Review Endometriosis, infertility and MicroRNA's: A review Mohummad Hasan Raza Raja a , Nida Farooqui a , Nadeem Zuberi b , Mussarat Ashraf a , Arfa Azhar a , Rozeena Baig a , Bisma Badar a , Rehana Rehman a, * a Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, Pakistan b Obstetrics and Gynecology, Aga Khan University, Karachi, Pakistan ARTICLE INFO Article History: Received 6 December 2020 Accepted 27 April 2021 Available online 3 May 2021 ABSTRACT The review aims to explore circulating small non- coding regulatory Ribonucleic Acids (miRNA) as biomarkers of endometriosis; a reproductive age group disorder. miRNA are linked with genetic, epigenetic and angiogenic fac- tors, hormones, cytokines, chemokines, oxidative stress (OS) markers, mediators of inflammation, hypoxia, angio- genesis and altered immune system contributing to the pathogenesis of endometriosis. Hormonal imbalance occurs by decreased levels of miRNAs -23a and miRNAs -23b and increase in miRNAs -:135a, 135b, 29c and 194 -3p. Angiogenesis by vascular endothelial growth factor is attributed to increased miRNAs -126, miRNAs -210, miRNAs -21, miRNAs -199a-5p and miRNAs 20A. OS upregulates miRNAs -302a by increased levels of Tumor Necrosis factor (TNF)-a, TNF- b and Interleukin -1b. Upregulation of miRNAs -199a and miRNAs -16 promotes inflammation and cell proliferation in the endometriotic lesions. The gold standard to diagnose endometriosis is laparoscopy, yet miRNA can be validated as diagnostic tool for detection, progression and prevention of endome- triosis in large, independent cohorts of women, with and without endometriosis © 2021 Elsevier Masson SAS. All rights reserved. Keywords: Endometriosis Micro RNA Oxidative stress Inflammation Angiogenesis Infertility 1. Introduction Endometriosis, described by the occurrence of extra-uterine endo- metrium, is a common gynecological condition in reproductive-age women [1]. It continues to be a common clinical presentation in 10% women of reproductive age group [2] with a prevalence of 16.8% endo- metriosis in Pakistani women [3]. The need to know about factors lead- ing to endometriosis is on the basis of the fact that fecundity rate of untreated women with endometriosis is lower i.e. 2-10% as compared to that in normal couples which is in the range of 15-20% per month [4]. Several theories have been hypothesized, however currently most evidence points strongly towards the phenomenon of retrograde men- struation [5].It often has a hereditary component, genes correlated with endometriosis can be categorized into: steroid and hormone receptors, cytokines/inflammation factors, adhesion molecules and matrix enzymes, and cell cycle regulated related gene [6]. A number of con- tributing predisposing factors (Fig. 1) are assumed to be the cause of the pathogenesis of endometriosis [7]. The common locations for pelvic endometriosis are fallopian tubes ovaries, Douglas-fir pouch and uter- ine ligaments (broadly broad and uterosacral ligaments) [8]. Endometri- otic embeds are also present outside the pelvis, i.e. diaphragm, lungs, gastrointestinal tract, pericardium and abdomen [9]. There are 3 main types of endometriosis present in pelvis peritoneal, ovarian, and infil- trating endometriotic disease. [10] Structurally, there are 3 forms of endometriotic lesions: red lesions, white lesions and black lesions. Red are characterized by great vascularization, although white are at late stages of red lesions, assuming the development of fibrosis and inflam- mation. black lesions have tissue breakdown and scarring with succes- sive development of scar tissue [11]. 1.1. Endometriosis and subfertility Subfertility is a relatively common finding in patients with endo- metriosis, with approximately 30-50% of women with endometriosis being sub fertile. Similarly, it has been reported that 25-50% of infer- tile women suffer from this disease [12]. Often this infertility, remains unexplained due to the delay in diagnosis, causing a signifi- cant degree of stress [13]. 1.2. Diagnosis of endometriosis Currently the diagnosis of endometriosis is accomplished through laparoscopy, which is considered as the gold standard. Upon diagnosis, a widely followed system of classifying the extent of the disease has been laid down by the American Soci- ety of Reproductive Medicine, ranging from Stage I (ectopic lesions are superficial with scarce adhesions) to Stage 4 (ectopic foci are extensive and deeply infiltrate bladder, bowels and/or * Corresponding author. E-mail addresses: nida.farooqui@aku.edu (R.A.N. Farooqui), nadeem.zuberi@aku. edu (A.P.D.N. Zuberi), mussarat.ashraf@aku.edu (S.T.M. Ashraf), arfa.azhar@aku.edu (S.I.D.A. Azhar), rozeena.baig@aku.edu (R.A.R. Baig), bismaquraishi@gmail.com (M.S.B. Badar), drrehana7@gmail.com, rehana.rehman@aku.edu (A.P.D.R. Rehman). https://doi.org/10.1016/j.jogoh.2021.102157 2468-7847/© 2021 Elsevier Masson SAS. All rights reserved. J Gynecol Obstet Hum Reprod 50 (2021) 102157 Contents lists available at ScienceDirect Journal of Gynecology Obstetrics and Human Reproduction journal homepage: www.elsevier.com