20th National Conference of the Indian Society for Assisted Reproduction (ISAR) 10th-12th April 2015, Chennai

1. Progesterone
rise
and
IVF
success
Sandro
C.
Esteves,
MD.,
PhD.
Medical
Director,
ANDROFERT
Andrology
&
Human
Reproduc=on
Clinic
Campinas,
BRAZIL
20th
Na>onal
Conference
of
the
Indian
Society
for
Assisted
Reproduc>on
-­‐
Chennai
2015

2. Learning
objec>ves
At
the
comple>on
of
this
presenta>on,
par>cipants
should
be
able
to:
1. Review
the
reasons
why
progesterone
levels
rise
in
s>mulated
cycles
2. Appraise
the
impact
of
progesterone
eleva>on
(PE)
on
the
day
of
hCG
in
cycle
outcome
3. Cri>cally
discuss
the
clinical
importance
of
measuring
P
on
the
day
of
hCG
for
decision
making
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 2
2015
ANDROFERT

3. Does
progesterone
rise
on
the
day
of
hCG
nega>vely
affect
implanta>on
rates?
a.
True
b.
False
c.
Uncertain
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 3
2015
ANDROFERT

4. P levels rise in the late follicular
phase in natural cycles
Speroff
L
et
al.
5th
Edi>on
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 4
2015
ANDROFERT
Progesterone
ng/mL

5. LH
FSH
Adapted
from
Smith
(Endocrinology
1993)
In:
Leão
&
Esteves
Clinics
2014
95%
P
produced
intrafollicularly
CYP17
not
present
✖
LH
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 5
2015
ANDROFERT

6. Devroey
et
al.
Fer/l
Steril
2012;
97(3):
561-­‐72
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 6
2015
ANDROFERT

7. Within
the
hCG
dose
of
0-­‐150
IU/d,
supplementa>on
with
hCG
increase
late
follicular
phase
P4
levels
LH
ac/vity
in
hMG
prepara/ons
is
driven
by
hCG
content
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 7
2015
ANDROFERT

8. Why
do
progesterone
levels
rise
in
late
follicular
phase
in
s>mulated
cycles?
Due
to
supraphysiological
s>mula>on
of
granulosa
cells
The
higher
the
number
of
GCs
under
s3mula3on,
the
higher
the
P
levels
Follicular
P
rise
associated
with:
N
follicles,
N
oocytes,
E2
levels
and
total
FSH
dose
Intrafollicular
P
is
a
terminal
product.
In
humans,
expression
of
CYP17
within
intra-­‐
follicular
ovarian
compartment
is
negligible
Wickenheisser
et
al.
2006;
Nguyen
et
al.
2013;
Bosch
et
al.
2010;
Xu
et
al,
2012;
Kolibianakis
et
al
2012;
Vene>s
et
al.
2012;
Griesinger
et
al
2013;
Ezcurra
&
Humaidan
2014
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 8
2015
ANDROFERT

9. Clinical
evidence
of
nega>ve
effect
of
progesterone
eleva>on
on
the
day
of
hCG
Fresh
Frozen-­‐thawed
Donor/recipient
63
studies;
N
=
55,199
9
studies;
N
=7,229
8
studies;
N
=
1,330
LBR/OPR
CPR
CPR
0.8-­‐1.1
OR:
0.72
(0.56
–
0.94)
OR:
1.03
(0.79
–
1.34)
OR:
1.18
(0.76
–
1.84)
1.2-­‐1.4
OR:
0.64
(0.53
–
0.77)
OR:
0.83
(0.62
–
1.32)
OR:
1.61
(0.64
–
4.05)
1.5-­‐1.75
OR:
0.62
(0.57
–
0.69)
OR:
1.13
(0.97
–
0.69)
-­‐
1.9-­‐3.0
OR:
0.67
(0.55
–
0.81)
OR:
1.03
(0.84
–
1.27)
OR:
0.51
(0.12
–
2.19)
P
ng/mL
Vene>s
et
al.,
Hum
Reprod
Update
2013
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 9
2015
ANDROFERT

10. Clinical
evidence
of
nega>ve
effect
of
progesterone
eleva>on
on
the
day
of
hCG
Xu
et
al,
2012
(N=11,055)
GnRH
agonist
Differen>al
effect
based
on
N
oocytes
retrieved
Ovarian
response
N
oocytes
Serum P
threshold
(ng/mL)
Poor
≤4
1.5
Intermediate
5-19
1.75
High
≥20
2.25
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 10
2015
ANDROFERT
Bosch
et
al.
2010
(N=4,032)
Irrespec>ve
of
GnRH
analogue;
Cut-­‐off
=
1.5
ng/mL

11. Griesinger et al. Fertil Steril 2013
6
RCT,
N=1866;
Antagonist
cycles
OPR
not
impaired
in
high
responders
with
P
eleva>on
Clinical
evidence
of
a
differen>al
effect
of
PE
on
the
day
of
hCG
based
on
ovarian
response
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 11
2015
ANDROFERT

12. • P
eleva>on
had
no
effect
on
oocyte/embryo
quality
and
PRs
Miller
et
al.
1996
• P
eleva>on
associated
with
N
follicles
and
retrieved
oocytes
but
not
with
CPR
(>1.5
ng/mL)
Yding
Andersen
et
al.
2011
• OPR
not
different
between
groups
(cutoff=1.5
ng/ml);
No
impact
of
early
or
late
GnRH
antagonist
ini>a>on
Hamdine
et
al.
2014
Clinical
evidence
of
NO
effect
of
PE
on
the
day
of
hCG
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 12
2015
ANDROFERT

13.
Requena
et
al.,
2850
cycles;
High
Responders
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 13
2015
ANDROFERT

14.
High
P
levels
associated
with
high
estradiol
levels
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 14
2015
ANDROFERT
Requena et al. Reprod Biol Endocrinol 2014

15. u Live
birth
rates
NOT
significantly
different
between
cycles
with
and
without
PE
(>1.5
ng/ml)
[OR:
0.78,
95%
CI:0.56–1.09]
u N
oocytes
and
female
age
main
confounders
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 15
2015
ANDROFERT

16. In
a
mul>variable
model,
PE
vs
LBR:
1. No
impact
in
poor
and
high
responders
2. Nega>ve
impact
in
normal
responders
Vene>s
C
A
et
al.
Hum
Reprod.
2015;30:684-­‐691
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 16
2015
ANDROFERT

17. Summary
evidence
on
PE
on
the
day
of
hCG
pregnancy
outcome
in
IVF
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 17
2015
ANDROFERT

18. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 18
2015
ANDROFERT
Never
measure
60%
Cut-­‐off
1.5
ng/
ml
(10%)
Cut-­‐off
based
on
N
oocytes
(30%)
Rou>ne
measurement
40%
Real
life
prac>ces
among
professionals
within
the
same
ins>tu>on
(Androfert;
n=10)

19. How
oqen
do
P4
levels
rise
in
s>mulated
cycles?
7.4%
8%
17%
Vene>s
et
al.
2015
Griesinger
et
al.
2013
Vene>s
et
al.
2013
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 19
2015
ANDROFERT

20. How
clinically
important
is
P
eleva>on
in
s>mulated
cycles?
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 20
2015
ANDROFERT

21. Transforma>on
of
the
OR:0.64
(95%
CI:
0.54–
0.76)
to
absolute
pregnancy
rate
reduc>on
(APRR)
with
95%
CIs
(dored
lines)
Vene>s
et
al.,
Hum
Reprod
Update
2013
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 21
2015
ANDROFERT
= 10% (95% CI: 6%-14%)

22. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 22
2015
ANDROFERT
✖
✖
10%
pregnancy
reduc>on
Expected:
18
preg.
(44x0.4)
Observed:
16
pregnancies
Overall
reduc>on
(2/400):
0.50%
70%
cycles
6-­‐18
oocytes
N
cycles
PE
(PE
rate
6.3%):
44
Unit
with
1000
cycles/year
40%
average
pregnancy
rate

23. Shall
we
rou>nely
measure
P4
levels
in
s>mulated
cycles?
We
have
to
monitor
1000
cycles
and
intervene
in
44
cycles
(with
high
P)
in
order
to
poten>ally
save
2
pregnancies
by
“freeze-­‐all”
and
subsequent
FET…
…assuming
our
vitrifica>on
program
delivers
the
same
PR
as
compared
with
fresh
transfers.
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 23
2015
ANDROFERT

24. This implies that NOT preventing
P elevation would have
theoretically led to a decrease in
overall pregnancy rate of less
than 1.0 percentage points (that
is, from 40.0% to 39.5%
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 24
2015
ANDROFERT

25. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 25
2015
ANDROFERT
It
is
a
great
fuss
about
something
of
lirle
importance

26. Conclusions (1)
• 95%
circula>ng
progesterone
produced
by
GC
in
ovarian
intrafollicular
compartment
– LH
ac/vity
(hCG
or
LH)
does
not
reduce
follicular
progesterone
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 26
2015
ANDROFERT
• P
measured
in
blood
is
the
sum
of
the
P
secreted
by
mul>ple
follicles
– It
not
necessarily
relates
to
worsening
of
cycle
outcomes

27. Conclusions (2)
• Conflic>ng
data
on
what
P
levels
detrimental
to
implanta>on
in
fresh
transfers
– P
levels
above
1.5
ng/mL
not
cri/cal
to
pa/ents
with
high
cohorts
• Clinical
relevance
of
rou>ne
measurement
of
progesterone
on
the
day
of
hCG
ques>onable
– Freeze-­‐all
policy
should
not
be
adopted
in
all
cycles
with
late
P4
levels
above
1.5
ng/ml
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 27
2015
ANDROFERT

28. Thank you
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