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

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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