Classic Polycystic Ovary Syndrome Research Articles

Metabolomics approach for the etiopathogenesis of polycystic ovarian syndrome

Polycystic ovary syndrome (PCOS) is a complex and multifaceted disorder that has been extensively studied from various angles, including genomics, metabolomics, and other multiomics approaches. This narrative review seeks to provide an updated understanding of PCOS, with a particular focus on metabolomics. PCOS encompasses four primary phenotypes: Classic PCOS with or without polycystic ovary morphology, ovulatory PCOS, and non-hyperandrogenic PCOS. Each phenotype exhibits distinct clinical and biochemical characteristics. Classic PCOS, characterized by hyperinsulinemia, insulin resistance (IR), and metabolic complications, has garnered significant attention in recent studies. In the pursuit of unraveling PCOS’s pathophysiology, researchers have embraced a multiomics approach, exploring the genome, epigenome, transcriptome, exosomes, proteome, and metabolome. The genomic landscape of PCOS includes genes related to androgen synthesis, regulation, insulin receptors, and growth factors, among others. Epigenetic mechanisms have also been investigated, revealing the roles of non-coding RNA, histone acetylation, and deacetylation. Transcriptomic biomarkers and mitochondrial RNAs targets, such as miR-9 and miR-32, have been explored in granulosa cells of PCOS patients. Metabolomics studies have identified various biomarkers and metabolic pathways that differentiate PCOS from healthy individuals. A diverse range of alterations in carbohydrate and lipid metabolism has been observed, shedding light on the underpinnings of PCOS-related metabolic dysfunction. These studies have uncovered numerous biomolecules with potential relevance to PCOS, including kininogen 1, cytoketatin 9, and many others. In addition, the intricate relationships between IR, inflammation, and metabolic factors have been elucidated. Recent research extends beyond high-end research centers, even using urine samples to identify metabolomic markers for PCOS. This approach has led to the discovery of distinct biomarker panels related to metabolic pathways that differentiate PCOS from healthy subjects. In summary, PCOS is a complex and heterogeneous condition, with multiomics studies offering promising avenues for a deeper understanding of its pathophysiology. These studies may ultimately provide valuable insights that can revolutionize the diagnosis and treatment of PCOS, ending a centurylong scientific expedition with a crescendo of discoveries.

FRI449 Self-reported Diagnosis Of Polycystic Ovary Syndrome In The Coronary Artery Risk Factor Development in Young Adults (CARDIA) Study

Abstract Disclosure: C. Kim: None. P. Schreiner: None. D. Siscovick: None. A. Wang: None. M. Wellons: None. I. Ebong: None. T. Vu: None. D. Appiah: None. J. Catov: None. E. Schisterman: None. Z. Yin: None. C.E. Lewis: None. Background Polycystic ovary syndrome (PCOS) is thought to be common, but may be underrecognized by women and their healthcare providers. Factors related to women’s self-report of PCOS diagnosis are not well-understood, particularly in population-based studies that are not based on specialist referrals. Objective To compare characteristics of women with self-reported PCOS vs. women who may have unrecognized PCOS vs. women without PCOS. We hypothesized that women who have classic PCOS characteristics, including hyperandrogenemia symptoms and cardiometabolic disorders, would be associated with higher self-report of PCOS, and that poorer social determinants of health (SDH), such as barriers to medical care, would be associated with unrecognized PCOS. Study design Analysis of an observational cohort study, the CARDIA Study. CARDIA is a population-based multi-center study that enrolled Black and White participants beginning in 1985-1986. Included in this analysis were women (n=2028) who responded to the question, “Did a doctor or nurse ever tell you that you had polycystic ovarian syndrome or polycystic ovarian disease?” at the Year 15 examination, when they were ages 33-45 years. Women who answered “yes” were defined as having self-reported PCOS. Women who answered “no or not sure” were defined as having unrecognized PCOS if they also had irregular menses between 20-30 years of age and hyperandrogenemia (defined as hirsutism or biochemical elevations in free testosterone or total testosterone) between 20-30 years of age. Exposures of interest included SDH, symptoms including irregular menses and hirsutism, and comorbid conditions including obesity and diabetes. Results: Forty-three (2.1%) of women had self-reported PCOS, 135 (6.7%) had unrecognized PCOS, and 1850 (91%) women were without PCOS. In polychotomous logistic regression models adjusting for age, race, and center, women with self-reported PCOS had greater odds of having obesity (OR 1.83, 95% CI 1.22, 2.75) and diabetes (OR 2.37, 95% CI 1.05, 5.33) compared to women without PCOS. Results were similar when women without biochemical androgens were excluded. Women with unrecognized PCOS were more likely to have hypertension (OR 1.68, 95% CI 1.03, 2.74) and food insecurity (OR 1.94, 95% CI 1.25, 3.01) but had similar likelihood of obesity and diabetes compared to women without PCOS. However, other SDH such as access to care and low education were not associated with self-report of PCOS nor with unrecognized PCOS. Conclusions Unrecognized PCOS is more common than self-reported PCOS. Women with self-reported PCOS have classic metabolic symptoms, while those with unrecognized PCOS have less traditional factors including hypertension and food insecurity. Presentation: Friday, June 16, 2023

Serum metabolomics profiling by proton nuclear magnetic resonance spectrometry of the response to single oral macronutrient challenges in women with polycystic ovary syndrome (PCOS) compared with male and female controls

BackgroundThe polycystic ovary syndrome (PCOS) is associated with insulin resistance, obesity and cardiometabolic comorbidities. We here challenged the hypothesis, using state-of-the-art proton nuclear magnetic resonance spectrometry (1H-NMRS) metabolomics profiling, that androgen excess in women induces a certain masculinization of postprandial metabolism that is modulated by obesity.Materials and methodsParticipants were 53 Caucasian young adults, including 17 women with classic PCOS consisting of hyperandrogenism and ovulatory dysfunction, 17 non-hyperandrogenic women presenting with regular menses, and 19 healthy men, selected to be similar in terms of age and body mass index (BMI). Half of the subjects had obesity. Patients were submitted to isocaloric separate glucose, lipid and protein oral challenges in alternate days and fasting and postprandial serum samples were submitted to 1H-NMRS metabolomics profiling for quantification of 36 low-molecular-weight polar metabolites.ResultsThe largest postprandial changes were observed after glucose and protein intake, with lipid ingestion inducing smaller differences. Changes after glucose intake consisted of a marked increase in carbohydrates and byproducts of glycolysis, and an overall decrease in byproducts of proteolysis, lipolysis and ketogenesis. After the protein load, most amino acids and derivatives increased markedly, in parallel to an increase in pyruvate and a decrease in 3-hydroxybutyric acid and glycerol. Obesity increased β- and d-glucose and pyruvate levels, with this effect being observed mostly after glucose ingestion in women with PCOS. Regardless of the type of macronutrient, men presented increased lysine and decreased 3-hydroxybutyric acid. In addition, non-obese men showed increased postprandial β-glucose and decreased pyroglutamic acid, compared with non-obese control women. We observed a common pattern of postprandial changes in branched-chain and aromatic amino acids, where men showed greater amino acids increases after protein intake than control women and patients with PCOS but only within the non-obese participants. Conversely, this increase was blunted in obese men but not in obese women, who even presented a larger increase in some amino acids compared with their non-obese counterparts. Interestingly, regardless of the type of macronutrient, only obese women with PCOS showed increased leucine, lysine, phenylalanine and tryptophan levels compared with non-obese patients.ConclusionsSerum 1H-NMRS metabolomics profiling indicated sexual dimorphism in the responses to oral macronutrient challenges, which were apparently driven by the central role of postprandial insulin effects with obesity, and to a lesser extent PCOS, exerting modifying roles derived from insulin resistance. Hence, obesity impaired metabolic flexibility in young adults, yet sex and sex hormones also influenced the regulation of postprandial metabolism.Graphical abstract

Endocrinological and Metabolic Heterogeneity Is Low in Japanese Women With Polycystic Ovary Syndrome

ObjectivesThis study aims to evaluate the endocrine differences among polycystic ovary syndrome (PCOS) phenotypes in Japanese women. Methods118 Japanese women that we diagnosed with PCOS agreed to be included in the study. The study group was classified into the following 4 phenotypes: (A) hyperandrogenism (HA); ovulatory disorder (OvD) and polycystic ovary morphology (PCOM); (B) HA and OvD; (C) HA and PCOM; and (D) OvD and PCOM. We also recruited 66 healthy Japanese women to the study as control participants. Age, body mass index, androgens, luteinizing hormone, follicle-stimulating hormone, and insulin resistance (IR) index were evaluated and compared. ResultsThe proportions of phenotypes A, B, C, and D were 57/120 (47.5%), 4/120 (3.3%), 13/120 (10.8%), and 46/120 (38.3%), respectively. The proportion of phenotype B was too small; therefore, phenotypes A and B were grouped as classical PCOS for intergroup comparisons. The luteinizing hormone/follicle-stimulating hormone ratio in the classical PCOS group was higher than that in the phenotype D group (P < 0.001). Androgen concentrations in the phenotype D group were significantly lower than those in the other groups (P < 0.01). Phenotype D was more common in lean women with PCOS. The surrogate marker of IR (homeostasis model assessment of IR) was not different irrespective of PCOS and its phenotypes. ConclusionsExcept for androgens, endocrine differences by PCOS phenotype are not evident, suggesting that diversity among patients with PCOS is relatively low in Japanese women.

Sexual function in Chinese women with different clinical phenotypes of polycystic ovary syndrome

Objective: To investigate sexual function stratified according to four clinical phenotypes of polycystic ovary syndrome (PCOS) and its association with clinical and quality of life parameters, and to compare these with healthy controls in Chinese women with PCOS. Methods: A cross-sectional study was designed in 1000 PCOS women and 500 control women aged 18–45 years. PCOS women were grouped into four clinical phenotypes according to the Rotterdam Criteria. FSFI (Female Sexual Function Index), SF-12 (the 12-item short form health survey) and clinical and hormonal characteristics likely to affect sexual function were determined. Results: 809 PCOS women and 385 control women with complete parameters were evaluated after screening. Phenotype A had a lower total FSFI mean score (23.14 ± 3.22) compared with phenotype D and control group (p < 0.05). The control group had the highest total FSFI mean score (24.98 ± 3.78). For the percentage at risk of sexual dysfunction, phenotype A (87.5%) and phenotype B (82.46%) had a higher risk of female sexual dysfunction (FSD) than that in phenotype C (75.34%), phenotype D (70.56%) and control group (61.30%) (p < 0.05). SF-12 mental domain scores were significantly lower in phenotypes A and B compared with phenotypes C and control group (p < 0.05). Infertility treatment, bioavailable testosterone, psychological factors, age and waist circumference presented negative correlation with female sexual function. Conclusions: The risk of FSD in PCOS women seemed to be associated with PCOS clinical phenotypes. The classical PCOS phenotype with oligo-ovulation and hyperandrogenism had a higher risk of sexual dysfunction.

Follicular fluid redox balance and DNA damage according to PCOS phenotype.

Classification of polycystic ovary syndrome (PCOS) according to their phenotypes is important in terms of understanding which parameter has clinical and laboratory implications. This study was designed to measure the follicular fluid total oxidant capacity (TOC) and total antioxidant capacity (TAC) and DNA degradation products of 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in patients with different PCOS phenotypes undergoing In-Vitro Fertilization/Intra-Cytoplasmic Sperm Injection (IVF/ICSI). Thirty women who were diagnosed with PCOS and twenty infertile patients who did not have the clinical and laboratory findings of PCOS were included. Women carrying at least two of the three parameters below were considered to have PCOS. (1) Biochemical or clinical manifestations of hyperandrogenism (HA); (2) Ovulatory dysfunction (OD); (3) Polycystic ovarian morphology (PCOM). Patients were then classified into four different PCOS phenotypes: (1) Phenotype A is also known as classical PCOS and meets all three criteria (HA/OD/PCOM). (2) Phenotype B has two criteria, HA and OD. (3) Phenotype C consists of HA and PCOM criteria. (4) Phenotype D is the non-hyperandrogenic form and consists of OD and PCOM criteria. Antagonist protocol was used in both PCOS and control groups. During oocyte pick-up, follicular fluid of the dominant follicle was collected. TAC and TOC levels, which are redox balance markers, and 8-OHdG levels, which are DNA degradation products, were measured in follicular fluid samples (FF). Follicular fluid 8-OHdG levels of all four types of phenotypes were significantly higher than the control group. When the phenotype groups were evaluated among themselves, FF-8-OHdG levels of each group were found to be similar. Serum TOC levels of each phenotype group were found to be significantly higher than the control group. TAC levels of the patients in the control group were significantly higher than the other four phenotype groups. Oxidative stress index (OSI) values were significantly higher in all four phenotype groups compared to the control group. OSI values of phenotype B and D groups were significantly higher than phenotypes A and C. In each phenotype of PCOS, TOC and OSI increased while TAC decreased. Increased OSI leads to DNA degradation and an increase in the level of 8-OHdG. The cumulative effect of oxidative stress and DNA degradation may be the main mechanism of PCOS-related subfertility.

Serum metabolomics profiling by proton nuclear magnetic resonance spectroscopy reveals sexual dimorphism and masculinization of intermediate metabolism in women with polycystic ovary syndrome (PCOS)

BackgroundThe polycystic ovary syndrome (PCOS) is associated with insulin resistance, obesity and cardiometabolic comorbidities. We here challenged the hypothesis, using state-of-the art proton nuclear magnetic resonance spectroscopy metabolomics profiling, that androgen excess in women induces also a certain masculinization of intermediate metabolism that is modulated by obesity.MethodsParticipants were 53 Caucasian young adults, including 17 women with classic PCOS consisting of hyperandrogenism and ovulatory dysfunction, 17 non-hyperandrogenic women presenting with regular menses, and 19 healthy men, selected in order to be similar in terms of age and body mass index (BMI). Half of the subjects had obesity defined by a body mass index ≥ 30 kg/m2. Subjects maintained the same diet unrestricted in carbohydrates for 3 days before sampling and maintained their lifestyle and exercise patterns prior and during the study. Plasma samples were submitted to proton nuclear magnetic resonance spectroscopy metabolomics profiling.ResultsObesity associated a metabolomics profile mainly characterized by increased branched chain and aromatic aminoacids. Regardless of obesity, this unfavorable profile also characterized men as compared with control women, and was shared by women with PCOS. Notably, the negative impact of obesity on metabolomics profile was restricted to women, with obese men showing no further deterioration when compared with their non-obese counterparts.ConclusionsSerum metabolomics profiling by proton nuclear magnetic resonance spectroscopy reveals sexual dimorphism, and masculinization of intermediate metabolism in women with PCOS, further suggesting a role for sex and sex hormones in the regulation of intermediate metabolism.

Validation of circulating microRNAs miR-142-3p and miR-598-3p in women with polycystic ovary syndrome as potential diagnostic markers.

Circulating miRNAs previously associated with androgen excess in women might be used as diagnostic biomarkers for polycystic ovary syndrome (PCOS). Models based on circulating miR-142-3p and miR-598-3p expression show good discrimination among women with and without PCOS, particularly when coupled with easily available measurements such as waist-to-hip ratio (WHR) and circulating LH-to-FSH (LH/FSH) ratios. The lack of standardization of the signs, methods, and threshold values used to establish the presence of the diagnostic criteria (hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology) complicates the diagnosis of PCOS. Certain biomarkers may help with such a diagnosis. We conducted a validation study to check the diagnostic accuracy for PCOS of several miRNAs that were associated with the syndrome in a small pilot study that had been previously carried out by our research group. This was a diagnostic test study involving 140 premenopausal women. We included 71 women with PCOS and 69 healthy control women in the study. Both groups were selected as to be similar in terms of body mass index. We used miRCURY LNA™ Universal RT microRNA PCR to analyse the five miRNAs that had shown the strongest associations with PCOS in a much smaller pilot study previously conducted by our group. We studied diagnostic accuracy using receiver operating characteristics (ROC) curve analysis. Only the expression of two miRNAs, miR-142-3p and miR-598-3p, of the five studied, was different between the women with PCOS and the non-hyperandrogenic controls. The diagnostic accuracy of the combination of these circulating miRNAs was good (area under the ROC curve (AUC) 0.801; 95% CI: 0.72-0.88) and was further improved when adding WHR (AUC 0.834, 95% CI: 0.756-0.912), LH/FSH ratio (AUC = 0.869, 95% CI: 0.804-0.934) or both (AUC = 0.895, 95% CI: 0.835-0.954). We developed several models by selecting different threshold values for these variables favouring either sensitivity or specificity, with positive and negative predictive values as high as 88% or 85%, respectively. Patients included here had the classic PCOS phenotype, consisting of hyperandrogenism and ovulatory dysfunction; hence, the present results might not apply to milder phenotypes lacking androgen excess. If confirmed in larger studies addressing different populations and PCOS phenotypes, these biomarkers may be useful to simplify the clinical diagnosis of this prevalent syndrome. This research was funded by Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (grants PI15/01686, PIE16/00050, PI18/01122 & PI21/00116) and co-funded by European Regional Development Fund 'A way to make Europe'. Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) are also initiatives of the Instituto de Salud Carlos III. The authors have no competing interests to disclose. N/A.

Oocyte and Embryo Quality of Infertile Patients with Classic Phenotype Polycystic Ovarian Syndrome after Controlled Ovarian Hyperstimulation

The polycystic ovary syndrome (PCOS) is a combination of conditions, closely associated with female infertility and metabolic syndrome. It is recognized mainly with a polycystic ovary morphology (PCOM) of increased ovarian volume and pearl chain-like follicles on ultrasound, producing a large cohort of growing follicles during controlled ovarian hyperstimulation (COH) that are frequently heterogeneous in size and with poor quantity or quality of mature oocytes. However, recent data has proposed controversial opinions. The objective of the present study was to evaluate the relationship between the classical phenotype PCOS and the oocyte and embryo quality after COH for intracytoplasmic sperm injection (ICSI). An observational case control study was conducted for a four years period at the IVF department of a private gynecological hospital. Infertile females under 39, who performed COH for ICSI were included. A total of 496 ICSI cycles were divided into two groups – a PCOS group with 109 ICSI cycles and a control group with tube infertility that encompasses 387 ICSI cycles. The main outcome measures were the quantity and quality of the retrieved oocytes and embryos as well as the ICSI outcomes (fertilization rate, implantation rate and clinical pregnancy rate). The statistical analyses were performed, using SPSS version 12.0 and MEDCALC® statistical software and statistical significance was considered at p &lt; 0.05. Significantly higher mean number of total oocytes (14±6.02 SD vs. 9±3.25 SD; p &lt; 0.0001) and meta-phase II oocytes (10±1.94 SD as opposed to 6±2.89 SD; p = 0.0001), as well as immature and atretic ones were retrieved in the PCOS group compared to the controls (p &lt; 0.0001). However, the fertilization rate did not differ among the two groups (66.8% and 62.4%, respectively). Despite obtaining significantly more embryos in the PCOS patients (9±5.17 SD vs. 6±2.96 SD; p &lt; 0.0001), there were no differences between the two groups regarding the figures of the top quality embryos (25.6% and 29%, respectively), implantation rate (19.7% and 19.95%, respectively) and clinical pregnancy rate (28.4% and 33.6%, respectively, NS). Patients with classic phenotype PCOS are not associated with poor oocyte and embryo quality or with unfavourable ICSI outcome after controlled ovarian hyperstimulation.

Long-Lasting Effects of Spironolactone after its Withdrawal in Patients with Hyperandrogenic Skin Disorders.

Hyperandrogenic skin disorders, such as hirsutism, acne and alopecia, affect approximately 10-20% of women of reproductive age, reducing quality of life and causing psychological impairment. Spironolactone is a commonly used antiandrogen, especially in women who are not sexually active or have contraindications to hormonal contraceptives. The aim of this study was to evaluate the effects of spironolactone, especially after its withdrawal, in patients with hyperandrogenic skin disorders. Retrospective analysis of 63 women with hyperandrogenic skin symptoms due to polycystic ovary syndrome (PCOS), treated with spironolactone for at least 6 months as first-line treatment. After a mean time of treatment of 25.7 months, all patients reported a significant improvement in hyperandrogenic skin disorders; only 5 patients were dissatisfied and required the addition of an oral contraceptive. The therapy was well tolerated and the most frequent side-effect was intermestrual bleeding in 68.2% of cases, affecting mainly classic PCOS phenotype. Thirthyeight patients showed prolonged effects 33.7 months after spironolactone withdrawal, whereas 20 relapsed 17.5 months after discontinuation. No significant difference in clinical and biochemical parameters was observed between these two groups both at baseline and after spironolactone treatment. Ovulatory PCOS patients were treated for a shorter time and reported earlier relapse than classic PCOS patients. Spironolactone is an effective and safe treatment for hyperandrogenic skin disorders, showing long-lasting effects even several months after its discontinuation.

The Relationship Between Insulin Resistance and Obesity and Serum Anti-Mullerian Hormone Level in Chinese Women with Polycystic Ovary Syndrome: A Retrospective, Single-Center Cohort Study.

Anti-Mullerian hormone (AMH) is vital in the pathophysiological process of polycystic ovary syndrome (PCOS). The exact relationship between obesity and insulin resistance (IR) with AMH levels remains unclear. A retrospective, single-center cohort study of 220 women with PCOS who underwent physical, endocrine, and metabolic assessments were performed. Patients were grouped by age, body mass indices (BMI), Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), and different phenotypes. Pearson correlation analysis assessed the correlation between AMH and HOMA-IR, BMI, and other PCOS indicators, and multiple linear regression analysis was performed to determine factors influencing AMH. In 220 patients with PCOS, serum AMH levels decreased with age and were significantly higher in the IR group than in the non-IR group (P < 0.01). AMH increased significantly in anovulatory patients with hyperandrogenemia and/or polycystic ovary, with no significant difference between obese and non-obese individuals. AMH levels correlated positively with luteinizing hormone (LH), LH/follicular stimulating hormone (FSH), testosterone, fasting insulin (FINS), and HOMA-IR levels; negatively with age and BMI levels (P < 0.05) and weakly with fasting plasma glucose in the classical PCOS phenotype (r=0.148, P < 0.05). Regression analysis showed that age, testosterone, FINS, LH, LH/FSH, and BMI influenced AMH levels (P < 0.05). Chinese women with PCOS-IR showed associations with greater AMH levels. AMH levels correlated positively with HOMA-IR levels and negatively with BMI. AMH combined with BMI and HOMA-IR levels may help determine PCOS severity.

PMON245 Clinical Phenotypes of Polycystic Ovary Syndrome (PCOS) in Nigerian Women: Preliminary Results of the Nigeria PCOS Epidemiology &amp; Phenotype (Nigeria-Pep) Study

Abstract Background Although the phenotype of polycystic ovary syndrome (PCOS) is heterogeneous, there is paucity of data on the prevalence and phenotype of PCOS in sub-Saharan Africa. Methods We studied 75 consecutive consenting women, aged 18-45 years, who presented with features suggestive of PCOS. A standardized proforma was used to obtain relevant information. Anthropometric measurements were determined, and terminal hair growth was assessed using the modified Ferriman-Gallwey (mF-G) method. All subjects underwent an oral glucose tolerance test (OGTT) and pelvic ultrasonography on day 2-7 of the menstrual cycle. An mF-G score of ≥ 6 was regarded as evidence of clinical hyperandrogenism (HA). Menstrual dysfunction (MD) was defined as menstrual cycle lengths &amp;gt;35 or &amp;lt;25 days. Polycystic Ovarian Morphology (PCOM) was defined as an antral follicle count (AFC) of ≥12 2-9 mm follicles and/or an ovarian volume ≥10 cm3, in at least one ovary. Results The mean (SD) age of the study population was 28.6 (5.8) years, and the mean (SD) body mass index (BMI) was 26.3 (5.6) kg/m2. Three (4.0%) participants were underweighted, 27 (36.0%) had normal BMI, 30 (40%) were overweight, and 15 (20.0%) were obese. The mean (SD) systolic and diastolic blood pressures were 107.4 (12.6) mmHg and 72.6 (8.2) mmHg, respectively. OGTT results indicated that the mean (SD) fasting blood glucose was 86.6 (10.6) mg/dl and the mean (SD) 2-hr. postprandial glucose was 109.8 (22.2) mg/dl. Two women had impaired glucose tolerance and one had type 2 diabetes mellitus. Of the 75 subjects recruited, 26 (34.7%) had HA, 54 (72.0%) had MD, and 63 (84.0%) had PCOM. Of all subjects, 20 (26.7%) had HA+MD+PCOM, consistent with PCOS Phenotype A; one (1.3%) had HA+MD only, consistent with Phenotype B; four (5.3%) had HA+PCOM only, consistent with Phenotype C; and 28 (37.3%) had MD+PCOM only, consistent with Phenotype D. In 22 (29.4%) no evidence of PCOS was found. Overall, our results indicate that of subjects evaluated clinically, 53 (70.6%) had PCOS. Conclusions Our preliminary results indicate that in a referral (clinical) population in Lagos, Nigeria, using only the clinical presentation without circulating androgen measures, PCOS was detected in two-thirds, with Phenotype D (aka, 'non-hyperandrogenic PCOS’) being the most common presentation (53%), followed by Phenotype A (aka 'classic or full PCOS’) observed in 38% of all women with PCOS seen. However, as 72% of all subjects had MD and 63% had PCOM, many more of these women could have been diagnosed with PCOS if the presence of hyperandrogenemia could have been demonstrated. Overall, these observations suggest that accurate measurement of circulating androgen, lacking in many parts of Sub-Sahara Africa, may be critical to accurately detecting PCOS in that region. Studies are ongoing. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Prevalence of PCOS and related hyperandrogenic traits in premenopausal women with type 1 diabetes: a systematic review and meta-analysis.

An increased prevalence of functional hyperandrogenism-including polycystic ovary syndrome (PCOS)-has been described in women with type 1 diabetes (T1D). However, heterogeneity between studies is frequent, and prevalence rates vary according to different criteria used for the diagnosis of PCOS and the population studied. We aimed to perform a systematic review and meta-analysis of the prevalence of PCOS and related hyperandrogenic traits in premenopausal women with T1D. This way, we intend to increase the precision of the estimates of prevalence of PCOS and related traits in women with T1D, and to explore sources of heterogeneity while providing prevalence estimates for clinically relevant subgroups such as the different phenotypes. We conducted a systematic review of the literature using Medline-OVID and Embase databases (Open Science Framework registry for systematic review protocols, https://osf.io/6cv9p/). Studies published up to 29 March 2021 were considered. We selected cross-sectional or prospective studies that reported, in patients with T1D, prevalence data on PCOS according to current definitions and different phenotypes, and/or prevalence rates of other related traits (hirsutism, hyperandrogenaemia, oligo-amenorrhoea and/or polycystic ovarian morphology: PCOM). Exclusion criteria for the review were studies addressing types of diabetes other than T1D; and studies using diagnostic definitions of PCOS different than those mentioned above. Two independent researchers performed data extraction. To assess the risk of bias, we used a tool developed specifically to appraise population-based prevalence studies. We selected 19 studies (1042 women) reporting the prevalence of PCOS and/or other hyperandrogenic traits. Regarding bias, 12 studies were considered of low-risk, and the remaining seven studies were considered intermediate risk. The pooled prevalence of PCOS when considering all possible phenotypes (ESHRE- American Society for Reproductive Medicine criteria) in T1D was 26% (95% CI: 19-34%; 13 studies, 684 women). Pooled prevalence of classic PCOS (US National Institutes of Health criteria) was 16% (95% CI: 10-22%; 9 studies, 614 women). Pooled prevalence of hyperandrogenic PCOS (Androgen Excess and PCOS Society criteria) was 26% (95% CI: 16-41%; 5 studies, 329 women). Hirsutism (24%), hyperandrogenaemia (29%), oligomenorrhoea (24%) and PCOM (34%) were also prevalent. Heterogeneity was high in almost all these meta-analyses. This systematic review and meta-analysis showed that PCOS and related hyperandrogenic traits are present in approximately one in every four women with T1D. Larger studies are needed to confirm this association, to address the effect of different variables on the occurrence of PCOS.

Hyperandrogenism in Women with Polycystic Ovarian Syndrome: Pathophysiology and Controversies

Polycystic ovary syndrome (PCOS) is an essential differential diagnosis of hyperandrogenism to consider in women, with most women presenting with irregular menses, infertility, and hirsutism. The diagnosis is challenging because it is a heterogenous disorder with significant variations in its associated features. Classic PCOS (hyperandrogenism plus ovulatory dysfunction) affects about 10% of reproductive-age women. Hyperandrogenism (clinical, biochemical, or both) is a hallmark of the syndrome. Approximately 60–76% of PCOS women are hirsute and hyperandrogenemia is observed in 75–90% of these women. Androgen assays are not always reliable at the lower levels detected in women with PCOS. This article will attempt to review the pathophysiology and controversies of hyperandrogenism in PCOS women, its clinical and biochemical presentations, and management.

Analysis of 2-Arachidonoylglycerol Levels in Polycystic Ovary Syndrome in the Context of Hormonal and Metabolic Alterations and Across the Classical Phenotypes.

Introduction: Ovarian folliculogenesis requires a fine balance between extra- and intra-ovarian factors. Endocannabinoids are found in the female reproductive system and are essential for a normal follicular growing process and ovulation. First, our study aimed to analyze levels of the endocannabinoid-2-arachidonoylglycerol (2-AG)-in patients with polycystic ovary syndrome (PCOS) and to compare with healthy controls. In addition, the study aimed to explore the association of 2-AG with hormonal and metabolic alterations, ovulatory dysfunction, and the presence of polycystic ovarian morphology (PCOM) across the classical PCOS phenotypes. Methods: Fifty-four women with PCOS were compared with 26 healthy controls. PCOS patients were diagnosed and phenotyped according to the Rotterdam criteria. Further analyses were performed with the classical PCOS phenotypes A and B comprising hyperandrogenism with oligo-anovulation with or without PCOM, respectively. Full medical history, clinical investigations, anthropometric measurements, laboratory tests, and ultrasound investigations were carried out in the follicular phase. Serum levels of 2-AG were measured by enzyme-linked immunosorbent assay. Results: PCOS patients (n=54) and healthy controls (n=26) showed similar metabolic parameters and anthropometric characteristics. PCOS patients were more hirsute than healthy women (p=0.001). Luteinizing hormone/follicle-stimulating hormone ratio and serum levels of androgens were significantly higher in the patient than in the control group (p=0.035, p<0.001, respectively). Free androgen index was also higher in the patient group (p=0.002). Serum levels of 2-AG did not significantly differ when comparing all PCOS patients versus healthy controls; however, further analysis of individual phenotype groups revealed that 2-AG levels in PCOS patients with phenotyope A (n=30) were significantly lower when compared with PCOS patients with phenotype B (n=20) and healthy controls (n=26). Conclusion: Serum levels of 2-AG were similar between PCOS patients and healthy controls. Nevertheless, phenotype A PCOS patients had significantly lower levels of the endocannabinoid compared with phenotype B patients and healthy controls. Collectively, these results suggest that overall serum levels of 2-AG are not a diagnostic marker for PCOS; however, their altered secretion or activity may influence normal follicular processes.

Analyzing the biochemical, clinical, and hormonal characteristics of patients with polycystic ovary syndrome

To analyze the biochemical, clinical, and hormonal characteristics of patients with four phenotypes of Polycystic ovary syndrome (PCOS). A total of 225 patients admitted to Medistate Kavacık Hospital Gynecology and Obstetrics outpatient clinic and Giresun University Faculty of Medicine Gynecology and Obstetrics clinic between January 2019 and January 2020 diagnosed as PCOS and healthy controls were included in the study. The revised Rotterdam criteria were applied to diagnose PCOS. The patients with PCOS were divided into Type I classic, Type II classic, Ovulatory and Normoandrogenic PCOS. Biochemical, clinical, and hormonal values were compared. The mean age of the participants is 28 (±5.7) and the mean body mass index (BMI) is 26.15 (±5.36). The mean Ferriman Gallwey Score (FGS) is 7.4(±5.4), which is normal. There is a statistically significant difference between the four PCOS groups and control group in terms of age (p-value=0.000), BMI (p- value=0.000), Luteinizing hormone / Follicle stimulating hormone (LH/FSH) (p-value=0.000), and fasting blood sugar (p-value=0.01). There is a statistically significant difference among the four phenotypes in terms of BMI (p-value =0.002), LH/FSH (p-value =0.000), LH (p-value =0.000), free T4 (p-value =0.01), fasting insulin (p-value =0.001), total testosterone (p-value =0.000), FGS (p-value =0.000), etc. Age, BMI, LH/FSH, FSH, LH, fasting blood sugar, and hirsutism are good predictors of PCOS.

Polycystic Ovary Syndrome: A Contemporary Clinical Approach.

Polycystic ovary syndrome (PCOS) is a frequent endocrine disease in women during the reproductive period. It is considered a complex metabolic disorder with long-term metabolic, as well as reproductive consequences. Main pathophysiological pathways are related to the increased androgen levels and insulin resistance. Nowadays, genetic origins of PCOS are acknowledged, with numerous genes involved in the pathogenesis of hyperandrogenemia, insulin resistance, inflammation, and disturbed folliculogenesis. Rotterdam diagnostic criteria are most widely accepted and four PCOS phenotypes have been recognized. Metabolic abnormalities are more common in phenotypes 1 and 2. Women with classic PCOS are more obese and typically have the central type of obesity, more prevalently displaying dyslipidemia, insulin resistance, and metabolic syndrome that could be associated with an increased risk of cardiovascular complications during life. Heterogeneity of phenotypes demands an individualized approach in the treatment of women with PCOS. Metabolic therapies involve a lifestyle intervention followed by the introduction of insulin sensitizers including metformin and inositols, glucagon-like peptide 1 receptor agonists (GLP-1 RA), as recently sodium-glucose cotransporter-2 (SGLT2) inhibitors. The addition of an insulin sensitizer to the standard infertility therapy such as clomiphene citrate improves ovulation and pregnancy rates. Our current review analyzes the contemporary knowledge of PCOS etiology and etiopathogenesis, its cardiometabolic risks and their outcomes, as well as therapeutic advances for women with PCOS.

Loss of anti-Müllerian hormone (AMH) immunoactivity due to a homozygous AMH gene variant rs10417628 in a woman with classical polycystic ovary syndrome (PCOS).

Anti-Müllerian hormone (AMH) is produced by granulosa cells of pre-antral and small antral ovarian follicles. In polycystic ovary syndrome (PCOS), higher levels of serum AMH are usually encountered due to the ample presence of small antral follicles and a high AMH production per follicular unit which have led to the proposal of AMH as a serum diagnostic marker for PCOS or as a surrogate for polycystic ovarian morphology (PCOM). However, heterozygous coding mutations of the AMH gene with decreased in vitro bioactivity have been described in some women with PCOS. Such mutation carriers have a trend toward reduced serum AMH levels compared to noncarriers, although both types of women with PCOS have similar circulating gonadotropin and testosterone (T) levels. This report describes a normal-weight woman with PCOS by NIH criteria with severely reduced AMH levels (index woman with PCOS). Our objective was to examine the molecular basis for her reduced serum AMH levels and to compare her endocrine characteristics to similar-weight women with PCOS and detectable AMH levels. Twenty normoandrogenic ovulatory (control) and 13 age- and BMI-matched women with PCOS (19-35 years; 19-25 kg/m2) underwent transvaginal sonography and serum hormone measures including gonadotropins, sex hormone-binding globulin, total and free T, androstenedione, dehydroepiandrosterone sulfate, estrone, estradiol and AMH. The latter was measured by ELISA (Pico-AMH: Ansh Labs, Webster, TX, USA). Women with PCOS and detectable AMH had higher serum AMH (10.82 (6.74-13.40) ng/ml, median (interquartile range)), total and free T (total T: 55.5 (49.5-62.5) ng/dl; free T: 5.65 (4.75-6.6) pg/ml) levels and greater total antral follicle count (AFC) (46 (39-59) follicles) than controls (AMH: 4.03 (2.47-6.11) ng/ml; total T: 30 (24.5-34.5) ng/dl; free T: 2.2 (1.8-2.45) pg/ml; AFC 16 (14.5-21.5) follicles, P < 0.05, all values), along with a trend toward LH hypersecretion (P = 0.06). The index woman with PCOS had severely reduced serum AMH levels (∼0.1 ng/ml), although she also had a typical NIH-defined PCOS phenotype resembling that of the other women with PCOS and elevated AMH levels. All women with PCOS, including the index woman with PCOS, exhibited LH hypersecretion, hyperandrogenism, reduced serum estrogen/androgen ratios and PCOM. A homozygous Ala515Val variant (rs10417628) in the mature region of AMH was identified in the index woman with PCOS. Recombinant hAMH-515Val displayed normal processing and bioactivity, yet had severely reduced immunoactivity when measured by the commercial pico-AMH ELISA assay by Ansh Labs. In conclusion, homozygous AMH variant rs10417628 may severely impair serum AMH immunoactivity without affecting its bioactivity or PCOS phenotypic expression. Variants in AMH can interfere with serum AMH immunoactivity without affecting the phenotype in PCOS. This observation can be accompanied by discordance between AMH immunoactivity and bioactivity.

Comparing the effect of sitagliptin and metformin on the oocyte and embryo quality in classic PCOS patients undergoing ICSI.

Insulin resistance plays a major role in the pathogenesis of polycystic ovary syndrome (PCOS). Therefore, there is a growing interest in the use of insulin sensitizer drugs in the treatment of PCOS. Research in recent years has shown that sitagliptin has been reported to improve ovarian cycles and ovulation in PCOS patients. We aimed to compare the effects of metformin and sitagliptin on PCOS individuals undergoing ICSI. Sixty PCOS patients were divided into 3 groups: metformin, sitagliptin, and placebo group. Treatment was carried out 2months before the start of the ovulation cycle and continued until the day of oocyte aspiration. The serum levels of total testosterone, estradiol, and fasting insulin along with the total number of retrieved, normal and abnormal MII, and fertilized oocytes, the number of transferred embryos (grades I, II and III), and biochemical and clinical pregnancy rates as well as the ovarian hyperstimulation syndrome (OHSS) were evaluated. There was a significant reduction in the serum levels of Insulin and total testosterone in the treated groups compared with the placebo. The number of mature and normal MII oocytes increased significantly in the treated groups compared with the placebo. Moreover, the number of immature oocytes decreased significantly and the number of grade I embryos increases significantly in the sitagliptin group compared with the placebo group. We conclude that sitagliptin can improve the maturation of oocytes and embryos' quality more effectively than metformin, in PCOS patients undergoing ICSI. Trial registration is NCT04268563 ( https://clinicaltrials.gov ).

SUN-008 Loss of Antimullerian Hormone Immunoreactivity Due to a Homozygous AMH Gene Mutation Rs10417628 in a Woman with Classical Polycystic Ovary Syndrome

Anti-Müllerian hormone (AMH), an inhibitor of primordial/small antral follicle development and Leydig cell androgen synthesis in mice, could exaggerate the polycystic ovary syndrome (PCOS) phenotype, given reports of PCOS-specific AMH loss-of-function mutations (1–3). This report describes a normal-weight PCOS woman with severely reduced AMH levels (index PCOS woman). It examines the molecular basis for her reduced serum AMH levels and also compares her endocrine characteristics to similar-weight PCOS women with detectable AMH. Twenty normo-androgenic ovulatory (control) and 13 age- and body mass index-matched PCOS women (19–35 years; 19–25 kg/m2) underwent transvaginal sonography and serum hormone measures. Wilcoxon rank-sum test compared clinical features of control and PCOS women with detectable AMH, which were then individually ranked by magnitude in all PCOS women. DNA analysis was performed by PCR amplification with direct gene sequencing. The identified mutation was introduced in hAMH-expression plasmids for functional analysis of AMH processing in HEK293 cells by Western blot and ELISA (pico-AMH assay, Ansh Labs, Webster, TX), and for bioactivity in KK-1/AMHR2 cells using a luciferase reporter. Unpaired t-test compared AMH-induced luciferase activity between wild type and mutant AMH. A homozygous AMH gene mutation rs10417628 involving a single base pair substitution in exon 5 (NG_012190.1:g.7705C>T, p.(Ala515Val)) was identified in the index PCOS woman. PCOS women with detectable AMH had higher serum AMH (10.82 [6.74–13.40] ng/mL, Median [IQR]), total/free testosterone (T) (total T: 55.5 [49.5–62.5] ng/dL; fT: 5.65 [4.75–6.6] pg/mL) levels and greater total antral follicle numbers (AFNs) (46 [39–59] follicles) than controls (AMH: 4.03 [2.47–6.11] ng/ml; total T: 30 [24.5–34.5] ng/dL; fT: 2.2 [1.8–2.45] pg/mL; AFNs 16 [14.5–21.5] follicles, P<0.05, all values), along with a trend toward LH hypersecretion (P=0.06). The index PCOS woman with the lowest AMH levels (0.1 ng/ml) did not have the highest serum total T/fT (total T: 89 ng/dL; fT: 7 pg/mL,) or LH levels nor the greatest AFN (43 follicles). In vitro analysis of cells expressing hAMH-515Val or hAMH-515Ala showed that hAMH515-Val, in contrast to hAMH515-Ala, was undetectable and severely reduced in the pico-AMH assay in cell lysates and supernatants, respectively. AMH protein processing and AMH-induced luciferase activity, however, did not differ between hAMH515Val and hAMH515Ala. Thus, homozygous AMH mutation rs10417628 in a PCOS woman can impair serum AMH immunoreactivity without affecting AMH bioactivity, perhaps because of conformational changes from the mutation that only interfere with its immunodetection but not its function.