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Embryologic origin of endometriosis: Analysis of 101 human female fetuses


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The etiology of endometriosis, a gynecological disease characterized by the presence of endometrial glands and stroma outside the uterine cavity, is still unknown. Our research group has recently demonstrated the presence of ectopic endometrium in human female fetuses at different gestational ages. In this manuscript we describe four new cases of fetal endometriosis found among a series of 52 female fetuses analyzed at autopsy. The anatomical localization of this ectopic endometrium, and its histological and immunohistochemical characteristics are depicted. We suggest that endometriosis is caused by dislocation of primitive endometrial tissue outside the uterine cavity during organogenesis. The clinical and pathological implications of these findings are discussed.
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Embryologic Origin of
Endometriosis: Analysis of 101
Human Female Fetuses
Fondazione Italiana Endometriosi, Rome, Italy
Department of Biochemistry, Section of Pathology, Second University of Naples, Naples, Italy
Department of Pathology, University of Trieste, Trieste, Italy
Department of Morphopathology, University of Naples ‘‘Federico II’’, Naples, Italy
The etiology of endometriosis, a gynecological disease characterized by the presence of endometrial glands and stroma outside the uterine
cavity, is still unknown. Our research group has recently demonstrated the presence of ectopic endometrium in human female fetuses at
different gestational ages. In this manuscript we describe four new cases of fetal endometriosis found among a series of 52 female fetuses
analyzed at autopsy. The anatomical localization of this ectopic endometrium, and its histological and immunohistochemical characteristics
are depicted. We suggest that endometriosis is caused by dislocation of primitive endometrial tissue outside the uterine cavity during
organogenesis. The clinical and pathological implications of these findings are discussed.
J. Cell. Physiol. 227: 1653–1656, 2012. ß2011 Wiley Periodicals, Inc.
Endometriosis is defined as the growth of endometrial glands
and stroma at extra-uterine sites (Giudice and Kao, 2004; Baldi
et al., 2008; Signorile et al., 2009a). The prevalence in the
general female population is 6–10%; the frequency increases to
35–60% in women with pain, infertility, or both, (Wheeler,
1992). Endometriosis is responsible for more than 100,000
hysterectomies each year in the United States alone (Carlson
et al., 1994). Despite the fact that this disease is quite common
among women, it is frequently misdiagnosed, the pathogenesis
is unknown and the diagnostic and therapeutic protocols are
still not fully adequate (Bulun, 2009).
The most widely accepted theory for the pathogenesis of
endometriosis is the retrograde menstruation/transplantation
(Sampson, 1927). However, this theory fails to explain the
presence of endometriosis under the peritoneum (the so-called
deep endometriosis) and in remote areas outside the peritoneal
cavity (Signorile and Baldi, 2010a). Indeed, in the last years new
pathogenetic mechanisms have been proposed, such as the
coelomic metaplasia hypothesis or the involvement of
circulating stem cells originating from bone marrow (Nisolle
and Donnez, 1997; Sasson and Taylor, 2008). Interestingly, it
has been postulated by pioneer scientists of this disease in the
late 19th and early 20th century, that endometriosis is caused
by small defects of embryogenesis (Knapp, 1999; Benagiano and
Brosens, 2006). The Mu¨llerian ducts, indeed, give rise to the
female reproductive tract, and this organogenesis is controlled
by complex molecular pathways including the anti-Mu¨llerian
hormone signaling (Klattig and Englert, 2007). Aberrant
differentiation or migration of the Mu¨llerian ducts during
embryogenesis could cause spreading of cells or tracts of cells in
the migratory pathway of fetal organogenesis across the
posterior pelvic floor, thus explaining the observation that
endometriosis is commonly found in the cul-de-sac, uterosacral
ligaments, and medial broad ligaments (Mai et al., 1998).
Recently, our research group has demonstrated the presence
of ectopic endometrium in a significant number of human
female fetuses (5 over 49 cases) analyzed by autopsy in
two different works (Signorile et al., 2009b; Signorile et al.,
Goal of this study was to significantly increase the number of
fetuses analyzed in order to better determine the real biological
impact of this phenomenon.
Materials and Methods
We collected at autopsy from three different institutions, a
series of 101 human female fetuses who died at different times
of gestation. The first 49 cases have been already described in
two precedent works (Signorile et al., 2009b; Signorile et al.,
2010b). The other 52 fetuses were analyzed essentially as
previously described. Briefly, pelvic organs were collected
en-block, fixed in paraformaldeyde and included in paraffin.
Histological analysis of the pelvic organs of the fetus was
performed using Hematoxylin/Eosin and Hematoxylin/Van
Gieson staining. For immunohistochemistry 5–7 mm specimen
sections embedded in paraffin, were cut, mounted on glass and
dried overnight at 378C. Tissue sections were quenched
sequentially in 3% hydrogen peroxide in aqueous solution and
blocked with PBS-6% non-fat dry milk (Biorad, Hercules, CA)
for 1 h at room temperature. Slides were then incubated at 48C
overnight at 1:100 dilution with the following antibodies: The
affinity-purified rabbit antibody ERafor the estrogen receptor
(Santa Cruz, Santa Cruz, CA; cat. # sc-542), the mouse
monoclonal antibody for CD10 (clone M7308) (Dako
Laboratories, Carpinteria, CA). After three washes in PBS to
remove the excess of antiserum, the slides were incubated with
*Correspondence to: Pietro G. Signorile and Alfonso Baldi,
Fondazione Italiana Endometriosi, Via E. Longoni, 81, 00159 Rome,
Italy. E-mail:;
Received 1 May 2011; Accepted 3 June 2011
Published online in Wiley Online Library
(, 15 June 2011.
DOI: 10.1002/jcp.22888
Journal of
Journal of
diluted goat anti-rabbit or anti-mouse biotinylated antibodies
(Vector Laboratories, Burlingame, CA) at 1:200 dilution in PBS-
3% non-fat dry milk (Biorad, Milan, Italy) 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 haematoxylin was used as the nuclear
counterstaining. Negative controls for each tissue section were
prepared by leaving out the primary antiserum. Positive
controls of breast, intestinal, and uterine tumor tissues
expressing each of the antigens analyzed, were run at the same
time. All samples were processed under the same conditions.
Experiments were performed in compliance with the Helsinki
Declaration and the protocols were approved by the ethics
committee of the Italian Endometriosis Foundation.
Pelvic organs were analyzed in their entirety. To this end, four
sections were taken every 150 microns and stained for
histology and for immunohistochemistry, as described in the
methods section. Indeed, we did not find any evidence of
macroscopical defects of the genital system in the fetus analyzed
(data not shown). We found in four out of 52 fetuses (7.7% of
cases), the presence of glandular structures outside the uterine
cavity, clearly resembling the structure of the primitive
endometrium and expressing estrogen receptor. Moreover,
the stroma surrounding these glandular structures expressed
both CD10 and estrogen receptor. The anatomical locations of
these endometrial structures were: Two cases in the recto-
vaginal septum, one case in the proximity of the Douglas pouch,
and one case in the mesenchimal tissue close to the posterior
wall of the uterus. To note, these anatomical sites are common
location for endometriosis in women (Baldi et al., 2008). To
note, the four fetuses were also screened for the most common
chromosomal abnormalities and found to have a normal
cariotype. Table 1 summarizes the characteristics of the four
fetuses and the anatomical locations of the glands. The
histological and immunohistochemical appearances of these
epithelial structures are depicted in detail in Figure 1. We
conclude that these structures must be ascribed to endometrial
tissue, misplaced outside the uterine cavity during the earlier
steps of organogenesis and displaying identical phenotype to the
endometrium present in the uterus.
The data of this manuscript give evidences for an embryological
origin of endometriosis, suggesting alterations in the fine tuning
of female genital structures organogenesis. Indeed, considering
all the 101 human female fetuses analyzed in this and in previous
works form our research group (Signorile et al., 2009b;
Signorile et al., 2010b), we found a total of nine cases of ectopic
endometrium (9% of the total). This incidence is very close to
the one found in the adult female population (Bulun, 2009).
Nevertheless, the existence of choristoma composed of
mu¨llerian remains in adult has been codified and named
mu¨llerianosis, even if this phenomenon has been interpreted,
but not demonstrated, as different from endometriosis (Batt
et al., 2007). In particular, we have carefully analyzed the
molecular phenotype of this ectopic endometrium, showing
that it expresses characteristic markers of the epithelium and of
the stroma of the genital tract, such as CA125, estrogen
receptor, and CD10. The histological and
immunohistochemical analysis of the eutopic and ectopic
endometrium shows a very similar phenotype, as already
described in our previous works (Signorile et al., 2009b;
Signorile et al., 2010b). This observation argues against the
hypothesis that this ectopic endometrium could disappear
during the final steps of organogenesis. We propose that this
ectopic endometrium would remain quiescent and
asymptomatic until puberty, when the hormonal inputs, would
cause its growth and, consequently, the onset of the symptoms
of endometriosis.
Interestingly, several data from the scientific literature
underline the fact that the uterus of women with endometriosis
displays some congenital alterations. Parker et al. (2006),
indeed, described alterations in the muscular characteristics of
the innermost myometrium, such as the thickness and fiber
orientation and abnormal JZ morphology, securely due to the
congenital alteration of uterine wall in patients with
endometriosis. Similarly, Kunz et al. (2000) have described that
infertile women with endometriosis show alterations of the
myometrial wall with an archimetral significantly expanded.
These alterations, moreover, are identical in patients with
adenomyosis, thus supporting the concept that endometriosis
and adenomyosis are the same diseases and that the defect is
primarily at uterine level. Nevertheless, it has also been shown
that endometriosis is more frequent in patients with Mu¨llerian
anomalies (Nawroth et al., 2006) and other genital anomalies
´n, 1986).
Moreover, the presence of the disease in early puberty and
exceptionally also in newborns (Diez Garcia et al., 1996; Batt
and Mitwally, 2003; Marsh and Laufer 2005; Ebert et al., 2009),
as well as in women affected by the Mayer–Rokitansky–Ku¨ ster–
Hauser, a syndrome characterized by congenital aplasia of the
uterus and the upper part of the vagina (Enatsu et al., 2000; Yan
and Mok, 2002; Balci et al., 2008), further supports the validity
of an embryological origin for endometriosis.
Increasing experimental evidences are showing that
exposure to toxicants during critical periods of pre- and peri-
natal development can have long-lasting effects. In particular,
the ability of endocrine disruptors to alter reproductive
function and health in females are quite well characterized,
thanks especially to the numerous works on the effects of
endocrine disruptors exposition in utero (Newbold et al.,
2009). Interestingly enough, there are several studies in humans
linking exposition to endocrine disruptors with insurgence of
endometriosis (Foster, 2008). In particular, a robust
epidemiological study on a wide cohort of patients with
endometriosis has shown that the rate of endometriosis is 80%
greater among women exposed to the endocrine disruptor
diethylstilbestrol in utero (Missmer et al., 2004). In very recent
works, indeed, we have described in mice exposed in utero to
the endocrine disruptor bisphenol A the presence of
endometriosis-like structures and premature ovarian failure
(Signorile et al., 2010c; Signorile et al., 2011), a phenotype, that
strictly recapitulates the clinical picture seen in women suffering
of endometriosis. This observation is in agreement with the
work by Huseby and Thurlow (1982), that have described a
similar phenotype in mice exposed prenatally to low dose of
diethylstilbestrol: Alterations in the genital tract consisting of
adenomyosis and enlargement of the cervix, and reduced
In conclusion, it is possible to claim that endometriosis is a
multi-factorial disease with multifaceted features.
Nevertheless, the demonstration of the presence of ectopic
endometrium in the female fetus in same anatomical locations
TABLE 1. Characteristics of the fetuses with endometriosis
No. Gestational age Cause of death
Location of ectopic
1 21 weeks Placental pathology Recto-vaginal septum
2 23 weeks Placental pathology Recto-vaginal septum
3 24 weeks Placental pathology Douglas pouch
4 24 weeks Placental pathology Posterior wall of the uterus
found in the adult patients affected by endometriosis and with a
frequency very similar, makes the embryogenetic theory on
endometriosis the only one scientifically proved and suggests
that this pathogenetic mechanism is prevalent in the genesis of
this disease. Several epidemiological and animal studies, finally,
suggest an important role for an abnormal estrogenic signaling
during embryogenesis in causing the endometriosis phenotype.
The clinical and therapeutic implications are clear-cut.
Endometriosis could still be regarded as a recurrent disease;
nevertheless recurrence could not be ascribed to the
retrograde menstruation, but to an incomplete surgical
intervention, since it is demonstrated that endometriosis
lesions could be also made up of microscopic foci (Redwine,
2003), and or to different timing of growth of the lesions in the
same patient, probably due to individual susceptibility that is a
typical phenomenon of the diseases inducted by endocrine
disruptors (Mori et al., 2003). Therefore surgery, if complete in
exhausted growth disease can be considered curative.
Contrarily, exposition to endocrine disruptors such as
synthetic estrogens or SERM chemical compounds, though
reducing the symptoms, could increase the growth of
endometriosis. Such studies shed new light on the pathogenesis
of this disease and, possibly, suggest suitable therapeutic targets
for both the typical phenotypes of endometriosis: Ectopic
endometrial tissue and infertility.
This work was supported by a grant from the Italian
Endometriosis Foundation.
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Fig. 1. Histological and immunohistochemical appearance of ectopic endometrium. Panel A: Case 1: Endometriosis in the recto-vaginal septum.
Histological appearance of the endometriotic gland; the vagina is visible in the upper right corner of the picture (Haematoxylin and Eosin, original
magnification T20). Panel B: Case 2: Endometriosis in the recto-vaginal septum. Histological appearance of the endometriotic gland
(Haematoxylin and Eosin, original magnification T20). Panel C: Case 3: Endometriosis in the proximity of the Douglas pouch. Histological
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... Recently, through a careful autopsy analysis, our research group has highlighted the presence of endometriotic structures in a significant number of female fetuses (41)(42)(43). It is interesting to note that these observations have been independently confirmed in subsequent work by other research groups (44). ...
... We have analyzed by autopsy a total number of one hundred female fetuses and found ten cases of with the presence of ectopic endometrium (41)(42)(43). In detail, we carried out a careful dissection of the entire pelvic excavation, analyzing it in its entirety through serial sections. ...
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Endometriosis is a gynecological disease characterized by the growth of endometrial glands and stroma outside the uterine cavity. The incidence of the disease is very high, there are currently no reliable early diagnostic tests, the therapies are only symptomatic and, consequently, the social impact of endometriosis is very important, also considering the related fertility problems. Despite this, the pathogenesis of endometriosis is still not fully defined. Retrograde menstruation and coelomic metaplasia are currently the most recognized pathogenetic hypotheses. Recent experimental evidences generated by our research group and by others have indicated an alteration of the fine-tuning of the female genital system developmental program during a critical window of time in the fetal life as the pathogenetic event prompting to the development of endometriosis later in life. Goal of this article is to present a revision of the recent literature about the different pathogenetic mechanisms proposed for endometriosis with particular emphasis on the embryologic theory. The possible clinical and pathological implications of these findings will be discussed.
... Bouquet De Joliniere et al. and Signorile et al. suggested the embryological background of endometriosis [131,132]. They propose that failures in establishing proper patterns of DNA during the critical embryonic development period might cause endometriosis. ...
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... years, research conducted by our group and others have produced experimental evidence in favor of an alteration of the fine-tuning of the female genital system development during fetal life as the pathogenic event predisposing to the progression of endometriosis later in life (8)(9)(10)(11)(12)(13). This model is also strengthened by the increase in the incidence of endometriosis in patients presenting uterine malformations (14). ...
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... According to the retrograde menstruation theory, implantation of eutopic endometrial tissue rather than cells results in the generation of endometriotic lesions. However, endometriosis is found, though very rarely, in premenarcheal girls who have experienced no menstruation [6,7] and even in the female fetus [8] and men [9,10]. Furthermore, despite the high prevalence of peritoneal endometriosis, it is very rare to microscopically detect the initial steps of endometrial tissue implants, including the attachment of the endometrial tissue to the peritoneum and its secondary proliferation and invasion [3,11,12]. ...
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... This can consequently cause the formation of endometriosis implants, that would remain until puberty. Lately, various research groups have produced substantial experimental data supporting a third theory, that claims the persistence of remnants of the embryonic Müllerian ducts in ectopic locations and its correlation with the endometriosis condition (13)(14)(15)(16). Molecular evidence attributes the ectopic dislocation of these embryonic remnants to the perturbation in the fine-tuning of the female genital system development during a critical window of time in the fetal life; these remnants would remain silent until puberty when, stimulated by estrogens, they would grow into endometriosis lesions (17,18). ...
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Background/aim: Endometriosis is a gynecological estrogen-dependent inflammatory disease due to ectopic endometrial tissue and often associated with pelvic pain. Despite its high prevalence, there are still uncertainties about its pathogenesis, diagnosis, and therapy. Patients and methods: This study presents a retrospective study conducted on 4,401 endometriosis patients, 584 of which underwent laparoscopic procedures. The archived data about clinical signs, magnetic resonance imaging (MRI) results, topography of the endometriosis lesions (obtained via laparoscopy) associated diseases, sample analysis and histological findings were analyzed. Next, the statistical associations between the information for each case, provided by these diagnostic tools were determined. Results: MRI is the most sensitive and specific diagnostic system for ovarian lesions, but poor in sensitivity and specificity for deep endometriosis lesions and not indicated for peritoneal lesions which remain the exclusive prerogative of laparoscopy. Clinical signs are essential for diagnosing deep lesions. The Ca125 and Ca19.9 markers have a poor reliability and their negativity in symptomatic patients has no clinical value, while in positive cases it could probably be used as a monitoring parameter. Conclusion: The results generated will help provide an accurate picture of the topography and distribution of endometriotic lesions. Correlation analyses between the data generated by the clinical-instrumental examinations and those on the site of the disease identified by laparoscopy, allow to define the predictive value of the clinical-instrumental signs in the diagnosis and localization of endometriotic disease.
... It is caused by development of endometrial-like glands and stroma outside the uterus, and though its exact pathogenesis remains unclear, it appears to involve a combination of contributing factors such as retrograde menstruation into the peritoneal cavity 2 , and an altered immune response 3,4 . Other theories on the origin of endometriotic lesions include the embryonic rest theory (prenatal endometrial precursor cells differentiate and become established in the pelvic region) [5][6][7] , coelomic metaplasia (transformation of the peritoneal mesothelium), lymphovascular metastasis (transportation of endometrial cells via lymphatics or blood), or endometrial stem/progenitor cells (reviewed in [8][9][10] ). However, other factors (anatomical, genetic, environmental, lifestyle, menstrual cycle dynamics, aberrant immune responses, etc.) [10][11][12][13][14] are likely involved as 90% of women experience retrograde menstruation 15 , but only about 10% develop endometriosis 13 . ...
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Endometriosis is a chronic, estrogen-dependent gynecological condition affecting approximately 10% of reproductive age women. The most widely accepted theory of its etiology includes retrograde menstruation. Recent reports suggest the uterus is not sterile. Thus, the refluxed menstrual effluent may carry bacteria, and contribute to inflammation, the establishment and growth of endometriotic lesions. Here, we compared and contrasted uterine bacteria (endometrial microbiota) in people with surgically confirmed presence (N = 12) or absence of endometriosis (N = 9) using next-generation 16S rRNA gene sequencing. We obtained an average of > 9000 sequence reads per endometrial biopsy, and found the endometrial microbiota of people with endometriosis was more diverse (greater Shannon Diversity Index and proportion of ‘Other’ taxa) than symptomatic controls (with pelvic pain, surgically confirmed absence of endometriosis; diagnosed with other benign gynecological conditions). The relative abundance of bacterial taxa enriched in the endometrial microbiota of people with endometriosis belonged to the Actinobacteria phylum (Gram-positive), Oxalobacteraceae (Gram-negative) and Streptococcaceae (Gram-positive) families, and Tepidimonas (Gram-negative) genus, while those enriched in the symptomatic controls belonged to the Burkholderiaceae (Gram-negative) family, and Ralstonia (Gram-negative) genus. Taken together, results suggest the endometrial microbiota is perturbed in people with endometriosis.
... Then these progenitor cells develop into adenomyosis in myometrium and peritoneal endometriosis since they acquire their own private mutations; therefore, their clonal trajectories diverge from eutopic endometrium early on [32]. This theory of stem cell dissemination may help explain reported cases of fetal and prepubescent endometriosis and adenomyosis [37][38][39]. ...
Adenomyosis and peritoneal endometriosis are common gynecologic lesions; they are characterized by aberrant locations of normal-appearing endometrium in myometrium and peritoneal surface, respectively. Both ectopic lesions are speculated to originate from uterine eutopic endometrium, which is composed of epithelium and stroma, but how these two different tissue types co-evolve in ectopic locations remain unclear. Here, we analyzed exome-wide mutations and global methylation in microdissected epithelium and stroma separately in paired adenomyosis, peritoneal endometriosis, and endometrium to investigate their relationship. Analyses of somatic mutations and their allele frequencies indicate mono-clonal development not only in epithelium but also in the stroma of adenomyosis and peritoneal endometriosis. Our preliminary phylogenetic study suggests a plausible clonal derivation in epithelium and stroma of both ectopic and eutopic endometrium from the same founder epithelium-stroma progenitor cells. While a patient-specific methylation landscape is evident, adenomyosis epithelium and stroma can be distinguished from normal-appearing eutopic endometrium and epigenetically less homogenous. In summary, endometrial stroma, like its epithelial counterpart, could be clonal and both ectopic and eutopic endometrium following divergent evolutionary trajectories. Our data also warrant future investigations into the role of endometrial stroma in the pathobiology of endometrium-related disorders. This article is protected by copyright. All rights reserved.
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Endometriosis is a chronic disease, influenced by internal and external environment, with long duration from intrauterine life with acme during childbearing, when it is associated to chronic pelvic pains, and infertility/subfertility. DNA hypermethylation of endometrial promoter PRs Hox genes and DNA hypomethylation of promoter ERβ gene is a possible explanation of estrogen dominance, progressive loss of progesterone signaling, followed by progesterone resistance in ectopic, and progesterone attenuance in eutopic endometrium, for failure of hormone therapy (HT), repeated recurrences after surgery, cancers after long time evolution. Animal models, human trials demonstrated progesterone (P4) and progestins influences over progression of disease pathological characteristics, associated to endometrial ER, PR aberrant expressions: ERα loss, and abnormal PRB/PRA ratio. P4 supplementation before mice induced-endometriosis protected from PRs depletion, action that can be translated in women according to the difference of 7 to 12 years between histologic onset and clinical symptoms/signs, parallel to progressive loss of PRs and PR-mediated signaling in ectopic and eutopic endometria. The animal studies have shown that a DNA methylation inhibitor alleviates lesion growth, and induces PRs target gene expression restoration. Continuous/extended contraceptives, dienogest- a new progestin, GnRH agonists/antagonists, aromatase inhibitors, SERM, SPRM, combinated molecules are therapeutic options/perspectives aiming restoration endometrial estrogen-progesterone balance, without disease’s cure. HT may be active alone, or surgery associated.
Endometriosis is an oestrogen-dependant reproductive disease, with genetic, vascular, neural, inflammatory and auto-immune characteristics. There are many theories about the etiology of endometriosis, however, all of these theories have limitations and do not explain all the locations that endometriosis is found or types of patients with endometriosis. The objective of this paper is to postulate the hypothesis that endometriosis is caused by Maternal Microchimerism, the presence of maternal cells in the fetus. A literature review was conducted, analysing the characteristics, current etiological theories of endometriosis, theory limitations and relationship of maternal microchimerism and endometriosis. At time of writing, there was no literature on maternal microchimerism and endometriosis. These results suggest that Maternal Microchimerism could be a cause of endometriosis. This could account for the genetic and auto-immune characteristics seen in people with endometriosis, inducing a micro-environment for vascular, neural and epigenetic changes. This could also account for account for endometriosis seen in non-menstruating patients, such as men, fetuses and post-menopausal women and endometriosis found in non-peritoneal locations. If the hypothesis of Maternal Microchimerism is correct, endometriosis could be considered a pregnancy-related disease that could affect all humans, changing the accepted demographics of patients and potentially new diagnostic techniques and treatment options for patients with endometriosis. Further studies are needed to test this hypothesis.
Technical Report
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Santé publique France a mis en place une surveillance épidémiologique nationale visant à suivre et analyser les indicateurs de santé reproductive en lien possible avec l'exposition aux perturbateurs endocriniens (PE). Elle s'inscrit dans la stratégie nationale sur les perturbateurs endocriniens et utilise des bases de données sanitaires existantes. L'endométriose a été sélectionnée parmi les indicateurs-clés à surveiller, sur la base du poids des preuves concernant le lien avec les PE. Cette étude examine la faisabilité de surveiller l'endométriose en France à partir des données du Système national des données de santé (SNDS), en particulier pour des objectifs de santé environnementale. Une équipe pluridisciplinaire rassemblant cliniciens spécialisés, épidémiologistes, statisticiens et scientifiques expérimentés dans l'exploitation des bases de données du SNDS a été constituée, afin d'élaborer une stratégie de repérage des nouveaux cas d'endométriose. Une revue bibliographique sur l'épidémiologie de l'endométriose et ses liens possibles avec l'exposition aux PE a été menée. Nous avons construit trois indicateurs, reflétant les prises en charge hospitalières pour endométriose, obtenus selon trois algorithmes de sélection des cas au sein du Programme de médicalisation des systèmes d'information (PMSI) :-Le premier est basé uniquement sur la sélection des codes CIM-10 pour l'endométriose (N80) en diagnostic principal, relié ou associé ;-Le deuxième utilise une approche complétant le premier algorithme avec les codes d'actes chirurgicaux issus d'un recensement national des codes effectivement utilisés en association avec l'endométriose, et pouvant conduire à un diagnostic histologique ; .-Le troisième, plus spécifique, s'attache à rechercher une sélection de codes d'actes chirurgicaux proposée par les experts pour identifier certaines formes spécifiques d'endométriose, comme les kystes endométriosiques de l'ovaire, supposées être codées de façon la plus homogène par les cliniciens. Pour chaque indicateur, un cas incident a été défini comme le premier séjour hospitalier sans occurrence de séjour codé endométriose dans les 5 années précédentes au moins.
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Mullerianosis may be defined as an organoid structure of embryonic origin; a choristoma composed of mullerian rests - normal endometrium, normal endosalpinx, and normal endocervix - singly or in combination, incorporated within other normal organs during organogenesis. A choristoma is a mass of histologically normal tissue that is " not normally found in the organ or structure in which it is located" ( Choristoma, 2006). Mullerian choristomas are a subset of non- mullerian choristomas found throughout the body. Histologically, endometrial- mullerianosis and endometriosis are both composed of endometrial glands and stroma, but there the similarity ends. Their pathogenesis is different. Sampson faced the same difficulty with pathogenesis and nomenclature when he wrote: " The nomenclature of misplaced endometrial or mullerian lesions is a difficult one to decide upon." " The term mullerian would be inclusive and correct, but unfortunately it suggests an embryonic origin." Sampson then divided " misplaced endometrial or mullerian tissue" into " four or possibly five groups, according to the manner in which this tissue reached its ectopic location" ( Sampson, 1925). Sampson's classification of heterotopic or misplaced endometrial tissue is based on pathogenesis: 1) " direct or primary endometriosis" [ adenomyosis]; " a similar condition occurs in the wall of the tube from its invasion by the tubal mucosa" [ endosalpingiosis]; 2) " peritoneal or implantation endometriosis;" 3) " transplantation endometriosis;" 4) " metastatic endometriosis;" and 5) " developmentally misplaced endometrial tissue. ( I admit the possibility of such a condition, but have never been able to appreciate it.)" ( Sampson, 1925). It is precisely this condition " developmentally misplaced endometrial tissue," [ mullerianosis] that is the subject of this review.
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Background Endometriosis is a gynecological disease defined by the histological presence of endometrial glands and stroma outside the uterine cavity. Women with endometriosis have an increased risk of different types of malignancies, especially ovarian cancer and non-Hodgkin's lymphoma. Though there are several theories, researchers remain unsure as to the definitive cause of endometriosis. Our objective was to test the validity of the theory of müllerianosis for endometriosis, that is the misplacing of primitive endometrial tissue along the migratory pathway of foetal organogenesis Methods We have collected at autopsy 36 human female foetuses at different gestational age. We have performed a morphological and immunohistochemical study (expression of oestrogen receptor and CA125) on the pelvic organs of the 36 foetuses included en-block and totally analyzed. Results In 4 out of 36 foetuses we found presence of misplaced endometrium in five different ectopic sites: in the recto-vaginal septum, in the proximity of the Douglas pouch, in the mesenchimal tissue close to the posterior wall of the uterus, in the rectal tube at the level of muscularis propria, and in the wall of the uterus. All these sites are common location of endometriosis in women. Conclusion We propose that a cause of endometriosis is the dislocation of primitive endometrial tissue outside the uterine cavity during organogenesis.
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Timed pregnant Balb-C mice were treated from day 1 of gestation to 7 days after delivery with the endocrine disruptor bisphenol a (BPA) (100, or 1,000 microg/kg/day). After delivery, pups were hold for three months; then, ovaries were analyzed in their entirety. We found that in the ovaries of BPA-treated animals the number of primordial follicles and of developing follicles was significantly lower than in the untreated animals. Moreover, the number of atretic follicles was significantly higher in the treated animals. Finally, we found that the animals displaying endometriosis-like phenotype had a more severe impairment of the ovaries in term of number of primordial and developing follicles in comparison with the other mice exposed to BPA. In conclusion, we describe for the first time a complex phenotype in mice, elicited by pre-natal exposition to BPA, that includes ovarian lesions and endometriosis. Considering the high incidence of endometriosis and of the premature ovarian failure associated to infertility in these patients, the data showed prompt a thoroughly reconsideration of the pathological framing of these lesions.
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In women with endometriosis, the peristaltic activity of the uterus is significantly enhanced and may even become dysperistaltic at midcycle. Since uterine peristalsis is confined to the endometrium and the subendometrial myometrium with its predominantly circular arrangement of muscular fibres it was assumed that this dysfunction might be associated with structural abnormalities that could be visualized by high resolution ultrasonography and magnetic resonance imaging (MRI). Therefore, the uteri of women with and without endometriosis were subjected to endovaginal sonography (EVS) and to MRI. In EVS, women with laparoscopically proven endometriosis and infertility exhibited an infiltrative expansion of the archimetra in that the halo surrounding the uterine endometrium and representing the subendometrial myometrium was significantly enlarged compared with controls. The expansion was more pronounced in older than in younger women. There was, however, no relationship between the width of the expansion and the severity of the endometriotic disease. Similar data were obtained by MRI in that the `junctional zone' in women with endometriosis and infertility was expanded in comparison with controls. The results of this study provide further support to the notion that endometriosis is primarily a uterine disease.
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The aetiology of endometriosis, a gynaecological disease defined by the histological presence of endometrial glands and stroma outside the uterine cavity, is still open to debate. Research has recently found evidence for endometriosis in human female fetuses at different gestational ages. This paper reports a new case of fetal endometriosis in a 25-week female fetus, deceased due to placental pathology, from a series of 13 female fetuses analysed at autopsy. The exact anatomical localization of this misplaced endometrium, as well as its histopathological and immunohistochemical characteristics are illustrated. The case suggests that endometriosis can be caused by dislocation of primitive endometrial tissue outside the uterine cavity during organogenesis.
The article below summarizes a roundtable discussion of a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research. Article discussed: Maayan-Metzger A, Schushan-Eisen I, Todris L, et al. Maternal hypotension during elective cesarean section and short-term neonatal outcome. Am J Obstet Gynecol 2010;202:56.e1-5. The full discussion appears at, pages e12-e14.
Endometriosis is an oestrogen-dependent disorder that can result in substantial morbidity, including pelvic pain, multiple operations, and infertility. New findings on the genetics, the possible roles of the environment and the immune system, and intrinsic abnormalities in the endometrium of affected women and secreted products of endometriotic lesions have given insight into the pathogenesis of this disorder and serve as the background for new treatments for disease-associated pain and infertility. Affected women are at higher risk than the general female population of developing ovarian cancer, and they also may be at increased risk of breast and other cancers as well as autoimmune and atopic disorders. Clinicians should assess and follow up affected women for these and other associated disorders. There will probably be a new repertoire of approaches for treatment and perhaps cure of this enigmatic disorder in the near future.
Endometriosis is a chronic gynecological disease characterized by the growth of endometrial tissue outside the uterine cavity. Exposure to endocrine disruptors during critical period of development causes long-lasting effects, being the genital system one of the targets. This study describes the effects on female genital system caused by developmental exposure to the endocrine-disrupting chemical bisphenol A (BPA) during pre- and peri-natal development in mice. To this end, timed pregnant Balb-C mice were treated from day 1 of gestation to 7 days after delivery with BPA (100, or 1000 microg/kg/day). After delivery, pups were held for 3 months; then, pelvic organs were analyzed in their entirety and livers of both pups and moms were studied for the presence of BPA. We found in the adipose tissue surrounding the genital tracts of a consistent number of treated animals, endometriosis-like structure with the presence of both glands and stroma and expressing both estrogen receptor and HOXA-10. Moreover, cystic ovaries, adenomatous hyperplasia with cystic endometrial hyperplasia and atypical hyperplasia were significantly more frequent in treated animals respect to the controls. Finally, BPA was found in the livers of exposed moms and female offspring. In conclusion, we describe for the first time an endometriosis-like phenotype in mice, elicited by pre-natal exposition to BPA. This observation may induce to thoroughly reconsider the pathogenesis and treatment of endometriosis, considering the high incidence of endometriosis and the problems caused by associated infertility.