An overview of polycystic ovary syndrome in aging women

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women, affecting 4.8 % to 18.6 % of women of reproductive age. Between 10 and 19 years of age, PCOS occurs in 3.39 % to 8.03 % of adolescents. Confirmation of diagnosis in adolescent age is difficult because manifestations of PCOS are similar to normal puberty signs (e. g., irregular menstrual cycle, acne, etc.). New evidence-based guidelines have been issued in 2018 highlighting the diagnostic criteria for establishing PCOS diagnosis in adolescents. These guidelines also recommend a separate identification of risk group patients – adolescent patients for whom both diagnostic PCOS criteria have not yet been confirmed and who should continue to be monitored. It is important to diagnose this disease as early as possible in order to initiate lifestyle adjustments and possibly also begin treatment in a timely manner.In the long term, PCOS increases the risk of developing infertility and type 2 diabetes, cardiovascular disease, insulin resistance and metabolic syndrome. Increased body weight occurring in 40–70 % of adolescents with PCOS significantly increases the risk of chronic non-communicable diseases at a later stage, and maintains PCOS symptoms. PCOS and associated symptoms reduce health-related quality of life (HRQOL). Binge eating is more common in patients with PCOS. The most effective tactics of therapy are lifestyle changes, so it is particularly important to recognise patients at increased risk of developing PCOS, to diagnose them early and to offer treatment that is most relevant to the needs of the individual and improves their quality of life.The aim of the doctoral thesis is to explore intergenerational, genetic, quality of life and binge eating aspects in teenagers with PCOS.The study contains several sections. To evaluate the intergenerational bond, 57 teenagers with PCOS and their mothers were included in Section I. The section studies the relationship between patients with PCOS and their mothers. In addition to PCOS patients, Section II also includes healthy adolescent patients and patients at risk. The role of the most common variation of protein-coding genes involved in the activity of the Hypothalamic-Pituitary-Ovarian axis (FSHR, ESR2, LHCGR, GNRHR) in PCOS development and in the PCOS clinical presentation was studied by including 63 adolescents with a diagnosis of PCOS, 67 healthy control patients and 22 patients at risk. The role of CYP21A2 gene variations in PCOS development and clinical phenotype was established in 55 PCOS patients, 49 control patients and 23 patients at risk. Additionally, components of HRQOL, binge eating and factors affecting the total HRQOL were analysed in 63 PCOS patients and 66 control patients. The study concluded that it was not possible to predict clinical symptoms associated with PCOS in adolescents based on PCOS symptoms in their mothers. The role of protein-coding gene variations that are involved in the functioning of sex hormones was also not found, in regard to PCOS development. However, it was found that the homozygous minor allele carriers within variations of specific genes (ESR2 rs4986938 and LHCGR rs2293275) had a higher total testosterone level in blood than patients who were not carriers of these alleles. The most important components that affected HRQOL in adolescents with PCOS were the diagnosis of PCOS as such, the degree of binge eating, and the percentile of the body mass index. At the same time, HRQOL was most affected by concerns about body hair and body weight. There was no difference in the frequency of binge eating between PCOS patients and adolescent control group patients.In this study, no link was found between the diagnosis of PCOS or associated symptoms in mothers and the phenotype of adolescents with PCOS. Individual alleles have been associated with the clinical presentation of PCOS. There is a better understanding of the components of HRQOL that affect PCOS the most and require particular attention in clinical practice. Further research with a larger sample-size is needed. Furthermore, longitudinal data on the population studied in this project would provide a more accurate insight into the development of the disease at a later age.

Can cluster analysis be used to differentiate between normo-ovulatory women with normal ovaries and normo-ovulatory women with polycystic ovarian morphology (PCOM) in a non-subjective manner? Cluster analysis can be used to accurately and non-subjectively differentiate between normo-ovulatory women with normal ovaries and normo-ovulatory women with PCOM. Currently, PCOM is diagnosed using a fixed threshold level, i.e. 12 or more follicles per ovary, and is one of the diagnostic criteria of polycystic ovary syndrome (PCOS). However, PCOM is also encountered in normo-ovulatory women, suggesting that it could just represent a normal variant. On the other hand, recent studies have shown subtle endocrine abnormalities in women with isolated PCOM that resemble those found in women with PCOS. Because of the strong correlation between anti-Müllerian hormone (AMH) and follicle number, a high serum AMH level has been proposed as a surrogate marker for PCOM and could, therefore, be integrated in the diagnostic classifications for PCOS. This was a retrospective observational cohort study. Original cohorts had been recruited for previous studies between 1998 and 2010. Two hundred ninety-seven regularly cycling women and 700 women with PCOS were eligible for inclusion. Cluster analysis was performed in 297 regularly cycling women. After exclusion of 'PCOM' clusters, each 'non-PCOM' cluster (young, n = 118 and old, n = 100) was included in the construction of a receiver operating characteristics curve to test the diagnostic performance of follicle number per ovary (FNPO) and serum AMH in discriminating similarly aged full-blown PCOS patients (n = 411 and 237, respectively) from normal regularly cycling non-PCOM women. The optimal number of clusters was four; age was the most important classifying variable, followed by the FNPO and serum AMH. Two distinct clusters of normo-ovulatory women with PCOM were isolated and differed solely by age, i.e. 'young' and 'old'. Both 'PCOM' clusters had their similarly aged counterpart of 'non-PCOM' clusters. Likewise, two clusters comprised women younger than 30 years, with (n = 28, 'PCOM regularly cycling women') or without (n = 118, 'normal regularly cycling women') features of PCOM (increased FNPO and/or serum AMH). The two other clusters in older women could be labelled 'normal regularly cycling women' or 'PCOM regularly cycling women' (n = 100 and 51, respectively). The prevalence of PCOM was significantly greater in old than in young regularly cycling women controls. In the young population, after exclusion of the 'PCOM regularly cycling women', the diagnostic performance of AMH, expressed by area under the curve (AUC) (AUC = 0.903; CI (0.876-0.930)) to differentiate PCOS women from normal regularly cycling women was similar to that using the FNPO (AUC = 0.915, CI (0.891-0.940)) (P = 0.25), confirming results from earlier studies. In the old population, the diagnostic performance of AMH was greater than that of FNPO (AUCs = 0.948 (0.927-0.970) vs 0.874 (0.836-0.912), respectively, P = 0.00035). Cut-off levels of AMH and antral follicle count distinguishing regularly cycling non-PCOM women from PCOS women were higher in young women than in older women. Data of normal women were obtained from earlier studies, aiming to measure normal endocrine values. Apparently, the strong effect of age in cluster analysis revealed a dichotomy in the age distribution among the cohort of regularly cycling women included. This was involuntary since in none of the original studies, eligibility was limited by age and there was considerable overlap in age ranges of the cohorts. Transvaginal ultrasound was performed using a 6.5-8 mHz probe and our data confirm that this threshold level for FNPO is still valid if using such probe frequencies, although the use of devices with a maximum frequency lower than 8 mHz has become obsolete. Obviously, newer ultrasound scanner using higher transducer frequency will facilitate the detection of more follicles. Our data support the use of AMH as a surrogate for ultrasound to define PCOM, which is one of the three items of the Rotterdam classification. They also show that age should be taken into account to define the optimal threshold. The fact that the prevalence of PCOM was increased in the older regularly cycling women, may be due to 'attenuated' PCOS, a phenomenon that has been described in ageing women with PCOS. These women might have had anovulatory cycles in the past and have become ovulatory with increasing age, and were, therefore, eligible for this study. However, since most women included at older age have had spontaneous pregnancies in the past, PCOM at older age may be associated with a subclinical form of PCOS, which may also be present in young regularly cycling women. No funding was received for this study. J.S.E.L. has received grants and support from Ferring, MSD, Organon, Merck-Serono, Schering Plough and Serono during recruitment and analysis of data for this study. S.L.F., A.D. and D.D. do not have any conflict of interest.

Study question What mechanisms are involved in the ovarian alterations of Polycystic Ovary Syndrome (PCOS) and Morphology? Summary answer PCOS patients associated a distinctive impairment of oxidative phosphorylation and dysregulated complement system in their follicular compartments not found in Polycystic Ovarian Morphology (PCOM) women. What is known already PCOS is a major cause of female infertility characterized by aberrant follicular development and hormonal imbalances leading to reproductive symptoms such as anovulation, poor oocyte quality, and hyperandrogenism. Likewise, PCOM is present in 16-25% of women with regular menses, but the clinical relevance of this ovarian phenotype and its correlation with PCOS remains unclear. Therefore, to establish the specific molecular mechanisms underlying the ovarian alterations in PCOS using High-throughput techniques will allow us to provide a better clinical management and a differential diagnosis with PCOM women. Study design, size, duration Cross-sectional molecular study including samples from 26 patients undergoing an IVF cycle between 2019-2022 at Hospital La Fe (Valencia, Spain). Eight women were considered PCOS, eleven PCOM and seven were control fertile patients. Granulosa cells (GCs) and follicular fluid (FF) samples were obtained during oocyte retrieval to perform RNA-seq and proteomic analysis, respectively. Participants/materials, setting, methods Women with two or more Rotterdam-criteria were considered as PCOS, while PCOM was defined by polycystic ovarian morphology on ultrasound with regular ovulatory cycles. RNA from GCs was obtained and sequenced using NextSeq500-Illumina to identify differentially expressed genes (DEGs) using DESeq2 (R-software). The proteome of FF samples was established by LC-MS/MS and differentially expressed proteins (DEPs) analyzed with limma package. Functional enrichment analysis of DEGs and DEPs (FDR< 0.05) was performed based on KEGG database. Main results and the role of chance RNA-seq data revealed clear distinctions between GCs from PCOS and control women, with 526 DEGs. By contrast, the transcriptomes of PCOS and PCOM were more similar, with only 34 DEGs. Notably, oxidative phosphorylation emerged as the most enriched pathway in both comparisons, showing a differential expression in PCOS. Indeed, 6 out of 12 shared DEGs (MT-TP, MT-ND4L, MT-ND2, MT-ATP8, MT-ND4, and MT-ATP6), were mitochondrial genes found upregulated in PCOS vs. PCOM and control samples. These findings suggest that granulosa cells from PCOS present a dysregulation in oxidative phosphorylation, potentially linked to alterations in those genes associated with the mitochondrial electron transport chain. The proteomic analysis showed 37 DEPs in the FF of PCOS compared with controls, being these DEPs mainly involved in the complement and coagulation cascades, PI3K-AKT pathway, oocyte meiosis and ferroptosis. Furthermore, the PCOS vs. PCOM analysis revealed 42 DEPs, significantly enriched also in complement and coagulation cascades, ferroptosis and glutathione metabolism. Interestingly, fifteen proteins were differentially expressed in both comparisons, with four of them related to the complement system (PROS1, C1S, C1QB and MASP2), suggesting that an alteration in this system at follicular fluid level might be one of the hallmarks of PCOS. Limitations, reasons for caution Further experimental studies are required to validate the specific changes identified in our study. Moreover, to establish how these alterations in the follicular compartments affect the oocytes of PCOS patients should also be explored. Wider implications of the findings Our study focused on specific mechanisms involved in PCOS ovarian alterations, providing new insights into potential biomarkers for an accurate diagnosis and management of this pathology. Dysregulations in oxidative phosphorylation and complement system might play a crucial role in PCOS multifactorial nature, contributing to impaired folliculogenesis and decreased oocyte quality. Trial registration number Not Applicable

Serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3) in IVF patients with polycystic ovary syndrome: correlations with outcome

The role of vitamin D in polycystic ovary syndrome

Increased monocyte chemoattractant protein-1 levels indicating early vascular damage in lean young PCOS patients

Periodontal disease in polycystic ovary syndrome

BackgroundThe human ovary is the target of autoimmune attack in cases of autoimmune disorders, which can cause ovarian dysfunction. Due to the higher prevalence of Hashimoto’s Thyroiditis (HT) in Polycystic Ovary Syndrome (PCOS) patients, we aimed to evaluate ovarian reserve and the effect of autoimmune exposure time on ovarian reserve in PCOS patients with HT by Anti-Müllerian hormone (AMH) levels.MethodsForty-six PCOS patients and 46 PCOS with HT diagnosed patients who are between 18 and 35 years old were recruited for this study. Detailed medical histories were obtained from all participants. Polycystic ovary image was evaluated and antral follicles were counted by transvaginal ultrasound. Modified Ferriman Gallwey score, body mass index, waist/hip ratio of the patients were examined. Hormonal, biochemical profiles and AMH levels of the patients were evaluated during the early follicular phase. The data of both groups were statistically analyzed with SPSS 18.0.Results20 (43.5%) patients in the PCOS group were fertile, 8 (17.4%) patients in the PCOS + HT group were fertile, fertility rate was significantly lower in PCOS + HT group. The mean AMH value was 8.8 ± 8.8 in the PCOS + HT group and 12.4 ± 8.1 in the PCOS group and it was significantly lower in the PCOS + HT group (p = 0.043). AMH values were significantly negatively correlated with anti-thyroid peroxidase antibody (anti-TPO) level and the duration of HT. There was a significant positive correlation between the anti-TPO level and the duration of HT.ConclusıonWe pointed out that the coexistence of PCOS and HT, two prevalent diseases of reproductive age, further diminished ovarian reserve. More exposure of the ovaries to autoantibodies can cause ovarian destruction, similar to the thyroid gland like HT. Because of all these close relations with PCOS and thyroid dysfunctions, we recommend evaluating both thyroid autoantibodies and hormone levels in PCOS patients at the first visit. Patients with PCOS + HT should be monitored more closely to determine the fertility treatment options and control premature ovarian failure (POF) table.

Role of PCSK9 in lipid metabolic disorders and ovarian dysfunction in polycystic ovary syndrome

Objective To investigate the changes in plasma very long chain fatty acids (VLCFAs) in polycystic ovary syndrome (PCOS) patients, and further to explore its relationship with obesity and insulin resistance. Methods Two hundred and five PCOS patients were screened out according to the diagnostic criteria of Rotterdam conference (2003), aged 18-40 years. A group of 117 healthy infertile women of corresponding period was taken as control. These women were chosen randomly from reproductive center due to the problems of uterine tube or males. The plasma hormone levels were examined. Ten kinds of plasma VLCFAs were detected by gas chromatography-mass spectrometry (GC-MS). Data between two groups analysis was performed by t test. Multiple stepwise regression analysis was used to analysize multiple factors of measurement data. Results Compared with normal individuals, plasma VLCFAs levels was disorder in PCOS patients. There is a lower C20: 4n-6/C20: 3n-6 in VLCFAs of PCOS patients, and a higher C20: 1n-9, C20: 2n-7, C20: 3n-6, C22: 4n-6, C20: 5n-3, C22: 5n-3 and C22: 6n-3, compared with the control group(t=0.539-6.155, all P<0.05). In the PCOS group, compared with non-obese patients, obese patients had a higher C20: 0, and lower C20: 3n-6 and C20: 2n-7 (t=-0.927, 2.452, 0.767, both P<0.05). Compared with non insulin resistance group, patients with insulin resistance had a higher C20: 0 and lower C20: 2n-7 and C22: 5n-3 levels (t=-2.064, 2.195, 2.183, both P<0.05). Multiple stepwise regression analysis showed that C20: 2n-7 and C20: 0 were independent risk factors of obesity and insulin resistance, respectively. Conclusions Disturbance metabolism of VLCFA existed in the PCOS patients. The decrease of C20: 2n-7 was probably an influence factor of obesity in PCOS patients and the increase of C20: 0 was probably an influence factor of insulin resistance in PCOS patients. Key words: Polycystic ovary syndrome; Obesity; Insulin resistance; Very long chain fatty acids

Oocyte developmental competence is altered in patients with polycystic ovary syndrome (PCOS); is gene expression in cumulus cells (CCs) from mature metaphase II oocytes of patients with PCOS altered as well? Compared with CCs from non-PCOS patients, the gene expression profile of CCs isolated from mature oocytes of patients with PCOS present alterations that could explain the abnormal folliculogenesis and reduced oocyte competence in such patients. Abnormal mRNA expression of several members of the insulin-like growth factor (IGF) family in CCs from PCOS patients was previously reported. Moreover, the whole transcriptome has been investigated in cultured CCs from PCOS patients. This retrospective study included six PCOS patients diagnosed following the Rotterdam Criteria and six non-PCOS patients who all underwent ICSI for male infertility in the assisted reproduction technique (ART) Department of Montpellier University Hospital, between 2009 and 2011. CCs from PCOS and non-PCOS patients who underwent controlled ovarian stimulation (COS) were isolated mechanically before ICSI. Gene expression profiles were analysed using the microarray technology and the Significance Analysis of Microarray was applied to compare the expression profiles of CCs from PCOS and non-PCOS patients. The gene expression profile of CCs from patients with PCOS was significantly different from that of CCs from non-PCOS patients. Specifically, CCs from women with PCOS were characterized by abnormal expression of many growth factors, including members of the epidermal growth factor-like (EGFR, EREG and AREG) and IGF-like families (IGF1R, IGF2R, IGF2BP2 and IGFBP2), that are known to play a role in oocyte competence. In addition, mRNA transcripts of factors involved in steroid metabolism, such as CYP11A1, CYP1B1, CYP19A1 and CYP2B7P1, were deregulated in PCOS CCs, and this could explain the abnormal steroidogenesis observed in these women. Functional annotation of the differentially expressed genes suggests that defects in the transforming growth factor β and estrogen receptors signalling cascades may contribute to the reduced oocyte developmental competence in patients with PCOS. Owing to the strict selection criteria (similar age, weight and reasons for ART), this study included a small sample size (six cases and six controls), and thus, further investigations using a large cohort of patients are needed to confirm these results. This study opens a new perspective for understanding the pathogenesis of PCOS. This work was partially supported by a grant from the Ferring Pharmaceutical. The authors of the study have no competing interests to report. Not applicable.

O-298: In vitro maturation, in vitro fertilization and embryo transfer (IVM-IVF) combined with low dose FSH over Metformin pretreatment and frozen-thawed cycles should be a routine ART option for polycystic ovarian syndrome (PCOS) patients

J.A. McNeil: None. J. Herndon: None. A.Y. Chang: None. C.J. Davidge-Pitts: None. O. Hamidi: None. Background: Testosterone therapy (TT) in individuals assigned female at birth (AFAB) is linked to an atherogenic lipid profile, including lower HDL cholesterol, elevated triglycerides, and LDL cholesterol. Polycystic ovary syndrome (PCOS), characterized by androgen excess, affects 16-20% of cisgender individuals AFAB. Recent data suggests a greater PCOS prevalence in transmasculine transgender/gender diverse (TGD) individuals at 23.8% to 38.8%. Whether TT in AFAB individuals with history of PCOS triggers more adverse metabolic changes than in TGD individuals without PCOS remains uncertain. While cohort studies haven't indicated increased cardiovascular (CV) risk with TT, it's unclear if specific subgroups, such as those with PCOS, develop more CV risk factors. Objective: To compare the effects of TT on CV risk factors in TGD individuals with a history of PCOS vs. TGD without PCOS. Methods: We retrospectively reviewed 454 records in a multispecialty TGD clinic to identify 62 with PCOS, and 132 controls without PCOS (1:2 case-control ratio) matched on age. Data included longitudinal vital signs, metabolic profiles, and details on psychiatric and medical conditions. PCOS diagnosis was validated using Rotterdam criteria. Exclusions comprised individuals under 14, those on puberty-suppressing gonadotropin-releasing hormone analogues, or already undergoing TT at the initial visit. Results: Among 454 subjects, 62 (13.7%) were diagnosed with PCOS. At baseline, PCOS was associated with significantly higher BMI (p &amp;lt; 0.01), SBP (p = 0.01), prevalence of obesity (p &amp;lt; 0.01), obstructive sleep apnea (OSA, p &amp;lt; 0.01), and type 2 diabetes mellitus (p = 0.01). History of PCOS was associated with greater metformin use (p &amp;lt; 0.001), CV disease history (p = 0.003), and transaminitis (p = 0.03). After weight adjustment, only baseline metformin use differed significantly between PCOS and controls. 140 (72.2%) received TT, 50 (80.6%) with PCOS and 90 (68.2%) controls. After weight adjustment, notable baseline changes in ALT (p = 0.006), HDL (p &amp;lt; 0.001), LDL (p &amp;lt; 0.001), hypertension, and hypertriglyceridemia prevalence (p=0.001) were observed in the full cohort on TT. Compared to controls, PCOS patients on TT exhibited higher hypercholesterolemia prevalence (p = 0.03) and elevated bioavailable testosterone (p = 0.04) after weight correction. Conclusions: TGD Individuals with PCOS had significantly worse CV risk profile compared to controls before starting TT attributed to greater weight. Significant changes in ALT, LDL, HDL, and prevalence of hypertriglyceridemia were seen across the entire TGD cohort treated with TT, but only hypercholesterolemia prevalence remained significantly higher in TGD PCOS cases on TT when corrected for weight. PCOS history was not associated with greater changes in CV risk factors in TGD individuals starting TT. Sunday, June 2, 2024

Increased total and phosphorylated glycogen synthase kinase-3 (GSK-3) in the adipocytes of patients with the polycystic ovary syndrome (PCOS)

Polycystic Ovary Syndrome (PCOS) is one of the most prevalent endocrine disorders among women of reproductive age and is characterized by chronic anovulation, hyperandrogenism, and polycystic ovarian morphology. Hyperandrogenism plays a central role in the pathophysiological and clinical manifestations of PCOS, with free testosterone recognized as the most biologically active androgen and an essential biochemical marker for diagnostic evaluation. However, comparative data between PCOS patients and healthy women in local clinical settings remain limited. This study aimed to compare free testosterone levels between women diagnosed with PCOS and healthy women during the period of July to September 2025. A comparative analytic cross-sectional design was used, involving two groups: women with clinically diagnosed PCOS and healthy women who met the inclusion criteria. A total of 30 participants were included using random sampling. Free testosterone levels were measured using the ezyme-linked immunosorbent assay (ELISA) method following standardized laboratory procedures. The normality test indicated that the data were not normally distributed; therefore, the Mann-Whitney test was applied for statistical analysis. The results showed that free testosterone levels were significantly higher in women with range of 34,92 ng/dL in the PCOS group and 22,49 ng/dL in the healthy groups, indicating a statistically significant difference between the two groups. These findings reinforce the role of elevated free testosterone as a key biochemical feature of PCOS and its contribution to hyperandrogenism. This study provides insight into the importance of hormonal assessment for diagnostic accuracy, early detection, and tailored therapeutic strategies for PCOS patients, particularly in the context of hormonal monitoring.