Treatment Of Ovarian Hyperstimulation Syndrome Research Articles

Reinfusion of peritoneal fluid elevates the level of plasma D-dimer in patients with early-onset ovarian hyperstimulation syndrome.

This study aimed to elucidate the factors that affect the dynamics of blood D-dimer in ovarian hyperstimulation syndrome (OHSS). We retrospectively reviewed medical records from two hospitals and extracted data obtained during assisted reproductive technology and OHSS treatment. Blood D-dimer levels during hospitalization were plotted against body weight. Other factors possibly related to blood D-dimer levels were also analyzed. The analysis included 10 patients with OHSS admitted between January 2013 and June 2023. In all patients, blood D-dimer levels increased significantly when they convalesced from OHSS and lost weight. None of the patients showed clinical signs of thrombosis, which was confirmed using imaging tests in 8 of 10 patients. Two patients underwent cell-free and concentrated ascites reinfusion therapy (CART), and their blood D-dimer levels increased dramatically after the procedure. Weight change and CART are associated with blood D-dimer dynamics in OHSS. Our results show that elevated blood D-dimer levels in patients with OHSS do not always represent the presence of thrombosis. Reinfusion of pooled D-dimer in ascites may explain the D-dimer surge during the recovery phase or after CART in these patients. Our study provides new perspectives on the clinical implications of D-dimer during OHSS.

ULTRASOUND IN THE PREVENTION, DIAGNOSIS AND MANAGEMENT OF OVARIAN HYPERSTIMULATION SYNDROME IN BAMAKO

Ovarian hyperstimulation or ovarian hyperstimulation syndrome (OHSS) is a direct complication of in vitro fertilization with heavy morbidity and, in some cases, even mortality. The physiology remains poorly defined but seems to be moving towards a cascade activation of coagulation through the vascular endothelial growth factor (VEGF). There are patient-specific or pacing-specific risk factors, but this complication can occur in the absence of these factors. Two types can be described: early OHSS linked to the onset of ovulation and late linked to pregnancy. The management is poorly defined and must adapt to the severity of OHSS by taking care of the added complications.The major complication is thrombotic with the particularity of affecting both the venous and arterial territories, which can induce serious complications such as strokes or myocardial infarction. Prevention of this thrombotic risk therefore remains the priority of OHSS management. Since few studies have been carried out on this subject, we have shown here the place of ultrasound in the prevention, diagnosis and treatment of ovarian hyperstimulation syndrome. Aims: - Identify the risk factors of OHSS. - Describe the sonographic signs of OHSS. - Show the role of the radiologist/sonographer in the management of OHSS. Subjects And Methods: This was a cross-sectional, descriptive study concerning 350 women collected between March 2018 and March 2022 in different medically assisted procreation centers in Bamako. The study population consisted of consenting women presenting for assisted reproduction assessment in whom risk factors, signs of hyperstimulation and even complications were identified. The risk factors were: high anti-Müllerian hormone (AMH), the young age of the patient and the count of antral follicles (AFC) with more than 14 follicles. The patients had a biological assessment, the ultrasounds were made by endo-cavitary way and by high way with devices of General electric Voluson E8, Vivid 3 and Logic9. Results: 350 women were recruited into our. The average age was 26 years with extremes ranging from 18 to 37 years. 60.85% of the patients were between 18 and 25 years old. The risk factors were: high anti-Müllerian hormone (AMH) (7%), the young age of the patient (88%) and the count of antral follicles or AFC>14 follicles (89.8%). The clinical signs of OHSS were abdominal distension (8.5%), abdominal pain (8.5%), nausea and vomiting (2.28%). Ultrasound signs, i.e. ascites, increased ovarian volume, presence of large ovarian follicles were present in 8.57% of patients. The number of punctured follicles varied between 10 and 30. In sum, hyperstimulation was recorded in 30 patients, i.e. 08.57% of the 30 patients who had the OHSS, 12 had a pregnancy. Conclusion: There are risk factors for OHSS that correspond to patients with good or even excessive ovarian reserves, as in the context of polycystic ovary syndrome. However, OHSS occurs in 33% of cases with no identified risk factor [1]. It is therefore advisable to carefully monitor ovarian stimulation in the context of In Vitro Fertilization with doses adapted to the patients and to remember that the best prevention remains the cancellation of the cycle without triggering or coasting, that is i.e. a cessation of gonadotropins. OHSS is a serious complication of PMA that can be life-threatening, so care and monitoring must be rigorous, adapted to each stage of the disease. The great variability of OHSS makes it difficult to draw up recommendations for clinical practice and it is therefore necessary to adapt the management according to each patient.

Aflibercept suppresses ovarian hyperstimulation syndrome: an experimental study in rats.

In this study, we aimed to determine the impact of the antiangiogenic medications, namely, aflibercept and cabergoline in the prevention and treatment of ovarian hyperstimulation syndrome in a rat model. A total of 36 female Wistar rats were randomly allocated to one of the five groups, including disease-free and ovarian hyperstimulation syndrome controls: Group no OHSS (control, n=6) received saline only intraperitoneally (i.p.); group just OHSS (ovarian hyperstimulation syndrome only, n=6) received 10 IU pregnant mare serum gonadotropin and 30 IU human chorionic gonadotropin subcutaneously to produce ovarian hyperstimulation syndrome; group cabergoline+OHSS (cabergoline+ovarian hyperstimulation syndrome, n=8) received 100 μg/kg oral cabergoline; group aflibercept (12.5 mg/kg)+OHSS (aflibercept+ovarian hyperstimulation syndrome, n=8) received 12.5 mg/kg i.p. aflibercept; and group aflibercept (25 mg/kg)+OHSS (aflibercept+ovarian hyperstimulation syndrome, n=8) received 25 mg/kg i.p. aflibercept. The groups were compared for ovarian weight, immunohistochemical vascular endothelial growth factor expression, spectrophotometric vascular permeability evaluated with methylene blue solution in peritoneal lavage, and body weight growth. Vascular endothelial growth factor immunoexpression was substantially greater in the just OHSS group (22.00±10.20%) than in the aflibercept (12.5 mg/kg)+OHSS (7.87±6.13%) and aflibercept (25 mg/kg)+OHSS (5.63±4.53%) groups (p=0.008 and p=0.005, respectively). Post-hoc tests indicated that cabergoline, 12.5 mg/kg aflibercept, and 25 mg/kg aflibercept decreased vascular permeability compared to the untreated ovarian hyperstimulation syndrome group (p=0.003, p=0.003, and p=0.001, respectively). JOH group had the heaviest ovaries, whereas aflibercept (25 mg/kg)+OHSS group had the lightest. In terms of body weight gain, cabergoline+OHSS group was substantially greater than the aflibercept (12.5 mg/kg)+OHSS and aflibercept (25 mg/kg)+OHSS groups (p=0.006 and p=0.007, respectively). Aflibercept, an antiangiogenic medication, decreased ovarian hyperstimulation syndrome by lowering the vascular permeability and vascular endothelial growth factor expression.

Ovarian Hyperstimulation Syndrome: A Case Report

BackgroundOvarian hyperstimulation syndrome is a rare, life-threatening obstetric emergency. Early recognition and prompt treatment of ovarian hyperstimulation syndrome are essential owing to the risk of long-term complications associated with this condition. Case PresentationA 30-year-old female presented to the emergency department with a chief complaint of abdominal pain. After assessment and diagnostic testing, she was diagnosed as having ovarian hyperstimulation syndrome. The patient was admitted for 24-hour observation. The patient was discharged home with instructions to follow up with an outpatient reproductive medicine clinic. One month after her visit to the emergency department, the patient has not had any complications related to the diagnosis. ConclusionThis manuscript outlines the case of a patient presenting to the emergency department with ovarian hyperstimulation syndrome that was promptly recognized and treated. It is important for emergency nurses to quickly identify the risk factors and clinical presentation of ovarian hyperstimulation syndrome to decrease the risk of long-term complications.

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.

Predictive Factors for Recovery Time in Conceived Women Suffering From Moderate to Severe Ovarian Hyperstimulation Syndrome.

ObjectiveThis study aimed to evaluate potential predictors for recovery time in pregnant patients with moderate to severe ovarian hyperstimulation syndrome (OHSS).MethodsA total of 424 pregnant patients with moderate to severe OHSS who underwent in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) were retrospectively identified. The clinical features and laboratory findings within 24 h after admission were collected. Treatment for OHSS was carried out according to standard procedures, including fluid replacement therapy, human albumin, aspirin, low-molecular-weight heparin, and paracentesis, when necessary. Patients were discharged from the hospital when the tmorning hematocrit was <40% and no obvious clinically relevant symptoms existed, such as abdominal distension, abdominal pain, and shortness of breath. Meanwhile, ultrasound indicating little pleural or abdominal effusion and biochemical abnormalities returning to normal were required. Spearman’s correlation analysis was used to assess the association between the blood-related parameters and recovery time. Multiple linear regression models were used to assess the relationship between the clinical or laboratory parameters and recovery time.ResultsThe median recovery time of these patients was 11 days. In Spearman’s correlation test, leukocytes, hemoglobin, platelets, hematocrit, creatinine, prothrombin time (PT), fibrinogen (Fib), D-dimer, and fibrinogen degradation products (FDPs) were positively correlated with recovery time. On the other hand, albumin and thrombin time (TT) were negatively correlated with recovery time. Multiple linear regression analysis showed that polycystic ovary syndrome (PCOS), hemoglobin, platelets, albumin, and Fib were significantly associated with the recovery time of patients with OHSS (p = 0.023, p < 0.001, p = 0.007, p < 0.001, and p = 0.019, respectively).ConclusionsIn pregnant patients with OHSS, PCOS and hypoalbuminemia were associated with a significantly longer recovery time. Meanwhile, the recovery time was longer when patients have high levels of hemoglobin, platelets, and Fib.

Ovarian hyperstimulation syndrome and its relation to pregnancy

Vytautas Abraitis1, Saulė Kržčonavičiūtė1, Marija Vaitkevičiūtė2 1 Department of Obstetrics and Gynecology, Medical Academy, Lithuanian University of Health Sciences, Eivenių g. 2, LT-50161 Kaunas, Lithuania 2 Medical Academy, Lithuanian University of Health Sciences, A. Mickevičiaus g. 9, LT-44307 Kaunas, Lithuania Abstract Introduction: Ovarian Hyperstimulation Syndrome (OHSS) is an iatrogenic complication manifested by suprafysiological ovarian stimulation. This syndrome is commonly related to assisted reproduction. OHSS has been associated with an increased risk of miscarriage, multiple pregnancies, and more severe clinical course of the syndrome. However, there are few studies examining the relationship between OHSS and pregnancy, and more consistent studies are needed. The aim – to discuss the characteristics of OHSS and it‘s possible links with pregnancy. Research method: systematic literature review was conducted. Articles, describing OHSS and its links to pregnancy, were selected. The review was done using the electronic database Pub-Med (Medline). Results: OHSS prevention is selected individually based on risk factors, anti-müllerian hormone concentration, and number of tertiary follicles. Mild to moderate OHSS may regress spontaneously and treatment is not always necessary. Patients who develop signs of severe OHSS should be hospitalized and treated with medication and (or) surgery. In case of unclear pathogenesis of the disease, only symptomatic treatment is possible. A correlation was observed between OHSS and an increased risk of miscarriage, preterm birth, gestational hypertension and low birth weight. Conclusions: OHSS is an iatrogenic complication that can occur at different stages and degrees due to variety of risk factors and prevention. Mild to moderate OHSS is often a transient condition, however, severe OHSS can be potentially life-threatening. The complications associated with OHSS are miscarriage and preterm birth, although there are also associations between this syndrome and gestational hypertension as well as low birth weight. Keywords: ovarian hyperstimulation syndrome, OHSS treatment, pregnancy.

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.

Pigment epithelium-derived factor (PEDF) negates hyperandrogenic PCOS features.

Polycystic ovary syndrome (PCOS), one of the most common female endocrine disorder, is a prevalent cause of infertility. Hyperandrogenism is a key feature in PCOS and is correlated with increased expression of VEGF and cytokines in the ovaries. We have previously shown that pigment epithelium-derived factor (PEDF), an endogenous protein, presents potent anti-angiogenic and anti-inflammatory activities in the ovary and negates the effects of cytokines and VEGF. Additionally, PEDF plays a role in both pathophysiology and treatment of ovarian-hyperstimulation syndrome (OHSS), frequently seen in PCOS patients. We established hyperandrogenic-PCOS models, both in vivo, using mice exposed prenatally to dihydrotestosterone (DHT) and, in vitro, using human primary granulosa cells (hpGCs) and human granulosa cell line (KGN). In PCOS-induced mice, the mRNA levels of I l-6, V egf and Amh were higher than those of control; yet, treatment with rPEDF decreased these levels. Moreover, treating OHSS-induced PCOS-mice with rPEDF alleviated all OHSS symptoms. Stimulation of hpGCs with DHT resulted in downregulation of PEDF mRNA expression, concomitantly with a significant increase in IL-6 and IL-8 mRNAs expression. However, co-stimulation of DHT with rPEDF attenuated the increase in cytokines expression. The anti-inflammatory effect of PEDF was found to be mediated via PPARγ pathway. Our findings suggest that rPEDF treatment may normalize the ovarian angiogenic-inflammatory imbalance, induced by PCOS-associated hyperandrogenism. Moreover, the therapeutic potency of PEDF in preventing OHSS symptomes offers a rationale for using PEDF as novel physiological treatment for PCOS sequels.

Artificial colloids versus human albumin for the treatment of ovarian hyperstimulation syndrome: A retrospective cohort study.

BackgroundThe optimal colloid solution for the treatment of ovarian hyperstimulation syndrome (OHSS) remains to be established.ObjectiveWe aimed to compare artificial colloids (AC) with human albumin (HA) for the treatment of OHSS.Materials and MethodsIn this retrospective cohort study, data for OHSS participants were collected from a national inpatient database in Japan. The participants received intravenous fluid management with AC (n = 156) or HA (n = 127). We compared the two groups in terms of the length of stay, development of post-treatment complications, and termination surgery.ResultsIn multivariable linear regression analyses for log-transformed length of stay with reference to the OHSS participants receiving AC, the regression coefficient (95% confidence interval) in participants receiving HA was 0.03 (-0.04-0.09, p = 0.42). Thromboembolism occurred in two participants in the HA group and three participants in the AC group. Two participants in the HA group suffered renal failure during hospitalization. No participants underwent termination surgery in the two groups.ConclusionThe present results showed comparable efficacy between AC and HA for the treatment of OHSS. There were no significant differences in post-treatment complications between the two groups.

Can a cyclooxygenase inhibitor be an option for treatment of ovarian hyperstimulation syndrome?

PurposeThis study aimed to investigate the role of a cyclooxygenase inhibitor in ovarian hyperstimulation syndrome (OHSS) treatment and compare it with cabergoline.Materials and methodsA total of 32 immature female Wistar albino rats were randomly divided into four groups, with each group consisting of eight rats. The first group received only saline for 6 consecutive days, and the remaining 24 rats were given 10 IU of recombinant follicle stimulating hormone subcutaneously on 5 consecutive days. On day 6, 30 IU of human chorionic gonadotropin was administered for OHSS induction. After the development of OHSS, while the second group had no further intervention, the third and fourth groups were given cabergoline and celecoxib daily for 6 days, respectively. Besides weight and hematocrit values, vascular endothelial growth factor (VEGF), IL-2, and endothelin-1 (ET-1) levels were evaluated.ResultsInitially, no significant differences were observed between the groups with respect to the evaluated parameters. Although there were no differences between the weight and hema-tocrit values at the end of treatment (P=0.158, P=0.674), the difference between group 1 and the other groups was statistically significant after OHSS was established (P=0.001, P=0.004). Comparison of the groups in terms of VEGF, ET-1, and IL-2 levels revealed that the difference between group 1 and the other groups was significant after OHSS was formed (P=0.012, P=0.018, P=0.015). After treatment, however, a significant difference was observed only between group 2 and the other groups (P=0.001, P=0.002, P=0.038).ConclusionAccording to these results, celecoxib significantly decreased VEGF, IL-2, and ET-1 levels as much as cabergoline and could reduce the extent of OHSS development.

What is the impact of short- and long-term supplementation of either cabergoline or clarithromycin on resolving rat ovarian hyperstimulation syndrome (OHSS) model?

This study aimed to evaluate the effects of coasting, cabergoline and clarithromycin in a rat ovarian hyperstimulation syndrome (OHSS) model. The 42 female Wistar rats were divided into seven groups: control, OHSS (was given 10 IU of pregnant mare serum gonadotropin for 4 consecutive days from day 22 and 30 IU hCG on the fifth day to induce OHSS ), coasting (hCG was applied on the 27th day after gonadotropin injections and the rats were decapitated on the 28th day), Cabergoline (100 mg/kg/d) and clarithromycin (100 mg/kg/d) were given (on the 26th day) with a short-term supplementation (on the 26th day) and long-term supplementation (from the 22nd to the 26th day) groups. The rats were decapitated on the 27th day. Cabergoline and clarithromycin significantly lowered VEGF-2 levels. Clarithromycin significantly reduced IL-1b and TNF-a and significantly increased IL-10 levels. Clarithromycin may be an effective drug for the treatment of OHSS. Impact statement What is already known on this subject? Ovarian hyper-stimulation syndrome (OHSS) is a self-limited disease, in which vascular endothelial growth factor (VEGF) plays the most important role and has a large clinical spectrum related with increased capillary permeability and fluid retention. Some treatment methods that block VEGF over-expression are used in treatment of OHSS. Clarithromycin is known to suppress the production of some pro-inflammatory molecules such as VEGF, IL-8, IL-1, IL-6 and TNF-a. In our study, we compared the efficacy of coasting, short- and long-term supplementation of clarithromycin and cabergoline on correcting OHSS parameters in an experimental study. What do the results of this study add? As a result of our study, we found that OHSS parameters improved better in early prophylactic treatment regimens. We have shown that clarithromycin may be a more effective treatment agent than coasting and cabergoline. What are the implications of these findings for clinical practice and/or further research? Although our study is important in that it is the first pilot study to show that clarithromycin is effective in the treatment of OHSS, there is a need for larger clinical trials.

Intensive treatment of ovarian hyperstimulation syndrome. Clinical guidelines (treatment protocol)

Ovarian hyperstimulation syndrome (OHSS) is a systemic disease that develops as a result of activation of the production of vasoactive mediators by the ovaries against the background of stimulation of superovulation. OHSS is characterized by an increase in the permeability of the capillary walls, which leads to the release of intravascular fluid into the extravascular space, its accumulation in the third space and hemoconcentration. Severe OHSS is characterized by the risk of thrombosis, impaired liver function, kidney function and the occurrence of adult respiratory distress syndrome (ARDS). In these clinical guidelines, the main provisions for the prognosis, diagnosis, prevention and intensive care of OHSS are presented, including the principles of treatment of intra-abdominal hypertension (IAH).

Zinc finger gene 217 (ZNF217) Promoted Ovarian Hyperstimulation Syndrome (OHSS) through Regulating E2 Synthesis and Inhibiting Thrombospondin-1 (TSP-1)

Zinc finger gene 217 (ZNF217) is a candidate gene of polycystic ovary syndrome (PCOS) which is vulnerable to ovarian hyperstimulation syndrome (OHSS). However, the relationship between ZNF217 and OHSS is largely unknown. Our study demonstrated that ZNF217 was mainly distributed in the granulosa cells of rat ovary. Significantly higher expression of ovarian ZNF217 was detected in OHSS rats, being consistent with serum 17β-estradiol concentration and ovarian aromatase. Moreover, OHSS rats also showed decreased ovarian TSP-1 mRNA, an acknowledged VEGF signaling suppressor. The same changes were detected in human granulosa cells and follicular fluid. Thus, the increased ZNF217 and decreased TSP-1 may participate in OHSS onset. In vitro experiment revealed that ZNF217 positively regulated E2 synthesis through promoting cAMP response element binding protein (CREB) and thereby CYP19A1 in KGN cells. Furthermore, ZNF217 negatively regulated TSP-1 in KGN cells while TSP-1 promoted claudin1 and inhibited nitric oxide (NO) in HUVECs and HAECs. Both of claudin1 and NO are responsible for the regulation of vascular permeability (VP). Therefore, we demonstrated that ZNF217 contributed to OHSS onset through promoting E2 synthesis and the increase of VP. Moreover, the increased ZNF217 and decreased TSP-1 provided new targets for the prevention or treatment of OHSS in the future.

In vivo intrabursal administration of bioactive lipid sphingosine-1-phosphate enhances vascular integrity in a rat model of ovarian hyperstimulation syndrome.

Can the bioactive lipid sphingosine-1 phosphate (S1P) act as an endothelial barrier-enhancing molecule and, in turn, restore the vascular integrity and homoeostasis in a rat model of ovarian hyperstimulation syndrome (OHSS). In vivo administration of S1P may prevent the early onset of OHSS and decrease its severity. Although advances in the prediction and treatment of OHSS have been made, complete prevention has not been possible yet. S1P in follicular fluid from women at risk of developing OHSS are lower in comparison from women who are not at such risk and administration of S1P in an OHSS rat model decreases ovarian capillary permeability. We used an animal model that develops OHSS in immature Sprague-Dawley rats. The rats were randomly divided into three groups: the control group, which was injected with 10 IU of pregnant mare's serum gonadotropin (PMSG), and 10 IU ofhCG 48 h later; the OHSS group, which was injected with excessive doses of PMSG (50 IU/day) for four consecutive days, followed by hCG; and the OHSS + S1P group, which was injected with the same doses of PMSG and hCG as the OHSS group and then treated with 5 μl S1P (1 mM) under the bursa of both ovaries, whereas the other groups of animals received the S1P vehicle. Rats were killed by decapitation 48 h after the hCG injection for ovary, endometrium and blood collection. The ovaries were weighed and then used for subsequent assays, while the serum was used for hormone assays. One of the ovaries from each rat (n = 6) was used for Western immunoblot and the other for immunohistochemical analysis. Statistical comparisons between groups were carried out. S1P administration reduced the ovarian weight (P < 0.05), and decreased the concentration of serum progesterone in the OHSS group compared to the OHSS group without treatment (P < 0.001). The percentage of antral follicles in the OHSS group was lower than that in the control group. S1P increased the percentage of antral follicles (P < 0.05) and decreased the percentage of corpora lutea (P < 0.01) and cystic structures in the OHSS group (P < 0.05). S1P had no effect on the expression levels of the enzymes 3β-hydroxysteroid dehydrogenase (3βHSD) or cholesterol side-chain cleavage enzyme (P450scc), but reduced the levels of steroidogenic acute regulatory protein (StAR) in OHSS rat ovaries (P < 0.05). S1P decreased the endothelial (P < 0.05) and periendothelial (P < 0.01) cell area in OHSS rat ovaries. S1P restored the levels of N-cadherin and VE-cadherin proteins to control values. Furthermore, S1P enhanced the levels of claudin-5, occludin (P < 0.05) and sphingosine-1-phosphate receptor 1 (S1PR1) in OHSS (P < 0.01). In addition, no histological differences were found in endometrium between OHSS and S1P-treated OHSS animals. The results of this study were generated from an in vivo OHSS experimental model, which has been used by several authors and our group due to the similarity between the rat and human angiogenic systems. Further studies in patients will be needed to evaluate the effects of S1P in the pathogenesis of OHSS. These findings concern the pathophysiological importance of S1P in OHSS. More studies on the regulation of endothelial cell barrier function by S1P in reproductive pathological processes and its therapeutic application are required. N/A. This work was supported by grants from ANPCyT (PICT 2012-897), CONICET (PIP 5471), Roemmers and Baron Foundations, Argentina. The authors declare no conflicts of interest.

Prevention and management of ovarian hyperstimulation syndrome

Ovarian hyperstimulation syndrome (OHSS) is a serious iatrogenic complication of ovarian stimulation. It is feasible to identify patients at risk, modify stimulation strategies to ameliorate risk, and initiate out-patient treatments that alter disease pathophysiology to reduce disease severity. Mitigation of OHSS risk and severity, through innovative approaches prior to treatment, during treatment and after treatment should now be standard care. This review summarizes recent developments and provides recommendations on the prevention and treatment of OHSS.

Electroacupuncture decreases the progression of ovarian hyperstimulation syndrome in a rat model

This study aimed to elucidate the effect of electroacupuncture treatment on preventing early ovarian hyperstimulation syndrome (OHSS) and the potential mechanisms involved using an induced rat model. The ovarian response was examined by measuring ovary weight, vascular permeability, levels of inflammation (interleukin-6), tumour necrosis factor alpha, chemokine ligand 2 (also known as monocyte chemoactic protein 1), vascular endothelial growth factor and hormone concentrations (oestradiol, progesterone, testosterone and prolactin). Sprague–Dawley female rats underwent ovarian stimulation to induce OHSS. Hyperstimulated rats received consecutive electroacupuncture treatment from 3 days before the beginning of pregnant mare serum gonadotrophin treatment or the time point of pregnant mare serum gonadotrophin treatment respectively, and last until 3 days after HCG administration. Electroacupuncture treatment reduced ovary weight and vascular permeability in hyperstimulated rats. Electroacupuncture treatment also reduced the levels of serum steroid hormones (progesterone and testosterone), inflammatory cytokines (interleukin-6, tumour necrosis factor alpha and monocyte chemotactic protein 1 and vascular endothelial growth factor in hyperstimulated rats. The results indicate that electroacupuncture can modulate endocrine hormone secretion and affect the secretion of inflammatory cytokines and vascular endothelial growth factor, and thus prevent the progress of OHSS. Electroacupuncture may provide a simple and effective method for the prevention and treatment of OHSS.

Opiate receptor blockade on human granulosa cells inhibits VEGF release

The objectives of this study were to determine whether the main opioid receptor (OPRM1) is present on human granulosa cells and if exogenous opiates and their antagonists can influence granulosa cell vascular endothelial growth factor (VEGF) production via OPRM1. Granulosa cells were isolated from women undergoing oocyte retrieval for IVF. Complementary to the primary cells, experiments were conducted using COV434, a well-characterized human granulosa cell line. Identification and localization of opiate receptor subtypes was carried out using Western blot and flow cytometry. The effect of opiate antagonist on granulosa cell VEGF secretion was assessed by enzyme-linked immunosorbent assay. For the first time, the presence of OPRM1 on human granulosa cells is reported. Blocking of opiate signalling using naloxone, a specific OPRM1 antagonist, significantly reduced granulosa cell-derived VEGF levels in both COV434 and granulosa-luteal cells (P < 0.01). The presence of opiate receptors and opiate signalling in granulosa cells suggest a possible role in VEGF production. Targeting this signalling pathway could prove promising as a new clinical option in the prevention and treatment of ovarian hyperstimulation syndrome.

RANZCOG CREI Consensus Statement on treatment of Ovarian Hyperstimulation Syndrome.

Ovarian hyperstimulation syndrome (OHSS) is an uncommon but important iatrogenic condition associated with considerable morbidity and a small risk of mortality. This document gathers the consensus of a group of fertility subspecialists to aid health professionals in the development of protocols and guidelines for the management of women with OHSS. To produce evidence-based consensus statements on the treatment of ovarian hyperstimulation syndrome (OHSS). The CREI Consensus Group met in 2013 and 2014 and identified issues for inclusion and review. Review of the available evidence was conducted and consensus statements prepared. Areas of dissent of expert opinion and for further research were noted. There is a paucity of good data regarding the treatment of this condition, and much of the treatment is supportive in nature. Most of the management recommendations are based on good clinical practice points, rather than evidence from randomised trials. OHSS is an uncommon but serious condition for which there are a number of proven preventative strategies. Once OHSS is present, the treatment of OHSS is mainly supportive, and more research is required to elucidate treatment options targeted specifically at the main causative factors, to better treat the condition.

Dopamine receptor 2 activation inhibits ovarian vascular endothelial growth factor secretion in vitro: implications for treatment of ovarian hyperstimulation syndrome with dopamine receptor 2 agonists

To ascertain whether vascular endothelial growth factor (VEGF) secretion by luteinized granulosa cells (GCs) is modulated by the dopaminergic system in a dose-dependent fashion and how this is related to the differential efficacy of dopamine receptor 2 (D2)-agonists (D2-ag) in preventing ovarian hyperstimulation syndrome (OHSS). The relationship between the dopaminergic system and VEGF secretion in luteinized GCs was evaluated. Archived human ovaries were immunostained to characterize D2 expression. University affiliated infertility center. Premenopausal women and egg donors. Luteinized GCs were cultured with the D2-ag cabergoline. Human ovarian sections were immunostained for D2. The VEGF was measured by ELISA and D2 expression was evaluated by In-Cell ELISA. The D2 expression throughout the luteal phase was characterized by immunohistochemistry. The VEGF secretion was decreased by the D2-ag in a dose-dependent fashion. The efficiency of this process was correlated with the amount of D2 expressed by luteinized GCs. A decrease in D2 expression in ovarian sections was observed during the late luteal phase. The efficacy of D2-ags in preventing OHSS might rely on their capacity to inhibit VEGF secretion by luteinized GCs. Because this capacity is dose-dependent, increasing the intraovarian concentration of D2-ags should be explored as a means of increasing the efficacy of these drugs in preventing OHSS.