INTRODUCTION
Endometriosis is a chronic, estrogen-dependent inflammatory, heritable disorder which is characterized by growth of endometrial tissue in sites other than the uterine cavity, most commonly in the pelvic cavity, including the ovaries, the uterosacral ligaments, and the pouch of Douglas.1 The disease affects approximately 10% of the women in reproductive age group.2 Despite not being at their normal anatomical positions these heterotopic endometrial tissues remain responsive to the circulating estrogen levels. Just like their normal anatomical counterparts these grow and shed with each cycle of ovulation. The shed endometrial glands and stroma incite strong chronic inflammatory response via cytokines leading to production of prostaglandins and ultimately fibrosis.3
Clinical diagnosis of endometriosis is often difficult due to the wide spectrum of symptoms which are mostly nonspecific. There are no pathognomonic features necessary and sufficient to define endometriosis. Endometriosis is typically defined by its histology: extra uterine lesions consisting of endometrial glands, stroma, and hemosiderin-laden macrophages.4 Based on location and depth, lesions are further described as superficial, ovarian endometrioma or deep endometriosis. Visual observation through transvaginal sonography (Fig. 1), laparoscopy (Fig. 2), and histopathological sampling are the gold standards.5 The most common complaints in endometriosis patients are dysmenorrhea (79%) and chronic pelvic pain (69%).6
The pathogenesis of endometriosis is still not definitive, though many theories have been proposed including retrograde menstruation, coelomic metaplasia, embryonic cell rest, lymphovascular metastasis, and stem cell.
Theories of Endometriosis7
- Sampson theory of retrograde menstruation: This is the most popular theory. This theory explains retrograde flow of menstrual blood from uterus through fallopian tubes into the peritoneal cavity. Endometrial fragments get implanted onto peritoneal surface at dependent sites like ovaries, uterosacral ligaments and pouch of Douglas (Figs. 3 and 4). Although this theory can explain pelvic endometriosis, it fails to explain distant endometriosis. Moreover, implantation of endometrial tissue has been shown to be dependent more on genetic predisposition and hormonal environment and not merely on retrograde menstruation.This theory is supported by laparoscopic findings of menstrual blood components during perimenstrual period.
- Halban's theory of lymphatic spread: This theory can explain endometriosis inflicting pelvic lymph nodes. This theory proposes that endometrial tissue can metastasize through the draining lymph channels of uterus to the lymph nodes.
- Meyer and Ivanoff theory of coelomic metaplasia: Mesothelial cells from peritoneal and ovarian surfaces may undergo metaplasia to endometrial tissue. This can occur due to chronic irritation by the menstrual blood. Alternatively, Müllerian remnants in form of primordial cells might get trapped into the peritoneum of posterior pelvic wall during embryogenesis and later undergo metaplasia under high serum estrogen levels. Stem cells can also transform into endometrial tissue under hyperestrogenic state.
- Direct implantation theory: This theory postulates that endometrial cells can directly get implanted at new sites and grow. These sites can be abdominal scar after hysterotomy, cesarean section or myomectomy and episiotomy scars. However, this theory does not explain endometriosis at other sites.
- Vascular theory: This is the least explained theory but it can explain endometriosis at distant sites like lungs and brain (Fig. 5).
- Genetic theory: A multifactorial or polygenic inheritance is seen in patients of endometriosis. There is 6−7 times increased risk in first degree relatives. However, such inheritance is observed in merely 10% of patients. Also concordance for endometriosis is frequently observed in monozygotic twin-pairs. Predisposed women are more prone to grow endometrium at ectopic sites. Genes responsible for increased susceptibility have been found to be EMX2—a transcriptional factor encoding proteins for reproductive tract development and PTEN—a tumor suppressor gene responsible for malignant transformation to endometroid adenocarcinoma in ovarian endometriosis. Both these genes are located within or near 20p13 locus. Other genes implicated in pathogenesis of endometriosis are those encoding for interleukin (IL)-15, glycodelin, Dickkopf-1, semaphoring E, aromatase, progesterone receptor (PR), and multiple angiogenic factors.
- Biomolecular theory: Patients of endometriosis have an impaired immune system response, increased production of cytokines and proinflammatory mediators, increased overall angiogenic activity, excessive estrogen production, and progesterone resistance. Peritoneal 3macrophages phagocytize menstrual debris in normal women. Ectopic endometriotic implants do not undergo phagocytosis and apoptosis due to decreased expression of metalloproteinase, CD36, and increased production of dissolved intercellular adhesion molecule-1. In patients of endometriosis due to subclinical peritoneal inflammatory response, activated macrophages secrete increasing amounts of proinflammatory cytokines like IL-1, IL-6, IL-8, monocyte chemoattractant protein (MCP)-1, regulated on activation, normal T-cell expressed and secreted (RANTES), tumor necrosis factor (TNF)-α, TNF-β, integrins, and angiogenic factors. These cytokines promote growth of endometrium at ectopic sites and makes them more resistant to apoptosis by further triggering release of more prostaglandins and proangiogenic vascular endothelial growth factor (VEGF). In addition, these cytokines have detrimental impact on sperm motility. They promote phagocytosis of sperms and can interfere with fertilization process. Prostaglandins also increase activity of aromatase (p450arom) and the production of tissue estrogen promoting an overall hyper estrogenic milieu.The most important factor in the pathogenesis of endometriosis is estrogen dysregulation and progesterone resistance. In normal females, there is dominance of alpha subtypes of estrogen receptors (ER-α). In endometriosis beta subtypes of estrogen receptors (ER-β) overwhelm alpha receptors. It is postulated that epigenetic mutation by hypomethylation of the CpG cluster of estrogen receptor genes is responsible for this change from alpha to beta dominance. The increased levels of ER-β suppress production of ER-α. This in turn reduces the formation of PRs, resulting in progesterone resistance in endometriosis. ER-β also regulates cell cycle progression and leads to increased proliferation of endometriotic cells.
- Environment theory: The most important toxin are dioxins (e.g. TCDD-2,3,7,8-tetracholorodibenzo-p-dioxin). These are by-products of industrial processing and often enter our body through food chain. These promote somatic mutation of endometrium by acting as transcription factors promoting increased ILs synthesis, activation of cytochrome P450, and alteration of tissue remodeling.
Among these existing theories on endometriosis pathogenesis, Sampson's retrograde menstruation theory is scientifically proven, easy to understand and widely acceptable.8 The theory is also supported by laparoscopic findings where menstrual blood components were found in peritoneal cavity. Consistently, Müllerian remnant theory also describes that spreading of primordial cells across the posterior pelvic wall may transform into endometrial tissue when exposed to high-level estrogenic stimulus.9
Technological progress in molecular biology has increased the interest in genetic polymorphism identification and 4its involvement in endometriosis development. A polygenic inheritance is seen in patients of endometriosis.10 The endometriotic tissue is sensitive to estrogen and progesterone. The two estrogenic receptor isoforms (ER-α, ER-β) are codified by two different genes (ESR1 and ESR2) with different tissue-specific distributions; they can join to different ligands and activate different genes for transcription. The influence of ESR1 has been correlated with severe endometriosis in various studies.11 There is 6−7 times increased risk in first degree relatives. Endometriotic genes responsible for increased susceptibility have been found to be EMX2—a transcriptional factor encoding proteins for reproductive tract development.12
Implantation failure in patients with endometriosis is directly associated with low endometrial HOXA10 levels. EMX2, a mammalian ortholog of Drosophila empty spiracles gene, is a transcription factor which is necessary for Müllerian duct and renal development.13 High endometrial HOXA10 expression occurs in mid-late secretory phase of the menstrual cycle. Conversely, it is observed that high levels of EMX2 mRNA were reported in the proliferative in association with the low levels of HOXA10.13
Long noncoding RNAs (lncRNAs) are a class of noncoding RNAs with at least 200 nucleotides.14 The major pathway involved in up regulating mRNAs in eutopic vs. normal endometrium included cytokine−cytokine receptor interaction, hypoxia-inducible factor-1 signaling, mitogen-activated protein kinase (MAPK) signaling, apoptosis, NF-κB signaling, and focal adhesions. Enrichment of mRNAs in innate immune response indicated correlation between immune factors and endometriosis.15
Endometriosis patients have an impaired immune system response, increased production of cytokines and proinflammatory mediators, increased overall angiogenic activity, excessive estrogen production, and progesterone resistance. Endometriotic cells have the ability to avoid immune surveillance, granting them easier implantation and growth in ectopic places. Cytokines like TNF-α, TNF-β, and integrins promote growth of endometrium at ectopic sites and makes them resistant to apoptosis.16 Whereas estrogen dysregulation and progesterone resistance are important factor in the pathogenesis of endometriosis. In healthy females, alpha subtype of estrogen receptors is dominant while beta subtype of estrogen receptor is seen in endometriosis. It is postulated that epigenetic mutation by hypomethylation of the CpG cluster of estrogen receptor genes is responsible for this change from alpha to beta dominance.17 The increased level of ER-β suppresses production of ER-α.
While treating these women, one should always keep in mind that genetic variability in humans can cause numerous mutations which alter at cellular and molecular level and maintain the development of illness. Understanding the role of genetics, epithelial progenitor cells will allow a more targeted and effective therapeutic approach to this poorly understood disorder.
REFERENCES
- Vercellini P, Viganò P, Somigliana E, et al. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol. 2014;10(5):261–75.
- Acién P, Velasco I. Endometriosis: A disease that remains enigmatic. ISRN Obstet Gynecol. 2013;(4):242149.
- Garai J, Molnar V, Varga T, et al. Endometriosis: harmful survival of an ectopic tissue. Front Biosci. 2006;11(1):595–619.
- Tabbara SO, Covell JL, Abbitt PL. Diagnosis of endometriosis by fine-needle aspiration cytology. Diagn Cytopathol. 1991;7(6):606–10.
- Woodward PJ, Sohaey R, Mezzetti TP Jr. Endometriosis: radiologic-pathologic correlation. Radiographics. 2001; 21(1):193–216.
- Fauconnier A, Chapron C, Dubuisson JB, et al. Relation between pain symptoms and the anatomic location of deep infiltrating endometriosis. Fertil Steril. 2002;78(4):719–26.
- Vinatier D, Orazi G, Cosson M, et al. Theories of endometriosis. Eur J Obstet Gynecol Reprod Biol. 2001;96(1):21–34.
- Holoch KJ, Lessey BA. Endometriosis and infertility. Clinic Obstet Gynecol. 2010;53(2):429–38.
- Suardika A, Pemayun TG. New insights on the pathogenesis of endometriosis and novel non-surgical therapies. J Turk Ger Gynecol Assoc. 2018;19(3):158–64.
- Simpson JL, Bischoff FZ, Kamat A, et al. Genetics of endometriosis. Obstet Gynecol Clin. 2003;30(1):21–40.
- Giudice LC, Burney RO, Becker C, et al. Genetics and genomics of endometriosis. In: Leung, Peter CK, Jie Q (Eds). Human Reproductive and Prenatal Genetics. Cambridge, MA: Academic Press; 2019. pp. 399–426.
- He B, Ni ZL, Kong SB, et al. Homeobox genes for embryo implantation: From mouse to human. Animal Models Exp Med. 2018;1(1):14–22.
- Daftary GS, Troy PJ, Bagot CN, et al. Direct regulation of β3-integrin subunit gene expression by HOXA10 in endometrial cells. Mol Endocrinol. 2002;16(3):571–9.
- Vigano P, Gaffuri B, Somigliana E, et al. Expression of intercellular adhesion molecule (ICAM)-1 mRNA and protein is enhanced in endometriosis versus endometrial stromal cells in culture. Mol Hum Reprod. 1998;4(12):1150–6.
- Chegini N, Williams RS. Cytokines and growth factor networks in human endometrium from menstruation to embryo implantation. In: HA Joseph (Ed). Cytokines in Human Reproduction. New York: Wiley-Liss; 2000. pp. 93–132.
- Koukoura O, Sifakis S, Spandidos DA. DNA methylation in endometriosis. Mol Med Rep. 2016;13(4):2939–48.