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Middle East Fertility Society Journal
Middle East Fertility Society
ISSN: 1110-5690
Vol. 12, Num. 3, 2007, pp. 158-160
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Middle
East
Fertility
Society
Journal,
Vol.
12,
No.
3,
2007,
pp.
158-160
DEBATE
Luteal
phase
support
in
assisted
reproduction
Code
Number:
mf07029
Commented by: Mohamed Yehia, MD
Professor
of
Obstetrics & Gynecology,
Faculty
of
Medicine,
Ain
Shams
University
Cairo,
Egypt
1-
Is
luteal
support
needed?
The
first
report
of
the
combined
use
of
pituitary
suppression
and
ovarian
hyperstimulation
in
in-vitro
fertilization
(IVF)
and
embryo
transfer
programmes
was
published
in
1984
(1).
Since
then,
the
advantages
of
gonadotrophin
hormone-releasing
hormone
analogues
(GnRHa)
have
been
well
documented;
the
cancellation
rate
has
been
decreased
through
the
prevention
of
premature
luteinizing
hormone
(LH)
surge,
follicular
recruitment
has
improved,
and
the
ovarian
response
to
hyperstimulation
has
been
better
synchronized,
thus
facilitating
the
scheduling
of
oocyte
retrieval
(OR).
This
pituitary
suppression
however,
results
in
an
impaired
gonadotrophin
production
later
on,
and
the
output
of
LH
remains
blocked
for
at
least
10
days
after
cessation
of
GnRHa
administration
(2,
3).
As
gonadotrophins
are
necessary
to
maintain
progesterone
output
by
the
corpus
luteum,
exogenous
luteal
support
is
mandatory.
However
several
reports
have
shown
that
corpus
luteum
function
and
luteal
phase
duration
are
shortened
in
IVF
cycles
regardless
of
the
protocol
used
for
multifollicular
induction.
In
comparing
HMG
either
alone
or
with
the
addition
of
GnRH
antagonist
cetorolix,
Tavaniotuo
et
al.
2001,
have
shown
that
LH
concentration
declines
at
the
mid
luteal
phase and
without
luteal
supplementation
the
corpus
luteum
function
will
be
disturbed
which
results
in
a
very
low
implantation
rate
(4).
The
induction
of
multiple
follicle
development
per
se
could
either
directly
or
indirectly
influence
the
duration
of
the
luteal
phase
(5);
the
removal
of
large
quantities
of
granulosa
cells
at
oocyte
retrieval
may
diminish
the
most
important
source
of
progesterone
synthesis
by
the
corpus
luteum,
thus
disrupting
the
luteal
phase
(6). supraphysiological
levels
of
steroids
[related
to
the
larger
number
of
corpora
lutea]
during
the
early
luteal
phase
could
directly
inhibit
LH
release
via
negative
feedback
actions
at
the
hypothalamic-pituitary
axis
(7).
A
meta-analysis
comparing
placebo
with
any
form
of
luteal
support
favored
the
addition
of
luteal
support
(8).
Vlaisavljevic
(2007)
compared
natural
IVF
cycles
with
and
without
luteal
support
and
concluded
that
even
in
a
natural
cycle
IVF
a
higher
pregnancy
rate
was
observed
if
HCG
was
administered
after
embryo
transfer
(9).
2-
What
is
the
best
regimen
for
luteal
support?
Human
chorionic
gonadotropin
(HCG),
progesterone,
with
or
without
estrogen
have
been
used
to
support
the
luteal
phase.
A-
Is
HCG
superior
to
progesterone?
In
comparing
HCG
and
progesterone
both
intramuscular
(I.M.)
and
vaginal-
a
meta-analysis
preformed
by
Pritts
and
Atwood
(2002)
found
no
differences
(10).
However,
in
a
recent
meta-analysis
comparing
progesterone
versus
human
chorionic
gonadotropin
(hCG)
alone
or
in
combination
with
progesterone,
it
was
concluded
that
hCG
was
superior
to
progesterone
as
luteal
phase
support
with
respect
to
pregnancy
rates
(8).
The
drawbacks
of
using
hCG
are
the
increased
risk
of
ovarian
hyperstimulation
and,
in
my
opinion,
the
other
drawback
stems
from
the
long
half
life
of
hCG
in
the
circulation
(about
8
days)
which
can
occasionally
lead
to
erroneous
diagnosis
of
pregnancy
with
its
distressing psychological
impact
on
the
patient.
B-Which
route
of
progesterone
administration
confers
more
reproductive
benefit:
oral,
I.M.
or
vaginal?
While
the
oral
route
is
the
patients
preference,
the
very
high
dose
needed
to
be
administered
to
reach
a
sufficient
progesterone
concentration
in
the
serum
will
lead
to
several
problems.
The
breakdown
products
from
the
metabolism
of
oral
progesterone
have
been
associated
with
sedation,
drowsiness,
and
other
hypnotic
effects,
as
well
as
flushing,
nausea,
and
fluid
retention.
In
addition,
several
studies
have
shown
the
superiority
of
vaginal
progesterone
(11,
12). In
comparing
vaginal
and
I.M routes,
both have
side
effects.
Intramuscular
injections
are
not
only
painful,
but
can
also
lead
to
inflammation
and
even
sterile
abscess
formation
at
the
injection
site
(13).
Severe
allergic
reactions
to
the
oil
used
as
a
vehicle
for
progesterone
injections
have
also
been
reported.
Acute
eosinophilic
pneumonia
was
reported
(14)
and
can
induce
severe
morbidity
in
otherwise
healthy
young
women.
Vaginal
application
of
progesterone
has
also
led
to
some
minor
side-effects
such
as
vaginal
discharge
and
irritation. Although
I.M.
injections
have
lead
to
higher
serum
levels
of
progesterone,
the
vaginal
formulations
have
been
shown
to
have
better
synchronization
effects
upon
the
endometrium
(15).
This
is
theorized
to
be
due
to
a
first
pass
uterine
effect
leading
to
higher
uterine
tissue
levels
and
lower
systemic
serum
levels
(16).
In
meta-analysis
by
Pritts
and
Atwood
2002,
however,
the
I.M.
route
conferred
higher
clinical
pregnancy
rate
(CPR)
and
delivery
rate
(DR)
than
the
vaginal
route.
Unfer
et
al.
(2004)
used
17
alpha-hydroxyprogesterone
caproate
every
3
days
(instead
of
the
routine
daily
dose)
versus
intravaginal
progesterone
in
IVF-embryo
transfer
cycles
in
a
prospective
randomized
study
and
found
the
former
superior
(17).
A
drawback
in
I.M.
progesterone
is
the
prolongation
of
luteal
phase
despite
the
absence
of
pregnancy.
Bleeding
eventually
occurs,
but
patients
often
feel
something
is
wrong
when
no
menstruation
occurs
and
she
is
not
pregnant.
Vaginal
progesterone
is
available
in
micronized
form,
cream
and
tablets.
At
the
present
no
definite
significant
difference
between
the
3
forms
was
found
,
however
vaginal
cream
is
used
once
daily
while
micronized
progesterone
requires
multiple
applications
(2-3
times/day).
C-When
to
start
luteal
support?
Mochtar
et
al.
(2006)
compared
the
effect
of
the
onset
of
luteal
support
on
pregnancy
rate,
and
found
no
significant
difference
whether
progesterone
support
started
at
hCG
injection,
at
oocyte
retrieval
or
at
ET
(18).
D-How
long
should
luteal
support
be
administrated?
There
is
no
consensus
regarding
the
duration
of
luteal
support.
Traditionally,
progesterone
is
administrated
for
8-10
weeks
after
positive
pregnancy
test,
however
no
difference
was
found
if
progesterone
was
withdrawn
immediately
after
positive
pregnancy
test
or
continued
for
8
weeks.
(19,
20).
E-Adding
estrogen
Several
investigators
have
noticed
that
the
level
of
estrogen
is
low
during
the
luteal
phase
in
IVF
cycles.
The
results
of
adding
estrogen
to
progesterone
produced
conflicting
data;
while
Gorkemli
et
al.
(2004)
found
an
increased
pregnancy
rate
(21),
Fatemi
et
al.
(2006)
found
no
differences
in
pregnancy
rate
or
implantation
rate
(22).
Conclusion
At
the
present
evidence
points
out
the
necessity
of
adding
luteal
support
to
any
protocol
of
controlled
hyperstimulation;
even
if
no
agonist
or
antagonist
is
used.
HCG
is
equivalent
to
progesterone
in
efficiency
but
is
associated
with
a
higher
incidence
of
hyperstimulation
syndrome.
Progesterone
intramuscularly
seems
to
yield
a
better
pregnancy
rate; however
the
side
effects
of
intramuscular
progesterone
make
local
vaginal
progesterone
cream
or
suppository
the
most
common
form
utilized
by
patients. Estrogen
addition
does
not
seem
to
offer
an
advantage
over
progesterone
alone
in
spite
of
sporadic
reports
of
the
contrary.
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