Efficacy and safety of follitropin delta for ovarian stimulation in vitro fertilization/ intracytoplasmic sperm injection cycles: a systematic review with meta-analysis.

BACKGROUND: Follitropin delta is a novel recombinant follicle stimulating hormone preparation uniquely expressed in a human fetal retinal cell line by recombinant DNA technology. To date, no systematic review was available about the safety and the efficacy of the follitropin delta. The objective of this study was systematically reviewing the available literature and to provide updated evidence regarding the efficacy-safety profile of follitropin delta when compared to other gonadotropin formulations for ovarian stimulation in in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) cycles. METHODS: An extensive search was performed to identify phase 1, phase 2 and phase 3 RCTs in humans focused on follitropin delta use for ovarian stimulation in IVF/ICSI cycles. The risk of bias and the overall quality of the evidence was analyzed. All data were extracted and analyzed using the intention-to-treat principle and expressed per woman randomized. RESULTS: A total of 7 RCTs (1 phase 1 RCT, 2 phase 2 RCTs and 4 phase 3 RCTs) were included in the qualitative analysis, whereas data of three phase 3 RCTs were meta-analyzed. All trials compared personalized recombinant follitropin delta treatment versus conventional recombinant follitropin alfa/beta administration in potentially normo-responder patients who receive ovarian stimulation in GnRH antagonist IVF/ICSI cycles. No difference between two regimens was detected for clinical pregnancy rate [odds ratio (OR) 1.06; 95% confidence intervals (CI): 0.90, 1.24; P = 0.49; I2 = 26%], ongoing pregnancy rate (OR 1.15; 95%CI: 0.90, 1.46; P = 0.27; I2 = 40%), and live birth rate (OR 1.18; 95%CI: 0.89, 1.55; P = 0.25; I2 = 55%). No data were available regarding cumulative success rates. The rate of adoption of strategies to prevent ovarian hyperstimulation syndrome (OHSS) development (OR 0.45; 95%CI: 0.30, 0.66; P < 0.0001; I2 = 0%), and the rate of both early OHSS (OR 0.62; 95%CI: 0.43, 0.88; P = 0.008; I2 = 0%) and all forms of OHSS (OR 0.61; 95%CI: 0.44, 0.84; P = 0.003; I2 = 0%) were significantly lower in the group of patients treated with personalized follitropin delta treatment compared to those treated with conventional follitropin alfa/beta administration. CONCLUSION: Personalized follitropin delta treatment is associated with a lower risk of OHSS compared to conventional follitropin alfa/beta administration in potentially normo-responder patients who receive ovarian stimulation in GnRH antagonist IVF/ICSI cycles. The absence of cumulative data does not allow definitive conclusions to be drawn regarding the comparison of the effectiveness of the two treatments. PROTOCOL STUDY REGISTRATION: CRD42023470352 (available at http://www.crd.york.ac.uk/PROSPERO ).

Comparison between hCG and GnRH Agonist for Ovulation Trigger in GnRH Antagonist In-Vitro Fertilization Cycles in a Tertiary Hospital in Malaysia: An observational study.

OBJECTIVE: hCG is commonly used as an ovulation trigger in IVF. Its usage is associated with OHSS. GnRH agonist is an alternative to hCG and is associated with reduced incidence of OHSS. This study compared the cycle outcomes of GnRH agonists with hCG as an ovulation trigger in IVF cycles. METHODS: The medical notes of 209 IVF cycles receiving GnRH agonist and hCG as ovulation trigger over 18 months were reviewed in this retrospective study. The number and quality of mature oocytes, the number and quality of embryos, pregnancy rates, and outcomes were compared using Independent T-test or One-way ANOVA for normal distribution. The Mann-Whitney test or Kruskal-Wallis test was used for not normally distributed. p<0.05 was considered statistically significant. RESULTS: The cycle outcomes of 107 GnRH agonist-trigger and 102 hCG-trigger were compared. The MII oocytes retrieved and 2PN count was significantly higher in the GnRH agonist trigger group (p<0.001). Clinical pregnancy rate and ongoing pregnancy were higher in the GnRH agonist trigger group but were not statistically significant. The GnRH agonist trigger group was associated with low OHSS than the hCG trigger group (n=2(1.9%) and n=12(11.8%) respectively, p=0.004). CONCLUSION: GnRH agonist trigger is an option as a final maturation trigger in high-responder women undergoing IVF or ICSI cycles.

Follitropin delta combined with menotropin in patients at risk for poor ovarian response during in vitro fertilization cycles: a prospective controlled clinical study.

BACKGROUND: The maximum daily dose of follitropin delta for ovarian stimulation in the first in vitro fertilization cycle is 12 µg (180 IU), according to the algorithm developed by the manufacturer, and based on patient's ovarian reserve and weight. This study aimed to assess whether 150 IU of menotropin combined with follitropin delta improves the response to stimulation in women with serum antimullerian hormone levels less than 2.1 ng/mL. METHODS: This study involved a prospective intervention group of 44 women who received 12 µg of follitropin delta combined with 150 IU of menotropin from the beginning of stimulation and a retrospective control group of 297 women who received 12 µg of follitropin delta alone during the phase 3 study of this drug. The inclusion and exclusion criteria and other treatment and follow-up protocols in the two groups were similar. The pituitary suppression was achieved by administering a gonadotropin-releasing hormone (GnRH) antagonist. Ovulation triggering with human chorionic gonadotropin or GnRH agonist and the option of transferring fresh embryos or using freeze-all strategy were made according to the risk of developing ovarian hyperstimulation syndrome. RESULTS: Women who received follitropin delta combined with menotropin had higher estradiol levels on trigger day (2150 pg/mL vs. 1373 pg/mL, p < 0.001), more blastocysts (3.1 vs. 2.4, p = 0.003) and more top-quality blastocysts (1.8 vs. 1.3, p = 0.017). No difference was observed in pregnancy, implantation, miscarriage, and live birth rates after the first embryo transfer. The incidence of ovarian hyperstimulation syndrome did not differ between the groups. However, preventive measures for the syndrome were more frequent in the group using both drugs than in the control group (13.6% vs. 0.6%, p < 0.001). CONCLUSIONS: In women with serum antimullerian hormone levels less than 2.1 ng/mL, the administration of 150 IU of menotropin combined with 12 µg of follitropin delta improved the ovarian response, making it a valid therapeutic option in situations where ovulation triggering with a GnRH agonist and freeze-all embryos strategy can be used routinely. TRIAL REGISTRATION: U1111-1247-3260 (Brazilian Register of Clinical Trials, available at https://ensaiosclinicos.gov.br/rg/RBR-2kmyfm ).

Effect of GnRH agonist trigger with or without low-dose hCG on reproductive outcomes for PCOS women with freeze-all strategy: a propensity score matching study.

PURPOSE: This study aimed to compare the effect of gonadotropin-releasing hormone agonist (GnRHa) trigger alone versus dual trigger comprising GnRHa and low-dose human chorionic gonadotropin (hCG) on reproductive outcomes in patients with polycystic ovary syndrome (PCOS) who received the freeze-all strategy. METHODS: A total of 615 cycles were included in this retrospective cohort study. Propensity score matching (PSM) was performed to control potential confounding factors between GnRHa-trigger group (0.2 mg GnRHa) and dual-trigger group (0.2 mg GnRHa plus 1000/2000 IU hCG) in a 1:1 ratio. Multivariate logistic regression was applied to estimate the association between trigger methods and reproductive outcomes. RESULTS: After PSM, patients with dual trigger (n = 176) had more oocytes retrieved, mature oocytes, and 2PN embryos compared to that with GnRHa trigger alone. However, the oocytes maturation rate, normal fertilization rate, and frozen embryos between the two groups were not statistically different. The incidence of ovarian hyperstimulation syndrome (OHSS) (14.8% vs. 2.8%, P < 0.001) and moderate/severe OHSS (11.4% vs. 1.7%, P < 0.001) were significantly higher in dual-trigger group than in GnRHa-alone group. Logistic regression analysis showed the adjusted odds ratio of dual trigger was 5.971 (95% confidence interval 2.201-16.198, P < 0.001) for OHSS. The pregnancy and single neonatal outcomes were comparable between the two groups (P > 0.05). CONCLUSION: For PCOS women with freeze-all strategy, GnRHa trigger alone decreased the risk of OHSS without damaging oocyte maturation and achieved satisfactory pregnancy outcomes.

Real-world practices of hormone monitoring during ovarian stimulation in assisted reproductive technology: a global online survey.

Objective: The aim of this study is to understand the global practice of routine hormonal monitoring (HM) during ovarian stimulation (OS) in the context of assisted reproductive technique (ART) treatment. Methods: An open-access questionnaire was available to 3,845 members of IVF-Worldwide.com from September 8 to October 13, 2021. The survey comprised 25 multiple-choice questions on when and how ultrasound (US) and hormone tests were conducted during ovarian stimulation OS. For most questions, respondents were required to select a single option. Some questions allowed the selection of multiple options. Results: In all, 528 (13.7%) members from 88 countries responded to the questionnaire. Most respondents (98.9%) reported using US to monitor OS cycles. HM was used by 79.5% of respondents during any of the cycle monitoring visits and was most commonly performed on the day of, or a day prior to final oocyte maturation. Overall, 87% of respondents claimed adjusting the dose of gonadotropin during OS, with 61.7% adjusting the dose based on hormonal levels. Oestradiol (E2) was the most frequently monitored hormone during all visits and was used by 74% of respondents for the prediction of ovarian hyperstimulation syndrome (OHSS). On or a day prior to ovulation triggering (OT), the number of respondents who measured progesterone increased from 34.3% in the second/third visit to 67.7%. Approximately one-third of respondents measured luteinizing hormone during all visits. Conclusion: Globally, most ART specialists (~80%) use HM, along with US, for monitoring OS, especially for the prevention of OHSS.

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: Aflibercept, an antiangiogenic medication, decreased ovarian hyperstimulation syndrome by lowering the vascular permeability and vascular endothelial growth factor expression.

Progestogens for prevention of luteinising hormone (LH) surge in women undergoing controlled ovarian hyperstimulation as part of an assisted reproductive technology (ART) cycle.

BACKGROUND: Currently, gonadotrophin releasing hormone (GnRH) analogues are used to prevent premature ovulation in ART cycles. However, their costs remain high, the route of administration is invasive and has some adverse effects. Oral progestogens could be cheaper and effective to prevent a premature LH surge. OBJECTIVES: To evaluate the effectiveness and safety of using progestogens to avoid spontaneous ovulation in women undergoing controlled ovarian hyperstimulation (COH). SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group trials register, CENTRAL, MEDLINE, Embase and PsycINFO in Dec 2021. We contacted study authors and experts to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that included progestogens for ovulation inhibition in women undergoing controlled ovarian hyperstimulation (COH). DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane, including the risk of bias (RoB) assessment. The primary review outcomes were live birth rate (LBR) and oocyte pick-up cancellation rate (OPCR). Secondary outcomes were clinical pregnancy rate (CPR), cumulative pregnancy, miscarriage rate (MR), multiple pregnancies, LH surge, total and MII oocytes, days of stimulation, dose of gonadotropins, and moderate/severe ovarian hyperstimulation syndrome (OHSS) rate. The primary analyses were restricted to studies at overall low and some concerns RoB, and sensitivity analysis included all studies. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We included 14 RCTs (2643 subfertile women undergoing ART, 47 women used oocyte freezing for fertility preservation and 534 oocyte donors). Progestogens versus GnRH antagonists We are very uncertain of the effect of medroxyprogesterone acetate (MPA) 10 mg compared with cetrorelix on the LBR in poor responders (odds ratio (OR) 1.25, 95% confidence interval (CI) 0.73 to 2.13, one RCT, N = 340, very-low-certainty evidence), suggesting that if the chance of live birth following GnRH antagonists is assumed to be 18%, the chance following MPA would be 14% to 32%. There may be little or no difference in OPCR between progestogens and GnRH antagonists, but due to wide Cs (CIs), we are uncertain (OR 0.92, 95%CI 0.42 to 2.01, 3 RCTs, N = 648, I² = 0%, low-certainty evidence), changing the chance of OPCR from 4% with progestogens to 2% to 8%. Given the imprecision found, no conclusions can be retrieved on CPR and MR. Low-quality evidence suggested that using micronised progesterone in normo-responders may increase by 2 to 6 the MII oocytes in comparison to GnRH antagonists. There may be little or no differences in gonadotropin doses. Progestogens versus GnRH agonists Results were uncertain for all outcomes comparing progestogens with GnRH agonists. One progestogen versus another progestogen The analyses comparing one progestogen versus another progestogen for LBR did not meet our criteria for primary analyses. The OPCR was probably lower in the MPA 10 mg in comparison to MPA 4 mg (OR 2.27, 95%CI 0.90 to 5.74, one RCT, N = 300, moderate-certainty evidence), and MPA 4 mg may be lower than micronised progesterone 100 mg, but due to wide CI, we are uncertain of the effect (OR 0.81, 95%CI 0.43 to 1.53, one RCT, N = 300, low-certainty evidence), changing the chance of OPCR from 5% with MPA 4 mg to 5% to22%, and from 17% with micronised progesterone 100 mg to 8% to 24%. When comparing dydrogesterone 20 mg to MPA, the OPCR is probably lower in the dydrogesterone group in comparison to MPA 10 mg (OR 1.49, 95%CI 0.80 to 2.80, one RCT, N = 520, moderate-certainty evidence), and it may be lower in dydrogesterone group in comparison to MPA 4 mg but due to wide confidence interval, we are uncertain of the effect (OR 1.19, 95%CI 0.61 to 2.34, one RCT, N = 300, low-certainty evidence), changing the chance of OPCR from 7% with dydrogesterone 20 to 6-17%, and in MPA 4 mg from 12% to 8% to 24%. When comparing dydrogesterone 20 mg to micronised progesterone 100 mg, the OPCR is probably lower in the dydrogesterone group (OR 1.54, 95%CI 0.94 to 2.52, two RCTs, N=550, I² = 0%, moderate-certainty evidence), changing OPCR from 11% with dydrogesterone to 10% to 24%. We are very uncertain of the effect in normo-responders of micronised progesterone 100 mg compared with micronised progesterone 200 mg on the OPCR (OR 0.35, 95%CI 0.09 to 1.37, one RCT, N = 150, very-low-certainty evidence). There is probably little or no difference in CPR and MR between MPA 10 mg and dydrogesterone 20 mg. There may be little or no differences in MII oocytes and gonadotropins doses. No cases of moderate/severe OHSS were reported in most of the groups in any of the comparisons. AUTHORS' CONCLUSIONS: Little or no differences in LBR may exist when comparing MPA 4 mg with GnRH agonists in normo-responders. OPCR may be slightly increased in the MPA 4 mg group, but MPA 4 mg reduces the doses of gonadotropins in comparison to GnRH agonists. Little or no differences in OPCR may exist between progestogens and GnRH antagonists in normo-responders and donors. However, micronised progesterone could improve by 2 to 6 MII oocytes. When comparing one progestogen to another, dydrogesterone suggested slightly lower OPCR than MPA and micronised progesterone, and MPA suggested slightly lower OPCR than the micronised progesterone 100 mg. Finally, MPA 10 mg suggests a lower OPCR than MPA 4 mg. There is uncertainty regarding the rest of the outcomes due to imprecision and no solid conclusions can be drawn.

Beyond the Umbrella: A Systematic Review of the Interventions for the Prevention of and Reduction in the Incidence and Severity of Ovarian Hyperstimulation Syndrome in Patients Who Undergo In Vitro Fertilization Treatments.

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

Dose Nomogram of Individualization of the Initial Follicle-Stimulating Hormone Dosage for Patients with Polycystic Ovary Syndrome Undergoing IVF/ICSI with the GnRH-Ant Protocol: A Retrospective Cohort Study.

INTRODUCTION: For high responders with polycystic ovary syndrome (PCOS), there is no clear recommendation for the initial follicle-stimulating hormone (FSH) dosage to ensure an optimal number of retrieved oocytes and avoid ovarian hyperstimulation syndrome (OHSS). The aim of this study was to determine the ideal initial FSH dosage of in patients with PCOS undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) using the gonadotropin-releasing hormone antagonist (GnRH-ant) protocol to obtain the optimal number of retrieved oocytes and minimize the risk of OHSS. METHODS: The data of 1898 patients with PCOS aged 20-40 years from January 2017 to December 2020 were retrospectively analyzed to explore the factors related to the number of retrieved oocytes. Statistically significant variables were used to construct a dose nomogram and it was then validated using an independent cohort of patients with PCOS from January 2021 to December 2021. RESULTS: Multivariate analyses demonstrated that body mass index (BMI) was the most significant factor to predict the number of retrieved oocytes compared to body weight (BW) and body surface area (BSA). Among patients with PCOS aged 20-40 years undergoing their first IVF cycles with the GnRH-ant protocol, age was not a significant predictor of the initial FSH dosage. We developed a nomogram based on BMI, basal FSH, basal luteinizing hormone (bLH), anti-Müllerian hormone (AMH), and antral follicle count (AFC) to calculate the ideal initial FSH dosage for patients with PCOS undergoing IVF/ICSI using the GnRH-ant protocol. In addition, low BMI and high bLH and AMH levels and AFC appear to be risk factors for OHSS. CONCLUSIONS: We clearly demonstrated that the initial FSH dosage for patients with PCOS undergoing IVF/ICSI with the GnRH-ant protocol may be calculated on the basis of the woman's BMI and ovarian reserve markers. The nomogram will help guide clinicians in the selection of the most appropriate initial FSH dose in the future.

A promising treatment for spontaneous ovarian hyperstimulation syndrome due to familial partial lipodystrophy: GnRH analogs combined with cyst aspiration.

PURPOSE: To present a patient with familial partial lipodystrophy (FPLD) and polycystic ovary syndrome (PCOS) who was admitted with spontaneous ovarian hyperstimulation syndrome (OHSS)-like extremely enlarged ovaries, which was successfully treated using gonadotropin-releasing hormone analogs and abdominal cyst aspiration in combination. METHOD: This is a descriptive case report of a single patient with FPLD and PCOS. RESULTS: Clinical improvement was achieved 6 months after therapy besides progressive reduction in total testosterone and DHEAS. Furthermore, there was a significant improvement in hyperinsulinemia and hypertriglyceridemia. Additionally, reduction in the size of ovarian cysts, reduction in the size and number of localizations of acanthosis nigricans, reduction in scores of mFGS, and weight loss were also observed. CONCLUSION: Although there are few reports in the literature describing the association between PCOS with FPLD, management of this novel spontaneous OHSS-like condition has not yet been clearly defined. In the case of extremely enlarged multicystic ovaries and severe hyperandrogenemia, GnRH analogs may be considered to prevent ovarian enlargement and reduce hyperandrogenemia, especially when other treatment options are inappropriate.

Interventions to prevent or reduce the incidence and severity of ovarian hyperstimulation syndrome: a systematic umbrella review of the best clinical evidence.

Ovarian hyperstimulation syndrome (OHSS) is a potentially life-threating iatrogenic complication of the early luteal phase and/or early pregnancy after in vitro fertilization (IVF) treatment. The aim of the current study was to identify the most effective methods for preventing of and reducing the incidence and severity of OHSS in IVF patients. A systematic review of systematic reviews of randomized controlled trials (RCTs) with meta-analysis was used to assess each potential intervention (PROSPERO website, CRD 268626) and only studies with the highest quality were included in the qualitative analysis. Primary outcomes included prevention and reduction of OHSS incidence and severity. Secondary outcomes were maternal death, incidence of hospital admission, days of hospitalization, and reproductive outcomes, such as incidence of live-births, clinical pregnancies, pregnancy rate, ongoing pregnancy, miscarriages, and oocytes retrieved. A total of specific interventions related to OHSS were analyzed in 28 systematic reviews of RCTs with meta-analyses. The quality assessment of the included studies was high, moderate, and low for 23, 2, and 3 studies, respectively. The certainty of evidence (CoE) for interventions was reported for 37 specific situations/populations and resulted high, moderate, and low-to-very low for one, 5, and 26 cases, respectively, while it was not reported in 5 cases. Considering the effective interventions without deleterious reproductive effects, GnRH-ant co-treatment (36 RCTs; OR 0.61, 95% C 0.51 to 0.72, n = 7,944; I2 = 31%) and GnRH agonist triggering (8 RCTs; OR 0.15, 95% CI 0.05 to 0.47, n = 989; I2 = 42%) emerged as the most effective interventions for preventing OHSS with a moderate CoE, even though elective embryo cryopreservation exhibited a low CoE. Furthermore, the use of mild ovarian stimulation (9 RCTs; RR 0.26, CI 0.14 to 0.49, n = 1,925; I2 = 0%), and dopaminergic agonists (10 RCTs; OR 0.32, 95% CI 0.23 to 0.44, n = 1,202; I2 = 13%) coadministration proved effective and safe with a moderate CoE. In conclusion, the current study demonstrates that only a few interventions currently can be considered effective to reduce the incidence of OHSS and its severity with high/moderate CoE despite the numerous published studies on the topic. Further well-designed RCTs are needed, particularly for GnRH-a down-regulated IVF cycles.

Introduce an optimal method of ovarian stimulation in the polycystic ovarian syndrome affected: a randomized controlled trial.

BACKGROUND: Currently, optimal method of ovarian stimulation (OS) to in-vitro fertilization (IVF) in the patients with polycystic ovarian syndrome (PCOS) is unknown. The present research aims to study the efficiency of minimal-OS method in treatment of infertile patients with PCOS and also the effect of gonadotropin type (recombinant FSH (r-FSH) vs. urinary Human menopausal gonadotropin (u-HMG)) on treatment cycles with GnRH-antagonist. METHODS: In this randomized controlled trial, a total of 120 eligible patients were randomly allocated into four groups of OS to IVF: minimal-OS with r-FSH, minimal-OS with u-HMG, mild-OS with r-FSH and mild-OS with u-HMG. IVF outcomes of groups were analyzed statically. RESULTS: The statistical analysis showed that there were significant differences among groups regarding stimulation duration (p < 0.0001), number of retrieved oocytes (p < 0.0001), number of obtained embryos (p < 0.0001). There were no statistically significant differences in fertilization rate (p = 0.289) and implantation rate (p = 0.757) among our participants. There were also significant differences among these four groups in terms of clinical pregnancy rate (/ET and /cycles) (p < 0.0001, p = 0.021, respectively) and live birth rate/cycles (p < 0.0001). Also cases of freeze all embryos due to prevention of ovarian hyper stimulation syndrome (OHSS) (p = 0.004). CONCLUSIONS: On the basis of present results the minimal-OS with u-HMG may be one of optimal methods of control OS in the patients with PCOS in respect to serum levels of estradiol on the day of triggering final oocyte maturation, total dose of prescribed gonadotropin, the optimal number of oocytes and embryos obtained, rate of clinical pregnancy and the incidence of OHSS risk. TRIAL REGISTRATION: NCT, NCT03876145. Registered 15/03/2019. Retrospectively registered, http://www. CLINICALTRIAL: gov/ NCT03876145.

Incidence and severity of ovarian hyperstimulation syndrome (OHSS) in high responders after gonadotropin-releasing hormone (GnRH) agonist trigger in "freeze-all" approach.

OBJECTIVE: To determine the incidence and severity of ovarian hyperstimulation syndrome (OHSS) in high responders (25-35 follicles with a diameter of ≥12 mm on day of triggering) who received a gonadotropin-releasing hormone (GnRH) agonist to trigger final follicular maturation. METHODS: We used individual data from women who participated in four different clinical trials and were high responders to ovarian stimulation in a GnRH antagonist protocol in this retrospective combined analysis. All women were evaluated for signs and symptoms of OHSS using identical criteria based on Golan's system (1989). RESULTS: High responders (n = 77) were of different ethnicities. There were no differences in baseline characteristics between women with or without signs and symptoms of OHSS. Mean ± standard deviation baseline data were: age, 32.3 ± 3.5 years; anti-Müllerian hormone, 42.4 ± 20.7 pmol/L; antral follicle count, 21.5 ± 9.2. Before triggering, duration of stimulation was 9.5 ± 1.6 days and the mean number of follicles with a diameter of ≥12 mm and ≥17 mm was 26.5 ± 4.4 and 8.8 ± 4.7, respectively. Mean serum estradiol (17,159 pmol/l) and progesterone (5.1 nmol/l) levels were high at 36 h after triggering. Overall, 17/77 high responders (22%) developed signs and symptoms of mild OHSS which lasted 6-21 days. The most frequently prescribed medication was cabergoline to prevent worsening of OHSS. No severe OHSS occurred and no OHSS cases were reported as serious adverse events. CONCLUSIONS: High responders receiving GnRH agonist for triggering should be informed that they may experience signs and symptoms of mild OHSS.

Maximize the safety and efficacy of fertility preservation by random start/dual ovarian stimulation for early breast cancer patients.

OBJECTIVE: What is the more efficient and safer protocol during controlled ovarian hyperstimulation (COH) for early-stage breast cancer patients seeking emergency fertility preservation before adjuvant chemo/radiotherapy? MATERIALS AND METHODS: This retrospective, case-series study involved two early-stage (Ia) breast cancer patients that requested for fertility preservation within 3 weeks. Random start/dual stimulation protocols with aromatase inhibitor (AI) were used to maximize oocyte yield and suppress serum estradiol (E2) level. RESULTS: E2 levels on trigger day during dual COH were between 112.0 and 407.0 pg/mL. Duration of COH could be shortened to only 17 days, and up to 41 oocytes were successfully retrieved with two retrievals. CONCLUSION: This remarkable efficient and safe protocol involves the combination of random start/dual stimulation with step-up AI dosage beforehand which not only maximize oocyte yield within the shortest possible timeframe, but also to maintain the low level of E2 to avoid over-stimulating estrogen-sensitive cancer cells and to decrease the risk of developing ovarian hyperstimulation syndrome (OHSS).

Severe early ovarian hyperstimulation syndrome following GnRH agonist trigger and freeze-all strategy in GnRH antagonist protocol; case report and literature review.

Ovarian hyperstimulation syndrome (OHSS) is characterized by increased vascular permeability, hemoconcentration and fluid leakage to the third space. The vast majority of OHSS cases occur following ovarian stimulation for IVF. This potentially lethal iatrogenic condition is one of the most serious complications of assisted reproductive technologies. We report one case of severe early OHSS after GnRH agonist trigger in a GnRH antagonist protocol and freeze-all approach without the administration of any hCG for luteal-phase support in a 34-year-old case of PCO with 7 years primary infertility. After oocyte retrieval the patient was seen at the emergency unit of the hospital with abdominal distension, pain, anuria, dyspnea, and OHSS symptoms. The diagnosis was OHSS with severe ascitis. She was admitted to the Intensive care unit (ICU). She was managed with oxygen by mask, intravenous fluids, anticoagulant and albumen, we performed a two-time vaginal ascites puncture, resulting in the removal of 7800mL of clear fluid in Intensive Care Unit with full recovery. This case study presents the clinical manifestations, investigation, progress, management, outcome and preventive measures. The patient was managed with no complications. Clinicians have to be aware that even the sequential approach to ovarian stimulation with a freeze-all approach and GNRH analog triggering does not completely eliminate OHSS in all patients.

Dydrogesterone supplementation in addition to routine micronized progesterone administration for luteal support in cycles triggered with lone GnRH agonist results in an acceptable pregnancy rate and avoids the need to freeze embryos.

BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) is reduced when using antagonist cycle with gonadotrophin releasing hormone (GnRH) agonist trigger before ovum pick up. This trigger induces short luteinizing hormone (LH) and follicle stimulating hormone (FSH) peaks, resulting in an inadequate luteal phase and a reduced implantation rate. We assessed whether the luteal phase can be rescued by supplementing with oral dydrogesterone (duphaston) in antagonist cycles after a lone GnRH agonist trigger. METHODS: A retrospective cohort study. The study group (N.=123) included women who underwent IVF. Patients received a GnRH-antagonist with a lone GnRH-agonist trigger due to imminent OHSS. The control group (N.=374) included patients who underwent a standard antagonist protocol with a dual trigger of a GnRH-agonist and human chorionic gonadotrophin (hCG). All the patients were treated with micronized progesterone (utrogestan) for luteal phase support. Study patients were given duphaston in addition. RESULTS: The fertilization rate was comparable between the two groups. The mean number of embryos transferred, the clinical pregnancy rate and the take-home baby rate were comparable between groups (1.5±0.6 vs. 1.5±0.5 and 46.3% vs. 41.2%, and 66.7% vs. 87.7%, respectively). No OHSS event was reported in either group. CONCLUSIONS: This study was the first to evaluate outcomes of duphaston supplementation for luteal support in an antagonist cycle with lone GnRH agonist trigger. The functionality of the luteal phase of those cycles could be restored by adding duphaston. This approach was found to be safe and prevented the need to postpone embryo transfer in case of pending OHSS.

Effect of ondansetron for preventing of ovarian hyperstimulation syndrome: in an experimental rat model.

Objective: Ovarian hyperstimulation syndrome is an iatrogenic condition that occurs in the treatment of infertility. There is no specific treatment available for OHSS. Cabergoline is a dopamine receptor 2 agonist and VEGF-VEGF2 receptor antagonist . Recently, cabergoline has been widely used to prevent the development of OHSS and reduce its severity Serotonin is known as a neurotransmitter and thought to have a role in the mechanism of angiogenesis and in signaling in endothelial cells. Serotonin is said to have similar effects to VEGF . Ondansetron is Selective Serotonin (5-HT3) Receptor Antagonist . It works by blocking the action of serotonin, a natural substance that may cause nausea and vomiting. In the clinical practice today, there is no choice other than cabergoline, to prevent occurrence and reduce severity of OHSS, and sometimes its effects are limited. Methods: In our study, we compared the effect of cabergoline and ondansetron. 32 immature rats were used and the OHSS model was created. Parameters such as hematocrit value , ovarian size, the number of follicles in the ovary, endometrial capillary congestion and thickness values were evaluated and compared. Results: As a result, in our study, it was seen that ondansetron was effective on OHSS in many parameters. It is thought to be as effective as cabergoline. When we look at the literature, this is the first study in which ondansetron was evaluated for this purpose. It would be good to show this effect of ondansetron with other studies.

Comparative clinical outcome following individualized follitropin delta dosing in Chinese women undergoing ovarian stimulation for in vitro fertilization /intracytoplasmic sperm injection.

BACKGROUND: To compare the efficacy and safety of follitropin delta in its individualized fixed-dose regimen with follitropin alfa in a conventional adjustable dosing regimen in Chinese women.  METHODS: This was a subgroup analysis of the randomized, multi-center, assessor-blind, non-inferiority trial (GRAPE) including 759 Chinese women (aged 20-40 years) recruited in 16 reproductive medicine clinics in China. Women were randomized in a 1:1 ratio to be treated with either follitropin delta dose based on anti-Müllerian hormone (AMH) and body weight or conventional dosing with follitropin alfa following a gonadotropin-releasing hormone (GnRH) antagonist protocol. The primary outcome was ongoing pregnancy rate assessed 10-11 weeks after embryo transfer in the fresh cycle (non-inferiority margin -10.0%). RESULTS: 378 in the follitropin delta group and 381 in the follitropin alfa group were randomized and exposed. Non-inferiority was confirmed with respect to ongoing pregnancy with rates of 31.0% vs. 25.7% for follitropin delta compared to follitropin alfa, estimated mean difference of 5.1% (95% confidence interval (CI) -1.3% to 11.5%). The clinical pregnancy rate (35.4% vs. 31.5%, P = 0.239) and live birth rate (31.0% vs. 25.5%, P = 0.101) were comparable between the follitropin delta group and the follitropin alfa group. Overall, the individualized follitropin delta treatment resulted in fewer oocytes retrieved compared to follitropin alfa treatment (10.3 ± 6.2 vs. 12.5 ± 7.5, P < 0.001), which was mainly due to fewer oocytes (10.5 ± 6.4 vs. 13.9 ± 7.8) in women with AMH ≥ 15 pmol/L. Accordingly there was a lower incidence of early ovarian hyper-stimulation syndrome (OHSS) and/or preventive interventions (6.1% vs. 11.0%, P = 0.013). A daily follitropin delta dose of 10.2 µg (95% CI: 9.3-11.2 µg) was estimated to provide the same number of oocytes retrieved as a starting dose of 150 IU/d of follitropin alfa. CONCLUSION: Follitropin delta in its individualized fixed-dose regimen showed similar efficacy and improved safety compared with follitropin alfa in a conventional adjustable dosing regimen in Chinese women. CLINICAL TRIAL REGISTRATION NUMBER: NCT03296527.

Ovarian Hyperstimulation Syndrome after GnRH Agonist Triggering and Freeze-All Protocol? Never Not, Hardly Ever: A Systematic Review of Case Reports.

INTRODUCTION: Ovarian hyperstimulation syndrome (OHSS) is a severe complication associated with controlled ovarian stimulation (COS). GnRH agonist (GnRH-a) triggering is considered an efficient strategy to prevent OHSS in the high-risk patient. METHODS: We performed a review of 11 cases of early and severe OHSS following GnRH-a triggering and freeze-all protocol. Electronic databases were searched from inception of each database until October 2021, to identify case reports and case series that reported OHSS after GnRH-a triggering and freeze-all approach describing patient demographics, COS protocol, and patient outcomes. RESULTS: From the literature review, it is possible to suggest that (1) following GnRH-a triggering, the risk of early and severe OHSS is not totally cancelled; (2) despite it is not possible to predict the event, polycystic ovary syndrome is the most common risk factor; (3) the use of GnRH antagonist starting from the day of PU may represent a valid strategy for preventing OHSS in women with high-risk profile; (4) following the unexpected onset of OHSS, measuring serum levels of human chorionic gonadotropin (hCG) is helpful to exclude an inadvertent exogenous administration or a pregnancy. CONCLUSION: The statement that OHSS risk is eliminated when GnRH-a triggering, a freeze-all strategy, and no hCG in the luteal phase may generate the idea that this event cannot occur. Although rare, these cases have been observed in a relatively short period of time.

A retrospective, matched case-control study of recombinant LH versus hMG supplementation on FSH during controlled ovarian hyperstimulation in the GnRH-antagonist protocol.

Background: The role of luteinizing hormone (LH) in controlled ovarian hyperstimulation (COH) requires more evidence for its efficacy. Several studies compared recombinant human LH (r-hLH) or human menopausal gonadotropin (hMG) in combination with recombinant human follicle-stimulating hormone (r-hFSH) but lack the results with GnRH-antagonist protocol and in Asians. Methods: This is a retrospective, single-center study inspecting women receiving GnRH antagonist protocol and r-hFSH+hMG or r-hFSH+r-hLH regimen for over five days for COH in the in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycle in Taiwan from 2013 to 2018. The outcomes of IVF/ICSI cycles were analyzed after propensity score matching between the two groups. A subgroup analysis was conducted in cycles in which women underwent their first embryo transfer (ET), including fresh ET and frozen ET (FET). Results: With a total of 503 cycles, the results revealed that the r-hFSH+r-hLH group performed better in terms of numbers of oocytes retrieved (r-hFSH+hMG vs. r-hFSH+r-hLH, 11.7 vs. 13.7, p=0.014), mature oocytes (8.7 vs. 10.9, p=0.001), and fertilized oocytes (8.3 vs. 9.8, p=0.022), while other outcomes were comparable. The analysis of first ET cycles also showed similar trends. Although the implantation rate (39% vs. 43%, p=0.37), pregnancy rate (52% vs. 53%, p=0.90), and live birth rate (39% vs. 45%, p=0.19) were not significantly different, the miscarriage rate was higher in the r-hFSH+hMG group than the r-hFSH+r-hLH group (26% vs. 15%, p<0.05) in first ET cycles. The cumulative pregnancy rate was significantly higher in the r-hFSH+r-hLH group (53% vs. 64%, p=0.02). No significant difference in rates of ovarian hyperstimulation syndrome (OHSS) was observed. Conclusion: The results support the hypothesis that the treatment of r-hLH+r-hFSH improves COH clinical outcomes in the IVF/ICSI cycle.