Metabolic Syndrome Rather Than Other Phenotypes in PCOS as a Predictive Indicator for Clinical Outcomes in IVF: Comprehensive Phenotypic Assessment across All PCOS Classifications.

Polycystic ovary syndrome (PCOS) is a well-recognized, multi-system metabolic disorder affecting fertility. Although various classification methods have been proposed to assess the phenotypic heterogeneity of PCOS, there is currently no reliable phenotype for predicting clinical IVF outcomes. This retrospective study, as a comprehensive phenotypic assessment across all PCOS classifications, aimed to identify dependable phenotypes that can serve as predictors for IVF and pregnancy outcomes. The study included 1313 PCOS patients who received their initial IVF treatment between January 2019 and December 2021. The phenotypes reflect the diverse metabolic and hormonal characteristics in this study. Phenotype A, within the Rotterdam criteria classification, exhibited the highest anti-Müllerian hormone levels (AMH), while phenotype D displayed the lowest Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) values. Both the hyperandrogenism (HA) phenotype within HA-based classification and the overweight phenotype within the body-mass-index-based classification showed increased HOMA-IR and metabolic syndrome (MetS). The MetS phenotype had higher free androgen index and a lower AMH. Notably, the MetS-based classification system demonstrated an independent association of MetS with cumulative live birth, preterm birth, and gestational diabetes mellitus as a contributing risk factor for PCOS patients undergoing IVF (p < 0.05). These findings carry noteworthy implications for advancing clinical management strategies for PCOS.

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.

Effects of Infertility Drug Exposure on the Risk of Borderline Ovarian Tumors: A Systematic Review and Meta-Analysis.

Whether infertility drug exposure increases the risk of borderline ovarian tumors (BOTs) remains controversial. The present study was conducted with a comprehensive search for studies published from January 1990 to December 2021 in the online databases Cochrane Library, PubMed, Web of Science and EMBASE. We considered the first diagnosis of a BOT as the primary outcome. The odds ratio (OR) was calculated with corresponding 95% confidence intervals (CIs) for the risk of BOTs in patients who were treated with infertility drugs. Ten studies, a total of 2,779,511 women, qualified for inclusion in this meta-analysis. The pooled OR of 1.56 (95% CI: 1.09-2.22) revealed a significant positive association between infertility drugs and an increased risk for BOTs, but for specific drugs, only CC plus Gn had statistical significance. No publication bias was detected using the Egger and Begg tests (p > 0.05). A significant difference in BOT incidence was observed among infertile women and nulliparous women who were treated with or without infertility drugs. In conclusion, the use of infertility drugs may increase the risk of BOTs, but a dose-dependent relationship was not observed between the number of assisted reproduction technology cycles and the risk of BOTs, and infertile women who successfully became pregnant might have a reduced risk. Registration: PROSPERO, CRD42022330775.

Adiposity and lipid metabolism indicators mediate the adverse effect of glucose metabolism indicators on oogenesis and embryogenesis in PCOS women undergoing IVF/ICSI cycles.

BACKGROUND: Polycystic ovary syndrome (PCOS) women have high incidences of dyslipidemia, obesity, impaired glucose tolerance (IGT), diabetes, and insulin resistance (IR) and are fragile to female infertility. Obesity and dyslipidemia may be the intermediate biological mechanism for the associations between glucose metabolism dysfunction and abnormal oogenesis and embryogenesis. METHODS: This retrospective cohort study was performed at a university-affiliated reproductive center. A total of 917 PCOS women aged between 20 and 45 undergoing their first IVF/ICSI embryo transfer cycles from January 2018 to December 2020 were involved. Associations between glucose metabolism indicators, adiposity and lipid metabolism indicators, and IVF/ICSI outcomes were explored using multivariable generalized linear models. Mediation analyses were further performed to examine the potential mediation role of adiposity and lipid metabolism indicators. RESULTS: Significant dose-dependent relationships were found between glucose metabolism indicators and IVF/ICSI early reproductive outcomes and between glucose metabolism indicators and adiposity and lipid metabolism indicators (all P < 0.05). Also, we found significant dose-dependent relationships between adiposity and lipid metabolism indicators and IVF/ICSI early reproductive outcomes (all P < 0.05). The mediation analysis indicated that elevated FPG, 2hPG, FPI, 2hPI, HbA1c, and HOMA2-IR were significantly associated with decreased retrieved oocyte count, MII oocyte count, normally fertilized zygote count, normally cleaved embryo count, high-quality embryo count, or blastocyst formation count after controlling for adiposity and lipid metabolism indicators. Serum TG mediated 6.0-31.0% of the associations; serum TC mediated 6.1-10.8% of the associations; serum HDL-C mediated 9.4-43.6% of the associations; serum LDL-C mediated 4.2-18.2% of the associations; and BMI mediated 26.7-97.7% of the associations. CONCLUSIONS: Adiposity and lipid metabolism indicators (i.e., serum TG, serum TC, serum HDL-C, serum LDL-C, and BMI) are significant mediators of the effect of glucose metabolism indicators on IVF/ICSI early reproductive outcomes in PCOS women, indicating the importance of preconception glucose and lipid management and the dynamic equilibrium of glucose and lipid metabolism in PCOS women.

Nomogram for Predicting Live Birth after the First Fresh Embryo Transfer in Patients with PCOS Undergoing IVF/ICSI Treatment with the GnRH-Ant Protocol.

Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility. A better understanding of factors associated with pregnancy outcomes and successful prediction of live birth after IVF/ICSI are important to guide clinical practice. This was a retrospective cohort study investigating live birth after the first fresh embryo transfer using the GnRH-ant protocol in patients with PCOS between 2017 and 2021 at the Reproductive Center of Peking University Third Hospital. A total of 1018 patients with PCOS were qualified for inclusion in this study. BMI, AMH level, initial FSH dosage, serum LH and progesterone levels on the hCG trigger day, and endometrial thickness were all independent predictors of live birth. However, age and infertility duration were not significant predictors. We developed a prediction model based on these variables. The predictive ability of the model was demonstrated well, with areas under the curve of 0.711 (95% CI, 0.672-0.751) and 0.713 (95% CI, 0.650-0.776) in the training cohort and validation cohort, respectively. Additionally, the calibration plot showed good agreement between the prediction and the observation (p = 0.270). The novel nomogram could be helpful for clinicians and patients in clinical decision-making and outcome evaluation.

Idiopathic retroperitoneal fibrosis with endometrial cancer: a case report and literature review.

BACKGROUND: Retroperitoneal fibrosis is a rare disease characterized by chronic nonspecific inflammation, which leads to clinical compression manifestations of retroperitoneal organs especially ureter. Approximately 70 percent of retroperitoneal fibrosis cases are idiopathic which has no clear etiology. This study reported a rare case of a 48-year-old woman presented with idiopathic retroperitoneal fibrosis and endometrial cancer. CASE PRESENTATION: A 48-year-old woman presented with irregular vaginal bleeding without abdominal pain, bloating or discomfort. The patient was diagnosed iRPF after splenectomy 13 years ago. Then she took prednisone for 2 years and took tamoxifen for about 11 years. She stopped taking the medication from October 2019 to May 2020 and then started taking tamoxifen again until November 2020. Two weeks after she stopped taking tamoxifen, she presented with irregular vaginal bleeding. Gynecological ultrasound revealed a thick endometrium with uneven echo enhancement and blood flow signals. Then diagnostic curettage was performed with pathological examination showed endometroid carcinoma. Later, the patient was admitted to Peking University Third Hospital for surgery. Preoperative imaging examinations, including CT, MRI, and PET/CT, all showed pelvic enlarged lymph nodes and they were highly suspected to have lymph node metastasis. The patient underwent laparoscopic surgical staging and enlarged lymph nodes in the pelvic and aortic regions were removed. Finally, the pathology confirmed that endometrioid adenocarcinoma and fibrosis, but there was no tumor infiltration in these enlarged lymph nodes. The patient is now in good condition. CONCLUSION: This case report stressed the difficulty to distinguish between lymph node metastasis and inflammatory hyperplasia by common imaging methods. Due to increased surgical difficulty among retroperitoneal patients, lymphadenectomy should be carefully evaluated to avoid additional surgical complications and over-treatment.

Effectiveness of High-risk Human Papillomavirus Testing for Cervical Cancer Screening in China: A Multicenter, Open-label, Randomized Clinical Trial.

IMPORTANCE: Evidence is needed regarding the introduction of high-risk human papillomavirus (hrHPV) testing into China's national cervical cancer screening program. OBJECTIVE: To evaluate hrHPV testing as a new screening modality for the national program. DESIGN, SETTING, AND PARTICIPANTS: This population-based, multicenter, open-label, randomized clinical trial took place across 20 primary health care centers in urban and rural areas across China. At least 3000 women aged 35 to 64 years per site were invited to participate, for a total of 60 732 women evaluated. INTERVENTIONS: At baseline, women were randomly assigned to cytology, hrHPV testing, or visual inspection with acetic acid and Lugol iodine (VIA/VILI) (rural only). Women who tested positive for hrHPV were randomized into cytology-triage, VIA/VILI-triage (rural only), or direct colposcopy arms. Regarding primary or triaging tests, women with cytological abnormalities or who tested positive with VIA/VILI were referred to colposcopy. After 24 months, combined screening of cytology, hrHPV testing, and VIA/VILI was performed, and all women with positive results were referred to colposcopy. MAIN OUTCOMES AND MEASURES: The primary outcomes were cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and CIN3+ yields. The secondary outcome was colposcopy referral rate. RESULTS: A total of 60 732 women were included in this study, with median (interquartile range) age of 47 (41-52) years. Among urban women, 8955 were randomized to cytology and 18 176 to hrHPV genotyping; among rural women, 11 136 were randomized to VIA/VILI, 7080 to cytology, and 15 385 to hrHPV testing. Participants who tested positive for hrHPV with direct colposcopy had higher risk ratios for disease yields at baseline (urban hrHPV vs cytology, CIN2+ 2.2 [95% CI, 1.6-3.2] and CIN3+ 2.0 [95% CI, 1.2-3.3]; rural hrHPV vs cytology, 2.6 [95% CI, 1.9-4.0] and 2.7 [95% CI, 2.0-3.6]; rural hrHPV vs VIA/VILI, 2.0 [95% CI, 1.6-2.3] and 2.3 [95% CI, 1.8-3.1]). At 24 months, baseline-negative women in the hrHPV arm had significantly lower risk ratios than those with cytology, or VIA/VILI for CIN2+ (0.3 [95% CI, 0.2-0.5], 0.3 [95% CI, 0.2-0.6]) and CIN3+ (0.3 [95% CI, 0.1-0.6], 0.4 [95% CI, 0.2-0.8]) in rural sites. The colposcopy referral rate for hrHPV-positive rural women was reduced to 2.8% by cytology triage, with significantly higher CIN2+ yields than cytology (2.1 [95% CI, 1.3-2.6]) or VIA/VILI arm (1.6 [95% CI, 1.03-2.1]). Genotyping for hrHPV with cytology triage significantly reduced the colposcopy referral rate compared with cytology (0.8 [95% CI, 0.7-0.9]) for urban women. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, testing for hrHPV was an effective primary screening method in primary health care centers. Incorporating hrHPV testing (polymerase chain reaction-based for urban areas, hybrid capture-based for rural areas) into China's national screening program is reasonable. TRIAL REGISTRATION: Chinese Clinical Trial Registry Identifier: ChiCTR1900022530.

Integrated Analysis To Identify Molecular Biomarkers Of High-Grade Serous Ovarian Cancer.

PURPOSE: Ovarian cancer is the leading cause of gynecologic cancer-related death worldwide. Early diagnosis of ovarian cancer can significantly improve patient prognosis. Hence, there is an urgent need to identify key diagnostic and prognostic biomarkers specific for ovarian cancer. Because high-grade serous ovarian cancer (HGSOC) is the most common type of ovarian cancer and accounts for the majority of deaths, we identified potential biomarkers for the early diagnosis and prognosis of HGSOC. METHODS: Six datasets (GSE14001, GSE18520, GSE26712, GSE27651, GSE40595, and GSE54388) were downloaded from the Gene Expression Omnibus database for analysis. Differentially expressed genes (DEGs) between HGSOC and normal ovarian surface epithelium samples were screened via integrated analysis. Hub genes were identified by analyzing protein-protein interaction (PPI) network data. The online Kaplan-Meier plotter was utilized to evaluate the prognostic roles of these hub genes. The expression of these hub genes was confirmed with Oncomine datasets and validated by quantitative real-time PCR and Western blotting. RESULTS: A total of 103 DEGs in patients with HGSOC-28 upregulated genes and 75 downregulated genes-were successfully screened. Enrichment analyses revealed that the upregulated genes were enriched in cell division and cell proliferation and that the downregulated genes mainly participated in the Wnt signaling pathway and various metabolic processes. Ten hub genes were associated with HGSOC pathogenesis. Seven overexpressed hub genes were partitioned into module 1 of the PPI network, which was enriched in the cell cycle and DNA replication pathways. Survival analysis revealed that MELK, CEP55 and KDR expression levels were significantly correlated with the overall survival of HGSOC patients (P < 0.05). The RNA and protein expression levels of these hub genes were validated experimentally. CONCLUSION: Based on an integrated analysis, we propose the further investigation of MELK, CEP55 and KDR as promising diagnostic and prognostic biomarkers of HGSOC.

The roles of metallothioneins in carcinogenesis.

Metallothioneins (MTs) are small cysteine-rich proteins that play important roles in metal homeostasis and protection against heavy metal toxicity, DNA damage, and oxidative stress. In humans, MTs have four main isoforms (MT1, MT2, MT3, and MT4) that are encoded by genes located on chromosome 16q13. MT1 comprises eight known functional (sub)isoforms (MT1A, MT1B, MT1E, MT1F, MT1G, MT1H, MT1M, and MT1X). Emerging evidence shows that MTs play a pivotal role in tumor formation, progression, and drug resistance. However, the expression of MTs is not universal in all human tumors and may depend on the type and differentiation status of tumors, as well as other environmental stimuli or gene mutations. More importantly, the differential expression of particular MT isoforms can be utilized for tumor diagnosis and therapy. This review summarizes the recent knowledge on the functions and mechanisms of MTs in carcinogenesis and describes the differential expression and regulation of MT isoforms in various malignant tumors. The roles of MTs in tumor growth, differentiation, angiogenesis, metastasis, microenvironment remodeling, immune escape, and drug resistance are also discussed. Finally, this review highlights the potential of MTs as biomarkers for cancer diagnosis and prognosis and introduces some current applications of targeting MT isoforms in cancer therapy. The knowledge on the MTs may provide new insights for treating cancer and bring hope for the elimination of cancer.

An unexpected invasive hydatidiform mole in a rudimentary uterine horn: A case report.

Rudimentary horns of the uterus develop as a result of a partial non-development of one Müllerian duct, a type of congenital uterine anomaly. Pregnancy in a rudimentary horn is uncommon and the outcome tends to be poor, with the majority of cases resulting in rupture between 10 and 15 gestational weeks, with significant risk of morbidity and mortality. Regardless of the availability of imagiological procedures and the advances being made in this field, the diagnosis of this type of ectopic pregnancy often only occurs during laparotomy or laparoscopy subsequent to abdominal pain and collapse. The present study describes a rare case of a uterine rudimentary horn pregnancy. The case was diagnosed by the high serum ß-HCG level, imageological results and dissection of the final pathological specimen, by combined hysteroscopy and laparoscopy. An ultrasound illustrated a suspicious gestational trophoblastic disease in the rudimentary uterine horn, with a rich blood flow signal at the right side of the uterus. A pelvic magnetic resonance image indicated that there was endometrial thickening and gestational trophoblastic disease in the rudimentary uterine horn. The patient was treated with surgery, including rudimentary horn dissection and diagnostic curettage; the ipsilateral adnexa was conserved as it appeared to be normal. Due to the apparent decline of the serum ß-HCG level and the reluctance for chemotherapy, the patient chose to undergo no further treatment and closed follow-up. At the time of writing, the patient is in a good condition. Only a small number of reports of a horn pregnancy with invasive hydatidiform mole are described by other studies, thereby increasing the clinical significance of this case.

Role of Lymphadenectomy for Uterine Sarcoma: A Meta-Analysis.

OBJECTIVE: Uterine sarcomas are rare, highly aggressive tumors with an unfavorable prognosis. The role of lymphadenectomy (LAD) remains controversial for this particular tumor type. To examine whether LAD can assist in prognosis or clinical benefits for uterine sarcoma patients, we performed a meta-analysis based on published studies. METHODS: We initially identified published studies by searching the PubMed database up to 30 November 2015. Study quality was evaluated systematically using the Newcastle-Ottawa Scale for assessing the quality of studies for inclusion in meta-analyses. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated using Stata software version 12.0. RESULTS: Our search retrieved 14 eligible studies, involving a total of 4867 patients, including 1356 (27.9%) patients who had LAD. The pooled RR for uterine leiomyosarcoma (uLMS) in patients with LAD in 5 trials was 0.90 (95% CI, 0.62-1.31) and for endometrial stromal sarcoma (ESS) in 11 trials was 0.96 (95% CI, 0.69-1.34), suggesting that there was no significant benefit of LAD in improving overall survival (P < 0.05). A random-effects model was chosen to estimate the RRs in view of the significant heterogeneity in the included studies (uLMS: Cochran Q test: P = 0.022, I = 64.9%; ESS: Cochran Q test: P = 0.005, I = 60.1%). No publication bias was detected by the Egger and Begg tests (uLMS: Begg: P = 0.221, Egger: P = 0.148; ESS: Begg: P = 1.000, Egger: P = 0.928). CONCLUSIONS: Based on currently available evidence, the findings of this meta-analysis suggest that LAD bears little prognostic or therapeutic benefit in patients with uterine sarcoma. Systematic LAD may not be recommended in patients with uLMS or ESS unless the patient has obvious extrauterine involvement, clinically suspicious enlarged nodes, or advanced sarcomas.

DHA2, a synthesized derivative of bisbibenzyl, exerts antitumor activity against ovarian cancer through inhibition of XIAP and Akt/mTOR pathway.

The analysis of dihydroptychantol (DHA) and its chemically synthesized macrocyclic bisbibenzyl derivatives (DHA1, 2 and 3) led to the selection of DHA2 as a potential drug candidate for ovarian cancer. The exposure of ovarian cancer SKOV3 cells to DHA2 resulted in the downregulation of the anti-apoptotic X-linked inhibitor of apoptosis protein (XIAP) and Bcl-2 and led to caspase-independent cell death. The overexpression of XIAP reversed DHA2-induced cell death, and the depletion of XIAP had the opposite effect. DHA2 could induce autophagy, as evidenced by increases in the formation of acidic vesicular organelles and the processing of LC3B-I to LC3B-II. Pretreatment with autophagy inhibitors potentiated DHA2-mediated cell death. We showed that typical PI3K/Akt signaling was involved in DHA2-mediated cell death. The overexpression of Akt almost completely reversed DHA2-induced cell death, and the inactivation of Akt significantly facilitated DHA2-induced cell death. The administration of DHA2 to xenograft mice reduced tumor growth by causing Akt inactivation, the conversion of LC3B and proliferation inhibition. Our study demonstrates that the inhibition of XIAP and the inactivation of Akt/mTOR facilitate the efficacy of DHA2 in ovarian cancer cells.

Riccardin D Exerts Its Antitumor Activity by Inducing DNA Damage in PC-3 Prostate Cancer Cells In Vitro and In Vivo.

We recently reported that Riccardin D (RD) was able to induce apoptosis by targeting Topo II. Here, we found that RD induced cell cycle arrest in G2/M phase in PC-3 cells, and caused remarkable DNA damage as evidenced by induction of γH2AX foci, micronuclei, and DNA fragmentation in Comet assay. Time kinetic and dose-dependent studies showed that ATM/Chk2 and ATR/Chk1 signaling pathways were sequentially activated in response to RD. Blockage of ATM/ATR signaling led to the attenuation of RD-induced γH2AX, and to the partial recovery of cell proliferation. Furthermore, RD exposure resulted in the inactivation of BRCA1, suppression of HR and NHEJ repair activity, and downregulation of the expressions and DNA-end binding activities of Ku70/86. Consistent with the observations, microarray data displayed that RD triggered the changes in genes responsible for cell proliferation, cell cycle, DNA damage and repair, and apoptosis. Administration of RD to xenograft mice reduced tumor growth, and coordinately caused alterations in the expression of genes involved in DNA damage and repair, along with cell apoptosis. Thus, this finding identified a novel mechanism by which RD affects DNA repair and acts as a DNA damage agent in prostate cancer.