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Ovarian hyperstimulation syndrome (OHSS) is a severe complication of controlled ovarian hyperstimulation (COH) during fertilization (IVF) treatment, characterized by increased capillary permeability. Vascular endothelial growth factor (VEGF) is a key mediator in OHSS, with serum VEGF levels correlating with its severity. In this study, we investigated the therapeutic potential of (-)-epigallocatechin-3-gallate (EGCG) and its derivative, Pro-EGCG, in mitigating OHSS. Using both and models, including primary human granulosa-lutein cells, the human granulosa-like tumor KGN cell line, and a rat OHSS model induced with pregnant mare serum gonadotropin, we found that EGCG and Pro-EGCG significantly reduced OHSS progression. This was supported by histological analyses, reductions in ovarian weight, and decreased VEGF expression at both transcriptomic and proteomic levels. Mechanistic studies revealed that EGCG and Pro-EGCG inhibit TGF-β-induced VEGF production through suppression of the TGF-β/Smad and PKA-CREB signaling pathways. RNA sequencing further validated the downregulation of VEGF expression following treatment. These findings highlight the potential of EGCG as a novel adjuvant therapy for managing OHSS, providing a mechanistic basis for its clinical application.

Polycystic ovarian syndrome (PCOS) is a widespread syndrome that poses unique challenges and constraints to the field of assisted reproductive technology. This condition is the most common cause of anovulation among infertile couples. Debate exists over the best therapeutic course of action when patients with PCOS proceed to IVF. In this review, we evaluate the best-performing and safest methods of IVF preparation, ovarian stimulation, trigger method for maturation of stimulated egg growth, and planning for embryo transfer. Pre-IVF considerations include being aware of individual AMH and vitamin D levels as well as BMI prior to selecting an ovarian stimulation protocol. Numerous supplements such as myo-inositol complement the benefits of lifestyle change and may enhance IVF performance including oocyte yield and pregnancy rate. Concerning stimulation protocols, antagonist cycles with the judicious use of GnRH agonist trigger, pre-treatment with metformin and vitamin D repletion may help mitigate the accompanied risk of ovarian hyperstimulation syndrome (OHSS). Following ovarian stimulation, PCOS patients typically undergo programmed frozen embryo transfer (FET) cycles which are more conducive for women with irregular cycles, but likely carry a higher risk of hypertensive disorders of pregnancy. However, newer stimulated FET protocols using Letrozole may offer improved outcomes. Overall, patients with PCOS require careful individual tailoring of their IVF cycle to achieve optimal results.

In vitro maturation (IVM) of human immature oocytes has been shown to be a viable option for patients at risk of ovarian hyperstimulation syndrome (OHSS), those seeking urgent fertility preservation and in circumstances where controlled ovarian stimulation is not feasible. Moreover, IVM techniques can be combined with ovarian tissue cryobanking to increase the chances of conception in cancer survivors. The clinical applications of IVM in the field of reproductive medicine are rapidly expanding and the technique is now classified as non-experimental. In contrast to conventional IVF (in vitro fertilization), IVM offers several advantages, such as reduced gonadotropin stimulation, minimal risk of ovarian hyperstimulation syndrome (OHSS), reduced treatment times and lower costs. However, the technical expertise involved in performing IVM and its lower success rates compared to traditional IVF cycles, still pose significant challenges. Despite recent advances, such as innovative biphasic IVM systems, IVM is still an evolving technique and research is ongoing to refine protocols and identify techniques to improve its efficiency and effectiveness. A comprehensive understanding of the distinct mechanisms of oocyte maturation is crucial for obtaining more viable oocytes through in vitro methods, which will in turn lead to significantly improved success rates. In this review, the present state of human IVM programs and future research directions will be discussed, aiming to promote a better understanding of IVM and identify potential strategies to improve the overall efficiency and success rates of IVM programs, which will in turn lead to better clinical outcomes.

Ovarian hyperstimulation syndrome (OHSS) is a potentially life-threating iatrogenic complication of the early luteal phase and/or early pregnancy after in vitro fertilization (IVF) treatment. The aim of the current study was to identify the most effective methods for preventing of and reducing the incidence and severity of OHSS in IVF patients. A systematic review of systematic reviews of randomized controlled trials (RCTs) with meta-analysis was used to assess each potential intervention (PROSPERO website, CRD 268626) and only studies with the highest quality were included in the qualitative analysis. Primary outcomes included prevention and reduction of OHSS incidence and severity. Secondary outcomes were maternal death, incidence of hospital admission, days of hospitalization, and reproductive outcomes, such as incidence of live-births, clinical pregnancies, pregnancy rate, ongoing pregnancy, miscarriages, and oocytes retrieved. A total of specific interventions related to OHSS were analyzed in 28 systematic reviews of RCTs with meta-analyses. The quality assessment of the included studies was high, moderate, and low for 23, 2, and 3 studies, respectively. The certainty of evidence (CoE) for interventions was reported for 37 specific situations/populations and resulted high, moderate, and low-to-very low for one, 5, and 26 cases, respectively, while it was not reported in 5 cases. Considering the effective interventions without deleterious reproductive effects, GnRH-ant co-treatment (36 RCTs; OR 0.61, 95% C 0.51 to 0.72, n  = 7,944; I 2  = 31%) and GnRH agonist triggering (8 RCTs; OR 0.15, 95% CI 0.05 to 0.47, n  = 989; I 2  = 42%) emerged as the most effective interventions for preventing OHSS with a moderate CoE, even though elective embryo cryopreservation exhibited a low CoE. Furthermore, the use of mild ovarian stimulation (9 RCTs; RR 0.26, CI 0.14 to 0.49, n  = 1,925; I 2  = 0%), and dopaminergic agonists (10 RCTs; OR 0.32, 95% CI 0.23 to 0.44, n  = 1,202; I 2  = 13%) coadministration proved effective and safe with a moderate CoE. In conclusion, the current study demonstrates that only a few interventions currently can be considered effective to reduce the incidence of OHSS and its severity with high/moderate CoE despite the numerous published studies on the topic. Further well-designed RCTs are needed, particularly for GnRH-a down-regulated IVF cycles.

Ovarian hyperstimulation syndrome (OHSS) is the main severe complication of ovarian stimulation for in vitro fertilization (IVF) cycles. The aim of the current study was to identify the interventions for the prevention of and reduction in the incidence and severity of OHSS in patients who undergo IVF not included in systematic reviews with meta-analyses of randomized controlled trials (RCTs) and assess and grade their efficacy and evidence base. The best available evidence for each specific intervention was identified, analyzed in terms of safety/efficacy ratio and risk of bias, and graded using the Oxford Centre for Evidence-Based Medicine (CEBM) hierarchy of evidence. A total of 15 interventions to prevent OHSS were included in the final analysis. In the IVF population not at a high risk for OHSS, follitropin delta for ovarian stimulation may reduce the incidence of early OHSS and/or preventive interventions for early OHSS. In high-risk patients, inositol pretreatment, ovulation triggering with low doses of urinary hCG, and the luteal phase administration of a GnRH antagonist may reduce OHSS risk. In conclusion, even if not supported by systematic reviews with homogeneity of the RCTs, several treatments/strategies to reduce the incidence and severity of OHSS have been shown to be promising.

Ovarian hyperstimulation syndrome (OHSS) is a serious iatrogenic complication in women undergoing induction of ovulation with human chorionic gonadotropin (hCG) for assisted reproductive techniques. Amphiregulin (AREG) is the most abundant epidermal growth factor receptor (EGFR) ligand expressed in human granulosa cells and follicular fluid and can be upregulated by luteinizing hormone (LH)/hCG. However, whether the expression levels of AREG, EGFR, and HER2 change in the granulosa cells of OHSS patients remains unknown. If it does, whether these molecules are involved in the development of OHSS requires investigation. In the present study, we showed that AREG, EGFR, and HER2 transcripts in granulosa cells as well as follicular fluid AREG proteins were elevated in OHSS patients. Increased AREG levels were associated with transcript levels and follicular content of vascular endothelial growth factor (VEGF), the marker for OHSS pathology. Treatment of cultured granulosa cells with AREG stimulated VEGF expression and secretion, with granulosa cells from OHSS patients showing more rapid and pronounced increases than the non-OHSS group. In addition, siRNA-mediated knockdown of EGFR and AREG attenuated the hCG-induced upregulation of VEGF. This study demonstrated that granulosa cell-secreted AREG plays an important role in the development of OHSS, suggesting that the EGFR/HER2-mediated signaling could be a novel drug target for the prevention and treatment of OHSS. Summary Sentence AREG-EGFR/HER2 partially mediates hCG-induced VEGF expression in human granulosa cells. Upregulation of AREG and EGFR/HER2 can enhance the hCG-induced VEGF expression which contributes to the development of OHSS.

As part of a conventional controlled ovarian hyperstimulation (COH) regimen, final follicular maturation is usually triggered by a single bolus dose of human chorionic gonadotropin (hCG). COH, which combines GnRH antagonist co-treatment with GnRH agonist(GnRHa) trigger, is often used in attempts to eliminate severe early ovarian hyperstimulation syndrome and to improve oocyte/embryo yield and quality. Recently, the combination of GnRHa, with hCG trigger has also been implemented into clinical practice. Here, we analyze and discuss published studies on various ways of triggering final follicular maturation, seeking to elucidate the appropriateness of each approach for specific patient subgroups.

PurposeTo evaluate self-reported survey data provided by US oocyte donors on their experiences with ovarian hyperstimulation syndrome and possible correlations between OHSS severity and number of oocytes retrieved, trigger type, and prior OHSS history.MethodsAn 85-question retrospective survey was administered online. Survey questions included demographic information, reasons for donating, immediate per-cycle experiences and outcomes, perceptions of informed consent, and perceived impact of donation on long-term health. Quantitative Data for this study was collected between February 2019 and September 2020 via QualtricsXM (January 2019), an online survey platform. Follow-up interviews were also conducted. Participants were recruited via fertility clinics, egg donation agencies, and online forum. The research was approved by the University of California, San Francisco Institutional Review Board (#14-14765).ResultsOf 420 initiated US oocyte donor online surveys, 289 (68%) respondents provided detailed information on per cycle experiences with ovarian hyperstimulation syndrome, number of oocytes retrieved, and trigger type over a total of 801 cycles. On cycles where donors reported receiving GnRH agonist triggers (n = 337), they reported milder OHSS compared to cycles with hCG or dual triggers. Among donors undergoing multiple retrieval cycles, the severity of OHSS in second cycles was strongly associated with OHSS severity in first cycles.ConclusionSelf-reported OHSS in oocyte donors is lower in GnRH antagonist stimulation protocols combined with GnRHa trigger and in cycles where donors reported fewer than 30 oocytes retrieved. Donors who reported severe OHSS on a prior cycle were significantly more likely to experience severe OHSS on a subsequent cycle.

Angiogenesis is strongly associated with ovarian hyperstimulation syndrome (OHSS) progression. Early growth response protein 1 (EGR1) plays an important role in angiogenesis. This study aimed to investigate the function and mechanism of EGR1 involved in OHSS progression. RNA-sequencing was used to identify differentially expressed genes. In vitro OHSS cell model was induced by treating KGN cells with human chorionic gonadotropin (hCG). In vivo OHSS model was established in mice. The expression levels of EGR1, SOX1, and VEGF were determined by Quantitative Real-Time polymerase chain reaction (qRT-PCR), Western blot, immunofluorescence staining, and immunochemistry assay. The content of VEGF in the culture medium of human granulosa-like tumor cell line (KGN) cells was accessed by the ELISA assay. The regulatory effect of EGR1 on SRY-box transcription factor 9 (SOX9) was addressed by luciferase reporter assay and chromatin immunoprecipitation. The ERG1 and SOX9 levels were significantly upregulated in granulosa cells from OHSS patients and there was a positive association between EGR1 and SOX9 expression. In the ovarian tissues of OHSS mice, the levels of EGR1 and SOX9 were also remarkedly increased. Treatment with hCG elevated the levels of vascular endothelial growth factor (VEGF), EGR1, and SOX9 in KGN cells. Silencing of EGR1 reversed the promoting effect of hCG on VEGF and SOX9 expression in KGN cells. EGR1 transcriptionally regulated SOX9 expression through binding to its promoter. In addition, administration of dopamine decreased hCG-induced VEGF in KGN cells and ameliorated the progression of OHSS in mice, which were companied with decreased EGR1 and SOX9 expression. EGR1 has a promoting effect on OHSS progression and dopamine protects against OHSS through suppression of EGR1/SOX9 cascade. Our findings may provide new targets for the treatment of OHSS.

Despite the proven superiority of various luteal phase support protocols (LPS) over placebo in view of improved pregnancy rates in fresh cycles of IVF (in vitro fertilization) and ICSI (intracytoplasmic sperm injection) cycles, there is ongoing controversy over specific LPS protocol selection, dosage, and duration. The aim of the present study was to identify the optimal LPS under six core aspects of ART success, clinical pregnancy, live birth as primary outcomes and biochemical pregnancy, miscarriage, multiple pregnancy, ovarian hyperstimulation syndrome (OHSS) events as secondary outcomes. Twelve databases, namely Embase (OVID), MEDLINE (R) (OVID), GlobalHealth (Archive), GlobalHealth, Health and Psychosocial Instruments, Maternity & Infant Care Database (MIDIRS), APA PsycTests, ClinicalTrials.gov, HMIC Health Management Information Consortium, CENTRAL, Web of Science, Scopus and two prospective registers, MedRxiv, Research Square were searched from inception to Aug.1st, 2023, (PROSPERO Registration: CRD42022358986). Only Randomised Controlled Trials (RCTs) were included. Bayesian network meta-analysis (NMA) model was employed for outcome analysis, presenting fixed effects, odds ratios (ORs) with 95% credibility intervals (CrIs). Vaginal Progesterone (VP) was considered the reference LPS given its’ clinical relevance. Seventy-six RCTs, comparing 22 interventions, and including 26,536 participants were included in the present NMA. Overall CiNeMa risk of bias was deemed moderate, and network inconsistency per outcome was deemed low (Multiple pregnancy χ 2 : 0.11, OHSS χ 2 : 0.26), moderate (Clinical Pregnancy: χ 2 : 7.02, Live birth χ 2 : 10.95, Biochemical pregnancy: χ 2 : 6.60, Miscarriage: χ 2 : 11.305). Combinatorial regimens, with subcutaneous GnRH-a (SCGnRH-a) on a vaginal progesterone base and oral oestrogen (OE) appeared to overall improve clinical pregnancy events; VP + OE + SCGnRH-a [OR 1.57 (95% CrI 1.11 to 2.22)], VP + SCGnRH-a [OR 1.28 (95% CrI 1.05 to 1.55)] as well as live pregnancy events, VP + OE + SCGnRH-a [OR 8.81 (95% CrI 2.35 to 39.1)], VP + SCGnRH-a [OR 1.76 (95% CrI 1.45 to 2.15)]. Equally, the progesterone free LPS, intramuscular human chorionic gonadotrophin, [OR 9.67 (95% CrI 2.34, 73.2)] was also found to increase live birth events, however was also associated with an increased probability of ovarian hyperstimulation, [OR 1.64 (95% CrI 0.75, 3.71)]. The combination of intramuscular and vaginal progesterone was associated with higher multiple pregnancy events, [OR 7.09 (95% CrI 2.49, 31.)]. Of all LPS protocols, VP + SC GnRH-a was found to significantly reduce miscarriage events, OR 0.54 (95% CrI 0.37 to 0.80). Subgroup analysis according to ovarian stimulation (OS) protocol revealed that the optimal LPS across both long and short OS, taking into account increase in live birth and reduction in miscarriage as well as OHSS events, was VP + SCGnRH-a, with an OR 2.89 [95% CrI 1.08, 2.96] and OR 2.84 [95% CrI 1.35, 6.26] respectively. Overall, NMA data suggest that combinatorial treatments, with the addition of SCGnRH-a on a VP base result in improved clinical pregnancy and live birth events in both GnRH-agonist and antagonist ovarian stimulation protocols.