Development and validation of a predictive model of abnormal uterine bleeding associated with ovulatory dysfunction: a case-control study.

BACKGROUND: Abnormal uterine bleeding associated with ovulatory dysfunction (AUB-O) is a typical gynecological disease that can affect women of various ages. Being able to identify women at risk of AUB-O could allow physicians to take timely action. This study aimed to identify the influencing factors of AUB-O in Chinese women, and then develop and validate a predictive model. METHODS: In this multicenter case-control study, 391 women with AUB-O and 838 controls who came from nine hospitals in Zhejiang province were recruited between April 2019 and January 2022. All the participants completed a structured questionnaire including general characteristics, lifestyle and habits, menstrual and reproductive history, and previous diseases. The predictive model was developed on a group of 822 women and validated on a group of 407 women. Logistic regression was adopted to investigate the influencing factors and develop the model, and validation was then performed. RESULTS: The independent predictive factors of AUB-O were age (OR 1.073, 95% CI 1.046-1.102, P < 0.001), body mass index (OR 1.081, 95% CI 1.016-1.151, P = 0.015), systolic blood pressure (OR 1.016, 95% CI 1.002-1.029, P = 0.023), residence (OR 2.451, 95% CI 1.727-3.478, P < 0.001), plant-based diet (OR 2.306, 95% CI 1.415-3.759, P < 0.001), fruits eating (OR 1.887, 95% CI 1.282-2.776, P = 0.001), daily sleep duration (OR 0.819; 95% CI 0.708-0.946, P = 0.007), multiparous (parity = 1, OR 0.424, 95% CI 0.239-0.752, P = 0.003; parity > 1, OR 0.450, 95% CI 0.247-0.822, P = 0.009), and history of ovarian cyst (OR 1.880, 95% CI 1.305-2.710, P < 0.001). The predictive ability (area under the curve) in the development group was 0.77 (95% CI 0.74-0.81), while in the validation group it was 0.73 (95% CI 0.67-0.79). The calibration curve was in high coincidence with the standard curve in the development group, and similar to the validation group. A tool for AUB-O risk calculation was created. CONCLUSIONS: Nine influencing factors and a predictive model were proposed in this study, which could identify women who are at high risk of developing AUB-O. This finding highlights the importance of early screening and the lifelong management of ovulatory disorders for women.

Association between serum vitamin A levels and premature ovarian insufficiency: a case-control, cross-sectional survey study.

BACKGROUND: Although vitamin A is known to play an important role in ovarian function, its association with ovarian insufficiency has not been reported yet. Therefore, the aim of the study was to explore the association between serum vitamin A levels and premature ovarian insufficiency (POI). METHODS: This cross-sectional survey included women with POI (n = 47) and normo-ovulatory controls (n = 67) who were enrolled between December 2016 and May 2018 in Zhejiang, China. The serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), anti-Müllerian hormone (AMH), vitamin A, and total cholesterol (TC) were measured for each participant. The association of TC-adjusted vitamin A levels with the risk of POI was assessed using binary logistic regression analysis. RESULTS: Serum vitamin A levels appeared to be slightly higher in the POI group than in the control group, but there was no evidence of a statistically significant difference (728.00 ± 176.00 µg/L vs. 503.93 ± 145.64 µg/L, p = 0.13). After adjustment for serum lipid levels, the serum vitamin A/TC ratio was significantly lower in the POI group than in the control group (143.14 ± 35.86 vs. 157.56 ± 35.21 µg/mmol, p = 0.04). Further, the serum vitamin A/TC ratio was significantly and inversely associated with POI risk (unadjusted odds ratio [OR] = 0.988, 95% confidence interval [CI]: 0.977-0.999, p = 0.04). The association remained after adjusting for confounding factors (age, BMI, annual household income, and education) (OR = 0.986, 95% CI: 0.972-0.999, p = 0.04). CONCLUSIONS: Serum vitamin A/TC ratio was inversely associated with POI risk. Therefore, the serum vitamin A/TC ratio may serve as a predictive factor for POI, and vitamin A supplementation may play help prevent or treat POI.

Metabolic profile of women with premature ovarian insufficiency compared with that of age-matched healthy controls.

OBJECTIVE: . To compare the metabolic profile of women with spontaneous premature ovarian insufficiency (POI) with that of age-matched healthy controls. STUDY DESIGN: . A cross-sectional case-control study was conducted using 1:1 matching by age. Women below the age of 40 with spontaneous POI who did not receive any medication (n = 303) and age-matched healthy women (n = 303) were included in this study. MAIN OUTCOME MEASURES: . Metabolic profiles, including serum levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), glucose, uric acid, urea and creatinine, were compared between women with POI and controls. For women with POI, factors associated with the metabolic profile were analyzed. RESULTS: . Women with POI were more likely to exhibit increased serum levels of TG (ß, 0.155; 95% CI, 0.086, 0.223) and glucose (0.067; 0.052, 0.083), decreased levels of HDL-C (-0.087; -0.123, -0.051), LDL-C (-0.047; -0.091, -0.003) and uric acid (-0.053; -0.090, -0.015), and impaired kidney function (urea [0.070; 0.033, 0.107]; creatinine [0.277; 0.256, 0.299]; eGFR [-0.234; -0.252, -0.216]) compared with controls after adjusting for age and BMI. BMI, parity, gravidity, FSH and E2 levels were independent factors associated with the metabolic profile of women with POI. CONCLUSION: . Women with POI exhibited abnormalities in lipid metabolism, glucose metabolism, and a decrease in kidney function. In women with POI, early detection and lifelong management of metabolic abnormalities are needed.

Label-free proteomics uncovers SMC1A expression is Down-regulated in AUB-E.

BACKGROUND: While heavy menstrual bleeding (HMB) is a prevalent symptom among women with abnormal uterine bleeding caused by endometrial disorder (AUB-E) seeking gynecologic care, the primary endometrial disorder remains poorly understood. METHODS: Five human endometrial samples from women with AUB-E and the age-matched healthy women were selected, respectively. Proteins from the samples were analyzed by a linear ion trap (LTQ)-Orbitrap Elite mass spectrometer based label-free proteomic approach. The purpose protein was validated by western blot and immunohistochemistry staining. RESULTS: A total of 2353 protein groups were quantified under highly stringent criteria with a false discovery rate of < 1% for protein groups, and 291 differentially expressed proteins were significantly changed between the two groups. The results showed that the down-regulation of structural maintenance of chromosomes protein 1A (SMC1A) in AUB-E patients. Next, this change in the glandular epithelial cells was validated by immunohistochemistry. CONCLUSION: The results indicated a novel mechanism for the cause of AUB-E, as down-expression SMC1A potentially regulated the cell cycle progression in endometrial glandular epithelium further led to bleeding.

Crosstalk between the muscular estrogen receptor α and BDNF/TrkB signaling alleviates metabolic syndrome via 7,8-dihydroxyflavone in female mice.

OBJECTIVE: 7,8-Dihydroxyflavone (7,8-DHF), a small molecular mimetic of brain-derived neurotrophic factor (BDNF), alleviates high-fat diet-induced obesity in female mice in a sex-specific manner by activating muscular tropomyosin-related kinase B (TrkB). However, the underlying molecular mechanism for this sex difference is unknown. Moreover, muscular estrogen receptor α (ERα) plays a critical role in metabolic diseases. Impaired ERα action is often accompanied by metabolic syndrome (MetS) in postmenopausal women. This study investigated whether muscular ERα is involved in the metabolic effects of 7,8-DHF. METHODS: For the in vivo studies, 72 female C57BL/6J mice were given a low-fat diet or high-fat diet, and both received daily intragastric administration of vehicle or 7,8-DHF for 24 weeks. The hypothalamic-pituitary-ovarian (HPO) axis function was assessed by investigating typical sex-related serum hormones and the ovarian reserve. Indicators of menopausal MetS, including lipid metabolism, insulin sensitivity, bone density, and serum inflammatory cytokines, were also evaluated. The expression levels of ERα and other relevant signaling molecules were also examined. In vitro, the molecular mechanism involved in the interplay of ERα and TrkB receptors was verified in differentiated C2C12 myotubes using several inhibitors and a lentivirus short hairpin RNA-knockdown strategy. RESULTS: Long-term oral administration of 7,8-DHF acted as a protective factor for the female HPO axis function, protecting against ovarian failure, earlier menopause, and sex hormone disorders, which was paralleled by the alleviation of MetS coupled with the production of ERα-rich, TrkB-activated, and uncoupling protein 1 (UCP1) high thermogenic skeletal muscle tissues. 7,8-DHF-stimulated transactivation of ERα at serine 118 (S118) and tyrosine 537 (Y537), which was crucial to activate the BDNF/TrkB signaling cascades. In turn, activation of BDNF/TrkB signaling was also required for the ligand-independent activation of ERα, especially at the Y537 phosphorylation site. In addition, Src family kinases played a core role in the interplay of ERα and TrkB, synergistically activating the signaling pathways related to energy metabolism. CONCLUSIONS: These findings revealed a novel role of 7,8-DHF in protecting the function of the female HPO axis and activating tissue-specific ERα, which improves our understanding of this sex difference in 7,8-DHF-mediated maintenance of metabolic homeostasis and provides new therapeutic strategies for managing MetS in women.

Single-nucleotide polymorphisms of the IL-12 gene lead to a higher cancer risk: a meta-analysis based on 22,670 subjects.

The associations between interleukin-12 (IL-12) gene polymorphisms and cancer risk have been discussed extensively, with controversial results. Therefore, we conducted the present meta-analysis to better assess the potential roles of IL-12 gene variation in cancer occurrence. Eligible articles were found via PubMed, Medline, EMBASE, Google Scholar and CNKI. Odds ratios and 95% confidence intervals were used to evaluate the associations between IL-12 gene polymorphisms and cancer risk. Thirty-one studies with 10,749 cancer patients and 11,921 healthy subjects were included in the analyses. The overall results showed that cancer risk was increased by IL-12A rs568408 (GG versus GA + AA: P = 0.004; G versus A: P = 0.005) and IL-12B rs3212227 (AA versus AC + CC: P = 0.004; CC versus AA + AC: P = 0.03; A versus C: P = 0.007) polymorphisms. Further subgroup analyses for IL-12A rs568408 and IL-12B rs3212227 revealed that the positive results could be impacted by the ethnicity of the population, cancer type and/or genotyping methods. However, we failed to detect any significant associations between the IL-12A rs2243115 polymorphism and cancer risk in either the overall or the subgroup analyses. The current study suggests that certain IL-12 gene polymorphisms serve as biological markers of cancer susceptibility.

Associations of common IL-4 gene polymorphisms with cancer risk: A meta-analysis.

Cancer incidence is dramatically increasing worldwide, therefore improved prediction and therapeutic methods are needed. Single nucleotide polymorphisms in cytokine genes may contribute to carcinogenesis. Interleukin (IL)­4 gene polymorphisms have been intensively studied with regard to their associations with cancer. However, the results of these previous studies remain inconclusive. The present study, therefore, aimed to conduct a meta­analysis of previously published studies in order to clarify the association of IL­4 with cancer risk. Eligible published articles were searched in Medline, PubMed, Embase and China National Knowledge Infrastructure databases up to March 2016. Odds ratios and 95% confidence intervals were used to identify potential associations between IL­4 genetic polymorphisms and the risk of cancer. A meta­analysis was then performed on 10,873 patients and 14,328 controls for IL­4 rs2243250 polymorphism, 3,970 patients and 5,686 controls for IL­4 rs2070874 polymorphism, and 1,896 patients and 2,526 controls for IL­4 rs79071878 polymorphism. A significant association with cancer risk was observed for rs2243250 and rs79071878 polymorphisms. In the subgroup analysis by cancer type, rs2243250 polymorphism was demonstrated to be associated with an increased risk of gastric cancer and breast cancer, rs2070874 polymorphism was correlated with leukemia and oral carcinoma, and rs79071878 polymorphism was relevant to bladder carcinoma risk. In the subgroup analysis by ethnicity, IL­4 rs2243250 polymorphism was demonstrated to be associated with cancer risk in both Caucasian and Asian populations, rs2070874 was associated with cancer risk in Asian populations, while rs79071878 polymorphism was associated with cancer risk in Caucasian populations. In conclusion, the present results suggested that the IL­4 rs2243250 and rs79071878 polymorphisms were associated with cancer susceptibility. Further subgroup analyses revealed that the effects of IL­4 gene polymorphisms on cancer risk may vary by cancer type and by ethnicity.

Human umbilical cord stem cell conditioned medium versus serum-free culture medium in the treatment of cryopreserved human ovarian tissues in in-vitro culture: a randomized controlled trial.

BACKGROUND: To reduce young female fertility loss, the in-vitro culture of cryopreserved ovarian cortical tissues (OCTs) is considered an effective approach without delaying treatment and undergoing stimulation medicine. However, ischemic damage and follicular loss during the in-vitro culture of OCTs are major technical challenges. Human umbilical cord stem cells (HUMSCs) and their conditioned medium (HUMSC-CM) have been considered to be potential resources for regeneration medicine because they secrete cytokines and enhance cell survival and function. The aim of this study was to determine whether HUMSC-CM improves the development of frozen-thawed in-vitro cultured ovarian tissues compared with a serum-free culture medium (SF-CM). METHODS: The thawed OCTs (n = 68) were cultivated in HUMSC-CM and SF-CM in vitro for 8 days, and the ovarian tissues were processed and analyzed by a classical histological evaluation. The microvessel density (MVD) and apotosis detection during in-vitro culture of OCTs were also performed. RESULTS: A significant difference in the rate of morphologically normal primordial follicles in the HUMSC-CM group was observed compared to that in the SF-CM group (group C) from days 2 to 4 (day 2: group B 58.0 ± 2.45% vs group C 32.0 ± 5.83%, p = 0.002; day 3: group B 55.5 ± 4.20% vs group C 21.0 ± 9.80%, p = 0.048; day 4: group B 52.0 ± 4.08% vs group C 21.5 ± 8.19%, p = 0.019). The microvessel density (MVD) detection showed a time-dependent increase and peaked on day 4. There was a significant difference between groups B (49.33 ± 0.58) and C (24.33 ± 3.79) (p = 0.036). The percentage of apoptotic follicles in group B was lower than that in group C on day 1 (13.75 ± 2.50% vs 27.0 ± 10.10%, p = 0.003), day 5 (11.75 ± 1.50% vs 51.0 ± 10.5%, p = 0.019) and day 7 (15.0 ± 5.10% vs 46.5 ± 21.75%, p = 0.018). CONCLUSIONS: These data have provided the first experimental evidence of the effect of HUMSC-CM on frozen-thawed OCTs in vitro. The results showed that the HUMSC-CM group provided a better protecting effect on the in-vitro culture of the cryopreserved OCTs compared to the SF-CM group.

Associations of IL-10 genetic polymorphisms with the risk of urologic cancer: a meta-analysis based on 18,415 subjects.

BACKGROUND: Interleukin-10 (IL-10) is a powerful modulator of anti-tumor immune responses. The IL-10 promoter region polymorphisms are known to regulate IL-10 production, and thus are thought to be implicated in tumorigenesis. Recently, the roles of these polymorphisms in urologic cancer have been extensively studied, with conflicting results. Therefore, we conducted the present meta-analysis to better elucidate the correlations between IL-10 polymorphisms and urologic cancer risk. METHODS: Eligible articles were searched in PubMed, Medline, Embase, Scopus and CNKI up to May 2016. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to detect any potential associations between IL-10 polymorphisms and the risk of urologic cancer. RESULTS: A total of 22 case-control studies including 8572 patients and 9843 controls were analyzed. The overall meta-analysis results showed that IL-10 -592C>A polymorphism was significantly associated with urologic cancer in CA versus AA (P = 0.04, OR 0.87, 95% CI 0.76-0.99) and AA versus CC+CA (P = 0.03, OR 1.15, 95% CI 1.02-1.31). Subgroup analyses by cancer types suggested there were significant associations between all the three investigated IL-10 polymorphisms and bladder cancer. However, subgroup analyses by ethnicity only detected a weak association between IL-10 -819C>T and Asian population. CONCLUSIONS: Our findings suggests that IL-10 -592C>A polymorphism may implicate with urologic cancer risk. Besides, promoter region polymorphisms of IL-10 may serve as potential biological markers, especially for bladder cancer. Furthermore, IL-10 -819C>T polymorphism may contribute to urologic cancer susceptibility in Asians while all the three studied variants of IL-10 did not relate to Caucasian urologic cancer predisposition.

[RESEARCH AND PROSPECT OF MESENCHYMAL STEM CELLS IN FEMALE FERTILITY PRESERVATION].

OBJECTIVE: Fertility preservation (FP) technology has gradually been concerned by scholars all over the world due to the increasing survival rate of cancer patients. To review the recent progress of mesenchymal stem cells (MSCs) in female FP. METHODS: The recent original literature about MSCs in female FP was extensively reviewed. RESULTS: MSCs have the advantages of rich source, easy isolation and amplification, and capacities for multipotential differentiation and migration so that they can be used to avoid the ethical and legal controversy which have great potential of FP for the damage of ovarian tissue and reproductive endocrine disorders. In addition, MSCs can be induced to differentiate into a specific condition, which is expected to be the resource in oocyte-like cells that can be used as a steady cell source for the future experiments and clinical application. CONCLUSION: MSCs have great potential to provide new research ideas for future FP technology.

Associations of insulin receptor and insulin receptor substrates genetic polymorphisms with polycystic ovary syndrome: A systematic review and meta-analysis.

AIM: Recently, the roles of insulin receptor (INSR) and insulin receptor substrate (IRS) polymorphisms in polycystic ovary syndrome (PCOS) have been extensively studied, with conflicting results. Therefore, we conducted the present systematic review and meta-analysis to better evaluate associations of INSR and IRS polymorphisms with PCOS. METHODS: We searched PubMed, Medline, EMBASE, Google Scholar and China National Knowledge Infrastructure for eligible articles up to December 2015. Odds ratios (OR) and 95% confidence intervals (CI) were used to evaluate associations of INSR and IRS polymorphisms with PCOS. RESULTS: A total of 28 articles including 2975 PCOS patients and 3011 control subjects were analyzed. The overall analyses and subgroup analyses revealed that IRS-1 Gly972Arg polymorphism was significantly associated with PCOS for the Caucasian population in GG versus GA (OR = 0.57, 95%CI 0.37-0.89), GG versus GA + AA (OR = 0.57, 95%CI 0.36-0.89), GA versus GG + AA (OR = 1.74, 95%CI 1.13-2.69) and G versus A (OR = 0.63 95%CI 0.43-0.92). Also, IRS-2 Gly1057Asp polymorphism was significantly associated with PCOS for the Asian ethnicity in GG versus GA (OR = 0.45, 95%CI 0.24-0.83), GG versus AA (OR = 0.32, 95%CI 0.19-0.53), GG versus GA + AA (OR = 0.35, 95%CI 0.21-0.57), AA versus GG + GA (OR = 2.14, 95%CI 1.43-3.20), and G versus A (OR = 0.43, 95%CI 0.32-0.58). However, we detected no significant association between INSR His 1058 C/T polymorphism and PCOS. CONCLUSION: Our findings suggest that IRS-1 Gly972Arg polymorphism is associated with PCOS in the Caucasian ethnicity, and IRS-2 Gly1057Asp polymorphism is correlated with PCOS in the Asian ethnicity. However, INSR His 1058 C/T polymorphism may not be implicated in PCOS. © 2016 Japan Society of Obstetrics and Gynecology.