evaluation and management of embryonic endometrial synchrony · evaluation and management of...
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Evaluation and Management of Embryonic – Endometrial Synchrony
Richard T. Scott, Jr, MD, HCLD
Clinical and Scientific Director,
Reproductive Medicine Associates of New Jersey
Professor and Director, Reproductive Endocrinology
Robert Wood Johnson Medical School, Rutgers University
Inadequate LH
Excessive LH
Inadequate LH
The Endometrial Transcriptome
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Factors regulating implantation
• Embryo
• Endometrium
• Synchrony
Norwitz ER, NEJM 2001
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Traditional View of Disorders of Embryonic-Endometrial Synchrony
• The Embryologists’ perspective – Temporal milestones of early development correlate
with subsequent performance • Early cleavage
• 6 or more cells on day 3
• Time lapse – Time at 2 cell stage, 3 cell stage, etc
• May be explained by failure to develop to the blastocyst stage
– Timing of blastulation • Day 5 blastocysts
• Day 6 blastocysts
• Day 7 blastocysts
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Day 5 versus Day 6 Fresh Blastocyst Transfer
0
5
10
15
20
25
Day 5 Day 6
Imp
lan
tati
on
Rat
e (
%)
Barrenetexea et al Fertil Steril 2005; 83:49-53
P<0.001
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Day 5 versus Day 6 Blastocysts
0
5
10
15
20
25
30
35
40
Day 5 Day 6
Imp
lan
tati
on
Rat
e (
%)
Cryo Embryo Transfers
0
5
10
15
20
25
30
35
40
Day 5 Day 6
Imp
lan
tati
on
Rat
e (
%)
Fresh Embryo Transfers
Shapiro et al Fertil Steril 2008; 89:20-6
P=0.0002 P=NS
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Traditional View of Disorders of Embryonic-Endometrial Synchrony
• The Endometrial Physiologists’ perspective – Luteal phase defects
• Endometrial biopsies
• Mid-luteal Progesterone assays
• Abnormal endometrial development (ultrasound)
• Thin endometria (late follicular)
• Hyperechoic endometria (late follicular)
• Hyper-contractile endometria (luteal)
• Abnormal timing for the window of receptivity – Evidenced by the transcriptome (ERA)
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Histologic Dating of the Endometrium is Imprecise
Murray et al Fertil Steril 2004; 81:1333
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Out of Phase Endometrial Biopsies are Equivalent in Fertile and Infertile Women
Coutifaris et al Fertil Steril 2004; 82:1264-72
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Serum Progesterone Levels..
• Natural cycle • Different in stimulated cycle with hCG present • Demonstrates tolerance for varying levels of P • May explain limited predictive value of serum P monitoring
Filicori et al J Clin Invest 1984;73:1638-47
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Varying Degrees of
Hyperechoic Endometria
and Clinical
Outcomes
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Impaired Receptivity
• Histology – Delayed or dysynchronous maturation
• Endocrinology – Progesterone
• Proteomics – Integrins
– Selectins
– Other candidates…
• Transcriptomics – Altered transcriptome profile (ERA™)
• Others…..
Adapted from www.iviomics.com
• Represents pathology – a deviation from a normal endometrial response • Should be reproducible from cycle to cycle
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Non-Traditional View of Embryonic-Endometrial Synchrony
• Can there be abnormalities in synchrony when:
–embryonic blastulation and expansion are completely normal?
– Endometrial receptivity is capable of being completely normal?
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Window of Receptivity
0
5
10
15
20
25
30
35
40
15 16 17 18 19 20 21 22
Del
iver
y R
ate
(%)
Cycle Day
• Day 15 = day 1 of P administration • Day 2 embryos • Documented a three day window of transfer
Navot et al Fertil Steril 1991;55:114-8
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Window of Receptivity
0
5
10
15
20
25
30
35
40
15 16 17 18 19 20 21 22
Del
iver
y R
ate
(%)
Cycle Day
• Day 15 = day 1 of P administration • Day 2 embryos • Documented a three day window of transfer Navot et al Fertil Steril 1991;55:114-8
• Pregnancies subsequently reported within a 5 day window
• Day 2 embryos.
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SUSTAINED IMPLANTATION RATES DECLINE OUTSIDE OF “OPTIMAL WINDOW”
Revisiting the Window of Receptivity
0
2
4
6
8
10
12
14
16
18
-1 0 1 2
Imp
lan
tati
on
Ra
te (
%)
Day Relative to Normal Synchrony
Prapas et al Hum Reprod 1998 13:720-3
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Delayed Implantation versus Poor Embryo Quality
Wilcox et al NEJM 1999
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www.origio.com
What goes wrong?
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• Fixed P exposure
• Evaluation of the endometrial transcriptome
• Unique patterns for each day
• Results – In phase – Pre-receptive – Post-receptive
Ruiz-Alonso et al Fertil Steril 2013
Adapted from www.iviomics.com
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• Diagnosis abnormalities in the endometrial response – Sufficient progesterone – Appropriate timing
• Reproducible – Intrinsic abnormality – Occurs in every cycle
• True deviation in normal physiology
• Most common in women with unexplained Recurrent Implantation Failure
Adapted from www.iviomics.com
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Dysynchrony
• Loss of the temporal coordination between the embryo and the endometrium
• BOTH the embryo and the endometrium have normal reproductive potential
• Is not automatically reproducible from cycle to cycle
• About timing of the stimulus..
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Dysynchrony versus Pathology
• Endometrial Pathology
– Accelerated or retarded rate of development
– Does NOT vary from cycle to cycle
• Dysynchrony
– Normal endometrial responsiveness
– Reflects an abnormality in the timing of the stimuli which induce endometrial receptivity
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Altered Window of Endometrial Receptivity
Onset of P Exposure
Blastocyst Expansion
Pathologic
Post -Receptive
Pre -Receptive
Onset of P Exposure
Blastocyst Expansion
Window of Receptivity
Normal
Onset of P Exposure
Blastocyst Expansion
Dysnchronous
Window of Receptivity
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Progesterone and clinical outcomes
• Serum Progesterone on day of HCG administration
• 2 critical breakpoints
• Could exogenous LH be the cause?
Silverberg KM, et al. J Clin Endocrinol Metab. 1991 Oct;73(4):797-803.
1.27 2.86
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Late follicular rise in progesterone
• Retrospective study
• 4032 patients
• P4 ≥ 1.5 ng/mL associated with lower ongoing pregnancy rates
Bosch E, et al. Hum Reprod. 2010; 25:2092-100
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Progesterone and the Endometrial Transcriptome
Adapted from S. Young, MD, PhD
2.5 mg/d IM
Leuprolide acetate 1 mg/d td sc
40 mg/d IM
5 mg/d IM
Estradiol 0.2 mg/d td
10 mg/d IM
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Progesterone Pharmacokinetics
Adapted from S. Young, MD, PhD
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Progesterone and the Endometrial Transcriptome
Adapted from S. Young, MD, PhD
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Rise in P4 with time after hCG administration
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
4 5 6 7 8 9 10 11 12 13 14+
Pro
gest
ero
ne
(n
g/m
L)
Hours Since hCG Administration
N=12,463
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0
5
10
15
20
25
<4 4-6 7-9 10-12 13-15 16-18 19-21 >22
# m
atu
re o
ocy
tes
retr
ieve
d
#follicles ≥ 14mm on day of hCG
0-2 2-4
4-6 6-8
>8
Controlling for the number of mature follicles increasing luteinization prognosticates more oocytes recovered
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Late follicular rise in progesterone
• Prior to hCG: suboptimal
• After hCG: – Accompanies optimal
mature oocyte yield
– ? Impact on endometrial receptivity
Bosch E, et al. Hum Reprod. 2010; 25:2092-100
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Natural Cycle
Onset of
LH Surge
Progesterone
Rise
Ovulation
Endometrial
Window of
Implantation
Embryonic
Window of
Implantation
time
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Stimulated Cycle Synchronous versus Dysynchronous
hCG
administration
Progesterone
Rise
Retrieval
time Endometrial
Window of
Implantation
Embryonic
Window of
Implantation
24h
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hCG
administration
time Endometrial
Window of
Implantation
Embryonic
Window of
Implantation
embryo and endometrium synchrony - revisited
Progesterone
Rise
24h
Ovulation
Franasiak et al ASRM 2013
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• Endometrium: difficult to measure and control for
• Embryo: Can assess embryonic development in the laboratory
How do you isolate the components impacting synchrony?
36.1% 35.3%
58.7% 59.1% 60.0% 60.0%
0%
10%
20%
30%
40%
50%
60%
70%
MOR B1 B2 B3 B4 B5-6
Sustained Implantation Rate by D5 Expansion
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Fresh day 6 embryo transfer Removes those embryos which do not progress to B2+
p <.05
52%
32%
63%
48%
0%
10%
20%
30%
40%
50%
60%
70%
<35 ≥35
D5 M-B1 D5 B2-B6
p <.005
Franasiak et al ASRM 2013
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time Endometrial
Window of
Implantation
Frozen synchronous cycle
Progesterone
Start
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Frozen day 6 embryo transfer
p =0.5
57%
37%
60%
42%
0%
10%
20%
30%
40%
50%
60%
70%
<35 ≥35
D5 M-B1 D5 B2-B6
p =0.3
Franasiak et al ASRM 2013
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Embryonic Endometrial Synchrony
It take two…..
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Progesterone and Impaired Implantation: A Pilot Study of Euploid Blastocysts
0
10
20
30
40
50
60
70
< 0 0 1 2 3 4 5 6 7 8 9 10 11 12 >12
Sust
ain
ed
Imp
lan
tati
on
Rat
e (
%)
Hours Relative to “Closure” of the Window
All patients had P levels < 1.5 ng/mL prior to the administration of hCG
Embryos need to be blastocysts by this point in time
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Older patients are more likely to have “slow” embryos
31%
46%
0%
10%
20%
30%
40%
50%
60%
70%
<35 years old ≥35 years old
Proportion of "Slow" Blastocysts
P<0.0001
Forman et al ASRM 2013
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Embryonic-Endometrial Asynchrony Increases with Maternal Age
0
10
20
30
40
50
60
70
80
Elev P Day 6 Blast OverallAsynch
% o
f Tr
eat
me
nt
Cyc
les
<30 31-34 35-40
• Retrospective
• 1,341 IVF cycles
• Thresholds for Asynchrony (either) – P >1.5 mg/mL on day of hCG – No blastulation prior to day 6
• Risk for asynchrony increases with maternal age
• Live birth predicted – Day 5 blastulation (P<0.0001) – P < 1.5 ng/mL (P=0.0002)
Shapiro BS et al Fertil Steril 2013 100:S287
P<0.01
(419) (436) (486)
Is it asynchrony or an intrinsic diminution in quality?
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LH-R FSH-R
Follicular Progesterone Elevations
Theca Cell Androgen
C21 C19
Granulosa Cell
C19 C18
The Two Cell Theory
Cholesterol C27
DHEA Progesterone
Circulation
C21
Estradiol
Cholesterol
C21 C27
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Optimal Ratio of exLH/exFSH
* Colors separate statistically definable groups
0
10
20
30
40
50
60
%
% Progesterone Elevation (>1.5 ng/mL)
Werner et al – Fertil Steril 2014
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Differences between response groups
Werner et al – Fertil Steril 2014
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Synchrony in Low Responders Experimental Design
Follow Up Clinical Outcomes
Vitrification: Max of 2 blast
transfer next cycle
or
or
Day 3 Embryo Transfer
Transfer order based on what was
available
19
99
-20
09
Cle
avag
e St
age
Tran
sfer
or
or
Expanded blastocyst by 6 AM day 6? No
Yes
Fresh transfer max of 2 blasts
20
09
-20
12
Ext
end
ed C
ult
ure
–
Bla
sto
cyst
Tra
nsf
er
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Number of Embryos Present on day 3 of in vitro development
0
10
20
30
40
50
60
1 2 3
Pro
po
rtio
n o
f C
ase
s (%
)
Number of Embryos Present on Day 3
Cleavage Transfer Blast Transfer
P<0.0007
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Sustained Implantation Rate Proportion of Embryos which Delivered
0
5
10
15
20
25
30
35
40
45
50
Cleavage Blastocyst
% o
f em
bry
os
tran
sfer
red
wh
ich
del
iver
ed
P<0.0001
1251 11025
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Delivery Rate Proportion of Transfers
0
5
10
15
20
25
30
35
40
45
50
Cleavage Blastocyst
% T
ran
sfer
s
P<0.00001
538 5001
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Fresh versus Cryopreserved Blastocyst Transfer Sustained Implantation Rates
0
10
20
30
40
50
60
Fresh Cryopreserved
%
P=0.75
80/174 122 / 280
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No Transfer Rate Proportion of Embryos which Delivered
0
2
4
6
8
10
12
14
16
18
Cleavage Blastocyst
%
P<0.00001
84 / 538 0 / 5001
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Intent to Treat Delivery Rate Delivery rate based relative to decision to transfer day 3 or go to blast
31
32
33
34
35
36
37
38
Cleavage Blastocyst
%
P<0.05
202 / 538 1670 / 5001
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Beware of Interference in your P Assay
• Patients receiving DHEA have elevated DHEA-SO4 levels
• These levels may falsely elevate P levels
• Assay dependent
Forman - RMANJ
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Summary
• Understanding of Embryonic-Endometrial synchrony is still evolving
• Active management of synchrony improves clinical pregnancy rates
• Each program will need to refine its own limits for synchronous transfer
• It may lead programs to consider cryo all cycles in the future
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Thoughts or Questions?