Cellular and molecular basis for endometriosis-associated infertility

Julie A W Stilley, Julie A. Birt, Kathy L. Sharpe-Timms, Sharpe-Timms KL
Cell and tissue research · 2012 · vol. 349(3) , pp. 849–862 · doi:10.1007/s00441-011-1309-0 · PMID:22298022 · PMC3429772 · W2055578068
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This paper investigates the cellular and molecular mechanisms underlying endometriosis-associated infertility, proposing that multifaceted and interwoven processes contribute to reproductive dysfunction.

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This paper is a narrative review that examines how endometriosis may cause infertility, drawing together evidence from studies of the hypothalamic-pituitary-ovarian axis, ovarian folliculogenesis and ovulation, and biochemical changes in ovarian compartments (including reports of altered hormone levels and growth factor/cytokine profiles in follicular fluid). It highlights findings that, in women with endometriosis, pituitary-ovarian feedback appears dysregulated (e.g., altered follicular phase length and delayed or abnormal LH surges), folliculogenesis is impaired (reduced numbers of preovulatory follicles, reduced estradiol concentrations), and ovulation may be dysfunctional due to abnormalities in LH receptor dynamics plus changes in proteolytic enzymes, cytokines, inflammatory mediators, and vasculature. A major caveat stated in the review is that mechanisms linking these abnormalities to infertility are not fully understood and the multifaceted nature of endometriosis complicates explanation and treatment development. This paper is centrally about endometriosis — it specifically reviews cellular and molecular mechanisms proposed to underlie endometriosis-associated infertility.

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Abstract

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.
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Animal

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.

Impact

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.

Concluding

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.

Infertility

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. Fig. 1 Factors associated with reduced fecundity in women with endometriosis Factors associated with reduced fecundity in women with endometriosis

Endometriosis

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 ). Fig. 3 Potential mechanisms of aberrant DNA methylation in endometriosis ( DNMT DNA methyltransferase, HDAC histone deacetylase) Potential mechanisms of aberrant DNA methylation in endometriosis ( DNMT DNA methyltransferase, HDAC histone deacetylase) 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. 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 Methylation dynamics during mammalian folliculogenesis and early mammalian embryo development ( blue paternal genome, red maternal genome) adapted from Reik W. et al., 2001 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 ).

Pituitary Ovarian

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.

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Condition tags

endometriosisinfertility

MeSH descriptors

Endometriosis Infertility, Female Oocytes Ovary Animals Embryo Implantation Endometriosis Endometriosis Female Humans Infertility, Female Infertility, Female Oocytes Ovary Pregnancy

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