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Differential regulation of osteopontin and CD44 correlates with infertility status in PCOS patients.

ABSTRACT: Endometrial receptivity is mediated by adhesion molecules at the endometrium-trophoblast interface where osteopontin (OPN) and CD44 form a protein complex that plays an important role in embryo recognition. Here, we undertook a prospective study investigating the expression and regulation of OPN and CD44 in 50 fertile and 31 infertile ovulatory polycystic ovarian syndrome (PCOS) patients in the proliferative and secretory phases of the natural menstrual cycle and in 12 infertile anovulatory PCOS patients. Endometrial biopsies and blood samples were evaluated for expression of OPN and CD44 using RT-PCR, immunohistochemistry and ELISA analysis to determine circulating levels of OPN, CD44, TNF-?, IFN-? and OPN and CD44 levels in biopsy media. Our findings highlighted an increased level of circulating OPN and CD44 in serum from infertile patients that inversely correlated with expression levels in endometrial tissue and positively correlated with levels secreted into biopsy media. OPN and CD44 levels positively correlated to each other in serum and media from fertile and PCOS patients, as well as to circulating TNF-? and IFN-?. In vitro analysis revealed that hormone treatment induced recruitment of ER? to the OPN and CD44 promoters with a concomitant increase in the expression of these genes. In infertile patients, inflammatory cytokines led to recruitment of NF-?B and STAT1 proteins to the OPN and CD44 promoters, resulting in their overexpression. These observations suggest that the endometrial epithelial OPN-CD44 adhesion complex is deficient in ovulatory PCOS patients and displays an altered stoichiometry in anovulatory patients, which in both cases may perturb apposition. This, together with elevated circulating and local secreted levels of these proteins, may hinder endometrium-trophoblast interactions by saturating OPN and CD44 receptors on the surface of the blastocyst, thereby contributing to the infertility associated with ovulating PCOS patients. KEY MESSAGES: • Endometrial epithelial OPN-CD44 adhesion complex levels are deficient in ovulatory PCOS patients contributing to the endometrial infertility associated with ovulating PCOS patients. • Circulating levels of OPN, CD44 and inflammatory cytokines TNF-? and IFN-? are altered in infertile PCOS patients. • Increased levels of both OPN and CD44 in biopsy media and serum inversely correlate with endometrial expression of these markers in endometrial tissue. • In infertile PCOS patients, high levels of oestrogens and inflammatory cytokines stimulate the recruitment of transcription factors to the OPN and CD44 promoters to enhance gene transcription. • Our study identifies a novel crosstalk between the CD44-OPN adhesion complex, ER?, STAT1 and NF-?B pathways modulating endometrial receptivity.

SUBMITTER: Paravati R

PROVIDER: S-EPMC7679339 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Differential regulation of osteopontin and CD44 correlates with infertility status in PCOS patients.

Paravati R R De Mello N N Onyido E K EK Francis L W LW Brüsehafer K K Younas K K Spencer-Harty S S Conlan R S RS Gonzalez D D Margarit Lavinia L

Journal of molecular medicine (Berlin, Germany) 20201013 12

Endometrial receptivity is mediated by adhesion molecules at the endometrium-trophoblast interface where osteopontin (OPN) and CD44 form a protein complex that plays an important role in embryo recognition. Here, we undertook a prospective study investigating the expression and regulation of OPN and CD44 in 50 fertile and 31 infertile ovulatory polycystic ovarian syndrome (PCOS) patients in the proliferative and secretory phases of the natural menstrual cycle and in 12 infertile anovulatory PCOS ...[more]

PMID: 33047155

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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.

Dataset Information

Differential regulation of osteopontin and CD44 correlates with infertility status in PCOS patients.

Publications

Differential regulation of osteopontin and CD44 correlates with infertility status in PCOS patients.

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