Luteal Phase Support In IVF

LUTEAL PHASE SUPPORT IN IVF
ABDULMAGID SARHAN
MD, FRCOG
ZAGAZIG UNIVERSITY

“Hormone administration during the
second phase of the stimulation
cycle to support the endometrium
and improve implantation.”

➢ Is LPS of benefit for IVF patients?
➢ What is the best dose and formulations of
drugs for LPS ?
➢ Which Is superior for LPS hCG or
Progesterone?
➢ Which is the best route for administration of
progesterone for LPS ?
➢ Is it beneficial to add estrogen to
➢ What are other hormones that can be
used?
➢ For how long should LPS continue after IVF ?

Is LPS of benefit for IVF patients?
✓ Elevated serum estradiol concentration
✓ Suppression of LH by continued down-
regulation by GnRH agonists
✓ hCG injection before OR
✓ Removal of of granulosa cells at OR
✓ Supra physiological E2/P4 in early luteal phase
➢ Abnormal luteal function after COS for IVF

LPS was a requirement for optimal outcome
after IVF.
Edwards & Steptoe. (1980) Br J Obstet Gynaecol 1980; 87: 737–56,
long protocol, lead to an endocrinological
disturbance during the luteal phase.
Smitz et al. (1992) Hum Reprod 1992; 7: 1225–9.,
Smitz et al. (2001) Acta Obstet Gynecol Scand 2001;80.
Luteolysis is also initiated prematurely in
antagonist co-treated IVF cycles}
(Albano et al., 1998; Beckers et al., 2002)

Meta-analysis of prospective, randomized
studies showed that LPS was clearly beneficial in
establishing a pregnancy after IVF, following
stimulation as part of a long protocol.
Soliman et al. (1994 ) Fertil Steril 1994
Pritts & Atwood, (2002) Hum Reprod. 2002

drugs for LPS ?

drugs for LPS ?
➢ There is much controversies about
➢ Type of drugs,
➢ Formulations,
➢ Doses,
➢ Combinations,
➢ Duration of treatment.

drugs for LPS ?
➢ The ideal LPS needs to be
➢ Simple,
➢ Effective,
➢ Acceptable to patients.

➢ The drugs normally used for LPS are:
➢ Human chorionic gonadotropin (hCG)
➢ Progesterone
➢ Estrogen
➢ GnRH-agonists

hCG versus Progesterone
Human chorionic gonadotrophin (hCG):
 Rescue corpus luteum
(Hutchins Williams et al. 1990)
 Improves the implantation by increasing
relaxin, integrin & placental ptn.
(Mochtar, 1998)
 Increase the risk of OHSS
(van der Linden et al., 2012)

hCG versu Progesterone
Progestagen:
➢ Improves endometrial receptivity
(Kolibianakis & Devroy, 2002)
➢ Promotes local VD and uterine musculature
quiescence by inducing nitric oxide synthesis
in decidua
(Bulletti & de Ziegler, 2005)
➢ Act as immunologic suppressant blocking Th1
and inducing release of Th2 cytokines
(Ng et al. 2002)
➢ ? value as regards miscarriage

OutcomeComparisonStudy
PR
entirely
comparable
32.0% and 31.7%
micronized vaginal
progesterone (600
mg/day) + oral E
valerate (6 mg/day),
Versus
hCG (2000 IU on days 4, 8
and 12 of the LP
Van Steirteghem et al.
(1988)
Hum Reprod 1988
A prospective, RCT,
91 patients
PR
Comparable
(18.1% vs 17.3%
hCG (n=72), 1500 IU,
Versus
im progesterone (n=49),
25 mg/day
Claman et al. (1992)
Hum Reprod 1992
A prospective RCT
PR
36.7% vs 35.3%,
IR
12% vs 14% y .
OHSS was
higher with hCG
2000 IU hCG (n=38)
Versus
50 mg progesterone i.m.
daily (n=39).
Araujo et al. (1994) J
Assist Reprod Genet
1994
A prospective RCT,
77 patients

Artini et al. J (1995) Endocrinol Invest.
Martinez et al., (2000) Gynecol Endocrinol.
Ludwig et al., (2001) Acta Obstet gynecol Scand
Ugur et al., (2001) Fertil Steril
In these studies GnRH-a long protocol was
used luteal support with hCG or intramuscular
or vaginal progesterone was used only during
luteal phase.
There was no difference in CPR, OPR, SAB.

The use of hCG led to
significantly better
implantation (19.0% vs
7.5%) and pregnancy
rates (31.4% vs 14.3%).
Due to the low
bioavailability (already
discussed in by the
authors).
Oral, micronized
progesterone (400
mg/day) versus
hCG (1500 IU)
(70 transfers in each
group),
Buvat et al. (1990)
(Fertil Steril 1990
in 171 embryo transfer
cycles.
- It was excluded from
the meta-analysis by
Soliman et al. (1994),

➢ There was no difference in CPR, OPR, SAB.
➢ hCG and progesterone have the same efficacy,
but hCG has an increased OHSS risk.
➢ Progesterone should be the first choice for
luteal phase support following ovarian
stimulation in the long protocol.

Progesterone
Synthetic Natural Micronized
Provera Prontogest Utrogestan caps
Depot provera Cyclogest Endometrin tab
Norplant Progestan caps
Megestrol acetate Crinone 8% gel
Northinderone Ellios caps
Duphaston

Progesterone (oral route)
➢ Convenience
➢ Side effects
➢ Sedation
➢ Drowsiness
➢ Only 10% of oral dose circulates as active P4
{first pass effect}
➢ No secretory transformation in patients with
oral micronized progesterone
(Devroey et al.1989; Bourgain et al. 1990)
➢ The clinical efficacy ?
➢ Less effective
➢ More variable

➢ After oral administration, progesterone is
broken down into numerous metabolites,
which have a negative effect on the (CNS)
and on the uterus.
➢ The serum levels rose briefly to 1.5 ng/ml, then
fell sharply below 0.5 ng/ml after 6 hours,
compared to 4 and 5 ng/ml for more than 24
hours after vaginal administration.
(Nahoul et al. (1993)

PR 28.8 % vs. 25%.
Ongoing PR 25.96 %
vs. 22.9%
Births per ET 23% vs.
22.2%
Non significant.
More side effects
with oral route
Oral
progesteron
e, 300
mg/day
(N=144)
Vaginal
progestero
ne gel (90
mg/day)
(N=139)
Pouly et al. (1996),
Hum Reprod 1996; 11:
2085–9.
Prospective,
randomized study
The implantation
rate 30.7%
vs.10.7%; p 0.01,
The ongoing
clinical pregnancy
rate 41.1% vs.20%
Not significant.
Oral
Utrogestan
capsules
(200 mg, 4
daily) (n=32)
Vaginal
Utrogestan
capsules
(100 mg,
twice daily)
(n=32)
Friedler et al. (2001)
Acta Obstet Gynecol
Scand, 2001;80
Prospective,
randomized male
factor infertility

The implantation
rate was
significantly better
with intramuscular
progesterone
(40.9% vs 18.1%; p
0.004).
Oral
progesteron
e (600 mg/
day
Intramuscular
progesteron
e (50
mg/day)
Licciardi et al. (1999)
Fertil Steril 1999; 71: 614–
18.
Only 43 patients
randomized,
terminated early for
ethical reasons.
No difference in CPR
and Implantation
rates in the 2 groups.
Oral
progesteron
e
IM
progesteron
e
Akira et al (2008)
Arch Gynecol Obstet
2008 277: 319-324, 40
patients
Clinical pregnancy
rates
(20 versus 25%)
Implantation rates
(9.1 versus 12.7%)
Oral
chlormadin
on acetate
600mg daily
50 mg i.m.
progesteron
e.
Iwase et al (2008)
Arch Gynecol Obstet 2008;
277:319–324.
prospective study 40
patients

➢ Conclusions
Oral dydrogesterone is effective drug, well
tolerated and accepted among patients and
can be considered for routine luteal support.
Oral dydrogesterone versus vaginal progesterone
gel in the luteal phase support: randomized
controlled trial
VlatkaTomicab JozoTomica Djurdj ZigmundovacKlaicb MiroKasumC KrunoslavKunaa
European Journal of Obstetrics & Gynecology and Reproductive Biology
Volume 186, March 2015, Pages 49-53

➢ Conclusions
Oral dydrogesterone seems to be as effective
as vaginal progesterone for LPS in ART cycles,
and appears to be better tolerated .

luteal phase support should be given
via the intramuscular or vaginal
routes.

Progesterone (IM route)
P4 in oil base
 Effective
 Reliable and consistent plasma levels of P4
 Rapidly absorbed in 2-8 hours
 P4 levels are maintained for 72 hours

Progesterone (IM route)
➢ Weak compliance:
➢ Painful injections (long, thick needles)
➢ Inflammatory reactions
➢ Rash
➢ Needs to be administered by nurse
➢ Occasional sterile abscess
➢ Occasional allergic reaction (oil vehicle)
➢ Acute eosinophilic pneumonia associated with
IM administration of progesterone as luteal
phase support after IVF: 5 case reports
Bouckaert et al. Human Reproduction 2004

Progesterone (Vaginal route)
➢ Target organ delivery
➢ High concentration in uterus and endometrium
➢ First uterine pass effect
➢ Good patient compliance:
➢ Minimal systemic side effects
➢ Self administered
➢ Gel or capsules are equally effective
(Daya & Grundy, 2004)

Progesterone (Rectal route)
➢ Rectal application resulted in serum
concentration during the first 8 h twice as high as
other forms.
(Chakmakijan & Zachariah, 1987)
➢ Good patient compliance
➢ No adequate studies

Progesterone (SC route)
➢ A new water-soluble progesterone
➢ Implantation rate, PR, LBR and early miscarriage
rate for Prolutex were similar to those for Crinone.
➢ The adverse event profiles were similar and
Prolutex was safe and well tolerated.

Progesterone

Progesterone (Vaginal versus IM routes)
IM progesterone is associated with the highest serum levels.
Vaginal progesterone increases endometrial tissue levels.

The ongoing CPR
comparably high, with
31% in the Crinone A
8% group vs. 22%
Vaginal
Crinone
A8% twice
daily
IM
progeste
rone 100
mg daily
Gibbons et al. Fertil
Steril 1998; 69: 96–101.
Higher pregnancies
(%) 45.7% vs. 30.6 %
Clinical pregnancies
(%) 34.3 % vs. 19.1 %
Ongoing pregnancies
28.9% vs. 11.0 %
Live births 22.1% vs.
8.0%
Vginal
progester
one gel,
90 mg
(N=52)
IM
progeste
rone50
mg
(N=52)
Abate et al. (1999)
Clin Exp Obstet Gynecol 1999;
16: 203–6.
A prospective, double-
blind, randomized,
tubal factor infertility

➢ .
The LBR per ET 50% vs.
53.5% Comparable
Majority preferred
vaginal progesterone;
(easier, (69.2%), less
painful (76.9%) and
less time-consuming
(61.5%).
Vaginal Progesterone
Versus
IM Progesterone
Damario et al.(1999)
Fertil steril
1999;72:830-6
The group given vaginal
progesterone had
previously significantly
more IVF attempts and
had longer stimulation.
The ongoing clinical
pregnancies was
similar between
groups – 34.9% VS.
32%
Vaginal progesterone
(Crinone 8%; 90 mg)
(N=100) Versus
IM progesterone, 50 mg
(N=106)
Chantilis et al. (1999)
Fertil Steril 1999
Prospective study with
a historical control
group
Pregnancy rates of
25.7% (19/74) VS.
29.5% (18/61)
Comparable
Vaginal Crinone A 8%
(N=61)
Versus
50-100 mg IM progesterone
(N=74)
Bieber et al. (1998)
Fertil Steril 1998; 70 (Suppl
1) Retrospective study

In a metanalysis on 5 studies
Artini et al. 1995,
Perino et al. 1997,
Abate et al. 1999,
Anserini et al. 2001,
Guesa et al. 20001)
➢ OPR and SAB were not different.
Pritts & Atwood, Hum Reprod. 2002

Is it beneficial to add estrogen to

Is it beneficial to add estrogen for LPS ?
The pregnancy
rates recorded in
both groups were
identical – 29%
No estrogen Versus
supplementation with
6 mg estradiol valerate
with 600 mg vaginal
progesterone daily.
Smitz et al. (1993)
Hum Reprod (1993) 8:40–45
Prospective Randomized
extensive study, 378
patients.
Pregnancy rates
per ET (28.0%
vs.26.5%
Birth rates per P
(78.6% vs. 76.1%
2 mg estradiol valerate
daily or no
supplementation after
with 50 mg
progesterone im. daily.
Lewin et al. (1994)
Fertil Steril 1994; 62: 121–5.
Prospective randomized
study, 100 consecutive
patients
? Better
Implantation rate
with estrogen
supplementation
Addition of estrogen to
a standard
progesterone LPS vs.
no estrogen
Pritts & Atwood (2002)
Human Reproduction, 2002;17,
2287-2299.
A meta-analysis of the
randomized trials

Significantly higher PR
E2 supplementation (PR
32.8 versus 23.1%). The
best pregnancy results
were with high dose E2
supplementation (PR
51.3%).
evaluated the effect
of different E2
supplementation
doses (0, 2, or 6 mg)
in agonist cycles (n =
231). compared with
no E2 substitution
Lukaszuk et al. (2005)
Fertil Steril (2005) 83:1372–
1376
Prospective
randomized study
Highest pregnancy rate
was achieved in group
C (45.56%), Addition of
6 mg E(2) valerate to P
support may encumber
the sharp decline in
luteal E(2) level.
On embryo transfer
day, only P (group A,
n = 90), P along with 6
mg E(2) valerate
either orally (group B,
n = 90), or vaginally
(group C, n = 90) for
luteal support.
Elgindy et al., Fertil
Steril, Fertil Steril
(2010) 1;93(7):2182-8.

Ludwig & Diedrich (2001)
Acta Obstetricia et Gynecologica Scandinavica
Controversy surrounds the benefits
derived from supplementation of
estrogen for luteal support.
Supplementary administration of
estradiol for luteal phase support
appears unnecessary, although the
data are inconsistent.
Further studies would undoubtedly be
worthwhile to more thoroughly
investigate this approach.
.

Kolibianakis et al. (2008) Hum Reprod
Four RCTs (n=587 patients)
CONCLUSIONS:
The currently available evidence
suggests that the addition of estrogen
to progesterone for luteal phase
support does not increase the
probability of pregnancy in IVF.

Gelbaya et al. (2008) Fertil Steril. 2008
Ten RCTs used Progesterone alone or
combined with estradiol valerate for LPS
The addition of E(2) to P for LPS has no
beneficial effect on pregnancy rates.
The data in the literature are limited and
heterogeneous.
A large multicenter, properly designed RCT
is needed to further clarify the role of luteal
E(2) supplementation in IVF

van der Linden et al. (2011)
Cochrane Database Syst Rev
Overall, the addition of other substances
such as estrogen or hCG did not seem to
improve outcomes
Huang et al., Fertil Steril. 2015
The best available evidence suggests that
E(2) addition during the luteal phase does
not improve IVF/ICSI outcomes through oral
medication, even with different daily doses.
Furthermore, RCTs that study other
administration routes are needed.

GnRHa in midluteal phase
GnRH receptor is expressed in the human
preimplantation embryos, endometrium,
corpus luteum
GnRHa has been shown to stimulate
trophoblast production of hCG
Studies:
Increased LBR
(Kyrou et al., 2008)
GnRHa Vs no tt GnRHa is beneficial
(Glujovsky et al., 2010)
Effective

GnRHa in midluteal phase
Martins et al., Ultrasound Obstet Gynecol. 2015
Metanalysis of 10 studies examining 3,056
women
There is evidence that adding GnRH
agonist during luteal phase improves
ongoing pregnancy.
However, this evidence is of very low quality
and there is no evidence about adverse
perinatal outcomes and congenital
malformations.
We therefore believe that including this
intervention on clinical practice would be
still premature

For how long should LPS continue after IVF ?
➢ The date of initiation and discontinuation of
supplemented hormones are not adequately
studied in the literature.
➢ Optimal progesterone supplementation
should begin on the day of oocyte retrieval or
1 day later – before embryo transfer on day 2.
➢ The luteo-placental shift, does not take place
until about the 8th–10th week of pregnancy.

Biochemical
pregnancy: 23% vs
18%
Ectopic pregnancy: 5
vs. 7 Abortion 11.5% vs
15%
Delivery rate. 63% vs.
64%
All similar.
200 pregnant women received
progesterone (control group)
and 200 pregnant women
received none (study group)
For three weeks after a positive
hCG test,
Schmidt et al.
(2001)
Fertil Steril (2001)
75:337–341
Delivery rate.
118 (78.7%) versus 126
(82.4%)
Not significant.
(n = 150) withdrew vaginal
progesterone from the day of
positive hCG
Versus (n = 153) continued
vaginal progesterone for 3
weeks of pregnancy
Nyboe et al.
(2002)
Hum Reprod (2002)
17:357–361
Similar on going PR
and bleeding
episodes in the two
groups.
Randomized 257 pregnant
patients after ICSI into either to
stop LPS on the day of US or to
continue for 3 weeks.
Aboulghar et al.
2008,
Human Reprod. 2008;
23:857-862

➢ The data provided from these studies did not
support traditional duration of LPS.

CONCLUSION

CONCLUSION
drugs for LPS ?
➢ Which Is superior for LPS hCG or
Progesterone?
➢ Which is the best route for administration of
➢ Is it beneficial to add estrogen to
➢ What are other hormones that can be
used?

CONCLUSION
YES

CONCLUSION
What is the best dose and formulations of drugs
for LPS ?
➢ Progesterone is first choice for LPS.
➢ I.M. and vaginal progesterone are equally
effective, but most patients will prefer vaginal
progesterone administration.
➢ Oral progesterone is clearly inferior to i.m. or
vaginal

CONCLUSION
What is the best dose and formulations of drugs
for LPS ?
➢ The optimal dose of progesterone has not
been studied in a scientific way in the
literature.
➢ No evidence to support co-tt to progesterone
including aspirin, heparin, viagra….apart from
midluteal phase GnRHa which seems
promising but needs further evaluation.

CONCLUSION
Is it beneficial to add estrogen to progesterone
for LPS ?
 The administration of estrogen for LPS is
probably not beneficial,
 Although a definitive conclusion can not be
drawn due to the controversial nature of the
data available.

CONCLUSION
➢ Progesterone supplementation should begin
on the day of oocyte retrieval or 1 day later –
before embryo transfer on day 2.
➢ Recent data available does not support the
extension of LPS to 8-10 weeks gestation.

Luteal Phase Support In IVF

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