Vitamin D3 reduces the symptoms of ovarian hyperstimulation syndrome in mice and inhibits the release of granulosa cell angiogenic factor through pentraxin 3.

It has been reported that the effective inhibition of vascular endothelial growth factor (VEGF) can prevent the progression of ovarian hyperstimulation syndrome (OHSS). The present study aimed to investigate the mechanism underlying the effect of vitamin D3 (VD3) on OHSS in mouse models and granulosa cells. The effects of VD3 administration (16 and 24 IU) on ovarian permeability were determined using Evans blue. In addition, ovarian pathology, corpus luteum count, inflammatory responses, and hormone and VEGFA levels were assessed using pathological sections and ELISA. Molecular docking predicted that pentraxin 3 (PTX3) could be a potential target of VD3, and therefore, the effects of human chorionic gonadotropin (hCG) and VD3 as well as PTX3 overexpression on the production and secretion of VEGFA in granulosa cells were also investigated using western blotting and immunofluorescence. Twenty-four IU VD3 significantly reversed the increase in ovarian weight and permeability in mice with OHSS. Additionally, VD3 diminished congestion and the number of corpus luteum in the ovaries and reduced the secretion levels of inflammatory factors and those of estrogen and progesterone. Notably, VD3 downregulated VEGFA and CD31 in ovarian tissues, while the expression levels of PTX3 varied among different groups. Furthermore, VD3 restored the hCG-induced enhanced VEGFA and PTX3 expression levels in granulosa cells, whereas PTX3 overexpression abrogated the VD3-mediated inhibition of VEGFA production and secretion. The present study demonstrated that VD3 could inhibit the release of VEGFA through PTX3, thus supporting the beneficial effects of VD3 administration on ameliorating OHSS symptoms.

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 ).

[Ovarian hyperstimulation syndrome with controlled ovarian stimulation after induction therapy for Philadelphia chromosome-positive acute lymphoblastic leukemia].

A 27-year-old woman with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia received induction therapy with dasatinib and prednisolone. From the time of diagnosis, oocyte storage was planned in accordance with the patient's wishes. After progesterone administration for suppression of menstruation, and blood cell recovery, ovarian stimulation was performed and a sufficient number of eggs was collected. The patient was considered at high risk for ovarian stimulation syndrome (OHSS) and received cabergoline and letrozole. However, ovarian enlargement and ascites were observed on ultrasonography 2 days after egg collection, and a diagnosis of moderate OHSS was made. Circulatory management was performed and low-molecular-weight heparin was administered. Dasatinib was discontinued due to the appearance of pleural effusion. Fluid retention improved after menstruation resumed, and the patient was able to continue consolidation with dasatinib and cord blood transplantation. Although tyrosine kinase inhibitors are expected to simplify planning of oocyte storage, the risk of complicating OHSS should be noted.

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 ).

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

BACKGROUND: Erythropoietin (Epo) is a potent vascular growth factor that induces angiogenesis and antiapoptotic signalling. We investigated whether the development of numerous follicles and corpora lutea during in vitro fertilization (IVF) cycle affects circulating Epo levels and further, if Epo could be used as a novel marker for ovarian hyperstimulation syndrome (OHSS). METHODS: 24 women were included in the uncomplicated IVF group and 35 women in the OHSS group. Repeated blood samples from both groups were analysed for Epo, progesterone, blood haemoglobin, and creatinine. Follicular fluid from the IVF group was analysed for Epo and progesterone. Repeated measure analysis was performed for the variables and circulating Epo levels were compared between the IVF group and early OHSS. Furthermore, related growth factors, vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 (HIF-1) were analysed from subgroup of women to test for correlation with Epo. RESULTS: During IVF, circulating Epo increased from natural mid-luteal phase to stimulated mid-luteal phase (median 9.5; 95% CI 7.2-13.4 IU/L and 12.5; 10.3-13.4 IU/L; p = 0.003). In cycles resulting in pregnancy, Epo level decreased 14 days after oocyte pick-up (OPU) and remained low thereafter. In cycles not resulting in pregnancy, Epo level increased again 35 days after OPU. Follicle fluid Epo concentration was 1.5 times higher than the serum concentration (median 15.4; 95% CI 10.4-19.2 IU/L vs. 10.2; 8.8-12.7; p = 0.006). There was no difference in circulating Epo concentration between early OHSS and uncomplicated IVF. Circulating Epo did not correlate with VEGF or HIF-1. CONCLUSIONS: Circulating Epo levels fluctuate during IVF cycle. We hypothesise this may suggest Epo's involvement in ovarian physiology and angiogenesis. However, Epo was not a clinical marker for OHSS.

Assisted Reproductive Technology in the Presence of Polycystic Ovary Syndrome: Current Evidence and Knowledge Gaps.

OBJECTIVE: In this narrative review, we discuss the current evidence as well as the knowledge gaps concerning assisted reproductive technology (ART) indications, protocols, and results in the presence of polycystic ovary syndrome (PCOS). METHODS: An electronic literature search was performed for English-language publications in the last decade in databases such as PubMed, Medline, the Web of Sciences, Embase, and Scopus. RESULTS: We found evidence that ovarian steroidogenesis and folliculogenesis are deeply altered by PCOS; however, the oocyte quality and pregnancy rates after ART are not affected. Patients with PCOS are more sensitive to the action of exogenous gonadotropins and more likely to develop ovarian hyperstimulation syndrome. This risk can be mitigated by the adoption of the gonadotropin-releasing hormone antagonist protocols for pituitary blockade and ovarian stimulation, along with frozen embryo transfer, without compromising the odds of achieving a live birth. Pregnancy complications, such as miscarriage, gestational diabetes, preeclampsia, and very preterm birth, are more frequent in the presence of PCOS, requiring more intense prenatal care. It remains uncertain whether weight reduction or insulin sensitizers used before ART are beneficial for the treatment outcomes. CONCLUSION: Although PCOS is not a drawback for ART treatments, the patients need special care to avoid complications. More in-depth studies are needed to uncover the mechanisms of follicular growth, gamete maturation, and endometrial differentiation during ART procedures in the presence of PCOS.

LH on GnRH-ant day to basal LH affects the IVF/ICSI outcome of PCOS women undergoing GnRH-antagonist protocol.

OBJECTIVE: The aim of this study was to investigate the influence of ratio of serum luteinizing hormone (LH) on gonadotropin-releasing hormone antagonist (GnRH-ant) day to basal LH (hLH/bLH) on in-vitro fertilization or intracytoplasmic sperm injection (IVF/ICSI) outcome in polycystic ovary syndrome (PCOS) women who received GnRH-ant protocol for controlled ovarian hyperstimulation (COH). METHODS: This retrospective study was conducted in women with PCOS (n = 1116) who underwent the GnRH-ant protocol for COH between 2015 and 2022 and were stratified as group A (hLH/bLH < 1, n = 489) and group B (hLH/bLH ≥ 1, n = 627) according to the variation of serum LH. The outcomes of COH and the first frozen embryo transfer (FET) cycle were compared between group A, B and the linear relationship between hLH/bLH ratio and IVF/ICSI outcomes were studied by multivariate linear regression analysis and restricted cubic spline (RCS) models. RESULTS: There were significant differences in baseline characteristics and outcomes between group A and B. Group A had higher levels of bLH, AMH, estradiol (E2) on GnRH-ant start day and lower levels of LH on GnRH-ant start day. Group B has better ovulation induction outcomes: more retrieved oocytes, normally fertilized oocytes (2PN), cleavage embryos, available embryos and high-quality blastocysts. Multivariate linear regression analysis found no statistically significant connection between hLH/bLH and clinical outcomes. RCS models showed hLH/bLH had nonlinear association with outcomes, including number of oocytes retrieved, 2PN, available embryos, incidence of OHSS, chemical pregnancy, clinical pregnancy, abortion and live birth. CONCLUSIONS: hLH/bLH ratio could be a more forward-looking indicator of clinical outcome in women with PCOS undergoing GnRH-ant protocols than LH on trigger day and the ratio of LH level on trigger day to basal LH. hLH/bLH = 1 may be the best condition for higher live birth rate and lower OHSS rate.

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.

TGF-ß1 and TGF-ß3, but not TGF-ß2, 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-ß1 (TGF-ß1) 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-ß family, TGF-ß2 and -ß3, remains unknown. We showed that all three TGF-ß isoforms were expressed in human follicular fluid. In comparison, TGF-ß1 was expressed at the highest level, followed by TGF-ß2 and TGF-ß3. Compared to non-OHSS patients, follicular fluid levels of TGF-ß1 and TGF-ß3 were significantly upregulated in OHSS patients. The same results were observed in mRNA levels of TGF-ß 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-ß isoforms downregulated the StAR expression with a comparable effect. Moreover, activations of SMAD3 signaling were required for TGF-ß isoforms-induced downregulation of StAR expression. This study indicates that follicular fluid TGF-ß1 and TGF-ß3 levels could be used as biomarkers and therapeutic targets for the OHSS.

Comparison of Steroidogenic and Ovulation-Inducing Effects of Orthosteric and Allosteric Agonists of Luteinizing Hormone/Chorionic Gonadotropin Receptor in Immature Female Rats.

Gonadotropins, including human chorionic gonadotropin (hCG), are used to induce ovulation, but they have a number of side effects, including ovarian hyperstimulation syndrome (OHSS). A possible alternative is allosteric luteinizing hormone (LH)/hCG receptor agonists, including the compound TP4/2 we developed, which remains active when administered orally. The aim was to study the effectiveness of TP4/2 (orally, 40 mg/kg) as an ovulation inducer in FSH-stimulated immature female rats, compared with hCG (s.c., 15 IU/rat). TP4/2 stimulated progesterone production and corpus luteum formation; time-dependently increased the ovarian expression of steroidogenic genes (Star, Cyp11a1, Cyp17a1) and genes involved in ovulation regulation (Adamts-1, Cox-2, Egr-1, Mt-1); and increased the content of metalloproteinase ADAMTS-1 in the ovaries. These effects were similar to those of hCG, although in some cases they were less pronounced. TP4/2, in contrast to hCG, maintained normal LH levels and increased the ovarian expression of the LH/hCG receptor gene, indicating preservation of ovarian sensitivity to LH, and did not cause a sustained increase in expression of vascular endothelial growth factor-A involved in OHSS. Thus, TP4/2 is an effective ovulation inducer that, unlike hCG, has a lower risk of OHSS and ovarian LH resistance due to its moderate stimulating effect on steroidogenesis.

Efficacies of different ovarian hyperstimulation protocols in elderly patients with poor ovarian response.

OBJECTIVE: The aim of the study was to explore which controlled ovarian hyperstimulation (COH) protocol is most suitable for elderly patients with poor ovarian response (POR) undergoing assisted reproductive technology (ART). PATIENTS AND METHODS: This retrospective cohort study evaluated clinical data from 2,660 patients from January 2017 and October 2020. The patients were divided into three groups: modified Gonadotropin-releasing hormone (GnRH) agonist protocol (1,225 patients), GnRH antagonist protocol (1,038 patients), and Mild stimulation protocol (397 patients). Clinical variables and pregnancy outcomes were compared among the three groups. RESULTS: The GnRH agonist protocol was associated with a higher number of oocyte number (3.99±2.82 vs. 3.02±1.34 vs. 2.51±1.14, p<0.001), a higher number of transferable embryos (1.39±1.32 vs. 1.24±1.24 vs. 1.18±1.11, p = 0.035), higher cumulative live birth rate [26.53% (323/1,225) vs. 22.44% (233/1,038) vs. 21.66% (86/397), p = 0.043], lower OHSS rate [5.14% (63/1,225) vs. 3.08% (32/1,038) vs. 2.02% (8/397), p = 0.005] than GnRH antagonist protocol and Mild stimulation protocol, the Mild stimulation protocol was associated with higher miscarriage rates [30.4% (24/71) vs. 25.0% (33/192) vs. 29.6% (35/168), p = 0.014] than the other two groups. CONCLUSIONS: The three protocols can be used in elderly patients with POR; however, if patients require more frozen-thawed embryo transfers to achieve better cumulative live birth rates, the modified GnRH agonist protocol may be the better choice. It should be emphasized that the mild stimulation had a slightly higher miscarriage rate than the other two groups.

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.

hMG addition affects the change in progesterone level during IVF stimulation and LBR: a retrospective cohort study.

BACKGROUND: Premature progesterone (P) rise during IVF stimulation reduces endometrial receptivity and is associated with lower pregnancy rates following embryo transfer (ET), which can influence provider recommendation for fresh or frozen ET. This study aimed to determine whether change in P level between in IVF baseline and trigger (𝚫P) is predictive of pregnancy outcome following fresh ET, and whether the ratio of gonadotropins influences P rise and, as a result, clinical pregnancy outcomes: clinical pregnancy rate (CPR) and live birth rates (LBR). METHODS: Retrospective cohort study at a single fertility center at an academic institution. The peak P level and 𝚫P were modeled in relation to prediction of CPR and LBR, and the ratios of hMG:rFSH were also modeled in relation to prediction of peak P level on day of trigger, 𝚫P, and CPR/LBR in a total of 291 patients undergoing fresh embryo transfer after controlled ovarian hyperstimulation-IVF (COH-IVF). RESULTS: 𝚫P correlates with CPR, with the most predictive range for success as 𝚫P 0.7-0.85 ng/mL (p = 0.005, 95% CI 0.635, 3.636; predicting CPR of 88.9%). The optimal range for peak P in regard to pregnancy outcome was 0.15-1.349 ng/mL (p = 0.01; 95% CI for coefficient in model 0.48-3.570). A multivariable logistic model for prediction of CPR and LBR using either peak or 𝚫P supported a stronger association between 𝚫P and CPR/LBR as compared to peak P. Furthermore, an hMG:rFSH ratio of > 0.6 was predictive of lowest peak P (p = 0.010, 95% CI 0.035, 0.256) and smallest 𝚫P (p = 0.012, 95% CI 0.030, 0.243) during COH-IVF cycles. Highest CPRs were observed within hMG:rFSH ratios of 0.3-0.4 [75.6% vs. 62.5% within and outside of the range, respectively, (p = 0.023, 95% CI 0.119, 1.618)]. Highest LBRs were seen within the range of 0.3-0.6 hMG:rFSH, [LBR of 55.4% vs. 41.4% (p = 0.010, 95% CI 0.176, 1.311)]. CONCLUSIONS: Our data supports use of 𝚫P to best predict pregnancy rates and therefore can improve clinical decision making as to when fresh ET is most appropriate. Furthermore, we found optimal gonadotropin ratios can be considered to minimize P rise and to optimize CPR/LBR, emphasizing the importance of luteinizing hormone (LH) activity in COH-IVF cycles.

Predictive models for starting dose of gonadotropin in controlled ovarian hyperstimulation: review and progress update.

Controlled ovarian hyperstimulation (COH) is an essential for in vitro fertilization-embryo transfer (IVF-ET) and an important aspect of assisted reproductive technology (ART). Individual starting doses of gonadotropin (Gn) is a critical decision in the process of COH. It has a crucial impact on the number of retrieved oocytes, the cancelling rate of ART cycles, and complications such as ovarian hyperstimulation syndrome (OHSS), as well as pregnancy outcomes. How to make clinical team more standardized and accurate in determining the starting dose of Gn is an important issue in reproductive medicine. In the past 20 years, research teams worldwide have explored prediction models for Gn starting doses. With the integration of artificial intelligence (AI) and deep learning, it is hoped that there will be more suitable predictive model for Gn starting dose in the future.

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.

In vitro maturation (IVM) of human immature oocytes: is it still relevant?

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

Analysis of controlled ovarian hyperstimulation protocols in women over 35 years old with poor ovarian response: a real-world study.

The objective of this study was to investigate the optimal controlled ovarian hyperstimulation (COH) protocol for patients aged 35 and above with poor ovarian response (POR), utilizing real-world data. This retrospective cohort study examined clinical information from a total of 4256 patients between January 2017 and November 2022. The patients were categorized into three groups: modified GnRH agonist protocol (2116 patients), GnRH antagonist protocol (1628 patients), and Mild stimulation protocol (512 patients). Comparative analysis was conducted on clinical variables and pregnancy outcomes across the three groups. The GnRH agonist protocol was associated with a higher number of oocyte number (4.02 ± 2.25 vs. 3.15 ± 1.52 vs. 2.40 ± 1.26, p < 0.001), higher number of transferable embryos (1.73 ± 1.02 vs. 1.35 ± 1.22 vs. 1.10 ± 0.86, p = 0.016), higher cumulative live birth rate 28.50(603/2116) vs. 24.94(406/1628) vs. 20.51(105/512), p < 0.001) than GnRH antagonist protocol and Mild stimulation protocol, the Mild stimulation protocol was associated with a higher miscarriage rates 16.27(62/381) vs. 16.61(48/289) vs. 32.22(29/90), p = 0.001) than the other two groups. Therefore, it can be concluded that all three protocols can be used in patients over 35 years old with poor ovarian response. However, if patients require more frozen-thawed embryo transfers to achieve better cumulative live birth rates, the modified GnRH agonist protocol may be the preferable option.

Cocktail treatment by GnRH-antagonist, letrozole, and mifepristone for the prevention of ovarian hyperstimulation syndrome: a prospective randomized trial.

OBJECTIVE: This study is aimed to determine the efficacy of a cocktail style treatment by combining GnRH-antagonist, letrozole, and mifepristone on the prevention of ovarian hyperstimulation syndrome (OHSS) in high-risk women. METHODS: This prospective, randomized controlled clinical trial was performed between January 2018 and December 2018. A total of 170 women who identified as high risk of OHSS during the ovarian hyperstimulation and underwent cryopreservation of whole embryos. On the day of oocyte retrieval, the combination group received 0.25 mg Cetrorelix for 3 d, 5 mg letrozole for 5 d, and 50 mg mifepristone for 3 d, the mifepristone group received 50 mg mifepristone for 3 d. A total of 156 cases were included in final analysis. All the frozen embryo transfer (FET) cycles were followed up until December 2021. RESULTS: The combination group showed significantly decreased incidence of moderate and severe OHSS than mifepristone group (20.5% vs. 42.3%), with remarkably reduced serum estradiol level on hCG + 3 and + 5 d, decreased ovarian diameter, and shortened luteal phase. Oocyte retrieval number, levels of estradiol on hCG + 0 and VEGF, and ovarian diameter on hCG + 5 were associated with the severity of the symptoms. There was no significant difference in cumulative live birth rates (LBRs) between the combination and mifepristone group (74.4% vs. 76.9%). CONCLUSIONS: The combination treatment effectively reduces the incidence of moderate/severe OHSS in high-risk women.