Optimizing the Management of the Poor Responder. Kaylen Silverberg, M.D. Texas Fertility Center Austin, Texas

Transcription

1 Optimizing the Management of the Poor Responder Kaylen Silverberg, M.D. Texas Fertility Center Austin, Texas

2 2 Choices Donor Oocytes Break, eat, visit, enjoy weather Listen to lecture Argue, get grumpy, be depressed... Until we conclude with Donor Oocytes

3 Agenda Definitions Pathophysiology Ovarian Reserve Testing Treatment Alternatives Novel Approaches

4 Who Is the Poor Responder?

5 Background Poor Responder 5-18% of all ART patients Diminished ovarian reserve Advanced age, Ovarian surgery, Idiopathic Definitions # mature follicles, retrieved oocytes Peak E2 levels Day 3 FSH, E2 levels Repetitive premature LH surges Over 20 published definitions (and climbing )

6 Poor Responder: Pathophysiology Declining oocyte quality Oocyte chromosomal degeneration (dissociated chromatids) a 23.7% < 34 yo 52% yo 95.8% >40 yo Mitochondrial DNA deletions increase with patient age b a Lim et al. Fertil Steril 1997;68:265 b Keefe et al. Fertil Steril 1995;6:577

7 Age Related Decline in Fertility % Delivery/ET 0 < Patient Age Rosenwaks, et al.

8 Hormonal Tests of Ovarian Reserve Day 3 FSH Levels Day 3 Estradiol Levels Inhibin B Levels AMH Clomiphene Challenge Testing

9 Day 3 FSH Levels FSH Level Cxl. Rate (%) < > 30 5% 10% 20% 40% Toner et al. Fertil Steril 1991 (n=1478) Indirect measure of ovarian reserve Pregnancy/delivery rates fall as FSH rises Begins to rise 5-6 years before menopause onset Predictive value supported by many other investigators Elevated D3 FSH portends poor response, but many poor responders have normal D3 FSH levels

10 Day 3 Estradiol Levels Author # Pts D3 E2 Cxl(%) Preg(%) Smotrich < 80 pg/ml 0.4% 37% > % 14.8% Licciardi 452 < 75 pg/ml 20 > 75 0 Proposed mechanism involves negative hypothalamic feedback on FSH, leading to false negative FSH levels Some studies suggest no incremental value over Day 3 FSH alone

11 Basal FSH & E2 Variability CD 2 CD 3 CD 4 CD FSH Estradiol Hansen et al Hum Reprod 1996;11:486

12 Predictors of Ovarian Reserve Normal Responders (n=84) Poor Responders (n=36) D3 FSH <0.001 D3 E D3 Inhibin <0.001 Antral Foll <0.001 # oocytes <0.001 Preg rate 31/77 3/ P Laszlo et al. Fertil Steril 2002;77:328

13 Clomiphene Citrate Challenge Testing (CCCT) Basal (D3) FSH, E2 CC 100 mg cycle days 5-9 Day 10 FSH, E2 Abnormal: Elevated Day 3 or Day 10 FSH Tanbo (1992): < 12: 32% cxl rate, 10% preg rate > 12: 85% cxl rate, 0% preg rate Loumaye (1990): < 26: 1% cxl rate, 28% preg rate > 26: 25% cxl rate, 0% preg rate

14 Sonographic Evaluation of Ovarian Reserve Antral follicle counts Ovarian volume Doppler imaging techniques

15 Antral Follicle Counts 2-5 mm antral follicles Typically measured on Day 2 or 3 Correlates with Day 3 FSH, amount of gonadotropin used, peak E2 level, # oocytes, and pregnancy rates a Better predictor of ovarian response than patient age, D3 FSH level b, or inhibin B level c,d Normal responders typically have > 10 antral follicles vs. < 5 for poor responders b,e a Chang et al. Fertil Steril 1998;69:505 b Beckers, et al. Hum Reprod 2000;15:43 c Fauser Fertil Steril 2000;74:629 d Laszlo et al. Fertil Steril 2002;77:328 e Beckers, et al. Fertil Steril 2002;78:291

16 Ovarian Volume vs. Pregnancy Rates < 3 cm 3-9 cm > 9 cm Smallest Ovary Total Ovarian Volume Syrop Fertil Steril 1995;64:1167

17 Poor Responder: Treatment Alternatives High Dose Gonadotropin Clomiphene Citrate plus High Dose hmg Letrozole Reduction/Elimination of GnRH-A Addition of LH GnRH-antagonists Growth Hormone, GH-RH Estrogen/Progesterone pretreatment Recombinant Gonadotropins vs. combo protocols Flare protocols Micro-dose Lupron Flare DHEA

18 High Dose Gonadotropin Therapy Laufer 1982 Land 1996 Karande 1990 Design R P R R N Hershlag 1996 Old/New hmg dose 150/225 Doubled 300/ / Change in E2 peak? YES NO Increase in # oocytes Improved Outcome? YES YES NO NO NO NO NO NO

19 High Dose hmg Plus Clomiphene Blankstein (1989) N=18, CC100 + hmg(75-150) Increased peak E2, improved follicular development 10/18 to retrieval (0/18 in prior cycle) Pantos (1990) N=271, CC hmg ( ) Data difficult to interpret as patients received different doses of hmg No improvement in stimulation or pregnancy rate Benadiva (1995) N=93, previously failed gonadotropins alone No improvement in cxl rate, peak E2, stimulation length Increased implantation rate and live birth rate Cycle cxl rates of 25-30% due to LH surge

20 Poor Responders: Letrozole N=147, OCP/hMG150/FSH225 Antagonist at 14mm Letrozole (n=71) Control (n=76) Oocytes Peak E NS PR/cycle (%) NS P Garcia-Velasco et al. Fertil Steril 2005;84:82

21 Poor Responders: Letrozole P,R;N=70, OCP/rFSH 450 ± Letrozole 5mg Antagonist flexible dosing Letrozole (n=35) Control (n=35) Total FSH <0.05 Cycle Cxl <0.05 PR/ET (%) NS P Ozmen, et al RBM online. 2009;19:478-85

22 Adjunctive GnRH-agonists Advantages Lower cancellation rates Prevents LH surge Higher peak E2 levels Greater number of retrieved oocytes Higher pregnancy rates Disadvantages Longer stimulations Direct ovarian suppression More exogenous gonadotropin required

23 Stop GnRH-a Protocol Administer luteal GnRH-a until onset of menses High dose gonadotropin therapy Faber: 12.5% cxl rate Over half of the patients produced > 10 oocytes, and had 3 embryos for transfer Clinical pregnancy rate 32.5% per transfer Dirnfield: No benefit Wang: 13.5% cxl rate Clinical pregnancy rate 20.5% per transfer Faber, et al. Fertil Steril 1998;69:826 Dirnfield et al. Fertil Steril 1999;72:406 Wang et al. J Asst Reprod Genet 2002;19:1

24 LH Supplementation P, R Controlled trial (n=84) rfsh, rlh Basal FSH 10, 40yo, 1 st IVF cycle No differences: OPR, implantation rate # days of gonadotropin, E2 level, # follicles, # oocytes, # embryos/et Barrenetxea, et al. Fertil Steril 2008;89:546-53

25 GnRH Antagonists Directly, quickly suppress pituitary FSH, LH production Lessen duration of direct ovarian suppressive effect Daily dose (0.25mg) vs single dose (3 mg) equally effective a,b,c Optimal size for antagonist initiation?? mm mm or larger?? a,b Olivennes et al Hum Reprod 1998;13:2411, RBM Online 6;4:432, 2003 c Albano et al Fertil Steril 1997;67:917

26 Agonist vs Antagonist: Data Cochrane review (2002) 1 5 studies Lower delivery rates with antagonist 0.79 (CI ) 5% absolute treatment effect, so for every 20 couples treated, there will be one more pregnancy with agonist Cochrane review (2006) 2 27 studies Significantly lower pregnancy/delivery rates with antagonist (p<0.05) 1 Al-Inany et al, Hum Reprod. 2002;17:874 2 Al-Inany et al, Cochrane Database Syst Rev. 2006;19:3

27 Oral Contraceptive Pre- Treatment Potential Advantages Prevents rescue of corpus luteum from previous cycle Blocks cyst development Synchronized follicular cohort development Allows better scheduling of cycles Decreases gonadotropin requirements?? Lower cancellation rates Greater number of retrieved oocytes Higher pregnancy rates Potential Disadvantages Longer stimulations?? Residual ovarian suppression Exacerbated ovarian suppression when combined with GnRH-a More exogenous gonadotropin required???

28 Oral Contraceptive Pretreatment Baseline Cysts > 10 mm (%) No OCPs OCPs P 24 0 < 0.05 E2 < 50 pg/ml (%) < 0.05 Peak E2 (pg/ml) 1688 (188) 2431 (501) < 0.05 # oocytes 9.9 (1.0) 11.8 (1.2) < 0.05 Fertilization (%) < 0.05 Testosterone (ng/ml) 41.9 (9.8) 25.1 (3.4) < 0.05 Gelety, TJ: ASRM abstract 010, 1997

29 Luteal Estrogen Outcome Variable E2 (n=57) No E2 (n=228) P Value % embryos > 7c 46.4 (%) 40.6%.05 Implantation Rate (%) Chemical Preg (%) Clinical Preg (%) Preg Loss (%) Delivery (%) Hill, et al. Fertil Steril 2009; 91:739-43

30 Recombinant FSH vs. Urinary FSH: Clinical Efficacy In randomized prospective statistically powered clinical studies, significantly more oocytes were retrieved and less medication required with r-fsh than with u-fsh. (Bergh 97; Frydman 98; Schats et al 2000) Pregnancy rates significantly improved FIVNAT 1999: data from 37,211 cycles Clinical pregnancy rates achieved with r-fsh were statistically higher than those achieved with urinary FSH (Daya et al 1999) Meta Analysis: 12 randomized controlled trials (2875 cases, Daya, 1999)

31 Short Flare GnRH Protocol Potential benefits: Initial stimulatory effect on FSH, LH Shortened stimulation Decreased gonadotropin requirements Potential detriments: Increased androgen production Corpus luteum rescue Diminished oocyte quality Decreased pregnancy rates Conflicting data in few, small studies

32 GnRH-A Flare Studies No change in peak E2 levels No change, to slight decrease in number of oocytes retrieved Most studies show increase in follicular phase and early luteal LH and progesterone production Increase in atretic oocytes Larger studies show no increase in pregnancy rates Katayama, et al Brzyski et al Dirnfeld et al. 1991

33 Micro Dose Lupron Flare: Higher E2 levels, more mature oocytes, no spont. LH surges, 90% with improved outcome, 9% preg rate (n=34) 1 Higher E2 levels, more mature oocytes, fewer cxl cycles, no LH surges, 50% preg rate used growth hormone as well (n=32) 2 Higher E2 levels, fewer cxl cycles, more patients to embryo transfer, 35% preg rate (n=34) 3 1 Scott RT, Navot D Fertil Steril 1994;61:880 2 Schoolcraft W, Schlenker T, et al Fertil Steril 1997;67:93 3 Surrey E, et al. Fertil Steril 1998;69:419

34 Materials and Methods Prospective, sequential trial of LLL and ULDLF protocols n=53 ( ) IVF LLL LA 0.5 mg (OCP overlap or LH timing) 0.25 mg with FSH initiation hcg 10,000 IU; 2 follicles > 18 mm Silverberg & Vaughn, ASRM, 1998

35 Materials & Methods ULDLF 21 days OCPs 3 days later, LA 40 µg BID 2 days later, FSH IU BID hcg 10,000 IU; 2 follicles >18 mm TVA 36 h post hcg D3 embryo transfer Progesterone in oil 25 mg IM; D2 start Silverberg & Vaughn, ASRM, 1998

36 Materials & Methods 4 analyses separate (n=112 cycles) completed both LLL & ULDLF (n=48) failed LLL/ completed ULDLF (n=35) failed ULDLF/ completed LLL (n=2) Statistical Analysis t test paired t test Silverberg & Vaughn, ASRM, 1998

37 Overall Results 53 poor responders 59 LLL cycles 53 ULDLF cycles Cycle Cancellation Rates LLL 22/59 (37.3%) ULDLF 6/53 (11.3%) (p<0.05) No spontaneous LH surges Silverberg & Vaughn, ASRM, 1998

38 Overall Results 45 % /30 18/42 13/42 22/59 LLL ULDLF /30 6/53 0 Clin Preg Delivery* Cxl Rate* * p < 0.05 Silverberg & Vaughn, ASRM, 1998

39 Results: Direct Comparisons LLL ULDLF P # cycles # with ET Stim (days) 11.0 (1.5) 10.8 (2.2) 0.8 Gonadotropin (IU) 4953 (1447) 6183 (1769) 0.01 E2 peak (pg/ml) 1160 (507) 1390 (803) 0.2 # oocytes retrieved 6.1 (2.5) 6.7 (3.7) 0.5 # oocytes fertilized 4.0 (2.0) 4.6 (2.6) 0.4 # embryos trans 3.5 (1.5) 3.6 (1.3) 0.8 Silverberg & Vaughn, ASRM, 1998

40 Results: Direct Comparisons /21 3/5 % /21 LLL /21 2/21 2/11 ULDLF 0 Clin Preg* Delivery* Losses* * p < Silverberg & Vaughn, ASRM, 1998

41 ULDLF Results: Previous LLL Failures /35 % / / TVA (%) Clin Preg (%) Delivery (%) Silverberg & Vaughn, ASRM, 1998

42 Summary Poor responders do poorly Comparing LLL and ULDLF: No differences in stimulation parameters No differences in # embryos transferred Yet significantly higher Preg/Deliv rates Evaluating LLL Failures 60% TVA, 23% Delivered Poor responders who fail LLL have excellent outcome with ULDLF Poor responders who complete LLL have higher delivery rate with ULDLF ULDLF represents a better option for poor responders than does the LLL protocol

43 Modified Micro-Dose Flare vs. GnRH Antagonist Flare (n=24) Antagonist (n=24) P Day 3 FSH 9 10 NS Cxl rate (%) NS # ampules NS Peak E < 0.05 # oocytes < 0.05 Fert (%) NS Preg/ET (%) NS Akman et al. Hum Reprod 2001;16:868

44 Poor Responders: Agonist vs Antagonist Conflicting Data: P,R n=534; higher OPR with microdose flare vs. Antagonist/Letrozole 1 P,R; higher OPR with antagonist 2 Meta analysis of 6 trials No differences in cycle cxl, # oocytes, pregnancy rate 3 1 Schoolcraft et al. Fertil Steril Lainas et al. Hum Reprod Franco et al. Reprod Biomed Online. 2006;13:618

45 Growth Hormone IGF-1 augments response of rat granulosa cells to FSH in vitro GH increases IGF-1 production GH appears to sensitize ovary to exogenous gonadotropins Unanswered Questions: Optimal Dosage? Are physiologic doses adequate? Only effective in GH deficient individuals? Adashi E, et al. Endocrin Rev 1985;6:400

46 Adjunctive Growth Hormone Homburg 1990 Ibrahim 1991 Owen 1991 Shaker 1992 Design P,R, Plac P P,R, Plac P R N Levron 1993 Stim hmg LLL/hMG Long foll GnRH/hMG Exog. Gonad. # Ooc LLL/hMG FSH/hMG Peak E2 No improvement in pregnancy rates

47 Growth Hormone: Larger Studies Midluteal LA/hMG; P,R, placebo controlled (n=42); GH 12 IU/d days 1, 3, 5, 7 of hmg 1 No differences: hmg dose, E2, #oocytes, #embryos, IGF-1 levels, preg rates LLLA/hMG; P, R, placebo controlled (n=40) 2 No differences: hmg dose, #oocytes Microdose flare; Retro (n=32) 2 Higher E2, More oocytes, Fewer cxl; 50% OPR; patients previously canceled 1 Younis et al. Fertil Steril 1992;58: Bergh et al. Fertil Steril 1994;62: Schoolcraft, et al. Fertil Steril 1997;67:93-7

48 GH: Cochrane Collaboration 9 studies (n=401) Only 6 on poor responders (n=302) Slight increase in LBR with GH Conclusion: Before recommending GH in IVF, further research is necessary GH should only be considered in the context of a clinical trial Harper, et al. Published online 7/8/09; up to date as of 5/27/03

49 GH-Releasing Factor P, R, placebo controlled; (n=196) LLL, FSH GRF 500µg BID (n=96) vs placebo (n=100) until hcg admin Significant increases in: GH and IGF-1 levels No effect on: Follicles >16mm, FSH dose, preg rate Howles, et al. Hum Reprod 1999;14:

50 DHEA Unknown mechanism IGF mediated (increases IGF-1) Suppressive effect on apoptosis Synergy with gonadotropins Possible reduction in aneuploidy Effect peaks after 4-5 months of use Several small retrospective studies show improvements in: CXL rate, Oocyte #, Preg rate, time to pregnancy 1 Improvement in oocyte production in poor responders 2 Reduction in SAb incidence (retrospective, n=73, p<0.05) 3 1 Gleicher N. Repro Biol Endocrin Barad D, Gleicher N. Fertil Steril Gleicher N, et al. Repro Biol Endocrin 2009

51 DHEA P, R trial, n=33 (51 cycles) a 75 mg/d DHEA Delivery 23% vs. 4% (controls, p<0.05) We would like to present how insufficient the current evidence of acceptable quality is to warrant a conclusion that DHEA supplementation is an effective treatment for women with diminished ovarian reserve. More studies needed b a Wiser, et al. Hum Reprod.2010;25:2496 b Yakin and Urman Hum Reprod Online, May 18,2011

52 Low Dose Aspirin Retro (n=1250) Study patients: Higher AFC, longer stim, more gonadotropin Higher E2 Lower fert rate NO DIFFERENCES in IR, OPR, SAB, LBR Frattarelli J, et al. Fertil Steril 2008;89:1113-7

53 Assisted Hatching Schoolcraft (1994): Significantly improved pregnancy rates in poor responders (64% vs. 19%) Stein (1995): Significant improvement in pregnancy rates in women > 38 yo with 3 previous IVF failures (24% vs. 7%) Tucker (1996): Significant improvement in clinical pregnancy rates, but no difference in delivery rates. Meldrum, Silverberg (1998): Significant improvement in clinical pregnancy rates in women > 40 yo but no improvement in delivery rates. Hellebaut (1996), Lanzendorf (1998): No differences in prospective, randomized trials

54 Donor Oocytes

55 Conclusions Day 3 FSH levels, AMH, antral follicle counts appear to be the best screening tests to identify poor responders The Clomiphene Citrate Challenge represents a good dynamic screening test

56 Probably Effective: Micro dose flare Possibly Effective GnRH Antagonists Recombinant FSH CC/hMG Letrozole Stop GnRH protocol Assisted Hatching Growth Hormone Conclusions

57 Conclusions Probably Ineffective High dose gonadotropins Pulsatile gonadotropins Adding LH Flare protocols GH-RH Baby Aspirin Inconclusive DHEA Definitely Effective: Donor Oocytes!