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Luteal phase support in ART

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Luteal phase support in ART

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Luteal phase support in ART

  1. 1. Luteal phase support in ART Aboubakr Elnashar Benha university Hospital, Egypt Aboubakr Elnashar
  2. 2. CONTENTS 1. WHY? 2. INDICATIONS 3. WHEN TO START? 4. WHEN TO STOP? 5. WHAT TO USE? 6. CO TREATMENT CONCLUSION Aboubakr Elnashar
  3. 3. 1. WHY? Abnormal luteal function after COS for IVF  Suppression of LH  Continued down-regulation by GnRHa  Removal of of granulosa cells at OR  Supra physiological E2/P4 in early luteal phase  hCG injection before OR Aboubakr Elnashar
  4. 4. 2. INDICATIONS 1.Agonist and antagonist protocols A. PR are significantly reduced in GnRHa ovarian stimulation without LPS (Daya & Gunby,2004) B. Both GnRHa and 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) Aboubakr Elnashar
  5. 5. 2. Frozen natural cycles? Controversial  LPS increases LBR after frozen ET (Bjuresten et al. 2010)  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 embryos derived from donor oocytes (Glujovsky et al.,2010)Aboubakr Elnashar
  6. 6. 3. WHEN TO START From day of OR or ET Not be later than day 3 after OR Aboubakr Elnashar
  7. 7. 4. WHEN TO STOP Minimum’ 14 days from the day of ET until the day of a positive HCG test. (Andersen et al., 2002) ‘Minimum’ 18 days following OR (Mochtar et al., 2006) 1st T progesterone supplementation in IVF support early pregnancy through 7 w by delaying a miscarriage but not improve LBR (Andersen et al, 2002, Aboulghar et al, 2008)  8-10 w of gestation. Aboubakr Elnashar
  8. 8. 5. WHAT TO USE FOR LPS?  hCG  Progesterone Aboubakr Elnashar
  9. 9. HCG:  Rescue corpus luteum (Hutchins Williams et al. 1990)  improves the implantation by increasing relaxin, integrin & placntal ptn (Mochtar, 1998)  increase the risk of OHSS (van der Linden et al., 2012) Aboubakr Elnashar
  10. 10. Aboubakr Elnashar
  11. 11. Aboubakr Elnashar
  12. 12. CompanyPrice (LE) FormMgGeneric name FormTrade name Ibsa7230 vag pessaries200ProgesteronVag or rectal Prontogest Ibsa10230 vag pessaries400 Ibsa82.510 amp100ProgesteronIM Actavis9015 vag pessaries200ProgesteronVag or rectal Cyclogest Actavis12515 vag pessaries400 Ferring20021 vag tab100ProgesteronvagEndometrin Serono236jell15 tube8 %ProgesteronevagCrinon Octoper2430 caps100ProgesteroneVag or oralUterocare Pharco1824100ProgesteroneVag or oralProgest Aboubakr Elnashar
  13. 13. Progestagen: 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
  14. 14. hCG Vs progesterone  hCG is better (Soliman, 1994)  No differences but OHSS is twice more common in hCG group (Pritts & Atwood, 2002)  hCG is equal to I.M. progesterone (Daya & Grundy, 2004; van der Linden et al., 2012) Aboubakr Elnashar
  15. 15. hCG +progesterone Vs progesterone alone Both are equally effective (van der Linden et al., 2012) Aboubakr Elnashar
  16. 16. 1. 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
  17. 17. 2. IM progesterone  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
  18. 18.  Side effects:  painful injections  inflammatory reactions  rash  needs to be administered by nurse (Lightman et al., 1999) Aboubakr Elnashar
  19. 19. 3. Vaginal progesterone  “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
  20. 20. Micronized progesterone: no dose finding studies. Most frequently: 300–600 mg daily, spread over 2- 3 dosages (Tavaniotou et al., 2000) Vaginal progesterone pessaries: no dose finding studies frequently used: 400-800 mg daily, spread over 3-4 doses (NG et al, 2002, Tay et al, 2005) Aboubakr Elnashar
  21. 21.  Vaginal gel  8% gel in a dose of 90 mg once daily no differences when administered twice daily (Tavaniotou et al, 2000)  Low dose or high dose vaginal progesterone gel Both are equally effective (van der Linden et al., 2012) Aboubakr Elnashar
  22. 22. Which vaginal preparation? Gel or capsules ? Both are equally effective (Daya & Grundy, 2004) 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
  23. 23. 4. 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
  24. 24. 5. SC A new water-soluble progesterone Implantation rate, PR, LBR and early miscarriage rate for Prolutex were similar to those for Crinone. The adverse event profiles were similar and Prolutex was safe and well tolerated. Aboubakr Elnashar
  25. 25. 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
  26. 26. Vaginal progesterone increases endometrial tissue levels (Fert.Steril, 2012) Aboubakr Elnashar
  27. 27. IM progesterone is associated with the highest serum levels (Fert.Steril, 2012) Aboubakr Elnashar
  28. 28. For IDEAL LPS: IM P for the Highest Serum levels and Vaginal P for increasing the Endometrial levels, Until Placental progesterone production adequate, around week 8-10 w of gestation. (Fert.Steril, 2012) Aboubakr Elnashar
  29. 29. Aboubakr Elnashar
  30. 30. 6. CO-TREATMENTS TO PROGESTERONE 1.Addition of E2 to progesterone No effect of oral estrogens (van der Linden et al., 2012) Transdermal estrogen is beneficial (van der Linden et al., 2012) No effect in antagonist protocol Aboubakr Elnashar
  31. 31. 2. Low dose aspirin  VD and decreased platelet aggregation increased ovarian and endometrial blood flow  ovarian responsiveness,  endometrial thickness,  IR  Decrease uterine contraction at the time of ET  Low-dose aspirin (100 mg/d) doesn’t improve ovarian responsiveness, blood flow, and PR (Dirckx et al., 2009; Lambers et al., 2009) Aboubakr Elnashar
  32. 32. 3. Piroxicam An oral dose 10 mg 1-2 h before ET significantly improves PR (Moon., 2004) Doesn’t improve PR (Dal and Borini, 2009) Aboubakr Elnashar
  33. 33. 100 mg q12h rectally for 3 doses from the night before ET does not improve PR in oocyte recipients (Bernabue, 2006) 4. Indomethacin Aboubakr Elnashar
  34. 34. 4. low dose heparin 5000 IU bid and aspirin 100 mg/day from the day of ET did not improve PR or IR (Stern et al., 2003) Aboubakr Elnashar
  35. 35. 5. Prednisolone 10 mg/d before or after ET does not increase PR (Ubaldi et al., 2002) Aboubakr Elnashar
  36. 36. 6. Viagra 25 mg qid vaginally from stimulation D1 to hCG day (Sher, 2002; Paulus,2002) Aboubakr Elnashar
  37. 37. 7. Ascorbic acid  Luteal regression is associated with ascorbate depletion and the generation of reactive oxygen species, which inhibit the action of LH and block steroidogenesis  No value (Griesinger et al.,2002) Aboubakr Elnashar
  38. 38. 8. GnRHa in midluteal phase  GnRH receptor is expressed in the human preimplantation embryos, endometrium, corpus luteum  GnRHa has been shown to stimulate trophoblast production of hCG  Increased LBR (MA: Kyrou et al., 2008) Aboubakr Elnashar
  39. 39. GnRHa Vs no tt GnRHa is beneficial (Glujovsky et al., 2010) Effective (van der Linden et al., 2012) Which GnRHa is more beneficial? No differences (Glujovsky et al., 2010) Aboubakr Elnashar
  40. 40. CONCLUSION  LPS is necessary to optimize the outcome of ART  LPS with hCG is not superior to P.  Supplementary hCG brings no advantage to P with hCG increases risk of OHSS as compared with P Aboubakr Elnashar
  41. 41.  The use of oral P is clearly inferior to IM or vaginal administration and is associated with an increased rate of side effects due to its metabolites  IM and vaginal P therapy seem to be equally effective Aboubakr Elnashar
  42. 42.  The administration of estrogen to supplement the luteal phase in standard stimulated IVF cycles needs further clarification and evidence  No evidence to support co-tt to progesterone including aspirin, heparin, viagra….apart from midluteal phase GnRHa which is promising and needs further evaluation Aboubakr Elnashar
  43. 43. Thank you Aboubakr Elnashar

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