a review on the luteal phase p devroey md phd centre for reproductive medicine dutch-speaking...
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A review on the luteal A review on the luteal phasephase
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
Learning objectivesLearning objectives
• Is the luteal phase defective after ovulation Is the luteal phase defective after ovulation
induction in anovulatory women ?induction in anovulatory 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 ?
Controlled ovarian superovulation Controlled ovarian superovulation for IVFfor 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 ?
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 ?
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 human gonadotrophins before injection of human
chorionic gonadotrophins (hCG) ?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 hours gonadotrophin stimulated cycles 36 hours
after injection of hCG ?after injection of hCG ?
Luteal phase supplementation Luteal phase supplementation or substitutionor substitution
• Is luteal phase supplementation mandatory in Is luteal phase supplementation mandatory in
GnRH - agonist / antagonist - gonadotrophin GnRH - agonist / antagonist - gonadotrophin
stimulated cycles ?stimulated cycles ?
Is there any influence on endometrial Is there any influence on endometrial histology during the follicular phase in histology during the follicular phase in
gonadotrophin stimulated cycles before the gonadotrophin stimulated cycles before the injection of hCG ?injection of hCG ?
YESYES or or NONO
Is there any influence on endometrial Is there any influence on endometrial histology during the follicular phase in histology during the follicular phase in
gonadotrophin stimulated cycles before the gonadotrophin stimulated cycles before the injection of hCG ?injection of hCG ?
YESYES or or NONO
AnswerAnswer : : YesYes
100 % secretory advancement in preovulatory 100 % secretory advancement in preovulatory endometria ( pre - hCG ) during ovarian endometria ( pre - hCG ) during ovarian stimulation stimulation
( Marchini FS 1991 )( Marchini FS 1991 )
Is there any influence on endometrial Is there any influence on endometrial histology in agonist / gonadotrophin histology in agonist / gonadotrophin
stimulated cycles 36 hours after hCG stimulated cycles 36 hours after hCG administration ?administration ?
YESYES or or NONO
Is there any influence on endometrial Is there any influence on endometrial histology in agonist / gonadotrophin histology in agonist / gonadotrophin
stimulated cycles 36 hours after hCG stimulated cycles 36 hours after hCG administration ?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 )
Is there any influence on endometrial Is there any influence on endometrial histology in antagonist / gonadotrophin histology in antagonist / gonadotrophin
stimulated cycles ?stimulated cycles ?
YESYES or or NONO
Is there any influence on endometrial Is there any influence on endometrial histology in antagonist / gonadotrophin histology in antagonist / gonadotrophin
stimulated cycles ?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 )
Endometrial biopsy on the day Endometrial biopsy on the day of ovulation , natural cycleof ovulation , natural cycle
No secretory featuresNo secretory features
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
Is there any relation between Is there any relation between endometrial advancement and ongoing endometrial advancement and ongoing
pregnancy rates ?pregnancy rates ?
YESYES or or NONO
Is there any relation between Is there any relation between endometrial advancement and ongoing endometrial advancement and ongoing
pregnancy rates ?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
Endometrial advancement persists in Endometrial advancement persists in the midluteal phasethe midluteal phase
YESYES or or NONO
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
Describe the LH concentration during the luteal Describe the LH concentration during the luteal phase ( post hCG ) in agonist gonadotrophin phase ( post hCG ) in agonist gonadotrophin
stimulated cyclesstimulated cycles
LOWLOW or or HIGHHIGH
Describe the LH concentration during the luteal Describe the LH concentration during the luteal phase ( post hCG ) in agonist gonadotrophin phase ( post hCG ) in agonist gonadotrophin
stimulated cyclesstimulated cycles
LOWLOW or or HIGHHIGH
AnswerAnswer : : LowLow
Smitz HR 1988Smitz HR 1988
Are the LH concentrations during the luteal phase Are the LH concentrations during the luteal phase ( post hCG ) in agonist - gonadotrophin stimulated ( post hCG ) in agonist - gonadotrophin stimulated
cycles similar to the LH concentrations in the cycles similar to the LH concentrations in the follicular phase ?follicular phase ?
YESYES or or NONO
Are the LH concentrations during the luteal phase Are the LH concentrations during the luteal phase ( post hCG ) in agonist - gonadotrophin stimulated ( post hCG ) in agonist - gonadotrophin stimulated
cycles similar to the LH concentrations in the cycles similar to the LH concentrations in the follicular phase ?follicular 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 ?
Is the luteal phase LH concentration ( post Is the luteal phase LH concentration ( post hCG ) in antagonist - gonadotrophin cycles hCG ) in antagonist - gonadotrophin cycles
normal or decreased ?normal or decreased ?
AnswerAnswer : : decreaseddecreased
Is the luteal phase LH concentration ( post Is the luteal phase LH concentration ( post hCG ) in antagonist - gonadotrophin cycles hCG ) in antagonist - gonadotrophin cycles
normal or decreased ?normal or decreased ?
Are the luteal phase concentrations Are the luteal phase concentrations ( post hCG ) similar in gonadotrophin alone ( post hCG ) similar in gonadotrophin alone versus antagonist gonadotrophin stimulated versus antagonist gonadotrophin stimulated
cycles ?cycles ?
YESYES or or NONO
Are the luteal phase concentrations Are the luteal phase concentrations ( post hCG ) similar in gonadotrophin alone ( post hCG ) similar in gonadotrophin alone versus antagonist gonadotrophin stimulated versus antagonist gonadotrophin stimulated
cycles ?cycles ?
YESYES or or NONO
AnswerAnswer : : YesYes
Tavaniotou HR Tavaniotou HR
20012001
Luteinizing hormone serum concentrations Luteinizing hormone serum concentrations in Clomid gonadotrophin antagonist or in Clomid 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
Is the luteal phase length normal after Is the luteal phase length normal after gonadotrophin stimulation in non IVF ?gonadotrophin stimulation in non IVF ?
YESYES or or NONO
Is the luteal phase length normal after Is the luteal phase length normal after gonadotrophin stimulation in non IVF ?gonadotrophin stimulation in non IVF ?
YESYES or or NONO
AnswerAnswer : : NoNo
Olson FS 1983Olson FS 1983
CyclesCycles 7878
Normal lengthNormal length 6060
ShortenedShortened 18 ( 23 % )18 ( 23 % )
StatementStatement : : GnRH antagonist can be safely GnRH antagonist can be safely
administered in gonadotrophin stimulated IUI administered in gonadotrophin stimulated IUI
cycles without luteal phase supplementationcycles without luteal phase supplementation
Ragni HR 2001Ragni HR 2001
Is the statement in contradiction with Is the statement in contradiction with the lecture ?the lecture ?
YESYES or or NONO
Is the statement in contradiction with Is the statement in contradiction with the lecture ?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
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
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 agonist Gonadotrophin-releasing hormone agonist
triggering : the way to eliminate ovarian triggering : the way to eliminate ovarian
hyperstimulation syndrome - a 20 years hyperstimulation syndrome - a 20 years
experienceexperience
Kol Sem Reprod Med 2010Kol Sem Reprod Med 2010
GnRH agonist triggeringGnRH agonist triggering
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
ReflexionReflexion
It is possible that down regulation of It is possible that down regulation of
pituitary receptors and reduced LH pituitary receptors and reduced LH
support for the corpus luteum may support for the corpus luteum may
occur even after a single administration occur even after a single administration
of GnRH agonistof GnRH agonist
Segal FS 1992Segal FS 1992
Cycle outcomeCycle outcomeBrusselsBrussels
AgonistAgonist hCGhCG
Stimulation (in patients)Stimulation (in 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
TriggeringTriggering GnRH agonist 0.2 mg GnRH agonist 0.2 mg Triptorelin Triptorelin
hCG 10 000hCG 10 000
Vaginal Vaginal progesteroneprogesterone
++ ++
Estradiol valerate Estradiol valerate ++ ++
DiscontinuationDiscontinuation -- --
Pregnancy ratePregnancy rate 5.6 %5.6 % 41.7 %41.7 %
Kolibianakis HR 2005
GnRH agonist triggering in a GnRH agonist triggering in a GnRH antagonist cycleGnRH antagonist cycle
GnRH agonist triggering in GnRH GnRH agonist triggering in GnRH antagonist cycles in OHSS risk antagonist cycles in OHSS risk
• AIM : avoiding OHSSAIM : avoiding OHSS
• Patients (n : 12)Patients (n : 12)
• > 25 follicles> 25 follicles
• GnRH agonist triggering and 1 500 hCG 35 GnRH agonist triggering and 1 500 hCG 35 hours laterhours later
• COC (n : 20)COC (n : 20)
• Ongoing pregnancies 50 % (6/12)Ongoing pregnancies 50 % (6/12)
• No OHSSNo OHSSHumaidan RBMO 2009Humaidan RBMO 2009
GnRH agonist triggering in GnRH GnRH agonist triggering in GnRH antagonist cycles (RCT) antagonist cycles (RCT)
GnRH agonist GnRH agonist + 1 500 hCG+ 1 500 hCG
hCG 10 000hCG 10 000
Patients (n)Patients (n) 152152 150150
Transfer rate (%)Transfer rate (%) 8686 9292
Delivery rate / patientDelivery rate / patient 36 / 152 (24 %)36 / 152 (24 %) 47 / 150 (31 %)47 / 150 (31 %)
Humaidan FS 2010
Oocyte donors (GnRHa donors)Oocyte donors (GnRHa donors)
TriggeringTriggering GnRHaGnRHa hCGhCG PP
Subjects (n)Subjects (n) 5050 5050
Age (y)Age (y) 2525 2525
rFSH dose (U)rFSH dose (U) 2 3002 300 2 3002 300
Eggs retrieved Eggs retrieved (mean)(mean)
1717 1919
OHSS rateOHSS rate 0 / 500 / 50 8 / 508 / 50 0.030.03
Melo RBMO 2009
ConclusionsConclusions
1.1. Ovarian superovulation (IVF) destroys Ovarian superovulation (IVF) destroys luteal phase functionluteal 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
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