Tailoring Ovarian Stimulation
Upcoming SlideShare
Loading in...5
×

Like this? Share it with your network

Share
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Be the first to like this
No Downloads

Views

Total Views
913
On Slideshare
913
From Embeds
0
Number of Embeds
0

Actions

Shares
Downloads
56
Comments
1
Likes
0

Embeds 0

No embeds

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
    No notes for slide

Transcript

  • 1. Advances in OBGYN Conference, Oman 2013 Tailoring Ovarian Stimulation Sandro C. Esteves, MD, PhD Director, ANDROFERT Andrology & Human Reproduction Clinic Campinas, Brazil
  • 2. Maximize beneficial effects of treatment Central Paradigm Individualization of Controlled Ovarian Stimulation (iCOS) High-quality Gametes and Embryos Optimal Endometrial Receptivity Esteves, 2 Minimize complications and risks
  • 3. Maximize Beneficial Effects Singleton live birth at term Esteves, 3 Minimize Complications and Risks Cycle Multiple Cancellation Pregnancy Risk of OHSS Poor Response OHSS Delvigne & Rozenberg Hum Reprod Update. 2003;9:77-96; Cantineau et al., Cochrane Database Syst Rev. 2007; 18:CD005356; Aboulghar. Fertil Steril. 2012;97:523-6.
  • 4. Who is Who in ART Up to 68% Infertile Patients (WHO II) with PCO in Clinical Practice Up to 45% Patients Aged ≥35 have Poor Response to Stimulation Esteves, 4 Reproductive Hormones Report - GCC Countries (Feb 2011) Bologna criteria: Ferraretti et al. Hum Reprod 2011.
  • 5. How to Tailor Ovarian Stimulation for IVF Using Ovarian Biomarkers Know the best biomarkers Understand how they work How to use them in COS Esteves, 5
  • 6. Tailoring Ovarian Stimulation Esteves SC – Oman Conference Nov 2013 http://www.androfert.com.br/review Esteves, 6
  • 7. Know the Biomarkers Hormonal Biomarkers FSH, Clomiphene citrate challenge test, Inhibin-B, Anti-Mullerian Hormone (AMH) Functional Biomarkers Antral Follicle Count (AFC) Genetic Biomarkers Single Nucleotide Polymorphisms for FSH, LH, E2 and AMH receptor genes Esteves, 7
  • 8. Evidence Level 1a Esteves, 8
  • 9. How AMH and AFC Work Esteves, 9
  • 10. AMH AFC Esteves, 10 Reflect No. pre-antral and small antral follicles (≤4-8mm) 2D-TVUS early follicular phase 2-10 mm (mean diameter) No. AF at a given time that can be stimulated by medication La Marca et al, Hum Reprod 2009;24:2264; Fleming et al, Fertil Steril 2012;98:1097; Broekmans et al. Fertil Steril, 2010; 94:1044-51; Scheffer et al. Hum Reprod 2003;18:700 .
  • 11. Low Inter-cycle Fluctuations (Fanchin et al, Hum Reprod 2005;20:923) AMH ICC: 0.89; 95% IC: 0.83–0.94 Can be assessed at any cycle day with a single measurement Low Intra-cycle Fluctuations (Hehenkamp et al. JCEM 2006;91:4057) Max. Variation: 17.4% Esteves, 11 ICC: 0.55; 95% IC: 0.39–0.71 Max. Variation: 108%
  • 12. Serum Levels: AMH Peak at age 25 and decrease with aging Early marker of diminished ovarian reserve Non-growing follicles (NGF) recruited per month Esteves, 12 Kelsey et al. Mol Hum Reprod 2012;18:79
  • 13. AMH ELISA assays with different performances: DSL and Immunotech Beckman-Couter gen II (AB DSL + Curves Im.) Fully automated ELISA (to be released) Lack international standardization and EQC Sample instability; measured levels altered by handling Collection in EDTA Storage at room temperature (up to 40% increase) No separation of serum from blood before postage Esteves, 13 Fleming et al. RBM online 2013;26:130; Nelson SM. Fertil Steril. 2013 Jan 8; Nelson & La Marca. RBM online 2011;23:411;
  • 14. Moderate to Low Inter-cycle Fluctuations AFC van Disseldorp et al, Hum Reprod 2010;25:221 Esteves, 14 ICC: 0.71 (95% CI: 0.63–0.77); 29% individual cycle variation High Inter- and Intra-observer Reproducibility Scheffer et al. Ultrasound Obstet Gynecol 2002;20:270
  • 15. Lack of standardization1 • Inclusion criteria for antral follicles AFC Ø  e.g., 2–5 mm or 2–10 mm • Method for counting and measuring follicles • Variable scanning techniques • Image optimization Improved standardization proposed2 Three-dimensional automated follicular tracking3 •  Reduce intra- and inter-observer variability •  Requires offline analysis 1Nelson SM. Fertil Steril. 2013 Jan 8; •  Costly 2 Broekmans et al., Fertil Steril, 2010; 94(3):1044-51; 3Raine-Fenning et al., Fertil Steril 2009;91:1469. Esteves, 15
  • 16. AMH and AFC are not accurate for pregnancy prediction Evidence Level 1a Broer et al. Fertil Steril 2009 ; Broer et al. Hum Reprod Update, 17:46; 2011 Esteves, 16
  • 17. How to Use AMH and AFC to Tailor OS Esteves, 17
  • 18. Biomarkers in OI In a group of 131 women undergoing conventional COS after pituitary downregulation for IVF: Population High- AMH* responder1 ng/mL Poor responder2 Cut-off Sensitivity Specificity Accuracy 2.1 85% 79% 0.82 0.82 76% 86% 0.88 *Beckman-Couter generation II assay; 1>20 oocytes retrieved; 2≤4 oocytes retrieved Esteves, 18 Leão RBF, Nakano FY, Esteves SC. #O-51: ASRM 2013
  • 19. iCOS Using Biomarkers High Responders AMH >2.1 Poor Responders AMH ≤ 0.82 Esteves, 19 rec-hFSH FbM 112.5 to 150 IU daily + GnRH antagonist rec-hFSH FbM + 75 IU rec-hLH + GnRH antagonist • Total daily dose: 262.5 to 375 IU Leão RBF, Nakano FY, Esteves SC. #O-51: ASRM 2013
  • 20. iCOS Using AMH vs. cCOS High Responders (N=70) 60 50 40 57.0 56.0 p=0.03 39.3 p=0.04 30 20 p=0.92 18.5 14.3 14.7 p=0.38 14.0 4.8 10 0 Observed Excessive Response (%) Oocytes retrieved (N) cCOS OHSS (%) Pregnancy (%) iCOS Leão RBF, Nakano FY, Esteves SC. #O-51: ASRM 2013 1Excessive Esteves, 20 response: >20 oocytes retrieved; *Pts. received GnRH-a trigger + embryo vitrification; Mild/severe OHSS reported
  • 21. Evidence Level 2b Biomarkers for iCOS in High Responders AMH (ng/mL) >2.1¶ GnRH Agonist Low-starting FSH dose (150 UI) (n=148) GnRH Antagonist (n=34) Days of Stimulation 13 (12-14) 9 (8-11)* No. Oocytes retrieved (n) 14 (10-19) 10 (8.5-13.5)* OHSS requiring hospitalization 20 (13.9%) 0 (0%)* 4 (2.7%) 1 (2.9%) 40.1% 63.6%* Cancellation CPR per transfer *P ≤ 0.01 Esteves, 21 ¶DSL assay; Adapted from Nelson SM et al . Anti-Müllerian hormone-based approach to controlled ovarian stimulation for assisted conception. Hum Reprod. 2009; 24(4):867-75.
  • 22. Accurate to Predict Ovarian Response AFC Cut-off point of 14 High sensitivity (81%) and specificity (89%) to predict excessive response1 Cut-off point of 4 Bancsi et al, Fertil Steril 2002;77:328 Moderate sensitivity (61%) and High specificity (88%) and to predict DOR2 1>20 Esteves, 22 Kwee et al, Fertil Steril 2008;90:737 oocytes retrieved in conventional COS; 2≤4 oocytes retrieved
  • 23. Evidence Level GnRH Antagonists in High Responders 1a 9 RCT; 966 PCOS women GnRH Antagonist X Agonist Weight Mean Difference (WMD)1; Relative Risk (RR)2 Duration of OS -0.74 (95% CI: -1.12; -0.36)1 Gonadotropin dose -0.28 (95% CI: -0.43; -0.13)1 Oocytes retrieved 0.01 (95% CI: -0.24; 0.26)1 Risk of OHSS (Moderate & Severe) 20% vs 32% 0.59 (95% CI: 0.45-0.76)2 Clinical PR 1.01 (95% CI: 0.88; 1.15)2 Miscarriage rate 0.79 (95% CI: 0.49; 1.28)2 ~40% reduction in moderate/severe OHSS by using antagonists rather than agonists Esteves, 23 Pundir J et al. RBM Online 2012; 24:6-22.
  • 24. Ovarian Aging Impaired Oocyte Quality Reduced Fertilization Rate Reduced Embryo Quality Increased Miscarriage Rates Westergaard et al., 2000; Esposito et al., 2001; Humaidan et al., 2002 Esteves, 24
  • 25. Normal LH “Window” Concept • Normal androgen and estrogen biosynthesis • Normal follicular growth and development • Normal oocyte maturation Reduced ovarian paracrine activity Androgen secretory capacity reduced Decreased numbers of functional LH receptors Reduced LH bioactivity Hurwitz & Santoro 2004 •  Piltonen et al., 2003 •  Vihko et al. 1996 •  Mitchell et al. 1995; Marama et al 1984 Balasch J, Fábreques F. Curr Opin Obstet Gynecol 2002, 14:265. Esteves, 25
  • 26. Level 1a LH Supplementation in DOR Regimen Mochtar et al, 2007 3 RCT (N=310) Poor responders Bosdou et al, 2012 7 RCT (N= 603) Poor responders Outcome Effect on Pregnancy r-hFSH+rLH vs. r-hFSH alone* OPR OR: 1.85 r-hFSH+rLH vs. r-hFSH alone* CPR LBR (only 1 RCT) Hill et al, 2012 7 RCT (N=902) Women advanced age ≥35 yrs. r-hFSH+rLH vs. r-hFSH alone CPR (95% CI: 1.10; 3.11) RD: +6%, (95% CI: -0.3; +13.0) RD: +19% (95% CI: +1.0; +36.0%) OR: 1.37 (95% CI: 1.03; 1.83) *long GnRH-a protocol; OR=odds-ratio; RD=risk difference Esteves, 26 Mochtar MH et al. Cochrane Database Syst Rev. 2007;2:CD005070; Bosdou JK et al, Hum Reprod Update 2012; 8(2):127-45. Hill MJ et al. Fertil Steril 2012; 97:1108-4.
  • 27. Sources of LH Activity Purity (LH content) hCG content (IU/vial) LH activity (IU/vial) Specific activity (LH/mg protein) Rec-hLH >99% 0 75 22,000 IU hMG-HP* 3% ~70 75* ≥ 60 IU *derives from hCG Adapted from ASRM Practice Committee. Fertil Steril. 2008; 90:S13-20. Esteves, 27
  • 28. Sources of LH Activity Matched case-control study; N=4,719 IVF pts. 35 30 P=0.02 25 Duration of Stimulation (days) 31 26 20 15 25 19 14 10 14 Mean No. oocytes retrieved IR (%) 5 0 Fixed 2:1 r-hFSH (150IU)/r-hLH (75IU) Esteves, 28 HMG rec-hFSH + HMG CPR per transfer (%) Buhler KF, Fisher R. Gynecol Endocrinol 2011;1-6.
  • 29. Sources of LH Activity Sources of LH Activity Beta unit hCG Longer in hCG; (Higher receptor affinity) LH Carboxyl terminal segment Absent in LH and present in hCG (Longer Half-life)
  • 30. hMG Grondal et al. 2009: r-FSH Sources of LH Activity GCs gene expression in pts. treated with hMG and rec-hFSH q  Lower expression of LH/hCG receptor gene and other genes involved in steroids biosynthesis in hMG group Down-regulation of receptors owed to constant ligand exposure to hCG (Menon et al. 2004) CYP11A activity decreased by 2.4 fold Lower steroids synthesis and P levels q  Higher potency of rec-hFSH inducing more LH/hCG receptors Esteves, 30 Grondal ML et al. Fertil Steril 2009; 91: 1820-1830. Menon KM et al. Biol Reprod 2004; 70:861-866
  • 31. How to Use LH in supplementation Our Method for LHCOS Patients (≥35 years) Diminished Ovarian Reserve (AMH ≤0.82 ng/mL) GnRH antagonist flexible protocol DOR: Recombinant FSH/LH (2:1 or 3:1 ratio) from stimulation D1; Normal ovarian reserve: 75 IU recLH added to rec-hFSH from D6 on 3   1   2   Menses   Esteves, 31 4   5   6   7   8   9   10   11   3   4   5   6   7   8   9   10   11   12  
  • 32. iCOS Using AMH vs cCOS Poor Responders (N=49) 80 60 72.0 p=0.02 46.6 45.0 40 20 p=0.06 23.3 p=0.03 3.5 p=0.51 20.0 26.8 4.8 0 Expected Poor Oocytes retrieved Cancellation (%) Pregnancy/cycle Response (%) (N) (%) cCOS iCOS Leão RBF, Nakano FY, Esteves SC. #O-51: ASRM 2013 Esteves, 32 Poor response: <5 oocytes retrieved;
  • 33. Take Home Messages AMH and AFC are currently the best biomarkers to predict ovarian response to COS. AMH and AFC are direct biomarkers of ovarian reserve. Both markers have similar accuracy to predict who is at risk of excessive and poor response in COS. After identifying ‘Who is Who’, mild stimulation and GnRH antagonists in pts. at risk of excessive response, and rec-hLH supplementation in DOR, are useful strategies to optimize outcomes in ART cycles. Esteves, 33