Journal of Biosciences

, Volume 42, Issue 2, pp 251–263 | Cite as

Estrogen is essential but not sufficient to induce endometriosis

  • Mosami Galvankar
  • Neha Singh
  • Deepak ModiEmail author


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.


Apoptosis endometriosis estrogen GFP mice transplantation 



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.


  1. 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 17 175–184CrossRefPubMedGoogle Scholar
  2. 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. 172 534–544CrossRefPubMedPubMedCentralGoogle Scholar
  3. 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
  4. Bulletti C, Coccia ME, Battistoni S and Borini A 2010 Endometriosis and infertility. J. Assist. Reprod. Genet. 27 441–447CrossRefPubMedPubMedCentralGoogle Scholar
  5. Bulun SE 2009 Endometriosis. N. Engl. J. Med. 360 268–79CrossRefPubMedGoogle Scholar
  6. 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 3960–3971CrossRefPubMedPubMedCentralGoogle Scholar
  7. Cummings AM and Metcalf JL 1995 Induction of endometriosis in mice: a new model sensitive to estrogen. Reprod. Toxicol. 9 233–238CrossRefPubMedGoogle Scholar
  8. Cunha GR and Lung B 1979 The importance of stroma in morphogenesis and functional activity of urogenital epithelium. In Vitro. 15 50–71CrossRefPubMedGoogle Scholar
  9. Giudice LC and Kao LC 2004 Endometriosis. Lancet 364 1789–99CrossRefPubMedGoogle Scholar
  10. 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.. 85 130–139CrossRefPubMedGoogle Scholar
  11. Godbole GB, Modi DN and Puri CP 2007 Regulation of homeobox A10 expression in the primate endometrium by progesterone and embryonic stimuli. Reproduction 134 513–523CrossRefPubMedGoogle Scholar
  12. 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 1930–1939CrossRefPubMedPubMedCentralGoogle Scholar
  13. 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 11–22CrossRefPubMedPubMedCentralGoogle Scholar
  14. 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 163 960–974CrossRefPubMedPubMedCentralGoogle Scholar
  15. 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. 20 936–941CrossRefPubMedGoogle Scholar
  16. 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 2092–2096CrossRefPubMedGoogle Scholar
  17. 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 4228–4235CrossRefPubMedPubMedCentralGoogle Scholar
  18. 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 1278–1286CrossRefPubMedGoogle Scholar
  19. Menni K, Facchetti L and Cabassa P 2016 Extragenital endometriosis: assessment with MR imaging. A pictorial review. Br. J. Radiol.. 89 20150672CrossRefPubMedGoogle Scholar
  20. Modi DN, Sane S and Bhartiya D 2003 Accelerated germ cell apoptosis in sex chromosome aneuploid fetal human gonads. Mol. Hum. Reprod.. 9 219–25CrossRefPubMedGoogle Scholar
  21. Osuga Y 2010 Current concepts of the pathogenesis of endometriosis. Reprod. Med. Biol. 9 1–7CrossRefGoogle Scholar
  22. Park J, Euhus DM and Scherer PE 2011 Paracrine and endocrine effects of adipose tissue on cancer development and progression. Endocr. Rev. 32 550–570CrossRefPubMedPubMedCentralGoogle Scholar
  23. Rizner TL 2009 Estrogen metabolism and action in endometriosis. Mol. Cell Endocrinol. 307 8–18CrossRefPubMedGoogle Scholar
  24. 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 1–14CrossRefGoogle Scholar
  25. 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. 6 104–113PubMedPubMedCentralGoogle Scholar
  26. Simmen RCM and Kelley AS 2016 Reversal of fortune: estrogen receptor-β in endometriosis. J. Mol. Endocrinol. 57 23–27CrossRefGoogle Scholar
  27. 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 40–51CrossRefPubMedGoogle Scholar
  28. Straub RH 2007 The complex role of estrogens in inflammation. Endocr. Rev. 28 521–574CrossRefPubMedGoogle Scholar
  29. Vercellini P, Vigano P, Somigliana E and Fedele L 2014 Endometriosis: pathogenesis and treatment. Nat. Rev. Endocrinol. 10 261–275CrossRefPubMedGoogle Scholar
  30. 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 90–97CrossRefPubMedGoogle Scholar
  31. 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 150 507–516CrossRefPubMedPubMedCentralGoogle Scholar
  32. Zeitoun KM and Bulun SE 1999 Aromatase: a key molecule in the pathophysiology of endometriosis and a therapeutic target. Fertil. Steril. 72 961–969CrossRefPubMedGoogle Scholar

Copyright information

© Indian Academy of Sciences 2017

Authors and Affiliations

  1. 1.Molecular and Cellular Biology LaboratoryNational Institute for Research in Reproductive HealthMumbaiIndia

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