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

1. DR.KALPANA M.D (O.G) F.N.B (reproductivemedicine)

2. LPD • Luteal 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 HCG • Role of HCG produced by the embryo is to maintain the C.L

3. NATURAL CYCLE • Progesterone Secretion peaks 4th day of ovulation. • Peak persist for 7th days then falls. • Menstruation starts 4days after the fall. • In pregnancy placental progesterone starts around 7 weeks.

5. IVF • IVF is not the first line of treatment for all patients with infertility • National guidelines for IVF focus on diagnosis & indications for IVF.

6. IVF • IVF was initially designed to overcome tubal infertility • Now it is the treatment of choice for unexplained infertility, male infertility, endometriosis ,an ovulation .

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

8. DENUDED OOCYTES

9. 2 PN EMBRYO

10. D2 & D3 EMBRYO

11. BLASTOCYST

12. LPD PREVALENCE • Luteal phase of all stimulated IVF cycles is abnormal • Edward et al 1980.

13. AETIOLOGY OF LPD • Removal 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

14. AETIOLOGY OF LPD • Prolonged 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.

15. AETIOLOGY OF LPD • HCG 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.

16. AETIOLOGY • Supra physiological levels of steroids produced by multiple C.L which inhibit LH Secretion from the pituitary . • Fauser and Devroey 2003.

17. IVF CYCLE • E2,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.

18. IUI • mild male factor infertility • unexplained infertility • minimal to mild endometriosis

19. COH • Natural Cycles • CC • CC+HMG • CC+FSH • HMG • FSH (Urinary, Pure, Rec) • HMG+FSH • GnRHa + HMG • GnRHa + FSH • GnRHa +HMG + FSH

20. 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

22. CC-|U| • No positive effect of P4 was found in CC cycles montivlle et al 2009.

23. 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

24. CC • Occupies E2, receptor in hypo thalamus stimulates GnRH secretion. • Increase the pituitary sensitivity to GnRH • FSH,LH secretions are increased .LH is responsible for the maintenance of C.L • Direct 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.

25. 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

26. Gn-IUI • RCT by erdem etal in 2009 concluded a beneficial effect (PR) of p4 in IUI cycles stimulated with Gn in patients with unexplained infertility

27. Pcos-Letrozole • P4 increase PR in Pcos patients stimulated with letrozole montville et al 2009

28. 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

29. LPS • LPS 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)

30. ROLE OF P4 IN THE LUTEAL PHASE • P4 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.

31. PREPERATION • Oral • I.M • Vaginal

32. ORAL • 10% of oral dose circulates (Liver first pass mechanism). • Increasing dose results in Somnolescence. • Lower I.R, P.R Increased Abortion rate.

33. I . M • Advantage – No first pass mechanism. • Disadvantage Painful Needs some one to give. Abscess Allergic reaction

34. IM P4 • Dose Vary between 25 to 100 mg/day with out any Significant difference in outcome. (Pritts and Atwood et al 2002)

35. VAGINAL • Advantage Self administered. Easily tolerated. Allergic reaction-rare Targeted delivery even though P4 level is low . Efficacy – equal to I.M.

36. VAGINAL P4 • There 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 doses • Tavaniotou et al 2000 • Further prospective RCT are essential to define the necessary dose of Vaginal P4 for LPS in IVF.

37. CRINONE 8% GEL • Preparation 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

38. 17 Hydroxy progesterone Caproate . Twice a week . PR, IR – Similar to daily IM injection.

39. HCG • HCG was found to be superior to P4. Meta analysis by No sarka et al 2005 Contra Indicated in OHSS

42. Dydro gesterone • Dydro 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.

43. E2 SUPPLEMENTATION • Improves PR. • Stimulates P4 receptors • E2 and P4 better PR than P4 alone.

44. E2 • E2 6mg/day significantly improved the PR in long protocol. Lukaszuk et al 2005 • No improvement in short GnRH agonist antag protocol.

45. GnRH AGONITS • Acts on the pituitary and increase LH Secretion. • Acts on the endometrium • pirard et al 2005 • Acts on the embryo • Trsarih et al 2006 • Triptorelin 0.1mg given 6 days after ICSI • HCG, 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.

46. LPS • P4 and ascorbic acid. • P4 and prednisolone. • P4 and asprin.

47. ONSET OF LPS • Timing of LPS is debatable • 3 days after OR - Williams et al 2001 • No difference between OR day and ET days - Baruffi et al 2003 • Should not be later than 3days after OR as 5day after HCG • HCG covers a maximum of 8 days

48. SUMMARY • LPS with HCG or progesterone results in increased PR • Vaginal and I.M. have comparable results • E2 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.

49. SUMMARY • With 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

50. Thank You