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EOFF 2012, Dubai – Nov 22Improving Success by Tailoring Ovarian Stimulation Sandro Esteves, M.D., Ph.D. Director, ANDROFERT Center for Male Reproduction & Infertility Campinas, BRAZIL
What is in it for me? Learn the primary factors affecting ovarian response to stimulation and the importance of knowing your patients’ profiles. Learn the best OS strategies to minimize complications in “high responders” while maintaining sustainable pregnancy results. Learn the best OS strategies to maximize pregnancy outcomes in “poor responders”.Esteves, 2
Improving Success by Tailoring Ovarian Stimulation Esteves, SC – EOFF 2012 Review this Lecture at: http://www.androfert.com.br/reviewEsteves, 3
Factors Determining Response to Ovarian Stimulation Demographics and anthropometrics (Age, BMI, Race) Genetic profile Cause of Infertility Years of Infertility Health status Nutritional statusEsteves, 4
Long- r-hFSH r-hFSH acting u-FSH HP FbM +r-hLH r-hFSH; Pituitary r-hFSH FbM u-FSH FSH u-hMG Puriity Horse and Safety, Quality, PMSG Specific Consistency and Patient Activity Convenience 1930s 1950 1980 1995 2003 2007 2010 Intramuscular administration sc Injector pens sc, subcutaneous; FbM, filled by Mass; HP, highly-purified Adapted from Lunenfeld. Hum Reprod Update 2004;10:453–67Esteves, 5
Urinary vs. Recombinant The endless debate… Meta- analyses of Number Number Statistical Clinical rec-hFSH vs of RCTs of significance significance HMG/HP- included couples HMG/uFSH Coomarasamy 7 2,159 LBR (RR = 1.18, 95% CI: 4% difference in et al, 2008 1.02 to 1.38, P<0.03) in LBR in favor of favor of HMG HMG (CI: 1%-?) Insufficient evidence Al Inany et al, 6 2,371 of a difference in odds None 2009 of pregnancy or live birth Van Wely et al, 28 7,339 Insufficient evidence None 2011 of a difference in odds of live birth Subgroup analysis of r- For a LBR of 25%, hFSH vs HMG in favor of use of rFSH rather HMG (OR 0.84, 95% CI than hMG would 0.72 TO 0.99; N=3,197) result in a LBR 19%-25% Coomarasamy et al, Hum Reprod. 2008;23:310-5; Al Inany et al, Gynecol Endocrinol. 2009;Esteves, 6 25:372-8; Van Wely et al. Cochrane Database Syst Rev. 2011; 2:CD005354
Define your patient population and your results by “Data Mining” your own database. What are the best strategies to individualize COS for my patient population? Search the literature for relevant studies that match your patient profile.Esteves, 7
Up to Prevalence of Infertile Patients (WHO II) with PCO in Clinical 68% Practice1 40 35 Cancellation Rate 30 < 4 oocytes 25 20 • Prevalence of Patients 15 with Poor Response to 10 5 Ovarian Stimulation2 0 < 30 30-35 years years 36-39 years 40-42 >42 Up to 45% Infertility years years Patients aged 35 or above1 1Reproductive Hormones Report - GCC Countries (Feb 2011) 2Bologna criteria: Ferraretti et al. Hum Reprod 2011.Esteves, 9
Reproductive Biology and Endocrinology 2009; 7:111. Unselected group of 865 NG down-regulated women Group A (hMG; N=299) Group B (HP-hMG; N=330) Group C (r-hFSH; N=236) Day Day 1 Day 6 of hCG Cycle day 21 Gonadotropin rFSH/hMG Individualized dose 112.5-450 UI Vaginal progesterone Agonist (nasal spray): Nafarelin acetate (400 mcg/day; fixed) mensesEsteves, 10 Day 2-5 of menses
Esteves et al. (observational study 2009) Outcome Measure HMG HP-hMG r-hFSH P- n=299 N=330 n=236 value Total gonadotropin dose (IU) 2,685 2,903 2,268 <0.01 Retrieved oocytes (N) 10.9 10.7 10.8 NS MII oocytes (N) 8.9 8.9 8.7 NS 2PN fertilization rate (%) 72 72 71 NS Implantation rate (%) 24 27 23 NS Live birth rate per cycle (%) 24.4 32.4 30.1 NS Moderate/severe OHSS(%) 2.3 1.8 1.3 NS Esteves et al, Reprod Biol Endocrinol. 2009; 7:111Esteves, 11
Esteves et al. (observational study 2009) Total Dose per Live Birth (IU)* To achieve a live birth, 10,000 52.2% 9,690 21-52% more HP- 7,000 21.6% 7,739 hMG and 6,324* hMG was 3,000 required 0 compared r-hFSH HP-hMG hMG with r-hFSH * Mean total dose per cycle/Live birth rate (≤35 years)Esteves, 12
Esteves et al. (observational study 2009) % Cycles with “Step-down” during ovarian stimulation 53.4* *P<0.01 18.7 20.3 HMG HP-HMG rec-hFSH (fbm)Esteves, 13
Improving Success by Tailoring Key Points Ovarian Stimulation Patient variability excludes the possibility of a single approach to controlled ovarian stimulation. Overall, recombinant and urinary gonadotropins have similar clinical efficacy. However, it is important to determine how a given protocol works for you by defining your patient population and data mining your experience.Esteves, 14
What are the best strategies to individualize COS for my patient population? Search the literature for relevant studies that match your patient profile.Esteves, 15
Central Paradigm Maximize Minimize beneficial effects complications of treatment and risks High-quality Cycle cancellation, oocyte yield OHSS, multiple pregnancyEsteves, 16 Fauser et al., 2008
Level 1a Female Age Negative Duration of infertility Predictors Basal FSH Type of infertility All reflecting Indication ovarian reserve Fertilization method Number of oocytes retrieved Positive Number of embryos transferred Predictor Embryo quality van Loendersloot et al.Esteves, 17 Hum Reprod Update 2010; 16: 577–589.
Level Pregnancy by number of oocytes 1a Markers of retrieved after mild (♦ ) or conventional ( ) ovarian stimulation for IVF Ovarian Response ⑤ ⑩ Age Biomarkers ● Hormonal Biomarkers FSH, Inhibin-B, AMH ● Functional Biomarkers Antral Follicle Count (AFC) ● Genetic Biomarkers Single Nucleotide Polymorphisms for FSH-R/LH/LH-R/E2-R/AMH-R Verberg M et al. Hum. Reprod. Update 2009;15:5-12Esteves, 18
Level 1a AMH = AFC >Inhibin B >FSH >Age Predictor of Poor Predictor of Excessive Response Response ● AFC studies AMH Studies Predictor of Pregnancy In ART ● AFC studies AMH Studies Broer et al. Hum Reprod Update 2011 Broer et al. Fertil Steril 2009Esteves, 19
Level AMH and AFC to Determine 2a Who is Who Prior to OS Response to Anti- Antral False Ovarian Mullerian Follicle Positive Stimulation Hormone Count Rate (ng/mL) Risk of Excessive Response (≥15 ≥ 3.5 > 15 oocytes or OHSS) Risk of Poor ~15% Response < 1.1 <5 (≤ 4 oocytes)* pmol/L X1000/140 *Bologna criteria: Ferraretti et al. Hum Reprod 2011; Broer et al. Hum Reprod Update 2011;Esteves, 20 Nelson et al. Hum Reprod. 2009; Broer et al. Fertil Steril. 2009; Hendricks et al. Fertil Steril 2007.
Level Low Starting Doses of 2a r-hFSH for Ovarian Stimulation in High Responders Clinical pregnancy rates/cycle started Individualized 60% dosing in 50% increments of 37.5 50.0% IU of folitropin alfa 40% possible by FbM 30% 35.3% 31.3% 31.1% technology 20% 20.0% Age (28-32) 10% Oocytes retrieved 0% 75 IU 112.5 IU 150 IU 187.5 IU 225 IU (8-12) Olivennes F, et al. The CONSORT study.Esteves, 22 Reprod Biomed Online. 2009;18:95–204.
Level GnRH Antagonist Protocol in 1a High Responders 9 RCT; 966 PCOS women Relative Risk Duration of ovarian stimulation -0.74 (95% CI -1.12; -0.36) Gonadotropin dose -0.28 (95% CI -0.43; -0.13) Oocytes retrieved 0.01 (95% CI -0.24-0.26) Risk of OHSS 20% vs 32% Mild 1.23 (95% CI 0.67-2.26) Moderate and Severe 0.59 (95% CI 0.45-0.76) Clinical PR 1.01 (95% CI 0.88; 1.15) Miscarriage rate 0.79 (95% CI 0.49; 1.28) 40% reduction in moderate/severe OHSS by using antagonists rather than agonistsEsteves, 23 Pundir J et al. RBM Online 2012; 24: 6-22.
Level GnRH Agonist for LH 1a Triggering in High Responders GnRH-a triggering (0.2-1.5 mg): antagonist protocol; Reduced if not eliminated risk for OHSS; Challenge is to rescue luteal phase: Vitrification and FET (Garcia-Velasco, Fertil Steril, 2012) Modified LP support (Humaidan et al., 2011) 11 RCT – 1,055 women (GnRH Agonist vs hCG triggering) Moderate/ LBR OPR severe OHSS Fresh autologous OR 0.44 OR 0.45 OR 0.10, cycles (8 RCT) (0.29 - 0.68) (0.31 - 0.65) (0.01 to 0.82) Donor recipient OR 0.90 OR 0.91 OR 0.06 cycles (3 RCT) (0.57 - 1.42) (0.59 -1.40) (0.01 - 0.31) Youssef et al. Cochrane Database Syst Rev. 2011Esteves, 24
Improving Success by Tailoring Key Points Ovarian Stimulation Best Strategies to Maintain Sustainable Pregnancy Results Evidence and Minimize Complications in “High” Responders Low Starting Doses of r-hFSH, preferably 2a filled by mass preparations GnRH Antagonists 1a GnRH Agonist for LH Triggering* 2b *Lower PR in fresh transfersEsteves, 25
Less Sensitive Ovaries On the other hand… • 15-20% of NG women have less sensitive ovaries Reduced oocyte quality • Older patients (≥35 years) • Poor responders Reduced Fertilization Rate • Slow/Hypo-responders Reduced Embryo Quality • Deeply suppressed endogenous LH (endometriosis) Increase Miscarriage Rates Westergaard et al., 2000; Esposito et al., 2001; Humaidan et al., 2002 Reduced Androgen Decreased Reduced ovarian LH receptor LH secretory numbers of paracrine poly- bioactivity capacity functional activity morphisms while reduced LH receptors imnuno- • Piltonen et al., reactivity Hurwitz & Alviggi et al., unchanged Santoro 2004 2006 2003 • Vihko et al. 1996 • Mitchell et al. 1995; Marama et al 1984Esteves, 26
Level GnRH Antagonists in Poor 1b Responders 14 RCT (1,127 patients) Duration of Number Cycle Clinical stimulation Oocytes cancellation Pregnancy retrieved -1.9 days -0.17 1.01 1.23 (-3.6; -0.12) (-0.69; 0.34) (0.71; 1.42) (0.92, 1.66) Limited Clinical Benefit Shortcomings: - Definition of poor responders - Different gonadotropins regimens for OSEsteves, 27 Pu D et al. Hum Reprod. 2011; 26: 2742.
Level 1a Meta-analytic Effect on Intervention Population Studies Pregnancy Kyrou et al,20091 Poor Higher LBR1,2,3 Growth Hormone1 Kolibianakis et al, 20092 responders Higher PR2 Duffy et al, 20103 Higher CPR3 Transdermal Poor Higher LBR Bosdou et al , 2012 Testosterone2 responders Higher CPR GH: IGF-1 and 2; oocyte quality and response to OS 4-24 UI/day; SC; different protocols Testosterone: increase in intra-ovarian androgens ~1mg/d nominal delivery rate; pre-OS (15-21d) Kolibianakis et al, Hum Reprod Update 2009,15:613-22; Kyrou et al, Fertil Steril̀ 2009;91: 749–66; Duffy et al, Cochrane Database Syst Rev 2010;1:CD000099; Mochtar MH et al. Cochrane Database Syst Rev.Esteves, 28 2007,2:CD005070; Bosdou JK et al, Hum Reprod Update 2012;8:127-45
Level LH Supplementation in Poor 1a Responders… Effect on Regimen Outcome Pregnancy Mochtar et al, 2007 r-hFSH+rLH vs. OR 1.85 3 RCT (N=310) OPR r-hFSH alone* (95% CI: 1.10; 3.11) Poor responders CPR RD: +6%, Bosdou et al, 2012 r-hFSH+rLH vs. (95% CI: -0.3; +13.0) 7 RCT (N= 603) r-hFSH alone* Poor responders LBR RD: +19% (only 1 RCT) (95% CI: +1.0; +36.0%) Hill et al, 2012 r-hFSH+rLH vs. 7 RCT (N=902) OR 1.37 r-hFSH alone CPR Women advanced (95% CI: 1.03; 1.83) age ≥35 yrs. *long GnRH-a protocol; OR=odds-ratio; RD=risk difference Mochtar MH et al. Cochrane Database Syst Rev. 2007;2:CD005070; Bosdou JK et al,Esteves, 29 Hum Reprod Update 2012; 8(2):127-45. Hill MJ et al. Fertil Steril 2012; 97:1108-4.
Level 1b LH Supplementation in Slow Responders… RCT 260 pts; “Steady” response on D8 (E2 <180pg/mL; >6 follicles <10mm) Mean No. oocytes retrieved IR (%) OPR (%) 40 32 22 18 14 10 9 11 6 FSH step-up (+150 UI) LH supplementation Normal Responders (+150 UI)Esteves, 30 De Placido et al. Hum Reprod. 2005; 20: 390-6.
What is the optimal LH supplementation protocol? Existing studies give us some clues but the optimal LH protocol has yet to be established How much LH should be used? Should the dose be fixed or flexible? At what stage of the cycle should LH be administered? FSH LH 2:1? 1:1? Fixed? Mimic of natural LH levels?Esteves, 31
Level 2a r-hFSH + r-hLH (2:1 fixed ratio) vs. urinary hCG-based LH Matched case-control study; N=4,719 pts.; long GnRH-a protocol 35 30 Duration of P=0.02 31 Stimulation (days) 25 26 25 Mean No. oocytes 20 retrieved 15 IR (%) 10 5 CPR per transfer (%) 0 2:1 r-hFSH+r- HMG rec-hFSH + hLH HMGEsteves, 32 Buhler KF, Fisher R. Gynecol Endocrinol 2011; 1-6.
LH activity derives from hCG in HMG; hCG is concentrated or added during purification; Lower gene expression (LH/hCG receptor, etc.) in granulosa cells of pts. treated with HMG: May reflect down-regulation of LH receptors by constant ligand exposure during the follicular phase due to longer half life and higher binding affinity of hCG to LHr. Preparations used are important for granulosa cell function and may influence the developmental competence of the oocyte and the function of corpus luteum. ASRM Practice Committee. Fertil Steril. 2008; 90:S13-20; Trinchard-Lugan I et al. Reprod Biomed Online 2002; 4:106-115; Menon KM et al. Biol Reprod 2004; 70:861-866;Esteves, 33 Grondal ML et al. Fertil Steril 2009; 91: 1820-1830.
Improving Success by Tailoring Key Points Ovarian Stimulation Best Strategies to Maximize Pregnancy Results Evidence and Minimize Complications in “Poor” Responders Adjuvant Therapy 1a LH supplementation Poor responders 1a Advanced age (≥35) 1a Slow/Hypo responders 1bEsteves, 34
Level A Final Word on LH 1b Supplementation: OI/IUI LH levels 1.2 UI/L (WHO group I) Higher follicular development pts. receiving LH (67% vs 20%; p=0.02): Shoham et al., 2008. Similar follicular development HMG vs FSH+rLH; higher cumulative PR after 3 cycles in FSH+LH (56% vs 23%; p=0.01): Carone et al., 2012. WHO group II Clomiphene-resistant: fewer intermediate-sized follicles and OHSS in LH-supl. vs FSH group; similar ovulation rate (Plateau, 2006); Previous over-response: higher monofollicular development in LH group (32% vs 13%; p=0.04): Hughes et al., 2005; IUI: higher monofollicular development in LH group without intermediate-size (42% vs 11%; p=0.03); lower cycle cancellation due to risk OHSS (-7% difference): Segnella et al., 2011.Esteves, 35