Pathogenesis of deep endometriosis

May combine two claims.

With the adenomyosis externa definition, most deep endometriosis lesions are unique (occasionally 2 and rarely 3) and big (mostly >1 cm in diameter).

“With this latter definition most deep endometriosis le-sions are unique (occasionally 2 and rarely 3) and big (mostly >1 cm in diameter).”

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

Endometriosis in the adolescent is characterized by angiogenic and hemorrhagic peritoneal and ovarian lesions.

“Endometriosis in the adolescent is characterized by angiogenic and hemorrhagic peritoneal and ovarian lesions.”

May combine two claims.

Adenomyosis externa lesions occasionally invade nerves and have some neurotropic effect.

“These adenomyosis externa lesions occasionally invade nerves (14) and have some neurotropic effect (15,16).”

• cites [14] Anaf, 2002, Hyperalgesia, nerve infiltration and nerve growth factor expression in deep adenomyotic nodules, peritoneal and ovarian endometriosis, Hum Reprod sourceNot checked yet

  Not checked in the free run.

• cites [15] Siquara De Sousa, 2015, Neural involvement in endometriosis: Review of anatomic distribution and mechanisms, Clin Anat sourceNot checked yet

  Not checked in the free run.

• cites [16] Anaf, 2004, Preferential infiltration of large bowel endometriosis along the nerves of the colon, Hum Reprod sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Early onset endometriosis in symptomatic adolescents is frequently severe and often involves extensive adhesions and even OMAs.

“A recent review study (35) on endometriosis in symptomatic adolescents has shown that early onset disease is frequently severe and often involves extensive adhesions and even OMAs.”

• cites [35] Brosens, 2013, Endometriosis in adolescents is a hidden, progressive and severe disease that deserves attention, not just compassion, Hum Reprod sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Functional transition of the endometrium to a fully P responsive tissue may be present at birth in newborns showing neonatal uterine bleeding, but in most girls full endometrial P response will be achieved during adolescence.

“Thus, functional transition of the endometrium to a fully P responsive tissue may be present at birth in newborns showing neonatal uterine bleeding but, in most girls, full endometrial P response will be achieved during adolescence.”

• cites [38] Brosens, 2017, The impact of uterine immaturity on obstetrical syndromes during adolescence, Am J Obstet Gynecol sourceNot checked yet

  Not checked in the free run.

May combine two claims. The quote only partly states this claim.

The lesions of premenarcheal and adolescent endometriosis include superficial angiogenic peritoneal implants and adhesions, and OMA can occasionally occur.

“The lesions include superficial angiogenic peritoneal implants and adhesions, and OMA can occasionally occur.”

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

Cyclic endometrial decidualization followed by menstrual shedding is confined to few species where placentation is characterized by deep trophoblast invasion and remodeling of the spiral arteries from their origin in the inner myometrium.

“Yet, it is striking that cyclic endometrial decidualization followed by menstrual shedding is confined to few species where placentation is characterized by deep trophoblast invasion and remodeling of the spiral arteries from their origin in the inner myometrium.”

May combine two claims.

In postmenopause, endometriosis can develop or be reactivated in the presence or absence of exogenous estrogens and can spread to various organs and structures causing obstructive lesions.

“In postmenopause, endometriosis can develop or be reactivated in the presence or absence of exogenous estrogens (Es) and can spread to various organs and structures causing obstructive lesions (Supplemental Table 1).”

• cites Supplemental Table 1Not checked yet

  Not checked in the free run.

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

The development of deep endometriosis at a later age suggests that deep infiltrating endometriosis is a delayed stage of endometriosis.

“The development of deep endometriosis at a later age suggests that deep infiltrating endometriosis is a delayed stage of endometriosis.”

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

The typical lesions of adult endometriosis are peritoneal, ovarian, and deep or adenomyotic endometriosis.

“The typical lesions are peritoneal, ovarian, and deep or adenomyotic endometriosis.”

Classified as probably not a substantial claim.

Deep endometriosis was described in the early nineties as adenomyosis externa with endometrial glands and stroma in fibromuscular tissue.

“Deep endometriosis was described in the early nineties as adenomyosis externa (11) with endometrial glands and stroma in fibromuscular tissue.”

• cites [11] Cornillie, 1990, Deeply infiltrating pelvic endometriosis: histology and clinical significance, Fertil Steril sourceNot checked yet

  Not checked in the free run.

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

The 5-mm definition of deep endometriosis was a mistake.

“At present we realize that this definition was a mistake and should be abandoned.”

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

The pathophysiology of deep endometriosis remains debated and the mechanisms of disease progression, as well as the role of genetics and epigenetics, still need to be unraveled.

“In conclusion the pathophysiology of deep endometriosis remains debated and the mechanisms of disease progression, as well as the role of genetics and epigenetics in the process, still needs to be unraveled.”

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

Subtle lesions are not a disease until epi(genetic) changes occur.

“Subtle lesions are not a disease until epi(genetic) changes occur.”

May combine two claims.

Deep endometriosis lesions seem to develop as a benign tumor, preferentially in the pouch of Douglas, with extension toward the uterine artery or the ureters, with a preferential invasion into the muscle of the bowel wall or the diaphragm, but not into the fat.

“These deep endometriosis lesions seem to develop as a benign tumor, preferentially in the pouch of Douglas, with extension toward the uterine artery or the ureters, with a preferential invasion into the muscle of the bowel wall or the diaphragm, but not into the fat.”

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

Because glandular activity was more in phase (~75%) with the menstrual cycle at depths >5 mm, deep endometriosis was defined as lesions >5 mm in the peritoneum.

“Because the glandular activity was more in phase (%75%) with the menstrual cycle at depths >5 mm deep endometriosis was defined as lesions >5 mm in the peritoneum (12).”

• cites [12] Koninckx, 1992, Deep endometriosis: a consequence of infiltration or retraction or possibly adenomyosis externa?, Fertil Steril sourceNot checked yet

  Not checked in the free run.

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

The 5-mm definition permits the inclusion of slightly deeper typical lesions.

“The 5-mm definition permits the inclusion of slightly deeper typical lesions.”

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

Deep endometriosis is a specific disease.

“A classification should reflect that deep endometriosis is a specific disease.”

Classified as probably not a substantial claim.

The definition of distinct endometriotic entities based on the difference in the tissue composition of the lesions (endometriotic nodules vs. adenomyotic nodules) is inconsistent with the very frequent presence of smooth muscle cells in endometriosis irrespective of its localization.

“Anaf et al. (45) concluded that the definition of distinct endometriotic entities based on the difference in the tissue composition of the lesions (endometriotic nodules vs. adenomyotic nodules) is inconsistent with the very frequent presence of smooth muscle cells in endometriosis irrespective of its localization.”

• cites [45] Anaf, 2000, Smooth muscles are frequent components of endometriotic lesions, Hum Reprod sourceNot checked yet

  Not checked in the free run.

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

In the absence of an animal model mimicking specific endometrial functions such as placentation, and permitting the induction of the different clinical manifestations of endometriosis, the pathophysiology remains debated with hypotheses, theories, and speculation.

“In the absence of an animal model mimicking specific endometrial functions such as placentation, and permitting the induction of the different clinical manifestations of endometriosis, the pathophysiology remains debated with hypotheses, theories, and speculation.”

May combine two claims.

The first phenotype characterized by poor sex steroid hormone response is along the Müllerian tract including the uterus, rectovaginal septum, and, to some extent, the uterine ligaments, and the second phenotype outside the Müllerian tract particularly the ovaries.

“The first phenotype characterized by poor sex steroid hormone response is along the M€ ullerian tract including the uterus, rectovaginal septum, and, to some extent, the uterine ligaments, and the second phenotype outside the M€ ullerian tract particularly the ovaries.”

• cites [53] Brosens, 2000, Redefining endometriosis: is deep endometriosis a progressive disease?, Hum Reprod sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The fibromuscular tissue in deep endometriosis shares characteristics with pathological wound healing, although the process could not be explained by TGF-b alone.

“Van Kaam et al. (47) characterized the fibromuscular tissue and showed that the tissue shared characteristics with pathological wound healing, although the process could not be explained by transforming growth factor-b (TGF-b) alone.”

• cites [47] Van Kaam, 2008, Fibromuscular differentiation in deeply infiltrating endometriosis is a reaction of resident fibroblasts to the presence of ectopic endometrium, Hum Reprod sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Hyperplasia of the surrounding smooth muscle and fibrous tissue results in nodule formation, and deep infiltrating endometriosis is focally associated with microendometriomas of 500-2,000 mm in diameter particularly in the submucosal layer of the vagina, rectum, or bladder.

“Hyperplasia of the surrounding smooth muscle and fibrous tissue results in nodule formation and, important, deep infiltrating endometriosis is focally associated with microendometriomas of 500-2,000 mm in diameter particularly in the submucosal layer of the vagina, rectum.or bladder.”

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

Uterine immaturity in adolescence is manifested by a higher risk of preeclampsia.

“Uterine immaturity in adolescence is manifested by a higher risk of preeclampsia.”

May combine two claims.

The two dominant phenotypes of ectopic endometrium largely depend on the localization and have a different sex steroid hormone response.

“The two dominant phenotypes of ectopic endometrium largely depend on the localization and have a different sex steroid hormone response (53).”

• cites [53] Brosens, 2000, Redefining endometriosis: is deep endometriosis a progressive disease?, Hum Reprod sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The many similarities between OMA and deep infiltrating endometriosis indicate that the two conditions share the same pathophysiology and very likely the same pathogenesis.

“The many similarities between OMA and deep infiltrating endometriosis (DIE) indicate that the two conditions share the same pathophysiology and very likely the same pathogenesis.”

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

The natural history of endometriosis is unclear.

“Its natural history is unclear.”

May combine two claims.

The differences between OMA and DIE may result from the different lesional microenvironments and from the difference in aging, as OMA is the typical severe lesion in adolescent whereas deep endometriosis is typical in the older adult.

“The differences may result from the different lesional microenvironments and, in addition, from the difference in the aging between both as the OMA is the typical severe lesion in adolescent whereas deep endometriosis is typical in the older adult.”

May combine two claims.

Misplaced endometrial glands and embryonic-like duct remnants were described in six of seven fetuses, supporting the theory that some subtypes of endometriosis are related to an abnormal embryogenesis.

“Misplaced endometrial glands and embryonic-like duct remnants were also described in six of seven fetuses, supporting the theory that some subtypes of endometriosis are related to an abnormal embryogenesis (58).”

• cites [58] Bouquet de, 2014, Endometriosis: a new cellular and molecular genetic approach for understanding the pathogenesis and evolutivity, Front SurgNot checked yet

  Not checked in the free run.

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

OMA is a most severe reproductive disease with an early onset in reproductive life and with great delay in diagnosis.

“The conclusion by Tosti et al. (50) that the specific pathogenic features, such as apoptosis, neuroangiogenesis, oxidative stress, and inflammation, may explain the more severe symptomatology of deep endometriosis should include that OMA is a most severe reproductive disease with an early onset in reproductive life and with great delay in diagnosis.”

• cites [50] Tosti, 2015, Pathogenetic mechanisms of deep infiltrating endometriosis, Reprod Sci sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The current long delay of diagnosis implicates increasing SMM and fibrosis and loss of sex steroid hormone response in all locations.

“The differentiation has also therapeutic implications, but the current long delay of diagnosis implicates increasing SMM and fibrosis and loss of sex steroid hormone response in all locations.”

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

OMA causes ovarian fibrosis.

“The fact that OMA causes ovarian fibrosis is a medical problem that should arouse widespread concern in clinicians worldwide.”

May combine two claims.

Infiltration by endometrial glands and stroma occurs into adjacent fibromuscular tissue along the loose connective tissue and penetration is arrested at the border of the underlying fat tissue.

“Cornillie et al. (11) showed that infiltration by endometrial glands and stroma occurs into adjacent fibromuscular tissue along the loose connective tissue and that penetration is arrested at the border of the underlying fat tissue.”

• cites [11] Cornillie, 1990, Deeply infiltrating pelvic endometriosis: histology and clinical significance, Fertil Steril sourceNot checked yet

  Not checked in the free run.

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

Whether normal or abnormal, endometriotic cells develop in an environment different from the uterus with its specific relationship to the junctional zone.

“Whether normal or abnormal, these cells develop in an environment different from the uterus with its specific relationship to the junctional zone.”

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

With the advancement in imaging techniques, OMA is increasingly diagnosed at an earlier stage when the endometrioma may be less fibrotic and more responsive to medical treatment.

“Fortunately, with the advancement in imaging techniques, the OMA is increasingly diagnosed at an earlier stage when the endometrioma may be less fibrotic and more responsive to medical treatment, making an evaluation of medical options critically important.”

May combine two claims.

Deep infiltrating endometriosis is found not only in the rectovaginal septum, but also in all fibromuscular pelvic structures such as the uterosacral and utero-ovarian ligaments and the muscular wall of pelvic organs.

“Deep infiltrating endometriosis is found not only in the rectovaginal septum, but also in all fibromuscular pelvic structures such as the uterosacral and utero-ovarian ligaments and the muscular wall of pelvic organs.”

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

The critical factor in the progression of endometriosis is aging.

“The critical factor in the progression of endometriosis is aging, but unfortunately the long delay in diagnosis of pelvic endometriosis prevents management at the early stage.”

May combine two claims.

Endometriotic lesions are wounds that undergo repeated injury and healing, highlighting the importance of platelets in the development of endometriosis.

“Their results suggested that endometriotic lesions are wounds that undergo repeated injury and healing, highlighting the importance of platelets in the development of endometriosis.”

• cites [48] Zhang, 2016, Platelets drive smooth muscle metaplasia and fibrogenesis in endometriosis through epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation, Mol Cell Endocrinol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Due to the commonality shared with endometriosis (i.e., cyclic bleeding), adenomyotic lesions behave just like endometriotic lesions, which are essentially wounds that undergo ReTIAR.

“Therefore, due to the commonality shared with endometriosis (i.e., cyclic bleeding), adenomyotic lesions behave just like endometriotic lesions, which are essentially wounds that undergo ReTIAR.”

May combine two claims.

The endometrium is the candidate because shredded menstrual endometrium is viable and has implantation potential.

“The endometrium is the candidate because shredded menstrual endometrium is viable, was demonstrated in 1927 (113) and has implantation potential as demonstrated by subcutaneous injection (114) as early as 1958.”

• cites [113] Cron, 1927, The viability of cast-off menstrual endometrium, Am J Obstet Gynecol sourceNot checked yet

  Not checked in the free run.

• cites [114] Ridley, 1958, Experimental endometriosis in the human, Am J Obstet Gynecol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Some deep endometriosis lesions-estimated at <1%-are fast progressive and have a different aspect during surgery.

“Some lesions-estimated at <1%-are fast progressive and they do have a different aspect during surgery.”

May combine two claims.

Instead of becoming at rest during pregnancy, some deep lesions do progress and can cause bowel, uterus, or bladder perforations.

“Instead of becoming at rest during a pregnancy, some deep lesions do progress and can cause bowel (65,66), uterus, or bladder perforations.”

• cites [65] Setubal, 2014, Bowel complications of deep endometriosis during pregnancy or in vitro fertilization, Fertil Steril sourceNot checked yet

  Not checked in the free run.

• cites [66] Vigano, 2015, Beyond infertility: obstetrical and postpartum complications associated with endometriosis and adenomyosis, Fertil Steril sourceNot checked yet

  Not checked in the free run.

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

Most deep endometriosis lesions are painful, especially during menstruation, but a minority (around 5%) does not cause pain.

“Most lesions are painful, especially during menstruation, but a minority (around 5%) does not cause pain.”

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

Clinical observation by surgeons suggests that the prevalence and severity of deep endometriosis is increasing during the past 20 years.

“Clinical observation by surgeons suggests that the prevalence and severity of deep endometriosis is increasing during the past 20 years (64).”

• cites [64] Koninckx, 2016, Epidemiology of subtle, typical, cystic, and deep endometriosis: a systematic review, Gynaecol Surg sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Glycodelins in concentrations as secreted by endometriosis cells in peritoneal fluid decrease natural killer activity, which can be viewed as an autoprotective mechanism of the endometriotic cell.

“Interestingly, glycodelins in concentrations as secreted by endometriosis cells in PF (107) decrease the natural killer activity (108), which can be viewed as an autoprotective mechanism of the endometriotic cell.”

• cites [107] Koninckx, 1992, CA-125 and placental protein 14 concentrations in plasma and peritoneal fluid of women with deeply infiltrating pelvic endometriosis, Fertil Steril sourceNot checked yet

  Not checked in the free run.

• cites [108] Okamoto, 1991, Suppression by human placental protein 14 of natural killer cell activity, Am J Reprod Immunol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

At the moment of clinical diagnosis most lesions are no longer progressive, although they had obviously progressed before.

“In addition, at the moment of clinical diagnosis most lesions are no longer progressive, although they had obviously progressed before.”

May combine two claims.

Natural killer activity is decreased in peritoneal fluid and in plasma of women with endometriosis, and after excision of deep endometriosis their activity remains low, whereas elevated CA-125 concentrations return to normal.

“The natural killer activity is decreased in PF and in plasma of women with endometriosis (103-105) and after excision of deep endometriosis their activity remains low, whereas elevated CA-125 concentrations return to normal (106).”

• cites [103] Oosterlynck, 1991, Women with endometriosis show a defect in natural killer activity resulting in a decreased cytotoxicity to autologous endometrium, Fertil Steril sourceNot checked yet

  Not checked in the free run.

• cites [104] Oosterlynck, 1992, The natural killer activity of peritoneal fluid lymphocytes is decreased in women with endometriosis, Fertil Steril sourceNot checked yet

  Not checked in the free run.

• cites [105] Tanaka, 1992, Decreased natural killer cell activity in women with endometriosis, Gynecol Obstet Invest sourceNot checked yet

  Not checked in the free run.

• cites [106] Oosterlynck, 1994, CO2-laser excision of endometriosis does not improve the decreased natural killer activity, Acta Obstet Gynecol Scand sourceNot checked yet

  Not checked in the free run.

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

This is a common observation for typical lesions and consistent with their burnt out aspect by pathology.

“This is a common observation for typical lesions and consistent with their burnt out aspect by pathology.”

May combine two claims.

When traumatized by clinical examination or by puncture for oocyte pick-up, deep endometriosis lesions seem to be activated and might start growing again.

“However, when traumatized by clinical examination or by puncture for oocyte pick-up, deep endometriosis lesions seem to be activated and might start growing again (63).”

• cites [63] Canis, 2016, Endometriosis may not be a chronic disease: an alternative theory offering more optimistic prospects for our patients, Fertil Steril sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The epidemiology of endometriosis is unclear because of a variable inclusion of subtle lesions and because of diagnostic uncertainties of hospital-based discharge records.

“The epidemiology of endometriosis is unclear because of a variable inclusion of subtle lesions and because of diagnostic uncertainties of hospital-based discharge records (64).”

• cites [64] Koninckx, 2016, Epidemiology of subtle, typical, cystic, and deep endometriosis: a systematic review, Gynaecol Surg sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Pelvic endometriosis is associated with a low-grade inflammation of the peritoneal cavity with higher concentrations of activated macrophages and thus with higher concentrations of many different cytokines and angiogenic factors.

“Pelvic endometriosis is associated with a low-grade inflammation of the peritoneal cavity with higher concentrations of activated macrophages and thus with higher concentrations of the many different cytokines (68-72) and angiogenic factors (73)(74)(75)(76)(77)(78)(79)(80)(81)(82)(83)(84)(85)(86)(87)(88)(89)(90)(91).”

• cites [68] Koninckx, 1998, Endometriotic disease: the role of peritoneal fluid, Hum Reprod Update sourceNot checked yet

  Not checked in the free run.

• cites [69] Barcz, 2000, Role of cytokines in pathogenesis of endometriosis, Med Sci MonitNot checked yet

  Not checked in the free run.

• cites [70] Harada, 2001, Role of cytokines in endometriosis, Fertil Steril sourceNot checked yet

  Not checked in the free run.

• cites [71] Wu, 2003, The role of cytokines in endometriosis, Am J Reprod Immunol sourceNot checked yet

  Not checked in the free run.

• cites [72] Kyama, 2009, Role of cytokines in the endometrial-peritoneal cross-talk and development of endometriosis, Front Biosci (Elite Ed) sourceNot checked yet

  Not checked in the free run.

• cites [73] Oosterlynck, 1993, Angiogenic activity of peritoneal fluid from women with endometriosis, Fertil Steril sourceNot checked yet

  Not checked in the free run.

• cites [74] Morgan, 1996, Angiogenesis in normal, hyperplastic, and neoplastic endometrium, J Pathol sourceNot checked yet

  Not checked in the free run.

• cites [75] Taylor, 1997, Angiogenesis and macrophage activation in endometriosisNot checked yet

  Not checked in the free run.

• cites [76] Healy, 1998, Angiogenesis: a new theory for endometriosis, Hum Reprod Update sourceNot checked yet

  Not checked in the free run.

• cites [77] Matsuzaki, 1998, Angiogenesis in endometriosis, Gynecol Obstet Invest sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Pluripotent stem cells were found in the endometrium and in the peritoneal cavity.

“More recently pluripotent stem cells were found in the endometrium and in the peritoneal cavity.”

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

For development on the chicken allantoic membrane, tissue integrity is important.

“For development on the chicken allantoic membrane, tissue integrity is important (115).”

• cites [115] Nap, 2003, Tissue integrity is essential for ectopic implantation of human endometrium in the chicken chorioallantoic membrane, Hum Reprod sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Mesothelial-to-mesenchymal transition in the peritoneal cavity is well known, with a specific role of platelets.

“Mesothelial-to-mesenchymal transition in the peritoneal cavity is well known (124, 125) with a specific role of platelets (48).”

• cites [124] Sandoval, 2016, Mesothelial-to-mesenchymal transition in the pathogenesis of post-surgical peritoneal adhesions, J Pathol sourceNot checked yet

  Not checked in the free run.

• cites [125] Cheng, 2017, Characteristics of Human endometrium-derived mesenchymal stem cells and their tropism to endometriosis, Stem Cells Int sourceNot checked yet

  Not checked in the free run.

• cites [48] Zhang, 2016, Platelets drive smooth muscle metaplasia and fibrogenesis in endometriosis through epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation, Mol Cell Endocrinol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The genetic/epigenetic hypothesis is consistent with heredity and clonality and explains why not all women with retrograde menstruation and implantation develop endometriosis.

“The genetic/epigenetic hypothesis is attractive as it is consistent with heredity and clonality and as it explains why not all women with retrograde menstruation and implantation develop endometriosis.”

May combine two claims.

Familial clustering of endometriosis is well established in humans and primates.

“Well established are familial clustering in humans (156) and primates (157).”

• cites [156] Kennedy, 1995, Familial endometriosis, J Assist Reprod Genet sourceNot checked yet

  Not checked in the free run.

• cites [157] Hadfield, 1997, Risk factors for endometriosis in the rhesus monkey (Macaca mulatta): a case-control study, Hum Reprod Update sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The hypothesis that genetic or epigenetic changes are a prerequisite for development into typical cystic or deep endometriosis is a unifying theory and compatible with all clinical manifestations of endometriosis.

“The hypothesis that genetic or epigenetic changes are a prerequisite for development into typical cystic or deep endometriosis is a unifying theory and compatible with all clinical manifestations of endometriosis.”

• AssumptionRests on an assumption: Microscopic and subtle endometriosis lesions are not associated with pain or infertility.
• AssumptionRests on an assumption: Most endometriosis lesions do not progress to more severe pathology.

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

The statement of Novak and De Lima was based on the association of adenomyosis and endometriosis, and observation confirmed more recently by the association of deep endometriosis and adenomyosis.

“The statement of Novak and De Lima (226) was based on the association of adenomyosis and endometriosis, and observation confirmed more recently by the association of deep endometriosis and adenomyosis.”

• cites [226] Novak, 1948, A correlative study of adenomyosis and pelvic endometriosis, with special reference to the hormonal reaction of ectopic endometrium, Am J Obstet Gynecol sourceNot checked yet

  Not checked in the free run.

• AssumptionRests on an assumption: Deep endometriosis and adenomyosis are morphologically very similar.

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

The importance of the original cell is weakened by pluripotent stem cells, some originating from bone marrow in adult life, and by mesothelial-to-mesenchymal transition.

“The importance of the original cell is weakened by pluripotent stem cells, some of them originating from bone marrow in adult life and by mesothelial-to-mesenchymal transition.”

May combine two claims.

ERs and PRs are present not only in glands and stroma but also in the smooth muscle component of deep endometriosis, and the expression of a-smooth muscle actin and collagen I in and around endometriotic lesions support the notion of the metaplastic process.

“That E receptors (ERs) and PRs are present not only in glands and stroma but also in the smooth muscle component of deep endometriosis (229), and the expression of a-smooth muscle actin and collagen I in and around endometriotic lesions support the notion of the metaplastic process (230).”

• cites [229] Noel, 2010, Estrogen and progesterone receptors in smooth muscle component of deep infiltrating endometriosis, Fertil Steril sourceNot checked yet

  Not checked in the free run.

• cites [230] Ibrahim, 2017, Myofibroblasts are evidence of chronic tissue microtrauma at the endometrial-myometrial junctional zone in uteri with adenomyosis, Reprod Sci sourceNot checked yet

  Not checked in the free run.

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

Deep endometriosis is a benign tumor.

“Deep endometriosis then becomes a benign tumor.”

May combine two claims.

Some mesenchymal/mesothelial cells of the peritoneal cavity, of mesothelial repair after surgery, and in endometrium and endometriosis are directly derived from bone marrow.

“Some of these mesenchymal/ mesothelial cells of the peritoneal cavity (48), of the mesothelial repair after surgery (126) and in endometrium and endometriosis (127-131) are directly derived from bone marrow.”

• cites [48] Zhang, 2016, Platelets drive smooth muscle metaplasia and fibrogenesis in endometriosis through epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation, Mol Cell Endocrinol sourceNot checked yet

  Not checked in the free run.

• cites [126] Lucas, 2007, Stem cells for mesothelial repair: an understudied modality, Int J Artif Organs sourceNot checked yet

  Not checked in the free run.

• cites [127] Fernandez Shaw, 1995, Bone marrow-derived cell populations in uterine and ectopic endometrium, Hum Reprod sourceNot checked yet

  Not checked in the free run.

• cites [128] Du, 2007, Contribution of bone marrow-derived stem cells to endometrium and endometriosis, Stem Cells sourceNot checked yet

  Not checked in the free run.

• cites [129] Zhang, 2012, A study in vitro on differentiation of bone marrow mesenchymal stem cells into endometrial epithelial cells in mice, Eur J Obstet Gynecol Reprod Biol sourceNot checked yet

  Not checked in the free run.

• cites [130] Sakr, 2014, Endometriosis impairs bone marrow-derived stem cell recruitment to the uterus whereas bazedoxifene treatment leads to endometriosis regression and improved uterine stem cell engraftment, Endocrinology sourceNot checked yet

  Not checked in the free run.

• cites [131] Moridi, 2016, Bone marrow stem cell chemotactic activity is induced by elevated CXCl12 in endometriosis, Reprod Sci sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In twin sisters, prevalence of endometriosis and age of onset are similar.

“In twin sisters a prevalence of endometriosis (158-161) and age of onset (162) are similar.”

• cites [158] Hadfield, 1997, Endometriosis in monozygotic twins, Fertil Steril sourceNot checked yet

  Not checked in the free run.

• cites [159] Moen, 1993, The familial risk of endometriosis, Acta Obstet Gynecol Scand sourceNot checked yet

  Not checked in the free run.

• cites [160] Moen, 1994, Endometriosis in monozygotic twins, Acta Obstet Gynecol Scand sourceNot checked yet

  Not checked in the free run.

• cites [161] Treloar, 1999, Genetic influences on endometriosis in an Australian twin sample, Fertil Steril sourceNot checked yet

  Not checked in the free run.

• cites [162] Kennedy, 1996, Age of onset of pain symptoms in non-twin sisters concordant for endometriosis, Hum Reprod sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Prevalence of endometriosis is increased by 6%-9% in first-degree relatives and by 15% for severe disease.

“Prevalence is increased by 6%-9% in first degree relatives (163, 164) and by 15% for severe disease (165, 166).”

• cites [163] Simpson, 1980, Heritable aspects of endometriosis. I. Genetic studies, Am J Obstet Gynecol sourceNot checked yet

  Not checked in the free run.

• cites [164] Coxhead, 1993, Familial inheritance of endometriosis in a British population. A case control study, J Obstet Gynecol sourceNot checked yet

  Not checked in the free run.

• cites [165] Kennedy, 1998, The genetics of endometriosis, J Reprod MedNot checked yet

  Not checked in the free run.

• cites [166] Kennedy, 1998, Magnetic resonance imaging to assess familial risk in relatives of women with endometriosis, Lancet sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Arcellana et al. observed in one neonate with the McKusick-Kaufman syndrome not only the presence of tubal regurgitation of menstrual debris, but in addition, for the first time, the serosal implantation of endometrial fragments.

“Arcellana et al. (31) observed in one neonate with the McKusick-Kaufman syndrome not only the presence of tubal regurgitation of menstrual debris, as also observed by Sampson (6, 7), but in addition, for the first time, the serosal implantation of endometrial fragments.”

• cites [31] Arcellana, 1996, McKusick-Kaufman syndrome with legal complications of hydrometrocolpos and congenital endometriosis, J PerinatolNot checked yet

  Not checked in the free run.

• cites [6] Sampson, 1925, Heterotopic or misplaced endometrial tissue, Am J Obstet Gynecol sourceNot checked yet

  Not checked in the free run.

• cites [7] Sampson, 1927, Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity, Am J Obstet Gynecol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Deep endometriosis is a specific disease, reflected in the distribution of deep lesions in all classes of The Revised American Fertility Society (AFS) classification with little association with cystic ovarian endometriosis.

“The interpretation that deep endometriosis is a specific disease is reflected in the distribution of deep lesions in all classes of The Revised American Fertility Society (AFS) classification with little association with cystic ovarian endometriosis (Fig. 4).”

• cites [234] Koninckx, 1991, Suggestive evidence that pelvic endometriosis is a progressive disease, whereas deeply infiltrating endometriosis is associated with pelvic pain, Fertil Steril sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The many associated effects are no longer considered the cause but either the consequence of (epi)genetic changes to endometriotic disease or they are factors signaling predisposition.

“The many associated effects are no longer considered the cause but either the consequence of (epi)genetic changes to endometriotic disease or they are factors signaling predisposition.”

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

Abundant retrograde menstruation will increase peritoneal mesothelial cell retraction and oxidative stress, thus facilitating implantation and subtle lesions and also (epi)genetic changes.

“Abundant retrograde menstruation, for example, will increase peritoneal mesothelial cell retraction and oxidative stress, thus facilitating implantation and subtle lesions and also (epi)genetic changes.”

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

It is hardly conceivable that blocks of myometrium and junctional zone/myometrium are the cause of deep endometriosis in humans.

“Second, it is hardly conceivable that blocks of myometrium and junctional zone/myometrium are the cause of deep endometriosis in humans.”

• AssumptionRests on an assumption: Spontaneous deep endometriosis has not been reported in primates.

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

Subtle and microscopic lesions are a physiologic condition until genetic/epigenetic changes occur.

“In addition it implies that subtle and microscopic lesions are a physiologic condition and that only after genetic/epigenetic changes into typical, cystic, or deep endometriosis does this occur.”

• AssumptionRests on an assumption: Microscopic and subtle endometriosis lesions are not associated with pain or infertility.
• AssumptionRests on an assumption: Most endometriosis lesions do not progress to more severe pathology.

May combine two claims.

These experiments emphasize the importance of tissue integrity and of the special relationship of endometrium and junctional zone for growth and development.

“These experiments, however, emphasize the importance of tissue integrity-as for the chicken allantoic membrane experiments (115)-and of the special relationship of endometrium and junctional zone for growth and development.”

• cites [115] Nap, 2003, Tissue integrity is essential for ectopic implantation of human endometrium in the chicken chorioallantoic membrane, Hum Reprod sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Sampson observed tubal reflux of menstrual shedding at the time of menstruation, but never reported the early stage of endometrial attachment to the mesothelium and invasion as documented by Witz et al. in experimental conditions.

“It is important to note that although Sampson observed tubal reflux of menstrual shedding (7) at the time of menstruation, but never reported the early stage of endometrial attachment to the mesothelium and invasion as documented by Witz et al. (32) in experimental conditions.”

• cites [7] Sampson, 1927, Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity, Am J Obstet Gynecol sourceNot checked yet

  Not checked in the free run.

• cites [32] Witz, 2003, Pathogenesis of endometriosis—current research, Hum Fertil (Camb) sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Endometriosis is a hereditary disease and about 50% of endometriosis lesions can be attributed to hereditary factors.

“Endometriosis is an hereditary disease and some 50% of endometriosis lesions can be attributed to hereditary factors (153-155).”

• cites [153] Sapkota, 2015, Genetic burden associated with varying degrees of disease severity in endometriosis, Mol Hum Reprod sourceNot checked yet

  Not checked in the free run.

• cites [154] Saha, 2015, The heritability of endometriosis, Fertil Steril sourceNot checked yet

  Not checked in the free run.

• cites [155] Baranov, 2015, Systems genetics view of endometriosis: a common complex disorder, Eur J Obstet Gynecol Reprod Biol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Dioxin and total body radiation can have genomic or epigenetic effects.

“Both can have genomic or epigenetic effects (193).”

• cites [193] Sofo, 2015, Correlation between dioxin and endometriosis: an epigenetic route to unravel the pathogenesis of the disease, Arch Gynecol Obstet sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Genome-wide scanning resulted in 10 significant loci and a significant association of six of these.

“Genome-wide scanning resulted in 10 significant loci and a significant association of six of these (167, 168).”

• cites [167] Zondervan, 2016, Beyond endometriosis genome-wide association study: from genomics to phenomics to the patient, Semin Reprod Med sourceNot checked yet

  Not checked in the free run.

• cites [168] Rahmioglu, 2015, Genome-wide enrichment analysis between endometriosis and obesity-related traits reveals novel susceptibility loci, Hum Mol Genet sourceNot checked yet

  Not checked in the free run.

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

It cannot be excluded that induction of deep endometriosis-like lesions by implantation of endometrium and myometrium signals that genetic/epigenetic modifications did occur.

“It cannot be excluded that the induction of deep endometriosis-like lesions by implantation of endometrium and myometrium signals that (epi)genetic modifications did occur (e.g., by the local environment as bleeding with oxidative stress).”