Transcript Luteal Phase Support in ART Cycles

Luteal Phase Support
in ART Cycles
Hsin-Yang Li
OB/GYN Dept.,
Taipei Veterans General Hospital
Luteal Phase Support
in ART Cycles
Why is luteal phase support needed in
ART cycles?
 What are the important elements of luteal
phase support? An evidence-based
approach.
 Promising methods to improve embryo
implantation rates of ART that await more
evidence.

Ovarian Stimulation in Assisted Reproductive Technology (ART)
to Obtain Multiple Oocytes
Multi-follicular Ovarian Stimulation
Oocyte Recovery
(Textbook of ART, 2nd Ed., 2004)
(Textbook of ART, 2nd Ed., 2004)
Two Commonly Used Ovarian Stimulation Protocols
(Textbook of ART, 2nd Ed., 2004;
Semin. Reprod. Med., 2002 )
Ovarian hyperstimulation is associated with
endometrial advancement in early luteal phase and
endometrial delay in mid-luteal phase
(Hum. Reprod., 2001; Trends Endocrinol. Metabol., 2004)
Pregnancy rates are significantly reduced in
GnRHa ovarian stimulation without luteal phase support
Abnormal Luteal Function After
Ovarian Stimulation for IVF: Mechanisms
Continued down-regulation by GnRHa
 LH 
 Induction of multiple follicles per se
 Removal of large quantities of granulosa
cells at oocyte retrieval
 Supraphysiological E2/P4 in early luteal
phase  negative feedback  LH 

The luteal phase is also defective in GnRHant cotreated ovarian
stimulation for IVF. Luteolysis started prematurely due to
negative feedback. Luteal phase support remains mandatory
for ovarian stimulation with GnRHant cotreatment in ART cycles.
(J. Clin. Endocrinol. Metab., 2003)
Timing of Luteal Support
1. Starting P4 at d3 after OR: better pregnancy rate than starting
at d6 after OR
2. 4-5 days of P4 therapy before ET is best for pregnancy
3. Suggestion: P4 supplement beginning on the day of OR and
continuing till 7-10 wks GA
(Textbook of ART, 2nd Ed., 2004)
Elements of Luteal Phase Support
HCG: 1500-2000 IU i.m. q3d for 4 doses
from oocyte retrieval
 P4: from oocyte retrieval to 7-10 weeks
1) progesterone in oil 25-100 mg i.m. qd
2) utrogestan 200 mg p.o. or vag. tid-qid
3) Crinone gel 90 mg vag. qd
 E2: from oocyte retrieval to 7-10 weeks
E2 valerate 2 mg p.o. bid

Routes of P4 Support
Oral route: Only 10% of the oral dose of P4 circulates as active P4
because of the first pass effect; dizziness
Vaginal Route: “Targeted drug delivery” from vagina to uterus, better
endometrial histology; vaginal discharge
Intramuscular route: Serum P4 levels well above the physiological range;
painful, sterile abscess and allergic response
(Textbook of ART, 2nd Ed., 2004)
(Cocrane Rev., 2004)
Pregnancy rate: I.M. P4 > Vag. P4 > Oral P4
(Cocrane Rev., 2004)
Crinone 8%: the first and only FDA-approved system for pregnancy support
(a bioadhesive vaginal gel containing 90 mg micronized P4)
Longer half life
Lower pt. to pt. variability
(Textbook of ART, 2nd Ed., 2004; Cocrane Rev., 2004)
The addition of E2 to progesterone in the luteal phase
does not enhance the probability of pregnancy.
(Cocrane
Rev., 2004)
Possible Roles of NSAID in ART
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Low dose aspirin   TXA2/PGI2 
vasodilatation and decreased platelet
aggregation  increased ovarian and
endometrial blood flow   ovarian
responsiveness,  endometrial thickness, 
implantation rate
NSAID may decrease uterine contraction at
the time of ET
The results of randomized controlled trials are
controversial.
Low-dose aspirin (100 mg/d from GnRHa D1) significantly improves
ovarian responsiveness, blood flow, and pregnancy rates in IVF patients.
Low-dose aspirin (100 mg/d
from stimulation D1) does not
improve ovarian
responsiveness and pregnancy
rates in IVF/ICSI patients.
(Hum. Reprod., 2005)
An oral dose 10 mg piroxicam 1-2 h before ET
significantly improves pregnancy rates
Indomethacin 100 mg q12h rectally for 3 doses from the night before ET
did not improve pregnancy rates in pregnancy rates in oocyte recipients
Heparin 5000 IU bid and aspirin 100 mg/day from the day of ET
did not improve pregnancy or implantation rates in
APA- or ANA-positive patients with IVF implantation failure.
Prednisolone 10 mg/d and aspirin 81 mg/d from stimulation D1
may increase pregnancy rates in patients with ANA and/or APA
Possible Roles of Viagra (sildenafil) in ART:
1. Improve uterine artery blood flow
2. Improve endometrial thickness
3. Increase embryo implantation rates
105 infertile women aged < 40 years, with normal ovarian reserve and at
least two consecutive prior IVF failures attributed to inadequate
endometrial development (< 9 mm), were given viagra 25 mg qid
vaginally from stimulation D1 to hCG day. Of 105 patients, 73 (70%;
Group A) attained an endometrial thickness of  9 mm, whereas 32 (30%;
Group B) did not.
(G. Sher,
Fertil. Steril.,
2002)
10 patients with 1-7 failed cycles of ART and thin endometrium (< 8 mm)
at previous ET were given viagra 25 mg qid vaginally from stimulation D3
to the evening before oocyte retrieval. Endometrial thickness increased
significantly after viagra treatment. 3 of the 10 patients conceived.
Possible Roles of GnRHa in
Enhancing Embryo Implantation
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Inadvertent GnRHa administration in the luteal
phase does not compromise pregnancy but
rather seems to improve implantation
GnRH receptor is expressed in the human
preimplantation embryos, endometrium, and
corpus luteum, implicating a direct effect of
GnRHa on the these targets
GnRHa has been shown to stimulate
trophoblast production of hCG.
Oocytes from each donor were shared by two recipients, one of whom
received a single dose of GnRHa (0.1 mg triptorelin) 6 days after ICSI,
and the other received placebo at the same time.
Recipient: pituitary down-regulation by GnRHa  oral E2 valerate 
oral E2 valerate + vaginal utrogestan ( GnRHa 6 days after ICSI)
GnRH agonist administration at the time of
implantation enhances embryo developmental
potential, probably by a direct effect on the embryo.
(Hum. Reprod., 2004)
Beneficial Effect of Luteal-phase GnRHa on Embryo Implantation
in GnRHa-treated Ovarian Stimulation Cycles
GnRHa
HCG Placebo or
GnRHa
ICSI ET
FSH + HMG
1
21
M2
C
H
C
G
ICSI
+
3d
ICSI
+
6d
E2 4 mg po + Utrogestan
400 mg Vag. qd
Luteal-phase GnRHa
(Triptorelin 0.1 mg 6 d after ICSI)
enhances embryo implantation
and live birth rates
(Hum. Reprod., 2006)
Beneficial Effect of Luteal-phase GnRHa on Embryo Implantation
in GnRHant-treated Ovarian Stimulation Cycles
GnRH
ant
Oral pill
HCG Placebo or
GnRHa
ICSI ET
FSH + HMG
1
21
M
C
2
6
H
C
G
ICSI
+
3d
ICSI
+
6d
E2 4 mg po + Utrogestan
400 mg Vag. qd
Luteal-phase GnRHa
(Triptorelin 0.1 mg 6 d after ICSI)
enhances embryo implantation
and live birth rates
(Hum. Reprod., 2006)
Conclusion
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Abnormal luteal function after ovarian stimulation in
ART is probably due to LH suppression by
supraphysiologic ovarian steroids
Patients not at risk of OHSS: hCG + vaginal or i.m.
P4
Patients at risk of OHSS (E2>3000 pg/ml or follicles
> 15): vaginal or i.m. P4
Thin endometrium and adequate E2 on stimulation
D7-8: consider use of aspirin or viagra till hCG day
Patients with multiple failures of ART despite
adequate follicular development and embryo quality:
consider aspirin and viagra from stimulation D1 and
GnRHa in the mid-luteal phase