2. Learning Objectives
• Describe the efficacy and safety
of Uterine Fibroid Embolization
• Describe medications being
studied for fibroid therapy
• Describe technologies being
developed for fibroid therapy
3. Uterine Fibroids
• Benign, monoclonal,
smooth muscle tumors
• Most common tumor of
the female reproductive
tract
• 20-77% of
premenopausal women
• Symptoms: Bleeding,
Bulk, and Fertility
4. Conventional Treatments for
Symptomatic Fibroids
• Expectant management
• Medical management
– (NSAIDs, OCPs, GnRH agonist)
• Endometrial Ablation
• Myomectomy (50,000 / year in US)
• Hysterectomy (250,000 / year in US)
• **Uterine Fibroid Embolization
(40,000 / year)
6. Perceptions of Hysterectomy
in Symptomatic Fibroid Patients
NOT Desiring Fertility
• 21% favorable
• 61% unfavorable
– 67% of black women
– 55% of white
women
Goldberg Obstet Gynecol 2008
7. New & Future Treatments
for Symptomatic Fibroids
• **Uterine Fibroid Embolization
(40,000 / year)
• Medical therapies:
GnRH Antagonists, Aromatase Inhibitors,
SPRMs
• Mirena®
IUD
• HIFUS
8. Uterine Fibroid Embolization
• First described as a primary treatment for fibroids
in 1995 by Jacque Ravina, MD, of France
• Increasingly popular minimally invasive
procedure performed by interventional radiologists
• >400,000 women have undergone UFE
15. Spies Obstet Gynecol 2001;98:29-34
Improvement in
symptoms
1 year
Menorrhagia 90%
Bulk 91%
•N = 200
16. REST Trial
NEJM 2007;356:360-70
• Randomized trial of Embolization versus
Surgical Treatment for fibroids
• 106 UFE; 43 hysterectomy + 8 myomectomy
• SF-36 scores same at 1 year
• Back to work: UFE (20 days) v Surgery (62)
• 9% of UFEs had repeat UFE or hysterectomy
• Conclusions: Faster recovery after UFE must be
weighed against 9% risk for retreatment.
17. REST Trial
CIRSE Annual Meeting, Valencia, Spain 2010
• 5 year outcomes
• Symptom and QOL outcomes similar
• Satisfaction scores similar (UFE 90% v.
surgery 87%)
• Re-intervention higher with UFE (26% UFE
v. 0% surgery)
• Initial cost benefit for UFE, equal after 5
years due to re-intervention
18. REST Trial
Moss BJOG 2011
• 5 year outcomes
• Symptom and QOL outcomes similar
• Satisfaction scores similar (UFE 90% v.
surgery 87%)
• Re-intervention higher with UFE (26% UFE
v. 0% surgery)
• Initial cost benefit for UFE, equal after 5
years due to re-intervention
20. Is UAE a good procedure
with desired future fertility?
Pregnancy after
Uterine Artery Embolization
Jay Goldberg, MD, Leonardo Pereira, MD,
Vincenzo Berghella, MD
Obstetrics & Gynecology 2002
21. Pregnancy after
Uterine Artery Embolization
(Goldberg Obstet Gynecol 2002)
Pregnancy
complication
PTD SAB Malpre-
sentation
PPH CS SGA
After UAE for
fibroids (%)
22 32 22 9 65 9
General
population
(%)
5-10 10-15 5 4-6 22 10
Similar results:
Walker AJOG 2006 & Pron Obstet Gynecol 2003
22. Pregnancy outcomes following
treatment for fibroids:
UAE vs Laparoscopic Myomectomy
AJOG 2004
Jay Goldberg, MD1
, Leonardo Pereira, MD1
, Vincenzo Berghella,
MD1
, James Diamond, PhD1
, Emile Daraï, MD2
, Piero Seinera,
MD3
, Renato Seracchioli, MD4
Jefferson Medical College, Philadelphia, USA1
, Tenon Hospital, Paris, France2
,
S. Anna Hospital, Turin, Italy3
, S. Orsola Hospital, Bologna, Italy4
23. Pregnancy complications following UFE &
Laparoscopic Myomectomy (LM) for fibroids
Complication UFE LM General
population
Odds
ratio
P-value
Preterm delivery 5/32
(16%)
3/104
(3%)
5-10% 6.2 0.008
Malpresentation 4/35
(11%)
3/104
(3%)
5% 4.3 0.046
Spontaneous
abortion
12/51
(24%)
20/133
(15%)
10-15% 1.7 0.175
Postpartum
hemorrhage
2/35
(6%)
1/104
(1%)
4-6% 6.3 0.093
Small for
gestational age
1/22
(5%)
8/95
(8%)
10% 0.5 0.541
Goldberg AJOG 2004
24. The Gyn as the gate
keeper for UFE
• Wall Street Journal article (October 24, 2004)
• Economic disincentive to refer
(Goldberg OBG Management 2003)
• Should UFE be offered to appropriate candidates
as part of an informed consent?
(Goldberg Obstet Gynecol Surv 2005 & Contemp OB/GYN 2005)
26. Tranexamic Acid
• Oral anti-fibrinolytic
• Lowers endometrial tissue plasminogen activator
(tPA)
• FDA approved for Rx of menorrhagia 11/09
– Used in Europe for > 10 years
• Contra-indicated in women at risk for thrombosis
– Do not use in combo with estrogen containing meds
• 1,300 mg po TID x up to 5 days during menses
• $174 for thirty 650-mg tablets
27. Tranexamic Acid
Lukes et al. ACOG 2010 abstract
• Double blind trial vs. placebo
• N = 294 women with menorrhagia
• Menstrual blood loss decreased by:
– 39% with 3900 mg daily
– 25% with 1950 mg daily
– 5% with placebo
28. Tranexamic Acid
Muse et al. ACOG 2010 abstract
• N = 187 women with menorrhagia
• Menstrual blood loss decreased by:
–38% with 3900 mg daily
–12% with placebo
29. Efficacy of Tranexamic Acid in
treatment of idiopathic and non-
functional heavy menstrual bleeding
Naoulou Acta Obstet Gyn Scand 2012
• Metanalysis of 10 studies
• Effective and safe
• 34-54% reduction in blood loss
• 46-83% improvement in QOL parameters
• “Limited evidence indicated potential
benefit in fibroid patients with
menorrhagia”
30. GnRH Antagonist
• High binding affinity for Pituitary receptors
• Dose dependent rapid drop in gonadal
steroids
• No initial flare as with Lupron®
• Faster response
• ↓ hypoestrogenic side effects than Lupron
• No major side effects
• Peptides too large for oral bioavailability
(**2 new oral GnRH Antagonists testing **)
31. GnRH Antagonist Cetrorelix®
for pre-op treatment
Engel Euro J Ob Gyn Repro Bio 2007
• Prospective, randomized v Placebo
n=109
• 22% ↓ in fibroid volume at 1 month*
• 100% ↓ in menorrhagia*
• 87% ↓ in pain*
32. GnRH Antagonist Elagolix®
• Orally available
• Ongoing clinical trials for fibroids and
endometriosis
• Estradiol suppressed by 24 hr. effects
rapidly reversed after discontinuation.
Struthers J Clin Endo & Metab 2009
33. Aromatase Inhibitors
Anastrazole (Arimidex)
• Block Estrogen Synthetase
ovarian & peripheral estrogen
production
• Quick: Decrease Estradiol levels after 1 day
• Significant in fibroid volume at 1 month
• No difference in FSH, LH levels
• Side effects: hypoestrogenic, rash
34. Anastrazole (Arimidex)
Varelas Obstet Gynecol 2007
• Aromatase Inhibitor used to treat advanced
breast cancer in postmenopausal women
• N = 35
• 56% decrease in fibroid volume
• 11% increase in Hgb
• 63% improved menstrual pattern
• Most effective if > 40 years
• No serious adverse events
35. Selective Estrogen Receptor
Modulators (SERMs)
• Cochrane Review 2008
• 3 studies totaling 215 patients
• Raloxifene
– lack of proliferative effect on endometrium
• No significant fibroid reduction or
clinical improvement
• RR of DVT/PE 3.1 (95% CI 1.5-6.2)
MORE study Ettinger 1999
36. Selective Progesterone Receptor
Modulators (SPRMs or PRMs)
• Fibroids responsive to Progesterone (P) as well as
Estrogen (E)
• P receptor ligands with uterine selectivity
• RU486 (Mifepristone)
– 47% reduction in fibroid volume, 41% amenorrhea
(Fiscella Obstet Gynecol 2006)
– 28% reduction in fibroid volume, increased Hgb
(Engman Human Reprod 2009)
– Antiglucocorticoid effects
– Political backlash due to use as abortifacient
37. PRM Associated
Endometrial Changes (PAEC)
• Asoprisnil®
(Schering & TAP)
– Phase III trials of PRM discontinued due to
EMB findings: ? endometrial hyperplasia
• PAEC classified at NIH workshop
• Novel, benign, multi-cystic effect on endometrium
39. Proellex®
(CDB-4124)
• Phase III trials of
PRM discontinued
due to hepatic side
effects of elevated
transaminases and
bilirubin
• Studies with vaginal
Proellex underway
40. Ulipristal (Ella®
)
• FDA approval for
emergency
contraception 2010
• Ongoing trials for
fibroid treatment
41. Ulipristal v placebo for
fibroids before surgery
Donnez NEJM 2012
• Prospective randomized DBPC 13 week
study. n = 237
• Bleeding controlled: 92% v 19%
• Amenorrhea: 82% v 6%
• Change in fibroid volume: -21% v +3%
42. GnRH Antagonists,
Aromatase Inhibitors, SPRMs
• Effective in treating bleeding and bulk
fibroid symptoms
• Oral medication
• Uterine preservation
• Avoid surgery
• Short and Long term
• GYN controlled
• Safety concerns
• Not coming to you any time soon
44. Mercorio Contraception 2003
• Italian non-comparitive study of Mirena IUD
for women with fibroids/menorrhagia
• Excluded “intracavitary abnormalities”
• 13% expulsions
• 22% withdrew for surgery
• PBAC score ↓ 69% at 1 year (p< 0.01)
– >100 (menorrhagia) in remaining 14/19 ♀
• Hemoglobin ↓ despite LNG-IUS and Iron
• Conclusion: Not for large fibroid uterus
45. Soysal Gynecol Obstet Invest 2005
• Turkish study comparing LNG-IUS to
Thermal Balloon EMA for submucosal
fibroids & menorrhagia
• PBAC score ↓ (392→37) and ↑ in Hgb
• No change in uterine size
• No ↑ in expulsion rate
• Conclusion: LNG-IUS safe and effective
46. MRI-Guided Focused High
Intensity UltraSound (HIFUS)
• Thermal lesions are
created within target
fibroids using MRI-
guided focused high
intensity ultrasound
• FDA approved in 2004
to treat uterine fibroids
• ExAblate 2000 System
InSightec & GE
47. Clinical outcomes of HIFUS
Stewart Fertil Steril 2006
• Prospective study n = 82 at 1 year
• 51% had 10-point improvement at 1
year Symptom Severity Score (SSS)
• 9% mean reduction in fibroid volume
48. MRI Guidance of
Focused Ultrasound
• Questions about long term
durability, larger volumes, fertility
• Performed by Radiologists, not
Gynecologists
• Logistical issues
• Not covered by insurers
55. Case Study #1
• 41-year-old gravida 0, desires fertility
• Menorrhagia, anemia, bulk symptoms,
infertility
• Only hysterectomy recommended by GYN
• US 20 cm uterus with multiple fibroids
• 18 week uterus
56. Case Study #1
Best treatment options?
18 wk, bleeding, bulk, infertility
1. Expectant management
2. Endometrial ablation
3. Mirena IUD
4. UFE
5. Myomectomy
6. Hysterectomy
57. Case Study #1
Best treatment options?
18 wk, bleeding, bulk, infertility
1.Expectant management
2. Endometrial ablation
3. Mirena IUD
4. UFE
5.Myomectomy
6. Hysterectomy
58. Case Study #2
• 45-year-old, no fertility desired
• Menometrorrhagia, pelvic pressure
• MRI 26 cm uterus with multiple,
including submucosal and
pedunculated, fibroids
• 24 week uterus
• EMB benign endometrium
59. Case Study #2
Best treatment options?
24 wk submucosal & pedunclulated
fibroids, bleeding, bulk, no fertility desired
1. Expectant management
2. Endometrial ablation
3. Mirena IUD
4. UFE
5. Myomectomy
6. Hysterectomy
60. Case Study #2
Best treatment options?
24 wk submucosal & pedunclulated
fibroids, bleeding, bulk, no fertility desired
1. Expectant management
2. Endometrial ablation
3. Mirena IUD
4. UFE
5. Myomectomy
6. Hysterectomy
61. Case #3
• 38-year-old, no fertility desired,
smoker
• Menorrhagia, anemia
• Prior myomectomy and C-section
• US 10 cm uterus with multiple
small, including 2 cm submucosal,
fibroids
• 9 week size uterus, negative EMB
62. Case Study #3
Best treatment options?
9wk, bleeding, smoker, no fertility desired
1. Expectant management
2. COCs
3. Endometrial ablation
4. Mirena IUD
5. UFE
6. Hysteroscopic myomectomy
7. Myomectomy
8. Hysterectomy
63. Case Study #3
Best treatment options?
9wk, bleeding, smoker, no fertility desired
1. Expectant management
2. COCs
3. Endometrial ablation
4. Mirena IUD
5. UFE
6. Hysteroscopic myomectomy
7. Myomectomy
8. Hysterectomy
64. New Fibroid Rx
Summary
• Majority of women unfavorable towards
hysterectomy
• UFE 17% failure rate at 5-7 years
• ? Promising meds: GnRH Antagonists,
Aromatase Inhibitors, & SPRMs
• Mirena IUD contraception & ↓ bleeding
• HIFU not quite there yet
• Many new technologies in development
Notas do Editor
FIGO Santiago, Chile 11/03
Many peptides are too large to have bioavailability if taken orally. Ganirelix (Organon/Schering), Abarilex (Serano/Merck KGAA Germany). Elagolix (Neurocrine Biosciences NBIX) has molecule small enough to be taken orally. Currently only endometriosis studies underway (PETAL study vs. Lupron).
Testosterone and andostrenedione to estrone and estradiol
