The Pathogenesis of Adenomyosis vis-à-vis Endometriosis

In the paper

“Sampson’s retrograde menstruation theory is the most widely accepted and has the most robust evidence [27].”

What the sources say

• Not checked yetcites [27] Vercellini, 2014, Endometriosis, pathogenesis and treatment, Nat. Rev. Endocrinol. source

In the paper

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

In the paper

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

What the sources say

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

In the paper

“Parity is consistently shown to be a risk factor, while smoking is inconsistently shown to be a protective factor [15,18].”

What the sources say

• Not checked yetcites [15] Vercellini, 2006, Adenomyosis, epidemiological factors, Best Pr. Res. Clin. Obs. Gynaecol. source
• Not checked yetcites [18] Taran, 2013, Adenomyosis, Epidemiology, Risk Factors, Clinical Phenotype and Surgical and Interventional Alternatives to Hysterectomy, Geburtshilfe Frauenheilkd source

In the paper

“Aside from their similar symptomologies, both are estrogen-dependent [10] and share many molecular aberrations.”

What the sources say

• Not checked yetcites [10] Kitawaki, 2006, Adenomyosis, the pathophysiology of an oestrogen-dependent disease, Best Pr. Res. Clin. Obs. Gynaecol. source

In the paper

“Adenomyosis, defined as the presence of endometrial glands and stroma infiltrated deep and haphazardly into the myometrium [1], is a common gynecologic disorder with poorly understood pathogenesis and pathophysiology [2,3,4].”

What the sources say

• Not checked yetcites [2] Bergeron, 2006, Pathology and physiopathology of adenomyosis, Best Pr. Res. Clin. Obs. Gynaecol. source
• Not checked yetcites [3] Vannuccini, 2017, Pathogenesis of adenomyosis, an update on molecular mechanisms, Reprod. Biomed. Online source
• Not checked yetcites [4] Donnez, 2018, Pathogenesis of uterine adenomyosis, invagination or metaplasia?, Fertil. Steril. source

In the paper

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

In the paper

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

In the paper

“The reported prevalence of adenomyosis varies greatly among different studies, from as low as 10% to as high as 57% [15,16].”

What the sources say

• Not checked yetcites [15] Vercellini, 2006, Adenomyosis, epidemiological factors, Best Pr. Res. Clin. Obs. Gynaecol. source
• Not checked yetcites [16] Bergholt, 2001, Prevalence and risk factors of adenomyosis at hysterectomy, Hum. Reprod. source

In the paper

“The clinical treatment strategy for the two diseases also seems to be similar, and the drugs to treat the two diseases can be used interchangeably [11].”

What the sources say

• Not checked yetcites [11] Vannuccini, 2018, Role of medical therapy in the management of uterine adenomyosis, Fertil. Steril. source

In the paper

“The risk profiles for adenomyosis are thus quite different from that of endometriosis, in which greater parity is a protective factor, while earlier age at menarche and shorter menstrual cycle length—factors that are consistent with Sampson’s retrograde menstruation theory for the etiology of endometriosis—are risk factors [23].”

What the sources say

• Not checked yetcites [23] Shafrir, 2018, Risk for and consequences of endometriosis, A critical epidemiologic review, Best Pract. Res. Clin. Obstet. Gynaecol. source

In the paper

“In fact, over 1000 genes are documented to be differentially expressed between adenomyotic lesions and eutopic endometrium [65] and close to 1000 genes are differentially expressed between ectopic and eutopic endometrium [66].”

What the sources say

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

In the paper

“In a nutshell, they showed that uterine peristalsis is critical for sperm transport, and women with endometriosis exhibit hyperperistalsis and dysperistalsis [38,39,40,41].”

What the sources say

• Not checked yetcites [38] Leyendecker, 1996, Uterine hyperperistalsis and dysperistalsis as dysfunctions of the mechanism of rapid sperm transport in patients with endometriosis and infertility, Hum. Reprod. source
• Not checked yetcites [39] Kunz, 1996, The dynamics of rapid sperm transport through the female genital tract, evidence from vaginal sonography of uterine peristalsis and hysterosalpingoscintigraphy, Hum. Reprod. source
• Not checked yetcites [40] Kunz, 1998, Sonographic evidence for the involvement of the utero-ovarian counter-current system in the ovarian control of directed uterine sperm transport, Hum. Reprod. Update source
• Not checked yetcites [41] Wildt, 1998, Sperm transport in the human female genital tract and its modulation by oxytocin as assessed by hysterosalpingoscintigraphy, hysterotonography, electrohysterography and Doppler sonography, Hum. Reprod. Update source

In the paper

“In sharp contrast to endometriosis, the exact pathogenesis of adenomyosis is largely a conundrum.”

In the paper

“Both theories have apparent limitations, i.e., difficulty in falsification, explaining existing data, and making useful predictions.”

In the paper

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

In the paper

“Indeed, the newly reported association between focal adenomyosis of the outer myometrium (FAOM) and deep endometriosis (DE) [61,62] suggests that not all subtypes of adenomyosis are the same and may have a different pathogenesis.”

What the sources say

• Not checked yetcites [61] Chapron, 2017, Relationship between the magnetic resonance imaging appearance of adenomyosis and endometriosis phenotypes, Hum. Reprod. source
• Not checked yetcites [62] Marcellin, 2018, Anterior Focal Adenomyosis and Bladder Deep Infiltrating Endometriosis, Is There a Link?, J. Minim. Invasive Gynecol. source

In the paper

“but inhibition of pituitary prolactin secretion during youth in mice suppressed the induction of adenomyosis [60], suggesting the potential role of prolactin in the pathogenesis of adenomyosis.”

What the sources say

• Not checked yetcites [60] Nagasawa, 1982, Stimulation of mammary tumorigenesis and suppression of uterine adenomyosis by temporary inhibition of pituitary prolactin secretion during youth in mice (41492), Proc. Soc. Exp. Biol. Med. source

In the paper

“More importantly, it is difficult, if not impossible, to devise an experiment to prove or disprove either theory.”

In the paper

“Thus, hypoxia may well be viewed as the single most important event following tissue injury, and, indeed, adaptation to hypoxic stress via HIF signaling plays a critical role in promoting wound healing processes [74,75].”

What the sources say

• Not checked yetcites [74] Andrikopoulou, 2011, Current Insights into the role of HIF-1 in cutaneous wound healing, Curr. Mol. Med. source
• Not checked yetcites [75] Hong, 2014, The Role of Hypoxia-Inducible Factor in Wound Healing, Adv. Wound Care source

In the paper

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

In the paper

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

In the paper

“it raises a tantalizing possibility that perioperative intervention could reduce the risk of adenomyosis, as in the case of a reduction in recurrence risk in endometriosis [100].”

What the sources say

• Not checked yetcites [100] Long, 2019, Perioperative Intervention by beta-Blockade and NF-kappaB Suppression Reduces the Recurrence Risk of Endometriosis in Mice Due to Incomplete Excision, Reprod. Sci. source

In the paper

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

In the paper

“Note that hypoxia-induced COX-2 overexpression can increase the production of not only PGE2 but also PGH2, which leads to increased production of thromboxane A2 (TXA2), a vasoconstrictor, a potent platelet activator, and a potent inducer of uterine contraction [99].”

What the sources say

• Not checked yetcites [99] Wilhelmsson, 1981, PGH2, TxA2 and PGI2 have potent and differentiated actions on human uterine contractility, Prostaglandins source

In the paper

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

In the paper

“Thus, the increased estrogen levels may induce an ERα-mediated OT/OTR system, enhancing uterine peristalsis.”

In the paper

“HIF-1α-induced COX-2 expression leads to elevated PGE2 levels, which can induce PGE2-mediated vascularization [87,88].”

What the sources say

• Not checked yetcites [87] Greenhough, 2009, The COX-2/PGE2 pathway, key roles in the hallmarks of cancer and adaptation to the tumour microenvironment, Carcinogenesis source
• Not checked yetcites [88] Tsujii, 1998, Cyclooxygenase regulates angiogenesis induced by colon cancer cells, Cell source

In the paper

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

In the paper

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

In the paper

“As adenomyosis shares with endometriosis in cyclic bleeding and thus ReTIAR”

What the sources say

• Not checked yetcites [104] Guo, 2018, Fibrogenesis resulting from cyclic bleeding, the Holy Grail of the natural history of ectopic endometrium, Hum. Reprod. source

In the paper

“In addition, increased estradiol levels would induce ERα, which further activate OT/OTR signaling pathway, causing increased peristalsis.”

In the paper

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

In the paper

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

In the paper

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

In the paper

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

In the paper

“The model depicted in Figure 3 is completely falsifiable.”

In the paper

“Unlike the TIAR theory, the EMID hypothesis is easily falsifiable, at least in mouse.”

In the paper

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

In the paper

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

In the paper

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

In the paper

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