Anti-Mullerian hormone gene polymorphism is associated with androgen levels in Chinese polycystic ovary syndrome patients with insulin resistance.
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ABSTRACT: Purpose
The objective of the study was to investigate whether genetic polymorphisms of the anti-Müllerian hormone (AMH) and its specific receptor anti-Müllerian hormone type II receptor (AMHRII) were associated with the hormone disorder and phenotype of polycystic ovary syndrome (PCOS).Methods
This case-control study included 141 PCOS patients and 123 normal women. Two polymorphisms of AMH and AMHRII and the clinical characteristics of participants such as body mass index (BMI), serum luteinizing hormone (LH), estradiol levels (E2), total testosterone levels (T), and homeostasis model assessment of insulin resistance (HOMA-IR) were analyzed with the case-control sample. Gene-gene interactions of AMH and AMHRII genes were analyzed based multifactor-dimensionality reduction method.Results
A significant difference of AMH gene polymorphisms were observed in IR-PCOS women and controls. The AMH and AMHRII gene polymorphisms were not found a significant difference in non-IR-PCOS and normal groups. To IR-PCOS women, genotypes of AMH were closely related to the serum levels of LH (P?=?0.000), testosterone (P?=?0.000) and HOMA-IR (P?=?0.038), while in the non-IR-PCOS and normal groups, no relationship was found. No impact of AMH and AMHRII gene-gene interactions was demonstrated.Conclusions
Our research suggests that the diversity of AMH genotypes in the AMH signal pathway may be connected with the susceptibility and phenotype of PCOS with insulin resistance.
SUBMITTER: Zheng MX
PROVIDER: S-EPMC4759001 | biostudies-literature | 2016 Feb
REPOSITORIES: biostudies-literature
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Project description:Context:Polycystic ovary syndrome (PCOS), a common endocrine condition, is the leading cause of anovulatory infertility. Objective:Given that common disease-susceptibility variants account for only a small percentage of the estimated PCOS heritability, we tested the hypothesis that rare variants contribute to this deficit in heritability. Design, Setting, and Participants:Unbiased whole-genome sequencing (WGS) of 80 patients with PCOS and 24 reproductively normal control subjects identified potentially deleterious variants in AMH, the gene encoding anti-Müllerian hormone (AMH). Targeted sequencing of AMH of 643 patients with PCOS and 153 control patients was used to replicate WGS findings. Main Outcome Measures:Dual luciferase reporter assays measured the impact of the variants on downstream AMH signaling. Results:We found 24 rare (minor allele frequency < 0.01) AMH variants in patients with PCOS and control subjects; 18 variants were specific to women with PCOS. Seventeen of 18 (94%) PCOS-specific variants had significantly reduced AMH signaling, whereas none of 6 variants observed in control subjects showed significant defects in signaling. Thus, we identified rare AMH coding variants that reduced AMH-mediated signaling in a subset of patients with PCOS. Conclusion:To our knowledge, this study is the first to identify rare genetic variants associated with a common PCOS phenotype. Our findings suggest decreased AMH signaling as a mechanism for the pathogenesis of PCOS. AMH decreases androgen biosynthesis by inhibiting CYP17 activity; a potential mechanism of action for AMH variants in PCOS, therefore, is to increase androgen biosynthesis due to decreased AMH-mediated inhibition of CYP17 activity.
| S-EPMC5546867 | biostudies-literature
Project description:ObjectiveWe intended to establish the threshold for anti-Mullerian hormone (AMH) in the diagnosis of polycystic ovary syndrome (PCOS) in China.MethodsA total of 771 women (653 with PCOS and 118 healthy controls) were enrolled. The serum AMH, follicle-stimulating hormone (FSH), luteinizing hormone (LH), FSH/LH, prolactin, estradiol, testosterone (T), dehydroepiandrosterone sulfate (DHEA-S), sex hormone-binding globulin (SHBG), 17?-OH progesterone (17?-OHP), fasting insulin (INS), fasting glucose, free androgen index (FAI%) and homeostasis model assessment for insulin resistance (HOMA-IR) index were analyzed, and the diagnostic utility of AMH, LH/FSH, T and INS was established using receiver operator characteristic (ROC) curves. With AMH, LH/FSH, T and INS as independent variables, a logistic regression model was established, and the ROC curve for combined detection was fitted with the probability value of the model.ResultsThe serum level of FSH, LH, LH/FSH, AMH, FAI%, 17?-OHP, fasting INS, T, SHBG, DHEA-S and HOMA-IR were altered in the PCOS patients. The best compromise between sensitivity and specificity was found at an AMH cut-off level of 8.16 ng/ml and 5.89 ng/ml for the age groups 20-29 and 30-39 years, with the corresponding area under the curve being 0.846 and 0.865 respectively. The area under the ROC curve for combined detection was 0.951, which was significantly greater than that of each index. Finally, the concentration of AMH was associated with FSH, LH, LH/FSH, T, and ovarian volume in PCOS patients.ConclusionThe optimal AMH diagnostic threshold for PCOS was 8.16 ng/ml (20-29 years) and 5.89 ng/ml (30-39 years) in the Chinese population of this study. Moreover, serum AMH, LH/FSH, T and INS could be used in combination to improve the diagnostic specificity and sensitivity for the detection of PCOS.
| S-EPMC6112651 | biostudies-literature
Project description:ContextThe polycystic ovary syndrome (PCOS) is a common and complex disease without a clear pattern of inheritance. Anti-Müllerian hormone (AMH) has an inhibitory effect on FSH-stimulated follicle growth. Serum AMH levels are higher in women with PCOS than in normo-ovulatory women. The elevated AMH levels may reflect abnormalities in AMH signaling.ObjectiveThe purpose of this study was to evaluate the association of the anti-Müllerian hormone receptor 2 (AMHR2) -482 A>G polymorphism (rs2002555) with the pathophysiology of PCOS.DesignAMHR2 -482 A>G polymorphism genotyping were performed in a large cohort of women with PCOS and in a healthy control group.Setting/subjectsA total of 858 Caucasian Greek women with PCOS and 309 healthy control women were studied.InterventionsGenotyping and hormonal measurements were preformed.Main outcome measuresHormone levels in women with PCOS were analyzed.ResultsThe AMHR2 polymorphism was more common in women with PCOS than in control women (P = .026). Homozygous AMHR2 -482 A>G gene polymorphisms (GG) were associated with decreased levels of LH (P = .003) and lower LH to FSH ratios (P = .01) in women with PCOS, as well as with lower prolactin levels (P = .004). No other associations related to AMHR2 -482 A>G polymorphisms were observed in women with PCOS or control women.ConclusionIn this study, the role of the AMHR2 -482 A>G gene polymorphism in the pathogenesis of PCOS was suggested by the association of the variant with PCOS risk. Thus, further research is needed to elucidate a possible association of the AMHR2 -482 A>G gene polymorphism with AMH signaling and impaired ovarian function and its clinical significance in women with PCOS.
| S-EPMC5399526 | biostudies-literature
Project description:Background:Various endocrine disorders have been reported in women of reproductive age, 10% of which is affected by polycystic ovary syndrome (PCOS). Objective:This study aimed to evaluate the correlation of anti-Müllerian hormone (AMH) levels with the metabolic syndrome in patients with PCOS. Materials and Methods:This cross-sectional study employed a consecutive sampling method using medical records from January 2013 to December 2017 at Dr. Cipto Mangunkusumo General Hospital polyclinic and Yasmin in vitro fertilization Clinic (Kencana), Jakarta, Indonesia. The primary outcome of the study was the AMH levels as independent variable correlated with metabolic syndrome. The secondary outcome was also the AMH levels correlated with each PCOS phenotype. The tertiary outcome was each PCOS phenotype as independent variable correlated with metabolic syndrome. Results:Women with phenotype 1 of PCOS had a median AMH level of 13.92 (range: 3.88-34.06) ng/ml. 21% patients had metabolic syndrome, with a median AMH level 7.65 (3.77-20.20) ng/ml, higher than the women without metabolic syndrome (p = 0.38). The most frequent phenotype in women with PCOS was phenotype 4, oligo- or anovulation and polycystic ovary morphology (OA/PCOM) in 41.3%. The most frequent phenotype in women with metabolic syndrome was phenotype 1, OA + PCOM + hyperandrogenism in 56.5%. Conclusion:All PCOS phenotypes exhibited significant correlations with the AMH level. Phenotype 1 (OA + PCOM + hyperandrogenism) was associated with the highest AMH level and was significantly associated with metabolic syndrome.
| S-EPMC7142316 | biostudies-literature
Project description:BackgroundThe majority of available studies on the AMH thresholds were not age-specific and performed the receiver operating characteristic curve (ROC) analysis, based on variations in sensitivity and specificity rather than positive and negative predictive values (PPV and NPV, respectively), which are more clinically applicable. Moreover, all of these studies used a pre-specified age categorization to report the age-specific cut-off values of AMH.MethodsA total of 803 women, including 303 PCOS patients and 500 eumenorrheic non-hirsute control women, were enrolled in the present study. The PCOS group included PCOS women, aged 20-40 years, who were referred to the Reproductive Endocrinology Research Center, Tehran, Iran. The Rotterdam consensus criteria were used for diagnosis of PCOS. The control group was selected among women, aged 20-40 years, who participated in Tehran Lipid and Glucose cohort Study (TLGS). Generalized additive models (GAMs) were used to identify the optimal cut-off points for various age categories. The cut-off levels of AMH in different age categories were estimated, using the Bayesian method.Main results and the role of chanceTwo optimal cut-off levels of AMH (ng/ml) were identified at the age of 27 and 35 years, based on GAMs. The cut-off levels for the prediction of PCOS in the age categories of 20-27, 27-35, and 35-40 years were 5.7 (95 % CI: 5.48-6.19), 4.55 (95 % CI: 4.52-4.64), and 3.72 (95 % CI: 3.55-3.80), respectively. Based on the Bayesian method, the PPV and NPV of these cut-off levels were as follows: PPV = 0.98 (95 % CI: 0.96-0.99) and NPV = 0.40 (95 % CI: 0.30-0.51) for the age group of 20-27 years; PPV = 0.96 (95 % CI: 0.91-0.99) and NPV = 0.82 (95 % CI: 0.78-0.86) for the age group of 27-35 years; and PPV = 0.86 (95 % CI: 0.80-0.94) and NPV = 0.96 (95 % CI: 0.93-0.98) for the age group of 35-40 years.ConclusionsApplication of age-specific cut-off levels of AMH, according to the GAMs and Bayesian method, could elegantly assess the value of AMH in discriminating PCOS patients in all age categories.
| S-EPMC8140506 | biostudies-literature
Project description:Background/aimsAlthough increased serum anti-Müllerian hormone (AMH) level has been suggested to be a surrogate marker of polycystic ovarian morphology (PCOM), its association with polycystic ovary syndrome (PCOS) is controversial, and its diagnostic value has not been determined. We aimed to observe the relationship between the AMH level and PCOS phenotypes and to determine the optimal cutoff value of AMH for the diagnosis of PCOS in young Korean women.MethodsWe recruited 207 women with PCOS (120 with PCOM and 87 without PCOM) and 220 regular cycling women with normoandrogenemia (100 with PCOM and 120 without PCOM). Subjects underwent testing at a single outpatient visit. Serum AMH level was measured.ResultsWomen with PCOS had higher serum AMH levels than did regular cycling women with normoandrogenemia (p < 0.05). Women with PCOM had higher serum AMH levels than women without PCOM, regardless of PCOS status (p < 0.05). The optimal AMH cutoff value for the diagnosis of PCOS was 10.0 ng/mL (71% sensitivity, 93% specificity). Serum AMH was an independent determinant of total testosterone after adjustment for age, body mass index, and the number of menses/year (β = 0.31, p < 0.01). An association between AMH and hyperandrogenism was only observed in women with PCOS, and it was independent of the presence of PCOM.ConclusionThe serum AMH level can be useful for the diagnosis of PCOS at any age less than 40 years, and the optimal cutoff value for the diagnosis of PCOS identified in this study of young Korean women was 10.0 ng/mL.
| S-EPMC5511935 | biostudies-literature
Project description:BackgroundPolycystic ovary syndrome (PCOS) is the most common reproductive-endocrine disorder affecting between 5 and 18% of women worldwide. An elevated frequency of pulsatile luteinizing hormone (LH) secretion and higher serum levels of anti-Müllerian hormone (AMH) are frequently observed in women with PCOS. The origin of these abnormalities is, however, not well understood.MethodsWe studied brain structure and function in women with and without PCOS using proton magnetic resonance spectroscopy (MRS) and diffusion tensor imaging combined with fiber tractography. Then, using a mouse model of PCOS, we investigated by electron microscopy whether AMH played a role on the regulation of hypothalamic structural plasticity.FindingsIncreased AMH serum levels are associated with increased hypothalamic activity/axonal-glial signalling in PCOS patients. Furthermore, we demonstrate that AMH promotes profound micro-structural changes in the murine hypothalamic median eminence (ME), creating a permissive environment for GnRH secretion. These include the retraction of the processes of specialized AMH-sensitive ependymo-glial cells called tanycytes, allowing more GnRH neuron terminals to approach ME blood capillaries both during the run-up to ovulation and in a mouse model of PCOS.InterpretationWe uncovered a central function for AMH in the regulation of fertility by remodeling GnRH terminals and their tanycytic sheaths, and provided insights into the pivotal role of the brain in the establishment and maintenance of neuroendocrine dysfunction in PCOS.FundingINSERM (U1172), European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement n° 725149), CHU de Lille, France (Bonus H).
| S-EPMC10070524 | biostudies-literature
Project description:Polycystic ovary syndrome (PCOS) is the main cause of female infertility worldwide and corresponds with a high degree of comorbidities and economic burden. How PCOS is passed on from one generation to the next is not clear, but it may be a developmental condition. Most women with PCOS exhibit higher levels of circulating luteinizing hormone, suggestive of heightened gonadotropin-releasing hormone (GnRH) release, and anti-Müllerian hormone (AMH) as compared to healthy women. Excess AMH in utero may affect the development of the female fetus. However, as AMH levels drop during pregnancy in women with normal fertility, it was unclear whether their levels were also elevated in pregnant women with PCOS. Here we measured AMH in a cohort of pregnant women with PCOS and control pregnant women and found that AMH is significantly more elevated in the former group versus the latter. To determine whether the elevation of AMH during pregnancy in women with PCOS is a bystander effect or a driver of the condition in the offspring, we modeled our clinical findings by treating pregnant mice with AMH and followed the neuroendocrine phenotype of their female progeny postnatally. This treatment resulted in maternal neuroendocrine-driven testosterone excess and diminished placental metabolism of testosterone to estradiol, resulting in a masculinization of the exposed female fetus and a PCOS-like reproductive and neuroendocrine phenotype in adulthood. We found that the affected females had persistently hyperactivated GnRH neurons and that GnRH antagonist treatment in the adult female offspring restored their neuroendocrine phenotype to a normal state. These findings highlight a critical role for excess prenatal AMH exposure and subsequent aberrant GnRH receptor signaling in the neuroendocrine dysfunctions of PCOS, while offering a new potential therapeutic avenue to treat the condition during adulthood.
| S-EPMC6098696 | biostudies-literature
Project description:ContextPolycystic ovary syndrome (PCOS) is a highly heritable, common endocrine disorder characterized by hyperandrogenism, irregular menses, and polycystic ovaries. PCOS is often accompanied by elevated levels of anti-Müllerian hormone (AMH). AMH inhibits follicle maturation. AMH also inhibits steroidogenesis through transcriptional repression of CYP17A1. We recently identified 16 rare PCOS-specific pathogenic variants in AMH.ObjectiveTo test whether additional members of the AMH signaling pathway also contribute to the etiology of PCOS.Participants/designTargeted resequencing of coding and regulatory regions of AMH and its specific type 2 receptor, AMHR2, was performed on 608 women affected with PCOS and 142 reproductively normal control women. Prediction tools of deleteriousness and in silico evidence of epigenetic modification were used to prioritize variants for functional evaluation. Dual-luciferase reporter assays and splicing assays were used to measure the impact of genetic variants on function.ResultsWe identified 20 additional variants in/near AMH and AMHR2 with significantly reduced signaling activity in in vitro assays. Collectively, from our previous study and as reported herein, we have identified a total of 37 variants with impaired activity in/near AMH and AMHR2 in 41 women affected with PCOS, or 6.7% of our PCOS cohort. Furthermore, no functional variants were observed in the 142 phenotyped controls. The functional variants were significantly associated with PCOS in our cohort of 608 women with PCOS and 142 controls (P = 2.3 × 10-5) and very strongly associated with PCOS relative to a larger non-Finnish European (gnomAD) population-based control cohort (P < 1 × 10-9).ConclusionThe AMH signaling cascade plays an important role in PCOS etiology.
| S-EPMC6543512 | biostudies-literature
Project description:Objective To analyze whether metformin treatment in patients with polycystic ovary syndrome (PCOS) results in a decrease of anti-Müllerian hormone (AMH) levels, we reviewed and analyzed PCOS studies which evaluated serum AMH levels before and after metformin treatment. Methods This is a systematic review and meta-analysis of self-controlled clinical trials. Databases including PubMed, Embase, and Web of Science library were searched to identify eligible studies published before February 2023. Random-effects models were applied to assess standardized mean differences (SMDs) with 95% confidence intervals (95% CI). Results The electronic-based search retrieved 167 articles of which 14 studies (12 publications) involving 257 women with PCOS were included. In general, AMH levels decreased significantly after metformin treatment [SMD (95% CI) of -0.70 (-1.13 to -0.28); P = 0.001]. Metformin exhibited a strong inhibitory effect on AMH levels for PCOS patients with age less than 28 [SMD − 1.24, 95% CI − 2.15 to − 0.32, P = 0.008]. Additionally, AMH levels significantly slid down in PCOS patients with no more than 6 months metformin treatment [SMD − 1.38, 95% CI − 2.18 to − 0.58, P = 0.0007], or with no more than a dose of 2000 mg/day [SMD -0.70, 95% CI -1.11 to -0.28; P = 0.001]. Notably, suppressive effects of metformin treatment were merely observed in patients with AMH levels at baseline higher than 4.7 ng/ml [SMD − 0.66, 95% CI − 1.02 to − 0.31, P = 0.0003]. Conclusion This meta-analysis provided quantitative evidence demonstrating that metformin significantly decreased AMH levels, especially for young patients and those with AMH levels at baseline higher than 4.7 ng/ml. Trial registration PROSPERO CRD42020149182. Supplementary Information The online version contains supplementary material available at 10.1186/s13048-023-01195-1.
| S-EPMC10303859 | biostudies-literature