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Endometriosis: The Role of Iron Overload and Ferroptosis

Abstract

Iron is an essential element for cell survival, and iron deficiency is a known risk factor for many reproductive disorders. Paradoxically, such disorders are also seen more commonly under conditions of iron excess. Here, we focus on the problem of iron overload in women’s health, using endometriosis as a model system. We propose (i) that a primary defect in endometriosis is abnormal eutopic endometrium characterized by resistance to ferroptosis, a process of iron-mediated non-apoptotic programmed cell death, which allows cells spread via retrograde menstruation to survive, implant, and establish endometriotic lesions within the abdominal cavity, and (ii) that dysregulated iron homeostasis may be critical to the subsequent pathophysiology of endometriotic lesions with localized iron overload and inflammation. We further investigate the association between endometriosis and hypercholesterolemia and suggest that an interaction between the mevalonate cholesterol biosynthetic pathway and ferroptosis signaling may provide a molecular basis to explain how it is that, in some women, endometrial tissues survive and thrive under ferroptotic pressure, colonize at ectopic sites, and expand into endometriotic lesions.

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References

  1. As-Sanie S, Black R, Giudice LC, Gray Valbrun T, Gupta J, Jones B, et al. Assessing research gaps and unmet needs in endometriosis. Am J Obstet Gynecol. 2019;221:86–94.

    Article  PubMed  Google Scholar 

  2. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997;67:817–21.

  3. Pearce CL, Templeman C, Rossing MA, Lee A, Near AM, Webb PM, et al. Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case-control studies. Lancet Oncol. 2012;13:385–94.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Halme J, Hammond MG, Hulka JF, Raj SG, Talbert LM. Retrograde menstruation in healthy women and in patients with endometriosis. Obstet Gynecol. 1984;64:151–4.

    CAS  PubMed  Google Scholar 

  5. Sampson JA. Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation. Am J Pathol. 1927;3:93–110.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Zondervan KT, Becker CM, Koga K, Missmer SA, Taylor RN, Vigano P. Endometriosis. Nat Rev Dis Primers. 2018;4:9.

    Article  PubMed  Google Scholar 

  7. Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012;98:511–9.

    Article  CAS  PubMed  Google Scholar 

  8. Sourial S, Tempest N, Hapangama DK. Theories on the pathogenesis of endometriosis. Int J Reprod Med. 2014;2014:179515.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Du H, Taylor HS. Contribution of bone marrow-derived stem cells to endometrium and endometriosis. Stem Cells. 2007;25(8):2082–6.

    Article  CAS  PubMed  Google Scholar 

  10. Lee B, Du H, Taylor HS. Experimental murine endometriosis induces DNA methylation and altered gene expression in eutopic endometrium. Biol Reprod. 2009;80(1):79–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Grechukhina O, Petracco R, Popkhadze S, Massasa E, Paranjape T, Chan E, et al. A polymorphism in a let-7 microRNA binding site of KRAS in women with endometriosis. EMBO Mol Med. 2012;4(3):206–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ghazal S, McKinnon B, Zhou J, Mueller M, Men Y, Yang L, et al. H19 lncRNA alters stromal cell growth via IGF signaling in the endometrium of women with endometriosis. EMBO Mol Med. 2015;7(8):996–1003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Li F, Alderman MH 3rd, Tal A, Mamillapalli R, Coolidge A, Hufnagel D, et al. Hematogenous dissemination of mesenchymal stem cells from endometriosis. Stem Cells. 2018;36(6):881–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Matarese G, De Placido G, Nikas Y, Alviggi C. Pathogenesis of endometriosis: natural immunity dysfunction or autoimmune disease? Trends Mol Med. 2003;9:223–8.

    Article  CAS  PubMed  Google Scholar 

  15. Siristatidis C, Nissotakis C, Chrelias C, Iacovidou H, Salamalekis E. Immunological factors and their role in the genesis and development of endometriosis. J Obstet Gynaecol Res. 2006;32:162–70.

    Article  PubMed  Google Scholar 

  16. D'Hooghe TM, Debrock S, Hill JA, Meuleman C. Endometriosis and subfertility: is the relationship resolved? Semin Reprod Med. 2003;21:243–54.

    Article  PubMed  Google Scholar 

  17. Endometriosis and infertility. Fertil Steril. 2006;86:S156–60.

  18. Somigliana E, Vigano P, Parazzini F, Stoppelli S, Giambattista E, Vercellini P. Association between endometriosis and cancer: a comprehensive review and a critical analysis of clinical and epidemiological evidence. Gynecol Oncol. 2006;101:331–41.

    Article  PubMed  Google Scholar 

  19. Brinton LA, Gridley G, Persson I, Baron J, Bergqvist A. Cancer risk after a hospital discharge diagnosis of endometriosis. Am J Obstet Gynecol. 1997;176:572–9.

    Article  CAS  PubMed  Google Scholar 

  20. Kumar S, Munkarah A, Arabi H, Bandyopadhyay S, Semaan A, Hayek K, et al. Prognostic analysis of ovarian cancer associated with endometriosis. Am J Obstet Gynecol. 2011;204:63 e1–7.

    Article  PubMed  Google Scholar 

  21. Melin A, Sparen P, Persson I, Bergqvist A. Endometriosis and the risk of cancer with special emphasis on ovarian cancer. Hum Reprod. 2006;21:1237–42.

    Article  CAS  PubMed  Google Scholar 

  22. Worley MJ, Welch WR, Berkowitz RS, Ng SW. Endometriosis-associated ovarian cancer: a review of pathogenesis. Int J Mol Sci. 2013;14:5367–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Czernobilsky B, Morris WJ. A histologic study of ovarian endometriosis with emphasis on hyperplastic and atypical changes. Obstet Gynecol. 1979;53:318–23.

    CAS  PubMed  Google Scholar 

  24. LaGrenade A, Silverberg SG. Ovarian tumors associated with atypical endometriosis. Hum Pathol. 1988;19:1080–4.

    Article  CAS  PubMed  Google Scholar 

  25. Sato N, Tsunoda H, Nishida M, Morishita Y, Takimoto Y, Kubo T, et al. Loss of heterozygosity on 10q23.3 and mutation of the tumor suppressor gene PTEN in benign endometrial cyst of the ovary: possible sequence progression from benign endometrial cyst to endometrioid carcinoma and clear cell carcinoma of the ovary. Cancer Res. 2000;60:7052–6.

    CAS  PubMed  Google Scholar 

  26. Worley MJ Jr, Liu S, Hua Y, Kwok JS, Samuel A, Hou L, et al. Molecular changes in endometriosis-associated ovarian clear cell carcinoma. Eur J Cancer. 2015;51:1831–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kato N, Sasou S, Motoyama T. Expression of hepatocyte nuclear factor-1beta (HNF-1beta) in clear cell tumors and endometriosis of the ovary. Mod Pathol. 2006;19:83–9.

    Article  CAS  PubMed  Google Scholar 

  28. Murphy AA, Santanam N, Parthasarathy S. Endometriosis: a disease of oxidative stress? Semin Reprod Endocrinol. 1998;16:263–73.

    Article  CAS  PubMed  Google Scholar 

  29. Murphy AA, Santanam N, Morales AJ, Parthasarathy S. Lysophosphatidyl choline, a chemotactic factor for monocytes/T-lymphocytes is elevated in endometriosis. J Clin Endocrinol Metab. 1998;83:2110–3.

    Article  CAS  PubMed  Google Scholar 

  30. Scutiero G, Iannone P, Bernardi G, Bonaccorsi G, Spadaro S, Volta CA, et al. Oxidative stress and endometriosis: a systematic review of the literature. Oxidative Med Cell Longev. 2017;2017:7265238.

    Article  CAS  Google Scholar 

  31. Xu W, Barrientos T, Andrews NC. Iron and copper in mitochondrial diseases. Cell Metab. 2013;17:319–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Nandal A, Ruiz JC, Subramanian P, Ghimire-Rijal S, Sinnamon RA, Stemmler TL, et al. Activation of the HIF prolyl hydroxylase by the iron chaperones PCBP1 and PCBP2. Cell Metab. 2011;14:647–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Norwitz ER, Schust DJ, Fisher SJ. Implantation and the survival of early pregnancy. N Engl J Med. 2001;345:1400–8.

    Article  CAS  PubMed  Google Scholar 

  34. Pringle KG, Kind KL, Sferruzzi-Perri AN, Thompson JG, Roberts CT. Beyond oxygen: complex regulation and activity of hypoxia inducible factors in pregnancy. Hum Reprod Update. 2010;16:415–31.

    Article  CAS  PubMed  Google Scholar 

  35. Ng SW, Norwitz SG, Norwitz ER. The impact of iron overload and ferroptosis on reproductive disorders in humans: implications for preeclampsia. Int J Mol Sci. 2019;20(13):pii: E3283. https://doi.org/10.3390/ijms20133283.

    Article  CAS  Google Scholar 

  36. Muckenthaler MU, Rivella S, Hentze MW, Galy B. A red carpet for iron metabolism. Cell. 2017;168:344–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hentze MW, Muckenthaler MU, Galy B, Camaschella C. Two to tango: regulation of mammalian iron metabolism. Cell. 2010;142:24–38.

    Article  CAS  PubMed  Google Scholar 

  38. Lane DJ, Merlot AM, Huang ML, Bae DH, Jansson PJ, Sahni S, et al. Cellular iron uptake, trafficking and metabolism: key molecules and mechanisms and their roles in disease. Biochim Biophys Acta. 1853;2015:1130–44.

    Google Scholar 

  39. Hirschhorn T, Stockwell BR. The development of the concept of ferroptosis. Free Radic Biol Med. 2019;133:130–43.

    Article  CAS  PubMed  Google Scholar 

  40. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017;171:273–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Feng H, Stockwell BR. Unsolved mysteries: how does lipid peroxidation cause ferroptosis? PLoS Biol. 2018;16:e2006203.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Dixon SJ, Stockwell BR. The role of iron and reactive oxygen species in cell death. Nat Chem Biol. 2014;10:9–17.

    Article  CAS  PubMed  Google Scholar 

  44. Xie Y, Hou W, Song X, Yu Y, Huang J, Sun X, et al. Ferroptosis: process and function. Cell Death Differ. 2016;23:369–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2017;13:91–8.

    Article  CAS  PubMed  Google Scholar 

  46. Kagan VE, Mao G, Qu F, Angeli JP, Doll S, Croix CS, et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol. 2017;13:81–90.

    Article  CAS  PubMed  Google Scholar 

  47. Seiler A, Schneider M, Forster H, Roth S, Wirth EK, Culmsee C, et al. Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death. Cell Metab. 2008;8:237–48.

    Article  CAS  PubMed  Google Scholar 

  48. Gaschler MM, Stockwell BR. Lipid peroxidation in cell death. Biochem Biophys Res Commun. 2017;482:419–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hinman A, Holst CR, Latham JC, Bruegger JJ, Ulas G, McCusker KP, et al. Vitamin E hydroquinone is an endogenous regulator of ferroptosis via redox control of 15-lipoxygenase. PLoS One. 2018;13:e0201369.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Linkermann A, Skouta R, Himmerkus N, Mulay SR, Dewitz C, De Zen F, et al. Synchronized renal tubular cell death involves ferroptosis. Proc Natl Acad Sci U S A. 2014;111:16836–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Tonnus W, Linkermann A. The in vivo evidence for regulated necrosis. Immunol Rev. 2017;277:128–49.

    Article  CAS  PubMed  Google Scholar 

  52. Skouta R, Dixon SJ, Wang J, Dunn DE, Orman M, Shimada K, et al. Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models. J Am Chem Soc. 2014;136:4551–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol. 2014;16:1180–91.

    Article  CAS  PubMed  Google Scholar 

  54. Li W, Feng G, Gauthier JM, Lokshina I, Higashikubo R, Evans S, et al. Ferroptotic cell death and TLR4/Trif signaling initiate neutrophil recruitment after heart transplantation. J Clin Invest. 2019;129:2293–304.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Garry R, Hart R, Karthigasu KA, Burke C. Structural changes in endometrial basal glands during menstruation. Br J Obstet Gynaecol. 2010;117:1175–85.

    Article  CAS  Google Scholar 

  56. Li A, Felix JC, Hao J, Minoo P, Jain JK. Menstrual-like breakdown and apoptosis in human endometrial explants. Hum Reprod. 2005;20:1709–19.

    Article  CAS  PubMed  Google Scholar 

  57. Dahmoun M, Boman K, Cajander S, Westin P, Backstrom T. Apoptosis, proliferation, and sex hormone receptors in superficial parts of human endometrium at the end of the secretory phase. J Clin Endocrinol Metab. 1999;84:1737–43.

    CAS  PubMed  Google Scholar 

  58. Sanfilippo JS, Wakim NG, Schikler KN, Yussman MA. Endometriosis in association with uterine anomaly. Am J Obstet Gynecol. 1986;154:39–43.

    Article  CAS  PubMed  Google Scholar 

  59. Darrow SL, Vena JE, Batt RE, Zielezny MA, Michalek AM, Selman S. Menstrual cycle characteristics and the risk of endometriosis. Epidemiology. 1993;4:135–42.

    Article  CAS  PubMed  Google Scholar 

  60. Cornillie FJ, Lauweryns JM, Brosens IA. Normal human endometrium.: an ultrastructural survey. Gynecol Obstet Investig. 1985;20:113–29.

    Article  CAS  Google Scholar 

  61. Verma V. Ultrastructural changes in human endometrium at different phases of the menstrual cycle and their functional significance. Gynecol Obstet Investig. 1983;15:193–212.

    Article  CAS  Google Scholar 

  62. Parmar T, Sachdeva G, Savardekar L, Katkam RR, Nimbkar-Joshi S, Gadkar-Sable S, et al. Protein repertoire of human uterine fluid during the mid-secretory phase of the menstrual cycle. Hum Reprod. 2008;23:379–86.

    Article  CAS  PubMed  Google Scholar 

  63. Cornelli U, Belcaro G, Cesarone MR, Finco A. Analysis of oxidative stress during the menstrual cycle. Reprod Biol Endocrinol. 2013;11:74.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Jiang QY, Wu RJ. Growth mechanisms of endometriotic cells in implanted places: a review. Gynecol Endocrinol. 2012;28:562–7.

    Article  PubMed  Google Scholar 

  65. Bullon P, Navarro JM. Inflammasome as a key pathogenic mechanism in endometriosis. Curr Drug Targets. 2017;18:997–1002.

    Article  CAS  PubMed  Google Scholar 

  66. Kobayashi H, Yamada Y, Kanayama S, Furukawa N, Noguchi T, Haruta S, et al. The role of iron in the pathogenesis of endometriosis. Gynecol Endocrinol. 2009;25:39–52.

    Article  CAS  PubMed  Google Scholar 

  67. Zeitoun K, Takayama K, Michael MD, Bulun SE. Stimulation of aromatase P450 promoter (II) activity in endometriosis and its inhibition in endometrium are regulated by competitive binding of steroidogenic factor-1 and chicken ovalbumin upstream promoter transcription factor to the same cis-acting element. Mol Endocrinol. 1999;13:239–53.

    Article  CAS  PubMed  Google Scholar 

  68. Attar E, Tokunaga H, Imir G, Yilmaz MB, Redwine D, Putman M, et al. Prostaglandin E2 via steroidogenic factor-1 coordinately regulates transcription of steroidogenic genes necessary for estrogen synthesis in endometriosis. J Clin Endocrinol Metab. 2009;94:623–31.

    Article  CAS  PubMed  Google Scholar 

  69. Bulun SE, Gurates B, Fang Z, Tamura M, Sebastian S, Zhou J, et al. Mechanisms of excessive estrogen formation in endometriosis. J Reprod Immunol. 2002;55:21–33.

    Article  CAS  PubMed  Google Scholar 

  70. Virani S, Edwards AK, Thomas R, Childs T, Tayade C. Blocking of stromal cell-derived factor-1 reduces neoangiogenesis in human endometriosis lesions in a mouse model. Am J Reprod Immunol. 2013;70:386–97.

    CAS  PubMed  Google Scholar 

  71. Arumugam K, Yip YC. De novo formation of adhesions in endometriosis: the role of iron and free radical reactions. Fertil Steril. 1995;64:62–4.

    Article  CAS  PubMed  Google Scholar 

  72. Lousse JC, Defrere S, Van Langendonckt A, Gras J, Gonzalez-Ramos R, Colette S, et al. Iron storage is significantly increased in peritoneal macrophages of endometriosis patients and correlates with iron overload in peritoneal fluid. Fertil Steril. 2009;91:1668–75.

    Article  PubMed  Google Scholar 

  73. D'Hooghe TM, Debrock S. Endometriosis, retrograde menstruation and peritoneal inflammation in women and in baboons. Hum Reprod Update. 2002;8:84–8.

    Article  PubMed  Google Scholar 

  74. Mori M, Ito F, Shi L, Wang Y, Ishida C, Hattori Y, et al. Ovarian endometriosis-associated stromal cells reveal persistently high affinity for iron. Redox Biol. 2015;6:578–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Chagovets VV, Wang Z, Kononikhin AS, Starodubtseva NL, Borisova A, Salimova D, et al. Endometriosis foci differentiation by rapid lipid profiling using tissue spray ionization and high resolution mass spectrometry. Sci Rep. 2017;7:2546.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Van Langendonckt A, Casanas-Roux F, Donnez J. Iron overload in the peritoneal cavity of women with pelvic endometriosis. Fertil Steril. 2002;78:712–8.

    Article  PubMed  Google Scholar 

  77. Van Langendonckt A, Casanas-Roux F, Eggermont J, Donnez J. Characterization of iron deposition in endometriotic lesions induced in the nude mouse model. Hum Reprod. 2004;19:1265–71.

    Article  PubMed  CAS  Google Scholar 

  78. Defrere S, Lousse JC, Gonzalez-Ramos R, Colette S, Donnez J, Van Langendonckt A. Potential involvement of iron in the pathogenesis of peritoneal endometriosis. Mol Hum Reprod. 2008;14:377–85.

    Article  CAS  PubMed  Google Scholar 

  79. Sharpe-Timms KL, Ricke EA, Piva M, Horowitz GM. Differential expression and localization of de-novo synthesized endometriotic haptoglobin in endometrium and endometriotic lesions. Hum Reprod. 2000;15:2180–5.

    Article  CAS  PubMed  Google Scholar 

  80. Piva M, Horowitz GM, Sharpe-Timms KL. Interleukin-6 differentially stimulates haptoglobin production by peritoneal and endometriotic cells in vitro: a model for endometrial-peritoneal interaction in endometriosis. J Clin Endocrinol Metab. 2001;86:2553–61.

    CAS  PubMed  Google Scholar 

  81. Origassa CS, Camara NO. Cytoprotective role of heme oxygenase-1 and heme degradation derived end products in liver injury. World J Hepatol. 2013;5:541–9.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Defrere S, Van Langendonckt A, Vaesen S, Jouret M, Gonzalez Ramos R, Gonzalez D, et al. Iron overload enhances epithelial cell proliferation in endometriotic lesions induced in a murine model. Hum Reprod. 2006;21:2810–6.

    Article  CAS  PubMed  Google Scholar 

  83. Jauniaux E, Poston L, Burton GJ. Placental-related diseases of pregnancy: involvement of oxidative stress and implications in human evolution. Hum Reprod Update. 2006;12:747–55.

    Article  CAS  PubMed  Google Scholar 

  84. Staff AC, Johnsen GM, Dechend R, Redman CWG. Preeclampsia and uteroplacental acute atherosis: immune and inflammatory factors. J Reprod Immunol. 2014;101:120–6.

    Article  PubMed  CAS  Google Scholar 

  85. Carden DL, Granger DN. Pathophysiology of ischaemia-reperfusion injury. J Pathol. 2000;190:255–66.

    Article  CAS  PubMed  Google Scholar 

  86. Melo AS, Rosa-e-Silva JC, Rosa-e-Silva AC, Poli-Neto OB, Ferriani RA, Vieira CS. Unfavorable lipid profile in women with endometriosis. Fertil Steril. 2010;93:2433–6.

    Article  CAS  PubMed  Google Scholar 

  87. Alizadeh M, Mahjoub S, Esmaelzadeh S, Hajian K, Basirat Z, Ghasemi M. Evaluation of oxidative stress in endometriosis: a case-control study. Caspian J Intern Med. 2015;6:25–9.

    PubMed  PubMed Central  Google Scholar 

  88. Tani A, Yamamoto S, Maegawa M, Kunimi K, Matsui S, Keyama K, et al. Arterial stiffness is increased in young women with endometriosis. J Obstet Gynaecol. 2015;35:711–5.

    Article  CAS  PubMed  Google Scholar 

  89. Santoro L, D'Onofrio F, Campo S, Ferraro PM, Tondi P, Campo V, et al. Endothelial dysfunction but not increased carotid intima-media thickness in young European women with endometriosis. Hum Reprod. 2012;27:1320–6.

    Article  CAS  PubMed  Google Scholar 

  90. Mu F, Rich-Edwards J, Rimm EB, Spiegelman D, Forman JP, Missmer SA. Association between endometriosis and hypercholesterolemia or hypertension. Hypertension. 2017;70:59–65.

    Article  CAS  PubMed  Google Scholar 

  91. Taskin O, Rikhraj K, Tan J, Sedlak T, Rowe TC, Bedaiwy MA. Link between endometriosis, atherosclerotic cardiovascular disease, and the health of women midlife. J Minim Invasive Gynecol. 2019;26:781–4.

    Article  PubMed  Google Scholar 

  92. Mu F, Rich-Edwards J, Rimm EB, Spiegelman D, Missmer SA. Endometriosis and risk of coronary heart disease. Circ Cardiovasc Qual Outcomes. 2016;9:257–64.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Tsai SJ, Wu MH, Lin CC, Sun HS, Chen HM. Regulation of steroidogenic acute regulatory protein expression and progesterone production in endometriotic stromal cells. J Clin Endocrinol Metab. 2001;86:5765–73.

    Article  CAS  PubMed  Google Scholar 

  94. Sharma I, Dhaliwal LK, Saha SC, Sangwan S, Dhawan V. Role of 8-iso-prostaglandin F2alpha and 25-hydroxycholesterol in the pathophysiology of endometriosis. Fertil Steril. 2010;94:63–70.

    Article  CAS  PubMed  Google Scholar 

  95. Shimada K, Skouta R, Kaplan A, Yang WS, Hayano M, Dixon SJ, et al. Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis. Nat Chem Biol. 2016;12:497–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Moosmann B, Behl C. Selenoproteins, cholesterol-lowering drugs, and the consequences: revisiting of the mevalonate pathway. Trends Cardiovasc Med. 2004;14:273–81.

    Article  CAS  PubMed  Google Scholar 

  97. Sokalska A, Hawkins AB, Yamaguchi T, Duleba AJ. Lipophilic statins inhibit growth and reduce invasiveness of human endometrial stromal cells. J Assist Reprod Genet. 2019;36:535–41.

    Article  PubMed  Google Scholar 

  98. Villanueva JA, Sokalska A, Cress AB, Ortega I, Bruner-Tran KL, Osteen KG, et al. Resveratrol potentiates effect of simvastatin on inhibition of mevalonate pathway in human endometrial stromal cells. J Clin Endocrinol Metab. 2013;98:e455–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Taylor HS, Alderman Iii M, D'Hooghe TM, Fazleabas AT, Duleba AJ. Effect of simvastatin on baboon endometriosis. Biol Reprod. 2017;97(1):32–8.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Moggio A, Pittatore G, Cassoni P, Marchino GL, Revelli A, Bussolati B. Sorafenib inhibits growth, migration, and angiogenic potential of ectopic endometrial mesenchymal stem cells derived from patients with endometriosis. Fertil Steril. 2012;98:1521–30 e2.

    Article  CAS  PubMed  Google Scholar 

  101. Carroll RG, Zaslona Z, Galvan-Pena S, Koppe EL, Sevin DC, Angiari S, et al. An unexpected link between fatty acid synthase and cholesterol synthesis in proinflammatory macrophage activation. J Biol Chem. 2018;293:5509–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Murphy AA, Palinski W, Rankin S, Morales AJ, Parthasarathy S. Macrophage scavenger receptor(s) and oxidatively modified proteins in endometriosis. Fertil Steril. 1998;69:1085–91.

    Article  CAS  PubMed  Google Scholar 

  103. Levy AP, Levy JE, Kalet-Litman S, Miller-Lotan R, Levy NS, Asaf R, et al. Haptoglobin genotype is a determinant of iron, lipid peroxidation, and macrophage accumulation in the atherosclerotic plaque. Arterioscler Thromb Vasc Biol. 2007;27:134–40.

    Article  CAS  PubMed  Google Scholar 

  104. Van Langendonckt A, Casanas-Roux F, Donnez J. Oxidative stress and peritoneal endometriosis. Fertil Steril. 2002;77:861–70.

    Article  PubMed  Google Scholar 

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Ng, SW., Norwitz, S.G., Taylor, H.S. et al. Endometriosis: The Role of Iron Overload and Ferroptosis. Reprod. Sci. 27, 1383–1390 (2020). https://doi.org/10.1007/s43032-020-00164-z

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Keywords

  • Ferroptosis
  • Endometriosis
  • Iron
  • Reactive oxygen species
  • Inflammation