treatment. The day 3 follicle-stimulating hormone (FSH) after treatment by PRP is lower with an SMD of - 0.25 compared to before treatment. The day 3 estradiol (E2) after treatment by PRP is higher with an SMD of 0.17 compared to before treatment. The anti-Mullerian hormone (AMH) after treatment by PRP is higher with an SMD of 0.44 compared to before treatment. The total oocytes number after treatment by PRP is higher with an SMD of 0.73 compared to before treatment. The number of MII oocytes after treatment by PRP is higher with an SMD of 0.63 compared to before treatment. The number of cleavage-stage embryos after treatment by PRP is higher with an SMD of 1.31 compared to before treatment. The number of day 5 embryo after treatment by PRP is higher with an SMD of 1.28 compared to before treatment. Pooled estimation of a meta-analysis of prevalence studies reported a prevalence of 22% for clinical pregnancy, 5% for spontaneous pregnancy and 21% for ongoing pregnancy following PRP therapy. Intra-ovarian injection of PRP improved ovarian reserve markers with increasing AFC, serum level of AMH and day 3 E2 and decreasing serum level of day 3 FSH. In addition, this treatment improved ART outcomes through the increasing of number total oocytes, number of MII oocytes, number of cleavage-stage embryos and number of day 5 embryos in POR women. Although treatment of POR women remains challenging, the use of intra-ovarian injection of autologous PRP in POR patients prior to IVF/ICSI cycles is a sign of new hope for increasing the success of IVF/ICSI. However, further well-organized, randomized controlled trials should be conducted to substantiate this result and recommend intra-ovarian injection of PRP as part of routine treatment in women with POR.

Background and Objectives: Polycystic ovary syndrome (PCOS) is a major cause of anovulatory infertility, and ovulation induction is the first-line treatment. If this fails, laparoscopic ovarian drilling (LOD) is used to induce mono-ovulations. There have been implications, that LOD can cause destruction of ovarian tissue and therefore premature ovarian failure. Furthermore, unexpected poor ovarian response (POR) to gonadotrophins can occur in PCOS women after LOD. There have been reports about FSH receptor polymorphisms found in women with PCOS that are related to higher serum FSH levels and POR to gonadotrophins. Materials and Methods: In the present study, we retrospectively analyzed data of 144 infertile PCOS women that had LOD performed before IVF. Results: Thirty of included patients (20.8%) had POR (≤3 oocytes) to ovarian stimulation with gonadotrophins. Women with POR had significantly higher median levels of basal serum FSH (7.2 (interquartile range (IQR), 6.0–9.2) compared to women with normal ovarian response (6.0 (IQR, 5.0–7.4); p = 0.006). Furthermore, women with POR used a significantly higher median cumulative dose of gonadotrophins (1875 IU (IQR, 1312.5–2400) for ovarian stimulation compared to women with normal ovarian response (1600 IU (IQR, 1200–1800); p = 0.018). Conclusion: Infertile PCOS women who experience POR after LOD have significantly higher serum FSH levels compared to women with normal ovarian response after LOD. As these levels are still within the normal range, we speculate that LOD is not the cause of POR. We presume that women with PCOS and POR after LOD could have FSH-R genotypes associated with POR and higher serum FSH levels.

The decline in fertility in aging women, especially those with poor ovarian response (POR) or primary ovarian insufficiency (POI), is a major concern for modern IVF centers. Fertility treatments have traditionally relied on gonadotropin- and steroid-hormone-based IVF practices, but these methods have limitations, especially for women with aging ovaries. Researchers have been motivated to explore alternative approaches. Ovarian aging is a complicated process, and the deterioration of oocytes, follicular cells, the extracellular matrix (ECM), and the stromal compartment can all contribute to declining fertility. Adjunct interventions that involve the use of hormones, steroids, and cofactors and gamete engineering are two major research areas aimed to improve fertility in aging women. Additionally, mechanical procedures including the In Vitro Activation (IVA) procedure, which combines pharmacological activators and fragmentation of ovarian strips, and the Whole Ovary Laparoscopic Incision (WOLI) procedure that solely relies on mechanical manipulation in vivo have shown promising results in improving follicle growth and fertility in women with POR and POI. Advances in the use of mechanical procedures have brought exciting opportunities to improve fertility outcomes in aging women with POR or POI. While the lack of a comprehensive understanding of the molecular mechanisms that lead to fertility decline in aging women remains a major challenge for further improvement of mechanical-manipulation-based approaches, recent progress has provided a better view of how these procedures promote folliculogenesis in the fibrotic and avascular aging ovaries. In this review, we first provide a brief overview of the potential mechanisms that contribute to ovarian aging in POI and POR patients, followed by a discussion of measures that aim to improve ovarian folliculogenesis in aging women. At last, we discuss the likely mechanisms that contribute to the outcomes of IVA and WOLI procedures and potential future directions.

Impact of bilateral intraovarian platelet-rich plasma in women with poor ovarian response or primary ovarian insufficiency: a retrospective study.

Premature ovarian insufficiency (POI) is a clinical syndrome defined by loss of ovarian activity before the age of 40 years. However, the etiology of approximately 90% patients remains unknown. Diminished ovarian reserve (DOR) and poor ovarian response (POR) are related to POI in clinic. The main purpose of this review was to evaluate the roles of microRNAs (miRNAs) in the pathogenesis and therapeutic potential for POI, DOR and POR. A literature search was conducted using six databases (PubMed, EMBASE, Web of Science, Cochrane Library, CNKI and Wangfang Data) to obtain relevant studies. This review enlightens expression profiles and functional studies of miRNAs in ovarian insufficiency in animal models and humans. Functional studies emphasized the role of miRNAs in steroidogenesis, granulosa cell proliferation/apoptosis, autophagy and follicular development by regulating target genes in specific pathways, such as the PI3K/AKT/mTOR, TGFβ, MAPK and Hippo pathways. Differentially expressed circulating miRNAs provided novel biomarkers for diagnosis and prediction, such as miR-22-3p and miR-21. Moreover, exosomes derived from stem cells restored ovarian function through miRNAs in chemotherapy-induced POI models. Differential miRNA expression profiles in patients and animal models uncovered the underlying mechanisms and biomarkers of ovarian insufficiency. Exosomal miRNAs can restore ovarian function against chemotherapy-induced POI, which needs further investigation to develop novel preventive and therapeutic strategies in clinical practice.