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Gut microbiota appears to be implicated in the development of a wide range of diseases affecting different organs and systems of the body. Alterations in composition, diversity and metabolites derived from the gut microbiota have been reported in preliminary animal and human studies of polycystic ovary syndrome (PCOS) indicating that microbiota might potentially be involved in development of the syndrome and its long-term metabolic health consequences. Our results suggest that gut microbiome of both lean and obese PCOS patients with full phenotype shows compositional alterations with similar bacterial richness and diversity compared to healthy women and that oral contraceptive use does not alter composition of gut microbiota in the syndrome. However, microbiota-dependent metabolite trimethylamine N-oxide (TMAO) and its precursors closely linked to cardiovascular disease are elevated in PCOS and oral contraceptive use is associated with reduction of these microbiome-dependent metabolites. Larger studies are needed to investigate whether dysbiosis has an implication in pathogenesis of PCOS and whether it could give rise to novel treatment opportunities. 

AE-PCOS 2022

Walter Futterweit Award in Clinical Research

### Welcome to the AE-PCOS Society's 20th Annual Meeting!


The AE-PCOS Society’s 20th Annual Meeting's theme will be Reflections and Directions. The meeting will aim to incorporate the perspectives of both long-time, contributing members of the Society and newer members of the Society, while highlighting the latest research findings in PCOS-related clinical and basic research.

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The AE-PCOS Society’s 20th Annual Meeting's theme are Reflections and Directions. The meeting aims to incorporate the perspectives of both long-time, contributing members of the Society and newer members of the Society, while highlighting the latest research findings in PCOS-related clinical and basic research.

technical paper

OBJECTIVE: Polycystic Ovary Syndrome (PCOS) is associated with increased cardiometabolic risk factors and incidence of cardiovascular disease (CVD). Currently, early screening of dyslipidemia, atherosclerotic CVD (ACVD) and heart function are not routine in the primary care of high-risk young women with and without PCOS. The aim of this study was to provide evidence-based research to aid the development of assessment guidelines for early detection of dyslipidaemia, cardiac dysfunction and ACVD in high-risk young women with and without PCOS. 

METHODS: A case-control study in high-cardiometabolic risk (body mass index (BMI>25) women aged 25-45 years with and without PCOS, matched for age and body mass index, and healthy weight controls was conducted. The main outcome measures included blood lipids, apoB-lipoproteins, carotid intima-media thickness (cIMT), carotid plaque and cardiac function using ultrasound and 2D/3D echocardiography. 

RESULTS: High-risk women with (n-45) and without PCOS (n=20) had a 25% higher total apoB, 30% higher non-HDL-C and 50% higher triglycerides compared to age-matched health weight controls (n=10). PCOS tended to have higher plasma triglycerides, total ApoB, non-HDL-C and remnant cholesterol compared to BMI-matched controls Those with PCOS had a significantly lower HDL-C compared to both BMI-age-matched and health-weight controls. Carotid plaque was 3- and 8-fold higher in those with PCOS compared to BMI-matched and healthy weight controls, respectively. Those with PCOS and BMI-matched controls had increased cIMT by 15% and early left ventricular global longitudinal strain by 10%, compared to healthy-weight controls.

CONCLUSIONS: High-risk PCOS and BMI-matched controls have early impairment in global cardiac function and increased ACVD, and this is associated with an atherogenic dyslipidemic profile. These results suggest early primary prevention screening and a risk-stratification model may be warranted in this high-risk population of young women to reduce risk of premature development and incidence of CVD.

This research is funded by Women and Children’s Health Research Institute and Mazankowski Heart Research Institute


Early Atherosclerosis in High-Risk Young Women With and Without Polycystic Ovary Syndrome 

OBJECTIVE: PCOS is the most common metabolic-endocrine disorder that can impact health and quality of life over a lifespan. It is important we understand the scope of health outcomes that impact the health and quality of life of those with PCOS in order to improve health care in this population. The aim of this study was to determine the incidence of co-morbidities in PCOS compared to an age-matched population. 
METHODS: We conducted a retrospective observational case-control study in those diagnosed with PCOS and age-matched controls using the Alberta Health Services Health Analytics database from 2002-2019 in Alberta, Canada. 
RESULTS: The incidence of high blood pressure, high blood lipids, diseases of the heart, kidney, gastrointestinal tract, pre-diabetes, eating disorders, mental illness, depression-anxiety, rheumatoid arthritis, respiratory infections and all cancers was 20-40% (p<0.0001) higher in PCOS (n=16531) compared to controls (n=49335). Overweight-obesity, non-alcoholic liver disease, Type 1 diabetes (T1D) and T2D had a 3-fold greater incidence in PCOS (p<0.0001). Cardiovascular disease and cerebrovascular disease were 60% higher in PCOS compared to controls (p<0.0001). 
CONCLUSION: These findings indicate PCOS is associated with a significantly greater incidence of co-morbidities and adverse health outcomes. This data provides evidence of the potential economic health care burden and lower quality of life in those with PCOS. The data may also indicate a need to improve education of patients and clinicians in raising awareness of health risks and implementation of preventative health care in this high-risk population. 
This work was funded by the Women and Children’s Health Research Institute and University of Alberta Medical Research Foundation.


PCOS is Associated with Increased Incidence of Co-morbidities in a Canadian Population Cohort

OBJECTIVE: Ovulatory dysfunction is usually caused by an endocrine disorder, of which polycystic ovary syndrome (PCOS) is the most common cause. PCOS is associated with normal estrogen levels and can be characterized by oligo-/anovulation resulting in decreased progesterone levels. It is suggested that decreased progesterone levels may lead to more autoimmune diseases in women with PCOS. In addition to PCOS, hyperprolactinemia (HPRL) is also a common endocrine disorder in women of reproductive age and it is often claimed that there is an association between HPRL and PCOS. The aims of this study are to determine whether women with PCOS have 1) a higher prevalence of thyroid dysfunction, 2) an increase of anti-thyroid peroxidase antibodies (TPOab), and 3) a higher prevalence of hyperprolactinemia compared to controls. 

METHODS: This retrospective cross-sectional study contains data of 1432 women with PCOS, who were diagnosed at a tertiary hospital (between 1993-2000), and 299 women without PCOS who conceived spontaneously and participated in a study between 2004-2007, of which 168 women gave birth to a child with a congenital heart disease and 131 women gave birth to a healthy child.

RESULTS: The median age of women with PCOS was 28.2 years [interquartile range (IQR) 24.6 - 31.7] and 32.8 years [IQR 29.7 - 35.8] of the controls (p<0.01). Median BMI of women with PCOS was higher compared to the controls (25.2 kg/m2 [IQR 21.9 - 30.8] versus 24.4 kg/m2 [IQR 22.3 - 17.5]; p<0.01). The prevalence of thyroid diseases in PCOS women was similar compared to controls (1.9% versus 2.7%; p=0.39 for hypothyroidism, 3.2% versus 2.7%; p=0.59 for subclinical hypothyroidism, and 0.5% versus 0%; p=0.99 for hyperthyroidism). TSH levels and the prevalence of positive TPOab were the same in both groups (1.55 mIU/L versus 1.48 mIU/L; p=0.54 and 5.7% versus 8.7%; p=0.12). FT4 levels were higher in women with PCOS (18.1 pmol/L versus 17.7 pmol/L; p<0.05). The prevalence of HPRL was higher in PCOS patients (7.0% versus 3%; p<0.05) and in this group 0.5% had a pituitary abnormality, such as macroprolactinomas. All these results were adjusted for age and BMI. 

CONCLUSIONS: The prevalence of thyroid diseases is not increased in women with PCOS. Although FT4 levels were significantly higher, they were well within the normal range. Hence, this finding is probably without any clinical relevance. Moreover, there was no difference in the prevalence of positive TPOab, indicating a similar risk for thyroid disease in women with PCOS versus controls. Although HPRL was more prevalent in PCOS patients this might be due to selection bias, because patients with HPRL are less likely to conceive spontaneously compared to our controls. However, as recommended in the guideline, thyroid diseases and HPRL should be excluded in women with symptoms of ovulatory dysfunction.

The Prevalence Of Thyroid Dysorders And Hyperprolactinemia In Women With Pcos Compared To Controls

BACKGROUND: The association between polycystic ovary syndrome (PCOS) and non-alcoholic fatty liver disease (NAFLD) is well documented and believed to be due to associated metabolic risk factors. NAFLD prevalence in PCOS is estimated to be between 25.4% and 68.8%. Saroglitazar Magnesium, a dual PPAR α/γ agonist, demonstrated lipid and glucose lowering effects with good safety profile in various clinical studies. In Letrozole-induced PCOS animal models, repeated doses of Saroglitazar magnesium reduced cystic follicle, improved insulin sensitivity, increased serum FSH, decreased LH/FSH ratio, decreased serum testosterone, and normalized ovary weight. 
OBJECTIVE: We are currently conducting a proof of concept study to evaluate the efficacy and safety of Saroglitazar Magnesium 4 mg in adult females (≥ 18 years) women with well characterized PCOS and NAFLD by measuring the magnetic resonance imaging proton-density fat-fraction (MRI-PDFF). The secondary objectives are changes in alanine aminotransferase (ALT) aspartate aminotransferase (AST), liver stiffness measurement (LSM), controlled attenuation parameter (CAP), serum-glucose, body mass index (BMI), body weight, lipid-profile, sex hormone binding globulin (SHBG), ovarian function and free androgen index (FAI). 
METHODS: Multicentre, phase 2a, randomized, double-blind, placebo-controlled study is currently ongoing across eight centres in US (NCT03617263) and Mexico. 90 eligible patients with ALT level ≥ 38 U/L & hepatic fat fraction ≥10% by MRI-PDFF are randomly assigned to either Saroglitazar Magnesium 4 mg or placebo arms in 1:1 ratio for 24 weeks. 
RESULTS: Of the 122 subjects (mean age of 29.9 ± 7 years) who have been screened from December 2018 to August 2022, 51 (41.8%) subjects have been randomized so far. Major reason of screening failure was ALT < 38 U/L in 58 (86.6%) patients. Subjects with screen failures had significantly lower mean ALT levels (27.6 ± 20.6 U/L vs 53.6 ± 44.5 U/L, p<0.001), lower AST levels (21.8 ± 18.2 U/L vs 36.0 ± 28.4 U/L, p=0.002), lower FAI (1.13 ± 0.97 vs 1.66 ± 1.16, p=0.007) and higher SHBG (66.7 ± 80.1 vs 42.6 ± 50.4, p=0.045) compared with subjects without screen failures at baseline. No other significant differences were observed. Of 51 subjects enrolled, 45 (88.2%) patients were obese, 37 (72.5%) had hyperinsulinemia, 47 (92.2%) had Hyperandrogenism, 8 (15.7%) had impaired fasting glucose and 5 (9.8%) patients had dyslipidaemia.
CONCLUSION: This is the only prominent ongoing interventional study in US for treatment of NAFLD in women with PCOS. Above baseline data will help endocrinologist, gynaecologist and hepatologist in better collaboration and awareness of the disease amongst PCOS patients. The results of this clinical trial will provide a strong basis for long term evaluation and potential management and treatment of patients with PCOS and NAFLD. 


Evidences VII – Ongoing Proof Of Concept Study Of Saroglitazar In Treatment Of NaFlD In Women With PCOS

OBJECTIVE: Polycystic ovary syndrome (PCOS), is associated with reduced health-related quality of life (QOL) and increased risk for depression and anxiety. These associations are partly due to the stressful and stigmatizing nature of PCOS symptoms, including hirsutism and negative body image stemming from BMI. However, the impact of the cumulative wear and tear in the stress response system (i.e. allostatic load (AL)), and of metabolic syndrome on these QOL outcomes is unknown. We assessed how AL and metabolic syndrome relate to physical and mental health related QOL in women with PCOS. 
METHODS: We performed a secondary analysis of baseline data from a randomized control trial (OWL-PCOS) in women with PCOS defined by Rotterdam criteria. Physical and mental health related QOL were assessed by the SF36 and PCOSQ. AL was calculated using the 12 factors: IGF-1, HDL, LDL, triglycerides, fasting glucose, fasting insulin, creatinine, systolic blood pressure, diastolic blood pressure, heart rate, waist-to-hip ratio, and BMI. High risk categories were calculated as the 75th percentile for all factors except for HDL in which the 25th percentile was used. An AL index was calculated for each participant as the sum of the number of factors in the risk category (0-12), with higher scores indicating more physiological dysregulation in the stress response system. We defined a high level of AL as an ALI of 4, based on convention. Metabolic syndrome was classified as meeting 3 of 5 NIH criteria. Wilcoxon rank sum tests were used to assess differences in QOL measures between high vs low AL, and with vs without metabolic syndrome. All analyses were performed in RStudio version 2022.07.1.
RESULTS: Among 90 women with PCOS, the mean age was 29 years old, the majority of which were White (84%), non-Hispanic (93%), nulliparous (83%) and not on any medications for depression (97%) or anxiety (98%). Thirty-six women had high AL and 27 women had metabolic syndrome. Women with high AL, had significantly higher summary scores on the SF36 Mental Component (p = 0.012) and lower scores on the SF36 Physical Component (p = 0.001), indicating higher mental health QOL and lower physical health QOL. On the PCOSQ, women with high AL had higher Emotional Wellbeing scores (p = 0.013), but no differences in Physical Wellbeing and General Wellbeing scores. Women with metabolic syndrome had lower SF36 Physical Component summary scores (p=0.039), indicating lower physical health related QOL. 
CONCLUSION: These findings suggest that among the constellation of symptoms experienced by women with PCOS, AL and metabolic syndrome are not primary drivers of adverse mental health outcomes in this population. 


Do allostatic load and metabolic syndrome contribute to mental health outcomes in women with polycystic ovary syndrome?

OBJECTIVE: Polycystic ovary syndrome (PCOS) is associated with increased risk for depression and anxiety, partly driven by BMI, hirsutism, and genetic factors. Although PCOS increases the odds of hypertension (HTN) by 1.5, the co-occurrence of PCOS + HTN in relation to symptoms of depression and anxiety is not well understood. Furthermore, few studies focus solely on these symptoms in Black women with PCOS. Here, we examine the impact of HTN on depression, anxiety, and fatigue symptoms in Black women with PCOS. 
METHODS: We preformed preliminary data analysis of a single cohort study of symptoms in adult Black women with PCOS or with PCOS + HTN. Both diagnoses were obtained from medical records. Depressive symptoms were measured by the PROMIS Depression short-form and the CESD-10. Anxiety was measured by the PROMIS Anxiety short-form and the state scale of the State-Trait Anxiety Inventory (STAI). Fatigue was measured by the PROMIS Fatigue short-form and the Multidimensional Fatigue Inventory (MFI). Wilcoxon rank sum tests were used to assess differences in symptoms between PCOS vs PCOS + HTN. All analyses were performed in RStudio version 2022.07.1.
RESULTS: Among 32 Black women with PCOS, the mean age was 34.7 years old, and the mean BMI was 39.8. Nine of the 32 women had PCOS + HTN. Women with PCOS + HTN demonstrated higher fatigue on the MFI (p = 0.015), more severe depression on the PROMIS Depression (p = 0.039) and CESD-10 (p = 0.046), and more severe anxiety symptoms on the STAI (p = 0.007). For those with PCOS + HTN, mean scores exceed cut points for clinical depression on the CESD-10 and clinical anxiety on the STAI. Women with PCOS + HTN also demonstrated a trend for higher fatigue on the PROMIS Fatigue as well as higher anxiety on the PROMIS Anxiety. 
CONCLUSION: Our findings highlight that the co-occurrence of HTN and PCOS in Black women may contribute to the severity of depression, anxiety, and fatigue symptoms. Our study also points toward the need to better understand the symptom experience of minority groups with PCOS, including racial, ethnic, sex, and gender. 
(Funding: 1P30NR-18090 [Pilot PI: LN])

Depression, Anxiety & Fatigue Among Black Women With Pcos With and Without Hypertension

WOMEN WITH PCOS EXPERIENCE DIFFERENT MENSTRUAL CYCLE EXPERIENCES THAN CONTROL DURING THE PANDEMIC. 

Prior, JC (1,3), Nelson, K (2,3), Shirin, S (3). 

(1) Department of Medicine Division of Endocrinology 
(2) University of British Columbia, Graduate Programme Vancouver, BC 
(3) Centre for Menstrual Cycle and Ovulation Research, Division of Endocrinology UBC, Canada 

OBJECTIVE: 
Although increasing studies now report reproduction in women with Polycystic Ovary Syndrome (PCOS), none have described menstrual cycle-related experiences. Our objective was to explore this by standardized daily Menstrual Cycle Diary©. Specifically, we compared PCOS “cases” with matched controls. We hypothesized in PCOS vs controls: greater levels of depression and lower levels of self-worth but similar levels of outside stress. 

METHODS: 
This is a single-cycle prospective case-control study using data from 112 community-dwelling women ages 19-35 years with approximately month-apart, spontaneous (not on hormonal contraception) menstrual cycles in the Menstruation Ovulation Study 2 (MOS2); all data were collected early in the SARS-CoV-2 pandemic. Six women self-reported PCOS. We matched them with random participants in a 3:1 ratio within five years of age and by BMI category. We did not adjust for ovulatory characteristics, given that 63% of all MOS2 cycles had ovulatory disturbances1. We described data while testing hypotheses by Mann-Whitney U and Chi-Square Tests. We also described Principal Component Analysis (PCA) patterns versus published mean 11-month data in normally ovulatory normal-weight women2. Data were analyzed using SPSS version 28. 

RESULTS: 
As expected, women living with PCOS (n=6) and controls (n=18) were similarly aged in the early 30s, with non-different mean BMIs in the low overweight range. PCOS women were more white with non-East Asian other ethnicities. Mean menstrual flow (ml/day) was significantly higher in controls than PCOS (p=0.009), with no difference in days of flow (p>0.721). There was also no significant difference in the duration of cramps (p>0.812), cramp intensity (p>0.415) or front breast tenderness (p>0.250). 

Our hypotheses of lower feelings of self-worth and higher feelings of depression with similar perceived outside stresses were not confirmed. Women with PCOS had significantly higher (p>0.001) feelings of depression than controls. There was no significant difference in feelings of self-worth; however, women with PCOS experienced significantly greater (p>0.001) outside stressors than controls. 

PCA patterns showed six rather than the expected five ‘Factors’, except for “Negative Moods” in Factor 1, which differed importantly in Factor loading structure from previous data in ovulatory women. Most interesting is that cramps and flow were not on the same factor but that “stretchy” cervical mucus loaded positively with interest in sex. 

CONCLUSIONS 
In conclusion, women with PCOs experience less menstrual flow/day than matched controls. They also experienced greater outside stresses and had more depression and similar feelings of self-worth as did the controls during the SARS-CoV-2 pandemic. 

REFERENCES 
Prior JC, Shirin S, Bos C, et al. Epidemic of Subclinical Ovulatory Disturbances During SARS-COV2 Pandemic—an Experiment of Nature. Endocrine Society podium presentation, Atlanta, Georgia, June, 2022. 

Allison B. Macbeth, Azita Goshtasebi, G. William Mercer & Jerilynn C. Prior (2021) Does Interest in Sex Peak at Mid-Cycle in Ovulatory Menstrual Cycles of Healthy, Community-Dwelling Women? An 11-Month Prospective Observational Study, Women's Reproductive Health, 8:2, 79-91, DOI: 10.1080/23293691.2021.1901519

Experiences of Women Living with Polycystic Ovary Syndrome: ​a case-control single-cycle daily Menstrual Cycle Diary © study during the SARS-CoV-2 pandemic.​

The aim was to investigate if AMH could be used as a surrogate for polycystic ovarian morphology in a large data set when diagnosing women with polycystic ovarian syndrome. In our data set the prevalence of PCOS was 13.6% when AMH was used as part of Rotterdam criteria. The hormonal and metabolic profile was typical for PCOS whe assesing AMH-indueced phenotypes.

Anti-Müllerian hormone is a useful tool in polycystic ovary syndrome diagnostics in large datasets

Objective: Polycystic ovary syndrome (PCOS) is associated with psychological morbidity including depression and anxiety and diminished sexual satisfaction. As vitamin D (vit D) deficiency has been linked to symptoms of PCOS, we explored the association of baseline total 25-hydroxyvitamin D (25[OH]D) and bioavailable 25- hydroxyvitamin D (bio-25[OH]D) with sexual dysfunction (SDy) and the impact of vit D replacement.
Methods: Reproductive age women with PCOS and SDy, using the Female Sexual Functioning Index (FSFI), and without severe depression, using the Beck Depression Inventory (BDI), were eligible. Subjects with SDy (FSFI <26.55) were allowed to choose either vit D 600U daily plus hormonal contraceptive (HC) (n=18) or vit D 600IU daily and non-HC (n=10). FSFI, BDI, and serum total and bio-25[OH]D were determined at baseline and at study completion. Initial comparisons between those with and without SDy to total and bio-25[OH]D status and changes in FSFI after treatment were analyzed and correlations between FSFI with demographics, pre-treatment total and free testosterone (tT and fT) levels, total and bio-25[OH]D, HC use, and BDI were performed.
Results: A total of 42 women without severe depression completed the FSFI with 28 (66.7%) having SDy. All FSFI domains including arousal, lubrication, orgasm, and pain were significantly lower compared to women without SDy at baseline and with no associations with respect to demographics, tT and fT, or total 25[OH]D and bio-25[OH]D. Vit D replacement was initiated with HC (n=18) or non-HC (n-10), and for those completing the study, FSFI (>26.5) improved in 61% (11/18), regardless of the treatment group. A time-treatment effect showed a significant change for the domain of orgasm, suggesting that HC had more of an impact than Vit D replacement on this scale. Improvement in sexual function as a dichotomous variable was not associated with age, BMI, other demographics, tT and fT, total and bio-25[OH]D, or HC use. 
Discussion: Vit D level was not associated with SDy or BDI, and while HC appeared to have more of an impact, standard Vit D supplementation could not account for the noted improvement in FSFI in women with PCOS.
Support: Grant from Patty Brisben Foundation, Cincinnati, OH


Total & Bioavailable 25-Hydroxyvitamin D is not associated with Improved Sexual Dysfunction Following Vitamin D Supplementation in Women with Polycystic Ovarian Syndrome

Walter Futterweit Award in Clinical Research

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Early Atherosclerosis in High-Risk Young Women With and Without Polycystic Ovary Syndrome

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