Lipidomic profiling of endometrial fluid in women with ovarian endometriosis†

Domı́nguez, Francisco; Ferrando, Marcos; Díaz-Gimeno, Patricia; Quintana, Fernando; Fernández, Gemma Martínez; Castells, Inés; Simón, Carlos

doi:10.1093/biolre/iox014

Cited by 39 publications

(28 citation statements)

References 22 publications

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“…Our results show that functions such as metabolism and biosynthesis of steroids and lipids were enriched in oocytes from women with endometriosis compared to oocytes from healthy donors. Lipid dysregulation in serum (Dutta et al, 2016) and endometrial fluid (Domínguez et al, 2017) has been demonstrated in both mouse models and women with endometriosis, as well as altered steroidogenesis in human granulosa cells (GCs) (…”

Section: Discussionmentioning

confidence: 99%

Single-cell RNA sequencing of oocytes from ovarian endometriosis patients reveals a differential transcriptomic profile associated with lower quality

Ferrero

Corachán

Aguilar³

et al. 2019

Human Reproduction

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STUDY QUESTION Do oocytes from women with ovarian endometriosis (OE) have a different transcriptomic profile than those from healthy women? SUMMARY ANSWER Oocytes from endometriosis patients, independently of whether they came from the affected ovary, exhibited a differential transcriptomic profile compared to oocytes from healthy egg donors. WHAT IS KNOWN ALREADY Studies of endometriosis have sought to determine whether OE affects oocyte quality. While many reports indicate that oocytes recovered from endometriotic ovaries may be affected by the disease, other studies have found no significant differences among oocyte/embryo quality and fertilization, implantation and pregnancy rates in women with endometriosis. STUDY DESIGN, SIZE, DURATION This prospective study compared metaphase II (MII) oocytes (n = 16) from endometriosis patients (n = 7) to oocytes (n = 16) from healthy egg donors (n = 5) by single-cell RNA sequencing (scRNA-seq). Participants were recruited between December 2016 and February 2018 at IVI-RMA Valencia and Vigo clinics. PARTICIPANTS/MATERIALS, SETTING, METHODS Human MII oocytes were collected from healthy egg donors and OE patients aged 18–34 years, with a body mass index of <30 and >6 pre-antral follicles. RNA was extracted, cDNA was generated and libraries were constructed and sequenced. scRNA-seq data libraries were processed and statistically analysed. Selected genes were validated by quantitative real-time PCR. MAIN RESULTS AND THE ROLE OF CHANCE Our scRNA-seq results revealed an effect of endometriosis on global transcriptome behaviour in oocytes from endometriotic ovaries. The highest number of differentially expressed genes (DEGs) was found when oocytes from women with OE were compared to oocytes from healthy donors [520 DEGs (394 upregulated and 126 downregulated)], independently of whether oocytes came from an affected or unaffected ovary. Among the top 20 significant DEGs in this comparison, most were upregulated, including APOE, DUSP1, G0S2, H2AFZ, ID4, MGST1 and WEE1. PXK was the only downregulated gene. Subsequently, functional analysis showed 31 enriched functions deregulated in endometriosis patients (Benjamini P < 0.1), being 16 significant enriched functions considering Benjamini P < 0.05, which involved in biological processes and molecular functions, such as steroid metabolism, response to oxidative stress and cell growth regulation. In addition, our functional analysis showed enrichment for mitochondria, which are an important cellular component in oocyte development. Other functions important in embryo development, such as angiogenesis and methylation, were also significantly enriched. LARGE SCALE DATA All raw sequencing data are submitted in Gene Expression Omnibus (GEO) under accession number (PRJNA514416). LIMITATIONS, REASONS FOR CAUTION This study was restricted only to OE and thereby other anatomical entities, such as peritoneal and deep infiltrating endometriosis, were not considered. This is a descriptive study with a limited number of samples reflecting the difficulty to recruit human oocytes, especially from women with endometriosis. WIDER IMPLICATIONS OF THE FINDINGS This study suggests that OE exhibits a global transcriptomic effect on oocytes of patients in OE, independently if they come from an affected or unaffected ovary and alters key biological processes and molecular functions related to steroid metabolism, response to oxidative stress and cell growth regulation, which reduce oocyte quality. STUDY FUNDING/COMPETING INTEREST(S) This research was supported by IVI Foundation, the Spanish Ministry of Economy and Competitiveness through the Miguel Servet programme (CPII018/00002 to F.D.), the Sara Borrell Program (CD15/00057 to H.F.) and the VALi+d Programe (Generalitat Valenciana); ACIF/2016/444 to A.C.). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER None

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Section: Discussionmentioning

confidence: 99%

Single-cell RNA sequencing of oocytes from ovarian endometriosis patients reveals a differential transcriptomic profile associated with lower quality

Ferrero

Corachán

Aguilar³

et al. 2019

Human Reproduction

Self Cite

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“…Despite several studies on metabolomics in various diseases, use of this approach is still sparse in endometriosis 10 – 12 . NMR and MS based metabolomics studies on endometrial fluid 13 , follicular fluid 14 , urine 10 , serum 15 and plasma 16 of endometriosis women have shown remarkable changes in their metabolite profile. Since endometrial tissue communicates with the blood directly or through extracellular fluids, several metabolites may be secreted into the blood stream.…”

Section: Introductionmentioning

confidence: 99%

Metabolomics reveals perturbations in endometrium and serum of minimal and mild endometriosis

Dutta

Singh

Joshi

et al. 2018

Sci Rep

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Endometriosis is a common benign gynecological disease, characterized by growth and proliferation of endometrial glands and stroma outside the uterus. With studies showing metabolic changes in various biofluids of endometriosis women, we have set upon to investigate whether endometrial tissue show differences in their metabolic profiles. 1H NMR analysis was performed on eutopic endometrial tissue of women with endometriosis and controls. Analysis was performed on spectral data and on relative concentrations of metabolites obtained from spectra using multivariate and univariate data analysis. Analysis shows that various energy, ketogenic and glucogenic metabolites have significant altered concentrations in various stages of endometriosis. In addition, altered tissue metabolites in minimal and mild stages of endometriosis were explored in serum of these patients to assess their role in disease diagnosis. For Stage I diagnosis alanine was found to have 90% sensitivity (true positives) and 58% specificity (true negatives). For Stage II diagnosis alanine, leucine, lysine, proline and phenylalanine showed significant altered levels in serum. While sensitivity of these serum metabolites varied between 69.2–100% the specificity values ranged between 58.3–91.7%. Further, a regression model generated with this panel of serum markers showed an improved sensitivity and specificity of 100% and 83%, respectively for Stage II diagnosis.

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“…The model presented here revealed that triacylglycerol (TG) and α‐amino acids are metabolites overs abundant in patients presenting with endometriosis. Intriguingly, Domínguez et al (), found reduced levels of saturated diacylglycerols and saturated TGs in the endometrial fluid of patients with endometriosis when compared with controls. Excessive accumulation of TGs, however, is associated with human diseases such as obesity, diabetes mellitus, and steatohepatitis.…”

Section: Discussionmentioning

confidence: 96%

Metabolomic profile as a noninvasive adjunct tool for the diagnosis of Grades III and IV endometriosis‐related infertility

Braga

Montani

Setti

et al. 2019

Molecular Reproduction Devel

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The aim of the present case‐control study was to develop a noninvasive adjuvant tool for the diagnosis of endometriosis. Serum samples from 100 patients undergoing intracytoplasmic sperm injection were split into two groups according to the cause of infertility: an endometriosis group (n = 50), consisting of samples derived from patients with Grade III and IV endometriosis, and a control group (n = 50), comprising samples derived from patients with isolated male factor infertility. The metabolomic profile of each sample was obtained, through mass spectrometry. Partial least squares discriminant analysis was able to clearly classify the endometriosis and control groups. Ten potential biomarkers were selected based on their importance for model prediction. These ions were used to build the receiver‐operating characteristic curve, which presented an area under the curve of 0.904 (95% confidence interval: 0.796–0.985). To validate the model, 30 other samples from infertile women without any evidence of endometriosis were tested. Considering these ions as possible biomarkers, the model was able to correctly classify 84% of the patients. Finally, a similar prediction potential was observed in the model validated set, when samples from the disease‐free group were tested. Serum metabolomics may be useful as a noninvasive adjunct tool for the selection of patients who must undergo laparoscopy for definitive endometriosis diagnosis.

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Lipidomic profiling of endometrial fluid in women with ovarian endometriosis†

Cited by 39 publications

References 22 publications

Single-cell RNA sequencing of oocytes from ovarian endometriosis patients reveals a differential transcriptomic profile associated with lower quality

Single-cell RNA sequencing of oocytes from ovarian endometriosis patients reveals a differential transcriptomic profile associated with lower quality

Metabolomics reveals perturbations in endometrium and serum of minimal and mild endometriosis

Metabolomic profile as a noninvasive adjunct tool for the diagnosis of Grades III and IV endometriosis‐related infertility

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