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A review on the A review on the luteal phaseluteal phase
P Devroey MD PhDP Devroey MD PhDCentre for Reproductive MedicineCentre for Reproductive Medicine
Dutch-speaking Brussels Free UniversityDutch-speaking Brussels Free University
Brussels - BelgiumBrussels - Belgium
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Learning objectivesLearning objectives
Is the luteal phase defective after Is the luteal phase defective after
ovulation induction in anovulatory ovulation induction in anovulatory
women ?women ?
Is the luteal phase defective after Is the luteal phase defective after
“controlled” ovarian superovulation ?“controlled” ovarian superovulation ?
If yes, which is the mechanism behind ?If yes, which is the mechanism behind ?
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Controlled ovarian Controlled ovarian superovulation for IVFsuperovulation for IVF
Are the luteal phase LH concentrations Are the luteal phase LH concentrations
normal after controlled ovarian normal after controlled ovarian
stimulation with gonadotrophins alone ?stimulation with gonadotrophins alone ? Are the luteal phase LH concentrations Are the luteal phase LH concentrations
normal after controlled ovarian normal after controlled ovarian
stimulation with the combination of stimulation with the combination of
GnRH agonists and gonadotrophins ?GnRH agonists and gonadotrophins ?
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Controlled ovarian superovulation for Controlled ovarian superovulation for IVF (continued)IVF (continued)
Are the luteal phase LH concentrations Are the luteal phase LH concentrations
normal after controlled ovarian stimulation normal after controlled ovarian stimulation
with the combination of GnRH antagonists with the combination of GnRH antagonists
and gonadotrophins ?and gonadotrophins ?
Are the luteal phase LH concentrations Are the luteal phase LH concentrations
normal after controlled ovarian stimulation normal after controlled ovarian stimulation
with the combination of clomiphene citrate with the combination of clomiphene citrate
and gonadotrophins ?and gonadotrophins ?
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EndometriumEndometrium
Is there any influence on endometrial Is there any influence on endometrial histology after the administration of histology after the administration of gonadotrophins before injection of gonadotrophins before injection of human chorionic gonadotrophins (hCG) ?human chorionic gonadotrophins (hCG) ?
Is there any influence on endometrial Is there any influence on endometrial histology in GnRH agonist/antagonist - histology in GnRH agonist/antagonist - gonadotrophin stimulated cycles 36 gonadotrophin stimulated cycles 36 hours after injection of hCG ?hours after injection of hCG ?
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Luteal phase supplementation or Luteal phase supplementation or substitution substitution
Is luteal phase supplementation Is luteal phase supplementation
mandatory in GnRH - agonist / antagonist mandatory in GnRH - agonist / antagonist
- gonadotrophin stimulated cycles ?- gonadotrophin stimulated cycles ?
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Is there any influence on Is there any influence on endometrial histology during the endometrial histology during the follicular phase in gonadotrophin follicular phase in gonadotrophin
stimulated cycles before the injection stimulated cycles before the injection of hCG ? of hCG ?
YESYES or or NONO
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Is there any influence on Is there any influence on endometrial histology during the endometrial histology during the follicular phase in gonadotrophin follicular phase in gonadotrophin
stimulated cycles before the injection stimulated cycles before the injection of hCG ? of hCG ?
YESYES or or NONO
AnswerAnswer : : YesYes
100 % secretory advancement in preovulatory endometria ( pre - hCG ) during ovarian stimulation 100 % secretory advancement in preovulatory endometria ( pre - hCG ) during ovarian stimulation ( Marchini FS 1991 )( Marchini FS 1991 )
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Is there any influence on Is there any influence on endometrial histology in agonist / endometrial histology in agonist /
gonadotrophin stimulated cycles 36 gonadotrophin stimulated cycles 36 hours after hCG administration ?hours after hCG administration ?
YESYES or or NONO
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Is there any influence on Is there any influence on endometrial histology in agonist / endometrial histology in agonist /
gonadotrophin stimulated cycles 36 gonadotrophin stimulated cycles 36 hours after hCG administration ?hours after hCG administration ?
YESYES or or NONO
AnswerAnswer : : YesYes
100 % ( n = 40 patients )100 % ( n = 40 patients )2 - 5 days advancement 2 - 5 days advancement ( Ubaldi FS 1997 )( Ubaldi FS 1997 )
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Is there any influence on Is there any influence on endometrial histology in antagonist / endometrial histology in antagonist /
gonadotrophin stimulated cycles ? gonadotrophin stimulated cycles ?
YESYES or or NONO
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Is there any influence on Is there any influence on endometrial histology in antagonist / endometrial histology in antagonist /
gonadotrophin stimulated cycles ? gonadotrophin stimulated cycles ?
YESYES or or NONO
AnswerAnswer : : YesYes
100 % ( n = 55 patients )100 % ( n = 55 patients )2 - 4 days advancement 2 - 4 days advancement ( Kolibianakis FS 2002 )( Kolibianakis FS 2002 )
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Endometrial biopsy on the day Endometrial biopsy on the day of ovulation , natural cycleof ovulation , natural cycle
No secretory featuresNo secretory features
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Endometrial biopsy on the day of Endometrial biopsy on the day of oocyte retrieval , GnRH agonist and oocyte retrieval , GnRH agonist and
gonadotrophin stimulation cyclegonadotrophin stimulation cycle
Clear secretory featuresClear secretory features
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Is there any relation between Is there any relation between endometrial advancement and endometrial advancement and
ongoing pregnancy rates ?ongoing pregnancy rates ?
YESYES or or NONO
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Is there any relation between Is there any relation between endometrial advancement and endometrial advancement and
ongoing pregnancy rates ?ongoing pregnancy rates ?
YESYES or or NONO
AnswerAnswer : : YesYes
≤ ≤ 3 days3 days > 3 days> 3 days PP
hMG / agonisthMG / agonist 10 / 3210 / 32 0 / 70 / 7
recFSH / antagonistrecFSH / antagonist 8 / 498 / 49 0 / 60 / 6
TOTALTOTAL 18 / 8118 / 81 0 / 130 / 13 < 0.05< 0.05
Endometrial advancementEndometrial advancement
Kolibianakis FS 2002Kolibianakis FS 2002
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Endometrial advancement Endometrial advancement persists in the midluteal phasepersists in the midluteal phase
YESYES or or NONO
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Patient
10987654321
Dif
fere
nce
of
his
tolo
gic
al t
o c
hro
no
logic
al d
atin
g (
day
s)
8
6
4
2
0
-2
-4
OPU
Midluteal phase
Histological regression of endometrium from oocyte retrieval to the midluteal phase
Kolibianakis, Bourgain, Platteau, Albano, Van Steirteghem, Devroey F S 80 2003
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Describe the LH concentration during the Describe the LH concentration during the luteal phase ( post hCG ) in agonist luteal phase ( post hCG ) in agonist
gonadotrophin stimulated cyclesgonadotrophin stimulated cycles
LOWLOW or or HIGHHIGH
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Describe the LH concentration during the Describe the LH concentration during the luteal phase ( post hCG ) in agonist luteal phase ( post hCG ) in agonist
gonadotrophin stimulated cyclesgonadotrophin stimulated cycles
LOWLOW or or HIGHHIGH
AnswerAnswer : : LowLow
Smitz HR 1988Smitz HR 1988
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Are the LH concentrations during the Are the LH concentrations during the luteal phase ( post hCG ) in agonist - luteal phase ( post hCG ) in agonist -
gonadotrophin stimulated cycles similar to gonadotrophin stimulated cycles similar to the LH concentrations in the follicular the LH concentrations in the follicular
phase ?phase ?
YESYES or or NONO
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Are the LH concentrations during the Are the LH concentrations during the luteal phase ( post hCG ) in agonist - luteal phase ( post hCG ) in agonist -
gonadotrophin stimulated cycles similar to gonadotrophin stimulated cycles similar to the LH concentrations in the follicular the LH concentrations in the follicular
phase ?phase ?
AnswerAnswer : : NoNo
Demoulin FS 1991Demoulin FS 1991
Before hCGBefore hCG 1.5 mIU / ml1.5 mIU / ml
12 hours after hCG12 hours after hCG 0.5 mIU / ml0.5 mIU / ml
96 hours after hCG 96 hours after hCG 0.2 mIU / ml0.2 mIU / ml P < 0.0001P < 0.0001
WHY ?WHY ?
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Is the luteal phase LH concentration Is the luteal phase LH concentration ( post hCG ) in antagonist - ( post hCG ) in antagonist - gonadotrophin cycles normal or gonadotrophin cycles normal or
decreased ?decreased ?
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Is the luteal phase LH concentration Is the luteal phase LH concentration ( post hCG ) in antagonist - ( post hCG ) in antagonist - gonadotrophin cycles normal or gonadotrophin cycles normal or
decreased ?decreased ?
AnswerAnswer : : decreaseddecreased
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Are the luteal phase concentrations Are the luteal phase concentrations ( post hCG ) similar in ( post hCG ) similar in gonadotrophin alone versus gonadotrophin alone versus
antagonist gonadotrophin stimulated antagonist gonadotrophin stimulated cycles ?cycles ?
YESYES or or NONO
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Are the luteal phase concentrations Are the luteal phase concentrations ( post hCG ) similar in ( post hCG ) similar in gonadotrophin alone versus gonadotrophin alone versus
antagonist gonadotrophin stimulated antagonist gonadotrophin stimulated cycles ?cycles ?
YESYES or or NONOAnswerAnswer : : YesYes
Tavaniotou HR 2001Tavaniotou HR 2001
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Luteinizing hormone serum Luteinizing hormone serum concentrations in Clomid concentrations in Clomid
gonadotrophin antagonist or gonadotrophin antagonist or gonadotrophin antagonist cyclesgonadotrophin antagonist cycles
0
5
10
15
-3 -2 -1 0 1 2 early mid late
Day Luteal phase
LH
le
ve
l (
IU/L
)
Tavaniotou F S 77 2002Tavaniotou F S 77 2002
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Is the luteal phase length normal Is the luteal phase length normal after gonadotrophin stimulation in after gonadotrophin stimulation in
non IVF ?non IVF ?
YESYES or or NONO
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Is the luteal phase length normal Is the luteal phase length normal after gonadotrophin stimulation in after gonadotrophin stimulation in
non IVF ?non IVF ?
YESYES or or NONO
AnswerAnswer : : NoNo
Olson FS 1983Olson FS 1983
CyclesCycles 7878
Normal lengthNormal length 6060
ShortenedShortened 18 ( 23 % )18 ( 23 % )
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StatementStatement : : GnRH antagonist can be GnRH antagonist can be
safely administered in gonadotrophin safely administered in gonadotrophin
stimulated IUI cycles without luteal stimulated IUI cycles without luteal
phase supplementationphase supplementation
Ragni HR 2001Ragni HR 2001
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Is the statement in Is the statement in contradiction with the lecture ?contradiction with the lecture ?
YESYES or or NONO
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Is the statement in Is the statement in contradiction with the lecture ?contradiction with the lecture ?
YESYES or or NONO
AnswerAnswer : : NoNo
Ragni HR 2001Ragni HR 2001
StimulationStimulation FSH + antagonistFSH + antagonist FSH aloneFSH alone
Mean no of folliclesMean no of follicles 2.72.7 3.23.2
FSH unitsFSH units 10801080 10541054
E2 ( ng/ml ) ( pre hCG)E2 ( ng/ml ) ( pre hCG) 500500 900900
LH ( U / L ) ( day 4 post hCG ) LH ( U / L ) ( day 4 post hCG ) 1.81.8 2.52.5
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Steroid serum concentrationsSteroid serum concentrations
NaturalNatural Stimulated cyclesStimulated cycles
Patients (n)Patients (n) 2525 44
Progesterone (Progesterone (g/L)g/L) 8.58.5 50.550.5
EE22 (ng/L) (ng/L) 92.092.0 549.5549.5
Tavaniotou Master Thesis Brussels 2000Tavaniotou Master Thesis Brussels 2000
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Luteal phase supplementation is Luteal phase supplementation is mandatory mandatory
hCG versus no treatment hCG versus no treatment
significantly bettersignificantly better
Vaginal progesterone versus no Vaginal progesterone versus no
treatment treatment
significantly bettersignificantly better
Pritts HR 17 Pritts HR 17
20022002
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hCG versus prog IM + EhCG versus prog IM + E22V V (RCT)(RCT)
hCGhCG Prog IM + EProg IM + E22VV
ET (n)ET (n) 269269 252252
Pregnancies (n)Pregnancies (n) 8181 7474
%% 3030 2929
Smitz unpublishedSmitz unpublished
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Progesterone IM + EProgesterone IM + E22V versus V versus vaginal progesterone + Evaginal progesterone + E22V (RCT)V (RCT)
Prog IMProg IM Vaginal progVaginal prog
ET (n)ET (n) 131131 131131
Pregnancies (n)Pregnancies (n) 4040 4646
%% 3030 3535
Smitz HR 1992Smitz HR 1992
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Vaginal progesterone versus Vaginal progesterone versus vaginal progesterone + Evaginal progesterone + E22V (RCT)V (RCT)
Vaginal progVaginal prog Vaginal prog + EVaginal prog + E22VV
ET (n)ET (n) 183183 195195
Pregnancies (n)Pregnancies (n) 6565 6464
%% 3535 3232
Smitz HR 1993Smitz HR 1993
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Is luteal support necessary in GnRH antagonist cycles?
Beckers et al 2004 JCEM
When 40 patients had been included, the study was canceled prematurely
because of observed premature luteal phase bleeding andextremely low pregnancy rates.
Fixed dose of rec FSH 150 IU, daily antagonist by a follicle of 14mm
By a follicle of 18mm patients were randomized to receive
rec hCG, rec LH, GnRH agonist
No luteal support
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Support of corpus luteum function remains mandatory after ovarian stimulation for IVF
with GnRH antagonist cotreatment.
Is luteal support necessary in GnRH antagonist cycles?
Beckers et al 2004 JCEM
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Is GnRH agonist triggering an Is GnRH agonist triggering an option ? option ?
PubMed 01.03.2011 n : 83 publicationsPubMed 01.03.2011 n : 83 publications
Gonadotrophin-releasing hormone Gonadotrophin-releasing hormone
agonist triggering : the way to agonist triggering : the way to
eliminate ovarian hyperstimulation eliminate ovarian hyperstimulation
syndrome - a 20 years experiencesyndrome - a 20 years experience
Kol Sem Reprod Med 2010Kol Sem Reprod Med 2010
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GnRH agonist GnRH agonist triggeringtriggering
GnRH-aGnRH-a hCGhCG
n : 84n : 84 n : 95n : 95
Age (years)Age (years) 3333 3434
Eggs (mean)Eggs (mean) 5.95.9 5.25.2
Embryos transferredEmbryos transferred 2.52.5 2.32.3
Pregnancy ratesPregnancy rates 20 %20 % 19 %19 %
Segal FS 1992
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ReflexionReflexion
It is possible that down regulation It is possible that down regulation
of pituitary receptors and reduced of pituitary receptors and reduced
LH support for the corpus luteum LH support for the corpus luteum
may occur even after a single may occur even after a single
administration of GnRH agonistadministration of GnRH agonist
Segal FS 1992Segal FS 1992
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Cycle outcomeCycle outcomeBrusselsBrussels
AgonistAgonist hCGhCG
Stimulation (in Stimulation (in patients)patients)
1818 2424
OPU (n)OPU (n) 1818 2424
ET (n)ET (n) 1515 2020
Ongoing pregnancy Ongoing pregnancy rate / started cyclerate / started cycle
1/18 (5.6 %)1/18 (5.6 %) 10/24 (41.7 %)10/24 (41.7 %)
Odds ratio (95 % CI) 0.11 (0.02 – 0.52)
P level = 0.005Kolibianakis HR 2005
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TriggeringTriggering GnRH agonist 0.2 GnRH agonist 0.2 mg Triptorelinmg Triptorelin
hCG 10 000hCG 10 000
Vaginal Vaginal progesteroneprogesterone
++ ++
Estradiol Estradiol valerate valerate
++ ++
DiscontinuationDiscontinuation -- --
Pregnancy ratePregnancy rate 5.6 %5.6 % 41.7 %41.7 %
Kolibianakis HR 2005
GnRH agonist triggering in GnRH agonist triggering in a GnRH antagonist cyclea GnRH antagonist cycle
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ConclusionsConclusions
1.1. Ovarian superovulation (IVF) Ovarian superovulation (IVF) destroys luteal phase functiondestroys luteal phase function
EndocrinologyEndocrinology Endometrium behaviourEndometrium behaviour
2.2. Luteal phase supplementation is Luteal phase supplementation is mandatorymandatory
3.3. The degree of luteal steroid The degree of luteal steroid production is the key factorproduction is the key factor