Luteal phase support is essential for IVF cycles. Progesterone has many forms and modalities: which to use? this talk is an attempt to answer this question

1. PROGESTERONE FOR LPS: META-
ANALYSIS AND COST BENEFIT
ANALYSIS
Hesham Al-Inany, M.D, PhD

2. OUTLINE OF THIS TALK
 What is the problem?
 How to deliver solid evidence if available
 Different modalities for LPS
 Vaginal capsules vs gel
 Conclusion

3. LUTEAL PHASE IN ART CYCLES
 Iatrogenic luteal phase defect due to
supraphysiological steroid levels in
stimulated cycles
Fatemi et al. Hum Reprod Update. 2007

4. QUESTIONS TO BE ANSWERED
 What is the best strategy for LPS
 Is combined strategy more effective
 How to choose between different modalities :-
(Safety, Effectiveness / convenience/ cost)

5. OUTLINE OF THIS TALK
 What is the problem?
 How to deliver solid answer for these questions?
 Different modalities for LPS
 Vaginal capsules vs gel
 Comments
 Conclusion

6. THE BEST EVIDENCE FOR DIFFERENT TYPES
OF QUESTION
Level Treatment Prognosis Diagnosis
I Systematic
Review of …
Systematic
Review of …
Systematic
Review of …
II Randomised
trial
Cohort
studies
Cross
sectional
III

7. 7
WHY RCTS?
Participants
RandomlyAssigned
Intervention
Group
Control Group
Follow-up
Follow-up
Intervention
Group
Control Group

8. ADVANTAGES OF SR
 Larger numbers & power
 Critical appraisal of studies

9. THE USE OF PROGESTERONE IN IVF
Nosarka et al. 2005.

10. Cochrane Review 2011
Pregnancy rates are significantly reduced in
ovarian stimulation without luteal phase support

11. DOES THE PROTOCOL AFFECT???
 Both agonists & Antagonists protocols require luteal
phase support (Kahraman et al, 2010)

12. OUTLINE OF THIS TALK
 What is the problem?
 How to deliver solid evidence if available
 Different modalities for LPS
 Vaginal capsules vs gel
 Conclusion

13. ELEMENTS OF LUTEAL PHASE SUPPORT
 HCG: 1500-2000 IU i.m. q3d for 4 doses from
oocyte retrieval
 P4: from oocyte retrieval to 7-10 weeks
1) Progesterone in oil 25-100 mg i.m. qd
2) Utrogestan® 200 mg p.o. or vag. tid
3) Crinone® gel 90 mg vag. aod or bid
Combined strategy
hCG + P4
E2 + P4
Prednisolone + P4

14. PRITTS, 2002
– hCG versus no treatment: significantly better
– IM and vaginal progesterone and versus no treatment:
significantly better
– hCG = vaginal and IM progesterone
BUT increased risk of OHSS
associated with hCG use!

15. (Cochrane Rev., 2011)

16. A SYSTEMATIC REVIEW: P+E2 VS. P
(GELBAYA ET AL, 2008)

17. PROGESTERONE PLUS PREDNISOLONE &
LOW DOSE ASPIRIN
No benefit on CPR (Mollo et al,2003, Ezzeldin et
al, 2003).

18. ROLE OF PROGESTERONE
2.0
2.5
3.0
3.5
4.0
4.5
Day 15 Day 16 Day 17 Day 18 Day 19 Day 20
UC Frequency/min
0%
5%
10%
15%
20%
25%
<3.0 3.1-4.0 4.1-5.0 >5.0
(Fanchin et al, 1998)(De Ziegler et al, 1996)
UC/min
UC = uterine contractions.

19. WHICH TYPE OF PROGESTERONE???

20. Progesterone in LPS
IM P Oral P Vaginal P
ROUTE
.

21. COMPOSITION

22. AVAILABLE IN THE MARKET
 Synthetic Natural Micronised
 Provera - Cyclogest - Utrogestan caps
 Depo-provera - Utrogest caps
 Norplant - Prontogest - Progestan caps
 Megestrol acetate - Ellios caps
 Nomegestrol acetate - Endometrin tab
 Northinderone - Crinone 8% gel
 Duphaston

23. IM PROGESTERONE
 Effective
 Painful (long, thick needles)
 Occasional sterile abscess
 Occasional allergic reaction (oil vehicle)*
 Needs to be administered by nurse, husband
 Acute eosinophilic pneumonia associated with IM administration of
progesterone as luteal phase support after IVF: 5case reports
* Bouckaert et al. Human Reproduction 2004; 19(8), 1806-1810

24. ENDOMETRIAL DIFFUSION: TARGETED DELIVERY
MICRONISED VAGINAL PROGESTERONE
Four hours after application
Bulletti et al. Hum Reprod. 1997;12:1073.
Progressive diffusion of progesterone from the cervix to
the fundus of the uterus
One hour after application

25. OUR SR: Vaginal vs. IM progesterone - CPR
Vaginal vs. IM progesterone – Ongoing pregnancy rate
Vaginal vs. IM progesterone – Live birth rate

26. IN OOCYTE DONATION RECIPIENTS
 vaginal progesterone showed better results than
intramuscular injection
 The study was small and retrospective
• Berger BM, Phillips JA., 2012

27. VAGINAL P4: 65% OF THE USE
 http://www.ivf-worldwide.com/survey/survey-
progesterone-results.html , August 2009

28. ORAL PROGESTERONE
 the convenience of oral administration is attractive,
 However, the first-pass hepatic metabolism after
oral administration requires higher doses
 The clinical efficacy of oral progesterone has been
debated
 The vaginal administration of P results in a greater
bioavailability with less relative variability than oral
P (Levine & Watson, 2000).

29. Vaginal vs. oral progesterone - Clinical pregnancy rate
Vaginal vs. oral progesterone – Ongoing pregnancy rate
OUR SR

30. Statistically significant retarded endometrial
development (“out phase endometrium”) in artificial
cycles treated with oral dydrogesterone has been
reported in several studies
Pellicer et al, 1989; Li et al, 1994, Fatemi et al, 2007
DG
Side effects
 Sedation
 Drowsiness
 DG can not be given vaginal

31. ORAL DG VS MICRONISED PROGESTERONE

32. AUTHORISED BODIES APPROVAL
 neither Duphaston nor Cyclogest are approved
(worldwide) for Luteal Phase Support indication in
ART
Only few trials available for Cyclogest:

33. OUTLINE OF THIS TALK
 What is the problem?
 How to deliver solid evidence if available
 Different modalities for LPS
 Vaginal : Capsules vs gel
 Conclusion

34. UTEROGESTAN VS CRINONE: LARGEST STUDY
Ganesh et al, Fertil Steril 2011

35. Our SR : Vaginal progesterone vs. Crinone 8% gel - Clinical
pregnancy rate
Vaginal progesterone vs. Crinone 8% gel – Live birth rate

36. DOSE ??
 Sensitivity analysis performed by excluding one trial
in which vaginal P gel was administered twice
instead of once on a daily basis did not reveal any
difference (OR 1.30, 95% CI 0.93–1.81; P¼.118).
 Our meta-analysis confirm previous findings from
other trials that there is no difference in
effectiveness between vaginal P gel and vaginal
capsules when used in IVF/ICSI cycles

37. MINOR SIDE EFFECTS
 (perineal irritation, leaking out, interference with
coitus) may limit the gel in favor of capsules Pezino et
al (2004)

38. HOW TO MAKE DECISION ABOUT DRUG
Crinone
vs
Uterogestan

39. Utrogestan® (200mg/caps) 400-600 mg/day 0.96 - 1.44€/day
Endometrin® (100 mg tablet) 200-300 mg/day 8.86 – 13.29€/day
Crinone® (8% vaginal gel) 90-180 mg/day 3.83 - 7.66€/day
i.e
Gel is at least 4 times more expensive than Capsules
4 € x 2weeks of LPS = ~65€ difference
If repeated 3 cycles: 195 €
COST

40. ECONOMIC ANALYSIS
 IVF/ICSI cycle, there are probabilities
- Pregnancy
- No pregnancy
- Abortion
- Repeat trial (usually up to 3 cycles)
- Stop trial

41. EXAMPLE : 1ST CYCLE
Start Cycle
10,000
Ovum Pickup
No OHSS
Ovum Pickup
OHSS
9810
190
Fertilization
& Transfer
No Oocytes
373+7=380
9437+183=9620
Clinical
Pregnancy
-ve βHCG
2982
6638
Ongoing
Pregnancy
Miscarriage
405
2577
3246
3392
Continue
Stop
Goal
!
Therefore, for a cohort of 10,000 individuals the expected,
mathematically exact, outcome at the end of the 1st cycle is
380+405+3392 = 4177 patients who will restart the cycle, and 2577
who achieved ongoing pregnancy, and 3246 who gave up on IVF
from the first trial

42. END RESULTS
 10,000 cohort women will cost at least 1,400,000€
difference in case of gel over capsule
 What would be the impact of such difference???
 With crinone: lower number of women restarting cycle,
and higher number of women stopping cycle
 With Uterogestan: higher number of women restarting
the cycle and lower number of women stopping cycle

43. WHEN DO YOU START PROGESTERONE?
1. Day of hCG
2. Day of OPU
3. Day of ET (day 3)
4. Day of ET (day 5)
Polling Question

44. HOW LONG SHOULD PROGESTERONE BE
ADMINISTERED?
1. Positive hCG
2. Up to 7 wks pregnancy
3. Up to 12 wks pregnancy
4. Up to 34 ws if multiple pregnancy
Polling Question

45. IN ALL CONDITIONS
 cost-effectiveness is optimal with Vaginal
progesterone caps regimen (Polyzos et al, 2009)

46. PATIENT PREFERENCES
 A recent era of developing patient preferences
studies to evaluate the patient acceptability and
satisfaction for a certain modality of treatment ove r
the other
 Unfortunately, no studies have been done in the
field of luteal phase support.

47. CONCLUSIONS (BY EVIDENCE)
 LPS is important in IVF/ICSI cycles
 hCG better not used in LPS as it increases OHSS
 IM progesterone has many side effects
 Oral progesterone is debatable
 Micronised progesterone has solid evidence of
effectiveness and convenience
 Micronised capsules are more cost effective than
progesterone gel

48. THANK YOU!