Endometriosis-associated pain is a complex condition that is traditionally difficult to treat, as the mechanisms of initiation and persistence seem to be, well in all fairness, all over the place. Dysmenorrhea, cyclical pain related to organ function, and persistent pelvic pain are all common symptoms of the condition. In words you may be more familiar with - severe cramps, painful bladder, painful urination or bowel movements and painful sex.
This pain often does not correlate with the extent of disease, some women can have little pain in severe cases, others agonizing pain and have the initial stages of endometriosis.
The various components of endometriosis-associated pain, such as peripheral sensitization, central sensitization, and cross sensitization, all of which are triggered by different factors. Peripheral sensitization is caused by inflammation or tissue damage, while central sensitization is caused by changes in the central nervous system. Cross sensitization occurs when pain is transferred from one area of the body to another.
All of these systems are activated by endometriosis via various pathways. These factors make the sensation of Endometriosis-associated Pain multi-faceted and further complicated by the complexity of endometriotic lesion development and the diversity of lesion placements.
However, factors that should always be highlighted include the alteration of pelvic nerve fibers, inflammation, secreted factors, and anything that drives neuronal growth. Additionally, how these painful stimuli are relayed.
If one highlights these important factors you naturally flow into the next concepts.
The peritoneal and visceral tissues are highly innervated with sensory, sympathetic, myelinated, and unmyelinated nerve fibers, presynaptic vesicles, and neuropeptides that can all sense pain, pressure, touch, friction, cutting, and temperature. In addition, here, there is a high presence of cytokines, angiogenic factors, and nerve growth factors that, when in presence of endometriotic lesions, can and does trigger inflammation and pain.
While it has been previously thought that the shedding of endometriotic lesions is cyclical and related to changes in the eutopic endometrium, recent research suggests that this may not always be the case. It is essential to recognize the heterogeneity of endometriotic lesions to better comprehend the complexity of Endometriosis-associated pain and its treatment. (This is why a multi-faceted approach to combating the condition is a must.)
The nerve endings in the peritoneal fluid can detect painful stimuli. Endometriosis lesions are a source of inflammation, cytokines, angiogenic factors, and nerve growth factors. The inflammatory components found in the peritoneal fluid and the lesions have been studied to assess if they can spark nociceptive pathways.
These components include interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), regulated upon activation, normal T cell expressed and secreted chemokine ligand 5 (CCL5) and tumor necrosis factor alpha (TNF-α), and chemokines including monocyte chemotactic protein 1 [chemokine ligand 2 (CCL2)]. These components have been found to be increased in the peritoneal fluid of endometriosis patients.
In the traditionally sense, it is also known that, like the endometrial tissue, most endometriosis lesions have cyclic bleeding in response to the shifts in estrogen and progesterone during the menstrual cycle. This generally does cause inflammation and pain, however, in cases of endometriosis the overall peripheral pain sensitization is augmented.
The result is generally associated with changes in the peripheral nervous system, including altered nerve density at lesion sites, changes in the peritoneal fluid, perineural invasion, and alterations in the sympathetic nervous system.
Significant nerve fiber density increases in endometriotic lesions compared to normal tissue have been demonstrated, and increased density of calcitonin gene-related peptide positive nerve fibers in lesions is associated with pain severity. Neurotrophins and other growth factors are increased in the peritoneal fluid of women with endometriosis. This increases perineural invasion which is associated with higher pain scores, dysmenorrhea, dyspareunia, persistent pelvic pain, sciatica and unilateral leg pain.
Central sensitization is also an issue when addressing endometriosis referred pain. Central sensitization refers to increased excitability of nociceptive neurons in the dorsal horn of the spinal cord in response to noxious stimuli, tissue injury or nerve damage, leading to decreased pain threshold, increased pain response and central facilitation.
Women with endometriosis demonstrate hyperalgesia, that is an increased sensitivity to feeling pain and an extreme response to pain, when compared to healthy pain-free controls.
Functional MRI has demonstrated increased resting-state connectivity between pain processing regions in women with Endometriosis-associated pain compared to those who have to healthy controls. Women with dysmenorrhea also have increased activation of pain processing regions and reduced levels of cortisol.
The hypothalamic-pituitary-adrenal (HPA) axis may be affected due to the presence of central sensitization. Those with ongoing pain show changes in the HPA axis, which has an effect on their reaction to pain. Research has shown that women with endometriosis have lower levels of cortisol than those without pain. The HPA axis is typically activated by stress in the short-term, but chronic exposure can lead to a decrease in its response.
This has been hypothesized to cause maladaptation of converging pain pathways, contributing to increased pain severity. In addition to its own mechanisms, endometriosis-associated pain can be complicated by a number of comorbid pain conditions, such as bladder pain syndrome, irritable bowel syndrome, abdomino-pelvic myalgia, and vulvodynia. These conditions can further contribute to the already complex pain mechanisms of endometriosis-associated pain.
The complexities of endometriosis-associated pain and the mechanisms responsible for its onset and maintenance make it a difficult condition to treat. This article explains the basic methodology and mechanisms of Endometriosis-associated pain and points out key concepts that need to be targeted. It is evident that peripheral sensitization, central sensitization, and cross-sensitization are therapeutic objectives to consider. It is important for clinicians to consider the biological, psychological, and social aspects of Endometriosis-associated pain in individual cases, and to detect the presence of other comorbid pelvic pain syndromes.
1. Rowlands IJ, Abbott JA, Montgomery GW, Hockey R, Rogers P, Mishra GD. Prevalence and incidence of endometriosis in Australian women: a data linkage cohort study. BJOG. (2021) 128:657–65. doi: 10.1111/1471-0528.16447
2. Clement PB. The pathology of endometriosis: a survey of the many faces of a common disease emphasizing diagnostic pitfalls and unusual and newly appreciated aspects. Adv Anat Pathol. (2007) 14:241–60. doi: 10.1097/PAP.0b013e3180ca7d7b
3. Koninckx PR, Ussia A, Adamyan L, Wattiez A, Gomel V, Martin DC. Pathogenesis of endometriosis: the genetic/epigenetic theory. Fertil Steril. (2019) 111:327–40. doi: 10.1016/j.fertnstert.2018.10.013
4. Sourial S, Tempest N, Hapangama DK. Theories on the pathogenesis of endometriosis. Int J Reprod Med. (2014) 2014:179515. doi: 10.1155/2014/179515
5. Kennedy S, Mardon H, Barlow D. Familial endometriosis. J Assist Reprod Genet. (1995) 12:32–4. doi: 10.1007/BF02214126
6. Isidor B, Latypova X, Ploteau S. Familial deep endometriosis: a rare monogenic disease? Eur J Obstet Gynecol Reprod Biol. (2018) 221:190–3. doi: 10.1016/j.ejogrb.2017.11.025
7. Rahmioglu N, Nyholt DR, Morris AP, Missmer SA, Montgomery GW, Zondervan KT. Genetic variants underlying risk of endometriosis: insights from meta-analysis of eight genome-wide association and replication datasets. Hum Reprod Update. (2014) 20:702–16. doi: 10.1093/humupd/dmu015
8. Fung JN, Rogers PAW, Montgomery GW. Identifying the biological basis of GWAS hits for endometriosis. Biol Reprod. (2015) 92:87. doi: 10.1095/biolreprod.114.126458
9. Pitot MA, Bookwalter CA, Dudiak KM. Müllerian duct anomalies coincident with endometriosis: a review. Abdominal Radiol. (2020) 45:1723–40. doi: 10.1007/s00261-020-02465-y
10. Sampson JA. Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol. (1927) 14:422–69.
11. Missmer SA, Hankinson SE, Spiegelman D, Barbieri RL, Malspeis S, Willett WC, et al. Reproductive history and endometriosis among premenopausal women. Obstet Gynecol. (2004) 104:965–74. doi: 10.1097/01.AOG.0000142714.54857.f8
12. Sampson JA. The development of the implantation theory for the origin of peritoneal endometriosis. Am J Obstet Gynecol. (1940) 40:549–57.
13. Schrodt GR, Alcorn MO, Ibanez J. Endometriosis of the male urinary system: a case report. J Urol. (1980) 124:722–3. doi: 10.1016/S0022-5347(17)55627-X
14. Pinkert TC, Catlow CE, Straus R. Endometriosis of the urinary bladder in a man with prostatic carcinoma. Cancer. (1979) 43:1562–7. doi: 10.1002/1097-0142(197904)43:4<1562::AID-CNCR2820430451>3.0.CO;2-W
15. Sharma N, Todhe P, Ochieng P, Ramakrishna S. Refractory thoracic endometriosis. BMJ Case Rep. (2020) 13:e235965. doi: 10.1136/bcr-2020-235965
16. Maniglio P, Ricciardi E, Meli F, Vitale SG, Noventa M, Vitagliano A, et al. Catamenial pneumothorax caused by thoracic endometriosis. Radiol Case Rep. (2018) 13:81–5. doi: 10.1016/j.radcr.2017.09.003
17. Sasson IE, Taylor HS. Stem cells and the pathogenesis of endometriosis. Ann N Y Acad Sci. (2008) 1127:106–15. doi: 10.1196/annals.1434.014
18. Taylor HS, Kotlyar AM, Flores VA. Endometriosis is a chronic systemic disease: clinical challenges and novel innovations. Lancet. (2021) 397:839–52. doi: 10.1016/S0140-6736(21)00389-5
19. Braun DP, Muriana A, Gebel H, Rotman C, Rana N, Dmowski WP. Monocyte-mediated enhancement of endometrial cell proliferation in women with endometriosis. Fertil Steril. (1994) 61:78–84. doi: 10.1016/S0015-0282(16)56456-5
20. Patel BG, Rudnicki M, Yu J, Shu Y, Taylor RN. Progesterone resistance in endometriosis: origins, consequences and interventions. Acta Obstet Gynecol Scand. (2017) 96:623–32. doi: 10.1111/aogs.13156
21. Carneiro MM, Filogônio IDDS, Costa LMP, De Ávila I, Ferreira MC. Accuracy of clinical signs and symptoms in the diagnosis of endometriosis. J Endometr. (2010) 2:63–70. doi: 10.1177/228402651000200203
22. Guerriero S, Saba L, Pascual MA, Ajossa S, Rodriguez I, Mais V, et al. Transvaginal ultrasound vs magnetic resonance imaging for diagnosing deep infiltrating endometriosis: systematic review and meta-analysis. Ultrasound Obstetr Gynecol. (2018) 51:586–95. doi: 10.1002/uog.18961
23. Chowdary P, Stone K, Ma T, Readman E, McIlwaine K, Druitt M, et al. Multicentre retrospective study to assess diagnostic accuracy of ultrasound for superficial endometriosis—Are we any closer? Aust N Zeal J Obstetr Gynaecol. (2019) 59:279–84. doi: 10.1111/ajo.12911
24. Nnoaham KE, Hummelshoj L, Kennedy SH, Jenkinson C, Zondervan KT. Developing symptom-based predictive models of endometriosis as a clinical screening tool: results from a multicenter study. Fertil Steril. (2012) 98:692–701.e5. doi: 10.1016/j.fertnstert.2012.04.022
25. Vercellini P, Fedele L, Aimi G, Pietropaolo G, Consonni D, Crosignani PG. Association between endometriosis stage, lesion type, patient characteristics and severity of pelvic pain symptoms: a multivariate analysis of over 1000 patients. Hum Reprod. (2007) 22:266–71. doi: 10.1093/humrep/del339
26. Howard FM. Laparoscopic evaluation and treatment of women with chronic pelvic pain. Am Assoc Gynecol Laparosc. (1994) 1:325–31.
27. Matorras R, Rodríguez F, Pijoan JI, Etxanojauregui A, Neyro JL, Elorriaga MA, et al. Women who are not exposed to spermatozoa and infertile women have similar rates of stage I endometriosis. Fertil Steril. (2001) 76:923–8. doi: 10.1016/S0015-0282(01)02833-3
28. Sutton CJG, Ewen SP, Whitelaw N, Haines P. Prospective, randomized, double-blind, controlled trial of laser laparoscopy in the treatment of pelvic pain associated with minimal, mild, and moderate endometriosis. Fertil Steril. (1994) 62:696–700. doi: 10.1016/S0015-0282(16)56990-8
29. Abbott J, Hawe J, Hunter D, Holmes M, Finn P, Garry R. Laparoscopic excision of endometriosis: a randomized, placebo-controlled trial. Fertil Steril. (2004) 82:878–84. doi: 10.1016/j.fertnstert.2004.03.046
30. Dunselman GA, Vermeulen N, Becker C, Calhaz-Jorge C, D'Hooghe T, De Bie B, et al. ESHRE guideline: management of women with endometriosis. Hum Reprod. (2014) 29:400–12. doi: 10.1093/humrep/det457
31. National Institute for Health and Care Excellence. Endometriosis: diagnosis and management, NICE guideline [NG73]. London, UK: National Institute for Health and Care Excellence (2017). Available online at: https://www.nice.org.uk/guidance/ng73/resources/endometriosis-diagnosis-and-management-pdf-1837632548293.
32. Royal Australian and New Zealand College of Obstetricians and Gynaecologists. Australian Clinical Practice Guideline for the Diagnosis and Management of Endometriosis Melbourne, Australia. (2021). Available online at: https://ranzcog.edu.au/RANZCOG_SITE/media/RANZCOG-MEDIA/Women%27s%20Health/Statement%20and%20guidelines/Clinical%20-%20Gynaecology/Endometriosis-clinical-practice-guideline.pdf?ext=.pdf (accessed August 14, 2021).
33. Bellelis P, Dias JA Jr, Podgaec S, Gonzales M, Baracat EC, Abrão MS. Epidemiological and clinical aspects of pelvic endometriosis - series of cases. Rev Assoc Med Bras. (2010) 56:467–71. doi: 10.1590/s0104-42302010000400022
34. Lukic A, Di Properzio M, De Carlo S, Nobili F, Schimberni M, Bianchi P, et al. Quality of sex life in endometriosis patients with deep dyspareunia before and after laparoscopic treatment. Arch Gynecol Obstet. (2016) 293:583–90. doi: 10.1007/s00404-015-3832-9
35. Maddern J, Grundy L, Castro J, Brierley SM. Pain in endometriosis. Front Cell Neurosci. (2020) 14:590823. doi: 10.3389/fncel.2020.590823
36. Surrey ES, Soliman AM, Johnson SJ, Davis M, Castelli-Haley J, Snabes MC. Risk of developing comorbidities among women with endometriosis: a retrospective matched cohort study. J Womens Health. (2018) 27:1114–23. doi: 10.1089/jwh.2017.6432
37. International Association for the Study of Pain. IASP Terminology: Pain Terms. Washington, D.C., USA: International Association for the Study of Pain (2021). Available online at: https://www.iasp-pain.org/Education/Content.aspx?ItemNumber=1698 (accessed August 14, 2021).
38. International Association for the Study of Pain. Classification of Chronic Pain. 2nd ed. Washington, DC, USA: IASP (2012). Available online at: iasp-pain.org/PublicationsNews/Content.aspx?ItemNumber=1673&nav ItemNumber=677 (accessed August 14, 2021).
39. Allaire C, Aksoy T, Bedaiwy M, Britnell S, Noga HL, Yager H, et al. An interdisciplinary approach to endometriosis-associated persistent pelvic pain. J Endometr Pelvic Pain Disord. (2017) 9:77–86. doi: 10.5301/jeppd.5000284
40. Grundström H, Gerdle B, Alehagen S, Berterö C, Arendt-Nielsen L, Kjølhede P. Reduced pain thresholds and signs of sensitization in women with persistent pelvic pain and suspected endometriosis. Acta Obstet Gynecol Scand. (2019) 98:327–36. doi: 10.1111/aogs.13508
41. Mooney SS, Grover SR. The persistent pelvic pain study: Factors that influence outcomes in women referred to a public hospital with chronic pelvic pain – A study protocol. Aust N Zeal J Obstetr Gynaecol. (2021) 61:E6–11. doi: 10.1111/ajo.13289
42. World Health Organisation. International Classification of Diseases 11th Revision. Geneva: World Health Organisation (2019). Available online at: https://icd.who.int/en (accessed August 14, 2021).
43. Engeler D, Baranowski AP, Berghmans B, Borovicka J, Cottrell A, Dinis-Oliveira P, et al. EAU Guidelines on Chronic Pelvic Pain: European Association of Urology. (2021). Available online at: https://uroweb.org/guideline/chronic-pelvic-pain/ (accessed August 14, 2021).
44. Coxon L, Horne AW, Vincent K. Pathophysiology of endometriosis-associated pain: a review of pelvic and central nervous system mechanisms. Best Pract Res Clin Obstetr Gynaecol. (2018) 51:53–67. doi: 10.1016/j.bpobgyn.2018.01.014
45. Latthe P, Mignini L, Gray R, Hills R, Khan K. Factors predisposing women to chronic pelvic pain: systematic review. BMJ. (2006) 332:749–55. doi: 10.1136/bmj.38748.697465.55
46. Berkley KJ, Rapkin AJ, Papka RE. The pains of endometriosis. Science. (2005) 308:1587–9. doi: 10.1126/science.1111445
47. Stratton P, Berkley KJ. Chronic pelvic pain and endometriosis: translational evidence of the relationship and implications. Hum Reprod Update. (2011) 17:327–46. doi: 10.1093/humupd/dmq050
48. Arnold J, Barcena de Arellano ML, Rüster C, Vercellino GF, Chiantera V, Schneider A, et al. Imbalance between sympathetic and sensory innervation in peritoneal endometriosis. Brain Behav Immun. (2012) 26:132–41. doi: 10.1016/j.bbi.2011.08.004
49. Arnold J, Vercellino GF, Chiantera V, Schneider A, Mechsner S, Barcena De Arellano ML. Neuroimmunomodulatory alterations in non-lesional peritoneum close to peritoneal endometriosis. Neuroimmunomodulation. (2012) 20:9–18. doi: 10.1159/000342163
50. Sulaiman H, Gabella G, Davis C, Mutsaers SE, Boulos P, Laurent GJ, et al. Presence and distribution of sensory nerve fibers in human peritoneal adhesions. Ann Surg. (2001) 234:256–61. doi: 10.1097/00000658-200108000-00016
51. Struller F, Weinreich FJ, Horvath P, Kokkalis MK, Beckert S, Königsrainer A, et al. Peritoneal innervation: embryology and functional anatomy. Pleura Peritoneum. (2017) 2:153–61. doi: 10.1515/pp-2017-0024
52. Tanaka K, Kuwahara-Otani S, Maeda S, Minato Y, Yagi H. Possible role of the myelinated neural network in the parietal peritoneum in rats as a mechanoreceptor. Anatomical Rec. (2017) 300:1662–9. doi: 10.1002/ar.23613
53. Oosterlynck DJ, Meuleman C, Waer M, Koninckx PR. Transforming growth factor-β activity is increased in peritoneal fluid from women with endometriosis. Obstet Gynecol. (1994) 83:287–92.
54. Bersinger NA, von Roten S, Wunder DM, Raio L, Dreher E, Mueller MD. PAPP-A and osteoprotegerin, together with interleukin-8 and RANTES, are elevated in the peritoneal fluid of women with endometriosis. Am J Obstet Gynecol. (2006) 195:103–8. doi: 10.1016/j.ajog.2005.12.010
55. McKinnon B, Bersinger NA, Wotzkow C, Mueller MD. Endometriosis-associated nerve fibers, peritoneal fluid cytokine concentrations, and pain in endometriotic lesions from different locations. Fertil Steril. (2012) 97:373–80. doi: 10.1016/j.fertnstert.2011.11.011
56. Mori H, Sawairi M, Nakagawa M, Itoh N, Wada K, Tamaya T. Peritoneal fluid lnterleukin-1β and tumor necrosis factor in patients with benign gynecologic disease. Am J Reprod Immunol. (1991) 26:62–7. doi: 10.1111/j.1600-0897.1991.tb00972.x
57. Khorram O, Taylor RN, Ryan IP, Schall TJ, Landers DV. Peritoneal fluid concentrations of the cytokine RANTES correlate with the severity of endometriosis. Am J Obstet Gynecol. (1993) 169:1545–9. doi: 10.1016/0002-9378(93)90433-J
58. Arici A, Tazuke SI, Oral E, Olive DL, Attar E. Monocyte chemotactic protein-1 concentration in peritoneal fluid of women with endometriosis and its modulation of expression in mesothelial cells. Fertil Steril. (1997) 67:1065–72. doi: 10.1016/S0015-0282(97)81440-9
59. Morotti M, Vincent K, Becker CM. Mechanisms of pain in endometriosis. Eur J Obstetr Gynecol Reprod Biol. (2017) 209:8–13. doi: 10.1016/j.ejogrb.2016.07.497
60. Patel BG, Lenk EE, Lebovic DI, Shu Y, Yu J, Taylor RN. Pathogenesis of endometriosis: interaction between endocrine and inflammatory pathways. Best Pract Res Clin Obstetr Gynaecol. (2018) 50:50–60. doi: 10.1016/j.bpobgyn.2018.01.006
61. Zheng P, Zhang W, Leng J, Lang J. Research on central sensitization of endometriosis-associated pain: a systematic review of the literature. J Pain Res. (2019) 12:1447–56. doi: 10.2147/JPR.S197667
62. Burney RO, Lathi RB. Menstrual bleeding from an endometriotic lesion. Fertil Steril. (2009) 91:1926–7. doi: 10.1016/j.fertnstert.2008.08.125
63. Colgrave EM, Bittinger S, Healey M, Dior UP, Rogers PAW, Keast JR, et al. Superficial peritoneal endometriotic lesions are histologically diverse and rarely demonstrate menstrual cycle synchronicity with matched eutopic endometrium. Hum Reprod. (2020) 35:2701–14. doi: 10.1093/humrep/deaa249
64. Kamergorodsky G, Ribeiro PAA, Galvão MAL, Abrão MS, Donadio N, de Barros Moreira Lemos NL, et al. Histologic classification of specimens from women affected by superficial endometriosis, deeply infiltrating endometriosis, and ovarian endometriomas. Fertil Steril. (2009) 92:2074–7. doi: 10.1016/j.fertnstert.2009.05.086
65. Tokushige N, Markham R, Russell P, Fraser IS. High density of small nerve fibres in the functional layer of the endometrium in women with endometriosis. Hum Reprod. (2006) 21:782–7. doi: 10.1093/humrep/dei368
66. Tokushige N, Russell P, Black K, Barrera H, Dubinovsky S, Markham R, et al. Nerve fibers in ovarian endometriomas. Fertil Steril. (2010) 94:1944–7. doi: 10.1016/j.fertnstert.2009.12.074
67. Anaf V, El Nakadi I, De Moor V, Chapron C, Pistofidis G, Noel JC. Increased nerve density in deep infiltrating endometriotic nodules. Gynecol Obstet Invest. (2011) 71:112–7. doi: 10.1159/000320750
68. Yan D, Liu X, Guo SW. Neuropeptides substance p and calcitonin gene related peptide accelerate the development and fibrogenesis of endometriosis. Sci Rep. (2019) 9:2698. doi: 10.1038/s41598-019-39170-w
69. Liu J, Liu X, Duan K, Zhang Y, Guo SW. The expression and functionality of transient receptor potential vanilloid 1 in ovarian endometriomas. Reprod Sci. (2012) 19:1110–24. doi: 10.1177/1933719112443876
70. Anaf V, Simon P, El Nakadi I, Fayt I, Simonart T, Buxant F, et al. Hyperalgesia, nerve infiltration and nerve growth factor expression in deep adenomyotic nodules, peritoneal and ovarian endometriosis. Hum Reprod. (2002) 17:1895–900. doi: 10.1093/humrep/17.7.1895
71. Siquara De Sousa AC, Capek S, Amrami KK, Spinner RJ. Neural involvement in endometriosis: review of anatomic distribution and mechanisms. Clin Anat. (2015) 28:1029–38. doi: 10.1002/ca.22617
72. Langebrekke A, Qvigstad E. Endometriosis entrapment of the obturator nerve after previous cervical cancer surgery. Fertil Steril. (2009) 91:622–3. doi: 10.1016/j.fertnstert.2008.03.024
73. Liang Y, Liu D, Yang F, Pan W, Zeng F, Wu J, et al. Perineural invasion in endometriotic lesions contributes to endometriosis-associated pain. J Pain Res. (2018) 11:1999–2009. doi: 10.2147/JPR.S168715
74. Pacchiarotti A, Milazzo GN, Biasiotta A, Truini A, Antonini G, Frati P, et al. Pain in the upper anterior-lateral part of the thigh in women affected by endometriosis: study of sensitive neuropathy. Fertil Steril. (2013) 100:122–6. doi: 10.1016/j.fertnstert.2013.02.045
75. Asante A, Taylor RN. Endometriosis: the role of neuroangiogenesis. Annu Rev Physiol. (2011) 73:163–82. doi: 10.1146/annurev-physiol-012110-142158
76. Kajitani T, Maruyama T, Asada H, Uchida H, Oda H, Uchida S, et al. Possible involvement of nerve growth factor in dysmenorrhea and dyspareunia associated with endometriosis. Endocr J. (2013) 60:1155–64. doi: 10.1507/endocrj.EJ13-0027
77. Tamburro S, Canis M, Albuisson E, Dechelotte P, Darcha C, Mage G. Expression of transforming growth factor β1 in nerve fibers is related to dysmenorrhea and laparoscopic appearance of endometriotic implants. Fertil Steril. (2003) 80:1131–6. doi: 10.1016/S0015-0282(03)01182-8
78. Ferrero S, Haas S, Remorgida V, Camerini G, Fulcheri E, Ragni N, et al. Loss of sympathetic nerve fibers in intestinal endometriosis. Fertil Steril. (2010) 94:2817–9. doi: 10.1016/j.fertnstert.2010.06.069
79. Wei Y, Liang Y, Lin H, Dai Y, Yao S. Autonomic nervous system and inflammation interaction in endometriosis-associated pain. J Neuroinflammation. (2020) 17:80. doi: 10.1186/s12974-020-01752-1
80. Ji RR, Kohno T, Moore KA, Woolf CJ. Central sensitization and LTP: do pain and memory share similar mechanisms? Trends Neurosci. (2003) 26:696–705. doi: 10.1016/j.tins.2003.09.017
81. Arendt-Nielsen L, Morlion B, Perrot S, Dahan A, Dickenson A, Kress HG, et al. Assessment and manifestation of central sensitisation across different chronic pain conditions. Eur J Pain. (2018) 22:216–41. doi: 10.1002/ejp.1140
82. Stratton P, Khachikyan I, Sinaii N, Ortiz R, Shah J. Association of chronic pelvic pain and endometriosis with signs of sensitization and myofascial pain. Obstet Gynecol. (2015) 125:719–28. doi: 10.1097/AOG.0000000000000663
83. May A. Structural brain imaging: a window into chronic pain. Neuroscientist. (2011) 17:209–20. doi: 10.1177/1073858410396220
84. As-Sanie S, Harris RE, Napadow V, Kim J, Neshewat G, Kairys A, et al. Changes in regional gray matter volume in women with chronic pelvic pain: a voxel-based morphometry study. Pain. (2012) 153:1006–14. doi: 10.1016/j.pain.2012.01.032
85. As-Sanie S, Kim J, Schmidt-Wilcke T. Functional connectivity is associated with altered brain chemistry in women with endometriosis-associated chronic pelvic pain. J Pain. 2015:S1526–5900. doi: 10.1016/j.jpain.2015.09.008
86. Vincent K, Warnaby C, Stagg CJ, Moore J, Kennedy S, Tracey I. Dysmenorrhoea is associated with central changes in otherwise healthy women. Pain. (2011) 152:1966–75. doi: 10.1016/j.pain.2011.03.029
87. Malykhina AP. Neural mechanisms of pelvic organ cross-sensitization. Neuroscience. (2007) 149:660–72. doi: 10.1016/j.neuroscience.2007.07.053
88. Hoffman D. Understanding multisymptom presentations in chronic pelvic pain: the inter-relationships between the viscera and myofascial pelvic floor dysfunction. Curr Pain Headache Rep. (2011) 15:343–6. doi: 10.1007/s11916-011-0215-1
89. Affaitati G, Costantini R, Tana C, Cipollone F, Giamberardino MA. Co-occurrence of pain syndromes. J Neural Transm. (2020) 127:625–46. doi: 10.1007/s00702-019-02107-8
90. Gao M, Koupil I, Sjöqvist H, Karlsson H, Lalitkumar S, Dalman C, et al. Psychiatric comorbidity among women with endometriosis: nationwide cohort study in Sweden. Obstetr Gynecol Survey. (2020) 75:744–5. doi: 10.1097/01.ogx.0000723716.77258.ae
91. Galambos A, Szabó E, Nagy Z, Édes AE, Kocsel N, Juhász G, et al. A systematic review of structural and functional MRI studies on pain catastrophizing. J Pain Res. (2019) 12:1155–78. doi: 10.2147/JPR.S192246
92. Surrey ES, Soliman AM, Yang H, Du EX, Su B. Treatment patterns, complications, and health care utilization among endometriosis patients undergoing a laparoscopy or a hysterectomy: a retrospective claims analysis. Adv Ther. (2017) 34:2436–51. doi: 10.1007/s12325-017-0619-3
93. Bryant C, Cockburn R, Plante AF, Chia A. The psychological profile of women presenting to a multidisciplinary clinic for chronic pelvic pain: high levels of psychological dysfunction and implications for practice. J Pain Res. (2016) 9:1049–56. doi: 10.2147/JPR.S115065
94. Sewell M, Churilov L, Mooney S, Ma T, Maher P, Grover SR. Chronic pelvic pain-pain catastrophizing, pelvic pain and quality of life. Scand J Pain. (2018) 18:441–8. doi: 10.1515/sjpain-2017-0181
95. McPeak AE, Allaire C, Williams C, Albert A, Lisonkova S, Yong PJ. Pain catastrophizing and pain health-related quality-of-life in endometriosis. Clin J Pain. (2018) 34:349–56. doi: 10.1097/AJP.0000000000000539
96. Chronic Pain Research Alliance. Impact of Chronic Overlapping Pain Conditions on Public Health and the Urgent Need for Safe and Effective treatment. Milwaukee, WI, USA: Chronic Pain Research Alliance (2015). Available online at: http://www.chronicpainresearch.org/public/CPRA_WhitePaper_2015-FINAL-Digital.pdf (accessed August 14, 2021).
97. van de Merwe JP, Nordling J, Bouchelouche P, Bouchelouche K, Cervigni M, Daha LK, et al. Diagnostic criteria, classification, and nomenclature for painful bladder syndrome/interstitial cystitis: an ESSIC proposal. Eur Urol. (2008) 53:60–7. doi: 10.1016/j.eururo.2007.09.019
98. Tirlapur SA, Kuhrt K, Chaliha C, Ball E, Meads C, Khan KS. The 'evil twin syndrome' in chronic pelvic pain: a systematic review of prevalence studies of bladder pain syndrome and endometriosis. Int J Surg. (2013) 11:233–7. doi: 10.1016/j.ijsu.2013.02.003
99. Cheng C, Rosamilia A, Healey M. Diagnosis of interstitial cystitis/bladder pain syndrome in women with chronic pelvic pain: a prospective observational study. Int Urogynecol J. (2012) 23:1361–6. doi: 10.1007/s00192-012-1711-5
100. Collings R, Healey M, Dior U, Erwin R, Rosamilia A, Cheng C. Effect of investigative laparoscopy on bladder pain syndrome: a prospective cohort trial. Int Urogynecol J. (2020) 31:1583–91. doi: 10.1007/s00192-019-04023-7
101. Wu CC, Chung SD, Lin HC. Endometriosis increased the risk of bladder pain syndrome/interstitial cystitis: a population-based study. Neurourol Urodyn. (2018) 37:1413–8. doi: 10.1002/nau.23462
102. Lotz M, Villiger P, Hugli T, Koziol J, Zuraw BL. Interleukin-6 and interstitial cystitis. J Urol. (1994) 152:869–73. doi: 10.1016/S0022-5347(17)32594-6
103. Birder LA. Pathophysiology of interstitial cystitis. Int J Urol. (2019) 26:12–5. doi: 10.1111/iju.13985
104. Rome Foundation. Rome IV Criteria Raleigh. North Carolina, USA: Rome Foundation (2016). Available online at: https://theromefoundation.org/rome-iv/rome-iv-criteria/ (accessed August 14, 2021).
105. Schomacker ML, Hansen KE, Ramlau-Hansen CH, Forman A. Is endometriosis associated with irritable bowel syndrome? A cross-sectional study. Eur J Obstetr Gynecol Reprod Biol. (2018) 231:65–9. doi: 10.1016/j.ejogrb.2018.10.023
106. DiVasta AD, Zimmerman LA, Vitonis AF, Fadayomi AB, Missmer SA. Overlap between irritable bowel syndrome diagnosis and endometriosis in adolescents. Clin Gastroenterol Hepatol. (2021) 19:528–37.e1. doi: 10.1016/j.cgh.2020.03.014
107. Wouters MM, Balemans D, Van Wanrooy S, Dooley J, Cibert-Goton V, Alpizar YA, et al. Histamine receptor H1-mediated sensitization of TRPV1 mediates visceral hypersensitivity and symptoms in patients with irritable bowel syndrome. Gastroenterology. (2016) 150:875–87.e9. doi: 10.1053/j.gastro.2015.12.034
108. Tillisch K, Mayer EA, Labus JS. Quantitative meta-analysis identifies brain regions activated during rectal distension in irritable bowel syndrome. Gastroenterology. (2011) 140:91–100. doi: 10.1053/j.gastro.2010.07.053
109. Frawley H, Shelly B, Morin M, Bernard S, Bø K, Digesu GA, et al. An International Continence Society (ICS) report on the terminology for pelvic floor muscle assessment. Neurourol Urodyn. (2021) 40:1217–60. doi: 10.1002/nau.24658
110. Phan VT, Stratton P, Tandon HK, Sinaii N, Aredo JV, Karp BI, et al. Widespread myofascial dysfunction and sensitisation in women with endometriosis-associated chronic pelvic pain: a cross-sectional study. Eur J Pain. (2021) 25:831–40. doi: 10.1002/ejp.1713
111. Fraga MV, Oliveira Brito LG, Yela DA, de Mira TA, Benetti-Pinto CL. Pelvic floor muscle dysfunctions in women with deep infiltrative endometriosis: an underestimated association. Int J Clin Pract. (2021) 75:e14350. doi: 10.1111/ijcp.14350
112. Meister MR, Shivakumar N, Sutcliffe S, Spitznagle T, Lowder JL. Physical examination techniques for the assessment of pelvic floor myofascial pain: a systematic review. Am J Obstet Gynecol. (2018) 219:497.e1-e13. doi: 10.1016/j.ajog.2018.06.014
113. Denneny D, Frawley HC, Petersen K, McLoughlin R, Brook S, Hassan S, et al. Trigger point manual therapy for the treatment of chronic noncancer pain in adults: a systematic review and meta-analysis. Arch Phys Med Rehabil. (2019) 100:562–77. doi: 10.1016/j.apmr.2018.06.019
114. Bornstein J, Goldstein AT, Stockdale CK, Bergeron S, Pukall C, Zolnoun D, et al. 2015 ISSVD, ISSWSH, and IPPS consensus terminology and classification of persistent vulvar pain and vulvodynia. J Sex Med. (2016) 13:607–12. doi: 10.1016/j.jsxm.2016.02.167
115. Smorgick N, Marsh CA, As-Sanie S, Smith YR, Quint EH. Prevalence of pain syndromes, mood conditions, and asthma in adolescents and young women with endometriosis. J Pediatr Adolesc Gynecol. (2013) 26:171–5. doi: 10.1016/j.jpag.2012.12.006
116. Graziottin A, Murina F, Gambini D, Taraborrelli S, Gardella B, Campo M. Vulvar pain: the revealing scenario of leading comorbidities in 1183 cases. Eur J Obstetr Gynecol Reprod Biol. (2020) 252:50–5. doi: 10.1016/j.ejogrb.2020.05.052
117. Bao C, Noga H, Allaire C, Williams C, Bedaiwy MA, Sadownik LA, et al. Provoked vestibulodynia in women with pelvic pain. Sex Med. (2019) 7:227–34. doi: 10.1016/j.esxm.2019.03.002
118. Gardella B, Porru D, Nappi RE, Daccò MD, Chiesa A, Spinillo A. Interstitial cystitis is associated with vulvodynia and sexual dysfunction-A case-control study. J Sex Med. (2011) 8:1726–34. doi: 10.1111/j.1743-6109.2011.02251.x