JBRA Assist. Reprod. 2010;14(4):43-46
ARTIGO DE REVISÃO
doi: 10.5935/1518-0557.2010.14.4.08
Genesis – Centre for Assistance in Human Reproduction, Brasília, Distrito Federal, Brazil
RESUMO
Keywords: Endometriosis, Human Reproduction, Infertility
ABSTRACT
Although up to 60% of women with endometriosis complain of infertility, knowledge on the etiopathogeny of such an association is still limited. Mechanical obstruction to reproductive processes is the most accepted phenomenon to explain infertility in women with endometriosis, but the diverse phenotypes of the disease and notorious biochemical changes in the pelvic-peritonial microenvironment lead us to a complex multifactorial net of possibly connected mechanisms. In this article, we revised classic and recently proposed non-obstructive etiopathogenic theories on endometriosis-related infertility, providing background to counseling and follow up of those patients in reproductive medicine clinics.
Palavras-chave: Endometriose, Reprodução Humana, Infertilidade
INTRODUCTION
Endometriosis is an estrogen-dependent disease which affects up to 10% of women in reproductive ages. Infertility is a complaint in approximately 60% of those women (Moura et al., 1999; Littman et al., 2005) and studies have postulated that more than a half of unexplained infertility cases would be associated with the disease in an eventual laparoscopy (Strathy, 1982; Hill, 1992).
Obstruction to reproductive steps is the most accepted phenomenon to explain infertility in women with endometriosis. Progressive inflammatory process and consequent peritoneal and tubal fibrosis lead to the formation of mechanical barriers due to pelvic adhesions and anatomic distortions. Mainly in moderate and severe stages of disease, oocytes’ extrusion and/or capture by tubal fimbriae may be impaired, and obstructions may either block oocytes’ progression along uterine tubes (Schenken et al., 1984). Ovarian endometriotic cysts, which are present in almost 45% of women with the disease (Busacca & Vignali, 2003), should either exert obstructive influence on reproductive physiology, especially because of the mass effect over healthy adjacent ovarian tissue. As a result of such a compression to gonadal blood supply, tissular ischemia occurs, with a probable significant and progressive depletion of follicles (Pabuccu et al., 2004). As a matter of fact, physiopathology of endometriosis-related infertility shall involve much more complex connections, including molecular changes in pelvic-peritonial and ovarian microenvironments, with negative influences on ovulation (Toya et al., 2000), fertilization, embryogenesis (Pellicer et al., 1995; Garrido et al., 2000; Lebovic et al., 2001) and embryo implantation (Lessey et al., 1994; Kao et al., 2003). Curiously, a twofold risk of preterm birth and small-for-gestational-age baby is reported for infertile women with ovarian endometriomas in comparison with community birth records (Fernando et al, 2009).
The aim of this review is to briefy describe non-obstructive etiopathogenic theories to explain endometriosis-related infertility and provide background to the elaboration of adequate counseling and therapeutic strategies in such a complex scenario.
OVARIAN RESERVE DEPLETION
A recent Brazilian study evaluated infertile women with minimal and mild endometriosis and pointed to the occurrence of significant reduction in serum levels of anti-müllerian hormone (AMH) in women with the disease, when compared with disease-free controls (Lemos et al., 2008). Since AMH has been associated with the real gonadal reserve of primordial follicles, the authors hypothesized that endometriosis should diminish the proper ovarian reserve. As a matter of fact, we recently found that basal levels of the follicle stimulating hormone (FSH) were significantly elevated among infertile women with endometriosis, when compared to exclusive male factor, but no interference of disease was observed on AMH levels (Carvalho et al, 2010). Since controversy has been raised, more studies are requested to determine or deny the speculated negative interference of endometriosis on the proper ovarian reserve.
DISRUPTION OF FOLLICULOGENESIS AND OOCYTE MATURATION
Endometriosis has been associated with folliculogenesis’ disruption, with the possibility of precocious luteinization (Schenken et al., 1984) and other dysfunctions. Some studies have suggested that impaired biological behavior of follicles and oocytes in women with endometriosis disrupts the reproductive process, but results regarding its interference with follicular function are still controversial. While some authors did not detect differences in basal levels of FSH between women with endometriosis and women with tubal factor, or between patients with different degrees of the disease (Lima et al., 2006), Hock et al. reported a significant increase in these levels among women with advanced endometriosis, supporting the idea of a progressive loss of the functional apparatus of the ovaries with the advance of the disease (Hock et al., 2001). We have recently studied infertile patients with endometriosis at the Service of Human Reproduction of the Faculty of Medicine of Ribeirão Preto, University of São Paulo, Brazil, and found that basal FSH levels were significantly elevated among them, when compared to exclusive male factor; we, then, definitely believe that endometriosis shall negatively influence follicular responsiveness to natural and/or exogenous gonadotropins (Carvalho et al, 2010).Also, IVF cycles in patients with minimum/mild endometriosis have been demonstrated to present with longer and insufficient follicular growth (Kao et al., 2003; ASRM, 2006), and hypothetical changes in granulosa cells’ kinetics shall be the cause of such a developmental alteration (Hull et al., 1987; Hughes et al., 1993). As a matter of fact, low quality oocytes and embryos (Jansen, 1986; Igarashi et al., 2005; Fedele et al., 1992a; Fedele et al., 1992b), low fertilization and implantation rates (Kao et al., 2003), and insufficient luteal function (Genbacev et al., 2003) are frequently found among infertile women with endometriosis. Barcelos et al have recently suggested that maturation of oocytes in patients with endometriosis shall be inadequate and maturity may be falsely indicated by normal morphological criteria. The authors found a greater proportion of oocytes in telophase I among those considered to be morphologically in metaphase II after in vitro maturation for patients with endometriosis (Barcelos et al., 2008).
COMPROMISED STEROIDOGENESIS
A negative effect on progesterone release by granulosa-lutein cells was even suggested by Gomes et al. as a consequence of chemical changes in peritoneal fluid of women with endometriosis; those authors hypothesized that such a compromise on ovarian steroidogenesis should be related to reproductive dysfunction in women with the disease (Gomes et al., 2008), agreeing with the theory previously defended by de Abreu et al., who showed reduced aromatase activity and insufficient basal production of estradiol in in vitro cultured granulosa cells of women with endometriosis submitted to ART (Abreu et al., 2006).
IMMUNOLOGICAL DISTURBANCES
They are probably a cornerstone in a complex process of interactions that results in reduced fertility in women with endometriosis. In these patients, excessive concentrations of cytokines produced by ovarian and immune cells may cause enzymatic changes and affect normal production of sexual steroids, androgen-to-estrogen physiologic aromatization, and follicular expression of estradiol and progesterone (Abae et al., 1994; Pellicer et al., 2000; Yoshida et al., 2004; Ulukus et al., 2006).Populations of lymphocytes, natural killers and macrophages have been demonstrated to be augmented in follicular fluid (FF) of women with endometriosis (Lachapelle et al., 1996), as well as interleukins (i.e. IL-1β, IL-6, IL-8, IL-10 and tumor necrosis factors) and decreased vascular endothelial growth factor (VEGF) were either found in FF of women with the disease (Pellicer et al., 1998; Garrido et al., 2000; Wunder et al., 2006).Increased cytokines in FF also seem to be highly concentrated in peritoneal fluid (PF) of women with endometriosis, which may be associated with macrophage abnormal activation, inflammatory distress and excessive neoangiogenesis (Wu & Ho, 2003). High concentrations of IL-6 and IL-8 in PF have been cited as responsible for low embryo quality (Gomez-Torres et al., 2002) and the increase of IL-6 have been related with decreased implantation rates (Pellicer et al., 1999).Activated macrophages’ excessive migration and elevated concentrations of immunomodulators (i.e. prostaglandins, interleukins, TNF, proteases and VEGF) are either found in PF and serum of women with endometriosis, and are probably responsible for the development of low vascularized follicles (Lucena & Cubillos, 1999), reduced embryo quality, low implantation rates (Pellicer et al., 2000) and abnormalities in granulosa cells cycles (Saito et al., 2002). Even the existence of an inhibitor of fimbriaecumulus interaction, with negative interference on tubal function, has been suspected (Lebovic et al., 2001).Leptin’s increased levels in PF of endometriosis patients shall play an important role in the immunopathogenesis of endometriosis and related infertility (Barcz et al., 2008). It probably affects local immune reactions in a proinflammatory way, especially by the infltration of CD3+ pan-T helper cells and CD4+ T helper cells (Milewski et al., 2008), stimulating neoangiogenesis. Unfortunately, controversies have been raised once leptin was negatively correlated with levels of IL-1β (Wertel et al., 2005; Bedaiwy et al., 2006).Finally, IgG and IgA secretion seem to be highly elevated in the endometrial environment of women with endometriosis, and may be associated with a reduced receptivity to embryos. In the same way, auto-antibodies against endometrial antigens have been demonstrated to be over expressed in those patients (Lebovic et al., 2001).
EMBRYO IMPLANTATION FAILURE
Hypothetical functional disorders of the endometrium of women with endometriosis have been raised by literature during the last years; several studies suggested that such disorders should definitely contribute to diminished fecundity rates (Lessey et al., 1994) and embryo implantation (Lessey et al., 1994; Kao et al., 2003), and impaired trophoblastic development (Genbacev et al., 2003; Kao et al., 2003).Recent studies related genetic mutations of endometrial progesterone receptors key physiopathological events in endometriosis-related infertility, leading to significantly low proportions of isoforms A and B, and responding for progesterone resistance and endometrial dysfunction (Attia et al., 2000; Igarashi et al., 2005; Bulun et al., 2006). Fazleabas has recently reported decreased responsiveness of the progesterone receptor and correspondent immunophilins, as well as epigenetic deregulation of progesterone genes in baboons, which reinforced such a mechanism for endometriosis-related infertility (Fazleabas, 2010). Furthermore, it is noticeable that progesterone resistance promotes elevation of estrogens levels (Bulun et al., 2006) and increased expression of metalloproteinases facilitating progression of endometriosis (Gaetje et al., 2007; Gilabert-Estellés et al., 2007).The association of those mutations with the ingestion of contaminated food by dioxins (pollutants derived from the incineration of general garbage and metals) is currently cited in literature.Miller et al have recently demonstrated clear differences in secretory phase glycosylation between patients with advanced endometriosis and healthy women, which should lead to abnormal epithelial differentiation and may be directly involved with embryo implantation failure (Miller et al, 2010), since a perfect interaction between the blastocyst and the endometrial glycocalyx is expected during embryo-maternal recognition and the establishment of a health pregnancy (Jones & Aplin, 2009).
MICRO-RNAS UNBALANCE OF GENE EXPRESSION
In a recently published systematic review, Teague et al suggested that microRNAs may play putative influence on the development of endometriotic lesions, controlling tissue damage (hypoxia, inflammation), cellular growth, proliferation and death, extracellular matrix remodeling and angiogenesis process (Teague et al, 2010). Literature has shown the function of microRNAs in post-transcriptional regulation of gene expression and control of normal and abnormal cellular functions (Kloosterman & Plasterk, 2006), and different expression of their target microRNAs in patients with endometriosis and other disorders of the reproductive system (Teague et al, 2009).
OXIDATIVE STRESS
It seems to enhance immune response in affected sites and the oxidative proinflammatory state of the PF and is believed to be an important mediator of endometriosis’ progression. Studies have pointed to the generation of reactive oxygen species (ROS) by inflammatory cells (i.e. eosinophils, neutrophils and macrophages) at endometriotic sites, by stimulating the development of the disease focuses and acting as an endometrial cell growth-promoter (Augoulea et al., 2009). Furthermore, highly concentrated serum ROS in patients with the disease probably induce oocyte degeneration and cause injuries to meiotic spindles and excessive embryo fragmentation (Guzick et al., 1999). Elevated concentrations of ROS derived from aggression to DNA and lipid peroxidation in granulosa cells have also been demonstrated in infertile women with endometriosis (Bayer et al., 1988); ROS may be augmented as a consequence of excessive production by apoptotic cells from endometriotic lesions, and by the over expression of pro-oxidative stress enzymes (i.e. xantine-oxidase) (Hull et al., 1987; Al Inany et al., 2000). Although controversial data have shown similar levels of lipid peroxidation between infertile women with endometriosis and disease-free controls (Amaral et al., 2005), Campos Petean et al. prospectively evaluated infertile women with endometriosis submitted to assisted reproduction techniques and found increased lipid peroxidation in their FF and serum, reinforcing the possible link with compromised quality of their oocytes (Campos Petean et al., 2008).
FINAL CONSIDERATIONS
Neither medical nor surgical approaches have been proven to significantly ameliorate fecundity rates among women with endometriosis, and even expectations on assisted reproduction techniques are controversial in literature; this should be explained in part by inconsistency of knowledge on the etiopathogeny of endometriosis-related infertility and its probable confounding net of non-obstructive mechanisms.
Literature have demonstrated that commonly used drugs, like progestins, danazol and GnRH analogues, may not be effective to improve fecundity rates among women with minimum to mild endometriosis (Bayer et al., 1988; Fedele et al., 1992) and several studies have suggested a similar efficacy between expectant and medical approaches to elevate reproductive potential, especially for young women with short duration of complaints (Thomas & Cooke, 1987; Hull et al., 1987; Hugues et al., 1993; Bayer et al., 1988; Telimaa, 1988; Fedele et al., 1992).
Albeit they are just in a speculative scenario, new treatment schemes are being investigated, including aromatase inhibitors, anti-estrogens, progesterone receptors’ modulators, statins and GnRH antagonists, which have been demonstrated to significantly reduce endometriotic lesions. In the same way, researches on proteogenomic pathways direct laboratories to develop drugs with specific targets in the endometriotic tissue.
In a brief future, inhibition of angiogenesis and matrix metalloprotease, and efficacious immune modulation are expected to be disposable; knowledge on microRNAs is, finally, expected to raise new propaedeutic and therapeutic approaches. At present it is the broad view of the negative influence of endometriosis over reproductive function that provides subsidies to counseling and follow up of those patients in services of reproductive medicine.
Lebovic DI, Mueller MD, Taylor RN. Immunobiology of endometriosis. Fertil Steril. 2001;75:1-10.
Wu MY, Ho HN. The role of cytokines in endometriosis. Am J Reprod Immunol. 2003;49:285-96.