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MON-208 Association Study of AMH Promoter Polymorphisms and Serum AMH Levels in PCOS Patients

ABSTRACT: Abstract Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women, is diagnosed based on three criteria, including a polycystic ovarian morphology (PCOM). Although the etiology of PCOS is not fully understood, a genetic component has been demonstrated. Women with PCOS have elevated serum Anti-Müllerian Hormone (AMH) levels, a hormone known to reflect the ovarian reserve. Furthermore, the AMH production per follicle is suggested to be higher in PCOS patients and this combined implies an aberrant regulation of ovarian AMH expression. Currently, some transcription factors, such as FOXL2 and SF1, have been demonstrated to play a role in the ovarian regulation of AMH promoter activity. However, still little is known about AMH gene regulation, particularly in women with PCOS. Hence, the aim of this study was to investigate the association of single nucleotide polymorphisms (SNPs) in the AMH promoter on serum AMH levels in a cohort of PCOS patients. A candidate gene association study was conducted. All two-allelic SNPs located in or nearby the AMH promoter (Chr19:2,245,353 – 2,250,827bp) with a minor allele frequency > 1% and an imputation quality r2 threshold above 0.75 were included. We included Caucasian PCOS women, diagnosed based on the Rotterdam criteria. AMH levels were measured with the picoAMH assay (Ansh Labs®, Houston, Texas, USA). The association between SNPs and serum AMH levels was assessed by linear regression with Wald test of significance, allele carrier model analysis with one-way analysis of covariance (ANCOVA). All statistical models were adjusted for age, BMI and total follicle count (TFC). AMH levels were natural log transformed to obtain a normal distribution. A p-value below 8.51e-03 was considered as statistically significant, based on Matrix Spectral Decomposition with an effective number of independent variables (VeffLi) of 6. All analyses were performed using R studio. We assessed 11 SNPs in 700 Caucasian PCOS women. Human AMH promoter polymorphism rs10406324 (-220 A/G) was associated with serum levels of AMH in the linear regression analysis (? = 0.52, p=6.08e-07). This association was also present in the dominant carrier model (AA: 9.85 ng/ml ± 0.27 (n=645) vs AG/GG: 7.60ng/ml ± 0.84 (n=54/n=1), p=6.48e-05, F = 16.2). The association of TFC and the polymorphism rs10406324, corrected for Age, BMI and AMH, showed an inverse trend compared to serum AMH levels (?=-8.00, p=3.75e-03), however this result was not significant in the carrier model (AA: 42.2 ± 0.88 (n=645) vs AG/GG: 43.6 ± 2.41 (n=54/n=1), p=0.60, F = 0.281). Moreover, this SNP was not in LD with any other SNP in the selected region. The human AMH promoter polymorphism rs10406324 is associated with serum AMH levels in Caucasian PCOS women. Replication and functional analyses are necessary to further elucidate the mechanisms by which this SNP affects the AMH promoter activity.

SUBMITTER: Moolhuijsen L

PROVIDER: S-EPMC6550828 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Project description:BackgroundTo study whether AMH levels were associated with miscarriage rates in index ART cycles undergoing fresh autologous transfers in PCOS and non-PCOS related infertility.MethodsIn the SART CORS database 66,793 index cycles underwent fresh autologous embryo transfers with AMH values reported within the last 1-year between 2014 and 2016. Cycles that resulted in ectopic or heterotopic pregnancies, or were performed for embryo/oocyte banking were excluded. Data were analyzed using Graphpad Prism-9. Odds ratios (OR) were calculated with 95% confidence intervals (CI) along with multivariate regression analysis adjusting for age, body mass index (BMI), and number of embryos transferred. Miscarriage rates were calculated as miscarriage per clinical pregnancies.ResultsOf the total 66,793 cycles, the mean AMH was 3.2 ng/ml and were not associated with increased miscarriage rates for AMH < 1 ng/ml (OR 1.1, CI 0.9-1.4, p = 0.3). Of the 8,490 PCOS patients, the mean AMH was 6.1 ng/ml and were not associated with increased miscarriage rates for AMH < 1 ng/ml (OR 0.8, CI 0.5-1.1, p = 0.2). Of the 58,303 non-PCOS patients, the mean AMH was 2.8 ng/ml and there was a significant difference in miscarriage rates for AMH < 1 ng/ml (OR 1.2, CI 1.1-1.3, p < 0.01). All findings were independent of age, BMI and number of embryos transferred. This statistical significance did not persist at higher thresholds of AMH. The overall miscarriage rate for all cycles, and cycles with and without PCOS were each 16%.DiscussionThe clinical utility of AMH continues to increase as more studies investigate its predictive abilities regarding reproductive outcomes. This study adds clarity to the mixed findings of prior studies that have examined the relationship between AMH and miscarriage in ART cycles. AMH values of the PCOS population are higher than the non-PCOS. The elevated AMH associated with PCOS decreases its utility in predicting miscarriages in IVF cycles as it may be representing the number of developing follicles rather than oocyte quality in the PCOS patient population. The elevated AMH associated with PCOS may have skewed the data; removing this sub-population may have unmasked significance within the non-PCOS associated infertility.ConclusionsAMH < 1 ng/mL is an independent predictor of increased miscarriage rate in patients with non-PCOS infertility.

Project description:BackgroundObesity is a state of excess body fat accumulation, and appears to be closely associated with polycystic ovary syndrome (PCOS). Notably, plausible biological pathways through which obesity can regulate anti-Müllerian hormone (AMH) production have been proposed, and women with PCOS characteristically have an increased AMH level. Body fat accumulation can be described by body fat percentage (BFP). However, the relationship between BFP and AMH still remains unclear.Materials and methodsA total of 87 controls and 156 PCOS patients were divided into lean and overweight/obese groups, and the PCOS patients were further divided into hyper-AMH and normal-AMH subgroups. Univariate regression was used to assess the unadjusted relationship between AMH and outcome variables, multivariable regression analysis was performed to test whether and how serum AMH levels were associated with BFP after adjusting for other co-variables. Receiver-operating characteristic (ROC) curve analyses were used to test the utility of BFP for the diagnosis of PCOS.ResultsBFP was higher in PCOS patients compared with controls, regardless of obesity. Serum AMH levels were negatively associated with BFP in the PCOS group (r = -0.371; P < 0.001) but not in the control group (r = -0.095; P = 0.385). Multivariable logistic regression analysis showed that elevated BFP was associated with a high risk of PCOS (odds ratio, 1.290; 95% confidence interval, 1.084-1.534, P = 0.004). Furthermore, the combination of BFP and serum AMH into a multivariate model gave an improved area under the curve (AUC) of 88.5%, with a sensitivity of 72.4% and specificity of 87.4%; the positive and negative predictive values were 91.2% and 63.9%, respectively. One limitation of this study is all the conclusion reported was based on small sample size.ConclusionsHerein, we described the negative correlation between BFP and serum AMH levels for the first time, and the present results highlight the importance of further investigation into the role of BFP, especially in body fat-related AMH change as it relates to the underlying pathogenesis of PCOS.

Project description:Study questionWhat is the correlation of serum anti-Müllerian hormone (AMH) levels between two frequently used laboratory assays?Summary answerA considerable difference was found in serum AMH levels measured with the two different assays, particularly for low AMH values.What is known alreadyAMH is regarded as being a robust, highly sensitive and specific biomarker for ovarian response and has become widely used as the basis for fertility treatment decisions. However, several available assays with different reference values, in addition to inter-laboratory variations and issues of sample stability, make interpretation of the AMH values and their clinical implications complicated.Study design size durationAn observational study was performed including 269 serum samples from infertile women, originating from a RCT conducted in 2013-2016 (www.clinicaltrials.gov NCT02013973).Participants/materials setting methodSerum AMH levels analysed with the Modified Beckman Coulter Gen II ELISA assay (Premix method) were compared to AMH levels analysed with the Beckman Coulter Gen II ELISA original assay (Gen II original). All samples were handled identically and analysed with the two assays in a parallel setting.Main results and the role of chanceThe slope of the regression line showed a mean of 18% higher values with the Premix method compared to the Gen II original assay, and more than 40% higher values for AMH levels in the lower range.Limitations reasons for cautionThe Gen II original assay is no longer in clinical use as it has been replaced by the Premix method, which, in turn, recently has been further developed into an automated method.Wider implications of the findingsThe finding of differences in AMH levels between assays is clinically important and may imply an incorrect classification in the assessment of ovarian reserve. The robustness of serum AMH as a marker for ovarian reserve and as a tool for fertility counselling has to be investigated further. There is an urgent need for international standards on interpretation of AMH values for different assays.Study funding/competing interestsFinancial support was received through Sahlgrenska University Hospital (ALFGBG-70940) and the Hjalmar Svensson Research Foundation. None of the authors declares any conflict of interest.

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MON-208 Association Study of AMH Promoter Polymorphisms and Serum AMH Levels in PCOS Patients

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