Endometriosis - novel approaches and controversies debated.

Defined by the extrauterine growth of estrogendependent endometrial-like epithelial and stromal cells, endometriosis is a common gynecological and systemic inflammatory disease affecting approximately 179 million people assigned female at birth (predominately cisgender women) worldwide. Although most frequently detected in the pelvic cavity, endometriotic lesions can be found throughout the body. Three main phenotypes include endometriomas, superficial, and deep endometriosis. Lesion appearance is variable and dependent on the tissue on which it grows. Hallmark features of endometriosis include pelvic pain and infertility; however, some people with endometriosis remain asymptomatic. Endometriosis is a disease whose impact on the health care system exceeds that of caring for women with Crohn’s disease, asthma, migraines, and rheumatoid arthritis (Simoens et al. 2007, 2011, 2012, Klein et al. 2014). Although a relatively common disease with a high economic burden, endometriosis remains underfunded and under-researched (As-Sanie et al. 2019). While important advances have been made over the years in defining the pathophysiology of endometriosis, the cause of endometriosis remains ill-defined, diagnosis continues to present challenges and therapeutic options are suboptimal. Patients frequently report dissatisfaction with current therapeutic options prompting the search for alternative treatments including non-hormonal alternatives. In a special series that will be running in Reproduction and Fertility over the coming months, international experts have been recruited to provide insights and perspectives into the latest advances in endometriosis research and treatment. We strive to succeed with this special series in summarizing the current state of ‘leading edge’ research and opinion in endometriosis. Though not exhaustive, the topics and authors capture this moment in time in endometriosis research. Although widely recognized to be an estrogendependent disease, numerous physiological pathways are known to be dysregulated in people with endometriosis including cell adherence, attachment, proliferation, apoptosis, angiogenesis, and tissue remodeling enzyme expression (Hey-Cunningham et al. 2013). That endometriosis may have a heritable component is not a new concept (Saha et al. 2015); however, specific gene mutations and gene regulation continue to be explored. Indeed, the mechanisms regulating different pathways dysregulated in endometriotic tissues are beginning to be teased apart with increasing attention focused on mechanisms regulating gene expression including chromatin architecture, long ncRNA, micro-RNA, and piwi-RNA. The role of gonadal steroids in modulating the expression of epigenetic regulators of gene expression in endometriosis is poorly understood. Early in this special series, the relationship between gonadal steroids and genomic regulation is reviewed by Dr Philippa Saunders. Given the prominent role of estrogen and the use of androgens as a therapeutic option in endometriosis suggests that hormone replacement therapy is a potential modifying factor in the transgender population that is beginning to receive attention. The prevalence of endometriosis and its implication in transgender men is summarized by Dr Cecile Ferrando in her review of this underserved population. The reproductive and gastrointestinal tract microbiome has been described by several investigators and dysbiosis has -21-0097 ID: XX-XXXX;