Update on Endometriosis Grampians Medicare Local 2nd September, BHS Russell Dalton Ballarat IVF Ballarat Endometriosis Clinic Obstetrics & Gynaecology Ballarat 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 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 Endometriosis images Micro 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 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 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 Endometriosis-Presenting symptoms Pelvic pain Dysmenorrhea Pain related to function of pelvic organs Bloating Psychological sequelae. Subfertility / Infertility 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 ? 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, 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 Ovulation Suppression via continuous hormonal regimen Reduces endometriosis activity Controls cyclical, dysmenorrhea. Options: OCP, Depo, Nuva Ring. Only standard preparations apart from GnRH analogues 2 Microlut/day Need to use combinations of other medications if alternatives needed 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 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 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 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 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 Miliary pattern Endometriosis Insert pic Post Laparoscopy Management Change of OCP: more progestagenic Norinyl 1 +/- additional norethisterone Other OCP Zoladex GnRH analogues ? Aromatase inhibitors + OCP / progestagens Nurse/ Clinician support. 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) 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 Endometriosis in the posterior fornix Endo in older womenUltrasound 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 CA 125 CA 125 cell surface antigen from derivatives of coelomic epith. 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 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 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 Endometrioma Add US & lapy image Bowel involvement usually bowel symptoms Show lapy image 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 Complex endometriosis surgery 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 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 . 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 25-30 yr old Healthy couple fecundability 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 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 Outcomes of Interventions: Natural attempts 200 couples planning pregnancy • 60% of pregnancies occur in 3 cycles of Rx No. Pregnancies(cumulative) 180 160 • 70% in 5 cycles of treatment 140 • Any intervention has similar shaped curve Number pregnant 120 100 No. Pregnancies(cumulative) 80 60 40 20 0 1 2 3 4 5 6 7 8 Cycle Number (mths) 9 10 11 12 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 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 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 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 Endometriomas reduces 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 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) 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.