Effectiveness of laparoscopic removal of isolated superficial peritoneal endometriosis for the management of chronic pelvic pain in women (ESPriT2): protocol for a multi-centre randomised controlled trial.

BACKGROUND: Endometriosis affects 190 million women and those assigned female at birth worldwide. For some, it is associated with debilitating chronic pelvic pain. Diagnosis of endometriosis is often achieved through diagnostic laparoscopy. However, when isolated superficial peritoneal endometriosis (SPE), the most common endometriosis subtype, is identified during laparoscopy, limited evidence exists to support the common decision to surgically remove it via excision or ablation. Improved understanding of the impact of surgical removal of isolated SPE for the management of chronic pelvic pain in women is required. Here, we describe our protocol for a multi-centre trial to determine the effectiveness of surgical removal of isolated SPE for the management of endometriosis-associated pain. METHODS: We plan to undertake a multi-centre participant-blind parallel-group randomised controlled clinical and cost-effectiveness trial with internal pilot. We plan to randomise 400 participants from up to 70 National Health Service Hospitals in the UK. Participants with chronic pelvic pain awaiting diagnostic laparoscopy for suspected endometriosis will be consented by the clinical research team. If isolated SPE is identified at laparoscopy, and deep or ovarian endometriosis is not seen, participants will be randomised intraoperatively (1:1) to surgical removal (by excision or ablation or both, according to surgeons' preference) versus diagnostic laparoscopy alone. Randomisation with block-stratification will be used. Participants will be given a diagnosis but will not be informed of the procedure they received until 12 months post-randomisation, unless required. Post-operative medical treatment will be according to participants' preference. Participants will be asked to complete validated pain and quality of life questionnaires at 3, 6 and 12 months after randomisation. Our primary outcome is the pain domain of the Endometriosis Health Profile-30 (EHP-30), via a between randomised group comparison of adjusted means at 12 months. Assuming a standard deviation of 22 points around the pain score, 90% power, 5% significance and 20% missing data, 400 participants are required to be randomised to detect an 8-point pain score difference. DISCUSSION: This trial aims to provide high quality evidence of the clinical and cost-effectiveness of surgical removal of isolated SPE. TRIAL REGISTRATION: ISRCTN registry ISRCTN27244948. Registered 6 April 2021.

Peritoneal fluid progesterone and progesterone resistance in superficial endometriosis lesions.

Peritoneal fluid in ovulatory women is an ovarian exudate with higher estrogen and progesterone concentrations than in plasma. In the follicular phase, progesterone concentrations are as high as plasma concentrations in the luteal phase. After ovulation, estrogen and progesterone concentrations in the peritoneal fluid are 5-10 times higher than in plasma, both in women with and without endometriosis. The histologically proliferative aspect without secretory changes of most superficial subtle lesions is not compatible with the progesterone concentrations in the peritoneal fluid. Therefore, we have to postulate a strong progesterone resistance in these lesions. The mechanism is unclear and might be a peritoneal fluid effect in women with predisposing defects in the endometrium, or isolated endometrial glands with progesterone resistance, or subtle lesions originating from the basal endometrium: the latter hypothesis is attractive since in basal endometrium progesterone does not induce secretory changes while progesterone withdrawal, not occurring in peritoneal fluid, is required to resume mitotic activity and proliferation. Hormone concentrations in the peritoneal fluid are an important factor in understanding the medical therapy of endometriosis. The effect of oestro-progestin therapy on superficial endometriosis lesions seems to be a consequence of the decreased estrogen concentrations rather than a direct progestin effect. In conclusion, the peritoneal fluid, being a secretion product of the ovarian follicule, deserves more attention in the pathophysiology and treatment of endometriosis.

Prevalence of Endometriosis and Peritoneal Pockets in Women with Infertility and/or Pelvic Pain.

OBJECTIVE: To evaluate the prevalence of endometriosis and peritoneal pockets and to analyze whether these pockets are associated with pain. METHODS: Analysis of prospectively registered data of all women undergoing laparoscopy for infertility or pelvic pain between 1988 and 2011 at KU Leuven University Hospital. RESULTS: Of 4497 women, 191 had 238 pockets, with a prevalence of 4.7% in women with infertility only, 4.9% in women with infertility and pelvic pain, and 3.5% in women with pelvic pain only (P = 0.045 for all infertility vs. pelvic pain only). Prevalence did not vary by age. Pockets were associated with endometriosis (P < 0.0001), which was found in 77% of women with pockets. Among women with infertility only, the prevalence of endometriosis was higher in women with pockets (P = 0.0001) than in women without. The prevalence of endometriosis was similar in women with infertility and pelvic pain or pelvic pain only. Pelvic pain as an indication for surgery was associated simultaneously (through logistic regression) with endometriosis (P < 0.0001) and pockets (P = 0.040). Pelvic pain severity was associated simultaneously with pockets (P = 0.0026) and the severity of subtle (P = 0.001), typical (P = 0.030), cystic ovarian (P = 0.051), and deep endometriosis (P < 0.0001). Pelvic pain severity was not associated with endometriosis in the pockets or the diameter or location of pockets. CONCLUSIONS: The prevalence of pockets was low, at between 3.5% and 5%. Women with infertility only and pockets had more endometriosis than women without. Severe pelvic pain and pelvic pain as an indication for surgery were associated with the presence of pockets as well as the presence and severity of endometriosis.

The epidemiology of endometriosis is poorly known as the pathophysiology and diagnosis are unclear.

As the diagnosis requires a laparoscopy, we only have data in women with pain and/or infertility. Endometriosis has been considered to be a single disease defined as 'endometrium like glands and stroma outside the uterus'. However, subtle, typical, cystic ovarian and deep endometriosis lesions should be considered to be different pathologies which occur in all combinations and with different severities. All large datasets, especially those based on hospital discharge records, consider endometriosis to be a single disease without taking into account severity. In particular, the variable prevalence and recognition of subtle lesions is problematic. Reliable surgical data are small series not permitting multivariate analysis. Endometriosis is a hereditary disease. The oxidative stress of heavy menstrual bleeding with retrograde menstruation and an altered pelvic microbiome are probably associated with increasingly severe endometriosis. Whether the prevalence is increasing, or whether endometriosis is associated with fat intake or an increased risk of cardiovascular disease is unclear.

The Pathogenesis of Endometriosis: Molecular and Cell Biology Insights.

The etiopathogenesis of endometriosis is a multifactorial process resulting in a heterogeneous disease. Considering that endometriosis etiology and pathogenesis are still far from being fully elucidated, the current review aims to offer a comprehensive summary of the available evidence. We performed a narrative review synthesizing the findings of the English literature retrieved from computerized databases from inception to June 2019, using the Medical Subject Headings (MeSH) unique ID term "Endometriosis" (ID:D004715) with "Etiology" (ID:Q000209), "Immunology" (ID:Q000276), "Genetics" (ID:D005823) and "Epigenesis, Genetic" (ID:D044127). Endometriosis may origin from Müllerian or non-Müllerian stem cells including those from the endometrial basal layer, Müllerian remnants, bone marrow, or the peritoneum. The innate ability of endometrial stem cells to regenerate cyclically seems to play a key role, as well as the dysregulated hormonal pathways. The presence of such cells in the peritoneal cavity and what leads to the development of endometriosis is a complex process with a large number of interconnected factors, potentially both inherited and acquired. Genetic predisposition is complex and related to the combined action of several genes with limited influence. The epigenetic mechanisms control many of the processes involved in the immunologic, immunohistochemical, histological, and biological aberrations that characterize the eutopic and ectopic endometrium in affected patients. However, what triggers such alterations is not clear and may be both genetically and epigenetically inherited, or it may be acquired by the particular combination of several elements such as the persistent peritoneal menstrual reflux as well as exogenous factors. The heterogeneity of endometriosis and the different contexts in which it develops suggest that a single etiopathogenetic model is not sufficient to explain its complex pathobiology.

The perioperative period: a critical yet neglected time window for reducing the recurrence risk of endometriosis?

While surgery is commonly the management of symptomatic endometriosis when patients do not respond to medical or supportive therapy, recurrence after surgery poses a serious challenge, and repeat surgery increases the risk of premature ovarian failure, adhesion and organ injury. Conceivably, the recurrent endometriotic lesions could arise from minimal residual lesions (MRLs) or from de novo lesions. However, several lines of evidence suggest that the former is more likely. So far, most, if not all, efforts to combat recurrence have been focused on postoperative medication of hormonal drugs to reduce recurrence risk through lesional dormancy and possibly atrophy. However, the perioperative period may exert a disproportionally high impact on the risk of recurrence; it is likely to be amendable for possible intervention but has been generally neglected. Indeed, many perioperative factors are known to or conceivably could facilitate the recurrence of endometriosis through the suppression of cell-mediated immunity due to the activation of adrenergic signaling and the release of prostaglandins. Perioperative use of ß-blockers and/or nuclear factor κB/jCycloxygenase 2 (NF-κB/COX-2) inhibitors may boost the cell-mediated immunity suppressed by surgery, resulting in the partial or even complete removal of MRLs and reduced recurrence risk. This is both biologically plausible and supported by a recent experimental study. We call for more research on possible perioperative interventions to reduce the recurrence risk of endometriosis. The potential payoff might be a substantial reduction in the risk of recurrence and cost when compared with the traditional approach of postoperative intervention.

Pathogenesis of endometriosis: the genetic/epigenetic theory.

OBJECTIVE: To study the pathophysiology of endometriosis. DESIGN: Overview of observations on endometriosis. SETTING: Not applicable. PATIENT(S): None. INTERVENTIONS(S): None. MAIN OUTCOME MEASURE(S): The hypothesis is compatible with all observations. RESULT(S): Endometriosis, endometrium-like tissue outside the uterus, has a variable macroscopic appearance and a poorly understood natural history. It is a hereditary and heterogeneous disease with many biochemical changes in the lesions, which are clonal in origin. It is associated with pain, infertility, adenomyosis, and changes in the junctional zone, placentation, immunology, plasma, peritoneal fluid, and chronic inflammation of the peritoneal cavity. The Sampson hypothesis of implanted endometrial cells following retrograde menstruation, angiogenic spread, lymphogenic spread, or the metaplasia theory cannot explain all observations if metaplasia is defined as cells with reversible changes and an abnormal behavior/morphology due to the abnormal environment. We propose a polygenetic/polyepigenetic mechanism. The set of genetic and epigenetic incidents transmitted at birth could explain the hereditary aspects, the predisposition, and the endometriosis-associated changes in the endometrium, immunology, and placentation. To develop typical, cystic ovarian or deep endometriosis lesions, a variable series of additional transmissible genetic and epigenetic incidents are required to occur in a cell which may vary from endometrial to stem cells. Subtle lesions are viewed as endometrium in a different environment until additional incidents occur. Typical cystic ovarian or deep endometriosis lesions are heterogeneous and represent three different diseases. CONCLUSION(S): The genetic epigenetic theory is compatible with all observations on endometriosis. Implications for treatment and prevention are discussed.

Celiac Plexus Block as a Predictor of Surgical Outcome for Sympathetically Mediated Abdominal Pain in a Case of Suspected Median Arcuate Ligament Syndrome: A Case Report.

Median arcuate ligament syndrome (MALS), also known as celiac artery compression syndrome, is an uncommon condition classically characterized by chronic abdominal pain, weight loss, and abdominal bruit. Chronic mesenteric ischemia caused by intermittent compression of the celiac artery by the MAL provokes upper abdominal pain that is sympathetically mediated via the celiac plexus. Because it is a diagnosis of exclusion, diagnosis of MALS in the clinical setting is typically challenging. We present an atypical case which highlights the utility of celiac plexus block as both an assistant diagnostic tool and a predictor of surgical outcomes for suspected MALS.

Endometriosis of the retrocervical septum is proposed to replace the anatomically incorrect term endometriosis of the rectovaginal septum.

We propose that the term retrocervical septum be added to the medical lexicon to designate the anatomic location of endometriosis of the septum that separates the vagina and posterior vaginal fornix from the rectovaginal pouch of Douglas. Use of the terms retrocervical septum and endometriosis of the retrocervical septum would correct the century-long misuse of the anatomically incorrect term, endometriosis of the rectovaginal septum.

Robot assisted laparoscopic documentation of endometriosis.

The increased confirmation of endometriosis noted using robotically assisted laparoscopy may be the result of multiple factors, including the three-dimensional view provided with the robot, increased attention and awareness while using new technology, increased time spent considering histologic documentation in preparation for publication, or general improvement with experience.