Fine particulate matter and polycystic ovarian morphology.

BACKGROUND: Polycystic ovary morphology (PCOM) is an ultrasonographic finding that can be present in women with ovulatory disorder and oligomenorrhea due to hypothalamic, pituitary, and ovarian dysfunction. While air pollution has emerged as a possible disrupter of hormone homeostasis, limited research has been conducted on the association between air pollution and PCOM. METHODS: We conducted a longitudinal cohort study using electronic medical records data of 5,492 women with normal ovaries at the first ultrasound that underwent a repeated pelvic ultrasound examination during the study period (2004-2016) at Boston Medical Center. Machine learning text algorithms classified PCOM by ultrasound. We used geocoded home address to determine the ambient annual average PM2.5 exposures and categorized into tertiles of exposure. We used Cox Proportional Hazards models on complete data (n = 3,994), adjusting for covariates, and additionally stratified by race/ethnicity and body mass index (BMI). RESULTS: Cumulative exposure to PM2.5 during the study ranged from 4.9 to 17.5 µg/m3 (mean = 10.0 µg/m3). On average, women were 31 years old and 58% were Black/African American. Hazard ratios and 95% confidence intervals (CI) comparing the second and third PM2.5 exposure tertile vs. the reference tertile were 1.12 (0.88, 1.43) and 0.89 (0.62, 1.28), respectively. No appreciable differences were observed across race/ethnicity. Among women with BMI ≥ 30 kg/m2, we observed weak inverse associations with PCOM for the second (HR: 0.93, 95% CI: 0.66, 1.33) and third tertiles (HR: 0.89, 95% CI: 0.50, 1.57). CONCLUSIONS: In this study of reproductive-aged women, we observed little association between PM2.5 concentrations and PCOM incidence. No dose response relationships were observed nor were estimates appreciably different across race/ethnicity within this clinically sourced cohort.

Substituting serum anti-Müllerian hormone for polycystic ovary morphology increases the number of women diagnosed with polycystic ovary syndrome: a community-based cross-sectional study.

STUDY QUESTION: Can serum anti-Müllerian hormone (AMH) replace polycystic ovary morphology (PCOM) determined by ultrasound as a diagnostic component of polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Despite good correlations between serum AMH and PCOM, the use of a high serum AMH as a proxy for PCOM resulted in the reclassification of PCOS in 5% of study participants, with the main effect being more women identified, although some women previously classified as having PCOS were no longer classified as such. WHAT IS KNOWN ALREADY: AMH has been proposed as an alternative to PCOM as a diagnostic component of PCOS. Previous studies are limited by poorly defining PCOS, use of infertile women as comparators, measurement of hormones by immunoassay that lack precision in the female range, low-resolution ovarian ultrasound and inconsistent handling and storage of serum samples. STUDY DESIGN, SIZE, DURATION: This is an Australian cross-sectional study of 163 non-healthcare-seeking women. PARTICIPANTS/MATERIALS, SETTING, METHODS: Serum AMH was measured by both the Ansh picoAMH assay and the Beckman Coulter Access 2 (BA2) assay, in parallel with androgens measured by liquid chromatography-tandem mass spectrometry, in blood samples of women, not pregnant, breast feeding or using systemic steroids, who also underwent high-resolution ovarian ultrasound. PCOS was determined by the Rotterdam criteria with PCOM defined by the Androgen Excess-PCOS Taskforce recommendation of ≥25 follicles in at least one ovary. Cut-off serum concentrations that best identified women as having PCOM were identified by receiver operator characteristic (ROC) curves. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 163 women, mean (SD) age 32.5 (5.5) years, who provided a blood sample and had both ovaries visualized on ultrasound were included in the analysis. Women with isolated PCOM had higher median (range) Ansh AMH and BA2 AMH concentrations than those with no PCOS characteristics [56.9 pmol/l (34.6, 104.2) versus 18.7 (3.2, 50.9), P = 0.002 and 38.5 pmol/l (22.2, 100.2) versus 16.7 (3.5, 38.9), P = 0.002, respectively]. An AMH ≥ 44.0 pmol/l, suggested by the ROC curve, identified 80.6% of women with PCOM, falsely identified 15.2% of women without PCOM as having PCOS and had a positive predictive value of 55.6%. The negative predictive value was 94.9%. An AMH BA2 assay cut-off of ≥33.2 pmol/l provided a sensitivity of 80.6%, a specificity of 79.5% and a positive predictive value for PCOM of 48.1%. The negative predictive value was 94.6% for PCOM. When serum AMH was used in the place of PCOM as a diagnostic criterion for PCOS, the Ansh assay resulted in an additional seven women classified as having PCOS and no longer classified one woman as having PCOS. For the BA2 assay, eight additional and two fewer women were classified as having PCOS. Overall, both assays resulted in six more women being classified as having PCOS. LIMITATIONS, REASONS FOR CAUTION: Women with functional hypogonadotrophic hypogonadism were not excluded and may have been misclassified as having an oligo-amenorrhoea-PCOM phenotype. As study participants were predominantly Caucasian/White, our findings cannot be generalized to women of other ethnicities. WIDER IMPLICATIONS OF THE FINDINGS: Although serum AMH reflects the number of developing ovarian follicles, the absolute values vary between assays and specific reference ranges for individual assays are required. Irrespective of the assay used, replacing PCOM with serum AMH to diagnose PCOS in a community-based sample altered the number of women classified as having or not having PCOS. Consequently, although overall the risk of women being identified as having PCOS would be increased, some women would no longer be classified as having this condition. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by the Norman Beischer Research Foundation and the Grollo-Ruzzene Foundation. S.R.D. is an NHMRC Senior Principal Research Fellow (Grant No. 1135843). S.R.D. reports unrelated support that includes grants from the NHMRC Australia, personal fees for educational activities from Besins Healthcare, Abbott Chile, BioFemme and Pfizer Australia, personal Advisory Board/consultancy fees from Theramex, Abbott Laboratories, Astellas, Mayne Pharmaceuticals, Roche Diagnostics, Lawley Pharmaceuticals and Que Oncology and has received institutional grant funding from Que Oncology and Ovoca research. The other authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Elevation of markers of endotoxemia in women with polycystic ovary syndrome.

STUDY QUESTION: Is polycystic ovary syndrome (PCOS) associated with an elevation of markers of endotoxemia? SUMMARY ANSWER: In women with PCOS serum levels of lipopolysaccharides (LPS), the LPS to high-density lipoprotein (HDL) ratio and LPS-binding protein (LBP) are significantly greater than those of normal control subjects. WHAT IS KNOWN ALREADY: Mononuclear cells from women with PCOS respond excessively to LPS by releasing pro-inflammatory cytokines. In rat ovarian theca-interstitial cell cultures LPS stimulates androgen production. STUDY DESIGN, SIZE, DURATION: Cross-sectional study comparing markers of endotoxemia in women with PCOS (n = 62), healthy ovulatory women with polycystic ovary morphology (PCOM, n = 39) and a control group of healthy ovulatory women without PCOM [normal (NL), n = 43]. PARTICIPANTS/MATERIALS, SETTING, METHODS: LPS was measured using a chromogenic assay. LBP was measured by ELISA. Total cholesterol and lipids were measured using a homogeneous enzyme colorimetric method. Androgens, gonadotrophins, prolactin, insulin, high-sensitivity C-reactive protein (hs-CRP) and sex hormone-binding globulin were determined by electrochemiluminescence assays. Glucose was measured using an enzymatic reference method with hexokinase. MAIN RESULTS AND THE ROLE OF CHANCE: Women with PCOS, when compared with NL subjects, had a significantly higher mean LPS (P = 0.045), LPS/HDL ratio (P = 0.007) and LBP (P = 0.01). Women with PCOM had intermediate levels of markers of endotoxemia. Comparison among all groups revealed that markers of endotoxemia correlated positively with testosterone level, ovarian volume, number of antral follicles and hirsutism score, but negatively with the number of spontaneous menses per year. In multiple regression analysis, all measures of endotoxemia correlated independently and positively with hs-CRP and with ovarian volume. LIMITATIONS, REASONS FOR CAUTION: This cross-sectional study reveals that markers of endotoxemia are associated with several clinical features observed in women with PCOS. However, responsible mechanisms and causation remain unknown. Steroid quantification was carried out by electrochemiluminescence assays and not by the current gold standard: liquid chromatography-mass spectrometry. Hence, the relationship of endotoxemia with features of PCOS and the extent to which endotoxemia contributes to reproductive and metabolic dysfunction warrants further investigation. WIDER IMPLICATIONS OF THE FINDINGS: This study reveals the novel observation that markers of endotoxemia are elevated in young and otherwise healthy women with PCOS without significant metabolic dysfunction. Moreover, the association of clinical and endocrine markers of PCOS with those of endotoxemia may represent a pathophysiologic link to reproductive dysfunction as well as metabolic and long-term cardiovascular risks associated with this disorder. STUDY FUNDING/COMPETING INTEREST(S): Intramural funding from Poznan University of Medical Sciences. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Anti-Müllerian hormone as a diagnostic tool for PCOS under different diagnostic criteria in an unselected population.

RESEARCH QUESTION: Is anti-Müllerian hormone (AMH) a valid tool to diagnose polycystic ovary syndrome (PCOS) according to different subsets of criteria among an unselected group of women? DESIGN: In this cross-sectional study, AMH concentrations were measured in an unselected group of women. The ability of AMH to diagnose PCOS according to National Institutes of Health (NIH), Rotterdam-2003 and Androgen Excess and PCOS Society (AE-PCOS) criteria was tested by using frozen serum aliquots (n = 392) that had been collected from a previous prevalence study of PCOS. RESULTS: The respective age and body mass index adjusted area under the curve (aAUC, 95% confidence interval) values were 0.80 (0.71-0.89), 0.74 (0.67-0.81) and 0.71 (0.64-0.79). When the definition of polycystic ovary morphology (PCOM) was set to an antral follicle count (AFC) of 20 instead of 12, the prevalence of syndrome dropped from 19.9% to 10.2% and from 15.3% to 8.9% according to Rotterdam-2003 and AE-PCOS criteria, respectively. In patients with Phenotype A, who had hyperandrogenism, ovulatory dysfunction and PCOM, AMH had an aAUC of 0.85 (0.77-0.92) to diagnose the syndrome. In Phenotypes B (hyperandrogenism + ovulatory dysfunction), C (hyperandrogenism + PCOM) or D (ovulatory dysfunction + PCOM), AMH had poor to fair ability to diagnose the syndrome. CONCLUSION: AMH has poor to fair validity to diagnose PCOS among an unselected group of women, except for patients bearing all features of the syndrome (Phenotype A). This finding is valid using the NIH, Rotterdam-2003 and AE-PCOS criteria and even after revising the definition of PCOM as AFC ≥20.

Ovarian Expression of Adipokines in Polycystic Ovary Syndrome: A Role for Chemerin, Omentin, and Apelin in Follicular Growth Arrest and Ovulatory Dysfunction?

Adipokines are a potential link between reproduction and energy metabolism and could partly explain some infertilities related to some pathophysiology, such as polycystic ovary syndrome (PCOS). However, adipokines were predominantly assessed in blood samples, while very little is known concerning their variations in follicular fluid (FF) and ovarian granulosa cells (GCs) of PCOS women. Thus, the objectives of our study were to investigate adiponectin, chemerin, resistin, visfatin, omentin, and apelin ovarian expression in PCOS women in comparison with controls and women with only a polycystic ovary morphology. In total, 78 women undergoing an in vitro fertilization procedure were divided into three groups: 23 PCOS women, 28 women presenting only ≥12 follicles per ovary (ECHO group), and 27 control women. Each group almost equally included normal weight and obese women. Follicular fluid (FF) concentration and granulosa cells (GCs) mRNA expression of adipokines and their receptors were assessed by ELISA and RT-qPCR, respectively. Omentin levels in FF and GC were higher in PCOS than in ECHO and control women, while apelin expression was increased in both PCOS and ECHO groups. FF chemerin concentration was predominant in normal-weight PCOS women compared to BMI (Body Mass Index)-matched ECHO and control women, while GC mRNA levels were higher in the obese PCOS group than in the ECHO one. Compared to PCOS, ECHO women had increased FF adiponectin concentrations and lower plasma AMH levels. The FF concentration of all adipokines was higher in obese subjects except for adiponectin, predominant in normal-weight women. In conclusion, women with PCOS expressed higher GC chemerin and omentin, whereas the ECHO group presented higher levels of FF adiponectin and apelin and lower plasma AMH and LH concentrations. Chemerin, omentin, and apelin expression was differently regulated in women with PCOS, suggesting their possible role in follicular growth arrest and ovulatory dysfunction characterizing PCOS pathogenesis.

Polycystic ovary morphology is associated with insulin resistance in women with polycystic ovary syndrome.

BACKGROUND/OBJECTIVES: Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by chronic anovulation, hyperandrogenism, polycystic ovary morphology (PCOM) and metabolic disturbances including insulin resistance and type 2 diabetes mellitus. Although insulin resistance could be associated with PCOM, recent studies have shown controversial results. The aim of this study was to determine the relationship between PCOM and insulin resistance. SUBJECTS/METHODS: This was a cross-sectional clinical study. A total of 679 women with PCOS who were diagnosed using the National Institute of Child Health and Human Disease (NICHD) criteria and 272 control women were analysed. We measured fasting glucose and insulin levels, 75 g oral glucose tolerance test-derived glucose and insulin levels, testosterone levels, ovarian volume and follicle number. RESULTS: Polycystic ovary morphology was described in 543 women (80.0%) with PCOS. Women with PCOS had significantly higher 2 hours postload glucose, fasting and 2 hours postload insulin levels, ovarian volume, ovarian follicle numbers and lower insulin sensitivity compared with those of the controls (all P<.01). In women with PCOS, ovarian volume and ovarian follicle number were negatively associated with the quantitative insulin sensitivity check index after adjusting for age, body mass index and total testosterone; however, this association was not observed in the controls. In the logistic regression analysis, increased ovarian follicle number was associated with decreased insulin sensitivity in women with PCOS. CONCLUSIONS: In PCOS, enlarged ovarian volume and follicle excess were associated with insulin resistance, and the number of ovarian follicles could be a predictor of insulin resistance.

Does the risk of metabolic disorders increase among women with polycystic ovary morphology? A population-based study.

STUDY QUESTION: Is polycystic ovary morphology (PCOM) associated with metabolic syndrome (MS), insulin resistance (IR) and dyslipidemia? SUMMARY ANSWER: No associations between PCOM and metabolic disorders were found. WHAT IS KNOWN ALREADY: Polycystic ovary morphology has a prevalence of 21-63% in healthy women of reproductive age. Results of studies focusing on metabolic abnormalities among females with PCOM, are insufficient and controversial. STUDY DESIGN, SIZE, DURATION: This was a cross-sectional population-based study from five provinces in Iran. A standard questionnaire was filled out during face-to-face interviews and clinical examinations were done. All study subjects were invited to undergo blood sampling and ultrasonographic assessment. PARTICIPANTS/MATERIALS, SETTING, METHODS: From a total of 1772 women, 809 participants met the inclusion criteria of this study, i.e. non-pregnant, reproductive-age, ovulatory, normo-androgenic, without hyperprolactinemia/thyroid dysfunction. Participants were divided into two groups; 126 women with PCOM on ultrasound assessment, as the case and 683 women with normal ovarian morphology, as the control groups. The association of PCOM with MS, IR and dyslipidemia were analyzed using logistic regression models, adjusted for confounding variables. MAIN RESULTS AND THE ROLE OF CHANCE: Mean systolic blood pressure (SBP), high density lipoprotein (HDL) and androstenedione (A4) serum levels of women with PCOM were significantly higher than in the normal group (P = 0.04, 0.05 and 0.008, respectively). Comparison between groups revealed dyslipidemia to be higher among controls. However the results of logistic regression models, after adjustment for possible confounding variables showed that there were no significant association between prevalence of MS, IR and dyslipidemia with PCOM. LIMITATIONS, REASONS FOR CAUTION: Due to the study being cross-sectional, blood samples were collected only once thus we did not measure serum concentrations of progesterone in the luteal phase, which determines subclinical anovulation. Moreover, due to budget limitations, enzyme immunoassay was used for androgenic measurements while mass spectrometry-based assays have been known as the gold standard method. However we defined our groups very strictly to overcome these limitations. WIDER IMPLICATIONS OF THE FINDINGS: It seems that biochemical and metabolic characteristics of women with PCOM do not differ significantly to those of normal women. To clarify the association between PCOM and metabolic characteristics, longitudinal studies investigating long-term metabolic disorders among women with PCOM are highly recommended. STUDY FUNDING/COMPETING INTEREST: No external funding was used for this study. No conflicts of interest are declared.

A genetic risk score is associated with polycystic ovary syndrome-related traits.

STUDY QUESTION: Is a genetic risk score (GRS) associated with polycystic ovary syndrome (PCOS) and its related clinical features? SUMMARY ANSWER: The GRS calculated by genome-wide association studies (GWASs) was significantly associated with PCOS status and its related clinical features. WHAT IS KNOWN ALREADY: PCOS is a heterogeneous disorder and is characterized by oligomenorrhea, hyperandrogenism and polycystic ovary morphology. Although recent GWASs have identified multiple genes associated with PCOS, a comprehensive genetic risk study of these loci with PCOS and related traits (e.g. free testosterone, menstruation number/year and ovarian morphology) has not been performed. STUDY DESIGN, SIZE, DURATION: This study was designed as a cross-sectional case-control study. We recruited 862 women with PCOS and 860 controls. Women with PCOS were divided into four subgroups: (1) oligomenorrhea + hyperandrogenism + polycystic ovary, (2) oligomenorrhea + hyperandrogenism, (3) oligomenorrhea + polycystic ovary and (4) hyperandrogenism + polycystic ovary. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Genomic DNA was genotyped for the PCOS susceptibility loci using the HumanOmni1-Quad v1 array. Venous blood was drawn in the early follicular phase to measure baseline metabolic and hormonal parameters. A GRS was calculated by summing the number of risk alleles from 11 single-nucleotide polymorphisms (SNPs) that were identified in previous GWASs on PCOS. A weighted GRS (wGRS) was calculated by multiplying the number of risk alleles for each SNP by its estimated effect (beta) obtained from the association analysis. MAIN RESULTS AND THE ROLE OF CHANCE: The GRS was higher in women with PCOS than in controls (8.8 versus 8.2, P < 0.01) and was significantly associated with PCOS after adjusting for age and BMI. An analysis of GRS quartiles (Q1 = 3-5, Q2 = 6-8, Q3 = 9-11, Q4 = 12-15) revealed that the subjects in the highest quartile showed a remarkable increased risk of PCOS compared with those in the lowest quartile (odds ratio = 6.28, P < 0.001). Free testosterone level, menstruation number per year, ovarian volume and ovarian follicle numbers were significantly associated with the GRS (in all cases, P < 0.01). The wGRS yielded similar results. LIMITATIONS, REASONS FOR CAUTION: We used 11 loci for the calculation of GRS, but a higher number of PCOS risk alleles was reported in previous studies. Therefore, further studies should assess the value of GRS including the additional SNPs related to PCOS. Although a GRS of ≥12 was significantly associated with PCOS, the GRS showed a poor predictive value; therefore, the use of genetic information based on current GWAS data only may present problems. WIDER IMPLICATIONS OF THE FINDINGS: The GRS could be used to identify asymptomatic individuals among people at risk and stratify them into accurate risk categories for the purpose of individualizing treatment approaches, which could potentially improve health outcomes. STUDY FUNDING/COMPETING INTERESTS: None of the authors have any conflicts of interest to declare. No funding was obtained for the study.

The Relationship of Anti-Mullerian Hormone in Polycystic Ovary Syndrome Patients with Different Subgroups.

PURPOSE: To explore the value of anti-Mullerian hormone (AMH) in patients with polycystic ovary syndrome (PCOS) with different phenotypes and ages, and to identify the relationship between hyperandrogenism (HA) and polycystic ovary morphology (PCOM), in a Chinese cohort. METHODS: A total of 2262 women (1631 with PCOS and 631 controls) were enrolled. The serum AMH and total testosterone (TT) were analyzed, the AMH levels of each subgroup were compared, and the value of each phenotype and age group of patients with PCOS was evaluated. RESULTS: The level of AMH in women with PCOS (mean±SD, 8.63±4.73 ng/mL) was higher than that in controls (5.57±3.31 ng/mL) (P<0.01). The level of AMH in the PCOM subgroup (11.19±6.4 ng/mL) was significantly higher than that in the HA subgroup (8.58±4.74 ng/mL) (P<0.01), and both were higher than that in controls (P<0.01). AMH was higher in PCOS patients than in controls, but the same values were found in subgroups of PCOS patients under 30 years old. CONCLUSION: AMH changed in different subgroups of PCOS, which was the possible reason why AMH was not a diagnostic indicator. However, AMH could help to differentiate between clinical subgroups, as it was strongly related with PCOM but not with HA. AMH changed substantially with age, but was stable in PCOS patients under 30 years old.

Effect of Prunus dulcis and Salvia hispenica in the management of polycystic ovary syndrome in Wistar rats.

OBJECTIVE: Research has shown that polycystic ovary syndrome (PCOS) is a common cause of infertility in women. The drugs used to treat PCOS tend to manage the symptoms rather than cure the disease. Furthermore, these drugs have severe side-effects and influence the quality of life for the patients. There is therefore a need for natural medicine that can effectively treat PCOS without side-effects. METHOD: PCOS was induced in adult female Wistar rats by daily oral administration of letrozole (1 mg/kg) for 21 days. From day 22 until the end of the experiment (day 36), these rats were given a daily oral dose of either Prunus dulcis (walnut) or Salvia hispenica (chia seed) alone, or in combination. Animals were subsequently examined for morphological, biochemical, and histopathological changes. RESULT: When compared with the control and standard groups, rats who had consumed P. dulcis and S. hispenica, either as individual agents or in combination, had significantly lower body and ovarian weights, and hormone concentrations were maintained at healthy levels. The presence of polyphenolic compounds in these substances induced ovulation in the PCOS model animals. CONCLUSION: This study demonstrated that animals fed with P. dulcis and S. hispenica either individually or in combination were able to overcome infertility. Hormone levels and metabolism were restored in these animals. Therefore, P. dulcis and S. hispenica can be used as therapeutic agents to treat patients who are infertile due to suboptimal oocyte competence and anovulation.

Increased serum chemerin concentrations in patients with polycystic ovary syndrome: Relationship between insulin resistance and ovarian volume.

BACKGROUND: Chemerin has been linked to adiposity, and insulin resistance (IR) which are the common characteristics of polycystic ovary syndrome (PCOS). Chemerin also shows inhibitory action on follicular steroidogenesis. We investigated the associations between chemerin and IR or polycystic ovary morphology in patients with PCOS. METHODS: A total of 148 women with newly diagnosed PCOS using Rotterdam criteria and 88 healthy individuals were enrolled. The recruited patients with PCOS were further stratified by tertiles of serum chemerin concentrations as follows: Group 1 (< 24.79 ng/ml), Group 2 (24.79-30.27 ng/ml), and Group 3 (> 30.27 ng/ml). RESULTS: Compared to controls, women with PCOS in each tertile had higher serum chemerin concentrations. By linear regression analysis, homeostasis model assessment-insulin resistance and ovarian volume showed significant associations with chemerin after adjusting for confounding factors (ß = 0.257, P = 0.028; ß = 0.276, P = 0.005, respectively). The odds ratios (ORs) for ovarian volume excess gradually increased across increasing tertiles of chemerin in the adjusted model [Group 1: reference; Group 2: OR 1.602; 95% confidence interval (CI): 1.170­2.194; Group 3: OR 1.857; 95% CI: 1.335-2.583]. CONCLUSIONS: Patients with PCOS showed increased serum chemerin concentrations as compared to healthy women. Individuals with higher chemerin tended to have higher risk for ovarian volume excess in patients with PCOS, regardless of adiposity.