Best practices of ASRM and ESHRE

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1 Best practices of ASRM and ESHRE Late submission Cortina d Ampezzo, Italy 1-3 March 2012 A joint meeting between the American Society for Reproductive Medicine and the European Society of Human Reproduction and Embryology

3 Diminished Ovarian Reserve: Stimulation and Oocyte Quality Glenn L. Schattman, M.D., F.A.C.O.G. Associate Professor Cornell Institute for Reproductive Medicine The Weill Medical College of Cornell University Diminished Ovarian Reserve Definition? ~ X oocytes ~ Maximal E2 level ~ Dose of gonadotropins ~ Prior failed cycles ~ No implantation despite X # of good quality embryos transferred No uniform definition! Ovarian Reserve The number and functional competence of the remaining primordial follicles and germ cells is designated as OVARIAN RESERVE. Functional ovarian reserve decreases with increasing chronological age in an individual. Goal of ovarian reserve testing is to predict response to ovarian stimulation Goal of ovarian stimulation is to stimulate an adequate number of oocytes without diminishing oocyte quality. Page 1 of 15

Reserve Testing Day 2/3 FSH/E2 AFC AMH ~ Best used for determining initial stimulation protocol ~ Both AMH and AFC have limited

4 Ovarian Reserve Testing (ORT) Basal levels ~ D2/3 FSH/E2 ~ Inhibin B ~ Anti Mullerian Hormone (AMH/MIS) Dynamic testing (stimulated) ~ CCCT ~ GAST ~ EFFORT Sonographic measures ~ Ovarian volume ~ Ovarian Blood flow ~ Antral Follicle Counts Ovarian Reserve Testing Day 2/3 FSH/E2 AFC AMH ~ Best used for determining initial stimulation protocol ~ Both AMH and AFC have limited value in predicting non-pregnancy * Should NOT be used to exclude treatment *Broer SL, et al Fertil Steril 2009;91 91: Page 2 of 15

5 Physiologic Stimulation The pharmacology of COH for IVF has been significantly influenced by the 2-cell, 2- gonadotropin theory. Historically follicular stimulation protocols have included both FSH and LH in an effort to mimic what occurs in the normal menstrual cycle. Clinical Implications Administration of FSH alone in patients with hypogonadotropic hypogonadism results in: Shoham et al. (1991) Schoot et al. (1994) Balasch et al. (1995) Kousta et al. (1996) Lower serum and follicular fluid E 2 Decreased endometrial thickness Reduced occurrence of ovulation Reduced fertilization rates Reduced pregnancy rates Reduced embryo cryosurvival LH Threshold and Ceiling Suppression of granulosa proliferation Follicular atresia (nondominant follicles) Premature luteinization (preovulatory follicle) Oocyte development compromised LH CEILING Normal follicular growth Paracrine signalling activated by FSH and LH Adequate granulosa proliferation and functional maturation Normal androgen and estrogen biosynthesis Full follicular and oocyte maturation LH THRESHOLD Follicular growth by FSH action (granulosa cell proliferation) Induction of granulosa cell aromatase activity by FSH No paracrine signalling between granulosa and theca No androgen (and estrogen) synthesis No full oocyte maturation Adapted from: Balasch and Fabregues (2002) Curr Opin Ob Gyn 14: Page 3 of 15

6 Androgens Androgens promote FSH induced granulosa cell differentiation ~ Synergistic to FSH in follicle recruitment ~ FSH protects t against follicle l atresia Increase granulosa cell FSH receptor concentration *In Rhesus monkeys: ~ Promotes initiation of PF growth ~ Increases # of growing small and pre-antral follicles *Vendola K et al Biol Reprod1999;61:353 Westergaard L, et al Cochrane Reviews 2009 Luteal GnRH Agonist Long Protocol LH+8 FSH hcg P4 FSH/HMG Menses Menses GnRH-a Luteal Suppression Ret ET Page 4 of 15

Stimulation Protocol 3500 3000 2500 2000 1500 1000 500 0 3 4 5 6 7 8 9 10 11 12 13 Estradiol 36 111 225 563 858 1174 1459 2721 3380 R ok <10 + 11,11, 13,12, 14,14, 17,14, 18,17, 20,18, 10 12,11 13,12

7 Stimulation Protocol Estradiol R ok < ,11, 13,12, 14,14, 17,14, 18,17, 20,18, 10 12,11 13,12 14,12, 16, L ok < ,11, 14,13, 15,15, 17,16, 10,10, 16, FSH ,000 HMG hcg 18 oocytes, 11/15 x2pn Pregnancy Outcome by Estradiol Group % <=39 > Estradiol >2000 Implantation Rate by Estradiol group % <=39 > Estradiol >2000 Page 5 of 15

8 Protocols for Poor Responders Increase dose of GN early follicular ~ Day 2 Gonadotropins/GnRH- antagonists ~ Flare short GnRH-agonist it protocols ~ CC, Tamoxifen or Letrozole with gonadotropins Synchronize antral follicles ~ OCP s, E2, E2/antagonist Increasing Dose of Gonadotropins Suspected poor responders ~ AFC <12 First IVF stimulation OCP x 3 weeks MDL 40ug BID 600 IU rfsh on day 3 Randomized 300 IU 450 IU 600 IU p Age 35.6± ± ±0.6 NS AFC 6.5± ± ±0.5 NS cancellation 10.5% 15.3% 14.2% NS # oocytes 5.2± ± ±0.6 NS #ET 2.3± ± ±0.2 NS IR 7.0% 5.5% 9.1% NS LBR/Stim 10.5% 7.7% 9.5% NS Berkkanoglu M et al Fertil Steril 2010;94:662 Decreasing Dose of GnRH-agonist 51 patients ~ 2 cycles ~ Similar stimulation regimen ~ Only difference was GnRH dose Standard Low dose Age 36.5 ± ± 3.6 Ampules used* 30.9± ± 5.9 E2 day HCG* 738± ± 572 MII oocytes 7.0± ± 4.6 # ET 2.2± ± 1.3 IR% Kowalik A et al JRM 1998;43:413 Page 6 of 15

9 GnRH agonist or antagonist in poor responders? Al-Inany Cochrane Review 2011 Agonist or Antagonist Prior poor response to Luteal GnRHa N=60 ~ Depot GnRHa (3.75 mg) on day 23 ~ Day 2 start with antag started with 2 follicles >14mm 375 IU/day r-fsh HCG 2 follicles 17mm Marci R et al RBM online 2005;11:189 Agonist or Antagonist GnRHa (30) GnRH antag (30) p Age 39.0± ± 2.9 retrievals Ampules 72.6 ± ± 4.3 < Oocytes 4.3 ± ± Ongoing pregnancies 0 4 Marci R et al RBM online 2005;11:189 Page 7 of 15

10 OCP/Microdose Leuprolide/6-8 amps GNs Protocol hcg IU FSH/HMG 35 mcg OCP x 21 days 40 mcg leuprolide acetate twice daily Day Retrieval The Center for Reproductive Medicine and Infertility Co-Flare Protocol: GnRH-a + Gonadotropins Gonadotropins Leuprolide acetate 6-8 AMPS FSH IU/day hcg 1 mg.5 mg Day Retrieval The Center for Reproductive Medicine and Infertility GnRH-antagonist vs. MDL Flare RCT 48 poor responders randomized No difference in baseline characteristics No difference in gonadotropin use Antag MDL Peak E2 (pg/ml) * Mean # oocytes * CPR 22% 26% Akman MA Human Reprod 2001;16: Page 8 of 15

11 GnRH-antagonist vs. MDL Flare RCT 24 poor responders randomized All patients received 300IU rfsh and 150IU HMG/day OCP used for MDL Antag MDL p Peak E2 1348± ± 276 NS (pg/ml) Mean # 8.9 ± ± 1.2 NS oocytes CPR 38.5% 36.4% NS Schmidt D et al Fertil Steril 2005;83:1568 GnRH-antagonist vs. MDL Flare 60 poor responders randomized All patients received 450 IU rfsh/day (up to 600IU/day) HCG 1 follicle >16mm Antag (25) MDL (30) Age 36.2 ± ± 0.8 Retrievals MII oocytes* 1.7 ± ± 1.5 OPR 21.4% 25% Malmusi S et al Fertil Steril 2005;84:402 CC or Aromatase Inhibitor/GN Co-Treatment hcg Clomiphene Citrate 100mg/d Letrozole 2.5mg/d 2 5 Cycle Day units Gonadotropins GnRHantagonist retrieval The Center for Reproductive Medicine and Infertility Page 9 of 15

12 Letrozole Prior poor response to stimulation 225IU rfsh IU HMG x 4 days Randomized ~ +/- letrozole 2.5 mg/day x 5 days Follicular fluid T, Δ4A significantly higher in letrozole group Garcia-Velasco J et al Fertil Steril 2005;84:82 Letrozole Letrozole (71) Control (76) p Age 36.5± ± CX- low response 15.5% 19.7% 0.82 CX- total 43.7% 44.7% 0.97 # Oocytes 6.1± ± IR PR/cycle 22.4% 15.2% 0.39 PR/ET 41.7% 28.9% 0.36 Multiples 46.7% 7.7% 0.04 Garcia-Velasco J et al Fertil Steril 2005;84:82 E2 Patch/GnRH Antagonist Protocol hcg hcg LH mg antag 0.1mg E2 Patch QOD IU FSH 150 IU HMG 0.1mg E2 Patch 0.25mg antag Day Retrieval The Center for Reproductive Medicine and Infertility Page 10 of 15

13 Luteal E2 administration Fanchin et al, ~ Prospective study to determine whether luteal E2 administration size discrepancies of antral follicles ~ 60 women / 120 cycles DAY 3 FSH levels & antral follicle measurements 30 women received luteal E2 / 30 control patient Repeat FSH & antral follicle measurements on CD 3/ day following E2 discontinuation Antral Follicle Sensitivity Estradiol FSH Suppression Luteal Phase Decreased antral follicle size Less heterogeneity of antral follicle size Follicular Phase Fanchin et al., Fertil Steril, 2003 Luteal E2 administration Follicle size in mm E2 administration & Antral Follicle Size E2 Group p =.001 Baseline D3 Control Group E2 D3 miu/ml Fanchin et al, 2003 E2 administration & serum FSH level E2 Group p =.001 Baseline FSH Control Group post E2 FSH Page 11 of 15

14 E2/Antagonist Priming Prior cycle E2/antagonist Days of stim 10.8± ±1.5 Ampules GN 53.0 ± ±16.8* E2 day HCG 873 ± ±562.3 # oocytes/mii 6.4/ /6.8* Dragisic K Fertil Steril 2005;84: E2 Priming Protocol Retrospective paired-cohort analysis Age <35 History of poor response despite high dose GN First IVF attempt at CRMI ~ E2/ant luteal suppression with IU GN/day ~ OCP MDL (40BID) with IU GN/day Shastri S Fertil Steril 2011;95:592 E2 Priming Protocol OCP MDL (69) E2/ant (117) p Age 32 ± ± 2.4 NS RD3 FSH 12.9 ± ± 5.7 NS # prior attempts 2.3 ± ± 1.5 <0.05 Cancellation rate 18.8% 10.3% NS Peak E ± ± 668 <0.05 Oocytes 8.7 ± ± 4.6 NS IR OPR/cycle started Fratarelli J Fertil Steril 2008;89: Page 12 of 15

15 Growth Hormone? Growth hormone modulates action of FSH on granulosa cells ~ Up-regulates synthesis of IGF-1 IGF-1 stimulates aromatase activity, E2 and P4 production and LH receptor formation Growth Hormone Duffy J Cochrane Reviews 2010 Growth Hormone Page 13 of 15

16 Androgen Priming In normal responders- no evidence of benefit* *Poor responders to luteal GnRHa ~ 450 IU day 1, 300 IU day 2, 150 IU days 3 &4 Randomized ~ Luteal GnRHa +/- TT (2.5 mg/day) x 5 days ~ 300IU rfsh IU HMG x 2 days ~ 300 IU HMG days 3 & 4 *Lossl K et al Human Reprod 2008;23:1820 Testosterone pre-treatment Testosterone (31) Control (31) Age 36.5 ± ± 2 NS AFC 4.7 ± ± 1.1 NS % retrieval # oocytes 5.1 ± ± IR CPR/cycle *Lossl K et al Human Reprod 2008;23:1820 DHEA Prior poor response to stimulation Randomized ~ +/-75 mg DHEA ~ Luteal GnRHa, 450 rfsh rlh DHEA 6 weeks (17) Control (16) DHEA >16 weeks (26) Control (25) Mean E2 HCG 572± ± ± ±487 # oocytes 2.8± ± ± ±2.4 LBR 3 (17.6%) 1 (6%) 6 (23.1%) 1 (4%) Wiser A et al Human Reprod 2010;25:2496 Page 14 of 15

17 Conclusion Individualization of stimulation protocols plays an important part in optimizing ART success. ~ Not only are risks to the patient reduced, but optimization of the stimulation may provide better quality eggs and improve the chances for success. As long as steroidogenesis is adequate (demonstrating adequate bioactive LH), supplemental LH does not appear to be necessary nor is it harmful. What to do with the Difficult Patient? Ensure that proper pre-treatment evaluation has been performed Stimulation protocols individualized to ensure maximal # of oocytes without compromising quality ~ Adhere to physiologic principles Learn from each cycle Insanity Doing the same thing over and over and expecting different results Albert Einstein Page 15 of 15

Treatment of Poor Responders

Treatment of Poor Responders Pathophysiology of Poor Responders Deficiency in systemic IGF 1 levels (Bahceci, 2007) Lower intra ovarian T levels Reduced FSH receptor expression (Cai, 2007) Bahceci, 2007,