Medical Management of Fibroids

Dr Dasgupta was invited to deliver a lecture on this topic in a CME organized by Alembic

1. Medical Management of Fibroid
1

2. 2
Dr Sujoy Dasgupta
MBBS (Gold Medalist, Hons)
MS (OBGY- Gold Medalist) DNB (OBGY)
MRCOG (London) FIAOG
Fellow- Reproductive Endocrinology & Infertility (ACOG)
Visiting Consultant,
•Bavishi Pratiksha Fertility Institute
•RSV Hospital
•Iris Hospital
•Behala balananda Brahmachary Hospital
•AMRI Hospitals
Secretary, Website Committee, Bengal Obstetric and Gynaecological Society
(BOGS)- 2017-18
Managing Committee Member, BOGS- 2017-18
Member, Quiz Committee, FOGSI East Zone 2017-19
Executive Committee Member, Medical College Ex-Student’s Association
•Peer-Reviewer, BMJ Case Reports, UK
•15 Publications- National & International Journals
•Lecture delivered- at 40 International, National, Regional Conferences
•Faculty, MRCOG Course, AICC RCOG East Zone

3. •Fibroids occur when a single
uterine smooth muscle connective
tissue cell replicates until a cluster
of cells form a mass that is distinct
from the normal muscular tissues.
•genetic factors (fibroids tend to run
in families)
•hormonal causes (fibroid tissue has
more estrogen and progesterone
receptors than normal uterine tissue
and therefore are more sensitive to
alteration of these two hormones
during the menstrual cycle).
4
Causes of Fibroids

4. •The management of symptomatic fibroids has been traditionally surgical
•No medical therapy can completely eliminate fibroids
•However alternative pharmacological treatments have been proposed to
control symptoms
•Choice of appropriate therapeutic modality depends on several factors
including :
1.Age & Parity
2.Child bearing expectations
3.Extent & Severity of
Symptoms
4.Size, number & location of
myomas
5.Proximity of menopause
6. Risk of Malignancy
Current Therapies for uterine fibroids:
Are they Satisfactory?

5. 6
Symptomatic Uterine Fibroids
Medical Therapy Surgical Therapy Other modalities
Non Hormonal
Hormonal
Open /Laparoscopic
Myomectomy &
Hysterectomy
Endometrial Ablation &
Hysteroscopic
Myomectomy
U A E
(Polyvinyl Particles)
Magnetic Resonance-
guided focused
Ultrasound Surgery
(MRgFUS)
& & &

6. Advantages
Uterus Preserved
Able to become
pregnant
Symptoms Usually Improve
Myomectomy

7. New Fibroid Growth
Symptoms May Not go
away
Need for future surgery
C section to
Deliver Babies
Major Surgery
Potential
Disadvantages
Myomectomy

8. 9
Advantages
No More Periods
Patient Satisfaction:
Very High
No Need For Contraception
Fibroids Can Not
Grow Back
No Change In
Hormones
Symptoms Go Away
Hysterectomy

9. Potential Disadvantages
Hysterectom
y
Unable to become pregnant
i.e.
Complete loss of fertility
Loss of Uterus
Need For Future Surgery
For ovary and other
complications
Risk for Surgical
Complications e.g.
Adhesions & Pelvic organs
injury and relaxations

10. Gn Rh Agonists
MEDICAL TREATMENT
NSAIDs
Oral Contraceptive pills
Progesterone Releasing
IUD
Progesterone
Pills
No Medical treatment
completely eliminates
Fibroids

11. OCPs
Often used to treat menorrhagia & dysmenorrhea
Breakthrough bleeding
Drawback: increase the size of myoma
LNG IUD
Leads to more irregular bleeding
System expulsion
GnRH agonists:
Monthly IM injections for 3-6 months
Effects are transient & the myoma usually return to the pre-therapy size within a
few months of discontinuation*
Suppresses estradiol
Cause hypoestrinism
#
67% patients report Hot flushes
Reduced BMD
*Drug Des Devel Ther. 2014 Feb 20;8:285-92.
#. Int J Endocrinol. 2012;2012:436174
Drawbacks of available medical therapies

12. 13
Progesterone
plays a vital role in promoting uterine fibroid growth
1. Human Reproduction Vol.21, No.9 pp. 2408–2416, 2006
2. Curr Opin Obstet Gynecol 2009;21:318-24
3. Eur J Obstet Gynecol Reprod Biol 2012 Aug 14
4. n engl j med 366;5
Newer pathology as authenticated by

13. Has stimulated interest in modulating the progesterone pathway
Thus, SPRMs* are innovative therapy in uterine
fibroid management
* Selective Progesterone Receptor Modulators
N Engl J Med. 2012 Feb 2;366(5):409-20
14
Role of progesterone in promoting the
growth of fibroids

14. •Selective Progesterone Receptor Modulators (SPRMs) are new
class of Progesterone receptor (PR) ligands displaying tissue-
selective agonist/antagonist/mixed activity on target cells
15
About SPRMs

15. 16
Ulipristal Acetate
(CDB 2914)
The only SPRM approved for the treatment
of Uterine Fibroids

16. Ulipristal Acetate Approval
17
16
th
Dec 201124
th
June 2013 2014

17. •A first-in-class, effective, well-tolerated
SPRM specifically designed for uterine
fibroids
•Reversible blockage of progesterone
receptors
#
•It binds progesterone receptors, but not
estrogen receptors
•No affinity on mineralocorticoid
receptors*
•Action only on fibroid cells & not in
normal myometrial cells
*http://link.springer.com/article/10.1007/BF03262118#page-1
About Ulipristal acetate

18. •Management of symptomatic uterine fibroids
•Pre-operatively to reduce the size & symptoms of fibroids
•Dosage : One tablet of 5 mg OD to be started during first week of
menstruation continuously for 3 months
19
Indications & Dosage

19. 20
Potent antiprogesterone action
Fibroids HPO axis Endometrium9336# 63$36%6&'()
6
6%6
'336&* 63$3
Decreasing Bcl-2 expression & TIMP
2
&
Increases TNF expression
Decreases fibroid size and volume
1,2
Inhibits ovulation
21426
)•••+3•/36
6•
16
Shows
Proapoptotic/antiproliferative
action
1
Induces amenorrhea
3
93336346%6 146
3/3
Decreases LH & FSH
levels1426•+3•/36
•

Shows antiproliferative
action
3
1.Fertil Steril. 2014 Jun;101(6):1565-73.e1-18.
2.Drug Des Devel Ther. 2014 Feb 20;8:285-92
3.N Engl J Med 2012; 366:421-432
*HPO: Hypothalamic-pituitary-ovarian axis
* Bcl2: B-Cell Lymphoma 2
* TIMP: Tissue Inhibitor of Metalloproteinase
Ulipristal : MOA

20. Reprod Sci. 2014 Sep 16.
Pharmacokinetics

21. Premya Study
Objective: Treatment with UPA in a Pre-operative setting
22
Multicentre, Prospective, non interventional Study
75 Centres in 10 EU countries
1473 patients with Symptomatic Fibroids
Premenopausal women & those who have been recommended surgery
5mg UPA OD for 3 months
Follow up was done at 3,6,9,12 and 15M post treatment
Mean age :42 yrs
25 % patients were between 30-40 yrs,12 % patients were >=50 yrs
14% patients had undergone myomectomy before
Premya Study Cont..

22. 23
CGI-I scale at 3 months:
61% patients “Much
improved” & “Very
improved”
•Out of total only 39% patients underwent surgical procedure during
12 months following treatment
•42% patients were not operated
•Using UPA prior to surgery : delays or avoids surgery by lastingly
improving symptoms, even after stopping treatment
•One can avoid surgery prior to menopause
•To avoid or delay surgery prior to pregnancy as there is a possibility
of avoiding complications secondary to myomectomy(by limiting the
risks of postoperative adhesions and their consequences on fertility)
PTB scale at 3 months:
88% patients
“greatly” &
“somewhat
improved”
Pain assessment score
Prior to treatment: 47
Post treatment: 8-15
(3-15 months period)
considering that 20% patients lost to follow up all
underwent surgery
J Gynecol Obstet Hum Reprod 46 (2017) 249–254

23. Ulipristal acetate does not disturb the surgical
planes in patients who had to undergo
myomectomy for removal of Uterine Fibroids
Clinical benefits of Ulipristal introduced before
scheduled surgery

24. Clinical benefits of Ulipristal introduced before
scheduled surgery
25
Prz Menopauzalny 2014; 13(1): 18-21
Correction of
patient’s
anemia
Reduction of
intraoperative
blood loss
Facilitation of
myomectomy
instead of
hysterectomy
Reduction of
operative time
Reduces the
need for blood
transfusion
•Even mild anaemia can lead to increased risk of morbidity & postoperative
mortality
•Intraoperative transfusion does not modify these risks
By reducing fibroid volume & correcting anaemia UPA allows for
less invasive surgery
J Gynecol Obstet Hum Reprod 46 (2017) 249–254

25. 26
VENUS II study
Quality of life with Ulipristal acetate (UPA) treatment of symptomatic uterine
fibroids (UF)
CONCLUSIONS: UPA 10 mg and 5 mg significantly improved quality of life .
Significant improvement in all UFS-QoL subscales demonstrates that UPA
treatment improves a woman’s ability to lead a normal life.
VENUS II Study
The Second US-Based Phase 3 Study of Ulipristal acetate (UPA) for the
treatment of Symptomatic Uterine Fibroids (UF)
CONCLUSIONS: Numerically greater responses in efficacy were observed with
UPA 10 mg vs 5 mg, though the safety profiles were similar.
Both UPA 10 mg and 5 mg were generally well tolerated
Latest ASRM 2017 Highlights

26. 27
Ulipristal acetate (UPA) treatment of symptomatic uterine fibroids (UF):
VENUS II subgroup analyses by race and BMI
CONCLUSIONS: UPA 10 mg and 5 mg showed higher responses than PBO in
the proportion of women achieving amenorrhea, regardless of race and BMI.
Both doses of UPA also led to increased QoL, with improvements in physical and
social activities compared with placebo in all subgroups evaluated.
Numerically greater responses were observed with UPA 10 mg vs 5 mg.

27. 28
Absolute & Relative Contraindications

28. 29
Special Warnings and Precautions

29. System Organ Very common Common Uncommon
Reproductive &
Breast
Amenorrhea
Endometrial
thickness
Pelvic pain, Hot
flushes, Breast
tenderness & ovarian
cyst
Breast swelling &
breast discomfort
CNS Headache Dizziness
ENT Nasopharyngitis Vertigo
GIT Abdominal pain &
Nausea
Dyspepsia, Dry
mouth, Constip
Psychiatric Disorder Anxiety, Emotional
disorder
Skin Acne Alopecia, Dry skin
General DisorderHot flushes Oedema, Fatigue
Renal Incontinence
Musculoskeletal Pain Back pain
Investigations
⇑
Blood Cholesterol
⇑
Trigly and Wt
⇑
Adverse Drug Reactions

30. Patients with
symptomatic
uterine fibroids
eligible for surgery
Age: 18 to 50 years
Fibroid related anemia
At least one fibroid ≥3 cm in
diameter & none >10 cm
Once daily oral Ulipristal 5 mg +
concomitant iron (80 mg)
N=96
Once daily oral Ulipristal 10 mg
+ concomitant iron (80 mg)
N=98
Placebo+ concomitant iron (80
mg)
N=48
Surgery
3 & 6
month
follow-
up visits
3 months
N Engl J Med. 2012 Feb 2;366(5):409-20
32
(1) Ulipristal Acetate Vs Placebo for Fibroid
Before Surgery

31. 33
N Engl J Med. 2012 Feb 2;366(5):409-20
•91% patients with control of uterine bleeding
•Fibroid volume reduction of ≥25% in 37% of pts
•Time to persistent amenorrhea :Approximately 50% of patients
in the 5 mg ulipristal group became amenorrhea within the
first 10 days
•Significant reduction in pain
CONCLUSION
Treatment with Ulipristal acetate effectively controls
excessive bleeding due to uterine fibroids & reduces
size of the fibroids

32. Premenopausal
women with
symptomatic
uterine fibroids
eligible for surgery
Age: 18 to 50 years
HMB
At least one fibroid ≥3 cm in
diameter & none >10 cm
Once daily oral Ulipristal 5
mg
N=97
Once daily oral Ulipristal 10
mg
N=103
3.75 mg leuprolide acetate
once monthly
N=101
Surgery
3 & 6
month
follow-
up visits
3 months
Treatment started within 4 days after the start of menstrual
period & was continued until week 13 after which patients
could go for surgery
N Engl J Med 2012; 366:421-432
34
(2) Ulipristal Acetate Vs Leuprolide
Acetate for Uterine Fibroids

33. •Excessive bleeding was controlled significantly more rapidly in UPA than
leuprolide (p<0.001)
•Amenorrhea was induced more rapidly (7 days) in UPA 5 mg than leuprolide (21
days) (p<0.001)
•Sustained effect seen up to 6 months after treatment cessation
•Median oestradiol levels were maintained in the mid-follicular range About 5% of
patients of reproductive age experiencing heavy menstrual bleeding have an
endometrial thickness of greater than 16 mm
•Oral UPA was not inferior to monthly inj.of leuprolide in women with symptomatic
fibroids before planned surgery & had a better side-effect profile
N Engl J Med 2012; 366:421-432
35

34. 3 months 3 months
Ulipristal
10 mg
3 months 3 months
PEARL III
N=203
PEARL III extension
N=132
Ulipristal
10 mg
Ulipristal
10 mg
Norethisterone acetate (NETA) or
placebo (10-day) (double-blind)
Menses
Double-blind NETA or placebo added after each course to explore any effect on histological endometrial changes & on
timing & magnitude of next menstruation, off treatment
Ulipristal
10 mg
Enrolled pre-menopausal women (18-48 years) with at least one fibroid ≥3 cm in diameter & none >10 cm, HMB
103 Placebo & 98 NETA 68 Placebo & 64 NETA
Fertil Steril. 2014 Jun;101(6):1565-73.e1-18.
36
(3) Long term treatment of Uterine Fibroids
with Ulipristal Acetate

35. 37
•Effectively controls bleeding & pain:78.5% Amenorrhea with first course &
90% with repeated course
•Reduces fibroid volume: 45% reduction in Fibroid volume with first course &
72% with repeated course
•Symptomatic improvement & fibroid volume shrinkage can be largely
maintained during the off-treatment periods
•Restore QoL
•Ovarian ultrasound – no significant change
•Change in hematology – no significant change
•Serum levels of E2 – no significant change
•Headache (16.3%) and nasopharyngitis (6.7%) were the most common
adverse events associated with UPA, but fewer were experienced after the first
course of treatment
•Changes in endometrial thickness
•Transient increase in endometrial thickness in <10% of pts
•No case of endometrial hyperplasia
Fertil Steril. 2014 Jun;101(6):1565-73.e1-18.
Effect & Outcome due to long term usage

36. •Limitations of SPRMs
•Endometrial changes unique to progesterone receptor modulators (PRM) are described and
referred to as PRM-associated endometrial changes (PAEC). It is therefore not always
possible to identity patients taking PRM on histology alone and it is therefore important to
inform the pathologist when sending a hysterectomy or an endometrial biopsy specimen.
•PAEC were evaluated in women taking short courses of SPRMs (asoprisnil, ulipristal acetate
and telapristone acetate) and no hyperplasia, premalignant or malignant lesions were
identified in these specimens.

•Due to the theoretical concerns, however, the use of ulipristal acetate is currently limited to
3 months.
•Although nonphysiological changes were seen frequently in the ulipristal group, these
changes had resolved 6 months after treatment demonstrating reversibility of these changes
and safety in this respect of their short-term use.
•At present, there do not appear to be any significant side effects of ulipristal acetate but it is
recommended that they be used with caution in those with severe asthma uncontrolled by
oral glucocorticoids and in those with hepatic dysfunction, hereditary problems of
galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
38

37. 39
Total volume of 3 largest fibroids
(cm
3
)
Ulipristal 5
mg
Ulipristal 10
mg
Baseline 42.6 43.6
After
treatment
Course 1
-38 -58.1
After
treatment
Course 1
-54.1 -58.0
Fertil Steril. 2014 Dec 30.
Secondary end-points: Surgery performed in only 3 &
5 patients receiving 5 & 10 mg of UPA

38. 40
56 patients
aged 29-47
yrs with
symptomatic
uterine
fibroids,
qualified for
surgical
treatment
Treatment
with
ulipristal at a
dose of 1x5
mg starting
on the first
day of
menstruation
Duration: 3
months
26 patients
did not go
for surgery
27 patients
went for
surgery
46.4%
9 patients
Follow-up
for 9
months
End-point analysis:
1.Volume of the dominant
fibroid
2.Cessation of menstrual
bleeding
3.Mean Hb%levels
4.Recurrence rate
Prz Menopauzalny 2014; 13(1): 18-21
(4) The effect of Ulipristal Acetate treatment on
symptomatic uterine multiple fibroids within 12 months
follow up

39. •Mean Hb prior to therapy was 10.1 g/dL rising to 12.6 g/dL after 12 weeks of
ulipristal treatment
•46.4% patients opted against scheduled surgery due to the fact that all the
clinical symptoms of fibroids had disappeared
•No recurrence of fibroid growth
•In 1/3
rd
of followed-up patients, the effect of 3 month ulipristal therapy
persisted for the next 9 months
41
Prz Menopauzalny 2014; 13(1): 18-21
Results

40. Retrospective analysis of a series of 52 patients included
Among 52 patients, 21 wished to conceive upon completion of treatment
Among the 21 who attempted to get pregnant, 15 succeeded (71%) totaling 18
pregnancies
Among the 18 pregnancies, 12 resulted in birth of 13 healthy babies & 6
ended in miscarriage
No regrowth of fibroids observed during pregnancy
This confirms the long-term effect after ulipristal therapy
Fertil Steril 2014;102:1404–9
42
(5) First series of 18 pregnancies after UPA
treatment for uterine fibroids

41. 43
Fertil Steril 2014;102:1404–9
Endometrium of sufficient quality for blastocyst implantation
Median time to achieve pregnancy after the end of treatment was 10 months
No maternal complications related to myoma. All babies were healthy
No regrowth of fibroids during pregnancy

42. 44

43. NICE Recommendations (2016)
<3 cm
1.LNG-IUS
2.Tranexaemic acid/
Mefenamic Acid/ COC
3.Norethisterone Day5-25
≥3 cm
•Hb <10.2 g/dl- UPA up to 4
courses (total 20 months)
•Hb ≥ 10.2 g/dl- Consider
UPA (Total 20 months)
45

44. NICE Recommendations (2016)
<3 cm
1.LNG-IUS
2.Tranexaemic acid/
Mefenamic Acid/ COC
3.Norethisterone Day5-25
Not resolved
Endometrial Ablation
≥3 cm
•Hb <10.2 g/dl- UPA up to 4
courses (total 20 months)
•Hb ≥ 10.2 g/dl- Consider
UPA (Total 20 months)
Not resolved
Myomectomy/ UAE
GnRH Ago→ Hysterectomy
46

45. Before Myomectomy
•Both GnRH or LA can be used
47

46. Before UAE
•GnRH agonist MUST be stopped
•UPA is safe
48

47. •Mifepristone
•Mifepristone has been associated with development of endometrial
changes in some reports

and its use in treatment of fibroids is
currently restricted to research settings.
•Ulipristal acetate
•It induces apoptosis in uterine fibroid cells and inhibits proliferation
of cells.
• There was no difference in the control of menstrual bleeding between
UA and leuprolide. However, UA was tolerated better and controlled
bleeding more rapidly than leuprolide.
49

48. Fibroids?
50

49. Experience with UPA
51

50. 54

51. 55