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MANAGEMENT OF POOR RESPONDERS IN IVF BY DR SHASHWAT JANI

MANAGEMENT OF POOR RESPONDERS IN IVF BY DR SHASHWAT JANI

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Management Of
Poor Response
Facts Or Myths
Dr. Shashwat Jani.
M.S. ( Gynec)
Diploma In Advance Endoscopy.
Consultant Assistant Professor,
Smt. N.H.L. Municipal Medical College,
Sheth V. S. General Hospital, Ahmedabad.
Mobile : +91 99099 44160.
E-mail : drshashwatjani@gmail.com
3-Sep-15 2Dr Shashwat Jani 9909944160
3-Sep-15 3Dr Shashwat Jani 9909944160
POOR RESPONDER ( ESHRE )
Two of the following three features
must be present:
Advanced maternal age (≥40 years) or any
other risk factor for POR;
A previous POR (≤3 oocytes with a
conventional stimulation protocol);
An abnormal ovarian reserve test (i.e. AFC <5–
7 follicles or AMH <0.5–1.1 ng/ml).
3-Sep-15 4Dr Shashwat Jani 9909944160
Bologna Criteria
( Ferraretti et al. ESHRE Consensus, Hum Reprod 2011 )
At least 2 of the following:
1 ) Advanced maternal age (≥40 years or risk
factor for POR)
2 ) Previous POR (≤3 oocytes with conventional
stimulation)
3 ) Abnormal ovarian reserve biomarker
AFC<5-7; AMH <0.5-1.1ng/Ml
Or:
• Two episodes of POR after maximal stimulation
3-Sep-15 5Dr Shashwat Jani 9909944160
3-Sep-15 6Dr Shashwat Jani 9909944160

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MANAGEMENT OF POOR RESPONDERS IN IVF BY DR SHASHWAT JANI

  • 1. Management Of Poor Response Facts Or Myths Dr. Shashwat Jani. M.S. ( Gynec) Diploma In Advance Endoscopy. Consultant Assistant Professor, Smt. N.H.L. Municipal Medical College, Sheth V. S. General Hospital, Ahmedabad. Mobile : +91 99099 44160. E-mail : drshashwatjani@gmail.com
  • 2. 3-Sep-15 2Dr Shashwat Jani 9909944160
  • 3. 3-Sep-15 3Dr Shashwat Jani 9909944160
  • 4. POOR RESPONDER ( ESHRE ) Two of the following three features must be present: Advanced maternal age (≥40 years) or any other risk factor for POR; A previous POR (≤3 oocytes with a conventional stimulation protocol); An abnormal ovarian reserve test (i.e. AFC <5– 7 follicles or AMH <0.5–1.1 ng/ml). 3-Sep-15 4Dr Shashwat Jani 9909944160
  • 5. Bologna Criteria ( Ferraretti et al. ESHRE Consensus, Hum Reprod 2011 ) At least 2 of the following: 1 ) Advanced maternal age (≥40 years or risk factor for POR) 2 ) Previous POR (≤3 oocytes with conventional stimulation) 3 ) Abnormal ovarian reserve biomarker AFC<5-7; AMH <0.5-1.1ng/Ml Or: • Two episodes of POR after maximal stimulation 3-Sep-15 5Dr Shashwat Jani 9909944160
  • 6. 3-Sep-15 6Dr Shashwat Jani 9909944160
  • 7. 3-Sep-15 7Dr Shashwat Jani 9909944160
  • 8. Management of Poor Responders “ One of the most challenging tasks in reproductive medicine...” 3-Sep-15 8Dr Shashwat Jani 9909944160
  • 9. 3-Sep-15 9Dr Shashwat Jani 9909944160
  • 10. 1. Identify Patient at Risk… 3-Sep-15 10Dr Shashwat Jani 9909944160
  • 11. RISK FACTORS… o Elder patients o High FSH, Small Ovaries o Previous poor response o Ovarian surgery especially in case of endometrioma , o Genetic defects, o Chemotherapy, o Radiotherapy, o Autoimmune disorders, o Single ovary, o Chronic smoking, o Unexplained infertility. 3-Sep-15 11Dr Shashwat Jani 9909944160
  • 12. Moreover, New risk factors of low ovarian response have been proposed: o Diabetes mellitus Type I . o Transfusion-dependent B - thalassemia , o Uterine artery embolization for the treatment of uterine leiomyoma . 3-Sep-15 Dr Shashwat Jani 9909944160 12
  • 13. “ Predicting ovarian response before starting hormonal stimulation is the only way to administer an efficient and safe treatment…” 3-Sep-15 13Dr Shashwat Jani 9909944160
  • 14. Predictors of Poor Ovarian Reserve  Age,  Biochemical parameters (basal FSH levels in the early follicular phase,  Serum antimullerian hormone [AMH]),  Morphological characteristics (antral follicular count [AFC] and ovarian volume) 3-Sep-15 14Dr Shashwat Jani 9909944160
  • 15. • FSH: Cut - off point > 11 IU/L* Sensitivity = 10%-30% (n false-negatives) Specificity = 83%-100% • AMH: Cut-off points <0.5-1.1 ng/mL Sensitivity >75% (e false-negatives) Specificity >85% • AFC: Cut-off points <5-7 Sensitivity >60% Specificity >85% *Standardized assays by WHO IRP 78/549; Esposito et al. Hum Reprod 2002; Bancsi et al. Fertil Steril 2002; Kwee et al. Fertil Steril 2008; ASRM Practice Committee, Fertil Steril 2012 3-Sep-15 15Dr Shashwat Jani 9909944160
  • 17. 1. GONADOTROPINS • When standard dose ( 225 – 300 IU ) fails … Dose increased up to 450 IU. • This approach is used since years…. ( CLASSICAL APPROACH ) 3-Sep-15 17Dr Shashwat Jani 9909944160
  • 18. • But, Now, RECENT STUDIES ( Prospective & Retrospective ) : No enhancement in Ovarian response OR Better pregnancy rates. 3-Sep-15 18Dr Shashwat Jani 9909944160
  • 19. Which gonadotropin preparations offer the highest oocyte yield? 3-Sep-15 19Dr Shashwat Jani 9909944160
  • 20. Recent Studies, Increase of FSH starting dose does not result in higher pregnancy rates and also found no differences between the starting dose of 300UI, 450UI, and 600 UI of gonadotropins in terms of retrieved oocytes, number of embryos obtained, and pregnancy rates. 3-Sep-15 20Dr Shashwat Jani 9909944160
  • 21. 2. GnRH Analogues… Since the era of Nineties…. Combination of Gonadotropins & GnRH agonists , started on the late luteal phase of previous cycle , considered the protocol of choice in Normo responder pts. Lower cancellation rates & Increased No. of Pre ovulatory follicles & better pregnancy rates. 3-Sep-15 21Dr Shashwat Jani 9909944160
  • 22. But, in Poor Responders..., It may induce excessive ovarian suppression…  For this reason, in patients with poor ovarian reserve the options could be… 3-Sep-15 22Dr Shashwat Jani 9909944160
  • 23. (i) To decrease the length of suppression by decreasing the duration of GnRH agonist use (short and ultrashort, mini- and microdose flareup regimens). (ii) To lower or to stop (after pituitary suppression) the dose of GnRH agonists initiated during the luteal phase . (iii) To use the GnRH antagonists in combination with gonadotropins to prevent premature LH rise during the mid-late follicular phase . 3-Sep-15 23Dr Shashwat Jani 9909944160
  • 24. In a recent meta analysis… • No statistically significant difference was present in clinical pregnancy rates per cycle randomized between the “GnRH agonist stopped protocol” and the “ standard agonist protocol” . • Moreover, duration of stimulation and total number of gonadotropins ampoules required as well as number of oocytes retrieved were not statistically different between the two groups. 3-Sep-15 24Dr Shashwat Jani 9909944160
  • 25. 3. GnRH Antagonists • Introduced 15 years ago … Advantages :  Increased Pt. Compliance.  Decreased No. of days of stimulations  Decreased amount of gonadotropins  Reduction in OHSS. 3-Sep-15 25Dr Shashwat Jani 9909944160
  • 26. • Recent meta-analysis of 14 randomized controlled studies, “ GnRH antagonist protocols resulted in a statistically significant lower duration of stimulation compared with GnRH agonist protocols but there was no significant difference in the number of oocytes retrieved, in the cycle cancellation rate, and in the clinical pregnancy rate. 3-Sep-15 26Dr Shashwat Jani 9909944160
  • 27. Advantages of Antagonists Over Agonists…  Possible to assess Ovarian Reserve by USG on D2 – D3 of cycle in which COS is planned.  With Antagonists , to prevent premature LH Surge , a new gonadotropins, a hybrid molecule with prolonged half life - Corifollitropin Alfa can be used.  It could exploit fully the reduced ovarian reserve by the rapid increase in the serum FSH concentration that would result in a significantly higher exposure of the small antral follicles to constant high levels of FSH during the early follicular phase. 3-Sep-15 27Dr Shashwat Jani 9909944160
  • 28. To Strengthen the effect of Exogenous Gonadotropins…. Proposed alternative Approaches… 3-Sep-15 28Dr Shashwat Jani 9909944160
  • 29. 1. ROLE OF GH  GH and IGF-1 levels in follicular fluid (FF) • Higher in successful IVF attempts • Decrease with ageing • Lower in poor responders  GH administration increases IGF-1 levels • IGF-1 enhances LH-mediated androgen production within the thecal compartment as well as FSH-mediated aromatization in GC (beneficial effect on steroidogenesis)  E2 levels in FF increased by GH therapy (beneficial effect on oocyte quality) Mendoza et al. Hum Reprod 2002; 2Bahceci et al. Eur J Obstet Gynecol Reprod Biol. 2007; 3Lucy MC. Reprod Fertil Dev. 2011; 4Speroff & Fritz 2005; 5Tesarik et al. Hum Reprod 2005. 3-Sep-15 29Dr Shashwat Jani 9909944160
  • 30. There are no very recent and robust data suggesting routine addition of GH in ovarian stimulation protocols for poor responders patients...!!! 3-Sep-15 30Dr Shashwat Jani 9909944160
  • 31. 2. Estradiol in Luteal Phase  Luteal Estradiol priming could improve synchronization of the pool of follicles available to controlled ovarian stimulation.  In a recent meta analysis of 8 selected studies from 1227 initially searched, the addition of estradiol in the luteal phase with or without the simultaneous use of GnRH antagonist decreases the risk of cycle cancellation and increases the chance of clinical pregnancy in poor responder patients. 3-Sep-15 31Dr Shashwat Jani 9909944160
  • 32. 3. Recombinant LH  In a very recent meta-analysis of 40 randomized controlled studies , significantly more oocytes were retrieved and significantly higher clinical pregnancy rates were observed with r-hFSH plus r-hLH VERSUS r-hFSH treatment in poor responders, suggesting that there is a relative increase in the clinical pregnancy rates of 30% in poor responders and that the addition of r-hLH to r-hFSH may be beneficial for women with poor ovarian response. 3-Sep-15 32Dr Shashwat Jani 9909944160
  • 33. Rationale of LH supplementation • Action of LH at the follicular level in a dose dependent manner increases androgen production • Androgens are then aromatized to estrogens and help restore the follicular milieu. • Action of LH at the GC level enhance responsiveness to FSH. • LH has also a direct positive effect on final oocyte maturation. 3-Sep-15 33Dr Shashwat Jani 9909944160
  • 34. 3-Sep-15 34Dr Shashwat Jani 9909944160
  • 35. 4. ANDROGENS  Produces by Theca cells.  Critical role in adequate follicular steroidogenesis and early follicular and granulosa cell development.  Increase FSH receptor expression in granulosa cells amplifying the effect of FSH and thus potentially enhance responsiveness of ovaries to FSH. 3-Sep-15 35Dr Shashwat Jani 9909944160
  • 36. DHEA A recent meta-analysis of four randomized controlled trials of adjuvant androgens (DHEA and testosterone) in poor responder patients showed a significantly higher ongoing pregnancy rate in the androgen supplementation group. 3-Sep-15 36Dr Shashwat Jani 9909944160
  • 37. TESTOSTERONE  Increased No. small preantral /antral follicles and granulosa/ theca cell proliferation by androgen treatment in primates.  PCOS-like morphological/functional changes by exposure to extra ovarian androgens (e.g., congenital adrenal hyperplasia, androgen-producing tumors, transsexuals)  Basal T level related to No. large follicles on hCG day and pregnancy outcome in poor responders.  Up-regulation of FSH receptor density by androgens (increased ovarian sensibility to FSH). • 1Weil et al. J Clin Endocrinol Metab 1999; 2Hugues & Durnerin. Reprod Biomed Online 2005; • 3Frattarelli & Peterson. Fertil Steril 2004. 3-Sep-15 37Dr Shashwat Jani 9909944160
  • 38. 5. ASPIRIN  Increased intra ovarian vascularity has been linked to improved delivery of gonadotropic hormones or other growth factors required for folliculogenesis.  On the other hand, impaired ovarian blood flow could contribute to poor ovarian response.  Based on this rationale, by enhancing ovarian vascularization with vasoactive substances such as aspirin, the ovarian response could theoretically improve. 3-Sep-15 38Dr Shashwat Jani 9909944160
  • 39.  The conclusion of a meta-analysis and a systematic review was that clinical pregnancy rate per embryo transfer was not found to be different between patients who received low- dose aspirin and the control group.  On the basis of updated evidence, a low dose of aspirin has no substantial positive effect on the likelihood of pregnancy and it should not be routinely recommended for women undergoing IVF. 3-Sep-15 39Dr Shashwat Jani 9909944160
  • 40. 6. NATURAL CYCLES IVF  Natural cycles IVF with or without minimal stimulation can be considered as an easy and cheap approach in the management of poor responders.  In younger women ( < 35 years ) results are encouraging with pregnancy rate 18 % per started cycle, 29 % per transfer, 31% per patients. 3-Sep-15 40Dr Shashwat Jani 9909944160
  • 41. 7. Oocyte Cryopreservation  Breakthrough in ART technologies.  Major societies like ESHRE, ASRM , ASCO acknowledged recently oocyte cryopreservation as a non experimental procedure which provides the required legal and moral support for widespread application.  Moreover, oocyte cryopreservation can also be used to preserve the fertility of all those women at risk to lose their ovarian potential over the time. 3-Sep-15 41Dr Shashwat Jani 9909944160
  • 42. 3. Management of poor responders in the IVF lab  Incomplete oocyte denudation  Laser-assisted ICSI  Standardization of lab environment and culture conditions  Oocyte/embryo banking with vitrification  Blastocyst culture for TE biopsy 3-Sep-15 42Dr Shashwat Jani 9909944160
  • 43. 4. TAILORING EMBRYO TRANSFER… • D2 vs D3 vs D5 • D6 ( or Frozen thawed blastocyst ) if TE biopsy. 3-Sep-15 43Dr Shashwat Jani 9909944160
  • 44. 3-Sep-15 44Dr Shashwat Jani 9909944160