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Cited by 427Endometriosis Research and TreatmentGynecological conditions and treatmentsEctopic Pregnancy Diagnosis and Management

Pathogenesis of endometriosis: The genetic/epigenetic theory

Open access
Koninckx, Philippe R., Ussia, Anastasia, Adamyan, Leila, Wattiez, Arnaud, Gomel, Victor, Martin, Dan C.·2019·Fertility and Sterility
DOI 10.1016/j.fertnstert.2018.10.013
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Abstract

OBJECTIVE To study the pathophysiology of endometriosis. DESIGN Overview of observations on endometriosis. SETTING Not applicable. PATIENT(S) None. INTERVENTIONS(S) None. MAIN OUTCOME MEASURE(S) The hypothesis is compatible with all observations. RESULT(S) Endometriosis, endometrium-like tissue outside the uterus, has a variable macroscopic appearance and a poorly understood natural history. It is a hereditary and heterogeneous disease with many biochemical changes in the lesions, which are clonal in origin. It is associated with pain, infertility, adenomyosis, and changes in the junctional zone, placentation, immunology, plasma, peritoneal fluid, and chronic inflammation of the peritoneal cavity. The Sampson hypothesis of implanted endometrial cells following retrograde menstruation, angiogenic spread, lymphogenic spread, or the metaplasia theory cannot explain all observations if metaplasia is defined as cells with reversible changes and an abnormal behavior/morphology due to the abnormal environment. We propose a polygenetic/polyepigenetic mechanism. The set of genetic and epigenetic incidents transmitted at birth could explain the hereditary aspects, the predisposition, and the endometriosis-associated changes in the endometrium, immunology, and placentation. To develop typical, cystic ovarian or deep endometriosis lesions, a variable series of additional transmissible genetic and epigenetic incidents are required to occur in a cell which may vary from endometrial to stem cells. Subtle lesions are viewed as endometrium in a different environment until additional incidents occur. Typical cystic ovarian or deep endometriosis lesions are heterogeneous and represent three different diseases. CONCLUSION(S) The genetic epigenetic theory is compatible with all observations on endometriosis. Implications for treatment and prevention are discussed.

AI snapshot

Written from the paper’s full text.

TL;DR

Koninckx proposes a polygenetic/polyepigenetic theory in which inherited and acquired genetic/epigenetic incidents explain endometriosis predisposition, heterogeneity, and progression from subtle lesions to typical, cystic, or deep disease. The theory is argued to be compatible with all observations, but it remains speculative and untested.

Key findings

  • Endometriosis is hereditary: risk is 6%–9% higher in first-degree relatives and 15% higher when relatives had severe disease; hereditary factors are estimated to account for 50% of endometriosis. GWAS identified 10 or 15 loci, and a meta-analysis identified five loci regulating sex steroid hormone pathways, five secondary signals, and 19 SNPs robustly associated with endometriosis.
  • The genetic/epigenetic theory holds that genetic and epigenetic incidents transmitted at birth explain predisposition and endometriosis-associated changes in endometrium, immunology, and placentation; additional transmissible incidents in a cell—ranging from endometrial to stem cells—are required for typical, cystic ovarian, or deep lesions. Subtle lesions are viewed as endometrium in a different environment until additional incidents occur.
  • Typical cystic ovarian and deep endometriosis lesions are heterogeneous and represent three different diseases; lesions are clonal in origin. Deep endometriosis lesions are generally unique, larger than 1 cm, with some 20% lymph node involvement; depth distribution shows two populations overlapping at 6 mm, and a >5 mm definition was later suggested.
  • Natural history is described as mostly non-progressive: most subtle lesions do not progress, most typical/cystic/deep lesions are not progressive after diagnosis, and most are not recurrent after surgery. Cystic ovarian endometriosis recurrence after stripping is less than 20% within 6 months; recurrence of deep endometriosis after complete excision is rare.

Methods

  • Design: overview of observations on endometriosis; setting not applicable; no patients and no interventions. Main outcome measure: the hypothesis is compatible with all observations.
  • Data: clinical, histologic, and biochemical observations and research on endometriotic tissues; the paper notes there is no nonhuman animal model with sufficient similarity to human myometrium, junctional zone, endometrium, placentation, and pregnancy disorders.
  • Analysis: narrative synthesis of observations and historical theories—Sampson’s retrograde menstruation/implantation, metaplasia, and the endometriotic disease theory—into a polygenetic/polyepigenetic mechanism, with figures and a table summarizing clinical observations.

Limitations

  • The paper states the theory “will remain a theory until disproven by new observations”; it can only speculate what combination of genetic and epigenetic incidents leads to typical, cystic, deep, or extragenital endometriosis, and redundancy of biologic processes can mask phenotypic effects.
  • The paper states that absence of experimentation limits views to clinical, histologic, and biochemical observations; natural history is unclear, progression of subtle lesions or from typical to cystic/deep lesions has not been observed directly, epidemiology is unclear, and recurrence data are limited. Some cited observations are personal or unpublished.
  • Evident from the text: this is a narrative hypothesis paper with no new primary data, no systematic review or meta-analysis, and no formal experimental test of the proposed mechanism.

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

Integrity signals

Registry

Crossref · 10.1016/j.fertnstert.2018.10.013

Cites

267 of 267 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 83 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Recurrence rates of deep endometriosis lesions after complete excision are rare.

    “Recurrence rates of deep endometriosis lesions after complete excision are rare (personal observations) (60).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Ianieri, 2018, Recurrence in deep infiltrating endometriosis: a systematic review of the literature, J Minim Invasive Gynecol source

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  • Premisecitation

    The risk of developing endometriosis is 6%-9% higher in first-degree relatives of women with endometriosis.

    “The risk of developing endometriosis is 6%-9% higher in first-degree relatives of women with endometriosis (34,35)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [34] Simpson, 1980, Heritable aspects of endometriosis. I. Genetic studies, Am J Obstet Gynecol source

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    • cites [35] Coxhead, 1993, Familial inheritance of endometriosis in a British population. A case control study, J Obstet Gynecol source

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  • Premisecitation

    A recent meta-analysis identified five loci regulating sex steroid hormone pathways, five secondary signals, and 19 single-nucleotide polymorphisms robustly associated with endometriosis.

    “A recent meta-analysis identified five loci regulating sex steroid hormone pathways, five secondary signals, and 19 single-nucleotide polymorphisms robustly associated with endometriosis (54)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Sapkota, 2017, Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism, Nat Commun source

      Not checked in the free run.

  • Premisecitation

    Endometriosis lesions are clonal, as demonstrated for typical, deep, and cystic ovarian endometriosis.

    “Endometriosis lesions are clonal, as demonstrated for typical (149), deep (150), and cystic ovarian (151-153) endometriosis.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [149] Wu, 2003, Resolution of clonal origins for endometriotic lesions using laser capture microdissection and the human androgen receptor (HUMARA) assay, Fertil Steril source

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    • cites [150] Mayr, 2003, Does endometriosis really have premalignant potential? A clonal analysis of laser-microdissected tissue, FASEB J source

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    • cites [151] Tamura, 1998, Analysis of clonality in human endometriotic cysts based on evaluation of X chromosome inactivation in archival formalin-fixed, paraffin-embedded tissue, Lab Invest

      Not checked in the free run.

    • cites [152] Yano, 1999, Molecular analysis of clonality in ovarian endometrial cysts, Gynecol Obstet Invest source

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    • cites [153] Jimbo, 1997, Evidence for monoclonal expansion of epithelial cells in ovarian endometrial cysts, Am J Pathol

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  • Premisecitation

    Endometriosis is a hereditary disease.

    “Endometriosis is a hereditary disease.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 20
  • May combine two claims. 24
  • The quote only partly states this claim. 1

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Findingown data

    Most deep endometriosis lesions do not or very slowly progress over time, but some lesions can be fast progressive.

    “Most deep endometriosis lesions do not (or very slowly) progress over time, but some lesions can be fast progressive (unpublished observations).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Most women with deep endometriosis have severe pain, especially during menstruation, but some large lesions (estimated 5%) are not painful.

    “Although most women with deep endometriosis have severe pain, especially during menstruation (65), some large lesions (estimated to be 5%) are not painful.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Koninckx, 1996, Diagnosis of deep endometriosis by clinical examination during menstruation and plasma CA-125 concentration, Fertil Steril source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Subtle endometriosis lesions decrease with age, whereas typical, cystic, and deep lesions increase with age, at least until menopause.

    “Subtle endometriosis lesions decrease with age, whereas typical, cystic, and deep lesions increase with age, at least until menopause (58).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Koninckx, 2016, Epidemiology of subtle, typical, cystic, and deep endometriosis: a systematic review, Gynaecol Surg source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.

    Premisenone given

    Endometriosis has a variable macroscopic appearance.

    “Endometriosis has a variable appearance.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Recurrence rates of cystic ovarian endometriosis after stripping are less than 20% within 6 months but vary with the surgeon and the technique used.

    “Recurrence rates of cystic ovarian endometriosis after stripping are less than 20% within 6 months (61, 62) but vary with the surgeon (63) and the technique used.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [61] Busacca, 1999, Recurrence of ovarian endometrioma after laparoscopic excision, Am J Obstet Gynecol source

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    • cites [62] Moscarini, 2014, Ovarian stripping versus cystectomy: recurrence of endometriosis and pregnancy rate, Arch Gynecol Obstet source

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    • cites [63] Muzii, 2011, The singer, not the song, J Minim Invasive Gynecol source

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  • May combine two claims.

    Premisecitation

    Endometriosis is associated with higher concentrations of Escherichia coli in menstrual blood, with vaginal infections, and with chronic endometritis.

    “Endometriosis is associated with higher concentrations of Escherichia coli in menstrual blood (134, 135), with vaginal infections (136), and with chronic endometritis (137).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [134] Khan, 2010, Escherichia coli contamination of menstrual blood and effect of bacterial endotoxin on endometriosis, Fertil Steril source

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    • cites [135] Khan, 2018, Bacterial contamination hypothesis: a new concept in endometriosis, Reprod Med Biol source

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    • cites [136] Lin, 2016, Increased risk of endometriosis in patients with lower genital tract infection: a nationwide cohort study, Medicine (Baltimore) source

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    • cites [137] Cicinelli, 2017, Higher prevalence of chronic endometritis in women with endometriosis: a possible etiopathogenetic link, Fertil Steril source

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  • May combine two claims.

    Premisecitation

    Low natural killer cell activity in plasma remains low whereas elevated CA-125 concentrations return to normal after surgical excision of deep endometriosis, suggesting that the NK cell defect is a cause and elevated CA-125 a consequence of endometriosis.

    “That the low natural killer (NK) cell activity in plasma remains low whereas the elevated CA-125 concentrations return to normal after surgical excision of deep endometriosis suggests that the NK cell defect is a cause and the elevated CA-125 a consequence of endometriosis (89).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Oosterlynck, 1994, CO2-laser excision of endometriosis does not improve the decreased natural killer activity, Acta Obstet Gynecol Scand source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cystic ovarian endometriosis causes pain in more than 80%, and deep endometriosis causes severe pain in the large majority of women.

    “Cystic ovarian endometriosis causes pain in more than 80%, and deep endometriosis causes severe pain in the large majority of women (27).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Koninckx, 1991, Suggestive evidence that pelvic endometriosis is a progressive disease, whereas deeply infiltrating endometriosis is associated with pelvic pain, Fertil Steril source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Endometriosis, especially cystic ovarian and deep endometriosis, and adenomyosis are associated with abnormal placentation, insufficient physiologic changes in the spiral arteries, and an increased risk of preterm birth, small for gestational age babies, and preeclampsia.

    “Endometriosis, especially cystic ovarian and deep endometriosis (130, 131), and adenomyosis (132, 133) are associated with abnormal placentation, insufficient physiologic changes in the spiral arteries, and an increased risk of preterm birth, small for gestational age (SGA) babies, and preeclampsia (131).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [130] Pan, 2017, Risk of gestational hypertension-preeclampsia in women with preceding endometriosis: a nationwide population-based study, PLoS One source

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    • cites [131] Koninckx, 2018, Endometriosis and pregnancy outcome, Fertil Steril source

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    • cites [132] Hasdemir, 2016, The role of adenomyosis in the pathogenesis of preeclampsia, Geburtshilfe Frauenheilkd source

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    • cites [133] Hashimoto, 2018, Adenomyosis and adverse perinatal outcomes: increased risk of second trimester miscarriage, preeclampsia, and placental malposition, J Matern Fetal Neonatal Med source

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  • May combine two claims.

    Premisecitation

    Genome-wide association studies identified 10 or 15 loci with single-nucleotide polymorphisms associated with severe endometriosis, located in DNA sequences regulating target genes.

    “Genomewide association studies identified 10 (50) or 15 (51) loci with single-nucleotide polymorphisms (52) associated with severe endometriosis, but located in DNA sequences regulating target genes (53).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [50] Rahmioglu, 2015, Genome-wide enrichment analysis between endometriosis and obesity-related traits reveals novel susceptibility loci, Hum Mol Genet source

      Not checked in the free run.

    • cites [51] Fung, 2018, Genetics of endometriosis: state of the art on genetic risk factors for endometriosis, Best Pract Res Clin Obstet Gynaecol source

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    • cites [52] Matalliotakis, 2017, The role of gene polymorphisms in endometriosis, Mol Med Rep source

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

    Premisenone given

    Endometriosis is a heterogeneous disease.

    “Endometriosis is a heterogeneous disease.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Estrogens stimulate growth, whereas progestogen therapy and pregnancy stop growth or cause decidualization and decrease endometriosis-associated pain.

    “Estrogens stimulate growth, whereas progestogen therapy and pregnancy stop growth or cause decidualization and decrease endometriosis-associated pain.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Clinical observations suggest that the prevalence and severity of deep endometriosis have markedly increased during the past 20 years.

    “Clinical observations suggest that the prevalence and severity of deep endometriosis have markedly increased during the past 20 years (58).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Koninckx, 2016, Epidemiology of subtle, typical, cystic, and deep endometriosis: a systematic review, Gynaecol Surg source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Progression of subtle lesions or progression from typical to cystic or deep lesions has not been observed directly.

    “However, progression of subtle lesions or progression from typical to cystic or deep lesions has not been observed directly (56).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Canis, 2016, Endometriosis may not be a chronic disease: an alternative theory offering more optimistic prospects for our patients, Fertil Steril source

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  • May combine two claims.

    Interpretationreasoning

    The clinical consequence is that lesions vary, that occasional lesions can be rapidly progressive, and that the effect of medical therapy can be variable between patients.

    “The clinical consequence is that lesions vary, that occasional lesions can be rapidly progressive, and that the effect of medical therapy can be variable between patients.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    If metaplasia indicates stable and transmissible genetic or epigenetic changes, this comes close to the genetic/epigenetic theory.

    “If, on the contrary, metaplasia indicates stable and transmissible genetic or epigenetic changes, this comes close to the genetic/epigenetic theory.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Typical, cystic, and deep lesions are benign tumors, which after an initial period of rapid growth stop growing or progress slowly and which do not recur after complete excision.

    “Typical, cystic, and deep lesions are benign tumors, which after an initial period of rapid growth stop growing or progress slowly and which do not recur after complete excision.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Endometriosis is associated with vaginal and pelvic infection and with an important metabolome in the uterine and peritoneal cavities.

    “In addition, we recently realized the association of endometriosis with vaginal and pelvic infection (78, 136, 138) and the presence of an important metabolome in the uterine and peritoneal cavities.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [78] Kobayashi, 2014, Pathogenesis of endometriosis: the role of initial infection and subsequent sterile inflammation, Mol Med Rep source

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    • cites [136] Lin, 2016, Increased risk of endometriosis in patients with lower genital tract infection: a nationwide cohort study, Medicine (Baltimore) source

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    • cites [138] Heidarpour, 2017, Prevalence of high-risk human papillomavirus infection in women with ovarian endometriosis, J Obstet Gynaecol Res source

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  • May combine two claims.

    Interpretationreasoning

    These defects might also explain the associated subfertility, with monthly fecundity rates below 10% being similar to women with unexplained infertility, the associated changes in the endometrium, and the associated pregnancy problems.

    “However, these defects might also explain the associated subfertility, with monthly fecundity rates below 10% being similar to women with unexplained infertility, the associated changes in the endometrium, and the associated pregnancy problems.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The endometriotic disease theory postulated that genetic incidents are required for the development of typical, cystic, or deep endometriosis.

    “The endometriotic disease theory (EDT) postulated (246) that genetic incidents are required for the development of typical, cystic, or deep endometriosis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [246] Koninckx, 1999, Implantation versus infiltration: the Sampson versus the endometriotic disease theory, Gynecol Obstet Invest source

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

    Interpretationnone given

    Subtle or microscopic lesions will progress to more severe lesions only if additional incidents happen.

    “Subtle or microscopic lesions will progress to more severe lesions only if additional incidents happen.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Local estrogen production and progesterone resistance were demonstrated in larger endometriosis lesions.

    “Local estrogen production (154) and progesterone resistance (155-162) were demonstrated in larger endometriosis lesions (154-163)”
    Quote in the paperNot a substantial claim0 of 9 sources checked
    • cites [154] Bulun, 2015, Molecular biology of endometriosis: from aromatase to genomic abnormalities, Semin Reprod Med source

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    • cites [155] Bulun, 2006, Progesterone resistance in endometriosis: link to failure to metabolize estradiol, Mol Cell Endocrinol source

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    • cites [156] Wang, 2009, Endometriosis is associated with progesterone resistance in the baboon (Papio anubis) oviduct: evidence based on the localization of oviductal glycoprotein 1 (OVGP1), Biol Reprod source

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    • cites [157] Bruner-Tran, 2010, Dioxin and endometrial progesterone resistance, Semin Reprod Med source

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    • cites [158] Bulun, 2010, 17β-Hydroxysteroid dehydrogenase-2 deficiency and progesterone resistance in endometriosis, Semin Reprod Med source

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    • cites [159] Al-Sabbagh, 2012, Mechanisms of endometrial progesterone resistance, Mol Cell Endocrinol source

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    • cites [160] Barragan, 2016, Human endometrial fibroblasts derived from mesenchymal progenitors inherit progesterone resistance and acquire an inflammatory phenotype in the endometrial niche in endometriosis, Biol Reprod source

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    • cites [161] Joshi, 2017, Progesterone resistance in endometriosis is modulated by the altered expression of microRNA-29c and FKBP4, J Clin Endocrinol Metab

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    • cites [162] Patel, 2017, Progesterone resistance in endometriosis: origins, consequences and interventions, Acta Obstet Gynecol Scand source

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  • May combine two claims.

    Interpretationcitation

    Incidents also occur in lesions, and a clonal origin does not exclude heterogeneity within a lesion as demonstrated for breast and other cancers.

    “Incidents also occur in lesions, and a clonal origin does not exclude heterogeneity within a lesion as demonstrated for breast (257) and other (258, 259) cancers.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [257] Geyer, 2010, Molecular analysis reveals a genetic basis for the phenotypic diversity of metaplastic breast carcinomas, J Pathol source

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    • cites [258] Dagogo-Jack, 2018, Tumour heterogeneity and resistance to cancer therapies, Nat Rev Clin Oncol source

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    • cites [259] McGranahan, 2017, Clonal heterogeneity and tumor evolution: past, present, and the future, Cell source

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

    Premisecitation

    The implantation theory was a reasonable hypothesis when formulated.

    “The implantation theory (1, 11, 201) was a reasonable hypothesis when formulated, while the metaplasia theory (31) was a histologic observation that did not consider genetic or epigenetic changes.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1] Sampson, 1927, Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity, Am J Obstet Gynecol source

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    • cites [11] Sampson, 1924, Benign and malignant endometrial implants in the peritoneal cavity, and their relation to certain ovarian tumors, Surg Gynecol Obstet

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    • cites [201] Sampson, 1925, Heterotopic or misplaced endometrial tissue, Am J Obstet Gynecol source

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

    Interpretationreasoning

    A better interpretation of metaplasia is that the underlying mechanisms can be reversible or irreversible changes, and both can be transmitted.

    “A better interpretation of metaplasia is that the underlying mechanisms can be reversible or irreversible changes, and both can be transmitted.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    If metaplasia is defined as metaplastic changes without permanent and transmissible genetic or epigenetic changes, the resulting endometriosis cells are genetically and epigenetically similar to endometrium and lesions after retrograde menstruation and implantation.

    “If metaplasia is defined as metaplastic changes without permanent and transmissible genetic or epigenetic changes, the resulting endometriosis cells are genetically and epigenetically similar to endometrium and lesions after retrograde menstruation and implantation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    High glycodelin concentrations in peritoneal fluid might protect early lesions from NK cell attack and could thus facilitate survival.

    “As an example, the high glycodelin concentrations in peritoneal fluid might protect early lesions from NK cell attack (261, 262) and could thus facilitate survival.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [261] Bolton, 1987, Identification of placental protein 14 as an immunosuppressive factor in human reproduction, Lancet source

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    • cites [262] Okamoto, 1991, Suppression by human placental protein 14 of natural killer cell activity, Am J Reprod Immunol source

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  • May combine two claims.

    Interpretationnone given

    The genetic/epigenetic theory is compatible with hereditary aspects and with a predisposition to develop endometriosis, and it explains why dioxin and total body radiation could increase the risk of endometriosis.

    “It is compatible with hereditary aspects and with a predisposition to develop endometriosis, and it explains why dioxin and total body radiation could increase the risk of endometriosis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The retrograde menstruation and implantation theory does not explain all clinical observations, such as extragenital endometriosis, endometriosis in women without endometrium and in men, or the clonal aspect.

    “The retrograde menstruation and implantation theory does not explain all clinical observations (Table 1), such as extragenital endometriosis (220), endometriosis in women without endometrium (31) and in men (33), or the clonal aspect (149).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [220] Davis, 2017, Extrapelvic endometriosis, Semin Reprod Med

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    • cites [31] Gruenwald, 1942, Origin of endometriosis from the mesenchyme of the celomic walls, Am J Obstet Gynecol source

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    • cites [33] Jabr, 2014, An unusual cause of abdominal pain in a male patient: endometriosis, Avicenna J Med source

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

    Interpretationnone given

    The clinical suggestion that typical, cystic, and deep endometriosis are three different diseases seems logical.

    “The clinical suggestion that typical, cystic, and deep endometriosis are three different diseases seems logical.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The genetic/epigenetic theory can explain the high prevalence in the peritoneal cavity and the increasing prevalence with increased retrograde menstruation.

    “It can explain the high prevalence in the peritoneal cavity and the increasing prevalence with increased retrograde menstruation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    New lesions can be formed after new incidents, and the probability that this happens increases with the cumulative genetic and epigenetic abnormalities transmitted at birth and acquired throughout life.

    “However, new lesions can be formed after new incidents, and the probability that this happens increases with the cumulative genetic and epigenetic abnormalities transmitted at birth and acquired throughout life.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationnone given

    The genetic/epigenetic theory is an update of the endometriotic disease theory by adding current knowledge of genetic and epigenetic changes and of the redundancy of cellular processes.

    “The genetic/epigenetic theory (Fig. 2) is an update of the EDT by adding current knowledge of genetic and epigenetic changes and of the redundancy of cellular processes.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Functional redundancy is a characteristic of many cellular processes.

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

    Interpretationnone given

    Subtle lesions are visualized as endometrium in a different environment until additional alterations appear.

    “Las lesiones sutiles se visualizan como endometrio en un entorno diferente hasta que aparecen alteraciones adicionales.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Deep endometriosis seems to be reactivated by trauma, such as by in vitro fertilization-related needle punctures for oocyte pick-up, triggering the subsequent development of more severe lesions and even a frozen pelvis.

    “Although the mechanisms of reactivation are not understood, deep endometriosis seems to be reactivated by trauma, such as by in vitro fertilization-related needle punctures for oocyte pick-up, triggering the subsequent development of more severe lesions and even a frozen pelvis (56), as frequently observed.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Canis, 2016, Endometriosis may not be a chronic disease: an alternative theory offering more optimistic prospects for our patients, Fertil Steril source

      Not checked in the free run.

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

    Interpretationnone given

    These models remain valid to study the effect of abnormal environments on (normal) endometrium.

    “These models remain valid to study the effect of abnormal environments on (normal) endometrium.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    The polygenetic/polyepigenetic theory is compatible with observations made up to now.

    “The polygenetic/ polyepigenetic theory is compatible with observations made up to now.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    The same mechanisms apply to adenomyosis.

    “It is suggested that the same mechanisms apply to adenomyosis.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Endometriosis lesions can remain dormant without progression for longer periods of time.

    “Similarly to uterine myomas, endometriosis lesions can remain dormant without progression for longer periods of time.”
    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 poor definition of metaplasia continues to create confusion.

    “The poor definition of metaplasia continues to create confusion.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Many words in the endometriosis literature are not clear.
40 of 40

  • The paper relies on this without support.

    There is no nonhuman animal model with sufficient similarity to the human myometrium, junctional zone, endometrium, placentation, and pregnancy disorders such as preeclampsia.

    “There is no nonhuman animal model with sufficient similarity to the human myometrium, junctional zone (JZ), endometrium, placentation, and pregnancy disorders, such as preeclampsia.”

  • The paper relies on this without support.

    Functional redundancy is a characteristic of many cellular processes.

    “Second, functional redundancy is a characteristic of many cellular processes.”

  • The authors state this as an assumption.

    The original cell can be an endometrial cell, a stem cell, or a bone marrow cell with inherited genetic and epigenetic defects.

    “The original cell can be an endometrial cell, a stem cell, or a bone marrow cell with their inherited genetic and epigenetic defects.”

  • The paper relies on this without support.

    Many words in the endometriosis literature are not clear.

    “Many words in the endometriosis literature are not clear.”

  • The paper relies on this without support.

    The meanings of words often change over time, especially after new clinical and molecular-biologic observations are added to the initial clinical, macroscopic, and microscopic descriptions.

    “This confusion stems from the fact that the meanings of words often change over time, especially after new clinical and molecular-biologic observations are added to the initial clinical, macroscopic, and microscopic descriptions.”
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?

  • Genetic and epigenetic conditions are conducive to the development of endometriosis, which is caused by environmental factors, or genetic and epigenetic changes caused by environmental factors are necessary to move from subtle changes to the disease stage.

    “It is believed that genetic and epigenetic conditions are rather conducive to the development of endometriosis, which is caused by environmental factors, or genetic and epigenetic changes caused by environmental factors are necessary to move from subtle changes in endometriosis to the disease stage [179].”

    From Endometriosis: Epidemiology, Classification, Pathogenesis, Treatment and Genetics (Review of Literature) (2021) · cites this paper as [179]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Twin-sister claim cites a study of nontwin sisters

    Minor

    The paper cites reference 44 for a claim about age of onset in twin sisters, but reference 44 is explicitly about nontwin sisters.

1 of 1

Cites

Flagged first, then by citations

23 of the 290 references couldn’t be matched to a known paper.

Research works printed but not linked: 9

  1. Rokitansky, 1860, Über Uterusdrüsen-Neubildung in Uterus- und Ovarial-Sarcomen, Zeitschr Ges Aerzte Wien, 16, 577
  2. Cullen, 1896, Adeno-myoma of the round ligament, Johns Hopkins Hosp Bull, 7, 112
  3. Cullen, 1896, Adenoma-myoma uteri diffusum benignum, J Hopkins Hosp Bull, 6, 133
  4. Cullen, 1919, The distribution of adenomyomata containing uterine mucosa, Am J Obstet Gynecol, 80, 130
  5. Batt, 2007, Mullerianosis, Histol Histopathol, 22, 1161
  6. Sampson, 1924, Benign and malignant endometrial implants in the peritoneal cavity, and their relation to certain ovarian tumors, Surg Gynecol Obstet, 38, 287
  7. Fallon, 1950, Endometriois: a report of 400 cases, R I Med J, 33
  8. Asencio FA, Ribeiro HA, Ribeiro PA, Mario M, Adamyan L, Ussia A, et al. Case reports and systematic review of estrogen independent symptomatic postmenopausal endometriosis. Gynecol Surgery 2018. In press.
  9. Meyer, 1923, Zur frage der Urnieren-genese van Adenomyomen, Zentralbl Gynakol, 15, 577

Cited by

Sorted by citations

Related

Authors
Koninckx, P. R., Ussia, A., Adamyan, L., Wattiez, A., Gomel, V., & Martin, D. C.
Affiliations
  • Università Cattolica del Sacro Cuore (IT)
  • Russian University of Medicine (RU)
  • Latifa Hospital (AE)
  • University of British Columbia (CA)
  • University of Tennessee Health Science Center (US)
Corresponding author
Koninckx, Philippe R.
ORCID
Venue
Fertility and Sterility
Publisher
Elsevier BV
Published
2019-02
Volume
111
Issue
2
Pages
327-340
ISSN
0015-0282 (ISSN-L)
DOI
10.1016/j.fertnstert.2018.10.013
OpenAlex
W2903882793
Semantic Scholar
bda1b43240a49c67f04356783de4dff519d10820
Cited by
427
References
290
Citations by year
2026: 35 · 2025: 60 · 2024: 52 · 2023: 80 · 2022: 61 · 2021: 76 · 2020: 44 · 2019: 19
FWCI
5.26
Type
journal article
Language
en
Open access
Licence
Locations
  • Fertility and Sterility (publishedVersion)
  • PubMed (publishedVersion)
  • Lirias (KU Leuven) (submittedVersion, other-oa)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
  • Health Sciences › Medicine › Obstetrics and Gynecology › Gynecological conditions and treatments
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Ectopic Pregnancy Diagnosis and Management
Keywords
endometriosis pathogenesis, genetic theory, epigenetic theory, retrograde menstruation, metaplasia, cystic ovarian lesions, deep infiltrating endometriosis, infertility, adenomyosis, peritonitis, placentation, stem cells
MeSH terms
Animals, Endometriosis, Endometrium, Female, Genetic Markers, Humans, Phenotype, Prognosis, Risk Factors, Genetic Predisposition to Disease, Heredity, Epigenesis, Genetic

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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