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Management of Poor Ovarian response
Definition <ul><li>No universal definition </li></ul><ul><li>General consensus: women with poor response to ovarian stimul...
Normal ovarian response DAYS FROM LH PEAK LH FSH 10  15  20  25  0  5  10  15 <ul><li>FSH stimulates follicle growth </li>...
Reserve <ul><li>Usually, ovarian function goes hand in hand with age, and as a woman becomes older, her ovarian response s...
<ul><li>Every girl is born with a finite number of eggs, and their number progressively declines with age.  </li></ul><ul>...
<ul><li>The infertility specialist is really not interested in the woman's calendar (or chronological age), but rather her...
Poor response <ul><li>OI (monofollicular ) </li></ul><ul><li>Superovulation (multifollicular) </li></ul>
Poor response & Monofollicular induction
Gold Standard: Clomiphene Citrate <ul><li>Dose: </li></ul><ul><li>50-150 mg./day. </li></ul><ul><li>starting day 2,3,4 or ...
Expected conception rate on clomiphene citrate <ul><li>40% of patients ultimately conceive. </li></ul><ul><li>80% can be e...
Clomiphene citrate failure <ul><li>Total lack of response (anovulatory). </li></ul><ul><li>Partial lack of response: </li>...
CC Resistant <ul><li>If still  anovulatory  after 6 months of continuous use the case is considered  “clomiphene resistant...
No ovulation: <ul><li>dose. </li></ul><ul><li>duration of  treatment (10 days). </li></ul><ul><li>add hMG. </li></ul>
The   Aromatase   Inhibitors <ul><li>Letrozole (Fimara 2.5 mg) </li></ul><ul><li>effective.  </li></ul><ul><li>It has the ...
Prolactin Reducing Medications <ul><li>Bromocryptine, Lisuride </li></ul><ul><li>Causes: </li></ul><ul><li>-   Pituitary a...
Metformin <ul><li>The addition of metformin in the CC-resistant patient is highly effective in achieving ovulation inducti...
gonadotrophins <ul><li>Conventional protocol: </li></ul><ul><li>150 IU for five days, then dose is adjusted. </li></ul><ul...
Ovarian Drilling <ul><li>There is no evidence that one modality of drilling is superior to the other. </li></ul><ul><li>It...
Cochrane Review <ul><li>no significant difference in pregnancy rates between laparoscopic ovarian drilling and gonadotroph...
Poor response & Multifollicular induction IVF/ICSI
Protocols for IVF  GnRH Antagonist Protocols GnRH  Agonist Protocols   225 IU per day (150 IU Europe) Individualized Dosin...
What is poor response in IVF <ul><li>Less than 5 follicles from both ovaries </li></ul><ul><li>Oocyte quality is not relat...
What to do  <ul><li>Increasing gonadotrophin in the same cycle does not result in significant improvement in the number of...
Cancellation <ul><li>Is a very good option in this cycle </li></ul><ul><li>Based on counselling the couples </li></ul><ul>...
In subsequent cycles <ul><li>Increasing gonadotrophin in the subsequent cycle does not seem to result in significant impro...
<ul><li>What should be the maximum FSH dose in IVF/ICSI in poor responders   </li></ul><ul><li>450IU/day </li></ul>
Protocols for IVF  GnRH Antagonist Protocols GnRH  Agonist Protocols   225 IU per day (150 IU Europe) Individualized Dosin...
Protocols for poor responders <ul><li>Long protocol with large doses of gonadotropins </li></ul><ul><li>Short protocol. </...
<ul><li>GnRh antagonist protocol are associated with lower total dose and shorter duration of stimulation when compared wi...
Short (flare up protocol): <ul><li>GnRH-a is started on day one or two of the cycle.  </li></ul><ul><li>Exogenous FSH admi...
Ultra-short protocol <ul><li>GnRHa is given for only three days with the flare up technique  </li></ul><ul><li>LH could be...
<ul><li>lower cancellation rates in the long protocol treatment group (versus stop and GnRHa flare-up protocols).  </li></ul>
Growth hormone <ul><li>Growth hormone may improve the number of oocytes but no difference in pregnancy rate </li></ul><ul>...
NC <ul><li>Minimal stimulation and natural cycle protocols are gaining interests in low responders </li></ul><ul><li>The h...
<ul><li>There is no single best protocol that can transform a low responder into a high responders </li></ul><ul><li>The e...
<ul><li>the efficacy of natural cycle IVF is hampered by high cancellation rates mainly due to untimely LH surge  </li></ul>
Prediction <ul><li>age  </li></ul><ul><li>FSH </li></ul><ul><li>Estradiol </li></ul><ul><li>Inhibin </li></ul><ul><li>anti...
<ul><li>The use of a wide range of tests suggests that no single test provides a sufficiently accurate result  </li></ul>
AMH <ul><li>If kits are available, AMH measurement could be the most useful in the prediction of ovarian response in anovu...
Poor response TI/IUI Gonadotrophins Modified natural cycle ” Antagonist “ IVM” IVF
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Management of poor ovarian response

  1. 1. Management of Poor Ovarian response
  2. 2. Definition <ul><li>No universal definition </li></ul><ul><li>General consensus: women with poor response to ovarian stimulation </li></ul><ul><li>OR </li></ul><ul><li>those with low ovarian reserve </li></ul>
  3. 3. Normal ovarian response DAYS FROM LH PEAK LH FSH 10 15 20 25 0 5 10 15 <ul><li>FSH stimulates follicle growth </li></ul><ul><li>LH surge induces ovulation </li></ul>
  4. 4. Reserve <ul><li>Usually, ovarian function goes hand in hand with age, and as a woman becomes older, her ovarian response starts declining. </li></ul>
  5. 5. <ul><li>Every girl is born with a finite number of eggs, and their number progressively declines with age. </li></ul><ul><li>A measure of the remaining number of eggs in the ovary is called the &quot;ovarian reserve&quot;; and as the woman ages, her ovarian reserve gets depleted. </li></ul>
  6. 6. <ul><li>The infertility specialist is really not interested in the woman's calendar (or chronological age), but rather her biological age - or how many eggs are left in her ovaries. </li></ul>
  7. 7. Poor response <ul><li>OI (monofollicular ) </li></ul><ul><li>Superovulation (multifollicular) </li></ul>
  8. 8. Poor response & Monofollicular induction
  9. 9. Gold Standard: Clomiphene Citrate <ul><li>Dose: </li></ul><ul><li>50-150 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>menstrual pattern </li></ul><ul><li>BBT, LH kits </li></ul><ul><li>day 21 progesterone. </li></ul>
  10. 10. Expected conception rate on clomiphene citrate <ul><li>40% of patients ultimately conceive. </li></ul><ul><li>80% can be expected to ovulate. </li></ul><ul><li>(Hancock 1973) </li></ul>
  11. 11. Clomiphene citrate failure <ul><li>Total lack of response (anovulatory). </li></ul><ul><li>Partial lack of response: </li></ul><ul><ul><li>No complete growth of follicles. </li></ul></ul><ul><ul><li>No LH rise. </li></ul></ul><ul><li>Conception failure: After 4-6 months of ovulation. </li></ul>
  12. 12. CC Resistant <ul><li>If still anovulatory after 6 months of continuous use the case is considered “clomiphene resistant” </li></ul>
  13. 13. No ovulation: <ul><li>dose. </li></ul><ul><li>duration of treatment (10 days). </li></ul><ul><li>add hMG. </li></ul>
  14. 14. The Aromatase Inhibitors <ul><li>Letrozole (Fimara 2.5 mg) </li></ul><ul><li>effective. </li></ul><ul><li>It has the following advantages: </li></ul><ul><li>1- It reduce E2 level. </li></ul><ul><li>2- It avoids the unfavorable effects on the endometrium frequently seen with CC </li></ul>
  15. 15. Prolactin Reducing Medications <ul><li>Bromocryptine, Lisuride </li></ul><ul><li>Causes: </li></ul><ul><li>- Pituitary adenoma (prolactinoma) </li></ul><ul><li>- Hyperactive lactotrophs. </li></ul><ul><li>- Medications: tranquilizers, hallucinogens, painkillers, alcohol,.. </li></ul>
  16. 16. Metformin <ul><li>The addition of metformin in the CC-resistant patient is highly effective in achieving ovulation induction. </li></ul><ul><li>Meta-analysis by Siebert et al, 2006 </li></ul>
  17. 17. gonadotrophins <ul><li>Conventional protocol: </li></ul><ul><li>150 IU for five days, then dose is adjusted. </li></ul><ul><li>OR </li></ul><ul><li>Fixed low dose protocol 75 IU for 10 days, then adjusted. </li></ul>
  18. 18. Ovarian Drilling <ul><li>There is no evidence that one modality of drilling is superior to the other. </li></ul><ul><li>It is suggested that the resumption of ovulation is temporary in many patients after drilling. </li></ul><ul><li>The incidence of adhesions varies from zero to 100% following drilling. </li></ul>
  19. 19. Cochrane Review <ul><li>no significant difference in pregnancy rates between laparoscopic ovarian drilling and gonadotrophins after 6–12 months follow up. But caution about ovarian reserve in LOD (Farquhar,2005) </li></ul>
  20. 20. Poor response & Multifollicular induction IVF/ICSI
  21. 21. 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
  22. 22. What is poor response in IVF <ul><li>Less than 5 follicles from both ovaries </li></ul><ul><li>Oocyte quality is not related to number of oocytes but to women age </li></ul><ul><li>Young women with poor response has good quality embryos and better chance of getting pregnant </li></ul>
  23. 23. What to do <ul><li>Increasing gonadotrophin in the same cycle does not result in significant improvement in the number of oocytes, embryos or pregnancies obtained </li></ul>
  24. 24. Cancellation <ul><li>Is a very good option in this cycle </li></ul><ul><li>Based on counselling the couples </li></ul><ul><li>Decision to continue is still valid especially with advanced age (more than 38 years old women) </li></ul>
  25. 25. In subsequent cycles <ul><li>Increasing gonadotrophin in the subsequent cycle does not seem to result in significant improvement in the number of pregnancies obtained but may improve number of ooctes </li></ul>
  26. 26. <ul><li>What should be the maximum FSH dose in IVF/ICSI in poor responders </li></ul><ul><li>450IU/day </li></ul>
  27. 27. 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
  28. 28. Protocols for poor responders <ul><li>Long protocol with large doses of gonadotropins </li></ul><ul><li>Short protocol. </li></ul><ul><li>Minidose of GnRH agonist protocol </li></ul><ul><li>Clomiphene / hMG protocol </li></ul><ul><li>Large doses of clomiphene protocol without hMG </li></ul><ul><li>GnRH antagonist protocols. </li></ul>
  29. 29. <ul><li>GnRh antagonist protocol are associated with lower total dose and shorter duration of stimulation when compared with standard long protocol </li></ul><ul><li>But no difference regarding pregnancy rate </li></ul>
  30. 30. 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>
  31. 31. 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>
  32. 32. <ul><li>lower cancellation rates in the long protocol treatment group (versus stop and GnRHa flare-up protocols). </li></ul>
  33. 33. Growth hormone <ul><li>Growth hormone may improve the number of oocytes but no difference in pregnancy rate </li></ul><ul><li>However, they are expensive and routine use can not be justified </li></ul>
  34. 34. NC <ul><li>Minimal stimulation and natural cycle protocols are gaining interests in low responders </li></ul><ul><li>The have comparable results with standard IVF ovarian stimulation </li></ul><ul><li>They are simple and cheaper </li></ul>
  35. 35. <ul><li>There is no single best protocol that can transform a low responder into a high responders </li></ul><ul><li>The expectations should be discussed with the patients. </li></ul><ul><li>It is preferable to opt for a simpler and less expensive regimen for ovarian stimulation (Sunkara et al, 2007) </li></ul>
  36. 36. <ul><li>the efficacy of natural cycle IVF is hampered by high cancellation rates mainly due to untimely LH surge </li></ul>
  37. 37. Prediction <ul><li>age </li></ul><ul><li>FSH </li></ul><ul><li>Estradiol </li></ul><ul><li>Inhibin </li></ul><ul><li>anti-Müllerian hormone </li></ul><ul><li>ovarian volume </li></ul><ul><li>antral follicle count </li></ul>
  38. 38. <ul><li>The use of a wide range of tests suggests that no single test provides a sufficiently accurate result </li></ul>
  39. 39. AMH <ul><li>If kits are available, AMH measurement could be the most useful in the prediction of ovarian response in anovulatory women. </li></ul><ul><li>It is done at any day of cycle </li></ul><ul><li>It is too expensive </li></ul><ul><li>Exact normal levels not yet well agreed upon </li></ul>
  40. 40. Poor response TI/IUI Gonadotrophins Modified natural cycle ” Antagonist “ IVM” IVF
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