Insights from genomic studies on the role of sex steroids in the aetiology of endometriosis

Abstract

Endometriosis is a chronic neuro-inflammatory disorder the defining feature of which is the growth of tissue (lesions) that resembles the endometrium outside the uterus. Estimates of prevalence quote rates of ~10% of women of reproductive age, equating to at least 190 million women world-wide. Genetic, hormonal and immunological factors have all been proposed as contributing to risk factors associated with the development of lesions. Twin studies report the heritable component of endometriosis as ~50%. Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) that appear over-represented in patients with endometriosis, particularly those with more extensive disease (stage III/IV). In different sample populations, there has been replication of SNPs near genes involved in oestrogen and other steroid regulated pathways including ESR1 (oestrogen receptor alpha), GREB1, HOXA10, WNT4 and MAPK kinase signalling. Comparisons with GWAS conducted on other patient cohorts have found links with reproductive traits (age at menarche) and disorders (fibroids, endometrial and ovarian cancer) and common co-morbidities (migraine, depression, asthma). In summary, genetic analyses have provided new insights into the hormone-regulated pathways that may contribute to increased risk of developing endometriosis some of which may act in early life. New studies are needed to clarify the relationship between the many SNPs identified, the genes that they regulate and their contribution(s) to development of different forms of endometriosis. We hope that more advanced methods allowing integration between GWAS, epigenetic and tissue expression data will improve risk analysis and reduce diagnositic delay.

Lay summary: Endometriosis is a debilitating reproductive disorder affecting ~10% of reproductive-age women, and those assigned female at birth, which causes a range of symptoms including chronic pain and infertility. The reason why some, but not all these individuals, develop the lesions that characterise the disease are poorly understood, but recently attention has focused on genetic risk factors to explain why the incidence is higher in some families. Studies on large cohorts of patients with comparison of their DNA to women without endometriosis or with other disorders have documented changes in genes associated with steroid hormone production or action. The results provide further evidence that endometriosis shares genetic risk factors with other disorders of the reproductive system and a platform for new ideas related to risk, biomarkers and therapies.

Keywords: androgens; endometriosis; genome-wide association studies (GWAS); oestrogens; single nucleotide polymorphism (SNP); women’s health.

Figure 1

Location and histology of endometriosis lesions. Endometriosis lesions are predominantly found in the pelvic cavity where they may be associated with the peritoneal wall (superficial peritoneal), the ovary (cysts/endometriomas) or as nodules (deep endometriosis) associated with areas of fibrosis and adhesions between bowel, bladder and vagina (lower left diagram shown as red circles). A histological section of a superficial peritoneal lesion (*) stained with H&E is shown above the diagram of the pelvic cavity. The lesion is supported by the peritoneal wall which has a layer of smooth muscle (M), and it contains stromal fibroblasts (S), myofibroblasts (fibrosis, F) and a gland surrounded by epithelial cells (G). The right-hand panel shows a diagrammatic representation of a lesion (surrounded by dotted pink line) mirroring the histology of the H&E image complemented by representation of additional cell types including nerves (yellow), blood vessels (brown) and immune cells (variety of colours). It also shows processes that contribute to lesion survival (angiogenesis), growth of nerves in lesions (neuroangiogenesis) and creation of a unique environment that has high concentrations of steroids (intracrine biosynthesis).