{"paper_id":"40854682-d958-4f4d-8a8c-38cde74b4a0a","body_text":"Endometriosis is a chronic inflammatory disease\ncaused by the presence of ectopic endometrial tissue,\nwhich reacts to changes in the ovarian steroids, oestrogen and progesterone as expressed by proliferation,\ndifferentiation, and bleeding ( 1 ).\nEstimating the exact prevalence of endometriosis is\na challenge since many women with this pathology are\nasymptomatic, while others may report non-specific\nsymptoms. It mostly occurs in women of reproductive\nage with a prevalence of 7-10% and 50% of women\nwith subfertility ( 2 ,  3 ), and is one of the most frequent\nchronic gynaecological diseases that often affects\nquality of life and fertility ( 4 ,  5 ).\nEndometriosis can take one of three forms, depending on the clinical presentation and management:\nperitoneal or superficial endometriosis, ovarian endometrioma (OMA), or deep infiltrating endometriosis\n(DIE). DIE is the most aggressive form, which affects\n20% of women who suffer from endometriosis ( 6 ).\nAt present, there is no clear agreement on the definition of DIE. Many authors define DIE as the presence of endometriotic lesions over 5 mm in depth under the\nperitoneal surface; others define it as a pathologic entity, which is called “adenomyosis externa”. The 5 mm\ndefinition allows the understanding of lightly deeper\nclassic lesions (type I). It would be more suitable to\ndefine DIE as adenomyosis externa with unique lesions (infrequently two or three) that are large (mainly\n>1 cm in diameter), and are reported as type II and\ntype III lesions ( 7 ). According to a recent Cochrane\nmeta-analysis, DIE is also defined as the infiltration\nof fibrous and muscular tissue in organs and anatomic\nstructures affected by endometriosis, including endometrial tissue, with no reference to the extent of lesion\ndepth underneath the peritoneum ( 8 ).\nRecent literature have shown that many factors contribute to the growth and development of endometriosis: genetic, hormonal, immunological factors play a\nrole, and even intestinal permeability may be involved\n( 9 - 12 ). In the absence of other types of endometriosis, the isolated presence of DIE was only observed\nin 6.5% of cases. Although it may be considered a\nseparate entity, they all may share similar pathogenic\npathways ( 13 ). To explain the pathogenesis of DIE, the Sampson’s theory has some limitations, such as\nthe fact that endometriosis is found in only 10% of\ncases but the physiological process of retrograde menstruation occurs in 90% of women, or the occurrence\nof the endometriosis in men. Instead, the pathophysiology of DIE may be explained by the role of endometrial stem/progenitor cells and coelomic epithelial\nand mesenchymal cells, which could be the origin of\npremenarcheal pelvic endometriosis. The onset of DIE\nin adulthood indicates that DIE could be a retarded\nstage of endometriosis ( 14 ). On the other hand, there\nis the hypothesis that the endometriotic cells undergo\ntumour-like genetic and epigenetic modifications, and\nthese changes influence the progression to DIE ( 15 ).\nThis theory could explain the existence of the three described phenotypes of endometriosis since they could\nbe based on different genetic mutations ( 11 ). The\nmore intense aggressiveness of DIE compared with\nthe other forms seems to be attributable to two main\nmechanisms: decreased apoptosis of endometrial cells\ninvolved in lesion sites and higher proliferation activity of those cells in response to the oxidative stress\ngenerated in these lesions ( 16 ). Furthermore, DIE is\ncharacterized by higher expression of invasive mechanisms (caused by matrix metalloproteinases and activins) and of neuroangiogenesis genes (nerve growth\nfactor, vascular endothelial growth factor) compared\nwith superficial and ovarian endometriosis ( 17 ).\nDIE lesions appear to expand as benign tumours,\npreferentially in the pouch of Douglas, with expansion\nto the uterosacral ligaments, torus uterinum, cardinal\nligament with uterine artery involvement, ureters, or\nbladder, with a preferential invasion into the anterior\nrectal wall [Fig.1, 18)].\nLaparoscopic view of posterior compartment deep infiltrating en- dometriosis (DIE).\nAssociated symptoms generally are related to the localizations [Table 1 ( 19 )].\nThe diagnosis of DIE and, more generally, endometriosis, is based on clinical and physical examination,\ninstrumental examination [ultrasound, magnetic resonance imaging (MRI), double-contrast barium enema\n(DCBE), cystoscopy, computed tomography (CT) scan],\nand, if surgery is needed, the identification and biopsy of\nlesions. With regard to clinical diagnosis, it is often difficult to obtain in asymptomatic patients or when there\nis an inadequate correlation between the severity of the\nendometriotic lesions and the intensity of the symptoms\n( 20 ,  21 ).\nMain localizations and associated symptoms of deep infiltrating\nendometriosis (DIE)\nThe choice of the best therapeutic approach for women with DIE is often challenging. Therapeutic options\ninclude medical and surgical treatment, and the decision\nshould be dictated by the patient’s medical history, disease stage, symptoms, severity, pregnancy desire, and\npersonal choice ( 22 ).\nMedical therapy has proved to be useful in both stopping the growth of lesions and inducing their regression,\nwith a consequent improvement of symptoms. In addition,\npharmacotherapy plays an important role in supporting\nsurgical therapy, either in the period immediately preceding or, even more, after surgery ( 23 ). Currently available\ntreatments include progestogens, combined oral contraceptives (COCs), danazol, gonadotropin-releasing hormone\n(GnRH) analogues and aromatase inhibitors (AI) ( Table 2 ).\nAn adequate lifestyle, a diet rich in vegetables and omega-3\npolyunsaturated fatty acids, and a parallel reduction of red\nmeat, coffee, and alcohol consumption might be important\nin endorsing and amplifying the benefits of medical therapy\n( 24 ). In addition, promising results have come from the use\nof substances that act on mastocyte function and inflammation, especially in women who cannot use hormone therapy\nor who seek to become pregnant ( 25 ).\nOverall, progestogens and COCs are proven to be particularly effective in managing the symptoms of patients\nwith DIE.\nNorethisterone acetate (NETA) and dienogest have the\nbest data in terms of their effects on DIE. A pilot study by\nFerrero et al. ( 26 ) proved the effectiveness of NETA (5\nmg/day) in improving intestinal symptoms and reducing\nthe volume of the endometriotic nodules of 40 patients\nwith colorectal endometriosis and stenosis of the lumen of\nthe bowel to <60%. At the end of the trial, 60% of patients\nstated their satisfaction with this therapy\nDifferent therapies for the medical treatment of deep infiltrating endometriosis (DIE)\nDienogest entered the market as a drug dedicated to the\ntreatment of endometriosis; many studies suggested its effectiveness in the management of rectovaginal or bowel\nendometriosis. Leonardo-Pinto et al. ( 27 ) prescribed dienogest (2 mg/day for 12 months) for 30 women who\nwere dissatisfied with their previous progestogen therapy.\nParticipants reported a significant reduction in intestinal\npain. However, the authors did not notice any decrease\nin bowel lesion size. Yela et al. ( 28 ) reported improved\nsymptoms, such as defecation pain, from the second\nmonth of therapy. After six months of therapy with dienogest (2 mg/day), they noted a reduction in the mean\nvolume of the bowel endometriotic nodules. Moreover,\nwith the same dosage of dienogest, Angioni et al. ( 29 ,\n 30 ) observed an improvement in symptoms and reduced\nnodules size in patients affected by bladder DIE. Similar\nresults for symptoms and cyst volume were obtained in\npatients with endometrioma, which suggested that the absence of endometriosis/endometrial bleeding could be a\nkey mechanism in these results.\nCOCs, by decreasing the nerve fibre density in DIE lesions, enhancing apoptosis, and regulating cell apoptosis\nin endometriotic cells, demonstrated optimistic results\n( 31 ). Since COCs supply a higher doses of oestrogen than\nwhat occurs physiologically, the rationale for their use has\nbeen questioned because their dose may stimulate endometriosis ( 32 ). Moreover, COCs may have additional side\neffects and contraindications compared with progestins.\nTherefore, European Society of Human Reproduction and\nEmbryology (ESHRE) guidelines recommend progestins\nas a first-line medical therapy ( 33 ).\nGnRH agonists (GnRHa) play an important role in\nthe treatment of endometriosis. Their effect on DIE has\nmainly been documented with remarkable results. Fedele et al. ( 34 ) evaluated the effect of these drugs (leuprolide acetate depot, 3.75 mg, one ampoule intramuscularly every 28 days for six months) in patients with\nsymptomatic rectovaginal nodules. Many of the patients\ndescribed improvement in their symptomatology during six months of treatment, but 85% of these patients\nrequired a new therapy cycle during the same year for\nan early recurrence of symptoms. Roman et al. ( 35 ), in\na study of patients with rectal endometriosis, reported\nthat Triptorelin (11.25 mg) plus one daily dose of percutaneous oestradiol (0.1%) had the same effectiveness\nin bowel endometriosis when administered three months\nbefore surgery to control digestive disorders and when\nprescribed after surgery in case of incomplete resection\nof the rectum DIE. Triptorelin acetate (3.75 mg, monthly\nintramuscular injection for six months) was evaluated by\nAngioni et al. ( 36 ) as a post-surgical medical treatment\nin patients with rectovaginal DIE. The outcomes of this\nresearch showed an improvement of symptoms in those\npatients in whom total eradication of the pathology was\nnot feasible.\nThe GnRH antagonist (GnRHant), Elagolix, is another\ndrug that is proving to be effective in the management of\nDIE. This drug has some advantages in comparison with\nGnRHa because of its oral formulation, rapid elimination\nfrom the body due to its short half-life, and a lower incidence of adverse events ( 37 ).\nDanazol, a 17 alpha-ethinyl testosterone derivative, operates principally by suppressing the luteinizing hormone\n(LH) wave and steroidogenesis. It has been shown to have\nsimilar pain control to GnRH-agonists. However, its hyperandrogenic side effects such as hirsutism, acne, weight\ngain, and deepening of the voice are common ( 38 ). At\npresent, the most common administration route for danazol is vaginal (vaginal ring, gel, or capsule) in order to reduce systemic side effects. A prospective study conducted\non 21 patients evaluated the effect of long-term treatment\nwith a low dose of vaginal danazol (200 mg/day) for 12\nmonths on DIE. The results demonstrated an improvement in pain within three months of treatment, with total\nresolution by six months, and the effect remained over the\n12 months of treatment, associated with a volume reduction of rectovaginal nodules ( 39 ).\nAIs inhibit the secretion of local oestrogen in endometriosis implants and, while they are not recommended for\nendometriosis therapy, many studies have examined their\nuse in DIE pain management. In combination treatment\nwith COCs, progestogens and GnRH analogues, AIs are\na therapeutic choice typically reserved for the management of severe endometriosis-associated pain. Increased\nfollicle-stimulating hormone (FSH) levels and successive\nsuperovulation would be induced by monotherapy with\nAIs offered to reproductive-age women, which culminate\nin ovarian cyst production due to the resultant increase in\nFSH. For this effect, AIs are associated with FSH-suppression drugs such as COCs, progestogens, or GnRHa\n( 40 ). In an open-label prospective randomized study, Ferrero et al. ( 41 ) evaluated the efficacy and tolerability of\nletrozole (2.5 mg/day) combined with NETA (2.5 mg/\nday) or Triptorelin (11.25 mg for three months) in the\ntreatment of pain produced by rectovaginal endometriosis\nfor six months. During therapy, chronic pelvic pain and\nprofound dyspareunia decreased considerably in both\ngroups with no substantial variation between the groups.\nThe reduction in the volume of endometriotic nodules\nwas significantly higher in the Triptorelin group, where,\n77.8% of women reported adverse reactions that included\nmenopause symptoms and loss of bone mineral density.\nThis study did not show indications that AIs may function\nbecause, when hormonal drugs are combined (letrozole\nplus NETA), the particular effect of each compound cannot be discriminated. On the other hand, AIs are ineffective unless they are combined with other medications that\nprevent ovulation. Due to a lack of data on the use of AIs\nfor the treatment of patients with endometriosis and, in\nparticular DIE, their use should be considered experimental. It should be considered only when patients are refractory to common hormonal or surgical therapy and in the\ncontext of a clinical study ( 42 ).\nSelective progesterone receptor modulators (SPRMs)\ncan have shifting impacts on progesterone receptors in\ndifferent tissues, ranging from being a pure agonist or\nmixed agonist/antagonist or a pure antagonist. Through\ntheir pro-apoptotic effects, anti-inflammatory effects (decreasing cyclooxygenase-2 expression) and reducing cell\nproliferation, as demonstrated by a decrease in Ki-67 expression, they can play a role to regression and atrophy of\nendometriotic lesions in mice.\nIn terms of selective oestrogen receptor modulators\n(SERMs), by reducing the proliferation of cell nuclear\nantigen and the expression of oestrogen receptor in the\nendometrium, promising results were reported in endometriosis treatment with the use of Bazedoxifene (BZA)\nin a mice model ( 43 ). Nevertheless, the effectiveness of\nboth SPRMs and SERMs for endometriosis management\nhave yet to be established in humans. In light of the most\nrecent discoveries, some angiogenic and proinflammatory\nfactors may have key roles in the pathogenesis of endometriosis. Therefore, drugs, such as anti-TNF-alpha, cyclooxygenase-2 inhibitors, growth factor inhibitors, and\nendogenous angiogenesis inhibitors have been tested for\nendometriosis treatment. However, there is still a lack of\nclinical evidence of the efficacy and safety for most of\nthese drugs ( 42 ).\nSurgical treatment of DIE is indicated in patients who\ndo not respond to medical therapy and have significantly\nsevere symptoms (e.g., hydronephrosis caused by ureteral\nstenosis or intestinal obstruction). The goal is complete\neradication of this pathology and the achievement of good\nlong-term outcomes in terms of pain relief and recurrence\nrates, while trying to respect the functional anatomy of the\ninvolved organs. Because of the complexity of surgery,\na multidisciplinary approach that involves colorectal surgeons and urologists is often essential to reduce the risk of\ncomplications and the hospital stay ( 44 ).\nDuring surgery for rectovaginal and bowel endometriosis, the surgeons can use a nerve-sparing laparoscopic\ntechnique to support urinary and bowel function, which\nallows for conserving the inferior hypogastric nerve\nplexus and identifying all of the anatomic structures in\nthe posterior and lateral parametrium prior to removing\nthe endometriotic lesions ( 45 ). A prospective study that\ncompared a patients who underwent the nerve-sparing\nprocedure and those treated with classical resection\nshowed shorter mean time of self-catheterization of the\ncatheter (40 days versus 121 days, respectively) and less\nsevere bladder, rectal, and sexual dysfunctions ( 46 ).\nAnother study by Angioni et al. ( 47 ) demonstrated that\nlaparoscopic radical excision of DIE with excision of the\nposterior vaginal fornix might be the best approach in\nterms of long-term well-being, even if the vagina is apparently disease-free.\nMost rectovaginal septum lesions arise from the posterior vaginal fornix and subsequently infiltrate the anterior rectal wall. The surgical approach for this kind of lesion\ncan be conservative and include nodulectomy and shaving of the lesion, discoid excision, or, in selected cases,\nradical surgery where the involved intestinal tract is resected. Small/mid-rectal nodules that only infiltrate the\nmuscular layer and are free of advanced stenosis of the\nrectal lumen can be completely removed without opening the bowel. The main advantage of rectal shaving is\nthe ability to treat a bowel infiltration without the need to\nopen and suture the rectal wall ( 48 ,  49 ). Complications\ninclude accidental intestinal perforation (2%), rectovaginal fistula (0.24%), intraoperative haemorrhage (0.08%),\nand catheterization for a maximum duration of six weeks\n(0.19%) ( 50 ). Roman et al. ( 51 ) stated that this technique\nhas a more beneficial impact on postoperative intestinal\nfunction compared to intestinal resection. As regards the\nrisk of recurrence of symptoms and lesions after this procedure, most publications describe recurrence of symptoms and lesions in <10% of cases. Conversely, according to Meuleman et al., the shaving technique should be\nreserved for superficial lesions, that is, those that do not\ncross the muscular layer ( 52 ).\nAn alternative closed technique has been suggested for\ncases of small anterior rectal wall small nodules localized\nup to the rectum-sigmoid junction that cross the muscular\nlayer and affect less than one-third of the circumference of\nthe involved intestinal tract. This technique uses a circular\nor linear stapler introduced transanally, which allows the\nexcision of a full-thickness patch of the rectal wall followed by closure with tightly stapled sutures ( 53 ). This\ntechnique allows for removal of localized endometriosis\nnodules and reduces postoperative infectious complications. The bowel is never opened during this procedure.\nAnother alternative approach was introduced by Roman\net al. ( 54 ), with the Rouen technique that utilized the Contour Transtar stapler (Ethicon Endosurgery) for treatment\nof large DIE nodules (5-6 cm diameter) that infiltrated the\nlow and mid-rectum. They reported a rectovaginal fistula\nrate of 7.2% and bladder dysfunction of 9% two years after they performed the Rouen technique in a series of 111\npatients. In this study, the risk of postoperative recurrence\nwas 1.8%.\nLaparoscopic colorectal segmental resection should be\nreserved for patients with multifocal intestinal lesions or\nlarge nodules (>3 cm), or in the presence of stenosis ( 48 ,\n 55 ). This procedure consists of a segmental bowel resection followed by termino-terminal colorectal anastomosis\n(side-to-end or end-to-end) performed with a transanal\ncircular stapler and a possible protective ileostomy that is\nrelated to the distance of the nodule from the anal sphincter. A temporary colostomy may be suggested for nodules\nsituated <6 cm from the anal verge ( 55 ). The most frequent complications of this procedure are leakage followed by rectovaginal fistula, with a reported incidence\nfrom major available studies that ranged between 1% and\n18%. This wide range was due to the variability of patient\ncharacteristics; however, most of all the height of rectal\ninvolvement and if, during the procedure, both vagina and\nrectum are opened ( 56 ). In surgery for bowel endometriosis, intestinal denervation is always an issue. Patients\nwho underwent segmental resection reported an improvement in symptoms like dyschezia, but less for problems\nlike constipation (even if the intestinal lumen obstruction\nhad been eradicated) ( 54 ). This problem could be caused\nby proximal sectioning of the inferior mesenteric artery\nwhere it is surrounded by autonomic nerve fibres, which\ncause sympathetic denervation of the rectal stump. Raffaelli et al. ( 57 ) showed good results in a prospective cohort study, suggesting resection with mesenteric vascular\nand nerve-sparing surgery that cut the mesentery near\nthe intestinal wall and preserved arteries and autonomic\nnerves of the mesenteric plexus.\nDIE can affect the ureter extrinsically (with glandular and stromal tissue inside the adventitia and the\nadjacent connective tissue) or intrinsically (endometriotic nodule intrusion on the muscle layer and basement membrane, invading the lumen) ( 58 ). The surgical procedure for ureteral endometriosis (UE) can be\nconservative (ureterolysis) or more aggressive (ureteroureterostomy, ureteroneocystostomy, nephrectomy)\n( 59 ). The best approach is often based on the surgeon’s\nexperience and the severity of the lesion. In theory, extrinsic lesions can be treated with ureterolysis, unlike\nintrinsic ones, which require removal of the involved\nsegment. In practice, it is difficult to establish the depth\nof the lesion and the involvement of the ureteral wall\nbefore surgery, when the only sign of an intrinsic lesion\ncould be the hydroureter. Soriano et al. ( 60 ), in a series\nof 45 patients with UE, suggested preoperative ureteral\nstenting in case of hydronephrosis, hydroureter, or abnormal urinary function to reduce the ureteral injury\nrate during surgery. Bosev et al. ( 61 ) and Uccella et al.\n( 62 ) showed that, in the hands of experienced surgeons,\nureterolysis might be performed with a low risk of\ncomplications (<1%). During the surgery, the dilemma\nexists about which level of ureterolysis could be considered sufficient, and how surgeons could predict the\nrecovery of its functionality. Bosev et al. ( 61 ) suggested inserting a stent if the ureter should still be dilated\nafter ureterolysis, since the surgeon could consider a\nresection of the stenotic segment or ureteroneocystostomy if it could not be decompressed. Instead, Soriano\net al. ( 60 ) recommended a ureteroneocystostomy as\na primary procedure in cases of ureteral fibrosis after\nureterolysis and especially when the obstruction is <2\ncm of the insertion of the bladder, or there is sizeable\nureteral stenosis. A higher risk of perioperative complications and recurrences in the presence of large endometriotic nodules (>3 cm) or hydronephrosis grade >2\nwas demonstrated in a case series by Uccella et al. ( 62 ).\nTwo techniques have been described for surgical treatment\nof bladder endometriosis, transurethral resection (TUR) and\npartial cystectomy (segmental bladder resection) ( 63 ). During laparoscopic partial cystectomy, the decision to perform ureteral cannulation depends on the position of the endometriotic nodule in the bladder wall and the distance from the\ninterureteric ridge ( 64 ). In many studies, partial cystectomy\nhas demonstrated its effectiveness with good long-term outcomes. Fedele et al. ( 65 ) showed how this technique could\nbe more effective in terms of symptom recurrence if a 1 cm\ndeep myometrial resection of the anterior uterine wall is\nadded during the procedure to eliminate all the adenomyotic\nfoci that could be under the vesical lesion. A combination of\nTUR and laparoscopic surgery was described by Pontis et al.\n( 66 ) with good results. In the case of significant endometriotic lesions, this combination allowed for complete removal\nof the nodule, sparing the removal of healthy bladder tissue\nand improving the patient’s quality of life.\n\nDIE is considered the most aggressive of the three phenotypes that constitute endometriosis because it can affect\nthe whole pelvis, subverting the anatomy and functionality of vital organs, with a profoundly negative impact on\nthe patient’s quality of life.\nOnce a diagnosis is determined, medical therapy can\ncontrol the symptoms and stop the development of pathology, keeping in mind the side effects derived from a longterm treatment and the risk of recurrence once suspended.\nSurgical treatment should be proposed only when strictly\nnecessary (failed hormone therapy, contraindications to\nhormone treatment, severity of symptoms, infertility), but\na conservative approach performed by a multidisciplinary\nteam is preferred when possible.\nThere are no studies in the literature that directly compare medical versus surgical therapy in the treatment of\nendometriosis. Therefore, superiority of one approach\nover the other cannot be established.\nAll therapeutic possibilities have to be explained by the\nphysicians in order to help the women make the right choice\nand minimize the impact of this disease on their lives.\nAs for future prospects, the goals of surgery are to make\ncurrent techniques as conservative as possible towards the\nfunction, and radical towards the disease. Instead, medical therapy is focusing on new discoveries in the field of\nneuroendocrinology and genomics.","source_license":"CC0","license_restricted":false}