{"paper_id":"33ddb042-5216-4f6a-a09a-ee62b48b1f27","body_text":"REVIEW ARTICLE\nLaparoscopic surgery for endometriosis-associated\ninfertility: a pathophysiologic approach\nGeetu Pahlajani & Tommaso Falcone\nReceived: 10 December 2009 / Accepted: 25 January 2010 / Published online: 9 March 2010\n# Springer-V erlag 2010\nAbstract Endometriosis has been one of the most\nconfusing gynecological d iseases since it was first\ndescribed. Whereas there is a reasonable body of\nevidence in literature to demonstrate an association\nbetween endometriosis and infertility, a definite cause\nand effect relationship has not been established. The\nmechanism by which endometriosis causes infertility\nremains an enigma. Virtually every aspect of reproduc-\ntion in women with endometriosis has been investigated\nand purported to be impaired. Impairment of implanta-\ntion and pregnancy rates seems to affect women with\nendometriosis. Whether this is due to poor quality\nembryos derived from impaired oocytes or endometrial\ndefects or both has been argued. Structural abnormali-\nties of the uterine wall and tube in women with\nendometriosis have also been described by other\nresearchers. Adding more confusion to this topic is the\naltered immune function and the peritoneal environment\nand their detrimental effects on the sperm motility and\nmorphology. This uncertain pathophysiology has\nresulted in the lack of consensus on the treatment of\nendometriosis-associated infertility. The aim of this\nreview is to describe the current pathophysiology of\nendometriosis-related infertility, how laparoscopic sur-\ngery may influence fertility rates.\nKeywords Laparoscopy . Endometriosis . Infertility .\nPathophysiology\nIntroduction\nInfertility is a distressing symptom associated with endo-\nmetriosis, and the exact mechanism and optimal choice of\nmanagement in the context of this disease remains obscure.\nIn spite of a great deal of effort about the pathogenesis of\ninfertility in endometriosis, it is still not clear how\nendometriosis compromises fertility. Although it is gener-\nally accepted that endometriosis is related to infertility, the\nmechanism underlying this effect and its impact on\nfecundity are less clear. This makes treatment very difficult\nsince surgery is directed at the peritoneal lesions which may\nnot be the only the factor affecting fertility. Fecundity is\ndefined as the probability of a woman giving live birth in a\ngiven month and ranges from 0.15 to 0.20 in normal\ncouples and decreases to 0.02 to 0.10 in untreated women\nwith endometriosis [ 1, 2]. Three-year cumulative pregnancy\nrates were found to be lower in women with endometriosis\n(36%) as compared with women with unexplained infertil-\nity (55%) [ 3]. Numerous studies have indicated poor\npregnancy outcomes in endometriosis to be associated with\npoor sperm function, poor ovarian reserve, lower oocyte/\nembryo quality, decreased endometrial receptivity, and\nimpaired implantation. In this review article, we discuss\nthe existing evidence of the effects of endometriosis on\nfertility.\nG. Pahlajani ( *)\nCleveland Clinic,\nMain Campus, OBGYN,\nCleveland, OH, USA\ne-mail: pahlajg@ccf.org\nT. Falcone\nObstetrics, Gynecology and Women ’s Health Institute,\nCleveland, OH, USA\nT. Falcone\nOffice of Professional Staff Affairs,\n9500 Euclid Ave-A81,\nCleveland, OH, USA\nGynecol Surg (2010) 7:319 –328\nDOI 10.1007/s10397-010-0564-5\n\nMechanism of infertility in women with endometriosis\nEndometriosis and the alterations in pelvic anatomy\nDistortion of the uterotubal anatomy has been proposed as\none of the mechanisms of reduced fertility in patients with\nendometriosis. Adhesions may cover or distort the anatomy\nof the fallopian tubes and ovaries, thereby impeding pick-\nup of oocytes by the fimbriae of the fallopian tube. Kissler\net al. in 2006 [ 4] reported that endometriosis leads to a\nsignificant restriction in uterotubal transport capacity. They\nconcluded that impeded hyperperistalsis and dysperistalsis\nin uterotubal transport associated with endometriosis may\nbe the reason of infertility in these women [ 4]. Severe\nendometriosis is also associated with pelvic adhesions and a\ndistortion of pelvic anatomy leading to a possible mechanic\nor anatomic disturbance of fertility [ 5, 6]. Another factor\ndistorting the pelvic anatomy and thus affecting fertility are\nlarge endometriomata seen in patients with extensive\nendometriosis. Somigliana et al. [ 7] in their study found\nthat just the mere presence of an endometrioma will\ndecrease the ovarian responsiveness to stimulation in in-\nvitro fertilization (IVF) cycles as compared with contralateral\nintact ovaries. They concluded that, especially in women with\nlarger endometriomas, this difference was more evident [ 7].\nMilingos et al. in a study found that laparoscopic removal of\nthese large endometriomata significantly improved the\nfertility outcomes [8]. Therefore, diminished pregnancy rates\nin endometriosis due to adhesions and impaired uterotubal\ntransport even with patent fallopian tubes and normal semen\nquality may be one of the factors of sub-fertility in these\npatients.\nEndometriosis and the sperm function\nThe endometriosis-associated immunoinflammatory\nchanges may have some adverse effects on the spermatozoa\nsince these cells have to stay for some time in the female\ngenital tract which is bathed by peritoneal fluid. Mansour et\nal. studied the correlation of endometriosis and sperm\ndamage and found positive relation between sperm damage,\nstage of endometriosis, and duration of infertility [ 9]. The\nsame group also studied the impact of peritoneal fluid from\nwomen with endometriosis on sperms and found a\nsignificant increase in sperm DNA damage (Fig. 1). They\nproposed this as one of the mechanisms of infertility in\npatients with endometriosis [ 10]. Whether this damage is\ndue to oxidative stress, cytokines, or nitric oxide on the\nsperms has been debated. There is compelling evidence in\nliterature that oxidative stress (OS) is increased in the\nperitoneal fluid (PF) in patients with endometriosis. This is\nthought to be due to increased production of reactive\noxygen species (ROS), defective antioxidant defense, or\nboth [ 11, 12]. Spermatozoa are susceptible to damage by\nROS due to limited antioxidant defense and high content of\npolyunsaturated fatty acids in their membranes [ 12]. ROS\nproduces infertility by damaging the sperm plasma and\nacrosomal membrane by lipid per oxidation, decreasing\nsperm motility, and the ability of the sperm to bind and\npenetrate the oocyte and causing DNA damage leading to\ndefective embryo [ 13–15].\nThe role of cytokines has been implicated in the\npathogenesis of endometriosis and related infertility.\nInterleukin-6 (IL-6) and its soluble receptor (sIL-6R) have\nbeen reported to be higher in the peritoneal fluid of infertile\npatients with endometriosis [ 16, 17]. Y oshida et al.\nproposed that combination of IL-6 and sIL-6R may be\nassociated with gp-130 expressed in the sperm and thus\nreducing sperm motility and contributing to the pathogen-\nesis of endometriosis-related infertility [ 18]. Macrophage\ninhibiting factor (MIF), another multifunctional cytokine\nhas been found to be significantly increased in the\nperitoneal fluid and endometrium of women with endome-\ntriosis [ 19, 20]. Carli et al. [ 21] in 2007 studied the dose-\ndependent effect of MIF on sperm capacitation and\nconcluded that high amounts of MIF had adverse effects\non capacitation and sperm motility. They suggested that\nincreased levels of MIF in women with endometriosis may\nplay a role in endometriosis-associated infertility [ 21].\nTumor necrosis factor alpha (TNF- α), a potent cytokine\nhas also been found to be increased in patients with\nendometriosis and has been proposed as a sensitive marker\nfor the non-surgical diagnosis of endometriosis [ 16, 22].\nSaid et al. in their study reported that pathological\nconcentrations of TNF- α can result in loss of sperm\nmotility, plasma membrane functional integrity, as well as\nDNA fragmentation [ 23]. The same group implicated that\ninfliximab, an anti-inflammatory drug, may be used to\nreverse the toxic effects of TNF- α on spermatozoa and thus\nhelp treat female infertility in endometriosis patients [ 24].\nDecreased sperm motility\nSperm DNA damage \nSPERM\nROSMIF IL-6\nNOTNF-α\nFig. 1 Diagram: factors affecting sperm function in endometriosis\n320 Gynecol Surg (2010) 7:319 –328\n\nAnother proposed mechanism of infertility in endome-\ntriosis is due to deleterious effect of nitric oxide (NO) on\nthe sperms. Osborn et al. in a study found that peritoneal\nmacrophages from women with endometriosis-associated\ninfertility express higher levels of inducible nitric oxide\nsynthase and produce more NO than fertile controls, and\nhigh levels of NO have a deleterious effect on sperm\nmotility and function [ 25, 26]. Moreover, Lampiao et al.\nfound that TNF- α and IL-6 have detrimental effect on the\nspermatozoa via an increase in NO production [ 27].\nEndometriosis and ovarian function\nGood quality embryos originate from good quality oocytes,\nwhich in turn originate from follicles with an adequate\nenvironment conditioned by the follicular fluid and the\nneighboring cells, which are able to influence their\nprogression [ 28]. Altered intrafollicular microenvironment\ninfluences the oocyte growth and development via a close\nrelationship with the granulose cells and other ovarian cell\ntypes. Mansour et al. found significant DNA damage in the\noocytes that were incubated in the peritoneal fluid of\npatients with endometriosis as compared with normal\ncontrols. The extent of damage was related to the duration\nof exposure to the PF of endometriosis [ 29]. Whether this\ndamage to oocytes is due to hormonal factors, cytokines,\nleucocytes, apoptic bodies, or OS has been studied and\ndocumented in literature. Studies have shown consistent\nevidence of subtle pituitary –ovarian dysfunction associated\nwith endometriosis, linked to considerable impairment of\noocyte fertilizing ability and a probable impairment of\ngranulosa cell steriodogenesis. Impaired follicular growth,\nreduction in circulating estradiol concentration during the\npre-ovulatory phase and of estradiol and progesterone\nduring the early luetal phase and disturbed luteinizing\nhormone surge pattern have been documented as a cause of\npoor oocyte quality and sub-fertility in endometriosis [ 30].\nSimilarly, other authors recorded zygote formation and\nembryo development in vitr o and reported that the\npercentage of abnormal embryos were higher in endometri-\notic patients [ 31]. Diaz et al. [ 32] in their study implicated\nthat even severe endometriosis did not affect the implanta-\ntion rate, and the poor pregnancy outcomes were probably\ndue to poor quality oocytes or embryos. They found no\nchange in the in-vitro fertilization-embryo transfer (IVF-\nET) outcomes in endometriotic patients receiving donor\noocytes [ 32]. However, contradictory results have been\nshown by other groups which found no change in granulose\nluteal cell steriodogenesis, normal maturation of oocytes,\nand embryo in the altered hormonal milieu [ 33, 34].\nApart from the endocrine environment, various paracrine\nfactors secreted by the granula cell and present in the\nfollicular fluid could interfere with the oocyte development.\nIn a study done by Pellicer et al. [ 35], serum IL-6 were\nfound to be increased in natural cycle in women with\nendometriosis and decreased in stimulated cycles in IVF.\nIL-6 was also increased in the follicular fluid of women\nwith endometriosis and released in higher amounts by\ngranulosa cells in these women. In addition, vascular\nendothelial growth factor (VEGF) has been found to be in\nlower concentrations in endometriotic patients [ 35], and\nelevated VEGF has also been correlated in IVF with good\nfollicular vascularization and health [ 36]. Garrido et al.\npostulated that infertility in patients with endometriosis\nmay be related to these changes in the follicular environ-\nment leading to altered oocytes which in turn results in poor\nquality of embryos [ 37]. Another study found that the\ngranula cells from endometriotic patients had an increased\nproduction of IL-1 β, IL-6, IL-8, and TNF- α compared with\nhealthy women, although the increase for TNF- α was more\nsignificant. Furthermore, HCG suppressed these cytokines\nin both the endometriotic and healthy women [ 38]. Whether\nthese changes in the follicular environment causes dis-\nturbances in the synchronization of oocyte maturation,\novulation, and uterine receptivity affecting the fertilization\nneed to be further investigated.\nAnother interesting theory postulated is the role of\novarian leukocytes on oocyte maturation and growth.\nLeukocyte present within the ovary may constitute as\npotential in situ modulators of ovarian function that act\nthrough the local secretion of numerous cytokines [ 39].\nLachapelle et al. found an increase in natural killer (NK)\ncells and monocytes (CD4) in endometriotic patients [ 40].\nIn contrast, another study using flow cytometry to deter-\nmine the presence of total leukocytes and their subsets in\nthe follicle from patients with endometriosis and healthy\ncontrols found no changes in the leukocyte portions and\nactivity [ 41]. Establishing the definite role of leukocytes in\noocyte maturation is difficult due to the aforementioned\nconflicting studies. The role of apoptic cells on folliculo-\ngenesis in endometriosis has also been studied. Toya et al.\nconcluded that in the granulosa cells of patients with\nendometriosis, an increased incidence of altered cell cycle\nand apoptic bodies are found as compared with healthy\ncontrols [ 42], and it has been found that a lower incidence\nof apoptic bodies in individual follicles has been associated\nwith better outcome of oocyte quality [ 43].\nThe role of OS has been implicated in various aspects of\nfemale reproduction and infertility including oocyte viabil-\nity and its ability to fertilize with the spermatozoa [ 44, 45].\nIncreased production of ROS by peritoneal macrophages\nand diminished peritoneal fluid antioxidant results in OS in\nthe peritoneal microenvironment of patients with endome-\ntriosis [ 46]. OS leads to localized pelvic inflammatory\nreaction resulting in increased concentrations of cytokines,\ngrowth factors, and other inflammatory mediators which in\nGynecol Surg (2010) 7:319 –328 321\n\nturn induce lipid peroxidation, resulting in the formation of\ncytotoxic lipid peroxides and DNA damage [ 46, 47]. One\nof the most popular markers for oxidative DNA damage\nand OS is 8-hydroxy-deoxyguanosine which is found to be\nincreased in infertile patients with endometriosis than\ninfertile patients with other causes [ 48]. These changes\ncaused by OS might lead to rapid cellular death and oocyte\ndegeneration.\nEndometriosis and fertilization\nThe effect of follicular fluid on the binding of human\nspermatozoa to the zona pellucida has been investigated in\nwomen with endometriosis. Qiao et al. suggested that\npatients with endometriosis had a stronger sperm –zona\nbinding inhibitory effect in their follicular fluid than\npatients without endometriosis which may contribute to\nimpairment of gamete interaction [ 49]. Additionally, sperm\nmixed with peritoneal fluid from women with endometri-\nosis has been shown to perform poorly on a zona-free\nhamster egg sperm penetration assay [ 50]. Barbara et al.\nfound that macrophage secretory products, particularly\nTNF-α, may interfere sperm –zona pellucida binding and\nmay lead to infertility in women with endometriosis [ 51].\nInterestingly, a retrospective study of the impact of\nendometriosis on IVF outcomes found that patients with\nstages 3 and 4 endometriosis had a poorer IVF-ET outcome\nthan patients with tubal infertility. The authors suggested\nthat maternal serum in patients with endometriosis adverse-\nly affects the fertilization rate, and this reduction in\nfertilization may be due to either decreased oocyte quality\nor the detrimental effect of the cumulus –corona complex\n[52]. However, Olivennes et al. [ 53] found no difference in\nthe pregnancy outcome in patients with endometriosis and\ntubal infertility. Pregnancy rates in pure endometriosis\npatients without other concomitant infertility factors were\nfound to be similar to those patients with tubal infertility\n[53].\nEndometriosis and implantation\nThere have been studies in literature suggesting impairment\nof implantation in patients with endometriosis [ 54].\nWhether this defect is due to abnormal endometrium or\ndefective embryos is debated (Table 1). Minici et al.\nsuggested that the milieu surrounding the uterine cavity,\nparticularly increased peritoneal levels of TNF- α, compro-\nmise the normal deciduali zation required for optimal\nimplantation [ 55]. Lessey et al. in their study reported a\nreduced expression of αvβ3 integrin, a cellular adhesive\nmolecule in the endometrium of patients with endometriosis\nduring the window of implantation [ 56]. Another study has\nshown that, in women with endometriosis, a significant\nincrease in endothelial nitric oxide synthase during the mid-\nluteal phase was concomitant with a drastic decrease in\nadhesion molecule αvβ3. Such imbalance may strongly\ncontribute to implantation defects [ 57]. In contrast to this,\nHii et al. found no difference in the glandular expression of\nαvβ3 integrin between endometriosis patients and normal\ncontrols [\n58]. In an interesting study, Matsuzaki demon-\nstrated that HOXA-10m-RNA and protein expression levels\nin the endometrial stromal cells were significantly lower\nduring the window of implantation in patients with\nendometriosis probably leading to infertility [ 59]. Hugo et\nal. in their study found that altered aromatase expression in\nthe eutopic endometrium of women with endometriosis\nmay hamper the ovum nidation, thus causing infertility\n[60]. However, Kao et al. [ 61] suggested alteration in\ncandidate genes contributing to implantation failure. Their\ndata supported that the dysregulation of selected genes such\nas BSEP , C4BP , IL-15, etc. may promote an inhospitable\nenvironment for embryonic implantation [ 61]. In a recent\nstudy, expression of EMX2, a transcription factor necessary\nfor reproductive tract development negatively regulated by\nHOXA10 gene, was found to be altered. The authors\nsuggested that high EMX2 and low HOXA10 in the\nperiimplantation endometrium of patients with endometri-\nosis alter the pattern of target gene expression, thus\ninhibiting implantation [ 62]. Another study indicated the\npossibility that infertile women with endometriosis have\nabnormal production of IL-11 and leukemia inhibitory\nfactor which may contribute to altered uterine receptivity\nand thus leading to infertility [ 63]. All of the above-\nmentioned studies found a defect in the endometrium\nimpairing the implantation in endometriosis patients. In\ncontrast, other authors have given impaired oocyte/embryo\nquality as an alternative explanation for decreased implan-\ntation. Sung et al. in their study concluded that endometri-\nosis in oocyte recipients does not lower implantation, and\nthe adverse effect of endometriosis on implantation is\nprobably due to the abnormal oocyte quality [ 64].This\nfinding was recently confirmed by Diaz et al. [ 32]i na\nstudy in which oocytes from healthy donors were divided in\nthe same cycle between different receivers with and without\nendometriosis. Recipients with stages 3 and 4 endometri-\nosis had the same implantation rate as controls [ 32].These\nstudies show that endometriosis does not impair implanta-\ntion in oocyte recipients, suggesting a defective quality of\noocytes/embryo as the cause of infertility in women with\nendometriosis.\nEndometriosis and immune-endocrine interaction\nThere is considerable evidence in literature indicating the\nassociation of humoral and cell-mediated immunity with\nendometriosis. The peritoneal fluid of women with endo-\n322 Gynecol Surg (2010) 7:319 –328\n\nmetriosis contains an increased number of immune cells\nwhich facilitate the development of endometriosis rather\nthan inhibiting it [ 65]. Autoantibodies, several cytokines,\nand growth factors display increased levels in the peritoneal\nfluid of women with endometriosis. Mathur et al. were the\nfirst to report IgG and IgA antibodies in the vaginal and\ncervical secretions of women with endometriosis [ 66].\nGleicher et al. [ 67] in their study found a wide variety of\nautoantibodies in endometriosis patients suggesting poly-\nclonal activation of B cell, characteristic of autoimmune\ndisease. They argued that ectopic endometrium might\ninduce an autoimmune response and contribute to infertility\nassociated with endometriosis [ 67]. Furthermore, treatment\nwith danazol and GnRH analog suppresses the antiendo-\nmetrial antibodies associated with endometriosis [ 68].\nAnother study showed that infertile women with endome-\ntriosis had various kinds of autoantibodies, especially\nagainst phospholipids in serum and the peritoneal fluids\nthat could reduce the success of spontaneous and artificial\nimplantation [ 68]. Although these data suggest that auto-\nantibodies may play a role in infertility associated with\nendometriosis, the importance of autoimmunity in patho-\ngenesis of infertility in these patients needs to be further\nexplored.\nCytokines are diverse proteins that play a central role in\nregulating cellular activity. Several studies have reported a\npotential link between cytokines and the pathogenesis of\nendometriosis. Interluekin-1 (IL-1) is one of the major\nproinflammatory cytokines found in the peritoneal fluid of\nwomen with endometriosis, and studies have found that IL-\n1m a yp l a yar o l ei nt h ei n f e r t i l i t ya s s o c i a t e dw i t h\nendometriosis [ 69, 70]. IL-1 has been found to inhibit\nmouse embryo development, impairing the capacity of\nsperm to penetrate the oocyte without altering the sperm\nmotility [ 71, 72]. In a recent study, it was suggested that an\nimbalance between IL-1 and its inhibitory soluble IL-1\nreceptor type 2 levels in peritoneal fluid of women with\nendometriosis may cause a defect in the local control of IL-\n1 and may be involved in the pathophysiology of\nendometriosis and its related infertility [ 73]. IL-6, another\npleiotropic cytokine, has been associated with reproductive\nphysiology and found to be increased in the peritoneal fluid\nof women with endometriosis [ 16, 17]. The elevated levels\nof IL-6 has been associated with poor sperm motility and\naltered follicular functions [ 18, 35]. Deura et al. in their\nstudy showed that IL-6 suppressed estrogen production and\naromatase activity in the granula cell line and may be\nassociated with infertility with endometriosis [ 74]. Another\ncytokine IL-17 has been found to induce IL-6 and TNF- α\nin the macrophages, which play a crucial role in the\npathogenesis of endometriosis and infertility [ 75]. Zhang et\nal. in their study found that IL-17 was significantly higher\nin patients with mild/minimal endometriosis and also when\nendometriosis was associated with infertility [ 76]. TNF-α is\nanother cytokine that plays a key role in the multitude of\ninflammatory processes. TNF- α has been implicated in the\npathophysiology of endometriosis and its associated infer-\ntility. It affects sperm motility and also shows embryotoxic\neffects [ 23, 55].\nRANTES (regulated on activation, normal T-cell\nexpressed and secreted) is another cytokine chemo-\nattractant for monocytes as well as memory T cells and\neosinophils. The level of RANTES is found to be increased\nin the peritoneal fluid of women with endometriosis, and its\nlevel correlates with the severity of disease [ 77]. Xu et al.\n[78] found poor IVF outcomes in endometriosis-related\ninfertility than in tubal infertility. They concluded that\nelevated follicular fluid RANTES evokes an altered\ninflammatory milieu within the follicular fluid environment\nleading to poor oocyte quality [ 78]. MIF is a multifunc-\ntional cytokine that regulates immune response, cell\nproliferation, and angiogenesis. Morin et al. found elevated\nlevels of MIF in the peripheral blood of women with\nendometriosis and suggested that MIF may adversely affect\nfertility in these women [ 79]. Monocyte chemo-tactic\nprotein 1 is a β chemokine produced mainly by the\nmonocytes, and macrophages have been found to be\nincreased in infertile patients with endometriosis [ 80].\nComplement, another component of the humoral immunity,\nhas been found to be altered in endometriosis. Kabut et al.\nin their study found increased concentrations of C3c and\ndecreased concentration of iC3b in the PF of women with\nFactor Level of the factor Reference\nTNF-α Increased Minci et al. [ 55]\nαvβ3 integrin Decreased Lessey et al. [ 56]\ne-NOS Increased Khorram et al. [ 57]\nHOXA-10m-RNA Decreased Matsuzaki et al. [ 59]\nAromatase expression Increased Hugo et al. [ 60]\nBSEP , C4BP ,IL-15 genes Dysregulated Kao et al. [ 61]\nEMX2 Increased Daftary et al. [ 62]\nIL-11, LIF Decreased Dimitriadis et al. [ 63]\nTable 1 Endometrial factors\nimpairing implantation\nGynecol Surg (2010) 7:319 –328 323\n\nendometriosis, both of which are derivatives of C3\ncomponent of the complement cascade [ 81]. A higher\nconcentration of iC3b, produced from the oviductal C3/C3b\nhas been found to enhance the development of blastocyst\nand also stimulate embryo development [ 82]. This de-\ncreased iC3b found in the PF of women with endometriosis\ncould lead to infertility. There is a controversy on the role\nof increased level of leptin in endometriosis-related\ninfertility. Leptin, a product of the obese gene, is a cytokine\nsimilar to various members of the interleukin family. Barcz\net al. suggested that the increased levels of leptin in\nperitoneal fluid in women with endometriosis may be\nassociated with infertility [ 83]. On the other hand, Bedaiwy\net al. in their study found that increased peritoneal fluid\nleptin levels may be associated with pain but not infertility\nin patients with endometriosis [ 84].\nEndometriosis is associated with changes in cell-\nmediated immunity as well. V arious components of cellular\nimmunity have been found to be altered in endometriosis.\nPeritoneal macrophages are the major resident cells in the\nperitoneal cavity, and their number, concentration, and\nactivity are higher in patients with endometriosis than\ncontrols [ 85]. NK cell activity in women with endometri-\nosis has been shown to have a decreased cytotoxic activity,\nwhich indicates alteration in immune response, and co-\nexisting with endometrial abnormalities [ 86]. These\nchanges in the peritoneal environment may also have a\nrole in endometriosis-related infertility [ 87]. Moreover,\ndanazol and GnRH analogs, which are commonly used\nfor treatment of endometriosis down-regulate humoral and\ncellular immunity concomitantly with their effect on\nendometriotic implants [ 88].\nHyperprolactinemia has been reported to exist in patients\nwith endometriosis-related infertility, but the role of\nprolactin (PRL) in infertile women with endometriosis is\nless clear [ 89]. In a study, it was suggested that altered PRL\nsecretion and decreased serum estradiol after thyrotrophin-\nreleasing hormone administration in infertile women with\nendometriosis was strongly related to a dysfunction of the\nhypothalamic–hypophyseal–ovarian axis and could be the\ncause of infertility in these patients [ 90]. Matrix\nmetalloproteinase-2 (MMP-2) has emerged as one of the\nkey participants in the adhesion and proliferation of shed\nmenstrual tissue in the pathogenesis of endometriosis [ 91].\nEstradiol has been shown to up-regulate the MMP-2 action\nleading to formation of endometriosis, and progesterone has\nbeen associated with down-regulation of MMP-2 action\ninhibiting the development of endometriosis [ 92]. MMP-2\nhas shown to have a role in ovulation and luteal function\n[93].\nThere is clear evidence from the above discussion on the\ninteraction between immune mediators and hormones on\nthe development of endometriosis and its associated\ninfertility. A better understanding of these interactions will\nset the stage for immune-targeted therapies not only for the\nmanagement of endometriosis but also its associated\ninfertility.\nEndometriosis and role of laparoscopy in management\nof infertility\nAlthough there is an association between endometriosis and\ninfertility, the discussion about exact causal relationship is\nstill ongoing. Nevertheless, laparoscopy has been used for\nthe diagnosis, staging, and treatment of endometriosis.\nVisual look of the disease through laparoscopy has become\nan integral part of management of infertility in endometri-\nosis. The effect of destruction of peritoneal endometriosis\n(ASRM stage I-II) by laparoscopy on pregnancy rates in\ninfertile women has been debated [ 94]. It is unclear how\nremoving or ablating a lesion by laparoscopy will improve\nthe alterations described above. Two randomized controlled\ntrials did not agree on the effect of laparoscopic ablation or\nexcision of endometriotic lesions on pregnancy rates. The\nlarger study, by the Canadian Collaborative Group on\nEndometriosis, showed that excision or laparoscopic abla-\ntion of minimal and mild endometriosis increased ongoing\npregnancy rates in infertile women (OR 1.95, 95% CI 1.18 –\n3.22) [ 95]. The number needed to treat in the Canadian\nstudy was nine. A smaller trial by an Italian group failed to\nshow significant impact on the live birth rate (OR 0.85,\n95% CI 0.32 –2.28) [\n96]. However, when these two results\nwere combined, the pooled odds ratio showed a significant\nimprovement in live birth rate following surgical treatment\n(OR 1.64, CI 1.05 –2.57) [ 97]. If we combine the Canadian\nand the Italian studies, the number needed to treat is 12.\nThus, there is reasonable evidence to treat minimal and\nmild endometriosis to improve the subsequent fertility\noutcome. Laparoscopic treatment of mild endometriosis\neither by excision or coagulation was shown to have no\ninfluence on the pregnancy rate and had similar outcomes\n[98].\nAn interesting study by Bedaiwy et al. on the impact of\ns u r g e r yo nI V Fo u t c o m ef o u n dn oi m p r o v e m e n ti n\npregnancy outcomes [ 99]. In light of the complex patho-\nphysiological changes taking place in the peritoneum in\nendometriosis, surgical removal of lesions may therefore\nnot necessarily have a substantial impact on fertility.\nSimilarly, laparoscopic treatment of ovarian endometri-\nosis (ASRM III-IV) showed varied outcomes and the\npregnancy rates ranged from 30% to 67% [ 100, 101].\nDespite the possible risk of loss of ovarian tissue and\ndisruption of blood supply leading to ovarian damage,\nliterature shows increased pregnancy rates following lapa-\nroscopic treatment of endometriomas [ 102]. In a recent\nCochrane review, it was concluded that the excision of the\n324 Gynecol Surg (2010) 7:319 –328\n\nendometriomas improves the subsequent spontaneous preg-\nnancy rates in comparison to drainage and ablation of the\nendometrioma [ 103]. The removal of endometriomata may\nbe associated with risk of damage to ovarian function.\nOvarian cystectomy may cause resection of the healthy\novarian cortex with follicles rather than excision of intra-\novarian cyst. Somigliana found fewer follicles in response\nto gonadotropin stimulation after laparoscopic removal of\nendometriomata thereby alte ring the ovarian response\nduring IVF [ 104]. Additionally, adverse changes in the\novarian artery blood flow have been reported following\nlaparoscopic stripping [ 105]. Nonetheless, careful removal\nof endometriomas will improve spontaneous fertility sub-\nstantially and should be removed.\nRecently, interest has been shown on the influence of\nlaparoscopic treatment of bowel endometriosis on post-\noperative fertility. Stepniewska et al. [ 106] in one of the\nlargest series retrospectively looked at the effect of\nlaparoscopic surgery for en dometriosis with colorectal\nsegmental resection on subsequent fecundity rate. They\nconcluded that complete removal of endometriosis with\nbowel segmental resection had better post-operative fertility\nthan removal of endometriosis without bowel resection\n[106]. Ferrero et al. in their study suggested that although\nspontaneous pregnancy may occur after bowel resection,\nthese patients may require infertility treatment, especially\nwomen ≥35 years [ 107]. V ercellini et al. [ 108] studied the\nrole of conservative surgery for rectovaginal endometriosis\non the fertility outcome. Their group concluded that, in\npatients with no other associated major infertility factors,\nsurgical resection of rectovaginal endometriosis did not\nimprove the pregnancy outcome [ 108].\nAnother interesting aspect is the impact of laparoscopic\nsurgery for recurrent endometriosis on subsequent fertility.\nFedele et al. [ 109] compared the 5-year cumulative\npregnancy after laparoscopic excision of primary versus\nrecurrent ovarian endometrioma in the same ovary as the\nprimary cyst. The 5-year cumulative pregnancy rate was\n40.8% after the first surgical procedure and 32.4% after the\nsecond procedure. The authors concluded that the effect of\nrepetitive laparoscopic surgery is similar to that observed\nafter first-line surgery and that the women with repetitive\nsurgery underwent assisted reproduction techniques more\nfrequently [ 109].\nConclusion\nPelvic endometriosis is frequently associated with infertility\neven when the affected women have functional, patent\ntubes. Beset with inadequate, inconclusive, and conflicting\ndata, it remains difficult to arrive at a consensus regarding\nthe exact mechanism of infertility in these patients. In this\nreview, we have discussed the various possible mechanisms\nthat can affect fertility which can later be a scope for future\nmanagement of the disease. Despite the lack of firmly\nestablished causal relation between endometriosis and\ninfertility, these develop ments may help improve the\nfertility rates in these patients. Laparoscopy still remains\nthe gold standard for the diagnosis and management of the\ndisease. Laparoscopic management of minimum to mild\nendometriosis has been shown to improve subsequent\nfertility outcomes, although it is unclear by how much it\nis improved. Laparoscopic removal of endometriomas will\nimprove spontaneous pregnancy rates significantly. Lapa-\nroscopic excision rather than drainage and ablation of\nendometrioma are recommended. 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