1 Endometriosis: Epidemiology and Aetiological Factors: Paola Vigano'

Best Practice & Research Clinical Obstetrics and Gynaecology
Vol. 18, No. 2, pp. 177–200, 2004

doi:10.1016/j.bpobgyn.2004.01.007
available online at http://www.sciencedirect.com
Endometriosis: epidemiology and aetiological

factors
Paola Viganò PhD
Research Biologist
Second Department of Obstetrics and Gynecology and Istituto Auxologico Italiano, Cusano Milanino,
University of Milan, Milano, Italy
Fabio Parazzini MD
Assistant Professor
First Department of Obstetrics and Gynaecology, Istituto di Ricerche Farmacologiche ‘Mario Negri’,
University of Milan, Milano, Italy
Edgardo Somigliana MD
Clinical Assistant
Second Department of Obstetrics and Gynaecology, University of Milan, Milano, Italy
Paolo Vercellini* MD
Associate Professor
Clinica Ostetrica e Ginecologica I, Istituto ‘Luigi Mangiagalli’, University of Milar,
Via Commenda 12, 20122 Milano, Italy
Estimates of the frequency of endometriosis vary widely. Based on the few reliable data, the
prevalence of the condition can reasonably be assumed to be around 10%. Although no
consistent information is available on the incidence of the disease, temporal trends suggest
an increase among women of reproductive age. This could be explained—at least in part
—by changing reproductive habits. Numerous epidemiological studies have indicated that
nulliparous women and women reporting short and heavy menstrual cycles are at increased
risk of developing endometriosis; data on other risk factors are less consistent. These
epidemiological findings strongly support the menstrual reflux hypothesis. Additional
evidence in favour of this theory includes the demonstration of viable endometrial cells in
* Corresponding author. Tel.: þ39-2-5799-2331; Fax: þ39-2-5518-5028.

E-mail address: paolo.vercellini@unimi.it (P. Vercellini).
1521-6934/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved.
178 P. Viganò et al
the menstrual effluent and peritoneal fluid, experimental implantation and growth of
endometrium within the peritoneal cavity, observation of some degree of retrograde
menstruation in most women undergoing laparoscopy during menses, and an association
between obstructed menstrual outflow and endometriosis.
Key words: aetiology; endometriosis; endometrium; epidemiology; implantation.
Endometriosis is one of the most common benign gynaecological conditions. To date, at

least 100 papers have been published on the epidemiology of endometriosis.1 These
studies have indicated consistently that nulliparous women and women reporting short
and heavy menstrual cycles are at an increased risk1,2; other factors have been studied but
the data are less consistent. These epidemiological findings support the retrograde reflux
hypothesis—just one of several theories (others include the induction theory, the celomic
metaplasia theory, and the embryonic rests theory3,4) that have been put forward to
explain the pathogenesis of endometriosis. Although not all of these alternative theories
have been abandoned, at present, retrograde menstruation is considered the primum
movens responsible for the development of the disease, at least in its form of peritoneal
implants.5 There is now a general consensus that peritoneal endometriotic lesions can be
attributed to the survival, adhesion, proliferation, invasion and vascularization of
endometrial tissue regurgitated through the fallopian tubes during menstruation, an idea
referred to as implantation theory.6 However, the pathogenesis of ovarian endometriosis
and of specific forms of deep endometriosis is still controversial.7 Thus, one of the main
debates is whether the different forms of the disease have a unique common aetiology or,
conversely, represent three separate entities with different pathogeneses.
This chapter briefly reviews the main findings on the descriptive and analytical
epidemiology of endometriosis and presents old and novel aspects in the aetiology of
the disease.
EPIDEMIOLOGY
Frequency
Few well-conducted studies have reported data on the prevalence of endometriosis and
no data are available on the frequency of the onset of the disease in a given period (its
incidence) in women without a previous diagnosis.
Differences in the prevalence of the disease vary by as much as 30 –40
times.8 – 15 Studies that have analysed the frequency of endometriosis in women
who underwent surgery for fibroids have suggested a prevalence of the condition
of about 10%10, but women with fibroids might share same risk factors with
endometriosis.13 In part, these large variations can be explained by differences in
the indications for laparoscopy and laparotomy, or merely by the differing degrees
of attention paid by surgeons to the accurate identification of endometriotic lesions
and by selective mechanisms drawing patients with suspected endometriosis
towards specialized centres. It is worth noting that there are no published studies
on representative samples of the general population. In general, it is difficult
to compare estimates of prevalence because the published studies include
women with different conditions, and are conducted in centres that apply
different diagnostic criteria and exhibit different levels of clinical interest in
endometriosis.
Endometriosis: epidemiology and aetiological factors 179
Selective mechanisms might also be involved in interpreting temporal trends of the

frequency of endometriosis, suggesting an increase in the incidence of pelvic
endometriosis in women of reproductive age.8,9 Although this increase could, at
least in part, be explained by changing reproductive habits, in the absence of well-
conducted studies, the time-pattern of the incidence of endometriosis is unknown.
Risk factors
Age
Pelvic endometriosis is rare before the menarche and tends to decrease after the menopause.
Studies conducted in women under 50 suggested that the frequency of endometriosis
increased with age until menopause, but more recent studies have not confirmed this.9,10
Different selection criteria can explain some of these discrepancies. For instance,
more young women now have undergone laparoscopy for infertility than was the case
20 years ago, when laparotomy was necessary to diagnose endometriosis. There is no
relationship between age at diagnosis and severity of the disease.
Social class and race

A greater frequency of endometriosis among women of higher social class has been
reported.14 – 16 However, this might be the result of a diagnostic ‘bias’, i.e. greater
attention is paid to pelvic pain or infertility in women of higher social class.
The same diagnostic bias might explain the higher frequency of the disease among
white women. Data on the prevalence in different races often do not take into account
the reason for admission for surgical procedures, which might be selectively associated
with a higher or lower likelihood of the disease being diagnosed. In the USA, where
most studies have been conducted, black women tend to experience lower
socioeconomic conditions than white women. The few studies that have evaluated
populations that were comparable for both indication to diagnostic procedure and
socioeconomic class did not find substantial differences in terms of prevalence of the
disease in women of different races.17
Menstrual and reproductive factors

Information on the relationship between menstrual history and risk of pelvic
endometriosis is scant. Epidemiological studies in the USA and Italy have suggested
that women with early menarche, short and heavy menstrual cycles are at a higher
risk.14,15,18,19 This could be explained as a higher likelihood of pelvic contamination
from menstrual endometrial material—the reflux hypothesis.20
As regards, obstetric history, clinical and epidemiological data suggest that parity is
inversely associated with the risk of endometriosis10,21,22, but, unlike most clinical data,
the few available epidemiological data have not generally shown any relationship
between age at first pregnancy, spontaneous abortion, and endometriosis.14,23
Oral contraceptive use

Data regarding any association between oral contraceptive (OC) use and endometriosis are
conflicting. In some studies, the risk of the disease was lower among current OC users.24
In a large cohort study (the Oxford Family Planning Association study), the rate of
endometriosis was lower among current or recent users than never users (relative risk
(RR) 0.4, 95% confidence interval (CI) 0.2 –0.7), whereas women who had stopped
the pill much earlier (. 2 – 4 years) had a higher risk (RR 1.8, 95% CI 1.0 – 3.1).25 A
similar pattern of risk (i.e. lower rate of the disease in current users and higher in ex-
OC users) was reported from two other cohort studies: the Royal College of General
Practitioners study and the Walnut Creek studies.26,27 Likewise, in a case-control study
conducted in Italy, ever users had a higher risk of pelvic endometriosis but the risk was
restricted to past users.28 – 31
It has been suggested that although OC use temporarily suppresses
endometriosis, previous OC use could increase the risk of the disease. It is
probable that the treatment with OC does not cure endometriosis and that
ectopic endometrial implants survive, although in atrophic form, ready for
reactivation when treatment stops.32
The various biological interpretations of the possible role of OC in
endometriosis include the suggestion that OC reduces the risk by suppressing
ovulation, because regular menses increase the risk of endometriosis.14 However,
endometrial tissue seeded into the peritoneum of castrated monkeys did not
require steroid supplementation, whereas estradiol and/or progesterone were
indispensable for the survival of implants.33 Thus, OC might favour the persistence
of endometriosis.
Dysmenorrhea is a frequent symptom of endometriosis and is also an important
indication for OC use. Thus, the higher risk forever and past users of OC might be due
to selective mechanisms and indication bias. Women with endometriosis-induced
dysmenorrhea might, to some extent, be selectively excluded from the ‘never OC
users’ category, thus raising the risk for ‘past OC users’. On the other hand, OC use
might reduce the likelihood of diagnosis of endometriosis, because OC reduces
dysmenorrhea so current users tend not to be investigated and diagnosed with
endometriosis. Women with undiagnosed endometriosis could thus swell the number
of controls who use OC, leading to an apparent protective effect for current users. In
any case, the lack of relation between total duration of OC use and endometriosis, and
the pattern of risk with time since last use, do not support a causal relationship.
It appears, therefore, that the risk of endometriosis is reduced only among current
(or recent) OC users, and any causal inference is hampered by the question of
indication bias, apart from the absence of a duration/risk relationship. Thus, before
drawing any causal inference, the role of selection and other biases must be considered
in the interpretation of epidemiological data regarding OC use and endometriosis.
Some of these uncertainties are attributable to the methodological difficulties of
epidemiological studies on endometriosis, specifically the problem of identifying the
control group.15 To overcome this problem, studies using different methodological
approaches and different control groups are needed.
Family history
It is suggested that the risk of endometriosis is higher in women whose mother or
sisters have the disease34 – 37 and that the disease might be more severe in women with
a family history.38 In 1980, Simpson et al reported about a six-fold risk of endometriosis
in sisters of affected women.35 A higher frequency of endometriosis in first-degree
relatives of affected women has also been reported in studies from Norway and Italy
(Table 1).
These findings, however, should be considered cautiously because information bias
cannot be excluded. Cases of endometriosis might tend to recall a family history of the
disease more accurately than in controls. Studies of family history of cancer have shown
Table 1. Main results of selected studies on family history of endometriosis and risk of the disease.
Reference, country, reference number Results
Simpson et al 1980, USA, 34 Six-fold increased risk of endometriosis in sisters of

affected women
Moen and Magnus 1993, OR 7.2 ðP , 0:05Þ of endometriosis for one first-degree
Norway, 36 relative with the disease
Moen 1994, Norway, 37 Six sisters of eight monozygotic twins with endometriosis
also had the disease
Gruppo italiano per lo OR 3.4 (P ¼ not significant) of endometriosis for one
studio dell’endometriosis 1997, Italy, first-degree relative with the disease
personal data
that, in general, the recall of cancer in first-degree relatives is satisfactory and

comparable for cases and controls but that recall in second-degree relatives is much
less reliable. However, although available data consider only first-degree relatives in a
family history of endometriosis, recall bias might be more important for benign
conditions.39,40 Further research focused particularly on genetic analyses is needed to
clarify the role of family involvement on the risk of endometriosis.41
Smoking, diet, and other lifestyle issues

Some studies have suggested that heavy smokers are at decreased risk of
endometriosis.14 This finding can be explained in terms of the recognized anti-
estrogenic effects of smoking. Available data on the relationship between smoking and
endometriosis risk are, however, limited and controversial.2,8,25
The relationship between an increased risk of endometriosis and alcohol, coffee,
smoking, or a diet rich in saturated fats42 has been analysed in several studies but
findings are controversial.2 A moderate intake of alcohol is related to increased levels of
estrogens, likewise a high intake of saturated fats is associated with increased risk of
other benign or malignant gynaecological conditions.43,44 However, further studies are
needed to better define the impact of dietetic factors on the risk of endometriosis.
Regular physical activity might be linked with lower levels of estrogens and reduced
endometriosis risk, but data on this issue are scanty.2
Body mass index

Overweight women have been suggested to be at lower risk of endometriosis.14,15,28
Women with an increased body mass index have more irregular menstrual cycles and
increased rates of anovulatory infertility. This might explain the association with
endometriosis.
Miscellaneous
Recent studies have suggested that exposure to dioxins might be a cause of
endometriosis.45,46 Should this finding be confirmed, it suggests that other
environmental factors—as well as hormonal ones—might be associated with the risk
of endometriosis. Some epidemiological data have also linked the risk of endometriosis
with the frequency of immune disorders.2,47,48 In particular, in the Endometriosis Family

Study, the prevalence of rheumatoid arthritis, systemic lupus erythematosus, hypo- or
hyperthyroidism, and multiple sclerosis was higher in women with endometriosis than
in controls. An association with non-Hodgkin lymphomas has also been suggested.49,50
This potential association is of particular interest in purely speculative terms because
these findings might support the hypothesis that the cause of endometriosis includes
immunological mechanisms.
AETIOLOGY OF ENDOMETRIOSIS
Peritoneal endometriosis
The mechanism of histogenesis referred to as implantation theory, or Sampson’s

theory, suggests that endometriotic lesions result from the reflux of viable endometrial
tissue through the fallopian tubes that implants on peritoneal surface or pelvic organs.4
Substantial evidence exist to support this hypothesis: (1) viable endometrial cells have
been demonstrated in the menstrual effluent and peritoneal fluid51; (2) endometrium
can be implanted experimentally and grown within the peritoneal cavity52; (3) all
women have some degree of retrograde menstruation53; (4) there is an association
between obstructed menstrual outflow and endometriosis.54,55 Transtubal dissemina-
tion appears to be the most common route of dissemination, although several other
routes of dissemination of transplanted endometrial cells have been observed, including
lymphatic and vascular channels and iatrogenic deposition.1
Animal models have added credence to the implantation model of endometriosis. TeLinde
and Scott conducted an experiment in monkeys by diverting menstrual flow to permit
intraperitoneal menstruation.56 Five of 10 monkeys developed extensive pelvic adhesions
and microscopic evidence of endometriosis. Similarly, D’Hooghe et al injected menstrual
endometrium in a retroperitoneal location in four baboons.57 All developed endometriosis,
and three of the four had progression of the implants after 12 months of observation.
Recent experiments by Witz et al have given further support to this theory,
specifically demonstrating that endometrium—both stroma and epithelium—can easily
and rapidly adhere to an intact mesothelium.58,59 The experimental model involved
plating explants of peritoneum and culturing them in the presence of endometrium in
form of cellular aggregates or isolated epithelial and stromal cells or menstruated
fragments.58 The attachment process was evaluated by transmission electron
microscopy and a confocal laser-scanning microscope. The results indicate that
endometrial attachment to an intact mesothelium occurs within 1 hours and that
transmesothelial invasion occurs between 1 and 18 –24 hours. Thus, and in contrast to
previous observations60, the intact mesothelium does not seem to constitute a defence
barrier to the adhesion of endometrial fragments and traumas to the mesothelial lining
are not a prerequisite for endometrial cell adhesion.
Based on all these findings, the pathogenesis of peritoneal implants is generally
thought to be based on the implantation of endometrial fragments regurgitated into
peritoneal cavity with retrograde menses.
Features of endometrium favouring ectopic implantation

Sampson’s hypothesis supporting retrograde menstruation as the critical phenomenon in
the development of endometriosis does not explain why the process—a physiological
occurrence—does not result in the disease in all women. From a pathogenetic point of
view, it is important to underline that in the last few years, in patients with endometriosis,
specific constitutive and/or acquired molecular alterations of eutopic and/or ectopic
endometrium favouring its implantation have been identified for all the processes
potentially involved in the phenomenon.3 Molecules involved in apoptosis, adhesion
molecules, growth and angiogenic factors, matrix metalloproteinases (MMPs), and the
mechanisms involved in the escape from the immune system have been recognized as
qualitatively or quantitatively different in eutopic and/or ectopic endometrium of women
with endometriosis compared to the endometrium of disease-free women. These
alterations, which might affect the physiological activity of endometrium, are thought to
explain why only some women develop the disease. A description of these altered
mechanisms will now be reviewed.
Two aspects have to be considered in this context:
1. Endometriosis itself favours a peritoneal inflammatory situation that could

contribute to the maintenance of the disease.61 Thus, it is possible that many of
the molecular alterations found in the ectopic endometrium of women with
endometriosis—but also even in eutopic endometrium and/or systemically—are
actually a consequence of the peritoneal inflammation rather than the cause of the
disease.
2. It has been hypothesized that some of the endometrial changes involved in
implantation might depend on specific predisposing genes.62 In endometriosis, the
initial genetic event might involve genes that regulate cellular attachment (e.g. MMPs
and integrins), unscheduled persistence (e.g. leukocytes or a cytokine receptor), or
steroid responsiveness (e.g. hormone responsiveness). As a result, refluxed
endometrial cells would adhere more readily to cellular surfaces within the
peritoneal cavity. Additional somatic mutations might arise as a second event. These
genes could involve inefficient metabolism of chemicals and/or toxins or cell cycle
regulators or tumour suppressor genes that might confer upon cells the invasive
features causing a more severe disease. Both genetic events might be somatic and,
therefore, acquired after birth in one or few cells, or the initial genetic event might
be germline and every single cell be susceptible to the same likelihood of a second
mutation. This model would be consistent with the polygenic and multifactorial
aetiology of endometriosis and would explain the 5-8% risk for first-degree relatives
to be affected.62,63 Interestingly, according to Simpson et al, there need not be many
genes involved—no more than three need to be pivotally involved; even fewer with
multiple alleles. This is also in line with the genetic basis of most adult-onset
conditions, including many in reproductive medicine such as leiomyomata and
polycystic ovarian syndrome.62 The current task, therefore, is to determine the
number and location of genes presumably pivotal for endometriosis.
Mechanisms of apoptosis
Programmed cell death, commonly referred to as apoptosis, is a fundamental process
responsible for maintaining homeostasis in multicellular organism.64 In contrast to
necrotic cell death, which is usually a result of trauma, programmed cell death is a
physiological process. Accumulating evidence suggests that apoptosis helps to maintain
cellular homeostasis during the menstrual cycle through the elimination of senescent
cells from the functional layer of the uterine endometrium during the late secretory
and menstrual phases of the cycle. This is followed by proliferation of new cells from the
basal layer during the proliferative phase.64 Gebel et al proposed that, in healthy
women, the majority of menstruated cells undergo programmed cell death and do not
survive.65 In women with endometriosis, however, the percentage of menstruated
endometrial cells undergoing apoptosis is greatly reduced, increasing the number of
surviving cells that could continue to exhibit physiological activity. In particular, these
authors have observed that endometrial tissue obtained from women with
endometriosis is significantly less susceptible to spontaneous apoptosis than
endometrial tissue from fertile controls. Spontaneous apoptosis of eutopic endome-
trium from patients with endometriosis and fertile controls, as assessed with an ELISA-
based cell-death detection kit and expressed as absorbance, was found to be 0.63 ^ 0.1
and 1.43 ^ 0.11, respectively. Moreover, decreased apoptosis was also observed in
ectopic versus eutopic endometrium.65
In keeping with this observation, an increase in the endometrial expression of
the anti-apoptotic gene, Bcl-2, has been demonstrated in patients affected.66 Bcl-2
expression in a normal endometrium varies with the menstrual cycle phase being
higher in proliferative glandular epithelium (this is consistent with a positive
regulation by estrogens). Meresman et al have shown a significantly increased Bcl-2
expression in the proliferative eutopic endometrium from women with endome-
triosis compared with that obtained from controls.66 Data from different groups
concerning Bcl-2 expression in ectopic endometrium are generally in keeping with
the observation that this tissue does not present the significant cyclical variations
for Bcl-2 that are observed in eutopic endometrium.67 However, whereas
Watanabe et al did not report an increased expression of Bcl-2 in ectopic samples
when compared to eutopic tissue68, Jones et al found that the number of Bcl-2-
positive stromal cells in ectopic endometrium was significantly higher than in
correspondent eutopic samples.69
The ability to escape from the immune recognition

The mechanisms by which regurgitated endometrial cells are cleared from the
peritoneal cavity in the majority of women are poorly understood. However, it has
been suggested that a peritoneal immunosurveillance involving different cell types might
subserve this role.3,70 In this regard, the pathogenesis of the disease is thought to be
associated with the capacity of endometrial cells to counteract an ongoing local
immunological response.71,72 In vivo and in vitro evidence shows that endometriosis
immunology exhibits features typical of cells that are capable of evading immuno-
surveillance. In general, these endometrial characteristics include:
† modification in the expression of human lymphocyte antigen (HLA) class I antigens

relevant to immune recognition73
† production of circulating antigens—such as soluble HLA or soluble intercellular
adhesion molecule-1—that can compete with surface antigens that are critical to
immune recognition74,75
† direct or indirect secretion of factors and cytokines—such as transforming growth
factor (TGF)-b and prostaglandin E2 (PGE2)—that are able to inhibit specific
lymphoid population functions76,77
† induction of apoptosis in immune cells through Fas-mediated mechanisms.78
As a support to the potential importance of the immune system in the development

of endometriosis, a dysfunction of natural immunity has been associated with the
development of the disease. At least nine independent investigators have reported a
functional defect of peripheral and/or peritoneal lymphoid population of natural killer
(NK) cells in patients with endometriosis.79 – 88 NK cells are cytotoxic effector
lymphocytes that, unlike cytotoxic T cells, do not rearrange antigen-specific cell-surface
receptors.89 They are, however, able to recognize and induce the lysis of deleterious
cells through complex interactions that have been examined in detail. NK cells are
normally present in peritoneal cavity and their reactivities are controlled by both
inhibitory and stimulatory receptors.89 Indeed, according to the recent model by which
NK cells recognize their targets, class I major histocompatibility complex (MHC)
proteins (which are expressed on most normal cells) would act as inhibitory receptors
and their engagement would prevent the NK-cell-mediated lytic process.89 However,
experimental evidence suggests that MHC class I expression on endometrial cells can
be subjected to a modulation that might affect their resistance to NK cell lysis.73
Moreover, particular stressful conditions can induce the expression of stimulatory
receptors on NK cells that can activate the innate immune response despite the
presence of conventional class I molecules on the targets.89 On these bases, NK cells
have been suggested to be operative in limiting ectopic implantation and growth of
retrogradely menstruated endometrial cells and, consequently, a defect of this disposal
system has been postulated to be a contributing cause to endometriosis initiation and
progression. It is still debatable whether the NK cell defect might be non-specific or
more specific for endometrial cells, and whether it might be biologically relevant for the
development of the disease or, conversely, represents a secondary event.90
Notwithstanding this uncertainty, most of the authors agree that, in humans, natural
killing is somehow decreased in endometriosis.
Strong confirmation of a functional defect in natural killing in women with
endometriosis, and a possible increased risk of the disease in specific immunocom-
promised cases, is provided by recent papers that have demonstrated increased levels
of killer cell inhibitory receptors (KIR) on NK cells of affected women.91,92 The KIR
molecules represent a multigenic family of Ig-like members that, unlike the T cell
receptor complex (CD3/TCR), can deliver an ‘off’ signal after binding polymorphic HLA
class I ligands. This interaction leads to the inhibition of natural cytotoxicity. Inhibitory
KIRs are found in three distinct isoforms: KIRs that recognize HLA-C are usually
monomeric glycoproteins of about 58 kDa with two immunoglobulin-like domains
(KIR2D); KIRs that are reactive with HLA-B are approximately 70 kDa monomeric
glycoproteins with three Ig-like domains (KIR3D); and KIRs that are reactive with HLA-
A also possess three extracellular Ig-like domains but are expressed as disulfide-linked
homodimer subunits of approximately 70 kDa.
The percentage of KIR2D L1 þ NK cells in peritoneal fluid and peripheral blood was
shown to be significant higher in women with endometriosis than in women without
the disease. This increase also correlates with the stage and Maeda et al reported that
the percentage of KIR2D L1 þ NK cells in peripheral blood after laparoscopic surgery
for endometriosis did not differ significantly from that before surgery, suggesting that
the increased KIR expression might be a primary event with pathogenetic
importance.88,91,92
Therefore, although specific aspects have to be further confirmed and clarified, from
the quite common concordance among different authors and from data obtained for
KIR expression, the peripheral and/or local inhibition of NK cell function in
endometriosis cannot be denied. A defect of the NK-cell-mediated cytolysis
and scavenging system that removes refluxed endometrial tissue might favour the
implantation and growth of endometrial cells within the peritoneal cavity.
Mechanisms of adhesion
Cell adhesion molecules, most notably the integrins and cadherins, are the main
mediators of cell –cell and cell –matrix adhesion and their expression might be
important for the initial adhesion of the exfoliated tissue.93 Evaluation of the
expression of E-cadherin by immunohistochemistry in eutopic endometrium, and in
peritoneal and ovarian endometriotic lesions, has revealed that the epithelial gland
cells express E-cadherin in all these tissues.94 However, in contrast to eutopic
endometrial glands, epithelial glands in peritoneal endometriotic lesions contain a
population of E-cadherin-negative cells. Absence of E-cadherin is known to be
involved in the acquisition of an invasive phenotype, and the E-cadherin gene is often
mutated in metastasizing carcinoma cells.95 – 98 Although mutations have not been
found in endometriotic tissue so far, the deregulation of the E-cadherin system in the
ectopic tissue might lead to a molecular phenotype similar to that of carcinoma cells
that have acquired mutations.
Many studies have also investigated the expression pattern of integrins under
physiological conditions in eutopic endometrium and in the pathological endometriotic
tissue.99 Many members of the integrin family are expressed by the endometrium
throughout the menstrual cycle. Integrins have been shown to form cell-surface
complexes with MMPs to facilitate matrix degradation and motility, thereby facilitating
directed cellular invasion.100 Differences in the expression patterns of specific integrins
between endometrial and endometriotic tissue might be of relevance because an
aberrant cell – matrix interactions might allow glandular structures to grow deeply into
the stroma, which would not otherwise be possible.93
Recently, however, hyaluronic acid and CD44 have been implicated in the interaction
of peritoneal mesothelium with endometrial cells.101 Peritoneal mesothelium produces
hyaluronic acid that is expressed along the cell membrane of peritoneal mesothelial
cells, contributes to the pericellular matrix, and is a major component of the
extracellular matrix ground substance. CD44 is the principal receptor for hyaluronic
acid. Endometrial stromal and epithelial cells express CD44. Hyaluronidase pretreat-
ment of mesothelial cells decreases the binding of endometrial stromal and epithelial
cells to mesothelium by 40%.101 These findings suggest that the hyaluronic acid/CD44
binding might be involved in the initial adherence of endometrium to peritoneal
mesothelium, although to date no difference in expression of these factors has been
observed in tissues from women with and without endometriosis.
The growth of ectopic cells

Direct evaluation of endometrial proliferation in relation to the presence or absence of
endometriosis has provided conflicting results.102,103 However, the demonstration of
alterations in factors affecting endometrial proliferation suggests that aberrant growth
contributes to the development of endometriosis.
Endometriosis requires estrogen for its continued growth and, if deprived of this
hormone, it tends to regress. Aromatase is a cytochrome P450 enzyme that catalyzes
the rate-limiting step in estrogen biosynthesis, the conversion of androgens to
estrogens. Endometriotic cysts and extraovarian endometriotic implants express high
levels of aromatase. PGE2 was identified as the most potent inducer of aromatase
activity in endometriotic cells and estrogen, in turn, was found to up-regulate PGE2
formation by stimulating cyclo-oxygenase type 2 enzyme. Thus, a positive feedback

loop for continous local estrogen and PGE2 production is established in the
pathological tissue itself. These findings suggest that the aberrant expression of
aromatase in endometriotic tissue might be involved in the pathogenetic mechanisms of
endometriosis, promoting survival and growth of the lesions.104
Together with steroid hormones, specific growth factors have been also
demonstrated to favour endometriotic cell proliferation.105 Basic fibroblast growth
factor (bFGF) is constitutively present in the human endometrium and, as a result of its
mitogenic and angiogenic activities, is probably involved in determining endometrial
tissue modifications during the menstrual cycle.106 We—as well as other investi-
gators—have demonstrated the presence of bFGF and its receptor in eutopic and
ectopic human endometrium.107 Moreover, in a recent study, we observed a significant
correlation between bFGF sense and its antisense mRNA levels in eutopic endometrial
cells derived from healthy (control) women; this is not the case in cells derived from
women affected by endometriosis.108 The antisense transcript (FGF-AS) is thought to
negatively regulate the expression of bFGF. In particular, during the late proliferative
phase of the menstrual cycle, patients demonstrated significantly higher bFGF mRNA
levels and significantly lower FGF-AS mRNA levels than controls. Thus, the ability of the
antisense transcript to negatively regulate bFGF expression by inducing degradation of
its mRNA seems to be less effective in the endometrium of affected patients, and this
might be a mechanism favouring ectopic proliferation.108 It is noteworthy that the
different expression of the sense and antisense bFGF transcripts in the endometrial
cells of women with and without endometriosis is particularly evident during the late
proliferative phase of the menstrual cycle. The effect of estrogens on bFGF expression
is still a matter of controversy. Some studies indicate that bFGF expression correlates
with estrogen levels throughout the menstrual cycle, whereas others have shown no
correlation.106,109,110 Our own research has not found relevant differences in bFGF
mRNA levels as a function of the menstrual cycle in stromal cells derived from controls,
thus confirming the absence of the estrogen effects. In contrast, bFGF mRNA levels in
cells derived from patients were significantly higher in the late proliferative phase and
this is, most likely, a consequence of the concomitant lower expression of the FGF-AS
transcript. These results lead us to speculate that, in women with endometriosis,
estrogens could indirectly influence bFGF expression by modulating the transcription
of its antisense RNA.108
Steroid responsiveness and receptor content

The action of progesterone is mediated by its cognate receptors, which belong to the
nuclear hormone receptor family. Two progesterone receptor (PR) isoforms have
recently been identified: namely PR-A and PR-B.111 PR-A is a 94-kDa protein, whereas
PR-B is a 114-kDa protein that contains additional 164 amino acids at its amino
terminal. Although the exact functions of each of these isoforms are still unclear, there
is increasing evidence that they are functionally different. PR-B tends to be a stronger
activator of progesterone target genes, whereas PR-A has been shown to act as a
dominant repressor of PR-B. PR-A also decreases the response to other steroid
hormones such as androgen and estrogen. PR isoforms have differential target gene
specificity and might interact differently with a given promoter. Furthermore, several
studies have shown that the differences between these isoforms are not only promoter
but also cell-specific. It is, therefore, conceivable that the alteration in the ratio of PR-A
to PR-B in certain target tissues modifies the overall progesterone action via differential
regulation of specific progesterone response genes.
There is some evidence to suggest that endometriosis is characterized by a
resistance to progesterone. Attia et al have shown that only PR-A transcripts are
present in endometriotic tissue sample, whereas both PR-A and PR-B transcripts are
readily detectable in all eutopic samples.111 Thus, progesterone resistance in
endometriotic tissue might be accounted for by the presence of the inhibitory PR
isoform PR-A and the absence of the stimulatory isoform PR-B. Other evidence to
support this observation comes from studies performed on 17-beta hydroxysteroid
dehydrogenase (HSD) type 2, which indicate that tissue expression and activity of the
enzyme, which is modulated by progesterone, vary greatly depending on the presence
or absence of the disease.112 The enzyme 17-beta HSD type 2 catalyzes the conversion
of estradiol to the less biologically active estrone. The previous paradigm-that 17-beta
HDS type 2 activity in the endometrium is elevated during the secretory phase by PR-
mediated action-has recently been shown to hold for diseased endometrium but not
for disease-free endometrium. Indeed, during the proliferative phase, the abundance of
mRNA and activity of 17-beta HSD type 2 are comparable in both disease-free and
diseased endometrium. However, during the secretory phase, whereas the abundance
of mRNA and the activity of 17-beta HDS type 2 increases four- to six-fold in diseased
endometrium, those of 17-beta HDS type 2 remain unchanged in disease-free
endometrium. Moreover, 17-beta HSD type 2 is not expressed in endometriotic tissue
during the luteal phase.111 This finding, which is probably a consequence of the lack of
PR-B in this tissue, could result in elevated concentrations of estradiol in endometriotic
implants, which is essential for their growth. All these data, together with the
observation of failure of endometriosis to regress in response to treatment with
progestins in a significant number of patients111, are strongly suggestive of selective
resistance of certain target genes to progesterone action in this disease.
The invasion of the peritoneum

Peritoneal invasion by endometrial tissue is thought to be dependent on MMPs and
their specific tissue inhibitors (TIMPs). This group of enzymes is important for the
control of extracellular matrix turnover. MMPs play a pivotal role in the cyclic changes
of growth and tissue breakdown that occur in the endometrium and, as expected, are
under the regulation of estrogen and progesterone.113 For the most part, MMPs are
synthesized during the proliferative phase and are thought to be stimulated by estrogen.
Conversely, progesterone decreases the transcription and secretion of MMPs.114,115
MMPs have been implicated in the pathogenesis of endometriosis. In a model of
endometriosis using nude mice and human endometrium, estrogen treatment
of endometrium increased MMP production and led to implantation of
ectopic endometrium.116 By contrast, progesterone treatment of endometrium
(which inhibits MMP production) or addition of TIMP-1 decreased ectopic implantation.
Recent reports suggest that eutopic endometrium from patients with endometriosis
might be more invasive and prone to peritoneal implantation as a result of altered
production of these proteolytic enzymes.117,118 Abnormal expression of specific
members of the MMP and TIMP families has been identified in both eutopic
endometrium of affected women and in ectopic endometrium.119 Moreover,
expression patterns of both MMPs and TIMPs in endometriotic tissue appear to vary
from eutopic tissue patterns, indicating that the cellular mechanisms regulating
these factors might be defective in diseased tissue.120,121 Endometriotic tissue in
the proliferative phase of the menstrual cycle expresses mRNA for the epithelial-
specific MMP matrilysin, as occurs in the normal eutopic tissue. Matrilysin mRNA can
also be detected in endometriotic lesions during the secretory phase, when this
enzyme is absent from eutopic tissue.120,121 Similarly, MMP1, MMP3, and MMP7 are
expressed constitutively in endometriotic lesions whereas they are highly regulated in
eutopic endometrium during the menstrual cycle.120
TIMPs regulate extracellular matrix remodelling by regulating the activity of MMPs.
Although endometriotic lesions produce significant amounts of TIMP-1 in vitro, TIMP-1
concentrations are lower in the peritoneal fluid of women with endometriosis in vivo;
further work is needed to explain these findings.122
Overall, misregulated MMP synthesis and secretion by endometriotic lesions,
combined with aberrant amounts of TIMP-1 in the peritoneal fluid, might derange the
normal proteolytic milieu of the peritoneal cavity thus inducing a more aggressive
behaviour and facilitating invasion of ectopic cells. The exact mechanisms that lead to
the aberrant expression of MMPs and TIMPs in endometriosis have yet to be defined.
The process of neovascularization

Vascularization of endometriotic implants is probably one of the most important
factors in the process of invasion of other tissues by endometrial cells.123 The
peritoneal environment is highly angiogenic, and increased activity and increased
amounts of angiogenic factors have been demonstrated in peritoneal fluid from
women with endometriosis. Laparoscopic examination of endometriotic tissue has
demonstrated this tissue-deriving blood from the surrounding peritoneum.
Angiogenesis is controlled by a number of inducers, including FGF, hepatocyte
growth factor, TGF-a and TGF-b, and inhibitors such as angiostatin, endostatin,
and thrombospondin.124 Of particular importance is a family of glycoproteins—the
vascular endothelial growth factor (VEGF) family—which is being seen as
increasingly significant in processes characterized by both physiological and
pathological angiogenesis.125
VEGF mRNA is present in normal endometrium and its expression is highest during
the secretory phase of the menstrual cycle. VEGF protein is localized predominantly in
endometrial glands; stromal staining is less abundant and more diffuse. Expression of the
VEGF gene in normal human endometrial cells is acutely up-regulated by estradiol in
vitro.126 Other factors known to up-regulate VEGF expression include ipoxia, IL-1b,
TGF-b, epidermal growth factor, and PGE2. The expression of VEGF by endometriotic
implants provides a mechanism for the neovascularization that is commonly observed
around these lesions. VEGF immunostaining has been observed in the epithelium of
endometriotic implants, particularly in haemorrhagic red implants.125
Elevated concentrations of VEGF-A have been also identified in the peritoneal fluid
of women with endometriosis, with the highest levels seen during the proliferative
phase of the cycle—a time at which the peritoneum is exposed to the retrograde
endometrium.127 There is a positive correlation between the severity of endometriosis
and the concentration of VEGF-A in the peritoneal fluid. The cellular sources of VEGF
in peritoneal fluid have not been precisely defined. Although there is evidence to
suggest that endometriotic lesions produce this factor, activated peritoneal
macrophages can also synthesize and secrete VEGF.128
Another factor with potent angiogenic and mitogenic activity is interleukin-8 (IL-8), a
cytokine that induces chemiotaxis of neutrophils.105,129 IL-8 mRNA and protein levels
in the endometrium are significantly higher during early proliferative and late secretory
phases than at mid-cycle.130 IL-8 receptors A and B are also expressed in the
endometrium, mostly localized in the stroma, and receptor expression is higher in the
eutopic endometrium of women with endometriosis than in the endometrium of
women without endometriosis. The cytokine has been found to be elevated in the
peritoneal fluid of women with endometriosis and the levels correlated with the
severity of the disease.131
Endometriosis-related inflammatory phenomena

Endometriosis can be considered to be an inflammatory disease—there is considerable
evidence of elevated levels of peritoneal fluid cytokines and growth factors, alterations
in B-cell activity, and an increased incidence of autoantibodies in women with
endometriosis. Moreover, peritoneal macrophages are increased in number, concen-
tration, and activity in women with the disease.61 Although it is certain that the elevated
cytokine levels or inflammation are a direct result of the disease, it is still unclear
whether the secretion of these pro-inflammation proteins and associated immune cells
into the peritoneal microenvironment contributes to the cascade of events that results
in the establishment and further progression of endometriosis. In this context, one
cytokine that has gained particular attention in the pathophysiology of endometriosis is
tumour necrosis factor (TNF)-a.
TNF-a is a pleiotropic cytokine with a range of beneficial and injurious effects,
depending on the quantity produced, its tissue localization, the local activity of TNF-
binding proteins, and the hormonal and cytokine milieu. In the human endometrium,
TNF-a has been implicated in the normal physiology of endometrial proliferation and
shedding.132 The greatest expression of protein and message is in the epithelial cells,
with most staining occurring during the secretory phase. Staining of stromal cells is also
detected, predominantly in the proliferative phase of the cycle, suggesting differential
local and hormonal regulation of this cytokine. Levels of TNF-a in the peritoneal fluid of
women with endometriosis have been demonstrated to be significantly higher than in
controls.133,134 The high levels of TNF-a detected suggest local release from activated
peritoneal macrophages.135,136
To support the claim that TNF-a is involved in the development and maintenance of
endometriosis, the evidence that TNF-a might directly or indirectly promote
proliferation, adhesion and invasion of endometrial cells, and the associated
angiogenesis seen in endometriosis must be considered. In particular, TNF-a is
supposed to induce:
† proliferation of endometrial cells since it acts sinergistically with FGF to promote

proliferation in an in vitro cell culture system137
† adherence of endometrial tissue to the peritoneum because pretreatment of
mesothelial cells with the cytokine increases adhesion of endometrial stromal cells.
Moreover, TNF-a can affect integrin-mediated adhesion to specific extracellular
matrix components138
† invasion of uterine endometrial fragments because the cytokine causes up-regulation
of several MMPs which could contribute to increased invasiveness139
† angiogenesis by stimulating gene and protein expression of the potent angiogenic
cytokine IL-8. Cultured mesothelial cells expresses TNF-a-inducible IL-8 mRNA and
secreted IL-8 protein.140
Given the ability of TNF-a to affect various processes, we have focused our attention on
this specific cytokine to describe how an inflammatory mediator might be involved in the
pathogenesis of endometriosis. However, other cytokines (IL-6, IL-1) and chemokines
(RANTES, monocyte chemiotactic protein-1) found to be increased in peritoneal fluid of
women with endometriosis might be similarly involved.61,105,133,141,142
Ovarian endometriosis
Three different models have been proposed to explain the pathogenesis of typical
ovarian endometriosis. It is intriguing to note that, from 1919, each of these theories
has been repetitively reproposed by different investigators, who supported them with
different and novel arguments. This gives an idea both of the complexity of the disease
and of the limited progress made in terms of finding its exact cause. Thus, the formation
of typical chocolate cysts might be due to:
† inversion and progressive invagination of the ovarian cortex after the accumulation
of menstrual debris derived from bleeding of superficial endometriotic implants,
which are located on the ovarian surface and adherent to the peritoneum
† the secondary involvement of functional ovarian cysts by endometrial implants
located on the ovarian surface
† metaplasia of the coelomic epithelium covering the ovary.
The first demonstration in favour of the first hypothesis was by Hughesdon who, by
serial sections of ovaries containing an endometrioma, reported that the first
momentum in the formation of 90% of typical chocolate cysts is represented by the
implantation of regurgitated endometrial tissue on the ovarian surface and subsequent
adhesion to the pelvic peritoneum.143 Most endometriomas would form by invagination
of the cortex after accumulation of menstrual debris from bleeding of these surface
endometrial implants adherent to the peritoneum. Using ovarioscopy and in situ
biopsies, Brosens et al confirmed that active endometrial implants are located at the
site of cyst inversion.144 The recent demonstration of the lateral asymmetry of ovarian
endometriotic cysts, which are more frequently found on the left side, supports this
theory.145 In the left adnexal region, the sigmoid colon leans on the left tube and ovary
and is often affixed to the pelvic brim by firm adhesions. This would create a
microenvironment around the left adnexa in which endometrial cells regurgitated
through the tubes would not be exposed to the current of the peritoneal fluid and
would more easily adhere, implant, and grow in the hemipelvis.
Sampson’s original theory related to a possible role for ovarian follicles in the
pathogenesis of endometriotic cysts146 was later supported by Nezhat et al who
observed that some large endometriomata had histological characteristics of luteal or
follicular ovarian cysts.147 More recently, Jain and Dalton showed, by serial transvaginal
tracking of ovarian follicles, that a chocolate cyst can develop from an ovarian follicle.148
In each of the cases reported by these authors, the diagnosis was successfully
confirmed laparoscopically. Biological data demonstrating that follicular fluid can
stimulate endometrial cell growth support this aetiopathogenetic model. Bahtiyar et al
reported that follicular fluid from patients with endometriosis could induce an
increased cell proliferation compared to follicular fluid from women without the
disease.149 In a subsequent study, our group demonstrated that, although both
peritoneal and follicular fluids could stimulate endometrial and endometriotic cell
growth in vitro, this effect was much more evident using follicular fluid, which,
therefore, would represent an extremely favourable environment for cellular

proliferation. This follicular fluid-mediated induction of endometrial cell growth
could not be merely due to steroid hormones because the control media used in this
study actually contained a concentration of hormones similar to that present in the
follicular fluids tested.150
However, there are also several arguments in favour of the hypothesis that the
mesothelium covering the ovary invaginates into the ovarian cortex, forming
mesothelial inclusions, and that coelomic metaplasia of these invaginated epithelial
inclusions is responsible for formation of endometriomata.151 These arguments include
the presence of epithelial invaginations in continuum with ectopic endometrial tissue,
the presence of multilocular endometriomata, and the metaplastic origin of epithelial
tumours of the ovary. Moreover, not all endometriomata are fixed to the peritoneum
and, consequently, would not be explained by theory of adhesion and bleeding of active
superficial implants. Finally, endometriomata have been described in patients with
Rokitansky– Kuster– Hauser syndrome who do not have retrograde menstruation.
Finally, the potential existence of different types of endometriomata that have a differing
histogenesis should perhaps be considered.151
‘Deep’ rectovaginal endometriosis
There are two hypotheses for this form of endometriosis:
† an adenomyotic nodule that originates by modifications of Mullerian rests and

progresses into endometriotic glands by a process of metaplasia
† the natural evolution of peritoneal endometriosis of the pouch of Douglas as a
consequence of its secondary infiltration.
The major arguments in favour of the rectovaginal septal origin of the deep nodule
by metaplasia are the histological characteristics of the lesions and the absence of
evolution of the rectal lesion after the removing of the nodule. Indeed, histologically,
rectovaginal endometriosis has the features of an adenomyotic nodule and, like an
adenomyoma, consists essentially of a circuscribed nodular aggregate of smooth
muscle, glandular epithelium, and scanty stroma. The fact that the stroma component in
the rectovaginal endometriotic nodule is very poor would indicate that the nodule is
different from peritoneal endometriosis, in which epithelial glands are surrounded
systematically by endometrial-type stroma. Moreover, the absence of evolution of the
rectal lesion after removal of the endometriotic glands would suggest that the lesion is
not evolutive; indeed, the apparent invasiveness of the lesions would be essentially
determined by a secondary proliferation of smooth cells induced by endometriotic cells
rather than by the invasion from ectopic endometrial cells.151
In contrast to the metaplasia theory, in a recent study we documented the
concomitant presence of deep peritoneal endometriotic nodules and other forms of
the disease in a large series of women.152 Overall, superficial implants, and/or
endometriotic ovarian cysts, and/or pelvic adhesions were observed in 93.5% of cases
of deep endometriosis. In only a small minority of women (6 out of 93, 6.5%) were deep
peritoneal implants the only observed form of the disease. Similar results were
observed when restricting the analysis to the subgroup of patients with large
rectovaginal and/or bladder endometriotic nodules.152 Moreover, patients with
endometriosis of the rectovaginal septum have about a one-third reduction in the
depth of the pouch of Douglas, an observation that would not be expected if the lesions
were of extraperitoneal origin.153 The rectovaginal septal origin of the deep nodule
would imply that the pouch of Douglas has a similar anatomical structure in women
with and without deep endometriosis. Alternatively, if the foci are a manifestation of an
intraperitoneal disease, the pouch of Douglas should be partly or completely
obliterated, which is actually the case.
Finally, from a histological point of view, Anaf et al—using immunochemistry
techniques with a monoclonal antibody against muscle-specific actin—recently
demonstrated that a smooth muscle component is in fact present in all types of
endometriotic lesions.154 However, they failed to observe this component in disease-
free peritoneum and thus hypothesized that the smooth muscle component might
result from the totipotential capacity of the pelvic and lower abdomen mesothelium to
differentiate. In other words, the implanted endometrium might cause a metaplastic
response in the underlying tissue. The entity of this metaplastic response might differ
according to location, thus explaining histological differences between the different
forms of endometriosis. In light of these findings, the definition of distinct
endometriotic entities based on the difference in the tissue composition of the lesions
(endometriotic lesions versus adenomyotic nodules) appears inconsistent. Also, it
cannot be ruled out that the same disease might originate from several different
ethiopathogenetic mechanisms. In this context, it is interesting to note that Fedele et al
reported four cases of bladder endometriosis resulting from the extension of
adenomyosis lesions of the anterior uterine wall to the bladder.155 However, although
possible, this extremely particular pathogenetic mechanism cannot explain the large
majority of cases of bladder endometriosis.
SUMMARY
Estimates of the frequency of endometriosis vary widely. Based on the few reliable data,
the prevalence of the condition is around 10%. Although there is no consistent
information on the incidence of the disease, temporal trends suggest an increase among
women of reproductive age. This can be partly explained by changing reproductive
habits. Numerous epidemiological studies have indicated that nulliparous women and
women reporting short and heavy menstrual cycles are at increased risk of developing
endometriosis. Data on other risk factors are less consistent.
The above epidemiological findings strongly support the menstrual reflux
hypothesis. There is also substantial biological evidence existing in women with
endometriosis favouring this theory: (1) reduction in the percentage of menstruated
cells undergoing programmed death; (2) increase in the endometrial expression of the
anti-apoptotic gene Bcl-2; (3) the ability of regurgitated endometrial cells to escape
peritoneal immunosurveillance by means of several antibody- and cell-mediated
mechanisms; (4) deregulation in the endometrial cells E-cadherin system and in the
expression pattern of integrins facilitating adhesion, matrix degradation, and invasion;
(5) endometrial expression of high levels of aromatase and bFGF stimulating mitotic
activity; (6) development of selective resistance of certain target genes to progesterone
action; (7) misregulation of endometrial MMP synthesis and secretion combined with
aberrant amounts of TIMP-1 facilitating cell invasion; and (8) increased peritoneal fluid
levels of VEGF and IL-8, which stimulate neoangiogenesis and vascularization of ectopic
implants. Epidemiological, surgical, and pathological data consistently suggest that
peritoneal, ovarian, and so-called ‘deep’ lesions constitute different expressions of a
single disease with a unique pathogenetic mechanism, i.e. retrograde menstruation.
Practice points
† epidemiological studies have consistently indicated that nulliparous women and
those reporting short and heavy menstrual cycles are at increased risk of
endometriosis
† the risk of endometriosis is reduced among current or recent OC users
† peritoneal, ovarian, and ‘deep’ endometriotic lesions constitute different
manifestations of a disease with a single origin, i.e. retrograde menstruation
Research agenda
† the higher incidence of autoimmune affections in women with endometriosis
† the potential resistance to progesterone in women with endometriosis for its
strong clinical implications
† the possibility of employing aromatase inhibitors in the treatment of
endometriosis
† candidate genes for the predisposition to the disease
† the mechanisms underlying the association between endometriosis and non-
Hodgkin’s lymphoma
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Best Practice & Research Clinical Obstetrics and Gynaecology

Vol. 18, No. 2, pp. 177–200, 2004

Endometriosis: epidemiology and aetiological

Paola Viganò PhD

* Corresponding author. Tel.: þ39-2-5799-2331; Fax: þ39-2-5518-5028.

Key words: aetiology; endometriosis; endometrium; epidemiology; implantation.

Endometriosis is one of the most common benign gynaecological conditions. To date, at

Selective mechanisms might also be involved in interpreting temporal trends of the

Social class and race

Menstrual and reproductive factors

Oral contraceptive use

Reference, country, reference number Results

Simpson et al 1980, USA, 34 Six-fold increased risk of endometriosis in sisters of

that, in general, the recall of cancer in first-degree relatives is satisfactory and

Smoking, diet, and other lifestyle issues

Body mass index

with the frequency of immune disorders.2,47,48 In particular, in the Endometriosis Family

The mechanism of histogenesis referred to as implantation theory, or Sampson’s

Features of endometrium favouring ectopic implantation

1. Endometriosis itself favours a peritoneal inflammatory situation that could

The ability to escape from the immune recognition

† modification in the expression of human lymphocyte antigen (HLA) class I antigens

As a support to the potential importance of the immune system in the development

The growth of ectopic cells

formation by stimulating cyclo-oxygenase type 2 enzyme. Thus, a positive feedback

Steroid responsiveness and receptor content

The invasion of the peritoneum

The process of neovascularization

Endometriosis-related inflammatory phenomena

† proliferation of endometrial cells since it acts sinergistically with FGF to promote

therefore, would represent an extremely favourable environment for cellular

‘Deep’ rectovaginal endometriosis

There are two hypotheses for this form of endometriosis:

† an adenomyotic nodule that originates by modifications of Mullerian rests and

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