High Tech in Endometriosi ed Infertilità Roma 04/Marzo 2009

CONVEGNO : High Tech in Endometriosi ed Infertilità
Roma 04 Marzo 2009
Con
L’Alto Patronato del Presidente
della Repubblica
•
•
•
•
•
E con il
Patrocinio della Presidenza del
Consiglio dei Ministri
Patrocino del Ministero del
Lavoro,della Salute e delle Politiche
Sociali
Patrocino del Ministero delle Pari
Opportunità
Patrocinio dell’INPS
Patrocinio dell’INAIL
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Lettura Magistrale :
Genesis of the Endometriosis
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Definition of Endometriosis
ECTOPIC ENDOMETRIUM
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
History of Endometriosis
1690
Daniel Shroen
early descriptions of what today we call endometriosis and adenomyosis.
Disputatio Inauguralis Medica de Ulceribus Ulceri
1776
Roederer, Broughton, Tailford, Duff, Ludgers
in the de ulceribus utero molestis observationibus descrived the desease
and the simptoms
1769
Arthur Duff
described the intense pain of endometriosis, and it was first seen
microscopically in the late 1800s.
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
History of Endometriosis
1860
Carl von Rokitansky
found endometrial glands in the myometrium and designated this finding
as ‘cystosarcoma adenoids uterinum’.
Over the following 60 years ‘adenomyoma’ were considered pat hologies
separate from the so-called ‘haemorrhagic ovarian cysts’ (endometriosis).
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
History of Endometriosis
1917
Thomas Stephen Cullen
researched the ‘mucosal invasion’ already observed by a
number of investigators in several parts of the lower abdominal
cavity. Cullen clearly identified the epithelial tissue invasion as
being made of ‘uterine mucosa’ and defined the mechanism
through which the mucosa invades the underlying tissue.
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
History of Endometriosis
1923
J.Sampson
created the term ‘endometriosis’.
Dr. John Sampson was the first person to hypothesize that
retrograde menstruation contributed to endometriosis 1927
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
History of Endometriosis
1972
C.C.Bird
The current definition of adenomyosis : ‘Adenomyosis may be
defined as the benign invasion of endometrium into the
myometrium, producing a diffusely enlarged uterus which
microscopically exhibits ectopic non-neoplastic, endometrial
glands and stroma surrounded by the hypertrophic and
hyperplastic myometrium’.
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Theories of the Endometriosis
Postulated
•
•
•
•
•
Iatrogenic transplantation - Endometriosis is accidentally transported during
surgery.
Coelomic Metaplasia - This theory holds that certain cells, when stimulated, can
transform themselves into a different kind of cells’.
The hereditary theory - Women with family members who have Endometriosis are
more likely, or are susceptible to developing the disease.
Liver disorders - The liver regulates and removes estrogen from the body. If the
function of the liver is compromised then serious health problems can emerge,
including Endometriosis.
Auto-immune disorder - This disease is an autoimmune disease . Autoimmune
diseases are now widely believed to occur based on genetic predisposition that may
be triggered by environmental and other external factors.
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Theories of the Endometriosis
Postulated
Retrograde menstruation - this theory was postulated
in the early 1927 by Dr Sampson. He speculated that
during menstruation, a certain amount of menstrual fluid
flowed backward from the uterus to ‘shower the pelvic
organs and pelvis lining’ with endometrium cells.
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Retrograde Menstruation Theory
Postulated
Present in 90% of women
does not explain
adenomyosis
retroperitoneal
extra abdominal
prepuberal*
post hysterectomy
prostatic
lack of endometriosis in all
placentals mammals
*An Esp Pediatr. 1996 Apr;44(4):397-8
[Neonatal ovarian endometriosis. Its conservative treatment]
Díez García R, Prieto Díez M, Aguilar Tremoya F.
Departamento de Pediatría y Cirugía Pediátrica, Hospital General Universitario Gregorio Marañón, Madrid.
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Diffusion of Endometriosis
PUBMED works
Endometriosis : Diffusion in the body
Brain
Spinal Cord
Pericardium
Lung
Diaphragm
Leg
Nois and Eye
Lips
Kidney
Bladder
Liver
Pancresas
Bowel
Adrenals
Breast
Skin
Prostate
N°
2
3
1
95
22
5
4
1
23
128
14
5
85
1
1
26
2
Total
410
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Theories of the Endometriosis
Proved
Embriologic theory - This theory
suggests that endometriosis is caused by
microscopic remnants of a women's
embryonic endometrial tissue (from when
she was an embryo), that later develops
into endometriosis.
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Fetal Weeks
Sexual Female Differentiation
0
4
5
Inattivation of one chromosome X
Initial development of Wolff ducts
Migration of primitive germ cells
6
9
Development of Muller ducts
Reduction of sensivity of Muller ducts
9
10
16
24
28
First meiotic profase in to the oogones
Regression of the Wolff ducts
First ovarian follicles
Complete Canalizzation of the vagina
End of moltiplication of oogones
PC Sizonenko in pediatric Endocrinology,edidet J.Bertrand,R.Rappaport,and PC Sizonenko.(Baltimore:Williams e Wilkins,1993),pp.8899.
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Muller ducts and Genital Tract
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Internal Female Genitalia
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Muller , Wolff Ducts and Gonad
7W
Mesonephro cranial Mesonephro caudal Paramesonephro Gonad
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Muller, Wolff Duct and Gonad
7W
Mesonephro Mesonefphro Paramesonephro Gonad
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Internal Genitalia
11 W
Tube Gonad Uterus Vagina
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Embriogenetic theory is demonstrated
1690 - 2009
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Uterus in mammals
• Bipartite
ungulates (deer, moose, elk etc.), carnivores (cats,
and dogs).
• Bicorn
pigs.
• Simplex
• humans, other primates and horses.
• Duplex
• rodents (such as mice, rats and guinea pigs),
marsupials and lagomorpha (rabbits and hares).
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Endometriosis is related to the Tipe of Uterus
Uterus Simplex
endometriosis
humans, other primates
and horses
Uterus Bipartite,
Bicorn, Duplex
absence of endometriosis
all others placentals
mammals
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Septum Uterus
The uterus is formed by the fusion of the two mullerian ducts.
During this fusion a resorption process eliminates the partition
between the two ducts to create a single cavity.
This process begins caudally and advances cranially, thus a
complete septum formation represents an earlier disturbance of this
absorption than the incomplete form.
Causes for incomplete absorption are not known.
Heinonen PK (March 2006). "Complete septate uterus with longitudinal vaginal septum". Fertil. Steril. 85 (3): 700–5.
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Human Uterine Malformations
Prevalence
•
general population
6,7%,
infertility population
7,3%,
recurrent miscarriages
16%
Sotirios H. Saravelos, Karen A. Cocksedge and Tin-Chiu Li. "Prevalence and diagnosis of congenital uterine anomalies in women with reproductive failure: a critical
appraisal.". Human Reproduction Update,
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Is there an association between septate uterus
and endometriosis?
Septate uterus (n = 120)
Endometriosis (%) 31 (25.8)
Controls (n = 486)
Endometriosis (%) 74 (15.2)
•
Human Reproduction Vol.21, No.2 pp. 542–544, 2006
Is there an association between septate uterus and endometriosis?
Frank Nawroth1,3, Gohar Rahimi2, Claudia Nawroth2, Dolores Foth2, Michael Ludwig1
and Torsten Schmidt2
1Endokrinologikum Hamburg, Centre for Hormone and Metabolic Diseases, Reproductive Medicine and Gynaecological Endocrinology,
and 2Department of Obstetrics and Gynaecology, University of Cologne, Germany
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Mullerianosis
•
Uterus-like mass of müllerian origin in the lumbosacral region causing
cord tethering. Report of two cases.
Sharma MC, Sarkar C, Jain D, Suri V, Garg A, Vaishya S.
Department of Pathology, All India Institute of Medical Sciences, New Delhi, India. [email protected]
Fertil Steril. 2005 Oct;84(4):1017.
•
Accessory uterine appendage may be a new Müllerian malformation.
Umobi MA, Meltz RC, Barmat LI.
Department of Obstetrics and Gynecology, Crozer-Chester Medical Center, Upland, Pennsylvania 19013, USA.
[email protected]
Hum Pathol. 2005 Aug;36(8):927-31.
•
Intra-abdominal ovarian-type mucinous cystadenoma associated with
fallopian tube-like structure and aberrant epididymal tissue in a male
patient.
Rizzardi C, Brollo A, Thomann B, Santirocco C, Melato M.
Unit of Pathology of the University of Trieste, Ospedale Maggiore, I-34125 Trieste, Italy. [email protected]
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Embriologic theory
Proved
Explains
adenomyosis
retroperitoneal
extra abdominal
prepuberal
post hysterectomy
prostatic
endometriosis only in
mammals with simplex
uterus
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Development of the uterus
Initial stratification of the uterine wall occurred at 14 WG. At this age, the endometrial
epithelium was simple columnar to pseudostratified and consisted of microvillous cells.
At 18-20 WG the endometrial epithelium became clearly pseudostratified, with active
ciliogenesis and a predominance of microvillous cells.
Primordia of tubular glands were present at 20 WG.
Microvillous cells still predominated in the endometrial epithelium at 21-22 WG and showed
morphological features of apoptosis.
The endometrial stroma at this stage was organizing into a thick lamina propria provided
with subepithelial capillary plexuses.
Our data showed that the epithelial differentiation and
distribution in the uterus occur in the human fetus in a similar
way as in the adult.
Archives of Histology and Cytology
Vol. 70 (2007) , No. 1 p.21-28
Ultrastructural dynamics of the human endometrium from 14 to 22 weeks of gestation
Fabrizio Barberini1), Sayoko Makabe2), Gianfranco Franchitto1), Silvia Correr1), Michela Relucenti1), Rosemarie Heyn1) and Giuseppe Familiari1)
1) Department of Anatomy, University of Rome “La Sapienza”
2) Department of Obstetrics and Gynaecology, Toho University
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Demonstration of embriogenetic Theory
n press
ECTOPIC ENDOMETRIUM IN HUMAN FETUSES IS A
COMMON EVENT AND SUSTAINS THE THEORY OF
MULLERIANOSIS IN THE PATHOGENESIS OF
ENDOMETRIOSIS
Pietro G. Signorile1*, Feliciano Baldi2, Rossana Bussani3, Mariarosaria D’Armiento4,
Maria De Falco5, Alfonso Baldi1,2*
1 Fondazione Italiana Endometriosi, Rome, Italy; 2 Dept Biochemistry, Sect Pathology, Second University of
Naples, Naples, Italy; 3 Dept. of Pathology, University of Trieste, Trieste, Italy; 4 Dept. Scienze Biomorfologiche,
University of Naples "Federico II", Naples, Italy. 5 Dept Evolutive and Comparative Biology, University of Naples
"Federico II", Naples, Italy.
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Demonstration of embriogenetic Theory
We speculated that, if the basis of endometriosis is
an alteration during organogenesis, it would be
possible to see ectopic endometrial tissue
dislocated outside the uterine cavity of human
female fetuses.
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Fetuses Enrolled
•
N° Gestational age Cause of death Presence of ectopic endometrium
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
5 23 weeks Placental pathology No
6 15 weeks Voluntary abortion No
7 20 weeks Voluntary abortion No
8 newborn Primary atypical pneumonia No
9 newborn Acute interstitial pneumonitis No
10 16 weeks Voluntary abortion No
11 23 weeks Placental pathology No
12 14 weeks Placental pathology No
13 21 weeks Voluntary abortion No
14 20 weeks Voluntary abortion No
15 20 weeks Voluntary abortion No
16 18 weeks Voluntary abortion No
17 19 weeks Voluntary abortion No
18 16 weeks Voluntary abortion No
19 23 weeks Placental pathology No
20 25 weeks Placental pathology No
21 newborn Acute interstitial pneumonitis No
22 newborn Primary atypical pneumonia No
23 20 weeks Voluntary abortion No
24 19 weeks Voluntary abortion No
25 newborn Cardiac malformation No
26 newborn Cardiac malformation No
27 20 weeks Voluntary abortion No
28 23 weeks Placental pathology No
29 19 weeks Voluntary abortion No
30 newborn Cardiac malformation No
31 newborn Cardiac malformation No
32 19 weeks Voluntary abortion No
33 newborn Acute interstitial pneumonitis No
34 20 weeks Voluntary abortion No
35 newborn Cardiac malformation No
36 21 weeks Placental pathology No
1
2
3
4
18 weeks Voluntary abortion
24 weeks Placental pathology
25 weeks Placental pathology
16 weeks Voluntary abortion
Yes : Ectopic Endometrium
Fondazione Italiana Endometriosi
Yes
Yes
Yes
Yes
High Tech in Endometriosi ed Infertilità
Methods
•
Pelvic organs were collected en-block, fixed in paraphormaldeyde and
included in paraffin. We performed histological analysis of the pelvic organs
for each fetus, using Hematoxylin/Eosin and Hematoxylin/Van Gieson
staining. For immunohistochemistry 5-7 μm specimen sections embedded in
paraffin, were cut, mounted on glass and dried overnight at 37°C. All
sections were then deparaffinized in xylene, rehydrated through a graded
alcohol series and washed in phosphate-buffered saline (PBS). PBS was
used for all subsequent washes and for antiserum dilution. Tissue sections
were quenched sequentially in 3% hydrogen peroxide in aqueous solution
and blocked with PBS-6% non-fat dry milk (Biorad, Hercules, CA, U.S.A.)
for 1 h at room temperature.
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Methods
•
Slides were then incubated at 4°C overnight at 1:100 dilution with the
following antibodies:
the affinity-purified rabbit antibody ERα for the estrogen receptor (Santa
Cruz, Santa Cruz, CA, USA; cat. # sc-542) and the mouse monoclonal
antibody M11 for CA125( Dako Laboratories, Carpinteria, CA, USA). After
three washes in PBS to remove the excess of antiserum, the slides were
incubated with diluted goat anti-rabbit or anti-mouse biotinylated antibodies
(Vector Laboratories, Burlingame, CA, U.S.A.) at 1:200 dilution in PBS-3%
non-fat dry milk (Biorad) for 1 h. All the slides were then processed by the
ABC method (Vector Laboratories) for 30 min at room temperature.
Diaminobenzidine (Vector Laboratories) was used as the final chromogen
and hematoxylin was used as the nuclear counterstain. Negative controls
for each tissue section were prepared by leaving out the primary antiserum.
Positive controls constituted of tumor tissues expressing either the estrogen
receptor or CA125, were run at the same time. All samples were processed
under the same conditions.
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Ectopic Endometrium Prevalence in Fetuses
Fetuses*
Adult
11%
10%-15%
* First observation
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Distribution of Ectopic Endometrium in the
Fetus
Case 1
25 weeks fetus
Ectopic endometrial structure in the deep recto-vaginal septum,
near perineal floor.
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Distribution of Ectopic Endometrium in the
Fetus
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Distribution of Ectopic Endometrium in the
Fetus
Case 2
24 weeks fetus
Ectopic endometrial structure in the proximity of the Douglas
pouch.
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Distribution of Ectopic Endometrium in the
Fetus
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Distribution of Ectopic Endometrium in the
Fetus
Case 3
18 weeks fetus
Ectopic endometrial structure in the rectal tube at the level of
muscularis propria
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Distribution of Ectopic Endometrium in the
Fetus
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Distribution of Ectopic Endometrium in the
Fetus
Case 4
16 weeks fetus
Ectopic endometrial structure in the mesenchimal tissue close
to the posterior wall of the uterus.
Ectopic endometrial structure in the miometrium, primitive nest
of adenomyosis
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Distribution of Ectopic Endometrium in the
Fetus
D
re
D’
*
u
bl
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
Conclusion
Past
Origin Endometriosis unknown
(chronic desease)
Present
Embriogenetic minimal defect at the
origin of the Endometriosis
(congenital disease)
Future
To define the molecular and organogenetic
misprogramming events causing the minimal
uterus
To develop new strategies for prevention,
diagnosis and therapy
defects in
Fondazione Italiana Endometriosi
High Tech in Endometriosi ed Infertilità
SI RINGRAZIANO
Il Presidente della Repubblica Italiana Giorgio Napolitano per l’Alto Patronato
La Presidenza del Consiglio dei Ministri per il Patrocinio
Il Ministero del Lavoro, della Salute e delle Politiche Sociali per Il Patrocinio
Il Ministero delle Pari Opportunità per il Patrocinio
Gli Enti INPS ed INAIL per il Patrocinio
Le 10.000 Donne iscritte all’Associazione Italiana Endometriosi
Lo staff dell’Associazione Italiana Endometriosi e della Fondazione Italiana Endometriosi
Lo staff medico e di ricerca
Le Università : Federico II e II Università di Napoli, Università di Trieste ed il CNR di Napoli
La EVENTI MADE IN ITALY
Il Rome American Hospital
UN RINGRAZIAMENTO PARTICOLARE A :
Roberta Riposati, Angela Ricci, Sara Alessandrini che con dedizione aiutano le donne
Fondazione Italiana Endometriosi