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Controlled ovarian stimulation in IVF

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Controlled ovarian stimulation in IVF

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Controlled ovarian stimulation in IVF

  1. 1. Benha University Hospital, Egypt Aboubakr Elnashar
  2. 2. CONTENTS 1. TYPES OF OVARIAN STIMULATION FOR IVF 2. DRUGS 3. GNRHa PROTOCOLS 4. GNRHan PROTOCOLS 5. TRIGGERING OF OVULATION 6. CYCLE CANCELLATION 7. INDIVIDUALIZATION OF COS Aboubakr Elnashar
  3. 3. MethodsAimPrevious terminology Recommended terminology No medicationSingle oocyte Unstimulated, spontaneous cycle 1. Natural cycle hCG only GnRHan and FSH/HMG add-back Single oocyte Semi-natural, controlled natural cycle IVF 2. Modified natural cycle Low dose FSH/HMG, oral compounds and GnRHan 2-7 oocytes Soft, minimal stimulation, ‘friendly’ IVF 3. Mild GnRHa or antagonist conventional FSH/HMG dose > 8 oocytes Standard, routine, COS 4. Conventional International Society for Mild Approaches in Assisted Reproduction (ISMAAR), 2007 1. TYPES OFOVARIAN STIMULATION FOR IVF Aboubakr Elnashar
  4. 4. GnRHa GnRHan No GnRH analogue long Short Ultra short Standard Mild Modified natural Mini Natural Protocols of ovarian stimulation in IVF Aboubakr Elnashar
  5. 5. 2. DRUGS Gonadtrophins GnRha GnRhan Aboubakr Elnashar
  6. 6. Preparation Trade name Route U.pr FSH LH Company PriceEP 1. HMG Pergonal, Humegon, Menogon Merional IM 95% 75 75 Serono Organon Ferring Ibsa 66 2. H.P.HMG Menopur Gonapur SC SC <5% <5% Ferring M pharm 118 85 3. Purified FSH Metrodine IM <5% 75 Urofillotropin <0.1 Serono 4. H.P.FSH Fostimon Metrodine HP Bravelle SC, IM <5% 75 Urofillotropin <0.001 Ibsa Serono Ferring 55 70 5. HCG Pregnyl Profasi IM 95% Organon Serono 6. H.P.HCG Choriomon SC,IM <5% Ibsa 33 I. Types of Gnt I. Urinary Gonadotropins Aboubakr Elnashar
  7. 7. Aboubakr Elnashar
  8. 8. II. Recombinant Gonadotropins Preparation Trade name Route Upr FSH LH Price Company 1. FSH Puregon (follitropin), Gonal F (follitropin) SC, IM - - 50 100 75 150 - - 180 Organon Serono 2. HCG Ovitrelle Choriogonadotropin SC - Serono 3. LH Luveris lutotropin SC - Serono Aboubakr Elnashar
  9. 9. Aboubakr Elnashar
  10. 10. Types of GnRHa PriceEPcompanyDoseRouteNamePreparation 750 1550 540 Abbot3.75 mg/4w 11.25 mg/12 w 2.8 ml, 1 ml daily IM, SC IM, SC Lupron Lucrin Leuprorelin 500Astrazenica3.6 mgSCZoladexGoserelin 605 266(7syr) FerringCR: 3.75mg, 0.1mg then 0.05 mg IM, SCDecapeptylTriptolerin Sanofi0.5 mg then 0.2 mgNasal, SCsuperfactBuserelin Pfaizer0.2 mg bidnasalSynarelNafarelin Aboubakr Elnashar
  11. 11. PriceCompanyRouteTradeGeneric 2500.25 mg 3 mg SeronoSCCetrotideCetrorelix 192 0.25 mgMSD MSD SCGanirelix Orgalutran Ganirelix Types of GnRhan Aboubakr Elnashar
  12. 12. Aboubakr Elnashar
  13. 13. 3. GNRHa PROTOCOLS GnRHa Produced by Modification of the native GnRH decapeptide at 6 & 10 positions Aboubakr Elnashar
  14. 14. Effects of GnRha Flare effect: Within 12 h and lasting 24-48 h : 5 fold increase of FSH 10 fold rise in LH & 4 fold elevation in E2. Continuous administration : opposite effects: internalization of the agonist /receptor complex & decrease in the number of receptors (down-regulation). : paradoxical suppression of the pituitary Gnt synthesis & liberation (desensitization). Aboubakr Elnashar
  15. 15. The decreased levels of FSH & LH: 1. Arrest of follicular development 2. Decrease in sex steroid levels to castrate levels. The pituitary blockade persist during agonist tt but it is reversible after therapy. Aboubakr Elnashar
  16. 16. (a)action of native GnRH on a gonadotroph; binding of GnRH to the receptor results in FSH and LH secretion. FSH and LH, in turn, stimulate the gonads to produce steroid hormones. (b) Binding of a GnRH agonist to the gonadotroph receptor produces an initial stimulation of FSH and LH, but subsequently suppression of gonadotropins occurs, with the resulting suppression of gonadal steroid production. (c) Binding of a GnRH antagonist to the gonadotroph receptor stimulates an immediate downregulation and desensitization, with resulting suppression of gonadotropin secretion and gonadal steroid Aboubakr Elnashar
  17. 17. Protocols Ultra-short (sequential): Based on initial stimulatory effect of GnRHa on Gnt secretion [flare- up effect] lasts for 1-2 days promotes simultaneous maturation of several follicles. GnRHa: from the 1st to 3rd day of the cycle. Gnt: from the 3rd day of the cycleAboubakr Elnashar
  18. 18. No evidence of a difference in the outcome of LBR in a comparison of GnRHa long, short or ultrashort protocols. PR was significantly higher in Long vs short protocols (Maheshwari A et al 2011. Cochrane , 2011) Aboubakr Elnashar
  19. 19. Short (Flare): GnRHa: from the 1st day of the cycle until the day of ovulation induction. Gnt: from the 3rd day of the cycle. Aboubakr Elnashar
  20. 20. Leuteal support FSH 75-300 IU Ovulation 5.000-10.000 IU hCG Short GnRHa protocol 75- 300/day IU /FSH 34 h. OPU TVS > 18 ml E2 Cycle ay 1 GnRHa 0.1mg/day 3rd day TVS E2 Aboubakr Elnashar
  21. 21. Long: GnRHa: From: 1st day (follicular) or middle of the luteal phase (D19-21) {1. inhibition of the pituitary function can be achieved earlier. 2. Higher fertilization & PR than therapy started on the 1st day of the cycle}. until a sufficient inhibition of Gnt release (10-14 days) Gnt while GnRHa therapy is maintained. Aboubakr Elnashar
  22. 22. Follicular phase Aboubakr Elnashar
  23. 23. Luteal support hCG 5-10000 IU 75-300 IU / FSH/day Long GnRHa Protocol (luteal phase) TVS E2 34 h. OPU20th day previous cycle TVS >18 ml E2 GnRHa 0.1mg/day < 50 pg/ml TVS E2 FSH 2 weeks Aboubakr Elnashar
  24. 24. -Criteria of suppression: Hormonal: E2 <50 pg/ml Progesterone < 1 ng/m LH <5 IU US: No ovarian cysts Endometrial thickness <6 mm predicts down regulation in 95% of cases Aboubakr Elnashar
  25. 25. Advantages: long protocol Vs Short & ultrashort (Cochrane review, 2000) superior in terms of 1. follicular development & 2. fertilization rate 3. number of embryos suitable for transfer 4. PR 5. more units of GN were needed  Midluteal is the optimal Gnt suppression & oocytes (Roman et al 1992,Huirne et al,2004) Aboubakr Elnashar
  26. 26. ,rFSH Vs other GN (HMG, hp-FSH, p-FSH), no evidence of difference in LBR or OHSS  42 trials, 9606 couples  Further research on these comparisons is unlikely to identify substantive differences in effectiveness or safety (Cochrane Database Syst Rev. 2011, Wely et al)  Use either u or rec Gnt for ovarian stimulation (NICE, 2013) Aboubakr Elnashar
  27. 27. Depot Vs daily No differences PR. Depot: longer duration higher doses of Gnt more luteal support depot (Cochrane review 2002) Aboubakr Elnashar
  28. 28. 4. GNRHan PROTOCOLS GnRHan Produced by Modification at 6, 10, & 1, 2, 3, 8 positions Effects Inhibition of LH & FSH immediately without the initial flare up effect of the Gnta. Mechanism of action Competitive receptor blockade. The suppression of LH is dose related. Larger doses of antagonist is associated with marked reduction of pregnancy rate in IVF cycles Aboubakr Elnashar
  29. 29. Aboubakr Elnashar
  30. 30. Protocols 1. Small daily dose (LubecK): HMG or FSH: From day 2 or 3 of the cycle & Cetrorelix or Ganirelix: 0.25 mg daily SC: from stimulation day 5 or 6 (fixed protocol) or leading follicle14 mm (Flexible protocol) onwards until the day of HCG (Diedrich et al,1994). Advantages: 1. Prevents premature LH surge 2. effective in terms of CPR/cycle & /ET (22% & 27%). 3. safe in terms of a low incidence of patients hospitalized due to OHSS. Aboubakr Elnashar
  31. 31. Aboubakr Elnashar
  32. 32. 2. Single dose(French): HMG or FSH: from day 2 or 3 of the cycle Cetrorelix: single dose, 3 mg SC, on stimulation day 7 (Olivennes et al,1998). HCG is given when the follicles are mature by U/S &/or E2. GnRha single dose can be given instead of HCG to reduce incidence of OHSS {shorter half life of the agonist compared to HCG}. Aboubakr Elnashar
  33. 33. Aboubakr Elnashar
  34. 34. Single Vs multiple (Olivennes et al,2003) Similar efficacy & safety Recommendations of GnRHan Consensus Workshop Group) No increase starting dose of Gnt Fixed antagonist appears superior to flexible. Optimal timing for HCG administration Agonist for triggering Luteal phase supplementation is required Aboubakr Elnashar
  35. 35. Agonists Vs Antagonists  LBR after COS for IVF does not depend on the type of analogue used for pituitary suppression (SR: Kolibianakis et al,2006)  Antagonist protocol:  short, simple with significant decrease in severe OHSS & amount of GN.  CPR, OPR/LBR were lower in antagonist group (Cochrane Database Systematic Review Al-Inany et al., 2006)  No evidence of a difference in LBR (Cochrane Database Syst Rev. 2011, Al-Inany et al, 2011) Aboubakr Elnashar
  36. 36. Aboubakr Elnashar
  37. 37. 5. TRIGGERING OF OVULATION 1. HCG Rational: The structure & action of HCG are very similar to those of LH. HCG induces final follicular maturation. Ovulation follow: IM injection of HCG at 37 h. Accordingly follicular puncture is performed earlier i.e. 32-34 h or 35 h after hCG administration. Aboubakr Elnashar
  38. 38. Usual dose: 10,000 IU administered 34-36 h before the scheduled time of oocyte retrieval. When: . At least 3 follicles >18 mm . E2: 150 pg/ml per >15mm follicles. . Endometrium: Thickness >8mm, Triple line Aboubakr Elnashar
  39. 39. Risk: OHSS long half life (30 H) with serum hCG detectable up to 14 days after the injection. :prolonged luteotrophic effect: multiple corpora lutea and supraphysiologic levels of VEGF (McClure et al., 1994). development of OHSS via the enhancement of capillary leak (Lesterhuis et al., 2009). Aboubakr Elnashar
  40. 40. Do not trigger ovulation with the intention of fresh ET in women who have: E2>3500 pm/l or >20 follicles on US (NICE, 2013) Aboubakr Elnashar
  41. 41. 2. GnRHa in antagonist cycles : pituitary endogenous LH surge which is enough to cause a trigger but does not last enough to result in OHSS. Itskovitz-Eldor et al., 2000 8 patients: an increased risk for OHSS (>20 follicles 11 mm and/or E2 3000 pg/ml). 0.2 mg triptorelin (Decapeptyl) to trigger ovulation None of the patients developed OHSS. Four clinical pregnancies A new treatment option reducing risk of developing OHSS in high responders cycle cancellation. Aboubakr Elnashar
  42. 42. 6. CYCLE CANCELLATION Define: discontinuation of ovarian stimulation prematurely without oocyte retrival. Incidence 12% of all IVF cycles are cancelled before egg collection. Womens age Cancellation rate Less than 35 7.7-10% 35-37 11.6-14.7% 38-40 14.6-19.5% Over 40 19.1-24.6%Aboubakr Elnashar
  43. 43. The main reasons 1.No or poor egg production (83%) 2.Patient’s personal reasons (10%) 3.Excessive response to ovarian stimulation and risk of developing OHSS (5%) 4.Medical illness (1%). (SART 2005 and HFEA 2006 Reports). Aboubakr Elnashar
  44. 44. Indications 1. Follicular growth is delayed: ovarian stimulation over 10 days: < 3 follicles > 16 mm & E2 < 600 pg/ml. 2. Basal LH is elevated: LH > 10 IU/l or a premature LH surge occurs 3. Elevated serum P4: >1.5 ng/ml is detected prior to ovulation induction. 4.OHSS is suspected: each ovary contains > 10 follicles < 16 mm & E2 > 3500 pg/ml Aboubakr Elnashar
  45. 45. 7. INDIVIDUALIZATION OF COS What? I. Selection of protocol II. Selection of Gnt starting dose. cCOS  Repeated cycle Outcome of previous cycles: If good: same protocol.  1st cycle: a. Empirical: based on either the clinician’s or a centre’s preference. b. Clinical criteria: Age, BMI, PCOS (Homburg and Insler, 2002; Arslan et al., 2005). Aboubakr Elnashar
  46. 46. FSH starting dose (IU/day) (Tronson & Gardner, 2000) 1st cycle <37 yr old: 150= 2 amp & PCOS: 112.5= 1.5 amp 37-39 yr: 225= 3 amp >40 yr: 300= 4 amp BMI>30 Kg/m (PCO excluded): increase by 75= 1 amp Severe endometriosis: increase by 75= 1 amp Previous Normal response(>4 follicles): same OHSS: 75= 1 amp Poor response: 450= 6 amp Adjust dose as cycle monitoring proceeds with U/S & E2. Do not use a dose of FSH>450 IU/d Aboubakr Elnashar
  47. 47. I. Individualization of stimulation protocol Correct prediction of ovarian response (especially extremes: poor and hyper response). By most sensitive markers of ovarian reserve. Ovarian reserve testing before the first IVF cycle categorize patients (NICE, 2013) High responseLow response 16 or more4 or lessTotal AFC 3.5 or more0.8 or less AMH ng/ml 4 or less8.9 or moreFSH IU/L Aboubakr Elnashar
  48. 48. A. Expectant low responder: Antagonist protocol 1. No evidence of superiority of one approach over another (Pu et al., 2011; Sunkara et al., 2013). 2. Antagonist is associated with  Reduced discomfort and treatment burden (Nelson et al. ,2009)  Fewer days of Gnt stimulation (10 Vs 14 d) (Pandian et al., 2010): improve patient compliance.  Lower Gnt consumption: lower cost  Drop in cycle cancellation  Prognosis remained poor, with CPR 16% with GnRHan Vs 11% with the GnRHa (Nelson et al., 2009). Aboubakr Elnashar
  49. 49. B. Expectant high responders: Antagonists Reduction of: high response {OHSS, cycle cancellation {risk of OHSS} (Al-Inany et al., 2007, 2011; Hosseini et al., 2010; Lainas et al., 2010; Tehraninejad et al., 2010). La marca et al, 2013 Aboubakr Elnashar
  50. 50. II. Individualization of Gnt Starting Dose: A. Simple models One or 2 parameters 1. AMH 2. AFC and age 3. AFC B. Complex models: > 2 parameters Aboubakr Elnashar
  51. 51. SELECTION OF PROTOCOL ACCORDING TO OVARIAN ReserveReserve ‘Low’ ‘Average’ ‘High’ AFC <7 7-14 >14 AMH <1.1 ng/ml 1.1-3.5 >3.5 Starting FSH dose IU Amp 375 5 225 3 150 2 Protocol - Antagonist -Microdose flare -Agonist stop -GH -Natural -Modified natural -Long protocol -Antagonist -Long protocol -Antagonist Aboubakr Elnashar
  52. 52. Benha University Hospital E-mail: elnashar53@hotmail.com Aboubakr Elnashar

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