Ovarian Hyperstimulation Syndrome Group Research Articles

Serum erythropoietin level is increased during stimulation for IVF but not in OHSS

BackgroundErythropoietin (Epo) is a potent vascular growth factor that induces angiogenesis and antiapoptotic signalling. We investigated whether the development of numerous follicles and corpora lutea during in vitro fertilization (IVF) cycle affects circulating Epo levels and further, if Epo could be used as a novel marker for ovarian hyperstimulation syndrome (OHSS).Methods24 women were included in the uncomplicated IVF group and 35 women in the OHSS group. Repeated blood samples from both groups were analysed for Epo, progesterone, blood haemoglobin, and creatinine. Follicular fluid from the IVF group was analysed for Epo and progesterone. Repeated measure analysis was performed for the variables and circulating Epo levels were compared between the IVF group and early OHSS. Furthermore, related growth factors, vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 (HIF-1) were analysed from subgroup of women to test for correlation with Epo.ResultsDuring IVF, circulating Epo increased from natural mid-luteal phase to stimulated mid-luteal phase (median 9.5; 95% CI 7.2–13.4 IU/L and 12.5; 10.3–13.4 IU/L; p = 0.003). In cycles resulting in pregnancy, Epo level decreased 14 days after oocyte pick-up (OPU) and remained low thereafter. In cycles not resulting in pregnancy, Epo level increased again 35 days after OPU. Follicle fluid Epo concentration was 1.5 times higher than the serum concentration (median 15.4; 95% CI 10.4–19.2 IU/L vs. 10.2; 8.8–12.7; p = 0.006). There was no difference in circulating Epo concentration between early OHSS and uncomplicated IVF. Circulating Epo did not correlate with VEGF or HIF-1.ConclusionsCirculating Epo levels fluctuate during IVF cycle. We hypothesise this may suggest Epo’s involvement in ovarian physiology and angiogenesis. However, Epo was not a clinical marker for OHSS.

#236 : Alleviating Effects of EGCG on Ovarian Hyperstimulation Syndrome and the Potential Modulating Mechanism

Background and Aims: Ovarian hyperstimulation syndrome (OHSS) is one of the most severe complications of COH during IVF treatment. Increased capillary permeability is a hallmark of the pathophysiology of OHSS, vascular endothelial growth factor (VEGF) is an important mediator in OHSS, and studies have established a correlation between serum VEGF levels and the severity of the OHSS. (-)-epigallocatechin-3-gallate (EGCG), the most prevalent and biologically active polyphenolic catechin in green tea, has been reported to produce a number of beneficial effects on humans. Numerous studies have shown that in many pathological processes, EGCG could inhibit VEGF and its receptor expression and have an angiogenesis effect. Herein, EGCG might have a therapeutic effect on OHSS. Methods: We investigated the role of EGCG in OHSS both in vitro and in vivo. Primary human granulosa-lutein (hGL) cells and a human granulosa-like tumor (KGN) cell line were cultured and treated for 24 hours with various concentrations of EGCG. In SD rats, an animal OHSS model was established by injecting pregnant mare serum gonadotropin (PMSG) and randomly assigning them to receive vehicle only or EGCG for three days. For comparison, all experiments were repeated 3-8 times. The effect of EGCG on KGN and hGL cells was determined by MTT assay. The body weight of rats was measured every day, and the ovary size and weight were measured after removal. Evans-blue was used to determine permeability. ELISA was used to measure serum estrogen and VEGF levels in rats. RNA and protein expressions of VEGF, VEGFR-2, TGF-[Formula: see text]1, and T[Formula: see text]R II were detected by qPCR and Western-blotting and immunostaining in vitro and in vivo experiments. Results: Our research found that giving rats EGCG prevented the development of OHSS, as evidenced by histological examination, ovarian weight, and morphology. When compared to the OHSS group, the EGCG treatment group had significantly lower ovary weight (147.9 vs 206.5 mg) (Fig. 1). Furthermore, when compared to OHSS rats, EGCG-treated rats have lower ovarian VEGF expression as measured by IHC and RT-qPCR. VEGF and E2 protein levels in the serum of the EGCG treatment group are significantly lower. EGCG exerted inhibitory effects on cell growth only in high dose (50 uM) and longtime (48 h) treatment in KGN and hGL cells. In KGN cells and hGL cells, EGCG significantly reduces the expression of VEGF and TGF-[Formula: see text] at the RNA and protein levels. Furthermore, EGCG inhibits TGF-[Formula: see text]1-induced VEGF production and secretion in KGN cells by suppressing TGF-[Formula: see text] expression and its traditional Smad signaling pathway. EGCG also downregulates VEGF expression through the 67-kDa laminin receptor-mediated PKA-CREB pathway (Fig. 2). Conclusions: EGCG inhibited VEGF via the TGF-[Formula: see text]1 classical-SMAD pathway and the 67LR-mediated CREB pathway, reducing ovarian inflammation and slowing the progression of OHSS in a rat model.

Pregnancy outcome in long- versus short-acting gonadotropin-releasing hormone agonist cycles in participants with normal ovarian reserve: An RCT.

There is no agreement on which of the 2 gonadotropin-releasing hormone (GnRH) agonist protocols are the most efficient, neither there is any consensus on which one yields a better clinical pregnancy percentage. The present study aims to compare the effectiveness of reduced dosages of long- and short-acting GnRH agonists on pregnancy outcomes. In this randomized controlled clinical trial, 400 women were randomly assigned to 2 groups (n = 200/group): the reduced dosage of long-acting GnRH agonist group (group 1, 1.25 mg Decapeptyl) and the short-acting GnRH agonist group (group 2, 0.5 mg/day Buserelin Acetate). The study was conducted at Mehr Medical Institute, Rasht, Iran between July 2019 and July 2020. Biochemical and clinical pregnancy were compared between groups. No significant differences were observed in the endometrial lining, the total number of retrieved and metaphase-II oocytes, progesterone, and serum estradiol levels on human chorionic gonadotropin day, fertilization rate, and top-quality embryos between the groups. The duration of induction (10.8 1.7 vs. 10 2.1, p 0.001) and the total dosage of gonadotropins (2939.4 945.9 vs. 2441 1247.1, p 0.001) were significantly greater in group 2 than in group 1. No significant differences were observed between the 2 groups in terms of implantation rate, chemical pregnancy rate, and clinical pregnancy rate. A higher percentage of ovarian hyperstimulation syndrome was observed in group 2 (p = 0.005). Due to a lower percentage of ovarian hyperstimulation syndrome in group 1 and similar assisted reproductive technology outcomes in both groups, the long protocol was found to be superior to the short protocol.

Pregnancy Outcomes Associated with Ovarian Hyperstimulation Syndrome: A Retrospective Cohort Study of Infertile Women.

To assess the relationship between ovarian hyperstimulation syndrome (OHSS) and adverse outcomes using population-based data in the United States. The hypothesis is that patients with OHSS were more likely to deliver preterm and more likely to have hypertensive disorders. This retrospective cohort study identified 94 patients with OHSS and 183 matched referents in eight counties in Minnesota. Data were collected regarding pregnancy history, infertility treatment, and pregnancy outcomes. Using the Rochester Epidemiology Project, study subjects were identified from female patients, aged 18 to 49 years, who were diagnosed with infertility from January 2, 1995 to December 1, 2017, and had a pregnancy greater than 20 weeks' gestation. The primary outcome was preterm delivery or hypertensive disorder of pregnancy incidence in the OHSS group when compared with control patients. Chi-squared test, t test, and multivariate logistic models were used where appropriate. Patients with OHSS were more likely to deliver preterm (odds ratio, 2.14; 95% confidence interval, 1.26-3.65; P < 0.01), and their neonates were more likely to be small for gestational age (odds ratio, 4.78; 95% confidence interval, 1.61-14.19; P < 0.01). No significant differences between the groups were observed in any other outcome. Patients with OHSS are more likely to deliver preterm if they undergo fresh transfer compared with a freeze all and subsequent frozen transfer (odds ratio, 3.03, 95% confidence interval, 1.20-7.66, P = 0.02). OHSS may lead to preterm birth and small-for-gestational-age neonates, which changes patient counseling and leads to arranging specialized obstetrical care for these patients with OHSS.

The investigation of cholinergic receptor muscarinic 1 activity in the rat ovary with induced ovarian hyperstimulation.

We look at the immunoreactivity of cholinergic receptor muscarinic 1 (CHRM1) in the ovarian tissues of rats with ovarian hyperstimulation syndrome (OHSS) considering the possibility that the muscarinic activity may contribute to the pathophysiology of OHSS. In this study, 14 immature female Wistar Albino rats were divided into two groups at random. The rats were 22 days old. Rats in the control group (n=7) were 22 days old, while those in the OHSS group (n=7) received 10 IU follicle-stimulating hormone subcutaneously over the course of four days and 30 IU human chorionic gonadotropin (hCG) on the fifth day to induce ovarian hyperstimulation. All the rats were sacrificed after all the groups' ovaries and blood samples were collected at the conclusion of the experiment. The left ovarian tissues were kept in aluminum foil at -80 °C, while the right ovarian tissues were kept in 10% formalin. Tissue vascular endothelial growth factor (VEGF), interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor (TNF)-α and malondialdehyde (MDA) levels were measured by The Enzyme Linked Immunosorbent Assay technique in the ovarian tissues. CHRM1 immunoreactivity was scored immunohistochemically. Ovarian weight, tissue IL-10, TNF-α, VEGF and MDA levels, and CHRM1 immunoreactivity were significantly increased in the OHSS group. Increased levels of CHRM1 activity may play a role in the pathophysiology of OHSS. With further studies, the effect of luteinizing hormone and hCG on the ovarian and hypothalamic cholinergic system can be further investigated, and useful information can be obtained in determining OHSS prevention strategies.

Treatment of Ovarian Hyperstimulation Syndrome in a Mouse Model by Cannabidiol, an Angiogenesis Pathway Inhibitor.

Studies suggest that ovarian hyperstimulation syndrome (OHSS) can be treated by reducing the level of vascular endothelial growth factor (VEGF). However, due to the side effects of commercially available VEGF-reducing drugs, they can be ruled out as a suitable treatment for OHSS; therefore, researchers are looking for new medications to treat OHSS. This study is aimed at investigating the effects of cannabidiol (CBD) in an OHSS model and to evaluate its efficacy in modulating the angiogenesis pathway and VEGF gene expression. For this purpose, 32 female mice were randomly divided into four groups (eight mice per group): control group, group 2 with OHSS induction, group 3 receiving 32 nmol of dimethyl sulfoxide after OHSS induction, and group 4 receiving 30 mg/kg of CBD after OHSS induction. The animals' body weight, ovarian weight, vascular permeability (VP), and ovarian follicle count were measured, and the levels of VEGF gene and protein expression in the peritoneal fluid were assessed. Based on the results, CBD decreased the body and ovarian weights, VP, and corpus luteum number compared to the OHSS group (p < 0.05). The peritoneal VEGF gene and protein expression levels reduced in the CBD group compared to the OHSS group (p < 0.05). Also, CBD caused OHSS alleviation by suppressing VEGF expression and VP. Overall, CBD downregulated VEGF gene expression and improved VP in OHSS.

Perinatal outcomes of singleton live births after late moderate-to-severe ovarian hyperstimulation syndrome: A propensity score-matched study.

To evaluate whether singleton live births achieved following in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) in women with late moderate-to-severe ovarian hyperstimulation syndrome (OHSS) is associated with adverse perinatal outcomes. This was a single-center retrospective cohort study conducted from January 2016 to June 2021.A total of 4,012 IVF/ICSI-fresh embryo transfer cycles that achieved singleton live births were included. According to the diagnosis of OHSS, the cycles were divided into two groups: late moderate-to-severe OHSS (MS-OHSS) group (n = 114) and non-OHSS group (n = 3,898). Multiple baseline covariates were controlled by propensity score matching, yielding 114 late MS-OHSS singleton live births matched to 337 non-OHSS singleton live births. The primary outcome of the study was normal term infant. The secondary outcomes were perinatal complications, gestational age at birth, birth weight, and birth height. Before propensity score matching, no significant difference in perinatal outcomes was identified between late MS-OHSS group and non-OHSS group. After matching maternal age, BMI, basal serum FSH level, basal serum AMH level, basal antral follicle count, type of stimulation protocol, day of embryo development for embryo transfer, number of embryo transfer, and number of oocytes retrieved, there was still no significant difference in obstetric outcomes and neonatal outcomes between the two groups. The findings demonstrate that the perinatal outcomes were similar between the two groups. However, because the sample size of patients with late MS-OHSS was limited in this study, further investigations are warranted using a larger sample size.

Global Transcriptional Profiling of Granulosa Cells from Polycystic Ovary Syndrome Patients: Comparative Analyses of Patients with or without History of Ovarian Hyperstimulation Syndrome Reveals Distinct Biomarkers and Pathways.

Ovarian hyperstimulation syndrome (OHSS) is often a complication of polycystic ovarian syndrome (PCOS), the most frequent disorder of the endocrine system, which affects women in their reproductive years. The etiology of OHSS is multifactorial, though the factors involved are not apparent. In an attempt to unveil the molecular basis of OHSS, we conducted transcriptome analysis of total RNA extracted from granulosa cells from PCOS patients with a history of OHSS (n = 6) and compared them to those with no history of OHSS (n = 18). We identified 59 significantly dysregulated genes (48 down-regulated, 11 up-regulated) in the PCOS with OHSS group compared to the PCOS without OHSS group (p-value < 0.01, fold change >1.5). Functional, pathway and network analyses revealed genes involved in cellular development, inflammatory and immune response, cellular growth and proliferation (including DCN, VIM, LIFR, GRN, IL33, INSR, KLF2, FOXO1, VEGF, RDX, PLCL1, PAPPA, and ZFP36), and significant alterations in the PPAR, IL6, IL10, JAK/STAT and NF-κB signaling pathways. Array findings were validated using quantitative RT-PCR. To the best of our knowledge, this is the largest cohort of Saudi PCOS cases (with or without OHSS) to date that was analyzed using a transcriptomic approach. Our data demonstrate alterations in various gene networks and pathways that may be involved in the pathophysiology of OHSS. Further studies are warranted to confirm the findings.

Outcomes of frozen embryo transfer in patients with and without ovarian hyperstimulation syndrome

"Introduction: One of the methods utilized to treat infertility is the use of frozen embryos. This technique is particularly employed in patients with ovarian hyperstimulation syndrome (OHSS), which leads to heightened blood estrogen levels. The purpose of this study was to compare the percentage of pregnancy and abortion between patients who used the frozen embryo method due to OHSS and others who practiced the same method for other reasons. Materials and Methods: This retrospective, cohort study was conducted on a total of 338 patients who visited in vitro fertilization (IVF) section of Kowsar Hospital of Urmia-Iran to employ the frozen embryo method (May 2013 to December 2015). The patients were classified into two groups, i.e. the OHSS group (N=150) and the non-OHSS group (N=188). Data were obtained and examined by evaluating the files in a questionnaire. Results: The two groups did not differ significantly with regard to their mean age (p = 0.57). There was also no statistically significant difference between the OHSS and non-OHSS groups regarding the quality of frozen embryo transferred (P = 0.17). Also, there was also no statistically significant difference between the two groups in terms of their pregnancy rate (OHSS = 30.0% vs. non-OHSS = 25.0%) and miscarriage rate (OHSS = 31.11% vs. non-OHSS = 24.44%) (p = 0.32 and p = 0.31, respectively). Conclusion: Ovum exposure to high estrogen during ovulation stimulation does not affect embryo implantation and miscarriage in patients with OHSS."

Coenzyme Q10 improves ovarian histology and attenuates the expression of angiogenesis-associated proteins in the ovary of rats with experimental hyperstimulation syndrome.

Objective(s):Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication characterized by many side effects. Coenzyme Q10 (CoQ10) is a protective lipophilic molecule with an extensive range of biological functions, but its possible protective effect on the ovary in OHSS has not as yet been studied. The present study aimed to investigate the potential protective effects of CoQ10 on ovarian histological and molecular alterations in an experimental model of OHSS in rats. Materials and Methods:Thirty female (2 months old) Wistar rats were randomly divided into 6 equal groups: control, OHSS, OHSS+CoQ10 (OHSS+ 200 mg/kg CoQ10 for 10 days), OHSS+ cabergoline (CAB) (OHSS+ 100 µg/kg CAB for 6 days), and CoQ10 and CAB (rats receiving similar doses to treatment groups.( In the end, the effects of treatments were assessed by measuring expressions of vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) in the ovary via western blotting, ovarian histomorphological alterations assessments, and serum estradiol and progesterone levels via ELISA. Results:There were histological alterations in OHSS groups, including the elevation of diameter and numbers of the corpus luteum and atretic follicles, and decreasing follicular reserve count, hyperemia, and hemorrhage at ovarian stroma. Treatment of OHSS groups with CAB and CoQ10 could decrease histological changes, serum estrogen and progesterone, and overexpression of VEGF and COX-2 proteins.Conclusion:Our results showed that ovarian histological and molecular alterations observed in experimental OHSS can be ameliorated by administration of CoQ10, indicating that CoQ10 can be used as new supportive care for OHSS patients.

Obstetric outcomes following ovarian hyperstimulation syndrome in IVF – a comparison with uncomplicated fresh and frozen transfer cycles

BackgroundWe aimed to assess the correlation between ovarian hyperstimulation syndrome (OHSS) in the early course of in vitro fertilization (IVF) pregnancies and obstetric outcomes.MethodsWe identified records of patients admitted due to OHSS following IVF treatment at our institution between 2008 and 2020. Cases were included if pregnancy resulted in a live singleton delivery (OHSS group). OHSS cases were matched at a 1:5:5 ratio with live singleton deliveries following IVF with fresh embryo transfer (fresh transfer group) and frozen embryo transfer (FET group), according to maternal age and parity. Computerized files were reviewed, and maternal, obstetric and neonatal outcomes compared.ResultsOverall, 44 OHSS cases were matched with 220 fresh transfer and 220 FET pregnancies. Patient demographics were similar between the groups, including body mass index, smoking and comorbidities. Gestational age at delivery, the rate of preterm births, preeclampsia and cesarean delivery were similar between the groups. Placental abruption occurred in 6.8% of OHSS pregnancies, 1.4% of fresh transfer pregnancies and 0.9% of FET pregnancies (p=0.02). On post-hoc analysis, the rate of placental abruption was significantly higher in OHSS pregnancies, compared with the two other groups, and this maintained significance after adjustment for confounders. Birthweights were 3017 ± 483, 3057 ± 545 and 3213 ± 542 grams in the OHSS, fresh transfer and FET groups, respectively (p=0.004), although the rate of small for gestational age neonates was similar between the groups.ConclusionsOHSS in the early course of IVF pregnancies is associated with an increased risk of placental abruption.

Nintedanib Treatment After Ovulation is an Effective Therapeutic Strategy for the Alleviation of Ovarian Hyperstimulation Syndrome (OHSS) in a Mouse Model.

PurposeOvarian hyperstimulation syndrome (OHSS) is a serious complication of controlled ovarian hyperstimulation. In this study, we hope to explore whether nintedanib, a tyrosine kinase inhibitor, can inhibit OHSS by blocking signaling of vascular endothelial growth factor in a mouse model. Considering that nintedanib been approved for the treatment of some diseases. We believe that nintedanib has important potential in the treatment of OHSS.MethodsFemale ICR mice aged 6–8 weeks with similar initial weights were used to establish the OHSS model. At 12 and 24 hours after human chorionic gonadotropin (hCG) trigger, we administered nintedanib by subcutaneous injection and analyzed the OHSS-related physiological characteristics and biochemical indices of the model mice within 48 hours after hCG-trigger.ResultsNintedanib significantly alleviated the symptoms of OHSS after hCG-trigger compared with those of OHSS group (weight change, P < 0.0001; ovarian weight, P < 0.0001, peritoneal exudation level, P < 0.01). Further investigation proved that the corpus luteum (number, P < 0.001; diameter, P < 0.0001) and luteal vessel (P < 0.0001) development were inhibited in the nintedanib administration group. Then, the vascular permeability test showed that the capillary bleeding points (P < 0.0001) were also significantly reduced in nintedanib administration group. Gene expression tests demonstrated that the intercellular connection-related genes expression in the nintedanib administration group was similar to that in the no-OHSS induced group. Further detection of coagulation and thrombosis indices indicated that the nintedanib administration in the OHSS model did not increase the risk of thrombosis or bleeding.ConclusionOur study demonstrated that nintedanib can alleviate and manage the symptoms of OHSS in a mouse model. These findings identify a feasible scheme for the prevention and treatment of OHSS in clinical practice in the future. Moreover, since the scheme can be implemented after ovulation, it will not cause potential adverse effects on gametogenesis, fertilization or embryonic development.

Pregnancy outcomes in patients with late-onset severe OHSS following different methods of ascetic fluid drainage and a comparison with non-OHSS IVF patients.

In this study, we aimed to identify whether there are any differences in pregnancy outcomes in patients with severe ovarian hyperstimulation syndrome (OHSS) following the drainage of ascites by central venous catheter or paracentesis. We also aimed to identify differences in pregnancy outcomes between severe OHSS patients and non-OHSS IVF patients. This was a retrospective cohort analysis carried out in a university-affiliated reproductive center between 2012 and 2019 featuring 359 women with severe OHSS following ascites draining and 345 non-OHSS women (matched by age and the number of oocytes retrieved). We investigated the rates of clinical pregnancy, multiple pregnancies, miscarriage, live birth, and preterm delivery, between the two groups. Within the OHSS group (central venous catheter group vs paracentesis group), we also analyzed the odds ratios and 95% confidence intervals of clinical pregnancy. The rate of biochemical pregnancy loss in non-OHSS patients was significantly higher than that of severe OHSS patients (11.1% vs. 0.6%; P < 0.05). Live birth rate and the rate of multiple pregnancy (twin pregnancy) were much higher in the severe OHSS group than in the non-OHSS group (88.9% vs. 73.5%; 57.6% vs. 28.1%, respectively). There was no significant difference between the rate of singleton and twin preterm delivery, and neonatal birth weight between the OHSS and the non-OHSS groups. Binary logistic regression analysis revealed that multiple pregnancy and the long superovulation protocol had high odds ratios (odds ratio (OR) = 2.53), thus suggesting that these are significant risk factors for severe OHSS. When considering the patients with severe OHSS and the manner in which they underwent ascites drainage, we found that the volume of ascites in the central venous catheter group was significantly higher than that in the abdominal paracentesis group (P < 0.05). There were no significant difference between the two groups with regards to the number of live births and the birth weight of singletons and twins (P>0.05), although the premature birth rate of singletons in abdominal paracentesis group was 9.3% (10/107), compared with 3.75% in the central venous catheter group (P < 0.05). Analysis indicated that for women undergoing in vitro fertilization embryo transfer (IVF-ET), a higher number of antral follicle count, COS long protocol, and multiple pregnancy may be risk factors for late-onset OHSS. Both paracentesis and central venous catheters are effective modalities for the management of ascites in patients with severe OHSS. Catheters represent a safe and effective way to treat patients who need to undergo repeated paracentesis.

A Histopathological Evaluation of Ovarian Hyperstimulation Syndrome on Reproductive and Vital Organs and the Role of the VEGF-PKA Pathway in a Mouse Model

Ovarian hyperstimulation syndrome (OHSS) is one of the most common and iatrogenic complications of in vitro fertilization therapy, which is an exaggerated response to excess hormones resulting in the development of a large number of maturing follicles. Although the complications of and reasons for the condition are well known, the overall histopathological effects on systemic organs and the extent of the damage have not been fully elucidated. Besides, the mechanism that underlies the situation is not very well known. The aim of the present work was to analyse the histopathological effects of OHSS on reproductive (uterus and ovary) and vital organs (liver and kidney) and the possible role of the VEGF-PKA pathway in triggering the condition. Balb/c mice were used to establish an OHSS model. The OHSS group were injected with overdose PMSG while the normal responder group were injected with an optimal dose. Histopathological evaluation was utilised in the liver, kidney, ovary, and uterus stained with hematoxylin and eosin, Masson’s trichrome, and periodic acid-Schiff stain. The expression profiles of VEGF (vascular endothelial growth factor), PKA (protein kinase A), and p-PKA (an activated form of PKA) were detected with immunohistochemistry and Western blotting. OHSS was demonstrated to have a negative histopathological effect on all of the organs analysed. These effects were associated with an overall increase in the expression levels of VEGF, PKA, and p-PKA. OHSS has a serious histopathological negative effect on the systemic and reproductive organs and is proven to affect overall health, and thus should be considered a dangerous complication during ART techniques. The activation of the VEGF-PKA pathway, which is indicated by the expression levels of VEGF, PKA, and p-PKA, is demonstrated to accompany this complication, which should be further elucidated to understand the mechanisms underlying the condition.

Transient receptor potential melastatin 2 ion channel activity in ovarian hyperstimulation syndrome physiopathology

Background/aimOvarian hyperstimulation syndrome (OHSS) is a complication of ovarian stimulation with increased vascular endothelial growth factor (VEGF) and vascular permeability in the ovarian tissue. Transient receptor potential melastatin 2 (TRPM2) is known to be associated with angiogenesis and vascular permeability. In this experimental study, we aimed to investigate the activity of TRPM2 in the development of OHSS. Materials and methodsFourteen immature female rats were divided into two groups. Group 1 was the control group, and Group 2 was the OHSS group that was exposed to 10 IU of subcutaneous application of FSH for four days and 30 IU of human chorionic gonadotropin (hCG) on the 5th day. At the end of the experiment, the ovaries were removed. The right ovarian tissues were stored in 10% formol for histopathological and immunohistochemical examination. The left ovarian tissues were stored at –80 °C for biochemical examinations. VEGF, tumor necrosis factor-alpha (TNF‐α) and malondialdehyde (MDA) levels were measured in the ovarian tissue. Congestion, edema, apoptosis and TRPM2 immunoreactivity were evaluated.ResultsThere was a significant increase in ovarian weight in the OHSS group compared to the control group. There was a significant increase in congestion, edema, apoptosis and TRPM2 immunoreactivity in the OHSS group. A significant increase in tissue levels of VEGF, TNF‐α and MDA was also found in the OHSS group compared to the control group. Conclusion As a result of our experiment, it was found that increased TRPM2 immunoreactivity on hyperstimulated rat ovary may be the reason or result of edema and congestion. Further studies are needed to discuss our results.

Exosomal miR-27 negatively regulates ROS production and promotes granulosa cells apoptosis by targeting SPRY2 in OHSS.

Ovarian hyperstimulation syndrome (OHSS) is one of the most dangerous iatrogenic complications in controlled ovarian hyperstimulation (COH). The exact molecular mechanism that induces OHSS remains unclear. In recent years, accumulating evidence found that exosomal miRNAs participate in many diseases of reproductive system. However, the specific role of miRNAs, particularly the follicular fluid‐derived exosomal miRNAs in OHSS remains controversial. To identify differentially expressed follicular fluid exosomal miRNAs from OHSS and non‐OHSS patients, the analysis based on miRNA‐sequence was conducted. The levels of 291 miRNAs were significantly differed in exosomes from OHSS patients compared with normal control, and exosomal miR‐27 was one of the most significantly down‐regulated miRNAs in the OHSS group. By using MiR‐27 mimic, we found it could increase ROS stress and apoptosis by down‐regulating the expression of p‐ERK/Nrf2 pathway by negatively regulating SPRY2. These data demonstrate that exosomal miRNAs are differentially expressed in follicular fluid between patients with and without OHSS, and follicular fluid exosomal miR‐27 may involve in the pathological process of OHSS development.

Electroacupuncture Reduces Oocyte Number and Maintains Vascular Barrier Against Ovarian Hyperstimulation Syndrome by Regulating CD200

Ovarian hyperstimulation syndrome (OHSS) is a common complication caused by ovulatory stimulation therapy, which manifests as an increase in ovarian volume, an increase in the number of oocytes retrieved, and increased vascular permeability throughout the body and especially in ovarian tissue. In our previous study, we found that electroacupuncture (EA) could prevent the progression of OHSS, by mainly affecting ovary. However, the specific molecules and the mechanism of this process were still unknown. In order to explore the underlying mechanism, OHSS rat model was established and EA treatment was performed, which was followed by proteomic analysis of ovaries. Results showed a significant increase in the expression level of CD200 in the ovaries of OHSS group treated with EA than those of OHSS group. Clinical data showed that the level of CD200 in follicular fluid was negatively correlated with the number of oocytes retrieved and serum E2 level. Further in vitro experiments showed a concentration-dependent role of human chorionic gonadotropin (hCG) in reducing CD200 and CD200R levels, and increasing inflammatory cytokine levels in cultured KGN cells. In human umbilical vein endothelial cells (HUVECs), the vascular barrier function was improved by CM (cultural medium from KGN cell) which treated with CD200Fc (CD200R agonist). Meanwhile, the results of in vivo experiments indicated that EA reduced the number of ovarian corpora lutea, decreased inflammatory response, and improved the vascular barrier function by increasing the expression of CD200 and CD200R in rat ovaries. These findings suggest that EA treatment may reduce oocyte number and maintain vascular barrier against OHSS through ovarian anti-inflammatory response mediated by CD200. Therefore, this study is the first to identify CD200 as a main of EA in the ovary and elucidate the possible mechanism of EA on preventing and treating OHSS, which provide a scientific basis for CD200 as an effector and indicator in EA treatment.

Factors Associated with Ovarian Hyperstimulation Syndrome (OHSS) Severity in Women With Polycystic Ovary Syndrome Undergoing IVF/ICSI.

IntroductionAge, polycystic ovary syndrome (PCOS), low body mass index (BMI), high antral follicle count (AFC), increased anti-Muller hormone (AMH) levels, and elevated serum estradiol (E2) concentrations are risk factors for ovarian hyperstimulation syndrome (OHSS). However, data on the relationship between risk factors and OHSS severity in patients with PCOS are rare.ObjectiveThis retrospective study examined the risk factors for OHSS and their effect on OHSS severity in patients with PCOS undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI).MethodThe records of 2,699 women were reviewed and included in this study. These women were diagnosed with PCOS during their first IVF/ICSI cycle between January 2010 and December 2017. We analyzed the association between each of the interrogated risk factors (including female age, BMI, AFC, basal serum E2, and the number of oocytes retrieved) and OHSS. The effects of each risk factor on OHSS severity were further explored. Logistic regression was performed as part of the above analysis.ResultsOf the 2,699 women with PCOS who underwent assisted reproductive technology (ART), 75.2% had a normal response to controlled ovarian hyperstimulation (COH), while 24.8% developed OHSS. All OHSS patients were younger and had lower BMIs and basal serum follicle-stimulating hormone (FSH) and E2 levels but higher AFCs than those in the normal group. AFC demonstrated a strong correlation with OHSS, with a cutoff value of 24 in patients with PCOS. A total of 19.5% of the patients had mild OHSS, while 80.5% had moderate OHSS. Compared with those in the moderate OHSS group, those in the mild OHSS group were older and had higher basal serum FSH levels and lower serum E2 and T levels. However, BMI and AFC were not different between the mild and moderate OHSS groups. Basal serum E2 showed a strong correlation with OHSS severity, with a cutoff value of 37.94 pg/ml.ConclusionsAFC is a strong marker of OHSS, and basal serum E2 is the best predictor of OHSS severity in women with PCOS undergoing IVF treatment.

Effect of kisspeptin-54 on ovarian levels of pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor (VEGF) in an experimental model of ovarian hyperstimulation syndrome (OHSS).

The purpose of this study was to investigate the effect of kisspeptin-54 on ovarian morphology and vascular endothelial growth factor (VEGF), pigment epithelium-derived factor (PEDF), protein kinase A (PKA) and protein kinase C (PKC) levels in an ovarian hyperstimulation syndrome (OHSS) rat model, which is a possible complication of controlled ovarian hyperstimulation. For this purpose, immature female Sprague-Dawley rats (25days old, 30-40g) were randomly divided into five groups (control, sham, OHSS model, short-term kisspeptin-54 administered OHSS model and long-term kisspeptin-54 administered OHSS model). Serum LH and FSH levels were determined by enzyme-linked immunosorbent assay. Immunohistochemistry and quantitative RT-PCR were performed for VEGF, PEDF, PKA and PKC in ovaries and granulosa cells, respectively. It was observed that there was dilatation in fallopian tubes and an abnormal increase in ovarian weight and volume in the OHSS group, and these morphologies decreased with kisspeptin-54 treatment. After the administration of kisspeptin-54 in the OHSS group, VEGF, PKA and PKC levels reduced and PEDF levels increased in both mRNA and protein levels. It was determined that in the OHSS model, VEGF increased as PEDF decreased, and kisspeptin-54 reduced the effects of OHSS. It was determined that long-term kisspeptin-54 treatment was more effective than short-term administration. It is considered that kisspeptin-54 is an agent that protects ovarian reserve and oocyte maturation in women at risk of OHSS.

Neutrophil:lymphocyte and estradiol:progesterone ratios as predictive markers for ovarian hyperstimulation syndrome (OHSS).

This study was based on the pathophysiology of the disease and aimed at predicting ovarian hyperstimulation syndrome (OHSS) by determining the importance of ratios obtained from the inflammatory process associated with oestradiol and progesterone in recent years. Out of 242 infertile women who underwent assisted reproductive therapy, 59 patients who developed OHSS were taken as the study group, while the remaining 122 normo-responder (NR) and 61 hyper-responder (HR) patients constituted the control group. The neutrophil to lymphocyte (NLR) and oestradiol/progesterone (EPR) ratios were found to be statistically significantly higher in the OHSS group (P <0.001). A multivariate logistic regression analysis revealed that the NLR (OR=2.410, P =0.001) and EPR (OR=1.701, P =0.028) were independent predictors for the development of OHSS. In conclusion, in OHSS inadequate progesterone levels may inhibit suppression of the exaggerated inflammatory process caused by high E2 levels, and NLR and EPR can be used to predict the development of OHSS in patients undergoing controlled ovarian hyperstimulation during in vitro fertilisation cycles.