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Estrogen is essential but not sufficient to induce endometriosis

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Abstract

Endometriosis is a common gynaecological disorder of unknown aetiology. Among the several factors, estrogen has been implicated as a causative factor in endometriosis. In the present study using mouse model, we assessed the role of estrogen in the initial implantation and growth of endometrium in ectopic locations. Uterine tissues from green fluorescent protein (GFP) mice were transplanted in to the peritoneum of wild type mice in presence and absence of estrogen. As compared to untreated controls, the implantation of uterine tissue at ectopic locations was higher when estrogen was administered to both host and donor animals. However, this effect was not sustained as lesions regressed within 14 days of treatment. Irrespective of the treatment, peritoneal adipose was the most preferred site of lesion establishment. The lesions did not have typical features of the endometriosis (presence of glands and stroma) even after estrogen treatment and the ectopic tissue underwent regression by apoptosis irrespective of treatment. Since estrogen promotes implantation of endometrial tissue to ectopic locations but failure of these ectopic lesions to grow and sustain even in high estrogenic environment we propose that estrogen is necessary but not sufficient to sustain endometriosis.

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References

  • Abid S, Gokral J, Maitra A, Meherji P, Kadam S, Pires E, Modi D 2008 Altered expression of progesterone receptors in testis of infertile men. Reprod. BioMed. Online 17 175–184

    Article  CAS  PubMed  Google Scholar 

  • Becker CM, Rohwer N, Funakoshi T, Cramer T, Bernhardt W, Birsner A, Folkman J and D’Amato RJ 2008 2-Methoxyestradiol inhibits hypoxia-inducible factor-1α and suppresses growth of lesions in a mouse model of endometriosis. Am. J. Pathol. 172 534–544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bedaiwy MA, Alfaraj S, Yong P, Casper R. 2017 New developments in the medical treatment of endometriosis. Fertil. Steril.. doi:10.1016/j.fertnstert.2016.12.025

  • Bulletti C, Coccia ME, Battistoni S and Borini A 2010 Endometriosis and infertility. J. Assist. Reprod. Genet. 27 441–447

    Article  PubMed  PubMed Central  Google Scholar 

  • Bulun SE 2009 Endometriosis. N. Engl. J. Med. 360 268–79

    Article  CAS  PubMed  Google Scholar 

  • Burns KA, Rodriguez KF, Hewitt SC, Janardhan KS, Young SL and Korach KS 2012 Role of estrogen receptor signaling required for endometriosis-like lesion establishment in a mouse model. Endocrinology 153 3960–3971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cummings AM and Metcalf JL 1995 Induction of endometriosis in mice: a new model sensitive to estrogen. Reprod. Toxicol. 9 233–238

    Article  CAS  PubMed  Google Scholar 

  • Cunha GR and Lung B 1979 The importance of stroma in morphogenesis and functional activity of urogenital epithelium. In Vitro. 15 50–71

    Article  CAS  PubMed  Google Scholar 

  • Giudice LC and Kao LC 2004 Endometriosis. Lancet 364 1789–99

    Article  PubMed  Google Scholar 

  • Godbole G and Modi D 2010 Regulation of decidualization, interleukin-11 and interleukin-15 by homeobox A 10 in endometrial stromal cells. J. Reprod. Immunol.. 85 130–139

    Article  CAS  PubMed  Google Scholar 

  • Godbole GB, Modi DN and Puri CP 2007 Regulation of homeobox A10 expression in the primate endometrium by progesterone and embryonic stimuli. Reproduction 134 513–523

    Article  CAS  PubMed  Google Scholar 

  • Greaves E, Cousins FL, Murray A, Esnal-Zufiaurre A, Fassbender A, Horne AW and Saunders PTK 2014 A novel mouse model of endometriosis mimics human phenotype and reveals insights into the inflammatory contribution of shed endometrium. Am. J. Pathol. 184 1930–1939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hamilton RT, Rettberg JR, Mao Z, To J, Zhao L, Appt SE, Register TC, Kaplan JR and Brinton RD 2011 Hippocampal responsiveness to 17β-estradiol and equol after long-term ovariectomy: Implication for a therapeutic window of opportunity. Brain Res. 1379 11–22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Han SJ, Jung SY, Wu S, Hawkins SM, Park MJ, Kyo S, Qin J, Lydon JP, Tsai SY, Tsai M, DeMayo FJ and O’Malley BW 2015 Estrogen receptor b modulates apoptosis complexes and the inflammasome to drive the pathogenesis of endometriosis. Cell 163 960–974

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harris HA, Bruner-Tran KL, Zhang X, Osteen KG and Lyttle CR 2005 A selective estrogen receptor-b agonist causes lesion regression in an experimentally induced model of endometriosis. Hum. Reprod. 20 936–941

    Article  CAS  PubMed  Google Scholar 

  • Hirata T, Osuga Y, Yoshino O, Hirota Y, Harada M, Takemura Y, Morimoto C, Koga K, Yano T, Tsutsumi O and Taketani Y 2005 Development of an experimental model of endometriosis using mice that ubiquitously express green fluorescent protein. Hum. Reprod. 20 2092–2096

    Article  CAS  PubMed  Google Scholar 

  • Huhtinen K, Desai R, Ståhle M, Salminen A, Handelsman DJ, Perheentupa A and Poutanen M 2012 Endometrial and endometriotic concentrations of estrone and estradiol are determined by local metabolism rather than circulating levels. J. Clin. Endocrinol. Metab. 97 4228–4235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin Y, Lai M, Lei H and Wing LC 2006 Neutrophils and macrophages promote angiogenesis in the early stage of endometriosis in a mouse model. Endocrinology 147 1278–1286

    Article  CAS  PubMed  Google Scholar 

  • Menni K, Facchetti L and Cabassa P 2016 Extragenital endometriosis: assessment with MR imaging. A pictorial review. Br. J. Radiol.. 89 20150672

    Article  PubMed  Google Scholar 

  • Modi DN, Sane S and Bhartiya D 2003 Accelerated germ cell apoptosis in sex chromosome aneuploid fetal human gonads. Mol. Hum. Reprod.. 9 219–25

    Article  CAS  PubMed  Google Scholar 

  • Osuga Y 2010 Current concepts of the pathogenesis of endometriosis. Reprod. Med. Biol. 9 1–7

    Article  Google Scholar 

  • Park J, Euhus DM and Scherer PE 2011 Paracrine and endocrine effects of adipose tissue on cancer development and progression. Endocr. Rev. 32 550–570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rizner TL 2009 Estrogen metabolism and action in endometriosis. Mol. Cell Endocrinol. 307 8–18

    Article  CAS  PubMed  Google Scholar 

  • Rudzitis-Auth J, Nenicu A, Nickels RM, Menger MD and Laschke MW 2016 Estrogen stimulates homing of endothelial progenitor cells to endometriotic lesions. Am. J. Pathol. 186 1–14

    Article  Google Scholar 

  • Shao R, Cao S, Wang X, Feng Y and Billig H 2014 The elusive and controversial roles of estrogen and progesterone receptors in human endometriosis. Am. J. Transl. Res. 6 104–113

    PubMed  PubMed Central  Google Scholar 

  • Simmen RCM and Kelley AS 2016 Reversal of fortune: estrogen receptor-β in endometriosis. J. Mol. Endocrinol. 57 23–27

    Article  Google Scholar 

  • Somigliana E, Vigano P and Vignali M 1999 Endometriosis and unexplained recurrent spontaneous abortion: pathological states resulting from aberrant modulation of natural killer cell function? Hum. Reprod. Update 5 40–51

    Article  CAS  PubMed  Google Scholar 

  • Straub RH 2007 The complex role of estrogens in inflammation. Endocr. Rev. 28 521–574

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Wilkosz S, Pullen N, de-Giorgio-Miller A, Ireland G and Herrick S 2011 Cellular exchange in an endometriosis-adhesion model using GFP transgenic mice. Gynecol. Obstet. Invest. 72 90–97

    Article  CAS  PubMed  Google Scholar 

  • Xiong W, Zhang L, Yu L, Xie W, Man Y, Xiong Y, Liu H and Liu Y 2015 Estradiol promotes cells invasion by activating b-catenin signaling pathway in endometriosis. Reproduction 150 507–516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zeitoun KM and Bulun SE 1999 Aromatase: a key molecule in the pathophysiology of endometriosis and a therapeutic target. Fertil. Steril. 72 961–969

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We express our gratitude to the staff of Experimental Animal Facility for providing the animals in timely manner. The help extended by Mr. Suryakant (NEC division, NIRRH) towards histological preparations is gratefully acknowledged. The study was financially supported by grants from Department of Biotechnology (BT/PR6587/MED/30/886/2010) to DM and intramural support from the Indian Council of Medical Research (ICMR), New Delhi. MG is a recipient of the ICMR- postdoctoral fellowship (6th batch). NS is financially supported by a JRF from a DBT project (BT/514/NE/TBP/2013) to DM.

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  1. Molecular and Cellular Biology Laboratory, National Institute for Research in Reproductive Health, Mumbai, 400 012, India

    Mosami Galvankar, Neha Singh & Deepak Modi

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  1. Mosami Galvankar
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  2. Neha Singh
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  3. Deepak Modi
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Correspondence to Deepak Modi.

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Corresponding editor: S Shivaji

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Galvankar, M., Singh, N. & Modi, D. Estrogen is essential but not sufficient to induce endometriosis. J Biosci 42, 251–263 (2017). https://doi.org/10.1007/s12038-017-9687-4

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  • DOI: https://doi.org/10.1007/s12038-017-9687-4

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