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Endometriosis is characterizedby thepresenceofendometriallike tissue outside the uterine cavity, usually represented by deepperitoneal, ovarian and/or infiltrative lesions1,2 and,more rarely, in extrapelvic sites.3 The estimated prevalence is of 5 to 10% of reproductive-age women,4–6 despite the suggestion of an actual lower prevalence, of up to 1.8%, in a recently published study based on a population of two million individuals.7 The incidence, in turn, is more difficult to be estimated, but seems to be between 1.3 to 1.6 cases per 1,000 women in this same age group.8 Even considering this wide variation, if extrapolating to the Brazilian female population aged between 15 and 50 years estimated in the last census of 2010, theremay be between 1 million and more than 5 million women with endometriosis, which is a very expressive number. Women with endometriosis may be asymptomatic or have varied symptoms, with themost frequent being pain (dysmenorrhea, dyskinesia, acyclic pain, dyspareunia) and infertility, followed by abnormal uterine bleeding and ovarian mass.9,10 Despite these associations, there are no clinical symptoms or signs that are goodpredictors of the disease,11,12which culminates in the difficulty of an accurate clinical diagnosis.13 Other important aspects are the absence of a correlation between the severity of symptoms and extent of the disease,14 the presence of endometriosis in a reasonable number of asymptomatic women,15 and the lack of knowledge about the events determining the natural evolution of the disease, be it spontaneous progression or regression.16 Nonetheless, the disease is associated with a significant psychological and social impact, negative repercussions on the woman’s quality of life17 and productivity,18 and relevant socioeconomic burden.19,20 Several theories havebeenproposed toexplain the origin of the disease, among which are theories of retrogrademenstruation (themostwidespreadandaccepted), celomicmetaplasia, lymphovascular metastasis, and, more recently, the theory of neonatal uterine bleeding.21,22Although reasonable, by themselves these theories do not explain the origin and evolution of the disease in all its nuances, and other factors need to be considered, such as: genetic, endocrine, immunological, inflammatory, and neuroangiogenic. Regardless of controversies, the eutopic endometrium in women with the disease definitely has peculiarities and a relevant role in the pathophysiological process of the disease.23–25 If we added genetic susceptibility26 and immune system dysfunction to this context, including autoimmunity and deficient immune surveillance,27–29 we would already have a plausible explanation for the question of why only some women develop the disease. Still, therewould be another question:what would be or what would lead to this initial alteration of the eutopic endometrium?Apotential explanationwould be thepresence of somatic mutations in the epithelial and/or stromal endometrial components. Despite their relevance to ovarian lesions (endometriomas), they do not appear to be crucial or significant in components of the eutopic endometrium.30 Another interesting element is the importance of endometrial progenitor cells, or endometrial stem cells in their broadest concept. However, although admittedly associated with the development of the lesion at ectopic sites,31 primary constitutive changes in these cells, when isolated from the eutopic endometrium, are still controversial. In this scenario of uncertainties about the triggering event of the first changes in the eutopic endometrium of womenwith endometriosis, it is worth discussing an equally interesting, although less explored, hypothesis of microbiological contamination. Some authors defend intrauterine microbial colonization as the trigger for pathophysiological events that culminate inendometriosis.32Furthermore, infections can trigger cumulative genetic and epigenetic changes with the potential to trigger or maintain endometriosis.33 Although recently published, the concept of an initial eutopic endometrial infection followed by sterile inflammation has been proposed before.34 These propositions are

What the Transcriptome of the Eutopic Endometrium from Women with Endometriosis tells us about the Disease Pathophysiology: A Brief Reflection