Hormones and Inflammation: An Update on Endometriosis

Endometriosis is a complex inflammatory, hormone-dependent disease that affects up to 10% of women in reproductive age, causing pain and infertility. Although the pathogenesis of this disease remains unknown, in the most recent decades, there has been a substantial progress toward unraveling the enigma associated with this disorder. The present chapter focuses on the influence of hormonal, immunological, and inflammatory pathways in the pathogenesis of endometriosis. The disease is characterized by an increased estrogen activity, which stimulates both eutopic and ectopic endometrial tissue proliferation; in addition, an aberrant response to progesterone, named progesterone resistance, has been shown. Stress hormones are involved in endometriosis pathogenesis. In the present chapter, the relevance of several key points in the inflammatory dysregulation contributing to endometriosis onset and progression, and related symptoms, will also be discussed. Immunological factors (cytokines, chemokines, and prostaglandins) as well as cell-mediated mechanisms play a major role in endometriosis-associated pain. Aberrant hormonal and inflammatory pathways contribute also to inflammatory comorbidities and adverse pregnancy outcome. Access this chapter Tax calculation will be finalised at checkout Purchases are for personal use only Similar content being viewed by others

Giudice LC. Endometriosis. N Engl J Med. 2010;362(25):2389–98. De Ziegler D, Borghese B, Chapron C. Endometriosis and infertility: pathophysiology and management. Lancet. 2010;376:730–8. Vercellini P, Viganò P, Somigliana E, Fedele L. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol. 2014;10(5):261–75. Zondervan KT, Becker CM, Koga K, Missmer SA, Taylor RN, Viganò P. Endometriosis. Nat Rev Dis Primers. 2018;4(1):9. Fung JN, Montgomery GW. Genetics of endometriosis: state of the art on genetic risk factors for endometriosis. Best Pract Res Clin Obstet Gynaecol. 2018;50:61–71. Grimstad FW, Decherney A. A review of the epigenetic contributions to endometriosis. Clin Obstet Gynecol. 2017;60:467–76. 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. Han SJ, Jung SY, Wu SP, Hawkins SM, Park MJ, Kyo S, et al. Estrogen receptor β modulates apoptosis complexes and the inflammasome to drive the pathogenesis of endometriosis. Cell. 2015;163(4):960–74. Riccio L d GC, Santulli P, Marcellin L, Abrão MS, Batteux F, Chapron C. Immunology of endometriosis. Best Pract Res Clin Obstet Gynaecol. 2018;50:39–49. 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 Obstet Gynaecol. 2018;50:50–60. Aznaurova Y, Zhumataev M, Roberts T, Aliper A, Zhavoronkov A. Molecular aspects of development and regulation of endometriosis. Reprod Biol Endocrinol. 2014;12(1):50. Kitawaki J, Kado N, Ishihara H, Koshiba H, Kitaoka Y, Honjo H. Endometriosis: the pathophysiology as an estrogen-dependent disease. J Steroid Biochem Mol Biol. 2002;83:149–55. Weiss G, Goldsmith LT, Taylor RN, Bellet D, Taylor HS. Inflammation in reproductive disorders. Reprod Sci. 2009;16:216–29. Reis FM, Petraglia F, Taylor RN. Endometriosis: hormone regulation and clinical consequences of chemotaxis and apoptosis. Hum Reprod Update. 2013;19(4):406–18. Amaral JD, Solá S, Steer CJ, Rodrigues CMP. Role of nuclear steroid receptors in apoptosis. Curr Med Chem. 2009;16(29):3886–902. Luisi S, Galleri L, Marini F, Ambrosini G, Brandi ML, Petraglia F. Estrogen receptor gene polymorphisms are associated with recurrence of endometriosis. Fertil Steril. 2006;85(3):764–6. Ferrero S, Remorgida V, Maganza C, Venturini PL, Salvatore S, Papaleo E, et al. Aromatase and endometriosis: estrogens play a role. Ann N Y Acad Sci. 2014;1317(1):17–23. Bulun SE, Cheng YH, Yin P, Imir G, Utsunomiya H, Attar E, et al. Progesterone resistance in endometriosis: link to failure to metabolize estradiol. Mol Cell Endocrinol. 2006;248:94–103. Bulun SE, Monsavais D, Pavone ME, Dyson M, Xue Q, Attar E, et al. Role of estrogen receptor-β in endometriosis. Semin Reprod Med. 2012;30(1):39–45. Morsch DM, Carneiro MM, Lecke SB, Araújo FC, Camargos AF, Reis FM, et al. C-fos gene and protein expression in pelvic endometriosis: a local marker of estrogen action. J Mol Histol. 2009;40(1):53–8. Cavallini A, Resta L, Caringella AM, Dinaro E, Lippolis C, Loverro G. Involvement of estrogen receptor-related receptors in human ovarian endometriosis. Fertil Steril. 2011;96(1):102–6. Bulun SE, Monsavais D, Pavone ME, Dyson M, Xue Q, Attar E, et al. Role of estrogen receptor-beta in endometriosis. Semin Reprod Med. 2012;30(1):39–45. Georgiou I, Syrrou M, Bouba I, Dalkalitsis N, Paschopoulos M, Navrozoglou I, et al. Association of estrogen receptor gene polymorphisms with endometriosis. Fertil Steril. 1999;72(1):164–6. Lovely LP, Fazleabas AT, Fritz MA, McAdams DG, Lessey BA. Prevention of endometrial apoptosis: Randomized prospective comparison of human chorionic gonadotropin versus progesterone treatment in the luteal phase. J Clin Endocrinol Metab. 2005;90(4):2351–6. Li HY, Chang SP, Yuan CC, Chao HT, Ng HT, Sung YJ. Nitric oxide induces extensive apoptosis in endometrial epithelial cells in the presence of progesterone: involvement of mitogen-activated protein kinase pathways. Mol Hum Reprod. 2001;7(8):755–63. Tang L, Zhang Y, Pan H, Luo Q, Zhu X-M, Dong M-Y, et al. Involvement of cyclin B1 in progesterone-mediated cell growth inhibition, G2/M cell cycle arrest, and apoptosis in human endometrial cell. Reprod Biol Endocrinol. 2009;7:144. Critchley HOD, Tong S, Cameron ST, Drudy TA, Kelly RW, Baird DT. Regulation of bcl-2 gene family members in human endometrium by antiprogestin administration in vivo. J Reprod Fertil. 1999;115:389–95. Hayashi A, Tanabe A, Kawabe S, Hayashi M, Yuguchi H, Yamashita Y, et al. Dienogest increases the progesterone receptor isoform B/A ratio in patients with ovarian endometriosis. J Ovarian Res. 2012;5(1):31. Patel B, Elguero S, Thakore S, Dahoud W, Bedaiwy M, Mesiano S. Role of nuclear progesterone receptor isoforms in uterine pathophysiology. Hum Reprod Update. 2015;21(2):155–73. Attia GR, Zeitoun K, Edwards D, Johns A, Carr BR, Bulun SE. Progesterone receptor isoform A but not B is expressed in endometriosis. J Clin Endocrinol Metab. 2000;85(8):2897–902. Burney RO, Talbi S, Hamilton AE, Kim CV, Nyegaard M, Nezhat CR, et al. Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis. Endocrinology. 2007;148(8):3814–26. Al-Sabbagh M, Lam EWF, Brosens JJ. Mechanisms of endometrial progesterone resistance. Mol Cell Endocrinol. 2012;358:208–15. Pavone ME, Reierstad S, Sun H, Milad M, Bulun SE, Cheng YH. Altered retinoid uptake and action contributes to cell survival in endometriosis. J Clin Endocrinol Metab. 2010;95(11):E300–9. Wieser F, Vigne JL, Ryan I, Hornung D, Djalali S, Taylor RN. Sulindac suppresses nuclear factor-kappaB activation and RANTES gene and protein expression in endometrial stromal cells from women with endometriosis. J Clin Endocrinol Metab. 2005;90(12):6441–7. Horie S, Harada T, Mitsunari M, Taniguchi F, Iwabe T, Terakawa N. Progesterone and progestational compounds attenuate tumor necrosis factor alpha-induced interleukin-8 production via nuclear factor kappa B inactivation in endometriotic stromal cells. Fertil Steril. 2005;83(5):1530–5. D’Amora P, Maciel TT, Tambellini R, Mori MA, Pesquero JB, Sato H, et al. Disrupted cell cycle control in cultured endometrial cells from patients with endometriosis harboring the progesterone receptor polymorphism PROGINS. Am J Pathol. 2009;175(1):215–24. Wieser F, Schneeberger C, Tong D, Tempfer C, Huber JC, Wenzl R. PROGINS receptor gene polymorphism is associated with endometriosis. Fertil Steril. 2002;77(2):309–12. De Carvalho CV, Nogueira-de-Souza NC, Costa AMM, Baracat EC, Girão MJBC, D’amora P, et al. Genetic polymorphisms of cytochrome P450c17α (CYP17) and progesterone receptor genes (PROGINS) in the assessment of endometriosis risk. Gynecol Endocrinol. 2007;23(1):29–33. Tariverdian N, Siedentopf F, Rücke M, Blois SM, Klapp BF, Kentenich H, et al. Intraperitoneal immune cell status in infertile women with and without endometriosis. J Reprod Immunol. 2009;80(1–2):80–90. Tariverdian N, Rücke M, Szekeres-Bartho J, Blois SM, Karpf EF, Sedlmayr P, et al. Neuroendocrine circuitry and endometriosis: progesterone derivative dampens corticotropin-releasing hormone-induced inflammation by peritoneal cells in vitro. J Mol Med. 2010;88(3):267–78. Novembri R, Borges LE, Carrarelli P, Rocha ALL, De Pascalis F, Florio P, et al. Impaired CRH and urocortin expression and function in eutopic endometrium of women with endometriosis. J Clin Endocrinol Metab. 2011;96(4):1145–50. Florio P, Reis F, Torres P, Calonaci F, Toti P, Bocchi C, et al. Plasma urocortin levels in the diagnosis of ovarian endometriosis. Obstet Gynecol. 2007;110(3):594–600. Torricelli M, De Falco G, Florio P, Rossi M, Leucci E, Viganò P, et al. Secretory endometrium highly expresses urocortin messenger RNA and peptide: Possible role in the decidualization process. Hum Reprod. 2007;22(1):92–6. Florio P, Vale W, Petraglia F. Urocortins in human reproduction. Peptides. 2004;25:1751–7. Carrarelli P, Luddi A, Funghi L, Arcuri F, Batteux F, Dela Cruz C, et al. Urocortin and corticotrophin-releasing hormone receptor type 2 mRNA are highly expressed in deep infiltrating endometriotic lesions. Reprod Biomed Online. 2016;33(4):476–83. Khan KN, Kitajima M, Hiraki K, Fujishita A, Sekine I, Ishimaru T, et al. Immunopathogenesis of pelvic endometriosis: role of hepatocyte growth factor, macrophages and ovarian steroids. Am J Reprod Immunol. 2008;60:383–404. Jabbour HN, Kelly RW, Fraser HM, Critchley HOD. Endocrine regulation of menstruation. Endocr Rev. 2006;27:17–46. Zlotnik A, Yoshie O. The chemokine superfamily revisited. Immunity. 2012;36:705–12. Galleri L, Luisi S, Rotondi M, Romagnani P, Cobellis L, Serio M, et al. Low serum and peritoneal fluid concentration of interferon-γ-induced protein-10 (CXCL10) in women with endometriosis. Fertil Steril. 2009;91(2):331–4. Agic A, Xu H, Rehbein M, Wolfler MM, Ebert AD, Hornung D. Cognate chemokine receptor 1 messenger ribonucleic acid expression in peripheral blood as a diagnostic test for endometriosis. Fertil Steril. 2007;87(4):982–4. Yang Y, Zhang X, Zhou C, Huang X, Lin J, Xu H. Elevated immunoreactivity of RANTES and CCR1 correlate with the severity of stages and dysmenorrhea in women with deep infiltrating endometriosis. Acta Histochem. 2013;115(5):434–9. Grandi G, Mueller MD, Papadia A, Kocbek V, Bersinger NA, Petraglia F, et al. Inflammation influences steroid hormone receptors targeted by progestins in endometrial stromal cells from women with endometriosis. J Reprod Immunol. 2016;117:30–8. Hirata T, Osuga Y, Hamasaki K, Yoshino O, Ito M, Hasegawa A, et al. Interleukin (IL)-17A stimulates IL-8 secretion, cyclooxygensase-2 expression, and cell proliferation of endometriotic stromal cells. Endocrinology. 2008;149(3):1260–7. Wu MH, Wang CA, Lin CC, Chen LC, Chang WC, Tsai SJ. Distinct regulation of cyclooxygenase-2 by interleukin-1β in normal and endometriotic stromal cells. J Clin Endocrinol Metab. 2005;90(1):286–95. Tosti C, Pinzauti S, Santulli P, Chapron C, Petraglia F. Pathogenetic mechanisms of deep infiltrating endometriosis. Reprod Sci. 2015;22:1053–9. Santulli P, Borghese B, Chouzenoux S, Vaiman D, Borderie D, Streuli I, et al. Serum and peritoneal interleukin-33 levels are elevated in deeply infiltrating endometriosis. Hum Reprod. 2012;27(7):2001–9. Kang YJ, Jeung IC, Park A, Park YJ, Jung H, Kim TD, et al. An increased level of IL-6 suppresses NK cell activity in peritoneal fluid of patients with endometriosis via regulation of SHP-2 expression. Hum Reprod. 2014;29(10):2176–89. Wu MH, Hsiao KY, Tsai SJ. Endometriosis and possible inflammation markers. Gynecol Minim Invasive Ther. 2015;4:61–7. Bullon P, Navarro JM. Inflammasome as a key pathogenic mechanism in endometriosis. Curr Drug Targets. 2017;18(9):997–1002. Hassa H, Tanir HM, Tekin B, Kirilmaz SD, Sahin Mutlu F. Cytokine and immune cell levels in peritoneal fluid and peripheral blood of women with early- and late-staged endometriosis. Arch Gynecol Obstet. 2009;279(6):891–5. Osuga Y, Koga K, Hirota Y, Hirata T, Yoshino O, Taketani Y. Lymphocytes in endometriosis. Am J Reprod Immunol. 2011;65:1–10. Takamura M, Koga K, Izumi G, Hirata T, Harada M, Hirota Y, et al. Simultaneous detection and evaluation of four subsets of CD4+ T lymphocyte in lesions and peripheral blood in endometriosis. Am J Reprod Immunol. 2015;74(6):480–6. Andreoli CG, Genro VK, Souza CA, Michelon T, Bilibio JP, Scheffel C, et al. T helper (Th)1, Th2, and Th17 interleukin pathways in infertile patients with minimal/mild endometriosis. Fertil Steril. 2011;95(8):2477–80. Gogacz M, Gałczyński K, Wojtaś M, Winkler I, Adamiak A, Romanek-Piva K, et al. Fas-related apoptosis of peritoneal fluid macrophages in endometriosis patients: understanding the disease. J Immunol Res. 2017;2017:3175394. Králíčková M, Fiala L, Losan P, Tomes P, Vetvicka V. Altered immunity in endometriosis: what came first? Immunol Investig. 2018;47(6):569–82. Allavena G, Carrarelli P, Del Bello B, Luisi S, Petraglia F, Maellaro E. Autophagy is upregulated in ovarian endometriosis: a possible interplay with p53 and heme oxygenase-1. Fertil Steril. 2015;103(5):1244–1251.e1. Santulli P, Marcellin L, Noël JC, Borghese B, Fayt I, Vaiman D, et al. Sphingosine pathway deregulation in endometriotic tissues. Fertil Steril. 2012;97(4):904–11. Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012;98:511–9. Kobayashi H, Higashiura Y, Shigetomi H, Kajihara H. Pathogenesis of endometriosis: the role of initial infection and subsequent sterile inflammation (Review). Mol Med Rep. 2014;9(1):9–15. Jiang C, Liu C, Guo J, Chen L, Luo N, Qu X, et al. The expression of Toll-like receptors in eutopic and ectopic endometrium and its implication in the inflammatory pathogenesis of adenomyosis. Sci Rep. 2017;7(1):7365. Edwards RP, Huang X, Vlad AM. Chronic inflammation in endometriosis and endometriosis-associated ovarian cancer: new roles for the “old” complement pathway. Oncoimmunology. 2015;4(5):e1002732. Sikora J, Wróblewska-Czech A, Smycz-Kubańska M, Mielczarek-Palacz A, Cygal A, Witek A, et al. The role of complement components C1q, MBL and C1 inhibitor in pathogenesis of endometriosis. Arch Gynecol Obstet. 2018;297(6):1495–501. Lambeau G, Gelb MH. Biochemistry and physiology of mammalian secreted phospholipases A2. Annu Rev Biochem. 2008;77(1):495–520. 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(2):373–80. Gori M, Luddi A, Belmonte G, Piomboni P, Tosti C, Funghi L, et al. Expression of microtubule associated protein 2 and synaptophysin in endometrium: high levels in deep infiltrating endometriosis lesions. Fertil Steril. 2016;105(2):435–43. Jess T, Frisch M, Jorgensen KT, Pedersen BV, Nielsen NM. Increased risk of inflammatory bowel disease in women with endometriosis: a nationwide Danish cohort study. Gut. 2012;61(9):1279–83. Alderman MH, Yoder N, Taylor HS. The systemic effects of endometriosis. Semin Reprod Med. 2017;35(3):263–70. Kvaskoff M, Mu F, Terry KL, Harris HR, Poole EM, Farland L, et al. Endometriosis: a high-risk population for major chronic diseases? Hum Reprod Update. 2015;21(4):500–16. Pennell LM, Galligan CL, Fish EN. Sex affects immunity. J Autoimmun. 2012;38:J282–91. Falconer H, Mwenda JM, Chai DC, Wagner C, Song XY, Mihalyi A, et al. Treatment with anti-TNF monoclonal antibody (c5N) reduces the extent of induced endometriosis in the baboon. Hum Reprod. 2006;21(7):1856–62. Nothnick WB. Treating endometriosis as an autoimmune disease. Fertil Steril. 2001;76:223–31. Sundqvist J, Falconer H, Seddighzadeh M, Vodolazkaia A, Fassbender A, Kyama C, et al. Endometriosis and autoimmune disease: association of susceptibility to moderate/severe endometriosis with CCL21 and HLA-DRB1. Fertil Steril. 2011;95(1):437–40. Bungum HF, Vestergaard C, Knudsen UB. Endometriosis and type 1 allergies/immediate type hypersensitivity: a systematic review. Eur J Obstet Gynecol Reprod Biol. 2014;179:209–15. Maggiore ULR, Ferrero S, Mangili G, Bergamini A, Inversetti A, Giorgione V, et al. A systematic review on endometriosis during pregnancy: diagnosis, misdiagnosis, complications and outcomes. Hum Reprod Update. 2016;22(1):70–103. Santulli P, Marcellin L, Menard S, Thubert T, Khoshnood B, Gayet V, et al. Increased rate of spontaneous miscarriages in endometriosis-affected women. Hum Reprod. 2016;31(5):1014–23. Zullo F, Spagnolo E, Saccone G, Acunzo M, Xodo S, Ceccaroni M, et al. Endometriosis and obstetrics complications: a systematic review and meta-analysis. Fertil Steril. 2017;108(4):667–672.e5. Vannuccini S, Clifton VL, Fraser IS, Taylor HS, Critchley H, Giudice LC, et al. Infertility and reproductive disorders: impact of hormonal and inflammatory mechanisms on pregnancy outcome. Hum Reprod Update. 2016;22(1):104–15. Pérez-López FR, Villagrasa-Boli P, Muñoz-Olarte M, Morera-Grau Á, Cruz-Andrés P, Hernandez AV. Association between endometriosis and preterm birth in women with spontaneous conception or using assisted reproductive technology: a systematic review and meta-analysis of cohort studies. Reprod Sci. 2018;25:311–9. Author information Authors and Affiliations Corresponding author Editor information Editors and Affiliations Rights and permissions Copyright information © 2019 International Society of Gynecological Endocrinology About this chapter Cite this chapter Pavone, D. et al. (2019). Hormones and Inflammation: An Update on Endometriosis. In: Berga, S., Genazzani, A., Naftolin, F., Petraglia, F. (eds) Menstrual Cycle Related Disorders. ISGE Series. Springer, Cham. https://doi.org/10.1007/978-3-030-14358-9_14 Download citation DOI: https://doi.org/10.1007/978-3-030-14358-9_14 Published: Publisher Name: Springer, Cham Print ISBN: 978-3-030-14357-2 Online ISBN: 978-3-030-14358-9 eBook Packages: MedicineMedicine (R0)