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What Have We Learned from Animal Models of Endometriosis and How Can We Use the Knowledge Gained to Improve Treatment of Patients?

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Animal Models for Endometriosis

Part of the book series: Advances in Anatomy, Embryology and Cell Biology ((ADVSANAT,volume 232))

Abstract

Endometriosis is a complex disorder with a high socio-economic impact. Development of effective novel drug therapies which can be given to women to relieve chronic pain symptoms without side effects such as hormone suppression is urgently required, but progress has been slow. Several different rodent models of ‘endometriosis’ have been developed, the majority of which mimic aspects of peritoneal disease (e.g. ‘lesions’ in peritoneal cavity either surgically or spontaneously attached to wall, mesentery, fat). Results obtained using these models have informed our understanding of aetiology including evidence for differential expression of regulatory factors in lesions and impacts on pain perception and fertility. Refinement of these models to ensure reproducibility, extension of models to replicate ovarian and deep disease, complementary in vitro approaches and robust experimental design are all needed to ensure preclinical drug testing results in positive findings in clinical trials and translation for patient benefit.

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References

  • Adewuyi EO et al (2020) Shared molecular genetic mechanisms underlie endometriosis and migraine comorbidity. Genes (Basel) 11(3):268

    Article  CAS  Google Scholar 

  • Afshar Y et al (2013) Changes in eutopic endometrial gene expression during the progression of experimental endometriosis in the baboon, Papio anubis. Biol Reprod 88(2):44

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Agarwal SK et al (2019) Clinical diagnosis of endometriosis: a call to action. Am J Obstet Gynecol 220(4):354 e351–354 e312

    Article  Google Scholar 

  • Agrawal S et al (2018) The miRNA mirage: how close are we to finding a non-invasive diagnostic biomarker in endometriosis? A systematic review. Int J Mol Sci 19(2):599

    Article  PubMed Central  CAS  Google Scholar 

  • Al Jishi T, Sergi C (2017) Current perspective of diethylstilbestrol (DES) exposure in mothers and offspring. Reprod Toxicol 71:71–77

    Article  PubMed  CAS  Google Scholar 

  • Bellofiore N, Cousins F, Temple-Smith P, Dickinson H, Evans J (2018) A missing piece: the spiny mouse and the puzzle of menstruating species. J Mol Endocrinol 61(1):R25–R41

    Article  CAS  PubMed  Google Scholar 

  • Birt JA, Taylor KH, Davis JW, Sharpe-Timms KL (2013) Developmental exposure of fetal ovaries and fetal germ cells to endometriosis in an endometriosis model causes differential gene expression in the preimplantation embryos of the first-generation and second-generation embryos. Fertil Steril 100(5):1436–1443. https://doi.org/10.1016/j.fertnstert.2013.07.007. Epub 2013 Aug 15. pubMed PMID: 23954358; PubMed Central PMCID: PMC3847911

    Article  CAS  PubMed  Google Scholar 

  • Bradman MJ, Ferrini F, Salio C, Merighi A (2015) Practical mechanical threshold estimation in rodents using von Frey hairs/Semmes-Weinstein monofilaments: towards a rational method. J Neurosci Methods 255:92–103

    Article  PubMed  Google Scholar 

  • Bruner-Tran KL, Osteen KG (2011) Developmental exposure to TCDD reduces fertility and negatively affects pregnancy outcomes across multiple generations. Reprod Toxicol 31(3):344–350

    Article  CAS  PubMed  Google Scholar 

  • Bruner-Tran KL et al (2017) Exposure to the environmental endocrine disruptor TCDD and human reproductive dysfunction: translating lessons from murine models. Reprod Toxicol 68:59–71

    Article  CAS  PubMed  Google Scholar 

  • Bulun SE, Zeitoun KM, Kilic G (2000) Expression of dioxin-related transactivating factors and target genes in human eutopic endometrial and endometriotic tissues. Am J Obstet Gynecol 182(4):767–775

    Article  CAS  PubMed  Google Scholar 

  • Bulun SE et al (2010) Estrogen receptor-beta, estrogen receptor-alpha, and progesterone resistance in endometriosis. Semin Reprod Med 28(1):36–43

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Couse JF et al (2001) Estrogen receptor-alpha knockout mice exhibit resistance to the developmental effects of neonatal diethylstilbestrol exposure on the female reproductive tract. Dev Biol 238(2):224–238

    Article  CAS  PubMed  Google Scholar 

  • Dehoux JP et al (2011) Is the baboon model appropriate for endometriosis studies? Fertil Steril 96(3):728–733 e723

    Article  PubMed  Google Scholar 

  • D’Hooghe TM et al (1996) The cycle pregnancy rate is normal in baboons with stage I endometriosis but decreased in primates with stage II and stage III-IV disease. Fertil Steril 66(5):809–813

    Article  PubMed  Google Scholar 

  • D’Hooghe TM et al (2009) Nonhuman primate models for translational research in endometriosis. Reprod Sci 16(2):152–161

    Article  PubMed  Google Scholar 

  • Donnez O et al (2015) Invasion process of induced deep nodular endometriosis in an experimental baboon model: similarities with collective cell migration? Fertil Steril 104(2):491–497. e492

    Article  PubMed  Google Scholar 

  • Eggers JC et al (2016) microRNA miR-200b affects proliferation, invasiveness and stemness of endometriotic cells by targeting ZEB1, ZEB2 and KLF4. Reprod BioMed Online 32(4):434–445

    Article  CAS  PubMed  Google Scholar 

  • Einspanier A et al (2006) Induction of endometriosis in the marmoset monkey (Callithrix jacchus). Mol Hum Reprod 12(5):291–299

    Article  CAS  PubMed  Google Scholar 

  • Fazleabas AT (2006) A baboon model for inducing endometriosis. Methods Mol Med 121:95–99

    PubMed  Google Scholar 

  • Forster R et al (2019) Macrophage-derived insulin-like growth factor-1 is a key neurotrophic and nerve-sensitizing factor in pain associated with endometriosis. FASEB J 33(10):11210–11222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Greaves E et al (2014) A novel mouse model of endometriosis mimics human phenotype and reveals insights into the inflammatory contribution of shed endometrium. Am J Pathol 184(7):1930–1939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Greaves E et al (2015) Estradiol is a critical mediator of macrophage-nerve cross talk in peritoneal endometriosis. Am J Pathol 185(8):2286–2297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Greaves E et al (2017) EP2 receptor antagonism reduces peripheral and central hyperalgesia in a preclinical mouse model of endometriosis. Sci Rep 7:44169

    Article  PubMed  PubMed Central  Google Scholar 

  • Groothuis PG, Guo SW (2018) Drug development in endometriosis and adenomyosis: it takes more just good science. Reprod Sci 25(9):1318–1329

    Article  PubMed  Google Scholar 

  • Guo SW, Groothuis PG (2018) Is it time for a paradigm shift in drug research and development in endometriosis/adenomyosis? Hum Reprod Update 24(5):577–598

    Article  PubMed  Google Scholar 

  • Guo S, Li Z, Yan L, Sun Y, Feng Y (2018) GnRH agonist improves pregnancy outcome in mice with induced adenomyosis by restoring endometrial receptivity. Drug Des Devel Ther 12:1621–1631

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harirchian P et al (2012) Lesion kinetics in a non-human primate model of endometriosis. Hum Reprod 27(8):2341–2351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hastings JM, Fazleabas AT (2006) A baboon model for endometriosis: implications for fertility. Reprod Biol Endocrinol 4(Suppl 1):S7

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Horne AW, Saunders PTK (2019) SnapShot: Endometriosis. Cell 179(7):1677–1677. e1671

    Article  CAS  PubMed  Google Scholar 

  • Horne AW, PTK S, Abokhrais IM, Hogg L, Endometriosis Priority Setting Partnership Steering G (2017) Top ten endometriosis research priorities in the UK and Ireland. Lancet 389(10085):2191–2192

    Article  PubMed  Google Scholar 

  • Horne AW et al (2019) Repurposing dichloroacetate for the treatment of women with endometriosis. Proc Natl Acad Sci U S A 116(51):25389–25391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hussein M et al (2016) c-Jun NH2-terminal kinase inhibitor bentamapimod reduces induced endometriosis in baboons: an assessor-blind placebo-controlled randomized study. Fertil Steril 105(3):815–824 e815

    Article  CAS  PubMed  Google Scholar 

  • Joshi NR et al (2015) Altered expression of microRNA-451 in eutopic endometrium of baboons (Papio anubis) with endometriosis. Hum Reprod 30(12):2881–2891

    CAS  PubMed  PubMed Central  Google Scholar 

  • Joshi NR et al (2017) Progesterone resistance in endometriosis is modulated by the altered expression of microRNA-29c and FKBP4. J Clin Endocrinol Metab 102(1):141–149

    PubMed  Google Scholar 

  • Lebovic DI et al (2010) Peroxisome proliferator-activated receptor-(gamma) receptor ligand partially prevents the development of endometrial explants in baboons: a prospective, randomized, placebo-controlled study. Endocrinology 151(4):1846–1852

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lian YL, Cheng MJ, Zhang XX, Wang L (2017) Elevated expression of transient receptor potential vanilloid type 1 in dorsal root ganglia of rats with endometriosis. Mol Med Rep 16(2):1920–1926

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Long M, Wan X, La X, Gong X, Cai X (2015) miR-29c is downregulated in the ectopic endometrium and exerts its effects on endometrial cell proliferation, apoptosis and invasion by targeting c-Jun. Int J Mol Med 35(4):1119–1125

    Article  CAS  PubMed  Google Scholar 

  • MacKay H, Abizaid A (2018) A plurality of molecular targets: The receptor ecosystem for bisphenol-A (BPA). Horm Behav 101:59–67

    Article  CAS  PubMed  Google Scholar 

  • Mao AJ, Anastasi JK (2010) Diagnosis and management of endometriosis: the role of the advanced practice nurse in primary care. J Am Acad Nurse Pract 22(2):109–116

    Article  PubMed  Google Scholar 

  • Mari-Alexandre J et al (2016) miRNAs regulation and its role as biomarkers in endometriosis. Int J Mol Sci 17(1):93

    Article  PubMed Central  CAS  Google Scholar 

  • McAllister SL, Dmitrieva N, Berkley KJ (2012) Sprouted innervation into uterine transplants contributes to the development of hyperalgesia in a rat model of endometriosis. PLoS One 7(2):e31758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McKinnon BD, Bertschi D, Bersinger NA, Mueller MD (2015) Inflammation and nerve fiber interaction in endometriotic pain. Trends Endocrinol Metab 26(1):1–10

    Article  CAS  PubMed  Google Scholar 

  • Miller JE et al (2017) Implications of immune dysfunction on endometriosis associated infertility. Oncotarget 8(4):7138–7147

    Article  PubMed  Google Scholar 

  • Morotti M, Vincent K, Brawn J, Zondervan KT, Becker CM (2014) Peripheral changes in endometriosis-associated pain. Hum Reprod Update 20(5):717–736

    Article  PubMed  Google Scholar 

  • Nilsson EE, Sadler-Riggleman I, Skinner MK (2018) Environmentally induced epigenetic transgenerational inheritance of disease. Environ Epigenet 4(2):dvy016

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Nishimoto-Kakiuchi A et al (2016) Characteristics of histologically confirmed endometriosis in cynomolgus monkeys. Hum Reprod 31(10):2352–2359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nishimoto-Kakiuchi A et al (2018) Spontaneous endometriosis in cynomolgus monkeys as a clinically relevant experimental model. Hum Reprod 33(7):1228–1236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nnoaham KE, Webster P, Kumbang J, Kennedy SH, Zondervan KT (2012) Is early age at menarche a risk factor for endometriosis? A systematic review and meta-analysis of case-control studies. Fertil Steril 98(3):702–712 e706

    Article  PubMed  PubMed Central  Google Scholar 

  • Nothnick WB, Healy C (2010) Estrogen induces distinct patterns of microRNA expression within the mouse uterus. Reprod Sci 17(11):987–994

    Article  CAS  PubMed  Google Scholar 

  • Nothnick WB, Graham A, Holbert J, Weiss MJ (2014) miR-451 deficiency is associated with altered endometrial fibrinogen alpha chain expression and reduced endometriotic implant establishment in an experimental mouse model. PLoS One 9(6):e100336

    Article  PubMed  PubMed Central  Google Scholar 

  • Nothnick WB, Swan K, Flyckt R, Falcone T, Graham A (2019) Human endometriotic lesion expression of the miR-144-3p/miR-451a cluster, its correlation with markers of cell survival and origin of lesion content. Sci Rep 9(1):8823

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pallacks C, Hirchenhain J, Krussel JS, Fehm TN, Fehr D (2017) Endometriosis doubles odds for miscarriage in patients undergoing IVF or ICSI. Eur J Obstet Gynecol Reprod Biol 213:33–38

    Article  PubMed  Google Scholar 

  • Qiu JJ et al (2019) The Exosomal long noncoding RNA aHIF is upregulated in serum from patients with endometriosis and promotes angiogenesis in endometriosis. Reprod Sci 26(12):1590–1602

    Article  CAS  PubMed  Google Scholar 

  • Rier SE, Martin DC, Bowman RE, Dmowski WP, Becker JL (1993) Endometriosis in rhesus monkeys (Macaca mulatta) following chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Fundam Appl Toxicol 21(4):433–441

    Article  CAS  PubMed  Google Scholar 

  • Sampson JA (1927) Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation. Am J Pathol 3(2):93–110 143

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sapkota Y et al (2017) Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism. Nat Commun 8:15539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schenken RS, Asch RH, Williams RF, Hodgen GD (1984a) Etiology of infertility in monkeys with endometriosis: measurement of peritoneal fluid prostaglandins. Am J Obstet Gynecol 150(4):349–353

    Article  CAS  PubMed  Google Scholar 

  • Schenken RS, Asch RH, Williams RF, Hodgen GD (1984b) Etiology of infertility in monkeys with endometriosis: luteinized unruptured follicles, luteal phase defects, pelvic adhesions, and spontaneous abortions. Fertil Steril 41(1):122–130

    Article  CAS  PubMed  Google Scholar 

  • Shafrir AL et al (2018) Risk for and consequences of endometriosis: a critical epidemiologic review. Best Pract Res Clin Obstet Gynaecol 51:1–15

    Article  CAS  PubMed  Google Scholar 

  • Sharpe RM, Skakkebaek NE (1993) Are oestrogens involved in falling sperm counts and disorders of the reproductive tract? Lancet 341:125–126

    Article  Google Scholar 

  • Simoens S et al (2012) The burden of endometriosis: costs and quality of life of women with endometriosis and treated in referral centres. Hum Reprod 27(5):1292–1299

    Article  PubMed  Google Scholar 

  • Stilley JA, Woods-Marshall R, Sutovsky M, Sutovsky P, Sharpe-Timms KL (2009) Reduced fecundity in female rats with surgically induced endometriosis and in their daughters: a potential role for tissue inhibitors of metalloproteinase 1. Biol Reprod 80(4):649–656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stilley JA, Birt JA, Sharpe-Timms KL (2012) Cellular and molecular basis for endometriosis-associated infertility. Cell Tissue Res 349(3):849–862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stillman RJ (1982) In utero exposure to diethylstilbestrol: adverse effects on the reproductive tract and reproductive performance in male and female offspring. Am J Obstet Gynecol 142:905–921

    Article  CAS  PubMed  Google Scholar 

  • Tappe-Theodor A, King T, Morgan MM (2019) Pros and cons of clinically relevant methods to assess pain in rodents. Neurosci Biobehav Rev 100:335–343

    Article  PubMed  PubMed Central  Google Scholar 

  • Taylor HS, Alderman Iii M, D’Hooghe TM, Fazleabas AT, Duleba AJ (2017) Effect of simvastatin on baboon endometriosis. Biol Reprod 97(1):32–38

    Article  PubMed  PubMed Central  Google Scholar 

  • Teague EM, Print CG, Hull ML (2010) The role of microRNAs in endometriosis and associated reproductive conditions. Hum Reprod Update 16(2):142–165

    Article  PubMed  CAS  Google Scholar 

  • Tyler C, Jobling S, Sumpter J (1998) Endocrine disruption in wildlife. Crit Rev Toxicol 28:319–361

    Article  CAS  PubMed  Google Scholar 

  • Vercellini P et al (2007) Association between endometriosis stage, lesion type, patient characteristics and severity of pelvic pain symptoms: a multivariate analysis of over 1000 patients. Hum Reprod 22(1):266–271

    Article  CAS  PubMed  Google Scholar 

  • Vercellini P, Vigano P, Somigliana E, Fedele L (2014) Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol 10(5):261–275

    Article  CAS  PubMed  Google Scholar 

  • Vigano P et al (2017) Time to redefine endometriosis including its pro-fibrotic nature. Hum Reprod 33:1–6

    Google Scholar 

  • Vitonis AF et al (2014) World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project: II. Clinical and covariate phenotype data collection in endometriosis research. Fertil Steril 102(5):1223–1232

    Article  PubMed  PubMed Central  Google Scholar 

  • Wodarski R et al (2016) Cross-centre replication of suppressed burrowing behaviour as an ethologically relevant pain outcome measure in the rat: a prospective multicentre study. Pain 157(10):2350–2365

    Article  PubMed  PubMed Central  Google Scholar 

  • Yan D, Liu X, Guo SW (2019) The establishment of a mouse model of deep endometriosis. Hum Reprod 34(2):235–247

    Article  CAS  PubMed  Google Scholar 

  • Yilmaz BD, Bulun SE (2019) Endometriosis and nuclear receptors. Hum Reprod Update 25(4):473–485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yovich JL, Rowlands PK, Lingham S, Sillender M, Srinivasan S (2019) Pathogenesis of endometriosis: look no further than John Sampson. Reprod BioMed Online 40:7–11

    Article  PubMed  Google Scholar 

  • Zhang L et al (2020) Serum exosomal microRNAs as potential circulating biomarkers for endometriosis. Dis Markers 2020:2456340

    PubMed  PubMed Central  Google Scholar 

  • Zondervan K et al (2002) The genetic epidemiology of spontaneous endometriosis in the rhesus monkey. Ann N Y Acad Sci 955:233–238; discussion 293–235, 396–406

    Article  PubMed  Google Scholar 

  • Zondervan KT, Becker CM, Missmer SA (2020) Endometriosis. N Engl J Med 382(13):1244–1256

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Research on reproductive physiology and disorders including endometriosis conducted in the Saunders Laboratory has been supported by grants from the Medical Research Council (MR/N024524/1, MR/P00265X/1, G1100356/1) and the European Union (MOMENDO, H2020-MSCA-RISE-2015).

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  1. Centre for Inflammation Research, The Queen’s Medical Research Institute, The University of Edinburgh, Edinburgh, UK

    Philippa T. K. Saunders

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  1. Philippa T. K. Saunders
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Correspondence to Philippa T. K. Saunders .

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  1. Division of Reproductive & Perinatal Research, The University of Missouri School of Medicine, Columbia, MO, USA

    Kathy L. Sharpe-Timms

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Saunders, P.T.K. (2020). What Have We Learned from Animal Models of Endometriosis and How Can We Use the Knowledge Gained to Improve Treatment of Patients?. In: Sharpe-Timms, K.L. (eds) Animal Models for Endometriosis. Advances in Anatomy, Embryology and Cell Biology, vol 232. Springer, Cham. https://doi.org/10.1007/978-3-030-51856-1_6

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