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Serdar Bulun, MD George H. Gardner Professor of Clinical Gynecology

Pathogenesis of Pain in Endometriosis. Serdar Bulun, MD George H. Gardner Professor of Clinical Gynecology Chief, Division of Reproductive Biology Research Department of Obstetrics and Gynecology Northwestern University, Chicago, IL. ENDOMETRIOSIS.

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Serdar Bulun, MD George H. Gardner Professor of Clinical Gynecology

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  1. Pathogenesis of Pain in Endometriosis Serdar Bulun, MD George H. Gardner Professor of Clinical Gynecology Chief, Division of Reproductive Biology ResearchDepartment of Obstetrics and Gynecology Northwestern University, Chicago, IL

  2. ENDOMETRIOSIS • Common cause of chronic pelvic pain and infertility • Polygenic inheritance and multifactorial etiology • 3-6 million women of reproductive age are affected in the USA • Responsible for 10%-15% • of all hysterectomies • performed in the USA

  3. STROMA GLANDS

  4. MEDICAL TREATMENT OPTIONS • Oral contraceptives • GnRH analogs • Progestins • Aromatase inhibitors • Selective Progesterone Receptor Modulators

  5. aromatase ENDOMETRIOSIS CHOLESTEROL ANDROSTENEDIONE StAR adrenal 3-Estradiol ANDROSTENEDIONE ESTRONE ANDROSTENEDIONE aromatase 1-Estradiol OVARY 2-Estradiol aromatase inhibitor GnRH-a OC FAT AND SKIN

  6. SF1 SF1 PRECURSOR Endometrium from Disease-free Women 1 COX-2 PRECURSOR PGE2 PGE2 aromatase PRECURSOR ESTROGEN Endometrium from Women with Endometriosis E 2 PGE2 COX-2 PGE2 PRECURSOR aromatase ESTROGEN E PRECURSOR COX-2 PGE2 3 PGE2 PRECURSOR Endometriosis Noble, et al, JCEM, 1996; Ota, et al, 2001

  7. NUCLEAR RECEPTORS (NR) NR NR P P BIOLOGIC FUNCTION e.g., DIFFERENTIATION PROTEIN PRODUCTS OF TARGET GENES NR P membrane receptor nonclassical Src CYTOPLASM MAPK steroid receptor orphan nuclear receptor NR NR P classical NUCLEUS TF Target gene NRE DNA

  8. NUCLEAR RECEPTORS AND ENDOMETRIOSIS ENDOMETRIUM (TISSUE) OVARIAN ENDOMETRIOMA (TISSUE) 14.1 142.4 9.3 >12,000 1.0 8.9 10 9 0.8 8 7 0.6 fold difference (mRNA by real-time PCR) 6 SF1 mRNA 5 0.4 4 3 0.2 2 1 PR-B Total PR ERβ E-IUM E-OSIS ERα Xu Q et al, BOR 2007

  9. EPIGENETIC DEFECTS IN ENDOMETRIOSISSF-1 HYPOMETHYLATION

  10. on exon1 exon2 exon3 Promoter CpG island off exon1 exon2 exon3 Methylation of CpG islands at promoters and gene expression Unmethylated CpG site Methylated CpG site

  11. SF1 GENE PROMOTER NORMAL SUBJECTS PATIENTS WITH ENDOMETRIOSIS

  12. SF1 PROMOTER IS NOT METHYLATED IN ENDOMETRIOSIS ENDOMETRIOSIS SF1 Transcription coactivating on complex exon1 exon2 exon1 exon2 exon1 exon2 mSin3A HDAC1 ENDOMETRIUM SF1 off MeCP2 exon1 exon2 exon1 exon2 exon1 exon2 unmethylated CpG island methylated CpG island Xu Q et al, JCEM 2007

  13. ROLE OF SF-1 IN ESTROGEN PRODUCTION

  14. B D A * p<0.05 p<0.01 * * 2.5 160 0.35 140 0.3 2.0 120 0.25 100 1.5 0.2 80 0.15 60 1 0.1 40 0.5 0.05 20 E-IUM E-OSIS E-IUM E-OSIS * 1.0 0.8 0.6 0.4 0.2 E-IUM E-OSIS PERITONEAL ENDOMETRIOSIS C p<0.001 p<0.01 * 0.7 0.6 0.5 P450scc mRNA (amol/mg 18S) StAR mRNA (amol/mg 18S) P450c17 mRNA (amol/mg 18S) 3HSDBII (amol/mg 18S) 0.4 0.3 0.2 0.1 E-OSIS E-OSIS E-IUM E-IUM G F E p<0.05 p<0.001 p<0.001 * 2.0 4 1.5 3 P450arom mRNA (amol/mg 18S) * LRH-1 mRNA (amol/mg 18S) SF-1 mRNA (amol/mg 18S) 2 1 1 0.5 un- detectable E-IUM E-OSIS E-IUM E-OSIS Attar and Tokunaga et al, JCEM, 2009

  15. OVARIAN ENDOMETRIOTIC STROMAL CELLS * 1.2 1.0 *p= 0.030 0.8 P450arom (amol/mg 18S) 0.6 * 0.4 0.2 0.0 E-IUM E-IUM E-OSIS E-OSIS PGE2: - + - + PGE2: - + - + 0.12 * 14 *p= 0.048 12 0.10 10 0.08 P450c17 (amol/mg 18S) P450scc (amol/mg 18S) 8 0.06 * 6 0.04 4 0.02 2 0.00 0 E-OSIS E-OSIS E-OSIS E-OSIS PGE2: - + - + B A * * 30 *p= 0.032 25 20 * StAR (amol/mg 18S) * 15 10 5 0 E-IUM E-IUM D C * 0.06 * 0.25 * 0.05 *p= 0.05 *p= 0.012 0.20 0.04 HSD3BI (amol/mg 18S) HSD3BII (amol/mg 18S) 0.15 0.03 0.10 0.02 * 0.05 0.01 0.00 0.00 E-IUM E-IUM E-OSIS E-OSIS E-IUM E-IUM E-OSIS E-OSIS PGE2: - + - + PGE2: - + - + F E *p= 0.042 E-IUM E-IUM E-IUM E-IUM E-OSIS E-OSIS PGE2: - + - + Attar and Tokunaga et al, JCEM, 2009

  16. ENDOMETRIOSIS 22 21 20 23 26 18 24 12 25 27 17 11 13 16 19 15 14 HO HO HO 9 1 2 10 8 3 5 7 6 4 CH3 CH3 CH3 CH3 O O O O C C C C HO O OH OH O OH O O O O O OH HO HO cholesterol StAR P450scc MITOCHONDRION HSD3B2 nmol/L ++++ pregnenolone PROGESTERONE +++ ++ + P450c17 P450c17 HSD3B2 17-hydroxyprogesterone 17-hydroxypregnenolone P450c17 P450c17 HSD3B2 HSD17B1 androstenedione testosterone dehydroepiandrosterone P450arom P450arom HSD17B1 pmol/L estrone ESTRADIOL

  17. SF1 ++ aromatase inhibitor ENDOMETRIOSIS TISSUE ++ PGE2 AA COX-2 ++ IL-1b VEGF ++ CHOLESTEROL StAR scc estradiol 3b-HSD-2 adrenal 17-OH-lase aromatase 17/20-lyase estrone androstenedione Noble et al, JCEM, 1997 Zeitoun et al, Mol Endo, 1999 Tamura et al, JBC, 2002 Tamura et al, JCEM, 2002 Tamura et al, JCEM, 2002 Attar and Tokunaga, et al, JCEM, 2009 Takayama et al, Fertil Steril, 1998 Ailawadi et al, Fertil Steril, 2004 Amsterdam et al, Fertil Steril, 2005

  18. Prememopausal on AI (Hypothetical) Prememopausal on AI + OC or P Aromatase E2 Aromatase E2 FSH LH FSH LH OC P GnRHa Aromatase Aromatase Follicle Development AI AI Aromatase Aromatase Peripheral Aromatase Peripheral Aromatase Postmenopausal on AI Hypothalamus Aromatase FSH LH Pituitary No Follicular Aromatase Ovary AI Endometriosis Aromatase Peripheral Tissues Peripheral Aromatase Takayama et al, Fertil Steril, 1998; Ailawadi et al, Fertil Steril, 2004; Soysal et al, Human Reproduction, 2004; Amsterdam et al, Fertil Steril, 2005; Attar and Bulun Fertil Steril, 2006

  19. 10 10 5 5 0 PREMENOPAUSAL WOMEN TREATED WITH LETROZOLE AND NORETHINDRONE ACETATE Pre- and Post-treatment Pain Scores (n=10) Average Pain Score p=0.0028 0 post-treatment Baseline Ailawadi, et al, Fertil Steril, 2004

  20. PREMENOPAUSAL WOMEN TREATED WITH LETROZOLE AND NORETHINDRONE ACETATE Before Treatment Ailawadi, et al, Fertil Steril, 2004

  21. PREMENOPAUSAL WOMEN TREATED WITH LETROZOLE AND NORETHINDRONE ACETATE Before Treatment Ailawadi, et al, Fertil Steril, 2004

  22. PREMENOPAUSAL WOMEN TREATED WITH LETROZOLE AND NORETHINDRONE ACETATE After Treatment for 6 Months Ailawadi, et al, Fertil Steril, 2004

  23. SIDE EFFECTS Mild hot flushes (2/day – 1/week) Sleepiness Mood swings Decreased libido No bone loss

  24. TREATMENT RECOMMENDATIONS • An aromatase inhibitor is the treatment of choice for persistent postmenopausal endometriosis • A combination of an aromatase inhibitor with an OC or GnRH analog may be used to treat endometriosis-related pain not responding to conventional treatments • Await results of randomized studies for the routine use of aromatase inhibitors for premenopausal endometriosis, uterine leiomyomata and ovulation induction

  25. EPIGENETIC DEFECTS IN ENDOMETRIOSISERb HYPOMETHYLATION

  26. Bisulfite sequencing: ERβ promoter 44481bp 10957bp TSS +1 Exon 0N Exon 0K Exon 1 Exon 0N Classical CpG island 556bp 100bp Bisulfite sequence PATIENTS WITH ENDOMETRIOSIS NORMAL SUBJECTS P< 0.001

  27. Pr 0N Pr 0K Methylated CpG island ERb gene Pr 0N Pr 0K HDAC1 + CBP mSin3a MeCP2 Unmethylated CpG island ENDOMETRIOSIS ENDOMETRIUM

  28. ROLE OF ERb IN PROSTAGLANDIN PRODUCTION

  29. PROSTAGLANDIN AND ESTRADIOLBIOSYNTHETIC PATHWAYS ANDROSTENEDIONE Aromatase ESTRONE ? PGE2 HSD17B1 mPGES-1 ESTRADIOL PGH2 COX-2 ARACHIDONIC ACID PLA2 PHOSPHOLIPIDS

  30. PROSTAGLANDIN AND ESTRADIOLBIOSYNTHETIC PATHWAYS ANDROSTENEDIONE Aromatase ESTRONE PGE2 HSD17B1 mPGES-1 ESTRADIOL PGH2 ERb COX-2 ARACHIDONIC ACID IL-1b VEGF PLA2 PHOSPHOLIPIDS

  31. ROLE OF ERb IN PROGESTERONE RESISTANCE

  32. E2 E1: E2 + P E2 Menses Secretory endometrium Proliferative endometrium _ _ ++++ _ _ ++++ 17b-HSD-2: (Epithelial) Bulun SE, et al, MCE, 2006

  33. OH HO OH O HO HO O HSD17B2 E2 HO E1 + EUTOPIC ENDOMETRIUM PROGESTERONE HSD17B2 E2 E1 progesterone resistance ENDOMETRIOSIS PROGESTERONE Zeitoun, et al, JCEM, 1998 Yang, et al, Mol Endo, 2001

  34. T47D 10 6 12 14 16 18 24 Cycle Day: 3 26 PR-B EUTOPIC ENDOMETRIUM PR-A PR-B ENDOMETRIOSIS PR-A Attia, et al, JCEM, 2000

  35. HDAC1 Prom 0N mSin3a MeCP2 ERb: CpG island ERb ERb ERb Prom A Prom C ERa gene ERa: ERb ERa ERb + PR-A PR-B PR-B: PR gene PR-A: ENDOMETRIOSIS ERb gene Trukhacheva et al, JCEM, 2009

  36. Bulun, SE, NEJM 2009 Cheng, Y, JCEM, 2008

  37. BIG PICTURE

  38. PGE2 SF1 methylation COX-2 arom HSD17B2 estradiol estrone CHOLESTEROL retinoic acid PR ERb methylation ERa Bulun et al, NEJM, 2009

  39. Bulun, SE, NEJM 2009

  40. NORMAL ENDOMETRIOSIS ROLE OF EPIGENETICS IN MECHANISM OF ENDOMETRIOSIS Painful menses Menses unmethylated promoter peritoneum peritoneum methylated promoter + OTHERS SF1 ERb FAILURE OF CELLS TO IMPLANT SURVIVAL AND IMPLANTATION OF ENDOMETRIOTIC CELLS CELLS CLEARED BY IMMUNE SYSTEM

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