Management of Conflicts Women with Fibroids- I have been on - - PDF document

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Sep 27, 2022 154 likes •246 views

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 I have spoken for Pfizer, Searchlight Options NAMS 2018 Wendy Wolfman MD FRCS(C) FACOG

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Management of Women with Fibroids- Why we Need New Options

NAMS 2018

Wendy Wolfman MD FRCS(C) FACOG Professor Department of Ob/Gyn University of Toronto

Director Menopause and POI Units Mt. Sinai Hospital

Conflicts

 I have been on advisory board for Pfizer, Searchlight,

Merck and Acerus

 I have spoken for Pfizer, Searchlight

Objectives

 To discuss impact of fibroids on a woman’s life  To discuss current options for treatments  To discuss reasons for women’s preference for non-

surgical options

Ms X Hausted

 41 yr old G3P0 menses q 23 days for 10 days  Uses 7 super tampons with pads- sometimes bleeds through her

clothes and misses work

 Bloated with lower abdominal discomfort and constipation  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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Fibroids

 Benign monoclonal hormonally sensitive to estrogen and

progesterone



smooth muscle tumors

 Somatic mutations of MED12 or HMGA2  Very common- 80%of black women and 70% of white women  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

 Effective medical therapies would improve lives of

women

Baird D Am J Obstet Gynecol 2003 Moravek Curr Opin Obstet Gynecol 2015 Cardoza ER A J Ostet Gynecol 2012 Stewart EA Minn Med 2012 Hartmann KE Obstet Gynecol 2006

Why do we need new

ptions?-

Lifetime prevalence of hysterectomy in US is 45%!!!!

3/4 of fibroid procedures are hysterectomy

200,000 of 600,000 hysterectomies are due to fibroids

Stewart NEJM 2015 Donnez Best Practice & Research Clinical Ob & Gyn 2018

Fibroid Risk Factors

Non controllable factors

 Age  Ethnicity  COMT polymorphism  Early menarche  ER polymorphism  Higher TGF-β3 serum

Lifestyle factors



High body mass-21% with each 10kg



Physical activity



Vit D deficiency



Use of OCP’s under 16



Progestin injectable reduces risk



Dietary –fruit, vegies, low fat dairy reduces risk



Tobacco, caffeine, and alcohol



Parity reduces risk

Mohamed Biol Reprod 2017 Wise LA Am J Epidemiol 2004 Baird D Epidemiology 2003 Pavone Best Pract Res Clin Obstet Gynaecol 2018 Wise LA Am J Clin Nutr 2011 Wise LA Epidemiology 2005

Symptoms Associated with Fibroids

 50% have no symptoms- no treatments necessary  Triad of symptoms-up to 50% need therapy

 BLEEDING  BULK  REPRODUCTIVE EFFECTS

Tropeano G, et al. Hum Reprod Update 2008 Downes E, et al. Eur J Obstet Gynecol Reprod Biol 2010

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Bleeding Symptoms

 Postulated causes-increased surface area, increased

vascularity, impaired contractility, endometrial ulceration, venous engorgement and uterine congestion

 60% Increased amount, length, intermenstrual and if severe

emergency visits



Heavy bleeding occurs in 33%



Produces anemia and may require transfusions

 Crampy pain in 75% - also occurs with bulk issues  Other causes of AUB should be ruled out  Bleeding stops at menopause

Borah B Am J Obstet Gynecol 2013 Wegienka Gobstet Gynecol 2003 Wu JM Obstet Gynecol 2007 Talaulikar Best Pract Res Clin Ostet Gynaecol 2018

Bulk Symptoms

 Pelvic pressure and cramps ,Back pain and leg pain  Bloating and abdominal distention  Urinary- frequency ,urgency and incontinence,-anterior

fibroids and increased size – rarely hydronephrosis

 Bowel-constipation  Gynae-Dyspareunia and dysmenorrhoea,  Rate of growth is unpredictable 89% shrinkage to 138%

growth, median 9% growth

 Rapid growth not necessarily=malignancy

Day Baird D Fertil Steril 2011 Parker W Obstet Gynecol 1994 Stewart NEJM 2015

Reproductive Dysfunction

 Infertility-diagnosis of exclusion and controversial  Recurrent pregnancy loss  Pregnancy complications

 Abnormal placentation  Premature Delivery  Malpresentation  Postpartum hemorrhage  SGA  Caesarian delivery

Hartmann K Am J Epidem 2017 Chen Y Him Reprod 2009 Pritts E Fertil Steril 2009 Klatsky P Am J Obstet Gynecol 2008

Effect of Uterine Fibroids

n Quality of Life

 Uterine fibroids may significantly decrease health-related

QOL

 includes sexuality, self-image, relationships, social,

emotional and physical well-being

 Societal burden: absenteeism, productivity impairment, and

economic loss.



Heavy menstrual bleeding is a major cause of physician visits and lost work days.

 QOL related to number of symptoms –most common back

(65%),fatigue 63%, bloating 61%, bleeding 51%, cramping with menses (63%) and heavy bleeding during menses (54%)

Soliman AM Curr Med Res Opin 2017 Fortin C Best Pract Res Clin Obstet Gynaecol 2018 Borah B Am J Obstet Gynecol 2013

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Diagnosis of Uterine Fibroids

 Clinical history-



Bleeding



Bulk



Reproductive problems



History of bleeding problems, Thyroid disease



Family history

 Rarely Inherited renal CA and Fibroids  Physical exam-abdominal, pelvic and speculum examinations  Atypical presentation



Hydronephrosis



Pain (degeneration

Khan AT, et al. Int J Womens Health 2014;6:95‐114

Diagnostic Work‐up



Investigate based on presentation and symptoms 

Abnormal uterine bleeding1  History, Physical  Pap test  Cultures  Endometrial biopsy as per guidelines to rule out pathology  Blood work-up (hemoglobin, ferritin)  TSH, prolactin  Ultrasound  Hysterosonogram, or hysteroscopy to rule out intracavity myoma  MRI

Uterine sarcomas are rare (3-7 / 10,000)2

 Incidence may be higher in patients undergoing surgery3  No diagnostic test determines sarcoma diagnosis  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;
3. Seidman MA, et al. PLoS One 2012;7:e50058

Classification of Fibroids

European Society of Hysteroscopy Classification:1 TYPE 0 – Intracavitary TYPE I – > 50% in cavity TYPE II – < 50% in cavity TYPE III – Serosal/intramural

Myoma to serosa distance

2 3 1 1 4 4 5 6 7 7 2-5 2-5 2 3 1 4 5 6 7 2-5

Leiomyoma Subclassification System2 S M‐ Submucosal 0: Pedunculated Intracavitary 1: <50% Intramural 2: ≥ 50% Intramural O – Other 3: Contacts endometrium; 100% Intramural 4: Intramural 5: Subserosal ≥50% Intramural 6: Subserosal < 50% Intramural 7: Subserosal Pedunculated 8: Other (specify eg. cervical, parasitic) Hybrid Leiomyomas (impact both endometrium and serosa) Example: 2‐5: Submucosal and subserosal, each with less than half the diameter in the endometrial and peritoneal cavities respectively.

1. Wamsteker K, et al. Obstet Gynecol 1993;82:736‐40
2. Munro MG, et al. Int J Gynaecol Obstet 2011;113:3‐13

Treatments for Uterine Fibroids



Conservative:



Medical



Surgical 

laparascopic, vaginal, abdominal, robotic  Endometrial Ablation-for AUB-first and second generation (failure rate associated with length and distortion of cavity)-heat, cold, mechanical  Myomectomy  Hysteroscopic-best treatment for type 0



Interventional 

Uterine Artery Embolization  MRI guided focused ultrasound  Radiofrequency ablation during laparoscopic  Hysterectomy-definitive and no recurrence Stewart NEJM 2015 Song Cochrane Database 2013 Deng Cochrane 2012

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Perfect Individual therapy

 Manage signs and symptoms and patient’s wishes

 Determined by age and fertility wishes  Determined by severity and acuity of symptoms  Determined by size of uterus and FIGO classification

 Sustained reduction in bulk  Restoration of anatomy  Normalization of bleeding  Fertility optimization  No serious side effects

Laughlin-Tommaso SK J Minim Invasive Gynecol 2018 Donnez Best Pract Res Clin Obstet Gynaecol 2018

Current Medical Management Options for Bleeding

 Non-hormonal- on bleeding

days

 Antiprostaglandins  Antifibrinolytics-tranexamic acid

All with iron

supplementation

Hormonal-throughout the

month 

Oral contraceptives



Progestins



Intrauterine progestin systems



Danazol



GNRH agonists with addback



Progesterone receptor modulators (SPRMs)-in Canada and Europe



Aromatase Inhibitors ACOG Obstet Gynecol 2011 Laughlin‐Tommaso S J Minim Invasive Gynecol 2018 SOGC Guidelines JOGC 2015

Non-Hormonal Treatments for Bleeding

 Non-steroidal anti-inflammatory–reduce bleeding 20-

40%-meta-analysis shows benefit versus placebo-less effective than tranexamic acid or LNG-IUS

 Tranexamic acid- antifibrinolytic –decreases fibrinolysis

in menses- reduces bleeding in RCT’s up to 40%-1 gm q6h- improves QOL

 No obvious increased thrombosis in studies-not

recommended with OCP

 Both used only during menses

Laughlin-Tommaso SK J Minim Invasive Gynecol 2018 Matteson K Obstet Gynecol 2013; Talaulikar Best Pract Res Clin Ostet Gynaecol 2018 Lukes A Obstet Gynecol 2010, Lethaby Cochrane Review 2013 Naoulou Acta Obstet Gynecol Scand 2012

Hormones to Treat Bleeding and Uterine Fibroids

 Used throughout the cycle and most provide contraception  Includes OCP’s, patches, rings, depo-medroxyprogesterone acetate

and levonorgestrel IUD, aromatase inhibitors, and GNRH inhibitors

 OCP ‘s reduce bleeding in observational data but may not reduce size  Depot MPA-Reduce fibroid risk by ~20%-depot 90% over 5 yrs  OCP’s contraindicated in patients with risk factors

(age > 35 years and smoking)

 Levonorgestrel 20 mcg/day IUD-treats amount and duration of

bleeding 80-90% at 1 yr conflicting studies of reduction in size- effective and safe treatment

 Higher expulsion rate with submucosal fibroids and larger cavities

Qin Arch Gynecol Obstet 2013, Stewart NEJM 2015 Marshall L Fertil Steril 1998 Harmon Q Hum Reprod 2015 Laughlin-Tommaso J Min Invasive Gynecol 2018

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Bulk Management Options

 No therapy necessary if asymptomatic  Also may treat bleeding  If the major issue is size and pressure symptoms

 Depends on patients fertility wishes  GNRH agonist + addback  HIFU  SPRM  If close to menopause try and temporize as most fibroids

shrink with estrogen deficiency

 Surgical

Gonadotropin-releasing hormone analogues

 GNRH agonists compete for GNRH receptor and first flare,

then inhibit the HPO axis reducing estrogen level

 Pre-operative treatment for both hysterectomy and

myomectomy reduces uterine and fibroid volume, anemia ,reduces intra-operative blood loss, enables minimalistic surgery, reduces complications

 Temporary reduction and fibroids regrow when therapy

stopped

 Side effects hot flushes, vaginal dryness, low mood and loss

f bone mass-

 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

SPERM’s

 Progesterone receptor modulator-mifepristone ,ulipristal acetate,

asoprisnil and telapristone acetate-affects fibroids, endometrium and pituitary

 Used in 3mo cycles with 2 mos off  Decreases symptoms and bulk  After 4 courses with 5 mg 70% amenorrheic by 4 mo and 65%

shrinkage

 8 cycles of 10 mg showed safety-9% had progesterone associated

endometrial changes (PAEC)-(reversible)

 Approved in Canada and Europe  Recent European warning of rare acute liver failure

Donnez Fertil Steril 2016 Fauser PloS One 2017 Ali Biol Reprod 2017

Aromatase Inhibitors ,Androgenic steroids, GNRH antagonists SERMS

 Letrozole or anastrozole block conversion of androgens to

estrogens in ovarian and peripheral tissue

 Shown to reduce volume, OR time and bleeding during

hysteroscopic and laparoscopic myomectomies

 Current evidence insufficient to recommend-hypoestrogenic side

effects, need contraception-temporary effects

 GNRH antagonists-competitive inhibition of GnRH-sc-alagolix and

ral-Ganirelix

 SERMS- 2/3 studies showed benefit of raloxifene  Danazol older treatment-relieves heavy bleeding- limited by side

effects-no RCT’s

Song Cochrane Database 2013 Deng Cochrane 2012 Talaulikar Best Pract Res Clin Obstet Gynaecol 2018

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Interventional Options to Treatment of Uterine Fibroids

Uterine artery embolization
Global treatment
Improves Q of L, fewer days in hospital
Reduces time to resume normal life
Reduces need for blood transfusion
Reduced time off compared to hysterectomy
Increased need for further treatments OR 6.99
Satisfaction similar to hysterectomy at 2-5 yr
Complications- pain, fever ,sepsis, relapse

 earlier menopause > age 45,reintervention 28%  Pregnancy-evidence limited-lower pregnancy rates, higher

miscarriage and more adverse outcomes than after myomectomy

Lethaby BMJ Clin Evid 2015 Ananthakrishnan CVR & Intervenal Radiol 2013 Ali Biol Reprod 2017 Carranza-Mamane J Obstet Gynaecol Can 2015

Interventional Approaches MRI-guided high intensity focused ultrasound-HIFU

Lethaby BMJ Clin Evid 2015 Ananthakrishnan CVR & Interventl Radiol 2013 Sandberg Fertil Steril 2018

 Limited availability  Thermal energy produces necrosis  contra-indications

 Fibroids near sacrum  Bowel overlying fibroid  Not more than 5 fibroids and <10 cm

 LBR 41% in 51 women  Reintervention 53.9% versus 14.4%

UAE 12.2% for myomectomy

 Side effects burns and neuropathies

Radiofrequency Volumetric Thermal Ablation

 Under laparoscopy or transvaginal (still investigational)  Energy delivered with hand piece via laparoscopy after

fibroid is identified with laparoscopic ultrasound

 Symptom severity and increase in Q of L to 3 yrs  One study showed more myomas treated, less OR time

and shorter hospital stays

 Reintervention 11% at 3 yrs

Laughlin-Tommaso J Miim Invasive Gynecol 2018

Why are Both Surgical and

Nonexcisional Options Unacceptable

 Conservative surgery and therapies has 25% recurrence

rate

 Risks of surgery-especially if medically unfit  3-4% risk of hysterectomy with abdominal myomectomy  Adhesion formation  Reproductive ramifications  Earlier menopause with hysterectomy and UAE  Psychological feelings

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What about menopause and fibroids?

 Symptoms tend to deteriorate in the perimenopause

related to fluctuation in hormones

 rapid growth a concern for malignancy-no evidence  Bleeding problems should stop and bulk decrease or

stabilize after LMP

 On HT, may increase bleeding, and slight growth

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