Polycystic Ovary Syndrome Phenotypes Research Articles

The additional value of ultrasound markers in the diagnosis of polycystic ovary syndrome

ObjectiveTo study the value of current definitions for follicle number per ovary and ovarian volume in the diagnosis of polycystic ovary syndrome (PCOS). DesignCross-sectional study. SubjectsWomen diagnosed with PCOS after standardized screening were eligible for inclusion in the PCOS group. Women without PCOS who underwent the same screening, had regular menstrual cycles, normal hormonal values, and no other endocrine pathology were eligible for inclusion. Exposure: -Main Outcome measuresFollicle number per ovary and ovarian volume in women with PCOS, stratified by age. Linear regression models to investigate the influence of BMI on follicle number per ovary and ovarian volume. Differences of follicle number per ovary and ovarian volume between the PCOS phenotypes and the additional value of ovarian volume compared to follicle number per ovary. ResultsA total of 2492 women (16 – 50 years) with PCOS and 152 women without PCOS were included. Most women with PCOS up to age 35 exhibit a follicle number per ovary ≥ 20 (87.8 – 100%) (using an ultrasound transducer ≥ 8 MHz) or ≥ 12 (95.1 – 98.6%) (using a transducer < 8 MHz), followed by a decline in follicle number per ovary above the age of 35. Median ovarian volume was below the 10 mL cut-off in every age group, for both ultrasound transducers. Follicle number per ovary and ovarian volume was higher in women with PCOS compared to women without PCOS in every age category. In our cohort, 13/2297 women with PCOS (0.6%) would not have received the diagnosis if ovarian volume was not considered as a marker for polycystic ovarian morphology. For both ultrasound transducers, women with phenotype A (ovulatory dysfunction + hyperandrogenism + polycystic ovarian morphology) exhibited the highest follicle number per ovary and ovarian volume, followed by phenotype D (ovulatory dysfunction + polycystic ovarian morphology), then phenotype C (hyperandrogenism + polycystic ovarian morphology), and then phenotype B (ovulatory dysfunction + hyperandrogenism) (all p-values < 0.001 after adjusting for age). No clinically significant correlation between BMI and follicle number per ovary or ovarian volume was observed. ConclusionCriteria to define follicle number per ovary should be established per age category, as follicle number per ovary decreases with age. Ovarian volume shows a less clear decline with age and has a lower discriminative power, and therefore could be excluded from the diagnostic criteria. follicle number per ovary does not need to be stratified by BMI.

The impact of hyperandrogenemia on pregnancy complications and outcomes in patients with PCOS: a systematic review and meta-analysis

ABSTRACT Background Polycystic ovary syndrome (PCOS) is a metabolic and reproductive disorder. Current research findings present conflicting views on the effects of different PCOS phenotypes on outcomes in pregnancy and for newborns. Methods This research study followed the guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA). A thorough search of literature was carried out using the Cochrane Menstrual Disorders and Subfertility Group trials register, Web of Science, and EMBASE databases from their start to December 2023. The search focused on studies examining the links between hyperandrogenic and non-hyperandrogenic PCOS phenotypes and risks in pregnancy and neonatology. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed using either a fixed-effects or random-effects model. Results Our analysis incorporated 10 research studies. Expectant mothers with a hyperandrogenic PCOS subtype had increased ORs for gestational diabetes mellitus (GDM) and preeclampsia (PE) compared to those with a non-hyperandrogenic PCOS subtype, with respective values of 2.14 (95% CI, 1.18–3.88, I2 = 0%) and 2.04 (95% CI, 1.02–4.08, I2 = 53%). Nevertheless, no notable differences were detected in ORs for outcomes like preterm birth, live birth, miscarriage, cesarean delivery, pregnancy-induced hypertension, small for gestational age babies, large for gestational age newborns, and neonatal intensive care unit admissions between pregnant women with hyperandrogenic PCOS phenotype and those without. Conclusions This meta-analysis highlights that the presence of hyperandrogenism heightens the risks of GDM and PE within the PCOS population. Healthcare providers ought to be aware of this connection for improved patient management.

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

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

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

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

Inositol Restores Appropriate Steroidogenesis in PCOS Ovaries Both In Vitro and In Vivo Experimental Mouse Models.

Androgen excess is a key feature of several clinical phenotypes of polycystic ovary syndrome (PCOS). However, the presence of FSH receptor (FSHR) and aromatase (CYP19A1) activity responses to physiological endocrine stimuli play a critical role in the pathogenesis of PCOS. Preliminary data suggest that myo-Inositol (myo-Ins) and D-Chiro-Inositol (D-Chiro-Ins) may reactivate CYP19A1 activity. We investigated the steroidogenic pathway of Theca (TCs) and Granulosa cells (GCs) in an experimental model of murine PCOS induced in CD1 mice exposed for 10 weeks to a continuous light regimen. The effect of treatment with different combinations of myo-Ins and D-Chiro-Ins on the expression of Fshr, androgenic, and estrogenic enzymes was analyzed by real-time PCR in isolated TCs and GCs and in ovaries isolated from healthy and PCOS mice. Myo-Ins and D-Chiro-Ins, at a ratio of 40:1 at pharmacological and physiological concentrations, positively modulate the steroidogenic activity of TCs and the expression of Cyp19a1 and Fshr in GCs. Moreover, in vivo, inositols (40:1 ratio) significantly increase Cyp19a1 and Fshr. These changes in gene expression are mirrored by modifications in hormone levels in the serum of treated animals. Myo-Ins and D-Chiro-Ins in the 40:1 formula efficiently rescued PCOS features by up-regulating aromatase and FSHR levels while down-regulating androgen excesses produced by TCs.

Targeted inhibition of kisspeptin neurons reverses hyperandrogenemia and abnormal hyperactive LH secretion in a preclinical mouse model of polycystic ovary syndrome.

Do hyperactive kisspeptin neurons contribute to abnormally high LH secretion and downstream hyperandrogenemia in polycystic ovary syndrome (PCOS)-like conditions and can inhibition of kisspeptin neurons rescue such endocrine impairments? Targeted inhibition of endogenous kisspeptin neuron activity in a mouse model of PCOS reduced the abnormally hyperactive LH pulse secretion and hyperandrogenemia to healthy control levels. PCOS is a reproductive disorder characterized by hyperandrogenemia, anovulation, and/or polycystic ovaries, along with a hallmark feature of abnormal LH hyper-pulsatility, but the mechanisms underlying the endocrine impairments remain unclear. A chronic letrozole (LET; aromatase inhibitor) mouse model recapitulates PCOS phenotypes, including polycystic ovaries, anovulation, high testosterone, and hyperactive LH pulses. LET PCOS-like females also have increased hypothalamic kisspeptin neuronal activation which may drive their hyperactive LH secretion and hyperandrogenemia, but this has not been tested. Transgenic KissCRE+/hM4Di female mice or littermates Cre- controls were treated with placebo, or chronic LET (50 µg/day) to induce a PCOS-like phenotype, followed by acute (once) or chronic (2 weeks) clozapine-N-oxide (CNO) exposure to chemogenetically inhibit kisspeptin cells (n = 6 to 10 mice/group). Key endocrine measures, including in vivo LH pulse secretion patterns and circulating testosterone levels, were assessed before and after selective kisspeptin neuron inhibition and compared between PCOS groups and healthy controls. Alterations in body weights were measured and pituitary and ovarian gene expression was determined by qRT-PCR. Acute targeted inhibition of kisspeptin neurons in PCOS mice successfully lowered the abnormally hyperactive LH pulse secretion (P < 0.05). Likewise, chronic selective suppression of kisspeptin neuron activity reversed the previously high LH and testosterone levels (P < 0.05) down to healthy control levels and rescued reproductive gene expression (P < 0. 05). N/A. Ovarian morphology was not assessed in this study. Additionally, mouse models can offer mechanistic insights into neuroendocrine processes in PCOS-like conditions but may not perfectly mirror PCOS in women. These data support the hypothesis that overactive kisspeptin neurons can drive neuroendocrine PCOS-like impairments, and this may occur in PCOS women. Our findings complement recent clinical investigations using NKB receptor antagonists to lower LH in PCOS women and suggest that pharmacological dose-dependent modulation of kisspeptin neuron activity may be a valuable future therapeutic target to clinically treat hyperandrogenism and lower elevated LH in PCOS women. This research was supported by NIH grants R01 HD111650, R01 HD090161, R01 HD100580, P50 HD012303, R01 AG078185, and NIH R24 HD102061, and a pilot project award from the British Society for Neuroendocrinology. There are no competing interests.

IL-18BP Therapy Ameliorates Reproductive and Metabolic Phenotypes in a PCOS Mouse Model by Relieving Inflammation, Fibrosis and Endoplasmic Reticulum Stress.

There is a chronic inflammation in PCOS patients, which is correlated with the pathogenesis of PCOS. IL-18 and IL-18BP are related with some inflammatory diseases, while less explored in PCOS. Whether IL-18BP could be a potential drug of PCOS remains unknown.IL-18 and testosterone levels were evaluated in serum of 10 non-PCOS control patients and 20 PCOS patients. Female C57/BL6 mice were gavaged with letrozole to induce PCOS mouse model and IL-18 level was evaluated in the serum of PCOS mouse model, and IL-18 is intraperitoneally injected in female mice, IL-18BP is intraperitoneally injected in the PCOS mice models. Then the body weights, estrous cycles, reproductive hormones and morphology of ovaries were analyzed. The level of ovarian chronic inflammation, fibrosis and endoplasmic reticulum (ER) stress are evaluated.IL-18 levels are increased in the serum of PCOS patients and PCOS mice models respectively. The serum DHEAS, iWAT weight and adipocyte size were increased in IL-18 group compared to the control group (P < 0.05). In the PCOS mouse model treated with IL-18BP, the body weight and serum LH/FSH ratio was decreased compared to the PCOS group (P < 0.05). The expression levels of inflammatory factors and fibrosis-related genes, the expression level of endoplasmic reticulum stress-related genes, and the ROS positive area of ovarian tissue was decreased (P < 0.05).IL-18 is involved in inducing PCOS phenotypes, while IL-18BP relieves PCOS phenotypes by alleviating ovarian chronic inflammation, fibrosis and ER stress in PCOS mice.

Effects of different PCOS phenotypes on placental three-dimensional power Doppler indices and placental volume during the first trimester

IntroductionThe aim of the present study was to evaluate the effects of different polycystic ovary syndrome (PCOS) phenotypes using first-trimester placental three-dimensional power Doppler indices and placental volume. MethodsIn this prospective case-control study, 170 pregnant women who met the inclusion criteria were divided into five groups according to PCOS phenotype: non-PCOS control (n = 34), PCOS phenotype A (n = 34), PCOS phenotype B (n = 34), PCOS phenotype C (n = 34), and PCOS phenotype D (n = 34). The primary outcomes determined in the present study were the differences in placental volume and placental flow index (FI), vascularization flow index (VFI), vascularization index (VI), and uterine artery pulsatility index (PI) betweenthe PCOS groups and control group. ResultsThe mean placental volume and VI were significantly decreased in the phenotype A, B, and C groups compared to the control group and PCOS phenotype D group. The mean FI and VFI were significantly decreased in the phenotype A and B groups compared to the control group and PCOS phenotype C and D groups. The mean testosterone, dehydroepiandrostenedione, sex-hormone binding globulin, free androgen index, and insulin resistance levels were significantly increased in the phenotype A, B, and C groups compared to the control group and PCOS phenotype D group. DiscusionThe results indicated that placental volume and placental vascular Doppler indices in the first trimester were more adversely affected in the PCOS A and B phenotypes than other PCOS phenotypes.

P-647 Association between PCOS phenotype-D and euploid blastocyst rate per cohort of inseminated oocytes: a matched case-control study versus idiopathic infertile women

Abstract Study question Is there any association between PCOS phenotype-D and oocyte competence defined as euploid blastocyst rate (EBR) per cohort of inseminated oocytes? Summary answer Although higher fertilization and blastulation rates were reported in PCOS phenotype-D women versus idiopathic infertile patients, the EBR per cohort of inseminated oocytes was comparable. What is known already Several studies report poorer oocyte quality and cumulative-live-birth-rate (CLBR) in hyperandrogenic PCOS phenotypes, as defined according to the Rotterdam criteria. Increased androgen concentrations in follicular fluids are indeed associated with elevated serum-LH levels, which can block dominant follicle development inducing atresia and negatively impact fertilization rates and embryo development. Limited evidence exists in phenotype-D PCOS patients, namely women characterized by oligomenorrhea, ovarian PCO morphology and absence of hyperandrogenism. Here, we report the embryological and clinical outcomes in these women during ICSI cycles with preimplantation genetic testing for aneuploidies (PGT-A) at the blastocyst stage. Study design, size, duration Retrospective propensity score matched (PSM) case-control study. Among PGT-A cycles conducted by naïve patients with own oocytes (2013-2021), we excluded FNA/TESE. 58 phenotype-D PCOS patients were identified according to the Rotterdam criteria. These patients were matched for maternal age, number of cumulus-oocyte-complexes (COCs), and sperm quality, with 58 patients with idiopathic infertility, regular cycles, normal ovarian morphology, and no sign of clinical hyperandrogenism. The primary outcome was EBR per cohort of inseminated oocytes. Participants/materials, setting, methods GnRH-antagonist ovarian stimulation, ICSI, blastocyst biopsy, qPCR/NGS-analysis to assess uniform aneuploidies and vitrified-warmed single blastocyst transfers were conducted. The PCOS and control groups were similar for age (35.6±3.0 versus 36.0±3.9 years), COCs (23.1±6.7 versus 23.5±7.6), sperm factor, primary/secondary infertility, hormonal values, BMI (23.8±5.3 versus 22.0±2.8), and duration of infertility (3.6±2.2 versus 3.6±2.0 years). All intermediate embryological and clinical outcomes were assessed as secondary endpoints. Linear/logistic regressions adjusted for confounders were conducted to confirm statistically-significant differences. Main results and the role of chance No difference was reported in maturation rates, but women with PCOS showed better fertilization rates per cohort of inseminated oocytes (76.9±15.2% versus 67.3±20.4%, Mann-Whitney-U-test&amp;lt;0.01), and blastulation rates per cohort of 2PN-zygotes (52±20.4% versus 43.7±20.7%, Mann-Whitney-U-test=0.03). Eventually, PCOS patients obtained more blastocysts than controls (5.8±3.1 versus 4.5±2.9, Mann-Whitney-U-test=0.02), despite similar numbers of metaphase-II oocytes in the groups (16.5±6.1 versus 16.5±7.0). All differences remained significant after adjusting for maternal age and sperm factor. Nevertheless, the euploidy rates per cohort of biopsied blastocysts were similar, thus involving comparable EBR per cohort of inseminated oocytes (21.7±14.1% versus 17.2±16%, Mann-Whitney-U-test=0.12). More patients obtained ≥1 euploid blastocyst in the PCOS versus the control group (N = 56/58, 96% versus N = 47/58, 81%, Fisher’s-exact-test=0.02), independently from maternal age, semen quality, and number of inseminated oocytes (Odds-Ratio: 6.5, 95%CI:1.3-33.7, p = 0.03). Lastly, all clinical outcomes per first vitrified-warmed euploid transfer were similar, thereby involving comparable LBRs (N = 28/54, 51.9% versus N = 26/47, 55.3% in the PCOS and control groups, p = 0.8; Odds-Ratio adjusted for blastocyst quality and day: 1.19, 95%CI:0.5-2.7, p = 0.68). Limitations, reasons for caution Although clinical hyperandrogenism was absent in both groups, biochemical hyperandrogenism was not assessed. Nonetheless, this pilot study paves the way for future more detailed investigations. 24% of cycles in the PCOS group were not concluded, therefore a CLBR comparison would be biased and was not reported. Wider implications of the findings The lower developmental competence in the control group suggests oocyte quality issues, other than chromosomal, underlying their “unexplained infertility” condition. In phenotype-D PCOS women, IVF is effective. Since &amp;gt;50% of this subgroup of women had already failed multiple ovulation-induction and/or intrauterine-insemination attempts, an early referral to IVF deserves further investigations. Trial registration number Not applicable

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

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

P-658 Identification of novel biomarkers for the detection of polycystic ovary syndrome (PCOS) in adolescents and adult women

Abstract Study question Can novel biomarkers be identified to distinguish between PCOS-positive cases and healthy PCOS-negative controls in women as early as adolescence? Summary answer Meteorin-like protein (METRNL), fibroblast growth factor binding protein-1 (FGFBP1) and leukotriene A4 hydrolase (LTA4H) identified PCOS as early as adolescence, independent of PCOS phenotype. What is known already International evidence-based guidelines recommend use of the Rotterdam criteria for PCOS diagnosis. Despite this guidance, diagnosing PCOS can be extremely challenging due to the heterogeneity of clinical presentation, and further complicated in adolescence and young adulthood due to overlap between signs of physiologic changes during puberty and common symptoms of PCOS (e.g., menstrual irregularity, excess male hormones/androgens, multiple follicles in ovaries). Timely diagnosis of PCOS allowing for appropriate monitoring, follow up and early intervention may reduce the risk of associated comorbidities. An unmet need exists for biomarkers/alternative tools to support earlier diagnosis of PCOS in adolescents/adult women of reproductive age. Study design, size, duration This was a retrospective study (October 2020–June 2023) using banked samples from women with PCOS (confirmed per Rotterdam criteria) and healthy controls who had participated in previous studies sponsored by/in collaboration with Roche Diagnostics. Candidate biomarkers identified by exploratory proteomics analysis (Olink Proximity Extension Assay) were verified by ELISA and receiver operating characteristic-area under the curve (ROC-AUC) analysis for their ability to discriminate PCOS cases and controls in women aged 15-45 years. Participants/materials, setting, methods Top-performing biomarkers from Olink discovery (n = 51 PCOS phenotype A; n = 37 controls) were selected for further validation based on AUC &amp;gt;0.970, biological relevance for PCOS and commercial ELISA availability. Serum biomarker concentrations/biomarker ratios were determined and ROC-AUC analysis conducted in two validation cohorts (Cohort 1: n = 90 cases [phenotype A, n = 30; B, n = 20; C, n = 20; D, n = 20]; n = 47 controls; Cohort 2: n = 240 cases [15-19 years, n = 70; 20-24 years, n = 99; 25-40 years, n = 71]; n = 48 controls, median 26.0 years). Main results and the role of chance Serum METRNL concentrations were numerically lower, and FGFBP1 and LTA4H concentrations numerically higher, in PCOS cases compared with controls. All three biomarkers distinguished PCOS cases and controls, regardless of PCOS phenotype A-D (Cohort 1: AUCs 0.91-0.99 [METRNL], 0.84-0.88 [FGFBP1] and 0.76-0.90 [LTA4H]), and across different age groups in women of reproductive age (Cohort 2: 15-19, 20-24 and 25-40 years; AUCs 0.88, 0.91 and 0.96 [METRNL], respectively; 0.90, 0.88 and 0.91 [FGFBP1], respectively; 0.74, 0.70 and 0.78 [LTA4H], respectively). Compared with results for the individual biomarkers, combining FGFBP1 with METRNL, and LTA4H with METRNL, as biomarker ratios further improved the ability to distinguish PCOS cases and controls, independent of PCOS phenotype A-D (Cohort 1: AUCs 0.95-1.00 [FGFBP1:METRNL] and 0.97-0.99 [LTA4H:METRNL]) and across age groups (Cohort 2: 15-19, 20-24 and 25-40 years; AUCs 0.91, 0.96 and 0.98 [FGFBP1:METRNL], respectively, and 0.91, 0.91 and 0.97 [LTA4H:METRNL], respectively). Findings were not impacted by adjustment for baseline body mass index. METRNL, FGFBP1 and LTA4H are linked to biological mechanisms associated with clinical manifestations and underlying characteristics of PCOS, i.e., metabolic pathways, inflammation and ovarian function. While METRNL has been described previously in adult PCOS, FGFBP1 and LTA4H findings are novel in this context. Limitations, reasons for caution These findings in retrospective samples warrant validation in additional independent prospective cohorts, particularly in adolescents and young adult women. Wider implications of the findings Reliable diagnosis of PCOS in adolescents and young adult women represents an unmet medical need. METRNL, FGFBP1 and LTA4H have potential use as biomarkers to support the detection of PCOS in adolescents and adult women, potentially shortening time to diagnosis and allowing for earlier and targeted intervention. Trial registration number not applicable

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

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

Metabolic and Inflammatory Profiles Across Infertile PCOS Phenotypes: Implications for Clinical Practice

Metabolic and Inflammatory Profiles Across Infertile PCOS Phenotypes: Implications for Clinical Practice

New characteristics of polycystic ovary syndrome phenotypes according to gas chromatography-mass spectrometry-based study of urinary steroid metabolome.

The most common cause of hyperandrogenism in women is polycystic ovary syndrome (PCOS), the prevalence of which among women of reproductive age ranges from 8.0 to 21%. The clinical manifestations of PCOS are diverse, and the degree of metabolic and hormonal disorders depends on the PCOS phenotype. The non-classic congenital adrenal hyperplasia (NCCAH) ranks second in the structure of diseases associated with hyperandrogenism. PCOS and NCCAH have a similar clinical picture and laboratory parameters, which requires differential diagnosis. Urinary steroid profiles were studied by gas chromatography-mass spectrometry. We revealed differences in glucocorticoid and androgen metabolism in women with different PCOS phenotypes, which is reflected in the clinical manifestation of the disease. It was evaluated the activity of enzymes involved in the metabolism of steroid hormones. In patients with NCCAH, it was found that polycystic ovarian changes are secondary and develop due to the presence of prolonged adrenal hyperandrogenism. The results obtained are important for understanding the mechanisms of disorders in various variants of hyperandrogenism and determining further tactics for managing patients.

Late diagnosis of partial 3β-hydroxysteroid dehydrogenase type 2 deficiency - characterization of a new genetic variant.

Congenital adrenal hyperplasia (CAH) is one of the most common inherited rare endocrine disorders. This case report presents two female siblings with delayed diagnosis of non-classical CAH 3β-hydroxysteroid dehydrogenase type 2 (3βHSD2D/HSD3B2) despite early hospital admission and apparent CAH manifestations such as infections, hirsutism, menstrual disturbances, and PCOS phenotype. Initially, sister 1 was misdiagnosed with PCOS and then 11-hydroxylase deficiency (CYP11B1), based on ultrasound, biochemical findings, and negative genetic testing for 21-hydroxylase deficiency (CYP21A2). Additional diagnostic workup was performed when sister 2also presented with symptoms of androgen excess. Genetic testing for CAH/steroid disorders finally revealed that both siblings were compound heterozygous for two variants in the HSD3B2 gene: a frameshift variant, c.558dup, p.(Thr187Hisfs*17) and a novel missense variant, c.65T>C, p.(Leu22Ser). A Synacthen test showed an insufficient cortisol increase. In vitro studies of the variants in a cell model revealed loss of function for the p.(Thr187Hisfs*17) and partial activity for p.(Leu22Ser) confirming non-classic CAH. Overlapping symptomatology and lack of specialized knowledge on steroid biosynthesis and associated rarest forms of CAH may explain the delayed diagnosis. However, with newer diagnostic methods comprising a less biased approach, very rare forms of non-classical CAH may no longer be overlooked in the future. Non-classic 3βHSD2 is likely underdiagnosed. Late diagnosis of mild non-classic 3βHSD2 does occur and one should be aware of this diagnosis. Early diagnosis of NCCAH may prevent many consequences such as severe hirsutism, prolonged menstrual irregularities, infertility, or even adrenal crisis with severe infections. Comprehensive steroid profiling and genetic testing should be used earlier, especially when in doubt about a diagnosis.

Normative Data for Modified Ferriman-Gallwey Score and the Prevalence of Hirsutism in Young South Indians.

The modified Ferriman-Gallwey score (mFGS) cut-offs to define hirsutism vary with ethnicity, whereas no such cut-offs are established for Indian women. Well-conducted studies that report the prevalence of hirsutism in Indian women are limited. Hence, this study was conducted to report the prevalence of hirsutism and population-specific cut-offs for mFGS in South-Indian women. In this cross-sectional, community-based study, adult women in reproductive age (18-40 years) were screened for hirsutism by two trained medical students. Hirsutism was assessed using the mFGS and case record file. A total of 453 women were included in the study [age: 22.15 ± 5.27 years; body mass index (BMI): 22.5 ± 3.58 kg/m2]. The median (IQR) mFGS was 1(0-3); only eight participants (1.8%) had mFGS ≥8, and all these eight women had at least another PCOS-related feature (irregular menstrual cycles and/or topical therapy-resistant acne). The median (IQR) mFGS in the PCOS phenotype group (n = 52), non-PCOS-phenotype group (n = 401), non-obese group (<25 kg/m2), non-PCOS-phenotype group (n = 322), obese group (≥ 25 kg/m2), non-PCOS-phenotype group (n = 79), overweight group (BMI: 23-25 kg/m2), non-PCOS-phenotype group (n = 74), normal BMI group (<23 kg/m2), and non-PCOS-phenotype group (n = 248) were 4 (1-6), 1 (0-2), 1 (0-2), 2 (1-3), 1 (0-2), and 1 (0-2), respectively. The 97.5th centile mFGS in all groups except the PCOS phenotype group and the obese and non-PCOS phenotype groups was 5. We propose a new mFGS cut-off of 5 in the South-Indian population for evaluation of hirsutism, and the prevalence rates of hirsutism in the South-Indian population were 1.8% and 9.9% using mFGS of ≥8 and ≥5 to define hirsutism, respectively.

PLASMA PROLIDASE ACTIVITY AND ITS RELATION WITH NUMBER OF CYSTS IN POLYCYSTIC OVARY SYNDROME

Background: Plasma prolidase, a Matrix Metalloproteinase (MMP), has a role in maintaining extracellular matrix remodelling in ovary. The aim of this study was to find out the activity and association with the clinical and biochemical parameters of plasma prolidase in different phenotypes of Polycystic Ovary Syndrome (PCOS). Methods: Total 90 women (16-22 years) with PCOS were enrolled in the study. Data regarding anthropometric measurements (weight, height, BMI and WHR) were taken. Transabdominal ultrasonography was done by trained sonographer. Hormonal tests (free testosterone, FSH, LH), and metabolic tests (including FBS) were done by chemiluminescence analyzer. Participants were divided into four groups. Group 1 (n=25), hyperandrogenism with oligo-anovulation (HO), Group 2 (n=26), polycystic ovary with oligo-anovulation (PO), Group 3 (n=20), hyperandrogenism with polycystic ovary (HP), Group 4 (n=19), with presence of all these three features (PHO). Five ml blood sample was taken for plasma Prolidase by Spectrophotometry. Kruskal Wallis test and spearman correlation were used for statistical analysis. Results: Among 90 women 52.2% had both polycystic ovaries, 13.3% has one polycystic ovary and 34.4% had normal ovaries on ultrasound. Median difference of plasma Prolidase, LH, FSH, free testosterone and HOMA-IR between groups were found statistically significant (p&lt;0.05). Plasma Prolidase had a direct relation (r=0.374) with number of cysts on ultrasound. Conclusion: Plasma Prolidase activity was high in PCOS phenotypes and positive correlation was found between Prolidase levels and number of cysts. Prolidase can be used as diagnostic and prognostic marker in PCOS. Pak J Physiol 2024;20(2):14-8

Structural changes in amide I and amide II regions of PCOS women analyzed by ATR-FTIR spectroscopy

The etiology of PCOS is complex and frequently mis or undiagnosed, which may enhance morbidity and reduce the quality of life. Attenuated total reflection- Fourier transform infrared (ATR-FTIR) spectroscopy examines the structural fingerprints of the biochemical compounds and can provide distinct FTIR spectra of the PCOS cases and controls. The present study recruited 61 PCOS cases and 38 control women. The student's t-test was used to compare BMI, WHR, and lipid profile. The FTIR spectral region was compared among both groups using the Mann-Whitney U test and multivariate analysis involved principal component analysis (PCA) and hierarchical cluster analysis (HCA). FTIR spectra of different phenotypes of PCOS were also analyzed using multivariate analysis. In univariate analysis, PCOS women had significantly higher WHR (p = 0.007), BMI (p = 0.04), triglycerides (p = 0.04), and VLDL (p = 0.02) than the controls. The spectral regions of amide I (1700-1600 cm-1) and amide II (1580-1480 cm-1), were significantly greater in the PCOS group than in the controls (p < 0.01 and p < 0.001, respectively). The PCA and HCA revealed a distinct molecular fingerprint for phenotype A (PCOM + OA + HA) and phenotype B (HA + OA).Our study postulated that the spectral regions of amide I and amide II can distinguish between PCOS cases and control women and it may be used for the diagnosis of cases.

Influence of state-of-the-art laboratory techniques on the phenotyping of women with polycystic ovary syndrome in the clinical setting.

Evidence-based guidelines for the management of polycystic ovary syndrome (PCOS) recommend clinical laboratories use liquid chromatography-tandem mass spectrometry (LC-MS/MS) for diagnosing biochemical hyperandrogenism. However, automated immunoassays are still mostly used in routine laboratories worldwide. Another hurdle for PCOS phenotyping in the clinical setting is ultrasound assessment of polycystic ovarian morphology. We address the impact of using state-of-the-art (LC-MS/MS) and of an anti-müllerian hormone (AMH) assay on the diagnosis of PCOS in routine practice. In a cross-sectional study, we included 359 premenopausal women consecutively evaluated because of symptoms of functional androgen excess or hyperandrogenemia, and finally diagnosed with PCOS. Patients were submitted to routine phenotyping based on serum androgen measurements by immunoassays and an ovarian ultrasound when necessary. Samples of all patients were also assayed by LC-MS/MS for hyperandrogenemia and for circulating AMH. The observed agreement between immunoassays and LC-MS/MS in identifying hyperandrogenemia was poor [78.0%; k(95%CI): 0.366 (0.283;0.449)]. The observed agreement between ultrasound and increased AMH was 27.3% [(95%CI): 0.060 (0.005; 0.115)]. Using LC-MS/MS changed PCOS phenotypes in 60(15.8%) patients. Fifty-two (18.3%) individuals with hyperandrogenemia by routine immunoassays no longer presented with androgen excess by LC-MS/MS. Overall diagnostic agreement between routine assessment using immunoassays and ultrasound and that derived from LC-MS/MS and the addition of AMH to US was moderate [weighted κ (linear weights): 0.512 (0.416;0.608)]. Immunoassays used in routine practice are unacceptably inaccurate for phenotyping women with PCOS. Our data cast some doubts upon the interchangeability of serum AMH and ultrasound examination for the diagnosis of PCOS.

Folate and Vitamin B12 Levels in Chilean Women with PCOS and Their Association with Metabolic Outcomes.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects women of reproductive age. Many women with PCOS have been found to have an unbalanced diet and deficiencies in essential nutrients. This study aimed to assess the levels of folate and vitamin B12 (B12) and their relationship with metabolic factors in women with PCOS. Anthropometric, clinical, and genetic analyses were conducted to evaluate markers related to one-carbon metabolism in women with PCOS and in a control group. The PCOS group had a higher BMI and HOMA-IR (1.7 vs. 3.1; p < 0.0001). HDL cholesterol levels were 23% lower and triglyceride levels were 74% higher in women with PCOS. Although there were no significant differences in folate and B12 levels between the PCOS and control groups, over 60% of women with PCOS had low B12 levels (<300 pg/mL) and high homocysteine levels. In addition, the MTHFR A1298C and C677T polymorphisms were not associated with PCOS. Moreover, erythrocyte folate levels were positively correlated with fasting glucose, triglycerides, and free androgen index, and negatively correlated with SHBG and LH levels. These results suggest that B vitamins may be associated with the metabolic phenotype in PCOS. This study emphasizes the potential link between folate, vitamin B12, and metabolic and hormonal outcomes in women with PCOS.