Development Of Ovarian Hyperstimulation Syndrome Research Articles

Severe Early-Onset Intrahepatic Cholestasis of Pregnancy Following Ovarian Hyperstimulation Syndrome with Pulmonary Presentation after In Vitro Fertilization: Case Report and Systematic Review of Case Reports.

Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-related liver disease, usually presented in the third trimester with pruritus, elevated transaminase, and serum total bile acids. Evidence shows that it can be developed in the first trimester, more commonly after in vitro fertilization (IVF) procedures, with the presence of ovarian hyperstimulation syndrome (OHSS). A literature search was conducted in the PubMed/MEDLINE database of case reports/studies reporting early-onset ICP in spontaneous and IVF pregnancies published until July 2023. Thirty articles on early-onset ICP were included in the review analysis, with 19 patients who developed ICP in spontaneous pregnancy and 15 patients who developed ICP in IVF pregnancies with or without OHSS. Cases of 1st and 2nd trimester ICP in terms of "early-onset" ICP were pooled to gather additional findings. Proper monitoring should be applied even before expected pregnancy and during IVF procedures in patients with known risk factors for OHSS and ICP development (patient and family history), with proper progesterone supplementation dosage and genetic testing in case of ICP recurrence.

#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.

TGF-β1 and TGF-β3, but not TGF-β2, are upregulated in the ovaries of ovarian hyperstimulation syndrome†.

Ovarian hyperstimulation syndrome (OHSS) is a life-threatening and potentially fatal complication during in vitro fertilization treatment. The levels of transforming growth factor-β1 (TGF-β1) are upregulated in human follicular fluid and granulosa-lutein cells (hGL) of OHSS patients and could contribute to the development of OHSS by downregulating steroidogenic acute regulatory protein (StAR) expression. However, whether the same is true for the other two members of the TGF-β family, TGF-β2 and -β3, remains unknown. We showed that all three TGF-β isoforms were expressed in human follicular fluid. In comparison, TGF-β1 was expressed at the highest level, followed by TGF-β2 and TGF-β3. Compared to non-OHSS patients, follicular fluid levels of TGF-β1 and TGF-β3 were significantly upregulated in OHSS patients. The same results were observed in mRNA levels of TGF-β isoforms in hGL cells and ovaries of OHSS rats. In addition, StAR mRNA levels were upregulated in hGL cells of OHSS patients and the ovaries of OHSS rats. Treatment cells with TGF-β isoforms downregulated the StAR expression with a comparable effect. Moreover, activations of SMAD3 signaling were required for TGF-β isoforms-induced downregulation of StAR expression. This study indicates that follicular fluid TGF-β1 and TGF-β3 levels could be used as biomarkers and therapeutic targets for the OHSS.

Comparison between Agonist Trigger with HCG Luteal Phase Supplementation vs HCG Trigger with Progesterone Luteal Phase Supplementation in Antagonist Controlled Hyperstimulation Cycle Regarding Clinical Pregnancy Rate

For the last two decades, exogenous progesterone administration has been used as luteal phase support (LPS) in connection with controlled ovarian stimulation combined with use of the human chorionic gonadotropin (hCG) trigger for the final maturation of follicles. The introduction of the GnRHa trigger to induce ovulation showed that exogenous progesterone administration without hCG supplementation was insufficient to obtain satisfactory pregnancy rates. This has prompted development of alternative strategies for LPS. Augmenting the local endogenous production of progesterone by the multiple corpora lutea has been one focus with emphasis on one hand to avoid development of ovarian hyper-stimulation syndrome and, on the other hand, to provide adequate levels of progesterone to sustain implantation. The present study evaluates the use of micro-dose hCG for LPS support and examines the comparison between conventional HCG trigger and progesterone luteal phase support vs Agnosit trigger and HCG microsdose luteal phase support as regards to pregnancy rate. Methods 100 patients were recruited for this trial Cases with Polycyctic ovaries were excluded from the study. The study was approved by Ethical committee of Ain Shams university. Patients received Gonal-F (Merck Serono S.p.A., Via delle Magnolie 15, I70026 Modugno (Bari), Italy.) in a dose ranginging between 150-300 IU for stimulation and the dose was adjusted according to response starting day 6. Premature LH surge was prevented with 0.25 mg of a GnRH antagonist (Cetrotide; Merck international) starting on day 6, when two or more follicles reach a size of 18–20 mm, patients were randamized into 2 groups of 50 each. Trigger of ovulation was done by a single dose of 0.2 mg triptorelin (Decapeptyl®ferring pharmaceutical company, Germany) and luteal phase support with daily 125 IU HCG injections in Group 1. Group 2 received A single dose of HCG 10000 IU was given followed by progesterone supplementation with 100mg IM progesterone (Prontogest® IBSA Swisserland). 2 Embryo were transferred and an ultrasound at 4 weeks after embryo transfer for cases with positive pregnancy test. As regards to clinical pregnancy group 1 had 28 of the 50 (56%) Positive clinical pregnancy while control was 26 of the 50 (52%), the difference was not statistically significant (P > 0.68). No cases of moderate or severe ovarian hyperstimulation were observed during the study. To conclude, Agonist trigger combined with microdose HCG had a comparable pregnancy rate resulst to HCG trigger and conventional progesterone support for luteal support without increasing the risk of ovarian hyper stimulation.

Risk of ovarian hyperstimulation syndrome in women with malignancies undergoing treatment with long-acting gonadotropin-releasing hormone agonist after controlled ovarian hyperstimulation for fertility preservation: a systematic review.

Fertility preservation is an important quality of life issue for women of reproductive age undergoing gonadotoxic treatment. The possibility of administering an adjuvant long-acting gonadotropin-releasing hormone agonist (GnRHa) with the aim of reducing the number of follicles susceptible to the effects of chemotherapy and thus reducing the risk of ovarian damage is considered in some international society guidelines, particularly in certain cancers such as breast cancer. Nowadays, the administration of long-acting GnRHa after controlled ovarian hyperstimulation (COH) for fertility preservation by cryopreservation of oocytes or embryos is increasingly used. However, cases of ovarian hyperstimulation syndrome (OHSS) have been reported following the use of long-acting GnRHa after COH for fertility preservation, indicating that the potential adverse effects of this treatment need to be further investigated. The aim of this systematic review was to comprehensively characterize patients who developed OHSS after treatment with long-acting GnRHa following COH for fertility preservation. A comprehensive search of major electronic databases through January 2023 was performed. Studies reporting the use of long-acting GnRHa after COH for fertility preservation and the development of OHSS were included. Risk of bias was assessed using a modified version of the Newcastle-Ottawa scale. Results were synthesized qualitatively. Three studies with five patients met the eligibility criteria. The majority of patients were diagnosed with breast cancer and all patients underwent COH for oocyte cryopreservation. OHSS occurred in all patients after administration of long-acting GnRHa. The interval between ovulation induction and administration of long-acting GnRHa thereafter ranged from 3 to 5 days. All patients were treated conservatively and recovered without complications. Current evidence suggests that the use of long-acting GnRHa after COH for fertility preservation may be associated with OHSS. Healthcare providers should thoroughly discuss the benefits and risks of this intervention with their patients before making a decision. Further studies are needed to fully elucidate the causal relationship between long-acting GnRHa and OHSS in this population.

Ovarian hyperstimulation syndrome following the use of GnRH agonist trigger of final oocyte maturation and freeze–all strategy

Rationale: The current literature has a surprising controversy regarding the use of low-dose human chorionic gonadotropin (hCG) for luteal support as an explanation for the development of ovarian hyperstimulation syndrome, and this is because of the gap in the listing of the predisposing factors that put women at an increased risk of ovarian hyperstimulation syndrome. Patient concerns: A case of 25-year-old woman presented with abdominal pain, distention, dyspnea, and nausea with a 6.5 kg increase in weight from baseline. Ultrasonographic examination showed bilaterally enlarged multicystic ovaries after gonadotropin-releasing hormone (GnRH) agonist triggering and cycle segmentation with no hCG rescue administration. Diagnosis: Moderate/severe ovarian hyperstimulation syndrome. Interventions: The woman was admitted to the hospital for medical management of moderate/severe ovarian hyperstimulation syndrome, and pain management was advanced to patient-controlled anesthesia with the start of low molecular weight heparin. On day 2, albumin therapy followed by a furosemide chase was started due to an increase in abdominal girth. On day 1, Cabergoline was maintained, and on day 2 the GnRH antagonist Cetrorelix was started. Outcomes: The woman’s clinical condition improved, and a clinical pregnancy was eventually achieved during the first cryo-warmed blastocyst cycle. Lessons: Ovarian hyperstimulation syndrome can still happen even after the use of GnRH agonist and avoidance of hCG support. Segmentation of in vitro fertilization with complete avoidance of hCG for luteal support remains the best approach.

Kallistatin prevents ovarian hyperstimulation syndrome by regulating vascular leakage.

Angiogenesis and increased permeability are essential pathological basis for the development of ovarian hyperstimulation syndrome (OHSS). Kallistatin (KS) is an endogenous anti‐inflammatory and anti‐angiogenic factor that participates in a variety of diseases, but its role in OHSS remains unknown. In this study, treating a human ovarian granulosa‐like tumour cell line KGN and human primary granulosa cells (PGCs) with human chorionic gonadotropin (hCG) reduced the expression of KS, but increased the expression of VEGF. Furthermore, we found that KS could attenuate the protein level of VEGF in both KGN cells and human PGCs. More interestingly, we observed that exogenous supplementation of KS significantly inhibited a series of signs of OHSS in mice, including weight gain, ovarian enlargement, increased vascular permeability and up‐regulation of VEGF expression. In addition, KS was proved to be safe on mice ovulation, progression of normal pregnancy and fetus development. Collectively, these findings demonstrated that KS treatment prevented OHSS, at least partially, through down‐regulating VEGF expression. For the first time, these results highlight the potential preventive value of KS in OHSS.

Lipid Analysis of Follicular Fluids by UHPLC-ESI-HRMS Discovers Potential Biomarkers for Ovarian Hyperstimulation Syndrome.

Ovarian hyperstimulation syndrome (OHSS) is a serious iatrogenic complication during ovarian stimulation. Even though the incidence of OHSS was relatively low in clinical practice, the consequence can be potentially devastating and life-threatening. Abnormal lipid metabolism may relate to the pathological development of OHSS, but there is still a research gap in the lipidomic research. So here in our study, an ultra-high-performance liquid chromatography coupled with electrospray ionization high-resolution mass spectrometry (UHPLC-ESI-HRMS) based lipidomic analysis was performed using follicular fluid samples obtained from 17 patients undergoing OHSS. The lipid profiles of OHSS patients were characterized by increased cholesterol ester (ChE) and decreased lysophosphatidylcholine (LPC), phosphatidylinositol (PI), sphingomyelin (SM), dimethylphosphatidylethanolamine (dMePE) and lysodimethylphosphatidylethanolamine (LdMePE). Totally 10 lipids including LPC(18:0), SM(d18:1/16:0), PC(18:0/18:1), PC(20:2/20:5), PC(16:0/18:1), TG(16:0/18:1/18:1), TG(16:0/18:2/18:2), TG(16:0/16:1/18:1), ChE(20:4) and TG(8:0/8:0/10:0) were selected as differential lipids. In conclusion, this study demonstrated the alteration of various lipids in OHSS patients, which suggested the key role of lipids during the development of OHSS and shed light on the further pathophysiological research of OHSS.

P-623 Outcomes of Ovarian Drilling

Abstract Study question Is it cost-effective performing laparoscopic ovarian drilling in patients with polycystic ovarian syndrome? Summary answer Laparoscopic ovarian drilling (LOD) is a cost-effective procedure and can potentially reduce the risk of ovarian hyperstimulation syndrome (OHSS) in subsequent IVF treatment What is known already LOD increases the chances of resumed regular menstruation as well as an increase in spontaneous ovulation when compared to patients treated with clomiphene citrate. An increase in spontaneous conception of pregnancy can be seen in LOD patients however this can be affected by the age of the patient but not necessarily by the BMI. In the 1980’s wedge resection was shown to be successful in ovulation induction, however this was abandoned with the emergence of urinary gonadotrophins and oral anti-oestrogens. Study design, size, duration This is a retrospective observational study performed in a single UK district general hospital. A total of 84 patients underwent laparoscopic ovarian drilling over a six-year period were identified from the hospital discharge code. All patients with a confirmed PCOS diagnosis according to the Rotterdam Criteria were included. Demographic details included age, body mass index, follicle-stimulating and luteinising hormone levels, Anti-Mullerian hormone (AMH) and antral follicle count and patient’s subsequent treatment details were analysed. Participants/materials, setting, methods We analysed the biochemical pregnancy, clinical pregnancy and livebirth rates of all patients who underwent LOD. We further evaluated the prognosis of the patients who did not achieve a live birth following LOD with subsequent fertility treatment such as ovulation induction treatment or in-vitro fertilisation (IVF). We also explored the rate OHSS after LOD. All data were obtained from the local hospital database system where patient’s demographic, treatment details and birth outcomes are recorded. Main results and the role of chance 38 out of the 84 (45%) patients had receive other forms of fertility treatment prior to the laparoscopic ovarian drilling, namely clomiphene or letrozole but failed to achieve a successful pregnancy. 26 (31%) of the patients ovulated spontaneously after the operation and conceived with 22 of them achieving a livebirth (26%). For patients who did not ovulate spontaneously or did not achieve a pregnancy after 6 months from the drilling, 28 patients then undergone further ovulation induction, with a 43% (13/28) clinical pregnancy and 29% (9/28) of livebirth rate. Further 35 patients went for IVF treatment with 21/35 (60%) achieving a livebirth. 6 out of the 35 (17%) had a ‘freeze all’ cycle due to high risk of development of moderate to severe OHSS. The OHSS rate in this high risk group of population was 8% (3/35). In conclusion, 61% (52/84) patients achieved a live birth of which, 26% was following laparoscopic drilling without any further treatment fertility treatment. For patients who underwent drilling and subsequently had IVF treatment, the development of OHSS is similar to the background rate quoted in literature rather than the much higher 20% in PCOS population (Delvigne et al, 2002) Limitations, reasons for caution The retrospective nature of the study with a relatively small sample size limited the generalisability of the results. There was a lack of strict inclusion criteria for patients who were offered drilling reflected by the wide range of AMH (18.9-176 pmol/l) and LH (0.8-33.4 iu/l) levels in our sample. Wider implications of the findings The response to treatment can also be dependent on the energy modality used. LOD has been shown to be cost effective when compared Gonadotrophin treatment which can lead to ovarian hyperstimulation. Some studies have reported similar pregnancy outcomes with both treatment options, however LOD has shown to be cost effective. Trial registration number not applicable

Sonographic Comparison between PCOS, Hyperstimulated Ovaries and Hyperreactio Luteinalis

Background: Polycystic Ovarian Syndrome (PCOS) is a highly prevalent endocrinological disorder of females characterized by hirsutism, infertility and bilaterally enlarged multicystic ovaries.It is also a risk factor for development of Ovarian Hyperstimulation Syndrome (OHSS) and Hyperreatcio luteinalis (HL). Aim: To identify the value of ultrasonography in distinguishing these three interlinked pathologies and highlight the need for additional relevant investigations to make confirmatory diagnosis of any of them. Method: We conducted a systematic search by using Google Scholar and PubMed as search engines to retrieve all the available English-language literature on ultrasonographic findings of PCOS, OHSS and HL published from 2016 to 2021 while following PRISMA Statement. Results: Out of 316 articles retrieved ,only 9 articles were found that met the preset inclusion and exclusion criteria and of which there were 8 case reports and 1 narrative review. Conclusion: PCOS, OHSS and HL are interrelated ovarian morphological abnormalities with almost same ultrasonographic features.Correlation of these features with other relevant lab investigations and clinical parameters is therefore necessary to make an individual diagnosis out of them. Keywords: Ultrasound features, PCOS, Polycystic ovarian syndrome, Ovarian Hyperstimulation syndrome, Multicystic ovaries

Calcium gluconate infusion is not as effective as dopamine agonists in preventing ovarian hyperstimulation syndrome.

The aim of the study was to compare the effectiveness of calcium gluconate and cabergoline therapy in the prevention of ovarian hyperstimulation syndrome (OHSS). Eight hundred and forty-five women who underwent GnRH antagonist protocol and at high risk for developing OHSS were divided into two groups, those given cabergoline (n=435) or calcium gluconate (n=410). In cabergoline group, 0.5 mg of cabergoline was administered once daily p.o. starting on the day of ovulation trigger and continued until the following 8 days. In calcium gluconate group, intravenous calcium gluconate was administered daily for four days starting on the day of oocyte pickup (OPU). 10 ml of 10% calcium gluconate solution was dissolved in 200 ml of physiological saline and administered by intravenous route within 40 minutes. Infusion was started within the first 30 minutes following the OPU and continued on the 1st, 2nd and 3rd days after OPU. Mild OHSS was developed in 367 (89%) patients receiving calcium gluconate infusion, while 251 patients (57%) in the cabergoline group developed mild OHSS. The frequency of mild OHSS in the calcium group was significantly higher than the cabergoline group (p<.001). Moderate OHSS was observed in 32 people (7.8%) in the calcium gluconate group, while it was observed in 184 people in the cabergoline group (42.3%). Calcium gluconate infusion significantly reduced the development of moderate OHSS compared to cabergoline therapy (p<.001). Severe OHSS developed in 11 patients (2.7%) in the calcium gluconate group, while severe OHSS did not develop in those given cabergoline (0%, p<.001). Clinical pregnancy, live birth and abortion rates were similar in the two groups. When logistic regression analysis was performed, a significant correlation was found between age, BMI, AMH, the number of antral follicle count, OHSS history, paracentesis, progesterone on the day of hCG, 2 PN zygotes, and HbA1c levels and the development of OHSS. No correlation was found between the use of metformin or cetrotide and the development of OHSS. Calcium gluconate treatment is not effective in the prevention of OHSS.

Tie1 contributes to the development of ovarian hyperstimulation syndrome under the regulation of EGR1 in granulosa cells

The expression of tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 1 (Tie1), a transmembrane protein expressed almost exclusively by endothelial cells, has been reported in granulosa cells. However, its significance in ovarian hyperstimulation syndrome (OHSS), which can occur after the injection of gonadotropins in infertile women undergoing controlled ovarian stimulation, is unknown. Here, we report significantly increased Tie1 and vascular endothelial growth factor (VEGF) expression in cultured granulosa cells from OHSS patients, as well as ovaries from rats with experimentally established OHSS, compared to controls, with the levels of both proteins also increasing in granulosa and SVOG cells (a nontumorigenic human granulosa-lutein cell line) treated with an acute dose of human chorionic gonadotropin (hCG). Tie1 silencing abolished the hCG-induced VEGF level in SVOG cells and attenuated the progression of OHSS in rats, as determined by histological analysis. Further studies in SVOG cells revealed that the hCG-induced upregulation of Tie1 expression involved the phosphoinositide 3-kinase/protein kinase B signaling pathway. We also report that early growth response protein 1 (EGR1), whose expression was also upregulated by hCG, bound directly to the Tie1 promoter and activated its transcription. Taken together, our results indicate that Tie1 may be a therapeutic target in cases of moderate-to-severe OHSS. Further studies are needed to address its clinical relevance.

Risk Factors and Method for Predicting Ovarian Hyperstimulation Syndrome (OHSS) in the In Vitro Fertilization Program

Ovarian hyperstimulation syndrome (OHSS) is the most severe and life-threatening complication of assisted reproductive technologies (ART). OHSS is based on an excessive ovarian response to ovarian stimulation; however, the pathogenesis has not been fully understood yet. The most serious complications of OHSS are thromboembolic complications and ovarian torsion. The current study describes the risk factors for the development of ovarian hyperstimulation syndrome and proposes a method for individual prediction of the syndrome. This study was designed to investigate 671 treatment cycles in the IVF program for 2009-2018. All patients were divided into 2 groups. Group 1 (n=56) included women who developed OHSS during the IVF procedure. Group 2 (n=615) consisted of women who did not have this complication during the IVF procedure. All the observation and examination outcomes were entered into a specially developed questionnaire, and then into an MS Excel spreadsheet. The material was processed by variable statistics using Statistica 10.0. Analyzing of the recorded data revealed that the rate of OHSS was higher in the group of younger women, 30.76±3.67 years, in comparison with 32.78±4.40 years in the group of patients without OHSS (p<0.05). The analysis of the initial phase of the reproductive system has confirmed that the group of patients with OHSS had a higher level of prolactin, 462.84±191.56 mIU/L in comparison with 363.43±187.84 mIU/L, which corresponded to the group of women without OHSS (p<0.05). Patients with OHSS significantly less often had obesity, in 7.15±1.04% of cases, while none of the patients from the group without OHSS suffered from it (p<0.05). OHSS is the most severe iatrogenic complication of ART, therefore it is extremely important to consider risk factors and take timely preventive measures. This study has established a high relationship between the above risk factors and ovarian hyperstimulation syndrome and proposed a model for predicting this syndrome.

Severe ovarian hyperstimulation syndrome with GnRH agonist trigger during the COVID pandemic: lessons learned from an unusual case

Background: Injectable gonadotropins stimulate multi-follicular recruitment and allows retrieval of multiple oocytes for assisted reproduction. The widespread utilization of gonadotropin releasing hormone agonist (GnRHa) to induce oocyte maturation for oocyte retrieval has nearly eliminated the risk of severe ovarian hyperstimulation syndrome (OHSS), and only a few cases have been reported in the literature. The rarity of severe OHSS may lead to the mistaken conclusion that gonadotropin stimulation can be safely administered with limited monitoring, even in high-risk patients. We present an unusual case of a woman with limited monitoring due to the COVID pandemic who developed severe OHSS before GnRH agonist trigger and oocyte. Case Presentation: A 29-year-old nulliparous woman with polycystic ovarian syndrome (PCOS) initiated ovarian stimulation for oocyte retrieval. She had a robust initial response, and developed worsening abdominal pain, bloating, nausea, vomiting, and decreased appetite before retrieval. GnRH agonist was given to “trigger ovulation and retrieval scheduled due to the low reported incidence of severe OHSS. Symptoms progressed, and on the morning of retrieval, ultrasound demonstrated bilaterally enlarged ovaries &gt;10cm and 48 oocytes were retrieved for a planned cryo-all cycle. She was hospitalized on the day of retrieval for severe OHSS and had two large-volume paracenteses. She was stable and discharged home by day 5, and symptoms markedly improved with the onset of menses. She has an ongoing pregnancy from her first frozen embryo transfer. Conclusion: We add a rare case of severe OHSS with a GnRHa trigger and cryo-all protocol with the onset of symptoms before GnRH agonist administration. Although rare, severe OHSS may still occur with a GnRHa trigger, and caution is needed when an initial robust response is identified. Here we also provide an opportunity to review the important patient risk factors for the development of OHSS and measures to reduce the risk in excessive responders.

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.

High ovarian GDF-8 levels contribute to elevated estradiol production in ovarian hyperstimulation syndrome by stimulating aromatase expression.

Rationale: Growth differentiation factor-8 (GDF-8), also known as myostatin, belongs to the transforming growth factor-beta (TGF-β) superfamily. GDF-8 is expressed in the ovary and regulates various ovarian functions. Ovarian hyperstimulation syndrome (OHSS) is one of the most serious disorders during in vitro fertilization treatment. Aromatase, encoded by the CYP19A1 gene, is the enzyme that catalyzes the final step in estradiol (E2) biosynthesis. It has been demonstrated that high serum E2 levels are associated with the development of OHSS. However, the effects of GDF-8 on aromatase expression and its roles in the pathogenesis of OHSS remain unclear.Methods: The effect of GDF-8 on aromatase expression and the underlying mechanisms were explored by a series of in vitro experiments in primary human granulosa-lutein (hGL) and KGN cells. Rat OHSS model and human follicular fluid samples were used to examine the roles of the GDF-8 system in the pathogenesis of OHSS.Results: We demonstrate that GDF-8 stimulates aromatase expression and E2 production in hGL and KGN cells. In addition, TGF-β type I receptor ALK5-mediated SMAD2/3 signaling is required for GDF-8-induced aromatase expression and E2 production. Using a rat OHSS model, we show that the aromatase and GDF-8 levels are upregulated in the ovaries of OHSS rats. Blocking the function of ALK5 by the administration of its inhibitor, SB431542, alleviates OHSS symptoms and the upregulation of aromatase. Clinical results reveal that the protein levels of GDF-8 are upregulated in the follicular fluid of OHSS patients. Moreover, the expression of GDF-8 is increased in hGL cells of OHSS patients.Conclusions: This study helps to elucidate the mechanisms mediating the expression of aromatase in human granulosa cells, which may lead to the development of alternative therapeutic approaches for 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.

Different Timing of Adjuvant Low Dose hCG and GnRH Agonist Trigger Protocol, in OHSS High-Risk Patient with Peak E2 Level &lt;4000 pg/mL

OBJECTIVE: The aim of the study is to compare the live birth rates between 1,500 I.U. of Human chorionic gonadotropin at the time of Gonadotropin-releasing hormone agonist trigger day or 35-36 h later on the oocyte pick-up day, without affecting the risk of significant ovarian hyperstimulation syndrome development in high-risk patients with peak E2 level &lt;4,000 pg/mL STUDY DESIGN: This single-center prospective cohort study encompassed the period from March 2016 to March 2018 year. A total of 216 patients entered for final analysis, underwent a flexible antagonist protocol, intracytoplasmic sperm injection, and embryo transfer on the 3rd or 5th day in autologous cycles. Patients were randomized in one of two groups: Group A- Dual trigger group - 1,500 IU of Human chorionic gonadotropin at the time of Gonadotropin-releasing hormone agonist trigger day and Group B- 1,500 IU of Human chorionic gonadotropin 35-36 h later, on the oocyte pick-up day. To compare the two groups, we used nonparametric and parametric statistical tests. Significant differences were considered all values of p&lt;0.05. RESULTS: There is no significant difference between the two (A vs B) groups according to the average number of retrieved oocytes (13.08 vs 14.41 p=0.08), M II oocytes (10.5 vs 10.95 p=0.46), GV (1.24 vs 1.52 p=0.09, the fertility rate (68.46% vs 64.04% p=0.07). The dual trigger group (A) had a significantly higher live birth rate (62.29% vs 42.37% p&lt;0.05) compared with the Gonadotropin-releasing hormone-a trigger group (B). There were no cases of moderate or severe ovarian hyperstimulation syndrome in both groups. CONCLUSION: Our study shows that in hyper responders where the E2 peak is &lt;4,000 pg/mL, the two approaches to the final oocyte maturation trigger have a correct outcome of the results, both in terms of the results from the in vitro fertilization and the low risk of ovarian hyperstimulation syndrome appearance.

Lipid Metabolic Disorders and Ovarian Hyperstimulation Syndrome: A Retrospective Analysis.

ObjectivesTo evaluate the effect of dyslipidemia on the incidence of moderate and severe Ovarian hyperstimulation syndrome (OHSS) in the duration of assisted reproduction technique (ART).MethodsThe study included 233 moderate and severe OHSS patients who received hospitalization after in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycles to avoid severe complications. They were divided into dyslipidemia group and normal lipid metabolism group to evaluate whether dyslipidemia contributes to the development of severe OHSS. Subgroup analysis was set to avoid deviation including the freeze-all group and fresh embryo transfer (ET) group according to whether the eligible women chose fresh embryo transfer immediately after their IVF or ICSI cycles. The main outcome measures included the incidence of moderate OHSS and severe OHSS, total gonadotropin dose, number of oocytes retrieved, age and body mass index (BMI). In the ET groups, the rate of pregnancy is also included for analysis.ResultsIn the freeze-all group, lipid metabolism was ultimately identified as the factor affecting the morbidity of severe OHSS and the ones with dyslipidemia were more likely to develop to severe OHSS (P < 0.05), while the incidence of severe OHSS among the ET groups had no statistical significance (P > 0.05).ConclusionThe findings of this study suggested that dyslipidemia might contribute to the development of OHSS, especially for those patients who chose the cryopreservation of all embryos. It is essential to consider the risk of OHSS in patients with dyslipidemia although they required cryopreservation of all embryos.

Rare genetic variants suggest dysregulation of signaling pathways in low- and high-risk patients developing severe ovarian hyperstimulation syndrome.

To investigate if rare gene variants in women with severe ovarian hyperstimulation syndrome (OHSS) provide clues to the mechanisms involved in the syndrome. Among participants in a prospective randomized study (Toftager et al. 2016), six women with predicted low and six women with predicted high risk of OHSS developing severe OHSS (grades 4 and 5, Golan classification) were selected. In the same cohort, six plus six matched controls developing no signs of OHSS (Golan grade 0) were selected. Whole-exome sequencing was performed. Analysis using a predefined in silico OHSS gene panel, variant filtering, and pathway analyses was done. We found no convincing monogenetic association with the development of OHSS using the in silico gene panel. Pathway analysis of OHSS variant lists showed substantial overlap in highly enriched top pathways (p value range p < 0.0001 and p > 9.8E-17) between the low- and high-risk group developing severe OHSS, i.e., "the integrin-linked kinase (ILK) signaling pathway" and the "axonal guidance signaling pathway," both being connected to vasoactive endothelial growth factor (VEGF) and endothelial function. Rare variants in OHSS cases with two distinct risk profiles enrich the same signaling pathways linked to VEGF and endothelial function. Clarification of the mechanism as well as potentially defining genetic predisposition of the high vascular permeability is important for future targeted treatment and prevention of OHSS; the potential roles of ILK signaling and the axonal guidance signaling need to be validated by functional studies.