Similar stem cells, different gene exclusions

"Tissue of DIE and SE appears to have similar stem cell-related genes. Nevertheless, there are differences in gene expression between SE and DIE." So the stem cells of superficial and deep infiltrating endometriosis are similar but the gene expression is different. So what causes the deep infiltrating to be expressed differently? Hormonal influence? Diet? Toxins? http://www.ncbi.nlm.nih.gov/pubmed/26426155

Since endo is most likely laid down embryonically, I don't know that this necessarily points to pathogenesis of endo (especially as the levels decrease after the removal of the lesions) but the presence of endo certainly produces an inflammatory state.

 

J Immunol. 2015 Aug 10. pii: 1501138.

IL-17A Contributes to the Pathogenesis of Endometriosis by Triggering Proinflammatory Cytokines and Angiogenic Growth Factors.

Ahn SH¹, Edwards AK¹, Singh SS², Young SL³, Lessey BA⁴, Tayade C⁵.

Author information

• ¹Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada;
• ²Department of Obstetrics and Gynecology, University of Ottawa, Ottawa, Ontario K1H 7W9, Canada;
• ³Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, NC 27514; and.
• ⁴Department of Obstetrics and Gynecology, Greenville Health System, Greenville, SC 29605.
• ⁵Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada; tayadec@queensu.ca.

Abstract

Endometriosis is a chronic, inflammatory disease characterized by the growth of endometrial tissue in aberrant locations outside the uterus. Neoangiogenesis or establishment of new blood supply is one of the fundamental requirements of endometriotic lesion survival in the peritoneal cavity. IL-17A is emerging as a potent angiogenic and proinflammatory cytokine involved in the pathophysiology of several chronic inflammatory diseases such as rheumatoid arthritis and psoriasis. However, sparse information is available in the context of endometriosis. In this study, we demonstrate the potential importance of IL-17A in the pathogenesis and pathophysiology of endometriosis. The data show a differential expression of IL-17A in human ectopic endometriotic lesions and matched eutopic endometrium from women with endometriosis. Importantly, surgical removal of lesions resulted in significantly reduced plasma IL-17A concentrations. Immunohistochemistry revealed localization of IL-17A primarily in the stroma of matched ectopic and eutopic tissue samples. In vitro stimulation of endometrial epithelial carcinoma cells, Ishikawa cells, and HUVECs with IL-17A revealed significant increase in angiogenic (vascular endothelial growth factor and IL-8), proinflammatory (IL-6 and IL-1β), and chemotactic cytokines (G-CSF, CXCL12, CXCL1, and CX3CL1). Furthermore, IL-17A promoted tubulogenesis of HUVECs plated on Matrigel in a dose-dependent manner. Thus, we provide the first evidence, to our knowledge, that endometriotic lesions produce IL-17A and that the removal of the lesion via laparoscopic surgery leads to the significant reduction in the systemic levels of IL-17A. Taken together, our data show a likely important role of IL-17A in promoting angiogenesis and proinflammatory environment in the peritoneal cavity for the establishment and maintenance of endometriosis lesions.
Copyright © 2015 by The American Association of Immunologists, Inc.

Origins of endo

From Endometriosis Update blog (lots of good info- check it out!!):

"Several studies have focused on characterising the endometrium of women with and without endometriosis and found that; yes the endometrium in women with endometriosis is indeed different. The endometrium from women with endometriosis appears to have a higher ability to survive, proliferate and invade, seemingly filling in the missing part of the retrograde menstruation theory.

But, like all great mystery stories, the case is never wrapped up in a neat little package so early on. In recent years more and more evidence is coming to the fore, challenging the theory of retrograde menstruation. In particular there is now quite a significant amount of evidence to show the displaced endometrium that defines endometriosis is, in fact, present before you were even born. There are also rare documented cases of endometriosis in men, women who cannot menstruate and non-menstruating primates; so clearly there is the need for some radical re-thinking.

Maybe we’ve had the whole thing upside-down; maybe it is not the endometrium that dictates the fate of endometriosis, but endometriosis that dictates the fate of the endometrium. A collaborative research effort has provided some evidence to this very end (you can read the full article here). The authors of this study experimentally induced endometriosis in baboons by injecting endometrial cells into the pelvic cavity and letting them form endometriotic implants. They then compared the expression of genes within the endometrium of the baboons with experimentally induced endometriosis and disease free baboons over the course of 16 months. What they found was that the presence of endometriosis (even in its very early stages) led to marked changes (a total of 4,331 genes were altered) in the normal endometrium.

This potentially turns accepted wisdom on its head, in that women with endometriosis are not born with a defective endometrium that gives rise to endometriosis via retrograde menstruation. Rather, if we are to take all the above evidence into account, it appears endometriosis is a condition you are born with that, when the endometriotic implants ‘mature’ lead to changes in the function of the normal endometrium, thus perhaps also accounting for the fertility issues women with endo suffer from." http://www.endo-update.blogspot.co.uk/.../turning-on-its...

Peritoneal endo lesions nerve fibers

"RESULT(S): Pain-conducting substance-P-positive nerve fibers were found to be directly colocalized with human peritoneal endometriotic lesions in 74.5% of all cases. The endometriosis-associated nerve fibers are accompanied by immature blood vessels within the stroma. Nerve growth factor and neutrophin-3 are expressed by endometriotic cells. Growth-associated protein 43, a marker of neural outgrowth and regeneration, is expressed in endometriosis-associated nerve fibers but not in existing peritoneal nerves. CONCLUSION(S): The data provide the first evidence of direct contact between sensory nerve fibers and peritoneal endometriotic lesions. This implies that the fibers play an important role in the etiology of endometriosis-associated pelvic pain. Moreover, emerging evidence suggests that peritoneal endometriotic cells exhibit neurotrophic properties." http://www.ncbi.nlm.nih.gov/pubmed/17412328

 

"RESULT(S): Peritoneal endometriosis-associated nerve fibers were found significantly more frequently in group A than in group B (82.6% vs. 33.3%). CONCLUSION(S): The present study suggests that the presence of endometriosis-associated nerve fibers in the peritoneum is important for the development of endometriosis-associated pelvic pain and dysmenorrhea." http://www.ncbi.nlm.nih.gov/pubmed/18980761

 

"RESULT(S): Lesions from the rectovaginal septum were significantly more likely to be associated with a nerve fiber and report more menstrual pain than lesions from other regions. The PF glycodelin concentrations were also significantly higher in samples with an endometriotic-associated nerve. In peritoneal endometriotic lesions significantly more menstrual pain was reported when endometriotic lesions were associated with nerve fibers, although no difference was observed between the cytokine concentrations. Ovarian endometriotic lesions were rarely associated with nerve fibers.
CONCLUSION(S):
The presence of endometriosis-associated nerve fibers appear to be related to both the pain experienced by women with endometriosis and the concentration of PF cytokines; however, this association varies with the lesion location." http://www.ncbi.nlm.nih.gov/pubmed/22154765


"There was no difference in the density of nerve fibers across the menstrual cycle in peritoneal endometriotic lesions. These findings may explain why patients with peritoneal endometriosis often have painful symptoms throughout the menstrual cycle." http://www.ncbi.nlm.nih.gov/pubmed/21334610


"Progestogens and combined oral contraceptives reduced nerve fiber density and nerve growth factor and nerve growth factor receptor p75 expression in peritoneal endometriotic lesions." http://www.ncbi.nlm.nih.gov/pubmed/18976764

"Pain generation in EM is an intricate interplay of several factors such as the endometriotic lesions themselves and the pain-mediating substances, nerve fibres and cytokine-releasing immune cells such as macrophages. These interactions seem to induce a neurogenic inflammatory process. Recently published data demonstrated an increased peptidergic and decreased noradrenergic nerve fibre density in peritoneal lesions. These data could be substantiated by in vitro analyses demonstrating that the peritoneal fluids of patients suffering from EM induced an enhanced sprouting of sensory neurites from chicken dorsal root ganglia and decreased neurite outgrowth from sympathetic ganglia. These findings might be directly involved in the perpetuation of inflammation and pain. Furthermore, the evidence of EM-associated smooth muscle-like cells seems another important factor in pain generation. The peritoneal endometriotic lesion leads to reactions in the surrounding tissue and, therefore, is larger than generally believed. The identification of EM-associated nerve fibres and smooth muscle-like cells fuel discussions on the mechanisms of pain generation in EM, and may present new targets for innovative treatments." http://www.ncbi.nlm.nih.gov/pubmed/24590000

"We could detect an increased sensory and decreased sympathetic nerve fibres density in peritoneal lesions compared to healthy peritoneum. Peritoneal fluids of patients with endometriosis compared to patients without endometriosis induced an increased sprouting of sensory neurites from DRG and decreased neurite outgrowth from sympathetic ganglia. In conclusion, this study demonstrates an imbalance between sympathetic and sensory nerve fibres in peritoneal endometriosis, as well as an altered modulation of peritoneal fluids from patients with endometriosis on sympathetic and sensory innervation which might directly be involved in the maintenance of inflammation and pain." http://www.ncbi.nlm.nih.gov/pubmed/21888965

   

March is Endometriosis Awareness month!

 

March is endometriosis awareness month and yellow is the color! Here are a few pictures that I have run across that are useful for profile pictures, cover photos, and general awareness:

 

? Link Between PCOS and endometriosis

Old (from 1989): "Pelvic endometriosis was observed in 15 of 91 women (16.5%) with laparoscopically confirmed polycystic ovary syndrome. There were no significant clinical differences among those with and those without endometriosis. The groups were of similar age, parity, and ponderal indices and had similar incidences of oligomenorrhea, hirsutism, and infertility; the serum concentrations of LH, FSH, LH/FSH, prolactin, testosterone, and dehydroepiandrosterone sulfate were also similar in each group. However, women with polycystic ovaries and endometriosis presented more frequently with regular menses (40 versus 14.5%; P = .05) and less frequently with secondary amenorrhea (0 versus 38.2%; P = .05) and galactorrhea (0 versus 9.2%; P = .05) than the women with polycystic ovaries alone. Endometriosis appears to be a coincidental finding in polycystic ovary syndrome, and its development does not modify significantly the clinical picture or biochemical profiles of these patients. However, menstrual patterns seem to be affected." http://www.ncbi.nlm.nih.gov/pubmed/2797642

2011: "The endocrinologic and metabolic abnormalities of women with polycystic ovary syndrome (PCOS) can result in a series of endometrial diseases. Abnormalities of hyperandrogenism and hyperinsulinemia that may be found in PCOS can elevate the levels of E2 indirectly, reduce progesterone secretion and induce some growth factors such as vascular endothelial growth factor (VEGF) and insulin-like growth factors (IGFs) over expression, which may have a major impact on endometriosis occurrence and development. We suppose that there is a possible connection between PCOS and endometriosis." http://www.sciencedirect.com/.../pii/S1001784412600133

Surgical Technique and "microscopic" endo

"Occult or microscopic lesions have been reported as early as 1986 from laparotomy procedures. Hopton and Redwine {7} have shown a linear inverse relationship between the distance of the viewing lens from the peritoneal surface and the incidence of OME; these authors claim that OME almost ceases to exist with close contact laparoscopy with less than 1cm separation of the laparoscope tip from the peritoneal surface (and with direct visualisation laparoscopy, suggesting that the use of video-assisted laparoscopy may impair visualisation) with incidences of OME ranging from 0% to 25% in various studies {1-7}. 

 

"Hopton and Redwine {7} have also highlighted the key factors that are likely to be influential on whether OME is diagnosed: the definition of normal peritoneum, the size and location of biopsies of 'normal peritoneum', the histological definition of endometriosis, and whether women undergoing laparoscopic assessment have recently been using hormonal suppressive therapy....

 

"The more careful the search for endometriosis – and the closer the laparoscope tip is applied to the peritoneal surface – the less chance of missing any endometriosis. - There is a strong place for clear definitions to standardise laparoscopy performed by all gynaecological surgeons in relation to (a) viewing distance from the laparoscope tip and (b) definitions of what constitutes abnormal peritoneum, particularly the subtle abnormalities highlighted by Redwine {5} and Redwine and Yocom {6}. The more meticulous the search for endometriosis and the combination of this search with meticulous excision of all lesions, the more likely endometriosis is to be eradicated through laparoscopic surgery."

http://f1000.com/prime/718213409