Pathogenesis of endometriosis: the genetic/epigenetic theory

In the paper

“Most deep endometriosis lesions do not (or very slowly) progress over time, but some lesions can be fast progressive (unpublished observations).”

In the paper

“Although most women with deep endometriosis have severe pain, especially during menstruation (65), some large lesions (estimated to be 5%) are not painful.”

What the sources say

• Not checked yetcites [65] Koninckx, 1996, Diagnosis of deep endometriosis by clinical examination during menstruation and plasma CA-125 concentration, Fertil Steril source

In the paper

“Subtle endometriosis lesions decrease with age, whereas typical, cystic, and deep lesions increase with age, at least until menopause (58).”

What the sources say

• Not checked yetcites [58] Koninckx, 2016, Epidemiology of subtle, typical, cystic, and deep endometriosis: a systematic review, Gynaecol Surg source

In the paper

“Endometriosis has a variable appearance.”

In the paper

“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.”

What the sources say

• Not checked yetcites [61] Busacca, 1999, Recurrence of ovarian endometrioma after laparoscopic excision, Am J Obstet Gynecol source
• Not checked yetcites [62] Moscarini, 2014, Ovarian stripping versus cystectomy: recurrence of endometriosis and pregnancy rate, Arch Gynecol Obstet source
• Not checked yetcites [63] Muzii, 2011, The singer, not the song, J Minim Invasive Gynecol source

In the paper

“Endometriosis is associated with higher concentrations of Escherichia coli in menstrual blood (134, 135), with vaginal infections (136), and with chronic endometritis (137).”

What the sources say

• Not checked yetcites [134] Khan, 2010, Escherichia coli contamination of menstrual blood and effect of bacterial endotoxin on endometriosis, Fertil Steril source
• Not checked yetcites [135] Khan, 2018, Bacterial contamination hypothesis: a new concept in endometriosis, Reprod Med Biol source
• Not checked yetcites [136] Lin, 2016, Increased risk of endometriosis in patients with lower genital tract infection: a nationwide cohort study, Medicine (Baltimore) source
• Not checked yetcites [137] Cicinelli, 2017, Higher prevalence of chronic endometritis in women with endometriosis: a possible etiopathogenetic link, Fertil Steril source

In the paper

“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).”

What the sources say

• Not checked yetcites [89] Oosterlynck, 1994, CO2-laser excision of endometriosis does not improve the decreased natural killer activity, Acta Obstet Gynecol Scand source

In the paper

“Cystic ovarian endometriosis causes pain in more than 80%, and deep endometriosis causes severe pain in the large majority of women (27).”

What the sources say

• Not checked yetcites [27] Koninckx, 1991, Suggestive evidence that pelvic endometriosis is a progressive disease, whereas deeply infiltrating endometriosis is associated with pelvic pain, Fertil Steril source

In the paper

“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).”

What the sources say

• Not checked yetcites [130] Pan, 2017, Risk of gestational hypertension-preeclampsia in women with preceding endometriosis: a nationwide population-based study, PLoS One source
• Not checked yetcites [131] Koninckx, 2018, Endometriosis and pregnancy outcome, Fertil Steril source
• Not checked yetcites [132] Hasdemir, 2016, The role of adenomyosis in the pathogenesis of preeclampsia, Geburtshilfe Frauenheilkd source
• Not checked yetcites [133] Hashimoto, 2018, Adenomyosis and adverse perinatal outcomes: increased risk of second trimester miscarriage, preeclampsia, and placental malposition, J Matern Fetal Neonatal Med source

In the paper

“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).”

What the sources say

• Not checked yetcites [50] Rahmioglu, 2015, Genome-wide enrichment analysis between endometriosis and obesity-related traits reveals novel susceptibility loci, Hum Mol Genet source
• Not checked yetcites [51] Fung, 2018, Genetics of endometriosis: state of the art on genetic risk factors for endometriosis, Best Pract Res Clin Obstet Gynaecol source
• Not checked yetcites [52] Matalliotakis, 2017, The role of gene polymorphisms in endometriosis, Mol Med Rep source

In the paper

“Endometriosis is a heterogeneous disease.”

In the paper

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

In the paper

“Clinical observations suggest that the prevalence and severity of deep endometriosis have markedly increased during the past 20 years (58).”

What the sources say

• Not checked yetcites [58] Koninckx, 2016, Epidemiology of subtle, typical, cystic, and deep endometriosis: a systematic review, Gynaecol Surg source

In the paper

“However, progression of subtle lesions or progression from typical to cystic or deep lesions has not been observed directly (56).”

What the sources say

• Not checked yetcites [56] Canis, 2016, Endometriosis may not be a chronic disease: an alternative theory offering more optimistic prospects for our patients, Fertil Steril source

In the paper

“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.”

In the paper

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

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [78] Kobayashi, 2014, Pathogenesis of endometriosis: the role of initial infection and subsequent sterile inflammation, Mol Med Rep source
• Not checked yetcites [136] Lin, 2016, Increased risk of endometriosis in patients with lower genital tract infection: a nationwide cohort study, Medicine (Baltimore) source
• Not checked yetcites [138] Heidarpour, 2017, Prevalence of high-risk human papillomavirus infection in women with ovarian endometriosis, J Obstet Gynaecol Res source

In the paper

“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.”

In the paper

“The endometriotic disease theory (EDT) postulated (246) that genetic incidents are required for the development of typical, cystic, or deep endometriosis.”

What the sources say

• Not checked yetcites [246] Koninckx, 1999, Implantation versus infiltration: the Sampson versus the endometriotic disease theory, Gynecol Obstet Invest source

In the paper

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

In the paper

“Local estrogen production (154) and progesterone resistance (155-162) were demonstrated in larger endometriosis lesions (154-163)”

What the sources say

• Not checked yetcites [154] Bulun, 2015, Molecular biology of endometriosis: from aromatase to genomic abnormalities, Semin Reprod Med source
• Not checked yetcites [155] Bulun, 2006, Progesterone resistance in endometriosis: link to failure to metabolize estradiol, Mol Cell Endocrinol source
• Not checked yetcites [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
• Not checked yetcites [157] Bruner-Tran, 2010, Dioxin and endometrial progesterone resistance, Semin Reprod Med source
• Not checked yetcites [158] Bulun, 2010, 17β-Hydroxysteroid dehydrogenase-2 deficiency and progesterone resistance in endometriosis, Semin Reprod Med source
• Not checked yetcites [159] Al-Sabbagh, 2012, Mechanisms of endometrial progesterone resistance, Mol Cell Endocrinol source
• Not checked yetcites [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
• Not checked yetcites [161] Joshi, 2017, Progesterone resistance in endometriosis is modulated by the altered expression of microRNA-29c and FKBP4, J Clin Endocrinol Metab
• Not checked yetcites [162] Patel, 2017, Progesterone resistance in endometriosis: origins, consequences and interventions, Acta Obstet Gynecol Scand source

In the paper

“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.”

What the sources say

• Not checked yetcites [257] Geyer, 2010, Molecular analysis reveals a genetic basis for the phenotypic diversity of metaplastic breast carcinomas, J Pathol source
• Not checked yetcites [258] Dagogo-Jack, 2018, Tumour heterogeneity and resistance to cancer therapies, Nat Rev Clin Oncol source
• Not checked yetcites [259] McGranahan, 2017, Clonal heterogeneity and tumor evolution: past, present, and the future, Cell source

In the paper

“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.”

What the sources say

• Not checked yetcites [1] Sampson, 1927, Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity, Am J Obstet Gynecol source
• Not checked yetcites [11] Sampson, 1924, Benign and malignant endometrial implants in the peritoneal cavity, and their relation to certain ovarian tumors, Surg Gynecol Obstet
• Not checked yetcites [201] Sampson, 1925, Heterotopic or misplaced endometrial tissue, Am J Obstet Gynecol source

In the paper

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

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [261] Bolton, 1987, Identification of placental protein 14 as an immunosuppressive factor in human reproduction, Lancet source
• Not checked yetcites [262] Okamoto, 1991, Suppression by human placental protein 14 of natural killer cell activity, Am J Reprod Immunol source

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [220] Davis, 2017, Extrapelvic endometriosis, Semin Reprod Med
• Not checked yetcites [31] Gruenwald, 1942, Origin of endometriosis from the mesenchyme of the celomic walls, Am J Obstet Gynecol source
• Not checked yetcites [33] Jabr, 2014, An unusual cause of abdominal pain in a male patient: endometriosis, Avicenna J Med source

In the paper

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

In the paper

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

In the paper

“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.”

In the paper

“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.”

In the paper

“Las lesiones sutiles se visualizan como endometrio en un entorno diferente hasta que aparecen alteraciones adicionales.”

In the paper

“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.”

What the sources say

• Not checked yetcites [56] Canis, 2016, Endometriosis may not be a chronic disease: an alternative theory offering more optimistic prospects for our patients, Fertil Steril source

In the paper

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

In the paper

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

In the paper

“It is suggested that the same mechanisms apply to adenomyosis.”

In the paper

“Similarly to uterine myomas, endometriosis lesions can remain dormant without progression for longer periods of time.”

In the paper

“The poor definition of metaplasia continues to create confusion.”