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Endometriosis is a leading cause of pain and infertility affecting millions of women globally. Herein, we characterize variation in DNA methylation (DNAm) and its association with menstrual cycle phase, endometriosis, and genetic variants through analysis of genotype data and methylation in endometrial samples from 984 deeply-phenotyped participants. We estimate that 15.4% of the variation in endometriosis is captured by DNAm and identify significant differences in DNAm profiles associated with stage III/IV endometriosis, endometriosis sub-phenotypes and menstrual cycle phase, including opening of the window for embryo implantation. Menstrual cycle phase was a major source of DNAm variation suggesting cellular and hormonally-driven changes across the cycle can regulate genes and pathways responsible for endometrial physiology and function. DNAm quantitative trait locus (mQTL) analysis identified 118,185 independent cis-mQTLs including 51 associated with risk of endometriosis, highlighting candidate genes contributing to disease risk. Our work provides functional evidence for epigenetic targets contributing to endometriosis risk and pathogenesis. Data generated serve as a valuable resource for understanding tissue-specific effects of methylation on endometrial biology in health and disease.

The endometrium is a complex multicellular tissue that is exqui sitely sensitive to the actions of sex steroids synthesised in the ovary (endocrine sys tem). Recent studies have highlighted a previously under-appreciated role for local (intracrine) metabolism in fine-tuning tissue function in both health and disease. In th is review we have focused on the impact of oestrogens and androgens on endometrial functi on summarising data from studies on normal endometrial physiology and disorder s including infertility, endometriosis and cancer. We consider the evidence that express ion of enzymes including aromatase, sulphatase and AKR1C3 by endometrial cells plays an important role in tissue function and malfunction and discuss results fro m studies using drugs targeting intracrine pathways to treat endometrial disorders. W e summarise studies exploring the spatial and temporal expression of oestrogen rece ptors (ERalpha/ESR1, ERbeta/ESR2 and GPER) and their role in mediating the impact of endogenous and synthetic ligands on cross-talk between vascular, immune, epith elial and stromal cells. There is a single androgen receptor gene and androgens play a k ey role in stromalepithelial cross-talk, scar-free healing of endometrium during menstruation and regulation of cell proliferation. The development of new recept or-selective drugs (SERMs, SARMs, SARDs) has reinvigorated interest in targeting receptor subtypes in treatment of disorders including endometriosis and endometrial cancer and so me show promise as novel therapies. In summary, understanding the mechanisms regul ated by sex steroids provides the platform for improved personalised treatment of en dometrial disorders as well as novel insights into the impact of steroids on processes such as tissue repair and regeneration. [ABSTRACT FROM AUTHOR]

Peripheral tissue metabolism of steroids (intracrinology) is now accepted as a key way in which tissues, such as the endometrium, can utilise inactive steroids present in the blood to respond to local physiological demands and 'fine-tune' the activation or inhibition of steroid hormone receptor-dependent processes. Expression of enzymes that play a critical role in the activation and inactivation of bioactive oestrogens (E1, E2) and androgens (A4, T, DHT), as well as expression of steroid hormone receptors, has been detected in endometrial tissues and cells recovered during the menstrual cycle. There is robust evidence that increased expression of aromatase is important for creating a local microenvironment that can support a pregnancy. Measurement of intra-tissue concentrations of steroids using liquid chromatography–tandem mass spectrometry has been important in advancing our understanding of a role for androgens in the endometrium, acting both as active ligands for the androgen receptor and as substrates for oestrogen biosynthesis. The emergence of intracrinology, associated with disordered expression of key enzymes such as aromatase, in the aetiology of common women's health disorders such as endometriosis and endometrial cancer has prompted renewed interest in the development of drugs targeting these pathways, opening up new opportunities for targeted therapies and precision medicine. [ABSTRACT FROM AUTHOR]