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Optimizing the
Management of the
Poor Responder
Kaylen Silverberg, M.D.
Texas Fertility Center
Austin, Texas
2 Choices
Donor Oocytes
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Agenda
Definitions
Pathophysiology
Ovarian Reserve Testing
Treatment Alternatives
Novel Approaches
Who Is the Poor
Responder?
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…)
Poor Responder:
Pathophysiology
Declining oocyte quality
Oocyte chromosomal degeneration (dissociated chromatids) a
23.7% < 34 yo
52% 35-39 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
Age Related Decline in
Fertility
0
10
20
30
40
50
60
<30 31-
33
34-
36
37-
39
40 41 42 43 44
Delivery/ET
Rosenwaks, et al.
%
Patient Age
Hormonal Tests of
Ovarian Reserve
Day 3 FSH Levels
Day 3 Estradiol Levels
Inhibin B Levels
AMH
Clomiphene Challenge Testing
Day 3 FSH Levels
FSH
Level
<15 15-20 20-25 > 30
Cxl. Rate
(%)
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
Day 3 Estradiol Levels
Smotrich
1995
292 < 80 pg/mL 0.4% 37%
> 80 18.5% 14.8%
Licciardi 452 < 75 pg/mL 20
> 75 0
Author # Pts D3 E2 Cxl(%) Preg(%)
• 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
Basal FSH & E2 Variability
0
10
20
30
40
50
60
70
FSH Estradiol
CD 2
CD 3
CD 4
CD 5
Hansen et al Hum Reprod 1996;11:486
Predictors of Ovarian Reserve
Normal
Responders
(n=84)
Poor
Responders
(n=36)
P
D3 FSH 6.6 12.9 <0.001
D3 E2 167 270 .58
D3 Inhibin 118 70 <0.001
Antral Foll 11.6 4.2 <0.001
# oocytes 9.5 2.1 <0.001
Preg rate 31/77 3/30 .003
Laszlo et al. Fertil Steril 2002;77:328
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
Sonographic Evaluation of
Ovarian Reserve
Antral follicle counts
Ovarian volume
Doppler imaging techniques
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
Ovarian Volume vs.
Pregnancy Rates
0
5
10
15
20
25
30
35
40
45
50
< 3 cm 3-9 cm > 9 cm
Smallest Ovary
Total OvarianVolume
Syrop Fertil Steril 1995;64:1167
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
High Dose Gonadotropin
Therapy
Laufer
1982
Land
1996
Karande
1990
Hershlag
1996
Design R P R R
N 55 126 34 48
Old/New
hMG dose
150/225 Doubled 300/450 225/300-600
Change in E2
peak?
YES NO
Increase in #
oocytes
YES YES NO NO
Improved
Outcome?
NO NO NO NO
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 100 + hMG (150-225)
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
Poor Responders: Letrozole
N=147, OCP/hMG150/FSH225
Antagonist at 14mm
Letrozole
(n=71)
Control
(n=76)
P
Oocytes 6.1 4.3 0.03
Peak E2 384 485 NS
PR/cycle (%) 22 15 NS
Garcia-Velasco et al. Fertil Steril 2005;84:82
Poor Responders: Letrozole
P,R;N=70, OCP/rFSH 450 ± Letrozole 5mg
Antagonist “flexible” dosing
Letrozole
(n=35)
Control
(n=35)
P
Total FSH 2980 3850 <0.05
Cycle Cxl 8.6 28.6 <0.05
PR/ET (%) 25.8 20 NS
Ozmen, et al RBM online. 2009;19:478-85
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
“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
LH Supplementation
P, R Controlled trial (n=84)
rFSH, rLH
Basal FSH ≥10, ≥40yo, 1st 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
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??
12-13 mm
14-15 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
Agonist vs Antagonist: Data
Cochrane review (2002) 1
5 studies
Lower delivery rates with antagonist 0.79 (CI 0.63-0.99)
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
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???
Oral Contraceptive Pretreatment
No OCPs OCPs P
Baseline Cysts >
10 mm (%)
24 0 < 0.05
E2 < 50 pg/mL (%) 62 100 < 0.05
Peak E2 (pg/mL) 1688 (188) 2431 (501) < 0.05
# oocytes 9.9 (1.0) 11.8 (1.2) < 0.05
Fertilization (%) 55.7 69.1 < 0.05
Testosterone
(ng/mL)
41.9 (9.8) 25.1 (3.4) < 0.05
Gelety, TJ: ASRM abstract 010, 1997
Luteal Estrogen
Hill, et al. Fertil Steril 2009; 91:739-43
Outcome
Variable
E2 (n=57) No E2 (n=228) P Value
% embryos > 7c 46.4 (%) 40.6% .05
Implantation Rate
(%)
19.7 21.8 .57
Chemical Preg
(%)
45.6 44.3 .86
Clinical Preg (%) 38.6 36.4 .76
Preg Loss (%) 30.8 32.7 .85
Delivery (%) 28.1 22.4 .36
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)
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
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. 1988
Brzyski et al. 1988
Dirnfeld et al. 1991
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
Materials and Methods
Prospective, sequential trial of LLL and ULDLF
protocols
n=53 (1997-1998)
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
Materials & Methods
ULDLF
21 days OCPs
3 days later, LA 40 µg BID
2 days later, FSH 225-300 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
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
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
Overall Results
0
5
10
15
20
25
30
35
40
45
Clin Preg Delivery* Cxl Rate*
LLL
ULDLF
22/59
6/53
18/42
9/30 13/42
3/30
%
* p < 0.05 Silverberg & Vaughn, ASRM, 1998
Results: Direct Comparisons
LLL ULDLF P # cycles 24 24
# with ET 21 21
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
Results: Direct
Comparisons
0
10
20
30
40
50
60
Clin Preg* Delivery* Losses*
LLL
ULDLF
11/21
9/21
2/21
%
* p < 0.001
3/5
2/11
5/21
Silverberg & Vaughn, ASRM, 1998
ULDLF Results: Previous
LLL Failures
0
10
20
30
40
50
60
TVA (%) Clin Preg (%) Delivery (%)
%
21/35
12/35
8/35
Silverberg & Vaughn, ASRM, 1998
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
Modified Micro-Dose Flare vs.
GnRH Antagonist
Flare (n=24) Antagonist (n=24) P
Day 3 FSH 9 10 NS
Cxl rate (%) 21 25 NS
# ampules 59 68 NS
Peak E2 1196 868 < 0.05
# oocytes 5.5 4.5 < 0.05
Fert (%) 81 72 NS
Preg/ET (%) 21.0 16.6 NS
Akman et al. Hum Reprod 2001;16:868
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. 2007 2 Lainas et al. Hum Reprod. 2008 3 Franco et al. Reprod Biomed Online. 2006;13:618
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
Adjunctive Growth Hormone
Homburg
1990
Ibrahim 1991 Owen 1991 Shaker
1992
Levron
1993
Design P,R, Plac P P,R, Plac P R
N 16 10 13 10 7
Stim hMG LLL/hMG Long foll
GnRH/hMG
LLL/hMG FSH/hMG
Exog .
Gonad.
# Ooc
Peak
E2
No improvement in pregnancy rates
Growth Hormone: Larger Studies
Midluteal LA/hMG; P,R, placebo controlled (n=42); GH 12 IU/d days 1, 3, 5, 7 of hMG1
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;58:575-80 2 Bergh et al. Fertil Steril 1994;62:113-20 3Schoolcraft, et al. Fertil Steril 1997;67:93-7
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
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;14:1939-43
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 pregnancy1
Improvement in oocyte production in poor responders2
Reduction in SAb incidence (retrospective, n=73, p<0.05)3
1Gleicher N. Repro Biol Endocrin 2011
2Barad D, Gleicher N. Fertil Steril 2005
3Gleicher N, et al. Repro Biol Endocrin 2009
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
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
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
Donor
Oocytes
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
Conclusions Probably Effective:
Micro dose flare
Possibly Effective
GnRH Antagonists
Recombinant FSH
CC/hMG
Letrozole
“Stop” GnRH protocol
Assisted Hatching
Growth Hormone
Conclusions
Probably Ineffective
High dose gonadotropins
Pulsatile gonadotropins
Adding LH
Flare protocols
GH-RH
Baby Aspirin
Inconclusive
DHEA
Definitely Effective:
Donor Oocytes!