Iron overload modulates follicular microenvironment via ROS/HIF-1α/FSHR signaling.

Iron is essential for the health of reproductive system, and women with iron overload suffer from ovarian dysfunction and lack effective treatment in fertility preservation. However, the underlying mechanism of the detrimental effects of iron overload on ovarian function remains ambiguous. Here, we confirmed the excess iron in the circumjacent follicle near endometriomas, which negatively impacted the oocyte development in the affected ovaries. Further, by integrating cell line and chronic iron overload mice model, we demonstrated that iron overload can function as a ROS inducer to amplify mitochondria damage, which significantly elevated the release of cytochrome C and ultimately induced the apoptosis of granular cells. Besides, for the first time, our findings revealed that disruption of HIF-1α/FSHR/CYP19A1 signaling was critical for decreased estrogen synthesis of granular cells in response to iron overload, which can lead to apparent oocyte maldevelopment and subfertility. Overall. this study uncovered that iron overload modulated the follicular microenvironment and generated a deleterious effect on female infertility via ROS/HIF-1α/FSHR signaling. These results might provide potential implications for future clinical risk management of patients with endometrioma and hemopathy.

A Validated Model for Individualized Prediction of Live Birth in Patients With Adenomyosis Undergoing Frozen-Thawed Embryo Transfer.

Purpose: This study aimed to develop a predictive tool for live birth in women with adenomyosis undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment. Methods: A total of 424 patients with adenomyosis who underwent frozen-thawed embryo transfer (FET) from January 2013 to December 2019 at a public university hospital were included. The patients were randomly divided into training (n = 265) and validation (n = 159) samples for the building and testing of the nomogram, respectively. Multivariate logistic regression (MLR) was developed on the basis of clinical covariates assessed for their association with live birth. Results: In total, 183 (43.16%) patients became pregnant, and 114 (26.88%) had a live birth. The MLR showed that the probability of live birth was significantly correlated with age [odds ratio (OR), 3.465; 95% confidence interval (CI), 1.215-9.885, P = 0.020], uterine volume (OR, 8.141; 95% CI, 2.170-10.542; P = 0.002), blastocyst transfer (OR, 3.231; 95% CI, 1.065-8.819, P = 0.023), twin pregnancy (OR, 0.328; 95% CI, 0.104-0.344, P = 0.005), and protocol in FET (P < 0.001). The statistical nomogram was built based on age, uterine volume, twin pregnancy, stage of the transferred embryo, and protocol of FET, with an area under the curve (AUC) of 0.837 (95% CI: 0.741-0.910) for the training cohort. The AUC for the validation cohort was 0.737 (95% CI: 0.661-0.813), presenting a well-pleasing goodness-of-fit and stability in this model. Conclusions: This visual and easily applied nomogram built on the risk factors of live birth in patients with adenomyosis provides useful and precise information for physicians on individualized decision-making during the IVF/ICSI procedure.

Ovarian Endometrioma Negatively Impacts Oocyte Quality and Quantity But Not Pregnancy Outcomes in Women Undergoing IVF/ICSI Treatment: A Retrospective Cohort Study.

Purpose: To determine the impact of ovarian endometrioma per se on in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) outcomes. Methods: This retrospective study was conducted using two groups. The endometrioma group consisted of 862 women with infertility who had ovarian endometriomas and underwent their first ovarian stimulation for IVF/ICSI treatment between January 2011 to December 2019 at a public university hospital. A non-endometrioma comparison group, comprising 862 women with other infertility factors, was matched according to maternal age, body mass index (BMI), and infertility duration. Ovarian reserve and response and IVF/ICSI and pregnancy outcomes between the two groups were analyzed. Multivariate logistic regression (MLR) analysis was conducted on the basis of clinical covariates assessed for their association with live birth. Results: The results showed that significantly lower antral follicle count (AFC), anti-Müllerian hormone (AMH), ovarian sensitivity index (OSI), oocyte maturation and fertilization rates, blastocyst rate, number of oocytes retrieved, and available embryos were found in women with endometrioma compared with the control, respectively (P < 0.05). The cumulative live birth rate per patient in women with endometrioma was lower than that of women without endometrioma (39.32% vs. 46.87%, P = 0.002). In women with endometrioma, those who underwent surgical intervention prior to IVF/ICSI treatment had higher maturation (86.03% vs. 83.42%, P = 0.003), fertilization (78.16% vs. 74.93%, P = 0.004), and top-quality embryo rates (42.94% vs. 39.93%, P = 0.097) but had fewer oocytes retrieved (8.01 ± 5.70 vs. 9.12 ± 6.69, P = 0.013) than women without surgery. However, live birth rates were comparable between women with endometrioma and women in the control group, regardless of whether they had a prior history of ovarian surgery. MLR analysis showed no correlation between endometrioma per se and live birth after being adjusted for number of top-quality embryos transferred and stage of embryo transfer. Conclusions: The data from this study supported the conclusion that ovarian endometrioma negatively impacts oocyte quality and quantity, but not overall pregnancy outcomes, in women undergoing IVF/ICSI treatment. Endometrioma lowers the cumulative live birth rate by decreasing the number of embryos. Surgical excision of endometrioma prior to IVF/ICSI can partly improve oocyte maturation and fertilization rates but not pregnancy outcomes.

Ultra-Long GnRH Agonist Protocol During IVF/ICSI Improves Pregnancy Outcomes in Women With Adenomyosis: A Retrospective Cohort Study.

Objective: This study aimed to compare the ultra-long gonadotropin-releasing hormone agonist (GnRH-a) protocol and the long GnRH-a protocol during in vitro fertilization (IVF) or intracytoplasmic sperm (ICSI) treatment on fertility outcomes in women with adenomyosis. Materials and Methods: This study was a retrospective cohort study. From January 2011 to May 2018, a total of 371 fresh IVF/ICSI cycles were included. Among the cycles included, 237 cycles of 212 women underwent the ultra-long GnRH-a protocol, while 134 cycles of 116 women underwent the long GnRH-a protocol. The rates of implantation, clinical pregnancy per embryo transfer, live birth, and early miscarriage were estimated between the compared protocols. Results: In the study, the early miscarriage rate in women undergoing the ultra-long GnRH-a protocol was significantly lower than those undergoing the long GnRH-a protocol (12.0% versus 26.5%, p = 0.045), whereas the differences in the rates of biochemical pregnancy, implantation, clinical pregnancy, and live birth in women between the two groups showed no statistical significance. The pregnancy outcomes were also sub-analyzed according to the adenomyotic region (diffuse and focal). As for diffuse adenomyosis, the rates of clinical pregnancy and live birth in women undergoing the ultra-long GnRH-a protocol were significantly higher than those undergoing the long GnRH-a protocol (55.3% versus 37.9%, p = 0.025; 43.4% versus 25.9%, p = 0.019, respectively). However, pregnancy outcomes showed no difference between the two protocols in women with focal adenomyosis. Conclusions: The ultra-long GnRH-a protocol during IVF/ICSI improves pregnancy outcomes in women with adenomyosis, especially in women with diffuse adenomyosis when compared with the long GnRH-a protocol.

Ferroptosis-Related Gene Signature Promotes Ovarian Cancer by Influencing Immune Infiltration and Invasion.

Ovarian cancer is a kind of gynecological malignancy with high mortality. Ferroptosis is a new type of iron-dependent cell death characterized by the formation of lipid peroxides and excessive accumulation of reactive oxygen species. Studies have shown that ferroptosis modulates tumor genesis, progression, and invasion, including ovarian cancer. Based on the mRNA expression data from TCGA, we construct a scoring system using consensus clustering analysis, univariate Cox regression analysis, and least absolute selection operator. Then, we systematically evaluate the relationship between score and clinical characteristics of ovarian cancer. The result from the prediction of biofunction pathways shows that score serves as an independent prognostic marker for ovarian cancer and affects tumor progression by modulating tumor metastasis. Moreover, immunocytes such as activated CD4 T cell, activated CD8 T cell, regulatory T cells, macrophage, and stromal cells, including adipocytes, epithelial cells, and fibroblast infiltrate more in the tumor microenvironment in a high-score group, indicating ferroptosis can also affect tumor immune landscape. Critically, four potentially sensitive drugs, including staurosporine, epothilone B, DMOG, and HG6-64-1 based on the scores, are predicted, and DMOG is recognized as a novel targeted drug for ovarian cancer. In general, we construct the scoring system based on ferroptosis-related genes that can predict the prognosis of ovarian cancer patients and propose that ferroptosis may affect ovarian cancer progression by mediating tumor metastasis and immune landscape. Novel drugs to target ovarian cancer are also predicted.

Development and validation of a model for individualized prediction of cervical insufficiency risks in patients undergoing IVF/ICSI treatment.

BACKGROUND: Women who conceived with in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) are more likely to experience adverse pregnancy outcomes than women who conceived naturally. Cervical insufficiency (CI) is one of the important causes of miscarriage and premature birth, however there is no published data available focusing on the potential risk factors predicting CI occurrence in women who received IVF/ICSI treatment. This study aimed to identify the risk factors that could be integrated into a predictive model for CI, which could provide further personalized and clinically specific information related to the incidence of CI after IVF/ICSI treatment. PATIENTS AND METHODS: This retrospective study included 4710 patients who conceived after IVF/ICSI treatment from Jan 2011 to Dec 2018 at a public university hospital. The patients were randomly divided into development (n = 3108) and validation (n = 1602) samples for the building and testing of the nomogram, respectively. Multivariate logistic regression was developed on the basis of pre-pregnancy clinical covariates assessed for their association with CI occurrence. RESULTS: A total of 109 patients (2.31%) experienced CI among all the enrolled patients. Body mass index (BMI), basal serum testosterone (T), gravidity and uterine length were associated with CI occurrence. The statistical nomogram was built based on BMI, serum T, gravidity and uterine length, with an area under the curve (AUC) of 0.84 (95% confidence interval: 0.76-0.90) for the developing cohort. The AUC for the validation cohort was 0.71 (95% confidence interval: 0.69-0.83), showing a satisfactory goodness-of-fit and discrimination ability in this nomogram. CONCLUSION: The user-friendly nomogram which graphically represents the risk factors and a pre-pregnancy predicted tool for the incidence of CI in patients undergoing IVF/ICSI treatment, provides a useful guide for medical staff on individualized decisions making, where preventive measures could be carried out during the IVF/ICSI procedure and subsequent pregnancy.

The prevalence of cervical insufficiency in Chinese women with polycystic ovary syndrome undergone ART treatment accompanied with negative prognosis: a retrospective study.

The objective of this study was to explore the correlation between cervical insufficiency (CI) and polycystic ovary syndrome (PCOS) in Chinese women undergoing assisted reproductive technology (ART) treatment. The retrospective study enrolled 2978 women including 1489 with PCOS and 1489 without PCOS, among which 34 women were diagnosed with CI (1.14%). The prevalence of CI in PCOS women was statistically higher than that in women without PCOS. Among those women with CI, 23 cases exhibited PCOS, and those cases had an average gestational age of 26.09 ± 5.91 weeks at the end of pregnancy, which was earlier than that of women without PCOS, and the pregnancy outcomes were worse than in the non-PCOS group though not statistically significant. Multivariable logistic regression showed that PCOS status (odds ratio: 2.050, 95% confidence interval: 1.009-4.206) were associated with increased risk of CI. Our study revealed that among those Chinese women who conceived by ART treatment, the prevalence of CI in women with PCOS was higher than that in women without PCOS. Co-morbidity of CI with polycystic ovarian syndrome negatively impacts prognosis.Impact statementWhat is already known on this subject? Women with PCOS have a higher rate of adverse obstetrical outcomes than women without PCOS.What the results of this study add? Women with PCOS were more likely to have pregnancies complicated with CI. Co-morbidity of cervical incompetence with PCOS negatively impacts prognosis.What the implications are of these findings for clinical practice and/or further research? Given these results, close surveillance of cervical changes during the second trimester in women with PCOS is necessary for reducing the risk of miscarriage related to CI.

The Effect of Growth Hormone on the Clinical Outcomes of Poor Ovarian Reserve Patients Undergoing in vitro Fertilization/Intracytoplasmic Sperm Injection Treatment: A Retrospective Study Based on POSEIDON Criteria.

The aim of this retrospective analysis is to explore whether growth hormone (GH) pretreatment is beneficial for patients with poor ovarian reserve undertaking in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment. Poor ovarian reserve patients with anti-Mullerian hormone (AMH) <1.2 ng/mL were recruited and divided into the GH adjuvant group (GH+ group) and the counterpart without GH pretreatment (GH- group). One-to-one case-control matching was performed to adjust essential confounding factors between the GH+ group and GH- group. A total of 676 cycles were included in the present study with 338 cycles in each group. Conventional ovarian stimulation protocols were applied for ART treatment. Patients were further divided into POSEIDON group 3 (PG3, age <35 years) and POSEIDON group 4 (PG4, age ≥35 years), based on POSEIDON criteria. The demographic data, cycle characteristics, and clinical outcomes between the GH+ group and GH- group, as well as in the further stratified analysis of PG3 and PG4 were compared. GH adjuvant showed a beneficial effect on the ovarian response and live birth rate in poor ovarian reserve patients. Further stratification revealed that in PG4, there was a significantly increased number of good-quality embryos in the GH+ group compared to the GH- group (1.58 ± 1.71 vs. 1.25 ± 1.55, P = 0.032), accompanied by a reduced miscarriage rate and a greatly improved live birth rate (29.89 vs. 17.65%, P = 0.028). GH adjuvant failed to promote the live birth rate in PG3. In conclusion, GH pretreatment is advantageous by elevating ovarian response and correlated with an improved live birth rate and reduced miscarriage rate in POSEIDON poor ovarian reserve patients older than 35.

Six-week pretreatment with growth hormone improves clinical outcomes of poor ovarian responders undergoing in vitro fertilization treatment: A self-controlled clinical study.

AIM: The purpose was to explore whether the 6 weeks of growth hormone (GH) pretreatment could increase the live birth rate of poor ovarian responders (POR). METHODS: This self-controlled, retrospective study was performed among 380 POR who had GH adjuvant (GH+) at a university-affiliated hospital in Guangzhou, China, from October 2010 to April 2016. Growth hormone was injected daily beginning with the previous menstruation and maintained until ovum pickup, for approximately 6 weeks. Clinical variables between the GH+ cycle and the other GH-free (GH-) cycle of each patient were compared. Both cycles were conducted with a similar conventional control ovarian hyperstimulation protocol for in vitro fertilization treatment. One to one case-control matching was performed to adjust essential confounding factors between GH+ cycles and GH- cycles. RESULTS: GH pretreatment improved embryo quality (1.14 ± 1.50 vs 0.11 ± 0.48, P < 0.05) and decreased miscarriage (18.8% vs 80.0%, P < 0.05) significantly, resulting in an increase in the live birth rate (23.5% vs 3.9%, P < 0.05). The oocyte utilization rate in GH+ cycles was remarkably improved, even with older patients and more failed previous attempts. Significant improvement in embryo quality was shown by an increased number of good-quality embryos and improved oocyte utilization rate after matching. CONCLUSIONS: The longer term use of low-dose GH administration for 6 weeks could be beneficial for the utilization of oocytes and for finally increasing the live birth rates of POR.