Jordan, Lebanon, Kuwait, Qatar, Bahrain – Nov 2012Individualization of Patient Treatment Sandro Esteves, M.D., Ph.D. Director, ANDROFERT Center for Male Reproduction & Infertility Campinas, BRAZIL
What is in it for me? Use of Biomarkers to Individualize Ovarian Stimulation Protocols Recent Advances in Injectable Gonadotropins Preparations Rec-FSH vs Urinary Products Agonist versus Antagonist GnRH To whom to give rec-hLH? Differences between rec-hLH and LH Activity in HMG Preparations? Strategies to Improve Ovarian Stimulation Best Protocols to Minimize Risks and Reduce Dropout Rates in IVF and IUI/OIEsteves, 2
Level ofevidence Individualization of Patient Treatment Lecture Structure Points I Consider Highly Relevant in Clinical Practice; Arguments Supported by Studies with High Level of Evidence. Level Type of evidence 1a Obtained from meta-analysis of randomised trials 1b Obtained from at least one randomised trial 2a Obtained from one well-designed controlled study without randomisation 2b Obtained from at least one other type of well-designed quasi- experimental study 3 Obtained from well-designed non-experimental studies (comparative and correlation studies, case series) 4 Obtained from expert committee reports or opinions or clinical experience of respected authoritiesEsteves, 3 Modified from Sackett et al. Oxford Centre for EBM Levels of Evidence (2009)
Individualization of Patient Treatment Esteves, SC – Nov 2012 Review this Lecture at: http://www.androfert.com.br/reviewEsteves, 4
What is in it for me? Use of Biomarkers to Individualize Ovarian Stimulation Protocols Recent Advances in Gonadotropins Preparations Rec-FSH vs urinary products GnRH Agonist versus Antagonist To whom to give rec-hLH? Differences between rec- hLH and LH activity in HMG preparations? Strategies to Improve Ovarian Stimulation Best Protocols to Minimize Risks and Reduce Dropout Rates in IVFEsteves, 5
Central Paradigm Maximize Minimize beneficial effects complications of treatment and risks High-quality Cycle cancellation, oocyte yield OHSS, multiple pregnancy Fauser BC et al: Predictors of ovarian response: progress towards individualized treatment in ovulationEsteves, 6 induction and ovarian stimulation. Hum Reprod Update 2008;14:1-14.
Factors Determining Response to Ovarian Stimulation Demographics and anthropometrics (Age, BMI, Race) Genetic profile Cause of Infertility Years of Infertility Health status Nutritional statusEsteves, 7
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 qualityEsteves, 8 van Loendersloot et al. Hum Reprod Update 2010; 16: 577–589.
Level 1a Use of Markers Pregnancy by number of oocytes retrieved after mild (♦ ) or conventional to Determine ( ) ovarian stimulation for IVF Ovarian Reserve ⑤ Age ⑩ 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, 9
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 2011Esteves, 10 Broer et al. Fertil Steril 2009
= remaining population of primordial and resting follicles Anti-Mullerian Hormone levels are correlated with the number of follicles at gonadotropin independent stage.Esteves, 11 La Marca et al. Hum Reprod 2009
Level 1b Antral Follicle Count (AFC) AFC alone on day 3 as a tool for predicting the number of retrieved oocytes in COS = Number of antral follicles present in the ovaries at a given time that can be stimulated into dominant follicle growth by exogenous Eldar-Geva et al. Fertil Steril 2005 gonadotropinsEsteves, 12 Devroey et al. Hum Reprod Update 2009
AMH and AFC Anti-Mullerian Antral Hormone Follicle (ng/mL) Count Cycle independent test; Simple and Advantages Intercycle stability inexpensive Variation in test No international assay interpretation and standards for standardization; Limitations measurements (DSL & Moderate intercycle Immunotech-Beckman) and interobserver variability Alviggi et al, Reprod Biol Endocrinol 2012; Broer et al, Hum Reprod Update 2011; Broekmans et al, Fertil Steril 2009; Broer et al, Fertil Steril 2009; van Disseldorp et al, Hum Reprod 2010, La MarcaEsteves, 13 et al, Hum Reprod 2006; Hansen et al, Fertil Steril 2003; Elter et al, Gynecol Endocrinol 2005.
Markers of Ovarian Response Antral Follicle Count (AFC) Use a systematic process for counting antral follicles: 1. Identify the ovary. Practical 2. Explore the dimensions in two planes (perform a scout sweep). Recommendations for 3. Decide on the direction of the sweep to measure and count follicles. Better Standardization: ● Cycle day 2-4 4. Measure the largest follicle in two dimensions. A. If the largest follicle is ≤10 mm in diameter: • Start to count from outer ovarian margin of the sweep to the opposite margin. ● Count all AF 2-10mm • Consider every round or oval transonic structure within the ovarian margins to be a follicle. ● Real-time 2 dimension • Repeat the procedure with the contralateral ovary. image adequate • Combine the number of follicles in each ovary to obtain the AFC. B. If the largest follicle is >10 mm in diameter: ● Transvaginal probe 7Mhz • Further ascertain the size range of the follicles by measuring each sequentially smaller follicle, in turn, until a follicle with a minimum diameter of %10 mm is found. • Perform a total count (as described) regardless of follicle diameter. • Subtract the number of follicles of >10 mm from the total follicle count.Esteves, 14 Broekmans et al., Fertil Steril, 2010; 94(3):1044-51
Use of Biomarkers to Individualize Ovarian Stimulation Protocols COS should maximize treatment beneficial effects (high-quality oocyte yield) and minimize risks (cancellation, OHSS, multiple pregnancy). Significant predictive factors for pregnancy in IVF are related to ovarian reserve. AMH levels and AFC accurately determine ovarian reserve. Results can be used to guide the choice of COS protocols. Both AMH and AFC have similar high accuracy to predict which patients are at risk of excessive and poor response to OS but should not be used to predict the chances of pregnancy success.Esteves, 15
What is in it for me? Use of Biomarkers to Individualize Ovarian Stimulation Protocols Recent Advances in Injectable Gonadotropins Preparations Rec-hFSH vs Urinary products GnRH Agonist versus Antagonist To whom to give rec-hLH? Differences between rec-hLH and LH activity in HMG preparations? Strategies to Improve Ovarian Stimulation Best Protocols to Minimize Risks and Reduce Dropout Rates in IVFEsteves, 16
• Incidence of Infertility (WHO II) 64% • Prevalence of Infertile Patients (WHO II) with PCO in Clinical 68% Practice OI, IUI, IVF Clomiphene Citrate 1st line in up to 56% of cases Shift after an average of 3 cycles Injectable GonadotropinsEsteves, 17 Reproductive Hormones Report - GCC Countries (Feb 2011)
Long- r-hFSH r-hFSH acting +r-hLH r-hFSH u-FSH HP FbM FbM Pituitary r-hFSH u-FSH FSH u-hMG Horse Puriity PMSG and Safety, Quality, 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-purifiedEsteves, 18 Adapted from Lunenfeld. Hum Reprod Update 2004;10:453–67
Level 1a 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, 19 25:372-8; Van Wely et al. Cochrane Database Syst Rev. 2011; 2:CD005354
Purity Mean specific LH Injected (FSH activity activity protein content) (IU/mg protein) per 75 IU (IU/vial) (mcg) hMG < 5% ~100 75 ~750 hMG-HP < 70% 2,000–2,500 75 ~33 rec-hFSH Follitropin – 7,000–10,000 0 8.1 beta Follitropin > 99% 13,645 0 6.1 alfaEsteves, 20 Bassett et al. Reprod Biomed Online 2005;10:169–177.
Conventional FbM: Novel Bioassay analitycal method High Protein content by Rat ovary mass weight variability gain Minimal batch-to- batch variability (1.6%) Urinary gonadotropins Follitropin beta Follitropin alfa Bassett et al. Reprod Biomed Online 2005;10:169–177;Esteves, 21 Driebergen et al. Curr Med Res Opin 2003;19:41–46.
Level 1b Number of Retrieved Oocytes by the Same Dose of rec-hFSH vs HP-HMG ↑ 1.5 oocytes (GnRH antagonist cycles) Devroey et al., 2012 ↑ 3.1 oocytes (GnRH antagonist cycles) Bosch et al., 2008 ↑ 1.8 oocytes MERIT Study, 2006 ↑ 2.8 oocytes (GnRH agonist cycles) Hompes et al., 2008 Devroey P et al, Fertil Steril. 2012;97:561-71; Bosch E et al, Hum Reprod. 2008;23:2346-51; Nyboe Andersen A, et al. Hum Reprod. 2006;21:3217–3227; Hompes PG et al, Fertil Steril. 2008;89:1685-93 ;Esteves, 22
Level 2a Total Dose per Live Birth (IU)* Reproductive Biology and Endocrinology 2009; 7:111. 10,000 52.2% 9,690 To achieve a live 7,000 21.6% 7,739 birth, 21-52% more HP-hMG 6,324* and hMG was 3,000 required compared with 0 rec-hFSH HP-hMG hMG rec-hFSH *Mean total dose per cycle/Live birth rate (≤35 years)Esteves, 23
Rec-hFSH vs Urinary products Overall, recombinant and urinary gonadotropins have comparable clinical efficacy, but this does not mean drugs are the same. Recombinant preparations have 3 major differences compared to urinary products: Higher purity and specific activity (SC delivery in very small volumes)) Higher dose precision (FbM) Higher potency (more oocytes retrieved)Esteves, 24
Prevent Can be OHSS by integrated in GnRH-a No flare spontaneous GnRH antagonist and OI cycles Antagonist effect with No hormonal protocol administration possible cyst withdrawal formation Gonadotropin administration Shorter Can exclude duration of early stimulation pregnancy Flare up Pituitary effect suppression Gonadotropin administration Long GnRH agonist Longer Agonist administration protocol treatment Pre-treatment cycle Treatment cycleEsteves, 25
1 2 3 pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2 Activation of the Antagonistic Regulation of Regulation of receptor GnRH receptor effect receptor affinity biological activity GnRH Antagonists Mode of ActionEsteves, 26
Why introduction of antagonists in clinical practice has been slow? Experience with Agonists Why change if it is working Clinicians’ concerns: Lower pregnancy rates Not been able to program aspirations on weekdays LH surge (more monitoring) Difficult to useEsteves, 27
Level 1a Probability of Live Birth N studies 45 22 Included IUI Yes No cycles N patients 7511 3176 Primary outcome OPR or LBR LBR Odds-ratio 0.86 0.86 (95% CI: 0.69-1.08) (95% CI: 0.72-1.02) 1. Al-Inany et al. Cochrane Database Syst Rev. 2011; 5:CD001750.Esteves, 28 2. Kolibianakis et al. Hum Reprod Update. 2006;12:651.
Pre-treatment with OCP 4 RCT; 847 patients Days of stimulation +1.41 (+1.13; +1.68) Level Gonadotropin consumption (UI) +542 (+127; +956) 1a No. oocytes retrieved 1.63 (-0.34; 3.61) Pregnancy rate (%) 0.74 (0.53; 1.03) Griesinger et al. Fertil Steril 2008; 90:1055-63 Flexible* (N=68) Fixed on Day 6 (N=72) P>0.05 Level 29.7 29.2 24.7 23.3 12.0 10.3 1b 9.7 9.9 Days of Dose No. Oocytes Pregnancy (%) stimulation gonadotropin *LH >10 IU/L, and/or mean follicle >12 mm, and/or (x75UI) serum E2 >150 pg/mL; No LH surge reportedEsteves, 29 Kolibianakis EM, et al. Fertil Steril. 2011; 95:558-62
Level 1b Day of hCG administration RCT ≥3 follicles of One day normogonadotropic ≥16mm later P women <40 yrs. on value antagonist COH N=52 N=54 No. Metaphase II 6.1 ± 4.9 9.2 ± 7.1 .009 oocytes Fertilization rate (%) 66.7 ± 23.4 70.1 ± 20.9 .44 Pregnancy rate (%) 34.6% 40.7% .55 Kyrou D et al. Fertil Steril. 2011; 96(5):1112-5.Esteves, 30 Kyrou D et al. Fertil Steril. 2011; 96(5):1112-5.
Recent Advances in Gonadotropins Preparations GnRH Agonist versus Antagonist Clinical Outcomes Evidence No difference in probability of live birth 1a (overall and subgroups) compared to agonists No difference in flexible or fixed GnRH 1b antagonist protocols OCP programming not detrimental 1b Delaying hCG by 1 day not detrimental 1bEsteves, 31
Normal • ~80% normogonadotropic women (WHO II) undergoing Ovarian Stimulation1-3 • 15-20% of NG women have less sensitive ovaries • Older patients (≥35 years)4 Low • Poor responders5 • Slow/Hypo-responders6 • Deeply suppressed endogenous LH (endometriosis)7 1. Alviggi et al. Reprod Biomed Online 2006;12:221; 2. Tarlatzis et al. Hum Reprod 2006;21:90; 3. Esteves et al. Reprod Biol Endocrinol 2009;7:111; 4. Marrs et al. Reprod Biomed Online 2004;8:175;5. Mochtar MH, Cochrane Database, 2007; 6. Alviggi, et al.Esteves, 32 RBMOnline 2009; 7. De Placido et al. Clin Endocrinol (Oxf) 2004;60:637;
LH • Theca cells Increase in LH drive LH • Granulosa cells Increase in FSH drive FSH Increasing the Number % Cycle Pregnancy Level Stimulation Dose of oocytes cancellation rates 1b retrieved FSH… Manzi et al, 1994 Klinkert et al, 2004 …is not associated with better IVF Berkkanoglu & Ozgur, 2010 outcomeEsteves, 33
Up to 45% Infertility Patients • Older patients (≥35 years) aged 35 or Less Sensitive Ovaries • Poor responders above • Slow/Hypo-responders • Deeply suppressed endogenous LH (endometriosis) Poor Responders* Hypo/Slow Responders At least 2 of the following: Normal markers of ovarian reserve Advanced maternal age (≥40 years) Hypo-responders: Previous POR (≤3 oocytes with a d1-d7: normal initial follicullar recruitment conventional stimulation protocol) using fixed starting dose of FSH; d7- Abnormal ovarian reserve test (AFC<5; d10: plateau on follicullar growth AMH <1.1) despite continuing same FSH dosage Or: Slow responders: 2 episodes of POR after maximal High doses of FSH (>3,000UI) to promote stimulation follicular growth; May indicate genetic polymorphisms of LH and/or FSH receptor Marrs et al. Reprod Biomed Online 2004;8:175 De Placido et al. Clin Endocrinol (Oxf) 2004;60:637; Ferraretti et al. Fertil Steril. 2004; 82:1521-6;Esteves, 34 Mochtar MH, Cochrane Database, 2007; Alviggi, et al. RBMOnline 2012
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, 35 Hum Reprod Update 2012; 8(2):127-45. Hill MJ et al. Fertil Steril 2012; 97:1108-4.
Level LH Supplementation in 1b Hypo/Slow Responders… RCT 260 pts; “Steady” response on D8 (E2 <180 pg/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, 36 De Placido et al. Hum Reprod. 2004; 20: 390-6.
Level To Whom to give LH 1b Supplementation in OI and IUI LH levels 1.2 UI/L (WHO group I) Higher follicular development pts. receiving LH (67% vs 20%; p=0.02): Shoham, 2008. Similar follicular development HMG vs FSH+rLH; higher cumulative PR after 3 cycles in FSH+LH (56% vs 23%; p=0.01): Carone, 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, 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 2011.Esteves, 37
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, 38
Alfa Unit Beta unit Carboxyl terminal (biological action segment and receptor affinity) (determines half-life) LH 92 AA; 121 AA Absent; half life of 20’ hCG Identical to LH 144 AA Present; half-life of 24h Higher receptor affinity Purity FSH LH activity (LH content) activity (IU/vial) (IU/vial) Rec-hLH >99% 0 75 Rec-hLH + rec-hFSH >99% 150 75 hMG-HP Unknown* 75 75* *derives primarily from the hCG component, which preferentially is concentrated during the purification process and sometimes was added to achieve the desired amount of LH-like biological activity.Esteves, 39 ASRM Practice Committee. Fertil Steril. 2008; 90:S13-20.
Level Differences in LH activity of rec-hLH 2a and HMG preparations 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, 40 Buhler KF, Fisher R. Gynecol Endocrinol 2011; 1-6.
Level 1a Lower expression of LH/hCG receptor gene as well as genes involved in in biosynthesis of cholesterol and steroids in granulosa cells in pts. treated with HMG preparations May reflect down-regulation of LH receptors, as shown in animals: Caused by a constant ligand exposure during the follicular phase due to longer half life and higher binding affinity of hCG to LHr May explain the observed lower progesterone levels: Caused by lower LH-induced cholesterol uptake, a decrease in the novo cholesterol synthesis and a decrease in steroid synthesis. Trinchard-Lugan I et al. Reprod Biomed Online 2002; 4:106-115; Menon KM et al. Biol ReprodEsteves, 41 2004; 70:861-866; Grondal ML et al. Fertil Steril 2009; 91: 1820-1830.
To whom to give rec-hLH? Differences between rec-hLH and HMG preparations 15-20% women have less sensitive ovaries and worse outcomes in IVF. LH supplementation to OS is an evidence- based strategy to maximize pregnancy results. LH activity in HMG is hCG-dependent: hCG is concentrated during purification or added to achieve the desired amount of LH-like biological activity. Lower expression of LH receptor gene in pts. Treated with HMG (LHr down-regulation). Preparations used are important for granulosa cell function and may influence the developmental competence of theEsteves, 42 oocyte and the function of corpus luteum.
What is in it for me? 1 Use of Biomarkers to Individualize Ovarian Stimulation Protocols Recent Advances in Gonadotropins Preparations Rec-FSH vs urinary products GnRH Agonist versus Antagonist To whom to give rec-hLH? Differences between rec- hLH and LH activity in HMG preparations? Strategies to Improve Ovarian Stimulation Best Protocols to Minimize Risks and Reduce Dropout Rates in IVFEsteves, 43
Strategies to Improve Ovarian Stimulation Up to 65% of couples dropout from IVF without achieving pregnancy before they complete 3 cycles Reasons Pregnancy loss 94% Psychological burden 49%-26% Unsuccessful cycle 87% Prognosis 40%-23% Waiting after ET 81% Waiting to find out how many 68% Cost of treatment 23%-0% eggs fertilized Relationship/divorce 15%-9% Result of pregnancy scan 47% Physical burden 7-6% Olivius K et al, Fertil Steril 2004;81:258; Land JA et al, Fertil Steril 1997; 68:278; Schroder AK, et al, RBM Online 2004; 5:600; Osmanangaoglu K et al, Hum Reprod 2002; 17:2655; Rajkhowa M et al, Hum Reprod 2006; 21:358; Brandes M et al, Hum Reprod 2009; 24:3127; Hammarberg K et al, HumEsteves, 44 Reprod 2001; 16:374.
Level 2a Patient Preferences 68% Easy of use 58% Reasons Dosing mechanism 43% 25% Less chance of error 26% 7% Folitropin alfa Follitropin beta Needle-free prefilled cartridge and reconstitution, • Allowed injections at ready-to-use reusable pen conventional home pen syringe • Improved pts. satisfaction (QOL) Weiss N. RBMonline 2007;15:31-7Esteves, 45
• Same injection device design for all gonadotropins; • Color-coded for differentiation; • Pre-filled, ready-to- use family of pens for fertility treatment.Esteves, 46
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, 48 Nelson et al. Hum Reprod. 2009; Broer et al. Fertil Steril. 2009; Hendricks et al. Fertil Steril 2007.
Level Reduced 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)Esteves, 49 Olivennes F, et al. The CONSORT study. 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, 50 Pundir J et al. RBM Online 2012; 24:6-22.
Level 1b Tailor OS in High Responders by AMH (AFC) Combination of Reduced rFSH Doses and GnRH Antagonist rec-hFSH 150UI AMH (ng/mL) >2.1 Agonist Antagonist Days of Stimulation 13 (12-14) 9 (8-11)* No. Oocytes retrieved (n) 14 (10-19) 10 (8.5-13.5)* OHSS 20 (13.9%) 0 (0%)* Cancellation 4 (2.7%) 1 (2.9%) CPR per transfer 40.1% 63.6%* *P ≤ 0.01 Adapted from Nelson SM et al . Anti-Müllerian hormone-based approach to controlledEsteves, 51 ovarian stimulation for assisted conception. Hum Reprod. 2009; 24(4):867-75.
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; In specific high risk patients for OHSS and egg donation programs should become the choice. 11 RCT – 1,055 women 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, 52
GnRH Agonist for LH Triggering in High Responders Challenge is to Rescue Luteal Phase Insufficiency. Options are: Vitrification and FET in subsequent natural cycle Level vs coasting and Fresh ET same cycle 2b CPR: 50% vs 29% (P<0.05) Garcia-Velasco, Fertil Steril, 2012 Modified luteal support improved delivery rate: Level hCG bolus OPU day (1,500 UI) or 3x 500 UI boluses; recLH; intense progesterone + estradiol; combined. 1b Delivery rates: 18% risk difference favoring hCG (before) X 6% (after modified luteal support). Humaidan et al. Hum Reprod Update 2011.Esteves, 53
20092009 Cycles with GnRH Antagonists 54% Rec-hFSH 45% 15% Rec-hFSH + HMG 43% 1999 2009 HMG 12% Data supplied by REDLARA and ICMARTEsteves, 54
Evidence-based Strategies to Optimize COS in Poor RespondersEsteves, 55
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, 56 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 Hormone Kolibianakis et al, 20092 responders Higher PR2 Duffy et al, 20103 Higher CPR3 Poor Higher LBR Testosterone Bosdou et al , 2012 responders Higher CPR Rec-hLH Mochtar et al, 20071 Poor Higher OPR1 supplementation Bosdou et al, 20122 responders1,2 Higher LBR2 to rec-hFSH Hill et al, 20123 Age ≥35 yrs3 Higher CPR3 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. 2007,2:CD005070; Bosdou JK et al, Hum Reprod Update 2012;8:127-45; Hill MJ et al. Fertil SterilEsteves, 57 2012;97:1108-4.
Strategies to Improve Success by Tailoring 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 Biomarkers to tailor OS 1b GnRH Agonist for LH Triggering1 1a 1Associated with lower pregnancy ratesEsteves, 58
Best Strategies to Maximize Pregnancy Results Evidence and Minimize Complications in “Poor” Responders GnRH Antagonists (lower OS duration) 1a Adjuvant Therapy 1a Growth hormone 1a Testosterone 1a LH supplementation Poor responders 1a Advanced age (≥35) 1a Slow/Hypo responders 1bEsteves, 59