The Pathogenesis of Adenomyosis vis-à-vis Endometriosis

In the paper

“In fact, EMID can robustly induce adenomyosis in mice (Hao et al., submitted for publication).”

What the sources say

• Not checked yetcites Hao et al., submitted for publication

In the paper

“This wide variability stems from variations in the histological criteria adopted for diagnosis and the techniques used to procure myometrial samples [15].”

What the sources say

• Not checked yetcites [15] Vercellini, 2006, Adenomyosis, epidemiological factors, Best Pr. Res. Clin. Obs. Gynaecol. source

In the paper

“A preponderance of evidence suggests that a history of receiving dilatation and curettage (D&C) procedures is a risk factor for adenomyosis [19,20,21,22].”

What the sources say

• Not checked yetcites [19] Parazzini, 1997, Risk factors for adenomyosis, Hum. Reprod source
• Not checked yetcites [20] Levgur, 2000, Adenomyosis, symptoms, histology, and pregnancy terminations, Obs. Gynecol.
• Not checked yetcites [21] Curtis, 2002, Disruption of the endometrial-myometrial border during pregnancy as a risk factor for adenomyosis, Am. J. Obs. Gynecol. source
• Not checked yetcites [22] Panganamamula, 2004, Is prior uterine surgery a risk factor for adenomyosis?, Obs. Gynecol. source

In the paper

“The different risk profiles and the different age-specific incidence between the two diseases indicate that they are likely to have different pathogenesis.”

In the paper

“Even in women with leiomyomas, women with both leiomyomas and adenomyosis are reported to be older than those with leiomyomas alone [24].”

What the sources say

• Not checked yetcites [24] Brucker, 2014, Clinical characteristics indicating adenomyosis coexisting with leiomyomas, a retrospective, questionnaire-based study, Fertil. Steril. source

In the paper

“The age-specific incidence of adenomyosis is very different from that of endometriosis, reaching its peak at the age interval of 46–50 years [17].”

What the sources say

• Not checked yetcites [17] Morassutto, C., Monasta, L., Ricci, G., Barbone, F., and Ronfani, L. (2016). Incidence and Estimated Prevalence of Endometriosis and Adenomyosis in Northeast Italy, A Data Linkage Study. PLoS ONE, 11. source

In the paper

“In particular, neonatal exposure to diethylstilbestrol followed by continuous hormonal treatment—even progesterone alone—also results in adenomyosis [58].”

What the sources say

• Not checked yetcites [58] Ostrander, 1985, Long-term responses of the mouse uterus to neonatal diethylstilbestrol treatment and to later sex hormone exposure, J. Natl. Cancer Inst.

In the paper

“Yet normal endometrial stromal cells are very different in behavior from endometriotic or even adenomyotic stromal cells.”

What the sources say

• Not checked yetcites [65] Herndon, 2016, Global Transcriptome Abnormalities of the Eutopic Endometrium from Women with Adenomyosis, Reprod. Sci. source
• Not checked yetcites [66] Wu, 2006, Transcriptional characterizations of differences between eutopic and ectopic endometrium, Endocrinology source

In the paper

“Consequent to vascular damage, activated platelets can also release an array of cellular growth factors and angiogenic factors such as PDGF and VEGF, as well as inflammatory mediators such as IL-8 [79,80,81].”

What the sources say

• Not checked yetcites [79] Holt, 1985, Biochemistry of alpha granule proteins, Semin. Hematol.
• Not checked yetcites [80] Gear, 2003, Platelet chemokines and chemokine receptors, linking hemostasis, inflammation, and host defense, Microcirculation source
• Not checked yetcites [81] Wagner, 2003, Platelets in inflammation and thrombosis, Arter. Thromb. Vasc. Biol. source

In the paper

“In iatrogenic trauma such as the D&C procedure, the injury to the endometrium can probably extend to the EMI.”

In the paper

“In addition, genes involved in estrogen biosynthesis, such as steroidogenic acute regulatory protein (StAR) and P450 aromatase, are upregulated in adenomyosis [48,49].”

What the sources say

• Not checked yetcites [48] Kitawaki, 1997, Expression of aromatase cytochrome P450 protein and messenger ribonucleic acid in human endometriotic and adenomyotic tissues but not in normal endometrium, Biol. Reprod. source
• Not checked yetcites [49] Yamamoto, 1993, Evidence for estrogen synthesis in adenomyotic tissues, Am. J. Obs. Gynecol. source

In the paper

“It is also challenging to use either theory to make some useful, previously unknown, predictions.”

In the paper

“Macrophage-secreted growth factors such as vascular endothelial growth factor (VEGF) and its receptor VEGFR1 and VEGFR2, platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and transforming growth factor-β (TGF-β) have been reported to be induced by hypoxia [76,77,78].”

What the sources say

• Not checked yetcites [76] Murdoch, 2005, Hypoxia regulates macrophage functions in inflammation, J. Immunol. source
• Not checked yetcites [77] Gerber, 1997, Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. Flt-1, but not Flk-1/KDR, is up-regulated by hypoxia, J. Biol. Chem. source
• Not checked yetcites [78] Kappel, 1999, Identification of vascular endothelial growth factor (VEGF) receptor-2 (Flk-1) promoter/enhancer sequences sufficient for angioblast and endothelial cell-specific transcription in transgenic mice, Blood source

In the paper

“These facts cast some shadows on the very foundation of the TIAR theory.”

In the paper

“In adenomyosis, OTR overexpression in myometrium, concomitant with uterine hyperactivity, has been reported and is found to correlate to the severity of dysmenorrhea [46].”

What the sources say

• Not checked yetcites [46] Guo, 2013, Dysmenorrhea and its severity are associated with increased uterine contractility and overexpression of oxytocin receptor (OTR) in women with symptomatic adenomyosis, Fertil. Steril. source

In the paper

“For example, prolonged and unopposed exposure to estrogens is found to induce adenomyosis in various animals [53,54,55,56,57].”

What the sources say

• Not checked yetcites [53] Lacassagne, 1935, Modifications progressive de I’uterus de la souris sous l’action prolongee de I’oestrone, C R Seances Soc. Bioi.
• Not checked yetcites [54] Nelson, 1937, Endometrial and myometrial changes, including fibromatous nodules, induced in the uterus of guinea pig by prolonged administration of oestrogenic hormone, Anat. Rec. source
• Not checked yetcites [55] Meissner, 1957, Endometrial hyperplasia, endometrial carcinoma, and endometriosis produced experimentally by estrogen, Cancer source
• Not checked yetcites [56] Crossen, 1950, Endometrial polyps and hyperplasia produced in an aged monkey with estrogen plus progesterone, AMA Arch. Pathol.
• Not checked yetcites [57] Lipschutz, 1967, Pathological changes induced in the uterus of mice with the prolonged administration of progesterone and 19-nor-contraceptives, Br. J. Cancer source

In the paper

“While both theories may be biologically plausible, neither theory, unfortunately, could fully explain the genesis of different subtypes of adenomyosis.”

In the paper

“It is well accepted that uterine peristalsis due to myometrial contraction originates from the JZ, while the outer myometrium remains quiescent [42].”

What the sources say

• Not checked yetcites [42] Campo, 2012, Infertility and adenomyosis, Obs. Gynecol. Int.

In the paper

“Similarly, the gene encoding for steroidogenic factor-1 (SF-1), the protein critically involved in estrogen biosynthesis, is also hypermethylated and silenced in normal endometrial stromal cells [69].”

What the sources say

• Not checked yetcites [69] Xue, 2007, Transcriptional activation of steroidogenic factor-1 by hypomethylation of the 5′ CpG island in endometriosis, J. Clin. Endocrinol. Metab. source

In the paper

“Third, uterine hyperperistalsis/dysperistalsis may be a result of archimetral hyperestrogenism [38,47].”

What the sources say

• Not checked yetcites [38] Leyendecker, 1996, Uterine hyperperistalsis and dysperistalsis as dysfunctions of the mechanism of rapid sperm transport in patients with endometriosis and infertility, Hum. Reprod. source
• Not checked yetcites [47] Leyendecker, 2004, Uterine peristaltic activity and the development of endometriosis, Ann. NY Acad. Sci. source

In the paper

“Currently, there are essentially two major prevailing and competing theories: invagination and metaplasia [4].”

What the sources say

• Not checked yetcites [4] Donnez, 2018, Pathogenesis of uterine adenomyosis, invagination or metaplasia?, Fertil. Steril. source

In the paper

“Even when stimulated with PGE2, the expression of most genes involved in estrogen biosynthesis, including StAR, SF-1, and aromatase, are still negligibly low, concomitant with the very low production of estradiol in normal endometrial stromal cells [70].”

What the sources say

• Not checked yetcites [70] Attar, 2009, Prostaglandin E2 via steroidogenic factor-1 coordinately regulates transcription of steroidogenic genes necessary for estrogen synthesis in endometriosis, J. Clin. Endocrinol. Metab. source

In the paper

“In addition, the grafting of a single anterior pituitary into the uterine lumen induced a high incidence of adenomyosis in some strains of mice [59]”

What the sources say

• Not checked yetcites [59] Mori, 1981, The induction of adenomyosis in mice by intrauterine pituitary isografts, Life Sci. source

In the paper

“In addition, ERβ is also hypermethylated and silenced in normal endometrial stromal cells [71].”

What the sources say

• Not checked yetcites [71] Xue, 2007, Promoter methylation regulates estrogen receptor 2 in human endometrium and endometriosis, Biol. Reprod. source

In the paper

“However, the JZ thickening, in and of itself, does not provide proof of mucosal invasion of the myometrium [37].”

What the sources say

• Not checked yetcites [37] Brosens, 1995, Uterine junctional zone, function and disease, Lancet source

In the paper

“In stark contrast to endometriotic stromal cells, in fact, the promoter of the gene coding for P450 aromatase is hypermethylated in normal endometrial stromal cells, and thus silenced [67,68].”

What the sources say

• Not checked yetcites [67] Izawa, 2008, An epigenetic disorder may cause aberrant expression of aromatase gene in endometriotic stromal cells, Fertil. Steril. source
• Not checked yetcites [68] Izawa, 2011, Demethylation of a nonpromoter cytosine-phosphate-guanine island in the aromatase gene may cause the aberrant up-regulation in endometriotic tissues, Fertil. Steril. source

In the paper

“The activation of HIF-1α and the formation of the HIF complex induce several angiogenic growth factor genes, including VEGF and stromal cell-derived factor-1 (SDF-1)/C-X-C motif chemokine 12 (CXCL12) [82,83,84].”

What the sources say

• Not checked yetcites [82] Forsythe, 1996, Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1, Mol. Cell. Biol. source
• Not checked yetcites [83] Ceradini, 2004, Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1, Nat. Med. source
• Not checked yetcites [84] Yamakawa, 2003, Hypoxia-inducible factor-1 mediates activation of cultured vascular endothelial cells by inducing multiple angiogenic factors, Circ. Res. source

In the paper

“It is clear from the above discussion that microtraumatization-induced estrogen production may not occur in the first place.”

In the paper

“However, the feed-forward loop, shown in Figure 1, that underpins the TIAR theory, is based on findings almost exclusively from endometriotic stromal cells.”

What the sources say

• Not checked yetcites [64] Bulun, 2005, Regulation of aromatase expression in estrogen-responsive breast and uterine disease, from bench to treatment, Pharm. Rev. source

In the paper

“Regardless, even within the TIAR framework it seems evident that the pathogenesis of adenomyosis differs from that of endometriosis [28,29,30].”

What the sources say

• Not checked yetcites [28] Leyendecker, 2015, Adenomyosis and endometriosis. Re-visiting their association and further insights into the mechanisms of auto-traumatisation. An MRI study, Arch. Gynecol. Obs. source
• Not checked yetcites [29] Leyendecker, 2011, A new concept of endometriosis and adenomyosis, tissue injury and repair (TIAR), Horm. Mol. Biol. Clin. Investig. source
• Not checked yetcites [30] Leyendecker, 2009, The pathophysiology of endometriosis and adenomyosis, tissue injury and repair, Arch. Gynecol. Obs. source

In the paper

“While these key molecular events are similar or even identical for the two diseases, their respective lesional microenvironments are not entirely the same.”

• Also stated in: § 4. Conclusions · plain

  “However, there are still some notable differences in microenvironment between the two conditions, as discussed above.”

In the paper

“The EMID hypothesis is also consistent with epidemiological data stating that iatrogenic uterine procedures such as induced abortion and D&C are a risk factor for adenomyosis.”

In the paper

“which may accelerate the tempo and pace of lesional fibrogenesis.”

In the paper

“Similarly, platelets stimulate the homing of BMDSCs, facilitating angiogenesis in injured and hypoxic tissues [92].”

What the sources say

• Not checked yetcites [92] Feng, 2011, A novel role for platelet secretion in angiogenesis, mediating bone marrow-derived cell mobilization and homing, Blood source

In the paper

“It is evident that, even within the TIAR or the EMID framework, adenomyosis has a different pathogenesis than that of endometriosis.”

• Also stated in: § 4. Conclusions · hedged

  “Consequently, and again, adenomyosis is not simply endometriosis of the uterus, at least from the pathogenesis perspective.”

• Also stated in: § 4. Conclusions · plain

  “In this sense, adenomyosis is not simply endometriosis of the uterus.”

In the paper

“From the above discussion, it is clear that adenomyosis and endometriosis have a different pathogenesis.”

In the paper

“Incidentally or not, SDF-1 plays a critical role in recruiting bone marrow derived stem cells (BMDSCs) to endometrium and ectopic endometrium [90,91].”

What the sources say

• Not checked yetcites [90] Moridi, 2017, Bone Marrow Stem Cell Chemotactic Activity Is Induced by Elevated CXCl12 in Endometriosis, Reprod. Sci. source
• Not checked yetcites [91] Wang, 2015, Chemoattraction of bone marrow-derived stem cells towards human endometrial stromal cells is mediated by estradiol regulated CXCL12 and CXCR4 expression, Stem. Cell Res. source

In the paper

“Therefore, therapeutics that capitalize on these differences may stand a better chance to be more efficacious for adenomyosis per se.”

In the paper

“The similarity in the natural history between endometriosis and adenomyosis may explain why many medications used primarily for treating endometriosis can and have been used also for treating adenomyosis.”

In the paper

“It overcomes several deficiencies of the TIAR theory by accommodating EMT and the recruitment of BMDSCs.”

In the paper

“One probable exception might be the abdominal wall endometriosis (AWE), which is associated with cesarean delivery and abdominal hysterectomy [102,103].”

What the sources say

• Not checked yetcites [102] Khan, 2017, Risk Factors, Clinical Presentation, and Outcomes for Abdominal Wall Endometriosis, J. Minim. Invasive Gynecol. source
• Not checked yetcites [103] Francica, 2012, Reliable clinical and sonographic findings in the diagnosis of abdominal wall endometriosis near cesarean section scar, World J. Radiol. source

In the paper

“It also may induce the release of PGE2.”

In the paper

“More remarkably, activated platelets can activate HIF-1α in endometrial and endometriotic stromal cells, effectively generating a state of hypoxia [97].”

What the sources say

• Not checked yetcites [97] Qi, 2019, Activated Platelets Induce Hypoxia-Inducible Factor-1α Expression Likely through Transforming Growth Factor-β1 in Human Endometrial Stromal Cells, Reprod. Dev. Med. source

In the paper

“As adenomyosis shares with endometriosis in cyclic bleeding and thus ReTIAR, the two diseases also share common key molecular events in lesional development, i.e., EMT, fibroblast-to-myofibroblast transdifferentation, smooth muscle metaplasia, and fibrogenesis [105,106].”

What the sources say

• Not checked yetcites [105] Liu, 2016, Corroborating evidence for platelet-induced epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation in the development of adenomyosis, Hum. Reprod. source
• Not checked yetcites [106] Shen, 2016, Transforming growth factor beta1 signaling coincides with epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation in the development of adenomyosis in mice, Hum. Reprod.

In the paper

“Notably, the proximity to myometrium means that adenomyotic lesions may experience stronger and more frequent contractions, and thus more mechanical stretch and strain, especially when the uterus is enlarged with thickening JZ”

In the paper

“It provides explanations as to why hyperperistalsis occurs.”

In the paper

“In addition, hypoxia also induces COX-2 [86].”

What the sources say

• Not checked yetcites [86] Kaidi, 2006, Direct transcriptional up-regulation of cyclooxygenase-2 by hypoxia-inducible factor (HIF)-1 promotes colorectal tumor cell survival and enhances HIF-1 transcriptional activity during hypoxia, Cancer Res. source

In the paper

“In fact, activated platelets can also upregulate the gene expression of StAR, SF-1 and aromatase, increasing the estrogen production significantly in endometriotic stromal cells [98].”

What the sources say

• Not checked yetcites [98] Qi, 2020, Platelets induce increased estrogen production through NF-κB and TGF-β1 signaling pathways in endometriotic stromal cells, Sci. Rep. source

In the paper

“The model also seems to be consistent with published data, i.e., an increased risk of adenomyosis in women with a history of D&C or in multiparous women [19,20,21,22].”

What the sources say

• Not checked yetcites [19] Parazzini, 1997, Risk factors for adenomyosis, Hum. Reprod source
• Not checked yetcites [20] Levgur, 2000, Adenomyosis, symptoms, histology, and pregnancy terminations, Obs. Gynecol.
• Not checked yetcites [21] Curtis, 2002, Disruption of the endometrial-myometrial border during pregnancy as a risk factor for adenomyosis, Am. J. Obs. Gynecol. source
• Not checked yetcites [22] Panganamamula, 2004, Is prior uterine surgery a risk factor for adenomyosis?, Obs. Gynecol. source

In the paper

“Hypoxia can also induce EMT [93,94].”

What the sources say

• Not checked yetcites [93] Liu, 2015, Hypoxia induced epithelial-mesenchymal transition and vasculogenic mimicry formation by promoting Bcl-2/Twist1 cooperation, Exp. Mol. Pathol. source
• Not checked yetcites [94] Xiong, 2016, Hypoxia-inducible factor 1alpha-induced epithelial-mesenchymal transition of endometrial epithelial cells may contribute to the development of endometriosis, Hum. Reprod. source

In the paper

“As a tissue trauma, EMID may also activate the hypothalamic–pituitary–adrenal (HPA) axis, causing the release of catecholamines, especially adrenaline/noradrenaline.”

In the paper

“Hence hypoxia-induced COX-2 expression would also lead to increased uterine peristalsis, effectively facilitating the perpetuation of the vicious cycle.”

In the paper

“In endometrial epithelial cells, the hypoxia-induced EMT is facilitated by enhanced autophagy [95].”

What the sources say

• Not checked yetcites [95] Liu, 2018, Autophagy contributes to hypoxia-induced epithelial to mesenchymal transition of endometrial epithelial cells in endometriosis, Biol. Reprod. source

In the paper

“Remarkably, hypoxic conditions alone can dramatically change the behavior of endometrial cells that are otherwise “normal”, manifesting in increased estrogen production and other “abnormal” phenotypes [96].”

What the sources say

• Not checked yetcites [96] Hsiao, 2015, Pathological functions of hypoxia in endometriosis, Front. Biosci. source

In the paper

“The EMID hypothesis is also consistent with epidemiological data stating that iatrogenic uterine procedures such as induced abortion and D&C are a risk factor for adenomyosis.”