Poor Ovarian Response Patients Research Articles

P62 promotes FSH-induced antral follicle formation by directing degradation of ubiquitinated WT1

In females, the pathophysiological mechanism of poor ovarian response (POR) is not fully understood. Considering the expression level of p62 was significantly reduced in the granulosa cells (GCs) of POR patients, this study focused on identifying the role of the selective autophagy receptor p62 in conducting the effect of follicle-stimulating hormone (FSH) on antral follicles (AFs) formation in female mice. The results showed that p62 in GCs was FSH responsive and that its level increased to a peak and then decreased time-dependently either in ovaries or in GCs after gonadotropin induction in vivo. GC-specific deletion of p62 resulted in subfertility, a significantly reduced number of AFs and irregular estrous cycles, which were same as pathophysiological symptom of POR. By conducting mass spectrum analysis, we found the ubiquitination of proteins was decreased, and autophagic flux was blocked in GCs. Specifically, the level of nonubiquitinated Wilms tumor 1 homolog (WT1), a transcription factor and negative controller of GC differentiation, increased steadily. Co-IP results showed that p62 deletion increased the level of ubiquitin-specific peptidase 5 (USP5), which blocked the ubiquitination of WT1. Furthermore, a joint analysis of RNA-seq and the spatial transcriptome sequencing data showed the expression of steroid metabolic genes and FSH receptors pivotal for GCs differentiation decreased unanimously. Accordingly, the accumulation of WT1 in GCs deficient of p62 decreased steroid hormone levels and reduced FSH responsiveness, while the availability of p62 in GCs simultaneously ensured the degradation of WT1 through the ubiquitin‒proteasome system and autophagolysosomal system. Therefore, p62 in GCs participates in GC differentiation and AF formation in FSH induction by dynamically controlling the degradation of WT1. The findings of the study contributes to further study the pathology of POR.

Interference of Bisphenol A on Cumulus Cells Development and Number of Retrieved Mature Oocytes in Unexpected Poor Ovarian Response Women: A Prospective Cohort Study.

This study aimed to investigate the relationship between follicular fluid Bisphenol A (BPA) concentrations with alterations in the expressions of NOTCH1-3, CASPASE 3/7, HLA-G, and ICAM-1 genes and the number of retrieved mature oocytes (MII oocyte) in the cumulus cells of infertile poor ovarian response stimulates women. In this prospective cohort study, 80 infertile unexpected poor ovarian response (POR) subjects were selected on the basis of subgroup 1a of the POSEIDON classification. They were divided into two groups: group 1 consisted of 40 women, each with a higher number of metaphase II (MII) oocytes (G1, 3-4 oocytes retrieved), while group 2 comprised of 40 women, each with a lower number of MII oocytes (G2, ≤2 oocytes retrieved). The expressions of the studied genes were evaluated by quantitative-real time polymerase chain reaction (PCR). The concentration of BPA in follicular fluid was measured with HPLC. The expression levels of NOTCH1-3, HLA-G, and ICAM-1 genes were significantly lower in G2 than G1 (P<0.05). Meanwhile, CASPASE 3/7 expression levels were higher in unexpected POR patients in G2 compared to G1 (P<0.05). There was a significant direct correlation between the levels of NOTCH1-3, HLA-G and ICAM-1 gene expressions and there was also a significant inverse correlation (P<0.05) between the levels of CASPASE 3/7, with the number of MII oocytes and embryo development between the two groups. The concentration of BPA in the follicular fluids of G2 was higher compared to G1 (P<0.05). A higher concentration of BPA was associated with a lower number of mature oocytes and oocyte quality in these patients. Also, alterations of NOTCH1-3, CASPASE 3/7, HLA-G, and ICAM-1 transcript levels in unexpected POR women were associated with BPA concentration.

Effect of medroxyprogesterone acetate dose in progestin-primed ovarian stimulation on pregnancy outcomes in poor ovarian response patients with different body mass index levels.

For the poor ovarian response (POR) population, the relationship between medroxyprogesterone acetate (MPA) dose in progestin-primed ovarian stimulation (PPOS) and clinical outcome is still unclear. This study aims to explore the effect of MPA dose in PPOS on clinical outcomes in POSEIDON group 3 and 4 patients with different body mass index (BMI) levels, hoping to provide clinical doctors with better options for controlled ovarian hyperstimulation (COH) programs. This is a retrospective analysis of 253 oocyte retrieval cycles of POSEIDON group 3 and 4 patients who underwent PPOS protocol in IVF/ICSI treatment at the Reproductive Medical Center of Renmin Hospital of Wuhan University from March 2019 to April 2022. The effects of different MPA doses (8 mg/d or 10 mg/d) on pregnancy outcomes were compared in normal BMI (18.5-24 kg/m2) and high BMI (≥24 kg/m2) patients, and multivariate logistic regression analysis was performed to analyze the factors affecting pregnancy outcomes. For normal BMI patients, the 8-mg/d MPA group had a higher embryo implantation rate (33.78% vs. 18.97%, P = 0.012). For high BMI patients, the 10-mg/d MPA group had a higher HCG positive rate (55.00% vs. 25.00%, P = 0.028), clinical pregnancy rate (50.00% vs. 20.00%, P = 0.025), and cumulative pregnancy rate (37.74% vs. 13.79%, P = 0.023) compared with the 8-mg/d MPA group. There was no significant difference in cumulative live birth rate between the 8-mg/d and 10-mg/d MPA groups in patients with normal or high BMI. The results of multivariate logistic regression showed a significant correlation between MPA dose and cumulative pregnancy in the high BMI population (OR = 0.199, 95% CI: 0.046~0.861, P = 0.031). For POR patients with high BMI, 10 mg/d of MPA in the PPOS protocol had a higher cumulative pregnancy rate than 8 mg/d of MPA, but it had no significant effect on the cumulative live birth rate.

Efficacy of intra-ovarian injection of autologous platelet-rich plasma in women with poor responders: a systematic review and meta-analysis.

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.

Comparison of luteal phase stimulation with follicular phase stimulation in poor ovarian response: a single-blinded randomized controlled trial

BackgroundIn the last decade, luteal-phase ovarian stimulation (LPOS) has been suggested as an alternative controlled ovarian stimulation (COS) protocol for in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles mainly in women with a history of poor ovarian response (POR). The present randomized controlled trial study aimed to compare the outcomes of follicular phase ovarian stimulation (FPOS) and LPOS protocols in POR cases undergoing ICSI cycles.MethodsSeventy-eight POR patients who met the Bologna criteria and underwent an ICSI cycle were included. In this study, 39 POR cases were allocated to the FPOS group, and 39 POR cases were allocated to the LPOS group. The primary outcome was the number of metaphase II (MII) oocytes. In addition, the total number of oocytes, number of top-quality day 3 embryo, day 3 embryo development rate, chemical pregnancy and clinical pregnancy rates were defined as secondary outcomes.ResultsThe obtained results demonstrated that the number of MII oocytes significantly increased in the LPOS group compared to the FPOS group (P = 0.007). However, there was no significant difference between the two groups regarding the number of GV and MI oocytes, number of top-quality day 3 embryos and day 3 embryo development rate among both categories of patients. Also, the number of total and MII oocytes was significantly higher in the LPOS group (P = 0.016).ConclusionThese results suggest that LPOS protocol effectively increases the number of mature oocytes in women with a history of POR.Trial registrationIRCT20210405050852N1 (Registered at Iranian registry of clinical trials; available at https://en.irct.ir/trial/55402).

Comparative efficacy of different growth hormone supplementation protocols in improving clinical outcomes in women with poor ovarian response undergoing assisted reproductive therapy: a network meta-analysis

Growth hormone (GH) has a long-standing history of use as an adjunctive therapy in the treatment of poor ovarian response (POR), but the optimal dosage and timing remains unclear. The aim of this study was to evaluate and compare the efficacy of different GH supplementation protocols through a network meta-analysis (NMA) and determine the optimal treatment protocol. This study was reported based on the Preferred Reporting Items for Systematic Reviews for Network Meta-Analysis (PRISMA-NMA) statement. Databases including PubMed, Web of Science, Cochrane Library and Embase were searched until June 2023. A total of 524 records were retrieved in our search, and 23 clinical studies comprising 4889 cycles were involved. Seven different GH protocols were identified. Results showed that compared to the control group, daily administration of 4–8 IU of GH during the follicular phase of the stimulation cycle had the best comprehensive therapeutic effects on improving the number of retrieved oocytes, mature oocytes, endometrial thickness, and reducing gonadotropin requirements in POR patients undergoing assisted reproductive therapy, with a relatively brief treatment duration and a moderate total GH dose. Subgroup analysis demonstrated that this protocol could significantly improve the clinical pregnancy rate of POR patients in the randomized controlled trials (RCT) subgroup and the African subgroup. Therefore, its clinical application is suggested. Besides, the potential advantages of long-term GH supplementation protocol (using GH for at least 2 weeks before oocyte retrieval) has merit for further research. Rigorous and well-designed multi-arm RCTs are needed in the future to confirm the conclusions drawn from this study.

Maternal and neonatal complications after IVF/ICSI-fresh embryo transfer in low-prognosis women under the POSEIDON criteria: a retrospective cohort study

BackgroundSeveral studies on pregnancy complications of poor ovarian response (POR) patients did not draw a consistent conclusion. The POSEIDON criteria introduces the concept of “low prognosis” and divides POR patients into four groups based on age, AFC and AMH for individualized management. We analyzed low-prognosis population and patients with regular ovarian response, compared maternal and neonatal complications and discussed the relevant risk factors.MethodsA retrospective cohort study was conducted of females who achieved a singleton clinical pregnancy after IVF / ICSI—fresh embryo transfer in a single center from January 2014 to March 2019. Participants with low prognosis, as defined by the POSEIDON criteria, were enrolled in the study groups. The controls were defined as AFC ≥ five and number of retrieved oocytes > nine. Maternal and neonatal complications were compared among those groups.ResultsThere were 2554 cycles in POSEIDON group 1, 971 in POSEIDON group 2, 141 in POSEIDON group 3, 142 in POSEIDON group 4, and 3820 in Control. Univariate analysis roughly showed that Groups 2 and 4 had an increased tendency of pregnancy complications. Multi-variable generalized estimating equations (GEE) analysis showed that the risks of GDM, total pregnancy loss, and first-trimester pregnancy loss in Groups 2 and 4 were significantly higher than in Control. The risk of hypertensive disorders of pregnancy (HDP) in Groups 2 and 3 increased, and Group 4 had an increased tendency without statistical significance. After classification by age, GEE analysis showed no significant difference in risks of all complications among groups ≥ 35 years. In patients < 35 years, the risk of HDP in POSEIDON group 3 was significantly higher than in controls (< 35 years), and there was no significant increase in the risk of other complications.ConclusionCompared to patients with regular ovarian response, low-prognosis population have increased tendency of maternal and neonatal complications. In low-prognosis patients, advanced age (≥ 35 years) might be the predominant risk factor for pregnancy complications. In those < 35 years, poor ovarian reserve could contribute to HDP.

The effects of flexible short protocol with gonadotropin-releasing hormone antagonist on preventing premature ovulation in poor responders

PurposeThe proportion of patients with poor ovarian response (POR) is increasing, but effective treatment remains a challenge. To control the hidden peaks of luteinizing hormone (LH) and premature ovulation for poor responders, this study investigated the efficacy of flexible short protocol (FSP) with gonadotropin-releasing hormone antagonist (GnRH-ant) on trigger day.MethodsThe 662 cycles of POR patients were retrospectively analyzed. The cohort was divided into control and intervention groups. The intervention group (group A) with 169 cycles received a GnRH-ant given on trigger day. The control (group B) with 493 cycles received only FSP. The clinical outcomes of the two groups were compared.ResultsCompared with group B, with gonadotropin-releasing hormone antagonist (GnRH-ant) on trigger day in group A the incidences of spontaneous premature ovulation decreased significantly (2.37% vs. 8.72%, P < 0.05). The number of fresh embryo-transfer cycles was 45 in group A and 117 in group B. There were no significant differences in clinical outcomes, including implantation rate, clinical pregnancy rate, live birth rate and the cumulative live birth rate (12.0% vs. 9.34%; 22.22% vs. 21.93%; 17.78% vs. 14.91%; 20.51% vs. 20%, respectively; P > 0.05) between the two group.ConclusionFSP with GnRH-ant addition on trigger day had no effect on clinical outcomes, but could effectively inhibit the hidden peaks of luteinizing hormone (LH) and spontaneous premature ovulation in POR. Therefore, it is an advantageous option for POR women.

Facilitation of Ovarian Response by Mechanical Force-Latest Insight on Fertility Improvement in Women with Poor Ovarian Response or Primary Ovarian Insufficiency.

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.

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

Anti-ovarian antibody (AOA) could be considered an independent marker for autoimmune ovarian disease and predicting future premature ovarian failure (POF). This study aims to investigate if AOA is associated with poor ovarian response (POR) and pro-inflammatory immune responses in women undergoing assisted reproductive technology (ART) cycles. Two hundred forty-eight women undergoing ART cycles were divided into four groups based on AOA test results and the presence of POR: POR(-)/AOA(-) group (N = 148), POR(+)/AOA(-) group (N = 34), POR (-)/AOA(+) group (N = 44), POR(+)/AOA(+) group (N = 22). The POR patients have a significantly higher prevalence of AOA than non-POR patients (P < 0.05). Peripheral blood CD56 + natural killer (NK) cell level (%), NK cytotoxicity, CD19 +CD5 + B-1 cell level (%), and IFN-γ/IL-10 producing T helper (Th) 1/Th2 cell ratios were significantly higher in POR(+)/AOA(+) group than those of other groups (P < 0.001, P < 0.005, P < 0.01, P < 0.05, respectively). TNF-α/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). Homocysteine and vitamin D levels of the POR(+)/AOA(+) group were significantly lower than those of other groups (P < 0.005, respectively). Plasminogen activator inhibiter-1 (PAI-1) level of POR(+)/AOA(+) group was significantly higher than that of POR(-)/AOA(-) group (P < 0.05). In the POR(+)/AOA(+) group, the prevalence of antiphospholipid antibodies was significantly higher than that of the POR(+)/AOA(-) group (P = 0.005). Women with autoimmune POR (POR(+)/AOA(+)) have dysregulated pro-inflammatory immune responses and metabolic factors. The diagnostic and therapeutic approaches for autoimmune POR should be differentiated from those for non-autoimmune POR.

Comparison of Cumulative Live Birth Rates between Flexible and Conventional Progestin-Primed Ovarian Stimulation Protocol in Poor Ovarian Response Patients According to POSEIDON Criteria: A Cohort Study.

To compare the cumulative live birth rate (CLBR) per oocyte retrieval cycle of a conventional progestin-primed ovarian stimulation (cPPOS) regimen with a flexible progestin-primed ovarian stimulation (fPPOS) regimen in poor ovarian response patients, according to POSEIDON criteria. Poor ovarian response women, according to POSEIDON criteria, who underwent the first PPOS protocol for in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) between January 2018 and December 2020 were included. The fPPOS group involved 113 participants, and the cPPOS group included 1119 participants. In the cPPOS group, medroxyprogesterone acetate (MPA) (10 mg/d) was administrated on the gonadotropin injection the same day as gonadotropin injections in the cPPOS group, while MPA was started either on the day when the leading follicle with mean diameter > 12mm was present and/or serum E2 was >300 pg/mL in the fPPOS protocol group. The primary outcome was CLBR. The fPPOS protocol had higher CLBR per oocyte retrieval cycle compared to the cPPOS group, even without a statistically significant difference (29.6% vs. 24.9%, p = 0.365). The fPPOS group had fewer numbers of retrieved oocytes (2.87 ± 2.03 vs. 3.76 ± 2.32, p < 0.001) but a higher MII oocyte rate (89.8% vs. 84.7%, p = 0.016). In addition, the number of available embryos in the two groups was comparable (1.37 ± 1.24 vs. 1.63 ± 1.38, p = 0.095). There were five women in the fPPOS group, and 86 women in the cPPOS group had a premature LH surge (4.2% vs. 6.8%, p = 0.261). In the fPPOS group, there was one instance of premature ovulation, while in the cPPOS group, there were six occurrences of premature ovulation (0.8 vs. 0.5%, p = 1.000). The novel fPPOS protocol appears to achieve higher CLBR even without significant differences and with MPA consumption compared with cPPOS protocol in low-prognosis patients.

O-206 Growth hormone supplementation reduces aneuploidy and improves the quality of aged oocytes by activating the JAK2-ERK1/2 pathway

Abstract Study question Does growth hormone (GH) supplementation improves the quality of oocytes in aged mice via reducing aneuploidy? Summary answer Daily injections of GH for 8 weeks reduces aneuploidy by activating JAK2-ERK1/2 pathway and improves the quality of oocyte in aged mice. What is known already Aging-induced low-quality oocytes, which are mainly caused by aneuploidy, decrease female fertility. However, few treatments are available to improve the poor quality of oocytes in aged women. Age-related decline in GH levels may be related to the insufficient reproductive potential in aged women. Several studies have reported that GH improves assisted reproductive technology outcomes in poor ovarian response patients, although its role is still controversial. In animal models, GH supplementation improved the oocyte quality by enhancing mitochondrial function. However, whether GH reduces the aneuploidy rate in aged oocytes, and if so the underlying mechanisms, are unclear. Study design, size, duration The aged (8-month-old) C57BL/6J female mice were used in the study. For the in vivo experiments, the aged mice were intraperitoneally injected with GH (GenSci, Changchun, China; 1.6 mg/kg body weight) or an equivalent volume of normal saline for 8 weeks; For the in vitro experiments, germinal vesicle (GV) oocytes from aged mice were treated with GH (200 ng/mL) or PBS in M16 medium. Participants/materials, setting, methods We counted oocytes by immunohistochemistry to assess ovarian reserve. The expression of growth hormone receptor and mitochondrial genes were measured by quantitative real-time PCR. Time–lapse incubator was utilized to record the developmental potential of early embryos. Immunofluorescence was performed to assess parameters of oocyte quality (mitochondrial functions, spindle/chromosome defects, and DNA damage). Chromosome spread and DNA sequencing were used to analyze aneuploidy rate. We performed quantitative proteomics analysis to identify the potential targets of GH. Main results and the role of chance Firstly, we found that GH promoted GHR expression in aged oocytes (30.64±1.70 vs 21.68±1.08, P &amp;lt; 0.001). GH ameliorated aging-induced decline in ovarian reserve of aged mice, with increased ovarian index (0.040%±0.0031 vs 0.023%±0.0019, P &amp;lt; 0.01), and number of antral follicles (8.67±1.2 vs 3.33±0.88, P &amp;lt; 0.05) compared to the controls. In addition, GH improved the quality of aged oocytes, representing restored mitochondrial functions (P &amp;lt; 0.05), decreased DNA damage (23.37±1.76 vs 38.35±2.52, P &amp;lt; 0.001) . As expected, GH promoted the fertilization rate (39.9%±1.10 vs 14.4%±0.62, P &amp;lt; 0.001) and early embryo development (P &amp;lt; 0.01) of aged oocytes. Of note, GH recovered the spindle/chromosome defects (42.6%±2.12 vs 63.9%±1.83, P &amp;lt; 0.01, and reduced aneuploidy rate (20.9%±1.61 vs 39.3%±1.84, P &amp;lt; 0.01) in aged oocytes. GH activated ERK1/2 expression to decrease aneuploidy rate in aged oocytes. In addition, JAK2 might be involved in the regulation of GH on ERK1/2 expression in aged oocytes. Altogether, GH restored age-related decline in oocyte number, and decreased the occurrence rate of aneuploidy by activating JAK2-ERK1/2 pathway, thereby improving the quality of aged oocytes. Limitations, reasons for caution The molecular action mechanism of GH to regulate aneuploidy remains to be determined. Besides, future work should be extended to human oocyte to determine whether this mechanism is conserved between mice and humans Wider implications of the findings Our work expounds a theoretical basis for application of GH to improve the fertility of aged women. Besides, the results also feed new ideas for the prevention and treatment of oocyte quality decline in assisted reproductive technology. Trial registration number not applicable

Effects of electroacupuncture on pregnancy outcome in poor ovarian response patients of kidney essence deficiency and undergoing in vitro fertilization-embryo transfer

To observe the effects of electroacupuncture (EA) on ovarian reaction, egg and embryo quality, as well as pregnancy rate in poor ovarian response (POR) patients of kidney essence deficiency and undergoing in vitro fertilization-embryo transfer (IVF-ET). Ninety-six patients who met the inclusion criteria were randomly divided into an EA group and a control group, with 48 cases in each group. Before IVF-ET, the patients in the EA group received EA, once daily, 2 or 3 treatments a week for 12 weeks. Before and after the treatment, traditional Chinese medicine (TCM) syndrome score and clinical pregnancy rate were assessed in two groups. The concentrations of serum follicle-stimulating hormone (FSH), luteinsing hormone, estradiol, progesterone and anti-mullerian hormone were detected by chemiluminescence; the contents of serum insulin-like growth factor-1, serum inhibin B (INHB) and Kisspeptin in follicular fluid were determined by enzyme linked immunosorbent assay (ELISA); the antral follicle counting (AFC) was detected by color Doppler ultrasonography; and the egg and embryo conditions were observed under microscope. Fourteen days after embryo transfer, the positive rate of serum hemchoriconic gonadotropin (HCG) and clinical pregnancy rate were calculated. After the treatment, the TCM syndrome score and level of serum FSH were reduced (P<0.05); the INHB in serum and AFC were increased (P<0.05) when compared with those before the treatment in the EA group. After the treatment, in comparison with the control group, the TCM syndrome score and level of serum FSH were lower (P<0.05); and the contents of serum INHB, AFC, the numbers of MⅡ eggs and high-quality embryos, as well as serum HCG positive rate were all increased (P<0.05) in the EA group. EA can relieve the clinical symptoms of TCM in POR patients of kidney essence deficiency and undergoing IVF-ET, increase the ovarian reserve, reduce the serum FSH level, and improve the content of serum INHB, and the quality of eggs and embryos. This therapy tends to improve the clinical pregnancy rate and clinical pregnancy outcome.

Effectiveness of letrozole in pituitary downregulated normogonadotrophic young women with an initial poor response.

It has been reported that 10 to 15% of young normogonadotrophic women show suboptimal response to standard long protocols. Letrozole (LE), an aromatase inhibitor, was shown to improve ovarian sensitivity to follicle stimulating hormone (FSH) and follicular response to gonadotrophin treatment in poor ovarian response patients. We reasoned that it might be possible to utilize LE in young normogonadotrophic patients with unexpected hypo-response in standard gonadotropin-releasing hormone agonist long protocol. A total of 652 patients defined as normogonadotrophic patients with unexpected hypo-response were divided into 2 groups, the +LE group and the +Gn group. +LE group: A fixed daily dose of 2.5 mg of LE was added on day 8 of stimulation. +Gn group: A fixed daily dose of 75 U of human menopausal gonadotrophin was added on day 8 of stimulation. The primary outcome measures were the number of oocytes obtained, fertilization rate, days of stimulation, and total FSH dosage. The secondary outcome measures were the implantation rate and ongoing pregnancy rate. There were no significant differences in the clinical and hormonal characteristics between the 2 groups. A shorter duration of stimulation and a lower dosage of recombinant FSH consumption on the day of human chorionic gonadotropin administration were all observed in the +LE group. Patients who received LE therapy showed a higher number of oocytes obtained and significantly higher fertilization rates. The implantation rate and ongoing pregnancy rate were comparable in both groups. LE significantly improves the number of oocytes obtained in patients with suboptimal response to standard gonadotropin-releasing hormone agonist long protocol.

Systematic review of acupuncture to improve ovarian function in women with poor ovarian response.

To determine the effect of acupuncture in treating poor ovarian response (POR). We searched MEDLINE (via PubMed), EMBASE, Allied and Complementary Medicine Database, CNKI, CBM, VIP database, Wanfang Database, and relevant registration databases from inception to January 30, 2023. In this review, both Chinese and English peer-reviewed literature were included. Only randomized controlled trials (RCTs) using acupuncture as an intervention for POR patients undergoing in vitro fertilization were considered. Seven clinical randomized controlled trials (RCTs) were eventually included for comparison (516 women). The quality of included studies was generally low or very low. For the meta-analysis, seven studies showed that compared with controlled ovarian hyperstimulation (COH) therapy, acupuncture combined with COH therapy could significantly increase the implantation rate (RR=2.13, 95%CI [1.08, 4.21], p=0.03), the number of oocytes retrieved (MD=1.02, 95%CI [0.72, 1.32], p<0.00001), the thickness of endometrium (MD=0.54, 95%CI [0.13, 0.96], p=0.01), and the antral follicle count (MD=1.52, 95%CI [1.08, 1.95], p<0.00001), reduce follicle-stimulating hormone (FSH) levels (MD=-1.52, 95%CI [-2.41, -0.62], p=0.0009) and improve estradiol (E2) levels (MD=1667.80, 95%CI [1578.29, 1757.31], p<0.00001). Besides, there were significant differences in the duration of Gn (MD=0.47, 95%CI [-0.00, 0.94], p=0.05) between the two groups. However, no statistical variation was observed in improving clinical pregnancy rate (CPR), fertilization rate, high-quality embryo rate, luteinizing hormone (LH) value, anti-mullerian hormone (AMH) value, or reducing the dose of gonadotropin (Gn) values between the acupuncture plus COH therapy group and the COH therapy group. Acupuncture combined with COH therapy is doubtful in improving the pregnancy outcome of POR patients. Secondly, acupuncture can also improve the sex hormone level of POR women, and improve ovarian function. Furthermore, more RCTs of acupuncture in POR are needed to be incorporated into future meta-analyses. PROSPERO, identifier CRD42020169560.

Novel deleterious splicing variant in HFM1 causes gametogenesis defect and recurrent implantation failure: concerning the risk of chromosomal abnormalities in embryos.

Poor ovarian response (POR) affects approximately 9% to 24% of women undergoing in vitro fertilization (IVF) cycles, resulting in fewer eggs obtained and increasing clinical cycle cancellation rates. The pathogenesis of POR is related to gene variations. Our study included a Chinese family comprising two siblings with infertility born to consanguineous parents. Poor ovarian response (POR) was identified in the female patient who had multiple embryo implantation failures occurring in subsequent assisted reproductive technology cycles. Meanwhile, the male patient was diagnosed with non-obstructive azoospermia (NOA). Whole-exome sequencing and rigorous bioinformatics analyses were conducted to identify the underlying genetic causes. Moreover, the pathogenicity of the identified splicing variant was assessed using a minigene assay in vitro. The remaining poor-quality blastocyst and abortion tissues from the female patient were detected for copy number variations. We identified a novel homozygous splicing variant in HFM1 (NM_001017975.6: c.1730-1G > T) in two siblings. Apart from NOA and POI, biallelic variants in HFM1 were also associated with recurrent implantation failure (RIF). Additionally, we demonstrated that splicing variants caused abnormal alternative splicing of HFM1. Using copy number variation sequencing, we found that the embryos of the female patients had either euploidy or aneuploidy; however, both harbored chromosomal microduplications of maternal origin. Our results reveal the different effects of HFM1 on reproductive injury in males and females, extend the phenotypic and mutational spectrum of HFM1, and show the potential risk of chromosomal abnormalities under the RIF phenotype. Moreover, our study provides new diagnostic markers for the genetic counseling of POR patients.

Efficacy of Artificial Oocyte Activation in Improving the Reproductive Outcome in Poor Responders: A Single Centre Cohort Study.

Achieving pregnancy in poor ovarian response patients is a challenge. Failed fertilization after ICSI, despite normal semen parameters is due to defects in oocyte activation. In-vitro activation of oocytes using Ca+2 agents can be useful in increasing the fertilization rates in these patients. This study aimed to evaluate the efficacy of artificial oocyte activation by calcium ionophores in poor responders in improving fertilization, cleavage, implantation and clinical pregnancy rates. This is a prospective, cohort study conducted on 120 patients having poor ovarian response, (POSEIDON criteria) undergoing in-vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment at Southend Fertility and IVF, New Delhi from 1st August 2019 to 31st March 2020. Exclusion criterion was patients with partners with abnormal semen parameters. After OPU patients were randomized into two groups, study group (n=50) underwent ICSI-AOA (ICSI followed by artificial oocyte activation) using calcium ionophore- GM508 Cult-Active Solution) while the controls (n=57) were subjected to ICSI only. Comparison of ICSI-AOA and ICSI groups showed: (i) number of fertilized oocytes - 2.42 vs. 2.16, p = 0.049 (ii) No. of cleavage stage embryos 2.32 vs. 1.96, p = 0.008 (iii) No. of grade A embryos 1.52 vs. 1.04, p = 0.009 (iv) fertilization rate - 89.00% vs. 83.04%, p = 0.093 (v) cleavage rate - 96.33% vs. 92.55%, p = 0.165 (vi) implantation rate - 27.14% vs. 11.74%, p = 0.098 (vii) clinical pregnancy rate - 34.3% vs. 20.5%, p = 0.167. The number of fertilized oocytes, grade A embryos and cleavage stage embryos formed after ICSI-AOA were statistically significantly more than ICSI. ICSI-AOA has not shown improvement in fertilization, cleavage, implantation and clinical pregnancy rate. From the present study the conclusive evidence cannot be drawn due to small sample size hence further studies are needed on a larger population.

Progestin-primed ovarian stimulation protocol with or without clomiphene citrate for poor ovarian responders: a retrospective cohort study

ObjectiveTo explore the efficacy of progestin-primed ovarian stimulation (PPOS) combined with clomiphene citrate (CC) versus PPOS protocol used alone on cycle characteristics and pregnancy outcomes for women with the poor ovarian response (POR).MethodsWe performed a retrospective cohort study and a total of 578 POR patients who underwent IVF/ICSI cycles were collected and divided into Group A (HMG 300 IU/d + MPA 10 mg/d) and Group B (HMG 300 IU/d + MPA 10 mg/d + CC 50 mg/d). The primary outcome measure was the number of oocytes retrieved, other outcome measures were cycle characteristics and clinical pregnancy rate.ResultsThe baseline information between the two groups were not statistically significant (P > 0.05). Compared with Group A, Group B had a lower total dose of human menopausal gonadotrophin (HMG) (2998.63 ± 1051.09 vs. 3399.18 ± 820.75, P < 0.001) and the duration of stimulation (10.21 ± 3.56 vs. 11.27 ± 2.56, P < 0.001). Serum luteinizing hormone level was higher in Group B on human chorionic gonadotrophin injection day (P < 0.001). The number of oocyte for retrieval, maturation, and fertilization were significantly lower in Group B than that in Group A (P < 0.001). However, the oocyte retrieval rate, maturation rate, fertilization rate, and viable embryo rate showed no statistical difference in the two groups (P > 0.05). After adjusting for confounders, the clinical pregnancy rate (OR 1.286; 95% CI 0.671–2.470) and live birth rate (OR 1.390; 95% CI 0.478–3.990) were comparable between the two groups.ConclusionsPPOS protocol combined with CC reduces the total dose of HMG and the duration of stimulation, and can also achieve similar oocyte yields and clinical pregnancy rate compared with the PPOS protocol used alone in poor ovarian responders.

Effect of Coenzyme Q10 and transcutaneous electrical acupoint stimulation in assisted reproductive technology: a retrospective controlled study

PurposeTo investigate the effects of coenzyme Q10 (CoQ10) and transcutaneous electrical acupoint stimulation (TEAS) pretreatment on pregnancy in patients with poor ovarian response (POR).MethodsA total of 330 POR patients who were pretreated with CoQ10 or CoQ10 combined with TEAS before their in vitro fertilization/intracytoplasmic sperm injection and embryo transfer (IVF/ICSI-ET) cycles and who were not pretreated were selected and divided into CoQ10 group (group A, n = 110), CoQ10 + TEAS group (group B, n = 110) and control group (group C, n = 110). For patients with 2 or more transfer cycles, only the information of the first cycle was included. Ovarian function, response to gonadotropin (Gn) stimulation, and pregnancy outcomes of the three groups were compared in the IVF/ICSI-ET cycles.ResultsAfter pretreatment, basal FSH, total Gn dosage and duration were comparable among the three groups (all p-value > 0.05), basal E2 in group B decreased significantly compared with the control group (p = 0.022). Endometrial thickness on the human chorionic gonadotropin (hCG) day, antral follicle counts (AFC), the numbers of oocytes, metaphase II (MII) eggs and excellent embryos in the two pretreatment groups were significantly increased compared with group C (all p-value < 0.001), but the rates of MII oocytes, fertilization and excellent embryos had no apparent change. The endometrial thickness on the day of hCG, the numbers of MII eggs and excellent embryos in group B were higher than those in group A (p < 0.001; p = 0.020; p = 0.027; respectively). The embryo implantation rate (IR), clinical pregnancy rate (CPR) and live birth rate (LBR) in group B were significantly higher than those in group C (p = 0.022; p = 0.010; p = 0.019; respectively), but not significantly different from group A.ConclusionCoQ10 alone or in combination with TEAS are effective methods for IVF/ICSI-ET adjuvant therapy, which can significantly improve ovarian reactivity, increase the numbers of retrieved eggs and superior embryos, and improve endometrial receptivity. Adjuvant TEAS on the basis of CoQ10 can significantly enhance pregnancy rates, but CoQ10 alone failed to present such an obvious effect.

Effects of sequential cleavage and blastocyst embryo transfer on pregnancy outcomes in patients with poor ovarian response

The management of patients with poor ovarian response (POR) remains a major challenge for fertility specialists in in vitro fertilization-embryo transfer (IVF-ET). In this retrospective cohort study, we aimed to evaluate the clinical effect of sequential transfer on pregnancy outcomes in patients with POR. A total of 3579 POR patients who underwent the first frozen embryo transfer (FET) cycle were enrolled from January 2018 to April 2021. The patients were divided into three groups according to the embryo transfer (ET) strategy adopted: a study group that included POR patients in whom a cleavage-stage embryo (day 3) and a blastocyst (day 5/6) were transferred (sequential transfer group), and two control groups in whom two cleavage-stage embryos (D3-dET group) or two blastocysts (D5/6-dET group) were transferred. The study group was matched with the control groups at a ratio of 1:4 by propensity score matching (PSM). The main pregnancy outcomes measured were the live birth rate and multiple pregnancy rate. After PSM, the live birth rate in the sequential transfer group was significantly higher than that in the D3-dET group (44.2% vs. 34.3%, P = 0.019), and was similar to that in the D5/6-dET group (44.2% vs. 45.3%; P = 0.90). In addition, there was no increase in the risk of multiple pregnancy among POR patients undergoing sequential transfer compared with both D3-dET (26.7% vs. 25.6%, P = 0.85) and D5/6-dET (26.7% vs. 28.4%, P = 0.97) groups. These findings imply that sequential transfer is an effective option for POR patients and could be utilized after careful consideration.