2. Introduction
• Fibroid – Benign, monoclonal tumor of
smooth muscle cells of the myometrium.
• Most common benign tumor of uterus
• Most are asymptomatic.
• It contain large aggregations of extracellular
matrix composed of collagen, elastin,
fibronectin and proteoglycans.
• Collagen type 1 and 3 are abundant, but
collagen fibrils are in disarray.
3. Epidemiology
• Incidence –
a) For 25 – 29 yrs age - 4.3/1000 women years
b) For 40 – 44 yrs age – 22.5/1000 women years
c) First degree relatives have 2.5 times
increased risk
d) Afro-American women have 2.9 times greater
risk than white women.
5. Genetic factors
- Fibroids are monoclonal.
- 40% have chromosomal abnormalities as
translocation between chromosomes 12 and 14,
deletions of chromosome 7 and trisomy of
chromosome 12. Cellular, atypical and large
fibroids are most likely show chromosomal
abnormalities.
- Remaining 60% may have yet undetected
mutations.
- More than 100 genes were found to be up- or
down-regulated in fibroid cells.
- Many of these genes regulate cell growth,
differentiation, proliferation and mitogenesis.
6. Hormonal factors
• Both estrogen and progesterone promote the
development of fibroids, as rarely observed
before puberty, most prevalent during
reproductive years and regress after
menopause.
• Factors that increase overall lifetime exposure
to estrogen, as obesity and early menarche,
increase the incidence.
• Decreased exposure to estrogen found with
smoking, exercise and increased parity is
protective.
7. • Increased levels of AROMATASE enzyme within fibroid
leads to de novo production of estradiol than in normal
myometrium.
• Increased concentration of progesterone receptors A
and B compared with normal endometrium.
• The highest mitotic counts are found in fibroids at peak
of progesterone production.
• GnRH agonists decrease the size of fibroids but
progestin given concurrently with GnRH prevents
decrease in size.
• Antiprogestine drugs, such as RU-486, Proellex
(CDB4124), ulipristal acetate (CDB2914) and
mifepristone, cause regression of fibroid size and
symptoms as well as a decrease in ECM formation in
fibroid.
8. Environmental factors
• An increased risk of fibroid development is linked to early life
exposure to genistein, a common source of dietary
phytoestrogens and tyrosine-kinase inhibitor of EGFR. Infant
fed with soy based formula have 6 to 11 times higher
exposure of genistein. High conc. of phytoestrogens has an
estrogenic effect in female reproductive tract during the
critical window of sensitivity to environmental estrogen,
including re-estrogenisation of vaginal cells at 6 month of age.
• There is also evidence that phenolic environmental estrogens
as BPA, Octyphenol and nonyphenol are involved. BPA is a
synthetic estrogen used during manufacturing of plastic
products and resins commonly found in packaging of foods.
• Differential levels of xeno-estrogens in blood serum and urine
conc. of patient with and without fibroid show correlation
between environmental estrogen exposure and incidence of
fibroid.
9. Growth factors
• Growth factors, proteins or polypeptides
produced locally by smooth muscle cells and
fibroblasts, appear to stimulate fibroid growth
primarily by increasing extra-cellular matrix.
• Over-expression of growth factors- act by-
TGF-β, bFGF- increase smooth muscle
proliferation
EGF, PDGF- increase DNA synthesis
TGF-β- stimulate extra-cellular matrix synthesis
TGF-β, EGF, IGF, Prolactin- promote mitogenesis
bFGF ,VEGF- promote angiogenesis
10. Cytogenetic factors
• Mediator complex subunit 12 (MED12) is an
important contributor to fibroid etiology.
• Mutations in exon 2 of MED12 are present
specifically in approximately 70% of fibroid.
• A small percentage of fibroid is due to familial
genetic mutations in the Fumarate Hydrase
(HLRCC) genes.
• Wang et al in 2007, revealed 45 miRNAs including
the let-7 family, miR-21, miR-23b, miR-29b and
miR-197 were significantly dysregulated in fibroid
tissue compared with healthy myometrial tissue.
11. • Cell Signaling Pathways as PI3K/AKT-mTOR
Pathway: identified as one of the most
upregulated signaling pathways in fibroid.
• PI3K and mTOR are necessary for estrogen-
dependent cell growth in fibroid and myometrial
cell cultures.
• A role of increased Ras/Ref/MEK/ERK signaling in
fibroid is likely, based on overexpression of
several proteins involved in the pathway.
• Shc, Grb2, and ERK and 15 distinct RTKs are more
highly expressed in fibroid compared with
healthy myometrium.
12. • Brosens et al revealed that submucous
fibroids have fewer cytogenetic abnormalities
when compared with intra-mural and sub-
serosal fibroids. (12% Vs 35% and 29%
respectively).
14. Management
1. 50 % cases are asymptomatic and do not
need treatment.
2. Watchful waiting – For women who are
mildly or moderately symptomatic.
3. Medical management
4. Surgical management- for pts with severe
anemia or ureteral obstruction or not
responding to medical therapy.
15. INDICATION OF TREATMENT IN
ASYMPTOMATIC FIBROIDS
• Infertility caused by a cornual fibroid blocking the
tube and habitual abortions due to a submucous
fibroid. Other causes of infertility and abortions
should be ruled out before myomectomy.
• Fibroid size > 12 weeks
• Pedunculated fibroid (can cause torsion)
• Broad ligament fibroid causing pressure on
ureters
• Pressure on bladder causing increased volume of
residual urine and increased chances of urinary
retention.
16. • Rapidly growing fibromyoma in a
postmenopausal women implying impending
malignancy
• When nature of the tumor cannot be
ascertained clinically.
17. Medical management
Indications-
1. Young women desirous of pregnancy
2. To improve menorrhagia and to correct anemia
before surgery
3. To minimize the size and vascularity of tumor in
order to facilitate surgery
4. In selected cases of infertility to facilitate
hysteroscopic or laparoscopic surgery
5. As an alternative to surgery in perimenopausal
women with high risk factors for surgery
6. Where postponement of surgery is planned
temporarily
18. Aims of medical treatment
1. To correct anemia
2. To decrease blood loss
3. To decrease size and vascularity of fibroid
19. To treat heavy menstrual bleeding-
1. Non-hormonal agents-
A) Anti-fibrinolytic agents- (Tranexamic acid)
FDA approved in 2009 for Heavy menstrual
bleeding.
MOA-
Lysine analog that competes for lysine binding
sites on plasminogen and plasmin, thus blocking
their interaction with fibrin.
It inactivates the plasminogen activator of the
endometrium and thus stops fibrinolysis and
degradation of the clotting complexes.
20. • Tranexamic acid is excreted in the urine and
dose reductions are necessary in patients with
renal impairment.
• Side effects- nausea and diarrhoea.
Thromboembolic events, disturbed colour
vision and allergic reactions are infrequent.
Thrombophlebitis of injected vein can occur.
• Dose: 10–15 mg/kg 2–3 times a day or 1–1.5 g
TDS oral, 0.5–1 g TDS by slow i.v. infusion
22. To decrease the size of fibroid
A) Anti-progesterones (RU486)
B) Antigonadotropins: Danazol, Gestrinone
C) Gonadotropin releasing hormone agonists
D) Gonadotropin releasing hormone antagonists
E) Selective progesterone receptor modulators
(SPRMs)
23.
24. Combined oral contraceptive (COC):
• MOA- Act by causing endometrial atrophy and
decreased production of prostaglandins.
• Therapeutic trial of 3-6 months can be tried
before more invasive treatment.
• Adv.- Useful for heavy menstrual bleeding and
dysmenorrhea associated with fibroids but
not for reducing bulk symptoms.
• Disadv.- High levels of both estrogen and
progesterone, which decreases risk of
developing new fibroids, but may lead to
increase in size of existing fibroids.
25. Anti-progesterone drugs
Mifepristone (RU 38486/RU 486)-
• A derivative of 19-nortestosterone.
• MOA- Partial agonist and competitive
antagonist at both A and B forms of PR.
• Mifepristone is active orally, but bioavailability
is only 25%.
• Largely metabolized in liver by CYP 3A4 and
excreted in bile; some enterohepatic
circulation occurs.
• t½-20–36 hr.
26. • Dose- 2.5 – 10 mg daily orally for 3-6 months.
• Adv.- Size reduction- 50%.
• S/E- Minor- Nausea, vomiting, headache, cramps.
Vasomotor symptoms (≈ 40%), endometrial
hyperplasia (unopposed estrogen)
• C/I- a) Age> 35 yrs
b) heavy smoker
c) Adrenal insufficiency
d) Corticosteroid therapy
• Ulipristal and Asoprisnil - Recently approved as
‘selective progesterone receptor modulator’
(SPRM) has anti-proliferative effects in the uterus.
27. Levonorgestrel IUS (LNG-IUS):
• Although it is FDA approved for the control of
heavy menstrual bleeding. there are no RCTs
evaluating its use in fibroids.
• Adv.- Symptom relief in menorrhagia and
adenomyosis associated with fibroids.
• C/I- 1) Uterus size > 12 weeks,
2) distorted uterine cavity with multiple
fibroids
3)submucous fiboid
28. Progesterone implants (DMPA) & POP:
• MOA- Endometrial atrophy
• Adv.- Improve symptoms of menorrhagia in
addition to providing contraception.
• Disadv.- Useful only as short-term option, as
progesterone is a growth factor for fibroids
although the overall effect is complex.
29. Antigonadotropins
Danazol:
• 17-α ethinyl testosterone
• MOA- Androgonadotropin and androgen
agonist action.
• Adv.- Induces amenorrhea and may thus help
in treatment of anemia related to fibroids but
does not reduce fibroid volume.
• Dose- 200-400 mg in divided doses for 3
months.
30. • Side effects –
Due to hypoestrogenic and androgenic
activity- weight gain, breast atrophy, hot
flashes, sweats, hirsutism and mood changes.
Virilization of female fetus in accidental
pregnancy (Barrier contraceptives
recommended).
Most changes reversible ( except- hirsutism
and hoarseness of voice- should discontinue
therapy)
• C/I- Liver disease
31. Gestrinone:
• Derivative of 19-norethisterone
• MOA- Androgen agonist and progesterone
agonist antagonist. Reduces SHBG so increased
testosterone. FSH and LH also reduced.
• Dose- 2.5 mg twice weekly from 1st day of cycle
with 2nd dose 3 days later repeated on same 2
days preferably at same time each week.
• Adv.- Reduces fibroid volume and also has a
prolonged post-treatment effect that persists
even at 18 months.
• Side-effects- Same as Danazol, but less marked.
32. GnRH agonists
• MOA- Sustained pituitary down-regulation and
suppression of ovarian function.
• Up regulation- Stimulation of anterior pituitary
to increase secretion of FSH and LH, known as
FLARE EFFECT, typically lasts 1 week.
• Down regulation- After 1-3 weeks, profound
suppression of secretion due to loss of pituitary
GnRH receptor sensitivity –> fall in FSH and LH
-> fall in Gonadotropins (Hypogonadotropic
hypogonadal state)
33. Dose-
• Lueprolide Acetate - 3.75 mg every 28 days/
11.25 mg every 3 month I/M
• Goserelin – 3.6 mg monthly/ 10.8 mg every 3
monthly S/C depot implant.
• Triptorelin – 3.75 mg monthly/ 11.25 mg every 3
monthly.
• Nafarelin – 200 mcg twice daily nasal spray
• Later 3 are not FDA approved.
• FDA approved mainly as pre-operative therapy
for fibroids, given 3-6 months prior to surgery
along with iron supplementation.
34. Adv.-
Fibroid volume reduces by 30% and total
uterine volume by 35%.
Improvement of menorrhagia, anemia and
pressure symptoms
Reduction of vascularity thus reduction in
blood loss during surgery
May facilitate laparoscopic / hysteroscopic
surgery and non descent vaginal hysterectomy
by reduction in size of fibroid.
35. Disadv.-
a. Rapid resumption of menses and increase in
uterine volume after discontinuing therapy.
b. High cost
• S/E- Hypoestrogenic symptoms (hot flushes,
mood changes, vaginal dryness and bone loss
with prolonged use).
• Add-back therapy with continuous combined HRT
(not COC) is given to minimize adverse effects.
Can be started 1 to 3 mths following therapy
initiation.
• Limitation- ACOG recommends no longer than 6
months use without add back therapy.
36. GnRH antagonists
• MOA- Bind to the GnRH receptor and provide
competitive inhibition of the naturally
occurring GnRH.
• Adv.- Immediate decline in gonadotropin
levels with an immediate therapeutic effect
within 24–72 hours, No flare effect.
• Disadv.- administered subcutaneously as
depot preparation to avoid first pass
metabolism. The blood peaks are slower to
develop and take longer to return to baseline.
37. • Other forms of administration include nasal
spray, sustained-release implants, and
injections of biodegradable microspheres.
• The immediate suppression of endogenous
GnRH by daily subcutaneous injection of the
GnRH antagonist ganirelix results in a 29%
reduction in fibroid volume within 3 weeks
treatment.
• A newer oral GnRH antagonist, Elagolix is
under study for fibroid and endometriosis and
may be more acceptable for use.
38. Selective Progesterone Receptor Modulators
(SPRM): (Ulipristal acetate and Mifepristone)
MOA-
Reversible blockage of progesterone receptors
Binds progesterone receptors, but not
estrogen receptors
Action only on fibroid cells & not on normal
myometrial cells
Induces apoptosis in uterine fibroid cells and
inhibits proliferation of cells.
41. PEARL
• Esmya was introduced in 2012 and has been
the subject of four phase 3 clinical studies in
the PGL4001 (ulipristal acetate) Efficacy
Assessment in Reduction of symptoms due to
uterine Leiomyomata (PEARL) programme,
which have been conducted consecutively
over the past 4 years
42.
43.
44. • PEARL III showed that ulipristal was effective
during long-term treatment, with no increase
in side effects over time.
• The most common side effect reported in
PEARL III was headache.
45. • Results of PEARL IV were comparable with
those of PEARL III and its extension.6 This
study thus supports the long-term use of
intermittent courses of ulipristal.
• Headaches and hot flushes were the most
commonly reported side effects and occurred
in ⩽11% of patients.
• Breast pain and discomfort occurred in ⩽3%
of patients, which decreased to ⩽1% over
subsequent treatment courses.
46. Adv- (1) oral dosing
(2) favorable side effect profile (less hot
flashes),
(3) efficacy similar to GnRHa
(4)40-50% reduction in fibroid volume and
relief from menorrhagia.
(5)The unique pattern of endometrial changes
is called ‘progesterone receptor modulator-
associated endometrial changes’ (PAECs) and is
mainly cystic glandular dilatation, seen as
endometrial thickening on ultrasound. It is not
endometrial hyperplasia/ precancer as far as the
current evidence goes. A combination of
mifepristone and LNG-IUS could prevent the
development of endometrial hyperplasia.
47. (6) Endometrial shedding after each therapy
cycle.
(7) Ulipristal acetate does not disturb the
surgical planes in patients who had to undergo
myomectomy for removal of Uterine Fibroids
(8) Improved quality of life, reduced menstrual
bleeding.
(9) Ulipristal acetate does not disturb the
surgical planes in patients who had to undergo
myomectomy for removal of Uterine Fibroids.
48.
49. Dose- Ulipristal acetate is given as 5-10 mg daily
for 13 weeks (one cycle)
• Upto 4 three-month treatment cycles with
5mg daily dose can be given.
• Mifepristone is given as 25mg/day for 3-6
months to reduce uterine volume and cause
amenorrhea, thereby improving quality of life.
50. • Disadv. - Transient elevation of trans-aminases
seen with high dose regimens.
- 4 cases of severe liver injury with need of liver
transplant and many others with varying
degrees of liver injury reported.
51. Selective estrogen receptor modulator
• Raloxifene and Tibolone
• Adv.- Used as add back therapy, prevent bone
loss.
• Only few studies are available, which show
variable results.
• Disadv.- Risk of venous thrombosis with
raloxifene.
52. Aromatase inhibitors:
• MOA- Effect of high levels of Aromatase enzyme
present in fibroid are antagonised.
• Dose- Anastrazole (1mg/d), letrazole (2.5mg/d)
and fadrozole
• Adv.- (1) Efficacious in reducing fibroid volume
and symptoms in women with fibroids upto 12
weeks size.
(2) Equivalent efficacy to GnRH, without the
flare effect, but are also associated with bone loss
with long-term use.
• Disadv.- nausea, dizziness, hot flashes, headache,
53. Others:
• somatostatin analogs, Vitamin D, cabergolin and
green-tea extract.
• Thus the role of medical treatment is either
stand-alone for short-term management of
symptoms or as a preoperative adjunct to reduce
size of fibroids to convert a technically difficult
procedure into an easier one.
• A purified bacterial collagenase from Clostridium
histolyticum (CCH) has recently been shown in ex
vivo leiomyoma tissue to significantly degrade the
altered collagen when injected into tumor tissue.
54.
55. 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
