9/26/2018

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

1 9/26/2018

Why do we need new Fibroids options?-  Benign monoclonal hormonally sensitive to estrogen and 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

2 9/26/2018

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

3 9/26/2018

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

4 9/26/2018

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   Restoration of anatomy  GNRH agonists with addback All with iron •  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- acetate effective than tranexamic acid or LNG-IUS and 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

5 9/26/2018

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 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 , GNRH antagonists SERMS  Progesterone receptor modulator- ,,  Letrozole or anastrozole block conversion of androgens to 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

6 9/26/2018

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

7 9/26/2018

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

8