Polycystic Ovary Syndrome Patients Research Articles

Decreased AMPK/SIRT1/PDK4 induced by androgen excess inhibits human endometrial stromal cell decidualization in PCOS

Polycystic ovary syndrome (PCOS) is a complex common endocrine disorder affecting women of reproductive age. Ovulatory dysfunction is recognized as a primary infertile factor, however, even when ovulation is medically induced and restored, PCOS patients continue to experience reduced cumulative pregnancy rates and a higher spontaneous miscarriage rate. Hyperandrogenism, a hallmark feature of PCOS, affects ovarian folliculogenesis, endometrial receptivity, and the establishment and maintenance of pregnancy. Decidualization denotes the transformation that the stromal compart of the endometrium must undergo to accommodate pregnancy, driven by the rising progesterone levels and local cAMP production. However, studies on the impact of hyperandrogenism on decidualization are limited. In this study, we observed that primary endometrial stromal cells from women with PCOS exhibit abnormal responses to progesterone during in vitro decidualization. A high concentration of testosterone inhibits human endometrial stromal cells (HESCs) decidualization. RNA-Seq analysis demonstrated that pyruvate dehydrogenase kinase 4 (PDK4) expression was significantly lower in the endometrium of PCOS patients with hyperandrogenism compared to those without hyperandrogenism. We also characterized that the expression of PDK4 is elevated in the endometrium stroma at the mid-secretory phase. Artificial decidualization could enhance PDK4 expression, while downregulation of PDK4 leads to abnormal decidualization both in vivo and in vitro. Mechanistically, testosterone excess inhibits IGFBP1 and PRL expression, followed by phosphorylating of AMPK that stimulates PDK4 expression. Based on co-immunoprecipitation analysis, we observed an interaction between SIRT1 and PDK4, promoting glycolysis to facilitate decidualization. Restrain of AR activation resumes the AMPK/SIRT1/PDK4 pathway suppressed by testosterone excess, indicating that testosterone primarily acts on decidualization through AR stimulation. Androgen excess in the endometrium inhibits decidualization by disrupting the AMPK/SIRT1/PDK4 signaling pathway. These data demonstrate the critical roles of endometrial PDK4 in regulating decidualization and provide valuable information for understanding the underlying mechanism during decidualization.

Effects of Metformin on CIMT and FMD in PCOS patients: a systematic review and meta-analysis

BackgroundThis study aims to analyze the efficacy of metformin on carotid intima media thickness (CIMT) and flow-mediated dilation (FMD) for patients with polycystic ovary syndrome (PCOS).MethodsA literature search of PubMed, Embase, and the Cochrane Library from inception to December 2023 was conducted. Then, after studies selection and data extraction, the mean difference (MD) with a 95% confidence interval (CI) was used to evaluate metformin efficacy in CIMT and FMD for PCOS patients. Heterogeneity was investigated through subgroup and sensitivity analysis. The protocol of our study has been registered in PROSPERO (CRD42024497239).ResultsA total of 12 studies with 248 patients were included. CIMT was lower in the endpoint group (after metformin) compared with the baseline group (before metformin) (MD = -0.11, 95% CI = -0.21 to -0.01, p = 0.04). FMD was higher in the endpoint group compared with the baseline group (MD = 3.25, 95% CI = 1.85 to 4.66, p < 0.01). No statistically significant difference was observed in nitroglycerin-mediated dilation (NMD) between the two groups (MD = 0.65, p = 0.51). Subgroup analysis showed that a relatively lower MD of CIMT in PCOS patients from Europe in the endpoint group compared with the baseline group (MD = -0.09, 95% CI = -0.14 to -0.04, p < 0.001). However, the MD in CIMT was not significantly different between the endpoint group and baseline group in PCOS patients from Asia (p = 0.270).ConclusionMetformin may have a beneficial effect on CIMT and FMD, but not on NMD, suggesting that metformin may help reduce cardiovascular events in PCOS patients. Notably, the clinical efficacy of metformin can be influenced by regional differences and study types.

Predicting TCM patterns in PCOS patients: An exploration of feature selection methods and multi-label machine learning models

BackgroundTraditional Chinese Medicine (TCM) offers individualized treatment for Polycystic Ovary Syndrome (PCOS) through pattern differentiation, but the subjectivity of TCM diagnoses can lead to inconsistent outcomes. Integrating machine learning (ML) offers an objective basis to support TCM diagnoses. This study aims to evaluate various feature selection techniques and multi-label ML algorithms to develop an effective predictive model for classifying TCM patterns in PCOS patients, thereby enhancing diagnostic standardization and treatment personalization. MethodsThe study utilized a dataset comprising 432 patients with PCOS, exhibiting one or more of five TCM patterns. Feature selection began with Variance Thresholding (VT), followed by a comparison of five advanced techniques: Statistical Analysis Test, Recursive Feature Elimination with Cross-Validation (RFECV), Least Absolute Shrinkage and Selection Operator Regression, BorutaShap, and ReliefF. To ascertain the most effective model for predicting PCOS TCM patterns, four ML algorithms—Support Vector Machine, Logistic Regression, Extreme Gradient Boosting (XGBoost), and Artificial Neural Networks—were evaluated against the identified feature set. ResultsVT reduced the feature count from 224 to 174. RFECV emerged as the most effective feature selection method, identifying 67 key features. XGBoost emerged as the top-performing model, demonstrating superior testing accuracy (0.7870), F1 score (0.9519), and Hamming loss (0.0481) with RFECV-optimized features. ConclusionsThe RFECV-XGBoost model proved effective for classifying TCM patterns in PCOS. It emphasizes the necessity of precise feature selection and the significant capabilities of ML in advancing TCM pattern diagnostics, marking a significant step toward enhancing precise and personalized healthcare in biomedical studies.

Effects of mind-body interventions on polycystic ovary syndrome: a comprehensive meta-analysis

BackgroundMind-body interventions (MBI) have emerged as a potential therapeutic approach, but their effectiveness in the treatment of Polycystic Ovary Syndrome (PCOS) remains inconclusive. This study systematically evaluates the effectiveness of MBI on quality of life, anthropometry, androgen secretion, glucose, and lipid metabolism in PCOS.MethodsA computer search was conducted across three databases: PubMed, the Cochrane Library, and EMBASE, to identify randomized controlled trials (RCTs) related to MBI for PCOS from their inception until July 2024. DerSimonian and Laird’s random-effects model and Stata 17.0 software was employed for our meta-analysis.ResultsTwelve RCTs were included. MBI significantly improved PCOSQ subscale scores, including emotional disturbances (MD: 7.75, 95% CI: 6.10 to 9.40), body hair (MD: 2.73, 95% CI: 0.54 to 4.91), menstrual problems (MD: 3.79, 95% CI: 2.89 to 4.69), and weight (MD: 1.48, 95% CI: 0.03 to 2.93). Furthermore, there was a reduction in depression levels (MD: -1.53, 95% CI: -2.93 to -0.13). Sensitivity analysis confirmed the robustness of PCOSQ-Emotional disturbances and PCOSQ-Menstrual problems, with a high GRADE level of evidence for these subscales. Secondary outcome measures, including waist-hip ratio, fasting blood glucose, and HOMA-IR exhibited statistically significant differences. Subgroup analysis revealed that obesity could influence treatment outcomes.ConclusionMBI can serve as an alternative therapy, modulating effect on the quality of life and depression in PCOS patients. Future well-designed, high-quality, and large-scale studies should be conducted to thoroughly assess the impact of different Mind-Body Interventions (MBI) on various PCOS phenotypes.Trial registrationPROSPERO (CRD42023472035).

Identification of MAP1LC3A as a promising mitophagy-related gene in polycystic ovary syndrome

Increasing evidence suggests that mitophagy is crucially involved in the progression of polycystic ovary syndrome (PCOS). Exploration of PCOS-specific biomarkers related to mitophagy is expected to provide critical insights into disease pathogenesis. In this study, we employed bioinformatic analyses and machine learning algorithms to determine novel biomarkers for PCOS that may be tied with mitophagy. A grand total of 12 differential expressed mitophagy-related genes (DE‐MRGs) associated with PCOS were identified. TOMM5 and MAP1LC3A among the 12 DE‐MRGs were recognized as potential marker genes by LASSO, RF and SVM‐RFE algorithms. The area under the ROC curve (AUROC) of MAP1LC3A were all greater than 0.8 both in the training set and validation sets. The CIBERSORT analysis indicated a potential association between alterations in the immune microenvironment of PCOS individuals and MAP1LC3A expression. In addition, we found that MAP1LC3A was positively related to the testosterone levels of PCOS patients. Overall, MAP1LC3A was identified as optimal PCOS-specific biomarkers related to mitophagy. Our findings created a diagnostic strength and offered a perspective for investigating the mitophagy process in PCOS.

The impact of the presence of hirsutism and hypertrichosis on the psychological state of women suffering from polycystic ovary syndrome and hyperandrogenism

This review article focuses on analyzing the impact of excessive hairiness, in the form of hirsutism and hypertrichosis, on the psychological state of women affected by polycystic ovary syndrome (PCOS) and hyperandrogenism. PCOS is one of the most common endocrine disorders in women, characterized by hyperandrogenism, insulin resistance and menstrual disorders, among others. Studies suggest that excessive body hair can have a significant impact on the quality of life and psychological state of PCOS patients, leading to lowered self-esteem, depression, anxiety and body dysmorphophobia. Despite numerous clinical observations, however, a complete understanding of the mechanisms underlying this association is lacking. The article underscores the need for further research to identify the biological and psychological mechanisms affecting the psychological state of women with excessive body hair in the context of PCOS and hyperandrogenism. As progress is made in this area, it will be possible to develop more effective management strategies and therapeutic interventions that can help improve the quality of life for these patients.

Transcriptome Analysis of Mesenchymal Progenitor Cells Revealed Molecular Insights into Metabolic Dysfunction and Inflammation in Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a female endocrine disorder with metabolic issues. Hyperandrogenism combined with hyperinsulinemia exacerbates the reproductive, metabolic, and inflammatory problems in PCOS patients. The etiology of PCOS is unclear. Patient-specific induced pluripotent stem cells (iPSCs) offer a promising model for studying disease mechanisms and conducting drug screening. Here, we aim to use mesenchymal progenitor cells (MPCs) derived from PCOS iPSCs to explore the mechanism of PCOS. We compared the transcriptome profiles of PCOS and healthy control (HC) iPSC-derived MPCs (iPSCMs). Moreover, we assess the impact of androgens on iPSCMs. In the comparison between PCOS and HC, the expression levels of 1026 genes were significantly different. A gene set enrichment analysis (GSEA) revealed that adipogenesis- and metabolism-related genes were downregulated, whereas inflammation-related genes were upregulated in the PCOS iPSCMs. Dysregulation of the TGF-β1 and Wnt signaling pathways was observed in the PCOS iPSCMs. Furthermore, there was impaired adipogenesis and decreased lipolysis in the PCOS iPSCMs-derived adipocytes. With testosterone treatment, genes related to metabolism were upregulated in the HC iPSCMs but downregulated in the PCOS iPSCMs. The impact of testosterone varied among HCs and PCOS iPSCMs, possibly because of a genetic predisposition toward PCOS. This study found specific signaling pathways that could serve as therapeutic targets for PCOS.

The Relationship between Thyroid Hormones and Insulin Resistance in Polycystic Ovary Syndrome Women.

This study aimed to investigate the changes in thyroid hormones in the serum of patients with polycystic ovary syndrome (PCOS) and their correlation with insulin resistance. This is a retrospective study. 84 patients having insulin resistance and 76 patients without insulin resistance were included. 90 women without history of PCOS were selected as a healthy control group. This study was conducted at Shijiazhuang Fourth Hospital. Blood samples were collected from each group on days 3-5 of their menstrual cycle, and their triiodothyronine (T3), thyroxine (T4), and thyroid-stimulating hormone (TSH) levels were analyzed and compared between groups. We investigated the changes of serum thyroid hormones in patients with PCOS and their correlation with insulin resistance. We found that serum levels of T3 and T4 were significantly decreased, while TSH levels were significantly increased in PCOS patients compared with HCs. Moreover, we found that patients with insulin resistance had significantly lower levels of serum T3 and T4 and higher levels of TSH compared to those PCOS participants without insulin resistance. This study was a retrospective and single-center study, which had selection bias, information bias, and confounding variables may affect the accuracy and reliability of the conclusion. Insulin resistance negative correlates with their serum T3, T4, and positive correlates with their TSH levels. Our results develop a combined test model with the serum T3, T4, and TSH levels for the clinical diagnosis of insulin resistance in PCOS women.

Circ_0043314 Modulates Proliferation and Apoptosis of Ovarian Granulosa Cells in Polycystic Ovarian Syndrome via the MicroRNA-146b-3p/Apelin 13 Axis.

Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder in women. At present, the pathogenesis has not been clarified, and the clinical application of drugs and lifestyle intervention may not prevent disease progression. This study aimed to investigate how circ_0043314 regulates ovarian granulosa cell biological functions to provide a theoretical basis for the treatment of patients with PCOS. MicroRNA (miR)-146b-3p/Apelin 13 axis was used to investigate the mechanism by which circ_0043314 regulated ovarian granulosa cell proliferation and apoptosis in PCOS via miR-146b-3p/Apelin 13 axis. Participants/Materials, Methods: Ovarian tissues (cortical tissues) from 35 PCOS patients and 35 normal controls, as well as HEK293T and human ovarian granulosa cell line (KGN, COV434), were included in this study. We examined the expression levels of circ_0043314, miR-146b-3p, and Apelin 13 in PCOS tissues. Ovarian granulosa cells were transfected with corresponding plasmids to clarify the influence of circ_0043314, miR-146b-3p, or Apelin 13 on proliferation and apoptosis of ovarian granulosa cells through MTT and flow cytometry assays. Moreover, the relationships among circ_0043314, miR-146b-3p, and Apelin 13 were analyzed through dual-luciferase and RNA immunoprecipitation assays. Circ_0043314 and Apelin 13 were highly expressed and miR-146b-3p was lowly expressed in ovarian tissues of PCOS compared with non-PCOS controls. Downregulation of circ_0043314 or upregulation of miR-146b-3p hindered ovarian granulosa cell proliferation and advanced its apoptosis. Downregulation of miR-146b-3p reversed the impacts of downregulation of circ_0043314, and overexpression of Apelin 13 counteracted the influences of upregulation of miR-146b-3p in ovarian granulosa cells. Mechanically, circ_0043314 could bind to miR-146b-3p, and miR-146b-3p directly targeted and modulated Apelin 13 expression. This study was limited by the lack of animal experiments. Our data demonstrated that circ_0043314 enhances ovarian granulosa cell proliferation and suppresses its apoptosis via miR-146b-3p/Apelin 13 axis.

The impact of type 2 diabetes on polycystic ovary syndrome in patients undergoing sleeve gastrectomy.

Does the concurrent type 2 diabetes mellitus (T2DM) aggravate the features and prognosis of PCOS in patients undergoing sleeve gastrectomy (SG)? For patients undergoing SG with obesity, concurrent T2DM is associated with aggravated metabolic but milder reproductive features of PCOS and did not attenuate the resumption of regular menstruation for up to 1 year after surgery. Women with T2DM have an increased risk of PCOS. However, whether concurrent T2DM further increases the disease burden and treatment difficulty of PCOS in patients with obesity requires further investigation. This was a single-center, two-arm, prospective, cohort study enrolling a total of 329 women with PCOS and scheduled for SG because of obesity at an university-affiliated hospital between January 2020 and August 2023, with a 1-year follow-up after surgery. Comparisons were made between patients with T2DM (PCOS+T2DM) and without (PCOS) to examine the impact of T2DM on the metabolic, reproductive, and psychological features of PCOS. The follow-up data of weight loss and menstruation were analyzed to determine the impact of T2DM on PCOS prognosis for up to 1 year after SG. After controlling for confounders, patients in the PCOS+T2DM group (n = 98) showed more severe insulin resistance, glucose intolerance, dyslipidemia, and non-alcoholic fatty liver disease (NAFLD) (NAFLD activity score 4.31 ± 1.15 versus 3.52 ± 1.42, P < 0.001) than those in the PCOS group (n = 149). In addition, the PCOS+T2DM group had a lower level of total testosterone (1.63 ± 0.69 versus 1.82 ± 0.76, P = 0.045), a lower ratio between luteinizing hormone and follicle-stimulating hormone (median 1.48 versus 1.68, P = 0.030), and a lower proportion of patients with polycystic ovarian morphology (88% versus 96%, P = 0.022) than the PCOS group. As a result, the two groups differed significantly in terms of the Rotterdam classification of PCOS (P = 0.009). No significant difference was detected by group in the psychological features of PCOS except a lower degree of emotional eating in the PCOS+T2DM group (P = 0.001). Although the PCOS+T2DM group took longer to resume regular menstruation after SG (P = 0.037), the two groups had similar proportions of patients with regular menstruation (85% versus 87%, P = 0.758) 1 year after SG, which was further confirmed by subgroup analyses by body mass index. The prognosis of PCOS after SG mainly focused on the results of menstruation rather than a complete evaluation of the remission of the disease. Our study showed that, for patients with obesity, concurrent T2DM is associated with aggravated metabolic but milder reproductive features of PCOS and did not attenuate the resumption of regular menstruation for up to 1 year after surgery. Our study also highlights the need for high-quality studies with a more comprehensive evaluation of the impact of T2DM on the prognosis of patients with PCOS after SG. This study was funded by the National Natural Science Foundation of China Grants (82100853), the Natural Science Foundation of Shandong Province of China (ZR2021QH028), and the Clinical Research Project of Shandong University (2020SDUCRCC024). The authors have no conflicts of interest. Chinese Clinical Trial Registry with No. ChiCTR1900026845.

Can We Harvest More Mature Oocytes by Repeating Gonadotropin-Releasing Hormone Agonist Doses in Polycystic Ovarian Syndrome Patients at Risk of OHSS in Antagonist Cycles? A Randomised Clinical Trial.

There is an ongoing debate about the optimal dosage of gonadotropin-releasing hormone (GnRH) agonist for oocyte triggering in polycystic ovarian syndrome (PCOS) patients at risk for ovarian hyperstimulation syndrome (OHSS). In this study, we intend to ascertain whether the use of repeated doses of a GnRH agonist for oocyte triggering in these patients can enhance the outcomes of controlled ovarian stimulation (COS) for in vitro fertilization/ intracytoplasmic sperm injection (IVF/ICSI) cycles. This randomised clinical trial enrolled 70 PCOS women candidates for IVF/ICSI with the standard antagonist protocol at Royan Institute (Tehran, Iran) from May 2020 to June 2022. Patients at risk of OHSS with oestradiol (E2) levels >3000 pg/ml on the day of trigger were randomly assigned to a control or experimental group. Group A (control group) patients received 0.2 mg triptorelin (Decapeptyl®) for final oocyte maturation. Group B (experimental group) patients received a second dose of 0.1 mg Decapeptyl®12 hours after their first dose, for a total dose of 0.3 mg. IVF/ICSI outcomes were compared between the groups. Ultimately, 35 women from the study group and 33 from the control group completed the treatment cycle. Both groups were comparable in terms of demographic characteristics, baseline hormonal profiles, and PCOS phenotypes. The dosage of gonadotropin, stimulation duration, number of retrieved oocytes, oocyte maturation rate, and oocyte recovery ratio did not significantly differ between the groups. No significant differences were found in terms of the number of blastocyst and cleavage embryos, nor the quality of obtained embryos between the groups. The mild to moderate OHSS rate was significantly lower in the study group (P=0.038). A second dose of GnRH agonist 12 hours after the first dose did not improve the number and maturity of oocytes, or pregnancy outcomes in PCOS patients (registration number: NCT04600986).

Risk of type 2 diabetes, MASLD and cardiovascular disease in people living with polycystic ovary syndrome.

Abstract Background Polycystic ovary syndrome (PCOS) is associated with adverse clinical outcomes that may differ according to PCOS phenotype. Methods Using UK Biobank data, we compared the incidence of type 2 diabetes (T2D), metabolic dysfunction associated steatotic liver disease, cardiovascular disease (CVD), hormone-dependent cancers, and dementia between PCOS participants and age- and body mass index-matched controls. We also compared multiorgan (liver, cardiac, and brain) magnetic resonance imaging (MRI) data and examined the impact of PCOS phenotype (hyperandrogenic and normoandrogenic) on these outcomes. Results We included 1008 women with PCOS (defined by diagnostic codes, self-reported diagnoses, or clinical/biochemical features of hyperandrogenism and a/oligoCmenorrhoea) and 5017 matched controls (5:1 ratio); median age, 61 years, body mass index, 28.4 kg/m². Adjusted Cox proportional hazard modeling demonstrated PCOS participants had greater incident T2D [hazard ratio (HR) 1.47; 95% confidence interval (CI), 1.11-1.95] and all-cause CVD (1.76; 1.35-2.30). No between-group differences existed for cancers or dementia. Liver MRI confirmed more PCOS participants had hepatic steatosis (proton density fat fraction &amp;gt;5.5%: 35.9 vs 23.9%; P = .02) and higher fibroinflammation (corrected T1 721.4 vs 701.5 ms; P = &amp;lt;.01) vs controls. No between-group difference existed for cardiac (biventricular/atrial structure and function) or brain (grey and white matter volumes) imaging. Normoandrogenic (but not hyperandrogenic) PCOS participants had greater incident all-cause CVD (1.82; 1.29-2.56) while hyperandrogenic (but not normoandrogenic) PCOS participants were more likely to have hepatic steatosis (8.96 vs 6.04 vs 5.23%; P = .03) with greater fibroinflammation (776.3 vs 707.7 vs 701.9 ms; P=&amp;lt;.01). Conclusion Cardiometabolic disease may be increased in PCOS patients with a disease phenotype-specific pattern.

Case Series: Severe meibomian gland loss in polycystic ovarian syndrome patients on estrogen-progesterone therapy: A case series

Purpose: To report the ocular surface and meibomian gland changes in polycystic ovarian syndrome (PCOS) women taking hormone supplementation. Methods: Case series. Results: Three women (27 ± 11 years) already diagnosed with PCOS presented with dry eye symptoms (mean OSDI, 37.5) for a mean duration of 13 months and were taking hormonal supplements for a mean duration of 60 ± 11 months. The hormonal supplements included oral estrogen (n=3), oral progesterone (n=3), antiandrogen cyproterone (n=1) and isotretinoin (n=1). Ocular surface evaluation revealed mean NIBUT of 9.9 ± 1.6 seconds and mean TMH of 0.27 ± 0.05 mm, assessed non-invasively using Oculus keratograph 5M (K5M). Meibography (K5M) showed near total loss of all meibomian glands (n=8/12 eyelids) with residual ghost glands in all four eyelids of two patients, and gland shortening alone in one patient. The gland morphology did not change following intense thermal pulsation treatment or cessation of hormonal therapy. Conclusions: Near-total irreversible meibomian gland loss was seen in two young PCOS women taking hormonal supplements. Collaboration between ophthalmologists and gynecologists is advisable for early detection and better understanding of dry eye disease (DED) progression in these patients.

Association between Coffee Consumption and Polycystic Ovary Syndrome: An Exploratory Case-Control Study.

Polycystic ovary syndrome (PCOS) is a leading cause of infertility, with an estimated worldwide prevalence between 5% and 15%. We conducted a case-control study with 121 PCOS patients and 155 controls to assess the association between coffee intake and the presence of having a diagnosis of PCOS in women in Murcia, Spain. The PCOS diagnosis was determined following Rotterdam criteria (the presence of two of the following three conditions: hyperandrogenism, oligo-anovulation, and/or polycystic ovarian morphology). Coffee consumption was assessed using a validated food frequency questionnaire. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multiple logistic regression. Coffee consumption was categorized into never, less than one cup per day, one cup per day, and two or more cups per day. We found a significant inverse linear trend: the higher the coffee consumption, the lower the probability of having PCOS in multivariable analysis (p-trend = 0.034). Women who presented with PCOS were less likely to drink one cup of coffee compared to those who had never drunk coffee (OR = 0.313, 95% CI: 0.141-0.69). The consumption of at least one cup of coffee per day may be associated with a decrease in PCOS symptoms.

CYP21A2 Intron 2 Genetic Variants Might Be Associated with the Clinical Characteristics of Women with PCOS.

Pathogenic variants in the CYP21A2 gene are related to the classic and non-classic forms of congenital adrenal hyperplasia (CAH). However, the role of CAH carrier status in the clinical presentation of polycystic ovarian syndrome (PCOS) is still unclear. Moreover, the possible associations of different CYP21A2 gene polymorphisms with metabolic and reproductive abnormalities in PCOS have not been investigated. Therefore, the present study aims to examine the prevalence of the most common CYP21A2 pathogenic variant IVS2-13A/C>G (c.293-13A/C>G) in Eastern European women with PCOS and to evaluate the associations between common intron 2 genetic polymorphisms and the clinical symptoms of the patients. Sixty consecutively recruited women with PCOS were genotyped for the CYP21A2 intron 2 IVS2-13A/C>G genetic variant. Additionally, CYP21A2 intron 2 polymorphic variants rs6453 (c.293-44G>T), rs6451 (c.293-67C>A/G), rs369651496 (c.293-104del), and rs6474 (c.308G>A/p.R103L) were tested and described. The clinical and hormonal characteristics were compared in women with PCOS and with polymorphic and wild-type genotypes. The heterozygous CYP21A2 pathogenic variant IVS2-13A/C>G was found in one of the investigated PCOS patients (1.67%) with a non-hyperandrogenic type of PCOS. The presence of the rs6453 (c.293-44G>T) T-allele was associated with increased levels of DHEAS (15.18 vs. 9.14 µmol/L, p = 0.003) compared to the wild-type genotype in the investigated group. The rs6451 (c.293-67C>A/G) minor alleles were associated with an earlier age of menarche in the patients (12.0 vs. 13.0 years, p = 0.007). The polymorphic rs369651496 minor 6G allele was related to a better lipid profile in the women with PCOS, while the rs6474 variant modulated the blood pressure of the patients. The presence of CYP21A2 genetic minor alleles of rs6467 (IVS2-13A/C, c.293-13A/C), rs6453 (c.293-44G>T), rs6451 (c.293-67C>A/G), rs369651496 (c.293-104del), and rs6474 (c.308G>A/p.R103L) might modulate the adrenal androgens, age of menarche, and metabolic features in women with PCOS. Further studies on 21-hydroxylase genetic variants (pathogenic and polymorphisms) in different ethnic groups might help reveal the influence of adrenal steroidogenesis on PCOS development, clinical manifestations, and lifelong cardiovascular risks.

Comparison of the Effect of Fenugreek and Metformin on Clinical and Metabolic Status of Cases with Polycystic Ovary Syndrome: A Randomized Trial.

It is hypothesized that fenugreek seeds are a rich source of fiber with anti-diabetic effects, which can help to lower blood glucose in patients with polycystic ovary syndrome (PCOS). In this study, the clinical and metabolic effects of fenugreek were compared to those of metformin in women with PCOS aged 16-40 years. In a randomized, triple-blind, parallel clinical trial, the efficacy of fenugreek 333 mg (n=55) was compared with metformin 500 mg (n=55), both administered three times a day in women with PCOS of reproductive age. Changes in some clinical outcomes and metabolic laboratory profile outcomes were evaluated at baseline and two months after the study. By the end of the intervention period, all investigated factors improved significantly in patients of both groups (p<0.05). Reduction in biometric indices (body mass index and waist-hip ratio), fasting blood sugar (FBS), and insulin resistance was significantly higher after metformin consumption (p<0.001). Metformin also significantly improved irregular menstruation (p=0.02). In contrast, fenugreek significantly improved patients' lipid profiles, including low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride (TG) compared to metformin (p<0.001). Both interventions improved the patient's hair loss and hirsutism. Fenugreek cannot substitute metformin in PCOS treatment. However, regarding its lipid-lowering ability and low frequency of adverse effects, it can be used as an adjuvant treatment in PCOS, especially in PCOS patients with hyper-lipidemia and severe hair loss.

P-679 The impact of polycystic ovary syndrome (PCOS) on placental pathology among singleton livebirths conceived following in-vitro fertilization (IVF) or ovulation induction/intrauterine insemination (OI/IUI) treatments

Abstract Study question Are there differences in placenta pathology between PCOS and non-PCOS infertility diagnosis among singleton livebirths conceived following either IVF or OI/IUI treatments? Summary answer PCOS diagnosis when compared to non-PCOS exhibits distinctive associations within the anatomic and vascular spectrum of placental pathology. What is known already Pregnancies of women with PCOS are at higher risk for maternal and neonatal morbidity. Available studies suggest a possible association of PCOS with hypoxia-induced placental findings among natural conceptions, and a possible role of chronic, low-grade inflammation on decidualization, trophoblast invasion, and placental vascularization. Given the high prevalence of PCOS among women seeking fertility treatments there is significant interest in human placental research. Nevertheless, the impact of PCOS on placental pathology among singleton livebirths conceived with fertility treatments remains unclear. Study design, size, duration Retrospective review of data from 1398 singleton livebirths with available placenta pathology. All pregnancies were conceived following fertility treatments (IVF:1004, OI/IUI: 394) at an academic fertility center and were delivered at the same hospital between 01/2004 and 04/2022. 1196 patients had an infertility diagnosis other than PCOS (uterine factor excluded) and 193 had been diagnosed with PCOS (based on Rotterdam criteria). Placenta pathology (classified as below) was compared between PCOS and non-PCOS patients. Participants/materials, setting, methods Placental findings were reviewed by one expert pathologist and classified further as anatomic, inflammatory, infectious, and vascular [including any features of fetal(FVM) or maternal(MVM) vascular malperfusion], using the Amsterdam Workshop Consensus definitions. Primary outcomes: anatomic, inflammatory, infectious, and vascular. Parametric/non-parametric tests were used as appropriate. Adjusted odds ratios(adjOR) with 95% confidence intervals (95%CI) were calculated utilizing logistic regression, controlling for potential confounders. Subanalyses were performed separating IVF from OI/IUI-conceptions, and fresh from frozen embryo transfers(FET). Main results and the role of chance PCOS compared to non-PCOS patients were younger, with higher BMI and AMH [mean (SD): 32.9(3.5) vs 35.1(3.8) years, p &amp;lt; 0.001; 26.1(5.5) vs 24.8(5.5)kg/m2, p = 0.003; 9.1(5.8) vs 3.5(3.4)ng/ml, p &amp;lt; 0.001, respectively]. Overall, neither unadjusted rates (35.2% vs 28.8%, p:0.072; 15.9% vs 11.8%, p = 0.115; 21.8% vs 20.0%, p = 0.568; 51.0% vs 57.3%, p = 0.103, PCOS vs. non-PCOS, respectively), nor adjOR (95%CI) [1.02(0.94-1.1), 1.01(0.95-1.08), 1.02(0.94-1.09), 0.96(0.88-1.05), non-PCOS: ref] showed any differences between groups in anatomic, inflammatory, infectious, and vascular abnormalities, respectively. When separating IVF from OI/IUI-conceptions, and fresh transfers from FETs, adjOR(95%CI) revealed no differences between groups in anatomic, inflammatory, and infectious abnormalities [OI/IUI: 1.01(0.87-1.16), 1.0(0.88-1.13), 1.0(0.88-1.13); Fresh ET: 1.01(0.9-1.14), 1.02(0.95-1.1), and 0.95(0.85-1.05); FET: 1.16(0.96-1.4), 1.0(0.87-1.16), and 1.11(0.93-1.33), for anatomic, inflammatory, and infectious abnormalities, respectively, non-PCOS: ref]. Interestingly, a lower rate of vascular abnormalities was noted among PCOS patients in OI/IUI [adjOR(95%CI): 0.83(0.73-0.96)], but not among fresh or FET cycles [adjOR(95%CI): 1.05(0.91-1.19), and 0.97(0.8-1.18), respectively]. In FET cycles, within vascular abnormalities, lower rates of high grade FVM among PCOS patients were noted [adjOR(95%CI): 0.96(0.93-0.99)]. Furthermore, and although anatomic abnormalities did not differ between groups, a lower incidence of single umbilical artery [adjOR(95%CI): 0.98(0.96-0.99)] was noted among PCOS patients in IVF cycles. Limitations, reasons for caution The study is limited by its retrospective design and focuses on an infertile population undergoing treatments, limiting generalizability. Comparisons with PCOS patients conceiving naturally may provide meaningful insights. Variability among PCOS phenotypes, and other environmental, and lifestyle factors might also alter a patient’s individual pregnancy risk for placental abnormalities. Wider implications of the findings PCOS may impact placental pathology in a distinct way, within the anatomic and vascular spectrum, which might differ from that of other infertility causes and might be further altered by the treatment protocol. Our study adds to the limited human placental research specific to pregnancy of women with PCOS. Trial registration number Not Applicable

O-257 Comparing the accuracy of the novel clustering model versus phenotype classification in predicting live birth in polycystic ovary syndrome women undergoing In-Vitro fertilization

Abstract Study question Is the clustering model more accurate than phenotype classification in predicting live birth in polycystic ovary syndrome (PCOS) women undergoing in vitro fertilization (IVF)? Summary answer Novel PCOS clusters, identified by patients’ endocrine and metabolic profiles, more accurately predict live birth rates in women undergoing IVF than the traditional phenotype classification What is known already PCOS is a heterogeneous condition that affects fertility and IVF success. It is classified based on three factors: hyperandrogenism (HA), ovulatory dysfunction (OD), and polycystic ovaries (PCOM). The ESHRE/ASRM classification system identifies four phenotypes: A (including all three factors), B (HA and OD), C (HA and PCOM), and D (OD and PCOM). Although this classification is widely used, its focus solely on clinical signs and symptoms, while neglecting underlying endocrine and metabolic factors, may limit its effectiveness in predicting fertility outcomes in PCOS patients. Therefore, classifying PCOS patients may require a more comprehensive and inclusive assessment approach. Study design, size, duration This prospective cohort study was conducted from June 2020 to August 2022 at a tertiary IVF center in Ho Chi Minh City, Vietnam. Clustering models were built based on the endocrine and metabolic profiles of 731 PCOS patients. Patients were grouped into novel clusters based on their endocrine and metabolic profiles and compared with traditional phenotypes classification. The primary outcome measured was the live birth rate. Participants/materials, setting, methods Patients aged 18–45, diagnosed with PCOS according to the Rotterdam 2003 criteria, and undergoing IVF treatment were included in the study. Patients with hypothyroidism, Cushing’s syndrome, congenital adrenal hyperplasia, or contraindications to hormonal treatment were excluded. We employed Gaussian Mixture Models for clustering, using endocrine and metabolic data as the key features. We then compared the accuracy of the clustering model with phenotype classification in predicting IVF outcomes using a logistic regression model. Main results and the role of chance We identified three distinct clusters among polycystic ovary syndrome (PCOS) patients. Cluster 0 (n = 298) was characterized by significant insulin resistance and dyslipidemia. Cluster 1 (n = 219) displayed the lean PCOS phenotype, and Cluster 2 (n = 214) had moderate insulin resistance with severe hyperandrogenism. Our findings indicated that Clusters 1 and 2 had a higher cumulative live birth rate (CLBR) (39.7% and 37.9% versus 28.5% in Cluster 0, p = 0.015) and lower gestational diabetes rates (8.68% and 6.07%, respectively) compared to Cluster 0 (12.4%, p = 0.048). Additionally, the prevalence of hypertensive disorders during pregnancy showed differences across clusters (3.69% in Cluster 1, 0.46% in Cluster 2, and 2.8% in Cluster 0, p = 0.059). In contrast, the traditional phenotype classification did not demonstrate significant differences in CLBR, gestational diabetes, and hypertensive disorders. The cluster-based method provided a more accurate prediction of CLBR using logistic regression, with an AUC of 0.67 (95% CI: 0.57-0.76) compared to 0.49 (95% CI: 0.41-0.59) for traditional classifications (p = 0.001) Limitations, reasons for caution This is a single-center study conducted on Vietnamese patients. Therefore, the generalizability may be limited. The novel clustering’s predictive value for IVF outcomes in PCOS patients requires further validation in prospective studies. Wider implications of the findings This study suggests a potential shift towards personalized IVF treatment strategies for PCOS, using machine learning-based PCOS clustering identified by patients’ endocrine and metabolic profiles. Trial registration number NCT04364087

COVID-19 and the need for special care for women with polycystic ovary syndrome: A systematic review

Objective The study investigates the association between coronavirus disease 2019 (COVID-19) and polycystic ovary syndrome (PCOS) and assess whether women with PCOS are at a higher susceptibility and risk for COVID-19 complications. Methods This review analyzes articles indexed in PubMed, Scopus, Google Scholar, and the Cochrane Library, focusing on the onset of the COVID-19 pandemic in December 1, 2019, until November 1, 2022. The quality of the evidence was assessed using the NIH quality assessment tool. The study was registered on PROSPERO (CRD42023371956) on January 12, 2023. Results A total of 11 observational studies were identified, totaling 22,155 PCOS patients. Despite the heterogeneity of the included studies, the findings of most of the studies were similar in terms of increased susceptibility and severity of COVID-19 infection in PCOS patients. PCOS patients were reported to have a 51% higher risk of COVID-19 infection than non-PCOS women (HR =1.51). Many causes have been identified to play a role, most notably the overactivation of the renin-angiotensin system (RAS) and elevated levels of RAS-associated proteins, decreased serum levels of neuropilin-1 (sNRP1), elevated serum biomarkers such as platelet degranulation and coagulation cascade markers increased acute phase response, and lower levels of vitamin D could render PCOS patients susceptible to a chronic inflammatory state, which can also lead to difficulties and severe consequences, when impacted by COVID-19. Furthermore, the COVID-19 pandemic also influenced psychological well-being, with an increase in the incidence and severity of depression and anxiety among PCOS patients in the COVID-19 pandemic era compared to healthy individuals. Conclusions Patients with PCOS are more likely to get infected with COVID-19 and display a higher affinity to severe infections and complications due to overlapping and confounding factors. These findings suggest that PCOS patients may need more medical attention when infected with COVID-19.

O-193 Age-related normograms of AMH in women with polycystic ovary syndrome using three different assays

Abstract Study question To develop an age-specific percentile distribution of anti-Müllerian hormone (AMH) in patients with polycystic ovary syndrome (PCOS) measured by three different assays. Summary answer Our age-related normograms may help to interpret AMH levels in PCOS patients and facilitate the use of AMH as a diagnostic tool across age ranges. What is known already In the last years, AMH assessment has gained widespread use in the clinical settings of several conditions. However, several challenges still exist to adopt the AMH as a marker of polycystic ovary morphology (PCOM), as included in the recently updated international guideline. Although different evaluations of age- and assay-specific reference ranges have been published in the last years, these studies have mainly been conducted in normo-ovulatory or infertile women and little is known about the higher range of AMH levels, especially in women with PCOS. Study design, size, duration Retrospective single-center cross-sectional study, including 2,725 women with PCOS who consulted the Reproductive Endocrinology and Infertility Clinic of the Erasmus University Medical Center, Rotterdam, The Netherlands. Participants/materials, setting, methods A total of 2,725 women aged 20 to 40 years with PCOS were included. PCOS was diagnosed according to the Rotterdam Criteria. Serum AMH levels were measured using the following AMH assays: (1) Gen II AMH ELISA, 2) picoAMH assay, and 3) Elecsys AMH plus assay. Age-specific centile curves were constructed using the LMS method. The correlations between AMH with clinical, endocrine, and ultrasound features were also evaluated. Main results and the role of chance To our knowledge, this is the first study with real-world data reporting AMH age-specific percentile nomograms in a large population of PCOS women using three different assays. The 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles were calculated according to a population/based approach per age (years) for the Gen II, the picoAMH, and the Elecsys assays. We also considered the age-percentile values of AMH in PCOS patients for the Gen II, the picoAMH and the Elecsys assays according to the cut-offs previously proposed in literature for each specific assay. Interestingly, in our population, a high percentage of women with polycystic ovarian morphology (PCOM) showed AMH levels lower than the cut-offs proposed. Serum AMH levels were significantly higher in patients with phenotype A compared to all other phenotypes for all three assays. For all three assays, we found a statistically significant positive correlation between AMH levels and LH, LH/FSH ratio, testosterone, androstenedione, FAI, mean follicular number, and mean ovarian volume. In contrast, AMH levels were negatively correlated with BMI in all groups. Limitations, reasons for caution This is a retrospective cross-sectional study. Longitudinal studies with a large cohort of women that could be followed for many years are needed to validate our nomogram. Wider implications of the findings AMH threshold levels can be influenced by several variables, making it difficult to identify a general cut-off to diagnose PCOM. Further research should overcome the concept of a single cut-off value. The results of the present study may help clinicians interpret AMH levels in PCOS patients across age ranges. Trial registration number In this retrospective cross-sectional study, 2,725 women who consulted the Reproductive Endocrinology and Infertility Clinic of the Erasmus University Medical Center, Rotterdam, The Netherlands, were included. The Medical Ethical Review Board of the Erasmus University Medical Center Rotterdam approved retrospective studies within this patient population, which includes women with ovulatory dysfunction (MEC-2020-0534).