"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
müllerian remains in adult has been codified and named
müllerianosis, 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
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 Müllerian
anomalies (Nawroth et al., 2006) and other genital anomalies
(Acién, 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–Kü 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
fecundity.
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 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.
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." http://webcache.googleusercontent.com/search?q=cache:GedzAtgFjI8J:www.researchgate.net/publication/51224104_Embryologic_origin_of_endometriosis_analysis_of_101_human_female_fetuses/file/e0b4951b9b2233d071.pdf+&cd=4&hl=en&ct=clnk&gl=us