United States

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&lt;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&lt;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&lt;0.05). The prevalence of HPRL was higher in PCOS patients (7.0% versus 3%; p&lt;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.

AE-PCOS 2022

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

hyperprolactinemia

tpoab

thyroid dysfunction

pcos

### 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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Please register for the AE-PCOS 2022 Conference to join the event.

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.

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.

poster

OBJECTIVE: Polycystic ovary syndrome (PCOS) is the most prevalent reproductive endocrinopathy in women. Symptoms and complications place a significant burden on servicewomen, negatively influencing health, and hindering military operational and worldwide readiness. Despite Congressional recognition of the seriousness of PCOS, research in military PCOS populations is limited. Furthermore, current military policies do not address specific healthcare needs and challenges experienced by women with PCOS. Our purpose was to explore and describe servicewomen’s experience of living with PCOS.
METHODS: Qualitative descriptive design using focus groups and individual interviews. Women with PCOS were recruited from military locations. Data were analyzed using constant comparative content analysis with Nvivo12.
RESULTS: Air Force, Army, Navy, and Marine Corps women (N = 23) from 20 different occupational specialties participated. Three major themes emerged: (1) PCOS symptoms: PCOS was all-consuming, impacting every aspect of their lives, (2) Navigating the military healthcare system: challenges and facilitators within the military healthcare system, and (3) navigating PCOS as a servicemember: how the military environment including policies and work environment influenced their experience with PCOS. Thirteen sub-themes revealed challenges with accurate, timely diagnosis, access, trust, and continuity of healthcare, self-esteem and body image issues, and workplace harassment resulting in mental stress, due to symptoms such as facial hair, acne, painful, unpredictable menstrual cycles, and weight. A determination to “push through” to complete their unit mission was also identified. 
CONCLUSIONS: Servicewomen living with PCOS have similar experiences regardless of duty title or service branch. Unlike their civilian counterparts, servicewomen face significant career-limiting consequences. Weight is a major stress-point for servicewomen. Time to diagnosis (months to years) and managing onerous symptoms negatively influence health and unit cohesiveness, degrading mission readiness. Future studies are needed to further elucidate military-specific challenges experienced by servicewomen with PCOS. Research is also needed to facilitate development of evidence-based policies and identify effective strategies that support the health and readiness of servicewomen.
(Tri-Service Nursing Research Program: N18-B05)
Disclaimer: The views expressed are solely those of the authors and do not reflect the official policy or position of the US Army, US Navy, US Air Force, the Department of Defense, or the US Government.
Hopkins, D.1, Walker, S.1, Siaki, L.2, Philips, A. 3, Wilson, C.4, Wallen, G.5
(1) Clinical Investigation Facility, David Grant Medical Center, Travis Air Force Base, CA
(2) Center for Nursing Science and Clinical Inquiry, Regional Health Command-Pacific, Tripler Army Medical Center, Honolulu HI
(3) Malcolm Grow Medical Clinics and Surgery Center, Joint Base Andrews, MD
(4) Graduate School of Nursing, Uniformed Services University, Bethesda, MD
(5) Branch Chief and Senior Investigator, Translational Biobehavioral and Health Disparities Branch, National Institutes of Health, Clinical Center, Bethesda, MD


The Experience of Living with Polycystic Ovary Syndrome in the Military

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

OBJECTIVE: Diagnosis of polycystic ovary syndrome (PCOS) is a time- and resource-consuming process. Circulating miRNAs associated with PCOS might serve as diagnostic biomarkers. The aim of this study is the validation of 5 miRNAs with the highest diagnostic potential identified previously by our group and test their diagnostic accuracy for PCOS in a larger clinical series of patients and controls.

METHODS: We studied 71 women with PCOS and 69 control women selected as to be similar in terms of body mass index. We used miRCURY LNA™ Universal RT microRNA PCR to analyze the 5 miRNAS showing the strongest associations with PCOS in a much smaller pilot study from our group

RESULTS: Only the expression of 2 miRNAs of the 5 studied here (miR-142-3p and miR-598-3p) was different between subjects with PCOS and non-hyperandrogenic controls. The diagnostic accuracy of the combination of these circulating miRNAs was fairly good [area under the ROC curve (AUC) 0.801; 95% confidence interval (95CI) 0.720-0.882] and turned to excellent when adding the waist-to-hip ratio (WHR, AUC 0.834, 95CI 0.756-0.912), the luteinizing hormone to follicle-stimulating hormone ratio (LH/FSH ratio, AUC 0.869, 95CI: 0.804-0.934) or both (AUC 0.895, 95CI 0.835-0.954).

CONCLUSION: Models based on circulating miR-142-3p and miR-598-3p expression show excellent discrimination among women with or without PCOS, particularly when coupled with easily available measurements such as WHR and LH/FSH ratio.

(Funded by grants PI15/01686, PIE16/00050, PI18/01122 and PI21/00116 from ISCIII. CIBERDEM IRYCIS & EDRF).

Validation Of Circulating Micrornas In Polycystic Ovary Syndrome (Pcos) Diagnosis

OBJECTIVE: Metabolomics is a powerful tool to characterize the organism phenotypes and can facilitate the identification of altered metabolites and molecular pathways in pathophysiological states. Metabolites are small intermediates or end products of cellular metabolism which reflect the response to endogenous and exogenous factors. In this regard, sex hormones and obesity are important modulators of whole-body metabolism, and obese individuals and women with polycystic ovary syndrome (PCOS) present with metabolic alterations that may also manifest in the postprandial period. Hence, we investigated the effect of obesity and sex hormones on the serum metabolomics profile after single macronutrient challenges in a series of young adults. 
METHODS: Seventeen non-hyperandrogenic control women, 19 women with PCOS, and 19 healthy men —equally distributed in obese and non-obese subgroups— were submitted to isocaloric oral glucose, lipid and protein loads. Serum samples were obtained at baseline, 1h and 2h after glucose and protein ingestion, or at 2h and 4h in the lipid challenge. Thirty-five low-molecular-weight polar metabolites were determined by 1H-NMR. Postprandial net changes were expressed as areas under the curve (AUC). The influence of macronutrient, group (women, PCOS, men), obesity, and their interactions on each metabolite were evaluated by univariate GLM for repeated measures analysis.
RESULTS: Twelve metabolites (glycine, alanine, proline, threonine, serine, asparagine, glutamine, glutamic acid, ornithine, isobutyric acid, citrate and glycerol) showed different AUCs among macronutrient loads, although neither obesity nor sex hormones exerted any influence. In contrast, the AUCs of 3-hydroxybutyric and pyroglutamic acids were lower in men compared with either control or PCOS women. Remarkably, we observed numerous interactions between group, and/or obesity, and/or macronutrient for several molecules, indicating that the effect of obesity was different (or even the opposite) in control and PCOS women compared with men, and depending on the type of macronutrient. These metabolites included, among others, branched-chain and aromatic amino acids, lysine, methylhystidine, beta-glucose and acetone. Furthermore, patients with PCOS exhibited a specific and unique response —different from that of women and men— for pyruvate, tryptophan, creatine and betaine. Finally, five metabolites (2-oxoisovaleric acid, creatinine, carnitine, acetate and choline) showed no differences among the distinct macronutrient challenges and no effect of obesity, sex or PCOS.
CONCLUSION: Altered postprandial metabolomic profiles in women with PCOS point to worse metabolic flexibility that is exacerbated by obesity.


Serum Metabolomics Profile After Oral Macronutrient Challenges: Influence Of Obesity And Polycystic Ovary Syndrome

Global gene expression and DNA methylation analyses show that metabolic pathways linked to insulin resistance are dysregulated in adipose tissue and skeletal muscle from women with polycystic ovary syndrome (PCOS). However, gene expression does not always translate to alterations in protein levels and changes in biological function. Therefore, we have taken a nontargeted approach, to reveal novel proteins associated with PCOS pathophysiology. Adipose tissue and skeletal muscle biopsies from 10 women with PCOS and 10 controls were subjected to global proteomic and phosphosite analysis. Differently expressed proteins (DEPs) between cases and controls were based on p<0.05 and a fold change >50%. 15 DEPs were found in adipose tissue and the upregulated proteins play a role in immune system processes including, HLA class I histocompatibility antigen and immunoglobulins. We identified 34 DEPs in skeletal muscle. Proteins involved in muscle contraction and actin filament organization pathways were downregulated and expression of myosin heavy chain I, which is specific for type I, or red fibres, was decreased in PCOS. A higher proportion of type I fibers leads to better insulin responsiveness but androgens may diminish highly oxidative and insulin-sensitive type I muscle fibres. Upregulated proteins were enriched in immunometabolic pathways. For example, perilipin- 1 expression, which is localized in intramuscular adipocytes, was increased in PCOS and may reflect lipotoxicity. 

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