Update on Endometriosis Grampians Medicare Local 2 nd September, BHS

1. Update on EndometriosisGrampians Medicare Local2nd September, BHS Russell Dalton Ballarat IVF Ballarat Endometriosis Clinic Obstetrics & Gynaecology Ballarat

2. The Aim today.. • Young women with possible endometriosis • Older women with suspected endometriosis • What to look for. • Treatment options & rationale for these • Aromatase inhibitors • The role of endometriosis in subfertility • The future of endometriosis treatment

3. Endometriosis • Common condition 2-10 % of women • Presents: varying stages of reproductive life • Later presentation , tends to be more severe • Ectopic endometrium, • Pelvis, mainly in dependent areas. • Peritoneal cavity • Rarely other locations, • Rarely in oestrogenised males

4. Endometriosis images • Micro

5. Endometriosis:what happens? • Theories: • In situ development: coelomic metaplasia • Induction theory: differentiation of mesenchymal cells • Transplantation Theory: implantation of retrograde menstruation • Need a process of: • Survival of detached cells, attachment & invasion of peritoneum, • Proliferation & Neo-vascularization

6. Why does it happen? • Endometriosis cells : marked resistance to Apoptosis • Role of CD 1347 cell membrane glycoprotein controlling cell migration & Cadherin lack ( Inhibits cell spread) • Matrix metallo-proteinases ( disrupt intercellular bonds) • Vascular &epithelial growth factors, cytokines, growth factors (VEGF) released by abnormally functioning leucocytes • Genetics: Clear familial association • 6-7x more prevalent in first degree relatives of affected women • ?disease of Epigenetic origins increasing evidence

7. Endometriosis- The cost • Major burden on Health services • Annual Healthcare costs (US) :$2801 per patient • Loss of productivity (US) $1023 per patient • Significant adverse influence on QOL & rates of depression. • Contributor in 50% of couples with infertility

8. Endometriosis-Presenting symptoms • Pelvic pain • Dysmenorrhea • Pain related to function of pelvic organs • Bloating • Psychological sequelae. • Subfertility / Infertility

9. Endometriosis in Young women • Difficult clinical challenge. • Often generalized Gynae symptoms: • Pain, irregular bleeding, bloating, headaches, lethargy • What is normal? • Other influences on symptoms: • puberty, relationships etc • Is something else going on ?

10. Endo in Young women • Clinical assessment: • Appropriate history including sexual history • NB Ballarat 40% higher teen mum rate than Vic average) • More specifically related to menstrual cycle, more likely to be endometriosis • Physical examination:limited due to age etc • Ultrasound : TA Sensitivity -limited • Exclude other causes – sepsis, IBD other bowel pathology,

11. Endo in Younger women.Treatment Principles • Our Goal: • Minimize symptoms & side effects • Stay out of Emergency Department • Stay off codeine/Narcotic based analgesia • Have High QOL / emotional well being scores • Suppression of ovulation

12. Ovulation Suppression • via continuous hormonal regimen • Reduces endometriosis activity • Controls cyclical, dysmenorrhea. • Options: • OCP, Depo, Nuva Ring. • Only standard preparations apart from GnRHanalogues • 2 Microlut/day • Need to use combinations of other medications if alternatives needed

13. Endometriosis & Mirena • Shown to reduce dysmenorrhea but not dyspareunia • Doesn’t suppress ovulation • Need equivalent of 50mcg levonorgestrol/day • So : Mirena(20 + microlut 30) Often used in conjunction with laparoscopy • Difficult insertion in nulliparous • Additional benefit with associated Adenomyosis

14. Endometriosis & Implanon • Observational study & small RCT • improvement of symptoms • Dysmenorrhea • Dyspareunia • Non menstrual pelvic pain • Similar to Depo for 12/12 ( Ovulation suppression) • ? Double dose Implanon

15. Endo in Younger Women • Treatment of pain: • Analgesics • NSAIDS: best for Gynaecological pain. Prob best for endo • Paracetamol /Codeine /doxylamine • Exercise: Consistent reduction in pain scores • Diet & Vitamins • Vegetarian diet, Increased dairy intake • Fich oilB1, B 6 : • Vitamin D starting 5 days pre menstrually

16. Endo in younger women:Pyschological support • CBT & Psychology. • General support: Clinician support, encourage compliance& continuous hormonal regimen. • Endometriosis Nurse: email, text &phone support • Allay concerns regarding side effects • Often treatment regimens require changing

17. Endometriosis in younger women • When to perform a laparoscopy: • Complex symptoms • Poor response. • Ultrasound abnormalities. • Abnormalities on examination (can be limited) • Findings are often mild endometriosis, • Occasional localised disease able to be excised. • Small biopsy required to confirm diagnosis

18. Miliary pattern Endometriosis • Insert pic

19. Post Laparoscopy Management • Change of OCP: • more progestagenic • Norinyl 1 +/- additional norethisterone • Other OCP • ZoladexGnRH analogues • ? Aromatase inhibitors + OCP / progestagens • Nurse/ Clinician support.

20. Endometriosis on older women ( 30yrs +) • CAN present as younger women do. • BUT usually more extensive/infiltrating • Elucidate localizing symptoms. • Ipsilateral dysmenorrhea & dyspareunia • Menstrual related dyschezia & sacral pain. • Bowel dysfunction • Generalized intermenstrual pelvic pain • Intermenstrual bleeding &menorrhagia • (?associated adenomyosis)

21. Endo in older women ( 30yrs +) • What to look for on examination. • Localized tenderness in the posterior & lateral fornix • Positioning of the cervix • Deviation laterally • Nodularity /crimping of the vagina • Mobility & tenderness of the uterus • ?associated Adenomyosis

22. Endometriosis in the posterior fornix

23. Endo in older women-Ultrasound Assessment • Look at pelvic organs, fibroids, cysts/endometriomata, endometrial, myometrial pathology • AND parametrial & pelvic side wall characteristics • Increased & discordant uterosacral & parametrial echoes • Pouch of Douglas peritoneal thickening • Rectosigmoid- cervicouterine tethering • Rectovaginal space tethering

24. CA 125 • CA 125 cell surface antigen from derivatives of coelomicepith. • Not a sensitive test, but often elevated, esp with endometriomas & more advanced disease • Other causes: menstruation, ovulation, Infection, fibroids, pregnancy, Ovarian cancer • Older the patient, more careful consideration of elevated level

25. Management • Same principles as for younger women • Ovulation suppression • Stable hormonal environment • Analgesia • May need combination therapy • Consider earlier surgical intervention for associated abnormalities on clinical/ultrasound examination

26. Endometrioma • Invagination of ovarian serosal endometriosis • - Damage ovaries • 80% associated with Pouch Endometriosis. • Surgical treatment requires care • Diff Diagnosis: Functional cyst, Dermoid. • Confirm with trial of OCP suppression

27. Endometrioma • Add US & lapy image

28. Bowel involvementusually bowel symptoms • Show lapy image

29. Bowel Involvement • Initial planning laparoscopy: EUA, Images • Combined Gynae & Colorectal surgical approach. • Often Zoladex to reduce volume & inflammation • Bowel prep, preop planning(nurse), consult x 2 • Strict systematic approach to surgery. • Disc excision,or segmental bowel resection, often “ultralow” anastamosis • Careful resection back to normal tissue

30. Complex endometriosis surgery

31. Endometriosis & Aromatase • Converts Androgen to Oestrogen • Aromatase inappropriately expressed in eutopic endometrium & endometroisis High levels of expression in endometriomas. Facilitates local production of Oestrogen. >> stimulates proliferation of endometriosis deposits

32. New Agent for Endometriosis • Aromatase inhibitors: • Anastrazole, Letrozole. (off label) • For those with refractory pain& minimal visible disease. • Add to current regimens • In combination with OCP or progestagen • Can be used in conjunction with Zoladex • Significant reduction in pain scores • Note: Bone loss Risk : Ca. Vit D supps .

33. Subfertility:What is normal Conception rate? • Age influenced. • Life plans • Other fertility factors • Male factor • Lifestyle Obesity, Smoking, • Ovulation. • 12 month definition is fairly blunt instrument

34. 25-30 yr old Healthy couple fecundability

35. Endometriosis & subfertility • Strong association. 40 -50% with subfertility • (OGB :70%of fertility pts have endometriosis) • Often have minimal pain. • Many couples have a number of contributing factors • Need to optimize each factor. • Older the woman more important to correct contributing factors

36. Endometriosis contributes to subfertility • Distortion of pelvic structures • Ovarian damage ( reduced reserve) • Abnormal Eutopic endometrium • Impaired fertilization (inflammatory mediators) • Poor oocyte quality • -Better pregnancy with normal donor eggs • -Worse rates from endometriosis egg donors

37. Outcomes of Interventions:Natural attempts • 200 couples planning pregnancy • 60% of pregnancies occur in • 3 cycles of Rx • 70% in 5 cycles of treatment • Any intervention has similar shaped curve

38. Fertility Treatment options • Expectant • Younger woman, couple desires • Surgery • Excision deposits, tubal patency, endometrial biopsy • Ovulation induction with IUI • Letrozole, FSH, Clomiphene • IVF. • Fertilization outside pelvis, embryo selection

39. Effects of Endometriosis on treatment outcomes • Subfertile couples with endometriosis have lower pregnancy rates. • Compared to male factor, tubal factor, idiopathic • Due to: • functional, proteomic abnormalities in Eutopic endometrium • Ongoing adverse effects of endometriosis on pelvic environment. Via inflammatory mediators • Reduced oocyte quality • Adverse effect correlates with severity, and age

40. Results of treatment on Endometriosis related fertility • Complex interpretation of influence of each component. • Surgical studies • Heterogeneous disease pattern • Inter patient variation & variable surgical techniques. • Different thresholds for intervention • Often multifactorial infertility • Age variations

41. Overall, we can say.. • Natural conception can still be pursued • Ovulation induction + IUI improves pregnancy rates • 2-3 cycles only • Excision surgery for mild-moderate reduces time to pregnancy. • Improves implantation rates • Improves natural conception rates. • Treatment of Endometriomasreduces oocyte yield, but increases natural conception rates & reduces infection rates from IVF, • “Long down regulation” with Zoladex prior to IVF improves pregnancy rates in women with severe endometriosis

42. The Future of Endometriosis treatment • Immunologically based Therapy influencing Leucocyte function Chemokine receptor 1 antagonist ( CCR-1) • Anti Nerve growth factor ( ANGF) • Endometriosis as an epigenetic disease • Hypermethylation of promoter genes cause aberrant expression esp of aromatase & cadherin 1 • Histone DeaCetylase Inhibitors ( HDACI s) may reverse hypermethylation : (Valproate)

43. Summary • Endometriosis is a common condition. • Young women: mild , use hormonal therapy • Older women; look for localizing symptoms • Ovulation suppression –range of options • Significant influence on fertility • Surgical management can be technically complex requiring multidisciplinary approach.