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Management of Conflicts Women with Fibroids- I have been on advisory board for Pfizer, Searchlight, Why we Need New Merck and Acerus Options I have spoken for Pfizer, Searchlight NAMS 2018 Wendy Wolfman MD FRCS(C) FACOG Professor Department of Ob/Gyn University of Toronto Director Menopause and POI Units Mt. Sinai Hospital
Objectives Ms X Hausted
To discuss impact of fibroids on a woman’s life 41 yr old G3P0 menses q 23 days for 10 days Uses 7 super tampons with pads- sometimes bleeds through her To discuss current options for treatments clothes and misses work To discuss reasons for women’s preference for non- Bloated with lower abdominal discomfort and constipation surgical options Hgb 98 known uterine fibroids for many years wants to retain her uterus as she still hopes to conceive doesn’t know how much longer she can continue doesn’t want OCP’s or an IUD and finds tranexamic acid minimally helpful
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Why do we need new Fibroids options?- Benign monoclonal hormonally sensitive to estrogen and progesterone Lifetime prevalence of smooth muscle tumors Somatic mutations of MED12 or HMGA2 hysterectomy in US is Very common- 80%of black women and 70% of white women 45%!!!! Symptoms related to location, location, location and size Responsible for reduction in quality of life , health burden and lost work days ($700 annually) accounting for $6-34 billion health costs 3/4 of fibroid procedures are hysterectomy Effective medical therapies would improve lives of 200,000 of 600,000 hysterectomies are due to fibroids women
Baird D Am J Obstet Gynecol 2003 Moravek Curr Opin Obstet Gynecol 2015 Cardoza ER A J Ostet Gynecol 2012 Stewart NEJM 2015 Stewart EA Minn Med 2012 Donnez Best Practice & Research Clinical Ob & Gyn 2018 Hartmann KE Obstet Gynecol 2006
Symptoms Associated with Fibroid Risk Factors Fibroids
Non controllable factors Lifestyle factors 50% have no symptoms- no treatments necessary Triad of symptoms-up to 50% need therapy Age High body mass-21% with each 10kg Ethnicity Physical activity BLEEDING COMT polymorphism Vit D deficiency BULK Use of OCP’s under 16 Early menarche Progestin injectable reduces risk REPRODUCTIVE EFFECTS ER polymorphism Dietary –fruit, vegies, low fat dairy reduces risk Higher TGF-β3 serum Tobacco, caffeine, and alcohol Parity reduces risk Mohamed Biol Reprod 2017 Wise LA Am J Epidemiol 2004 Baird D Epidemiology 2003 Tropeano G, et al. Hum Reprod Update 2008 Pavone Best Pract Res Clin Obstet Gynaecol 2018 Wise LA Am J Clin Nutr 2011 Downes E, et al. Eur J Obstet Gynecol Reprod Biol 2010 Wise LA Epidemiology 2005
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Bleeding Symptoms Bulk Symptoms Postulated causes-increased surface area, increased Pelvic pressure and cramps ,Back pain and leg pain vascularity, impaired contractility, endometrial ulceration, venous engorgement and uterine congestion Bloating and abdominal distention 60% Increased amount, length, intermenstrual and if severe Urinary- frequency ,urgency and incontinence,-anterior emergency visits fibroids and increased size – rarely hydronephrosis Heavy bleeding occurs in 33% Bowel-constipation Produces anemia and may require transfusions Gynae-Dyspareunia and dysmenorrhoea, Crampy pain in 75% - also occurs with bulk issues Rate of growth is unpredictable 89% shrinkage to 138% Other causes of AUB should be ruled out growth, median 9% growth Bleeding stops at menopause Rapid growth not necessarily=malignancy Borah B Am J Obstet Gynecol 2013 Wegienka Gobstet Gynecol 2003 Day Baird D Fertil Steril 2011 Wu JM Obstet Gynecol 2007 Parker W Obstet Gynecol 1994 Talaulikar Best Pract Res Clin Ostet Gynaecol 2018 Stewart NEJM 2015
Effect of Uterine Fibroids Reproductive Dysfunction on Quality of Life
Infertility-diagnosis of exclusion and controversial Uterine fibroids may significantly decrease health-related QOL Recurrent pregnancy loss includes sexuality, self-image, relationships, social, emotional and physical well-being Pregnancy complications Societal burden: absenteeism, productivity impairment, and Abnormal placentation economic loss. Premature Delivery Heavy menstrual bleeding is a major cause of physician Malpresentation visits and lost work days. Postpartum hemorrhage QOL related to number of symptoms –most common back SGA (65%),fatigue 63%, bloating 61%, bleeding 51%, cramping Caesarian delivery with menses (63%) and heavy bleeding during menses (54%) Hartmann K Am J Epidem 2017 Chen Y Him Reprod 2009 Soliman AM Curr Med Res Opin 2017 Pritts E Fertil Steril 2009 Fortin C Best Pract Res Clin Obstet Gynaecol 2018 Klatsky P Am J Obstet Gynecol 2008 Borah B Am J Obstet Gynecol 2013
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Diagnosis of Uterine Fibroids Diagnostic Work‐up
Clinical history- Investigate based on presentation and symptoms Bleeding Abnormal uterine bleeding1 Bulk History, Physical Reproductive problems Pap test Cultures History of bleeding problems, Thyroid disease Endometrial biopsy as per guidelines to rule out pathology Family history Blood work-up (hemoglobin, ferritin) TSH, prolactin Rarely Inherited renal CA and Fibroids Ultrasound Hysterosonogram, or hysteroscopy to rule out intracavity myoma Physical exam-abdominal, pelvic and speculum examinations MRI
Atypical presentation • Uterine sarcomas are rare (3-7 / 10,000)2 3 Hydronephrosis Incidence may be higher in patients undergoing surgery No diagnostic test determines sarcoma diagnosis Pain (degeneration Risk-radiation, tamoxifen
1. Lefebvre G, et al. J Obstet Gynaecol Can 2003;25:396‐418; 2. Brooks SE, et al. Gynecol Oncol 2004;93:204‐8; Khan AT, et al. Int J Womens Health 2014;6:95‐114 3. Seidman MA, et al. PLoS One 2012;7:e50058
Classification of Fibroids Treatments for Uterine Fibroids European Society of Hysteroscopy Classification:1 Leiomyoma Subclassification System2 TYPE 0 –Intracavitary S M‐ Submucosal Conservative: TYPE I –> 50% in cavity 0: Pedunculated Intracavitary TYPE II –< 50% in cavity 3 1: <50% Intramural 2-5 4 Medical TYPE III – Serosal/intramural 1 2: ≥ 50% Intramural 00 Surgical O –Other 6 2 laparascopic, vaginal, abdominal, robotic 3: Contacts endometrium; 100% Intramural5 7 Endometrial Ablation-for AUB-first and second 4: Intramural generation (failure rate associated with length and 5: Subserosal ≥50% Intramural distortion of cavity)-heat, cold, mechanical 6: Subserosal < 50% Intramural Myomectomy 7: Subserosal Pedunculated Hysteroscopic-best treatment for type 0 8: Other (specify eg. cervical, parasitic) Interventional Hybrid Leiomyomas Uterine Artery Embolization (impact both endometrium and serosa) MRI guided focused ultrasound Example: Radiofrequency ablation during laparoscopic 2‐5: Submucosal and subserosal, each with less than half the diameter in the endometrial and peritoneal Hysterectomy-definitive and no recurrence Myoma to serosa cavities respectively. distance Stewart NEJM 2015 1. Wamsteker K, et al. Obstet Gynecol 1993;82:736‐40 2. Munro MG, et al. Int J Gynaecol Obstet 2011;113:3‐13 Song Cochrane Database 2013 Deng Cochrane 2012
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Current Medical Management Perfect Individual therapy Options for Bleeding
Manage signs and symptoms and patient’s wishes Non-hormonal- on bleeding • Hormonal-throughout the Determined by age and fertility wishes days month Determined by severity and acuity of symptoms Antiprostaglandins Oral contraceptives Determined by size of uterus and FIGO classification Antifibrinolytics-tranexamic acid Progestins Intrauterine progestin systems Sustained reduction in bulk Danazol Restoration of anatomy GNRH agonists with addback All with iron • Progesterone receptor modulators Normalization of bleeding supplementation (SPRMs)-in Canada and Europe Aromatase Inhibitors Fertility optimization No serious side effects
Laughlin-Tommaso SK J Minim Invasive Gynecol 2018 ACOG Obstet Gynecol 2011 Donnez Best Pract Res Clin Obstet Gynaecol 2018 Laughlin‐Tommaso S J Minim Invasive Gynecol 2018 SOGC Guidelines JOGC 2015
Non-Hormonal Treatments Hormones to Treat Bleeding and for Bleeding Uterine Fibroids Used throughout the cycle and most provide contraception Non-steroidal anti-inflammatory–reduce bleeding 20- 40%-meta-analysis shows benefit versus placebo-less Includes OCP’s, patches, rings, depo-medroxyprogesterone acetate effective than tranexamic acid or LNG-IUS and levonorgestrel IUD, aromatase inhibitors, and GNRH inhibitors OCP ‘s reduce bleeding in observational data but may not reduce size Tranexamic acid- antifibrinolytic –decreases fibrinolysis in menses- reduces bleeding in RCT’s up to 40%-1 gm Depot MPA-Reduce fibroid risk by ~20%-depot 90% over 5 yrs q6h- improves QOL OCP’s contraindicated in patients with risk factors (age > 35 years and smoking) No obvious increased thrombosis in studies-not recommended with OCP Levonorgestrel 20 mcg/day IUD-treats amount and duration of bleeding 80-90% at 1 yr conflicting studies of reduction in size- Both used only during menses effective and safe treatment Laughlin-Tommaso SK J Minim Invasive Gynecol 2018 Matteson K Obstet Gynecol 2013; Higher expulsion rate with submucosal fibroids and larger cavities Talaulikar Best Pract Res Clin Ostet Gynaecol 2018 Qin Arch Gynecol Obstet 2013, Stewart NEJM 2015 Lukes A Obstet Gynecol 2010, Lethaby Cochrane Review 2013 Marshall L Fertil Steril 1998 Naoulou Acta Obstet Gynecol Scand 2012 Harmon Q Hum Reprod 2015 Laughlin-Tommaso J Min Invasive Gynecol 2018
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Gonadotropin-releasing Bulk Management Options hormone analogues No therapy necessary if asymptomatic GNRH agonists compete for GNRH receptor and first flare, then inhibit the HPO axis reducing estrogen level Also may treat bleeding Pre-operative treatment for both hysterectomy and myomectomy reduces uterine and fibroid volume, anemia If the major issue is size and pressure symptoms ,reduces intra-operative blood loss, enables minimalistic Depends on patients fertility wishes surgery, reduces complications GNRH agonist + addback Temporary reduction and fibroids regrow when therapy HIFU stopped SPRM Side effects hot flushes, vaginal dryness, low mood and loss If close to menopause try and temporize as most fibroids of bone mass- shrink with estrogen deficiency Surgical Add-back (with HT, MPA or tibolone or TSEC) can allow longer use Lethaby Cochrane Database Syst Rev 2017 Perez-Lopez Maturitas 2014 De Milliano PLoS One 2017
Aromatase Inhibitors ,Androgenic SPERM’s steroids, GNRH antagonists SERMS Progesterone receptor modulator-mifepristone ,ulipristal acetate, Letrozole or anastrozole block conversion of androgens to asoprisnil and telapristone acetate-affects fibroids, endometrium oestrogens in ovarian and peripheral tissue and pituitary Shown to reduce volume, OR time and bleeding during Used in 3mo cycles with 2 mos off hysteroscopic and laparoscopic myomectomies Decreases symptoms and bulk Current evidence insufficient to recommend-hypoestrogenic side effects, need contraception-temporary effects After 4 courses with 5 mg 70% amenorrheic by 4 mo and 65% shrinkage GNRH antagonists-competitive inhibition of GnRH-sc-alagolix and oral-Ganirelix 8 cycles of 10 mg showed safety-9% had progesterone associated endometrial changes (PAEC)-(reversible) SERMS- 2/3 studies showed benefit of raloxifene Approved in Canada and Europe Danazol older treatment-relieves heavy bleeding- limited by side effects-no RCT’s Recent European warning of rare acute liver failure Song Cochrane Database 2013 Deng Cochrane 2012 Donnez Fertil Steril 2016 Talaulikar Best Pract Res Clin Obstet Gynaecol 2018 Fauser PloS One 2017 Ali Biol Reprod 2017
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Interventional Options to Interventional Approaches MRI-guided high Treatment of Uterine Fibroids intensity focused ultrasound-HIFU • Uterine artery embolization Limited availability • Global treatment Thermal energy produces necrosis • Improves Q of L, fewer days in hospital • Reduces time to resume normal life contra-indications • Reduces need for blood transfusion Fibroids near sacrum • Reduced time off compared to hysterectomy Bowel overlying fibroid • Increased need for further treatments OR 6.99 Not more than 5 fibroids and <10 cm • Satisfaction similar to hysterectomy at 2-5 yr LBR 41% in 51 women • Complications- pain, fever ,sepsis, relapse earlier menopause > age 45,reintervention 28% Reintervention 53.9% versus 14.4% Pregnancy-evidence limited-lower pregnancy rates, higher UAE 12.2% for myomectomy miscarriage and more adverse outcomes than after myomectomy Lethaby BMJ Clin Evid 2015 Side effects burns and neuropathies Ananthakrishnan CVR & Intervenal Radiol 2013 Lethaby BMJ Clin Evid 2015 Ali Biol Reprod 2017 Ananthakrishnan CVR & Interventl Radiol 2013 Carranza-Mamane J Obstet Gynaecol Can 2015 Sandberg Fertil Steril 2018
Radiofrequency Volumetric Why are Both Surgical and Thermal Ablation Nonexcisional Options Unacceptable Under laparoscopy or transvaginal (still investigational) Conservative surgery and therapies has 25% recurrence rate Energy delivered with hand piece via laparoscopy after fibroid is identified with laparoscopic ultrasound Risks of surgery-especially if medically unfit
Symptom severity and increase in Q of L to 3 yrs 3-4% risk of hysterectomy with abdominal myomectomy One study showed more myomas treated, less OR time Adhesion formation and shorter hospital stays Reproductive ramifications
Reintervention 11% at 3 yrs Earlier menopause with hysterectomy and UAE
Psychological feelings
Laughlin-Tommaso J Miim Invasive Gynecol 2018
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What about menopause and fibroids? Conclusions
Symptoms tend to deteriorate in the perimenopause Fibroids are very common hormonally sensitive benign related to fluctuation in hormones tumors
rapid growth a concern for malignancy-no evidence Fibroids have a large impact on quality of life, work loss and economic costs for women Bleeding problems should stop and bulk decrease or stabilize after LMP Current medical therapies are not adequate for each individual woman On HT, may increase bleeding, and slight growth Surgical therapy is definitive but not always the preferred choice
Colacurci N Maturitas 2000 Palomba S Eur J Obstet Gynecol Reprod Biol 2002 Polatti F Maturitas 2000 Idowu BM Rev Bras Ginecol Obstet 2017 Srinivasan V Menopause 2018
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