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Cellular and molecular basis for endometriosis-associated infertility.
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PMID:  22298022     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Endometriosis is a gynecological disease characterized by the presence of endometrial glandular epithelial and stromal cells growing in the extra-uterine environment. The disease afflicts 10%-15% of menstruating women causing debilitating pain and infertility. Endometriosis appears to affect every part of a woman's reproductive system including ovarian function, oocyte quality, embryo development and implantation, uterine function and the endocrine system choreographing the reproductive process and results in infertility or spontaneous pregnancy loss. Current treatments are laden with menopausal-like side effects and many cause cessation or chemical alteration of the reproductive cycle, neither of which is conducive to achieving a pregnancy. However, despite the prevalence, physical and psychological tolls and health care costs, a cure for endometriosis has not yet been found. We hypothesize that endometriosis causes infertility via multifaceted mechanisms that are intricately interwoven thereby contributing to our lack of understanding of this disease process. Identifying and understanding the cellular and molecular mechanisms responsible for endometriosis-associated infertility might help unravel the confounding multiplicities of infertility and provide insights into novel therapeutic approaches and potentially curative treatments for endometriosis.
Authors:
Julie A W Stilley; Julie A Birt; Kathy L Sharpe-Timms
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Review    
Journal Detail:
Title:  Cell and tissue research     Volume:  349     ISSN:  1432-0878     ISO Abbreviation:  Cell Tissue Res.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-10-22     Completed Date:  2013-03-27     Revised Date:  2014-04-24    
Medline Journal Info:
Nlm Unique ID:  0417625     Medline TA:  Cell Tissue Res     Country:  Germany    
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Languages:  eng     Pagination:  849-62     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Embryo Implantation
Endometriosis / complications,  pathology*
Female
Humans
Infertility, Female / etiology,  pathology*
Oocytes / pathology*
Ovary / pathology*
Pregnancy
Grant Support
ID/Acronym/Agency:
057445//PHS HHS; R01 HD057445/HD/NICHD NIH HHS; T32 DK007690/DK/NIDDK NIH HHS
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Journal ID (nlm-ta): Cell Tissue Res
Journal ID (iso-abbrev): Cell Tissue Res
ISSN: 0302-766X
ISSN: 1432-0878
Publisher: Springer-Verlag, Berlin/Heidelberg
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© The Author(s) 2012
Received Day: 31 Month: 10 Year: 2011
Accepted Day: 6 Month: 12 Year: 2011
Electronic publication date: Day: 3 Month: 2 Year: 2012
pmc-release publication date: Day: 3 Month: 2 Year: 2012
Print publication date: Month: 9 Year: 2012
Volume: 349 Issue: 3
First Page: 849 Last Page: 862
ID: 3429772
PubMed Id: 22298022
Publisher Id: 1309
DOI: 10.1007/s00441-011-1309-0

Cellular and molecular basis for endometriosis-associated infertility
Julie A. W. StilleyAff1
Julie A. BirtAff1
Kathy L. Sharpe-TimmsAff1 Address: timmsk@health.missouri.edu
Division of Reproductive and Perinatal Research, Department of Obstetrics, Gynecology and Women’s Health, The University of Missouri School of Medicine, 1 Hospital Drive, N 625 HSC, DC051.00, Columbia, MO 65212 USA

Endometriosis

Endometriosis is a gynecological disease characterized by the presence of endometrial glandular and stromal cells existing in the extra-uterine environment (Benagiano and Brosens 1991). These extra-uterine glands and stroma, called endometriotic lesions, can be found on the ovaries and on the surfaces of pelvic cavity organs (Koger et al. 1993; Remorgida et al. 2007). Endometriosis, although not malignant, occurs spontaneously in women and non-human primates that menstruate, causing pain and infertility.

Because the disease requires expensive and invasive surgical procedures to diagnose, estimates of the prevalence of endometriosis are difficult to establish. Estimates show that endometriosis affects 10%–15% of all women of reproductive age (Allaire 2006). These women often suffer for years before the diagnosis of endometriosis is made (Hadfield et al. 1996).

A significant economic burden is imposed by endometriosis. Recent estimates of the costs of surgical removal of endometriotic lesions are 17.3 billion dollars per year in the USA alone (Simoens et al. 2007). Indirect costs such as the loss of work productivity attributable to the debilitating chronic pelvic pain accounts for an estimated 4.7 billion dollars lost in the USA (Simoens et al. 2007). Without doubt, a more effective treatment for this disease needs to be developed.

Endometriosis (originally named adenomyoma) was described 150 years ago by Rokitansky as the occurrence of epithelial glands and stroma, resembling those found in the mucosal lining of the uterus, growing elsewhere in the peritoneal cavity (Benagiano and Brosens 1991). The way that the endometrium-like lesions became established outside of the uterus was unclear but several hypotheses were proposed.

In 1940, the current widely accepted explanation for endometriosis was put forward. Sampson posed a unique theory of the pathogenesis of endometriosis called retrograde menstruation. Retrograde menstruation occurs when naturally shed endometrium sloughs off but, instead of exiting though the cervix, it moves out of the oviducts and into the peritoneal cavity by retrograde movement. Up to 90% of all women are estimated to experience some amount of retrograde menstruation but only a portion of women develop endometriosis (Ozkan et al. 2008; Seli et al. 2003). A combination of retrograde menstruation, eutopic endometrial anomalies such as the altered synthesis and secretion of proteins and gene expression and abnormalities in the immune system might be involved in the pathogenesis of endometriosis (Chegini et al. 2003; Fowler et al. 2007; Sharpe-Timms 2001; Siristatidis et al. 2006; Ulukus et al. 2006; Wu and Ho 2003).

Other workers have hypothesized that an increase in telomerase production in the sloughed endometrium during retrograde menstruation has “enhanced replicative capacity” aiding the establishment of ectopic lesions (Hapangama et al. 2008). Additional hypotheses include: the induction theory in which, during menstruation, the sloughing endometrium gives off “factors” that cause changes in the surface epithelium of the ovary leading to the differentiation of endometrium-like tissue and migration to the peritoneal cavity; the in situ theory in which totipotent cells remain undifferentiated from the fetus surviving into adulthood and during the reproductive years, becoming activated and thus differentiating into endometriotic lesions (Nap et al. 2004). Endometrial stem cells might contribute to the pathogenesis of endometriosis and explain some rare and extreme cases of endometriosis (Sasson and Taylor 2008). Probably, a combination of mechanisms is involved during the development of the disease.

The main symptoms of endometriosis are pain and infertility (Allaire 2006; Berkley et al. 2005; Giudice and Kao 2004). The mechanisms of these symptoms in endometriosis are not known. Not all patients experience the same symptoms with endometriosis. Indeed, some women with endometriosis do not learn about their disease until after elective sterilization surgery. No cure is available for endometriosis and current treatments focus on reducing the pain associated with the disease often causing cessation or chemical alteration of the reproductive cycle. Treatments are not curative and may cause detrimental side effects. Further, many treatments are inappropriate for patients seeking treatment for infertility.


Infertility in women with endometriosis

Historically, endometriosis-associated infertility in women has been associated with subtle, explicit, or multifaceted abnormalities (Cahill and Hull 2000; Doody et al. 1988; Garrido et al. 2002, 2003; Groll 1984; Hahn et al. 1986; Hull et al. 1998; Tanbo et al. 1995; Tummon et al. 1988). Indeed, endometriosis appears to affect every part of a woman’s reproductive tract (Fig. 1). Many women with minimal, mild, or moderate endometriosis experience difficulties conceiving and maintaining pregnancy, neither of which can be accounted for by anatomical obstructions (Burns and Schenken 1999). It is estimated that 50% of endometriosis patients are subfertile (Bulletti et al. 2010). The following information characterizes reproductive irregularities associated with endometriosis.


Pituitary-ovarian feedback

In the normal cycle of fertile women, the pituitary secretes follicle stimulated hormone (FSH) and luteinizing hormone (LH) to stimulate growing ovarian follicles. These follicles provide positive and negative feedback to the pituitary culminating in an LH surge to signal ovulation at the optimum time (Senger 2005). However, in women with endometriosis, a pituitary-ovarian axis dysfunction has been noted altering feedback pathways thereby preventing normal cyclic changes in the ovary. The length of the follicular phase is extended in endometriosis (Cahill et al. 1995; Cheesman et al. 1982) when compared with controls. Additionally, women with endometriosis seem to have abnormal patterns of LH secretion. The LH surge is delayed in endometriosis with lower levels of LH being present and occasionally biphasic surges occur leading to abnormal urinary hormone profiles (Bancroft et al. 1992; Cahill et al. 1995; Tummon et al. 1988; Williams et al. 1986). These problems can impair follicular growth, ovulation and corpus luteum development in the ovary specifically with respect to the timing of ovarian events.


Impact on the ovary
Folliculogenesis

During the normal follicular phase, follicular growth is controlled by a balance of hormones. When FSH causes follicles to grow and develop, these follicles produce estradiol, activin and inhibin, which, in turn, provide a feedback mechanism to control the hypothalamus-pituitary-ovarian axis. While the follicles are growing in size, the cells within the follicle are changing. Visibly, an antrum forms and is filled with follicular fluid. Within the follicle, follicular cells develop LH receptors, which prepare the follicle for ovulation (Senger, 2005).

Folliculogenesis is impaired in women with endometriosis. The number of preovulatory follicles, follicular growth, dominant follicle size and follicular estradiol concentrations are reduced in ovaries of endometriosis patients (Doody et al. 1988; Tummon et al. 1988; Cahill et al. 1995; Dlugi et al. 1989). The follicular fluid of patients with endometriosis have been reported to have altered hormone profiles including reduced estrogen, androgen and progesterone and increased activin (Cahill and Hull 2000). Further, the follicular fluid from patients has been shown to contain factors such as cytokines and growth factors that might promote the maintenance of endometriotic lesions and lead to a suboptimum follicular environment (Abae et al. 1994; Bahtiyar et al. 1998; Pellicer et al. 1998).

Ovulation

The process of ovulation is impaired in women with endometriosis. During normal ovulation, the LH surge starts a cascade of events in the follicle that leads to the expulsion of the oocyte-cumulus complex. Several protective layers including the granulosa, follicular basement membrane and theca must be overcome within each ovulating follicle. To achieve this, changes in proteolytic enzymes, cytokines, inflammatory molecules, steroid hormones and vasculature must occur (Espey 1980, 1994).

In women with endometriosis, mechanisms that facilitate normal ovulation are impaired. As mentioned before, the LH surge might be altered; however, others suggest that a deficiency in follicular LH receptors (Ronnberg et al. 1984). Additionally, lower levels of estrogen and progesterone have been noted in the serum and urine of women with endometriosis (Brosens et al. 1978; Cheesman et al. 1982; Cunha-Filho et al. 2003; Smith et al. 2002; Trinder and Cahill 2002; Tummon et al. 1988). Changes in proteolytic enzymes (Ebisch et al. 2007; Smedts et al. 2006; Wunder et al. 2005), cytokines (Carlberg et al. 2000; Garrido et al. 2000; Pellicer et al. 1998; Wunder et al. 2006), inflammatory molecules (Carlberg et al. 2000; Lachapelle et al. 1996; Wunder et al. 2006) and the vasculature (Abae et al. 1994; Garrido et al. 2000; Pellicer et al. 1998), all of which are required for normal ovulation, can also be found in the follicles of women with endometriosis. Collectively, these data provide evidence of mechanisms that could cause ovulatory dysfunction in endometriosis.

A phenomenon exists whereby oocytes become trapped in a luteinizing corpus hemorrhagicum. This failure of ovulation, defined as luteinized unruptured follicle syndrome (LUFs), has been associated with endometriosis and infertility in women (Donnez and Thomas 1982; Kaya and Oral 1999; Marik and Hulka 1978; Mio et al. 1992; Muse and Wilson 1982). Peritoneal concentrations of steroid hormones, including progesterone and estradiol, are reported to decrease in women with LUFs; however, whether this is a cause or consequence of the phenomenon is unclear (Koninckx et al. 1980). Whereas the mechanism causing this syndrome remains unknown, any one of the factors necessary for follicular rupture could contribute to failed ovulation.

Luteal function

After ovulation in normal cycles, the granulosa and theca cells of the ovulated follicle differentiate into luteal cells. The main function of this transformation is to produce progesterone to prepare the reproductive tract for successful implantation and pregnancy (Owen 1975). Altered luteal function has been noted in endometriosis patients and affects both large and small luteal cells (Cheesman et al. 1983; Cunha-Filho et al. 2003). Early luteal events, specifically patterns of estrogen and progesterone secretion, are altered in women with endometriosis (Cheesman et al. 1982). Indeed, endometriosis patients with luteal defects secrete less progesterone than those from healthy patients (Cunha-Filho et al. 2003). Women with endometriosis who have a luteal deficiency are more likely to experience infertility (Cunha-Filho et al. 2001).


Impact on oocyte quality

Women with endometriosis ovulate fewer oocytes than healthy women (Al-Fadhli et al. 2006; Bergqvist and D'Hooghe 2002; Cahill and Hull 2000; Kumbak et al. 2008; Mahutte and Arici 2001; Yanushpolsky et al. 1998) and those oocytes ovulated by women with endometriosis are sometimes compromised (Garrido et al. 2000, 2002, 2003; Navarro et al. 2003; Pellicer et al. 2000). A recent study has shown that women with endometriosis exhibit an increase in apoptosis of the cumulus cells surrounding the oocyte (Díaz-Fontdevila et al. 2009). Apoptosis in ovarian cells is a good indicator of poor oocyte quality (Nakahara et al. 1997). Death of cumulus cells probably leads to reduced oocyte quality and maturation attributable to the loss of the essential support that the cumulus cells give to the oocyte (e.g., pyruvate, hormones, growth factors; Russell and Robker 2007).

Morphology is one indicator of the potential for each oocyte to produce an embryo. Oocyte morphological characteristics includes extracytoplasmic and cytoplasmic defects. Extracytoplasmic defects that seem to impair fertilization rate include abnormal first polar body extrusion and a large perivitelline space (Rienzi et al. 2008). Cytoplasmic defects disrupting fertilization rate include cytoplasmic granularity, central location of cytoplasmic granularity and the presence of vacuoles (Rienzi et al. 2008). Morphological analysis is, however, a subjective evaluation and does not completely correlate with the outcome.

The potential of the development of biomarkers clearly to identify “good” versus “bad” oocytes is exciting. Potential targets recently investigated include nuclear export factor CRM1 in high-quality pig oocytes and components of the ubiquitin-proteasome pathway in low-quality pig oocytes (Powell et al. 2010). Despite this, current methods of visualizing these markers requires oocyte fixation rendering them unusable for use in artificial reproductive techniques. Investigators are trying to discover ways of using proteomic methodology to detect these biomarkers in oocyte maturation medium.

Assisted reproductive therapies can help restore fertility in women with endometriosis but unfortunately produce inconsistent results. Some studies have shown that the pregnancy outcome with use of in vitro fertilization (IVF) is similar in women with and without endometriosis (Bergendal et al. 1998; Geber et al. 1995; Huang et al. 1997). Women with endometriosis undergoing IVF treatments involving oocytes from a non-affected individual show normal implantation and pregnancy rates (Simon et al. 1994). However, other workers have reported that fertilization and/or embryo cleavage rates after IVF, both in stimulated and unstimulated cycles, are significantly lower in endometriosis compared with controls (Cahill and Hull 2000; Harlow et al. 1996; Hull et al. 1998; Tanbo et al. 1995). Fertilization and embryo cleavage rates remain impaired in women with endometriosis after spermatozoa from their partners are substituted with spermatozoa from donors (Groll 1984; Hull et al. 1998). Additionally, implantation rates of oocytes from donors with endometriosis are reduced in recipients who do not have endometriosis (Navarro et al. 2003).

Several factors from a woman with endometriosis contribute to the failure of a spermatozoon to fertilize a potentially compromised oocyte. An increase in peritoneal macrophages during endometriosis can lead to increased phagocytosis of healthy spermatozoa that might have otherwise been able to fertilize the ova (Muscato et al. 1983). Uterine/oviductal sperm transport is impaired in endometriosis (Kissler et al. 2005, 2006, 2007; Leyendecker et al. 1996). This impairment emerges in the early stages of endometriosis (Kissler et al. 2007). The peritoneal fluid of patients with endometriosis has a negative impact on sperm binding to the zona pellucida of the oocyte in vitro (Coddington et al. 1992). Peritoneal fluid of women with endometriosis has been shown to increase DNA fragmentation in sperm from healthy donors (Mansour et al. 2009b). Interleukin-6 (IL-6) and its soluble receptor, which are present in the peritoneal fluid of women with endometriosis (Harada et al. 1997), reduce sperm motility (Iwabe et al. 2002; Yoshida et al. 2004). Additionally, endometriosis negatively impacts sperm binding to the oviductal epithelium (Reeve et al. 2005).


Impact on embryo development

Endometriosis negatively impacts embryo development (Table 1). Because of the use of assisted reproductive techniques, data are available about embryo quality and rates of cleavage, implantation and pregnancy loss. Aberrant nuclear and cytoplasmic events in embryos from women with endometriosis are six times more likely compared with women without endometriosis (Brizek et al. 1995). These events include cytoplasmic fragmentation (Brizek et al. 1995), darkened cytoplasm (Brizek et al. 1995), reduced cell numbers (Garrido et al. 2002; Pellicer et al. 1995; Tanbo et al. 1995) and increased frequency of arrested embryos (Garrido et al. 2000; Yanushpolsky et al. 1998) leading to significantly fewer transferable blastocysts (Garrido et al. 2002; Pellicer et al. 1995). Additionally, the quality of embryos that develop from endometriosis patients has been shown to be reduced (Brizek et al. 1995; Cahill and Hull 2000; Garrido et al. 2000, 2002; Pellicer et al. 1995; Yanushpolsky et al. 1998). Treatment with a gonadotrophin-releasing hormone agonist that temporarily causes regression of the endometriotic lesions and cessation of reproductive cyclicity helps to improve embryo quality in these patients (Takahashi et al. 2004).

Inflammatory cytokines in the peritoneal fluid of women with endometriosis provide a plausible hypothesis to explain decreased embryo quality from such women. Exposure of the embryo to peritoneal fluid while in the reproductive tract can cause these defects (Esfandiari et al. 2005; Furukubo et al. 1998; Gomez-Torres et al. 2002). Murine embryos cultured in the presence of peritoneal fluid from women with endometriosis have decreased rates of development after the two-cell stage (Taketani et al. 1992). In a similar study, murine embryos cultured in the presence of human peritoneal fluid from women with endometriosis show increased rates of DNA fragmentation and apoptosis compared with treatment by control peritoneal fluid (Mansour et al. 2009a). Further, embryos cultured in the presence of IL-6 (found in the peritoneal fluid of women with endometriosis) arrest at the blastocyst stage or earlier (Iwabe et al. 2002). Even sera from women with endometriosis are embryo toxic to murine embryos in vitro (Abu-Musa et al. 1992; Ito et al. 1996; Tzeng et al. 1994).

Apoptosis or programmed cell death of the embryo can occur through several mechanisms associated with endometriotic lesions such as increased concentrations of inflammatory cytokines or reactive oxygen species (ROS; Agic et al. 2006; Jana et al. 2010; Zeller et al. 1987; Fig. 2). Inflammatory cytokines such as tumor necrosis factor-α can activate caspase-dependent signaling pathways to increase apoptosis (Hu 2003). ROS can cause mitochondrial damage and DNA strand breaks (Lao et al. 2009). This might also encourage the cell to undergo programmed cell death or apoptosis.

ROS have been implicated as a potential source of endometriosis-related infertility (Augoulea et al. 2009). Early studies have shown increased concentrations of ROS and lipid peroxides in the peritoneal fluid from women with endometriosis (Murphy et al. 1998; Zeller et al. 1987). More recent studies have demonstrated no difference in the amount of ROS in the peritoneal fluid (Agarwal et al. 2003) but a decrease in the antioxidants present (Jackson et al. 2005). This suggests that antioxidant protection is decreased in the peritoneal fluid from women with endometriosis, an occurrence that could negatively affect embryo development (Augoulea et al. 2009).


Impact on uterine receptivity

Uterine receptivity, which allows the developing embryo to implant, is a complex process involving regulation by hormones, cytokines, adhesion molecules and other factors (Aghajanova et al. 2008). In women, uterine receptivity can be marked by the expression of integrins, specifically αVβ3 (Donaghay and Lessey 2007). Integrins are cell surface receptors that mediate intracellular signals. Notably, about 50% of women with endometriosis have decreased or, in some cases, absent expression of endometrial αVβ3 (Donaghay and Lessey 2007). These data are correlated to the ~50% of patients with endometriosis who, even with assisted reproductive technologies, cannot conceive (Donaghay and Lessey 2007; Lessey 2002).

HOXA10, which is known to be a potent stimulator of αVβ3 expression, is a transcription factor and member of the Homeobox family of genes expressed by the normal endometrium (Eun Kwon and Taylor 2004). Decreased endometrial expression and altered methylation of HOXA10 have been reported in women with endometriosis providing a potential mechanism for the deficiency of αVβ3 (Donaghay and Lessey 2007; Eun Kwon and Taylor 2004; Taylor et al. 1999; Vitiello et al. 2007). Other uterine biomarkers of implantation such as glycodelin A, osteopontin, leukemia inhibitory factor and lysophosphatidic acid receptor 3 are reduced in women with endometriosis (Giudice et al. 2002; Wei et al. 2009).

Together with a general decrease in the expression of key uterine receptivity factors, steroid hormone pathways are altered in endometriosis. Normally at the time of implantation, estrogen receptors are downregulated; however, women with endometriosis have an upregulation of endometrial estrogen receptors (Lessey et al. 1988). Aromatase is also aberrantly expressed by the endometrium of women with endometriosis, increasing the amount of active estradiol (Attar and Bulun 2006). To exacerbate altered estrogen during receptivity even further, 17β-hydroxysteroid dehydrogenase-2 is downregulated thereby inhibiting estradiol inactivation leading to a local increase in estrogen action (Giudice et al. 2002).

Conversely, progesterone actions, which are required for endometrial receptivity, are reduced (Bulun et al. 2006). An increase in progesterone compared with estrogen must occur for successful endometrial receptivity to the implanting blastocyst. Progesterone resistance has been reported in eutopic and ectopic endometrium (Giudice and Kao 2004). Differential expression of the isoforms of the progesterone receptor occurs in endometriosis: isoform A is present but B is not, most likely because of aberrant methylation of its promoter (Attia et al. 2000; Wu et al. 2006). Further, stromal cells of endometriotic lesions do not express 17 β-hydroxysteriod dehydrogenase type 2 thereby preventing the conversion of estradiol2 to estradiol1, usually induced by progesterone (Bulun et al. 2006). Reduced progesterone receptors and decreased levels of estrone lead to high levels of estradiol furthering the progesterone resistance. Collectively, these data provide evidence for mechanisms involved in reduced uterine receptivity.


Impact on embryo implantation

Quantifying embryo implantation in women with endometriosis is difficult and has led to inconsistent results. Women with endometriosis are reported to experience implantation failure more often than controls (Arici et al. 1996; Cahill and Hull 2000; Simon et al. 1994). However, others disagree (Geber et al. 1995; Sung et al. 1997). Much of the evidence regarding the success or failure of implantation originates from IVF data. Implantation rates are difficult to determine because of the variation in patient procedures, including differences in the numbers of embryos transferred and the selection of the most ideal sperm, oocyte and embryo. Nonetheless, a significant decrease in implantation per embryo transferred in IVF (Arici et al. 1996; Cahill and Hull 2000; Pellicer et al. 1995) has been found in association with endometriosis.

Decreased rates of embryo implantation are an additional aspect of infertility in women with endometriosis (Arici et al. 1996; Cahill and Hull 2000; Garrido et al. 2000; Yanushpolsky et al. 1998). Defects in embryo implantation might be associated with hormone level alterations, embryo anomalies and/or endometrial anomalies as described. For example, embryo anomalies can include slow growth and delayed blastocyst hatching, which are detrimental for implantation of the embryo in the uterine endometrium (Bazer et al. 2009).


Impact on the uterus: risk of miscarriage

Together with difficulty in establishing pregnancy, women with endometriosis can have an increased risk of miscarriage and even recurrent miscarriage (Tomassetti et al. 2006; Yanushpolsky et al. 1998). The mechanisms behind these spontaneous pregnancy losses are unknown but are probably multifaceted including but not limited to, B cell immunodeficiency and autoantibodies (Gleicher et al. 1989; Mahutte and Arici 2001).

Investigators disagree about the increased risk of spontaneous pregnancy loss after implantation (Al-Azemi et al. 2000; Diaz et al. 2000; Matalliotakis et al. 2008a, 2008b; Metzger et al. 1986; Olive et al. 1982; Pittaway et al. 1988; Wheeler et al. 1983; Yanushpolsky et al. 1998). Some studies suggest no increased risk of loss (Al-Azemi et al. 2000; Diaz et al. 2000; Pittaway et al. 1988). However, many of these investigations include women who have undergone IVF treatment with stimulated cycles and selection of the most favorable embryos to be transferred, both of which could have affected the outcome. Metzger et al. (1986) have however noted that abortion rates drop to zero after surgical intervention in women with endometriosis, suggesting that endometriosis itself does indeed play a role in these losses. Although definitive proof that endometriosis causes spontaneous pregnancy loss is lacking, women with endometriosis have an increased risk of spontaneous abortion.


Impact on peritoneal milieu

Endometriotic lesions secrete proteins and/or change the peritoneal environment in a way that has been hypothesized to affect the establishment, maintenance and symptoms of endometriosis. These substances include but are not limited to: prostaglandins (Chishima et al. 2007; Drake et al. 1981; Moon et al. 1983; Muzii et al. 1996; Sondheimer and Flickinger 1982); haptoglobin (Piva and Sharpe-Timms 1999; Sharpe-Timms 2005; Sharpe-Timms et al. 1998, 2002); cytokines such as IL-1, IL-6, IL-8 and IL-10; growth factors, such as vascular endothelial growth factor, nerve growth factor, transforming growth factor-β1 and 2, insulin-like growth factor-2 (Anaf et al. 2002; Gazvani and Templeton 2002; Sharpe-Timms 2001; Taylor et al. 2002); cellular remodeling enzymes, such as the matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of metalloproteinase, TIMPs; Chung et al. 2001; Osteen et al. 1996, 2003; Sharpe-Timms et al. 1995; Zhou and Nothnick 2005). Whereas the consequences of these and other molecules secreted from the lesions are not fully known, the altered milieu in the peritoneal fluid can clearly lead to changes in the reproductive tract.


Endometriosis is an heritable disease

Susceptibility to endometriosis is hypothesized to be heritable based on the increased risk of developing endometriosis if a family member is affected (Simpson et al. 2003). Retrospective studies have shown that women with a first-degree relative with endometriosis are 5%–8% more likely to have endometriosis (Simpson et al. 2003). Having a sister with endometriosis increases the risk of developing endometriosis by 5.2-fold (Stefansson et al. 2002).

Genome-wide studies have identified several potential loci that have mutations in women with endometriosis. Treloar et al. (2005) have found, in a genome-wide linkage study of over 1,000 sister-pair families, that women with endometriosis have a possible susceptibility locus on chromosome 10q26. This portion of the DNA includes coding regions for several reproductively important genes including EMX2, a gene required for reproductive tract development and PTEN, a tumor suppressor gene (Treloar et al. 2005). However, according to a review by Bischoff and Simpson (2004), genetic mutations in this region, or any other loci identified in population studies, of the DNA cannot alone account for the heritability of endometriosis.


Endometriosis is an epigenetic disease

Because of the lack of evidence to substantiate the idea of a common genetic mutation in endometriosis, the familial tendency of endometriosis might alternatively be attributable to epigenetic reprogramming during embryonic or fetal development (Dean et al. 2003). Epigenetics is a new exciting field that affects many disciplines of science from fetal origins of adult disease, assisted reproductive techniques, cancer biology, to other diseases without a link to a specific genetic anomaly (Dean et al. 2005). Epigenetics is the study of alterations to the cytosine base pairs and histone modifications that affect gene expression but are not mutations of the DNA itself.

In endometriosis, epigenetic changes might arise by several mechanisms (Fig. 3). Endometriotic lesion secretory products or inflammatory mediators from elevated numbers of peritoneal macrophages and other immune cells present in the peritoneal fluid might affect the methylation status of the genome of the embryo or fetus (Hill et al. 1988). This can occur by changing the gene expression of enzymes such as DNA methyltransferases (DNMTs) and histone-modifying enzymes such as histone deacetylases (Haaf 2006). One suggestion is that, in ectopic endometrium of women with endometriosis, DNMT1, DNMT3A and DNMT3B are over-expressed when compared with control levels (Wu et al. 2007).

Inflammatory mediators might cause increased DNA methylation by a secondary mechanism (Ushijima and Okochi-Takada 2005). ROS associated with inflammation cause DNA damage such as halogenated pyrimidines, which mimic methylated cytosines (Lao et al. 2009; Valinluck and Sowers 2007). These halogenated pyrimidines cause DNMT1 to recognize the hemi-methylation of the DNA leading to the methylation of the opposite strand of DNA (Lao et al. 2009; Valinluck and Sowers 2007).

These aberrant methylation marks established during gametogenesis or gestation might persist through childhood and cause an increased risk for endometriosis. Aberrant epigenetic programming in endometriosis might begin during several events critical to the establishment of pregnancy such as oocyte maturation (Nafee et al. 2008), pre-implantation embryo development (Latham and Schultz 2001) and implantation (Paulson et al. 1990).

The methylation level of the oocyte genome remains low until the oocyte is activated during folliculogenesis (Nafee et al. 2008; Fig. 4). Upon follicular activation and recruitment, methylation marks are established (Nafee et al. 2008). No studies to date have focused on the effect of endometriosis on the establishment of methylation marks during oocyte maturation and follicular development.

Shortly after fertilization the paternal genome of the zygote in the mouse, rat and human undergoes active demethylation (Fig. 4; Dean et al. 2003; Zaitseva et al. 2007). The maternal zygotic genome undergoes a passive demethylation process from fertilization to the 8-cell stage in mice (Dean et al. 2003). Incomplete erasure of methylation marks can lead to increased incidence of disease later in life (Junien et al. 2005).

During embryonic development most of the epigenetic marks must be erased to allow for pluripotency. The growing embryo must make the transition from translating protein from maternally derived mRNA to transcribing its own mRNA for translation (Latham and Schultz 2001). The maternal to embryonic transition (MET) has been shown to occur at the 2-cell stage in mice, the 4-cell stage in rats and the 8-cell stage in human and bovine embryos (Telford et al. 1990). Within about two cell divisions from the MET, most maternal transcripts are degraded and the embryonic genome is transcriptionally active (Zeng et al. 2004). The time period immediately following this transition is ideal for studying the impact of endometriosis on embryo gene expression and epigenetic status, rather than maternal transcripts.

Another important part of embryo development is re-methylation of the embryonic genome to allow for differentiation of the cell lines (Fig. 4). By the blastocyst stage of development, methylation marks return to the genome as the blastomeres differentiate into various cell lineages including the trophoblast and inner cell mass (Reik et al. 2001). During this period of re-methylation, the embryo is hypothesized to be highly sensitive to stressors such as temperature changes and ROS exposure, which can cause aberrant methylation and possibly lead to embryo death or embryo growth problems such as those seen in endometriosis (Khosla et al. 2001).

Anomalous methylation during any part of embryo development might cause an arrested cell cycle and apoptosis of the blastomeres or inhibition of embryo implantation in the endometrium (Feil 2009). Whereas this aberrant methylation might not directly affect subsequent cell cycles, it might represent the embryonic origin of an adult disease such as endometriosis, as methylation marks are not easily removed once established (Nafee et al. 2008).

Human and rat embryo implantation is both an embryonic and maternal process (Paulson et al. 1990). Once embryos reach the blastocyst stage of development, they hatch from the zona pellucida and implant in the uterine endometrium. The maternal tissue must be correctly organized for implantation, which necessitates the patterning of gene expression of genes such as HOXA10 (Eun Kwon and Taylor 2004; Vitiello et al. 2007). For example, the suppression of HOXA10 by methylation might lead to failed implantation.

Evidence of epigenetic modifications in the eutopic endometrium has been described in adults with endometriosis. Genes important for implantation, such as HOXA10 and progesterone receptor isoform B (PR-B), are differentially methylated in the eutopic endometrium of women with endometriosis compared with controls (Lee et al. 2009; Wu et al. 2006). This aberrant methylation is correlated to the differential expression of these genes seen in the eutopic endometrium of women with endometriosis (Lee et al. 2009; Wu et al. 2006).


Animal models of endometriosis

Because of the ethical limitations of working with human embryos and experimentation in women, animal models of endometriosis are frequently used to study the anomalies associated with endometriosis (Sharpe-Timms 2002). Common rodent models of endometriosis include the rat (Vernon and Wilson 1985), rabbit (Schenken and Asch 1980) and mouse (Cummings and Metcalf 1995) models. These models have many advantages such as decreased cost and ethical limitations compared with working on primates (D'Hooghe et al. 2009; Grummer 2006; Sharpe-Timms 2002). Endometriosis is induced in rodents by autologous surgical transplantation of endometrial tissue from the animal’s own uterus into the arterial cascade of the small intestine (Sharpe-Timms 2002). These implants mimic human endometriotic lesions in that they establish a blood source, are influenced by the cycle stage and hormonal levels and show signs of causing decreased fertility (Vernon and Wilson 1985).

One advantage of the rat model is that the rat estrous cycle lasts 4-5 days, compared with the typical 28-day menstrual cycle in women, thereby allowing many studies to be completed in a short period of time (Sharpe-Timms 2002). Moreover, reproductive cycle stage can easily be monitored by using vaginal cytology (Sharpe-Timms 2002).

The rat model of endometriosis, because of its many similarities to endometriosis in women, has been used to understand mechanisms of subfertility (Table 1). Vernon and Wilson validated the rat model of endometriosis in 1985. In this model, the presence of endometrial implants in the peritoneum caused a decrease in fecundity by 28% at day 14 of pregnancy and by 48% at term (Vernon and Wilson 1985). Others have shown that the cytokine milieu of the peritoneal fluid changes in rats with surgically induced endometriosis in a similar fashion to that of humans (Umezawa et al. 2008). We have demonstrated that the peritoneal fluid components can enter the uterine horns via the oviduct and possibly affect embryonic or eutopic-endometrial quality (Stilley et al. 2009).

Rats with endometriosis have also been shown to experience more spontaneous abortions and to have a decreased litter size (Pal et al. 1999), an increased incidence of LUFS (Moon et al. 1993) and increased early embryonic mortality when compared with sham-operated controls (Stilley et al. 2009). This similarity to subfertility seen in human endometriosis makes the rat model a suitable alternative for studying the effects of endometriosis.

Based on the rat model, studies from our laboratory have shown that TIMP1 is increased in the ovarian theca of antral follicles, associated with decreased follicle numbers, LUFS and poor embryo quality (Stilley et al. 2009). Further, reducing levels of intraperitoneal fluid TIMP1 in Endo rats by a TIMP1-function-blocking antibody mitigates the impact of endometriosis on the ovary (Stilley et al. 2010). Conversely, increasing TIMP1 in rats by sham surgery decreases ovarian function to levels similar to those of Endo rats with fewer numbers of follicles and corpora lutea and poor embryo quality (Stilley et al. 2010). In addition to these observations, work at our laboratory has shown that TIMP1 is able to act independently of MMP action to impair the ovulatory function through changes to pathways involved in extracellular matrix production, angiogenesis and apoptosis (Stilley and Sharpe-Timms 2011).

Interestingly, research at our laboratory has also demonstrated that daughters of rats with endometriosis have similar embryo anomalies as their mothers (Stilley et al. 2009). By combining these findings suggesting an epigenetic inheritance of endometriosis-like embryo anomalies in a rat model of endometriosis (Stilley et al. 2009), the recent advances in the field of epigenetics (Burdge and Lillycrop 2010) and the development of possible treatments to prevent these aberrant epigenetic marks during development (Waterland et al. 2008), we are presently testing the hypothesis that endometriosis-associated subfertility is multigeneration with an epigenetic mode of inheritance in offspring from mothers with endometriosis. Epigenetic heritability of subfertility in endometriosis is a unique idea that has not been previously postulated.


Concluding remarks

Endometriosis seems to impact, in a negative manner, every part of the reproductive process subtly but significantly (Fig. 1). However, to date, a cause and effect relationship between endometriosis and reduced fecundity has not been established. Infertility associated with endometriosis can be even more puzzling, as not every patient experiences the same symptoms. Therefore, not all patients respond to therapies in the same way, making treatments particularly difficult to develop. Nonetheless, research into therapeutic modalities for subfertility associated with endometriosis needs to be continued, particularly with regard to targeting the molecular mechanisms. Animal models have proven to be valuable in providing insights into principles of mechanisms underlying subfertility in endometriosis, when such studies in women are ethically restricted.


Notes

Funding source in the manuscript is supported in part by NIH 057445 to KST.

Open Access

This article is distributed under the terms of the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution and reproduction in any medium, provided the original author(s) and source are credited.


References
Abae M,Glassberg M,Majercik MH,Yoshida H,Vestal R,Puett D. Immunoreactive endothelin-1 concentrations in follicular fluid of women with and without endometriosis undergoing in vitro fertilization-embryo transferFertil SterilYear: 199461108310878194621
Abu-Musa A,Takahashi K,Kitao M. Effect of serum from patients with endometriosis on the development of mouse embryosGynecol Obstet InvestYear: 1992331571601612528
Agarwal A,Saleh RA,Bedaiwy MA. Role of reactive oxygen species in the pathophysiology of human reproductionFertil SterilYear: 20037982984312749418
Aghajanova L,Hamilton AE,Giudice LC. Uterine receptivity to human embryonic implantation: histology, biomarkers, and transcriptomicsSemin Cell Dev BiolYear: 20081920421118035563
Agic A,Xu H,Finas D,Banz C,Diedrich K,Hornung D. Is endometriosis associated with systemic subclinical inflammation?Gynecol Obstet InvestYear: 20066213914716679772
Al-Azemi M,Bernal AL,Steele J,Gramsbergen I,Barlow D,Kennedy S. Ovarian response to repeated controlled stimulation in in-vitro fertilization cycles in patients with ovarian endometriosisHum ReprodYear: 200015727510611191
Al-Fadhli R,Kelly SM,Tulandi T,Tanr SL. Effects of different stages of endometriosis on the outcome of in vitro fertilizationJ Obstet Gynaecol CanYear: 20062888889117140505
Allaire C. Endometriosis and infertility: a reviewJ Reprod MedYear: 20065116416816674010
Anaf V,Simon P,El Nakadi I,Fayt I,Simonart T,Buxant F,Noel JC. Hyperalgesia, nerve infiltration and nerve growth factor expression in deep adenomyotic nodules, peritoneal and ovarian endometriosisHum ReprodYear: 2002171895190012093857
Arici A,Oral E,Bukulmez O,Duleba A,Olive DL,Jones EE. The effect of endometriosis on implantation: results from the Yale University in vitro fertilization and embryo transfer programFertil SterilYear: 1996656036078774295
Attar E,Bulun SE. Aromatase and other steroidogenic genes in endometriosis: translational aspectsHum Reprod UpdateYear: 200612495616123052
Attia GR,Zeitoun K,Edwards D,Johns A,Carr BR,Bulun SE. Progesterone receptor isoform A but not B is expressed in endometriosisJ Clin Endocrinol MetabYear: 2000852897290210946900
Augoulea A,Mastorakos G,Lambrinoudaki I,Christodoulakos G,Creatsas G. The role of the oxidative-stress in the endometriosis-related infertilityGynecol EndocrinolYear: 200925758119253102
Bahtiyar MO,Seli E,Oral E,Senturk LM,Zreik TG,Arici A. Follicular fluid of women with endometriosis stimulates the proliferation of endometrial stromal cellsHum ReprodYear: 199813349234959886538
Bancroft K,Williams CAV,Elstein M. Pituitary–ovarian function in women with minimal or mild endometriosis and otherwise unexplained infertilityClin EndocrinolYear: 199236177181
Bazer F,Spencer T,Johnson G,Burghardt R,Wu G. Comparative aspects of implantationReproductionYear: 200913819520919502456
Benagiano G,Brosens I. The history of endometriosis: identifying the diseaseHum ReprodYear: 199169639681761667
Bergendal A,Naffah S,Nagy C,Bergqvist A,Sjoblom P,Hillensjo T. Outcome of IVF in patients with endometriosis in comparison with tubal-factor infertilityJ Assist Reprod GenetYear: 1998155305349822979
Bergqvist A,D'Hooghe T. Mini symposium on pathogenesis of endometriosis and treatment of endometriosis-associated subfertility. Introduction: the endometriosis enigmaHum Reprod UpdateYear: 20028798311866243
Berkley KJ,Rapkin AJ,Papka RE. The pains of endometriosisScienceYear: 20053081587158915947176
Bischoff F,Simpson JL. Genetics of endometriosis: heritability and candidate genesBest Pract Res Clin Obstet GynaecolYear: 20041821923215157639
Brizek CL,Schlaff S,Pellegrini VA,Frank JB,Worrilow KC. Increased incidence of aberrant morphological phenotypes in human embryogenesis—an association with endometriosisJ Assist Reprod GenetYear: 1995121061127670267
Brosens IA,Koninckx PR,Corveleyn PA. A study of plasma progesterone, oestradiol-17beta, prolactin and LH levels, and of the luteal phase appearance of the ovaries in patients with endometriosis and infertilityBr J Obstet GynaecolYear: 197885246250638091
Bulletti C,Coccia ME,Battistoni S,Borini A. Endometriosis and infertilityJ Assist Reprod GenetYear: 20102744144720574791
Bulun SE,Cheng YH,Yin P,Imir G,Utsunomiya H,Attar E,Innes J,Julie Kim J. Progesterone resistance in endometriosis: link to failure to metabolize estradiolMol Cell EndocrinolYear: 20062489410316406281
Burdge GC,Lillycrop KA. Nutrition, epigenetics, and developmental plasticity: implications for understanding human diseaseAnnu Rev NutrYear: 20103031533920415585
Burns WN,Schenken RS. Pathophysiology of endometriosis-associated infertilityClin Obstet GynecolYear: 19994258661010451772
Cahill DJ,Hull MG. Pituitary-ovarian dysfunction and endometriosisHum Reprod UpdateYear: 20006566610711830
Cahill DJ,Wardle PG,Maile LA,Harlow CR,Hull MG. Pituitary-ovarian dysfunction as a cause for endometriosis-associated and unexplained infertilityHum ReprodYear: 199510314231468822432
Carlberg M,Nejaty J,Froysa B,Guan Y,Soder O,Bergqvist A. Elevated expression of tumour necrosis factor alpha in cultured granulosa cells from women with endometriosisHum ReprodYear: 2000151250125510831550
Cheesman KL,Ben N,Chatterton RT Jr,Cohen MR. Relationship of luteinizing hormone, pregnanediol-3-glucuronide, and estriol-16-glucuronide in urine of infertile women with endometriosisFertil SterilYear: 1982385425487128839
Cheesman KL,Cheesman SD,Chatterton RT Jr,Cohen MR. Alterations in progesterone metabolism and luteal function in infertile women with endometriosisFertil SterilYear: 1983405905956226540
Chegini N,Roberts M,Ripps B. Differential expression of interleukins (IL)-13 and IL-15 in ectopic and eutopic endometrium of women with endometriosis and normal fertile womenAm J Reprod ImmunolYear: 200349758312765345
Chishima F,Hayakawa S,Yamamoto T,Sugitani M,Karasaki-Suzuki M,Sugita K,Nemoto N. Expression of inducible microsomal prostaglandin E synthase in local lesions of endometriosis patientsAm J Reprod ImmunolYear: 20075721822617295901
Chung HW,Wen Y,Chun SH,Nezhat C,Woo BH,Lake Polan M. Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-3 mRNA expression in ectopic and eutopic endometrium in women with endometriosis: a rationale for endometriotic invasivenessFertil SterilYear: 20017515215911163831
Coddington CC,Oehninger S,Cunningham DS,Hansen K,Sueldo CE,Hodgen GD. Peritoneal fluid from patients with endometriosis decreases sperm binding to the zona pellucida in the hemizona assay: a preliminary reportFertil SterilYear: 1992577837861555689
Cummings AM,Metcalf JL. Induction of endometriosis in mice: a new model sensitive to estrogenReprod ToxicolYear: 199592332387579907
Cunha-Filho JS,Gross JL,Lemos NA,Brandelli A,Castillos M,Passos EP. Hyperprolactinemia and luteal insufficiency in infertile patients with mild and minimal endometriosisHorm Metab ResYear: 20013321622011383925
Cunha-Filho JS,Gross JL,Bastos de Souza CA,Lemos NA,Giugliani C,Freitas F,Passos EP. Physiopathological aspects of corpus luteum defect in infertile patients with mild/minimal endometriosisJ Assist Reprod GenetYear: 20032011712112735387
D'Hooghe TM,Kyama CM,Chai D,Fassbender A,Vodolazkaia A,Bokor A,Mwenda JM. Nonhuman primate models for translational research in endometriosisReprod SciYear: 20091615216119208783
Dean W,Santos F,Reik W. Epigenetic reprogramming in early mammalian development and following somatic nuclear transferSemin Cell Dev BiolYear: 2003149310012524012
Dean W,Lucifero D,Santos F. DNA methylation in mammalian development and diseaseBirth Defects Res C Embryo TodayYear: 2005759811116035040
Diaz I,Navarro J,Blasco L,Simon C,Pellicer A,Remohi J. Impact of stage III-IV endometriosis on recipients of sibling oocytes: matched case-control studyFertil SterilYear: 200074313410899493
Díaz-Fontdevila M,Pommer R,Smith R. Cumulus cell apoptosis changes with exposure to spermatozoa and pathologies involved in infertilityFertil SterilYear: 2009912061206818692783
Ding GL,Chen XJ,Luo Q,Dong MY,Wang N,Huang HF. Attenuated oocyte fertilization and embryo development associated with altered growth factor/signal transduction induced by endometriotic peritoneal fluidFertil SterilYear: 2010932538254420045520
Dlugi AM,Loy RA,Dieterle S,Bayer SR,Seibel MM. The effect of endometriomas on in vitro fertilization outcomeJ In Vitro Fert Embryo TransfYear: 198963383412517506
Dodds WG,Miller FA,Friedman CI,Lisko B,Goldberg JM,Kim MH. The effect of preovulatory peritoneal fluid from cases of endometriosis on murine in vitro fertilization, embryo development, oviduct transport, and implantationAm J Obstet GynecolYear: 19921662192241733197
Donaghay M,Lessey BA. Uterine receptivity: alterations associated with benign gynecological diseaseSemin Reprod MedYear: 20072546147517960531
Donnez J,Thomas K. Incidence of the luteinized unruptured follicle syndrome in fertile women and in women with endometriosisEur J Obstet Gynecol Reprod BiolYear: 1982141871907160529
Doody MC,Gibbons WE,Buttram VC Jr. Linear regression analysis of ultrasound follicular growth series: evidence for an abnormality of follicular growth in endometriosis patientsFertil SterilYear: 19884947513275551
Drake TS,O'Brien WF,Ramwell PW,Metz SA. Peritoneal fluid thromboxane B2 and 6-keto-prostaglandin F1 alpha in endometriosisAm J Obstet GynecolYear: 19811404014046894667
Ebisch IMW,Steegers-Theunissen RPM,Sweep FCGJ,Zielhuis GA,Geurts-Moespot A,Thomas CMG. Possible role of the plasminogen activation system in human subfertilityFertil SterilYear: 20078761962617123524
Esfandiari N,Falcone T,Goldberg JM,Agarwal A,Sharma RK. Effects of peritoneal fluid on preimplantation mouse embryo development and apoptosis in vitroReprod Biomed OnlineYear: 20051161561916409713
Espey LL. Ovulation as an inflammatory reaction—a hypothesisBiol ReprodYear: 198022731066991013
Espey LL. Current status of the hypothesis that mammalian ovulation is comparable to an inflammatory reactionBiol ReprodYear: 1994502332388142541
Eun Kwon H,Taylor HS. The role of HOX genes in human implantationAnn N Y Acad SciYear: 2004103411815731295
Feil R. Epigenetic asymmetry in the zygote and mammalian developmentInt J Dev BiolYear: 20095319120119378254
Fowler PA,Tattum J,Bhattacharya S,Klonisch T,Hombach-Klonisch S,Gazvani R,Lea RG,Miller I,Simpson WG,Cash P. An investigation of the effects of endometriosis on the proteome of human eutopic endometrium: a heterogeneous tissue with a complex diseaseProteomicsYear: 2007713014217124717
Furukubo M,Fujino Y,Umesaki N,Ogita S. Effects of endometrial stromal cells and peritoneal fluid on fertility associated with endometriosisOsaka City Med JYear: 19984443549834618
Garrido N,Navarro J,Remohi J,Simon C,Pellicer A. Follicular hormonal environment and embryo quality in women with endometriosisHum Reprod UpdateYear: 20006677410711831
Garrido N,Navarro J,Garcia-Velasco J,Remoh J,Pellice A,Simon C. The endometrium versus embryonic quality in endometriosis-related infertilityHum Reprod UpdateYear: 200289510311866246
Garrido N,Pellicer A,Remohi J,Simon C. Uterine and ovarian function in endometriosisSemin Reprod MedYear: 20032118319212917788
Gazvani R,Templeton A. Peritoneal environment, cytokines and angiogenesis in the pathophysiology of endometriosisReproductionYear: 200212321722611866688
Geber S,Paraschos T,Atkinson G,Margara R,Winston RM. Results of IVF in patients with endometriosis: the severity of the disease does not affect outcome, or the incidence of miscarriageHum ReprodYear: 199510150715117593525
Giudice LC,Kao LC. EndometriosisLancetYear: 20043641789179915541453
Giudice LC,Telles TL,Lobo S,Kao L. The molecular basis for implantation failure in endometriosisAnn N Y Acad SciYear: 200295525226411949953
Gleicher N,el-Roeiy A,Confino E,Friberg J. Reproductive failure because of autoantibodies: unexplained infertility and pregnancy wastageAm J Obstet GynecolYear: 1989160137613802500021
Gomez-Torres MJ,Acien P,Campos A,Velasco I. Embryotoxicity of peritoneal fluid in women with endometriosis. Its relation with cytokines and lymphocyte populationsHum ReprodYear: 20021777778111870135
Groll M. Endometriosis and spontaneous abortionFertil SterilYear: 1984419339356427022
Grummer R. Animal models in endometriosis researchHum Reprod UpdateYear: 20061264164916775193
Haaf T. Methylation dynamics in the early mammalian embryo: implications of genome reprogramming defects for developmentCurr Top Microbiol ImmunolYear: 2006310132216909904
Hadfield R,Mardon H,Barlow D,Kennedy S. Delay in the diagnosis of endometriosis: a survey of women from the USA and the UKHum ReprodYear: 1996118788808671344
Hahn DW,Carraher RP,Foldesy RG,McGuire JL. Experimental evidence for failure to implant as a mechanism of infertility associated with endometriosisAm J Obstet GynecolYear: 1986155110911133777056
Hapangama DK,Turner MA,Drury JA,Quenby S,Saretzki G,Martin-Ruiz C,Zglinicki T. Endometriosis is associated with aberrant endometrial expression of telomerase and increased telomere lengthHum ReprodYear: 2008231511151918456668
Harada T,Yoshioka H,Yoshida S,Iwabe T,Onohara Y,Tanikawa M,Terakawa N. Increased interleukin-6 levels in peritoneal fluid of infertile patients with active endometriosisAm J Obstet GynecolYear: 19971765935979077612
Harlow CR,Cahill DJ,Maile LA,Talbot WM,Mears J,Wardle PG,Hull MG. Reduced preovulatory granulosa cell steroidogenesis in women with endometriosisJ Clin Endocrinol MetabYear: 1996814264298550788
Hill JA,Faris HM,Schiff I,Anderson DJ. Characterization of leukocyte subpopulations in the peritoneal fluid of women with endometriosisFertil SterilYear: 1988502162223294043
Hu X. Proteolytic signaling by TNFalpha: caspase activation and IkappaB degradationCytokineYear: 20032128629412824002
Huang HY,Lee CL,Lai YM,Chang MY,Chang SY,Soong YK. The outcome of in vitro fertilization and embryo transfer therapy in women with endometriosis failing to conceive after laparoscopic conservative surgeryJ Am Assoc Gynecol LaparoscYear: 199742993039154777
Hull MG,Williams JA,Ray B,McLaughlin EA,Akande VA,Ford WC. The contribution of subtle oocyte or sperm dysfunction affecting fertilization in endometriosis-associated or unexplained infertility: a controlled comparison with tubal infertility and use of donor spermatozoaHum ReprodYear: 199813182518309740433
Ito F,Fujino Y,Ogita S. Serum from endometriosis patients impairs the development of mouse embryos in vitro—comparison with serum from tubal obstruction patient and plasmanateActa Obstet Gynecol ScandYear: 1996758778809003085
Iwabe T,Harada T,Terakawa N. Role of cytokines in endometriosis-associated infertilityGynecol Obstet InvestYear: 200253192511834864
Jackson LW,Schisterman EF,Dey-Rao R,Browne R,Armstrong D. Oxidative stress and endometriosisHum ReprodYear: 2005202014202015817589
Jana SK,K NB,Chattopadhyay R,Chakravarty B,Chaudhury K. Upper control limit of reactive oxygen species in follicular fluid beyond which viable embryo formation is not favorableReprod ToxicolYear: 20102944745120406678
Junien C,Gallou-Kabani C,Vige A,Gross MS. Nutritional epigenomics of metabolic syndrome (in French)Med Sci (Paris)Year: 200529Spec No.445216598905
Kaya H,Oral B. Effect of ovarian involvement on the frequency of luteinized unruptured follicle in endometriosisGynecol Obstet InvestYear: 19994812312610461004
Khosla S,Dean W,Brown D,Reik W,Feil R. Culture of preimplantation mouse embryos affects fetal development and the expression of imprinted genesBiol ReprodYear: 20016491892611207209
Kissler S,Hamscho N,Zangos S,Gatje R,Muller A,Rody A,Dobert N,Menzel C,Grunwald F,Siebzehnrubl E,et al. Diminished pregnancy rates in endometriosis due to impaired uterotubal transport assessed by hysterosalpingoscintigraphyBJOGYear: 20051121391139616167942
Kissler S,Hamscho N,Zangos S,Wiegratz I,Schlichter S,Menzel C,Doebert N,Gruenwald F,Vogl TJ,Gaetje R,et al. Uterotubal transport disorder in adenomyosis and endometriosis—a cause for infertilityBJOGYear: 200611390290816753046
Kissler S,Zangos S,Wiegratz I,Kohl J,Rody A,Gaetje R,Doebert N,Wildt L,Kunz G,Leyendecker G,et al. Utero-tubal sperm transport and its impairment in endometriosis and adenomyosisAnn N Y Acad SciYear: 20071101384817344532
Koger KE,Shatney CH,Hodge K,McClenathan JH. Surgical scar endometriomaSurg Gynecol ObstetYear: 19931772432468356497
Koninckx PR,Moor PD,Brosens IA. Diagnosis of the luteinized unruptured follicle syndrome by steroid hormone assays on peritoneal fluidBJOGYear: 198087929934
Kumbak B,Kahraman S,Karlikaya G,Lacin S,Guney A. In vitro fertilization in normoresponder patients with endometriomas: comparison with basal simple ovarian cystsGynecol Obstet InvestYear: 20086521221618073487
Lachapelle MH,Hemmings R,Roy DC,Falcone T,Miron P. Flow cytometric evaluation of leukocyte subpopulations in the follicular fluids of infertile patientsFertil SterilYear: 199665113511408641486
Lao VV,Herring JL,Kim CH,Darwanto A,Soto U,Sowers LC. Incorporation of 5-chlorocytosine into mammalian DNA results in heritable gene silencing and altered cytosine methylation patternsCarcinogenesisYear: 20093088689319279184
Latham KE,Schultz RM. Embryonic genome activationFront BiosciYear: 20016D748D75911401780
Lee B,Du H,Taylor HS. Experimental murine endometriosis induces DNA methylation and altered gene expression in eutopic endometriumBiol ReprodYear: 200980798518799756
Lessey BA. Implantation defects in infertile women with endometriosisAnn N Y Acad SciYear: 200295526528011949954
Lessey BA,Killam AP,Metzger DA,Haney AF,Greene GL,McCarty KS Jr. Immunohistochemical analysis of human uterine estrogen and progesterone receptors throughout the menstrual cycleJ Clin Endocrinol MetabYear: 1988673343402455728
Leyendecker G,Kunz G,Wildt L,Beil D,Deininger H. Uterine hyperperistalsis and dysperistalsis as dysfunctions of the mechanism of rapid sperm transport in patients with endometriosis and infertilityHum ReprodYear: 199611154215518671502
Mahutte NG,Arici A. Endometriosis and assisted reproductive technologies: are outcomes affected?Curr Opin Obstet GynecolYear: 20011327527911396650
Mansour G,Abdelrazik H,Sharma RK,Radwan E,Falcone T,Agarwal A. L-carnitine supplementation reduces oocyte cytoskeleton damage and embryo apoptosis induced by incubation in peritoneal fluid from patients with endometriosisFertil SterilYear: 2009912079208618394615
Mansour G,Aziz N,Sharma R,Falcone T,Goldberg J,Agarwal A. The impact of peritoneal fluid from healthy women and from women with endometriosis on sperm DNA and its relationship to the sperm deformity indexFertil SterilYear: 200992616719409553
Marik J,Hulka J. Luteinized unruptured follicle syndrome: a subtle cause of infertilityFertil SterilYear: 197829270274147778
Matalliotakis I,Cakmak H,Dermitzaki D,Zervoudis S,Goumenou A,Fragouli Y. Increased rate of endometriosis and spontaneous abortion in an in vitro fertilization program: no correlation with epidemiological factorsGynecol EndocrinolYear: 20082419419818382905
Matalliotakis I,Cakmak H,Fragouli Y,Goumenou A,Mahutte N,Arici A. Epidemiological characteristics in women with and without endometriosis in the Yale seriesArch Gynecol ObstetYear: 200827738939317922285
Metzger DA,Olive DL,Stohs GF,Franklin RR. Association of endometriosis and spontaneous abortion: effect of control group selectionFertil SterilYear: 19864518223943647
Mio Y,Toda T,Harada T,Terakawa N. Luteinized unruptured follicle in the early stages of endometriosis as a cause of unexplained infertilityAm J Obstet GynecolYear: 19921672712731442941
Moon CE,Bertero MC,Curry TE,London SN,Muse KN,Sharpe KL,Vernon MW. The presence of luteinized unruptured follicle syndrome and altered folliculogenesis in rats with surgically induced endometriosisAm J Obstet GynecolYear: 19931696766828372879
Moon YS,Gomel V,Yuen BH,Nickerson KG. The role of prostaglandin F in the symptoms of endometriosisCan Med Assoc JYear: 19831294584596883236
Murphy AA,Palinski W,Rankin S,Morales AJ,Parthasarathy S. Evidence for oxidatively modified lipid-protein complexes in endometrium and endometriosisFertil SterilYear: 199869109210949627298
Muscato JJ,Haney AF,Weinberg JB. Sperm phagocytosis by human peritoneal macrophages: a possible cause of infertility in endometriosisObstet Gynecol SurvYear: 198338177178
Muse KN,Wilson EA. How does mild endometriosis cause infertility?Fertil SterilYear: 1982381451527049739
Muzii L,Marana R,Brunetti L,Romanini ME,Vavala VV,Mancuso S,Vacca M. Production of prostaglandin F2alpha by the different forms of endometriosisJ Am Assoc Gynecol LaparoscYear: 19963S339074191
Nafee TM,Farrell WE,Carroll WD,Fryer AA,Ismail KM. Epigenetic control of fetal gene expressionBJOGYear: 200811515816817970798
Nakahara K,Saito H,Saito T,Ito M,Ohta N,Takahashi T,Hiroi M. The incidence of apoptotic bodies in membrana granulosa can predict prognosis of ova from patients participating in in vitro fertilization programsFertil SterilYear: 1997683123179240262
Nap AW,Groothuis PG,Demir AY,Evers JLH,Dunselman GAJ. Pathogenesis of endometriosisBest Pract Res Clin Obstet GynaecolYear: 20041823324415157640
Navarro J,Garrido N,Remohi J,Pellicer A. How does endometriosis affect infertility?Obstet Gynecol Clin North AmYear: 20033018119212699265
Olive DL,Franklin RR,Gratkins LV. The association between endometriosis and spontaneous abortion. A retrospective clinical studyJ Reprod MedYear: 1982273333387120211
Osteen KG,Bruner KL,Sharpe-Timms KL. Steroid and growth factor regulation of matrix metalloproteinase expression and endometriosisSemin Reprod EndocrinolYear: 1996142472558885055
Osteen KG,Yeaman GR,Bruner-Tran KL. Matrix metalloproteinases and endometriosisSemin Reprod MedYear: 20032115516412917785
Owen JA. Physiology of the menstrual cycleAm J Clin NutrYear: 1975283333381091131
Ozkan S,Murk W,Arici A. Endometriosis and infertility: epidemiology and evidence-based treatmentsAnn N Y Acad SciYear: 200811279210018443335
Pal AK,Biswas S,Goswami SK,Kabir SN. Effect of pelvic endometrial implants on overall reproductive functions of female ratsBiol ReprodYear: 19996095495810084971
Paulson RJ,Sauer MV,Lobo RA. Factors affecting embryo implantation after human in vitro fertilization: a hypothesisAm J Obstet GynecolYear: 1990163202020232256515
Pellicer A,Oliveira N,Ruiz A,Remohi J,Simon C. Exploring the mechanism(s) of endometriosis-related infertility: an analysis of embryo development and implantation in assisted reproductionHum ReprodYear: 199510Suppl 291978745306
Pellicer A,Albert C,Mercader A,Bonilla-Musoles F,RemohI J,Simón C. The follicular and endocrine environment in women with endometriosis: local and systemic cytokine productionFertil SterilYear: 1998704254319757870
Pellicer A,Albert C,Garrido N,Navarro J,Remohi J,Simon C. The pathophysiology of endometriosis-associated infertility: follicular environment and embryo qualityJ Reprod Fertil SupplYear: 20005510911910889840
Pittaway DE,Vernon C,Fayez JA. Spontaneous abortions in women with endometriosisFertil SterilYear: 1988507117153181482
Piva M,Sharpe-Timms KL. Peritoneal endometriotic lesions differentially express a haptoglobin-like geneMol Hum ReprodYear: 19995717810050665
Powell MD,Manandhar G,Spate L,Sutovsky M,Zimmerman S,Sachdev SC,Hannink M,Prather RS,Sutovsky P. Discovery of putative oocyte quality markers by comparative ExacTag proteomicsProteomics Clin ApplYear: 2010433735121137054
Reeve L,Lashen H,Pacey AA. Endometriosis affects sperm-endosalpingeal interactionsHum ReprodYear: 20052044845115550494
Reik W,Dean W,Walter J. Epigenetic reprogramming in mammalian developmentScienceYear: 20012931089109311498579
Remorgida V,Ferrero S,Fulcheri E,Ragni N,Martin DC. Bowel endometriosis: presentation, diagnosis, and treatmentObstet Gynecol SurvYear: 20076246147017572918
Rienzi L,Ubaldi FM,Iacobelli M,Minasi MG,Romano S,Ferrero S,Sapienza F,Baroni E,Litwicka K,Greco E. Significance of metaphase II human oocyte morphology on ICSI outcomeFertil SterilYear: 2008901692170018249393
Ronnberg L,Kauppila A,Rajaniemi H. Luteinizing hormone receptor disorder in endometriosisFertil SterilYear: 19844264686327403
Russell DL,Robker RL. Molecular mechanisms of ovulation: co-ordination through the cumulus complexHum Reprod UpdateYear: 20071328931217242016
Sasson IE,Taylor HS. Stem cells and the pathogenesis of endometriosisAnn N Y Acad SciYear: 2008112710611518443337
Schenken RS,Asch RH. Surgical induction of endometriosis in the rabbit: effects on fertility and concentrations of peritoneal fluid prostaglandinsFertil SterilYear: 1980345815877450077
Seli E,Berkkanoglu M,Arici A. Pathogenesis of endometriosisObstet Gynecol Clin North AmYear: 200330416112699257
Senger PL. Pathways to pregnancy and parturitionYear: 20052PullmanCurrent Conceptions
Sharpe-Timms KL. Endometrial anomalies in women with endometriosisAnn N Y Acad SciYear: 200194313114711594534
Sharpe-Timms KL. Using rats as a research model for the study of endometriosisAnn N Y Acad SciYear: 200295531832711949958
Sharpe-Timms KL. Haptoglobin expression by shed endometrial tissue fragments found in peritoneal fluidFertil SterilYear: 200584223016009149
Sharpe-Timms KL,Penney LL,Zimmer RL,Wright JA,Zhang Y,Surewicz K. Partial purification and amino acid sequence analysis of endometriosis protein-II (ENDO-II) reveals homology with tissue inhibitor of metalloproteinases-1 (TIMP-1)J Clin Endocrinol MetabYear: 199580378437878530636
Sharpe-Timms KL,Piva M,Ricke EA,Surewicz K,Zhang YL,Zimmer RL. Endometriotic lesions synthesize and secrete a haptoglobin-like proteinBiol ReprodYear: 1998589889949546730
Sharpe-Timms KL,Zimmer RL,Ricke EA,Piva M,Horowitz GM. Endometriotic haptoglobin binds to peritoneal macrophages and alters their function in women with endometriosisFertil SterilYear: 20027881081912372461
Simoens S,Hummelshoj L,D'Hooghe T. Endometriosis: cost estimates and methodological perspectiveHum Reprod UpdateYear: 20071339540417584822
Simon C,Gutierrez A,Vidal A,Santos MJ,Tarin JJ,Remohi J,Pellicer A. Outcome of patients with endometriosis in assisted reproduction: results from in-vitro fertilization and oocyte donationHum ReprodYear: 199497257298046030
Simpson JL,Bischoff FZ,Kamat A,Buster JE,Carson SA. Genetics of endometriosisObstet Gynecol ClinYear: 2003302140
Siristatidis C,Nissotakis C,Chrelias C,Iacovidou H,Salamalekis E. Immunological factors and their role in the genesis and development of endometriosisJ Obstet Gynaecol ResYear: 20063216217016594919
Smedts AM,Lele SM,Modesitt SC,Curry TE. Expression of an extracellular matrix metalloproteinase inducer (basigin) in the human ovary and ovarian endometriosisFertil SterilYear: 20068653554216876164
Smith M,Keay S,Margo F,Harlow C,Wood P,Cahill D,Hull M. Total cortisol levels are reduced in the periovulatory follicle of infertile women with minimal and mild endometriosisAm J Reprod ImmunolYear: 200247525611885559
Sondheimer SJ,Flickinger G. Prostaglandin F2 alpha in the peritoneal fluid of patients with endometriosisInt J FertilYear: 19822773756126450
Stefansson H,Geirsson RT,Steinthorsdottir V,Jonsson H,Manolescu A,Kong A,Ingadottir G,Gulcher J,Stefansson K. Genetic factors contribute to the risk of developing endometriosisHum ReprodYear: 20021755555911870102
Stilley JA, Sharpe-Timms KL (2011) TIMP1 contributes to ovarian anomalies in both an MMP-dependent and independent manner in a rat model. Biol Reprod (in press)
Stilley JA,Woods-Marshall R,Sutovsky M,Sutovsky P,Sharpe-Timms KL. Reduced fecundity in female rats with surgically induced endometriosis and in their daughters: a potential role for tissue inhibitors of metalloproteinase 1Biol ReprodYear: 20098064965619020297
Stilley JA,Birt JA,Nagel SC,Sutovsky M,Sutovsky P,Sharpe-Timms KL. Neutralizing TIMP1 restores fecundity in a rat model of endometriosis and treating control rats with TIMP1 causes anomalies in ovarian function and embryo developmentBiol ReprodYear: 20108318519420410455
Sung L,Mukherjee T,Takeshige T,Bustillo M,Copperman AB. Endometriosis is not detrimental to embryo implantation in oocyte recipientsJ Assist Reprod GenetYear: 1997141521569090558
Takahashi K,Mukaida T,Tomiyama T,Goto T,Oka C. GnRH antagonist improved blastocyst quality and pregnancy outcome after multiple failures of IVF/ICSI-ET with a GnRH agonist protocolJ Assist Reprod GenetYear: 20042131732215587144
Taketani Y,Kuo TM,Mizuno M. Comparison of cytokine levels and embryo toxicity in peritoneal fluid in infertile women with untreated or treated endometriosisAm J Obstet GynecolYear: 19921672652701442940
Tanbo T,Omland A,Dale PO,Abyholm T. In vitro fertilization/embryo transfer in unexplained infertility and minimal peritoneal endometriosisActa Obstet Gynecol ScandYear: 1995745395437618453
Taylor HS,Bagot C,Kardana A,Olive D,Arici A. HOX gene expression is altered in the endometrium of women with endometriosisHum ReprodYear: 1999141328133110325287
Taylor RN,Lebovic DI,Mueller MD. Angiogenic factors in endometriosisAnn N Y Acad SciYear: 20029558910011949968
Telford NA,Watson AJ,Schultz GA. Transition from maternal to embryonic control in early mammalian development: a comparison of several speciesMol Reprod DevYear: 199026901002189447
Tomassetti C,Meuleman C,Pexsters A,Mihalyi A,Kyama C,Simsa P,D'Hooghe TM. Endometriosis, recurrent miscarriage and implantation failure: is there an immunological link?Reprod Biomed OnlineYear: 200613586416820110
Treloar SA,Wicks J,Nyholt DR,Montgomery GW,Bahlo M,Smith V,Dawson G,Mackay IJ,Weeks DE,Bennett ST,et al. Genomewide linkage study in 1,176 affected sister pair families identifies a significant susceptibility locus for endometriosis on chromosome 10q26Am J Hum GenetYear: 20057736537616080113
Trinder J,Cahill DJ. Endometriosis and infertility: the debate continuesHum Fertil (Camb)Year: 20025S21S2711897911
Tummon IS,Maclin VM,Radwanska E,Binor Z,Dmowski WP. Occult ovulatory dysfunction in women with minimal endometriosis or unexplained infertilityFertil SterilYear: 1988507167203181483
Tzeng CR,Chien LW,Chang AC,Chen AC. Effect of peritoneal fluid and serum from patients with endometriosis on mouse embryo in vitro developmentZhonghua Yi Xue Za Zhi (Taipei)Year: 1994541451487954053
Ulukus M,Cakmak H,Arici A. The role of endometrium in endometriosisJ Soc Gynecol InvestigYear: 20061346747616990031
Umezawa M,Sakata C,Tanaka N,Kudo S,Tabata M,Takeda K,Ihara T,Sugamata M. Cytokine and chemokine expression in a rat endometriosis is similar to that in human endometriosisCytokineYear: 20084310510918595729
Ushijima T,Okochi-Takada E. Aberrant methylations in cancer cells: where do they come from?Cancer SciYear: 20059620621115819717
Valinluck V,Sowers LC. Inflammation-mediated cytosine damage: a mechanistic link between inflammation and the epigenetic alterations in human cancersCancer ResYear: 2007675583558617575120
Vernon MW,Wilson EA. Studies on the surgical induction of endometriosis in the ratFertil SterilYear: 1985446846944054348
Vitiello D,Kodaman PH,Taylor HS. HOX genes in implantationSemin Reprod MedYear: 20072543143617960527
Waterland RA,Travisano M,Tahiliani KG,Rached MT,Mirza S. Methyl donor supplementation prevents transgenerational amplification of obesityInt J Obes Relat Metab DisordYear: 20083213731379
Wei Q,St. Clair JB,Fu T,Stratton P,Nieman LK. Reduced expression of biomarkers associated with the implantation window in women with endometriosisFertil SterilYear: 2009911686169118672236
Wheeler JM,Johnston BM,Malinak LR. The relationship of endometriosis to spontaneous abortionFertil SterilYear: 1983396566606840309
Williams CA,Oak MK,Elstein M. Cyclical gonadotrophin and progesterone secretion in women with minimal endometriosisClin Reprod FertilYear: 198642592683096552
Wu MY,Ho HN. The role of cytokines in endometriosisAm J Reprod ImmunolYear: 20034928529612854733
Wu Y,Strawn E,Basir Z,Halverson G,Guo SW. Promoter hypermethylation of progesterone receptor isoform B (PR-B) in endometriosisEpigeneticsYear: 2006110611117965625
Wu Y,Strawn E,Basir Z,Halverson G,Guo SW. Aberrant expression of deoxyribonucleic acid methyltransferases DNMT1, DNMT3A, and DNMT3B in women with endometriosisFertil SterilYear: 200787243217081533
Wunder DM,Mueller MD,Birkhäuser MH,Bersinger NA. Steroids and protein markers in the follicular fluid as indicators of oocyte quality in patients with and without endometriosisJ Assist Reprod GenetYear: 20052225726416021855
Wunder DM,Mueller MD,Birkhäuser MH,Bersinger NA. Increased ENA-78 in the follicular fluid of patients with endometriosisActa Obstet Gynecol ScandYear: 20068533634216553183
Yanushpolsky EH,Best CL,Jackson KV,Clarke RN,Barbieri RL,Hornstein MD. Effects of endometriomas on ooccyte quality, embryo quality, and pregnancy rates in in vitro fertilization cycles: a prospective, case-controlled studyJ Assist Reprod GenetYear: 1998151931979565848
Yoshida S,Harada T,Iwabe T,Taniguchi F,Mitsunari M,Yamauchi N,Deura I,Horie S,Terakawa N. A combination of interleukin-6 and its soluble receptor impairs sperm motility: implications in infertility associated with endometriosisHum ReprodYear: 2004191821182515166129
Zaitseva I,Zaitsev S,Alenina N,Bader M,Krivokharchenko A. Dynamics of DNA-demethylation in early mouse and rat embryos developed in vivo and in vitroMol Reprod DevYear: 2007741255126117290422
Zeller JM,Henig I,Radwanska E,Dmowski WP. Enhancement of human monocyte and peritoneal macrophage chemiluminescence activities in women with endometriosisAm J Reprod Immunol MicrobiolYear: 19871378823605484
Zeng F,Baldwin DA,Schultz RM. Transcript profiling during preimplantation mouse developmentDev BiolYear: 200427248349615282163
Zhou HE,Nothnick WB. The relevancy of the matrix metalloproteinase system to the pathophysiology of endometriosisFront BiosciYear: 20051056957515574393

Figures

[Figure ID: Fig1]
Fig. 1 

Factors associated with reduced fecundity in women with endometriosis



[Figure ID: Fig2]
Fig. 2 

Mechanisms by which endometriosis affects apoptosis signaling in embryo development (TNF-α tumor necrosis factor-α)



[Figure ID: Fig3]
Fig. 3 

Potential mechanisms of aberrant DNA methylation in endometriosis (DNMT DNA methyltransferase, HDAC histone deacetylase)



[Figure ID: Fig4]
Fig. 4 

Methylation dynamics during mammalian folliculogenesis and early mammalian embryo development (blue paternal genome, red maternal genome) adapted from Reik W. et al., 2001



Tables
[TableWrap ID: Tab1] Table 1 

Embryo defects in endometriosis (IVF in vitro fertilization, PF peritoneal fluid, GD gestational day, Pre-implant pre-implantation)


Experimental design Development Defect in endometriosis Citation
Women with endometriosis
IVF retrospective Zygote and greater Aberrant nuclear and cytoplasmic events Brizek et al. 1995
IVF retrospective 4-Cell Lower percentage of embryos reached 4-cell stage at 48 h Yanushpolsky et al. 1998
IVF retrospective Pre-implant Reduced blastomere number. Increased number embryos arrested Pellicer et al. 1995
IVF retrospective Pre-implant Decreased blastomere cleavage rates Tanbo et al. 1995
IVF retrospective Pre-implant No difference in embryo quality Arici et al. 1996
Exposed murine embryos in vitro to human sera Pre-implant Embryo toxicity Abu-Musa et al. 1992; Ito et al. 1996
Exposed 2-cell murine embryos in vitro to human sera and PF Pre-implant Increased embryo toxicity Tzeng et al. 1994
Exposed 2-cell murine embryos in vitro to human PF Pre-implant High embryo toxicity Gomez-Torres et al. 2002
Exposed murine embryos in vitro to human PF Pre-implant No effect on embryo development Dodds et al. 1992
Exposed 2-cell murine embryos in vitro to human PF Pre-morula blastocyst Decreased total cell number. Increased arrested embryos Esfandiari et al. 2005
Murine embryos incubated in human PF Pre-implant DNA fragmentation and increased apoptosis Mansour et al. 2009b
Murine embryos cultured in vitro with human PF Oocyte Decreased fertilization rates Ding et al. 2010
Pre-Implant Decreased development potential
Animal models of endometriosis
Rat model GD14 Decreased number of pups Vernon and Wilson 1985
Term
Rat model; PF treatment Pre-implant Decreased embryonic development rates Furukubo et al. 1998
Rat model 2-Cell Nuclear fragmentation Stilley et al. 2009
8-Cell Delayed or arrested cleavage
Rat model Zygote Improper distribution of microtubules Stilley et al. 2010
Increased cellular stress


Article Categories:
  • Review

Keywords: Keywords Endometriosis, Infertility, Ovary, Oocytes and embryos, Endometrium.

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