DR.KALPANA M.D (O.G) F.N.B (reproductive medicine)

LPDLuteal phase is defined as the period between

ovulation and either the establishment of a pregnancy or menstruation

Luteal phase of a natural cycle is characterized by the formation of a corpus luteum which secretes E2, P4

After implantation, blastocyst secretes HCGRole of HCG produced by the embryo is to

maintain the C.L

NATURAL CYCLEProgesterone Secretion peaks 4th day of

ovulation.Peak persist for 7th days then falls.Menstruation starts 4 days after the fall.In pregnancy placental progesterone starts

around 7 weeks.

IVFIVF is not the first line of treatment for all

patients with infertilityNational guidelines for IVF focus on

diagnosis & indications for IVF.

IVFIVF was initially designed to overcome tubal

infertilityNow it is the treatment of choice for

unexplained infertility, male infertility, endometriosis ,an ovulation .

Introduction of ICSI for severe forms of male infertility has widened the scope of IVF

DENUDED OOCYTES

2 PN EMBRYO

D2 & D3 EMBRYO

BLASTOCYST

LPD PREVALENCELuteal phase of all stimulated IVF cycles is

abnormal Edward

et al 1980.

AETIOLOGY OF LPDRemoval of granulose cells during OR results

in reduced P4

OR in natural cycle did not reduce P4 secretion and did not shorten the luteal phase.

Kerin et al 1981

AETIOLOGY OF LPDProlonged effect of GnRH agonist prevents

LH rise results in LPD Smitz et al 1992.Antag cycles also resulted in short luteal

phase and reduced PR Albanoct al 1998.

AETIOLOGY OF LPDHCG used as a trigger suppress LH

production .Miyake et al 1979.HCG in unstimulated cycles did not reduce

LH level Tavaniotou Derroey et al 2003.

AETIOLOGYSupra physiological levels of steroids

produced by multiple C.L which inhibit LH Secretion from the pituitary .

Fauser and Devroey 2003.

IVF CYCLEE2,P4 levels are supra physiological because

of multiple corpus luteum, Results in decreased in I.R

Duration of steroid production is 1-3 days shorter than normal cycle.

Abrupt fall is E2,P4 compared to natural cycle.

IUI

mild male factor infertility unexplained infertilityminimal to mild endometriosis

COHNatural Cycles CCCC+HMGCC+FSHHMGFSH (Urinary, Pure, Rec)HMG+FSHGnRHa + HMGGnRHa + FSHGnRHa +HMG + FSH

Number of trials of IUI ?

Pregnancies resulting from IUI occur during early treatment cycles.

Eighty-eight percent of pregnancies occur in the first three cycles of IUI and 95.5% within the first four cycles (Morshedi M et al, 2003).

Continued IUI beyond four trials

is not recommended

CC-|U|No positive effect of P4 was found in CC

cycles montivlle et al 2009.

CC|U|

In normo ovualatory patients stimulated with CC for |U| P4 did not increase PR [8.7 Vs 9.3%]

This is the first RCT analyzing the effect of P4, in CC stimulated cycle.

D.kyrou et al H.R 2010.Vol:25 issue:10

CC

Occupies E2, receptor in hypo thalamus stimulates GnRH secretion.

Increase the pituitary sensitivity to GnRHFSH,LH secretions are increased .LH is

responsible for the maintenance of C.LDirect effect on the ovary makes the granulosa

cells more sensitive to Gn So E2,P4 levels are increased

CC occupies hypo thalamic E2 receptor for a longer period than E2, this is the resaon for the greater luteal LH concetration.

Summary:

luteal phase P4 support did not increase PR in normo ovulatory women <37,years and stimulated with CC for |U|.

This was the first RCT to test the need for luteal support in |U| cycles and it was under powered .

Further studies are needed. Ky rou

et al H.R 2010 Vol:25

Gn-IUIRCT by erdem etal in 2009 concluded a

beneficial effect (PR) of p4 in IUI cycles stimulated with Gn in patients with unexplained infertility

Pcos-Letrozole

P4 increase PR in Pcos patients stimulated with letrozole montville et al 2009

Should luteal phase support be introduced in ovarian stimulation/IUI programmes? It is recommended to apply luteal phase support in

stimulated IUI cycles only when proven cost-effective.

Further trials are mandatory to investigate both endometrial and hormonal profile changes in the luteal phase after mild ovarian stimulation, and the cost-effectiveness of luteal support in IUI programmes

Fertility and SterilityVolume 91, Issue 6 , Pages 2508-2513, June 2009

LPSLPS is used to describe the administration of

medication which support the implantation process.

Different doses, duration and types of treatment have been evaluated.

How ever, there is no agreement regarding the optimal supplementation scheme (Fatem et al 2006)

ROLE OF P4 IN THE LUTEAL PHASEP4 causes Secretary change of the endo

metrium. Improves endo metrial receptivity.Causes local vaso dilatation.Induce nitric oxide synthesis in the decidua

and makes the uterus quie scent. Kolibiankis and devroey 2002.

PREPERATIONOralI.MVaginal

ORAL10% of oral dose circulates (Liver first pass

mechanism).Increasing dose results in Somnolescence.Lower I.R, P.R Increased Abortion rate.

I . MAdvantage – No first pass mechanism.Disadvantage Painful

Needs some one to give.AbscessAllergic reaction

IM P4Dose Vary between 25 to 100 mg/day with

out any Significant difference in outcome. (Pritts and Atwood et al 2002)

VAGINALAdvantage

Self administered.Easily tolerated.Allergic reaction-rareTargeted delivery even thoughP4 level is low

. Efficacy – equal to I.M.

VAGINAL P4There is recent evidence in the literature that

vaginal P4 is at least as effective as I M P4 in stimulate cycle

Simunic et al 2007.300 – 600 mg of natural micronized P4 is

divided in 2-3 dosesTavaniotou et al 2000Further prospective RCT are essential to

define the necessary dose of Vaginal P4 for LPS in IVF.

CRINONE 8% GELPreparation contains 90mg micronized P4 in

emulsion.It adheres to vaginal epithelium.Advantage

- long half life - Patient to patient variability in

absorption is less

. 8% gel = 200mg tid - Vaginal capsule

17 Hydroxy progesterone Caproate. Twice a week. PR, IR – Similar to daily IM injection.

HCGHCG was found to be superior to P4. Meta analysis by No sarka et al 2005

Contra Indicated in OHSS

Dydro gesteroneDydro gesterone and P4 were associated with

similar PR. Chakravarty el al

2005.Vaginal P4 was more effective than oral

Dydro gesterone in Creating in phase endometrium .

Fatemi et al 2007.

E2 SUPPLEMENTATIONImproves PR.Stimulates P4 receptors E2 and P4 better PR than P4 alone.

E2E2 6mg/day significantly improved the PR in

long protocol. Lukaszuk et al 2005No improvement in short GnRH agonist antag

protocol.

GnRH AGONITSActs on the pituitary and increase LH Secretion.Acts on the endo metrium pirard et al 2005Acts on the embryo Trsarih et al 2006Triptorelin 0.1mg given 6 days after ICSIHCG, E2, P4 levels increased Despite this encouraging results, Great concern exists

about the possible adverse effect on Oocyte, embryos Lambalk, Homburg et al

2006 Larger RCT needed.

LPSP4 and ascorbic acid.P4 and prednisolone.P4 and asprin.

ONSET OF LPSTiming of LPS is debatable 3 days after OR - Williams et al 2001No difference between OR day and ET days - Baruffi et al 2003Should not be later than 3days after OR as

5day after HCGHCG covers a maximum of 8 days

SUMMARYLPS with HCG or progesterone results in increased

PRVaginal and I.M. have comparable resultsE2 addition is beneficial in long GnRH agonist

protocol., but not in short GnRH agonist and antag protocol

It is too early to recommend the use of GnRH agonist in LPS

Since the cause of LPD in IVF is related to the supra physiological levels of steroids milder stimulation protocols should be used to eliminate LPD.

SUMMARYWith a growing tendency towards the

transfer of a reduced number of embryos (fauser, Devroey et al 2003) with an increasing number of European investigators advocating SET (Papanikolaou et al 2006) attitude should shift towards milder Stimulation protocol to eliminate LPD

Patient selectionCOHFollicular studyIUI

IUI

mild male factor infertility unexplained infertilityminimal to mild endometriosis

COHNatural Cycles CCCC+HMGCC+FSHHMGFSH (Urinary, Pure, Rec)HMG+FSHGnRHa + HMGGnRHa + FSHGnRHa +HMG + FSH

Number of trials of IUI ?

Pregnancies resulting from IUI occur during early treatment cycles.

Eighty-eight percent of pregnancies occur in the first three cycles of IUI and 95.5% within the first four cycles (Morshedi M et al, 2003).

Continued IUI beyond four trials

is not recommended

DENUDED OOCYTES

2 PN EMBRYO

D2 & D3 EMBRYO

BLASTOCYST

Success doesn’t mean the absence of failures. It means the attainment of the ultimate objective. It means winning the war not just the battle

IVF CYCLEGn RH antag with Gn RH a as a frigger most

affected.HCG in hibits pituifary LH Result in LPD.

ADVANTAGE OF P4Quietening effect on uterus .No dys synchrony between gland and stroma.E.T. During 2 nd 4 th day of p4 support

improves I.R.

SUMMARYTill 7 weeks Ovarian production of hormones

is Critical.Vaginal route has promising results.

IM Vs VAGINAL P4Meta analysis published in 2002 by pritts and

At wood included 5 RCT.PR, delivery rates were significantly higher in

I.M Progesterone.Despite the conclusion of pritts analysis,

Vaginal P4 has a viable alternative to I.M injection which is associated with high side effects.

IUI CYCLERagni et al in 2001 analysed luteal phase

hormone profile in Gn stimulated cycles with or with out antag.

No adverse effect of antag on luteal phase P4 level or the duration of the luteal phase.

Gn-IUI