Evaluation of Etiological Factors Associated With Abnormal Uterine Bleeding Among Teenage Girls in a Tertiary Care Center: A Cross-Sectional Study.

BACKGROUND: Abnormal uterine bleeding (AUB) refers to irregularities in the frequency, regularity, duration, and volume of menstrual cycles, impacting about one-third of women at some point in their lives, during menarche and perimenopausal periods. This study aims to evaluate the various causes of menstrual disorders in teenage girls. MATERIALS AND METHODS: This cross-sectional study was conducted in the Department of Obstetrics and Gynecology at AVMCH, Pondicherry, with ethical clearance. It included 150 girls aged 13-18 years who presented with menstrual disorders. Data were collected through structured interviews and clinical evaluations, focusing on menstrual history, socioeconomic status, associated symptoms, and investigations. Statistical analysis was performed using IBM SPSS Statistics for Windows, Version 23 (Released 2015; IBM Corp., Armonk, New York, United States). RESULTS: Among the etiological factors, 61.3% of patients had anovulatory dysfunction, 16.6% had early onset of PCOS, 6% of patients had hypothyroidism, 16% had ovulatory dysfunction, and 0.6% had coagulation disorder. Overall, ovulatory dysfunction (AUB-O) was predominant in teenage girls. CONCLUSION: This study helps in the early identification of the etiology of adolescent AUB and the appropriate management of menstrual disorders to improve well-being and enhance reproductive function in the future.

Prevalence and accurate diagnosis of polycystic ovary syndrome (PCOS) in adolescents across world regions: a systematic review and meta-analysis.

OBJECTIVES: To examine the global prevalence of PCOS among adolescents across world regions, comparing the 2003 Rotterdam consensus criteria with the current International Evidence-based PCOS Guideline criteria which omits polycystic ovarian morphology (PCOM). DESIGN: Systematic review and meta-analysis, Prospero CRD42022372029. METHODS: OVID MEDLINE, All EBM, PsycInfo, EMBASE and CINAHL were searched from 1990 to November 2023 for studies assessing the prevalence of PCOS in unselected adolescent populations. RESULTS: Overall, 15708 articles were identified. After removal of duplicates, 11868 titles and abstracts and 445 full texts were assessed. Of these, 24 articles reporting on 23 studies from five world regions were included. In meta-analysis of 20 studies (n=14010 adolescents), global prevalence was 9.8% (95% CI 7.2, 12.3) according to original Rotterdam criteria, and 6.3% (95% CI 3.9, 8.8) according to International Evidence-based Guideline criteria. Global PCOS prevalence based on self-report was 9.8% (95% CI 5.5, 14.1).Grouped by WHO region, prevalence ranged from 2.9% (95% CI 2.0, 3.9) in the Western Pacific region to 11.4% (95% CI 7.1, 15.7) in the South-East Asia region according to guideline criteria. CONCLUSION: This paramount global meta-analysis on adolescent PCOS diagnosis directly informed the 2023 International PCOS Guideline. Guideline criteria generated a global PCOS prevalence of 6.3%, compared with 9.8% on Rotterdam criteria (including PCOM). Excluding PCOM, which overlaps with normal pubertal transition, is expected to deter over-diagnosis. To avoid under-diagnosis, the Guideline recommends identifying those with either irregular cycles or hyperandrogenism as being "at risk"; this group should undergo longitudinal serial evaluations until adulthood.

Association of Hyperandrogenaemia With Hypertension and Cardiovascular Events in Pre-menopausal Women- A Prospective Population-Based Cohort Study.

OBJECTIVE: The present study aimed to clarify the conflicting association of premenopausal hyperandrogenaemia (HA) with the development of hypertension and CVDs in women. DESIGN: A population-based cohort study including 5889 women. METHODS: The association of serum testosterone (T), sex hormone-binding globulin (SHBG), and free androgen index (FAI) at age 31 with blood pressure (BP) and hypertension (BP ≥140/90 mmHg and/or use of antihypertensive medication) at ages 31 and 46 and with CVDs (angina pectoris [AP] and/or acute myocardial infarction [AMI] n=74, transitory cerebral ischemia [TIA] and/or stroke n=150) and combined CVD events (AP, AMI, stroke, heart failure, or CVD mortality n=160) by age 53 was investigated. RESULTS: T and FAI were positively associated with systolic and diastolic BP at ages 31 and 46 in the multivariable model. Compared to their lowest quartile, the highest quartiles of T and FAI were positively associated with hypertension at age 31 in the multivariable model. During the 22-year follow-up, FAI was positively associated with increased risk of AP/AMI (hazard ratio [HR]:2.02, 95%CI:1.06-3.85) and overall CVD events or mortality (HR:1.54, 95%CI:1.02-2.33) in the unadjusted models. However, the significance disappeared after adjusting for BMI. CONCLUSIONS: Women with HA at premenopausal age had an elevated risk of hypertension, and together with BMI, increased risk of CVD events and CVD mortality during the 22-year follow-up. However, because of several study limitations regarding ethnicity and BMI characteristics, a longer follow-up of this cohort and future studies in ethnically diverse populations are needed to verify the results.

Evaluating the diagnostic accuracy of androgen measurement in polycystic ovary syndrome: a systematic review and diagnostic meta-analysis to inform evidence-based guidelines.

BACKGROUND: Biochemical hyperandrogenism is a hallmark and diagnostic feature of polycystic ovary syndrome (PCOS). However, the most accurate androgen measurement for assessing biochemical hyperandrogenism in PCOS diagnosis remains uncertain. OBJECTIVE AND RATIONALE: This systematic review aimed to assess different androgen measures [including total testosterone (TT), calculated free testosterone (cFT), free androgen index (FAI), androstenedione (A4), dehydroepiandrosterone sulfate (DHEAS), and dihydrotestosterone (DHT)] for accuracy in diagnosing biochemical hyperandrogenism in women with PCOS, to inform the 2023 International PCOS Evidence-based Guidelines. SEARCH METHODS: To update evidence from the 2018 International PCOS Guidelines, a systematic search from 3 July 2017 to 23 June 2023 was conducted across Medline (Ovid), CINAHL, all EBM, EMBASE, and PsycInfo for articles evaluating androgens in the diagnosis of biochemical hyperandrogenism. The revised Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) was used to assess the risk of bias and applicability. A diagnostic test accuracy meta-analysis was performed using STATA 18 software. Summary sensitivity and specificity were calculated with 95% CIs using the bivariate model, while the hierarchical summary receiver operating characteristics (ROC) model was used to produce a summary ROC curve. OUTCOMES: Of 23 studies reviewed, 18 were included in the meta-analysis, with data from 2857 participants (1650 with PCOS and 1207 controls). For diagnosing biochemical hyperandrogenism in PCOS, the pooled sensitivity, specificity, and AUC with 95% CI were for TT: 0.74 (0.63-0.82), 0.86 (0.77-0.91), and 0.87 (0.84-0.90); cFT: 0.89 (0.69-0.96), 0.83 (0.79-0.86), and 0.85 (0.81-0.88); FAI: 0.78 (0.70-0.83), 0.85 (0.76-0.90), and 0.87 (0.84-0.90); A4: 0.75 (0.60-0.86), 0.71 (0.51-0.85), and 0.80 (0.76-0.83); and DHEAS: 0.75 (0.61-0.85), 0.67 (0.48-0.81), and 0.77 (0.73-0.81), respectively. In subgroup analyses, liquid chromatography with tandem mass spectrometry (LC-MS/MS) had superior sensitivity for measuring cFT, FAI, A4, and DHEAS, and superior specificity for measuring TT, cFT, and FAI, compared to the direct immunoassay method. WIDER IMPLICATIONS: Our results directly informed the 2023 International PCOS Guideline recommendations to use TT and FT as the first-line laboratory tests to assess biochemical hyperandrogenism in the diagnosis of PCOS. cFT should be assessed by equilibrium dialysis or ammonium sulfate precipitation, or calculated using FAI. If TT or cFT are not elevated, A4 and DHEAS could also be considered, noting their poorer specificity. Laboratories should utilize LC-MS/MS for androgen measurement given its high accuracy. Future studies should focus on establishing optimal normative cut-off values in large, unselected, and ethnically diverse cohorts of women. REGISTRATION NUMBER: The review protocol was prepublished in the 2023 PCOS Guideline Technical Report (https://www.monash.edu/__data/assets/pdf_file/0010/3379591/TechnicalReport-2023.pdf).

Association between IL-6 -174 G/C (rs1800795) and IL-1A -889 C/T (rs1800587) cytokine variants with polycystic ovary syndrome in Iranian women: A case-control study.

BACKGROUND AND AIM: Infertility in women has various causes, one of which is ovulation disorders. Polycystic ovary syndrome (PCOS) affecting ovulation is a complex idiopathic disease in which genetic polymorphisms may be involved. This study aimed to investigate the relationship between IL-6 -174 G/C and IL-1A -889 G/A cytokine polymorphisms with polycystic ovary syndrome in a population of Iranian women. MATERIALS AND METHODS: In this case-control pilot study, 120 PCOS patients (60 infertile, LPI, and 60 women with recurrent pregnancy abortion, LPA) and 60 controls, CTRLs) participated. After genomic DNA extraction from peripheral blood, we investigated for the polymorphisms rs1800795 of the IL-6 -174 and rs1800587 of the IL-1A-889 using specific primers and PCR-RFLP followed by NlaIII enzyme digestion and PCR-ARMS techniques. RESULTS: There was a significant difference in the studied groups in terms of clinical characteristics (p-value < 0.05) except for the levels of HDL and LDL. Regarding demographic and clinical characteristics of patients, a significant correlation was observed between C/G and G/G genotypes of rs1800795 and FBS level (p value = 0.002). Also, rs1800587 showed a substantial relationship between CC and CT genotypes with the level of LH in LPI and the level of FBS in the LPAs (p value = 0.04). There was no significant difference between the frequencies of rs1800795 and frequencies of rs1800587 genotypes in the three studied groups (p value > 0.05).The studied variants were in Hardy-Weinberg equilibrium. CONCLUSION: The present work showed that rs1800795 and rs1800587 were not directly associated with PCOS in Iranian patients while the SNPs showed an indirect relationship with some factors affecting the disease. However, using genome-wide association analysis is a proper suggestion to obtain more reliable information about the disease's genetic view. To our knowledge, this is the first report that implicates the role of the examined SNPs in an Iranian PCOS population.

Insulin resistance and insulin secretory defect among Bangalee PCOS women: a case-control study.

Insulin resistance (IR) is a well-recognized covariate of Polycystic Ovarian Syndrome (PCOS) with varying burden and risk factors among populations. The relationship of insulin secretory defect or ISD with PCOS is less understood. The presence of IR and ISD as well as their covariates have been explored in the present case-control study among young adult to early middle-aged, normal weight to obese, Bangalee women with PCOS. A number of 158 PCOS [age 23 (15-34) years, Median (Range)] and 126 Non-PCOS [24 (19-34) years] females were recruited purposively with PCOS diagnosed following Modified Rotterdam Criteria 2003. Hormones were measured by CLIA method and lower abdominal ultrasonography was done by trained personnel. IR and ISD were assessed by homeostasis model assessment with 75th percentile values of HOMA-IR (2.4) and HOMA%B (143) in Non-PCOS group considered as the cut-off values. Hyperandrogenism (HA) was measured by calculating Fasting Androgen Index (FAI). HOMA-IR was high among 52% of PCOS and 28% of Non-PCOS women. Body Mass Index (BMI) and HA were independently associated covariates of IR (p < 0.001). HOMA%B was compromised among 48% of PCOS subjects and the deficiency showed independent association (p < 0.001) with 2 h glycemia on OGTT in Non-PCOS and HA in PCOS groups. The data suggest insulin resistance as a major risk factor for PCOS among Bangalee women with obesity and hyperandrogenemia as its major covariates. The findings also indicate that presence of impaired insulin secretion is a major determinant of hyperglycemia and, consequently, of higher T2DM risk among young women in this population.

Evaluation of Digit Ratios in Youth With Polycystic Ovary Syndrome.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is a common syndrome often observed during adolescence, characterized by ovulatory dysfunction and hyperandrogenism. It is determined that, when female fetuses are exposed to high levels of androgens, it increases their likelihood of developing PCOS in later ages. The 2D:4D digit ratio, which measures the length of the index finger compared to the ring finger, is a precise anatomical indicator of the degree of prenatal androgen exposure. Higher digit ratios in individuals have been associated with outcomes typically attributed to females. In the adolescent age group, the relationship between PCOS and androgen exposure during the antenatal period is not clear. AIM: The study was aimed to evaluate digit ratios in adolescents with PCOS. METHODS: The study included 38 adolescent girls with PCOS, and 40 healthy adolescent girls were selected as the control group. The digit ratio (2D:4D) was evaluated by digital calipers, and the digit ratios of the patient and control groups were compared. RESULTS: The mean age in the PCOS group was 15.99±1.18 years, while the control group had a mean age of 16.02±1.06 years. The right-hand 2D:4D digit ratio was significantly lower in the PCOS group (0.93±0.02) compared to the control group (1.00±0.01, p<0.001). Similarly, the left-hand 2D:4D digit ratio was also lower in the PCOS group (0.98±0.03) compared to the control group (1.00±0.01, p<0.001). There was a moderate negative correlation between the left-hand 2D:4D ratio and the modified Ferriman-Gallwey score (mFGS) (r=0.53, p=0.01). Nevertheless, there was not a significant association found between the 2D:4D ratio of the right hand and mFGS. CONCLUSION: This study demonstrates that PCOS patients have significantly lower both-hand 2D:4D ratios than healthy controls, suggesting prenatal androgen exposure. Recognizing anatomic markers in adolescence may predict the development of PCOS. The findings align with previous research linking low digit ratios to androgen exposure and various reproductive outcomes.

Evaluation of carotid artery elasticity and its influencing factors in non-obese PCOS patients using a technique for quantitative vascular elasticity measurement.

Objectives: To evaluate the intima-media thickness (IMT) and elasticity of the carotid artery in non-obese polycystic ovary syndrome (PCOS) patients using a quantitative technique for vascular elasticity measurement and to explore the influencing factors. Methods: Sixty non-obese patients without metabolic and cardiovascular diseases who were diagnosed with PCOS in the Women and Children's Hospital of Chongqing Medical University from January to December 2022 were prospectively selected (case group), and 60 healthy volunteers matched for body mass index were included as the control group. Body weight, height, heart rate, blood pressure, and waist-to-hip ratio were recorded. Fasting blood samples were drawn from the elbow vein to measure hormone levels including total testosterone (TT), sex hormone-binding globulin (SHBG), fasting plasma glucose (FPG), fasting insulin (FINS), lipids, and homocysteine (Hcy). The insulin resistance index (HOMA-IR) and free androgen index (FAI) were calculated. Ultrasound elastography was used to measure the IMT and elastic function parameters of the right carotid artery, including vessel diameter, wall displacement, stiffness coefficient, and pulse wave velocity. Differences in various parameters between the two groups were analyzed, and correlations between the carotid stiffness coefficient and other serological indicators were assessed using Spearman correlation analysis. Results: No significant differences in age, body mass index, heart rate, systolic blood pressure, and diastolic blood pressure were observed between the two groups (all P>0.05), while the waist-to-hip ratio (WHR) was higher in the case group than in the control group (P<0.05).The hormone level serological indicators TT and FAI were higher in the case group than in the control group, and SHBG was lower in the case group than in the control group (all P<0.05). The metabolism-related serum indicators LDL-C, HDL-C, FPG, triglycerides, and total cholesterol levels were not statistically different between the two groups (all P>0.05), and serum FINS, HOMA-IR, and Hcy levels were significantly higher in the case group than in the control group (all P<0.05).No significant difference in carotid artery diameter was observed between the case group and control group (P>0.05). The carotid artery displacement in the case group was significantly smaller than that in the control group (P<0.05), and carotid IMT, hardness coefficient, and pulse wave propagation velocity were greater in the case group than in the control group (all P<0.05). The carotid elastic stiffness coefficient was positively correlated with WHR, TT, SHBG, FAI, FINS, HOMA-IR and Hcy to varying extents and negatively correlated with SHBG. Conclusion: In non-obese PCOS patients with no metabolic or cardiovascular disease, the carotid stiffness coefficient was increased and correlated with indicators of hyperandrogenism, insulin resistance, and hyperhomocysteinemia.

Hyperandrogenic eumenorrheic NON-PCOS women versus women with PCOS after the GnRH-agonist stimulation test preceded by suppression of adrenal steroidogenesis with dexamethasone.

The subject of polycystic ovary syndrome (PCOS) has been extensively covered in the literature; however, there is a paucity of data regarding eumenorrheic women with hyperandrogenism and/or hyperandrogenemia without ultrasound evidence of PCO morphology (EuHyperA), and even less data on the comparison between PCOS and EuHyperA subjects. It has previously been shown that around half of PCOS women exhibit a hyper-response of serum 17-hydroxy-progesterone (17-OHP) to the stimulation by GnRH-agonists, also indicated as functional ovarian hyperandrogenism (FOH). Often, this stimulation test is preceded by suppression of the adrenal steroidogenesis with oral dexamethasone (Dex). FOH has been associated with an increase of the P450c17 activity in the ovaries driven by elevated insulin levels. Interestingly, treatment of women with PCOS with Dex suppression and GnRH-agonist stimulation (buserelin) highlighted the possible existence of two clusters of patients: hyper-responders (HR) and normal responders (NR). In this retrospective study, we included 15 hyper-responders (HR) EuHyperA, 34 normal responders (NR) EuHyperA, 62 HR-PCOS and 45 NR-PCOS. The demographic characteristics, glucose-metabolism indices, and the hormonal response to Dex or buserelin were analyzed, with both intra-group and inter-group comparisons performed. The rate of FOH was significantly greater in PCOS than EuHyperA women. Compared to HR-PCOS, HR-EuHyperA had [i.] significantly greater age at observation; [ii.] lower cortisol, 17-OHP, Δ4-androstenedione (Δ4-ASD), total testosterone (TT), LH, and buserelin-stimulated whole curve of dehydroepiandrosterone sulfate (DHEAS), 17-OHP, Δ4-ASD and TT. Compared to NR-PCOS, NR-EuHyperA had [i.] significantly greater FSH, and buserelin-stimulated whole curve of DHEAS; [ii.] significantly lower post-HD Dex Δ4-ASD, TT, buserelin-stimulated whole curve of 17-OHP, Δ4-ASD and TT. Compared to NR-PCOS, HR-PCOS had [i.] significantly greater body mass index (BMI), homeostasis model assessment for insulin resistance (HOMA-IR), cortisol, DHEAS, Δ4-ASD, TT, FT, FAI, E2, and insulin AUC0-120min (area under the curve) at oral glucose tolerance test (OGTT); [ii] higher levels of post-LD and post-HD Dex 17-OHP, Δ4-ASD, TT, post-HD Dex DHEAS (with greater levels indicating weaker adrenal suppression), whole curve of DHEAS, 17-OHP, Δ4-ASD, TT and LH; [iii] significantly lower sex-hormone binding globulin (SHBG). Even if most of the parameters evaluated were statistically similar in the two sets of comparisons, interesting differences were observed. Women with PCOS exhibit higher androgen levels at baseline, after adrenal suppression and at the buserelin test, further to a higher ovarian volume. Of note, the percentage of women with HOMA-IR≥2.5 and serum insulin levels were greater in PCOS group compared to EuHyperA women. Moreover, within women with PCOS, the HR subgroup has higher insulin levels compared to the NR subgroup, when OGTT is performed. The alteration of the glucose-insulin balance and elevation of circulating androgens were more pronounced in PCOS, thus indicating that [i.] metabolic alterations might be crucial in the onset of PCOS itself and, [ii] EuHyperA might represent a milder form of PCOS.

Association of candidate gene (INSR & THADA) polymorphism with polycystic ovary syndrome: meta-analysis and statistical power analysis.

Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder that impacts women before reaching menopause. In addition to notable features (irregular ovulation, elevated androgen levels, and the existence of numerous ovarian cysts), individuals with PCOS frequently encounter diverse metabolic, cardiovascular, and psychological conditions. The onset of PCOS is influenced by a combination of factors, and various genetic variations are believed to play a significant role in its progression. The objective of the current study was to explore the link between genetic variations in the candidate genes thyroid-adenoma-associated (THADA) gene and insulin receptor (INSR) and susceptibility to developing PCOS. We conducted an extensive search across various databases, including Google Scholar, PubMed, Science Direct, Scopus, and EMBASE, to compile relevant case-control studies and literature reviews for subsequent statistical analysis. In the present study, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist was followed, a guideline for Systematic Reviews and Meta-Analysis. While a previous meta-analysis explored the correlation between INSR rs1799817 and THADA rs13429458 and their association with susceptibility to PCOS, our current study did not integrate any findings from these prior investigations. Our research encompassed articles published between 2017 and 2023, and we employed MetaGenyo software to assess the collected data. Statistical power analysis was performed using G*Power 3.1 software. Odds ratios and their corresponding 95% confidence intervals were calculated for each genetic model. Fifteen studies that met the criteria were analyzed. Out of these, ten studies, involving 1,189 cases and 1,005 controls, examined the INSR rs1799817 gene polymorphism, while five studies, including 783 cases and 553 controls, investigated the THADA rs13429458 gene polymorphism. The meta-analysis results indicated that there was no statistically significant association between the INSR rs1799817 gene polymorphism and the risk of PCOS (p>0.05). In contrast, the THADA rs13429458 gene polymorphism showed a significant association with PCOS risk under the over-dominant model (p<0.05). The present meta-analysis demonstrated a notable association between the THADA rs13429458 gene polymorphism and the likelihood of developing PCOS. Further rigorous studies with expanded sample sizes and diverse ethnic representation will be important to comprehensively evaluate and validate these findings.

Use of placental-derived mesenchymal stem cells to restore ovarian function and metabolic profile in a rat model of the polycystic ovarian syndrome.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disturbance that affects many women worldwide and is characterized by chronic anovulation, hyperandrogenism, and ovarian dysfunction. Placenta-derived mesenchymal stem cells (PDMSCs) are derived from the placenta and have advantages over other sources of MSCs in terms of availability, safety, and immunomodulation. MATERIALS AND METHODS: In this experimental study, twenty female Wistar rats were assigned to four groups (n = 5) including control, sham, PCOS, and PCOS+PDMSCs groups. Then, PCOS was induced in the rats through administering letrozole for 21 days. PDMSCs (1 × 106 cells) were injected through the tail vein. Fourteen days after the cell infusion, evaluation was performed on the number of healthy follicles, corpus luteum, and cystic follicles as well as the levels of testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), fasting blood glucose, fasting insulin, and insulin resistance. Moreover, the serum levels of cholesterol, triglyceride (TG), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) were measured. Liver function was also determined by the evaluation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. RESULTS: The number of corpus luteum and primordial, primary, secondary, and antral follicles was significantly elevated in the PCOS+PDMSCs group compared to the PCOS group. However, the number of cystic follicles significantly decreased in the PCOS+PDMSCs group. The LH and testosterone levels also decreased significantly, while FSH levels increased significantly in the PCOS+PDMSCs group. The levels of fasting blood glucose, fasting insulin, and insulin resistance notably decreased in the PCOS+PDMSCs group. Moreover, the lipid profile improved in the PCOS+PDMSCs group along with a significant decrease of cholesterol, LDL, and TG and an increase in HDL. The PCOS+PDMSCs group exhibited marked decreases in the AST and ALT levels as well. CONCLUSION: The results of this study suggest that PDMSCs are a potential treatment option for PCOS because they can effectively restore folliculogenesis and correct hormonal imbalances, lipid profiles and liver dysfunction in a rat model of PCOS. However, further research is needed to establish the safety and effectiveness of PDMSCs for treating PCOS.

The Pathophysiological Mechanism and Clinical Treatment of Polycystic Ovary Syndrome: A Molecular and Cellular Review of the Literature.

Polycystic ovary syndrome (PCOS) is a prevalent metabolic disorder among women of reproductive age, characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovaries. The pathogenesis of PCOS involves a complex interplay of genetic and environmental factors, including insulin resistance (IR) and resultant hyperinsulinemia. Insulin receptors, primarily in skeletal muscle, liver, and adipose tissue, activate downstream signaling pathways like PI3K-AKT and MAPK-ERK upon binding. These pathways regulate glucose uptake, storage, and lipid metabolism. Genome-wide association studies (GWASs) have identified several candidate genes related to steroidogenesis and insulin signaling. Environmental factors such as endocrine-disrupting chemicals and lifestyle choices also exacerbate PCOS traits. Other than lifestyle modification and surgical intervention, management strategies for PCOS can be achieved by using pharmacological treatments like antiandrogens, metformin, thiazolidinediones, aromatase inhibitor, and ovulation drugs to improve insulin sensitivity and ovulatory function, as well as combined oral contraceptives with or without cyproterone to resume menstrual regularity. Despite the complex pathophysiology and significant economic burden of PCOS, a comprehensive understanding of its molecular and cellular mechanisms is crucial for developing effective public health policies and treatment strategies. Nevertheless, many unknown aspects of PCOS, including detailed mechanisms of actions, along with the safety and effectiveness for the treatment, warrant further investigation.

Prevalence and diagnosis of polycystic ovary syndrome (PCOS) in adolescents - what's new in 2023? Systematic review.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting approximately 5 to 18% of women of reproductive age and 3 to 11% of teenagers. The diagnostic criteria used in adult patients are not suitable for the diagnosis of adolescent patients, because some of the features may be physiological for puberty, so research is still ongoing to improve the criteria for diagnosing PCOS in teenagers. Polycystic ovary syndrome is associated with hormonal and metabolic changes and may predispose to the occurrence of many other diseases, such as obesity, metabolic syndrome, hypertension, type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). Due to the high prevalence of PCOS and the various health problems it brings, it is necessary to select adolescent girls from the risk group, make an efficient diagnosis, start appropriate treatment, and lead the patient through a lifestyle change as soon as possible. Researchers' attention is increasingly focused on patients presenting with PCOS already in their teenage years. In our work, we want to look at the latest reports regarding the prevalence, pathophysiology and diagnosis of PCOS in adolescent girls.

Metabolic characteristics of different phenotypes in reproductive-aged women with polycystic ovary syndrome.

Objective: Polycystic ovary syndrome (PCOS) is an endocrine metabolic disorder in reproductive-aged women. The study was designed to investigate the metabolic characteristics of different phenotypes in women with PCOS of reproductive age. Methods: A total of 442 women with PCOS were recruited in this cross-sectional study. According to different phenotypes, all women were divided into three groups: the chronic ovulatory dysfunction and hyperandrogenism group (OD-HA group, n = 138), the chronic ovulatory dysfunction and polycystic ovarian morphology group (OD-PCOM group, n = 161), and the hyperandrogenism and polycystic ovarian morphology group (HA-PCOM group, n = 143). The metabolic risk factors and prevalence rates of metabolic disorders among the three groups were compared. Results: The body mass index (BMI), waist circumference, and waist-to-hip ratio (WHR) of women from the OD-HA group and HA-PCOM group were significantly higher than those of women from the OD-PCOM group (p < 0.05). The serum insulin concentration and homeostasis model assessment of insulin resistance (HOMA IR) at 2 h and 3 h after oral glucose powder in women from the OD-HA group and HA-PCOM group were significantly higher than those from the OD-PCOM group (p < 0.05). The serum total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) in women from the OD-HA group and HA-PCOM group were significantly higher than those in women from the OD-PCOM group (p < 0.05). The prevalence rates of impaired glucose tolerance (IGT), type 2 diabetes mellitus (T2DM), insulin resistance (IR), metabolic syndrome (MS), nonalcoholic fatty liver disease (NAFLD), and dyslipidemia of women with PCOS were 17.9%, 3.6%, 58.4%, 29.4%, 46.6%, and 43.4%, respectively. The prevalence rates of IGT, IR, MS, NAFLD, and dyslipidemia of women in the OD-HA group and HA-PCOM group were significantly higher than those of women in the OD-PCOM group (p < 0.05). T concentration (>1.67 nmol/L) and Ferriman-Gallwey (F-G) score (>3) significantly increased the risk of metabolic disorders in women with PCOS (p < 0.05). Conclusion: The phenotypes of OD-HA and HA-PCOM in women with PCOS were vulnerable to metabolic disorders compared to OD-PCOM. Thus, the metabolic disorders in women with PCOS especially those with the HA phenotype should be paid more attention in order to reduce long-term complications.

Practise Updates: Diagnosis and Management of Idiopathic Hirsutism.

Idiopathic hirsutism (IH) is a common clinical condition with multiple diagnostic and therapeutic uncertainties. There are no clear recommendations for the diagnosis and management of the condition. This practice update was developed to guide the primary care physicians and the specialists in better and more systematic management of IH particularly in the Indian context. Twelve experienced members consisting of eminent endocrinologists, physicians, a dermatologist, a gynaecologist and a psychiatrist were invited by the Integrated Diabetes and Endocrine Academy (IDEA). A literature search was performed using online databases from PubMed, Cochrane Library and Google Scholar. Published articles from peer-reviewed indexed journals, with a preference for meta-analyses and randomized controlled trials, were selected. A meeting took place with all the 12 members individually giving their opinions on predetermined questions of interest. After the initial meeting during IDEACON 2023, two more meetings were held and the practice update was formulated after voting. Practice updates were made on important areas such as the cut-off for modified Ferriman-Gallwey Score for the Indian population, conditions to be excluded before diagnosing IH, when to refer to specialists, investigations in a suspected case of IH and choice of therapies for its management.

The Impact of Diet-Induced Weight Loss on Inflammatory Status and Hyperandrogenism in Women with Polycystic Ovarian Syndrome (PCOS)-A Systematic Review and Meta-Analysis.

Background: Currently, the primary strategy for addressing polycystic ovarian syndrome (PCOS) involves lifestyle modifications, with a focus on weight loss. The purpose of this meta-analysis was to assess the impact of weight loss through dietary interventions on inflammatory status and hyperandrogenism in PCOS women. Methods: A comprehensive search was conducted to identify randomised controlled trials (RCTs) and cohort studies assessing the impact of diet-induced weight loss on circulating inflammatory markers (CRP, IL-6, IL-1ß, TNF-α), androgens (testosterone, androstenedione), SHBG, and luteinising hormone (LH) in PCOS women. The quality and risk of bias of the included studies were assessed using the Cochrane Collaboration's tool for RCTs and the Newcastle-Ottawa Scale for cohort studies. Data were entered into RevMan software v5.9 for the calculation of standard mean difference (SMD) and the 95% confidence interval (95%CI) of circulating inflammatory markers, androgens, and LH between baseline and post-weight loss values. Results: Eleven studies (n = 323) were eligible for the systematic review, of which nine (n = 286) were included in the meta-analysis. Pooled analysis of data revealed a statistically significant decrease in circulating CRP (SMD 0.39, 95%CI 0.22, 0.56; 9 studies, n = 286), IL-6 (SMD 0.37, 95%Cl, 0.12, 0.61; 3 Studies, n = 140), TNF-α (SMD 0.30, 95%Cl, 0.07, 0.53; 4 Studies, n = 162), androstenedione (SMD 0.36, 95%Cl, 0.13, 0.60; 4 studies, n = 147) and LH (SMD 0.30, 95% Cl, 0.09, 0.51; 5 studies, n = 197) after weight loss compared to baseline levels among PCOS women. A meta-analysis of five studies (n = 173) showed a statistically significant increase in circulating SHBG after weight loss compared to baseline levels (SMD -0.43, 95%Cl, -0.65, -0.21). Conclusions: These findings suggest that weight loss induced by dietary interventions seems to improve PCOS-related chronic inflammation and hyperandrogenism. The possible causative relationship between the improvement in inflammation and hyperandrogenism remains to be determined.

Hereditary Severe Insulin-resistance Syndrome and Acanthosis Nigricans Caused by Novel Mutations in the INSR Gene.

Most cases associated with Hereditary Severe Insulin Resistance Syndrome (H-SIRS) are linked to mutations in the insulin receptor (INSR) gene. Patients with H-SIRS typically manifest symptoms of hyperinsulinemia, insulin resistance, and diabetes mellitus. Other symptoms include impaired glucose regulation, hyperandrogenism, and the presence of acanthosis nigricans (AN). In this report, we present two cases of H-SIRS in female children exhibiting various symptoms, such as hyperinsulinemia, fasting hypoglycemia, postprandial hyperglycemia, overweight, fatty liver, hyperandrogenism, and varying degrees of AN. One patient also presented with mental retardation. Gene sequencing identified specific mutations in the INSR gene for both patients: c.2663A > G (p.Tyr888Cys) and c.38_61del (p.Pro13_Ala20del). These mutations have the potential to disrupt the interaction between INSR and insulin, leading to abnormal insulin signaling, insulin resistance, and various clinical manifestations.

The Association Between Obesity and Polycystic Ovary Syndrome: An Epidemiologic Study of Observational Data.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common female cardiometabolic-reproductive disorder. It is unclear whether the global obesity epidemic is impacting the high PCOS prevalence. OBJECTIVE: To determine the association between the prevalence of PCOS and obesity. MATERIALS AND METHODS: A systematic review was conducted to identify population studies on PCOS prevalence globally through July 2023. Linear regression and random-effect models were applied to examine the association of mean body mass index (BMI) or obesity prevalence with the prevalence of PCOS diagnosed by 1990 National Institutes of Health (NIH), 2003 Rotterdam (Rotterdam), and 2006 Androgen Excess-PCOS (AE-PCOS) criteria. Subgroup analyses were also conducted for recruitment methods and study quality. RESULTS: Fifty-eight studies with 85 956 adults from 24 countries were included. Considering all available data, a borderline association was observed between PCOS and obesity prevalence when using the AE-PCOS but not the NIH or Rotterdam criteria. Alternatively, subgroup analysis of studies with better recruitment methods demonstrated a significant positive association of population mean BMI or obesity prevalence with PCOS prevalence when using the Rotterdam or AE-PCOS criteria, while using only high-quality studies revealed an association using NIH as well as Rotterdam and AE-PCOS criteria. Overall, we observed that a 1% increase in obesity prevalence resulted in an approximately 0.4% increase in PCOS prevalence by the Rotterdam criteria. CONCLUSION: The prevalences of PCOS and obesity appear to be modestly associated, although our data cannot establish causality. This study also emphasizes the need to undertake only high-quality studies in assessing PCOS epidemiology.

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.

Endoplasmic reticulum stress-mediated ferroptosis in granulosa cells contributes to follicular dysfunction of polycystic ovary syndrome driven by hyperandrogenism.

RESEARCH QUESTION: Does hyperandrogenaemia affect the function of ovarian granulosa cells by activating ferroptosis, and could this process be regulated by endoplasmic reticulum stress? DESIGN: Levels of ferroptosis and endoplasmic reticulum stress in granulosa cells were detected in women with and without polycystic ovary syndrome (PCOS) undergoing IVF. Ferroptosis and endoplasmic reticulum stress levels of ovarian tissue and follicle development were detected in control mice and PCOS-like mice models, induced by dehydroepiandrosterone. An in-vitro PCOS model of KGN cells was constructed with testosterone and ferroptosis inhibitor Fer-1. Endoplasmic reticulum stress inhibitor, tauroursodeoxycholate (TUDCA), determined the potential mechanism associated with excessive induction of ferroptosis in granulosa cells related to PCOS, and levels of ferroptosis and endoplasmic reticulum stress were detected. RESULTS: Activation of ferroptosis and endoplasmic reticulum stress occurred in granulosa cells of women with PCOS and the varies of PCOS-like mice. The findings in KGN cells demonstrated that testosterone treatment results in elevation of oxidative stress levels, particularly lipid peroxidation, and intracellular iron accumulation in granulosa cells. The expression of genes and proteins associated with factors related to ferroptosis, mitochondrial membrane potential and ultrastructure showed that testosterone activated ferroptosis, whereas Fer-1 reversed these alterations. During in-vitro experiments, activation of endoplasmic reticulum stress induced by testosterone treatment was detected in granulosa cells. In granulosa cells, TUDCA, an inhibitor of endoplasmic reticulum stress, significantly mitigated testosterone-induced ferroptosis. CONCLUSIONS: Ferroptosis plays a part in reproductive injury mediated by hyperandrogens associated with PCOS, and may be regulated by endoplasmic reticulum stress.