Molecular Biology of Endometriosis: From Aromatase to Genomic Abnormalities

 

 Buy Article Permissions and Reprints

Abstract

Endometriosis has been initially described as the presence of ectopic endometrial tissue on pelvic organs or in extrapelvic sites; and this has been used as its key pathologic feature ever since. Endometriosis responds to fluctuations in estrogen and progesterone by growth and inflammation, leading to pain aggravated by menses. It was proposed that pelvic endometriosis primarily originate from retrograde menstruation of a critical number of eutopic endometrial cells with stem characteristics. This postulate is supported by the molecular defects found in ectopic endometriotic tissue. Genome-wide differences in CpG methylation between eutopic endometrial and endometriotic stromal cells are present. Defective CpG methylation affecting several genes that encode key transcription factors such as GATA6, steroidogenic factor-1, and estrogen receptor-β in endometriosis gives rise to overproduction of local estrogen and prostaglandins and suppression of progesterone receptor. Progesterone receptor deficiency leads to progesterone resistance, resulting in decreased retinol uptake and retinoic acid production and altered retinoic acid action. These molecular defects collectively give rise to poor cellular differentiation, enhanced survival, and increased inflammation, which are the biological hallmarks of endometriotic tissue.

• References

• 1 Noble LS, Simpson ER, Johns A, Bulun SE. Aromatase expression in endometriosis. J Clin Endocrinol Metab 1996; 81 (1) 174-179
  CrossrefPubMedGoogle Scholar
• 2 Noble LS, Takayama K, Zeitoun KM , et al. Prostaglandin E2 stimulates aromatase expression in endometriosis-derived stromal cells. J Clin Endocrinol Metab 1997; 82 (2) 600-606
  CrossrefPubMedGoogle Scholar
• 3 Bulun SE. Endometriosis. N Engl J Med 2009; 360 (3) 268-279
  CrossrefPubMedGoogle Scholar
• 4 Attar E, Tokunaga H, Imir G , 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 (2) 623-631
  CrossrefPubMedGoogle Scholar
• 5 Zeitoun K, Takayama K, Sasano H , et al. Deficient 17beta-hydroxysteroid dehydrogenase type 2 expression in endometriosis: failure to metabolize 17beta-estradiol. J Clin Endocrinol Metab 1998; 83 (12) 4474-4480
  CrossrefPubMedGoogle Scholar
• 6 Xue Q, Lin Z, Yin P , et al. Transcriptional activation of steroidogenic factor-1 by hypomethylation of the 5′ CpG island in endometriosis. J Clin Endocrinol Metab 2007; 92 (8) 3261-3267
  CrossrefPubMedGoogle Scholar
• 7 Xue Q, Lin Z, Cheng YH , et al. Promoter methylation regulates estrogen receptor 2 in human endometrium and endometriosis. Biol Reprod 2007; 77 (4) 681-687
  CrossrefPubMedGoogle Scholar
• 8 Monsivais D, Dyson MT, Yin P , et al. ERβ- and prostaglandin E2-regulated pathways integrate cell proliferation via Ras-like and estrogen-regulated growth inhibitor in endometriosis. Mol Endocrinol 2014; 28 (8) 1304-1315
  CrossrefPubMedGoogle Scholar
• 9 Pavone ME, Dyson M, Reirstad S , et al. Endometriosis expresses a molecular pattern consistent with decreased retinoid uptake, metabolism and action. Hum Reprod 2011; 26 (8) 2157-2164
  CrossrefPubMedGoogle Scholar
• 10 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-E309
  CrossrefPubMedGoogle Scholar
• 11 Cheng YH, Utsunomiya H, Pavone ME, Yin P, Bulun SE. Retinoic acid inhibits endometrial cancer cell growth via multiple genomic mechanisms. J Mol Endocrinol 2011; 46 (2) 139-153
  CrossrefPubMedGoogle Scholar
• 12 Ma JJ, Monsivais D, Dyson MT , et al. Ligand-activated peroxisome proliferator-activated receptor β/δ modulates human endometrial cancer cell survival. Horm Cancer 2013; 4: 358-370
  CrossrefPubMedGoogle Scholar
• 13 Mittal N, Malpani S, Dyson M , et al. Fenretinide: a novel treatment for endometrial cancer. PLoS ONE 2014; 9 (10) e110410
  CrossrefPubMedGoogle Scholar
• 14 Cheng YH, Yin P, Xue Q, Yilmaz B, Dawson MI, Bulun SE. Retinoic acid (RA) regulates 17beta-hydroxysteroid dehydrogenase type 2 expression in endometrium: interaction of RA receptors with specificity protein (SP) 1/SP3 for estradiol metabolism. J Clin Endocrinol Metab 2008; 93 (5) 1915-1923
  CrossrefPubMedGoogle Scholar
• 15 Lin BC, Suzawa M, Blind RD , et al. Stimulating the GPR30 estrogen receptor with a novel tamoxifen analogue activates SF-1 and promotes endometrial cell proliferation. Cancer Res 2009; 69 (13) 5415-5423
  CrossrefPubMedGoogle Scholar
• 16 Xue Q, Zhou YF, Zhu SN, Bulun SE. Hypermethylation of the CpG island spanning from exon II to intron III is associated with steroidogenic factor 1 expression in stromal cells of endometriosis. Reprod Sci 2011; 18 (11) 1080-1084
  CrossrefPubMedGoogle Scholar
• 17 Xue Q, Xu Y, Yang H , et al. Methylation of a novel CpG island of intron 1 is associated with steroidogenic factor 1 expression in endometriotic stromal cells. Reprod Sci 2014; 21 (3) 395-400
  CrossrefPubMedGoogle Scholar
• 18 Dyson MT, Roqueiro D, Monsivais D , et al. Genome-wide DNA methylation analysis predicts an epigenetic switch for GATA factor expression in endometriosis. PLoS Genet 2014; 10 (3) e1004158
  CrossrefPubMedGoogle Scholar
• 19 Takayama K, Zeitoun K, Gunby RT, Sasano H, Carr BR, Bulun SE. Treatment of severe postmenopausal endometriosis with an aromatase inhibitor. Fertil Steril 1998; 69 (4) 709-713
  CrossrefPubMedGoogle Scholar
• 20 Abushahin F, Goldman KN, Barbieri E, Milad M, Rademaker A, Bulun SE. Aromatase inhibition for refractory endometriosis-related chronic pelvic pain. Fertil Steril 2011; 96 (4) 939-942
  CrossrefPubMedGoogle Scholar
• 21 Dyson MT, Bulun SE. Cutting SRC-1 down to size in endometriosis. Nat Med 2012; 18 (7) 1016-1018
  CrossrefPubMedGoogle Scholar
• 22 Langoi D, Pavone ME, Gurates B, Chai D, Fazleabas A, Bulun SE. Aromatase inhibitor treatment limits progression of peritoneal endometriosis in baboons. Fertil Steril 2013; 99 (3) 656-662.e3
  CrossrefPubMedGoogle Scholar
• 23 Pavone ME, Bulun SE. Aromatase inhibitors for the treatment of endometriosis. Fertil Steril 2012; 98 (6) 1370-1379
  CrossrefPubMedGoogle Scholar
• 24 Bulun SE, Cheng YH, Pavone ME , et al. Estrogen receptor-beta, estrogen receptor-alpha, and progesterone resistance in endometriosis. Semin Reprod Med 2010; 28 (1) 36-43
  Article in Thieme ConnectPubMedGoogle Scholar
• 25 Bulun SE, Monsavais D, Pavone ME , et al. Role of estrogen receptor-β in endometriosis. Semin Reprod Med 2012; 30 (1) 39-45
  Article in Thieme ConnectPubMedGoogle Scholar
• 26 Attar E, Bulun SE. Aromatase inhibitors: the next generation of therapeutics for endometriosis?. Fertil Steril 2006; 85 (5) 1307-1318
  CrossrefPubMedGoogle Scholar