United States

Aim: To summarize the effects of metformin treatment on markers of hyperandrogenism in patients diagnosed with PCOS.
Data source: A systematic review, with meta-analysis, of randomized placebo-controlled clinical trials that evaluated the effects of metformin treatment in adult patients with PCOS on the levels of hyperandrogenism markers from the recommendations of The Cochrane Handbook for Systematic Reviews of Interventions.
Data extraction: The literature search, data extraction, risk of bias, and the assessment of certainty of evidence were performed independently by two reviewers using a structured form. The results were combined by applying the random effect and the effect measure presented as a standardized mean difference (SMD). Significant values were considered as p&lt;0.05 with 95% CI. Furthermore, sensitivity analyzes were performed in order to explore possible heterogeneity between studies.
Data synthesis: Were included 18 studies in the quantitative evaluation. A significant reduction in total testosterone levels was seen in the metformin-treated group when compared to the control group after combining the results [SMD: -0.46 (95% CI: -0.89 to -0.02)]. Therefore, metformin proved to be effective in reducing total testosterone levels, a finding confirmed by the sensitivity analysis, and the same was observed for FAI values – a measure influenced by testosterone levels.
Conclusion: We showed that metformin proved to be effective in reducing total testosterone levels, a finding confirmed by the sensitivity analysis, and the same was observed for FAI values – a measure influenced by testosterone levels. The protocol of this study was registered at Prospero (CRD42021235761).


AE-PCOS 2022

Influence of metformin on hyperandrogenism in women with Polycystic Ovary Syndrome: a systematic review and meta-analysis of randomized clinical trials

### 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.

The recorded content will be available to registrants only for three months after the meeting. 


To gain access to this event page you are required to register. 

For tickets to the event, please register [here](https://secure.ae-society.org/np/clients/aesociety/eventRegistration.jsp?forwardedFromSecureDomain=1&event=2). 

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.

Aim: To summarize the effects of metformin treatment on markers of hyperandrogenism in patients diagnosed with PCOS.
Data source: A systematic review, with meta-analysis, of randomized placebo-controlled clinical trials that evaluated the effects of metformin treatment in adult patients with PCOS on the levels of hyperandrogenism markers from the recommendations of The Cochrane Handbook for Systematic Reviews of Interventions.
Data extraction: The literature search, data extraction, risk of bias, and the assessment of certainty of evidence were performed independently by two reviewers using a structured form. The results were combined by applying the random effect and the effect measure presented as a standardized mean difference (SMD). Significant values were considered as p<0.05 with 95% CI. Furthermore, sensitivity analyzes were performed in order to explore possible heterogeneity between studies.
Data synthesis: Were included 18 studies in the quantitative evaluation. A significant reduction in total testosterone levels was seen in the metformin-treated group when compared to the control group after combining the results [SMD: -0.46 (95% CI: -0.89 to -0.02)]. Therefore, metformin proved to be effective in reducing total testosterone levels, a finding confirmed by the sensitivity analysis, and the same was observed for FAI values – a measure influenced by testosterone levels.
Conclusion: We showed that metformin proved to be effective in reducing total testosterone levels, a finding confirmed by the sensitivity analysis, and the same was observed for FAI values – a measure influenced by testosterone levels. The protocol of this study was registered at Prospero (CRD42021235761).


poster

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

OBJECTIVE: The original description of PCOS was based on the cystic morphology of the ovaries. Serum Anti Mullerian Hormone (AMH) concentration reflects follicular reserve of the ovaries and high AMH concentrations correlate with PCO morphology. The presence of three different definitions and four different phenotypes of PCOS indicates heterogeneity of the syndrome. Our goal was to examine if phenotyping based on serum AMH can help to understand the mechanisms underlying the clinical heterogeneity. 
METHODS: 
Subjects: The EPIC EMR was used to retrospectively review the charts of 123 patients who were referred to the PCOS clinic at the UC Davis Medical Center. Patients who did not meet the Rotterdam Criteria for PCOS, who were on were on hormonal contraception, or diagnosed with a different pathology (i.e. congenital adrenal hyperplasia, pituitary tumor, premature ovarian failure) were excluded. The remaining 92 patients were included in the final analysis. Variables: Anthropometric data (age, BMI), sex/adrenal steroids (testosterone, SHBG, bio-available-T, free-T, DHEA-S,17OHP), pituitary hormones (LH, FSH, prolactin) and metabolic (HgA1C, total-cholesterol, HDL-C, LDL-C and triglyceride) were collected.
RESULTS: 
The distribution for AMH was skewed to right and therefore a rank-based quartile classification was used. AMH concentrations (ng/mL) in these quartiles were: 1st: 2.4±1.3 (n = 31); 2nd: 5.2±0.6 (n = 14); 3rd: 7.8±0.9 (n = 24) and 4th: 18.9±10.7 (n = 23). Age did not differ among groups. The following variables differed significantly (p < 0.05) in the highest AMH group (4th) when compared with the other quartiles (1st, 2nd, or 3rd) using non-parametric pairwise tests: BMI: Highest AMH group was thinner (BMI:27.1±5.9) vs. (range:28.9±6.2 to 30.5±6.5); had higher testosterone (ng/dL): (52.6±27.8) vs (29.6±13.4 to 34.9±17.7); had higher free-testosterone (ng/dL): (8.0±6.8) vs. (4.9±±2.7 to 5.4±3.0); had higher 17OHP (ng/dL): (86.7±58.8) vs. (36.8±22.2 to 46.2±39.2); had higher HDL-C (mg/dL): (56.7±13.6) vs. (44.4±5.8 to 46.4±8.7).
CONCLUSIONS:
The phenotyping based on serum AMH concentrations demonstrated that the PCOS women with highest serum AMH differ from the rest: They are thinner, have higher androgen levels. They appear to have more favorable metabolic profiles. AMH-based phenotyping may help to understand the differences between various clinical presentations of PCOS, and potentially guide the treatment approaches. 


Anti-Mullerian Hormone (Amh) Based Phenotyping Of Pcos Women

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. 

Proteomic analysis of skeletal muscle and adipose tissue from women with PCOS

Management of type 1 and type 2 diabetes with PCOS

Distinct genetic architectures of PCOS subtypes

This presentation reviews the latest evidence concerning the association of COVID-19 in women with PCOS. Topics within it will include whether women with PCOS are known to be at greater risk for COVID-19 and whether they are at a higher likelihood of severe disease.

Risk of SARS-COV-2 infection and PCOS

Vanden Brink H1,2,3*, Burgert TS2, Barral R4,5,6, Gadiraju, M5, Lujan ME1*

1Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA; 
2Division of Endocrinology, Children’s Mercy Hospital, Kansas City, MO, USA; 
3Department of Nutrition, Texas A&M University, College Station, TX, USA; 
4Adolescent Medicine, Children’s Mercy Hospital, Kansas City, MO, USA; 
5University of Missouri Kansas City School of Medicine, Kansas City, MO, USA; 
6 University of Kansas Medical Center, Kansas City, KS, USA

Introduction: Assessment of ovarian features are discouraged in the diagnosis of PCOS in adolescence owing to a lack of normative data and historically poor image quality via transabdominal ultrasonography. However, we have recently shown that ovarian morphology is adequately resolved via transabdominal ultrasound in adolescents and that follicle number and ovarian size reflect circulating AMH within the first gynecological year. Whether ovarian features at this early gynecological stage predict menstrual cycle status at two-years post-menarche (2YR-PM) is unknown. 

Methods: Menstrual records of 19 adolescent females who were evaluated at 6-10 months post-menarche (PM) were collected as a part of a prospective cohort study. Menstrual cycle status was determined at 2YR-PM as regular (three previous inter-menstrual intervals within 21-45 days) or irregular (at least one of the three previous inter-menstrual intervals <21 or >45 days). At 6-10 months PM, participants underwent a fasting blood draw, anthropometry, bioimpedance, and a transabdominal ultrasound of the ovaries. Differences in reproductive and metabolic features at 6-10 months PM were contrasted in those who were regular versus irregular at 2YR-PM via Mann-Whitney U-Tests. Whether reproductive features assessed at 6-10 months PM predicted menstrual cycle status at 2YR-PM was determined via logistic regression analyses.

Results: At 2YR-PM, 6/19 adolescents met the criteria for regular menstrual cycles and 13/19 met the criteria for irregular menstrual cycles. There were no differences in the metabolic profile nor in clinical or biochemical measures of androgens status at 6-10 months PM between those who ultimately achieved regular vs irregular menstrual cycles (P>0.05). However, adolescents with irregular menstrual cycles at 2YR-PM had higher LH concentrations (4.8 [3.5-5.5] vs 3.0 [2.4-3.8] mIU/mL; P=0.025), AMH (5.6 [5.1-7.3] vs 3.0 [1.6-4.5] ng/mL, P=0.023), and tended to have higher numbers of antral follicles 2-5mm in diameter (FNPO 2-5mm) (19 [14-25] vs 10 [7-16], P=0.06) at 6-10 months PM. The likelihood of regular menstrual cycles at 2YR-PM decreased with higher AMH (Odds Ratio 0.49 [0.24-0.98], P=0.01), LH (OR: 0.33 [0.13-1.09], P=0.019) and tended to decrease with greater FNPO 2-5mm (OR: 0.89 [0.76-1.03], P=0.05) at 6-10 months PM. 

Conclusion: Ovarian features and serum LH may serve as early, clinically feasible biomarkers of future persistent menstrual irregularity with defective folliculogenesis preceding metabolic and androgenic derangements  in the timeline to aberrant reproductive maturation. Whether adolescents with persistent menstrual irregularity meet criteria for PCOS will be determined upon conclusion of the cohort study.  

Funding: National Institutes of Health (R21-HD095372), Canadian Institutes of Health Research (Postdoctoral Fellowship #171268). 


Reproductive features captured within the first gynecological year predict persistent menstrual irregularity at two years post-menarche

Objective: Polycystic ovary syndrome (PCOS) is a common condition with endocrine-metabolic dysfunction, and is highly heritable. Yet, there is limited research on how offspring are affected, and the age of onset, if any. We established a cohort of women with PCOS and matched controls along with their offspring to evaluate the effects of maternal PCOS on the offspring, as well as any differential impact between boys and girls. 
Methods: Among Chinese women from our PCOS registry (diagnosed based on the 2003 Rotterdam diagnostic criteria), we invited those who have children to participate in a follow-up study, and evaluated both the mothers and their sons (PCOSs) and daughters (PCOSd). For controls, we recruited women from the Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) Study, who did not have PCOS or GDM, together with their sons (Cs) and daughters (Cd), for comparison. All offspring aged 15-25 years were included in the current analysis, and all have undergone a detailed assessment with questionnaire, anthropometric assessment, a standardized 75g OGTT for glycemic status evaluation and biochemical tests. Difference between groups were evaluated using independent sample t-test or Mann-Whitney U test for continuous variables, while Chi-square (X2) or Fisher’s exact tests were used for categorical variables. 
Result: A total of 21 PCOSs and 18 PCOSd (mean age 19.86 ± 3.98 and 18.33 ± 2.30, respectively) as well as 26 Cs and 45 Cd (mean age 17.27 ± 0.67 and 17.58 ± 0.84, respectively) were recruited to date. We noted a high prevalence of menstrual irregularity in PCOSd when compared with Cd (PCOSd: 8/18 (44.4%) vs Cd: 7/44 (15.9%), p<0.005). We also found that the frequency of elevated androgen levels was 8/18 (44.4%) and 11/33 (33.3%) in PCOSd and Cd, respectively (p=0.433). PCOSd were significantly more centrally obese than Cd (PCOSd: 5/18 (27.8%) vs Cd: 2/45 (4.4%), p=0.007). Yet, such significant difference was not observed when comparing between PCOSs and Cs. There was no significant difference in the prevalence of dyslipidemia (PCOSs: 13/21 (61.9%) vs Cs: 9/21 (42.9%), p=0.217; PCOSd: 3/18 (16.7%) vs Cd: 5/34 (14.7%), p=0.852), hypertension (none for both PCOSs and Cs; PCOSd: 1/18 (5.6%) vs Cd: 1/45 (2.2%), p=0.465) and metabolic syndrome (AHA/NHLBI) (PCOSs: 3/21 (14.3%) vs Cs: 0/26; Pd: 2/18 (11.1%) vs Cd: 0/45) in both gender between offspring of mothers with and without PCOS. There is a trend towards higher frequency of glucose abnormalities when comparing PCOSd vs Cd (PCOSs: 2/21 (9.5%) vs Cs: 1/21 (4.8%), p=0.549; PCOSd: 4/18 (22.2%) vs Cd: 2/34 (5.9%), p=0.079), although there was no significant difference.
Conclusion: PCOSd have increased risk of menstrual irregularity and central obesity compared to Cd. No difference in cardiometabolic traits were observed between PCOSs and Cs. Our preliminary results shed some light on the potential long-term cardiometabolic burden on PCOSd. 


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Influence of metformin on hyperandrogenism in women with Polycystic Ovary Syndrome: a systematic review and meta-analysis of randomized clinical trials

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