Hyperandrogenism In Polycystic Ovary Syndrome Research Articles

Depression, Anxiety, and Risk of Metabolic Syndrome in Women With Polycystic Ovary Syndrome: A Longitudinal Study.

Patients with PCOS are at high risk of depression, anxiety, and metabolic syndrome (MetSyn), a key predictor of cardiovascular disease. The impact of depression and/or anxiety on MetSyn is unknown in this population. To compare the risk of developing MetSyn in patients with PCOS with and without a history of depression and/or anxiety. Retrospective longitudinal cohort study (2008-2022) with median follow-up of 7 years. Tertiary care ambulatory practice. Patients with hyperandrogenic PCOS and at least 2 evaluations for MetSyn ≥3 years apart (n=321). N/A. The primary outcome was risk of developing MetSyn. We hypothesized that this risk would be higher with a history of depression and/or anxiety. At the first visit, 33.0% had a history of depression and/or anxiety, with a third prescribed antidepressants or anxiolytics. Depression and/or anxiety increased risk of developing MetSyn during the study period (adjusted hazard ratio [aHR] 1.45, 95% CI 1.02-2.06, p=0.04) with an incidence of MetSyn of 75.3 compared to 47.6 cases per 100 person-years among those without (p=0.002). This was primarily driven by depression (aHR 1.56, 95% CI 1.10-2.20, p=0.01). Patients with PCOS and depression and/or anxiety have a high risk of developing MetSyn, with a stronger association between depression and MetSyn. Our findings highlight the urgent need for guideline-directed screening for depression and anxiety at time of diagnosis of PCOS as well as screening at subsequent visits to facilitate risk stratification for metabolic monitoring and early intervention in this high-risk group.

Hyperandrogenism associated with polycystic ovary syndrome may have a protective effect against fracture risk in female athletes: A pilot study.

Polycystic ovary syndrome (PCOS), characterized by polycystic ovaries, anovulation, and hyperandrogenism, is believed to be an evolutionary mismatch disease. Past research has examined PCOS as a uniform disease, despite variation in phenotypes across diagnostic categories, but establishing an evolutionary mismatch requires a focus on individual traits. We suggest PCOS hyperandrogenism may have been beneficial in ancestral environments because it reduced fracture risk and associated morbidity and mortality due to increased bone mineral density (BMD). We test this hypothesis by assessing fracture frequency, a proxy for BMD, in highly active females with and without PCOS hyperandrogenism. Sixty-seven reproductive-aged women were surveyed and grouped as: high intensity interval training (HIIT; a proxy for metabolic and physical stress) athletes with hyperandrogenic PCOS (31.24%), HIIT athletes without PCOS (29.85%), and nonathletes with hyperandrogenic PCOS (38.81%). Fracture occurrence was compared between the groups using independent samples Kruskal-Wallis tests for non-normally distributed data, and multiple regression analysis was used to examine anthropometrics, lifestyle and reproductive factors, PCOS status, and exercise frequency on fracture occurrence. Fracture occurrence was higher in non-PCOS athletes (3.8 ± 4.3) than PCOS-athletes (1.2 ± 1.4, p = .11) and PCOS-non-athletes (1.0 ± 1.4, p < .01). PCOS-athletes and nonathletes did not differ significantly in fracture occurrence (p = .33). These results were independent of factors associated with bone health. These preliminary findings suggest females with PCOS-related hyperandrogenism may be less likely to experience bone fractures and provide an initial step to explaining why PCOS has persisted despite marked negative reproductive consequences in modern populations.

Resistance and aerobic training increases genome-wide DNA methylation in women with polycystic ovary syndrome

ABSTRACT Physical activity is a first-line treatment for polycystic ovary syndrome (PCOS). Resistance or aerobic exercise improves metabolic complications, reproductive outcomes, and quality of life in PCOS. DNA methylation reprogramming during exercise may be the major modifier behind these changes. We sought to evaluate genome-wide DNA methylation changes after supervised resistance and aerobic exercise in women with PCOS. Exercises were performed in 56 women with PCOS (resistance, n = 30; aerobic, n = 26), for 16 weeks (wks), three times per week, in 50-minute to one-hour sessions. Anthropometric indices and hormonal and metabolic parameters were measured before and after training. Genome-wide leukocyte DNA methylation was analysed by Infinium Human MethylationEPIC 850K BeadChip microarrays (Illumina). Both resistance and aerobic exercise improved anthropometric indices, metabolic dysfunction, and hyperandrogenism in PCOS after the training programme, but no differences were observed between the two exercises. Resistance and aerobic exercise increased genome-wide DNA methylation, although resistance changed every category in the CpG island context (islands, shores, shelve, and open sea), whereas aerobic exercise altered CpG shores and the open sea. Using a stringent FDR (>40), 6 significantly differentially methylated regions (DMRs) were observed in the resistance exercise cohort and 14 DRMs in the aerobic cohort, all of which were hypermethylated. The increase in genome-wide DNA methylation may be related to the metabolic and hormonal changes observed in PCOS after resistance and aerobic exercise. Since the mammalian genome is hypermethylated globally to prevent genomic instability and ageing, resistance and aerobic exercise may promote health and longevity through environmentally induced epigenetic changes.

Metabolome implies increased fatty acid utilization and histone methylation in the follicles from hyperandrogenic PCOS women

Well-balanced metabolism is essential for the high-quality of oocytes, and metabolic fluctuations of follicular microenvironment potentially encourage functional changes in follicle cells, ultimately impacting the developmental potential of oocytes. Here, the global metabolomic profiles of follicular fluid from PCOS women with ovarian hyperandrogenism and non-hyperandrogenism were depicted by untargeted metabolome and transcriptome. In parallel, functional methods were employed to evaluate the possible impact of dysregulated metabolites on oocyte and embryo development. Our findings demonstrated that PCOS women exhibited distinct metabolic features in follicles, such as the increase in fatty acid utilization and the downregulation in amino acid metabolism. And intrafollicular androgen levels were positively correlated with contents of multiple fatty acids, suggesting androgen as one of the contributing factors to the metabolic abnormalities in PCOS follicles. Moreover, we further demonstrated that elevated levels of α-linolenic acid and H3K27me3 could hinder oocyte maturation, fertilization, and early embryo development. Hopefully, our data serve as a broad resource on the metabolic abnormalities of PCOS follicles, and advances in the relevant knowledge will allow the identification of biomarkers that predict the progression of PCOS and its poor pregnancy outcomes.

Androgen excess: a hallmark of polycystic ovary syndrome.

Polycystic ovarian syndrome (PCOS) is a metabolic, reproductive, and psychological disorder affecting 6-20% of reproductive women worldwide. However, there is still no cure for PCOS, and current treatments primarily alleviate its symptoms due to a poor understanding of its etiology. Compelling evidence suggests that hyperandrogenism is not just a primary feature of PCOS. Instead, it may be a causative factor for this condition. Thus, figuring out the mechanisms of androgen synthesis, conversion, and metabolism is relatively important. Traditionally, studies of androgen excess have largely focused on classical androgen, but in recent years, adrenal-derived 11-oxygenated androgen has also garnered interest. Herein, this Review aims to investigate the origins of androgen excess, androgen synthesis, how androgen receptor (AR) signaling mediates adverse PCOS traits, and the role of 11-oxygenated androgen in the pathophysiology of PCOS. In addition, it provides therapeutic strategies targeting hyperandrogenism in PCOS.

Oocyte quality is impaired in a hyperandrogenic PCOS mouse model by increased Foxo1 expression

One of the most important characteristics of patients with polycystic ovary syndrome (PCOS) is excess androgen, which has adverse effects on pregnancy outcomes and increases the risk of offspring developing metabolic disorders. Foxo1 has been shown to play an important role in PCOS, but whether it has an affect on oocyte’s quality in PCOS remains unclear. The current research investigated the effect of excess androgen exposure on mouse oocyte quality, as well as the possible molecular mechanism. Timelapse incubator was used to culture oocytes in vitro and evaluate the maturation process. The level of reactive oxygen species (ROS) and mitochondrial membrane potential were detected by laser confocal microscope. Immunofluorescence staining assays were performed to examine the expression of Foxo1 and γ-H2AX. Relative mRNA level of Foxo1 and Caspase3 were examined by RT-qPCR. Results showed Germinal vesicle breakdown and maturation rates of oocytes from hyperandrogenic PCOS mice were significantly decreased in vitro, while in vitro maturation showed a marked delay from the germinal vesicle breakdown to metaphase II stage in PCOS group. Expression levels of reactive oxygen species, Foxo1, Caspase3, and γ-H2AX were significantly increased, whereas mitochondrial membrane potential was significantly decreased in oocytes from PCOS mice. These results indicate that excess androgen exposure induced oxidative stress, which further induced high expression of Foxo1, resulting in more DNA damage and apoptosis in oocytes. The current findings provide new knowledge for exploring the mechanism of decreased oocyte quality in hyperandrogenic PCOS.

An Evolutionary Model for the Ancient Origins of Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy of reproductive-aged women, characterized by hyperandrogenism, oligo-anovulation and insulin resistance and closely linked with preferential abdominal fat accumulation. As an ancestral primate trait, PCOS was likely further selected in humans when scarcity of food in hunter-gatherers of the late Pleistocene additionally programmed for enhanced fat storage to meet the metabolic demands of reproduction in later life. As an evolutionary model for PCOS, healthy normal-weight women with hyperandrogenic PCOS have subcutaneous (SC) abdominal adipose stem cells that favor fat storage through exaggerated lipid accumulation during development to adipocytes in vitro. In turn, fat storage is counterbalanced by reduced insulin sensitivity and preferential accumulation of highly lipolytic intra-abdominal fat in vivo. This metabolic adaptation in PCOS balances energy storage with glucose availability and fatty acid oxidation for optimal energy use during reproduction; its accompanying oligo-anovulation allowed PCOS women from antiquity sufficient time and strength for childrearing of fewer offspring with a greater likelihood of childhood survival. Heritable PCOS characteristics are affected by today's contemporary environment through epigenetic events that predispose women to lipotoxicity, with excess weight gain and pregnancy complications, calling for an emphasis on preventive healthcare to optimize the long-term, endocrine-metabolic health of PCOS women in today's obesogenic environment.

Hepatokines: the missing link in the development of insulin resistance and hyperandrogenism in PCOS?

The liver plays a critical role in several metabolic pathways, including the regulation of glucose and lipid metabolism. Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease worldwide, is closely associated with insulin resistance (IR) and metabolic syndrome (MetS). Hepatokines, newly discovered proteins secreted by hepatocytes, have been linked to the induction of these metabolic dysregulations. Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women of reproductive age, has been associated with NAFLD and IR, while hyperandrogenism additionally appears to be implicated in the pathogenesis of the latter. However, the potential role of hepatokines in the development of metabolic disorders in PCOS has not been fully investigated. Therefore, the aim of this review is to critically appraise the current evidence regarding the interplay of hepatokines with NAFLD, hyperandrogenism, and IR in PCOS.

GC-MS analysis and in silico docking of constituents of Cinnamomum malabatrum against CYP450 17α and CYP450 19 (Aromatase)- Key targets for hyperandrogenism.

Poly cystic ovary syndrome (PCOS) is considered as one of the common hormonal disorders affecting 6-20% of women in their reproductive age with characteristic features include anovulatory infertility, hyperandrogenism, cystic follicles and insulin resistance. The gene CYP play an important role in pathophysiology of hyperandrogenism associated with PCOS. An elevated androgens are reported in PCOS condition due to overexpression of the enzyme CYP450 17 α: . As well as diminished levels of aromatase (CYP450 19) were observed in several hyperandrogenic PCOS patients. The powdered leafy material of Cinnamomum malabatrum was subjected to Soxhlet extraction. The plant extract was subjected to Gas chromatography-MS analysis (GC-MS), and the chromatogram obtained revealed the presence of active chemical constituents like 1(10),9(11)-B-Homolanistadiene for the first time and other potential compounds. Hypothesis has raised to interpret the efficiency of phytoconstituents of Cinnamomum malabatrum on these enzyme targets and which may be a novel drug candidate for the treatment and maintenance of hyperandrogenism associated with PCOS. Thus, the results obtained from the in-silico study of Cinnamomum malabatrum leaf extract using computational approaches indicate that the phytoconstituents have good affinities for the selected two key targets. ADME and PASS studies has been performed for active phytoconstituents homolanistadiene, β-sitosterol, cycloartenol and a pyrazole derivative, and results revealed the Lipinski drug-likeness and pharmacological potential. In conclusion, this work throws a new insight into the possibility of the active phytoconstituents on binding the two active CYP45017 α and CYP45019 aromatase enzymes which facilitates development of novel compounds for hyperandrogenism associated with PCOS.

Role of anti mullerian hormone (AMH) in diagnosis of polycystic ovarian syndrome (PCOS) in Indian women

: Transvaginal ultrasound is an important part of the Rotterdam criteria, which are commonly used to diagnose polycystic ovary syndrome (PCOS). Specifically, the presence of polycystic ovarian morphology (PCOM) is a key factor in the criteria. Another useful indicator of PCOM is the Anti-Mullerian hormone (AMH) level.The objective is to evaluate the diagnostic accuracy of serum Anti-Mullerian hormone (AMH) in identifying polycystic ovary syndrome (PCOS) and determine whether it can be used as a substitute for polycystic ovarian morphology (PCOM) in the Rotterdam criteria. Additionally, we aim to investigate the relationship between AMH levels and hyperandrogenism in PCOS patients.A study was out in SSH BHU various parameters will be used in diagnosis. Serum AMH Radiology: By Transvaginal Sonography single observer obtained dimensions for ovarian volume and the maximum number of follicles in one section. AMH levels will be estimated using commercially available Gen-II ELISA assay. Biochemical evaluation will be done in the Department of Bio-Chemistry IMS BHU. The Anti-Mullerian hormone (AMH) serum levels will be measured using a commercially available ultra-sensitive Gen-II enzyme-linked immunosorbent assay (ELISA) kit from Beckman Coulter, CA. The ELISA has a lower limit of detectability (LoD) of 0.08 ng/ml, a lower limit of quantification (LoQ) of 0.17 mg/ml, and an intra-assay coefficient of variation of 5.8%. The unit of measurement is ng/mL (1ng/mL=7.14 pmol/L). The study showed that Anti-Mullerian hormone (AMH) levels were markedly higher in individuals with polycystic ovary syndrome (PCOS) than in controls. While AMH alone was not a reliable diagnostic marker for PCOS, the findings suggested that incorporating AMH levels as an additional factor in the existing Rotterdam criteria could improve the accuracy of PCOS diagnosis. Therefore, AMH levels have the potential as a useful adjunct marker for the diagnosis of PCOS.

Efficacy and safety of anti-androgens in the management of polycystic ovary syndrome: a systematic review and meta-analysis of randomised controlled trials

Anti-androgens and combined oral contraceptive pills (COCPs) may mitigate hyperandrogenism-related symptoms of polycystic ovary syndrome (PCOS). However, their efficacy and safety in PCOS remain unclear as previous reviews have focused on non-PCOS populations. To inform the 2023 International Evidence-based Guideline in PCOS, we conducted the first systematic review and meta-analysis investigating the efficacy and safety of anti-androgens in the management of hormonal and clinical features of PCOS. We systematically searched MEDLINE, Embase, PsycInfo, All EBM reviews, and CINAHL up to 28th June 2023 for randomised controlled trials (RCTs) examining oral anti-androgen use, alone or in combination with metformin, COCPs, lifestyle, or other interventions, in women of any age, with PCOS diagnosed by Rotterdam, National Institutes of Health or Androgen Excess & PCOS Society criteria, and using a form of contraception. Non-English studies and studies of less than 6 months duration or which used the same anti-androgen regimen in both/all groups were excluded in order to establish efficacy for the clinical outcomes of interest. Three authors screened articles against selection criteria and assessed risk of bias and quality using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. Critical outcomes (prioritised during guideline development for GRADE purposes) included weight, body mass index (BMI), irregular cycles, hirsutism, liver function, and quality of life. Random effects meta-analyses were conducted where appropriate. This study is registered with PROSPERO, CRD42022345640. From 1660 studies identified in the search, 27 articles comprising 20 unique studies were included. Of these, 13 studies (n=961) were pooled in meta-analysis. Seven studies had a high risk of bias, nine moderate and four low. Anti-androgens included finasteride, flutamide, spironolactone, or bicalutamide. In meta-analysis, anti-androgens+lifestyle were superior to metformin+lifestyle for hirsutism (weighted mean difference [WMD] [95% CI]:-1.59 [-3.06,-0.12], p=0.03; I2=74%), SHBG (7.70nmol/l [0.75, 14.66], p=0.03; I2=0%), fasting insulin and fasting insulin: glucose ratio (-2.11 μU/ml [-3.97,-0.26], p=0.03; I2=0% and-1.12 [-1.44,-0.79], p<0.0001, I2=0%, respectively), but were not superior to placebo+lifestyle for hirsutism (-0.93, [-3.37, 1.51], p=0.45; I2=76%) or SHBG (9.72nmol/l [-0.71, 20.14], p=0.07; I2=31%). Daily use was more effective for hirsutism than use every three days (-3.48 [-4.58,-2.39], p<0.0001, I2=1%), and resulted in lower androstenedione levels (-0.30ng/ml [-0.50,-0.10], p=0.004; I2=0%). Combination treatment with anti-androgens+metformin+lifestyle resulted in lower testosterone compared with metformin+lifestyle (-0.29nmol/l [-0.52,-0.06], p=0.01; I2=61%), but there were no differences in hirsutism when anti-androgens+metformin+lifestyle were compared with either anti-androgens+lifestyle or metformin+lifestyle. In limited meta-analyses (n=2 trials), combining anti-androgens with COCP resulted in poorer lipid profiles compared with COCP±placebo, with no differences in other outcomes. Current evidence does not support the use of anti-androgens preferentially to COCPs to treat hyperandrogenism in PCOS. Anti-androgens could be considered to treat hirsutism in PCOS, where COCPs are contraindicated, poorly tolerated, or present a sub-optimal response after a minimum 6-month period, with consideration of clinical context and individual risk factors and characteristics. National Health and Medical Research Council (NHMRC) of Australia Monash University.

Relationship between nonalcoholic fatty liver disease and hyperandrogenemia in adolescents with polycystic ovary syndrome.

Nonalcoholic fatty liver disease (NAFLD) is common in adults with polycystic ovary syndrome (PCOS), and several studies on adults have investigated its influencing factors. However, factors associated with NAFLD in adolescents with PCOS remain unknown. This study aimed to investigate the presence of NAFLD in adolescents with PCOS using the noninvasive methods of vibration-controlled transient elastography (VCTE) and ultrasonography (USG), along with assessing NAFLD-related metabolic and hormonal risk factors. This study included patients aged 12-18 years who were diagnosed with PCOS according to the Rotterdam criteria. The control group included young women with similar age and body mass index (BMI) z scores, who had menstruated regularly for more than 2 years. Patients with PCOS were divided into hyperandrogenemia and nonhyperandrogenemia groups based on serum androgen level. USG was performed on all patients to evaluate the presence of hepatic steatosis. Liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) were assessed using VCTE (Fibroscan). Clinical, laboratory, and radiological data were compared between groups. This study included 124 adolescent girls aged 12-18 years (61 with PCOS, 63 controls). BMI z scores were similar between groups. Waist circumference and total cholesterol, triglyceride, and alanine aminotransferase levels were higher in the PCOS versus the control group. The presence of hepatic steatosis on USG was similar between groups. However, the rate of hepatic steatosis on USG was higher in patients with hyperandrogenic PCOS (P=0.01). LSM and CAP measurements were similar between groups. No increase in prevalence of NAFLD was observed among adolescents with PCOS. However, hyperandrogenemia is a risk factor for NAFLD. Therefore, adolescents with PCOS and elevated androgen level should be screened for NAFLD.

Mitoguardin2 Is Associated With Hyperandrogenism and Regulates Steroidogenesis in Human Ovarian Granulosa Cells.

Polycystic ovary syndrome (PCOS) is an endocrinopathy characterized by hyperandrogenism, anovulation, and polycystic ovaries, in which hyperandrogenism manifests by excess androgen and other steroid hormone abnormalities. Mitochondrial fusion is essential in steroidogenesis, while the role of mitochondrial fusion in granulosa cells of hyperandrogenic PCOS patients remains unclear. In this study, mRNA expression of mitochondrial fusion genes mitoguardin1, -2 (MIGA 1, -2) was significantly increased in granulosa cells of hyperandrogenic PCOS but not PCOS with normal androgen levels, their mRNA expression positively correlated with testosterone levels. Dihydrotestosterone (DHT) treatment in mice led to high expression of MIGA2 in granulosa cells of ovulating follicles. Testosterone or forskolin/ phorbol 12-myristate 13-acetate treatments increased expression of MIGA2 and the steroidogenic acute regulatory protein (StAR) in KGN cells. MIGA2 interacted with StAR and induced StAR localization on mitochondria. Furthermore, MIGA2 overexpression significantly increased cAMP-activated protein kinase A (PKA) and phosphorylation of AMP-activated protein kinase (pAMPK) at T172 but inhibited StAR protein expression. However, MIGA2 overexpression increased CYP11A1, HSD3B2, and CYP19A1 mRNA expression. As a result, MIGA2 overexpression decreased progesterone but increased estradiol synthesis. Besides the androgen receptor, testosterone or DHT might also regulate MIGA2 and pAMPK (T172) through LH/choriogonadotropin receptor-mediated PKA signaling. Taken together, these findings indicate that testosterone regulates MIGA2 via PKA/AMP-activated protein kinase signaling in ovarian granulosa cells. It is suggested mitochondrial fusion in ovarian granulosa cells is associated with hyperandrogenism and potentially leads to abnormal steroidogenesis in PCOS.

Carnosol inhibits KGN cells oxidative stress and apoptosis and attenuates polycystic ovary syndrome phenotypes in mice through Keap1-mediated Nrf2/HO-1 activation.

Excessive oxidative stress and apoptosis of ovarian granulosa cells lead to abnormal follicular development and ovulation disorders in polycystic ovary syndrome (PCOS). Carnosol is a plant-derived polyphenol that has been proven to exhibit several cell protective effects. In this study, we established hyperandrogenic PCOS models both in vitro and in vivo. In the humanovariangranulosacellline,KGN cells, decreased viability and mitochondrial membrane potential, and upregulated reactive oxygen species (ROS) level and apoptosis induced by DHT were partly reversed by carnosol. Western blotting results showed that carnosol treatment inhibited the DHT-activated mitochondrial apoptotic pathway by activating nuclear factor-erythroid 2-related factor (Nrf2)/heme oxygenase 1 (HO-1). Knockdown of Nrf2 by transfecting with siRNA or inhibiting HO-1 by zinc protoporphyrin (ZnPP) blocked the protective effects of carnosol. Computational modeling and pull-down assay results confirmed the direct binding of carnosol to kelch-like ECH-associated protein 1 (Keap1). In vivo results showed that the intraperitoneal administration of carnosol (50 and 100 mg/kg) improved estrous cycle disorders, polycystic ovary, and decreased elevated androgen in the PCOS mice. In summary, Carnosol has an effective role in inhibiting oxidative stress and apoptosis in DHT-treated KGN cells and protecting against mouse PCOS phenotypes through the Keap1-mediated activation of Nrf2/HO-1 signaling.

Insulin resistance is associated with increased circulating lipocalin-2 levels in polycystic ovary syndrome: a systematic review and meta-analysis.

This meta-analysis was conducted to compare the circulating lipocalin-2 levels in polycystic ovary syndrome (PCOS). Relevant studies were retrieved by online database and manual searching. The standardized mean differences (SMDs) with 95% confidence intervals (CIs) were obtained by a random-effects meta-analysis. The subgroup analysis based on the Body Mass Index (BMI) and the homeostasis model assessment-estimated insulin resistance (HOMA-IR) was conducted. Meta-analysis of correlations and meta-regression were performed for the associations of lipocalin-2 with the metabolic and hormonal covariates. The funnel plot analysis was used for publication bias. The combined effect size including a total of 13 studies showed no significant difference in lipocalin-2 levels between PCOS and control groups. However, the subgroup meta-analysis based on insulin resistance showed a significant difference in the circulatory lipocalin-2 levels in PCOS as compared to controls in both HOMA-IR<3 (SMD=-1.15, Z=2.42, P=0.02) and HOMA-IR>3 subgroups (SMD=0.91, Z=2.43, P=0.02). There were significant associations of lipocalin-2 with age, BMI, estrogen and hyperandrogenism in PCOS. Lipocalin-2 level alterations in PCOS are associated to insulin resistance. More is the insulin resistance, higher is the lipocalin-2 level in PCOS as compared to controls.

Hyperandrogenic Symptoms Are a Persistent Suffering in Midlife Women with PCOS; a Prospective Cohort Study in Sweden.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder among women, and the majority suffers from hyperandrogenism. Hyperandrogenism causes psychological morbidity and impaired quality of life in women with PCOS during the reproductive years, but data on prevalence and impact during midlife are lacking. Thus, this study aimed to address whether hyperandrogenism persists into midlife and, if so, what impact it has on quality of life. In order to answer this question, we performed a multicenter prospective cohort study, where we included women already diagnosed with PCOS who had reached the age of 45 years or more and age-matched controls. All participants underwent a physical exam, structured medical interview, biochemical testing and filled out self-assessment questionnaires. More than 40% of the women with PCOS and 82% of those who presented with the hyperandrogenic phenotype at the diagnostic work-up still suffered from hirsutism. Circulating testosterone levels were similar between women with PCOS and controls while free androgen index was higher in women with PCOS, independent of weight. Women with hyperandrogenic PCOS expressed persisting concerns regarding hirsutism at the follow-up assessment. In conclusion, women with PCOS who present with hyperandrogenic symptoms at the time they are diagnosed with PCOS have a higher risk of persistent androgenic symptoms and impaired quality of life in midlife.

OR15-5 Cognitive Function in Reproductive Aged Individuals with Polycystic Ovary Syndrome

Abstract PCOS by Rotterdam criteria is defined by the presence of at least two of the following: oligomenorrhea, hyperandrogenism and polycystic ovaries. Although not required for diagnosis, PCOS often has metabolic manifestations, particularly insulin resistance. In studies of non-PCOS populations, it appears a nexus may exist between insulin resistance and neuropsychological outcomes, such as cognitive performance (particularly executive function skills), cognitive aging, and depression. Cognitive performance, such as verbal and spatial skills, may also be impacted by gonadal hormones. It is therefore surprising that the relationship between PCOS and neuropsychological outcomes has been only minimally investigated. This study was therefore designed to measure and compare cognition in Rotterdam-PCOS subjects with and without hyperandrogenism and to test the hypothesis that executive function performance (cognitive control, verbal fluency and working memory) is lower in those with hyperandrogenism. Methods Forty-eight sequential subjects with PCOS were recruited from a multi-disciplinary PCOS clinic. Those with clinical/biochemical hyperandrogenism (in addition to oligomenorrhea/polycystic ovaries) were designed "NIH-PCOS" (n=35); while those without hyperandrogenism (only oligomenorrhea and polycystic ovaries) were designated "non-androgenic PCOS" (n=13). Neuropsychological test administration and scoring were performed by trained personnel. Verbal and perceptual reasoning were measured with Wechsler Adult Intelligence Scale (WAIS); memory was measured by California Verbal Learning Trials (long delay recall), and processing speed by WAIS symbol search. Executive functions were measured with Delis-Kaplan System: Stroop and Trail Making (cognitive control); Design and Verbal Fluency (generativity); WAIS: Digit Span (working memory); and Weschler Memory Scale: Symbol Span (working memory). Sample-based z-scores were calculated for cognitive outcomes. We compared z-scores using linear regressions, adjusting for age, race, and years of education. A composite executive function score was calculated as the mean z-score on all six executive function tests. Results Groups were similar for age and BMI, but NIH-PCOS showed greater mean (SD) Homa-IR (4.2 (6.1) vs. 1.82 (1.9); p=.06), compared to non-androgenic PCOS. Cognitive performance was similar for measures of "pre-morbid" IQ, including verbal and perceptual reasoning, memory and processing speed. However, subjects with NIH-PCOS demonstrated lower relative performance for executive functions (β-coefficient for executive function composite z-score: -0.44, 95% CI: -0.79, -0.09; p=0.016). Subdomains showing decreased performance (β-coefficient) included verbal fluency (-0.62; p=.04), working memory (-0.75; p=.04) and cognitive control (-0.53; p=.05). We additionally assessed cognitive performance in relation to insulin resistance (Homa &amp;gt;2.1). Considering non-androgenic PCOS without insulin resistance as referent, NIH-PCOS subjects with insulin resistance showed the lowest performance on the executive function composite score, followed by those with NIH-PCOS without insulin resistance (p-trend = .001). Conclusion People with hyperandrogenic PCOS may experience challenges in executive functioning compared to non-androgenic counterparts. Additional research is needed to confirm findings in larger cohorts and to investigate the role of modifiable factors. Presentation: Sunday, June 12, 2022 12:00 p.m. - 12:15 p.m.

Long-term environmental exposure of darkness induces hyperandrogenism in PCOS via melatonin receptor 1A and aromatase reduction.

Polycystic ovary syndrome (PCOS) is a common and complex disorder impairing female fertility, yet its etiology remains elusive. It is reported that circadian rhythm disruption might play a crucial role in PCOS pathologic progression. Here, in this research, we investigated the effect of environmental long-term circadian rhythm dysfunction and clarified its pathogenic mechanism in the development of PCOS, which might provide the targeted clinical strategies to patients with PCOS. Female SD rats were used to construct a circadian rhythm misalignment model with constant darkness (12/12-h dark/dark cycle), and the control group was kept under normal circadian rhythm exposure (12/12-h light/dark cycle) for 8 weeks. We measured their reproductive, endocrinal, and metabolic profiles at different zeitgeber times (ZTs). Different rescue methods, including melatonin receptor agonist and normal circadian rhythm restoration, and in vitro experiments on the KGN cell line were performed. We found that long-term darkness caused PCOS-like reproductive abnormalities, including estrous cycle disorder, polycystic ovaries, LH elevation, hyperandrogenism, and glucose intolerance. In addition, the expression of melatonin receptor 1A (Mtnr1a) in ovarian granulosa cells significantly decreased in the darkness group. Normal light/dark cycle and melatonin receptor agonist application relieved hyperandrogenism of darkness-treated rats. In vitro experiments demonstrated that decreased MTNR1A inhibited androgen receptor (AR) and CYP19A1 expression, and AR acted as an essential downstream factor of MTNR1A in modulating aromatase abundance. Overall, our finding demonstrates the significant influence of circadian rhythms on PCOS occurrence, suggests that MTNR1A and AR play vital roles in pathological progression of hyperandrogenism, and broadens current treatment strategies for PCOS in clinical practice.

NUTRITIONAL EDUCATION (FACE-TO-FACE AND VIDEO INSTRUCTION) FOR POLYCYSTIC OVARY SYNDROME RESULTS IN GREATER REDUCTION IN BMI AND HEMOGLOBIN A1C THAN CALORIC RESTRICTION, EXERCISE AND METFORMIN

Polycystic ovary syndrome (PCOS) affects approximately 12% of women of reproductive age and increases risk of obesity, diabetes, heart disease, cancer and infertility. Metabolic inflexibility associated with PCOS makes weight loss difficult and has made nutritional education for this condition challenging and time-consuming. Hyperinsulinemia drives hyperandrogenism in PCOS. Research shows that carbohydrates from dairy and starch-based foods have greater insulinogenic properties than carbohydrates from non-starchy vegetables and fruits.

Declining muscle NAD+ in a hyperandrogenism PCOS mouse model: Possible role in metabolic dysregulation

Polycystic ovary syndrome (PCOS) is a common endocrine disorder, defined by reproductive and endocrine abnormalities, with metabolic dysregulation including obesity, insulin resistance and hepatic steatosis. Recently, it was found that skeletal muscle insulin sensitivity could be improved in obese, post-menopausal, pre-diabetic women through treatment with nicotinamide mononucleotide (NMN), a precursor to the prominent redox cofactor nicotinamide adenine dinucleotide (NAD+). Given that PCOS patients have a similar endocrine profile to these patients, we hypothesised that declining NAD levels in muscle might play a role in the pathogenesis of the metabolic syndrome associated with PCOS, and that this could be normalized through NMN treatment. Here, we tested the impact of NMN treatment on the metabolic syndrome of the dihydrotestosterone (DHT) induced mouse model of PCOS. We observed lower NAD levels in the muscle of PCOS mice, which was normalized by NMN treatment. PCOS mice were hyperinsulinaemic, resulting in increased adiposity and hepatic lipid deposition. Strikingly, NMN treatment completely normalized these aspects of metabolic dysfunction. We propose that addressing the decline in skeletal muscle NAD levels associated with PCOS can normalize insulin sensitivity, preventing compensatory hyperinsulinaemia, which drives obesity and hepatic lipid deposition, though we cannot discount an impact of NMN on other tissues to mediate these effects. These findings support further investigation into NMN treatment as a new therapy for normalizing the aberrant metabolic features of PCOS.