Cumulative live birth rate of in vitro fertilization cycle via progestin-primed ovarian stimulation versus gonadotropin-releasing hormone antagonist protocol in infertile women with normal ovarian reserve: an open-label, randomized controlled trial.

This study aimed to evaluate the cumulative live birth rate (cLBR) of progestin-primed ovarian stimulation (PPOS) protocol versus gonadotropin-releasing hormone antagonist (GnRH-ant) protocol for in vitro fertilization (IVF) cycle in infertile women with normal ovarian reserve (NOR). Infertile women with NOR who underwent their first IVF cycle were enrolled in an open-label randomized controlled trial. Patients were randomly assigned 1:1 to receive a freeze-all strategy with delayed embryo transfer (PPOS group, n = 174) and fresh embryo transfer first (GnRH-ant group, n = 174). The primary outcome was the cLBR per aspiration. The cLBR between the PPOS group and GnRH-ant group were comparable (55.75% vs. 52.87%, p = 0.591). A premature luteinizing hormone surge was not observed in the PPOS group, while there were six cases (3.45%) in the GnRH-ant group, but no premature ovulation in either of the groups. The pregnancy outcomes, including implantation rate, clinical pregnancy rate and miscarriage rate, were all comparable. In addition, the number of retrieved oocytes, mature oocytes and viable embryos were similar (all p > 0.05) between the two groups.

The E3 Ubiquitin Ligase SYVN1 Plays an Antiapoptotic Role in Polycystic Ovary Syndrome by Regulating Mitochondrial Fission.

Polycystic ovary syndrome (PCOS) is one of the most common hormonal disorders among premenopausal women. PCOS is accompanied by many other reproductive, endocrinal, and metabolic disorders thus amassing the difficulties encountered by the women affected. However, there is limited information on its molecular etiology. Synoviolin (SYVN1) is an E3 ubiquitin ligase that is thought to participate in the pathology of PCOS. However, the expression and function of SYVN1 in PCOS are unknown. In this study, we found that downregulation of SYVN1 expression was followed by increased apoptosis in the granulosa cells (GCs) of patients with PCOS. Subsequent in vitro experiments indicated that the overexpression of SYVN1 inhibited apoptosis and mitochondrial fission. Furthermore, using immunoprecipitation and western blotting, we identified that SYVN1 promoted the degradation of Drp1 via the proteasome-dependent pathway. Additionally, we generated a PCOS model in female Sprague Dawley rats and treated them with an SYVN1 inhibitor, LS-102. We observed that the inhibition of SYVN1 increased Drp1 levels and exacerbated the degeneration of GCs in the PCOS rat model. Finally, in vitro and in vivo experiments showed that SYVN1 inhibits apoptosis and mitochondrial fission by promoting Drp1 degradation in GCs. These results highlight the function of SYVN1 in PCOS and provide a potential target for the clinical treatment of PCOS.

Effect of previous wedge resection for interstitial pregnancy on pregnancy and neonatal outcomes following frozen-thawed embryo transfer (FET) cycles of IVF/ICSI: a retrospective study.

OBJECTIVE: The present study aimed to evaluate pregnancy and neonatal outcomes in women, with a previous history of wedge resection for interstitial pregnancy, in frozen-thawed embryo transfer (FET) cycles of IVF/ICSI. METHODS: The present study involved a retrospective case-control assessment of 75 cases and 375 control subjects over 6 years in a single center. To compare pregnancy and neonatal outcomes between cases, treated using wedge resection, and controls without any previous history of ectopic pregnancy, propensity score matching (1:5) was utilized. The study also compared subgroups in the case group. RESULTS: Women with previous wedge resection exhibited higher rates of ectopic pregnancy and uterine rupture rate as compared to control subjects (9.1% vs 1.3%, P = 0.025 and 4.5% vs 0%, P = 0.035, respectively). No statistically significant differences were recorded between the two cohorts with regard to clinical pregnancy rate, live birth rate, and neonatal outcomes. For pregnancy type subgroup analysis, Z-score and rates of large for gestational age were recorded to be significantly lower in twin pregnancy subgroup when compared with singleton pregnancy subgroup (0.10 (- 0.59, 0.25) vs 0.50 (- 0.97, 1.39), P = 0.005; 4.5% vs 26.1%, P = 0.047, respectively). CONCLUSION: The results of the present study indicated that previous wedge resection correlated to a higher risk of ectopic pregnancy and uterine rupture. However, it might not be related to an increased risk of adverse neonatal outcomes. The study recommended cesarean section in these patients. Further studies are required to verify the validity of current recommendations.

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

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

WEE1 promotes endometriosis via the Wnt/ß-catenin signaling pathway.

BACKGROUND: Endometriosis, the presence of active endometrial tissue outside the lining membrane of the uterine cavity, is a common disease in women of childbearing age. The ectopic endometrium has some characteristics of tumor tissue, including invasive and migratory abilities. In addition, endometriosis is associated with inflammation and reduced cellular apoptosis. METHODS: Western blot analysis, qPCR, immunohistochemistry, immunofluorescence microscopy, Transwell assay, wound healing assay, and TUNEL staining. RESULTS: Interleukin-1ß (IL-1ß) induced WEE1 expression in endometrial stromal cells (ESCs), suggesting that WEE1 may be upregulated during the endometriosis-induced inflammatory response. Overexpression of WEE1 in cultured ESCs promoted ESC migration while inhibiting apoptosis, whereas WEE1 knockdown reduced ESC migration while promoting apoptosis. Inhibition of WEE1 attenuates fibrosis in ESCs and female C57BL/6 J mice. This pro-fibrotic effect of WEE1 was significantly decreased by treatment with the Wnt/ß-catenin inhibitor XAV939, suggesting that WEE1 acts via the Wnt/ß-catenin signaling pathway. CONCLUSION: Our study demonstrates that WEE1 promotes ESC migration and fibrosis via the Wnt/ß-catenin signaling pathway. Thus, WEE1 may serve as a potential therapeutic target for the treatment of endometriosis.

Strengthened luteal phase support for patients with low serum progesterone on the day of frozen embryo transfer in artificial endometrial preparation cycles: a large-sample retrospective trial.

BACKGROUND: Low serum progesterone on the day of frozen embryo transfer (FET) is associated with diminished pregnancy rates in artificial endometrium preparation cycles, but there is no consensus on whether strengthened luteal phase support (LPS) benefits patients with low progesterone on the FET day in artificial cycles. This single-centre, large-sample retrospective trial was designed to investigate the contribution of strengthened LPS to pregnancy outcomes for groups with low progesterone levels on the FET day in artificial endometrium preparation cycles. METHODS: Women who had undergone the first artificial endometrium preparation cycle after a freeze-all protocol in our clinic from 2016 to 2018 were classified into two groups depending on their serum progesterone levels on the FET day. Routine LPS was administered to group B (P ≥ 10.0 ng/ml on the FET day, n = 1261), and strengthened LPS (routine LPS+ im P 40 mg daily) was administered to group A (P < 10.0 ng/ml on the FET day, n = 1295). The primary endpoint was the live birth rate, and the secondary endpoints were clinical pregnancy, miscarriage and neonatal outcomes. RESULTS: The results showed that the clinical pregnancy rate was significantly lower in group A than in group B (48.4% vs 53.2%, adjusted risk ratio (aRR) 0.81, 95% confidence interval (CI) 0.68, 0.96), whereas miscarriage rates were similar between the two groups (16.0% vs 14.7%, aRR 1.09, 95% CI 0.77, 1.54). The live birth rate was slightly lower in group A than in group B (39.5% vs 43.3%, aRR 0.84, 95% CI 0.70, 1.0). Birthweights and other neonatal outcomes were similar between the two groups (P > 0.05). CONCLUSIONS: The results indicated that the serum progesterone level on the FET day was one of the risk factors predicting the chances of pregnancy in artificial endometrium preparation cycles, and strengthened LPS in patients with low progesterone on the FET day might help to provide a reasonable pregnancy outcome in artificial cycles, although further prospective evidence is needed to confirm this possibility.

Progestin-primed milder stimulation with clomiphene citrate yields fewer oocytes and suboptimal pregnancy outcomes compared with the standard progestin-primed ovarian stimulation in infertile women with polycystic ovarian syndrome.

BACKGROUND: Oral progestin has recently been used to prevent premature LH surges in ovarian stimulation, and this progestin-primed ovarian stimulation (PPOS) is effective and safe in patients with different ovarian reserves. The current data are lacking regarding how to individualize the gonadotropin dose and regimen for women with polycystic ovarian syndrome (PCOS). A retrospective cohort trial was performed to evaluate the efficacy of progestin-primed milder stimulation with clomiphene citrate (CC) compared to the standard progestin-primed ovarian stimulation (PPOS) protocol for infertile women with PCOS. METHODS: A total of 220 PCOS women were collected and classified into the study group (HMG 150 IU/d + CC 50 mg/d + MPA 10 mg/d) and control group (HMG 225 IU/d + MPA 10 mg/d). Ovulation was triggered by GnRH agonist 0.1 mg and hCG 1000 IU when dominant follicles matured. Viable embryos were cryopreserved for later transfer. The primary endpoint was the ongoing pregnancy rate. Secondary outcomes included the cycle characteristics and the live birth rate. RESULT(S): The study group consumed less HMG (1470.0 ± 360.1 IU vs 1943.8 ± 372.0 IU, P < 0.001) and harvested fewer oocytes than the control group (12.2 ± 7.4 vs 18.2 ± 9.7, P < 0.001). The study group showed a higher mid-follicular LH concentration (4.49 ± 2.49 mIU/ml vs 2.52 ± 2.09 mIU/ml, P < 0.05) but no endogenous LH surge. No between-group difference was found in the incidence of ovarian hyperstimulation syndrome (OHSS) (0.91% vs 0.91%, P > 0.05). The cumulative ongoing pregnancy rate and live birth rate per patient were lower but did not reach significance compared with the control group (71.8% vs 81.8 and 64.5% vs 75.5%, respectively, both P > 0.05). CONCLUSION(S): The milder PPOS with CC in PCOS women led to lower oocyte yields and suboptimal pregnancy outcomes compared to the standard PPOS treatment. The two regimens both achieved a low incidence of OHSS. The results from the CC combination regimen provide a new insight for developing a more patient-friendly protocol for PCOS women.

Comparison of neonatal outcomes following progesterone use during ovarian stimulation with frozen-thawed embryo transfer.

Progesterone soft capsules (brand name: Utrogestan) were demonstrated to be an effective oral alternative to prevent premature LH surges both in normal-ovulatory and polycystic ovarian syndrome (PCOS) patients. However, its safety in terms of neonatal outcomes is unclear. To evaluate whether Utrogestan use increase the risk of adverse neonatal outcomes compared with short protocol in patients undergoing IVF/ICSI treatments in combination with frozen-thawed embryo transfer (FET), we performed a retrospective analysis including 1008 FET cycles, with embryos originated from either Utrogestan + hMG protocol (n = 499), or short protocol (n = 509), which led to 546 live-born infants. The neonatal characteristics regarding preterm birth (PTB), low birth weight (LBW), gestational age and mode of delivery were comparable in the two groups. The incidence of live-birth defect was 0.68% (2/293) in the Utrogestan + hMG protocol compared with 0.79% (2/253) in the short protocol. No early neonatal death or intrauterine death were recorded in either group. To date, the data do not indicate an elevated rate of abnormality at birth after progesterone use during ovarian stimulation but further study with larger populations is needed to confirm these results.

Use of Utrogestan during controlled ovarian hyperstimulation in normally ovulating women undergoing in vitro fertilization or intracytoplasmic sperm injection treatments in combination with a "freeze all" strategy: a randomized controlled dose-finding study of 100 mg versus 200 mg.

OBJECTIVE: To compare the clinical characteristics in a Utrogestan and hMG protocol with the use of different doses of Utrogestan in normally ovulating women undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatments. DESIGN: Prospective controlled study. SETTING: Tertiary-care academic medical center. PATIENT(S): A total of 150 infertile patients undergoing IVF/ICSI treatments. INTERVENTION(S): Utrogestan and hMG were administered simultaneously beginning on cycle day 3. The dose of Utrogestan was 100 mg/d in the study group and 200 mg/d in the control group. When the dominant follicles reached mature, 0.1 mg GnRH agonist was used for trigger. Viable embryos were cryopreserved in both protocols for later transfer. MAIN OUTCOME MEASURE(S): The primary outcome measure was the incidence of premature LH surge. Secondary outcomes included the embryo results and clinical pregnancy outcomes. RESULT(S): Consistent LH suppression was achieved during controlled ovarian hyperstimulation with Utrogestan at 100 mg, and the number of patients with profound LH suppression (LH <1.2 IU/L) in the low-dose group was significantly less than that in the high-dose group. The number of oocytes retrieved in the low-dose group was similar to that in the high-dose group (9.87 ± 5.77 vs. 10.25 ± 5.43). No significant differences were observed in the number of mature oocytes, viable embryos, clinical pregnancy rate, or implantation rate. CONCLUSION(S): Utrogestan at 100 mg is as effective as Utrogestan at 200 mg in reducing premature LH surge during controlled ovarian hyperstimulation. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR-OOC-14005277.

The Utrogestan and hMG protocol in patients with polycystic ovarian syndrome undergoing controlled ovarian hyperstimulation during IVF/ICSI treatments.

Poor oocyte quality is a main concern for decreased reproductive outcomes in women with polycystic ovarian syndrome (PCOS) during controlled ovarian hyperstimulation (COH). A primary way to improve oocyte quality is to optimize the COH protocol. It was demonstrated that the viable embryo rate per oocyte retrieved in the Utrogestan and hMG protocol, a novel regimen based on frozen-thawed embryo transfer (FET), is statistically higher than that in the short protocol. Thus, a retrospective study was conducted to evaluate the endocrine characteristics and clinical outcomes in PCOS patients subjected to the Utrogestan and hMG protocol compared with those subjected to the short protocol.One hundred twenty three PCOS patients enrolled in the study group and were simultaneously administered Utrogestan and human menopausal gonadotropin (hMG) from cycle day 3 until the trigger day. When the dominant follicles matured, gonadotropin-releasing hormone agonist (GnRH-a) 0.1 mg was used as the trigger. A short protocol was applied in the control group including 77 PCOS women. Viable embryos were cryopreserved for later transfer in both groups. The primary outcome was the viable embryo rate per oocyte retrieved. The secondary outcomes included the number of oocytes retrieved, fertilization rate, and clinical pregnancy outcomes from FET cycles.The pituitary luteinizing hormone (LH) level was suppressed in most patients; however, the LH level in 13 women, whose basic LH level was more than 10 IU/L, surpassed 10 IU/L on menstruation cycle day (MC)9-11 and decreased subsequently. No significant between-group differences were observed in the number of oocytes retrieved (13.27 ±â€Š7.46 vs 13.1 ±â€Š7.98), number of viable embryos (5.57 ±â€Š3.27 vs 5 ±â€Š2.79), mature oocyte rate (90.14 ±â€Š11.81% vs 93.02 ±â€Š8.95%), and cleavage rate (97.69 ±â€Š6.22% vs 95.89 ±â€Š9.57%). The fertilization rate (76.11 ±â€Š19.04% vs 69.34 ±â€Š21.81%; P < 0.05), viable embryo rate per oocyte retrieved (39.85% vs 34.68%; P < 0.05), biochemical pregnancy rate (71.72% vs 56.67%; P < 0.05), clinical pregnancy rate (64.65% vs 51.65%; P < 0.05), and implantation rate (46.46% vs 31.35%; P < 0.05) in the study group were significant higher than those in the control group.This study shows that the Utrogestan and hMG protocol was feasible to improve the oocyte quality, possibly providing a new choice for PCOS patients undergoing IVF/ICSI treatments in combination with embryo cryopreservation.