This document discusses animal models that are used in endometriosis research. It notes that while endometriosis occurs naturally only in humans and some primates, animal models allow researchers to study the pathogenic processes and evaluate potential treatments. Commonly used models include transplanting human or rodent uterine tissue onto the chicken chorioallantoic membrane (CAM) or into the peritoneal cavity of immunocompetent or immunodeficient rodents. These models have provided insights into mechanisms of invasion, angiogenesis, and hormone responsiveness in endometriosis, as well as evaluation of drugs targeting these processes. However, each model also has limitations for studying certain aspects of the disease.

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Human Reproduction Update, Vol.12, No.5 pp. 641–649, 2006 doi:10.1093/humupd/dml026
Advance Access publication June 14, 2006
Animal models in endometriosis research
Ruth Grümmer
Institute of Anatomy, University Hospital Essen, Essen, Germany
E-mail: ruth.gruemmer@uni-essen.de
Endometriosis is a common gynaecological disease, defined as the presence of endometrial tissue outside the uterus,
causing pelvic pain and subfertility in ~10% of women of reproductive age. Current therapies lead to pain relief,
however, do not address the causes and entail severe side effects. Still little is known about the pathogenic processes
leading to the development and maintenance of endometriosis. Because endometriosis occurs spontaneously only in
humans and some non-human primates, animal models of induced endometriosis have been developed and are of
high value for the evaluation of pathophysiological mechanisms underlying the development of this disease. These
experimental models include the autotransplantation of uterine fragments into the peritoneal cavity of rodents and
non-human primates or the heterotransplantation of human endometrial or endometriotic tissue to immunodeficient
mice or onto the chicken chorioallantoic membrane (CAM). This review describes the animal models for endometrio-
sis and assesses their different potentials and limitations in regard to endometriosis research, with the aim of develop-
ing novel non-invasive diagnostic tools and improved strategies for the treatment of endometriosis in women.
Key words: animal model/CAM/endometriosis/non-human primates/rodents
The need for animal models in endometriosis research
Endometriosis is one of the most frequent benign gynaecological
diseases; it is thought to occur in 7–10% of women (Wheeler,
1989) but may even affect up to 60% of women of reproductive
age with pelvic symptoms or disturbance of fertility (Pellicer
et al., 2001; Giudice and Kao, 2004). Yet, little is known about the
pathogenic processes leading to the development and maintenance
of this disease, and currently available medical therapies are unsat-
isfactory, because they focus on treating the symptoms rather than
curing the causes. In addition, they cannot be used for prolonged
duration because of severe secondary side effects (Rice, 2002).
Thus, there is a definite need to develop new drugs to provide spe-
cific and more efficient therapeutic alternatives that eliminate
endometriotic lesions, prevent recurrences and do not interfere
with the fertility potential.
One widely accepted mechanism for the development of perito-
neal endometriotic lesions is the adhesion and growth of endome-
trial fragments deposited into the peritoneal cavity via retrograde
menstruation (Sampson, 1927). However, because retrograde
menstruation occurs in nearly all women of reproductive age
(Halme et al., 1984), impairment of additional factors is needed
for the establishment and maintenance of these ectopic lesions.
Because, at the time of clinical presentation, most women already
have established endometriosis, it is hardly possible to give exper-
imental evidence for physiological roles in the pathogenesis of this
disease in humans. In addition, ethical considerations limit the
performance of controlled experiments, and it is not possible to
monitor the disease progression without performing repeated
laparoscopies. Thus, research into the fundamental mechanisms
by which menstrual endometrium adheres, invades and establishes
a functional vasculature to persist in an ectopic site, as well as the
development of new therapeutical approaches, is best performed
in experimental animal models.
Because menstrual shedding is a requirement for the spontane-
ous development of this disease, endometriosis occurs naturally
only in humans and some non-human primates. Non-human pri-
mates have been extensively used for the investigation of endome-
triosis; however, the very high costs of animal handling limit the
use of monkeys as an experimental model. For this reason, the
establishment of small laboratory animals, especially rodents, as
models for endometriosis by the transplantation of pieces of
endometrial tissue to ectopic sites has greatly extended in recent
years. This review provides a survey of commonly used animal
models and their application for different challenges.
CAM assay
Characterization of the CAM assay
The chicken chorioallantoic membrane (CAM) model can be con-
sidered as an animal model in the broader sense. Originally, it had
been developed to study the invasive, metastatic and angiogenic
potential of neoplastic cells (Scher et al., 1976; Armstrong et al.,
1982). It has been established as a model for endometriosis by cul-
turing fragments of human endometrial tissue on the basal layer of
the CAM of fertilized chicken eggs after prior incubation for 7–10
days (Malik et al., 2000; Maas et al., 2001). Endometrial fragments
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from the proliferative and secretory phase of the menstrual cycle
as well as the menstrual endometrium invade across the epithe-
lium into the mesenchymal layer and develop endometriosis-like
lesions in this layer of the CAM within 3 days after grafting of the
human tissue (Maas et al., 2001; Nap et al., 2003, 2004). It was
shown that these endometrial fragments needed to contain intact
glandular structures as well as stromal components.
Application of the CAM assay
Angiogenesis could be documented by ingrowth of vessels from
the CAM into the human endometrial fragments (Maas et al.,
2001). The anti-angiogenic factors endostatin, TNP-470 and
anti-vascular endothelial growth factor (VEGF) antibodies all
significantly decreased the angiogenic response to endometrial
transplants (Nap et al., 2005). Endometrial fragments of
women with and without endometriosis showed no significant
differences in VEGF expression or angiogenic induction in this
assay (Gescher et al., 2005). In contrast, Oosterlynck et al.
(1993) demonstrated that peritoneal fluid of women with
endometriosis induced significantly higher angiogenic
responses in the CAM than peritoneal fluid of women without
endometriosis.
Because the CAM contains extracellular matrix components
similar to the ECM of the human peritoneum (Giannopoulou
et al., 2001), it can be used to investigate the invasive potential
of endometriotic tissue. Nap et al. (2004) demonstrated that the
expression profiles of matrix metalloproteinases (MMPs) were
similar in experimentally induced endometriosis in CAMs
compared with human endometriosis and that the development
of early endometriotic lesions in the CAM model was pre-
vented by inhibiting MMP-1, -2, -3, -7 and -13 activity.
According to Wolber et al. (2003), relative concentrations of
MMP-1 mRNA, but not MMP-2 mRNA, increased strongly
after culture on the CAM.
Evaluation of the CAM assay
The CAM assay is well suited for the investigation of mechanisms
involved in invasion and angiogenesis during the first steps in the
establishment of endometriotic lesions, for example, by the inhibi-
tion of factors known to participate in these processes. The ectopic
lesions are easily accessible and can be simply monitored during
the course of an experiment. This endometriosis model is hardly
applicable for the investigation of immunological or inflammatory
responses or to analyse long-term drug effects in the course of the
disease.
Rodent models
In contrast to humans and non-human primates, estrous animals do
not shed their endometrial tissue and therefore do not develop
endometriosis spontaneously. However, endometriosis can be
induced by transplanting endometrial tissue to ectopic sites. These
models are classified into two types, homologous and heterologous
models. Homologous models have been employed utilizing the sur-
gical transplantation of endometrium of the same or syngeneic ani-
mals in immunocompetent animals, whereas in heterologous
models, human endometrial fragments are transferred either intra-
peritoneally or subcutaneously to immunodeficient mice.
Autotransplantation of endometrium to immunocompetent mice
and rats
Characterization of the homologous model
Autotransplantation of uterine tissue to ectopic sites of small labo-
ratory animals has been established not only in rats (Golan et al.,
1984; Jones, 1984; Vernon and Wilson, 1985; Rajkumar et al.,
1990; Sharpe et al., 1991) and mice (Cummings and Metcalf,
1995; Somigliana et al., 1999; Rossi et al., 2000) but also in ham-
sters (Steinleitner et al., 1991b) and rabbits (Schenken and Asch,
1980; Dunselman et al., 1989; Homm et al., 1989; Rock et al.,
1993). Of those non-primate models, mainly rat and mouse mod-
els have been further developed in recent years. In these models of
endometriosis, uteri are removed and cut into small pieces which
are then reintroduced, mostly by suturing, into the peritoneal cav-
ity. In most of these studies, endometrium was not separated from
myometrium; thus, both compartments were implanted (Vernon
and Wilson, 1985; Cummings and Metcalf, 1995). In the rat, the
uterine tissue develops into fluid-filled, ovoid, cystic structures
composed of myometrial and endometrial tissue. The cysts grow
but stabilize their size by ∼2 months and remain viable for at least
10 months (Vernon and Wilson, 1985).
In the mouse, the ectopic uterine fragments show histological
characteristics of the human disease, including the formation of
multiple, highly vascularized lesions containing endometrial
glands, stroma and cysts, independent of their peritoneal localiza-
tion in the abdomen (Cummings and Metcalf, 1995). A limited
number of experiments separating the endometrium from the myo-
metrium, only inoculating the endometrium to ectopic sites, have
been performed in rats (Katsuki et al., 1998) and mice
(Somigliana et al., 1999; Hirata et al., 2005; Yao et al., 2005). In
the study of Somigliana et al. (1999), isolated endometrial tissue
was minced and reintroduced into the peritoneal cavity of recipi-
ent, syngeneic animals. Both donor and recipient mice had been
ovariectomized and received estrogen treatment. In this study, all
recipient animals revealed evidence of peritoneal endometriosis
after 3 weeks, and neovascularization was observed at the surface
of the lesions. However, the ‘take-rate’, that is the number of
lesions recovered after a known number of endometrial fragments
have been randomly inoculated, was on average 30% of the inocu-
lated tissue.
For better identification of size and localization of ectopic
endometriotic lesions after transplantation, Hirata et al. (2005)
developed a homologous mouse model using ‘green mice’ that
ubiquitously express green fluorescent protein (GFP) as
donors and transplanted the fluorescent endometrial tissue into
recipient mice. They could show that the weight of endometriotic
lesions significantly correlated with the measured fluorescence
intensity. This fluorescence was significantly higher in the estrogen-
supplemented mice as compared with control animals, supporting
the estrogen dependency of these ectopic endometrial lesions.
Application of the homologous model
Endometriosis is known to be an estrogen-dependent disease in
women, and the suppression of the serum estrogen level supports
the regression of those ectopic lesions (Lapp, 2000; Rice, 2002).
Autotransplanted uterine tissue in the rodent model shows steroid
hormone dependency, and thus, this model has been widely used
for determining the responsiveness of ectopic lesions to steroid
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3. Animal models in endometriosis research
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hormones as well as to drugs interfering with steroid action. Cor-
responding to the situation in humans, the growth of the ectopic
endometrial tissue in both rodent species was shown to be estro-
gen dependent (Vernon and Wilson, 1985; Rajkumar et al., 1990;
Rossi et al., 2000). In rats which had been ovariectomized 3 weeks
after engrafts of uterine tissue, the ectopic fragments recovered
much better in animals treated with estrogen alone after ovariec-
tomy than in those with combined estrogen and progesterone treat-
ment (Schor et al., 1999). Fang et al. (2004) confirmed the
important role for estrogen as a factor determining the size of the
implants in mice and demonstrated that the antiproliferative
effect of progesterone on the estrogen-dependent growth of
endometriotic tissue is mediated by intact progesterone receptor,
because this estrogen-dependent growth could be suppressed by
progesterone in uterine tissues of wild-type but not of progester-
one receptor-deficient mice.
According to the situation in women, the regression of uterine
ectopic implants could be induced in rats by generating a hypoes-
trogenic state, for example, by ovariectomy (Kudoh et al., 1997),
by the application of GnRH agonists (Sakata et al., 1990; Wright
and Sharpe-Timms, 1995; Kudoh et al., 1997), by synthetic pro-
gestational compounds such as levonorgestrel or dienogest (Jones,
1984; Katsuki et al., 1998) or by danazol treatment (Sakata et al.,
1990). Corresponding effects could be achieved in this model by
reducing the estrogen concentration by the application of anti-
estrogens (Saito et al., 2003), by using the selective estrogen
receptor modulator raloxifen (Yao et al., 2005) or by treatment
with aromatase inhibitors which interfere with estrogen synthesis
(Yano et al., 1996; Kudoh et al., 1997).
Moreover, the autologous rat model in particular has been
extensively used for studies of immune-modulating drugs and
anti-inflammatory agents in endometriosis. Uchiide et al. (2002)
demonstrated that uterine autotransplantation in rats induces the
infiltration of allergic inflammatory-related cells in peritoneal
stroma attached to the ectopic uterine tissue. Immunomodulation
by intraperitoneal or subcutaneous treatment with interferon-α-2b
in the rat reduced the size of induced lesions as monitored by con-
secutive laparotomies over a period of up to 4 months (Ingelmo
et al., 1999) as did the application of the immunomodulator
loxoribine in rats (Keenan et al., 1999) and the intraperitoneal
injection of interleukin-12 in a syngeneic mouse model
(Somigliana et al., 1999).
In addition, the development of experimentally induced
endometriosis in rats was inhibited by recombinant human
tumour necrosis factor (TNF)-binding protein-1 (r-hTBP-1),
which is the soluble form of TNF receptor type I (D’Antonio
et al., 2000). This effect was also seen after treatments of rats
with pentoxifylline, an anti-inflammatory substance reported to
reduce the production of inflammatory cytokines without induc-
ing a hypoestrogenic state (Nothnick et al., 1994), as well as
with ciglitazone, a ligand for proliferator-activated receptor-γ
(PPAR-γ) (Lebovic et al., 2004). Moreover, the initial develop-
ment of ectopic implants in rats has been reduced by cyclooxy-
genase-2 (COX-2) inhibitors (Matsuzaki et al., 2004) and also by
the application of various non-steroidal anti-inflammatory drugs
such as celecobix, indomethacin, sulinac and ibuprofen (but not
aspirin) in a mouse model for endometriosis (Efstathiou et al.,
2005).
Furthermore, this rodent model provides the opportunity to
investigate the effect of environmental contaminants on the estab-
lishment of ectopic uterine implants. It has been demonstrated that
exposure to dioxin preceding the surgical induction of endometri-
osis produces a dose-dependent increase in endometriotic site
diameter in rats and mice, which was much stronger in mice
(Cummings et al., 1996).
Recently, in an interesting approach, Dinulescu et al. (2005)
described the first mouse model of de-novo endometriosis. Activa-
tion of the oncogene K-ras in ovarian surface epithelial cells, but
not in cells of the peritoneal lining, resulted in the development of
benign epithelial lesions with histomorphological features of
human endometriosis. In addition to developing ovarian lesions,
nearly half the mice also developed peritoneal endometriosis 8
months after the K-ras activation of ovarian surface epithelial
cells. In combination with a conditional deletion of Pten, which
has been implicated in the progression of ovarian endometriosis to
endometrioid ovarian carcinoma in humans (Sato et al., 2000), K-
ras expression even induced metastatic endometrioid ovarian ade-
nocarcinomas. However, to date, no mutations of K-ras have been
found in human endometriosis (Vercellini et al., 1994; Otsuka
et al., 2004).
The hallmark symptoms of endometriosis in women include
severe pelvic pain and significantly reduced fertility (Elsheikh
et al., 2003). The influence of ectopic lesions on fertility has been
investigated in laboratory rodents. Although Cummings and
Metcalf (1996) did not observe a decrease in fertility in mice, a
reduced fecundity could be observed in rats with artificially
induced endometriosis (Vernon and Wilson, 1985), which could
be due in part to an increased number of luteinized unruptured
ovarian follicles (Moon et al., 1993). In addition, a role of pelvic
adhesions has not be excluded. Moreover, peritoneal inflamma-
tory cell hyperactivation could have an effect on fertility in
endometriosis. This was supported by the work of Steinleitner
et al. (1991a), demonstrating that macrophage-mediated subfertil-
ity in the mouse model could be compensated by pentoxifylline, a
drug that reverses the effect of macrophage hyperactivation, and
that the drug-mediated inhibition of macrophage activation
enhanced fertility in a hamster endometriosis model (Steinleitner
et al., 1991b).
Recently, studies have been published investigating the effect of
ectopic endometrial lesions on pain behaviour in the rat model of
endometriosis. Here, the autotransplanted ectopic endometrial
cystic fragments develop their own innervation including sympa-
thetic efferent as well as sensory fibres (Berkley et al., 2004),
which may have a general influence on the nervous system. This is
supported by the finding that vaginal nociception was increased in
rats with endometrial cysts similar to the situation in women with
endometriosis. In addition, those rats also displayed vaginal
hyperalgesia (Berkley et al., 2001), one of the symptoms of
increased pelvic pain in women. It is speculated that neuroactive
agents contained in the endometrial cysts may activate nociceptive
afferents influencing central neural mechanisms associated with
vaginal nociception as well as with reproduction via viscero–
visceral interactions (Cason et al., 2003; Berkley et al., 2004). It
remains to be elucidated whether the rats exhibit chronic pelvic
pain symptoms other than vaginal hyperalgesia in this model of
endometriosis.
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Evaluation of the homologous model
There are relevant differences between rodent and human repro-
ductive physiology; consequently, these models possess limita-
tions. Because rodents do not menstruate, they do not develop
spontaneous endometriosis, and the disease has to be induced
artificially by the autotransplantation of uterine tissue. In addi-
tion, in most of these rodent studies, the uterine fragments which
were transplanted included the myometrial layer which could
affect the development of the lesions. When evaluating the
weight and size of the ectopic lesions, the myometrium could
make up a considerable proportion, not representing the situation
of human endometriotic lesions.
Despite these limitations, the rodent model offers significant
advantages. Apart from the limited costs and the opportunity to
perform studies in large groups of genetically similar animals,
long-term studies can be performed because there is no rejection
of the autotransplanted ectopic tissue. It is well suited for the
investigation of mechanisms involved in the peritoneal attachment
of endometrial cells as well as of effects of therapeutical drugs and
chemicals, and it allows the evaluation of ectopic lesions at differ-
ent time intervals. Moreover, the homologous rodent model of sur-
gically induced endometriosis provides a well-characterized
immune system and thus is appropriate and extensively used to
study the effect of immune-modulating drugs and anti-inflamma-
tory agents on endometriosis. Furthermore, in regard to new
insights in the aetiology of endometriosis obtained by genomic
and proteomic approaches, transgenic mice models may gain
importance as models of endometriosis to examine functions
driven by single genes.
Xenotransplantation of human endometrium to immunodeficient
mice
Characterization of the heterologous model
Because causal factors for the development and maintenance of
endometriosis could originate in the endometrium itself and may
not be present in the rodent endometrium, models have been
developed by implanting human endometrial tissue instead of
autologous endometrium into immunodeficient mouse strains.
Most widely used for this purpose is the athymic nude mouse,
which lacks mature T lymphocytes. Human endometrial fragments
from the proliferative or secretory phase of the menstrual cycle
(Zamah et al., 1984; Bergqvist et al., 1985; Zaino et al., 1985;
Bruner et al., 1997; Nisolle et al., 2000; Grummer et al., 2001;
Beliard et al., 2002) as well as the menstrual endometrium
(Nisolle et al., 2000; Van Langendonckt et al., 2004; Eggermont
et al., 2005) have been successfully implanted either subcutane-
ously or intraperitoneally into nude mice. These fragments implant
and form endometriotic-like lesions which resemble those found
in patients in terms of macroscopic and histological appearance,
whereas the stage of the menstrual cycle at the time of collecting
the human tissue seems to have no impact on the development of
those ectopic lesions (Nisolle et al., 2000). Preservation of estro-
gen and progesterone receptors and steroid responsiveness have
been demonstrated in the ectopic human tissue (Zamah et al.,
1984; Bruner et al., 1997, 1999; Grummer et al., 2001). Angio-
genesis guarantees the maintenance of the transplants and the
transport of systemically applied drugs to the human endometrial
tissue. The establishment of blood vessels of mouse origin occurred
from just 4 days after transplantation onwards, independent of the
localization of the ectopic lesions (Grummer et al., 2001; Hull
et al., 2003).
When endometrial tissue was randomly inoculated into the peri-
toneal cavity, peritoneal adhesion occurred from 2 days after
implantation onwards. The sites of implantation of the endometrial
fragments were preferentially the gut, the muscles of the abdominal
wall, the liver and the adipose fat surrounding abdominal organs
(Grummer et al., 2001; Fortin et al., 2003). However, studies from
our group as well as others revealed that the recovery rate is highly
variable from one animal to another and in average does not exceed
30% (Bruner et al., 1997; Grummer et al., 2001). This ‘take-rate’ is
further reduced after in vitro culturing of endometrial tissue for 24
h before transplantation but could be enhanced to 100% by suturing
the human endometrial fragments to different intraperitoneal sites
(Grummer et al., 2001). This is favourable, in regard to drug test-
ing, because a difference in the number of lesions in the two groups
of animals could be due to different ‘take-rates’ at the beginning of
the experiment rather than to the effect of a drug.
For non-invasive detection and quantification of implanted
endometrial tissue, Tabibzadeh et al. (1999) loaded dissociated
glands and stromal cells with a lipophylic fluorescent dye (DiO)
before in vivo transplantation. However, an effect of the solvent
[dimethylsulphoxide (DMSO) and absolute ethanol] on the
endometrial tissue cannot be excluded. An interesting approach
that is better for monitoring of subcutaneously or intraperitoneally
transplanted endometrial fragments was recently described by
Fortin et al. (2003). They transduced endometrial fragments of the
proliferative phase with GFP cDNA before implantation, resulting
in a transient fluorescence of the endometrial tissue allowing opti-
cal in vivo imaging of the implantation and development of
ectopic lesions. Because adenoviruses are transient expression
vectors, they observed that fluorescence of endometrial tissue
fades out around the third or fourth week, limiting the non-inva-
sive follow-up to this time frame. In addition, when using GFP as
a reporter gene, in vivo quantification would probably be limited
to subcutaneous lesions, which can be directly visualized through
the skin of living mice, because the wavelength of GFP-emitted
light from intraperitoneal fragments is absorbed by surrounding
tissues. Thus, this model allows dynamic studies of lesion by mon-
itoring implantation and development. However, a yet unknown
interaction between GFP and lesions or applicated drugs might
interfere with the studies.
Because, in the heterologous mouse model, human tissue is
transplanted, the time frame for maintenance of intact and well-
preserved tissue is limited. In most of the studies performed, cul-
ture of human endometrium in nude mice does not exceed a period
of 4 weeks. From 3 weeks after inoculation onwards, dedifferenti-
ation parameters and lymphocyte infiltration can be observed
(Grummer et al., 2001).
Because longer maintenance of human tissue in this animal
model would be advantageous for special experimental
approaches, mice with an even more defective immune system
have been established as heterologous models for endometriosis.
Human endometrial tissue has successfully been transplanted to
severe combined immunodeficient (SCID) mice (Aoki et al.,
1994; Kaufmann et al., 1995; Awwad et al., 1999) as well as to
non-obese diabetic (NOD)-SCID mice (Grummer et al., 2001),
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5. Animal models in endometriosis research
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both of which show a combined congenital deficiency in T- and B-
lymphocyte function. Compared with the nude mouse model,
human endometrium engrafted in SCID/NOD-SCID mice
revealed a higher ‘take-rate’ of fragments (Aoki et al., 1994) and a
better preserved morphology and expression of steroid hormone
receptors over a period of 4 weeks (Grummer et al., 2001).
Although these mice lack B and T lymphocytes, they do have
some natural killer (NK) cell activity. Recently, Matsuura-Sawada
et al. (2005) cultured human endometrial tissue subcutaneously in
NOD/SCID/γ Cnull
(NOG) immunodeficient mice which are addi-
tionally defective in NK-cell activity. In this model, they repro-
duced one human menstrual cycle of 28 days by hormone
application in ovariectomized animals. At the level of histology,
they showed cyclic changes also observed in eutopic human
endometrium but without signs of decidualization.
Greenberg and Slayden (2004) subcutaneously engrafted
human endometriotic tissue in transgenic recombinase-activating
gene-2 knockout [RAG-2/γ(c)KO] mice, which are not only
devoid of B and T lymphocytes but also lack NK cells. Only
endometriotic biopsy specimens that contained endometrium-like
glands developed visible lesions. Red peritoneal lesions, but not
biopsy specimens of ovarian endometrioma, established grafts at a
high rate. In this animal model for endometriosis, they mimicked
four consecutive human menstrual cycles by applying estrogen
and progesterone via hormone-releasing capsules. The established
grafts were well-vascularized and maintained steroid hormone
receptors.
Application of the heterologous model
Animal models of endometriosis based on the xenotransplantation
of human endometrium permit the elucidation of mechanisms
involved in the establishment of endometriosis as well as testing
the effects of potential therapeutical compounds on human tissue.
One approach to prevent the development of peritoneal endometri-
osis could target the adherence of endometrial tissue to and the
invasion of the peritoneal lining. MMPs are involved in such inva-
sion processes (Hudelist et al., 2005; Zhou and Nothnick, 2005). It
could be shown that MMPs are regulated by steroid hormones and
cytokines in endometrial tissue and that the suppression of MMPs
inhibits the establishment of ectopic lesions by human
endometrium in nude mice (Bruner et al., 1997, 1999; Bruner-
Tran et al., 2002).
Another therapeutical target discussed is the development of
new blood vessels, which is essential for the persistence of ectopic
endometriotic lesions. Endometrial xenografts in nude mice have
been shown to produce high levels of VEGF (Nisolle et al., 2000),
and anti-angiogenic agents such as soluble VEGF receptor (sflt-1)
and VEGF-A-antibodies significantly inhibited the growth of
endometriotic lesions in nude mice (Hull et al., 2003).
Because endometriosis is an estrogen-dependent disease, the
responsiveness of human ectopic lesions to steroid hormones has
been investigated in this mouse model. Pretreatment of human
endometrial cells with estrogen alone or in combination with a
progestin, but not with progestin alone, before injection into the
peritoneal cavity of nude mice resulted in a higher percentage of
animals developing endometriotic-like lesions (Beliard et al.,
2002). Using optical in vivo imaging, Fortin et al. (2004) demon-
strated a significantly reduced lesion size in estrogen-untreated
versus estrogen-treated ovariectomized nude mice.
Recent studies have identified aberrations in the expression of
aromatase and 17β-hydroxysteroid reductase-2 in human endome-
triotic lesions (Zeitoun et al., 1998; Bulun et al., 1999; Zeitoun
and Bulun, 1999), suggesting a role for steroid-metabolizing
enzymes in the pathogenesis of endometriosis. We could demon-
strate that the transcription of estrogen-metabolizing enzymes is
maintained in human endometrial tissue cultured in nude mice and
is regulated by the exogenously applied drugs danazol, dydroges-
terone and medroxyprogesterone acetate, which are used in the
treatment of endometriosis and are known to interact with the
estrogen metabolism, as well as by an aromatase inhibitor
(Gruemmer et al., 2005).
In contrast to the homologous rodent model, mice used in the
heterologous models have a deficient immune system and thus are
hardly used in studies evaluating the effect of immune-modulating
drugs. Application of an inhibitor of COX-2, which is known to be
up-regulated at sites of inflammation, had no influence on the
number or size of ectopic endometrial lesions in nude mice (Hull
et al., 2005). However, anti-inflammatory components, contained
for example in peritoneal fluid of women, could be investigated in
this model. Tabibzadeh et al. (1999) demonstrated that endome-
trial cells suspended in peritoneal fluid of women without
endometriosis established significantly less ectopic lesions than
those suspended in peritoneal fluid of women with endometriosis
after intraperitoneal injection into nude mice.
Evaluation of the heterologous model
This model shares the advantages described for the homologous
model, such as easy availability and low costs, as well as some of
the limitations such as differences between rodent and human
physiology. However, it does not provide an intact immune sys-
tem. Yet, the heterologous mouse model for endometriosis repre-
sents a promising tool for experimental approaches evaluating the
aetiology of this disease and for therapeutic testing of pharmacolog-
ical and hormonal modulations because it is based on human
endometrium. For these investigations, human endometrial tissue
can be taken from women with and without endometriosis as well as
from endometriotic lesions. Regulatory mechanisms, for example,
after drug administration, can be evaluated in the human ectopic tis-
sue in an in vivo situation. Long-term studies that are not feasible in
women can be performed, and the hormonal status of the human
menstrual cycle can be mimicked in ovariectomized animals.
Recently established methods using fluorescence allow in vivo
imaging and may improve the quantification of both size and
number of the ectopic lesions. In addition, techniques using mag-
netic resonance imaging (MRI) for in vivo monitoring of the
lesions are in progress.
Primate models
Characterization of the primate model
Menstruating primates develop spontaneous endometriosis, estab-
lishing ectopic lesions histologically identical and at similar sites
compared with the human disease (MacKenzie and Casey, 1975;
D’Hooghe et al., 1991; Dick et al., 2003). Spontaneous endometri-
osis does not develop with a high frequency in all monkeys but
could be shown to increase with time in capture possibly because
of less pregnancies leading to a higher number of consecutive
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6. R.Grümmer
646
menstrual cycles with increased exposure to retrograde menstrua-
tion (D’Hooghe et al., 1996a). Although spontaneous endometrio-
sis has been reported for 11 species of non-human primates (for
review, see Story and Kennedy, 2004), most studies have been
performed in rhesus macaques and baboons.
Because spontaneous endometriosis in monkeys develops
slowly over a period of several years, methods have been
employed for the artificial induction of this disease. In the first
studies, menstrual flow was diverted into the abdomen by reposi-
tioning the cervix of rhesus monkeys (Te Linde and Scott, 1950)
and later by occluding the cervix to increase the amount of retro-
grade menstruation in baboons (D’Hooghe et al., 1994). In addi-
tion, surgical induction of the disease can be performed by
suturing fragments of endometrial tissue at ectopic sites or by
seeding the peritoneal cavity with fragments of endometrial tissue
(D’Hooghe et al., 1995b; Yang et al., 2000; Fazleabas et al.,
2002). D’Hooghe et al. (1995b) induced endometriosis in a
baboon model by intraperitoneal injection of endometrial tissue,
demonstrating that endometriosis developed similarly to that
observed in the spontaneous disease and that ectopic lesions were
induced more efficiently by inoculating menstrual endometrium
compared with luteal phase endometrium. Although, in this study,
menstrual endometrium was extracted from each baboon by uter-
ine curettage, thus also containing endometrial cell layers not
physiologically shed during menstruation, other studies used shed
menstrual endometrium obtained using a pipelle (Fazleabas et al.,
2002, 2003). By this means, induced ectopic endometrial lesions
in the baboon could be shown to express estrogen receptor-β,
MMP-7, VEGF and aromatase (Fazleabas et al., 2002, 2003).
Ongoing efforts focus on the non-invasive diagnosis for the identifi-
cation of intraperitoneal lesions using MRI (Zondervan et al., 2004).
These methods of induced endometriosis in non-human pri-
mates have been extensively reviewed previously (D’Hooghe,
1997; D’Hooghe and Debrock, 2002; Story and Kennedy, 2004;
Fazleabas, 2005).
Application of the primate model
Many studies have been performed evaluating spontaneous
endometriosis on the one hand and using artificially induced
endometriosis on the other hand.
It could be shown that elevated estrogen levels as well as fre-
quent hysterotomies, but not laparoscopies, lead to an increased
risk for the development of spontaneous endometriosis (Hadfield
et al., 1997) and that genetic predisposition also seems to contrib-
ute to a higher risk for this disease (Zondervan et al., 2004).
Regression of peritoneal endometriotic lesions could be demon-
strated after the application of progesterone receptor modulators,
either alone or in combination with a GnRH analogue, in induced
endometriosis in cynomologous monkeys (Grow et al., 1996). The
influence of environmental compounds on the development of
spontaneous endometriosis was proven by exposure of rhesus
monkeys to dioxin or polychlorinated biphenyls (PCBs), which
resulted in a dose-dependent increase in incidence and severity of
endometriosis (Rier et al., 1993; Vanden Heuvel et al., 1994;
DeVito et al., 1995).
The primate model is well suited to investigate the role of the
immune system on the development and progression of endome-
triosis. Subclinical peritoneal inflammation occurs in baboons
during menstruation as well as after the intrapelvic injection of
endometrium, as demonstrated by an increase in peritoneal fluid
leukocyte concentration and the amount of peritoneal fluid cells
positive for TNF-α, transforming growth factor (TGF-β1) and cer-
tain leukocyte markers (D’Hooghe et al., 2001). It was shown that
immunosuppression led to an increase in the number and size of
spontaneously developed endometriotic lesions (D’Hooghe et al.,
1995a). Neutralization of TNF-α with r-hTBP-1 inhibits the
development of endometriotic lesions and adhesions after the arti-
ficial induction of the disease (D’Hooghe et al., 2006), and a
decrease in active red lesion number and surface area was
observed in female baboons with spontaneous peritoneal endome-
triosis after neutralizing TNF activity by treatment with etanercept
(Barrier et al., 2004).
With regard to the impact of endometriosis on fertility, it was
proven that mild-to-severe endometriosis leads to lower preg-
nancy rates in baboons (D’Hooghe et al., 1996b) as well as to a
reduction in chemical and term pregnancy rates in another monkey
species, Macaca fascicularis (Schenken et al., 1984). Whether
these effects on fertility are due to peritoneal adhesions and/or to
immunological responses is still to be investigated. In addition, a
feedback effect of the endometriotic lesions on the eutopic
endometrium is discussed, and it has to be evaluated whether the
differences in fecundity result in, or are the result of, endometrio-
sis. Whether the peritoneal presence of ectopic implantation sites
influences the physiology of the eutopic endometrium can effec-
tively be investigated in the primate model. Recently, an increase
in the angiogenic factor Cyr61, which is known to be deregulated
in the endometrium of women with endometriosis (Absenger
et al., 2004), could be demonstrated in the eutopic endometrium of
baboons following peritoneal inoculation with menstrual
endometrium (Gashaw et al., 2006). This study provides evidence
for a feedback mechanism from established lesions to induce a
shift in gene expression patterns in the eutopic endometrium in the
baboon.
Evaluation of the primate model
There is no doubt that primate models for endometriosis are most
closely related to the situation in humans and thus are most appro-
priate to investigate the numerous aspects of this disease, includ-
ing the initiation and progression of endometriosis, immunological
parameters, inheritance patterns as well as feedback mechanisms
on the eutopic endometrium. They reveal many similarities to
women with respect to pelvic anatomy, reproductive physiological
characteristics and immunological features. Primates develop
endometriosis spontaneously, and the disease can also be induced
for research purposes. They represent the only experimental
model, allowing the comparison of parameters in spontaneous
endometriosis with parameters before and after disease induction,
thus gaining information about cause and effect of the disease.
However, ethical considerations and particularly the high costs of
performing experiments using primates limit the use of this model
in endometriosis research.
Conclusions
Animal models of endometriosis are of extreme value and indis-
pensable for the evaluation of pathophysiological mechanisms
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7. Animal models in endometriosis research
647
underlying the development of this prevalent gynaecological dis-
ease. This review summarizes different commonly used animal
models, their potentials limitations. These have to be weighted up
when designing experimental approaches with regard to their
applicability, for example, considering species-specific character-
istics of metabolism or reproductive physiology, as well as to their
cost–effect ratio. New insights into the aetiology of endometriosis
will be obtained using genomic and proteomic approaches. In this
regard, transgenic mice models might gain importance as models of
endometriosis to examine functions driven by single genes. In gen-
eral, animal models will help to develop novel non-invasive diag-
nostic tools and improved therapeutical approaches for a better
treatment of endometriosis in women.
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Submitted on March 15, 2006; resubmitted on May 5, 2006; accepted on May 20,
2006
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