{"paper_id":"c28177a7-eacb-4063-96e2-55698945996b","body_text":"CLINICAL IMPLICA TIONS\nStress, inflammation and endometriosis: are patients stuck\nbetween a rock and a hard place?\nBettina Toth\nPublished online: 20 February 2010\n# Springer-V erlag 2010\nEndometriosis belongs to the most frequent non-malignant\ndiseases in women during childbearing years [ 1]. The\ndisease depends on a complex interaction of immunologic,\ngenetic, hormonal and environmental factors often leading\nto pelvic pain with dysmenorrhoea, dyspareunia and\ndyschezia [2, 3]. In the peritoneal cavity of affected women,\nchemoattraction of macrophages accompanied by immune\ncell infiltration could be detected [ 4]. The symptoms of\nendometriosis are also a product of the local inflammatory\nresponse, e.g. tumour necrosis factor alpha and glycodelin\ncorrelated positively with the level of menstrual pain in the\nperitoneal fluid of affected patients [ 5]. Endometriosis is an\noestrogen-dependent disease and established treatment\nstrategies (temporarily) suppress ovarian oestrogen produc-\ntion with known side effects like perimenopausal symp-\ntoms. A myriad of possible points of application for\nprogestogens have been postulated. Beside reduced serum\noestrogen levels leading to suppressed gonadotropin re-\nlease, progestogens cause decidualization in eutopic and\nectopic endometrium, inhibit angiogenesis by suppressing\nplasminogen activator activity and decrease intraperitoneal\ninflammation [ 6].\nEndometriosis is also determined by neurovegetative\nfactors. Pain is a major cause of physical, psycho-social,\nemotional and professional or work-related impairment\namong women with endometriosis. Recently, several\nstudies indicated specific nerve fibres present in endometri-\notic tissue with existing parallels between density of small\nnerve fibres and pain severity [ 6–8]. In a double-blind\nstudy, Fraser et al. employed diagnostic laparoscopy and\nsubsequent nerve fibre analysis in endometrial biopsies for\ndiagnostic purposes. They were able to show that nerve\nfibre analysis in endometrial biopsies was nearly as reliable\nfor diagnosing endometriosis as laparoscopy performed by\nexperienced gynaecological laparoscopists [ 8]. Fraser et al.\nwere also able to show that combined oral contraceptives\nand progestogens significantly reduced nerve fibre density\nand nerve growth factor and cognate receptors in peritoneal\nendometriotic lesions [ 6].\nGiven the severe clinical symptoms of endometriosis,\nsuch as chronic pain and infertility, it is not surprising that\npatients with endometriosis often report poor quality of life,\nhigh stress perception and depressive symptoms. Also,\npatients suffering from endometriosis-related dyspareunia\nforbear from informing their (sexual) partners implicating a\ntendency towards a withdrawal and possibly leading to\nstigmatization and self-pity, further increasing (emotional)\nstress [ 9]. Siedentopf et al. [ 10] reported a reduced quality\nof life, increased stress perception and depressive symp-\ntoms in patients with endometriosis, associated with a\nperitoneal cytokine profile in favour of inflammation.\nHowever, analyses of the ex vivo samples did not allow\nto confirm a positive correlation between psycho-social and\ninflammatory markers.\nThe wealth of published evidence supporting that (1)\nendometriosis is associated with a poor quality of life and\nB. Toth ( *)\nDepartment of Gynecological Endocrinology and Reproductive\nMedicine, Ruprecht Karl-University Heidelberg,\nV oßstr. 9,\n69115 Heidelberg, Germany\ne-mail: bettina.toth@med.uni-heidelberg.de\nJ Mol Med (2010) 88:223 –225\nDOI 10.1007/s00109-010-0595-4\n\nhigh stress perception; (2) endometriosis is an inflammatory\ndisease, and (3) stress and poor quality of life may cause\ninflammation, strongly suggested that women with endo-\nmetriosis are stuck between a rock and a hard place within\nthe vicious circle of high stress perception, inflammation\nand disease progression. The recent study by Tariverdian,\nSiedentopf, et al. targeted this complex interaction and\nunveiled a neuroendocrine circuitry in endometriosis,\naffecting the equilibrium of the endocrine and immune\nsystem [11]. They were able to demonstrate that changes of\nthe hormonal axis (low progesterone levels) results in\nincreased inflammation (cytokine secretion by peritoneal\ncells). Further, they confirmed that mediators of the stress\nresponse, such as corticotrophin releasing hormone, aggra-\nvated the inflammatory response in peritoneal lymphocytes.\nStrikingly, this stress hormone induced response could be\nabrogated in the presence of a progesterone derivative.\nOne of the pathomechanisms of endometriosis postu-\nlates that retrograde menstruation leads to viable\nendometrial cells in the peritoneal cavity, endometrial-\nperitoneal adhesion and ectopic implantation. An\ninflammatory environment additionally supports the inva-\nsion and maintains endometriosis (Fig. 1). Arck et al.\nhypothesized that the perpetuation of inflammation results\nfrom stress-induced decrease of progesterone opposed by\nhigh levels of stress hormones. Hence, disruption of this\nneuroendocrine circuitry by using progestogens or im-\nproved stress coping may be beneficial for patients with\nendometriosis.\nFuture research in endometriosis should integrate this\n“Brain-body-brain cross talk ” rather than analysing single\npathways. These timely endeavours may help to establish\na “fingerprint ” for endometriosis and implicate new\ntreatment strategies. Further more, stress factors leading\nto physical, psycho-social, professional or work related\nand emotional impairment among women with endome-\ntriosis should attract notice and coping mechanisms\nshould be established.\nRetrograde  \nMenstruation \nViable endometrial cells  \nin peritoneal cavity \nEndometrial-Peritoneal  \nAdhesion \nEctopic Implantation  \nand Invasion \nGrowth and Maintenance \nof Endometriosis \n Increased Number of PF Cells \nDecreased Immune Surveillance \n Defective NK cells \n Secretion of ICAM \n Abnormal apoptosis \n Quality of PF Cells  \n increased number of activated  \n  macrophages \n increased levels of IL-6,  IL-8, TNF \n \n Perpetuation of Inflammation \n up-regulation of MMPs, \n  IL-1, TNF \n suppression of TIMPs \nInitiation of Angiogenesis \n increased angiogenesis \n increased expression of VEGF \n increased DC presentation of \n  autoantigens \n activated T cells \n reduced NK activity \n increased autoantibodies \nFig. 1 Pathomechanism of Endometriosis. Retrograde menstruation\ncould lead to viable endometrial cells in the peritoneal cavity with an\nincreased number of cells in the peritoneal fluid ( PF) and decreased\nimmune surveillance. The quality of PF cells is dominated by\nincreased numbers of activated macrophages and increased levels of\nInterleukin (IL)-6, -8 as well as tumour necrosis factor ( TNF).\nEndometrial cells can adhere to the peritoneum further aggravating\nthe perpetuation of inflammation with an up-regulation of MMPs, IL-\n1 and TNF paralleled by suppression of TIMPs. When ectopic\nimplantation and invasion occurs, angiogenesis is mandatory with\nincreased expression of vascular endothelial growth factor ( VEGF).\nDisease progression with growth and maintenance of endometriosis is\naccompanied by increased dendtritic cell presentation of auto antigens,\nactivated T cells, reduced natural killer ( NK) cell activity and\nincreased autoantibodies. ICAM inter-cellular adhesion molecule,\nMMP matrix metalloprotease, TIMP tissue inhibitor of metallopra-\nteases. Modified after Kyama et al., Reprod Biol Endocrinol, 2003\n[12]\n224 J Mol Med (2010) 88:223 –225\n\nReferences\n1. Toth B, Hornung D, Scholz C, Djalali S, Friese K, Jeschke U\n(2007) Peroxisome proliferator-activated receptors: new players in\nthe field of reproduction. Am J Reprod Immunol 58:289 –310\n2. Halme J, Becker S, Hammond MG, Raj MH, Raj S (1983)\nIncreased activation of pelvic macrophages in infertile women\nwith mild endometriosis. Am J Obstet Gynecol 145:333 –337\n3. Klein NA, Pergola GM, Rao-Tekmal R, Dey TD, Schenken RS\n(1993) Enhanced expression of resident leukocyte interferon gamma\nmRNA in endometriosis. Am J Reprod Immunol 30:74–81\n4. Cirkel U, Ochs H, Mues B, Zwadlo G, Sorg C, Schneider HP\n(1993) Inflammatory reaction in endometriotic tissue: an\nimmunohistochemical study. Eur J Obstet Gynecol Reprod Biol\n48:43–50\n5. Scholl B, Bersinger NA, Kuhn A, Mueller MD (2009)\nCorrelation between symptoms of pain and peritoneal fluid\ninflammatory cytokine concentr ations in endometriosis. Gyne-\ncol Endocrinol 23:1 –6\n6. Tokushige N, Markham R, Russell P , Fraser IS (2009) Effect of\nprogestogens and combined oral contraceptives on nerve fibers in\nperitoneal endometriosis. Fertil Steril 92:1234 –1239\n7. Bokor A, Kyama CM, V ercruysse L, Fassbender A, Gevaert O,\nV odolazkaia A et al (2009) Density of small diameter sensory\nnerve fibres in endometrium: a semi-invasive diagnostic test for\nminimal to mild endometriosis. Hum Reprod 24:3025 –3032\n8. Al-Jefout M, Dezarnaulds G, Cooper M, Tokushige N, Luscombe\nGM, Markham R et al (2009) Diagnosis of endometriosis by\ndetection of nerve fibres in an endometrial biopsy: a double blind\nstudy. Hum Reprod 24:3019 –3024\n9. Oehmke F, Weyand J, Hackethal A, Konrad L, Omwandho C,\nTinneberg HR (2009) Impact of endometriosis on quality of life: a\npilot study. Gynecol Endocrinol 23:1 –4\n10. Siedentopf F, Tariverdian N, Rucke M, Kentenich H, Arck PC\n(2008) Immune status, psychosocial distress and reduced quality\nof life in infertile patients with endometriosis. Am J Reprod\nImmunol 60:449 –461\n11. Tariverdian N, Rucke M, Szekeres-Bartho J, Blois SM, Karpf EF,\nSedlmayr P , et al. (2010) Neuroendocrine circuitry and endome-\ntriosis: progesterone derivative dampens corticotropin-releasing\nhormone-induced inflammation by peritoneal cells in vitro. J Mol\nMed 10.1007/s00109-009-0559-8\n12. Kyama CM, Debrock S, Mwenda JM, D ’Hooghe TM (2003)\nPotential involvement of the immune system in the development\nof endometriosis. Reprod Biol Endocrinol 2(1):123\nJ Mol Med (2010) 88:223 –225 225","source_license":"CC0","license_restricted":false}