Natural History Of Endometriosis Research Articles

Do we want to know the enormity of women's severe menstrual disorders and chronic pelvic pain?

ObjectiveThe purpose of this paper is to call for a nationwide study to assess the prevalence and incidence of women health problems related to menstrual disorders and severe pelvic pain. RationaleThe exact prevalence and incidence of endometriosis, adenomyosis, severe painful menstrual disorders, and of severe chronic pelvic pain are unknown. These issues severely impact women's quality of life and represent huge costs for our societies. Using adapted questionnaires, recent progresses in diagnosis and increased fundings announced by politicians, we can and should change this situation by performing a nationwide study to assess prevalence and incidence of these women problems in the French general population. The huge, anticipated costs of this study do appear quite reasonable when accounting for the enormous costs and societal consequences of endometriosis, menstrual disorders and severe pelvic pain. ConclusionThese long-awaited data will improve our understanding of the causes, consequences, and natural history of endometriosis. These data will allow women to better understand that pain is not always related to endometriosis, thus preventing unjustified fears. Physicians will be able to adapt and improve medical managements, particularly the diagnosis. Politicians will have the tools to improve women's health and gender equality.

Natural history of endometriosis in pregnancy: ultrasound study of morphology of deep endometriosis and ovarian endometrioma.

To assess the morphological appearance of deep endometriosis and ovarian endometrioma in pregnancy using pelvic ultrasound examination. This was a prospective observational cohort study conducted over 3 years at University College London Hospital, which is a tertiary level referral unit for early pregnancy complications and an accredited endometriosis center. All women who participated provided written consent and were invited for surveillance ultrasound examination at the time of their routine scans in pregnancy. All scans were performed by a single operator to eliminate interobserver variability. The change in size of ovarian endometrioma and nodules was reported as change in their mean diameter. Ovarian endometrioma with irregular thick inner walls, hyperechoic papillary projections and/or high vascularity and hyperechoic nodules with moderate to high vascularity were reported as decidualized. Sixty-five women with a live, normally sited pregnancy and concomitant ultrasound features of deep and/or ovarian endometriosis were included in the study. The median age of the study population was 34 (range, 23-44) years, and the median gestational age at presentation was 7 + 6 (range, 3 + 6 to 18 + 0) weeks. From the cohort, 47/65 (72%) were nulliparous, 48/65 (74%) had a previous diagnosis of endometriosis and 19/65 (29%) conceived via in-vitro fertilization. There were 10/65 (15% (95% CI, 7-24%)) women with ovarian endometrioma alone, 28/65 (43% (95% CI, 31-55%)) with endometriotic nodules alone and the remaining 27/65 (42% (95% CI, 30-54%)) had both. Of the women with ovarian endometrioma who underwent follow-up, 29/34 (85% (95% CI, 73-97%)) experienced cyst regression, 2/34 (6% (95% CI, 0-14%)) experienced cyst growth, and in 3/34 (9% (95% CI, 0.0-18%)) women, cyst size was unchanged. In 10/34 (29% (95% CI, 14-45%)), there was complete resolution of all cysts. Of the women with nodules who underwent follow-up, 43/51 (84% (95% CI, 74-94%)) experienced nodule regression, 2/51 (4% (95% CI, 0-9%)) experienced nodule growth and, in 6/51 (12% (95% CI, 3-21%)) women, nodule size was unchanged. In 4/51 (8% (95% CI, 0-15%)) women, there was complete resolution of all nodules. In 5/37(14% (95% CI, 3-25%)) women who attended postnatal follow-up, complete resolution of all endometriotic lesions occurred during pregnancy. In 10/34 (29% (95% CI, 14-45%)) women with ovarian endometrioma and 27/51 (53% (95% CI, 39-67%)) women with nodules, a pattern of growth was observed in the first and second trimesters, followed by regression later in pregnancy. Features of decidualization were observed in 17/34 (50% (95% CI, 33-67%)) women with ovarian endometrioma, most commonly in the first trimester, and in 25/51 (49% (95% CI, 35-63%)) women with nodules, most commonly in the second trimester. For the majority of women, despite features of decidualization being common in the first and second trimesters, ovarian endometrioma and deep nodules regress during pregnancy. Morphological changes of endometriosis in pregnancy are difficult to differentiate from characteristics of malignant lesions. Better understanding of the appearance of endometriosis in pregnancy is vital to minimize intervention and help counsel women regarding their condition. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Natural progression of deep pelvic endometriosis in women who opt for expectant management.

The natural history of endometriosis is poorly understood, and despite numerous studies, the rate of the disease progression and optimal treatment planning in women who are asymptomatic or experience mild symptoms not requiring treatment are unknown. The aim of this study was to assess the behavior of deep endometriosis in women who are managed expectantly without any medical or surgical intervention. A retrospective cohort study of women diagnosed with deep endometriosis on transvaginal ultrasound scan at the Department of Gynecology, University College London Hospitals and The Gynecology Ultrasound Centre, London, UK, from April 2007 to April 2022. All women attended for at least two ultrasound scans which were carried out by a single expert ultrasound examiner and at least 6 months apart. The number and position of endometriotic nodules were recorded, and the mean diameter of each nodule was calculated from measurements taken in three orthogonal planes. During the study period, 1922 women were found to have moderate or severe deep endometriosis on pelvic ultrasound examination. A total of 135 premenopausal women who were managed expectantly fitted the inclusion criteria. The median number of endometriotic nodules per woman at the initial visit was 2 (range: 0-7), and the median follow-up time was 666 days (181-2984). In the follow-up period, 50/135 women (37%, 95% CI: 29-46) developed additional nodules or experienced an increase in nodule size, and 17/135 women (13%, 95% CI: 8-19) had a regression in the number or size of the nodules. In the remaining 68/135 women (50%, 95% CI: 42-59) the disease remained static during the follow-up. The median change in mean diameter of nodules during the study period per woman was +0.13 mm (-11.67 - +5.83), with an annual growth rate of +0.09 mm/year (-6.65 - +6.45). In our study we found evidence of deep endometriosis progression in just over a third of women. In view of this, asymptomatic or mildly symptomatic women diagnosed with deep endometriosis could be reassured that their disease is unlikely to worsen with time.

Cancer driver mutations in endometriosis: Variations on the major theme of fibrogenesis.

BackgroundOne recent study reports cancer driver mutations in deep endometriosis, but its biological/clinical significance remains unclear. Since the natural history of endometriosis is essentially gradual progression toward fibrosis, it is thus hypothesized that the six driver genes reported to be mutated in endometriosis (the RP set) may play important roles in fibrogenesis but not necessarily malignant transformation.MethodsExtensive PubMed search to see whether RP and another set of driver genes not yet reported (NR) to be mutated in endometriosis have any roles in fibrogenesis. All studies reporting on the role of fibrogenesis of the genes in both RP and NR sets were retrieved and evaluated in this review.ResultsAll six RP genes were involved in various aspects of fibrogenesis as compared with only three NR genes. These nine genes can be anchored in networks linking with their upstream and downstream genes that are known to be aberrantly expressed in endometriosis, piecing together seemingly unrelated findings.ConclusionsGiven that somatic driver mutations can and do occur frequently in physiologically normal tissues, it is argued that these mutations in endometriosis are not necessarily synonymous with malignancy or premalignancy, but the result of enormous pressure for fibrogenesis.

Progressive development of endometriosis and its hindrance by anti-platelet treatment in mice with induced endometriosis

We have recently shown that platelets drive smooth muscle metaplasia (SMM) and fibrogenesis in endometriosis through epithelial-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transdifferentiation (FMT). To see whether this is true in vivo, this prospective, randomized, and serially evaluated mouse investigation was conducted. Endometriosis was induced in female Balb/C mice, which were then randomly divided into two groups: Tanshinone IIA (TAN) and control (CTL) groups. TAN mice were treated with TAN but CTL mice received none. Every week until the 6th week after induction, five mice from each group were killed. Lesion weight was measured and lesion samples were subjected to immunohistochemistry and histochemistry analysis of platelet aggregation (CD41), E-cadherin, TGF-β1, phosphorylated Smad3, α-SMA, collagen I, CCN2, LOX, desmin and SM-MHC, and the extent of fibrosis was evaluated by Masson trichrome staining. It was found that endometriotic lesions exhibited progressive cellular changes consistent with the progressive EMT, FMT, SMM, and fibrogenesis. TAN treatment resulted in significant hindrance of EMT, FMT, SMM and fibrogenesis, and reduced lesion weight (all P-values <0.05). These data corroborate the notion that endometriotic lesions undergo progressive EMT and FMT, giving rise to SMM and ultimately fibrosis. This understanding sheds new light onto the natural history of endometriosis.

Cellular Changes Consistent With Epithelial-Mesenchymal Transition and Fibroblast-to-Myofibroblast Transdifferentiation in the Progression of Experimental Endometriosis in Baboons.

We have recently shown that platelets play important roles in development of endometriosis and proposed that endometriotic lesions are essentially wounds that undergo repeated tissue injury and repair (ReTIAR). Further investigation indicated that endometriotic lesions, stimulated by platelet-derived transforming growth factor β1 (TGF-β1), activate the TGF-β1/Smad3 signaling pathway and undergo epithelial-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transdifferentiation (FMT), resulting in increased cellular contractility and collagen production and increased smooth muscle metaplasia (SMM), leading to fibrosis. Using serially dissected endometriotic tissue samples from baboons with induced endometriosis, we tested the hypothesis of progressive EMT, FMT, SMM, and fibrosis through TGF-β1/Smad activation using immunohistochemistry and immunoflurescence staining analyses. We found that platelets are aggregated in endometriotic lesions, and vimentin expression was increased in the epithelial compartment of the lesions as they progressively developed. We also found that the number of smooth muscle cells (SMCs) appeared to increase with time as lesions progressed and was concomitant with the increased vimentin-positive glandular epithelial cells in the lesions. As lesion development progressed, TGF-β1 and phosphorylated-Smad3 staining was elevated and the number of α-smooth muscle actin-positive myofibroblasts and highly differentiated SMCs increased in the stromal compartment, which correlated with the increasing extent of fibrosis. These results, taken together, provide support for the notion that ReTIAR occurs in the endometriotic lesions, resulting in EMT and FMT, leading to SMM and ultimately fibrosis as lesions progress. Consequently, our data also provide corroborative evidence that platelets drive the EMT and FMT in endometriotic lesions over time, promoting SMM and resulting ultimately in fibrosis in the endometriotic lesions. These findings cast a new light on the natural history of endometriosis which so far has been elusive.

Structural and molecular features of the endomyometrium in endometriosis and adenomyosis

BACKGROUND Adenomyosis and endometriosis were initially described as 'adenomyoma'. When the retrograde menstruation theory became widely accepted to explain the pathogenesis of endometriosis, since it does not explain adenomyosis, the two conditions came to be seen as distinct entities. However, emerging evidence suggests that both diseases may be linked to changes in the inner portion of the myometrium. In addition, similar anomalies were found in the eutopic endometrium of the two conditions and the debate has re-opened. A common origin for both adenomyosis and endometriosis would have relevance not only for understanding uterine function and pathophysiology, but also for clinical management and treatment. METHODS The Scopus and Medline databases were searched for all original articles published in English up to the end of 2012. Search terms included 'adenomyosis'; 'endometriosis'; 'endometrium'; 'eutopic endometrium'; 'inner myometrium'; 'junctional zone'. Special attention was paid to articles comparing features of eutopic endometrium in the two conditions. RESULTS A number of similarities exist between adenomyosis and endometriosis and, by using magnetic resonance and laparoscopy, it was found that, at least in some subgroups, the two conditions often coexist. In both situations the inner myometrium (or junctional zone) is altered, although alterations are much more marked in adenomyosis where a thickness >12 mm is today considered sufficient for diagnosis. Research has shown differences between the eutopic endometrium of women with both diseases when compared with controls. There is an immune dysfunction and there are alterations of adhesion molecules, cell proliferation and apoptosis. An increase in cytokines and inflammatory mediators has also been observed. Finally, the presence of oxidative stress and anomalies in free-radical metabolism may alter uterine receptivity. When the two conditions were compared, dissimilarities were also observed in the extent of apoptosis inhibition and in the expression of some inflammatory mediators. It is not clear if observed differences are primarily related to presenting symptoms. Finally, both conditions are steroid dependent and research suggests a role for epigenetic mechanisms. The analysis indicates that much of the published research may have been influenced by the method of diagnosis and/or has not been controlled for the presenting symptoms, the concomitant presence of both diseases or full consideration of fluctuations within cycle phase. CONCLUSIONS It is difficult to draw firm conclusions from existing evidence since major diagnostic limitations still exist and there is a systematic bias in clinical presentation. In addition, scanty information is available on the natural history of endometriosis and no studies exist on the natural history of adenomyosis. Notwithstanding these limitations, a number of similarities, but also some differences have been found between the eutopic endometrium in the two diseases. These findings need to be taken with considerable caution as the few instances where the research was repeated yielded conflicting results.

Gene expression profiling of peripheral blood mononuclear cells in endometriosis identifies genes altered in non-gynaecologic chronic inflammatory diseases

Pelvic inflammatory phenomena have been suggested as critical players in the natural history of endometriosis. However, to what extent these events could affect the systemic immunologic status remains to be clarified. Here, we compared the gene expression profile in peripheral blood mononuclear cells from endometriosis patients in the severe diseased stage with the profile after a conventional surgical treatment for removal of endometriotic lesions and adhesions. Microarray analysis included four patients suffering from severe endometriosis in which blood samples were obtained few days before the surgical intervention and again 6 months later. Real-time quantitative PCR analyses on a larger population were performed for some genes up-regulated in the diseased stage in a case-control approach. Among the 17,665 probe signals detected in the microarray, n = 26 genes resulted up-regulated and n = 15 were down-regulated in the diseased stage. Five genes up-regulated in diseased stage (FBJ Murine osteosarcoma viral oncogene homolog gene, dual specificity phosphatase 1, pre-B-cell colony enhancing factor 1, adrenomedullin and S100 calcium binding protein P) were exactly those shown as up-regulated in peripheral leukocytes of psoriasis patients in a very similar study design (diseased versus 'cured' stage), with a 5.2 × 10(-11) hypergeometric probability that this event could occur by chance. Endometriosis induces the expression of genes in peripheral leukocytes already identified in non-gynaecologic chronic inflammatory diseases, thus revealing the disease as a local affliction with relevant consequences at the systemic level. Although the commonality of gene expression with other inflammatory diseases prevents the use of these genes as non-invasive diagnostic markers, from a clinical standpoint, the idea that the surgical intervention may reduce the expression of peripheral leukocyte genes represents a novel finding.

Macrophages Are Alternatively Activated in Patients with Endometriosis and Required for Growth and Vascularization of Lesions in a Mouse Model of Disease

The mechanisms that sustain endometrial tissues at ectopic sites in patients with endometriosis are poorly understood. Various leukocytes, including macrophages, infiltrate endometriotic lesions. In this study, we depleted mouse macrophages by means of either clodronate liposomes or monoclonal antibodies before the injection of syngeneic endometrial tissue. In the absence of macrophages, tissue fragments adhered and implanted into the peritoneal wall, but endometriotic lesions failed to organize and develop. When we depleted macrophages after the establishment of endometriotic lesions, blood vessels failed to reach the inner layers of the lesions, which stopped growing. Macrophages from patients with endometriosis and experimental mice, but not nonendometriotic patients who underwent surgery for uterine leiomyomas or control mice, expressed markers of alternative activation. These markers included high levels of scavenger receptors, CD163 and CD206, which are involved in both the scavenging of hemoglobin with iron transfer into macrophages and the silent clearance of inflammatory molecules. Macrophages in both inflammatory liquid and ectopic lesions were equally polarized, suggesting a critical role of environmental cues in the peritoneal cavity. Adoptively transferred, alternatively activated macrophages dramatically enhanced endometriotic lesion growth in mice. Inflammatory macrophages effectively protected mice from endometriosis. Therefore, endogenous macrophages involved in tissue remodeling appear as players in the natural history of endometriosis, required for effective vascularization and ectopic lesion growth.

Role of shigella infection in endometriosis: A novel hypothesis

Endometriosis is the presence of endometrial cells and stroma at ectopic sites outside the uterine cavity. The natural history of endometriosis is uncertain, its etiology unknown, the clinical presentation inconsistent, diagnosis difficult and the treatment poorly standardized. It causes significant morbidity due to pelvic pain and infertility among 15-25% of women during their reproductive age. The benign disease causes peritoneal inflammation, fibrosis, adhesions and ovarian cysts but displays features of malignancy, like neo-vascularization, local invasion and distant metastasis. Mechanical, hormonal, immunological, environmental and genetic factors have been implicated in its etiology but provide inconclusive explanations. Present study was carried out on ectopic and eutopic endometriotic tissue specimens collected during laproscopy/laprotomy from cases of endometriosis. mRNA was isolated from the tissues and converted to cDNA by RT and subsequently subjected to differential display Polymerase Chain Reaction using seven sets of arbitrary primers. A unique band was identified only in the ectopic endometriotic tissue, which was sequenced. BLAST search results revealed sequence homology to shigella bacterial DNA leading us to hypothesize that infection may be playing a role in the etiology of endometriosis. This is the first report implicating the role of bacterial infection in the etiology of endometriosis. Shigella is known to invade the mucosa of the colon through the feco-oral route causing Shigellosis. The pathogenesis of shigellosis involves inflammation, ulceration, haemorrhage, tissue destruction and fibrosis of the colonic mucosa resulting in abdominal pain and diarrhoea/dysentery, this is similar to the pathogenesis of endometriosis which also involves inflammation, haemorrhage, tissue destruction and fibrotic adhesions of the pelvic peritoneum resulting in abdominal pain and infertility. The non-motile shigella bacteria invade the deeper mucosal layers by travelling from cell to cell of colonic epithelium, reaching the lamina propria of the colonic mucosa. We propose that, by the same mechanism, the bacteria travel across the colon wall to reach the outer peritoneal surface of the colon, which is in close proximity to the posterior uterine surface in the Pouch of Douglas, the site which incidentally happens to be the commonest site of early endometriosis. Our hypothesis therefore proposes that shigella or shigella-like organisms may be the trigger for the initiation of immunological changes in the pelvic peritoneum causing endometriosis. Once the endometrial cells are implanted at ectopic sites they are sustained by hormones and angiogenic factors. Hence "Infection hypothesis" provides a novel explanation for the etiopathogenesis of endometriosis.

Endometriosis and associated pathology

The natural history of endometriosis, including the belief that it is a progressive disease, is reviewed with the help of a large, cross-sectional, prospective study and a smaller longitudinal study. Two studies are reviewed that address the role of growth factors in the development of endometriosis. These studies demonstrated that the peritoneal fluid of patients with endometriosis contained significant growth factor activity against human endometrial stromal cells. In a mouse model, macrophage-derived factors stimulated endometrial cell proliferation. The possible correlation between endometriosis and decreased bone mineral density, which was reported by an earlier study, is reviewed. Recent data, however, have shown no correlation between bone mineral density and endometriosis. Finally, several reports on the usefulness of endometrial antibodies and serum CA 125 levels in the diagnosis and treatment of patients with endometriosis are reviewed. These data suggest that both endometrial antibodies and CA 125 measurements may be useful in the diagnosis and treatment of patients with endometriosis.

Conservative laparoscopic excision of endometriosis by sharp dissection: life table analysis of reoperation and persistent or recurrent disease

ObjectiveTo determine the long-term outcome after laparoscopic excision of endometriosis. DesignThis longitudinal unmatched study evaluated surgical outcome using follow-up questionnaires and evaluation of reoperations with results presented in life table format. SettingSurgery was performed by a private practitioner at a referral center. PatientsAll 359 patients undergoing laparoscopic excision of endometriosis between December 12, 1980, and March 31, 1990, were studied. InterventionsEndometriosis, including deeply invasive disease, was completely excised laparoscopically using 3-mm scissors and graspers. Adjunctive medical therapy was not used. Main Outcome MeasuresExtent of disease present at reoperation and quarterly rates of reoperation and recurrent/persistent disease are used as indicators of efficacy of surgery. ResultsInterval rates of reoperation and recurrence/persistence of disease and extent or invasiveness of disease when found at reoperation did not increase with the passage of time after surgery. The maximum cumulative rate of recurrent or persistent disease was 19%, achieved in the 5th postoperative year. ConclusionLaparoscopic excision of endometriosis results in a low rate of minimal persistent/recurrent disease. The natural history of endometriosis after surgery suggests a rather static nature of the disease.

Pathophysiology of mild endometriosis: review of literature

Endometriosis is a puzzling condition and the literature is characterized by a large number of uncontrolled reports on its aetiology and pathophysiology. In particular the relationship between mild endometriosis and subfecundity is uncertain. This paper critically reviews the published literature on the pathogenesis, prevalence, menstrual symptomatology and natural history of endometriosis. Furthermore, factors implicated in causing subfecundity in relation to endometriosis and the impact of various treatments in enhancing fertility among women with mild endometriosis have been assessed.