Download PDF
Semin Reprod Med 2020; 38(02/03): 129-143
DOI: 10.1055/s-0040-1716687
Review Article

Adenomyosis: Mechanisms and Pathogenesis

Junyu Zhai 
1   Department of Obstetrics, Gynecology and Reproductive Sciences, Center for Reproductive Sciences, University of California, San Francisco, San Francisco, California
2   Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China
3   Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, People's Republic of China
,
Silvia Vannuccini 
4   Division of Obstetrics and Gynecology, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Careggi University Hospital, Florence, Italy
5   Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
,
Felice Petraglia 
4   Division of Obstetrics and Gynecology, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Careggi University Hospital, Florence, Italy
,
Linda C. Giudice 
1   Department of Obstetrics, Gynecology and Reproductive Sciences, Center for Reproductive Sciences, University of California, San Francisco, San Francisco, California
› Author Affiliations Funding This review was supported by the NIH Eunice Kennedy Shriver National Institute for Child Health and Human Development (P50 HD055764-12 [LCG]).
› Further Information
    Permissions and Reprints

Abstract

Adenomyosis is a common disorder of the uterus, and is associated with an enlarged uterus, heavy menstrual bleeding (HMB), pelvic pain, and infertility. It is characterized by endometrial epithelial cells and stromal fibroblasts abnormally found in the myometrium where they elicit hyperplasia and hypertrophy of surrounding smooth muscle cells. While both the mechanistic processes and the pathogenesis of adenomyosis are uncertain, several theories have been put forward addressing how this disease develops. These include intrinsic or induced (1) microtrauma of the endometrial–myometrial interface; (2) enhanced invasion of endometrium into myometrium; (3) metaplasia of stem cells in myometrium; (4) infiltration of endometrial cells in retrograde menstrual effluent into the uterine wall from the serosal side; (5) induction of adenomyotic lesions by aberrant local steroid and pituitary hormones; and (6) abnormal uterine development in response to genetic and epigenetic modifications. Dysmenorrhea, HMB, and infertility are likely results of inflammation, neurogenesis, angiogenesis, and contractile abnormalities in the endometrial and myometrial components. Elucidating mechanisms underlying the pathogenesis of adenomyosis raise possibilities to develop targeted therapies to ameliorate symptoms beyond the current agents that are largely ineffective. Herein, we address these possible etiologies and data that support underlying mechanisms.

Keywords

adenomyosis - mechanisms - pathogenesis - metaplasia - endometrial–myometrial interface


Publication History

Article published online:
08 October 2020

© 2020. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Brosens JJ, de Souza NM, Barker FG. Uterine junctional zone: function and disease. Lancet 1995; 346 (8974): 558-560
    CrossrefPubMedGoogle Scholar
  • 2 Naftalin J, Jurkovic D. The endometrial-myometrial junction: a fresh look at a busy crossing. Ultrasound Obstet Gynecol 2009; 34 (01) 1-11
    CrossrefPubMedGoogle Scholar
  • 3 Zhang Y, Zhou L, Li TC, Duan H, Yu P, Wang HY. Ultrastructural features of endometrial-myometrial interface and its alteration in adenomyosis. Int J Clin Exp Pathol 2014; 7 (04) 1469-1477
    PubMedGoogle Scholar
  • 4 Uduwela AS, Perera MA, Aiqing L, Fraser IS. Endometrial-myometrial interface: relationship to adenomyosis and changes in pregnancy. Obstet Gynecol Surv 2000; 55 (06) 390-400
    CrossrefPubMedGoogle Scholar
  • 5 Hricak H, Alpers C, Crooks LE, Sheldon PE. Magnetic resonance imaging of the female pelvis: initial experience. AJR Am J Roentgenol 1983; 141 (06) 1119-1128
    CrossrefPubMedGoogle Scholar
  • 6 Rasmussen CK, Hansen ES, Dueholm M. Two- and three-dimensional ultrasonographic features related to histopathology of the uterine endometrial-myometrial junctional zone. Acta Obstet Gynecol Scand 2019; 98 (02) 205-214
    CrossrefPubMedGoogle Scholar
  • 7 Mehasseb MK, Bell SC, Brown L, Pringle JH, Habiba M. Phenotypic characterisation of the inner and outer myometrium in normal and adenomyotic uteri. Gynecol Obstet Invest 2011; 71 (04) 217-224
    CrossrefPubMedGoogle Scholar
  • 8 Tetlow RL, Richmond I, Manton DJ, Greenman J, Turnbull LW, Killick SR. Histological analysis of the uterine junctional zone as seen by transvaginal ultrasound. Ultrasound Obstet Gynecol 1999; 14 (03) 188-193
    CrossrefPubMedGoogle Scholar
  • 9 Kishi Y, Shimada K, Fujii T. et al. Phenotypic characterization of adenomyosis occurring at the inner and outer myometrium. PLoS One 2017; 12 (12) e0189522
    CrossrefPubMedGoogle Scholar
  • 10 Ijland MM, Evers JL, Dunselman GA, van Katwijk C, Lo CR, Hoogland HJ. Endometrial wavelike movements during the menstrual cycle. Fertil Steril 1996; 65 (04) 746-749
    CrossrefPubMedGoogle Scholar
  • 11 Kunz G, Beil D, Deininger H, Wildt L, Leyendecker G. The dynamics of rapid sperm transport through the female genital tract: evidence from vaginal sonography of uterine peristalsis and hysterosalpingoscintigraphy. Hum Reprod 1996; 11 (03) 627-632
    CrossrefPubMedGoogle Scholar
  • 12 de Vries K, Lyons EA, Ballard G, Levi CS, Lindsay DJ. Contractions of the inner third of the myometrium. Am J Obstet Gynecol 1990; 162 (03) 679-682
    CrossrefPubMedGoogle Scholar
  • 13 Lyons EA, Taylor PJ, Zheng XH, Ballard G, Levi CS, Kredentser JV. Characterization of subendometrial myometrial contractions throughout the menstrual cycle in normal fertile women. Fertil Steril 1991; 55 (04) 771-774
    CrossrefPubMedGoogle Scholar
  • 14 Hoad CL, Raine-Fenning NJ, Fulford J, Campbell BK, Johnson IR, Gowland PA. Uterine tissue development in healthy women during the normal menstrual cycle and investigations with magnetic resonance imaging. Am J Obstet Gynecol 2005; 192 (02) 648-654
    CrossrefPubMedGoogle Scholar
  • 15 Noe M, Kunz G, Herbertz M, Mall G, Leyendecker G. The cyclic pattern of the immunocytochemical expression of oestrogen and progesterone receptors in human myometrial and endometrial layers: characterization of the endometrial-subendometrial unit. Hum Reprod 1999; 14 (01) 190-197
    CrossrefPubMedGoogle Scholar
  • 16 Aguilar HN, Mitchell BF. Physiological pathways and molecular mechanisms regulating uterine contractility. Hum Reprod Update 2010; 16 (06) 725-744
    CrossrefPubMedGoogle Scholar
  • 17 Kurowicka B, Franczak A, Oponowicz A, Kotwica G. In vitro contractile activity of porcine myometrium during luteolysis and early pregnancy: effect of oxytocin and progesterone. Reprod Biol 2005; 5 (02) 151-169
    PubMedGoogle Scholar
  • 18 Frankl O. Adenomyosis uteri. Am J Obstet Gynecol 1925; 10: 680-684
    CrossrefPubMedGoogle Scholar
  • 19 Sampson JA. Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol 1927; 14: 422-469
    CrossrefPubMedGoogle Scholar
  • 20 Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril 2012; 98 (03) 511-519
    CrossrefPubMedGoogle Scholar
  • 21 Benagiano G, Brosens I, Habiba M. Structural and molecular features of the endomyometrium in endometriosis and adenomyosis. Hum Reprod Update 2014; 20 (03) 386-402
    CrossrefPubMedGoogle Scholar
  • 22 Bergeron C, Amant F, Ferenczy A. Pathology and physiopathology of adenomyosis. Best Pract Res Clin Obstet Gynaecol 2006; 20 (04) 511-521
    CrossrefPubMedGoogle Scholar
  • 23 Curtis KM, Hillis SD, Marchbanks PA, Peterson HB. Disruption of the endometrial-myometrial border during pregnancy as a risk factor for adenomyosis. Am J Obstet Gynecol 2002; 187 (03) 543-544
    CrossrefPubMedGoogle Scholar
  • 24 Mehasseb MK, Taylor AH, Pringle JH, Bell SC, Habiba M. Enhanced invasion of stromal cells from adenomyosis in a three-dimensional coculture model is augmented by the presence of myocytes from affected uteri. Fertil Steril 2010; 94 (07) 2547-2551
    CrossrefPubMedGoogle Scholar
  • 25 Friedl P, Gilmour D. Collective cell migration in morphogenesis, regeneration and cancer. Nat Rev Mol Cell Biol 2009; 10 (07) 445-457
    CrossrefPubMedGoogle Scholar
  • 26 Donnez O, Orellana R, Van Kerk O, Dehoux JP, Donnez J, Dolmans MM. Invasion process of induced deep nodular endometriosis in an experimental baboon model: similarities with collective cell migration?. Fertil Steril 2015; 104 (02) 491-7.e2
    CrossrefPubMedGoogle Scholar
  • 27 García-Solares J, Donnez J, Donnez O, Dolmans MM. Pathogenesis of uterine adenomyosis: invagination or metaplasia?. Fertil Steril 2018; 109 (03) 371-379
    CrossrefPubMedGoogle Scholar
  • 28 Li J, Yanyan M, Mu L, Chen X, Zheng W. The expression of Bcl-2 in adenomyosis and its effect on proliferation, migration, and apoptosis of endometrial stromal cells. Pathol Res Pract 2019; 215 (08) 152477
    CrossrefPubMedGoogle Scholar
  • 29 Jones RK, Searle RF, Bulmer JN. Apoptosis and bcl-2 expression in normal human endometrium, endometriosis and adenomyosis. Hum Reprod 1998; 13 (12) 3496-3502
    CrossrefPubMedGoogle Scholar
  • 30 Herndon CN, Aghajanova L, Balayan S. et al. Global transcriptome abnormalities of the eutopic endometrium from women with adenomyosis. Reprod Sci 2016; 23 (10) 1289-1303
    CrossrefPubMedGoogle Scholar
  • 31 Guo J, Chen L, Luo N. et al. LPS/TLR4-mediated stromal cells acquire an invasive phenotype and are implicated in the pathogenesis of adenomyosis. Sci Rep 2016; 6: 21416
    CrossrefPubMedGoogle Scholar
  • 32 Liu X, Shen M, Qi Q, Zhang H, Guo SW. Corroborating evidence for platelet-induced epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation in the development of adenomyosis. Hum Reprod 2016; 31 (04) 734-749
    CrossrefPubMedGoogle Scholar
  • 33 Zhao L, Zhou S, Zou L, Zhao X. The expression and functionality of stromal caveolin 1 in human adenomyosis. Hum Reprod 2013; 28 (05) 1324-1338
    CrossrefPubMedGoogle Scholar
  • 34 Xu XY, Zhang J, Qi YH, Kong M, Liu SA, Hu JJ. Linc-ROR promotes endometrial cell proliferation by activating the PI3K-Akt pathway. Eur Rev Med Pharmacol Sci 2018; 22 (08) 2218-2225
    PubMedGoogle Scholar
  • 35 Tokyol C, Aktepe F, Dilek FH, Sahin O, Arioz DT. Expression of cyclooxygenase-2 and matrix metalloproteinase-2 in adenomyosis and endometrial polyps and its correlation with angiogenesis. Int J Gynecol Pathol 2009; 28 (02) 148-156
    CrossrefPubMedGoogle Scholar
  • 36 Li T, Li YG, Pu DM. Matrix metalloproteinase-2 and -9 expression correlated with angiogenesis in human adenomyosis. Gynecol Obstet Invest 2006; 62 (04) 229-235
    CrossrefPubMedGoogle Scholar
  • 37 Xiang Y, Sun Y, Yang B. et al. Transcriptome sequencing of adenomyosis eutopic endometrium: a new insight into its pathophysiology. J Cell Mol Med 2019; 23 (12) 8381-8391
    CrossrefPubMedGoogle Scholar
  • 38 Chen YJ, Li HY, Huang CH. et al. Oestrogen-induced epithelial-mesenchymal transition of endometrial epithelial cells contributes to the development of adenomyosis. J Pathol 2010; 222 (03) 261-270
    CrossrefPubMedGoogle Scholar
  • 39 Khan KN, Kitajima M, Hiraki K, Fujishita A, Nakashima M, Masuzaki H. Involvement of hepatocyte growth factor-induced epithelial-mesenchymal transition in human adenomyosis. Biol Reprod 2015; 92 (02) 35
    PubMedGoogle Scholar
  • 40 Oh SJ, Shin JH, Kim TH. et al. β-Catenin activation contributes to the pathogenesis of adenomyosis through epithelial-mesenchymal transition. J Pathol 2013; 231 (02) 210-222
    CrossrefPubMedGoogle Scholar
  • 41 Zhou W, Peng Z, Zhang C, Liu S, Zhang Y. ILK-induced epithelial-mesenchymal transition promotes the invasive phenotype in adenomyosis. Biochem Biophys Res Commun 2018; 497 (04) 950-956
    CrossrefPubMedGoogle Scholar
  • 42 Hu R, Peng GQ, Ban DY, Zhang C, Zhang XQ, Li YP. High-expression of neuropilin 1 correlates to estrogen-induced epithelial-mesenchymal transition of endometrial cells in adenomyosis. Reprod Sci 2020; 27 (01) 395-403
    CrossrefPubMedGoogle Scholar
  • 43 Shen M, Liu X, Zhang H, Guo SW. Transforming growth factor β1 signaling coincides with epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation in the development of adenomyosis in mice. Hum Reprod 2016; 31 (02) 355-369
    PubMedGoogle Scholar
  • 44 Zhu B, Chen Y, Shen X, Liu X, Guo SW. Anti-platelet therapy holds promises in treating adenomyosis: experimental evidence. Reprod Biol Endocrinol 2016; 14 (01) 66
    CrossrefPubMedGoogle Scholar
  • 45 Ibrahim MG, Chiantera V, Frangini S. et al. Ultramicro-trauma in the endometrial-myometrial junctional zone and pale cell migration in adenomyosis. Fertil Steril 2015; 104 (06) 1475-83.e1 , 3
    CrossrefPubMedGoogle Scholar
  • 46 Kunz 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 (08) 2309-2316
    CrossrefPubMedGoogle Scholar
  • 47 Yang G, Im HJ, Wang JH. Repetitive mechanical stretching modulates IL-1beta induced COX-2, MMP-1 expression, and PGE2 production in human patellar tendon fibroblasts. Gene 2005; 363: 166-172
    CrossrefPubMedGoogle Scholar
  • 48 Mowa CN, Hoch R, Montavon CL, Jesmin S, Hindman G, Hou G. Estrogen enhances wound healing in the penis of rats. Biomed Res 2008; 29 (05) 267-270
    CrossrefPubMedGoogle Scholar
  • 49 Leyendecker G, Kunz G, Wildt L, Beil D, Deininger H. Uterine hyperperistalsis and dysperistalsis as dysfunctions of the mechanism of rapid sperm transport in patients with endometriosis and infertility. Hum Reprod 1996; 11 (07) 1542-1551
    CrossrefPubMedGoogle Scholar
  • 50 Kunz G, Noe M, Herbertz M, Leyendecker G. Uterine peristalsis during the follicular phase of the menstrual cycle: effects of oestrogen, antioestrogen and oxytocin. Hum Reprod Update 1998; 4 (05) 647-654
    CrossrefPubMedGoogle Scholar
  • 51 Leyendecker G, Wildt L, Mall G. The pathophysiology of endometriosis and adenomyosis: tissue injury and repair. Arch Gynecol Obstet 2009; 280 (04) 529-538
    CrossrefPubMedGoogle Scholar
  • 52 Leyendecker G, Bilgicyildirim A, Inacker M. 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 (04) 917-932
    CrossrefPubMedGoogle Scholar
  • 53 Carrarelli P, Yen CF, Arcuri F. et al. Myostatin, follistatin and activin type II receptors are highly expressed in adenomyosis. Fertil Steril 2015; 104 (03) 744-52.e1
    CrossrefPubMedGoogle Scholar
  • 54 Zhou S, Yi T, Liu R. et al. Proteomics identification of annexin A2 as a key mediator in the metastasis and proangiogenesis of endometrial cells in human adenomyosis. Mol Cell Proteomics 2012; 11 (07) 017988
    CrossrefPubMedGoogle Scholar
  • 55 Chun S, Kim YM, Ji YI. Uterine adenomyosis which developed from hypoplastic uterus in postmenopausal woman with Mayer-Rokitansky-Kuster-Hauser syndrome: a case report. J Menopausal Med 2013; 19 (03) 135-138
    CrossrefPubMedGoogle Scholar
  • 56 Hoo PS, Norhaslinda AR, Reza JN. Rare case of leiomyoma and adenomyosis in Mayer-Rokitansky-Kuster-Hauser syndrome. Case Rep Obstet Gynecol 2016; 2016: 3725043
    PubMedGoogle Scholar
  • 57 Ferenczy A. Pathophysiology of adenomyosis. Hum Reprod Update 1998; 4 (04) 312-322
    CrossrefPubMedGoogle Scholar
  • 58 Schwab KE, Gargett CE. Co-expression of two perivascular cell markers isolates mesenchymal stem-like cells from human endometrium. Hum Reprod 2007; 22 (11) 2903-2911
    CrossrefPubMedGoogle Scholar
  • 59 Masuda H, Anwar SS, Bühring HJ, Rao JR, Gargett CE. A novel marker of human endometrial mesenchymal stem-like cells. Cell Transplant 2012; 21 (10) 2201-2214
    CrossrefPubMedGoogle Scholar
  • 60 Gargett CE, Schwab KE, Zillwood RM, Nguyen HP, Wu D. Isolation and culture of epithelial progenitors and mesenchymal stem cells from human endometrium. Biol Reprod 2009; 80 (06) 1136-1145
    CrossrefPubMedGoogle Scholar
  • 61 Chen YJ, Li HY, Chang YL. et al. Suppression of migratory/invasive ability and induction of apoptosis in adenomyosis-derived mesenchymal stem cells by cyclooxygenase-2 inhibitors. Fertil Steril 2010; 94 (06) 1972-1979 , 1979.e1–1979.e4
    CrossrefPubMedGoogle Scholar
  • 62 Götte M, Wolf M, Staebler A. et al. Increased expression of the adult stem cell marker Musashi-1 in endometriosis and endometrial carcinoma. J Pathol 2008; 215 (03) 317-329
    CrossrefPubMedGoogle Scholar
  • 63 Inoue S, Hirota Y, Ueno T. et al. Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations. Nat Commun 2019; 10 (01) 5785
    CrossrefPubMedGoogle Scholar
  • 64 Gargett CE. Uterine stem cells: What is the evidence?. Hum Reprod Update 2007; 13 (01) 87-101
    CrossrefPubMedGoogle Scholar
  • 65 Alawadhi F, Du H, Cakmak H, Taylor HS. Bone marrow-derived stem cell (BMDSC) transplantation improves fertility in a murine model of Asherman's syndrome. PLoS One 2014; 9 (05) e96662
    CrossrefPubMedGoogle Scholar
  • 66 Garcia L, Isaacson K. Adenomyosis: review of the literature. J Minim Invasive Gynecol 2011; 18 (04) 428-437
    CrossrefPubMedGoogle Scholar
  • 67 Chan RW, Schwab KE, Gargett CE. Clonogenicity of human endometrial epithelial and stromal cells. Biol Reprod 2004; 70 (06) 1738-1750
    CrossrefPubMedGoogle Scholar
  • 68 Vannuccini S, Tosti C, Carmona F. et al. Pathogenesis of adenomyosis: an update on molecular mechanisms. Reprod Biomed Online 2017; 35 (05) 592-601
    CrossrefPubMedGoogle Scholar
  • 69 Yi KW, Kim SH, Ihm HJ. et al. Increased expression of p21-activated kinase 4 in adenomyosis and its regulation of matrix metalloproteinase-2 and -9 in endometrial cells. Fertil Steril 2015; 103 (04) 1089-1097.e2
    CrossrefPubMedGoogle Scholar
  • 70 Gargett CE, Masuda H. Adult stem cells in the endometrium. Mol Hum Reprod 2010; 16 (11) 818-834
    CrossrefPubMedGoogle Scholar
  • 71 Schüring AN, Schulte N, Kelsch R, Röpke A, Kiesel L, Götte M. Characterization of endometrial mesenchymal stem-like cells obtained by endometrial biopsy during routine diagnostics. Fertil Steril 2011; 95 (01) 423-426
    CrossrefPubMedGoogle Scholar
  • 72 Spitzer TL, Rojas A, Zelenko Z. et al. Perivascular human endometrial mesenchymal stem cells express pathways relevant to self-renewal, lineage specification, and functional phenotype. Biol Reprod 2012; 86 (02) 58
    CrossrefPubMedGoogle Scholar
  • 73 Musina RA, Belyavski AV, Tarusova OV, Solovyova EV, Sukhikh GT. Endometrial mesenchymal stem cells isolated from the menstrual blood. Bull Exp Biol Med 2008; 145 (04) 539-543
    CrossrefPubMedGoogle Scholar
  • 74 Vannuccini S, Petraglia F. Recent advances in understanding and managing adenomyosis. F1000 Res 2019; 8: 8
    CrossrefPubMedGoogle Scholar
  • 75 Chapron C, Tosti C, Marcellin L. et al. Relationship between the magnetic resonance imaging appearance of adenomyosis and endometriosis phenotypes. Hum Reprod 2017; 32 (07) 1393-1401
    CrossrefPubMedGoogle Scholar
  • 76 El-Shennawy GA, Elbialy AA, Isamil AE, El Behery MM. Is genetic polymorphism of ER-α, CYP1A1, and CYP1B1 a risk factor for uterine leiomyoma?. Arch Gynecol Obstet 2011; 283 (06) 1313-1318
    CrossrefPubMedGoogle Scholar
  • 77 Bulun SE, Chen D, Moy I, Brooks DC, Zhao H. Aromatase, breast cancer and obesity: a complex interaction. Trends Endocrinol Metab 2012; 23 (02) 83-89
    CrossrefPubMedGoogle Scholar
  • 78 Tsuchiya M, Tsukino H, Iwasaki M. et al. Interaction between cytochrome P450 gene polymorphisms and serum organochlorine TEQ levels in the risk of endometriosis. Mol Hum Reprod 2007; 13 (06) 399-404
    CrossrefPubMedGoogle Scholar
  • 79 Artymuk N, Zotova O, Gulyaeva L. Adenomyosis: genetics of estrogen metabolism. Horm Mol Biol Clin Investig 2019; 37 (02) 37
    PubMedGoogle Scholar
  • 80 Tong 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: 17-21
    CrossrefPubMedGoogle Scholar
  • 81 Thomas P, Pang Y, Filardo EJ, Dong J. Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells. Endocrinology 2005; 146 (02) 624-632
    CrossrefPubMedGoogle Scholar
  • 82 Hong DG, Park JY, Chong GO. et al. Transmembrane G protein-coupled receptor 30 gene polymorphisms and uterine adenomyosis in Korean women. Gynecol Endocrinol 2019; 35 (06) 498-501
    CrossrefPubMedGoogle Scholar
  • 83 van Kaam KJ, Romano A, Schouten JP, Dunselman GA, Groothuis PG. Progesterone receptor polymorphism +331G/A is associated with a decreased risk of deep infiltrating endometriosis. Hum Reprod 2007; 22 (01) 129-135
    CrossrefPubMedGoogle Scholar
  • 84 Kitawaki J, Obayashi H, Ishihara H. et al. Oestrogen receptor-alpha gene polymorphism is associated with endometriosis, adenomyosis and leiomyomata. Hum Reprod 2001; 16 (01) 51-55
    CrossrefPubMedGoogle Scholar
  • 85 Ye H, He Y, Wang J. et al. Effect of matrix metalloproteinase promoter polymorphisms on endometriosis and adenomyosis risk: evidence from a meta-analysis. J Genet 2016; 95 (03) 611-619
    CrossrefPubMedGoogle Scholar
  • 86 Kang S, Zhao X, Xing H. et al. Polymorphisms in the matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 and the risk of human adenomyosis. Environ Mol Mutagen 2008; 49 (03) 226-231
    CrossrefPubMedGoogle Scholar
  • 87 Kang S, Li SZ, Wang N. et al. Association between genetic polymorphisms in fibroblast growth factor (FGF)1 and FGF2 and risk of endometriosis and adenomyosis in Chinese women. Hum Reprod 2010; 25 (07) 1806-1811
    CrossrefPubMedGoogle Scholar
  • 88 Kang S, Zhao J, Liu Q, Zhou R, Wang N, Li Y. Vascular endothelial growth factor gene polymorphisms are associated with the risk of developing adenomyosis. Environ Mol Mutagen 2009; 50 (05) 361-366
    CrossrefPubMedGoogle Scholar
  • 89 Liu Q, Li Y, Zhao J. et al. [Association of single nucleotide polymorphisms in VEGF gene with the risk of endometriosis and adenomyosis]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2009; 26 (02) 165-169
    PubMedGoogle Scholar
  • 90 Wang Y, Qu Y, Song W. Genetic variation in COX-2 -1195 and the risk of endometriosis and adenomyosis. Clin Exp Obstet Gynecol 2015; 42 (02) 168-172
    CrossrefPubMedGoogle Scholar
  • 91 Liu X, Guo SW. Aberrant immunoreactivity of deoxyribonucleic acid methyltransferases in adenomyosis. Gynecol Obstet Invest 2012; 74 (02) 100-108
    CrossrefPubMedGoogle Scholar
  • 92 Nie J, Liu X, Guo SW. 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 (11) 995-1005
    CrossrefPubMedGoogle Scholar
  • 93 Liu X, Guo SW. Valproic acid alleviates generalized hyperalgesia in mice with induced adenomyosis. J Obstet Gynaecol Res 2011; 37 (07) 696-708
    CrossrefPubMedGoogle Scholar
  • 94 Liu X, Guo SW. A pilot study on the off-label use of valproic acid to treat adenomyosis. Fertil Steril 2008; 89 (01) 246-250
    CrossrefPubMedGoogle Scholar
  • 95 Wen J, Lv R, Ma H. et al. Zc3h13 regulates nuclear RNA m6A methylation and mouse embryonic stem cell self-renewal. Mol Cell 2018; 69 (06) 1028-1038.e6
    CrossrefPubMedGoogle Scholar
  • 96 Zhai J, Li S, Sen S. et al. m6A RNA methylation regulators contribute. to eutopic endometrium and myometrium dysfunction in adenomyosis. Front Genet 2020; 11: 716
    CrossrefPubMedGoogle Scholar
  • 97 Pan SC, Gardner WU. Carcinomas of the uterine cervix and vagina in estrogen- and androgen-treated hybrid mice. Cancer Res 1948; 8 (07) 337-345
    PubMedGoogle Scholar
  • 98 Takahashi K, Nagata H, Kitao M. Clinical usefulness of determination of estradiol level in the menstrual blood for patients with endometriosis. Nippon Sanka Fujinka Gakkai Zasshi 1989; 41 (11) 1849-1850
    PubMedGoogle Scholar
  • 99 Kitawaki J, Noguchi T, Amatsu 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 (03) 514-519
    CrossrefPubMedGoogle Scholar
  • 100 Kitawaki 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 (09) 3292-3296
    PubMedGoogle Scholar
  • 101 Ezaki K, Motoyama H, Sasaki H. Immunohistologic localization of estrone sulfatase in uterine endometrium and adenomyosis. Obstet Gynecol 2001; 98 (5, Pt 1): 815-819
    PubMedGoogle Scholar
  • 102 Mehasseb MK, Panchal R, Taylor AH, Brown L, Bell SC, Habiba M. Estrogen and progesterone receptor isoform distribution through the menstrual cycle in uteri with and without adenomyosis. Fertil Steril 2011; 95 (07) 2228-2235 , 2235.e1
    CrossrefPubMedGoogle Scholar
  • 103 Wang S, Duan H, Zhang Y, Wang L, Zhang H, Li G. [Mechanism of 17β-estrogen on intracellular free calcium regulation in smooth muscle cells at the endometrial-myometrial interface in uteri with adenomyosis]. Zhonghua Fu Chan Ke Za Zhi 2015; 50 (07) 510-515
    PubMedGoogle Scholar
  • 104 Mori T, Nagasawa H, Takahashi S. The induction of adenomyosis in mice by intrauterine pituitary isografts. Life Sci 1981; 29 (12) 1277-1282
    CrossrefPubMedGoogle Scholar
  • 105 Singtripop T, Mori T, Park MK, Sakamoto S, Kawashima S. Development of uterine adenomyosis after treatment with dopamine antagonists in mice. Life Sci 1991; 49 (03) 201-206
    CrossrefPubMedGoogle Scholar
  • 106 Yamashita M, Matsuda M, Mori T. Increased expression of prolactin receptor mRNA in adenomyotic uterus in mice. Life Sci 1997; 60 (17) 1437-1446
    CrossrefPubMedGoogle Scholar
  • 107 Nagasawa H, Mori T. Stimulation of mammary tumorigenesis and suppression of uterine adenomyosis by temporary inhibition of pituitary prolactin secretion during youth in mice (41492). Proc Soc Exp Biol Med 1982; 171 (02) 164-167
    CrossrefPubMedGoogle Scholar
  • 108 Łupicka M, Socha BM, Szczepańska AA, Korzekwa AJ. Prolactin role in the bovine uterus during adenomyosis. Domest Anim Endocrinol 2017; 58: 1-13
    CrossrefPubMedGoogle Scholar
  • 109 Sengupta P, Sharma A, Mazumdar G. et al. The possible role of fluoxetine in adenomyosis: an animal experiment with clinical correlations. J Clin Diagn Res 2013; 7 (07) 1530-1534
    PubMedGoogle Scholar
  • 110 Andersson JK, Khan Z, Weaver AL, Vaughan LE, Gemzell-Danielsson K, Stewart EA. Vaginal bromocriptine improves pain, menstrual bleeding and quality of life in women with adenomyosis: a pilot study. Acta Obstet Gynecol Scand 2019; 98 (10) 1341-1350
    CrossrefPubMedGoogle Scholar
  • 111 Nowak RA, Mora S, Diehl T, Rhoades AR, Stewart EA. Prolactin is an autocrine or paracrine growth factor for human myometrial and leiomyoma cells. Gynecol Obstet Invest 1999; 48 (02) 127-132
    CrossrefPubMedGoogle Scholar
  • 112 Mori T, Singtripop T, Kawashima S. Animal model of uterine adenomyosis: is prolactin a potent inducer of adenomyosis in mice?. Am J Obstet Gynecol 1991; 165 (01) 232-234
    CrossrefPubMedGoogle Scholar
  • 113 Takemura M, Nomura S, Kimura T. et al. Expression and localization of oxytocin receptor gene in human uterine endometrium in relation to the menstrual cycle. Endocrinology 1993; 132 (04) 1830-1835
    CrossrefPubMedGoogle Scholar
  • 114 Guo SW, 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 (01) 231-240
    CrossrefPubMedGoogle Scholar
  • 115 Nie J, Liu X. Leonurine attenuates hyperalgesia in mice with induced adenomyosis. Med Sci Monit 2017; 23: 1701-1706
    CrossrefPubMedGoogle Scholar
  • 116 Bruner-Tran KL, Gnecco J, Ding T, Glore DR, Pensabene V, Osteen KG. Exposure to the environmental endocrine disruptor TCDD and human reproductive dysfunction: Translating lessons from murine models. Reprod Toxicol 2017; 68: 59-71
    CrossrefPubMedGoogle Scholar
  • 117 Bruner-Tran KL, Duleba AJ, Taylor HS, Osteen KG. Developmental toxicant exposure is associated with transgenerational adenomyosis in a murine model. Biol Reprod 2016; 95 (04) 73
    CrossrefPubMedGoogle Scholar
  • 118 Newbold RR, Jefferson WN, Padilla-Banks E. Long-term adverse effects of neonatal exposure to bisphenol A on the murine female reproductive tract. Reprod Toxicol 2007; 24 (02) 253-258
    CrossrefPubMedGoogle Scholar
  • 119 Bennett LM, McAllister KA, Malphurs J. et al. Mice heterozygous for a Brca1 or Brca2 mutation display distinct mammary gland and ovarian phenotypes in response to diethylstilbestrol. Cancer Res 2000; 60 (13) 3461-3469
    PubMedGoogle Scholar
  • 120 Huang PC, Tsai EM, Li WF. et al. Association between phthalate exposure and glutathione S-transferase M1 polymorphism in adenomyosis, leiomyoma and endometriosis. Hum Reprod 2010; 25 (04) 986-994
    CrossrefPubMedGoogle Scholar
  • 121 Ota H, Igarashi S, Hatazawa J, Tanaka T. Is adenomyosis an immune disease?. Hum Reprod Update 1998; 4 (04) 360-367
    CrossrefPubMedGoogle Scholar
  • 122 Ota H, Igarashi S. Expression of major histocompatibility complex class II antigen in endometriotic tissue in patients with endometriosis and adenomyosis. Fertil Steril 1993; 60 (05) 834-838
    CrossrefPubMedGoogle Scholar
  • 123 Wang F, Wen Z, Li H, Yang Z, Zhao X, Yao X. Human leukocyte antigen-G is expressed by the eutopic and ectopic endometrium of adenomyosis. Fertil Steril 2008; 90 (05) 1599-1604
    CrossrefPubMedGoogle Scholar
  • 124 Chiang CM, Hill JA. Localization of T cells, interferon-gamma and HLA-DR in eutopic and ectopic human endometrium. Gynecol Obstet Invest 1997; 43 (04) 245-250
    CrossrefPubMedGoogle Scholar
  • 125 Ota H, Maki M, Shidara Y. et al. Effects of danazol at the immunologic level in patients with adenomyosis, with special reference to autoantibodies: a multi-center cooperative study. Am J Obstet Gynecol 1992; 167 (02) 481-486
    CrossrefPubMedGoogle Scholar
  • 126 Wang F, Li H, Yang Z, Du X, Cui M, Wen Z. Expression of interleukin-10 in patients with adenomyosis. Fertil Steril 2009; 91 (05) 1681-1685
    CrossrefPubMedGoogle Scholar
  • 127 Li B, Chen M, Liu X, Guo SW. Constitutive and tumor necrosis factor-α-induced activation of nuclear factor-κB in adenomyosis and its inhibition by andrographolide. Fertil Steril 2013; 100 (02) 568-577
    CrossrefPubMedGoogle Scholar
  • 128 Carrarelli P, Yen CF, Funghi L. et al. Expression of inflammatory and neurogenic mediators in adenomyosis. Reprod Sci 2017; 24 (03) 369-375
    CrossrefPubMedGoogle Scholar
  • 129 Baigent SM. Peripheral corticotropin-releasing hormone and urocortin in the control of the immune response. Peptides 2001; 22 (05) 809-820
    CrossrefPubMedGoogle Scholar
  • 130 Tsatsanis C, Androulidaki A, Dermitzaki E, Gravanis A, Margioris AN. Corticotropin releasing factor receptor 1 (CRF1) and CRF2 agonists exert an anti-inflammatory effect during the early phase of inflammation suppressing LPS-induced TNF-alpha release from macrophages via induction of COX-2 and PGE2. J Cell Physiol 2007; 210 (03) 774-783
    CrossrefPubMedGoogle Scholar
  • 131 Vergetaki A, Jeschke U, Vrekoussis T. et al. Differential expression of CRH, UCN, CRHR1 and CRHR2 in eutopic and ectopic endometrium of women with endometriosis. PLoS One 2013; 8 (04) e62313
    CrossrefPubMedGoogle Scholar
  • 132 Brawn J, Morotti M, Zondervan KT, Becker CM, Vincent K. Central changes associated with chronic pelvic pain and endometriosis. Hum Reprod Update 2014; 20 (05) 737-747
    CrossrefPubMedGoogle Scholar
  • 133 Huang Y, Zheng W, Mu L, Ren Y, Chen X, Liu F. Expression of tyrosine kinase receptor B in eutopic endometrium of women with adenomyosis. Arch Gynecol Obstet 2011; 283 (04) 775-780
    CrossrefPubMedGoogle Scholar
  • 134 Huang HY, Yu HT, Chan SH, Lee CL, Wang HS, Soong YK. Eutopic endometrial interleukin-18 system mRNA and protein expression at the level of endometrial-myometrial interface in adenomyosis patients. Fertil Steril 2010; 94 (01) 33-39
    CrossrefPubMedGoogle Scholar
  • 135 Mao X, Wang Y, Carter AV, Zhen X, Guo SW. The retardation of myometrial infiltration, reduction of uterine contractility, and alleviation of generalized hyperalgesia in mice with induced adenomyosis by levo-tetrahydropalmatine (l-THP) and andrographolide. Reprod Sci 2011; 18 (10) 1025-1037
    CrossrefPubMedGoogle Scholar
  • 136 Armstrong L, Medford AR, Uppington KM. et al. Expression of functional toll-like receptor-2 and -4 on alveolar epithelial cells. Am J Respir Cell Mol Biol 2004; 31 (02) 241-245
    CrossrefPubMedGoogle Scholar
  • 137 Vannuccini S, Luisi S, Tosti C, Sorbi F, Petraglia F. Role of medical therapy in the management of uterine adenomyosis. Fertil Steril 2018; 109 (03) 398-405
    CrossrefPubMedGoogle Scholar
  • 138 Yang Y, Bin W, Aksoy MO, Kelsen SG. Regulation of interleukin-1beta and interleukin-1beta inhibitor release by human airway epithelial cells. Eur Respir J 2004; 24 (03) 360-366
    CrossrefPubMedGoogle Scholar
  • 139 Hayden MS, Ghosh S. Regulation of NF-κB by TNF family cytokines. Semin Immunol 2014; 26 (03) 253-266
    CrossrefPubMedGoogle Scholar
  • 140 Kojima H, Aizawa Y, Yanai Y. et al. An essential role for NF-kappa B in IL-18-induced IFN-gamma expression in KG-1 cells. J Immunol 1999; 162 (09) 5063-5069
    CrossrefPubMedGoogle Scholar
  • 141 McEvoy AN, Bresnihan B, FitzGerald O, Murphy EP. Cyclooxygenase 2-derived prostaglandin E2 production by corticotropin-releasing hormone contributes to the activated cAMP response element binding protein content in rheumatoid arthritis synovial tissue. Arthritis Rheum 2004; 50 (04) 1132-1145
    CrossrefPubMedGoogle Scholar
  • 142 Krantz KE. Innervation of the human uterus. Ann N Y Acad Sci 1959; 75: 770-784
    CrossrefPubMedGoogle Scholar
  • 143 Carrarelli P, Luddi A, Funghi L. et al. Urocortin and corticotrophin-releasing hormone receptor type 2 mRNA are highly expressed in deep infiltrating endometriotic lesions. Reprod Biomed Online 2016; 33 (04) 476-483
    CrossrefPubMedGoogle Scholar
  • 144 Apfel SC. Neurotrophic factors and pain. Clin J Pain 2000; 16 (02) S7-S11
    CrossrefPubMedGoogle Scholar
  • 145 Zhang X, Lu B, Huang X, Xu H, Zhou C, Lin J. Endometrial nerve fibers in women with endometriosis, adenomyosis, and uterine fibroids. Fertil Steril 2009; 92 (05) 1799-1801
    CrossrefPubMedGoogle Scholar
  • 146 Zhang X, Lu B, Huang X, Xu H, Zhou C, Lin J. Innervation of endometrium and myometrium in women with painful adenomyosis and uterine fibroids. Fertil Steril 2010; 94 (02) 730-737
    CrossrefPubMedGoogle Scholar
  • 147 Choi YJ, Chang JA, Kim YA, Chang SH, Chun KC, Koh JW. Innervation in women with uterine myoma and adenomyosis. Obstet Gynecol Sci 2015; 58 (02) 150-156
    CrossrefPubMedGoogle Scholar
  • 148 Li Y, Zhang SF, Zou SE, Xia X, Bao L. Accumulation of nerve growth factor and its receptors in the uterus and dorsal root ganglia in a mouse model of adenomyosis. Reprod Biol Endocrinol 2011; 9: 30
    CrossrefPubMedGoogle Scholar
  • 149 Chen Y, Zhu B, Zhang H, Liu X, Guo SW. Epigallocatechin-3-gallate reduces myometrial infiltration, uterine hyperactivity, and stress levels and alleviates generalized hyperalgesia in mice induced with adenomyosis. Reprod Sci 2013; 20 (12) 1478-1491
    CrossrefPubMedGoogle Scholar
  • 150 Wang F, Shi X, Qin X, Wen Z, Zhao X, Li C. Expression of CD56 in patients with adenomyosis and its correlation with dysmenorrhea. Eur J Obstet Gynecol Reprod Biol 2015; 194: 101-105
    CrossrefPubMedGoogle Scholar
  • 151 Nie J, Liu X, Zheng Y, Geng JG, Guo SW. Increased immunoreactivity to SLIT/ROBO1 and its correlation with severity of dysmenorrhea in adenomyosis. Fertil Steril 2011; 95 (03) 1164-1167
    CrossrefPubMedGoogle Scholar
  • 152 Wang J, Deng X, Yang Y, Yang X, Kong B, Chao L. Expression of GRIM-19 in adenomyosis and its possible role in pathogenesis. Fertil Steril 2016; 105 (04) 1093-1101
    CrossrefPubMedGoogle Scholar
  • 153 Harmsen MJ, Wong CFC, Mijatovic V. et al. Role of angiogenesis in adenomyosis-associated abnormal uterine bleeding and subfertility: a systematic review. Hum Reprod Update 2019; 25 (05) 647-671
    CrossrefPubMedGoogle Scholar
  • 154 Hillen F, Griffioen AW. Tumour vascularization: sprouting angiogenesis and beyond. Cancer Metastasis Rev 2007; 26 (3-4): 489-502
    CrossrefPubMedGoogle Scholar
  • 155 Huang TS, Chen YJ, Chou TY. et al. Oestrogen-induced angiogenesis promotes adenomyosis by activating the Slug-VEGF axis in endometrial epithelial cells. J Cell Mol Med 2014; 18 (07) 1358-1371
    CrossrefPubMedGoogle Scholar
  • 156 Schindl M, Birner P, Obermair A, Kiesel L, Wenzl R. Increased microvessel density in adenomyosis uteri. Fertil Steril 2001; 75 (01) 131-135
    CrossrefPubMedGoogle Scholar
  • 157 Goteri G, Lucarini G, Montik N. et al. Expression of vascular endothelial growth factor (VEGF), hypoxia inducible factor-1alpha (HIF-1alpha), and microvessel density in endometrial tissue in women with adenomyosis. Int J Gynecol Pathol 2009; 28 (02) 157-163
    CrossrefPubMedGoogle Scholar
  • 158 Ota H, Igarashi S, Tanaka T. Morphometric evaluation of stromal vascularization in the endometrium in adenomyosis. Hum Reprod 1998; 13 (03) 715-719
    CrossrefPubMedGoogle Scholar
  • 159 Nie J, Liu X, Guo SW. Immunoreactivity of oxytocin receptor and transient receptor potential vanilloid type 1 and its correlation with dysmenorrhea in adenomyosis. Am J Obstet Gynecol 2010; 202 (04) 346.e1-346.e8
    CrossrefPubMedGoogle Scholar
  • 160 Brainard AM, Korovkina VP, England SK. Potassium channels and uterine function. Semin Cell Dev Biol 2007; 18 (03) 332-339
    CrossrefPubMedGoogle Scholar
  • 161 Mechsner S, Grum B, Gericke C, Loddenkemper C, Dudenhausen JW, Ebert AD. Possible roles of oxytocin receptor and vasopressin-1α receptor in the pathomechanism of dysperistalsis and dysmenorrhea in patients with adenomyosis uteri. Fertil Steril 2010; 94 (07) 2541-2546
    CrossrefPubMedGoogle Scholar
  • 162 Shi H, Li R, Qiang J, Li Y, Wang L, Sun R. Computed tomography perfusion imaging detection of microcirculatory dysfunction in small intestinal ischemia-reperfusion injury in a porcine model. PLoS One 2016; 11 (07) e0160102
    CrossrefPubMedGoogle Scholar
  • 163 Chen Y, Li D, Zhang Z, Takushige N, Kong BH, Wang GY. Effect of siRNA against β-NGF on nerve fibers of a rat model with endometriosis. Reprod Sci 2014; 21 (03) 329-339
    CrossrefPubMedGoogle Scholar
  • 164 Lertvikool S, Sukprasert M, Pansrikaew P, Rattanasiri S, Weerakiet S. Comparative study of nerve fiber density between adenomyosis patients with moderate to severe pain and mild pain. J Med Assoc Thai 2014; 97 (08) 791-797
    PubMedGoogle Scholar
  • 165 Liu X, Nie J, Guo SW. Elevated immunoreactivity to tissue factor and its association with dysmenorrhea severity and the amount of menses in adenomyosis. Hum Reprod 2011; 26 (02) 337-345
    CrossrefPubMedGoogle Scholar
  • 166 Campo S, Campo V, Benagiano G. Adenomyosis and infertility. Reprod Biomed Online 2012; 24 (01) 35-46
    CrossrefPubMedGoogle Scholar
  • 167 Xiao Y, Li T, Xia E, Yang X, Sun X, Zhou Y. Expression of integrin β3 and osteopontin in the eutopic endometrium of adenomyosis during the implantation window. Eur J Obstet Gynecol Reprod Biol 2013; 170 (02) 419-422
    CrossrefPubMedGoogle Scholar
  • 168 Fischer CP, Kayisili U, Taylor HS. HOXA10 expression is decreased in endometrium of women with adenomyosis. Fertil Steril 2011; 95 (03) 1133-1136
    CrossrefPubMedGoogle Scholar
  • 169 Van Langendonckt A, Casanas-Roux F, Donnez J. Oxidative stress and peritoneal endometriosis. Fertil Steril 2002; 77 (05) 861-870
    CrossrefPubMedGoogle Scholar
  • 170 Yu O, Schulze-Rath R, Grafton J, Hansen K, Scholes D, Reed SD. Adenomyosis incidence, prevalence and treatment: United States population-based study 2006-2015. Am J Obstet Gynecol 2020; 223 (01) 94.e1-94.e10
    CrossrefPubMedGoogle Scholar