Optimizing the
Management of the
Poor Responder
Kaylen Silverberg, M.D.
Texas Fertility Center
Austin, Texas
San Antonio, Texas
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
Agenda
 Definitions
 Pathophysiology
 Ovarian
Reserve Testing
 Treatment Alternatives
 Novel Approaches
Who Is the Poor
Responder?
Background
Poor Responder
 10-24% of all ART patients
 Diminished ovarian reserve
 Advanced age, Ovarian surgery, Idiopathic
Definitions
 # mature follicles, retrieved oocytes
 Peak E2 levels
 Antral follicle counts
 Day 3 FSH, E2, AMH levels
 Repetitive premature LH surges
 Over 20 published definitions (and climbing…)
Bologna Criteria for Poor
Responders

At least 2 of the following criteria:
 Advanced maternal age (≥ 40 yo) or “any
other risk factor for poor ovarian response”
 Poor prior response to stimulation (≤ 3
oocytes when receiving at least 150 IU
gonadotropin)
 Abnormal ovarian reserve testing (AFC < 7,
AMH < 1.1 ng/mL)
ESHRE 2011
Poor Responder:
Pathophysiology



a
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
Lim et al. Fertil Steril 1997;68:265
b Keefe et al. Fertil Steril 1995;6:577
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
<15
Level
Cxl. Rate 5%
(%)
15-20
20-25
> 30
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
Author
# Pts
Smotrich 292
1995
Licciardi 452
D3 E2
Cxl(%)
Preg(%)
< 80 pg/mL 0.4%
37%
> 80
18.5%
< 75 pg/mL
14.8%
20
> 75
0
• Proposed mechanism involves negative hypothalamic
feedback on FSH, leading to false negative FSH levels
•Most studies suggest no incremental value over
Day 3 FSH alone (ASRM Practice Committee, 2015)
Basal FSH & E2 Variability
70
60
50
CD 2
CD 3
CD 4
CD 5
40
30
20
10
0
FSH
Hansen et al Hum Reprod 1996;11:486
Estradiol
Predictors of Ovarian Reserve
Normal
Responders
Poor
Responders
(n=36)
P
12.9
<0.001
D3 FSH
(n=84)
6.6
D3 E2
D3 Inhibin
167
118
270
70
.58
<0.001
Antral Foll
# oocytes
Preg rate
11.6
9.5
31/77
4.2
2.1
3/30
<0.001
<0.001
.003
Laszlo et al. Fertil Steril 2002;77:328
AMH as a Predictor of Ovarian
Reserve
Retro analysis of 2 multicenter RCTs
comparing AMH to AFC
 n=519 and 686
 Reviewed long GnRH-A and GnRH-ant
cycles
 AMH more strongly correlated with oocyte
yield (r=0.56 vs. 0.28; agonist), (r=0.55 vs.
0.33; antagonist)

Nelson SM, et al; Fertil Steril 2015;103:923
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
Better test than basal FSH (ASRM Practice Committee,
2015)
Sonographic Evaluation of
Ovarian Reserve
 Antral
follicle counts
 Ovarian volume (not
recommended by ASRM, 2015)
 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
Poor Responder:
Treatment Alternatives













High Dose Gonadotropin
Priming (OCPs, Estrogen, Testosterone)
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, CoQ10
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
YES
NO
Change in
E2 peak?
Increase in
# oocytes
YES
YES
NO
NO
Improved
Outcome?
NO
NO
NO
NO
High Dose hMG Plus
Clomiphene

Blankstein (1989)




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=18, CC100 + hMG(75-150)
Increased peak E2, improved follicular development
10/18 to retrieval (0/18 in prior cycle)
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

Oocytes
Peak E2
PR/cycle (%)
Letrozole
(n=71)
6.1
384
22
Garcia-Velasco et al. Fertil Steril 2005;84:82
Control
(n=76)
4.3
485
15
P
0.03
NS
NS
Poor Responders: Letrozole
P,R;N=70, OCP/rFSH 450 ± Letrozole 5mg
 Antagonist “flexible” dosing

Total FSH
Cycle Cxl
PR/ET (%)
Letrozole
(n=35)
2980
8.6
25.8
Ozmen, et al RBM online. 2009;19:478-85
Control
(n=35)
3850
28.6
20
P
<0.05
<0.05
NS
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
Addition of Exogenous r-LH



Meta analysis of 3 studies
No increase in pregnancy rates (OR 1.3, CI
0.8-2.11)
No differences:
 # oocytes retrieved
 Dose of FSH
 Duration of stimulation
 Cycle cxl rate
Fan et al. Gynecol Endocrinol. 2013;29:278-84
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




Cochrane review (2006) 2


1
2
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
27 studies
Significantly lower pregnancy/delivery rates with antagonist
(p<0.05)
Al-Inany et al, Hum Reprod. 2002;17:874
Al-Inany et al, Cochrane Database Syst Rev. 2006;19:3
Oral Contraceptive PreTreatment
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, higher gonadotropin doses in poor responders
Residual ovarian suppression
Exacerbated ovarian suppression when combined with GnRH-a
Oral Contraceptive Pretreatment
No OCPs
OCPs
P
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
Baseline Cysts >
10 mm (%)
Gelety, TJ: ASRM abstract 010, 1997
Are OCPs suppressive?
Yes:
No:

Kolibianakis Hum Rep
2006








•
–
RCT, OCP/Antag vs LPL
No diff in IR, PR, LBR
Lower E, Less days stim
•
•
–
Meta- analysis/ OCP vs No
OCP
Lower PR, increased drug
requirement (CI crossed 1)
Bendickson Clin Exp 2006
•
RCT, OCP/Antag vs LPL
No diff in IR, PR, #
embryos
Gasia-Velasco F&S 2011
Griesinger F&S 2005
•
RCT antag w/w/o OCP
No diff
Barmat F&S 2005

–
OCP vs No OCP
Increased drug requirement
No diff in PR
Cochrane Review, 2010:
•
•
•
OCP vs no OCP
Increase drug requirement
Lower PR
Luteal Estrogen
Outcome
Variable
% embryos > 7c
E2 (n=57)
No E2 (n=228)
P Value
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
Hill, et al. Fertil Steril 2009; 91:739-43
Luteal Estrogen Priming: Meta
Analysis
2260 studies evaluated; 8 included
 468 women exposed to luteal estrogen
 621 controls
 Lower risk of cycle cxl (RR 0.6, CI 0.450.78)
 Improved pregnancy rate (RR1.33, CI 1.021.72)

Reynolds, et al. Hum Reprod 2013
Luteal Testosterone






Used in the luteal phase to increase responsiveness to FSH/HMG
More eggs, better quality
Bosdou Hum Repo Update 2012
 11% increase in LBR
Kim F&S 2011
 Transdermal T Gel
 RCT: 21 days
 Higher IR, PR
 Fewer days less drug better quality embryos
Fabrigues Hum Rep 2009
 Improved response to FSH
Massin Hum Rep 2006
 No difference
Comparative Trials
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)
Micro Dose Lupron Flare:



1
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
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
45
40
18/42
35
%
30
25
22/59
13/42
9/30
LLL
ULDLF
20
15
10
5
6/53
3/30
0
Clin Preg
* p < 0.05
Delivery*
Cxl Rate*
Silverberg & Vaughn, ASRM, 1998
Results: Direct Comparisons
LLL
# cycles
# with ET
Stim (days)
Gonadotropin (IU)
E2 peak (pg/mL)
# oocytes retrieved
# oocytes fertilized
# embryos trans
ULDLF
24
21
11.0 (1.5)
4953 (1447)
1160 (507)
6.1 (2.5)
4.0 (2.0)
3.5 (1.5)
Silverberg & Vaughn, ASRM, 1998
24
21
10.8 (2.2)
6183 (1769)
1390 (803)
6.7 (3.7)
4.6 (2.6)
3.6 (1.3)
P
0.8
0.01
0.2
0.5
0.4
0.8
Results: Direct
Comparisons
60
3/5
50
%
11/21
40
9/21
LLL
ULDLF
30
20
5/21
2/11
10
2/21
0
Clin Preg*
* p < 0.001
Delivery*
Losses*
Silverberg & Vaughn, ASRM, 1998
ULDLF Results: Previous
LLL Failures
60
21/35
50
40
%
30
12/35
20
8/35
10
0
TVA (%)
Clin Preg (%)
Silverberg & Vaughn, ASRM, 1998
Delivery (%)
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
Day 3 FSH
Cxl rate (%)
# ampules
Peak E2
# oocytes
Fert (%)
Preg/ET (%)
Flare
(n=24)
9
21
59
1196
5.5
81
21.0
Akman et al. Hum Reprod 2001;16:868
Antagonist
(n=24)
10
25
68
868
4.5
72
16.6
P
NS
NS
NS
< 0.05
< 0.05
NS
NS
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
Lainas et al. Hum Reprod. 2008
3 Franco et al. Reprod Biomed Online. 2006;13:618
2
CC/low dose FSH/Antagonist vs.
Agonist/high dose FSH




RCT, n=695
Group A(n=355)
 Shorter stim, lower total FSH dose
 Lower peak E2
Group B (n=340)
 Lower cxl rate
 More oocytes, more mature ooc, more embryos
No diffs:
 Implantation rate, ongoing (12 week) IUP
Revelli A, et al. J Assist Reprod Genet 2014;31:809
Modified Natural Cycle
Cohort study (n=111)
 All patients had previous failed
conventional IVF cycle within 3 months
with ≤ 3 oocytes on ≥ 300 IU/day FSH
 GnRH-ant and 150-225 IU hMG started
once largest follicle ≥ 13 mm
 Live birth rate < 1%

Kedem, et al. Fertil Steril 2014;101:1624-8
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
Design P,R, Plac
Ibrahim
1991
Owen 1991
Shaker
1992
Levron
1993
P
P,R, Plac
P
R
13
10
7
N
16
10
Stim
hMG
LLL/hMG Long foll
GnRH/hMG
LLL/hMG FSH/hMG
Exog .
Gonad.
# Ooc
Peak
E2
No improvement in pregnancy rates
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
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
More recent (2014) RCTs show no difference
1Gleicher
N. Repro Biol Endocrin 2011
2Barad D, Gleicher N. Fertil Steril 2005
3Gleicher N, et al. Repro Biol Endocrin 2009
DHEA




a
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
Wiser, et al. Hum Reprod.2010;25:2496
b Yakin and Urman Hum Reprod Online, May 18,2011
DHEA




RCT double blind pilot
N=32
All patients received Rx x 12 weeks before
IVF
No differences:
 AFC, AMH
 Ovarian response
 IVF outcome
Yeung TWY, et al. Fertil Steril 2014;102:108-15
DHEA





RCT
N=208, AMH<1 or D3 FSH > 15, & AFC <4
Microdose flare
All patients received Rx x 12 weeks before
IVF
No differences:
 # oocytes, fert rates (sl higher in study
group)
 Pregnancy rates (sl higher in control group)
Kara M et al. Eur J OB/GYN 2014;173:63-5
CoQ 10
600-800 mg/day softgels
 Casper’s retrospective Canadian study in
animal and human models showed
improved embryo quality
 Only 1 RCT

Co Q-10
Double blind, placebo controlled RCT
 IVF/ICSI 35-43 yo, n=39
 1° Outcome: post-meiotic aneuploidy rates
 600 mg/day
 Aneuploidy: 46.5% (S) vs. 62.8% (C)
 Clin Preg Rate: 33% (S) vs. 26.7% (C)
 LBR: 25% (S) vs. 26.7% (C)

Bentov Y, et al. Clin Med Insights Reprod Health 2014;8:31-8
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

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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
Other Options
Acupuncture
 Herbal therapy
 Fish oil
 Megavitamins
 Freeze all
 Pre-transfer “scratch”biopsy
 Intrauterine hCG
 Embryo “Glue”

Donor
Oocytes
CONCLUSIONS
ASRM Practice Committee
Opinion - 2015

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Basal FSH most commonly used, but AFC and AMH
promising due to less variability
Single basal FSH has limited utility due to variability
Basal E2 has little value alone
Very low AMH has high specificity for DOR
Low AFC has high specificity for DOR
Pregnancy rates are not improved by waiting for normal
FSH (in women with previously elevated level)
CCCT more sensitive than basal FSH
No proven “battery” of tests has been shown to reliably
predict DOR
Fertil Steril 2015;103:e9-e17
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
 Standard Flare protocols
Definitely Effective:
 GH-RH
Donor Oocytes!
 Baby Aspirin
Inconclusive
 DHEA
 CoQ-10