Laparoscopic surgery for endometriosis-associated infertility: a pathophysiologic approach
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- Pahlajani, G. & Falcone, T. Gynecol Surg (2010) 7: 319. doi:10.1007/s10397-010-0564-5
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Endometriosis has been one of the most confusing gynecological diseases since it was first described. Whereas there is a reasonable body of evidence in literature to demonstrate an association between endometriosis and infertility, a definite cause and effect relationship has not been established. The mechanism by which endometriosis causes infertility remains an enigma. Virtually every aspect of reproduction in women with endometriosis has been investigated and purported to be impaired. Impairment of implantation and pregnancy rates seems to affect women with endometriosis. Whether this is due to poor quality embryos derived from impaired oocytes or endometrial defects or both has been argued. Structural abnormalities of the uterine wall and tube in women with endometriosis have also been described by other researchers. Adding more confusion to this topic is the altered immune function and the peritoneal environment and their detrimental effects on the sperm motility and morphology. This uncertain pathophysiology has resulted in the lack of consensus on the treatment of endometriosis-associated infertility. The aim of this review is to describe the current pathophysiology of endometriosis-related infertility, how laparoscopic surgery may influence fertility rates.
KeywordsLaparoscopy Endometriosis Infertility Pathophysiology
Infertility is a distressing symptom associated with endometriosis, and the exact mechanism and optimal choice of management in the context of this disease remains obscure. In spite of a great deal of effort about the pathogenesis of infertility in endometriosis, it is still not clear how endometriosis compromises fertility. Although it is generally accepted that endometriosis is related to infertility, the mechanism underlying this effect and its impact on fecundity are less clear. This makes treatment very difficult since surgery is directed at the peritoneal lesions which may not be the only the factor affecting fertility. Fecundity is defined as the probability of a woman giving live birth in a given month and ranges from 0.15 to 0.20 in normal couples and decreases to 0.02 to 0.10 in untreated women with endometriosis [1, 2]. Three-year cumulative pregnancy rates were found to be lower in women with endometriosis (36%) as compared with women with unexplained infertility (55%) . Numerous studies have indicated poor pregnancy outcomes in endometriosis to be associated with poor sperm function, poor ovarian reserve, lower oocyte/embryo quality, decreased endometrial receptivity, and impaired implantation. In this review article, we discuss the existing evidence of the effects of endometriosis on fertility.
Mechanism of infertility in women with endometriosis
Endometriosis and the alterations in pelvic anatomy
Distortion of the uterotubal anatomy has been proposed as one of the mechanisms of reduced fertility in patients with endometriosis. Adhesions may cover or distort the anatomy of the fallopian tubes and ovaries, thereby impeding pick-up of oocytes by the fimbriae of the fallopian tube. Kissler et al. in 2006  reported that endometriosis leads to a significant restriction in uterotubal transport capacity. They concluded that impeded hyperperistalsis and dysperistalsis in uterotubal transport associated with endometriosis may be the reason of infertility in these women . Severe endometriosis is also associated with pelvic adhesions and a distortion of pelvic anatomy leading to a possible mechanic or anatomic disturbance of fertility [5, 6]. Another factor distorting the pelvic anatomy and thus affecting fertility are large endometriomata seen in patients with extensive endometriosis. Somigliana et al.  in their study found that just the mere presence of an endometrioma will decrease the ovarian responsiveness to stimulation in in-vitro fertilization (IVF) cycles as compared with contralateral intact ovaries. They concluded that, especially in women with larger endometriomas, this difference was more evident . Milingos et al. in a study found that laparoscopic removal of these large endometriomata significantly improved the fertility outcomes . Therefore, diminished pregnancy rates in endometriosis due to adhesions and impaired uterotubal transport even with patent fallopian tubes and normal semen quality may be one of the factors of sub-fertility in these patients.
Endometriosis and the sperm function
The role of cytokines has been implicated in the pathogenesis of endometriosis and related infertility. Interleukin-6 (IL-6) and its soluble receptor (sIL-6R) have been reported to be higher in the peritoneal fluid of infertile patients with endometriosis [16, 17]. Yoshida et al. proposed that combination of IL-6 and sIL-6R may be associated with gp-130 expressed in the sperm and thus reducing sperm motility and contributing to the pathogenesis of endometriosis-related infertility . Macrophage inhibiting factor (MIF), another multifunctional cytokine has been found to be significantly increased in the peritoneal fluid and endometrium of women with endometriosis [19, 20]. Carli et al.  in 2007 studied the dose-dependent effect of MIF on sperm capacitation and concluded that high amounts of MIF had adverse effects on capacitation and sperm motility. They suggested that increased levels of MIF in women with endometriosis may play a role in endometriosis-associated infertility .Tumor necrosis factor alpha (TNF-α), a potent cytokine has also been found to be increased in patients with endometriosis and has been proposed as a sensitive marker for the non-surgical diagnosis of endometriosis [16, 22]. Said et al. in their study reported that pathological concentrations of TNF-α can result in loss of sperm motility, plasma membrane functional integrity, as well as DNA fragmentation . The same group implicated that infliximab, an anti-inflammatory drug, may be used to reverse the toxic effects of TNF-α on spermatozoa and thus help treat female infertility in endometriosis patients .
Another proposed mechanism of infertility in endometriosis is due to deleterious effect of nitric oxide (NO) on the sperms. Osborn et al. in a study found that peritoneal macrophages from women with endometriosis-associated infertility express higher levels of inducible nitric oxide synthase and produce more NO than fertile controls, and high levels of NO have a deleterious effect on sperm motility and function [25, 26]. Moreover, Lampiao et al. found that TNF-α and IL-6 have detrimental effect on the spermatozoa via an increase in NO production .
Endometriosis and ovarian function
Good quality embryos originate from good quality oocytes, which in turn originate from follicles with an adequate environment conditioned by the follicular fluid and the neighboring cells, which are able to influence their progression . Altered intrafollicular microenvironment influences the oocyte growth and development via a close relationship with the granulose cells and other ovarian cell types. Mansour et al. found significant DNA damage in the oocytes that were incubated in the peritoneal fluid of patients with endometriosis as compared with normal controls. The extent of damage was related to the duration of exposure to the PF of endometriosis . Whether this damage to oocytes is due to hormonal factors, cytokines, leucocytes, apoptic bodies, or OS has been studied and documented in literature. Studies have shown consistent evidence of subtle pituitary–ovarian dysfunction associated with endometriosis, linked to considerable impairment of oocyte fertilizing ability and a probable impairment of granulosa cell steriodogenesis. Impaired follicular growth, reduction in circulating estradiol concentration during the pre-ovulatory phase and of estradiol and progesterone during the early luetal phase and disturbed luteinizing hormone surge pattern have been documented as a cause of poor oocyte quality and sub-fertility in endometriosis . Similarly, other authors recorded zygote formation and embryo development in vitro and reported that the percentage of abnormal embryos were higher in endometriotic patients . Diaz et al.  in their study implicated that even severe endometriosis did not affect the implantation rate, and the poor pregnancy outcomes were probably due to poor quality oocytes or embryos. They found no change in the in-vitro fertilization-embryo transfer (IVF-ET) outcomes in endometriotic patients receiving donor oocytes . However, contradictory results have been shown by other groups which found no change in granulose luteal cell steriodogenesis, normal maturation of oocytes, and embryo in the altered hormonal milieu [33, 34].
Apart from the endocrine environment, various paracrine factors secreted by the granula cell and present in the follicular fluid could interfere with the oocyte development. In a study done by Pellicer et al. , serum IL-6 were found to be increased in natural cycle in women with endometriosis and decreased in stimulated cycles in IVF. IL-6 was also increased in the follicular fluid of women with endometriosis and released in higher amounts by granulosa cells in these women. In addition, vascular endothelial growth factor (VEGF) has been found to be in lower concentrations in endometriotic patients , and elevated VEGF has also been correlated in IVF with good follicular vascularization and health . Garrido et al. postulated that infertility in patients with endometriosis may be related to these changes in the follicular environment leading to altered oocytes which in turn results in poor quality of embryos . Another study found that the granula cells from endometriotic patients had an increased production of IL-1β, IL-6, IL-8, and TNF-α compared with healthy women, although the increase for TNF-α was more significant. Furthermore, HCG suppressed these cytokines in both the endometriotic and healthy women . Whether these changes in the follicular environment causes disturbances in the synchronization of oocyte maturation, ovulation, and uterine receptivity affecting the fertilization need to be further investigated.
Another interesting theory postulated is the role of ovarian leukocytes on oocyte maturation and growth. Leukocyte present within the ovary may constitute as potential in situ modulators of ovarian function that act through the local secretion of numerous cytokines . Lachapelle et al. found an increase in natural killer (NK) cells and monocytes (CD4) in endometriotic patients . In contrast, another study using flow cytometry to determine the presence of total leukocytes and their subsets in the follicle from patients with endometriosis and healthy controls found no changes in the leukocyte portions and activity . Establishing the definite role of leukocytes in oocyte maturation is difficult due to the aforementioned conflicting studies. The role of apoptic cells on folliculogenesis in endometriosis has also been studied. Toya et al. concluded that in the granulosa cells of patients with endometriosis, an increased incidence of altered cell cycle and apoptic bodies are found as compared with healthy controls , and it has been found that a lower incidence of apoptic bodies in individual follicles has been associated with better outcome of oocyte quality .
The role of OS has been implicated in various aspects of female reproduction and infertility including oocyte viability and its ability to fertilize with the spermatozoa [44, 45]. Increased production of ROS by peritoneal macrophages and diminished peritoneal fluid antioxidant results in OS in the peritoneal microenvironment of patients with endometriosis . OS leads to localized pelvic inflammatory reaction resulting in increased concentrations of cytokines, growth factors, and other inflammatory mediators which in turn induce lipid peroxidation, resulting in the formation of cytotoxic lipid peroxides and DNA damage [46, 47]. One of the most popular markers for oxidative DNA damage and OS is 8-hydroxy-deoxyguanosine which is found to be increased in infertile patients with endometriosis than infertile patients with other causes . These changes caused by OS might lead to rapid cellular death and oocyte degeneration.
Endometriosis and fertilization
The effect of follicular fluid on the binding of human spermatozoa to the zona pellucida has been investigated in women with endometriosis. Qiao et al. suggested that patients with endometriosis had a stronger sperm–zona binding inhibitory effect in their follicular fluid than patients without endometriosis which may contribute to impairment of gamete interaction . Additionally, sperm mixed with peritoneal fluid from women with endometriosis has been shown to perform poorly on a zona-free hamster egg sperm penetration assay . Barbara et al. found that macrophage secretory products, particularly TNF-α, may interfere sperm–zona pellucida binding and may lead to infertility in women with endometriosis . Interestingly, a retrospective study of the impact of endometriosis on IVF outcomes found that patients with stages 3 and 4 endometriosis had a poorer IVF-ET outcome than patients with tubal infertility. The authors suggested that maternal serum in patients with endometriosis adversely affects the fertilization rate, and this reduction in fertilization may be due to either decreased oocyte quality or the detrimental effect of the cumulus–corona complex . However, Olivennes et al.  found no difference in the pregnancy outcome in patients with endometriosis and tubal infertility. Pregnancy rates in pure endometriosis patients without other concomitant infertility factors were found to be similar to those patients with tubal infertility .
Endometriosis and implantation
Endometrial factors impairing implantation
Level of the factor
Minci et al. 
Lessey et al. 
Khorram et al. 
Matsuzaki et al. 
Hugo et al. 
BSEP, C4BP,IL-15 genes
Kao et al. 
Daftary et al. 
Dimitriadis et al. 
Endometriosis and immune-endocrine interaction
There is considerable evidence in literature indicating the association of humoral and cell-mediated immunity with endometriosis. The peritoneal fluid of women with endometriosis contains an increased number of immune cells which facilitate the development of endometriosis rather than inhibiting it . Autoantibodies, several cytokines, and growth factors display increased levels in the peritoneal fluid of women with endometriosis. Mathur et al. were the first to report IgG and IgA antibodies in the vaginal and cervical secretions of women with endometriosis . Gleicher et al.  in their study found a wide variety of autoantibodies in endometriosis patients suggesting polyclonal activation of B cell, characteristic of autoimmune disease. They argued that ectopic endometrium might induce an autoimmune response and contribute to infertility associated with endometriosis . Furthermore, treatment with danazol and GnRH analog suppresses the antiendometrial antibodies associated with endometriosis . Another study showed that infertile women with endometriosis had various kinds of autoantibodies, especially against phospholipids in serum and the peritoneal fluids that could reduce the success of spontaneous and artificial implantation . Although these data suggest that autoantibodies may play a role in infertility associated with endometriosis, the importance of autoimmunity in pathogenesis of infertility in these patients needs to be further explored.
Cytokines are diverse proteins that play a central role in regulating cellular activity. Several studies have reported a potential link between cytokines and the pathogenesis of endometriosis. Interluekin-1 (IL-1) is one of the major proinflammatory cytokines found in the peritoneal fluid of women with endometriosis, and studies have found that IL-1 may play a role in the infertility associated with endometriosis [69, 70]. IL-1 has been found to inhibit mouse embryo development, impairing the capacity of sperm to penetrate the oocyte without altering the sperm motility [71, 72]. In a recent study, it was suggested that an imbalance between IL-1 and its inhibitory soluble IL-1 receptor type 2 levels in peritoneal fluid of women with endometriosis may cause a defect in the local control of IL-1 and may be involved in the pathophysiology of endometriosis and its related infertility . IL-6, another pleiotropic cytokine, has been associated with reproductive physiology and found to be increased in the peritoneal fluid of women with endometriosis [16, 17]. The elevated levels of IL-6 has been associated with poor sperm motility and altered follicular functions [18, 35]. Deura et al. in their study showed that IL-6 suppressed estrogen production and aromatase activity in the granula cell line and may be associated with infertility with endometriosis . Another cytokine IL-17 has been found to induce IL-6 and TNF-α in the macrophages, which play a crucial role in the pathogenesis of endometriosis and infertility . Zhang et al. in their study found that IL-17 was significantly higher in patients with mild/minimal endometriosis and also when endometriosis was associated with infertility . TNF-α is another cytokine that plays a key role in the multitude of inflammatory processes. TNF-α has been implicated in the pathophysiology of endometriosis and its associated infertility. It affects sperm motility and also shows embryotoxic effects [23, 55].
RANTES (regulated on activation, normal T-cell expressed and secreted) is another cytokine chemo-attractant for monocytes as well as memory T cells and eosinophils. The level of RANTES is found to be increased in the peritoneal fluid of women with endometriosis, and its level correlates with the severity of disease . Xu et al.  found poor IVF outcomes in endometriosis-related infertility than in tubal infertility. They concluded that elevated follicular fluid RANTES evokes an altered inflammatory milieu within the follicular fluid environment leading to poor oocyte quality . MIF is a multifunctional cytokine that regulates immune response, cell proliferation, and angiogenesis. Morin et al. found elevated levels of MIF in the peripheral blood of women with endometriosis and suggested that MIF may adversely affect fertility in these women . Monocyte chemo-tactic protein 1 is a β chemokine produced mainly by the monocytes, and macrophages have been found to be increased in infertile patients with endometriosis . Complement, another component of the humoral immunity, has been found to be altered in endometriosis. Kabut et al. in their study found increased concentrations of C3c and decreased concentration of iC3b in the PF of women with endometriosis, both of which are derivatives of C3 component of the complement cascade . A higher concentration of iC3b, produced from the oviductal C3/C3b has been found to enhance the development of blastocyst and also stimulate embryo development . This decreased iC3b found in the PF of women with endometriosis could lead to infertility. There is a controversy on the role of increased level of leptin in endometriosis-related infertility. Leptin, a product of the obese gene, is a cytokine similar to various members of the interleukin family. Barcz et al. suggested that the increased levels of leptin in peritoneal fluid in women with endometriosis may be associated with infertility . On the other hand, Bedaiwy et al. in their study found that increased peritoneal fluid leptin levels may be associated with pain but not infertility in patients with endometriosis .
Endometriosis is associated with changes in cell-mediated immunity as well. Various components of cellular immunity have been found to be altered in endometriosis. Peritoneal macrophages are the major resident cells in the peritoneal cavity, and their number, concentration, and activity are higher in patients with endometriosis than controls . NK cell activity in women with endometriosis has been shown to have a decreased cytotoxic activity, which indicates alteration in immune response, and co-existing with endometrial abnormalities . These changes in the peritoneal environment may also have a role in endometriosis-related infertility . Moreover, danazol and GnRH analogs, which are commonly used for treatment of endometriosis down-regulate humoral and cellular immunity concomitantly with their effect on endometriotic implants .
Hyperprolactinemia has been reported to exist in patients with endometriosis-related infertility, but the role of prolactin (PRL) in infertile women with endometriosis is less clear . In a study, it was suggested that altered PRL secretion and decreased serum estradiol after thyrotrophin-releasing hormone administration in infertile women with endometriosis was strongly related to a dysfunction of the hypothalamic–hypophyseal–ovarian axis and could be the cause of infertility in these patients . Matrix metalloproteinase-2 (MMP-2) has emerged as one of the key participants in the adhesion and proliferation of shed menstrual tissue in the pathogenesis of endometriosis . Estradiol has been shown to up-regulate the MMP-2 action leading to formation of endometriosis, and progesterone has been associated with down-regulation of MMP-2 action inhibiting the development of endometriosis . MMP-2 has shown to have a role in ovulation and luteal function .
There is clear evidence from the above discussion on the interaction between immune mediators and hormones on the development of endometriosis and its associated infertility. A better understanding of these interactions will set the stage for immune-targeted therapies not only for the management of endometriosis but also its associated infertility.
Endometriosis and role of laparoscopy in management of infertility
Although there is an association between endometriosis and infertility, the discussion about exact causal relationship is still ongoing. Nevertheless, laparoscopy has been used for the diagnosis, staging, and treatment of endometriosis. Visual look of the disease through laparoscopy has become an integral part of management of infertility in endometriosis. The effect of destruction of peritoneal endometriosis (ASRM stage I-II) by laparoscopy on pregnancy rates in infertile women has been debated . It is unclear how removing or ablating a lesion by laparoscopy will improve the alterations described above. Two randomized controlled trials did not agree on the effect of laparoscopic ablation or excision of endometriotic lesions on pregnancy rates. The larger study, by the Canadian Collaborative Group on Endometriosis, showed that excision or laparoscopic ablation of minimal and mild endometriosis increased ongoing pregnancy rates in infertile women (OR 1.95, 95% CI 1.18–3.22) . The number needed to treat in the Canadian study was nine. A smaller trial by an Italian group failed to show significant impact on the live birth rate (OR 0.85, 95% CI 0.32–2.28) . However, when these two results were combined, the pooled odds ratio showed a significant improvement in live birth rate following surgical treatment (OR 1.64, CI 1.05–2.57) . If we combine the Canadian and the Italian studies, the number needed to treat is 12. Thus, there is reasonable evidence to treat minimal and mild endometriosis to improve the subsequent fertility outcome. Laparoscopic treatment of mild endometriosis either by excision or coagulation was shown to have no influence on the pregnancy rate and had similar outcomes .
An interesting study by Bedaiwy et al. on the impact of surgery on IVF outcome found no improvement in pregnancy outcomes . In light of the complex pathophysiological changes taking place in the peritoneum in endometriosis, surgical removal of lesions may therefore not necessarily have a substantial impact on fertility.
Similarly, laparoscopic treatment of ovarian endometriosis (ASRM III-IV) showed varied outcomes and the pregnancy rates ranged from 30% to 67% [100, 101]. Despite the possible risk of loss of ovarian tissue and disruption of blood supply leading to ovarian damage, literature shows increased pregnancy rates following laparoscopic treatment of endometriomas . In a recent Cochrane review, it was concluded that the excision of the endometriomas improves the subsequent spontaneous pregnancy rates in comparison to drainage and ablation of the endometrioma . The removal of endometriomata may be associated with risk of damage to ovarian function. Ovarian cystectomy may cause resection of the healthy ovarian cortex with follicles rather than excision of intraovarian cyst. Somigliana found fewer follicles in response to gonadotropin stimulation after laparoscopic removal of endometriomata thereby altering the ovarian response during IVF . Additionally, adverse changes in the ovarian artery blood flow have been reported following laparoscopic stripping . Nonetheless, careful removal of endometriomas will improve spontaneous fertility substantially and should be removed.
Recently, interest has been shown on the influence of laparoscopic treatment of bowel endometriosis on post-operative fertility. Stepniewska et al.  in one of the largest series retrospectively looked at the effect of laparoscopic surgery for endometriosis with colorectal segmental resection on subsequent fecundity rate. They concluded that complete removal of endometriosis with bowel segmental resection had better post-operative fertility than removal of endometriosis without bowel resection . Ferrero et al. in their study suggested that although spontaneous pregnancy may occur after bowel resection, these patients may require infertility treatment, especially women ≥35 years . Vercellini et al.  studied the role of conservative surgery for rectovaginal endometriosis on the fertility outcome. Their group concluded that, in patients with no other associated major infertility factors, surgical resection of rectovaginal endometriosis did not improve the pregnancy outcome .
Another interesting aspect is the impact of laparoscopic surgery for recurrent endometriosis on subsequent fertility. Fedele et al.  compared the 5-year cumulative pregnancy after laparoscopic excision of primary versus recurrent ovarian endometrioma in the same ovary as the primary cyst. The 5-year cumulative pregnancy rate was 40.8% after the first surgical procedure and 32.4% after the second procedure. The authors concluded that the effect of repetitive laparoscopic surgery is similar to that observed after first-line surgery and that the women with repetitive surgery underwent assisted reproduction techniques more frequently .
Pelvic endometriosis is frequently associated with infertility even when the affected women have functional, patent tubes. Beset with inadequate, inconclusive, and conflicting data, it remains difficult to arrive at a consensus regarding the exact mechanism of infertility in these patients. In this review, we have discussed the various possible mechanisms that can affect fertility which can later be a scope for future management of the disease. Despite the lack of firmly established causal relation between endometriosis and infertility, these developments may help improve the fertility rates in these patients. Laparoscopy still remains the gold standard for the diagnosis and management of the disease. Laparoscopic management of minimum to mild endometriosis has been shown to improve subsequent fertility outcomes, although it is unclear by how much it is improved. Laparoscopic removal of endometriomas will improve spontaneous pregnancy rates significantly. Laparoscopic excision rather than drainage and ablation of endometrioma are recommended. The role of bowel surgery in fertility outcome requires more research.
Conflict of interest
There is no conflict of interest. There have been no financial interest/arrangements with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this article.