{"paper_id":"9dcfbd3b-706d-43b3-a94f-957cf85610ce","body_text":"Research Article\nClinical Obstetrics, Gynecology and Reproductive Medicine\nClin Obstet Gynecol Reprod Med, 2019        doi: 10.15761/COGRM.1000262\n Volume 5: 1-7\nISSN: 2059-4828\n“Endometriosis”: A neuro-etiologic framework for its \ncauses and consequences\nYANG Bing Xin, GU Ni Hao, JIANG Ji Lan, XU Hong*, ZHANG Hui Juan and Quinn MJ*\nDepartments of Gynaecology & Pathology, Shanghai Jiao Tong University, China\nAbstract\nIn recent decades the gynecologic response to “endometriosis” has been to excise, or ablate, its deposits with high rates of recurrent pain. However, there is growing \ndissatisfaction with surgical outcomes, and, a chorus of clinicians recently called for an improved clinical approach. They want to enhance the use of “clinical” diagnosis \nto improve “delays in diagnosis”, “bring about more rapid relief ”, “limit disease progression” and “prevent sequelae”. This ambitious agenda is not just a “call to action”; \nit implies a fundamental shift in approach – though the details of that “shift” were not detailed in the article. \nIn the “autonomic denervation” view of the pathogenesis of “endometriosis”, there are two key pathogenic principles that govern its laparoscopic appearances. Firstly, \ninjuries to uterotubal nerves result in uterotubal dysmotility and retrograde menstruation with, ectopic endometrium deposited in the pelvis. “Difficult”, first labors, \nstraining on the toilet and gynecologic surgery cause the initial pelvic neural injuries. Secondly, ectopic endometrium attaches to anatomic sites of tissue injury e.g. \ninjured uterosacral ligaments, injured peritoneal surfaces, hip replacements, etc if endometrium is available at the time of the injury. Breast feeding mothers do not have \n\"available\" endometrium. “Endometriosis” with accompanying injuries to pelvic autonomic nerves, may result in a surprisingly wide range of clinical consequences. \nThese include “pain in response to light touch”, sensitization of central nervous system, hyperplasia of the endometrium and myometrium, and, narrowing of adjacent \nmyometrial arterioles resulting in pregnancy complications. Concurrent, or contiguous, injuries at other levels of the sympathetic chain may result in hypertension, \ninflammatory bowel disease, thyroid dysfunction, Sjogren’s syndrome and other “autoimmune” diseases. \nRe-framing the condition as an injury to pelvic autonomic nerves with widespread, neurologic consequences consequences, may be a more appropriate, clinical \nframework than attributing such wide-ranging symptoms to isolated deposits of “ectopic endometrium”?\n*Correspondence to: MJ Quinn, MD, LLM, Dept OBGYN, Shanghai Jiao \nTong University, International Peace Maternal and Child Health Hospital, 910 \nHengshan Road, Xujiahui, Shanghai, CHINA, PR 200030, E-mail: mjquinn001@\nicloud.com\nXU Hong, MD, Dept OBGYN, Shanghai Jiao Tong University, International \nPeace Maternal and Child Health Hospital, 910 Hengshan Road, Xujiahui, \nShanghai, CHINA, PR 200030, E-mail: xuhong169@126.com\nReceived: August 20, 2019; Accepted: August 28, 2019; Published: August 30, \n2019\nIntroduction\nWhat is the primary evidence that ectopic endometrium causes \ncyclic, premenstrual pain? In Figure 1a there is 1160g of ectopic \nendometrium in a painless uterus. In Figure 1b there is 260g of ectopic \nendometrium with intrauterine bleeding from every surface of the \nspecimen – again, in a painless uterus. Y et, we are asked to believe \nthat a single spot of ectopic endometrium is sufficient to confine its \nnulliparous owner to one week in bed with chronic pelvic pain, every \nmonth (Figure 1c)? And, the asymmetric injuries to the uterosacral \nligaments are unrelated to the condition (Figure 1d)? In our submission, \nthere is no evidence that ectopic endometrium, of itself, causes cyclic, \npremenstrual pain. So, what causes pain, bleeding and infertility in 10% \nof the female population, or, 30-50% of women with pain and infertility \n[1-3]? In this account, difficult first labours [4], straining on the toilet [5] \nand gynecologic procedures [6], particularly complications of medical \nand surgical evacuation, cause injuries to uterotubal nerves (Figure 1, \nTable 1). These injuries cause uterotubal dysperistalsis with retrograde \nmenstruation of endometrium, with-attaching to sites of tissue injury \nin the pelvis [7,8].\nIn his original 1921 account, JA Sampson recorded “increasing \nconstipation” in 3/23 patients with the condition, and, a number \nhad previous difficult deliveries [9]. Indeed, his remarks are entirely \nconsistent with injuries to pelvic nerves causing pelvic neuropathic pain\n“Twelve of the 17 symptomatic patients sought relief for pain, three \nfor increasing constipation, and one each for uterine bleeding and \nsterility. The amount of pain and abnormal bleeding were quite variable, \nand often absent. Sampson concluded: “It is very difficult to decide \nwhether or not these cysts cause profuse or irregular (too frequent) \nmenstruation. ” As for pelvic pain, he concluded that “there is usually \nnothing characteristic about the pain present in this condition nor is \nthere necessarily any relation between the extent of the adhesions and \nthe severity of the pain. ”\nPathogenesis of chronic, neuropathic, pelvic pain\nIn simple, pathogenetic terms, injuries to uterotubal nerves \nresult in (1) uterotubal dysmotility that results, in turn, in retrograde \nmenstruation with ectopic endometrium (2) attaching to different \ninjuries in the pelvis creating different laparoscopic appearances \n(or phenotypes (Figure 2) [2-4]. Much of the clinical confusion has \nresulted from (i) the dichotomous appearances of symmetric and \nasymmetric appearances of “deep endometriosis” (Figure 2c-d), (ii) the \npresence of chronic pelvic pain in women without evidence of ectopic \nendometrium [10]. Such phenotypes may be resolved by a thoughtful \nsurgeon asking “What caused these injuries?” rather than “Where is \n\nBing Xin Y (2019) “Endometriosis”: A neuro-etiologic framework for its causes and consequences\nClin Obstet Gynecol Reprod Med, 2019        doi: 10.15761/COGRM.1000262\n Volume 5: 2-7\nthe en dometriosis ?” . One key confusion has been the dichotomous, \nlaparoscopic appearances of stage IV , nulliparous “endometriosis” \nand stage IV , multiparous, “endometriosis” . In the former, the surgeon \nobserves a pelvis full of ectopic endometrium but in the young, \nnulliparous woman it is almost always caused by straining on the toilet \nwhere the uterosacral ligaments are hypertrophic and symmetric, and, \nthe treatment is better diet and and bowel habits [2-4]. In the older, \nmultiparous women the uterosacral ligaments are thin, attenuated and \nasymmetric because she sustained her injuries during a “difficult” first \nlabor [6]. The extent of the visible, ectopic endometrium may depend \non whether she breast-fed (no ectopic endometrium) or she bottle-fed \nher baby (major ectopic endometrium) [2,3]. \nNot that we need to perform diagnostic laparoscopy [11] since \nasking three questions in a thoughtful, precise manner will provide \nmost of the answers to the sources of chronic pelvic pain (Table 1)? \nAdditional ultrasound [12] or MR imaging [13,14] will tell you if there \nis concurrent adenomyosis and what form that takes (Table 2) since \nthere are distinguishable patterns of adenomyosis and leiomyoma, \nthat are often concurrent with “endometriosis” [15,16]. Injuries to \nuterotubal nerves result in tubal dysmotility in some forms of infertility \nthat are best dealt with by ART since surgery to endometriomas will \nreduce ovarian reserve [17]. Endometriomas (-OMA) may be examples \nof retrograde ectopic endometrium adhering to monthly ovarian “tissue \ninjuries” where ovulatory follicles leave substantial areas of tissue injury \nthat may form OMA-s without any significant contributing neural \ninjuries, beyond that causing the “retrograde menstruation” [18]. They \nare painless. Extrapelvic “endometriosis” is another matter though the \nusual sites e.g Caesarean section scar, episiotomy, hip fractures, lung, \netc are typically associated with prior injury [18]. In these presentations \nthe pain coincides with the onset of menstruation whereas in pelvic \n“endometriosis” the pain usually precedes, and then improves, with the \nFigure 1. Photographs of four phenotypes of endometriosis-adenomyosis.  (A) 1160g of \npainless adenomyosis, (B) 260g of painless adenomyosis, (C) single deposit of endometriosis \non the anterior border of the right uterosacral ligament, (D) “deep” endometriosis with \nlarge volumes of ectopic endometrium attached to injured uterosacral ligaments containing  \nlarge numbers of injured uterotubal nerves with extensive neovascularisation of peritoneal \nsurfaces\nFigure 2. Different patterns of injury to the uterosacral ligaments and their contained \nuterotubal nerves presenting a chronic pelvic pain (B, C) without “endometriosis”. \nComplete loss of uterine nerves (D) is painless. (A) Normal uterosacral ligaments, \n(B) asymmetric injuries to the uterosacral ligaments following surgical abortion, (C) \nsymmetrical attenuation of the uterosacral ligaments following medical abortion, (D) \ncomplete loss of all uterosacral tissue following medical and surgical abortions\n(1) Bowel habits \n(a) How are your bowels?\n(b) Do you go to the toilet once per day, once per week, or once per month?\n(c) Do you strain, or, use physical efforts to open your bowels?\n(2) First labors\n(a) Were there any difficulties in your first labor?  \n(induced, prolonged, excessive uterine activity, fetal weight >4000g, \nmalpresentations, operative vaginal delivery, etc all double the risk of “severe” \npelvic pain at 47 months postpartum)\n(b) When did the pain start?  \n(In a one-child family, pain starts typically, at 4-5 years postpartum; in a two child \nfamily, pain starts typically 7-8 years after first baby)\n(3) Other gynecologic procedures \n(a) Have you had any other pregnancies (miscarriages or terminations)?\n(b) How were they managed?  (medical or surgical procedures)\n(c) Did you suffer any complications?  (uterine tachysystole, re-evacuation, etc)\nTable 1. Three questions to ascertain the source of chronic pelvic pain caused by injuries \nto pelvic autonomic nerves.  Positive findings with any sequence of questions should be \nconfirmed by asking when the pain started ?  There is usually a 3-5 year “neuroproliferative” \ninterval between the injury and clinical presentation that enables sufficient neural density \nto cause “hyperalgesiae” or “allodyniae” (“ pain or discomfort in response to light touch”)\nType 1 Diffuse, symmetric, painless adenomyosis\nThis woman presents with the effects of a mass on her pelvic organs in her 30-40’s e.g \nfrequency passing urine or constipation. There is complete avulsion of the uterosacral \nligaments (and uterotubal nerves) usually by surgical management of second trimester \nabortions.  There are no nerves in the uterus or Fallopian tubes.  The uterus weighs from \n250-1250g.  \nType 2 Irregular, asymmetric, painful adenomyosis \nThe woman presents with painful periods in her 30-40’s.  There is a partial injury to \nthe uterosacral ligaments combined with over-vigorous curettage of the endometrial \ncavity.  There is aberrant reinnervation around the endometrial glands at the endometrial-\nmyometrial interface.  The uterus weighs from 80-150g\nType 3 Focal, asymmetric, adenomyoma \nThe woman presents with localized pain, or, the effects of a pelvic mass on adjacent organs \nin her 30-40’s.  There is a focal injury to the uterotubal nerves in the uterosacral ligaments \nwith some torn nerve fibers that may lead to reinnervation, or, the enlarging tumor may \n“stretch” as it enlarges, resulting in localized pain.  There is loss of nerve fibers in adjacent \nmyometrial nerve bundles.  The uterus weighs 100-500g.\nType 4 Embryologic, or unusual, adenomyosis\nEmbryologic remnants or unusual patterns of pedunculated, polypoid adenomyosis may \ncontribute to this category of adenomyosis.\nTable 2. The “Shanghai system” of classification of adenomyosis describes injuries to \nnerves at different anatomic sites and subsequent development of different patterns of \nadenomyosis (29, Types 1-3).  The full spectrum of adenomyosis is best observed in China \nwhere, typically, different injuries during gynecologic surgery lead to the later development \nof adenomyosis.  Injuries to nerves in myomas were originally described by Savitskii (57-\n59) and “endometriosis” by Atwal (4).  All three major gynecologic pathologies may derive \nfrom neural injuries at different anatomic sites.\n\nBing Xin Y (2019) “Endometriosis”: A neuro-etiologic framework for its causes and consequences\nClin Obstet Gynecol Reprod Med, 2019        doi: 10.15761/COGRM.1000262\n Volume 5: 3-7\nonset of bleeding. Eventually, bleeding on to reinnervated peritoneal \nsurfaces may contribute to, and extend, the duration of pain [19]. \nAnother clinical feature suggesting the neuropathic origins of the \ncondition are the very distressing, clinical presentations of women in \ntheir 60-70’s with recurrent, chronic pelvic pain [20]. Typically, they \nhad a “difficult” first labor in their 20’s, had an early hysterectomy, \nexperienced a decade of relief around their menopause only to be \ninvestigated by multiple clinical departments because of “new-onset” of \npelvic pain in their 60-70’s. These women are immensely relieved by your \ndiagnosis of neuropathic pelvic pain on the basis of a detailed clinical \nhistory as it saves them further investigations by gastroenterologists, \nurologists, radiologists and pain teams, who are justifiably concerned \nabout this de novo, clinical presentation.\nCauses of chronic, neuropathic, pelvic pain\nAny traumatic injury to the pelvis may cause injuries to pelvic \nautonomic nerves though there are three common sources of injury: \nthese are “constipation” , childbirth and gynaecologic surgery where a \nvolsellum is applied to the cervix, followed by traction e.g. evacuation \nof the uterus [2,3]. Affected pelvic organs include the isthmus of the \nuterus, cervix, and vagina as well as the uterosacral-ligament complex \ni.e all those anatomic structures at the junction of the uterus and cervix. \nAlthough Fallopian tube, bladder, urethra, and rectum, and, their \nligamentary supports may also be affected by neuropathic injuries in \ndifferent shapes of pelvis with different patterns of straining [21-24].\n“Constipation”\nThe word “constipation” means different things to different \npeople [25]. In this context it means physical efforts to start or finish, \ndefecation, which afflicted 20-30% of an urban, UK population in 1993 \n[26]. Expulsive efforts with open sphincters lead to injuries to pelvic \n(and other) autonomic nerves depending on the nature and pattern \nof straining. The consequence is perivascular nerve fiber proliferation \n(PVNFP), where there are multiple layers of abnormal, injured nerves \naround small arterioles [27] (Figure 3e) that leads to a wide range \nof clinical consequences (Table 3). Dilating arterioles in the second \nhalf of the menstrual cycle cause “pain in response to light touch” \n(hyperalgesiae, or, allodyniae)\nChildbirth\n“Difficult” (induced) first labors that result in prolonged, \naugmented, first and second stages, or, result in the malpresentation \nof a 4000g baby that requires operative vaginal delivery, are a potent \nsource of pelvic autonomic neuropathy [3,28]. The histologic pattern \nis much more chaotic with widespread “collateral spro uting” of nerve \nbundles (Figure 3d), that is pathognomonic for prior traumatic injury. \nAgain, increasing blood flow in the second half of the menstrual cycle \ncauses “pain in response to light touch” along with a wide range of other \nconsequences.\nGynecologic surgery\nApplying a volsellum to the cervix followed by traction, has the \npotential to cause wide-ranging injuries to pelvic autonomic nerves \nfrom complete avulsion of the uterosacral ligaments (and all uterotubal \nnerves) that leads to diffuse, symmetric, painless adenomyosis, to, loss \nof individual nerve fibers that create the conditions for myometrial \ndenervation and development of myomas at different sites in the uterus \n[29] (Table 2).\nConsequences of chronic, neuropathic, pelvic pain \n(Table 3)\nThere are a surprisingly wide range of clinical consequences \nof injuries to pelvic autonomic nerves (Table 3). These have been \ndiscussed in previous articles [2,3]. This account provides a neuro-\netiologic framework to explain many of the clinical “associations” of \n“endometriosis” that are the subject of many recent contributions to \nthe literature.\nSpecific clinical “associations” of endometriosis\nThere are a wide range of clinical associations of “endometriosis” \nthat have emerged in the past decade, that do not have any apparent \nexplanation. We offer a neuro-etiologic framework to explain these \nphenomena. \nAdverse obstetric outcomes \nIn a meta-analysis in 2017, Zullo [30] records “higher risks of \npreterm birth (OR 1.63), miscarriage (OR 1.75); placenta praevia \n(OR 3.03); small-for-gestational-age babies (OR 1.27), Caesarean \ndelivery (OR 1.57), though no change in the incidence for gestational \nhypertension or preeclampsia. Many authors note the increased risk \nof the “great” obstetric syndromes in women with the classic Dixon-\nRobertson-Brosens lesion that was initially observed in the placental bed \nby AT Hertig, 1945 [31-33] (Figure 3e-f). We note a similar lesion in the \n“great” gynecologic syndromes where instead of a “halo of hyalinization” \n(Figure 3f) there is a “halo of injured nerves” (Figure 3e) [34,35]. It \nhas been proposed that both result from injuries to uterine nerves. The \n“halo of injured nerves” is the “classic” injury in chronic pelvic pain \nwith, or without, “endometriosis” leading to severe, premenstrual, \ncyclic pain – the clinical hallmark of “severe endometriosis” . In our \nsubmission these histologic appearances in both “classic” obstetric \nand gynecologic syndromes arise from denervatory injuries to the \n1) Tissue hyperplasia.  Endometrial hyperplasia (myoma), myometrial hyperplasia (adenomyosis), cervical hyperplasia are consequences of estrogen-dependent hyperplasia.\n2) Tissue hypoplasia. In non-estrogen -dependent tissues there is atrophy of denervated tissues e.g. bladder, bowel, vagina, vulva, etc. \n3) Loss of visceral function. Early pregnancy loss, loss of cervical function in labor (cervix will not dilate), or at hysteroscopy (cervix will not open easily). \n4) Loss of visceral motility. Dyspolar uterine and tubal motility leads to infertility, retrograde menstruation, and, dysfunctional labor.\n5) Opportunist infection. E.coli in preterm labor, vulvovaginal Candidiasis, bacterial vaginosis in gynecology.\n6) Pain. Reinnervation leads to “pain in response to light touch” (hyperalgesia or allodyniae) e.g. dysmenorrhea, vulvovaginal pain, “mesh” pain, etc\n7) CNS sensitization. Interstitial cystitis,  chronic pain syndromes, postmenopausal pain, chronic vulval pain, etc \n8) Induction of purinergic. “stretch” receptors as secondary mechanisms of intercellular communication e.g. preeclampsia, etc\n9) Viscero-visceral reflexes the uterorenal reflex leads to activation of a corticomedullary vascular “shunt” in preeclampsia.  Associated with wider activation of the autonomic nervous \nsystem including headache, migraines, nausea, vomiting, restlessness, fatigue, etc\n10) Ischemia-thrombosis Injuries to visceral vasomotor nerves cause narrowing of arterioles through secondary hyperplasia of the denervated arteriole.  Pregnancy complications including \nplacental abruption and placental infarction may result from narrowing of visceral arterioles.\nTable 3. Some, wide-ranging, pathologic consequences of pelvic autonomic denervation-reinnervation around the body\n\nBing Xin Y (2019) “Endometriosis”: A neuro-etiologic framework for its causes and consequences\nClin Obstet Gynecol Reprod Med, 2019        doi: 10.15761/COGRM.1000262\n Volume 5: 4-7\nuterus with their wide-ranging consequences (Table 3). It is therefore \nno surprise that women with this pattern of “endometriosis” have \nadverse pregnancy outcomes compared to controls. The “surprise” \nin these observations, is that women with “endometriosis” . do not \nappear to suffer excessive rates of pre-eclampsia [30].\nInflammatory bowel disease\nThe small and large bowel receive innervation from adjacent \nsympathetic segments (T8-9) to the uterus (T10-L2) and, may develop \ncontiguous injuries at different levels of the sympathetic chain [36] \n(Figure 4). Both patterns of inflammatory bowel disease demonstrate \nneural abnormalities though there are no accounts in the literature of \npatterns of neural injury in the mesentery of affected bowel. We know \nthat mice with loperamide-induced constipation develop a condition \nthat is histologically indistinguishable from ulcerative colitis [37]. \nThese observations raise the concern that contiguous injuries at \nT8-9, may be an extension of uterine injuries (T10-L2) e.g. through \ndifferent patterns of “constipation” , leading to the co-presentations of \ninflammatory bowel disease and “endometriosis” [27].\nHypertension and coronary artery disease\nIn, 116,430 women in the Nurses Health Study (1989-2009), the \nrelative risk of combined patterns of coronary heart disease was 3.08 \nin women aged less than 40 years [38]. That risk increased across the \nage range if hysterectomy and oophorectomy had been performed. The \nuterus and kidneys are supplied from the same sympathetic segments \n(T10-L2) so that any injury to the innervation to the uterus, may also \nresult in injury to the innervation of the kidney including its vasomotor \nnerves. We already know that widespread visceral arteriolar narrowing \nin hypertension [39] arises from injuries to vasomotor nerves resulting \nfrom stress, hyperglycemia and persistent physical efforts during \ndefecation [40,41]. \nExtrapelvic symptoms and “endometriosis”\nIt is a common clinical observation that women with chronic \npelvic pain with, or without, “endometriosis” present with a range of \nextrapelvic symptoms that include headache, nausea, vomiting, fatigue, \nlassitude, etc particularly when they are experiencing pelvic symptoms \n[42]. Similar clinical presentations are a feature of chronic pelvic pain \nin pregnancy between 16 weeks and delivery, often mislabeled as \n“symphysis-pubis dysfunction” where the weight of the gravid uterus \non prior, mature pelvic injuries often characterised by avulsion of the \nlevator ani from its origin over obturator internus [43]. They cause \nintense pain throughout pregnancy (Table 4).\nKJ Franklin described viscero-visceral reflexes [44] where there \nare direct autonomic connections of one viscus with another, and \nmore generally, where irritation of peritoneal surfaces has marked \nFigure 3 (A-F). Neuro-immunohistochemical features of “endometriosis-adenomyosis”.  \n(A) The endometrial-myometrial nerve plexus of Krantz is injured in different patterns \nof adenomyosis. (B) Widespread aberrant reinnervation in the uterine isthmus, cervix, \nuterosacral ligaments and vagina, cause symptoms of pain and bleeding in “endometriosis”. \n(C) Loss of uterotubal nerves in myometrial nerve bundles are diagnostic of a “pre-uterine”, \nneural injury. (D) “Collateral sprouting” of a nerve bundle is pathognomonic of a prior \ntraumatic injury to the nerve bundle that may contribute to impaired uterotubal function \nand infertility. (E) Perivascular nerve fiber proliferation around a narrowed uterine arteriole \n(“halo of injured nerves”) creates conditions for premenstrual pain. (F) Perivascular “halo \nof hyalinization” in a pregnant uterus (The Dixon-Robertson-Brosens lesion) results from \ninjuries to uterine nerves (Fig. 3e) though in pregnancy the nerves do not extend to the \nplacental bed; their sheaths create the “halo of hyalinization”.  All of the “great” obstetric \nand gynecologic syndromes derive from injuries to the uterine nerves\n1) Take a subtle, and precise, clinical history regarding injuries to pelvic autonomic \nnerves related to constipation, childbirth and gynecologic surgery.  Avoid physical \nexamination; it is painful, non-productive, and, you are going to have a (life)long \nrelationship with this woman.\n2) Use radiological techniques e.g. TVS /MRI to establish the presence or absence \nof “-OMAs” and adenomyosis.  Recognise and respond to the different types of \nadenomyosis (Shanghai system, types I-III (29).\n3) Provide advice regarding diet, bowel habits and exercise where appropriate.  Enable \nstrategies for pain relief, reducing pelvic blood flow and mood management.  \nRecognise  wide-ranging extrapelvic symptoms, risk of hypertension, IBD, etc.(35, \n37, 41, 44) \n4) IVF is an appropriate technique to bypass uterotubal nerve injuries though it will have \nprofound consequences for obstetric outcomes since the uterotubal neurologic injuries \nthat caused the infertility, also contribute to adverse obstetric outcomes.\n5) Consider preparatory endometrial ablation to improve Mirena IUS retention rates in \nwomen with chronic pelvic pain associated with type 2 adenomyosis, in women who \nhave completed their reproductive careers. \n6) Surgery eg TAH and BSO is palliative ; it is neither definitive nor curative in the \ncontext of pelvic neuropathic pain.  Recurrence rates are high. \n7) Recognise postmenopausal pain promptly, and, explain appropriately to provide \nreassurance and avoid unnecessary investigations. \n8) Prevent injuries to women on your labour ward.  “Neuroprotective” intrapartum care \navoids induction of nulliparous labor, excessive uterine activity, prolonged labors, \n“difficult” operative vaginal delivery, prioritises Ventouse over forceps, etc. \n9) Prevent injuries to women in our gynecologic services by avoiding excessive traction \nto the cervix, or, over -vigorous curettage, or, other forms of surgical excision e.g \nLEEP/LLETZ\n10) Avoid using the term ‘endometriosis”.  It is largely an epiphenomenon to underlying \ninjuries to pelvic autonomic nerves (2, 3).  Wider injuries to the sympathetic division \nof the autonomic nervous system may be responsible for many other important, \nclinical associations e.g. inflammatory bowel disease, hypertension, “autoimmune \ndisease”. etc (35, 37, 44)\nTable 4. Strategies for improving contemporary clinical care of women with chronic pelvic \npain with, or without, “endometriosis”.  Recognizing the lifelong consequences of injuries \nto pelvic autonomic nerves is an important first step in managing chronic pelvic pain.   \nPrevention is a necessary strategy that should form an integral part of our clinical practice\n\nBing Xin Y (2019) “Endometriosis”: A neuro-etiologic framework for its causes and consequences\nClin Obstet Gynecol Reprod Med, 2019        doi: 10.15761/COGRM.1000262\n Volume 5: 5-7\nphysiologic effects. More recently there has been considerable interest \nin viscero-visceral hyperalgesia in different pain models specifically in \nrelation to painful pelvic symptoms typical of “endoemtriosis’ [45,46]. \nExtrapelvic symptoms may best be understood as being triggered by \nthe prior pelvic injury in chronic pelvic pain resulting in all kinds of \nsympathetic and vagal reflexes depending on the site, nature and extent \nof the initial pelvic injury.\n “Autoimmune” diseases \nIn this 2019 meta-analysis [47], this group confirm “an increased \nco-morbidity of autoimmune diseases including SLE, SS, RA, thyroid \ndisorders, coeliac disease, multiple sclerosis, inflammatory bowel \ndisease, and Addisons disease” in women with “endometriosis” though \nthe evidence for these associations is “weak” [46]. Since the Seattle \ngroup described an “early, marked, sustained and islet-selective” loss of \nsympathetic nerves in bottle-fed babies [48], and, an accompanying rat \nmodel in type 1 diabetes mellitus [49], there has been the hypothesis that \n“autoimmune” disease is primarily a matter of autonomic denervation \nwith the autoantibodies being secondary to the primary, neural injury \n[50]. If physical efforts during defecation play a role in stage IV , \nnulliparous “endometriosis” then there is the risk that similar physical \nefforts may also injure sequential endocrine glands though this should \nonly be a “weak” association. Temporary, postpartum “autoimmune” \ndisorders may also reflect the short term impact of a difficult, second \nstage of labor [51,52] ?\nThough the evidence is variable, there is a plausible relationship \nbetween women with chronic pelvic pain with, or without, \n“endometriosis” and wider injuries through varying mechanisms \nto the sympathetic nervous system that may explain these otherwise \ninexplicable associations. These provide additional weight to the \nneuro-etiologic framework for chronic pelvic pain with, or without, \n“endometriosis” .\nAchieving neuro-etiologic “causation”\nClearly the neuro-etiologic associations of endometriosis-\nadenomyosis-myoma may be bolstered by an appropriate, animal \nmodel. Most animals do not eat low-fiber diets, and, do not have \ndifficulties with their bowel habits or vaginal deliveries, By necessity \nany such model will be contrived to some extent. “Endometriosis” may \nbe created in baboons by ligation of the cervix [53,54] though this is \nsimply an obstructive pattern of “endometriosis” that does not engage \nneuro-etiologic injuries. One, recent suggestion has been to administer \nloperamide (an anti-diarrhoeal agent) to mice, we know this creates \na condition analogous to ulcerative colitis and inflammatory bowel \ndisease in the four-legged posture [37,55]. Any animal model needs to \nreflect the etiology of the condition where possible. It is not surprising it \nhas been difficult to achieve this in “endometriosis” given the efficiency \nthat most animals have concerning their diets, bowel habits, and \nreproductive capacity.\nEven without an animal model there is increasing evidence \nfor neuro-etiologic injuries in “endometriosis” , adenomyosis and \nleiomyoma [56]. Savitskii noted the absence of nerves in leiomyoma \nthough we observe loss of nerves in adjacent nerve bundles together \nwith leashes of injured arterioles adjacent to small myomas [57-59]. \nMany colleagues have reported neural injuries in “endometriosis-\nadenomyosis” [60-71] though undoubtedly the most entertaining has \nbeen the suggestion that injuries to nerve bundles in the cervix are \n“induced” by deposits of ectopic endometrium [72]. Any textbook \nof pathology explains that “collateral sprouting of nerve bundles” \nis pathognomonic for prior traumatic injury; deposits of ectopic \nendometrium do not cause traumatic injuries ? Our group has already \nexplained a potential classification of four types of adenomyosis \nbased on different types of neuro-etiologic injury sustained during \ngynecologic surgery, or, in childbirth, with evidence for the site of the \nneurologic injury [29] (Table 2).\nConclusion\nThe etiology of “endometriosis” has become a matter of “religious” \nbelief. Y ou either believe that deposits of ectopic endometrium \ncause cyclic, premenstrual pain, or, you are prepared to contemplate \na neurologic explanation. In our submission, “endometriosis” \nmay best be regarded as a lifelong injury to the pelvic autonomic \nsystem with wide-ranging consequences in other parts of the \nbody through a series of varying, neuro-pathologic mechanisms. \nDeposits of ectopic endometrium are largely epiphenomena to \nunderlying injuries to pelvic nerves. This account offers a framework \nof autonomic denervation-reinnervation that may better explain \nmany of the causes and consequences of “endometriosis” . Notably, \nthere is a clinical explanation for many of the “remote” clinical \nassociations of “endometriosis” that have been described in the past \ndecade e.g. extrapelvic manifestations, inflammatory bowel disease, \n“autoimmune” disease, and, hypertension. \nFigure 4. Sympathetic chains arise from T1-L2.  Injuries to pelvic nerves may have wide-\nranging consequences that may include cervical sympathetic nerves and the thoracolumbar \nchain to account for many of the “unexplained” clinical associations of “endometriosis”\n\nBing Xin Y (2019) “Endometriosis”: A neuro-etiologic framework for its causes and consequences\nClin Obstet Gynecol Reprod Med, 2019        doi: 10.15761/COGRM.1000262\n Volume 5: 6-7\nStepping into this “new” paradigm provides a comprehensible, \netiologic explanation that is a great relief to many women, even though \nthey have to contemplate a lifetime of neuropathic pain. It avoids \nmany surgical interventions. Prevention of iatrogenic injury takes on \ngreater significance as we struggle with the complexity of contemporary \nintrapartum management that is not “neuroprotective” in any sense \nof the word. High rates of nulliparous inductions of labor promote \nmaternal “neuropathic” injuries. Simply understanding the potential \nconsequences of applying a volsellum to the anterior lip of the cervix \nshould be sufficient to concern most gynecologists ? The essential \n“shift” is not to move to a “clinical” paradigm as suggested by recent \n“calls to action” [1], but it is to embrace a full, neurologic re-wiring of \nour specialty ? This will enable an improved understanding of many \nother pelvic neuropathic pain syndromes e.g. irritative bladder, urethral \nsyndrome, “mesh” syndromes, irritable bowel syndromes, cervical \ndenervation-reinnervation and its consequences in labor, ectopic \npregnancy, abdominal pain in parous pregnancy, as well as many of \nthe “great” obstetric syndromes including pre-eclampsia [73,74]. It \nis surprising how satisfying a single step from empiric chaos into a \ncoherent framework can be?\nReferences\n1. Agarwal SK, Chapron C, Giudice LC, Laufer MR, Leyland N, et al. (2019) Clinical \ndiagnosis of endometriosis: a call to action. 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Clin Obstet Gynecol Reprod Med 5: 1-7.","source_license":"CC0","license_restricted":false}