1. LUTEAL PHASE SUPPORT IN ART { AN EVIDENCE BASED APPROACH}
DR DEEPTHI BAWA
CONSULTANT IN REPRODUCTIVE MEDICINE
ASTER CMI HOSPITAL
BANGALORE
INDIA

2. Luteal phase is defined as the period between ovulation and either the establishment of a pregnancy or the onset of menstrual cycle two weeks later

3. AFTER OVULATION Corpus Luteum Progestrone & Estrogen
Secretory Menstruation of Endometrium
Cascade of Molecular events
Receptive to Implantation of Embryo

4. AFTER IMPLANTATION HCG Progestrone & Estrogen
Desidualization of the Endometrial Stroma
Supports early embryonic development

5. Luteoplacental unit by 5th gestational week

6. Once upon a time…..
In 1949 , the premature onset of menses was recognized as indicative of a luteal phase deficiency of progesterone production, which was shown to be correctable by exogenous progesterone administration ( Jones , 1979 )
The prevalence of a luteal phase defect in natural cycles in normo-ovulatory patients with primary or secondary infertility was demonstrated to be about 8.1%
Rosenberg et al., 1980

7. APRIL 2015
In Summary , currently there is no reproducible pathophysiologically relevant & clinically practical standard to diagnose LPD & distinguish fertile from infertile women .
The roles of BBT , urinary LH detection kits , luteal progesterone levels , endometrial biopsy & other diagnostic studies have not been established & performance of these tests cannot be recommended .

8. Contents Why Indications When to start ? When to stop ? What to use ?
Co treatment
Conclusion

9. 1.WHY ??? Abnormal Luteal Function after COS for IVF Suppression of LH
Continued down-regulation by GnRHa
Removal of Granulosa cells at oocyte retrieval
Supra Physiological E2/P4 in early luteal phase
HCG injection before oocyte retrieval

10. 2. INDICATIONS Agonist and Antagonist protocol ( Day & Gunby , 2004 )
A. PR are significantly reduced in GnRHa ovarian stimulation without LPS
( Day & Gunby , 2004 )
B. Both GnRHa & Antagonist IVF cycles : abnormal LPD in all stimulated IVF cycles
C. Luteolysis is also initiated prematurely in antagonist co- treated IVF cycles
( Albano et al., 1998 ; Beckers et al., 2002 )

11. Frozen natural cycles ? Controversial
LPS increases LBR after frozen ET
(Bjuresten et al )
LPS has no effect on ongoing PR in HCG – induced natural frozen – thawed ET cycles
( Kyrou et al.2010 )
Endometrial preparation for women undergoing ET with frozen embryos or embyros derived from donor oocytes
(Glujovsky et al.,2010)

12. OPTIMAL TIMING OF INITIATION IN IVF CYCLE
24 to 48hrs after oocyte retrieval for initiation of supplement with optimal cycle results.

13. 3. When to stop ??? Limited data
Can be safely withdrawn after first positive B-hcg result (Nyboe Anderson et al- prospective study –vag 600mg )
No advantage to continue support beyond first USG viability study(Aboulghar and collegues)
3 randomized study comparing early and late cessation of prog combined studies of Nyboe, Anderson and Aboulghar  concluded progesterone supplementation beyond first positive Beta hCG may be unnecessary

14. 4 .What to use for LPS ???
HCG
PROGESTERONE

15. HOW TO CHOOSE ???
Optimally Efficacious
Minimal side effects 
Ease of administration 
Convenience
          (2011 Cochrane review compared vaginal progesterone , IM progesterone & HCG injection – reported similar IVF pregnancy rates , but odds for OHSS complication 20 hold higher with HCG than with progesterone .)  

16. HCG :
Rescue corpus luteum (Hutchins Williams et al. 1990) 
Improves the implantation by increasing relaxin, integrin & placental ptn (Mochtar, 1998)
Increase the risk of OHSS (van der Linden et al., 2012) Aboubakr Elnashar)

17. PROGESTERONE SUPPORT IN IVF
Definite benefit (van der Linden et al., 2012) 
Improves endometrial receptivity (Kolibianakis & Devroy, 2002) 
Promotes local VD and uterine musculature quiescence by inducing nitric oxide synthesis in decidua (Bulletti & de Ziegler, 2005) 
Act as immunologic suppressant blocking Th1 and inducing release of Th2 cytokines  (Ng et al. 2002) 
No value as regards miscarriage (van der Linden et al., 2012) Aboubakr Elnashar

18. Oral progesterone
Only 10% of oral dose circulates as active P4 {first pass effect} 
No secretory transformation of the endometrium in patients with POF who had been treated with oral micronized progesterone (Devroey et al.1989; Bourgain et al. 1990) Aboubakr Elnashar

19. IM progesterone SIDE EFFECTS
Serum P4 levels well above the physiological range with adequate endometrial secretory changes 
Dose: natural progesterone in oil, 25 and 100 mg/d: No significant difference in outcome (Costabile et al., 2001, Pritts & Atwood, 2002) Aboubakr Elnashar
SIDE EFFECTS 
Welts , infection , abscess, allergic reaction & pulmonary complication , inconvenient to administer & painful . 
    Subcutaneous Aqueous , lyophilized progesterone injection (25mg daily )

20. Vaginal progesterone DOSE
“Targeted drug delivery” from vagina to uterus: better endometrial histology
High uterine progesterone concentrations {anatomically close blood vessels: uterine first pass effect} (Cicinelli et al., 2000, de Ziegler et al., 1995) Aboubakr Elnashar)
DOSE 
Micronized Progestrone capsule mg daily 
Vaginal cream/gel 90mg once or twice daily ( Crinone 8% )

21. Which vaginal preparation???
Gel or capsules ?
Both are equally effective
Capsule: solid evidence of effectiveness and convenience (Elenany et al, 2011) more cost effective than gel
Gel is at least 4 times more expensive than Capsules No difference exists regarding CPR between vaginal P gel and all other vaginal preparations for LPS (MA: Polyzoz et al, 2010) Aboubakr Elnashar 
Progestrone vaginal ring ( MILPROSA ) - once a week insertion compared with crinone gel daily – no statistical difference , in PR , LBR , but 3 hold higher vaginal discharge with ring . 

22. Rectal application
Resulted in serum concentration during the first 8h twice as high as other forms
No prospective RCT to compare the rectal administration of progesterone with other administration routes for IVF
(Chakmakijan & Zachariah, 1987) Aboubakr Elnashar

23. Oral or I.M. progesterone ? 
               Definitely  -  I.M. progesterone (Daya & Grundy, 2004) 
Oral or vaginal progesterone ?
            Definitely - vaginal progesterone (Daya & Grundy, 2004) 
I.M. or vaginal progesterone ? 
           Both are equally effective No difference in CPR (Daya & Grundy, 2004; MA: Zarutiski & Philips, 2009) Aboubakr Elnashar

24. OPTIMAL LUTEAL PHASE SUPPORT IN GnRH AGONIST – TRIGGERED CYCLE
Half life of HCG – 2.3days 
In addition to effecting the final oocyte maturation , it also contributes to OHSS 
Current evidence suggest GnRH agonist & HCG triggered cycles results in equalent oocyte maturity but , GnRH trigger are associated with much lower OHSS rates . 
In IVF cycles were pituitary secretion achieved with antagonist cycles there is a option to use GnRH Agonist trigger(Triptoriline 0.2mg or rHCG 250mcg )  instead of HCG .
All cycles that do not involve fresh embryo transfer ( egg donor , Fertility preservation ) should be triggered with GnRH agonist only . 
GnRh agonist triggered cycles are associated with higher degree of luteal phase impairment compared with HCG triggered cycles , but addition of small doses of HCG ( 1500 IU / IM  on day of oocyte retrieval ) , not associated with OHSS .

25. PROGESTERONE IN FET CYCLES & DONOR OOCYTE RECIPIENT CYCLE
No endogenous progesterone production , therefore there is a need for luteal phase "creation" or replacement .
Only 2 small prospective studies compared IM progesterone 50mg /.day & crinone gel 90mg BD in FET cycle , were blastocyst was transferred , found no difference in clinical implantation or LBR .

26. Estrogen - co treatment with progesterone
No proven improved outcome
More studies are needed to evaluate the potential benefits of vaginal Estradiol (6mg) supplementation .
Elgandy .etal , conducted a randomized study in patient undergoing ICSI cycle in long agonist protocol , concluded that addition of vaginal estradiol in luteal phase , improved the PR . 

27. TO CONCLUDE
PROGESTRONE SUPPLEMENTATION IN LUTEAL PHASE LEADS TO HIGHER PR 
VAGINAL PROGESTRONE ARE EQUALLY EFFECTIVE & TOLERATATED THAN IM 
ONCE DAILY CRINONE GEL OR TWICE OR THRICE ENDOMETRIN OR MICRONIZED PROGESTRONE TID ARE OPTIMAL DOSE OF VAGINAL PROGESTRONE 
VAGINAL SUPPLEMENTATION BEST STARTED WITHIN 24-48HRS OF OOCYTE RETRIVAL 
NO NEED FOE SERUM PROGESTRONE LEVEL MONITORING WITH VAGINAL SUPPLEMNTATION 
CONTINUED LPS SUPPORT IN EARLY PREGNANCY BEYOND 1ST POSITIVE PREGANCY TEST IS OF LITTLE VALUE 

28. Cont..
IVF CYCLES THAT DO NOT INVOLVE FRESH ET IS BEST CONDUCTED WITH GNRH ANTAGONIST PITUTARY SUPRESSION & GnRH AGONIST TRIGGER 
GnRH ANTAG CYCLE TRIGGERED WITH AGONIST , INVOLVING FRESH ET SHOULD HAVE MODIFIED LUTEAL PHASE SUPPORT INCLUDING SMALL DOSE OF HCG OR LH , IN ADDITION TO PROGESTRONE SUPPORT 
NEW DEVELOPMENT RELATED WITH SC & ORAL SYNTHETIC PREPARATION REQUIRE CAREFUL ATTENTION . 
No evidence to support co-tt to progesterone including aspirin, heparin, Viagra….apart from midluteal phase GnRHa which is promising and needs further evaluation .