Nouveau paradigme de prise
en charge thérapeutique
de l’endométriose
Professor Charles Chapron, M.D
Head and Chair
SCGP past-President
SEUD past-President
Université Paris Cité,
Faculté de Médecine,
Assistance Publique - Hôpitaux de Paris (AP-HP),
HU Paris Centre (HUPC), CHU Cochin,
Department of Obstetrics and Gynecology II
and Reproductive Medicine,
Paris - France
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Professor Charles Chapron,
Head and Chair,
Department of Obstetrics and Gynecology II and Reproductive Medicine
 Endometriosis: The implantation theory

Stroma

Glands

Sampson JA AJOG (1927)

 Endometriosis: The implantation theory

Three phenotypes
- SUP: Superficial peritoneal endometriosis
- OMA: Ovarian endometrioma
SUP OMA DIE
- DIE: Deep infiltrating endometriosis
Endometriosis: The implantation theory

- Heterotopic endometrial glands and stroma within myometrium

- Local inflammatory response
- Variable degree of adjacent myometrial hyperplasia

Adenomyosis SUP OMA DIE

SUP: superficial lesion; OMA: endometrioma; DIE: deep infiltrating endometriosis

 Adenomyosis: Prevalence
TV US MRI

Figure 2.
. 2D and 3D-T
TVS imaging of an adenomyo
otic uterus in u
under 30 years old nulligravid
d women, show
wing some

typical 2D
D sonographic features
f of diffu
fuse adenomyos
sis and 3D eval
luation of JZ. (A)
( cal myometrial thickening
asymmetric

of the ute
erine walls (po
osterior wall considerably thicker than ante
erior wall) wit
th heterogeneo
ous myometrium
m (*); (B)

presence of straight ves

ssels, into the hypertrophic a
and asymmetric
cal uterine wa
alls at Power Doppler
D examin
nation and

DIFFUSE
presence of
o hypoechoic striation in the myometrium (p
parallel shadow
wing) (*); (C) myometrial
m anec
choic lacunae or
o cysts (*);

(D) hetero
ogeneous myom
metrium (*); (E)
) 3D-TVS mult
tiplanar view an
nd volume contrast imaging (V

N DIFFUSE
VCI) modality in order to

Mean age N
Mean age
obtain a coronal
c image of
o the uterine ex
xternal profile and
a the cavity, with visualizat
tion of JZ that appeared as a hypoechoic
h

Adenomyosis Adenomyosis
zone arou
und the endometrium; (F) 3D
D-TVS coronal plane of uteru
us showing the
e JZ as an hyp
poechoic zone around the

endometri
ium.

This article is protected by copyr

right. All righ
hts reserved

156 31.5 ± 5.5 292

24 years 101 (34.6%)
53 (33.9%) (range 17 to 41 years)
(range 23-27 years)

Pinzauti et al., Ultrasound Obstet Gynecol (2015) Chapron et al., Hum Reprod (2017)
 Adenomyosis: clinical impacts Adenomyosis and menorrhagia

Table VII Results of univariable analysis looking at

associations between demographic and clinicalTV
477
Uterine adenomyosis and IVF outcome 971

US
factors Clinical pregnancy rates
and the objective assessment of menstrual loss (n 5 304). Naftalin et al.,
Variable Category/ Ratio (95% CI) P-value Hum Reprod Lazzeri et al
term
(2014)
........................................................................................
a
Vercelllini et al.,
Age Linear term 0.58 (0.30, 1.13) ,0.001
Figure

typical

of the
2D
D

ute
2.
.

erine
2D and

sonographic

walls
3D-T
TVS

(po
f

osterior
imaging

features of

wall
of

diffu
fuse
an adenomyo

adenomyos

considerably
otic

sis

thicker
uterus

and Quadratic term

3D

than
in

eval
u
under

luation

ante
erior
30

of

wall)
1.05 (1.00, 1.10)
years

JZ.

wit
th
(
old

(A)
nulligravid

asymmetric

heterogeneo
cal

ous
d women,

myometrial

myometrium
m
show
wing some

thickening

(*); (B)
Human Reprod
BMIa (2014)
presence of straight ves
ssels, into the hypertrophic a
and asymmetric
cal uterine wa
alls at Power Doppler
D examin
nation and

– 1.16 (1.01, 1.32) 0.03

Mean age DIFFUSE Adenomyosis
presence o
of hypoechoic striation in the myometrium (p
parallel shadow
wing) (*); (C) m
myometrial anec
choic lacunae o
or cysts (*);

(D) hetero
ogeneous myom
metrium (*); (E)
) 3D-TVS mult
tiplanar view an
nd volume contrast imaging (V
VCI) modality in order to

N
obtain a c
coronal image o
of the uterine ex
xternal profile a
and the cavity, with visualizat
tion of JZ that appeared as a h
hypoechoic

zone arou

endometri
und

ium.
the endometrium; (F) 3D
Ethnicity
D-TVS coronal plane
Caucasian
of uteru
us
1showing
0.36
the
e JZ as an hyp
poechoic zone around the

Asian 1.18 (0.82, 1.71) Lazzeri et al 5

Afro-Caribbean 1.32 (0.95, 1.82)
This article is protected by copyr
right. All righ
hts
Oriental
reserved
0.97 (0.55, 1.71)

Downloaded from http://humrep.oxfordjournals.org/ at Assistance Publique Hopitaux de Paris on March 28, 2014
Other 1.39 (0.86, 2.25)
24 years Gravidity 1560 1 ,0.001
1 53 (33.9%)
0.69 (0.51, 0.93)
(range 23-27 years) 2– 3 1.54 (1.13, 2.09) Lazzeri et alFigure 2 The relationship between increasing numbers of ultrasound 5
4+ 1.42 (1.02, 1.97)
features of adenomyosis and objectively assessed menstrual loss by pic- Figure 2 Forest plot showing individual and combined effect size estimates and 95% confidence intervals (CIs) in studies that evaluated the likelihood of
Pinzauti et al., Ultrasound
Parity Obstet
0 Gynecol
1 (2015)
,0.001
torial blood loss analysis p
chart
< (PBAC;
0.05 n ¼ 304).
clinical pregnancy in infertile women with or without adenomyosis undergoing IVF/ICSI. Horizontal lines indicate 95% CIs; boxes show the study-specific
1 0.93 (0.68, 1.26) p < 0.05
weight; diamond represents combined effect size; dashed line indicates the overall estimate.
2 2.16 (1.36, 3.43)
3+ 1.57 (1.14, 2.15) VAS DM
Adenomyosis No 1 MRI
selection bias. This also allowed the inclusion of a relatively large
0.06 Live birth rate with crude numbers was reported in three studies Finally, in a meta-regression model, no association was observed
Yes number of women with a greater range of symptoms and varying
1.31 (0.99, 1.73) (Chiang et al., 1999; Costello et al., 2011; Youm et al., 2011), with a between prevalence of endometriosis and the likelihood of clinical preg-
Mantel–Haenszel pooled RR of 0.70 (95% CI, 0.56–0.87; I 2 ¼ 44.2%, nancy. Moreover, when combining the studies by Mijatovic et al. (2010)
Any fibroids No 1 ,0.001 degrees of severity of adenomyosis who are likely, therefore, to be P ¼ 0.166; Supplementary data, Fig. S5). Martı́nez-Conejero et al. and Ballester et al. (2012) in which only women with a concomitant diag-
Yes 1.70 (1.33, 2.17) more representative of the population of women attending gynaecology (2011) reported a live birth rate per cycle of 26.8% (88/328) in the ade- nosis of endometriosis were included, a clinical pregnancy was achieved
Lazzeri et al 5
Submucous (SM) No 1 ,0.001 clinics. In addition, this was a prospective study with clearly defined inclu- nomyosis group and of 37.1% (123/331) in the no adenomyosis group. after IVF/ICSI in 15/41 (36.6%) women with adenomyosis and in
fibroids Yes 2.31 (1.64, 3.25) sion criteria and a standardized approach to the ultrasound examinations Lazzeri et al.,TheThedifference was statistically significant. 58/108 (53.7%) in those without adenomyosis, with a common RR of
common RR of clinical pregnancy per patient was 1.05 (95% 0.65 (95% CI, 0.23–1.84; I 2 ¼ 76.3%, P ¼ 0.040). On the other hand,
Fibroids (combined) None 1 ,0.001 that were all performed p by< 0.05a single highly trained operatorReprod using Sci CI, 0.75–1.48; I ¼ 0.0%, P ¼ 0.698) in the two studiespinfor
2
which a the findings of the two studies with the lower prevalence of concomitant
2010; Costello<et al., 0.05
Figure 2. Visual analog scale score dysmenorrhea and dyspareunia befor
Non-SM fibroids 1.35 (1.01, 1.79) advanced, modern ultrasound equipment. The use of a subjective assess- groups Alongand protocol
B;was P adopted (Mijatovic
waset al., endometriosis (Salimsignificant.
et al., 2012, 8.0%; Thalluri and Tremellen, 2012,
SM fibroids DIFFUSE
2.47 (1.74, 3.49) (2014) < .05 considered statistically
2011), whereas it was 0.58 (95% CI, 0.38–0.88) after pooling 2.3%)stilldemonstratedagreatlyreducedlikelihoodofclinicalpregnancy
Mean age Polyps No N 1 Adenomyosis 0.01
ment of menorrhagia is consistent with recent national guidance (NICE,
data from the four studies in which a short GnRH agonist down- after IVF/ICSI in the adenomyosis group (13/57 ¼ 22.8%) compared
2007) for clinicians, while the use of PBACs allowed menstrual loss to be histological regulation findings,
was used (Maubon etthe al., 2010;
use Youmof 2011; with
et al.,TVS the no-adenomyosis groupis(186/431
examination part ¼ 43.2%;
of common RR,
Yes 1.88 (1.16, 3.04)
assessed as a continuous variable, therefore accounting for severity of clinical Salim et al., 2012; Thalluri
practice forandaTremellen, 2012; I 2 ¼ 64.8%, P ¼ diagnosis
noninvasive 0.52 (95% CI, 0.32–0.85;of I 2 ¼adenomyo-
0.0%, P ¼ 0.908).
sis.8,32,330.036;
Therefore,
Fig. 4). TVS is low cost and high accurate method
a
Odds ratios given for 5-unit increase in explanatory variable. menorrhagia. There was a good level of agreement between subjective for the diagnosis offor diagnosis
adenomyosis, using MRI when transvagi-
Two studies used MRI (Maubon et al., 2010; Ballester
and objective assessment of menorrhagia, so we used both methods nal ultrasound 8 Discussion
VAS DP et al., 2012), withisa common
We found
0.40 (95% CI,in
inconclusive.
the I2present
RR of clinical pregnancy per patient of
¼ 0.0%, P ¼ 0.847).study that the incidence of adeno-
31.5 ± 5.5 292 to assess the severity of menorrhagia in this study.
myosis in figureDIE
0.25–0.64;
istheinresultsthe of thesame
The corresponding
remaining sixorder
In the present
with(95%CI,5–45%)reduction
meta-analysis, adenomyosis
Naftalin etinthelikelihoodofclinical
al showing
was associated with a 28%

Table VIII Results of multivariable analysis looking at

101 (34.6%) There is a lack of consensus in the literature regarding the relationship by TVS TVUS
after pooling
a strong association
studies in which
(40%) between adenomyosis and
pregnancyininfer-

DIE only
was used for diagnosis (Chiang et al., 1999; Mijatovic et al.,
(range 17 to 41 years)
associations between demographic and clinical factors Figure 2. Visual analog scale score for dysmenorrhea and dyspareunia before surgery (A) DIE + AdOsis
between adenomyosis and menorrhagia. This is not surprising bearing in endometriosis 2010;
and 3examinationCostello
to 6 months after
35
et al.,
and DIE
2011; Youm
underlying
et al., 2011; only
Salim et al.,
the crucial
2012; Thalluri
tile women who underwent IVF/ICSI with autologous oocytes. A similar
DIE
detrimental
role +
effect AdOsis
of
was
the transva-
observed when the number of IVF/ICSI cycles
ginal in surgical
the pretherapeuticaltreatment (B) in assessment. In our
groups A and mindB; that thewas
P < .05 majority of studies
Figure
considered wereanalog
2.statistically
Visual retrospective
scale score
significant. in nature and mainly andstudy,
for dysmenorrhea and Tremellen,
dyspareunia before 2012) surgery
was 0.84 (95% (A) CI, 0.68–1.04;
and
2
I3 26.1%,6P months
¼to ¼ was chosen as denominator
after surgical (pregnancy rate per cycle).(B)
treatment However,
in the
and the objective assessment of menstrual loss (n 5 304).
Chapron et al., Hum Reprod (2017) included populationsgroups of womenA andundergoing
B; P < .05 was Before surgery
consideredThese
hysterectomy. statistically
studiessignificant.
the TVS
0.239; Fig. 5).
diagnosis
lated with pain and abnormal uterine bleeding,
of adenomyosis was also well corre-
difference in pregnancy rate between women with or without adeno-
thus supporting
We analysed separately prospective and retrospective trials. The myosis was no longer statistically significant when selecting studies in
After surgery
histological findings, the use of TVS examination is part of
Variable Category Ratio (95% CI) P-value used differing criteria for the diagnosis of adenomyosis and few of them the hypothesis of a possible common pathogenesis and clinics
clinical practice for a noninvasive diagnosis of adenomyo- of the 2 overallRRofclinicalpregnancyperpatientobservedinthefourprospect-
diseases. The most common hypothesis which women underwent for only the
one IVF/ICSI
patho-cycle. These overall esti-
........................................................................................
sis. 8,32,33
attempted to
Therefore, TVS quantify
is low severity
histological
cost and of disease.
findings, In the
high accurate addition,
use
method none
of TVS of the studies genesis
examination is part ofivestudies (Chiang
of adenomyosis etal.,1999;Maubon etal.,2010;Ballesteretal.,2012;
includes mates should be considered with
that endometrial caution. Quantitative
stroma, in heterogeneity
2
Gravidity 0 1 ,0.001for the diagnosis
controlled
of adenomyosis,
for the presence
clinical
8
using
of
MRI for
concomitant
practice when transvagi-
apathology and
noninvasive their potential
diagnosis of adenomyo- Salimetal.,2012)was0.55(95%
direct contact with the CI,0.32–0.96;I
underlying ¼ 54.4%, P ¼ 0.087),myometrium,
among studies was high and,invaginates
in the general analysis, it was reduced
nal ultrasound is inconclusive. whereas 2
1 0.73 (0.55, 0.97) sis.8,32,33
thatTherefore, TVSofisadeno- a itstructurally
was 0.84 (95% CI, 0.67–1.06;weakened I ¼ 32.0%, P ¼ 0.220) myometrium
in the below the 50% threshold only by excluding the study by Maubon et al.
We found effect
inonthethe volumestudy
present of menstrual the loss. Our
incidence studylow cost and high accurate
has clearly shown that or method invades
four retrospective ones (Mijatovic et al., and/or
2010; Costello etreepithelization.
al., 2011; (2010). However, the36-38
during
upper 95%Mechan-
periods
Figu
confidence limit of the resulting
2 –3 1.49 (1.12, 1.99) myosis in DIE is in the samefor orderthe with
diagnosis
Naftalin et al showing using MRI when of
of adenomyosis, regeneration,
transvagi- healing, befor
4+ 1.55 (1.10, 2.08) by TVS aseverity of adenomyosis
strong association (40%) correlates
between with the
adenomyosis
nal ultrasound is inconclusive. amount 8 of menstrual loss.
and ical Youm et al.,to
damage 2011;and/or
Thalluri and Tremellen,
physical 2012; Fig. 6). disruption pooled estimate
of (RR
the ¼ 0.80) was
endometrial–slightly above unity (1.02). B; P <
35

Fibroids (combined) None 1

endometriosisThe severity of adenomyosis
and underlying
,0.001ginal examination in the pretherapeutical
is
the crucial difficult
role to
We found inassessment. ofexpress in
the transva-
the present In studyquantitative terms myometrial interface may be due to dysfunctional uterine
that the incidence of adeno-
our hyperperistalsis and/or dysfunctional contractility of the suben- T
Non-SMa fibroids 1.33 (1.01, 1.75) study, the as TVSthe diagnosis
lesions areofoftenmyosis poorly
adenomyosisin DIE defined and
is inalso
was theycorre-
the well
same may
order bewith
disseminated
Naftalin et aldometrial
showing myometrium. Dislocation of basal endometrium also myo
a lated with pain and abnormalby TVS ableeding,
uterine strong association (40%)
thus supporting between adenomyosis and 39
Endometriosis and adenomyosis: Relationship

Osis patients’ N DIFFUSE FOCAL

phenotype Adenomyosis Adenomyosis

Controls 55 20 (36.4%) 3 (5.4%)

Endometriosis 237 81 (34.2%) 119 (50.2%)

SUP 40 8 (20.0%) 3 (7.5%)

OMA 31 14 (45.2%) 6 (19.3%)
DIE 166 59 (35.5%) 110 (66.3%)
Chapron et al., Hum Reprod (2017)
Rethinking endometriosis diagnosis
Questionning Imaging

TVUS TRUS MRI

Patients with a high

SUP OMA DIE AdOsis
risk of endometriosis
Endometriosis phenotypes + cartography

Chapron C et al., Nat Rev Endocrinol (2019)

 The shift towards clinical diagnosis
Surgical diagnosis

Sir W Osler
(1849-1919)

Questionning
Listen to your patient,
he is telling you the diagnosis

Imaging

SUP OMA DIE AdOsis

Histology
Endometriosis phenotypes

“Moving from a histological to a clinical definition opens the door

to an approach that emphasizes symptoms and their origins.”
Chapron C et al., Nat Rev Endocrinol (2019)
 which was confirmed in the second- which is the largest ever published and allowed us to have
ses of uterine fibroids, another con- sufficient statistical power to detect subtle differences in
is symptom.19 Taken together, our symptom frequency between groups; (ii) the direct and stan-
P is associated with early-onset rather dardized data acquisition through a validated questionnaire;
Isolated Superficial Endometriosis
Dependent variable Prevalence in the Prevalence in the Crude Adjusted
ma- SUP group control group prevalence ratio prevalence ratio
(n = 203) (n = 1292) (95% CI) (95% CI)

Primary infertility 67/202 (33%) 236/1292 (18%) 1.82 (1.45–2.28) 1.83 (1.46–2.24)
Dysmenorrhea 164/203 (81%) 720/1286 (56%) 1.44 (1.33–1.57) 1.43 (1.31–1.52)
(moderate or
severe)
Deep dyspareunia 92/198 (47%) 369/1234 (30%) 1.55 (1.31–1.85) 1.50 (1.25–1.75)
(moderate or
severe)

Reis - Chapron et al., Reprod Sci (2020)

The prevalence ratios were adjusted for age, body mass index, and smoking habits
 Endometriosis and infertility:
1306 Conservative versus surgical management in DIE

Expectant Management
22/61 (36%)

Surgical Management
15/44 (34%)

N = 105 infertile women with RV-DIE

Follow up 24 months Vercellini et al., AJOG (2006)
Figure 1 Cumulative 24-month probability of becoming
pregnant in 105 infertile women with rectovaginal endometri-
osis according to the treatment modality adopted: (dashed
line) radical conservative surgery at laparotomy (n = 44);
 Endometriosis and infertility:
ORIGINAL ARTICLE: ENDOMETRIOSIS

FIGURE 2
Conservative versus surgical management in DIE

Cumulative live birth rate (LBR) according to the follow-up time in women with
Finland Retrospective N =5 43 Rectovaginal endometriosis (CONS) or operatively (OPER). Right: Women treated operatively with rectovagi
Surgery vs conservative Tuominen,
Tuominen. RVE and pregnancy outcome. Fertil Steril 2020. et al., Fertil Steril (2021)
 Fertility and Sterility®

Endometriosis and infertility:

TABLE 2 Conservative versus surgical management in DIE
Outcomes of pregnancy and the first delivery of the women with rectovaginal endometriosis treated either conservatively or operatively.
CONS (n [ 183) OPER (n [ 360)
Outcome n % N % OR (95% CI)
MAR during follow-up 89/183 48.6 149/360 41.4 1.34 (0.94–1.92)
CPR
Total 102/183 55.7 181/360 50.3 1.25 (0.87–1.78)
Spontaneous 37/102 36.3 92/181 50.8 0.55 (0.34–0.91)
LBRa
Total 87/183 47.5 153/360 42.5 1.23 (0.86–1.75)
Spontaneous 34/87 39.1 82/153 53.6 0.56 (0.33–0.95)
Time to delivery (y), median (IQR) 2.2 (2.3) 2.4 (2.3) !0.11 (!0.29 to 0.06)
Follow–up time (y), mean " SD 4.9 " 3.3 5.6 " 3.6 !0.74 (!1.36 to !0.11)
Pregnancy complications
Patients with Patients with
Women
Finland with complication(s)
Retrospective N = 543 46/88
spontaneous LBR
52.3 89/155 57.4
spontaneous LBR
0.81 (0.48–1.37)
Preterm birth
Rectovaginal <37 wk
endometriosis 13/86
34/183 = 18.6%15.1 30/150 20.0
82/360 = 22.8% 0.71 (0.35–1.45)
Pretermvsbirth
Surgery <32 wk
conservative 0/88 — 6/148 4.1 —
Tuominen, et al., Fertil Steril (2021)
Gestational hypertension 2/88 2.3 9/155 5.8 0.41 (0.09–2.00)
Preeclampsia 6/88 6.8 11/155 7.1 1.09 (0.38–3.17)
Placenta previa 8/88 9.1 19/155 12.3 0.80 (0.32–1.99)
Gestational diabetes 14/88 15.9 12/155 7.7 2.90 (1.21–6.96)
 Table VI Determinants for severity of painful

OMA: Determinant for painful symptoms severity

symptoms results from multiple logistic regression
analysis.
(Multiple logistic regression analysis)
Independent Variable expressed as OR (95%IC)
........................................................................................
Dysmenorrhoea Main DIE lesion: intestinea 5.2 (2.7 – 10.3)
Bilateral endometrioma 2.8 (1.4 – 5.6)
Deep dyspareunia Main DIE lesion: USLa 2.0 (1.1 – 3.5)
Non-cyclic chronic pelvic Main DIE lesion: USLa 2.1 (1.1 – 4.3)
pain Left sided endometrioma 3.5 (1.7 – 7.1)
Previous surgeries for 2.2 (1.1 – 4.5)
endometriosis
Gastrointestinal Main DIE lesion: intestinea 7.1 (3.3 – 15.3)
symptoms
LU symptoms Main DIE lesion: vaginaa 13.4 (3.2 – 55.8)
Hematuria 10.0 (1.3 – 77.6)

DIE, deeply infiltrating endometriosis; USL, uterosacral Chapron et al., Hum Reprod (2012)
ligament(s).
a
According to a previously published surgical classification for DIE by Chapron et al.
(2006).
All P , 0.05.
 Endometriosis and Pelvic Pain
Osis WITH Osis WITHOUT p
chronic pain chronic pain

N = 248 N = 224

Endometrioma 114 (46%) 126 (56%) 0.032

Leuenberger et al., Eur J Pain (2022)

 Deeply infiltrating endometriosis
Results according to the presence of OMA (n = 500 patients)

Main DIE lesion R OR 95% CI p - value

USL 0.118 - - NS
Vagina 5.98 1.70 1.1 - 2.6 .014
Bladder 0.137 - - NS
Intestine 34.5 3.59 2.3 - 5.6 < 0.0001
Ureter 8.6 3.91 1.4 – 10.’ .003
Chapron et al., Fertil Steril (2009)
 Deeply infiltrating endometriosis
Results according to the presence of OMA (n = 500 patients)
OMA : No OMA : Yes p - value

Mean number of DIE lesions 1.64 ± 1.0 2.51 ± 1.72 < 0.0001
rAFS scores
Implants 6.7 ± 4.9 28.1 ± 10.1 < 0.0001
Adhesions 16.5 ± 23.7 36.2 ± 28.7 < 0.0001
Total 23.6 ± 25.7 65.6 ± 33.1 < 0.0001
Chapron et al., Fertil Steril (2009)
 Painful OMAs
Modern management
OMAs DIE
VAS

<7 ≥7

« Isolated » « Severe » OMAs USL

Intestine Vagina
OMAs Ureter Bladder

Specific preoperative work-up imaging: Chapron - Santulli et al.,

Referral center Hum Reprod (2012)
Painful ovarian endometrioma
 Lost at follow-up 14 (12.0%)
Hormonal therapies 8 (6.8%)
Surgery 5 (4.3%)

OMA: Spontaneous ovulation rate

Pregnancies
Total
90 (76.9%)
117 (100%)
(n = 244)

Pregnancies
Number of patients conceiving during the 105 (43.0%)
study protocol (n, %)
Patients conceiving during the study protocol (n, %)*
without concomitant deep endometriosis 29 (47.5%; 35.0 – 60.0%)
with concomitant deep endometriosis 76 (41.5%; 34.4 – 48.6%)
Last cycle evaluated before conceiving 4 (3 – 5)
(median, median, 25th – 75th percentiles)
Side of ovulation when conceiving (n, %; 95% CI)**
Healthy ovary 56 (53.3%; 43.3 – 63.1%)
Affected ovary 49 (46.7%; 36.9 – 56.7%)
Pregnancy outcome (n, %)
Miscarriages 11 (10.5%)
Maggiore et al., Hum Reprod (2015)
Second trimester voluntary termination 2 (1.9%)
of pregnancy
Pre-term pregnancies 4 (3.8%)
TABLE 2
Ovarian reserve and OMA recurrence
Comparison of ovarian reserve before second surgery in case subjects and at similar follow-up in control subjects.
Homolateral No OMA
Variable Case (n [ 18)
OMA recurrence
Control (n [ 18)
recurrence P value
AMH (ng/mL), mean " SD 2.7 " 1.9 3.1 " 1.9 .59
Basal FSH (mIU/mL), mean " SD 8.7 " 3.9 8.4 " 3.7 .85
Total AFC (n), median (range) 8 (4–15) 9 (5–15) .37
AFC in the healthy ovary (n), median (range) 5.5 (3–9) 6 (2–12) .54
AFC in the affected ovary (n), median (range) 2 (1–6) 3 (1–5) .24
Volume of the affected ovary in case subjects and of the previously 95.0 " 22.2 6.8 " 0.4 <.001
operated ovary in control subjects (cm3), mean " SEM
Volume of the healthy ovary (cm3), mean " SEM 6.9 " 0.3 6.6 " 0.3 .44
Note: Abbreviations as in Table 1.
Ferrero et al., Fertil Steril (2015)
Ferrero. Ovarian reserve and recurrent surgery. Fertil Steril 2015.
6

Endometriosis: Risk factors associated with

Table II Factors associated with presentation for
infertility
infertility—multiple logistic regression model. (N = 870)

Variable OR (95% CI) P

........................................................................................
Age .32 yearsa 1.9 (1.4 – 2.5) ,0.001
Gravidity .0 0.7 (0.6 – 0.9) ,0.001
Peritoneal superficial endometriosis 3.1 (1.9 – 4.9) ,0.001
Previous history of surgery for endometriosis 1.9 (1.3 – 2.2) ,0.001

CI, confidence interval; OR, odds ratio; ASRM: American Society for Reproductive
Medicine classification.
a
Binary variable .32 versus ≤32 years.
OMA per se is not associated with presentation for infertility
Santulli - Chapron et al., Hum Reprod (2016)
conceive. The general consensus is that OMA larger than 4 cm should be
surgically removed (Dunselman et al., 2014), both to reduce pain and to
 Endometriosis and infertility: Impact of surgery
Endometrioma and ovarian reserve

12 months post operative AMH decrease

Pregnancies rates

100

90
39%
80 decrease
70

60
57%
50 decrease
40

30

20

10

0
Before Surgery Unilateral Cystectomy Bilateral Cystectomy
Metaanalysis
12 studies
Younis YS et al., HRU (2019)
Rethinking endometriosis management
Clinical impact of endometriotic lesions

Pain Endometriotic Infertility

lesions

YES SUP YES

Controversial OMA Controversial
YES DIE Controversial
YES Adenomyosis Yes
Endometriosis - Adenomyosis: Management
E
N
D
O
Pelvic pain Hormonal Ttt
M
E
T
R
O
T
I
C Bleeding Surgery

L
E
S
I
O Infertility ART
N
S
Chapron (2022)
Symptomatic endometriosis:
Limitations for surgical treatment
Althought surgery allows
for exeresis of endometriotic lesions,
it does not treat
the underlying cause of the disease

Chapron et al., Nat Rev Endocrinol (2019)

 Symptomatic endometriosis:
Rationale for medical treatment
- Endometriosis is a chronic inflammatory disease and it requires lifelong management

- Surgical exeresis of endometriotic lesions has no effect on retrograde menstruation

- Medical treatments decrease inflammation, which is a key aspect of endometriosis pathogenesis

- Surgery is inefficient for treating pain due to central sensitization

- Numerous inadequate unecessary surgical procedures are performed for endometriosis

- High rates of symptoms and lesions recurrences after surgical treatment only

- Coexisted adenomyosis conservative surgery is difficult and controversial

Chapron et al., Nat Rev Endocrinol (2019)

Endometriosis: Guidelines
Leyland N, Casper R, Laberge P, Singh SS, SOGC Endometriosis: diagnosis and management.
Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du
Canada : JOGC 2010; 32 (7 Suppl 2): S1-32.

American College of Obstetricians and Gynecologists. ACOG: Practice bulletin no. 114:
Management of endometriosis. Obstet Gynecol 2010; 116 (1): 223-36.

Johnson NP, Hummelshoj L, World Endometriosis Society Montpellier C. Consensus on current

management of endometriosis. Human reproduction 2013; 28 (6): 1552-68.

Dunselman GA, Vermeulen N, Becker C, et al. ESHRE guideline: management of women with
endometriosis. Human Reproduction 2014; 29 (3): 400-12.

National Institute for Health and Care Excellence (NICE): Diagnosis and management of
endometriosis: summary of NICE guidance. BMJ 2017; 358: 4227.
 Endometriosis-related pelvic pain:
Hormonal treatments: a STEPWISE approach

- First line: Low cost drugs

- Oral contraceptives: cyclic, continuous
- Progestogens: oral, IUD

- Second line: High cost drugs

- Dienogest
- GnRH analogues: IM
- GnRH antagonist

Vercellini et al., Fertil Steril (2016)

Endometriosis: is it a progressive disease ?
Evolution of % Mean duration
recto-sigmoid DIE nodules of amenorrhea
between two MRI
(38.2 ± 21.1 months)

Stability 60.5 8.5 months

Regression 11.6 21 months Progression of %
Progression 27.9 7.5 months recto-sigmoid DIE lesion
p < 0.001
Never amenorrhea 39
No continuous amenorrhea 34
Continuous amenorrhea 0

Netter et al., Hum Reprod (2019)

 Endometriosis with no infertility
nor immediate desire for pregnancy

Painful endometriosis:
Rethinking the management Pelvic pain

Fertility 1st line: COC, P, or DNG

preservation ? 2nd line: GnRHa

LONG TERM
Medical Treatment
Adaptated from Chapron et al.,
Nat Rev Endocrinol (2019)
Success Failure
Fertility
preservation
if OMA ?

Complete surgical
Follow-up: Success Post op Medical Treatment exeresis

Questioning
Clinical examination Medical Treatment first rather
TVUS than repetitive surgery Real recurrence
 TABLE 2
Endometriosis-related infertility of adhesions, ablation of peritoneal endometriosis, and chro-
mopertubation. Moreover, the benefits of ovarian cystec-
tomy have never been demonstrated
Pregnancy forPrevious
women resolved to
FERTILITY AND STERILITY! N surgery for Osis p

CONTROVERSY: IS THE OUTCOME OF

In vitro fertilization/intracytoplasmic sperm injection
cycle outcomes in women with an endometrioma present undergoing VOL. ART treatment.
81, NO. 5, MAY 2004Indeed, in the setting of ART,
at the beginning of the stimulation compared with the impact
Copyright ofSociety
©2004 American distortions YES
of pelvic anatomy and
for Reproductive Medicine tuboperito- No

IVF AFFECTED BY ENDOMETRIOSIS?

Published by Elsevier Inc.
women with a previously removed ovarian endometrioma neal inflammatory factors
Printed on acid-free might be greatly(nmitigated.
paper in U.S.A.
= 167) (n = 61)
by laparoscopic cystectomy. Conservative ovarian surgery also poses risks. Because
Endometrioma Endometrioma theDIE
lining of endometrioma228
patients is surrounded by follicle-
49 (29.3%) 34 (55.7%) 0,0002
removed present enclosed oocytes, removal or ablation of the cyst wall might

Removal of endometriomas before in vitro

(147 cycles) (63 cycles) P value Intestinal
inadvertently
publication
injure +normal 137
(33), it was
Intestinal - reported
20 (19.6%)
ovarian tissue. In one recent
91that 54%29of(44.6%)
endometrioma
16 (45.7%)
18 (69.2%)
0,0002

fertilization does not improve fertility

No. of oocytes retrieved 10.8 " 0.6 11.8 " 0.9 .378
No. of mature oocytes 8.7 " 0.6 8.4 " 0.8 .780 cyst walls excised by stripping techniques also contained
100

Fertilization rate (%) 76.5 69.9 .051 recognizable ovarian tissue. The potential for loss of ovarian

outcomes: a matched, case–control study

No. of embryos/cycle 6.0 " 0.4 6.4 " 0.6 .582 reserve is particularly high
80
DIE infertile women
if significant bleeding is encoun-

Cumulative Live Birth Rate

No. of embryos transferred 2.7 " 0.1 2.8 " 0.1 .281 N = 228 patients
tered during the cyst wall dissection or the endometrioma is
Implantation rate (%) 12.8 14.1 .958 60
440 cycles
very large. In addition, women undergoing such procedures Maignien, Santulli,
Positive !-hCG (%) 30.2 28.8 .480 388 transfers
Clinical pregnancy rate (%) 25.4 22.7 .776 necessarily assume all the other potential risks of surgery,
40
p= 0.0003
Chapron
Multiple pregnancy rateJuan
(%) A. Garcia-Velasco, a including
b injury to athe bowel, urinary tract, and large vessels. Reprod Sci (2020)
7.9 M.D.,12.1
Neal G. Mahutte,
.545 M.D., José Corona, M.D.,
20

Biochemical pregnancy (%) 3.9 a 3.0 a .817 b

Although studies have suggested that cystectomy for
Miscarriage rate (%) Victor Zúñiga, M.D.,
3.9 Juan Gilés,
6.1 M.D., Aydin
.636Arici, M.D., and 0
0 1 2 3 4

Cancellation rate (%) Antonio Pellicer,6.3 M.D.c,d 7.6 .844 ovarian endometriosis might reduce the
Sur ge r y + (95%CI):
ovarian
Cycle response to
8.0% (2.4-18.2) 15.1% (7.0-26.1) 20.7% (10.1-33.9) 26.0% (10.0-45.4)

Note: Data are presented as mean " SEM or %.

gonadotropins (13, 15), not all investigators agree. Donnez et
Sur ge r y - (95%CI): 15.5% (5.6-30.1) 31.9% (19.0-45.4) 41.6% (26.3-56.2) 51.3% (30.1-69.0)

Garcia-Velasco etInstituto
al., Valenciano
Fertil
Garcia-Velasco. IVF and endometriosis.
Steril
FertildeSteril
(2004)
Infertilidad, al. (16) performed a retrospective analysis of 85 women with
2004. Rey Juan Carlos University, Madrid, Spain; Hospital Universitario Dr Peset,
Valencia University, Valencia, Spain; and Yale University School of Medicine,
severe New Haven, Connecticut
endometriosis who underwent laparoscopic vaporiza-
tion of the internal cyst wall. In vitro fertilization outcomes
oocyte development (9, 11). Higher rates of granulosa cell were similar in women with endometriosis compared with
apoptosis have beenObjective:
reported To investigate
in women whether
withconservative surgery on ovarian
endometriosis womenendometriomas
with tubalbeforefactor
an IVF infertility.
cycle These investigators also
 Endometriosis and infertility: ART
Page 39 of 47 Draft Manuscript Submitted to Human Reproduction for Peer Review

LBR in case of unoperated bowel deep endometriosis

N = 101

LBR = 65/101 (64%)

Associated OMA: 74 (73%)

Pregnancies rates
Associated Adenomyosis: 89 (88%)

The cumulative live birth rates after four ART cycles using conservative and optimistic Kaplan-Meier
Maignien
methods, in the C, Santulli
study P, Chapron C et al., Fertil Steril (2021)
population.
Note: ART = assisted reproductive technology

98x71mm (300 x 300 DPI)

 Surgery versus ART
Surgery
Fertility results
Negative impact on ovarian reserve
Reduced responsivenessto COS
Limits Ineffectiveness of IUI
Major complications (DIE)
Recurrences of Osis and pain
Incomplete repetitive surgeries
Advantages Treatment of painful symptoms
Avoid very low risk of ovarian cancer
ART
Low risk of TOA
Low risk of disease progression
Multiples pregnancies
Obstetrical and perinatal outcomes
No suitable for pain management
Exeresis of OMA and DIE lesion does
appear to be necessary before ART
 My personal
approach
+ Endometriosis pathogenesis: infammation
+ Non surgical endometriosis diagnosis Surgery must be
+ Efficiency of medical treatments performed when
+ ART results without previous surgery the patient want
+ Limits and risks of surgery to be pregnant
+ Rapid onset of pregnancy after surgery

Chapron et al., Nat Rev Endocrinol (2019)

 My personal
approach
New strategy for endometriosis management:
Chapron et al.,

To plan the best moment Nat Rev Endocrinol

(2019)

to perform the surgery

Long term
Medical
treatment

Once only in « the endometriosis life »

 Infertility
work-up
1

Ovarian reserve
Time available for In Vivo
1

« Emergency
ART »

In principle
NO surgery

Ovarian suppression
!"#$%"&'"()#Borghese *+!#,-*.(/+ (3 months)
0-"#1*+2"3#456768 IVF / ICSI
 Rethinking
endometriosis
Chapron et al.,
Nat Rev Endocrinol (2019)
Surgery ART

Ovarian reserve

Patients’ desire and priorities

Age
Infertility duration
Associated infertility factors
Previous surgery for Osis (specifically OMA)
Pelvic pain intensity
Ovarian endometrioma
Associated adenomyosis
 Rethinking
endometriosis
Surgery

Ovarian reserve Satisfactory

Patients’ desire and priorities Patient choice

Age Young
Chapron et al.,
Infertility duration Short Nat Rev Endocrinol (2019)
Associated infertility factors No
Previous surgery for Osis (specifically OMA) No
Pelvic pain intensity Intense
Ovarian endometrioma No
Associated adenomyosis No
 Rethinking
endometriosis
Chapron et al.,
Nat Rev Endocrinol (2019)
Surgery ART

Ovarian reserve Satisfactory Decreased

Patients’ desire and priorities Patient choice Patient choice

Age Young Old

Infertility duration Short Long
Associated infertility factors No Yes
Previous surgery for Osis (specifically OMA) No Yes
Pelvic pain intensity Intense Low
Ovarian endometrioma No Yes
Associated adenomyosis No Yes
IE
EE
Rethinking
W
REVIEWS
W
W S
SS
endometriosis management
aaa a
Endometriosis
Endometriosis
Endometriosis Immediate
Immediate
Endometriosis
Immediate Post-operative
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Immediate Post-operative
Post-operative Repetitive
Repetitive
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Repetitive ART
ART
Current approach
diagnosis
diagnosis
diagnosis first
first
first
diagnosis
surgery
surgery
surgery medical
medical
medical
first surgery
treatment
treatment
treatment
medical treatment
surgeries
surgeries
surgeries
surgeries
ART
ART

bbb Endometriosis life

Endometriosis life
Three modern management options

Endometriosis life
Endometriosis
Endometriosis
non-surgicalb
Endometriosis Endometriosis
ART life
Long-term
Long-term
Long-term AAsingle, complete,
A single,
single, complete,
complete, Long-term
Long-term
Long-term
non-surgical ART
1 non-surgical
diagnosis
diagnosis
medical treatment
medical
medical treatment
treatment conservative
conservative
conservative surgery
surgery
surgery
ART medical treatment
medical
medical treatment
treatment
diagnosis Endometriosis
Long-term A single, complete, Long-term
non-surgical Desire totreatment ART
Desire
medical
Desire to
to conservative surgery medical treatment
diagnosis become
become
become
pregnant
pregnant
pregnant
Desire to
c c Endometriosis
become life
Endometriosis life
c Endometriosis life
Endometriosis
Endometriosis Long-term pregnant Long-term
Endometriosis
non-surgical Long-term ART Long-term
2 non-surgical
non-surgical
diagnosis
diagnosis
Long-term
medical treatment
medical treatment
medical treatment
ART
ART
Long-term
medical treatment
medical treatment
medical treatment
diagnosis
c Endometriosis
Desire to to
Desire
life
Desire
become
become to
Endometriosis become
pregnant
Long-term pregnant
pregnant Long-term
non-surgical ART
medical treatment medical treatment
diagnosis
d d Endometriosis life
Endometriosis life
d Endometriosis life
Endometriosis
Endometriosis
Endometriosis
non-surgical
Long-term
Long-term ART Desire toLong-term
Long-term A single, appropriate
A single, appropriate
3 non-surgical
non-surgical
diagnosis
Long-term
medical treatment
medical treatment
ART
ART
Long-term
become medical treatment
medical treatment A single,
definitive
definitive appropriate
surgery
surgery
diagnosis medical treatment medical treatment definitive surgery
diagnosis pregnant
Desire to to
Desire
become
Desire
become to
pregnant
become
d
pregnant
Endometriosis
pregnant life Adaptated from Chapron et al.,
6 |6Approaches for management ofofendometriosis. a |a
Fig.
Fig.
Fig. 6
| Approaches
|centres
Approaches
for management
Endometriosis
for management of
endometriosis.
∣Timeline
endometriosis. a
The
| The
| The
conventional
conventional andandcurrent
currentNat Rev Endocrinol (2019)
approach
approach followed
followed bybymost
most
clinical for endometriosis management.
clinical centres for endometriosis management. b
Long-term
b ∣Timeline for for aconventional
a proposed
proposed and current
management
management approach
strategy
Long-term
strategythat
that followed
takes into by
A single,
takes most
account
intoappropriate
account
clinical centres for non-surgical b ∣Timeline ART
endometriosis
endometriosis asas aendometriosis
a lifelong
lifelongcondition management.
condition (endometriosismedical
(endometriosis life). This
treatment
life). for
This a the
is the
is proposed
first option
first management
that
option can
that can strategy
bebefollowed
medical that
treatment
followed if takes
if the intosurgery
patient
definitive
the patient account
wishes
wishes
endometriosis diagnosis
as a lifelong
to become
to become pregnant
pregnant butbut is condition
is unable
unable toto (endometriosis
dodo sosospontaneously.
spontaneously. life). This
TheThe is the firstwith
difference
difference option
the
with that can be followed
conventional
the conventional and
and if the approach
current
current patient wishes
approach
to
(FIG.become
6a)
(FIG. is that
6a) pregnant
assisted
is that assistedbut is unable to
reproductive
reproductive do so spontaneously.
technologies
technologies (ART)
(ART) are The
are difference
provided
provided toto with the
younger
younger conventional
patients
patientswhowhohaveand
haveonlycurrent
only approach
undergone
undergone a a
single operation,
is that which
assisted increases
reproductivetheir likelihood
technologies of becoming
(ART) are pregnant.
provided After childbirth, medical treatment can be
(FIG. 6a)
single operation, which increases their likelihood of becoming pregnant. Desire to After childbirth, medical treatment can be a
to younger patients who have only undergone
provided
single until
operation,the patient
which wishes
increases totheir
become pregnant
likelihood again.
of becoming c |cThis panel
pregnant.
| This shows
After a management
childbirth, medicalstrategy that
treatment can
can be
be
provided until the patient wishes to become pregnant again. become
panel shows a management strategy that can be
followed
provided if a patient
until the refuses
patient or is
wishes unsuitable
to become for surgery.
pregnant In
followed if a patient refuses or is unsuitable for surgery. In this context, this
again. c |
context,
This the
panel patient
shows can
a be given
management ART without
strategy previous
that
the patient can be given ART without previous can be
pregnant
endometriosis surgery. In this situation, it is possible for the patient to avoid undergoing surgery for their endometriosis
Rethinking endometriosis management
Multi - disciplinary patient approach
E
N
D
O
E
Surgery ART
T
R
I
O Medical treatments
T
I
C

L Multidisciplinary surgical team: Laboratory techniques:

E - Gynecological - IVF and ICSI
S - Intestinal - Frozen transfers
I - Urologists - Fertility preservation (3)
- Analgesics drugs
O - Thoracic
N
- Hormonal treatments
S

CELEC: Cochin Endometriosis Life Center of Excellence

Veille sur vous, votre cycle menstruel
et votre endométriose