Page 1
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Dominique de Ziegler
Foch-ART Center Suresnes France
Pr Jean Marc AyoubiPr René FrydmanPr Philippe BouchardDr Paul PirteaDr Marine Poulain
Disclosures: D. de Ziegler, MD
Served on the advisory board of: • IBSA Pharmaceuticals
• Ferring Pharmaceuticals• Teva Pharmaceuticals• Seventure Partners
• Nath Goldberg and Myer, LLC
Holds equity interest in:• Ultrast Inc.
• Medicalship Sagl.
Page 2
Donor egg and frozen embryo transfer (FET)
Inflammation: Chronic endometritis (CE)
Role of the microbiota
Window of endometrial vulnerability
Endometriosis and the uterus
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 3
Donor egg and frozen embryo transfer (FET)
Inflammation: Chronic endometritis (CE)
Role of the microbiota
Window of endometrial vulnerability
Endometriosis and the uterus
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 4
35 years later:Never surpaased
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 5
0 1 2 3 4 weeks
E2
P4300
0.4
0.2
(mg)
20 24-6
Day 20 Day 24
Endometrial glands Endometrial stroma
(mg)
Window of receptivity (WOR): controlled by duration of exposure to P4
Page 6
0 1 2 3 4 weeks
E2
P4300
0.4
0.2
(mg)
20 24-6
Window of receptivity (WOR): controlled by duration of exposure to P4
(mg)
WOR
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 7
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 8
Parenteral Oral Vaginal Transdermic
Poorbioavailability
Poor permeability
First described
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 9
Parenteral Oral Vaginal Transdermic
Poorbioavailability
Poor permeability
First described
New self-injectable P4 (25mg/d)
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 10
25 & 50mg: 100% decidua-lized endomriumNo difference between the 2 doses tested
de Ziegler et al. Fertil Steril 2013
The Endometrium and IVF
Page 11
Sator et al. Gyn End 2013;29:205-8.
de Ziegler et al. Fertil Steril 2013
0
2
4
6
8
10
12
0 1 2 3 4 5 6 7 8 9 10 11
Days since the beginning of treatment
Pro
gest
ero
ne n
g/m
l
MEAN progesterone level
(ng/ml)x 50 mg
MEAN progesterone level
(ng/ml)x 25 mg
steady state
The Endometrium and IVF
Page 13
The Endometrium and IVF
Page 16
Fertil Steril 2019
Page 17
Progesterone production increases during early pregnancy
Progesterone production luteal phase 25mg/day
Page 19
Donor egg and frozen embryo transfer (FET)
Inflammation: Chronic endometritis (CE)
Role of the microbiota
Window of endometrial vulnerability
Endometriosis and the uterus
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 20
de Ziegler D, Borghese B, Chapron C. The Lancet 2010;376:730-8..
Chronic endometritis (CE): Often associated w/ endometriosis
Page 21
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 22
Fertil Steril 2017
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 23
Reproductive Sciences 2016
Page 24
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 25
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 26
Endometrial stromal fibroblasts gene expression when exposed to E2 and P4 in women w/ (red) and w/o endometriosis (blue).
Resistance to progesterone lifted by ovarian suppression
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 28
Reprod Biomed Online 2015;31:647–54.
We can, therefore conclude, that the endometrial
receptivity gene signature during the window of
implantation, as determined by the ERA array, is similar
in infertile women with and without endometriosis, also after sub-analysis for different stages of endometriosis.
Page 29
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 30
The deferred ET option (Def-ET)
The bottle neck of ART
The GnRH trigger option
no hCGAntagonist
temporary ovarian suppression
GnRH-a vs. OC
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 31
de Ziegler D, Borghese B, Chapron C. The Lancet 2010;376:730-8..
Endometrial receptivity in endometriosis
Ovarian effects on endometrium
Our workinghypothesis
To optimize endometrial receptivity, disconnect uterus from ovaries
The Endometrium and IVF
Page 32
Donor egg and frozen embryo transfer (FET)
Inflammation: Chronic endometritis (CE)
Role of the microbiota
Window of endometrial vulnerability
Endometriosis and the uterus
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 33
Fertil Steril 2016;105:844-54.
Chronic EndometritisHistology on endometrial biopsies
Bacteriology
Hysteroscopy: micropolyps
Classical
Genic Signature
Page 34
Fertil Steril 2018 in press
Page 35
Ongoing PROngoing PR
Clinical PR
Implantation R
CE
Page 36
Ongoing PR
Clinical PR
Implantation R
curedCE
Page 38
Plus One 2014
2014
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 39
Fertil Steril 2017
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 40
Fertil Steril 2017
42.338.5 38.5
15.4 14.1 14.1
0
20
40
60
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 41
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 43
Fertility Sterility 2019
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 44
2019
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 46
Donor egg and frozen embryo transfer (FET)
Inflammation: Chronic endometritis (CE)
Role of the microbiota
Window of endometrial vulnerability
Endometriosis and the uterus
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 47
Fertility Sterility 2017
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 48
2017
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 49
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 50
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 51
2019
The Endometrium and IVF
Page 54
Donor egg and frozen embryo transfer (FET)
Inflammation: Chronic endometritis (CE)
Role of the microbiota
Window of endometrial vulnerability
Endometriosis and the uterus
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 55
The endometrium is vulnerable to alterations created by hormone imbalances that are susceptible of inducing lasting obstetrical consequences
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 56
0 1 2 3 4 weeks
E2
P4300
0.4
0.2
(mg)
20 24-6
Window of receptivity (WOR): controlled by duration of exposure to P4
(mg)
WOR
Window of endometrial vulnerability (WEV)
New concept: Window of Endometrial Vulnerability (WEV)
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 57
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 59
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 60
Low birth weight
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 61
The results of this cumulative meta-analysis confirm that the
decreased risks of small for gestational age, low birth weight and
preterm delivery and increased risks of large for gestational age
and high birth weight associated with pregnancies conceived from
frozen embryos have been consistent in terms of direction
and magnitude of effect over several years, with increasing
precision around the point estimates.
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 62
Munro et al. MHR, 2010
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 63
Donor egg and frozen embryo transfer (FET)
Inflammation: Chronic endometritis (CE)
Role of the microbiota
Window of endometrial vulnerability
Endometriosis and the uterus
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Page 64
Chronic endometritis, endometriosis and the microbiota’s role in implantation
Dominique de Ziegler
Foch-ART Center Suresnes France
Pr Jean Marc AyoubiPr René FrydmanPr Philippe BouchardDr Paul PirteaDr Marine Poulain