Association Of Endometriosis With Polymorphisms Of The Estrogen Receptor Alpha- And Progesterone Receptor Genes Revisited

Abstract

Endometriosis is a hereditary condition defined as the growth of endometrium-like tissue outside the uterus, affecting an estimated 5-10% of women of reproductive age (1) and imposing great economic and healthcare burdens (2). The growth occurs mostly on the pelvic peritoneum, rectovaginal septum, and ovaries, and in rare cases in the abdominal wall, diaphragm, pleura, pericardium, and peripheral and central nervous systems (3, 4). Endometriosis is generally thought to result from retrograde menstruation of endometrial cells through the fallopian tubes to reach the abdomino-pelvic cavity where they settle and implant, thereby eliciting an inflammatory response that leads to the formation of scars and adhesions, pelvic pain, dysmenorrhea, dyspareunia, dysuria, and infertility (5, 6). A variant on this theory assumes that endometrial cells reach through the lymph vessels to cause endometriosis in lymphatic nodes and distal locations (7). Alternatively, endometriosis could be caused by coelomic metaplasia, i.e. the transformation of peritoneal epithelium lining under the influence of stimuli (8).

Current diagnosis depends mainly on surgical examination, which is expensive and could mis the disease altogether. Furthermore, the necessary infrastructure and skills for such a procedure could be lacking in undeveloped regions and regions with increased instability due to armed conflicts and/or natural disasters. There is, therefore, a growing need for simple, non-invasive diagnostic tools to facilitate early detection and treatment initiation. Despite great efforts, this has not been achieved yet, mainly because the disease mechanism is still far from clearly understood.

The contribution of genetic factors to the variation in endometriosis has been estimated to be 47%, with the other 53% attributed to unique environmental factors (9). However, endometriosis is a heterogenous condition, involving many genetic factors each with a small effect size (10, 11). This means that very large studies are required to identify genetic factors that can only explain a small fraction of disease variance.

Genetic studies of endometriosis have been performed both at single gene level (SNP analysis) (reviewed in 12) and genome level (genome wide association studies, GWAS) (13; 14). The former is based on assumptions about the etiology of the disease whereas the latter is agnostic to such assumptions. Both approaches have contributed to our current understanding of the underlying biology in endometriosis. In this minireview we focus on association studies of the estrogen receptor 1 alpha (ESR1) and progesterone receptor (PGR) genes. We also discuss the relevance of progesterone resistance or estrogen dominance (defined here as higher estrogen to progesterone ratio) in light of these genetic changes.