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Understanding pathogenesis of endometriosis and new treatment modalities Erkut Attar, M.D. PhD. Istanbul University Istanbul Medical School Department of Obstetrics & Gynecology Division of Reproductive Endocrinology & Infertility In memory of Professor Oktay Kadayıfcı The Golden Rule: Treat others how you want to be treated... 2 Endometriosis? ■ Affects nearly 1 in 7 women of reproductive age ■ Third most common gynecologic disorder that requires hospitalization, and a leading cause of hysterectomy ■ Literature and other available data suggest that endometriosis places a considerable burden on patients and society ■ No new treatment modalities since the last two decades Current areas of research in the etiopathogenesis of endometriosis ■ ■ ■ ■ ■ ■ Immunology Environmental Science Genetics Cancer Biology Hormonal factors Steroidogenesis Attar E Endometriosis. In: The Endometrium, Ed. Fazlebas A. 2nd Edition, Taylor Francis Books Ltd Normal Endometrium and Endometriosis 5 ENDOMETRIUM (NORMAL) ENDOMETRIUM (ENDOMETRIOSIS) ENDOMETRIOTIC TISSUE COUP-TF COUP-TF WT-1 COX2 PGE2 COUP-TF WT-1 SF-1 StAR? Aromatase COX2 E2 PGE2 WT-1 SF-1 StAR Aromatase COX2 E2 PGE2 Attar E and S.E. Bulun, Hum Reprod Update.2005; 0: 341 Epithelial Cell Arachidonic Acid IL1- COX-2 VEGF INFLAMMATION Cholesterol PGE2 cAMP E2 GROWTH StAR Aromatase Adrenal Ovary E1 A Endometriotic Cell Attar E and S.E. Bulun, Hum Reprod Update.2005; 0: 341 Molecular distinction between endometrium and endometriotic tissue 8 Disrupted paracrine action of progesterone 11 Epigenethic Changes in Endometriosis 12 Speculated Changes in DNA Methylation from Genetic or E 13 New Drugs? ■ Local aromatase gene expression and enzyme activity were demonstrated in endometriotic implants ■ Recently, we showed that aromatase enzyme inhibitors treat endometriosis successfully ■ However, current aromatase inhibitors cause total body estrogen deprivation regardless of promoter use PII regulates aromatase synthesis in endometriotic cells AA COX-2 PGE2 PGH2 cAMP Co-Act (1) C/EBP Enh CRS Placenta AROMATASE Co-Act (2) SF-1 X PII II NRHS Skin/ Adipose Brain Bone Adipose/ Cancer Ovary/ Endometriosis ATG I.2a 5´ Coding region I.4 I.1 I.7 I.f I.6 I.3 PII II 3´ X AG/GACT COMMON SPLICE SITE TELOMERE CYP19 CENTROMERE What is NaBu? ■ ■ ■ ■ ■ ■ A natural compound A four carbon fatty acid Inhibits histone deacetylase activity inhibits growth arrest and induces cell differentiation induces apoptosis in vitro in cancer cells MECHANISM of anti-neoplastic activity? Why it is important to test this compound in endometriosis? ■ ■ ■ ■ orally administered clinically evaluated in a phase I study for a solid tumor inhibits aromatase expression A NEW DRUG for the treatment endometriosis? Endometriotic Cells 24h Treatment 0.5 0.4 PMol/mg 0.3 *p<0.01 * 0.2 **p<0.01 ** 0.1 0.0 Control 5 mM/mL 10 mM/mL 15 mM/mL The effect of NaBu on JEG-3 Cells (Choriocarcinoma cell line) 18 *P<0.05 16 **P<0.05 ** * 14 pmol/mg 12 10 8 6 4 2 0 C NaBu cAMP cAMP+NaBU NaBu inhibits ATF-2 binding to Promoter II NaBu (mM/mL) 0 5 10 15 A B C A: ATF-2 B: IgG C:Input Summary PGE2 or cAMP PKA p38 TauT PKC JNK SB202190 AS601245 P ATF-2 P c-jun Promoter II Animal Models of Endometriosis NaBu use in an animal model Conclusion ■ Nutrition: Treatment and Prevention? ■ ■ ■ ■ ■ Vitamin D, RA and... Food intake Prevention during pregnancy? Histone deacetylase inhibitors (NaBU) More... 25 Thank You… Northwestern Group Serdar. Bulun, MD. (PI) Dong Chen, PhD. Santanu Deb.,PhD. Masahi Demura, MD. Veysel Fenkci,MD. Gonca Imir,MD. Scott Reieresterad Hiroki Utsinomia, MD. Bertan Yılmaz,PhD. Ping Yin, PhD. Istanbul Group Rukset Attar, MD., PhD. Narter Yeşildağlar, MD. Pelin Balcık, MS
