Pathogenesis of uterine adenomyosis: invagination or metaplasia?
2018; Elsevier BV; Volume: 109; Issue: 3 Linguagem: Inglês
10.1016/j.fertnstert.2017.12.030
ISSN1556-5653
AutoresJavier García-Solares, Jacques Donnez, Olivier Donnez, Marie‐Madeleine Dolmans,
Tópico(s)Endometrial and Cervical Cancer Treatments
ResumoAdenomyosis is a commonly diagnosed estrogen-dependent gynecological disorder that causes pelvic pain, abnormal uterine bleeding, and infertility. Despite its prevalence and severity of symptoms, its pathogenesis and etiology have not yet been elucidated. The aim of this manuscript is to review the different hypotheses on the origin of adenomyotic lesions and the mechanisms involved in the evolution and progression of the disease. Two main theories have been proposed to explain the origin of adenomyosis. The most common suggests involvement of tissue injury and the repair mechanism and claims that adenomyosis results from invagination of the endometrial basalis into the myometrium. An alternative theory maintains that adenomyotic lesions result from metaplasia of displaced embryonic pluripotent Müllerian remnants or differentiation of adult stem cells. Previous investigations performed in human adenomyotic lesions and corroborated by studies in mice supported the involvement of the epithelial-mesenchymal transition process in the early stages of progression and spread of adenomyosis. However, studies conducted in a recently developed baboon model indicate that collective cell migration may be implicated in the later events of invasion. This suggests that the invasiveness of this complex uterine disorder is not driven by a single mechanism of migration but by a time-dependent combination of two processes. Adenomyosis is a commonly diagnosed estrogen-dependent gynecological disorder that causes pelvic pain, abnormal uterine bleeding, and infertility. Despite its prevalence and severity of symptoms, its pathogenesis and etiology have not yet been elucidated. The aim of this manuscript is to review the different hypotheses on the origin of adenomyotic lesions and the mechanisms involved in the evolution and progression of the disease. Two main theories have been proposed to explain the origin of adenomyosis. The most common suggests involvement of tissue injury and the repair mechanism and claims that adenomyosis results from invagination of the endometrial basalis into the myometrium. An alternative theory maintains that adenomyotic lesions result from metaplasia of displaced embryonic pluripotent Müllerian remnants or differentiation of adult stem cells. Previous investigations performed in human adenomyotic lesions and corroborated by studies in mice supported the involvement of the epithelial-mesenchymal transition process in the early stages of progression and spread of adenomyosis. However, studies conducted in a recently developed baboon model indicate that collective cell migration may be implicated in the later events of invasion. This suggests that the invasiveness of this complex uterine disorder is not driven by a single mechanism of migration but by a time-dependent combination of two processes. Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/28903-25375 Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/28903-25375 Adenomyosis is a commonly encountered benign uterine disease, affecting 19.5% of women of reproductive age (1Devlieger R. D’Hooghe T. Timmerman D. Uterine adenomyosis in the infertility clinic.Hum Reprod Update. 2003; 9: 139-147Crossref PubMed Scopus (161) Google Scholar). Histopathologically, it is characterized by the presence of ectopic endometrial tissue (endometrial glands and/or stroma) in the myometrium, surrounded by hyperplastic and hypertrophic smooth muscle (2Bird C.C. McElin T.W. Manalo-Estrella P. The elusive adenomyosis of the uterus—revisited.Am J Obstet Gynecol. 1972; 112: 583-593Abstract Full Text PDF PubMed Scopus (337) Google Scholar, 3Siegler A.M. Camilien L. Adenomyosis.J Reprod Med. 1994; 39: 841-853PubMed Google Scholar). Ectopic endometrial implants are known to follow different distribution patterns in the myometrium, giving rise to two main forms of the disease: focal and diffuse. Adenomyosis is described as focal when a circumscribed nodular collection is identified but considered diffuse when different groups of endometriotic glands and stroma are distributed throughout the myometrium (4Kishi Y. Suginami H. Kuramori R. Yabuta M. Suginami R. Taniguchi F. Four subtypes of adenomyosis assessed by magnetic resonance imaging and their specification.Am J Obstet Gynecol. 2012; 207: 114.e1-114.e7Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 5Van den Bosch T. Dueholm M. Leone F.P. Valentin L. Rasmussen C.K. 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Millischer A.E. et al.Relationship between the magnetic resonance imaging appearance of adenomyosis and endometriosis phenotypes.Hum Reprod. 2017; 32: 1393-1401Crossref PubMed Scopus (133) Google Scholar). The clinical presentation of adenomyosis includes pelvic pain, abnormal uterine bleeding, and infertility (7Guo S.W. Mao X. Ma Q. Liu X. Dysmenorrhea and its severity are associated with increased uterine contractility and overexpression of oxytocin receptor (OTR) in women with symptomatic adenomyosis.Fertil Steril. 2013; 99: 231-240Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 8Naftalin J. Hoo W. Pateman K. Mavrelos D. Foo X. Jurkovic D. Is adenomyosis associated with menorrhagia?.Hum Reprod. 2014; 29: 473-479Crossref PubMed Scopus (62) Google Scholar, 9Vercellini P. Consonni D. Dridi D. Bracco B. Frattaruolo M.P. Somigliana E. 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Symptoms and classification of uterine adenomyosis, including the place of hysteroscopy in diagnosis.Fertil Steril. 2018; 109: 380-388Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). Imaging techniques, such as transvaginal ultrasound and magnetic resonance imaging, have led to major advances, allowing new conservative treatments to be developed for adenomyosis (13Thain S. Tan H.H. Approaches to adenomyomectomy.Gynecol Min Invas Ther. 2015; 4: 49-54Abstract Full Text Full Text PDF Scopus (12) Google Scholar, 14Liu X. Yu S. Guo S.-W. A pilot study on the use of andrographolide to treat symptomatic adenomyosis.Gynecol Min Invas Ther. 2014; 3: 119-126Abstract Full Text Full Text PDF Scopus (12) Google Scholar, 15Streuli I. Dubuisson J. Santulli P. de Ziegler D. Batteux F. Chapron C. An update on the pharmacological management of adenomyosis.Expert Opin Pharmacother. 2014; 15: 2347-2360Crossref PubMed Scopus (53) Google Scholar, 16Bazot M. Daraï E. Role of vaginal ultrasound and MRI in the diagnosis of uterine adenomyosis.Fertil Steril. 2018; 109: 389-397Abstract Full Text Full Text PDF Scopus (123) Google Scholar). However, the gold standard for its diagnosis is still histological examination after surgery, which will be elaborated upon by Gordts et al. (12Gordts S. Grimbizis I. Campo R. Symptoms and classification of uterine adenomyosis, including the place of hysteroscopy in diagnosis.Fertil Steril. 2018; 109: 380-388Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar) and Bazot et al. (16Bazot M. Daraï E. Role of vaginal ultrasound and MRI in the diagnosis of uterine adenomyosis.Fertil Steril. 2018; 109: 389-397Abstract Full Text Full Text PDF Scopus (123) Google Scholar) Endometriosis and adenomyosis are closely linked diseases (6Chapron C. Tosti C. Marcellin L. Bourdon M. Lafay-Pillet M.C. Millischer A.E. et al.Relationship between the magnetic resonance imaging appearance of adenomyosis and endometriosis phenotypes.Hum Reprod. 2017; 32: 1393-1401Crossref PubMed Scopus (133) Google Scholar, 17Leyendecker G. Bilgicyildirim A. Inacker M. Stalf T. Huppert P. Mall G. et al.Adenomyosis and endometriosis. Re-visiting their association and further insights into the mechanisms of auto-traumatisation. An MRI study.Arch Gynecol Obstet. 2015; 291: 917-932Crossref PubMed Scopus (137) Google Scholar, 18Kunz G. Beil D. Huppert P. Noe M. Kissler S. Leyendecker G. Adenomyosis in endometriosis—prevalence and impact on fertility. Evidence from magnetic resonance imaging.Hum Reprod. 2005; 20: 2309-2316Crossref PubMed Scopus (315) Google Scholar), their rate of coexistence varying according to the endometriosis phenotype involved, as recently demonstrated by Chapron et al. and Leyendecker et al.(6Chapron C. Tosti C. Marcellin L. Bourdon M. Lafay-Pillet M.C. Millischer A.E. et al.Relationship between the magnetic resonance imaging appearance of adenomyosis and endometriosis phenotypes.Hum Reprod. 2017; 32: 1393-1401Crossref PubMed Scopus (133) Google Scholar, 17Leyendecker G. Bilgicyildirim A. Inacker M. Stalf T. Huppert P. Mall G. et al.Adenomyosis and endometriosis. Re-visiting their association and further insights into the mechanisms of auto-traumatisation. An MRI study.Arch Gynecol Obstet. 2015; 291: 917-932Crossref PubMed Scopus (137) Google Scholar, 18Kunz G. Beil D. Huppert P. Noe M. Kissler S. Leyendecker G. Adenomyosis in endometriosis—prevalence and impact on fertility. Evidence from magnetic resonance imaging.Hum Reprod. 2005; 20: 2309-2316Crossref PubMed Scopus (315) Google Scholar). They also share a number of features in terms of symptomatology, histology, and molecular alterations (19Li B. Chen M. Liu X. Guo S.W. Constitutive and tumor necrosis factor-alpha-induced activation of nuclear factor-kappaB in adenomyosis and its inhibition by andrographolide.Fertil Steril. 2013; 100: 568-577Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, 20Donnez O. Van Langendonckt A. Defrere S. Colette S. Van Kerk O. Dehoux J.P. et al.Induction of endometriotic nodules in an experimental baboon model mimicking human deep nodular lesions.Fertil Steril. 2013; 99: 783-789.e3Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 21Donnez O. Orellana R. Van Kerk O. Dehoux J.P. Donnez J. Dolmans M.M. Invasion process of induced deep nodular endometriosis in an experimental baboon model: similarities with collective cell migration?.Fertil Steril. 2015; 104: 491-497.e2Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). Nevertheless, there are several differences in their pathogenesis and pathogenic mediators (22Benagiano G. Brosens I. Habiba M. Structural and molecular features of the endomyometrium in endometriosis and adenomyosis.Hum Reprod Update. 2014; 20: 386-402Crossref PubMed Scopus (156) Google Scholar). Despite its prevalence and the severity of symptoms, little is known about the pathogenesis and etiology of adenomyosis. The present manuscript therefore sets out to review the different pathogenic theories on adenomyosis, as well as available animal models to study the disease. Although the pathogenesis and etiology of adenomyosis remain unkown, two main theories have been proposed in the literature: invagination of the endometrial basalis as a result of activation of the tissue injury and repair (TIAR) mechanism and metaplasia of displaced embryonic pluripotent Müllerian remnants or differentiation of adult stem cells. Steroid hormones play a central role in the etiology of adenomyosis. Indeed, supraphysiological estrogen production (hyperestrogenism) due to local paracrine activity in the eutopic and ectopic endometrium of patients with adenomyosis may be a preliminary status, contributing to the origin of the disease. This concept is supported by the elevated levels of E2 often observed in the menstrual blood of women with adenomyosis compared with peripheral blood levels (23Rizner T.L. The important roles of steroid sulfatase and sulfotransferases in gynecological diseases.Front Pharmacol. 2016; 7: 30Crossref PubMed Scopus (65) Google Scholar). Gene polymorphisms causing increased production (aromatase cytochrome P450-1B1 [CYP1B1] 432 C/G and cyclooxygenase-2 [COX-2] 1195 G/A) and decreased metabolism (catechol-O-methyltransferase [COMT] 158 G/A) of estrogens are associated with a higher risk of adenomyosis development (24Wang Y. Qu Y. Song W. Genetic variation in COX-2-1195 and the risk of endometriosis and adenomyosis.Clin Exp Obstet Gynecol. 2015; 42: 168-172PubMed Google Scholar, 25Tong X. Li Z. Wu Y. Fu X. Zhang Y. Fan H. COMT 158G/A and CYP1B1 432C/G polymorphisms increase the risk of endometriosis and adenomyosis: a meta-analysis.Eur J Obstet Gynecol Reprod Biol. 2014; 179: 17-21Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar). For this reason, hyperestrogenism is suggested to result from increased local aromatization and decreased local estrogen metabolism in the eutopic and ectopic endometrium of patients with adenomyosis. Indeed, as shown by Kitawaki et al., aromatase cytochrome P450, a heme-containing enzyme that catalyzes reactions involved in steroidogenesis, is not present in the endometrium of disease-free uteri. It is, however, found in the eutopic endometrium of patients with adenomyosis, promoting estrogen biosynthesis and higher estrogenic bioavailability due to local aromatization of circulating androgens (T) into E2 (26Kitawaki J. Noguchi T. Amatsu T. Maeda K. Tsukamoto K. Yamamoto T. et al.Expression of aromatase cytochrome P450 protein and messenger ribonucleic acid in human endometriotic and adenomyotic tissues but not in normal endometrium.Biol Reprod. 1997; 57: 514-519Crossref PubMed Scopus (252) Google Scholar). Reduced conversion of E2 to the less potent estrone was also observed in the eutopic and ectopic endometrium of patients with adenomyosis, as a consequence of decreased expression of 17-β hydroxysteroid dehydrogenase type 2 (17-β HSD2) enzyme (27Kitawaki J. Koshiba H. Ishihara H. Kusuki I. Tsukamoto K. Honjo H. Progesterone induction of 17beta-hydroxysteroid dehydrogenase type 2 during the secretory phase occurs in the endometrium of estrogen-dependent benign diseases but not in normal endometrium.J Clin Endocrinol Metab. 2000; 85: 3292-3296Crossref PubMed Google Scholar). P typically counteracts estrogen-promoted proliferation in healthy endometrium, but not in patients with adenomyosis. In these subjects, stromal cells of the endometrial functionalis and basalis show lower immunoreactivity for isoform B of the P receptor (PR-B) in eutopic endometrium compared with disease-free endometrium, leading to loss of its action and finally a mechanism of P resistance (28Mehasseb M.K. Panchal R. Taylor A.H. Brown L. Bell S.C. Habiba M. Estrogen and progesterone receptor isoform distribution through the menstrual cycle in uteri with and without adenomyosis.Fertil Steril. 2011; 95 (2235.e1): 2228-2235Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar, 29Jichan N. Xishi L. Guo S.W. Promoter hypermethylation of progesterone receptor isoform B (PR-B) in adenomyosis and its rectification by a histone deacetylase inhibitor and a demethylation agent.Reprod Sci. 2010; 17: 995-1005Crossref PubMed Scopus (81) Google Scholar). Hence, during the secretory phase of the cycle, estrogen-driven proliferative effects on the endometrium are not adequately harnessed by P, fostering abnormal endometrial proliferation. Moreover, in adenomyosis, hyperestrogenism may promote elevated oxytocin-mediated uterine activity, resulting in increased mechanical strains and stresses that could injure cells in the junctional zone (JZ) close to the fundocornual raphe (17Leyendecker G. Bilgicyildirim A. Inacker M. Stalf T. Huppert P. Mall G. et al.Adenomyosis and endometriosis. Re-visiting their association and further insights into the mechanisms of auto-traumatisation. An MRI study.Arch Gynecol Obstet. 2015; 291: 917-932Crossref PubMed Scopus (137) Google Scholar, 30Leyendecker G. Wildt L. A new concept of endometriosis and adenomyosis: tissue injury and repair (TIAR).Horm Mol Biol Clin Investig. 2011; 5: 125-142PubMed Google Scholar, 31Leyendecker G. Wildt L. Mall G. The pathophysiology of endometriosis and adenomyosis: tissue injury and repair.Arch Gynecol Obstet. 2009; 280: 529-538Crossref PubMed Scopus (287) Google Scholar, 32Shaked S. Jaffa A.J. Grisaru D. Elad D. Uterine peristalsis-induced stresses within the uterine wall may sprout adenomyosis.Biomech Model Mechanobiol. 2015; 14: 437-444Crossref PubMed Scopus (24) Google Scholar). Altered endometrial proliferation and hyperperistalsis-induced tissue microtrauma in the JZ due to supraphysiological estrogen production may therefore enhance endometrial intramyometrial invagination (Figure 1, Figure 2A ).Figure 2Theories on the origin of adenomyosis. (A) Invagination of the endometrial basalis into the myometrium, after TIAR mechanism activation. (B, C) De novo formation of lesions: (B) after metaplasia of displaced embryonic pluripotent remnants or (C) from differentiation of endometrial and stromal stem cells deposited in the myometrium after retrograde menstruation.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Indeed, as evidence of tissue microtrauma, levels of anti-smooth muscle antibody–positive and collagen I–positive myofibroblasts are significantly higher in the JZ of women with adenomyosis than in those without (33Ibrahim M.G. Sillem M. Plendl J. Chiantera V. Sehouli J. Mechsner S. Myofibroblasts are evidence of chronic tissue microtrauma at the endometrial-myometrial junctional zone in uteri with adenomyosis.Reprod Sci. 2017; 24: 1410-1418Crossref PubMed Scopus (31) Google Scholar). The TIAR mechanism is then activated in response to tissue autotraumatization (17Leyendecker G. Bilgicyildirim A. Inacker M. Stalf T. Huppert P. Mall G. et al.Adenomyosis and endometriosis. Re-visiting their association and further insights into the mechanisms of auto-traumatisation. An MRI study.Arch Gynecol Obstet. 2015; 291: 917-932Crossref PubMed Scopus (137) Google Scholar, 30Leyendecker G. Wildt L. A new concept of endometriosis and adenomyosis: tissue injury and repair (TIAR).Horm Mol Biol Clin Investig. 2011; 5: 125-142PubMed Google Scholar, 31Leyendecker G. Wildt L. Mall G. The pathophysiology of endometriosis and adenomyosis: tissue injury and repair.Arch Gynecol Obstet. 2009; 280: 529-538Crossref PubMed Scopus (287) Google Scholar). This mechanism leads to a specific physiological process that promotes local production of interleukin-1 and induces activation of COX-2, causing production of prostaglandin E2. Steroidogenic acute regulatory protein and P450 aromatase are subsequently activated, allowing T formation and aromatization to E2 and contributing to the hyperestrogenic status of the eutopic endometrium. E2 exerts its proliferative and healing effects by means of estrogen receptors (ERs, ER-β in this case). However, in normal healing, increased production of estrogens ceases, but in the uterus, they stimulate oxytocin-mediated hyperperistalsis through ER-α, which inhibits the healing process (Fig. 1B). Thus, a positive feedback mechanism is generated, by which chronic hyperperistalsis in the JZ promotes repeated cycles of autotraumatization, leading to constant disruption of the muscular fibers in the myometrial wall. This worsens with each cycle and consequently increases invagination of the endometrial basal layer into the myometrium, eventually leading to establishment of adenomyotic lesions (Figure 1, Figure 2A). Moreover, as expression of matrix metalloproteinases (MMPs) -2 and -9 was found to be significantly higher in the eutopic endometrium of adenomyotic lesions than in the endometrium of disease-free women (34Li T. Li Y.G. Pu D.M. Matrix metalloproteinase-2 and -9 expression correlated with angiogenesis in human adenomyosis.Gynecol Obstet Invest. 2006; 62: 229-235Crossref PubMed Scopus (70) Google Scholar), it is possible that these proteases may also be involved in the intramyometrial endometrial invagination process. In addition, because they may present with tissue damage to the endometrial-myometrial interface, cesarean delivery, increased birth rates, and prior uterine surgery were revealed by a number of retrospective studies to be risk factors for adenomyosis (35Parazzini F. Vercellini P. Panazza S. Chatenoud L. Oldani S. Crosignani P.G. Risk factors for adenomyosis.Hum Reprod. 1997; 12: 1275-1279Crossref PubMed Scopus (161) Google Scholar, 36Templeman C. Marshall S.F. Ursin G. Horn-Ross P.L. Clarke C.A. Allen M. et al.Adenomyosis and endometriosis in the California Teachers Study.Fertil Steril. 2008; 90: 415-424Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 37Riggs J.C. Lim E.K. 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Similarly, as their histology reveals typical features of adenomyosis with smooth muscle hyperplasia and fibrosis, deep endometriotic nodules were also suggested to be a possible consequence of Müllerian rest differentiation, at least in some cases, or the result of an adenomyotic tumoral process originating from the cervix, as suggested by Donnez et al. over 20 years ago (44Donnez J. Nisolle M. Casanas-Roux F. Brion P. Da Costa Ferreira N. Stereometric evaluation of peritoneal endometriosis and endometriotic nodules of the rectovaginal septum.Hum Reprod. 1996; 11: 224-228Crossref PubMed Scopus (41) Google Scholar, 45Donnez J. Nisolle M. Casanas-Roux F. Bassil S. Anaf V. Rectovaginal septum, endometriosis or adenomyosis: laparoscopic management in a series of 231 patients.Hum Reprod. 1995; 10: 630-635Crossref PubMed Scopus (163) Google Scholar, 46Donnez J. Nisolle M. Gillerot S. Smets M. Bassil S. Casanas-Roux F. 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Rectovaginal septum adenomyotic nodules: a series of 500 cases.Br J Obstet Gynaecol. 1997; 104: 1014-1018Crossref PubMed Scopus (143) Google Scholar), or the posterior part of the cervix and form a cervical adenomyotic nodule that may extend posteriorly in the direction of the exterior wall of the rectum. Deep lesions are plainly different from peritoneal endometriosis (44Donnez J. Nisolle M. Casanas-Roux F. Brion P. Da Costa Ferreira N. Stereometric evaluation of peritoneal endometriosis and endometriotic nodules of the rectovaginal septum.Hum Reprod. 1996; 11: 224-228Crossref PubMed Scopus (41) Google Scholar, 47Nisolle M. Donnez J. Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities.Fertil Steril. 1997; 68: 585-596Abstract Full Text PDF PubMed Scopus (943) Google Scholar), and their histology is clearly identical to that of uterine adenomyosis. The Müllerian metaplasia theory is further supported by case reports of confirmed adenomyosis in the rudimentary muscular uterine wall of patients with Rokitansky-Kuster-Hauser syndrome (absence of functional endometrium) (48Enatsu A. Harada T. Yoshida S. Iwabe T. Terakawa N. Adenomyosis in a patient with the Rokitansky-Kuster-Hauser syndrome.Fertil Steril. 2000; 73: 862-863Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 49Chun S. Kim Y.M. Ji Y.I. Uterine adenomyosis which developed from hypoplastic uterus in postmenopausal woman with Mayer-Rokitansky-Kuster-Hauser syndrome: a case report.J Menopausal Med. 2013; 19: 135-138Crossref PubMed Google Scholar, 50Hoo P.S. Norhaslinda A.R. Reza J.N. Rare case of leiomyoma and adenomyosis in Mayer-Rokitansky-Kuster-Hauser syndrome.Case Rep Obstet Gynecol. 2016; 2016: 3725043PubMed Google Scholar). 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