Endometriosis pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Joseph Nasr, M.D.[2] Aravind Kuchkuntla, M.B.B.S[3]
Overview
The exact pathogenesis of endometriosis is not clear; several theories have been set forth. The Sampson theory of retrograde menstruation, the coelomic metaplasia theory, and the lymphatic and vascular dissemination theory explain the implantation and invasion of the endometrial tissue outside the uterine cavity. Immunologic factors and genetic factors are also thought to play a role in the pathogenesis of endometriosis.
Pathophysiology
Pathogenesis
The exact pathogenesis of endometriosis remains incompletely understood. Several mechanisms have been proposed to explain the presence of viable, hormonally responsive <u>endometrial tissue</u> outside the uterine cavity.[1][2][3][4][5]
Translocation of Endometrial Cells
Sampson's Theory of Retrograde Menstruation
Sampson's theory proposes that viable endometrial tissue passes in a retrograde fashion through the fallopian tubes into the peritoneal cavity during menstruation, where it implants onto pelvic structures and organs.[1]
Clinical observations supporting this theory include the increased risk of endometriosis in patients with cervical stenosis and congenital outflow obstruction, conditions that increase retrograde menstrual efflux and facilitate peritoneal implantation.
However, retrograde menstruation alone does not fully explain the occurrence of endometriosis in premenarcheal girls or rare cases identified in newborns.[6]
Lymphatic and Vascular Dissemination
Endometrial cells may also disseminate via lymphatic or hematogenous pathways, which may account for lesions identified at distant or extrapelvic sites.
Stem Cell Theory
Experimental evidence suggests that endometrial stem cells from the basalis layer and bone marrow–derived stem cells may migrate via retrograde, lymphatic, or hematogenous routes, contributing to the development of ectopic lesions.
Implantation and Survival of Ectopic Endometrial Cells
The mere presence of endometrial cells outside the uterine cavity does not constitute endometriosis. Translocated cells must adhere to surrounding tissues, evade immune surveillance, survive, and respond to estrogen stimulation.
Factors facilitating implantation and survival include:
- Endometrial stromal cells, which are essential for tissue adhesion
- Resistance of ectopic cells to cell-mediated immunity
- Increased proliferative capacity
- Increased aromatase expression leading to elevated local estrogen concentrations
- Aberrant integrin expression enhancing attachment and invasion
Invasion and Growth
Endometrial glandular cells contribute to tissue invasion.[7]
Degradation of the extracellular matrix due to increased proteolytic activity allows invasion and establishment of lesions. Matrix metalloproteinases and plasmin facilitate extracellular matrix breakdown and lesion expansion.
Hormonal Dependence and Proliferation
The eutopic endometrium proliferates in response to estrogen. Estrogen production depends on aromatase activity, which catalyzes the conversion of ovarian androstenedione into estrone.[8]
Ectopic endometrial tissue demonstrates increased aromatase expression, resulting in elevated local estrogen levels and enhanced proliferation.
Additionally, endometriotic tissue exhibits progesterone resistance, impairing normal regulation of estrogen-driven proliferation. Progesterone resistance contributes to persistent lesion growth and survival.
Reduction of excess estrogen stimulation and correction of progesterone resistance form the basis of medical therapy.
Immune Dysregulation and Peritoneal Inflammation
Pathophysiological changes extend beyond the ectopic lesions themselves. Endometriosis is associated with immune dysregulation and increased inflammatory activity within the pelvic environment.[9][10][11]
Alterations include:
- Increased inflammation and angiogenesis within mesothelial cells of the pelvic peritoneum
- Recruitment of immune cells
- Sustained production of proinflammatory cytokines
- Altered immune responsiveness within the uterine endometrium
These immune abnormalities contribute to lesion persistence and chronic inflammation.[9][10][11]
Neuroangiogenesis
Endometriosis lesions demonstrate coordinated neurogenesis and neovascularization.[9][10][11]
New nerve fiber growth toward lesions and new blood vessel formation support lesion survival and contribute to pain generation.
The interaction between inflammatory mediators, immune cells, and sensory nerves sustains a self-perpetuating inflammatory microenvironment.
Pain Mechanisms
Pelvic pain in endometriosis is multifactorial and may involve a combination of nociceptive, neuropathic, and nociplastic mechanisms.[12][13]
Nociceptive Pain
Nociceptive pain results from activation of peripheral nociceptors due to localized inflammation surrounding lesions.[12]
Lesions release proinflammatory cytokines and pain mediators that stimulate and amplify nociceptive signaling.
Neuropathic Pain
Neuropathic pain may result from:
- Peripheral sensitization
- Direct nerve fiber infiltration by lesions
- Injury to nerves during surgical intervention[12]
Lesions may rarely involve nerves such as the pudendal, obturator, or sciatic nerve.[12]
Pelvic organ cross-sensitization may occur when neuronal activity in one pelvic organ sensitizes adjacent organs through shared spinal pathways.[12]
Nociplastic Pain and Central Sensitization
Nociplastic pain refers to altered pain processing within the central nervous system.[12][13]
It manifests as:
- Widespread body pain
- Fatigue
- Memory difficulties
- Sleep disturbances[13]
Immune activation surrounding lesions may alter systemic immune signaling, contributing to central sensitization within the spinal cord and brain.[12][13]
This leads to:
- Amplification of ascending pain signals
- Loss of descending pain inhibition
- Generalized sensory hypersensitivity
Nociplastic pain may explain why:
- Lesion number and subtype are weakly associated with pain severity[14][15]
- Surgical removal of lesions does not alleviate pain in all patients
- Pain may recur without evidence of recurrent lesions[12][13]
Neuroendocrine Contribution
Compromised function of the hypothalamic-pituitary axis and sympathetic-adrenal medullary systems may further amplify immune dysregulation and pain signaling.[12][13]
Mechanisms of Infertility
Endometriosis may impair fertility through multiple mechanisms, including:
- Impaired ovarian function
- Adhesions causing tubal obstruction
- Dysfunction of the uterine endometrium[11]
These mechanisms reflect both structural distortion and molecular alterations in the reproductive environment.
Commonly Affected Sites
Endometriosis most commonly affects dependent areas of the pelvis, with the ovaries being the most frequent site.[16]
Other commonly affected sites include:
- Pelvic peritoneum lining the uterus
- Posterior cul-de-sac
- Round and broad ligaments of the uterus
- Lymph nodes
Less common sites include:
- Cervix[17]
- Vagina
- Vulva
- Rectosigmoid[18]
- Anterior abdominal wall[19]
- Surgical scars[20]
- Urinary bladder
- Kidney[21]
- Lungs
- Urinary tract
Genetics and Immune Factors
Genetic predisposition contributes to disease susceptibility. Polymorphisms in genes involved in cell-mediated immunity and aromatase activity have been described in women with endometriosis.[22][23]
Polymorphisms in genes encoding <cytokines and toll-like receptors have also been associated with increased risk.
A positive family history of endometriosis in a first-degree relative is associated with approximately a six-fold increased risk of developing the disease.
Associated Conditions
Endometriosis is associated with an increased risk of developing ovarian cancer.[24][25]
Gross Pathology
The gross appearance of lesions depends on location, duration, menstrual cycle phase, and degree of fibrosis.
On laparoscopy, pelvic endometriosis may appear as raised, dark, non-hemorrhagic lesions. Lesions may also appear brown, black, white, yellow, pink, or clear depending on vascularity and hemorrhagic content.
Ovarian endometriosis may present as a cyst containing dark, thick, hemolyzed blood, commonly referred to as a “chocolate cyst.”
Advanced disease may result in fibrosis and pelvic adhesions visible during laparoscopy.
Microscopic Pathology
Histologic examination demonstrates the presence of endometrial glandular epithelium and endometrial stromal cells within ectopic sites.
References
- ↑ 1.0 1.1 Bulun, Serdar E. (2009). "Endometriosis". New England Journal of Medicine. 360 (3): 268–279. doi:10.1056/NEJMra0804690. ISSN 0028-4793.
- ↑ Greene AD, Lang SA, Kendziorski JA, Sroga-Rios JM, Herzog TJ, Burns KA (2016). "Endometriosis: where are we and where are we going?". Reproduction. 152 (3): R63–78. doi:10.1530/REP-16-0052. PMC 4958554. PMID 27165051.
- ↑ Nothnick W, Alali Z (2016). "Recent advances in the understanding of endometriosis: the role of inflammatory mediators in disease pathogenesis and treatment". F1000Res. 5. doi:10.12688/f1000research.7504.1. PMC 4760268. PMID 26949527.
- ↑ Begum T, Chowdhury SR (2013). "Aetiology and pathogenesis of endometriosis - a review". Mymensingh Med J. 22 (1): 218–21. PMID 23416836.
- ↑ Benagiano G, Habiba M, Brosens I (2012). "The pathophysiology of uterine adenomyosis: an update". Fertil Steril. 98 (3): 572–9. doi:10.1016/j.fertnstert.2012.06.044. PMID 22819188.
- ↑ Templeman C (2009). "Adolescent endometriosis". Obstet Gynecol Clin North Am. 36 (1): 177–85. doi:10.1016/j.ogc.2008.12.005. PMID 19344855.
- ↑ Smarr MM, Kannan K, Buck Louis GM (2016). "Endocrine disrupting chemicals and endometriosis". Fertil Steril. 106 (4): 959–66. doi:10.1016/j.fertnstert.2016.06.034. PMID 27424048.
- ↑ Patel S (2017). "Disruption of aromatase homeostasis as the cause of a multiplicity of ailments: A comprehensive review". J Steroid Biochem Mol Biol. 168: 19–25. doi:10.1016/j.jsbmb.2017.01.009. PMID 28109841.
- ↑ 9.0 9.1 9.2 Saunders PTK, Horne AW. Endometriosis: etiology, pathobiology, and therapeutic prospects. Cell. 2021;184(11):2807-2824. doi:10.1016/j.cell.2021.04.041
- ↑ 10.0 10.1 10.2 Zondervan KT, Becker CM, Missmer SA. Endometriosis. N Engl J Med. 2020;382(13):1244-1256. doi:10.1056/NEJMra1810764
- ↑ 11.0 11.1 11.2 11.3 Horne AW, Missmer SA. Pathophysiology, diagnosis, and management of endometriosis. BMJ. 2022;379:e070750. doi:10.1136/bmj-2022-070750
- ↑ 12.0 12.1 12.2 12.3 12.4 12.5 12.6 12.7 12.8 Coxon L, Demetriou L, Vincent K. Current developments in endometriosis-associated pain. Cell Rep Med. 2024;5(10):101769. doi:10.1016/j.xcrm.2024.101769
- ↑ 13.0 13.1 13.2 13.3 13.4 13.5 Kaplan CM, Kelleher E, Irani A, Schrepf A, Clauw DJ, Harte SE. Deciphering nociplastic pain: clinical features, risk factors and potential mechanisms. Nat Rev Neurol. 2024;20(6):347-363. doi:10.1038/s41582-024-00966-8
- ↑ Pashkunova D, Darici E, Senft B, et al. Lesion size and location in deep infiltrating bowel endometriosis: correlation with gastrointestinal dysfunction and pain. Acta Obstet Gynecol Scand. 2024;103(9):1764-1770. doi:10.1111/aogs.14921
- ↑ Vercellini P, Fedele L, Aimi G, Pietropaolo G, Consonni D, Crosignani PG. Association between endometriosis stage, lesion type, patient characteristics and severity of pelvic pain symptoms: a multivariate analysis of over 1000 patients. Hum Reprod. 2007;22(1):266-271. doi:10.1093/humrep/del339
- ↑ Fritel X (2007). "[Endometriosis anatomoclinical entities]". J Gynecol Obstet Biol Reprod (Paris). 36 (2): 113–8. doi:10.1016/j.jgyn.2006.12.003. PMID 17275210.
- ↑ Park HM, Lee SS, Eom DW, Kang GH, Yi SW, Sohn WS (2009). "Endometrioid adenocarcinoma arising from endometriosis of the uterine cervix: a case report". J Korean Med Sci. 24 (4): 767–71. doi:10.3346/jkms.2009.24.4.767. PMC 2719211. PMID 19654969.
- ↑ Hernández-Ramírez DA, Cravioto-Villanueva A, Barragan-Rincón A (2008). "[Rectal endometriosis: entity difficult to diagnose.]". Rev Gastroenterol Mex. 73 (3): 159–62. PMID 19671503.
- ↑ Collins AM, Power KT, Gaughan B, Hill AD, Kneafsey B (2009). "Abdominal wall reconstruction for a large caesarean scar endometrioma". Surgeon. 7 (4): 252–3. PMID 19736896.
- ↑ Chung MK, Jarnagin B (2009). "Early identification of interstitial cystitis may avoid unnecessary hysterectomy". JSLS. 13 (3): 350–7. PMC 3015962. PMID 19793476.
- ↑ Dirim A, Celikkaya S, Aygun C, Caylak B (2009). "Renal endometriosis presenting with a giant subcapsular hematoma: case report". Fertil Steril. 92 (1): 391.e5–7. doi:10.1016/j.fertnstert.2009.04.013. PMID 19476941.
- ↑ Fan W, Huang Z, Xiao Z, Li S, Ma Q (2016). "The cytochrome P4501A1 gene polymorphisms and endometriosis: a meta-analysis". J Assist Reprod Genet. 33 (10): 1373–1383. doi:10.1007/s10815-016-0783-4. PMC 5065559. PMID 27525656.
- ↑ Blakemore J, Naftolin F (2016). "Aromatase: Contributions to Physiology and Disease in Women and Men". Physiology (Bethesda). 31 (4): 258–69. doi:10.1152/physiol.00054.2015. PMID 27252161.
- ↑ Thomsen LH, Schnack TH, Buchardi K, Hummelshoj L, Missmer SA, Forman A; et al. (2017). "Risk factors of epithelial ovarian carcinomas among women with endometriosis: a systematic review". Acta Obstet Gynecol Scand. 96 (6): 761–778. doi:10.1111/aogs.13010. PMID 27565819.
- ↑ Lassus H, Pasanen A, Bützow R (2015). "[Is endometriosis a premalignant condition to ovarian carcinoma?]". Duodecim. 131 (19): 1777–84. PMID 26638662.