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. 

Walter Futterweit Award in Clinical Research

OBJECTIVE: To contrast the diagnostic accuracy of 3D ultrasonographic markers of ovarian morphology to 2D ultrasonography and serum anti-Müllerian hormone (AMH) levels for detection of polycystic ovary syndrome (PCOS). Any gains in diagnostic accuracy when combining ovarian markers was also explored.

METHODS: 30 women with PCOS based on the National Institutes of Health (NIH) criteria and 30 age- and body mass index (BMI)-matched controls were evaluated. Transvaginal ultrasound scans (GE Voluson E or S Series; 5-12 MHz) and blood draws were conducted during the early follicular phase for women with regular cycles or at a random time for women with irregular cycles. Ovarian images were analyzed for the number of 2-9mm antral follicles in the entire ovary (FNPO), number of 2-5mm antral follicles (FNPO2-5mm) and 6-9mm antral follicles (FNPO6-9mm), and ovarian volume (OV) using 3D and 2D ultrasonography by one of six trained raters. 3D versus 2D ovarian markers were compared using Bland-Altman agreement statistics for matched-pair analysis. Diagnostic accuracy of ovarian markers for PCOS was determined by Receiver Operating Characteristic (ROC) curve analysis. Stepwise logistic regression analysis determined if combinations of ultrasonographic markers or AMH yielded greater diagnostic potential than single parameters.

RESULTS: 3D measurements of FNPO, FNPO2-5mm, and OV had greater diagnostic accuracy for PCOS compared to their 2D counterparts. The most accurate markers for PCOS were 3D FNPO (AUC=0.938) and 3D FNPO2-5mm (AUC=0.933), followed by 2D FNPO (AUC=0.922) and 2D FNPO2-5mm (AUC=0.906). Despite overall agreement between 3D and 2D FNPO measures, 3D ultrasonography overcounted FNPO2-5mm (2.00 ± 3.68, P=0.006) and undercounted FNPO6-9mm (-3.00 ± 3.49, P<0.001) in women with PCOS. AMH (AUC=0.898) had greater diagnostic accuracy than 3D and 2D OV (AUC=0.854 and 0.849, respectively), but remained inferior to both 3D and 2D follicle counts. The addition of OV or AMH did not improve diagnostic accuracy for follicle counts. However, the addition of AMH did substantially improve the diagnostic accuracy of 3D OV (AUC=0.918) and 2D OV (AUC=0.911).

CONCLUSIONS: 3D ultrasonographic markers of ovarian morphology outperformed 2D markers in the diagnosis of PCOS, with 3D markers of follicle excess being the most accurate measure overall. AMH had inferior diagnostic accuracy compared to FNPO across both modalities but was superior to OV. Addition of AMH improved the predictive power of OV on 2D and 3D ultrasonography thereby offering a robust alternative when image quality prevents an accurate assessment of follicle counts.

(This study was funded by the National Institutes of Health Grant [R01HD09374, R56HD089962, UL1 TR000457-06, T32DK007158-41] and the Canadian Institute of Health Research [FRN 146182].)


3D Markers of ovarian morphology outperform 2D ultrasonography and Anti-Müllerian hormone in the diagnosis of PCOS

Women with polycystic ovary syndrome (PCOS) have poorer work ability and higher disability retirement rate at midlife - A Northern Finland Birth Cohort 1966 Study

OBJECTIVE: Polycystic ovarian syndrome (PCOS), the most common endocrine disorder in women of reproductive age, is associated with cardiometabolic comorbidities. Information on cardiovascular disease (CVD) event risk associated with PCOS is mixed limited by sample size, diagnostic criteria, and years of follow up especially in US cohorts. Metformin, a drug traditionally used to treat patients with type 2 diabetes (T2D), is first line treatment for many women with PCOS We hypothesize that women with PCOS are at increased risk for developing cardiovascular diseases CVD and that metformin may play a protective role in disease progression.
METHODS: We leveraged the Penn Medicine electronic health record (EHR) which contains diagnosis information for 2,514,400 women. We calculated relative risk (RR) of being diagnosed with CVD or thrombotic disease (based on diagnosis codes) for women who were also diagnosed with PCOS or PCOS + T2D. For both RR calculations, our cases were women aged 15-50 who had at least one visit with PCOS diagnosis with or without T2D diagnosis. Controls were women aged 15-50 without a PCOS diagnosis but who had at least one visit for T2D. We also calculated RR of being diagnosed with CVD or thrombotic event for women aged 15-50 with at least one PCOS + T2D diagnosis who were treated with the drug metformin. Controls were women aged 15-50 with a PCOS +T2D diagnosis but were not treated with metformin.
RESULTS: Of the 945,670 women aged 15-50, 22,030 (2.3%) had at least one visit for PCOS diagnosis while 2,010 (0.2%) had PCOS and T2D. We found that the risk for CVD for women with PCOS was 1.35 times that of age matched controls (95% CI 1.29 ± 1.43, p = 1.76e-28) and the risk for thrombotic disease was 2.02 times that of age matched controls (95% CI 1.81 ± 2.26, p = 5.25e-37). We found that women with PCOS + T2D had decreased risk for CVD (RR = 0.26, 96% CI 0.23 ± 0.29, p = 6.21e-140) and thrombotic disease (RR = 0.60, 95% CI 0.47 ± 0.77, p = 3.02e-05). Because many women with T2D are prescribed metformin, we wanted to know if a metformin prescription had a protective effect on being diagnosed with CVD or thrombotic disease. By calculating RR, we found that women with PCOS + T2D who were prescribed metformin were 15% less likely of developing CVD (RR = 0.85, 95% CI 0.77 ± 0.93, p = 5.03e-05) and 4% less likely of developing TD (RR = 0.96, 95% CI 0.83 ± 1.12, NS) compared to patients that were never prescribed metformin.
CONCLUSIONS: In a large longitudinal cohort of women diagnosed with PCOS, we showed that a PCOS diagnosis was associated with an increased risk of CVD events. We also showed that PCOS patients who also had T2D diagnosis had decreased risk of CVD, which we observed was potentially associated by the protective effects of the drug metformin. Due to the high prevalence of CVD in women, longitudinal studies are needed to uncover the molecular, genetic, and pharmacogenomic pathways underlying disease progression in women with PCOS.

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