reproductive medicine Review Pathophysiological Basis of Endometriosis-Linked Stress Associated with Pain and Infertility: A Conceptual Review Debabrata Ghosh 1,* , Ludmila Filaretova 2, Juhi Bharti 3, Kallol K. Roy 3, Jai B. Sharma 3 1, and Jayasree Sengupta y 1 Laboratory of Molecular Physiology, Department of Physiology, All India Institute of Medical Sciences, New Delhi 110029, India; [email protected] 2 Laboratory of Experimental Endocrinology, Pavlov Institute of Physiology, Russian Academy of Sciences, St. Petersburg 199034, Russia; fi[email protected] 3 Department of Obstetrics and Gynaecology, All India Institute of Medical Sciences, New Delhi 110029, India; [email protected] (J.B.); [email protected] (K.K.R.); [email protected] (J.B.S.) * Correspondence: [email protected] Presently retired. y Received: 7 May 2020; Accepted: 3 June 2020; Published: 8 June 2020 Abstract: Women with endometriosis are often under stress due to the associated pain, infertility, inflammation-related and other comorbidities including cancer. Additionally, these women are also under stress due to taboos, myths, inter-personal troubles surrounding infertility and pain of the disease as well as due to frequent incidences of missed diagnosis and treatment recurrence. Often these women suffer from frustration and loss of valuable time in the prime phase of life. All these complexities integral to endometriosis posit a hyperstructure of integrative stress physiology with overt differentials in effective allostatic state in women with disease compared with disease-free women. In the present review, we aim to critically examine various aspects of pathophysiological basis of stress surrounding endometriosis with special emphasis on pain and subfertility that are known to affect the overall health and quality of life of women with the disease and promising pathophysiological basis for its effective management. Keywords: allostasis; comorbidity; endometriosis; infertility; inflammation; pain 1. Introduction Endometriosis occurs due to the growth of endometrium-like tissue outside the uterus. As summarized in Figure1, it is a complex disorder that is influenced by genetic, epigenetic and environmental factors [1–5]. Endometrial cells, stem cells and bone marrow cells with genetic and epigenetic defects after implantation and metaplasia within an abnormal environment of the peritoneal cavity progress to form the typical ectopic lesions in ovary, peritoneum and rectovaginal compartments [6,7]. Endometriosis is associated with chronic inflammatory disorder state along with pelvic pain affecting 10–15% women during their reproductive years, as well as with primary infertility in 50% women [8–10]. Reprod. Med. 2020, 1, 32–61; doi:10.3390/reprodmed1010004 www.mdpi.com/journal/reprodmed Reprod. Med. 2020, 1, FOR PEER REVIEW 2 Reprod. Med. 2020, 1 33 Reprod. Med. 2020, 1, FOR PEER REVIEW 2 FigureFigureFigure 1.1. A 1. simplifiedsimplifiedA simplified schema schema of of histogenesis histogenesis of endometriosis endometriosis involving involving several several predisposing, predisposing,predisposing, triggeringtriggeringtriggering andand and progressionprogression progression factors.factors. factors. It ItIt isis notablenotable th thatthatat dysregulated dysregulated allostatic allostatic load load at the at local thethe locallocaland andand systemicsystemicsystemic levels levels plays plays plays critical critical critical role role role in in the the the inducement inducement inducement ofof ectopic ofectopic ectopic lesions lesions lesions of ofendometriosis. endometriosis. of endometriosis. Adapted Adapted from Adapted from fromGhoshGhosh Ghosh et al.et et [11].al. al. [11]. [ 11(A]. )( A (ALaparoscopic) )Laparoscopic Laparoscopic viewview view ofof ofright right ovarianovarian ovarian endometrioma endometrioma endometrioma with with with severe severe adhesion adhesionadhesion obliterating the pouch of Douglas. (B) Low magnification histopathological features of an ovarian obliteratingobliterating thethe pouchpouch ofof Douglas.Douglas. (B)) LowLow magnificationmagnification histopathologicalhistopathological features ofof anan ovarianovarian endometriotic cyst with circumscribed stromal nodule and epithelial lining seen (B). endometrioticendometriotic cystcyst withwith circumscribedcircumscribed stromalstromal nodulenodule andand epithelialepithelial lininglining seenseen (B(B).). Endometriosis impairs the quality of life due to chronic and severe acyclic pelvic pain with EndometriosisEndometriosis impairs the quality of life duedue toto chronicchronic andand severesevere acyclicacyclic pelvicpelvic painpain withwith associated dysmenorrhea, dyspareunia, gastrointestinal problems, fatigue and headaches [12,13]. associatedassociatedBeside dysmenorrhea,pelvicdysmenorrhea, pain, endometriosis dyspareunia, is associated gastrointestinalgastrointe with stinalsubfertility. problems, The fecundity fatigue rate and for headaches a couple with [12,13]. [12 ,13]. BesideBesidethe pelvic woman pain, pain, partner endometriosis endometriosis having endometriosis is is associated associated is withreduced with subfertility. subfertility.to 2–10%, The as The comparedfecundity fecundity to rate 15–20% ratefor a for coupleamong a couple with withthe womanendometriosis-free the woman partner partner having controls having endometriosis [14]. endometriosis This is true is for re is ducedthe reduced Caucasian to to2–10%, 2–10%, population, as as compared compared and more to to so15–20% for Asian amongamong endometriosis-freeendometriosis-freewomen [15,16]. controls [[14].14]. This is true for the CaucasianCaucasian population,population, and more soso forfor AsianAsian womenwomen [[15,16].15Stress,16]. from endometriosis-associated pain and infertility, although well perceived, appears StressenigmaticStress fromfrom due endometriosis-associatedendometriosis-associated to underlying multifactorial painpain comp andandlexities. infertility,infertility, Women althoughalthoughwith endometriosis wellwell perceived,perceived, often suffer appearsappears enigmaticenigmaticfrom several duedue to to inflammation-linked underlying underlying multifactorial multifactorial and other complexities. compcomorbiditieslexities. Women (see Women Figure with with2 endometriosis for details).endometriosis often often suffer suffer from severalfrom several inflammation-linked inflammation-linked and other and comorbiditiesother comorbidities (see Figure (see Figure2 for details). 2 for details). Figure 2. The comorbidities associated with endometriosis. The incidence of developing several comorbidities was significantly higher among women with endometriosis as compared to women without endometriosis. For details, see references [17–21]. FigureFigure 2.2. The comorbiditiescomorbidities associatedassociated withwith endometriosis.endometriosis. The incidence of developingdeveloping severalseveral comorbiditiescomorbidities waswas significantlysignificantly higherhigher amongamong womenwomen withwith endometriosisendometriosis asas comparedcompared toto womenwomen withoutwithout endometriosis.endometriosis. ForFor details,details, seesee referencesreferences [[17–21].17–21]. Reprod. Med. 2020, 1 34 Reprod. Med. 2020, 1, FOR PEER REVIEW 3 AsAs aa result,result, womenwomen withwith endometriosisendometriosis areare oftenoften surroundedsurrounded byby taboos,taboos, myths,myths, scourgescourge ofof subfertility,subfertility, painpain ofof diseasedisease andand missedmissed diagnosisdiagnosis andand treatmenttreatment [[22].22]. DelaysDelays inin thethe diagnosisdiagnosis andand initiationinitiation ofof treatmenttreatment forfor thethe diseasedisease inin factfact occuroccur duedue toto thesethese counterproductivecounterproductive factorsfactors operativeoperative bothboth atat the the individual individual patient patient level level and and at the at medicalthe medical level resultinglevel resulting in frustration in frustration and loss and of valuable loss of timevaluable in the time prime in phasethe prime of life phase of the patientof life of [22 the–25 ].patient While [22–25]. endometriosis While isendometriosis generally considered is generally to be benign,considered the moderateto be benign, probability the moderate that endometriosis probability maythat beendometriosis associated with may incidences be associated of ovarian with andincidences extra-ovarian of ovarian cancers and extra-ovarian adds to the mounting cancers adds stress to on the the mounting women astressffected on by the the women disease affected [6,11]. Aby dramatic the disease image [6,11]. hoisted A dramatic by the World image Endometriosis hoisted by the Research World Endometriosis Foundation attempts Research to encapsulateFoundation theattempts stress ofto endometriosisencapsulate the that stress affects of an endometrio estimated 200sis millionthat affects women an worldwideestimated (see200 Figuremillion3 ).women In the presentworldwide narrative (see Figure review, 3). we In aimthe present to examine narrative various re aspectsview, we of aim stress to physiologyexamine various during aspects endometriosis of stress withphysiology special during emphasis endometriosis on pain and with infertility special that emphas can aisffect on thepain overall and infertility health and that quality can affect of life the of womenoverall health with the and disease. quality At of the life end, of women a brief discussionwith the disease. on the At future the courseend, a brief of targeted discussion