Number of oocytes and progesterone levels in IVF: Do they matter?

IMPART, Dubai 2013

Number of Oocytes and
Progesterone Levels in IVF
Success
Do they matter?
Sandro C. Esteves, MD, PhD
Director, ANDROFERT
Andrology & Human Reproduction Clinic
Campinas, Brazil

Number of oocytes and
progesterone levels in IVF success
http://www.androfert.com.br/review

ANDROFERT

ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 2
2013 DECEMBER

ANDROFERT
androfert.com.br

Learning Objectives
Importance of number of oocytes and its
relation to live birth
Differences between gonadotropin
preparations in oocyte yield
Effect of progesterone levels at the day of
hCG administration on pregnancy
chances
Cumulative live birth rates as a measure of
success in IVF
Esteves, 3

ANDROFERT, Referral Center for Male Reproduction

Evidence
Level
1a

Predictive factors for pregnancy
in ART

Female Age
Duration of infertility
Basal FSH
Type of infertility
Indication
Fertilization method
Number of oocytes retrieved
Number of embryos
transferred Embryo quality

Negative
Predictors

Positive
Predictor

van Loendersloot et al. Hum Reprod Update 2010
Esteves, 4


Number of oocytes retrieved and
live birth rates
Observed live birth rate

Predicted live birth rate

45%
number of oocytes that best
optimized LBR was 15

Live birth rate (%)

40%
35%

30%
25%

450,135 IVF cycles

20%

15%
10%
5%

0%
1

Esteves, 5

2

3

4

5

6

7

8

9 10 11 12 13 14 15 20 25 30 35 40
Oocyte number
Sunkara et al. Hum Reprod 2011

...in all age groups

Esteves, 6


Gonadotropin Preparations
and Oocyte Yield

Esteves, 7


Evidence
Level
1b

RCT and meta-analyses comparing oocyte
yield with different gonadotropins
↑ 1.5 oocytes (GnRH antagonist cycles)
Devroey et al., 2012

No. Oocytes
retrieved higher
with Rec-FSH vs.
hMG, HP-hMG,
and uFSH

↑ 2.1 oocytes (16 RCT; different protocols)
Lehert et al., 2010
↑ 3.1 oocytes (GnRH antagonist cycles)
Bosch et al., 2008
↑ 2.8 oocytes (GnRH agonist cycles)
Hompes et al., 2008
↑ 1.8 oocytes (GnRH agonist cycles)
MERIT Study, 2006

Esteves, 8


It relates to the way the
drug is made, filled and
delivered

Protein content in
solution by mass
(FbM) in rec-FSH

Protein
content

hMG

hMG-HP

Specific
activity
(IU/mg protein)

Injected
protein per
75 IU (mcg)

< 5%

~100

~750

< 70%

2,000–2,500

~33

13,645

Size Exclusion High
Performance Liquid
Chromatography
(SE- HPLC)

6.1

rec-hFSH* > 99%

*Follitropin alfa; Bassett et al. Reprod Biomed Online 2005
Esteves, 9


Quantity vs. Quality
which one come first?
• Oocyte/embryo quality?
• Endometrial receptivity?

Esteves, 10


Morphology-based embryo quality
and number of oocytes
Embryo quality score

Implantation rate (%)

A large oocyte
1,301 cycles
23
cohort was the
17
main factor that
increased the
3,8
4,5
chance of having
at least one good
1-6 oocytes
embryo
7-15 oocytes

27

p<0.001
4,8

>15 oocytes
Devreker et al Hum Reprod 1999
Esteves, 11


Aneuploidy and Oocyte Yield

Aneuploidy rate %

60

634 patients; 3,688 oocytes; PB biopsy

50

<35 years

40

35-40 years
>40 years

30
20
10
0

p<0.001

The higher the oocyte cohort, the higher the
number of EUPLOID oocytes in all age groups
1-5 oocytes

6-10 oocytes >10 oocytes
Haaf et al Fertil Steril 2009

Esteves, 12


Aneuploidy and Oocyte Yield
• Array CGH analysis in D3 and D5 embryos
• 7753 embryos from 990 patients
• Linear regression analysis adjusted by maternal age

Higher
aneuploidy rate in
older women
irrespective of
embryo number

Higher number of
euploid embryos
with increased
cohort size
Ata et al Reprod Biomed Online. 2012

Esteves, 13


What we have learned
There is a strong association between the
number of oocytes retrieved and live birth
rates in IVF
The optimum number of oocytes needed to
maximize IVF outcomes seems to be about 15
Recombinant gonadotropin preparations are
more potent and result in an increased oocyte
yield
Esteves, 14


What we have learned
Aneuploidy in oocytes increases with maternal
age, but it is unaffected by cohort size in
women aged 35 or older

Among young women, an increased incidence of
aneuploid oocytes seems to be associated with
higher oocyte cohort
The higher the cohort size, the higher the number
of euploid oocytes and embryos regardless of
age
Esteves, 15


How to get the best results
oocyte quality vs. quantity

Increasing oocyte yield is an opportunity to have
more euploid embryos
The goal is to obtain ~15 oocytes avoiding OHSS
COS should be tailored to the individual
phenotype, maximizing the number of oocyte
yield for poor responders and fine-tuning for
hyper-responders

Esteves, 16


More is good, but does it affect
implantation?
• Oocyte/embryo quality?
• Endometrial receptivity?

Esteves, 17


Effect of progesterone levels on
pregnancy in IVF – Do they matter?
Fresh

Frozen-thawed

Donor/recipient

P
ng/mL

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

OR: 1.18
(0.76 – 1.84)

OR: 0.64

OR: 1.03
(0.79 – 1.34)
OR: 0.83
(0.62 – 1.32)

(0.64 – 4.05)

OR: 0.62

(0.57 – 0.69)

OR: 1.13

(0.97 – 0.69)

-

OR: 0.67

OR: 1.03

OR: 0.51

(0.55 – 0.81)

(0.84 – 1.27)

(0.12 – 2.19)

1.2-1.4
1.5-1.75

1.9-3.0

(0.56 – 0.94)
(0.53 – 0.77)

OR: 1.61

P levels not related to oocyte and embryo
quality, nor with fertilization and cleavage rates
Venetis et al., Hum Reprod Update 2013
Esteves, 18


Progesterone levels in
stimulated cycles
Number of oocytes
Estradiol levels
FSH dose
Rec-hFSH vs. hMG

positively
associated
with P levels

Bosch et al. 2008, 2010; Xu et al, 2012;
Kolibianakis et al 2012; Venetis et al. 2012; Griesinger et al 2013
Esteves, 19


No CYP17
LH

Esteves, 20

FSH
LH

hMG

Grondal et al. 2009:

r-FSH

P levels with rec-hFSH and hMG
GCs gene expression in pts. treated with
hMG and rec-hFSH
 Lower expression of LH/hCG receptor
gene and other genes involved in
steroids biosynthesis with hMG
Down-regulation of receptors owed to
constant ligand exposure to hCG
(Menon et al. 2004)

CYP11A activity decreased by 2.4-fold
Lower steroids synthesis and P levels

 Higher potency of rec-hFSH inducing

more LH/hCG receptors
Esteves, 21

Grondal ML et al. Fertil Steril 2009; 91: 1820-1830.
Menon KM et al. Biol Reprod 2004; 70:861-866

What we know about progesterone
levels in stimulated cycles
Most circulating Progesterone (95%) is produced in
the intrafollicular compartment by granulosa cells
Higher serum P are related to more follicles
developed (more GCs) and more oocytes retrieved

Treatment with rec-hFSH results in higher P levels
than hMG
Rec-hFSH has higher FSH bioactivity (increased GCs and
oocyte yield
HMG induces underexpression of genes involved in
steroids synthesis
Bosch et al,. Hum Reprod. 2008 ;23(10):2346-51;
Grøndahl ML, et al. Fertil Steril 2009; 91(5): 1820-30.
Esteves, 22


Progesterone levels
and pregnancy
Bosch et al. 2010 (N=4,032)
Irrespective of GnRH analogue;
Cut-off = 1.5 ng/mL
Xu et al, 2012 (N=11,055)
GnRH agonist
Ovarian
response

Number of
oocytes

Serum P
threshold
(ng/mL)

Poor

≤4

1.5

Intermediate

5-19

1.75

High

≥20

■ Fresh
■ FET

2.25

Esteves, 23


Do we need to measure P levels at hCG
day in stimulated cycles?
How often P4 rise:
Overall: 8.4%
Low-responder: 4.5%
High-responder: 19%

6 RCT, N=1866; Antagonist cycles

OPR not impaired in
high responders
with P elevation
Ongoing PR: OR = 0.55 (0.37–0.81)
Griesinger et al. Fertil Steril 2013
Esteves, 24


Effects of progesterone levels at hCG day
on pregnancy
Intrafollicular P4 is a terminal product. It cannot be
converted to estradiol by GCs under the effect of
gonadotropins containing hCG. The expression of
CYP17 needed for this pathway is negligible
Conflicting data on what levels Progesterone is
detrimental to implantation in fresh transfers. P levels
not so critical in women with high oocyte yield
Adequate number of embryos for freezing and FET is an
opportunity to overcome any detrimental effect of P4
on the endometrium
Wickenheisser et al. Trends Endocrinol Metab. 2006; 17(2): 65-71;
Nguyen PT et al. J Theor Biol. 2013; 332: 52-64.
Esteves, 25


ANDROFERT

Number of oocytes and cumulative
live birth rate

Esteves, 26

+25.0%

Female Age ≤38
+18.8%

40,4%

ET #1 (fresh)
822
332/822

50.5%

48,0%

ET #2 (FET)
239
63/239

ET #3
(FET) 49

17/49

Cumulative live birth to improve
treatment outcome in ART
Pillar #1 – IVF facilities

Esteves, 28


Esteves & Bento. RBM Online 2013

Cumulative pregnancy to improve
Pillar #2 – Blastocyst Culture
Identify the embryos with
optimal development potential
Meta-analysis of eight RCT with
1,654 patients
LBR with Blastocyst vs. Cleavage-stage ET
35% x 28%; OR: 1.39; 95% CI: 1.10-1.76
Papanikolaou E et al. Hum Reprod 2008
Esteves, 31


Identification of Embryos with Optimal
Development Potential

Time-lapse Technology
Videomicrography + Computer Vision Software

(Eeva; Auxogyn)

Wong et al, 2010

Esteves, 32


Cumulative pregnancy to optimize
Pillar #3 – Vitrification
Vitrification vs. Slow-freezing
Ongoing PR: 35% x 27%;
OR: 1.82; 95% CI: 1.04-3.20

Meta-analysis of five RCT with
765 cycles

AbdelFahez et al . RBM Online 2010

Vitrification is simpler and faster
than Slow Freezing
Esteves, 33


Cumulative pregnancy rate as a
strategy to improve success in IVF
The most important endpoint
for the patient
Allow estimation of likelihood
of delivery in relation to no.
oocytes/embryos obtained
and prognostic factors such
as age

Esteves, 34


Conclusions (1)
The number of oocytes retrieved is a key factor for
optimizing live birth rates
COS should be tailored to the individual phenotype,
maximizing the number of oocyte yield for poor
responders and fine-tuning for hyper-responders

Among gonadotropin preparations, recombinant
FSH gives the highest oocyte yield
Higher FSH bioactivity, which is related to the way the
drug is made, filled and delivered
Esteves, 35


Conclusions (2)
Progesterone levels on hCG day are related to
number of follicles developed (GCs) and
oocytes retrieved
No conclusive data on P levels detrimental to
implantation in fresh transfers
Progesterone cannot be converted to estradiol under
the effect of gonadotropins containing LH activity
Adequate number of viable embryos for freezing and
FET can overcome any detrimental effect of P on
the endometrium
Esteves, 36


Conclusions (3)
Cumulative live birth is a key strategy to
optimize success in ART
Stimulation Protocol and Number of Oocytes
ART Facilities

Tools to Identify the Most Viable Embryos
Cryopreservation Program (Vitrification)

Esteves, 37


Number of oocytes and progesterone levels in IVF: Do they matter?

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