Article

Progesterone and progesterone receptor modulators in the management of symptomatic uterine fibroids

University of London, Londinium, England, United Kingdom
European journal of obstetrics, gynecology, and reproductive biology (Impact Factor: 1.7). 08/2012; 165(2). DOI: 10.1016/j.ejogrb.2012.07.023
Source: PubMed
ABSTRACT
The majority of symptomatic uterine fibroids are currently treated by surgical interventions (myomectomy or hysterectomy) or radiological treatments (uterine artery embolisation or focussed ultrasound surgery). None of these treatments is a panacea, and what is conspicuous is the lack of an effective long-term medical therapy for a disorder so common among women of reproductive age. It has been known for some time that progesterone and its receptors enhance proliferative activity in fibroids and this has raised the possibility that anti-progestins and (PRMs) could be useful in the medical management of fibroids. Some of the compounds which have produced promising results in recent clinical trials or research studies include mifepristone, CDB-4124 (telapristone), CP-8947, J-867 (asoprisnil) and CDB-2914 (ulipristal acetate or UA). UA has recently completed Phase III clinical trials with very encouraging results, and has now acquired a licence for clinical use in Europe. While considerable research has yet to be done on the long-term safety and efficacy of UA there is nevertheless good reason for optimism on the emergence of effective medical therapy in the form of UA and possibly other PRMs.
Review
Progesterone
and
progesterone
receptor
modulators
in
the
management
of
symptomatic
uterine
fibroids
Vikram
Sinai
Talaulikar
*
,
Isaac
Manyonda
Department
of
Obstetrics
&
Gynaecology,
St.
George’s
Hospital
and
University
of
London,
Cranmer
Terrace,
Tooting,
London
SW17
0RE,
United
Kingdom
Contents
1.
Introduction
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135
2.
Progesterone,
the
progesterone
receptor
and
receptor
antagonists/modulators .
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136
3.
The
levonorgestrel
intrauterine
system
(LNG-IUS).
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136
4.
Progesterone
receptor
modulators
(PRMs)
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137
4.1.
Mechanisms
of
action.
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137
4.2.
Evidence
for
effectiveness
of
PRMs
in
treatment
of
uterine
fibroids
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137
4.3.
Mifepristone
(RU-486)
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4.4.
CDB-4124
(telapristone)
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4.5.
J-867
(asoprisnil)
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4.6.
CDB-2914
(ulipristal
acetate
or
UA).
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5.
Adverse
effects
and
limitations
associated
with
long-term
use
of
PRMs
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138
5.1.
Endometrial
hyperplasia
and
thickening
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6.
Conclusion
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139
References
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139
1.
Introduction
Fibroids
are
the
most
common
tumour
of
women
during
reproductive
life.
They
are
symptomatic
in
50%
of
women
who
have
them,
with
the
peak
incidence
of
symptoms
occurring
among
women
in
their
30s
and
40s
[1].
Symptoms
include
menstrual
disturbance
(commonly
menorrhagia
and
dysmenorrhoea),
pres-
sure
symptoms
such
as
increased
urinary
frequency,
pelvic
pain,
constipation
and
potential
interference
with
reproduction.
Fibroids
can
also
cause
symptoms
(including
abnormal
bleeding)
in
the
menopause
[2].
Thus
although
benign,
fibroids
have
a
major
impact
on
women’s
health
and
their
quality
of
life.
Current
treatment
options
for
the
woman
with
symptomatic
fibroids
include
abdominal
hysterectomy,
conventional
abdominal
myomectomy,
laparoscopic
and
vaginal
myomectomy
[3,4]
and
the
radiological
interventions
uterine
artery
embolisation
(UAE)
European
Journal
of
Obstetrics
&
Gynecology
and
Reproductive
Biology
165
(2012)
135–140
A
R
T
I
C
L
E
I
N
F
O
Article
history:
Received
29
January
2012
Received
in
revised
form
3
June
2012
Accepted
25
July
2012
Keywords:
Progesterone
receptor
modulators
PRM
Fibroids
A
B
S
T
R
A
C
T
The
majority
of
symptomatic
uterine
fibroids
are
currently
treated
by
surgical
interventions
(myomectomy
or
hysterectomy)
or
radiological
treatments
(uterine
artery
embolisation
or
focussed
ultrasound
surgery).
None
of
these
treatments
is
a
panacea,
and
what
is
conspicuous
is
the
lack
of
an
effective
long-term
medical
therapy
for
a
disorder
so
common
among
women
of
reproductive
age.
It
has
been
known
for
some
time
that
progesterone
and
its
receptors
enhance
proliferative
activity
in
fibroids
and
this
has
raised
the
possibility
that
anti-progestins
and
(PRMs)
could
be
useful
in
the
medical
management
of
fibroids.
Some
of
the
compounds
which
have
produced
promising
results
in
recent
clinical
trials
or
research
studies
include
mifepristone,
CDB-4124
(telapristone),
CP-8947,
J-867
(asoprisnil)
and
CDB-2914
(ulipristal
acetate
or
UA).
UA
has
recently
completed
Phase
III
clinical
trials
with
very
encouraging
results,
and
has
now
acquired
a
licence
for
clinical
use
in
Europe.
While
considerable
research
has
yet
to
be
done
on
the
long-term
safety
and
efficacy
of
UA
there
is
nevertheless
good
reason
for
optimism
on
the
emergence
of
effective
medical
therapy
in
the
form
of
UA
and
possibly
other
PRMs.
ß
2012
Elsevier
Ireland
Ltd.
All
rights
reserved.
*
Corresponding
author.
Tel.:
+44
0208725
3695/2858.
E-mail
address:
vtalauli@sgul.ac.uk
(V.S.
Talaulikar).
Contents
lists
available
at
SciVerse
ScienceDirect
European
Journal
of
Obstetrics
&
Gynecology
and
Reproductive
Biology
jou
r
nal
h
o
mep
ag
e:
w
ww
.elsevier
.co
m
/loc
ate/ejo
g
rb
0301-2115/$
see
front
matter
ß
2012
Elsevier
Ireland
Ltd.
All
rights
reserved.
http://dx.doi.org/10.1016/j.ejogrb.2012.07.023
Page 1
[5]
and
magnetic
resonance-guided
focused
ultrasound
surgery
(MRgFUS)
[6].
Hysterectomy
is
unacceptable
to
the
woman
wishing
to
retain
fertility
potential,
while
conventional
myomec-
tomy
is
associated
with
risks
of
adhesions,
morbidity
and
indeed
mortality.
Both
laparoscopic
and
vaginal
myomectomy
require
skills
that
are
not
commonplace
and
there
are
limitations
on
the
size
and
number
of
fibroids
that
can
be
treated
by
these
modalities.
UAE
is
now
widely
used
in
the
United
States
(US)
and
Western
Europe
but
is
still
under
evaluation,
has
a
range
of
complications
including
premature
ovarian
failure,
chronic
vaginal
discharge
and
in
rare
cases
pelvic
sepsis,
and
may
have
limited
efficacy
where
the
fibroids
are
large
[7].
MRgFUS,
which
has
major
cost
implications
by
its
requirement
for
MRI,
was
approved
by
the
US
Food
and
Drug
Agency
(FDA)
in
2004,
while
the
National
Institute
for
Health
and
Clinical
Excellence
(NICE)
in
the
United
Kingdom
has
recom-
mended
that
the
procedure
be
used
in
an
audit
and
research
setting
[8].
Thus
none
of
the
available
treatments
is
a
panacea.
Given
the
choice,
many
women
would
opt
to
avoid
major
surgery
or
indeed
even
the
less
invasive
radiological
procedures.
There
is
therefore
a
need
for
medical
therapy
that
has
efficacy
equivalent
or
superior
to
surgery,
does
not
interfere
with
reproduction,
has
minimal
side
effects
and
is
relatively
cheap.
Current
medical
therapeutic
approaches
exploit
the
observa-
tions
that
uterine
fibroids
have
significantly
increased
concentra-
tions
of
both
estrogen
and
progesterone
receptors
compared
with
normal
myometrium
[9,10],
and
that
ovarian
steroids
influence
fibroid
growth.
Most
available
therapies
are
therefore
hormonal
or
act
on
the
relevant
hormones
or
their
receptors
to
interfere
with
fibroid
growth.
Gonadotrophin-releasing
hormone
(GnRH)
analo-
gues
have
been
the
most
widely
used,
and
while
they
do
cause
fibroid
regression,
they
can
only
be
used
in
the
short
term,
as
temporising
measures
in
the
perimenopausal
woman,
or
pre-
operatively
to
reduce
fibroid
size
and
influence
the
type
of
surgery,
restore
haemoglobin
levels
and
apparently
reduce
blood
loss
at
operation.
They
are
notorious
for
rebound
growth
of
the
fibroids
upon
cessation
of
therapy
and
have
major
side-effects.
Selective
estrogen
receptor
modulators
(SERMs)
such
as
raloxifene
have
been
shown
to
induce
fibroid
regression
in
post-
but
not
pre-
menopausal
women.
Experience
with
these
drugs
is
limited,
however,
and
they
are
associated
with
significant
side
effects.
There
are
also
suggestions
that
the
levonorgestrel
intrauterine
system
(LNG-IUS)
can
cause
dramatic
reduction
in
menstrual
flow
in
women
with
fibroids,
but
as
yet
there
are
no
randomised
trials
of
its
use
in
these
women,
where
rates
of
expulsion
of
the
device
appear
to
be
high.
This
review
discusses
the
role
of
progesterone
and
progesterone
receptor
modulators
(PRMs)
in
the
treatment
of
symptomatic
uterine
fibroids.
2.
Progesterone,
the
progesterone
receptor
and
receptor
antagonists/modulators
Progesterone
plays
a
crucial
part
in
human
reproductive
physiology.
Its
physiological
effects
impact
the
processes
of
endometrial
differentiation,
ovulation,
implantation,
successful
development
of
the
embryo,
development
of
the
mammary
gland
and
regulation
of
central
signals
from
the
hypoth alamic–
pituit ary
(HP)
axis.
The
effects
of
progesterone
on
target
tissues
are
mediated
via
the
progesterone
receptor
(PR),
which
belongs
to
the
nuclear
receptor
family
[11].
The
PR
exists
as
three
separate
isoforms
(A,
B
and
C)
expressed
from
a
single
gene
[11].
The
PR
functions
as
a
ligand-activated
transcription
factor
to
regulate
the
expression
of
specific
sets
of
target
genes.
PR
antagonists
oppose
the
biological
actions
of
progesterone
by
inhibiting
PR
activation.
Progesterone
has
dual
actions
on
fibroid
growth.
It
stimulates
growth
by
up-regulating
EGF
and
Bcl-2
and
down-regulating
tumor
necrosis
factor-alpha
expression
while
it
inhibits
growth
by
down-regulating
IGF-I
expression
[12,13].
While
it
has
long
been
established
that
estrogen
promotes
fibroid
growth,
recent
biochemical
and
clinical
studies
have
suggested
that
progesterone
and
the
PR
may
also
enhance
proliferative
activity
in
fibroids
[12,13].
These
observations
have
therefore
raised
the
possibility
that
anti-progestins
and
agents
or
molecules
that
modulate
the
activity
of
the
PR
could
be
useful
in
the
medical
management
of
uterine
fibroids.
Since
the
emergence
of
mifepristone
(RU-486),
the
first
PR
antagonist,
more
than
25
years
ago ,
hundreds
of
steroidal
as
well
as
non-steroidal
compounds
displaying
progesterone
antagonist
(PA)
or
mixed
agonist/antagonist
activity
have
been
synthesised.
Collectively,
they
are
known
as
progesterone
receptor
modulators
(PRMs).
These
compounds
have
a
huge
potential
for
use
in
the
treatment
of
a
number
of
pathological
conditions
of
the
female
reproductive
system
including
uterine
fibroids,
endometriosis
and
dysfunctional
uterine
bleeding,
and
as
potential
contraceptives.
Some
of
the
PRMs
which
have
been
the
subject
of
recent
clinical
trials
or
research
studies
in
relation
to
fibroid
treatment
include
mifepristone,
CDB-4124
(telapris-
tone),
CP-8947
and
J867
(asoprisnil)
and
CDB-2914
(ulipristal
acetate).
3.
The
levonorgestrel
intrauterine
system
(LNG-IUS)
The
LNG-IUS,
which
first
appeared
on
the
market
in
1990s,
has
transformed
the
management
of
menorrhagia
over
the
last
two
decades.
It
proved
highly
effective
in
reducing
menstrual
blood
loss
and
is
now
considered
an
alternative
to
the
surgical
treatment
of
menorrhagia
[14].
The
system
consists
of
a
T-shaped
intrauterine
device
sheathed
with
a
reservoir
of
levonorges trel
that
is
released
at
the
rate
of
20
mcg/day.
Hormone
release
at
the
target
organ
minimises
systemic
side
effects.
It
exerts
its
clinical
effect
by
preventing
endometrial
proliferation
and
consequently
reduces
both
the
duration
of
bleeding
and
the
amount
of
menstrual
loss
[15].
The
LNG-IUS
has
been
shown
to
reduce
menstrual
blood
loss
by
94%
by
three
months
and
to
be
well
accepted
by
most
women
when
used
for
menorrhagia
[16].
In
a
landmark
study,
Lahteenmaki
et
al.
[17]
randomised
women
on
surgical
waiting
lists
to
continue
with
their
current
medical
regimen
or
to
use
an
LNG-IUS:
64%
women
using
the
LNG-IUS
cancelled
their
surgery
to
continue
using
the
LNG-IUS,
compared
to
only
14%
of
women
not
using
the
system.
Other
studies
followed
which
showed
that
the
LNG-IUS
was
a
cost
effective
alternative
to
hysterectomy
during
the
first
year
[18,19].
At
present
there
are
no
randomised
trials
of
the
use
of
LNG-IUS
in
menorrhagic
women
with
uterine
myomas.
There
are
of
course
reports
of
its
use
in
these
women,
with
striking
reductions
in
menorrhagia
being
reported
[20].
Although
some
women
with
large
intramural
myomas
had
spontaneous
expulsion
of
LNG-IUS
at
various
intervals,
they
wanted
re-insertion
of
the
device
because
of
remarkable
reduction
in
menorrhagia
[21].
Significant
increases
in
haemoglobin
levels
were
observed
after
insertion
of
the
devices,
but
no
significant
differences
were
noted
in
myoma
volume
and
uterine
volume,
as
assessed
by
MRI
examination
pre-
treatment
and
at
12
months
of
use
[20,21].
The
absence
of
any
change
in
myoma
volume
is
intriguing,
since
theoretically
it
might
be
expected
that
the
progesterone
released
from
the
device
could
stimulate
fibroid
growth.
There
is
therefore
an
obvious
need
for
further
research
in
this
area
[22].
It
would
be
interesting
to
establish
whether
expulsion
of
the
device
is
dependent
upon
the
size
or
number
or
location
of
the
fibroids:
it
is
reasonable
to
assume
that
submucous
fibroids,
or
large
intramural
fibroids
distorting
the
cavity,
would
be
associated
with
an
increased
risk,
but
at
present
there
are
no
data
to
provide
the
evidence
base
to
better
advise
patients.
V.S.
Talaulikar,
I.
Manyonda
/
European
Journal
of
Obstetrics
&
Gynecology
and
Reproductive
Biology
165
(2012)
135–140
136
Page 2
4.
Progesterone
receptor
modulators
(PRMs)
4.1.
Mechanisms
of
action
The
following
mechanisms
of
action
have
been
proposed
for
the
effect
of
PRMs
on
fibroids
(Fig.
1):
(a)
Ulipristal
down-regulates
the
expression
of
angiogenic
growth
factors
such
as
vascular
endothelial
growth
factor
(VEGF)
and
their
receptors
in
cultured
fibroid
cells
[23]
resulting
in
suppression
of
neovascularisation,
cell
proliferation
and
survival
[12].
(b)
Ulipristal
and
asoprisnil
inhibit
proliferation
of
cultured
fibroid
cells
and
induce
apoptosis
by
up-regulating
cleaved
caspase
3
and
down
regulating
Bcl-2
[12,23,24].
(c)
Ulipristal
also
increases
the
expression
of
matrix
metallopro-
teinases
(MMPs)
and
decreases
the
expression
of
tissue
inhibitor
of
metalloproteinases
(TIMPs)
and
collagens
in
cultured
fibroid
cells.
This
may
reduce
collagen
deposition
in
the
extracellular
spaces
of
fibroids,
impairing
tissue
integrity
[12,23,25].
(d)
CP-8947
inhibits
leiomyoma
cell
proliferation
and
decreases
extracellular
matrix
(ECM)
component
production,
without
disrupting
myometrial
cell
proliferation
[26].
(e)
Asoprisnil
and
ulipristal
have
been
shown
to
modulate
the
ratio
of
progesterone
receptor
isoforms
(PR-A
and
PR-B)
in
cultured
leiomyoma
cells
[27].
They
decreased
the
cell
viability;
suppressed
the
expression
of
growth
factors,
angiogenic
factors
and
their
receptors
in
those
cells;
and
induced
apoptosis
by
activating
the
mitochondrial
and
tumor
necrosis
factor-related
apoptosis-inducing
ligand
(TRAIL)
pathways
and
eliciting
endoplasmic
reticulum
stress.
Furthermore,
these
compounds
suppressed
types
I
and
III
collagen
synthesis
in
cultured
leiomyoma
cells
without
affecting
such
synthesis
in
cultured
normal
myometrial
cells
[27].
(f)
Mifepristone
and
asoprisnil
have
also
been
associated
with
a
decrease
in
uterine
artery
blood
flow.
Daily
doses
of
mifepristone
(2–5
mg),
telapristone
(12.5–50
mg)
and
ulipristal
(5–10
mg)
inhibit
ovulation
in
normal
women
[12,28–31]
but
asoprisnil,
in
contrast,
is
not
so
effective
in
inhibiting
ovulation
[32].
The
amenorrhea
occurring
with
PRMs
is
associated
with
levels
of
estradiol
in
the
early
follicular
phase
range
of
the
normal
menstrual
cycle
[12,28–33].
4.2.
Evidence
for
effectiveness
of
PRMs
in
treatment
of
uterine
fibroids
A
number
of
clinical
trials
have
established
the
potential
of
PRMs
in
the
treatment
of
uterine
fibroids.
They
are
associated
with
a
reduction
in
pain,
bleeding,
size
of
fibroids
and
overall
improvement
in
quality
of
life.
Unlike
long-acting
GnRH
analogues,
they
do
not
have
the
drawbacks
of
the
profound
estrogen
deficiency
and
decrease
in
bone
mineral
density.
4.3.
Mifepristone
(RU-486)
Most
readers
will
be
familiar
with
mifepristone
as
the
drug
used
for
medical
termination
of
pregnancy,
with
or
without
misopros-
tol.
Mifepristone
is
a
high
progesterone
receptor
affinity
anti-
progestin.
For
purposes
of
pregnancy
termination,
it
is
used
in
doses
of
200–800
mg,
and
its
efficacy
is
well
proven.
Early
reports
of
the
use
of
mifepristone
for
the
treatment
of
fibroids
date
back
to
2002,
when
De
Leo
et
al.
used
doses
ranging
from
12.5
to
50
mg
daily
and
reported
a
reduction
in
uterine/fibroid
volume
of
40–
50%,
with
amenorrhea
in
most
subjects
[34].
This
report
was
corroborated
by
a
paper
a
year
later
from
a
group
who
used
mifepristone
at
a
dose
of
5
or
10
mg
per
day
for
one
year,
and
found
that
it
was
effective
in
decreasing
mean
uterine
volume
by
50%,
while
amenorrhea
occurred
in
40–70%
of
the
subjects
[35].
Adverse
effects
included
vasomotor
symptoms,
but
no
change
in
bone
mineral
density
was
noted.
Hot
flashes
were
increased
over
Progesterone
Receptor
Modulators
(PRMs)
Ulipristal, Asoprisnil
Ind
uctio
n of
cell
apopto
sis (↑ Caspa
se 3
and ↓ Bacl-2)
and
modulation of PR ratio
Mifepristone
↑ ER,
↑ PR,
↑ AR and
antiproliferative
effect
on endometrium
Ulipristal,
Asoprisnil
Down regulation of
growth/an
giogenic
factors and receptors
Ulipristal, CP-8947,
Aspoprisnil
↑ MMPs, ↓ TIMPs
Reduce
d c
olla
gen
deposition
Ulipristal, CP-8947,
Aspoprisnil
Activate
mitochondrial/TRAIL
pathways ↑ ER
stres
s
Ulipristal, CP-8947
Supression of
neovasculari
sation and
cell proliferation
Ulipristal,
Mifepristone
Inhi
bit
ion o
f
Ovulation
Mifepristone
Asoprisnil
↓ Uterine
blood
flow
Fig.
1.
Mechanisms
of
action
of
progesterone
receptor
modulators
on
uterine
fibroids
(ER
estrogen
receptors,
PR
progesterone
receptors
and
AR
androgen
receptors).
V.S.
Talaulikar,
I.
Manyonda
/
European
Journal
of
Obstetrics
&
Gynecology
and
Reproductive
Biology
165
(2012)
135–140
137
Page 3
baseline
in
the
10
mg
group,
but
5
mg
per
day
did
not
increase
the
incidence
of
vasomotor
symptoms.
Simple
hyperplasia
was
noted
in
28%
of
the
women.
This
study
therefore
suggested
that
a
dose
as
low
as
5
mg
per
day
of
mifepristone
may
be
efficacious
for
the
treatment
of
uterine
fibroids,
with
few
side
effects
[35].
Antiglucocorticoid
effects
of
long
term
use
of
mifepristone
are
usually
only
seen
with
doses
exceeding
200
mg
daily
[36].
The
same
group
of
researchers
then
followed
up
their
preliminary
findings
with
a
randomised
controlled
trial
(RCT)
on
the
use
of
mifepristone
for
the
treatment
of
uterine
fibroids.
This
was
a
small
study
which
included
42
women
in
a
double-blind
placebo-
controlled
study
design
over
a
period
of
6
months
[37].
They
reported
that
overall
quality
of
life
was
improved
significantly,
and
anaemia
rates
and
uterine
volume
were
reduced
significantly.
The
hyperplasia
seen
in
some
women
may
limit
the
use
of
this
drug
among
those
desiring
a
long-term
medical
therapeutic
alternative.
The
apparent
effectiveness
of
mifepristone,
however,
in
reducing
myoma
volume
and
improving
fibroid-related
symptoms
and
quality
of
life,
and
the
minimal
side-effects,
all
point
to
a
need
for
a
large
RCT
with
sufficient
power
to
define
its
true
place
in
the
medical
management
of
uterine
fibroids.
A
combination
of
mifepristone
and
the
LNG-IUS
could
prove
especially
useful
as
the
IUS
would
obviate
the
development
of
endometrial
hyperplasia
while
also
promoting
a
reduction
in
menstrual
flow.
In
another
RCT,
100
women
were
assigned
to
mifepristone
5
or
10
mg
daily
for
3
months
without
a
placebo
group:
with
both
doses,
there
were
equivalent
reductions
in
fibroid
and
uterine
volumes
and
symptomatic
improvements
[38].
4.4.
CDB-4124
(telapristone)
A
clinical
trial
(phase
I/II)
evaluated
the
efficacy
of
telapristone
in
symptomatic
fibroids.
This
small
3-month
study
comprising
30
women,
compared
oral
doses
of
12.5,
25
and
50
mg
telapristone
with
the
GnRH
analogue
leuprolide
and
a
placebo
[39].
There
was
a
significant
reduction
in
tumor
size
and
reduced
bleeding
with
telapristone
treatment.
4.5.
J-867
(asoprisnil)
Asoprisnil
has
high
tissue
selectivity
and
binds
to
progesterone
receptors
with
a
3-fold
greater
binding
affinity
than
progesterone
[40].
The
initial
phase
I
studies
established
that
asoprisnil
induced
a
reversible
suppression
of
menstruation,
while
having
variable
effects
on
ovulation
[32].
The
phase
II
multi-centre
double-blind
placebo-controlled
studies
by
the
same
group
of
researchers
compared
the
efficacy
and
safety
of
three
doses
(5,
10
and
25
mg
and
placebo)
in
129
women
over
12
weeks
[41,42].
Asoprisnil
reduced
the
uterine
and
fibroid
volumes
in
a
dose
dependent
manner.
There
was
a
dose
dependent
decrease
in
menorrhagia
scores
in
women
with
menorrhagia
at
baseline,
while
amenorrhea
rates
increased
as
the
dose
increased
(28.1%
with
5
mg,
64.3%
with
10
mg
and
83.3%
with
25
mg),
but
with
no
increase
in
the
rates
of
unscheduled
bleeding
in
all
three
asoprisnil
groups.
Compared
to
placebo,
haemoglobin
levels
were
improved
in
all
three
treatment
groups,
while
adverse
effects
were
evenly
distributed.
The
initial
clinical
trials
of
asoprisnil
suggested
endometrial
thickening
to
be
one
of
the
important
side
effects
of
the
drug.
Overall
safety
data
available
so
far,
however,
have
been
reassuring
and
its
impact
on
bone
mineral
density,
fertility,
recurrence
rates
of
fibroids
and
endometrial
hyperplasia
are
still
under
evaluation.
4.6.
CDB-2914
(ulipristal
acetate
or
UA)
In
Phase
II
and
III
clinical
trials,
a
number
of
issues
have
been
addressed
using
UA.
In
the
first
trial
[43]
in
which
UA
was
given
at
10
mg
or
20
mg
in
comparison
against
placebo
for
three
cycles,
UA
showed
a
92%
reduction
in
bleeding
versus
19%
with
placebo.
Leiomyoma
volume
was
significantly
reduced
with
UA
(29%
versus
6%;
p
=
0.01).
UA
eliminated
menstrual
bleeding
and
inhibited
ovulation
(%
ovulatory
cycles
20%
on
UA
versus
83%
with
placebo;
p
=
0.001).
UA
also
improved
the
concern
scores
of
the
uterine
leiomyoma
symptom
quality
of
life
subscale
(p
=
0.04).
One
woman
on
UA
developed
endometrial
cystic
hyperplasia
without
evidence
of
atypia.
No
serious
adverse
events
were
reported.
UA
did
not
suppress
estradiol
and
there
were
no
differences
in
serum
estradiol
levels
between
the
treatment
and
placebo
groups
(median
estradiol
was
greater
than
50
pg/ml
in
all
groups).
The
numbers
studied
were
small,
however,
with
22
patients
being
allocated
and
18
completing
the
three
cycles
or
90–120
day
trial
[43].
A
more
recent
randomised,
double
blind,
placebo
controlled
trial
of
efficacy
and
tolerability
has
also
demonstrated
positive
results
when
UA
was
administered
for
3–6
months,
showing
good
control
of
bleeding,
reduction
in
fibroid
size,
and
improvement
in
quality
of
life
in
the
treatment
group
[44].
UA
has
recently
successfully
completed
two
Phase
III
clinical
trials
(PEARL
I
and
II)
in
Europe,
demonstrating
its
efficacy
and
safety
for
the
treatment
of
symptomatic
uterine
fibroids
in
patients
eligible
for
surgery
[45,46].
PEARL
I
compared
treatment
with
oral
UA
for
up
to
13
weeks
at
a
dose
of
5
mg
per
day
(96
women)
or
10
mg
per
day
(98
women)
with
placebo
(48
women)
in
patients
with
fibroids,
menorrhagia
and
anaemia.
All
patients
received
iron
supplementation.
The
co-primary
efficacy
end
points
were
control
of
uterine
bleeding
and
reduction
of
fibroid
volume
at
week
13,
after
which
patients
could
undergo
surgery.
At
13
weeks,
uterine
bleeding
was
controlled
in
91%
of
the
women
receiving
5
mg
of
UA,
92%
of
those
receiving
10
mg
of
UA,
and
19%
of
those
receiving
placebo
(p
<
0.001
for
the
comparison
of
each
dose
of
UA
with
placebo).
Treatment
with
UA
for
13
weeks
effectively
controlled
excessive
bleeding
due
to
uterine
fibroids
and
reduced
the
size
of
the
fibroids.
PEARL
II
was
a
double-blind
non-inferiority
trial,
which
randomly
assigned
307
patients
with
symptomatic
fibroids
and
excessive
uterine
bleeding
to
receive
three
months
of
daily
therapy
with
oral
UA
(at
a
dose
of
either
5
mg
or
10
mg)
or
once-
monthly
intramuscular
injections
of
the
GnRH
analogue
leuprolide
acetate
(at
a
dose
of
3.75
mg).
The
primary
outcome
was
the
proportion
of
patients
with
controlled
bleeding
at
week
13,
with
a
pre-specified
non-inferiority
margin
of
20%.
Uterine
bleeding
was
controlled
in
90%
of
patients
receiving
5
mg
of
UA,
in
98%
of
those
receiving
10
mg,
while
the
figure
for
leuprolide
acetate
was
89%.
Both
UA
doses
were
non-inferior
to
once
monthly
leuprolide
acetate
in
controlling
uterine
bleeding
and
were
significantly
less
likely
to
cause
hot
flashes
[46].
5.
Adverse
effects
and
limitations
associated
with
long-term
use
of
PRMs
5.1.
Endometrial
hyperplasia
and
thickening
A
National
Institute
of
Health
(NIH)
sponsored
workshop
evaluated
endometrial
specimens
from
women
receiving
mifep-
ristone,
asoprisnil
and
UA
[12,47,48].
Pathologists
were
blinded
to
agent,
dose
and
exposure
interval.
It
was
concluded
that
there
was
little
evidence
of
mitosis,
consistent
with
the
anti-proliferative
effect
of
PRMs.
No
biopsy
demonstrated
atypical
hyperplasia.
There
was
asymmetry
of
stromal
and
epithelial
growth
and
prominent
cystically
dilated
glands
with
both
admixed
estrogen
(mitotic)
and
progestin
(secretory)
epithelial
effects.
This
histology
has
not
previously
been
encountered
in
clinical
practice.
The
panel
designated
these
changes
as
PRM
associated
endometrial
changes
(PAECs)
[12,47,48].
Despite
the
paucity
of
mitoses,
pathologists
may
associate
the
cystic
glandular
dilatation
observed
with
PRMs
V.S.
Talaulikar,
I.
Manyonda
/
European
Journal
of
Obstetrics
&
Gynecology
and
Reproductive
Biology
165
(2012)
135–140
138
Page 4
with
simple
hyperplasia
and
should
be
aware
of
the
potential
diagnostic
pitfalls
of
misdiagnosing
hyperplasia
in
women
receiving
PRMs
[12,49].
In
another
study,
biopsies
were
obtained
from
58
premenopausal
women
participating
in
clinical
trials
of
the
telapristone.
Biopsies
were
obtained
at
3
and
6
months,
and
women
were
receiving
daily
doses
of
oral
therapy
that
ranged
from
12.5
to
50
mg.
Of
the
174
samples,
103
contained
histologic
changes
not
seen
in
the
normal
menstrual
cycle
[50].
Whereas
the
majority
of
the
histology
was
atrophic,
novel
cystic
changes
were
seen
with
increasing
doses.
Cystically
dilated
glands
with
mixed
secretory
and
mitotic
features
were
noted
[50].
These
lesions
are
not
considered
to
be
premalignant
and
no
malignancies
were
found.
A
few
studies
have
reported
endometrial
thickening
detected
on
ultrasound
after
use
of
high
or
low
dose
mifepristone
[51,52].
During
three
months’
treatment
with
ulipristal
in
normal
women,
no
thickening
was
observed
and
examination
of
hysterectomy
specimens
after
three
months
of
asoprisnil
(10
or
25
mg)
showed
that
when
compared
with
placebo,
there
was
a
trend
for
decreased
endometrial
thickness
[12,31].
With
use
of
telapristone
in
the
treatment
of
fibroids,
there
was
a
minimum
increase
in
endometrial
thickness
of
3.3
and
4.2
mm
with
the
12.5
and
25
mg
doses,
respectively,
after
three
months
of
treatment
[12].
It
has
been
suggested
that,
unlike
in
the
situation
where
there
is
unopposed
estrogen
effect,
the
endometrial
thickening
in
women
on
PRMs
is
related
to
cystic
glandular
dilation
and
not
endometrial
hyperplasia.
The
overall
evidence
emerging
from
the
recent
clinical
trials
regarding
the
safety
of
PRMs
appears
to
be
reassuring.
Clinicians
detecting
endometrial
thickening
in
women
treated
with
PRMs
need
to
be
aware
that
administration
of
PRMs
for
longer
than
3
months
may
lead
to
endometrial
thickening.
This
is
related
to
cystic
glandular
dilation,
not
endometrial
hyperplasia
and
pathologists
need
to
be
aware
of
PAEC
and
avoid
misclassifying
the
appearance
as
hyperplasia.
It
is
also
important
to
consider
the
limitations
of
the
current
data
while
describing
the
effects
of
PRMs
on
the
endometrium.
Most
existing
studies
have
described
the
endometrial
changes
over
short
periods
(months)
of
follow-up,
but
atypical
hyperplasia
and
possibly
malignant
change
take
years
to
develop.
Long
term
studies
are
therefore
necessary
to
evaluate
such
outcomes.
Although
breakthrough
bleeding
has
been
reported
as
one
of
the
side
effects
of
PRMs,
sufficient
data
assessing
their
long
term
use
are
not
available.
It
is
also
argued
that
PRMs
are
not
useful
for
the
treatment
of
large
fibroids
as
they
cause
only
a
modest
decrease
in
their
size.
Larger
clinical
trials,
however,
with
varying
doses
and
duration
of
therapy
of
PRMs
in
future
will
be
able
to
provide
a
definite
answer
to
this
question.
6.
Conclusion
The
ideal
medical
therapy
for
the
treatment
of
symptomatic
fibroids
is
arguably
a
tablet
that
is
taken
by
mouth,
once
a
day
or
even
better
still,
once
a
week,
with
minimal
if
any
side
effects,
which
rapidly
induces
fibroid
regression
and
thus
a
resolution
of
symptoms
but
without
affecting
fertility.
While
such
a
magic
bullet
does
not
yet
exist,
PRMs
have
for
years
tantalized
the
clinician
with
their
simplicity
of
administration,
potentially
minimal
side
effects
profile
and
likely
low
costs.
Among
the
PRMs,
ulipristal
acetate
has
undoubtedly
stolen
the
march
on
its
competitors.
The
manufac-
turer-sponsored
Pearl
I
and
II
trials
reported
that
whether
given
at
a
5
mg
or
10
mg
dose,
ulipristal
is
highly
effective
at
reducing
menstrual
blood
loss,
effecting
amenorrhoea
in
75%
of
recipients
within
10
days,
and
has
many
attributes
that
arguably
render
it
not
only
non-inferior
but
potentially
superior
to
GnRH
analogues,
not
least
the
absence
of
estrogen
suppression
and
its
consequences,
with
a
more
rapid
return
of
menstruation
upon
cessation
of
therapy,
and
a
more
persistent
shrinkage
of
fibroids
at
six
months
post-treatment.
Researcher-led
studies
are
now
required
to
reproduce
these
data,
and
to
evaluate
the
long-term
efficacy
and
safety,
especially
with
regard
to
the
endometrium,
metabolism
and
of
course
reproductive
function.
The
manufacturers
have
secured
a
licence
for
the
use
of
ulipristal
acetate
in
most
of
Western
Europe
including
the
UK,
and
thus
a
variety
of
trials
can
now
be
undertaken
that
should
help
establish
the
true
role
of
UA.
It
would
be
most
unfortunate,
however,
if
research
on
other
PRMs
were
to
cease,
since
the
quest
for
the
magic
bullet
must
be
sustained
to
definitively
treat
the
commonest
tumour
of
women
of
reproduc-
tive
age.
Conflicts
of
interest
Neither
of
the
authors
has
any
conflicts
of
interest
to
declare.
No
funding
was
received
for
preparation
of
this
manuscript.
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  • Source
    • "Thus it appears that the differential expression of these genes and the enrichment of the above pathways is necessary for tumor onset and progression. Estrogen and related genes: Fibroids are hormonally mediated and it is also well documented in the literature that accordingly estrogen and progesterone receptors and prostaglandins promote proliferation of fibroids (see [29, 34]). Not surprisingly, we found the estrogen receptor ESR-1 to be up-regulated in tumors of all sizes. "
    Full-text · Article · Feb 2016 · BMC Bioinformatics
  • Source
    • "Additionally, UPA increases the expression of matrix metalloproteinases (MMPs) and decreases the expression of tissue inhibitor of metalloproteinases (TIMPs) and collagens in cultured fibroid cells. Thus, UPA may impair fibroid tissue integrity by reducing the deposition of collagen in the extracellular spaces.21 "
    [Show abstract] [Hide abstract] ABSTRACT: Uterine fibroids are the most common benign tumors of the female genital tract. The management of symptomatic fibroids has traditionally been surgical; however, alternative pharmacological approaches have been proposed to control symptoms. To date, gonadotropin-releasing hormone analogs are the only available drugs for the preoperative treatment of fibroids. However, the US Food and Drug Administration recently authorized ulipristal acetate (UPA), an oral selective progesterone-receptor modulator, for the same indication. UPA is a new, effective, and well-tolerated option for the preoperative treatment of moderate and severe symptoms of uterine fibroids in women of reproductive age. According to clinical data, UPA shows several advantages: it is faster than leuprolide in reducing the fibroid-associated bleeding, it significantly improves hemoglobin and hematocrit levels in anemic patients, and it grants a significant reduction in the size of fibroids, which lasts for at least 6 months after the end of the treatment. Furthermore, UPA displays a better tolerability profile when compared to leuprolide; in fact, it keeps estradiol levels at mid follicular phase range, thereby reducing the incidence of hot flushes and exerting no impact on bone turnover. On the grounds of this evidence, the administration of 5 mg/day ulipristal acetate for 3 months is suggested for different patient categories and allows for planning a treatment strategy tailored to meet an individual patient's needs.
    Full-text · Article · Feb 2014 · Drug Design, Development and Therapy
  • Source
    • "Most existing studies have described the endometrial changes over short periods (months) of follow-up, but atypical hyperplasia and possibly malignant change take years to develop. Long-term studies are therefore necessary to evaluate such outcomes.94 "
    [Show abstract] [Hide abstract] ABSTRACT: Uterine fibroids are a major cause of morbidity in women of a reproductive age (and sometimes even after menopause). There are several factors that are attributed to underlie the development and incidence of these common tumors, but this further corroborates their relatively unknown etiology. The most likely presentation of fibroids is by their effect on the woman's menstrual cycle or pelvic pressure symptoms. Leiomyosarcoma is a very rare entity that should be suspected in postmenopausal women with fibroid growth (and no concurrent hormone replacement therapy). The gold standard diagnostic modality for uterine fibroids appears to be gray-scale ultrasonography, with magnetic resonance imaging being a close second option in complex clinical circumstances. The management of uterine fibroids can be approached medically, surgically, and even by minimal access techniques. The recent introduction of selective progesterone receptor modulators (SPRMs) and aromatase inhibitors has added more armamentarium to the medical options of treatment. Uterine artery embolization (UAE) has now been well-recognized as a uterine-sparing (fertility-preserving) method of treating fibroids. More recently, the introduction of ultrasound waves (MRgFUS) or radiofrequency (VizAblate™ and Acessa™) for uterine fibroid ablation has added to the options of minimal access treatment. More definite surgery in the form of myomectomy or hysterectomy can be performed via the minimal access or open route methods. Our article seeks to review the already established information on uterine fibroids with added emphasis on contemporary knowledge.
    Full-text · Article · Jan 2014 · International Journal of Women's Health
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