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Cited by 165Endometriosis Research and TreatmentGynecological conditions and treatmentsUterine Myomas and Treatments

The Pathogenesis of Adenomyosis vis-à-vis Endometriosis

Open access
Guo, Sun-Wei·2020·Journal of Clinical Medicine
DOI 10.3390/jcm9020485PMC PMC7073526
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Abstract

Adenomyosis is used to be called endometriosis interna, and deep endometriosis is now called adenomyosis externa. Thus, there is a question as to whether adenomyosis is simply endometriosis of the uterus, either from the perspective of pathogenesis or pathophysiology. In this manuscript, a comprehensive review was performed with a literature search using PubMed for all publications in English, related to adenomyosis and endometriosis, from inception to June 20, 2019. In addition, two prevailing theories, i.e., invagination—based on tissue injury and repair (TIAR) hypothesis—and metaplasia, on adenomyosis pathogenesis, are briefly overviewed and then critically scrutinized. Both theories have apparent limitations, i.e., difficulty in falsification, explaining existing data, and making useful predictions. Based on the current understanding of wound healing, a new hypothesis, called endometrial-myometrial interface disruption (EMID), is proposed to account for adenomyosis resulting from iatrogenic trauma to EMI. The EMID hypothesis not only highlights the more salient feature, i.e., hypoxia, at the wounding site, but also incorporates epithelial mesenchymal transition, recruitment of bone-marrow-derived stem cells, and enhanced survival and dissemination of endometrial cells dispersed and displaced due to iatrogenic procedures. More importantly, the EMID hypothesis predicts that the risk of adenomyosis can be reduced if certain perioperative interventions are performed. Consequently, from a pathogenic standpoint, adenomyosis is not simply endometriosis of the uterus, and, as such, may call for interventional procedures that are somewhat different from those for endometriosis to achieve the best results.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that adenomyosis is not simply endometriosis of the uterus, because the two conditions have different risk profiles, age-specific incidence, and likely pathogenesis. It critiques the invagination/TIAR and metaplasia theories and proposes the endometrial–myometrial interface disruption (EMID) hypothesis, centered on iatrogenic trauma, hypoxia, EMT, and bone-marrow-derived stem cell recruitment.

Key findings

  • Reported adenomyosis prevalence varies widely, from 10% to 57%; in a population-based study in Northeast Italy, estimated prevalence was 0.18% for adenomyosis versus 1.14% for endometriosis, with adenomyosis incidence peaking at ages 46–50 years.
  • Parity is consistently a risk factor for adenomyosis, smoking is inconsistently protective, and a history of dilatation and curettage (D&C) is suggested as a risk factor; this risk profile differs from endometriosis, where greater parity is protective and earlier menarche/shorter menstrual cycles are risk factors.
  • The review criticizes both prevailing adenomyosis theories—invagination/TIAR and metaplasia—as difficult to falsify, unable to fully explain existing data, and limited in making useful predictions; it notes the TIAR feed-forward loop is based almost exclusively on endometriotic stromal cells, whereas normal endometrial stromal cells have hypermethylated/silenced aromatase, SF-1, and ERβ.
  • The proposed EMID hypothesis holds that iatrogenic trauma to the endometrial–myometrial interface causes hypoxia, platelet aggregation, increased estrogen production, TGF-β1/VEGF/PDGF/COX-2/SDF-1 signaling, elevated PGE2, EMT, bone-marrow-derived stem cell recruitment, and impaired cell-mediated immunity, promoting survival and myometrial implantation of displaced endometrial cells; it predicts perioperative interventions may reduce adenomyosis risk.

Methods

  • Comprehensive review with a PubMed literature search for all English publications related to adenomyosis and endometriosis from inception to June 20, 2019.
  • Briefly overviews and critically scrutinizes the two prevailing adenomyosis pathogenesis theories—invagination/TIAR and metaplasia—then proposes the EMID hypothesis based on current understanding of wound healing.
  • No primary experimental data are reported in this review; it mentions that EMID can robustly induce adenomyosis in mice (Hao et al., submitted for publication) as cited/unpublished evidence.

Limitations

  • The paper states the EMID hypothesis may account for adenomyosis arising from iatrogenic trauma and perhaps persistent hyperperistalsis-induced EMID, but probably not focal adenomyosis of the outer myometrium (FAOM) or extrinsic/exterior adenomyosis.
  • The paper states the model is by no means final or complete and is subject to change or modification; other aiders and abettors may yet be identified, and upstream cues or risk factors for hyperperistalsis-induced EMID need elucidation.
  • Evident from the text: as a narrative review, it does not report a systematic review protocol, risk-of-bias assessment, or meta-analysis, and the mouse induction evidence is cited as submitted/unpublished rather than detailed in the paper.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3390/jcm9020485

Cites

108 of 108 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 89 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    EMID can robustly induce adenomyosis in mice.

    “In fact, EMID can robustly induce adenomyosis in mice (Hao et al., submitted for publication).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hao et al., submitted for publication

      Not checked in the free run.

  • Premisecitation

    Wide variability in adenomyosis prevalence stems from variations in histological criteria and techniques for myometrial sampling.

    “This wide variability stems from variations in the histological criteria adopted for diagnosis and the techniques used to procure myometrial samples [15].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Vercellini, 2006, Adenomyosis, epidemiological factors, Best Pr. Res. Clin. Obs. Gynaecol. source

      Not checked in the free run.

  • Premisecitation

    A history of dilatation and curettage (D&C) procedures is a risk factor for adenomyosis.

    “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].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [19] Parazzini, 1997, Risk factors for adenomyosis, Hum. Reprod source

      Not checked in the free run.

    • cites [20] Levgur, 2000, Adenomyosis, symptoms, histology, and pregnancy terminations, Obs. Gynecol.

      Not checked in the free run.

    • cites [21] Curtis, 2002, Disruption of the endometrial-myometrial border during pregnancy as a risk factor for adenomyosis, Am. J. Obs. Gynecol. source

      Not checked in the free run.

    • cites [22] Panganamamula, 2004, Is prior uterine surgery a risk factor for adenomyosis?, Obs. Gynecol. source

      Not checked in the free run.

  • Interpretationreasoning

    Different risk profiles and age-specific incidence between adenomyosis and endometriosis indicate they likely have different pathogenesis.

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

    In women with leiomyomas, those with both leiomyomas and adenomyosis are older than those with leiomyomas alone.

    “Even in women with leiomyomas, women with both leiomyomas and adenomyosis are reported to be older than those with leiomyomas alone [24].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] Brucker, 2014, Clinical characteristics indicating adenomyosis coexisting with leiomyomas, a retrospective, questionnaire-based study, Fertil. Steril. source

      Not checked in the free run.

  • May combine two claims. 31
  • Classified as probably not a substantial claim. 15

  • May combine two claims.

    Premisecitation

    Sampson's retrograde menstruation theory is the most widely accepted and has the most robust evidence for endometriosis pathogenesis.

    “Sampson’s retrograde menstruation theory is the most widely accepted and has the most robust evidence [27].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Vercellini, 2014, Endometriosis, pathogenesis and treatment, Nat. Rev. Endocrinol. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    D&C and perhaps other uterine surgeries may disrupt the endometrial-myometrial interface and facilitate invasion, implantation, embedding, and establishment of endometrial colonies within the myometrial wall, increasing adenomyosis risk.

    “The D&C procedure, and perhaps other uterine surgeries as well, may disrupt the endometrial–myometrial interface (EMI) and facilitate the invasion, implantation, embedding, and establishment of endometrial colonies within the myometrial wall, increasing the risk of adenomyosis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In a population-based study in Northeast Italy, estimated prevalence of adenomyosis is 0.18%, lower than endometriosis at 1.14%.

    “In a rare population-based study, the estimated prevalence of adenomyosis in Northeast Italy is reported to be 0.18%, much lower than that of endometriosis (1.14%) [17].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Parity is consistently a risk factor for adenomyosis, while smoking is inconsistently protective.

    “Parity is consistently shown to be a risk factor, while smoking is inconsistently shown to be a protective factor [15,18].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [15] Vercellini, 2006, Adenomyosis, epidemiological factors, Best Pr. Res. Clin. Obs. Gynaecol. source

      Not checked in the free run.

    • cites [18] Taran, 2013, Adenomyosis, Epidemiology, Risk Factors, Clinical Phenotype and Surgical and Interventional Alternatives to Hysterectomy, Geburtshilfe Frauenheilkd source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Adenomyosis and endometriosis are both estrogen-dependent and share many molecular aberrations.

    “Aside from their similar symptomologies, both are estrogen-dependent [10] and share many molecular aberrations.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Kitawaki, 2006, Adenomyosis, the pathophysiology of an oestrogen-dependent disease, Best Pr. Res. Clin. Obs. Gynaecol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Adenomyosis is a common gynecologic disorder with poorly understood pathogenesis and pathophysiology.

    “Adenomyosis, defined as the presence of endometrial glands and stroma infiltrated deep and haphazardly into the myometrium [1], is a common gynecologic disorder with poorly understood pathogenesis and pathophysiology [2,3,4].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [2] Bergeron, 2006, Pathology and physiopathology of adenomyosis, Best Pr. Res. Clin. Obs. Gynaecol. source

      Not checked in the free run.

    • cites [3] Vannuccini, 2017, Pathogenesis of adenomyosis, an update on molecular mechanisms, Reprod. Biomed. Online source

      Not checked in the free run.

    • cites [4] Donnez, 2018, Pathogenesis of uterine adenomyosis, invagination or metaplasia?, Fertil. Steril. source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisereasoning

    Adenomyosis and endometriosis both involve ectopic endometrium, but in different locations.

    “The definition of adenomyosis is essentially the presence of ectopic endometrium within the myometrium, very similar to that of endometriosis, which is the presence of ectopic endometrium outside of the uterine cavity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    From a pathogenesis standpoint, adenomyosis is not simply endometriosis of the uterus; it shares similar developmental features but probably not the causes.

    “Hence, the short answer to the question would be: adenomyosis is not simply endometriosis of the uterus; rather, it shares with endometriosis similar developmental features but probably not the causes.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Reported prevalence of adenomyosis varies from 10% to 57%.

    “The reported prevalence of adenomyosis varies greatly among different studies, from as low as 10% to as high as 57% [15,16].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [15] Vercellini, 2006, Adenomyosis, epidemiological factors, Best Pr. Res. Clin. Obs. Gynaecol. source

      Not checked in the free run.

    • cites [16] Bergholt, 2001, Prevalence and risk factors of adenomyosis at hysterectomy, Hum. Reprod. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The clinical treatment strategy for adenomyosis and endometriosis is similar, and drugs to treat the two diseases can be used interchangeably.

    “The clinical treatment strategy for the two diseases also seems to be similar, and the drugs to treat the two diseases can be used interchangeably [11].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Vannuccini, 2018, Role of medical therapy in the management of uterine adenomyosis, Fertil. Steril. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Risk profiles for adenomyosis differ from endometriosis: greater parity is protective in endometriosis, while earlier menarche and shorter menstrual cycle length are risk factors.

    “The risk profiles for adenomyosis are thus quite different from that of endometriosis, in which greater parity is a protective factor, while earlier age at menarche and shorter menstrual cycle length—factors that are consistent with Sampson’s retrograde menstruation theory for the etiology of endometriosis—are risk factors [23].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Shafrir, 2018, Risk for and consequences of endometriosis, A critical epidemiologic review, Best Pract. Res. Clin. Obstet. Gynaecol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Over 1000 genes are differentially expressed between adenomyotic lesions and eutopic endometrium, and close to 1000 genes are differentially expressed between ectopic and eutopic endometrium.

    “In fact, over 1000 genes are documented to be differentially expressed between adenomyotic lesions and eutopic endometrium [65] and close to 1000 genes are differentially expressed between ectopic and eutopic endometrium [66].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [65] Herndon, 2016, Global Transcriptome Abnormalities of the Eutopic Endometrium from Women with Adenomyosis, Reprod. Sci. source

      Not checked in the free run.

    • cites [66] Wu, 2006, Transcriptional characterizations of differences between eutopic and ectopic endometrium, Endocrinology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Uterine peristalsis is critical for sperm transport, and women with endometriosis exhibit hyperperistalsis and dysperistalsis.

    “In a nutshell, they showed that uterine peristalsis is critical for sperm transport, and women with endometriosis exhibit hyperperistalsis and dysperistalsis [38,39,40,41].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [39] Kunz, 1996, The dynamics of rapid sperm transport through the female genital tract, evidence from vaginal sonography of uterine peristalsis and hysterosalpingoscintigraphy, Hum. Reprod. source

      Not checked in the free run.

    • cites [40] Kunz, 1998, Sonographic evidence for the involvement of the utero-ovarian counter-current system in the ovarian control of directed uterine sperm transport, Hum. Reprod. Update source

      Not checked in the free run.

    • cites [41] Wildt, 1998, Sperm transport in the human female genital tract and its modulation by oxytocin as assessed by hysterosalpingoscintigraphy, hysterotonography, electrohysterography and Doppler sonography, Hum. Reprod. Update source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Premisenone given

    The exact pathogenesis of adenomyosis is largely a conundrum.

    “In sharp contrast to endometriosis, the exact pathogenesis of adenomyosis is largely a conundrum.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Both invagination and metaplasia theories have apparent limitations: difficulty in falsification, explaining existing data, and making useful predictions.

    “Both theories have apparent limitations, i.e., difficulty in falsification, explaining existing data, and making useful predictions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Hyperperistalsis may induce COX-2 expression and higher PGE2 production in endometrial stromal cells, but it is unlikely to further induce increased estrogen production.

    “Thus, hyperperistalsis may induce COX-2 expression and higher PGE2 production in endometrial stromal cells, but it is unlikely to further induce increased estrogen production.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The newly reported association between focal adenomyosis of the outer myometrium and deep endometriosis suggests not all subtypes of adenomyosis are the same and may have different pathogenesis.

    “Indeed, the newly reported association between focal adenomyosis of the outer myometrium (FAOM) and deep endometriosis (DE) [61,62] suggests that not all subtypes of adenomyosis are the same and may have a different pathogenesis.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [61] Chapron, 2017, Relationship between the magnetic resonance imaging appearance of adenomyosis and endometriosis phenotypes, Hum. Reprod. source

      Not checked in the free run.

    • cites [62] Marcellin, 2018, Anterior Focal Adenomyosis and Bladder Deep Infiltrating Endometriosis, Is There a Link?, J. Minim. Invasive Gynecol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inhibition of pituitary prolactin secretion during youth in mice suppressed induction of adenomyosis, suggesting a potential role of prolactin.

    “but inhibition of pituitary prolactin secretion during youth in mice suppressed the induction of adenomyosis [60], suggesting the potential role of prolactin in the pathogenesis of adenomyosis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Nagasawa, 1982, 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. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    It is difficult, if not impossible, to devise an experiment to prove or disprove either invagination or metaplasia theory.

    “More importantly, it is difficult, if not impossible, to devise an experiment to prove or disprove either theory.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Hypoxia may be the single most important event following tissue injury, and adaptation to hypoxic stress via HIF signaling plays a critical role in promoting wound healing.

    “Thus, hypoxia may well be viewed as the single most important event following tissue injury, and, indeed, adaptation to hypoxic stress via HIF signaling plays a critical role in promoting wound healing processes [74,75].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [74] Andrikopoulou, 2011, Current Insights into the role of HIF-1 in cutaneous wound healing, Curr. Mol. Med. source

      Not checked in the free run.

    • cites [75] Hong, 2014, The Role of Hypoxia-Inducible Factor in Wound Healing, Adv. Wound Care source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Injury to the endometrial-myometrial interface constitutes trauma, leading to subsequent tissue hypoxia in myocytes and fibroblasts.

    “Hence, the injury to the EMI constitutes a trauma, leading to subsequent tissue hypoxia in myocytes and fibroblasts.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Even though adenomyotic lesions may resemble DE lesions in look and feel, their developmental paths may be similar but not entirely the same, due to their different microenvironment.

    “Even though adenomyotic lesions (used to be called endometriosis interna) may resemble DE lesions (now called adenomyosis externa [107]) in their look and feel, their developmental paths may be similar but not entirely the same, due to their different microenvironment.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Perioperative intervention could reduce the risk of adenomyosis, as in the case of a reduction in recurrence risk in endometriosis.

    “it raises a tantalizing possibility that perioperative intervention could reduce the risk of adenomyosis, as in the case of a reduction in recurrence risk in endometriosis [100].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [100] Long, 2019, Perioperative Intervention by beta-Blockade and NF-kappaB Suppression Reduces the Recurrence Risk of Endometriosis in Mice Due to Incomplete Excision, Reprod. Sci. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    These surgical procedures would result in direct implantation of endometrial cells ectopically within the abdominal wall.

    “Conceivably, these surgical procedures would result in the direct implantation of endometrial cells ectopically within the abdominal wall.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Hypoxia-induced COX-2 overexpression increases production of PGE2 and PGH2, leading to increased TXA2, a vasoconstrictor, platelet activator, and uterine contraction inducer.

    “Note that hypoxia-induced COX-2 overexpression can increase the production of not only PGE2 but also PGH2, which leads to increased production of thromboxane A2 (TXA2), a vasoconstrictor, a potent platelet activator, and a potent inducer of uterine contraction [99].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [99] Wilhelmsson, 1981, PGH2, TxA2 and PGI2 have potent and differentiated actions on human uterine contractility, Prostaglandins source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Release of adrenaline/noradrenaline and PGE2 can reduce cell-mediated immunity, promoting survival of spread and displaced endometrial cells.

    “The release of adrenaline/noradrenaline and PGE2 can reduce cell-mediated immunity, promoting the survival of spread and displaced endometrial cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Increased estrogen levels may induce an ERα-mediated OT/OTR system, enhancing uterine peristalsis.

    “Thus, the increased estrogen levels may induce an ERα-mediated OT/OTR system, enhancing uterine peristalsis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    HIF-1α-induced COX-2 expression leads to elevated PGE2 levels, which can induce PGE2-mediated vascularization.

    “HIF-1α-induced COX-2 expression leads to elevated PGE2 levels, which can induce PGE2-mediated vascularization [87,88].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [87] Greenhough, 2009, The COX-2/PGE2 pathway, key roles in the hallmarks of cancer and adaptation to the tumour microenvironment, Carcinogenesis source

      Not checked in the free run.

    • cites [88] Tsujii, 1998, Cyclooxygenase regulates angiogenesis induced by colon cancer cells, Cell source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The EMID hypothesis can explain genesis of adenomyosis induced by iatrogenic trauma, may also explain pathogenesis due to persistent hyperperistalsis that causes EMID, but probably not FAOM or extrinsic/exterior adenomyosis.

    “While it can explain the genesis of adenomyosis induced by iatrogenic trauma, it may also explain the pathogenesis of adenomyosis due to persistent hyperperistalsis that causes EMID, but probably not FAOM or extrinsic/exterior adenomyosis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    Perioperative intervention when iatrogenic procedures such as D&C are performed may reduce the risk of developing adenomyosis in the first place.

    “For example, perioperative intervention when iatrogenic procedures such as D&C are performed may reduce the risk of developing adenomyosis in the first place.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Adenomyosis shares with endometriosis cyclic bleeding and thus ReTIAR.

    “As adenomyosis shares with endometriosis in cyclic bleeding and thus ReTIAR”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [104] Guo, 2018, Fibrogenesis resulting from cyclic bleeding, the Holy Grail of the natural history of ectopic endometrium, Hum. Reprod. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Increased estradiol levels would induce ERα, further activating OT/OTR signaling and causing increased peristalsis.

    “In addition, increased estradiol levels would induce ERα, which further activate OT/OTR signaling pathway, causing increased peristalsis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Interventions carefully tailored to adenomyosis should be more effective in management and prevention.

    “That adenomyosis is not simply endometriosis of the uterus implies that, when it comes to management and prevention, interventions that are carefully tailored to adenomyosis should be more effective.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Even for adenomyosis, there might be two or more different pathogenic origins; FAOM or extrinsic/external adenomyosis might originate from invasion of neighboring deep endometriosis lesions.

    “In fact, even for adenomyosis, there might be two or more different pathogenic origins, for example, the FAOM, or extrinsic or external adenomyosis, might originate from the invasion of neighboring DE lesions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Catecholamines and PGE2 impair cell-mediated immunity, promoting survival of displaced and dispersed cells that spread to the endometrial-myometrial interface and possibly beyond.

    “Together, these catecholamines and PGE2 would impair the cell-mediated immunity, promoting the survival of displaced and dispersed cells that spread to the EMI and possibly beyond due to the procedure.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Uterine procedures using different energy sources result in different severities of injury and bleeding patterns, and resultant EMID would lead to differential risk of developing adenomyosis.

    “In addition, since uterine procedures using different energy sources result in different severities of injury and bleeding patterns, the resultant EMID would lead to differential = risk of developing adenomyosis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationnone given

    The model depicted in Figure 3 is completely falsifiable.

    “The model depicted in Figure 3 is completely falsifiable.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    The EMID hypothesis is easily falsifiable, at least in mouse.

    “Unlike the TIAR theory, the EMID hypothesis is easily falsifiable, at least in mouse.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    When EMID occurs, resultant tissue hypoxia leads to platelet aggregation, increased estrogen production, induction of TGF-β1, VEGF, PDGF, COX-2, and SDF-1 signaling, elevated PGE2, EMT, and increased BMDSC recruitment, promoting mobility and implantation of endometrial cells to the myometrium.

    “Thus, when EMID occurs, such as in the D&C procedure, the resultant tissue hypoxia would lead to platelet aggregation, increased estrogen production, induction of the TGF-β1, VEGF, PDGF, COX-2, and SDF-1 signaling and the resultant elevated PGE2 production, induction of EMT, and increased recruitment of BMDSCs in the wound site, all of which can promote the mobility and implantation of endometrial”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    EMID may induce EMT in adjacent endometrial epithelial cells and enhance their mobility and invasiveness, resulting in crossing of the endometrial-myometrial interface to the myometrium by endometrial epithelial cells.

    “Thus, EMID may induce EMT in adjacent endometrial epithelial cells and enhance their mobility and invasiveness, resulting in the crossing of EMI to the myometrium by endometrial epithelial cells.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Use of coagulation might lead to a lower risk of adenomyosis than the D&C procedure.

    “For example, the use of coagulation might lead to a lower risk of adenomyosis than the D&C procedure.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The EMID model can account for genesis of adenomyosis arising from iatrogenic trauma such as uterine procedures, but perhaps not for adenomyosis induced by other causes.

    “This model can at least account for the genesis of adenomyosis arising from iatrogenic trauma such as uterine procedures, but perhaps not for adenomyosis induced by other causes.”
    Quote in the paperSubstantial claim
42 of 42

  • The paper relies on this without support.

    The molecular mechanisms of wound healing in non-endometrial tissues apply to the endometrial–myometrial interface and adenomyosis pathogenesis.

    “Based on the current understanding of wound healing, a new hypothesis, called endometrial-myometrial interface disruption (EMID), is proposed to account for adenomyosis resulting from iatrogenic trauma to EMI.”

  • The paper relies on this without support.

    The mouse EMID model is a valid model for human adenomyosis.

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

  • The paper relies on this without support.

    Normal endometrial stromal cells studied in vitro reflect normal endometrial stromal cells in vivo.

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

  • The paper relies on this without support.

    Iatrogenic procedures are common in gynecological practice nowadays.

    “iatrogenic procedures aplenty nowadays in gynecological practice”

  • The paper relies on this without support.

    Many medications used primarily for treating endometriosis can and have been used also for treating adenomyosis.

    “many medications used primarily for treating endometriosis can and have been used also for treating adenomyosis”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Cites

Flagged first, then by citations

8 of the 116 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Lacassagne, 1935, Modifications progressive de I’uterus de la souris sous l’action prolongee de I’oestrone, C R Seances Soc. Bioi., 35, 320

Cited by

Sorted by citations

Related

Authors
Guo, S.-W.
Affiliations
Fudan University (CN)
Corresponding author
Guo, Sun-Wei
ORCID
Guo, Sun-Wei
Venue
Journal of Clinical Medicine
Publisher
MDPI AG
Published
2020-02-10
Volume
9
Issue
2
Pages
485
ISSN
2077-0383 (ISSN-L)
DOI
10.3390/jcm9020485
PMC
PMC7073526
OpenAlex
W3005308188
Semantic Scholar
5a6ac6de5d69707a16c5a1e3292560d153248759
Cited by
165
References
116
Citations by year
2026: 26 · 2025: 18 · 2024: 30 · 2023: 22 · 2022: 32 · 2021: 28 · 2020: 8
FWCI
3.33
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Clinical Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
National Natural Science Foundation of China (81530040, 81771553)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
  • Health Sciences › Medicine › Obstetrics and Gynecology › Gynecological conditions and treatments
  • Health Sciences › Medicine › Obstetrics and Gynecology › Uterine Myomas and Treatments
Keywords
adenomyosis, endometriosis, wound healing, hypoxia, epithelial-mesenchymal transition, bone marrow-derived stem cells, iatrogenic injury, perioperative interventions, deep infiltrating endometriosis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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