Genetic and epigenetic characteristics in ovarian tissues from polycystic ovary syndrome patients with irregular menstruation resemble those of ovarian cancer.
ABSTRACT: BACKGROUND:Irregular menstruation is clinically associated with an increased risk for ovarian cancer and disease-related mortality. This relationship remains poorly understood, and a mechanism explaining it has yet to be described. METHODS:Ovarian tissues from women with polycystic ovary syndrome (PCOS) and regular menstruation (n?=?10) or irregular menstruation (n?=?10) were subjected to DNA methylation sequencing, real-time PCR array, whole-exome sequencing, and bioinformatics analysis. RESULTS:We demonstrated that ovarian tissue from PCOS patients with irregular menstruation displayed global DNA hypomethylation, as well as hypomethylation at several functionally and oncologically significant regions. Furthermore, we showed that several cancer-related genes were aberrantly expressed in ovarian tissue from patients with irregular menstruation, and that their mRNA and microRNA profiles shared appreciable levels of coincidence with those from ovarian cancer tissue. We identified multiple point mutations in both the BRCA1 and MLH1 genes in patients with irregular menstruation, and predicted the potential pathogenicity of these mutations using bioinformatics analyses. CONCLUSIONS:Due to the nature of ovarian cancer, it is important to broaden our understanding of the pathogenesis and risk factors of the disease. Herein, we provide the first description of a genetic and epigenetic basis for the clinical relationship between irregular menstruation and an increased risk for ovarian cancer.
Project description:Polycystic ovaries and irregular menstruation/anovulation are important diagnostic criteria along with hyperandrogenism as per the Androgen Excess Society-2006 criteria for polycystic ovarian syndrome (PCOS). In the etiopathogenesis of PCOS, one of the candidate genes causing ovarian failure is the luteinizing hormone (LH) chorionic gonadotropin hormone receptor (LHCGR). Our aim was to study the association of LHCGR polymorphism (rs2293275) with PCOS in our study population.Genetic case-control study from multiple gynecological centers from Hyderabad, a cosmopolitan city in South India. The study involved 204 women with PCOS and 204 healthy, sex-, and age-matched controls. Anthropometric and biochemical profiles were taken in a well-designed pro forma. Isolation of deoxyribonucleic acid (DNA) and genotype analysis were done for the entire study population using the polymerase chain reaction-restriction fragment length polymorphism method followed by 12% polyacrylamide gel electrophoresis.In this study, we have demonstrated an association between LHCGR (rs2293275) polymorphism and PCOS. The frequency of the G allele was 0.60 in PCOS and 0.49 in controls (odds ratio [OR] 1.531, confidence interval [CI] 1.16-2.01, and p-value=0.0026), which indicates that the G allele is associated with PCOS in our population. The GG genotype conferred a significant risk of developing PCOS (OR 3.36, CI 1.96-5.75, and p-value<0.0001). We found a significant association of the GG allele with body-mass index, waist to hip ratio, insulin resistance, LH, and LH/follicle-stimulating hormone (FSH) ratio in PCOS when compared with controls. The AA allele showed high basal FSH levels.This study suggests that LHCGR (rs2293275) polymorphism is associated with PCOS and could be used as a relevant molecular marker to identify women with the risk of developing PCOS in our population and may provide an understanding about the etiology of PCOS.
Project description:Long and irregular menstrual cycles, a hallmark of polycystic ovary syndrome (PCOS), have been associated with higher androgen and lower sex hormone binding globulin levels and this altered hormonal environment may increase the risk of specific histologic subtypes of ovarian cancer. We investigated whether menstrual cycle characteristics and self-reported PCOS were associated with ovarian cancer risk among 2,041 women with epithelial ovarian cancer and 2,100 controls in the New England Case-Control Study (1992-2008). Menstrual cycle irregularity, menstrual cycle length, and PCOS were collected through in-person interview. Unconditional logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (95% CIs) for ovarian cancer risk overall, and polytomous logistic regression to evaluate whether risk differed between histologic subtypes. Overall, we observed no elevation in ovarian cancer risk for women who reported periods that were never regular or for those reporting a menstrual cycle length of >35 days with ORs of 0.87 (95% CI?=?0.69-1.10) and 0.83 (95% CI?=?0.44-1.54), respectively. We observed no overall association between self-reported PCOS and ovarian cancer (OR?=?0.97; 95% CI?=?0.61-1.56). However, we observed significant differences in the association with menstrual cycle irregularity and risk of ovarian cancer subtypes (pheterogeneity ?=?0.03) as well as by BMI and OC use (pinteraction ?<?0.01). Most notable, menstrual cycle irregularity was associated with a decreased risk of high grade serous tumors but an increased risk of serous borderline tumors among women who had never used OCs and those who were overweight. Future research in a large collaborative consortium may help clarify these associations.
Project description:OBJECTIVES:To measure the prevalence and correlates of abnormal menstruation among women living with HIV (WLWH) in Canada. METHODS:We used cross-sectional questionnaire data from the community-based Canadian HIV Women's Sexual and Reproductive Health Cohort Study (CHIWOS), which enrolled WLWH aged ?16 from British Columbia (BC), Ontario, and Quebec. For this analysis, we excluded women >45 years, who had primary amenorrhea, were pregnant, on hormonal contraception, or who reported history of endometrial cancer, last menstrual period >12 months ago, or premature ovarian failure. The primary outcome was abnormal menstruation (Yes vs No) based on responses to five questions about menstrual regularity, frequency, volume, duration, and intermenstrual bleeding in the six months prior to interview. An exploratory multivariable logistic regression analysis examined independent correlates of abnormal menstruation. RESULTS:Of 1422 women enrolled, 521 (37%) met eligibility criteria. Overall, 55.9% (95% CI:52%-60%) reported abnormal menstruation. In adjusted analyses, abnormal menstruation was associated with having a biologic sister/mother who entered menopause before age 40 (AOR 5.01, 95%CI 1.39-18.03), Hepatitis B co-infection (AOR 6.97, 95%CI 1.52-31.88), current smoking (AOR 1.69, 95%CI 1.55-3.41); and currently taking antiretroviral therapy (ART) (AOR 2.36, 95%CI 1.25-4.45) compared to being ART-naïve. Women in BC had higher adjusted odds of abnormal menstruation (AOR 2.95, 95%CI 1.61-5.39), relative to women in Ontario and Quebec. CONCLUSIONS:Over half of WLWH in this analysis had abnormal menstruation. Correlates of abnormal menstruation include genetic, socio-behavioural factors (province of residence, smoking), Hepatitis B co-infection, and current ART use.
Project description:Research question Whether SARS-CoV-2 infection has effects on ovarian reserve, sex hormone and menstruation of women of child-bearing age. Design This is a retrospective, cross-sectional study. Clinical and laboratory data from 237 women of child-bearing age diagnosed with COVID-19 were retrospectively reviewed. Menstrual data from 177 patients were analyzed. Blood samples from the early follicular phase were tested for sex hormones and Anti-mullerian hormone (AMH). Results Among 237 patients confirmed with COVID-19, severely ill patients had more comorbidities than mildly ill patients (34% vs 8%), especially for patients with diabetes, hepatic disease and malignant tumors. Among 177 patients with menstrual records, 45 (25%) patients presented with menstrual volume changes, and 50 (28%) patients had menstrual cycle changes, mainly a decreased volume (21%) and a prolonged cycle (19%). The average sex hormone and AMH levels of women of child-bearing age with COVID-19 were not different from those of age-matched controls. Conclusions; Average sex hormone levels and ovarian reserve did not change significantly in COVID-19 women of child-bearing age. Nearly one-fifth of patients exhibited a menstrual volume decrease or cycle prolongation. The menstruation changes of these patients might be the consequence of transient sex hormone change cause by suppression of ovarian function that soon resumed after recovery.
Project description:BACKGROUND:Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with an estimated prevalence of 4-21% in reproductive aged women. Recently, the Ovarian Cancer Association Consortium (OCAC) reported a decreased risk of invasive ovarian cancer among women with self-reported PCOS. However, given the limitations of self-reported PCOS, the validity of these observed associations remains uncertain. Therefore, we sought to use Mendelian randomization with genetic markers as a proxy for PCOS, to examine the association between PCOS and ovarian cancer. METHODS:Utilizing 14 single nucleotide polymorphisms (SNPs) previously associated with PCOS we assessed the association between genetically predicted PCOS and ovarian cancer risk, overall and by histotype, using summary statistics from a previously conducted genome-wide association study (GWAS) of ovarian cancer among European ancestry women within the OCAC (22 406 with invasive disease, 3103 with borderline disease and 40 941 controls). RESULTS:An inverse association was observed between genetically predicted PCOS and invasive ovarian cancer risk: odds ratio (OR)=0.92 [95% confidence interval (CI)=0.85-0.99; P?=?0.03]. When results were examined by histotype, the strongest inverse association was observed between genetically predicted PCOS and endometrioid tumors (OR?=?0.77; 95% CI?=?0.65-0.92; P?=?0.003). Adjustment for individual-level body mass index, oral contraceptive use and parity did not materially change the associations. CONCLUSION:Our study provides evidence for a relationship between PCOS and reduced ovarian cancer risk, overall and among specific histotypes of invasive ovarian cancer. These results lend support to our previous observational study results. Future studies are needed to understand mechanisms underlying this association.
Project description:Women with polycystic ovary syndrome (PCOS) have been reported to have an elevated serum advanced glycation end product (AGE) level. However, the effect of AGEs on the pathophysiological ovarian granulosa cells of PCOS is still unclear. In this study, five indented BSA-derived AGE products were used to evaluate their effect on the function of human granulosa cells. We found that the proliferation of both primary human ovarian granulosa (hGC) cells and human granulosa-like tumor (KGN) cells were inhibited by treatment with these five AGE products. The progesterone secretion level was also reduced in both hGC and KGN cells by treatment with these AGE products through downregulation of LH receptor/cAMP regulatory activity. The granulosa cell layer and serum progesterone level were reduced in rats by treatment with MG-BSA; moreover, an increased number of follicle cysts and an irregular estrous cycle were observed. MG-BSA treatment had a similar effect on the phenotypes of the DHEA-induced PCOS model. Additionally, the insulin resistance and hepatic lesions seen in the DHEA-induced PCOS model were observed in the MG-BSA treatment group. Taken together, we found that AGEs exert a toxic effect on ovarian granulosa cells, ovarian morphology, and the estrous cycle that mimics the DHEA-induced PCOS phenotypes.
Project description:BACKGROUND:Women with irregular menstruation should be considered to benefit from the ovarian stimulation. However, most literature did not separate ovulatory disorders from normal menstrual cycles. Our purpose was to assess the superiority of ovarian mild stimulation compared with the natural cycle in IUI for subfertile couples when the women with regular menstruation. METHODS:A retrospective study in a single medical center in which 2413 couples with 3573 IUI cycles were studied from 2013 to 2018. The results of IUI in natural cycles versus low-dose HMG induced cycles were analyzed. RESULTS:For young women (age?<?35?years) with normal menstrual cycle, HMG induced ovulation combined with IUI can improve clinical pregnancy outcome (13.55% in two follicular induced cycles vs. 7.23% in natural cycles, p?<?0.01); even if only one follicle was induced, the clinical pregnancy rate was increased to 10.32% (p?<?0.01). When two growth follicles were induced in HMG cycles, a remarkable improvement of the live birthrate (10.28% vs. 5.91% in natural cycles, p?<?0.05) was noted. Simultaneously, twin pregnancy rates were increased to 20.69% (p?<?0.01). Twin pregnancies showed significantly increased risk of both ectopic pregnancy and preterm birth (p?=?0.00 for both). For advanced women (age???35?years) with regular menstrual cycle, ovulation induction didn't improve clinical pregnancy and live birthrates, while age was the only relevant factor. CONCLUSIONS:Combining HMG induced ovulation and IUI can improve pregnancy outcome in young women with normal menstrual cycles. 1-2 follicles with diameter???14?mm served as the purpose of ovulation induction. Further, both twin and ectopic pregnancy rate in HMG cycles with two growth follicles were significantly higher than those in natural cycles were. Therefore, doctors must evaluate the risk before making choices and inform the patients to achieve the best results. For advanced women with normal menstrual cycles, natural IUI cycles were optional.
Project description:This systematic review aimed at summarizing and evaluating the evidence from randomized controlled trials (RCTs) using acupuncture to treat polycystic ovarian syndrome (PCOS), specifically focusing on ovulation rate, menstrual rate, and related hormones.Fifteen databases were searched electronically through February 2016. Our review included RCTs of women with PCOS; these RCTs compared acupuncture with sham acupuncture, medication, or no treatment. Two reviewers independently extracted data. Data were pooled and expressed as mean differences (MDs) for continuous outcomes and risk ratios for dichotomous outcomes, with 95% confidence intervals (CIs) using a random-effects model.We found a low level of evidence that acupuncture is more likely to improve ovulation rate (MD 0.35, 95% CI: 0.14-0.56) and menstruation rate (MD 0.50, 95% CI: 0.32-0.68) compared with no acupuncture. We found statistically significant pooled benefits of acupuncture treatment as an adjunct to medication in luteinizing hormone (LH), LH/follicular stimulating hormone (FSH) ratio, testosterone, fasting insulin, and pregnancy rates, but the level of evidence was low/very low.There is limited evidence to judge the efficacy and safety of acupuncture on key reproductive outcomes in women with PCOS. Large-scale, long-term RCTs with rigorous methodological input are needed.
Project description:BACKGROUND:Women with polycystic ovary syndrome (PCOS) manifest a host of ovarian defects like impaired folliculogenesis, anovulation, and poor oocyte quality, which grossly affect their reproductive health. Addressing the putative epigenetic anomalies that tightly regulate these events is of foremost importance in this disorder. We therefore aimed to carry out DNA methylome profiling of cumulus granulosa cells and assess the methylation and transcript expression profiles of a few differentially methylated genes contributing to ovarian defects in PCOS. A total of 20 controls and 20 women with PCOS were selected from a larger cohort of women undergoing IVF, after carefully screening their sera and follicular fluids for hormonal and biochemical parameters. DNA extracted from cumulus granulosa cells of three women each, from control and PCOS groups was subjected to high-throughput, next generation bisulfite sequencing, using the Illumina HiSeq 2500® platform. Remaining samples were used for the validation of methylation status of some identified genes by pyrosequencing, and the transcript expression profiles of these genes were assessed by quantitative real-time PCR. RESULTS:In all, 6486 CpG sites representing 3840 genes associated with Wnt signaling, G protein receptor, endothelin/integrin signaling, angiogenesis, chemokine/cytokine-mediated inflammation, etc., showed differential methylation in PCOS. Hypomethylation was noted in 2977 CpGs representing 2063 genes while 2509 CpGs within 1777 genes showed hypermethylation. Methylation differences were also noted in noncoding RNAs regulating several ovarian functions that are dysregulated in PCOS. Few differentially methylated genes such as aldo-keto reductase family 1 member C3, calcium-sensing receptor, resistin, mastermind-like domain 1, growth hormone-releasing hormone receptor and tumor necrosis factor, which predominantly contribute to hyperandrogenism, premature luteolysis, and oocyte development defects, were explored as novel epigenetic candidates in mediating ovarian dysfunction. Methylation profiles of these genes matched with our NGS findings, and their transcript expression patterns correlated with the gene hypo- or hypermethylation status. CONCLUSION:Our findings suggest that the epigenetic dysregulation of genes involved in important processes associated with follicular development may contribute to ovarian defects observed in women with PCOS.