Study question Does the D19S884 allele 8 (A8) equally affect the pathogenesis and ovarian gene expression of PCOS and PCOM patients? Summary answer A8-allele produces metabolic, endocrine, and ovarian alterations regardless diagnose. The mechanisms involved in PCOM alterations are different from those of the ovarian phenotype of PCOS. What is known already The specific D19S884 allele 8 of the FBN3 gene may be related to polycystic ovarian syndrome (PCOS) clinical manifestations. The A8 allele participates in alternative splicing of FBN3 and produces Asprosin-3, related to glucose modulation, and Fibrillin-3. Fibrilin-3 is an extracellular matrix protein, and together with a dysregulation of the Hippo pathway, could be responsible for constraining follicular growth in the PCOS ovaries. However, it is still unknown how these pathways act in PCOS, and whether these mechanisms are also involved in pathophysiology of polycystic ovarian morphology (PCOM) in apparently normal women with regular menses. Study design, size, duration Cross-sectional and descriptive study with 139 women (24-39 years-old) undergoing an IVF cycle between 2019-2022 at Hospital La Fe (Valencia, Spain). Thirty-one patients were considered PCOS, twenty-eight were classified as PCOM while the remaining eighty were controls. After recruitment women were screened for A8 allele, metabolic status, hormone profile, follicular fluid protein determination and expression of Hippo pathway and extracellular matrix genes. The IVF cycle parameters were recorded to determine their relationship with study variables. Participants/materials, setting, methods Women with two or more Rotterdam-criteria were considered as PCOS. PCOM patients were defined by polycystic ovarian morphology on ultrasound with regular ovulatory cycles. Genomic DNA was isolated from blood samples to assess the presence of A8 allele by capillary electrophoresis and FBN3 concentration was measured on follicular fluid by ELISA. TaqMan qPCR assay was used to analyze the expression of Hippo pathway (BIRC1 and CCN2) and extracellular matrix (ECM) genes in cumulus cells. Main results and the role of chance PCOS patients showed statistically significant metabolic and endocrine alterations with higher BMI, free androgen index (FAI), and glucose levels compared to controls. Despite having increased AMH levels (PCOS:45.0±21.7; PCOM:33.8±21.5; Control:17.6±7.19pmol/L, p < 0.05), and AMH/AFC ratio (PCOS:1.9±0.9; Control:1.2±0.5, p = 0.008), PCOS showed lower fertilization rates (PCOS:64±26; Control:80±18%, p = 0.008), reduced good quality (PCOS:0.6±1.0; Control:1.3±1, p = 0.003) and transferred embryos (PCOS:1.3±0.9; Control:1.9±1.0, p = 0.018). In PCOM, metabolic and androgen profiles were not different from controls. Although AMH, AFC (PCOM:24.4±13.7; Control:15.5±7.1, p = 0.007) and aspirated follicles (PCOM:17.3±5.7; Control:14.3±7.0, p = 0.026) were increased, fewer embryos were transferred (PCOM:1.2±1.1; Control:1.9±1.0, p = 0.027). PCOM women also showed ovarian downregulation of the Hippo-pathway (CCN2-PCOM:-4.8±10.8; Control:0.1±3.0, p = 0.010) and increased FBN3 concentration (PCOM:19.6±8.8; Control:14.7±5.6ng/ml, p=N.S). The A8 allele was detected in 17% of our patients: 4% PCOS, 50% PCOM and 46% controls. Overall, A8 presence associated a Hippo-pathway downregulation (BIRC1-A8+:-2.7±4.5; A8-:0.3±2.2, p = 0.034) and increased ECM expression (EMILIN1-A8+:2.1±1.0; A8-:1.2±1.5, p = 0.04). Interestingly, in controls, higher glucose (A8+:95.1±6.7; A8-:83.5±10.1mg/dl, p = 0.002), cholesterol (A8+:182.5±11.1; A8-:165.4±27.3mg/dl, p = 0.029), LDL (A8+:117.8±10.4; A8-:83.9±29.4mg/dl, p = 0.002), and DHEAS levels (A8+:2633.0±670.7; A8-:1585.8±670.0ng/ml, p = 0.026) were found, consistent with a reduction in HDL (A8+:51.8±8.8; A8-:67.4±15.43mg/dl, p = 0.026) and a downregulation of the Hippo-pathway (BIRC1-A8+:-4.8±4.6; A8-:0.2±4.6, p = 0.013). In PCOM, A8+ promoted higher FAI (A8+:1.6±1.5; A8-:0.8±0.7, p=N.S), and less embryos obtained (A8+:5.9±3.8; A8-:10.7±3.8, p = 0.04). Limitations, reasons for caution Due to the low prevalence of A8 in our PCOS population, its effects cannot be evaluated in this group. Further validation of gene expression results by RNA-seq will be required to assess the broad spectrum of ovarian transcriptomic changes induced by both, the PCOM phenotype and the A8 allele. Wider implications of the findings Polycystic ovarian morphology is not unique to clinical disorder of PCOS and the triggering mechanisms appear to be distinct from those observed in women with regular cycles. Our findings suggest that the presence of A8 allele impacts on metabolic profile, androgen levels, and ovarian pathway dysregulations, despite the clinical diagnose. Trial registration number Not applicable
Study question Does exist a correlation between the presence of D19S884 allele 8 (A8) and Hippo pathway dysregulation with the metabolic and ovarian PCOS profiles? Summary answer The presence of the A8 allele affects insulin resistance and hyperandrogenism. Moreover, PCOS ovarian phenotype could be related to a dysregulation of Hippo pathway genes. What is known already The specific D19S884 A8 allele of the FBN3 gene has been associated with an increased probability of polycystic ovarian syndrome (PCOS). D19S884 participates in FBN3 alternative splicing and produces Asprosin-3 and Fibrilin-3 proteins that may be related to PCOS clinical manifestations. Asprosin-3 has been recently identified as a glucose modulator and could be related to metabolic profiles of PCOS. Fibrilin-3 is an extracellular matrix protein, and together with a dysregulation of the Hippo pathway, could be responsible for constraining follicular growth in the PCOS ovaries. Study design, size, duration Descriptive and cross-sectional study with 93 women (25-37 years old) undergoing an IVF cycle between 2019 and 2021 at Hospital la Fe (Valencia, Spain). Thirty patients were considered PCOS while the remaining sixty-three were non-PCOS controls. After recruitment women were screened for A8 allele, metabolic status, hormone profile and Hippo pathway genes. The IVF cycle parameters were recorded to determine their relationship with study variables. Participants/materials, setting, methods Patients with two or more Rotterdam-criteria or with polycystic ovarian morphology (PCOM) were considered as PCOS. After signed informed consent, blood samples and cumulus cells were obtained at egg retrieval. Hormone and metabolic parameters were analyzed and the homeostasis model assessment of insulin resistance (HOMA-IR) established. Genomic DNA was isolated to assess the presence of A8 allele by capillary electrophoresis. The expression of Hippo pathway genes, BIRC1 and CCN2, was analyzed by Taqman qPCR assay. Main results and the role of chance PCOS patients showed increased body mass index (Control:23.2±3.7; PCOS:25.3±4.5, p = 0.04) antimüllerian hormone levels (Control:17.7±7.7pmol/L; PCOS:39.7±22.9pmol/L, p = 0.00), antral follicle count (Control:15±7; PCOS:27±13, p = 0.001) and a reduced number of good quality embryos (Control:1.3±0.9; PCOS:0.8±1.0, p = 0.02). The A8 allele was detected in 15% of the recruited patients, with a 13% incidence in controls and 19% in PCOS. Interestingly, PCOS A8+ patients presented the PCOM phenotype. Women with the A8 allele (A8+) showed higher DHEAS levels (A8-:1899.7±1256.9; A8+:2642.5±555.2, p = 0.046) and free androgen index (A8-:1.1±0.8; A8+:2.0±1.2, p = 0.046) when compared to A8- ones. Similar results were obtained when the comparison was made according to clinical diagnose (Control A8+ vs. Control A8- and PCOS A8+ vs PCOS A8-). Moreover, the overall A8+ patients associated an increase in glucose levels (A8-:85.7±10.9mg/dL; A8+:93.0±6.01mg/dL, p = 0.02) and HOMA-IR (A8-:1.7±1.1; A8+:2.5±1.2). These metabolic findings were observed in control women with the allele but not in PCOS. The PCOS group showed a downregulation of CCN2 (Fold-change (FC): -3.8±9.1, p = 0.02) in cumulus cells. Interestingly, those women with the A8 allele showed downregulated BIRC1 levels (FC A8+: -2.7±4.8 and A8-: 0.2±2.7; p = 0.04). These gene dysregulations could be related with a deficient oocyte-cumulus communication, abnormal follicular growth and an ovarian stroma stiffness alteration. Limitations, reasons for caution These promising results need to be confirmed in a larger population of PCOS to allow validation of the observed effects according to PCOS sub-phenotypes. Moreover, transcriptomic analysis and functional enrichment assays should be carried out to clarify the contribution of Hippo pathway and A8 allele to PCOS pathogenesis. Wider implications of the findings The obtained results suggest that the presence of the A8 allele influences the metabolic profile related to insulin resistance and androgen levels, as well as the activation status of Hippo pathway. Moreover, this signaling pathway seems to be dysregulated in PCOS patients, suggesting its possible role in the ovarian phenotype. Trial registration number Not applicable
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