Ovarian Stimulation Protocols


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  • HYPOTHALAMUS is a thumb-sized area in the base of the brain that controls many body functions and regulates the pituitary gland. PITUITARY GLAND is a finger-tip sized gland beneath the hypothalamus.
  • 06/08/10
  • 06/08/10
  • 06/08/10
  • 06/08/10
  • 06/08/10
  • 06/08/10
  • 06/08/10
  • Ovarian Stimulation Protocols

    2. 2. Ovulation Induction <ul><li>Monofollicular development </li></ul><ul><li>Multifollicular development </li></ul><ul><li>Complications </li></ul><ul><li>Novel protocol </li></ul>
    3. 3. Ovulation Induction <ul><li>Monofollicular development </li></ul><ul><li>Multifollicular development </li></ul><ul><li>Complications </li></ul><ul><li>Novel protocol </li></ul>
    4. 4. Clomiphene Citrate <ul><li>Dose: </li></ul><ul><li>50-100 mg./day. </li></ul><ul><li>starting day 2,3,4 or 5 for 5 days. </li></ul><ul><li>Monitoring: </li></ul><ul><li>ultrasound </li></ul><ul><li>BBT, LH kits </li></ul><ul><li>day 21 progesterone. </li></ul>
    5. 5. Unexplained Infertility <ul><li>CC appears to improve pregnancy rates in women with unexplained subfertility </li></ul><ul><li>Meta-analysis by Hughes et al, 2000 </li></ul>
    6. 6. Anovulatory cycles <ul><li>Clomiphene citrate (all doses) was associated with an increased pregnancy rate per treatment cycle </li></ul><ul><li>Meta-analysis by Hughes et al, 2000 </li></ul>
    7. 7. hCG vs. LH monitoring <ul><li>If normoovulatory (e.g male factor), LH monitoring is preferred </li></ul><ul><li>If ovulatory dysfunction: hCG is preferred </li></ul><ul><li>Meta-analysis by Kosmos et al, 2007 </li></ul>
    8. 8. CC Resistant <ul><li>If still anovulatory after 6 months of continuous use the case is considered “clomiphene resistant” </li></ul>
    9. 9. No ovulation: <ul><li>dose. </li></ul><ul><li>duration of treatment (10 days). </li></ul><ul><li>add hMG. </li></ul>
    10. 10. Tamoxifen <ul><li>No significant benefit of Tamoxifen over CC </li></ul><ul><li>Meta-analysis by Stiener et al, 2005 </li></ul>
    11. 11. Combination therapies <ul><li>CC and other agents (metformin, NAC) can be used in CC resistant cases. </li></ul><ul><li>Alternative strategies for the CC-resistant woman include : ovarian drilling </li></ul>
    12. 12. So what do we use in Practice? Clomiphene Citrate Antagonists TI AIH hMG or FSH ______________________________________________ hMG or FSH
    13. 13. Ovulation Induction <ul><li>Monofollicular development </li></ul><ul><li>Multifollicular development </li></ul><ul><li>Complications </li></ul><ul><li>Novel protocol </li></ul>
    14. 14. Your Aim should be .. .. <ul><li> PROTOCOL </li></ul><ul><li>RESULTS </li></ul><ul><li> </li></ul><ul><li> </li></ul><ul><li> COMPLICATIONS </li></ul>BEST Most SUITABLE AVOID
    15. 15. IVF / ICSI cycles <ul><li>Multifollicular development with </li></ul><ul><li>gonadotropin administration is still an </li></ul><ul><li>integral component for ovarian stimulation in </li></ul><ul><li>IVF / ICSI cycles </li></ul>
    16. 16. IVF ICSI Gonadotrophins hMG, FSH, rec-FSH + GnRHa - long -short -u-short Antagonists +GnRH antagonist Always LP++
    17. 17. Protocols for IVF GnRH Antagonist Protocols GnRH Agonist Protocols 225 IU per day (150 IU Europe) Individualized Dosing of FSH/HMG 250  g per day antagonist Individualized Dosing of FSH/HMG GnRHa 1.0 mg per day up to 21 days 0.5 mg per day of GnRHa 225 IU per day (150 IU Europe) Day 6 of FSH/HMG Day of hCG Day 1 of FSH/HMG Day 6 of FSH/HMG Day of hCG 7 – 8 days after estimated ovulation Down regulation Day 2 or 3 of menses Day 1 FSH/HMG OCP
    18. 18. Starting dose <ul><li>Depends on Age , weight </li></ul><ul><li>Usually 3 amp / day in average weight women between 28-35 ys </li></ul>
    19. 19. GnRH-a protocols: <ul><li>down regulation of the pituitary gonadotrophic function </li></ul><ul><li>This will allow prevention of premature LH surge, until full oocyte maturity can be reached. </li></ul>
    20. 20. Short (flare up protocol): <ul><li>GnRH-a is started on day one or two of the cycle. </li></ul><ul><li>Exogenous FSH administration, then is started on day 3 of the cycle to continue follicular stimulation, meanwhile complete pituitary desensitization occur. </li></ul>
    21. 21. Advantages of short protocol <ul><li>1. Shortening the stimulation time. </li></ul><ul><li>2. Reducing the amount of GnRH used. </li></ul><ul><li>3. Reducing the amount of hMG used. Thus the total cost of the procedure will be lower. </li></ul>
    22. 22. The protocol was criticized for being unphysiological, and increases the LH levels in the early stages of the follicular phase, which might be harmful to the growing follicles.
    23. 23. The long protocol <ul><li>GnRH-a is given for two to three weeks. Down regulation of the pituitary gland is achieved as confirmed by the very low level of serum E2. </li></ul><ul><li>The GnRH is usually started in the mid luteal phase or early in the early follicular phase. </li></ul><ul><li>hMG therapy is started after down regulation </li></ul>
    24. 24. Disadvantages of long protocol <ul><li>It is more expensive </li></ul><ul><li>takes longer time. </li></ul><ul><li>Larger dose of GnRH analogue </li></ul><ul><li>larger number of ampoules of hMG </li></ul>
    25. 25. A meta analysis of 22 randomized trials comparing long and short protocols demonstrated the superiority of the long protocol of GnRH agonist regarding clinical pregnancy rate. (Daya 1999)
    26. 26. Ultra-short protocol <ul><li>GnRHa is given for only three days with the flare up technique </li></ul><ul><li>LH could be suppressed till the mid cycle </li></ul><ul><li>This protocol will help to retrieve more oocytes with a minimal risk of premature LH surge. </li></ul>
    27. 27. Ultra-long protocol <ul><li>GnRH could be given for three months before the start of hMG. </li></ul><ul><li>May be used in patients with severe endometriosis before the start of the treatment </li></ul><ul><li>Pregnancy rate appears to be improved in this sub-group of patients. (Sallam et al, 2004) </li></ul>
    28. 28. Protocols for poor responders <ul><li>Long protocol with large doses of gonadotropins </li></ul><ul><li>Clomiphene / hMG / antagonist protocol </li></ul>
    29. 29. Type of Gonadotropin / / / 3% glycoproteins 97% other proteins FSH 75 I.U LH 75 I.U. + detectable amounts of hCG
    30. 30. Recombinant FSH <ul><li>Batch to batch consistency </li></ul><ul><li>Free from urinary proteins </li></ul><ul><li>Can be produced in limitless quantities </li></ul>
    31. 31. <ul><li>In 1995 € 5.0 million </li></ul><ul><li> </li></ul><ul><li>volume increased by <100% </li></ul><ul><li>In 2000 € 26.8million </li></ul><ul><li> Zwart-van Rijkom et al,2002 </li></ul>Concerns Price
    32. 32. Impact of high cost <ul><li>The decision to adopt a more expensive treatment could result in a lower number of cycles of IVF/ICSI treatment especially if patients are paying for it. </li></ul>
    33. 33. LH supplementation: is it needed!! <ul><li>Lisi et al. , 2001 </li></ul><ul><li>Filicori et al, 2001 </li></ul><ul><li>Westergaard et al. , 2001 </li></ul><ul><li>Tesarik and Mendoza, 2002 </li></ul><ul><li>Commenges-Ducos et al, 2002 </li></ul>Schats et al,2000 Balasch et al, 2001 Daya 2002 Balasch et al, 2003
    34. 34. Efficacy <ul><li>Should be based upon most up to date evidence </li></ul><ul><li>RCTs are considered the gold standard </li></ul>
    35. 35. Most important outcome <ul><li>Live birth rate </li></ul><ul><li>Per </li></ul><ul><li>woman </li></ul>
    36. 36. Effectiveness <ul><li>Meta-analysis of: </li></ul><ul><li>Truly randomized controlled trials </li></ul><ul><li>IVF/ICSI cycles </li></ul><ul><li>Al-Inany et al, 2005 </li></ul>
    37. 37. Live Birth / Ongoing Pregnancy rate O.R.: 1.21 (95% CI 0.95-1.54)
    38. 38. Significant result with Long Protocol O.R.: 1.26 (95% CI 1.00-1.60)
    39. 39. NNT <ul><li>23 </li></ul>
    40. 40. How to Explain!! <ul><li>LH was shown to improve the implantation rate Gordon et al, 2001 Ganirelix dose-finding study ,1998 Schoolcraft et al, 1999 </li></ul>
    41. 41. How To Explain <ul><li>GnRH agonist down-regulation may result in profound suppression of LH concentration (< 1 IU/l) , impairing adequate oestradiol synthesis </li></ul><ul><li>Fleming et al, 2000 </li></ul>
    42. 42. Agonist vs antagonist
    43. 43. ongoing pregnancy/ live-birth rate <ul><li>O.R = 0.82, 95% CI = 0.69 to 0.98 </li></ul>
    44. 44. Pregnancy per woman O.R = 0.80, 95% CI = 0.69 to 0.92
    45. 45. <ul><li>The absolute treatment effect (ATE) was calculated to be </li></ul><ul><li>4.5%. </li></ul><ul><li>number needed to treat (NNT) </li></ul><ul><li>22 </li></ul>
    46. 46. This means That <ul><li>for every 22 subfertile couples undergoing IVF/ ICSI program, one additional pregnancy can be expected in the GnRH agonist treated group </li></ul>
    47. 47. Incidence of OHSS R.R. = 0.61, 95% CI = 0.42 to 0.89
    48. 48. No difference <ul><li>Spontaneous miscarriage Rate </li></ul><ul><li>Multiple pregnancy rate </li></ul>
    49. 49. In Favor of Antagonist <ul><li>much shorter duration of GnRH analogue treatment (OR -20.90, 95% CI -22.20 to -19.60) </li></ul><ul><li>less days of stimulation (OR -1.54, 95% CI -2.42 to -0.66). </li></ul><ul><li>reduction in the amount of gonadotrophins (OR -4.27, 95% CI -10.19 to 1.65) </li></ul>
    50. 50. The Future <ul><li>Prevention of severe OHSS in women downregulated with GnRH agonist and with high risk of OHSS </li></ul>
    51. 51. (GnRH) antagonists <ul><li>A unique Idea </li></ul><ul><li>Administration when follicle reach 16 mm </li></ul><ul><li>Continue hMG (step down protocol) </li></ul><ul><li>Monitor by E2 </li></ul><ul><li>Not more than 3 days </li></ul>
    52. 52. Luteal Phase Support <ul><li>Micronised Progesterone tablets </li></ul><ul><ul><li>Oral: 100-200 mg 2-4X/day </li></ul></ul><ul><ul><li>Vaginal: 100-200 mg 2X/day </li></ul></ul><ul><ul><li>Rectal: 100-200 mg 2X/day </li></ul></ul><ul><ul><li>Progesterone Sup. </li></ul></ul><ul><ul><li>200-400 mg vag. or rectally 1-2X/day </li></ul></ul><ul><ul><li>P rogesterone gel (8%) </li></ul></ul><ul><ul><li>IM Progesterone 100 mg 1x/day </li></ul></ul>
    53. 53. Ovulation Induction <ul><li>Monofollicular development </li></ul><ul><li>Multifollicular development </li></ul><ul><li>Complications </li></ul><ul><li>Novel protocol </li></ul>
    54. 54. Complications of Ovulation Stimulation Drugs. OHSS Multiple Gestation
    55. 55. OHSS. <ul><li>-large fragile ovaries. </li></ul><ul><li>-haemoconcentration </li></ul><ul><li>-oliguria </li></ul><ul><li>-ascites </li></ul><ul><li>-pleural effusion </li></ul>
    56. 56. Complications of Ovulation Stimulation Drugs. OHSS Prevention of TI/IUI withhold hCG use “coasting” use Antagonist IVF
    57. 57. Complications of Ovulation Stimulation Drugs. <ul><li>4-folds higher incidence of twins & HRMG </li></ul>Multiple Gestation
    58. 58. Ovulation Induction <ul><li>Monofollicular development </li></ul><ul><li>Multifollicular development </li></ul><ul><li>Complications </li></ul><ul><li>Novel protocol </li></ul>
    59. 59. Reversed hMG/CC <ul><li>HP-hMG 75 IU starting from the 3 rd day of cycle for four days. </li></ul><ul><li>Followed by 50 mg of CC (Clomid, Aventis Pharm) three times daily starting from the fourth day of hMG and continued until the day of hCG injection. </li></ul>
    60. 60. Novel protocol 75 IU/HMG CD3 CD7 150 mg CC hCG IUI DF ≥ 18 mm 34-36h
    61. 61. Control group 75 IU/HMG CD3 hCG IUI DF ≥ 18 mm CD7 34-36h
    62. 62. Results (cont.) Variable HMG/CC (n=110) HMG (n=107) P value LH on day of hCG (miu/ml) for cases with no premature LH surge 7.3 ± 1.8 7.8 ± 2.2 NS Number of Follicles ≥ 16 mm 2.4 ± 0.97 1.3 ± 1.1 P < 0.05 * Number of patients with premature LH surge 6 (5.45%) 17 (15.89%) P<0.001 * End. Thickness (mm) 5.9 ± 0.7 4.9 ± 1.9 NS Clinical Pregnancy 11 (10%) 9 (8.41%) NS
    63. 63. For whom <ul><li>This protocol is especially suitable for young women, for those with unexplained infertility or mild male factor i.e good responders </li></ul><ul><li>it may also be suitable for PCOS women to avoid the risk of severe OHSS </li></ul>
    64. 64. <ul><li>This is a novel protocol for OI </li></ul><ul><li>The protocol is simple, safe and appears to be very cost effective. </li></ul>
    65. 65. Take Home Message <ul><li>Monofollicular development: CC </li></ul><ul><li>Multifollicular development : hMG/agonist </li></ul><ul><li>Complications: OHSS </li></ul><ul><li>Novel protocol: hMG / CC </li></ul>
    66. 66. THANK YOU