Endometriosis and infertility: is there a cause and effect relationship?

An association between endometriosis and infertility has long been noted. Endometriosis affects approximately 5% of the general population. In infertile women, the prevalence may be as high as 30%. Multiple studies, the majority of which are retrospective, indicate that the monthly fecundity of patients with endometriosis may be decreased by half compared to women without the disease. The precise cause-effect relationship between endometriosis and infertility remains controversial. In advanced cases of endometriosis, with distorted pelvic anatomy, the mechanism of infertility is more easily explained. Recent evidence suggests that treatment of early-stage endometriosis may increase pregnancy rates. Many etiologies of infertility in early-stage endometriosis have been proposed. These include endocrine dysfunctions such as luteal phase defect and luteinized unruptured follicle syndrome. In the last 15 years, alterations in the local pelvic immune environment have been the subject of multiple basic science investigations. Unfortunately, there is no satisfactory hypothesis that unequivocally explains the association of early stages of endometriosis with infertility.     

Luteinized unruptured follicle in the early stages of endometriosis as a cause of unexplained infertility.

OBJECTIVE: We attempted to clarify the relationship between luteinized unruptured follicle, which occurs in the early stages of endometriosis, and unexplained infertility. STUDY DESIGN: Seventy patients who had unexplained infertility were reviewed. RESULTS: Laparoscopic examination showed that 47 patients (67%) had endometriosis; of these, 40 (85%) had minimal or mild disease. The incidence of luteinized unruptured follicle was higher (p < 0.05) in patients who had endometriosis (35%/patient and 25%/cycle) compared with patients who did not have endometriosis (11%/patient and 7%/cycle). Degenerated oocyte cumuli were collected in 6 (43%) of 14 luteinized unruptured follicles diagnosed by transvaginal ultrasound. CONCLUSIONS: These results show that luteinized unruptured follicle is common in patients who have mild or minimal endometriosis and that it may be one of the causes of endometriosis-associated infertility. Transvaginal ultrasound-guided follicular puncture of luteinized unruptured follicle during the mid luteal phase may be useful in establishing a definitive diagnosis of luteinized unruptured follicle.     

Reproductive disorders affecting fertility in endometriosis

The classical concept of endometriosis as a cause of infertility is challenged. Traditionally, both surgical and medical therapy of endometriosis-associated infertility has focused on eliminating or reducing the visible implants. The classic 6-month medical approach has been a failure, and surgery may moderately enhance fertility, but its benefit in the absence of adhesions is still doubtful. Recent studies have shown that endometriosis is characterized by an aberrant response to sex steroid hormones, resulting in pleiotropic dysfunctions of the reproductive system involving the uterine, peritoneal and ovarian micro-environment. Studies on endometriosis and IVF have been highly relevant in revealing the pleiotropic dysfunctions in patients with endometriosis, although the results should be interpreted with caution. The conclusion seems to support the view that infertility in patients with endometriosis is primarily dysfunctional, rather than lesional, in origin. It is concluded that the place of medical therapy in endometriosis should be reviewed and that the surgical approach needs to be complemented by appropriate medical therapy to restore fertility.     

Conservative treatment of endometriosis

The patients with endometriosis have shown a significant increase in frequency in our country. In the recent years, the incidence of endometriosis in gynecological outpatients is probably 3%. In infertile patients, endometriosis has been demonstrated by laparoscopy in 20-30% of cases. The pregnancy rate of women with endometriosis has been noted to be 80-85% in the internal endometriosis and 50-60% in the external endometriosis. The risk of infertility is greater in women with external endometriosis than in women with internal endometriosis. The causes of infertility are multiple and additive. Mechanical interference with the reproductive function plays a predominant role. Pelvic adhesions involving ovaries and fallopian tubes interfere mechanically with ovulation, ovum pick-up and ovum transport. According to Brosens et al. the frequency of LUF syndrome is in excess of 79% in the patients with endometriosis. Another antifertility effect of endometriosis may involve coital avoidance due to dyspareunia, hyperprolactinemia, increased phagocytosis of spermatozoa and altered prostaglandin secretion in peritoneal fluid. Conservative treatment of endometriosis is associated with improvement infertility and the post-treatment pregnancy rate has become an acceptable indicator of the effectiveness of therapy. The choice of therapeutic approach depends on several factors including age of the patient, extent of the disease, extent and location of pelvic adhesions and other coexisting infertility factors. Several hormonal regimens have been recommended for the treatment of endometriosis. They include androgen, progestogens and pseudopregnancy, danazol-induced pseudomenopause, gestrinone and LH-RH agonists.(ABSTRACT TRUNCATED AT 250 WORDS)     

Focusing on surgery results in infertile patients with deep endometriosis

Abstract

Infertility is a common problem in patients with endometriosis and the involved mechanisms are still not completely known. The management of infertility in endometriosis patients includes surgery as well as assisted reproductive technology. Laparoscopic surgery has shown better results in infertility patients with endometriosis in comparison to laparotomy procedures. Laparoscopic surgery has proposed benefits in both minimal to moderate diseases. However, while there may be some benefits with severe diseases, there is still not enough evidence to recommend laparoscopic surgery as the recommended surgery when the main goal is to obtain fertility. We performed a MEDLINE search for articles on fertility in women with deep infiltrating endometriosis (DIE) published between 1990 and April 2015 using the following keywords: “endometriosis”, “deep infiltrative endometriosis”, “infertility”, “fertility after surgery”, “laparoscopy surgery”, “laparotomy”, “pregnancy”, “fertility outcome”, “bladder endometriosis”, and “ureteral endometriosis”. The aim of this review was to analyze the results of available clinical studies (randomized controlled or not controlled studies; retrospective cohort studies; or case–control and prospective studies) and guidelines on surgical treatment of infertile endometriosis patients, and pregnancy outcomes after surgery.     

Medical management of endometriosis and infertility

Objective: To review the literature on the use of medical management of endometriosis and infertility.

Design: Literature review.

Result(s): Endometriosis is a common finding in women with infertility, but the mechanism by which it renders a woman infertile remains unclear. Despite many years of controversy and debate, there remains a strong bias against medical treatment for endometriosis-associated infertility. A review of the current literature suggests that medical management of endometriosis may be effective in selected patients and in certain settings, including patients undergoing IVF.

Conclusion(s): A closer look at the question of medical management of endometriosis reveals that much remains to be learned before a final decision can be made about the use of medical therapies, such as GnRH agonists, for endometriosis and associated infertility.     

Association of endometriosis and spontaneous abortion: effect of control group selection

Endometriosis has been associated with an increased incidence of spontaneous abortion, compared with the abortion rate of the general population. To assess whether a separate control group would affect these conclusions, we studied 139 consecutive infertility patients with laparoscopically proven endometriosis to determine the incidence of spontaneous abortion. Ninety-five of these patients underwent conservative surgical resection of endometriosis, and 44 patients opted for expectant management. There was no significant difference between these two groups in average age, duration of infertility, or proportion of patients with primary infertility. The average spontaneous abortion rate before diagnosis for all patients was 63.1%. After surgical treatment, the abortion rate dropped to 0% (P less than 0.000001) for all stages of disease. However, even in those patients who received expectant management only, the abortion rate fell to 16.7% and 21.4% for mild and moderate endometriosis, respectively (P less than 0.001). These results suggest that the spontaneous abortion rate in untreated endometriosis may not be as high as previously reported and may not be significantly different from the rate in the general population. The data also emphasize the need for well-defined control groups when assessing the effects of a treatment regimen.     

Evaluation of serum prolactin levels in patients with endometriosis and infertility.

The aim of this study was to clarify the significance of serum prolactin concentrations in patients with infertility and endometriosis. Forty patients with infertility and laparoscopically proven endometriosis were recruited into the study. Basal serum prolactin levels and prolactin levels after TRH administration were measured. The mean basal serum prolactin concentrations were 12.5, 16.5, 19.5, and 26.5 ng/ml and those after thyrotropin-releasing hormone (TRH) administration were 88.3, 114.2, 125.3 and 138.8 ng/ml in patients with stages I, II, III and IV endometriosis, respectively. A statistically significant relationship was found between the basal serum prolactin levels as well as those after TRH injection and the stage of the endometriosis. The patients were divided in two groups. Group I consisted of 20 patients who did not receive any treatment, while group II consisted of 20 patients who were initially treated with GnRH analogues for 24 week and subsequently with several therapeutic schemes in order to improve their fecundity. The pregnancy rate was not different between the two groups. The patients, however, who did not become pregnant had higher serum prolactin concentrations after TRH administration as compared to those who conceived. We conclude that occult hyperprolactinemia may be a cause of infertility in patients with endometriosis.     

Clinical Predictors of Endometriosis in the Infertility Population: Is There a Better Way to Determine Who Needs a Laparoscopy?

ObjectiveEndometriosis is a known contributor to infertility, but the gold standard for its diagnosis is surgical. Therefore, it is important for clinicians to be able to predict which women with infertility are at high risk for endometriosis and thus should be offered laparoscopy. We sought to identify the clinical predictors of endometriosis in the infertility population.MethodsWe conducted a retrospective review of patients at an academic infertility centre. The primary outcome was identification of endometriosis at laparoscopy, and we used logistic regression to test clinical variables for their ability to predict endometriosis.ResultsPrimary infertility, dysmenorrhea, and uterosacral/cul-de-sac nodularity were significant independent predictors of finding endometriosis at laparoscopy. Other clinical variables (including hysterosalpingogram findings) were not independent predictors of endometriosis, and physicians with an endometriosis-focused practice were more likely to diagnose endometriosis at laparoscopy.ConclusionKey predictors of endometriosis in the infertility population are primary infertility, dysmenorrhea, and uterosacral/ cul-de-sac nodularity. These results will be used to develop and validate a formal clinical prediction model for endometriosis in infertile women.     

Infertility in patients with bowel endometriosis

The impact of bowel endometriosis on fertility is unclear, and the optimal management of patients who wish to conceive is not well-defined. Infertile patients with bowel endometriosis may either undergo surgery to enhance fertility or assisted reproductive technology (ART). It is necessary to consider that some complications may occur in patients undergoing ART because of the ovarian stimulation needed during these procedures. Interpretation of the available data on fertility outcomes after colorectal surgery for deep endometriosis is difficult as several studies do not distinguish patients with real infertility from those wishing to conceive without proven infertility and outcomes of complex surgery are operator-dependent. The effect of bowel surgery to increase the likelihood of spontaneous conception is yet to be established. Limited data are available on fertility outcomes after the removal of endometriotic nodules without the excision of bowel endometriotic implants.     

The effect of endometriosis on in vitro fertilization outcome

AIM: Endometriosis is a leading cause of pelvic pain and infertility. Implantation of endometrial cells to the peritoneal surface can lead to a spectrum of disease severity with the most severe causing extensive pelvic adhesions and anatomic distortion. Infertility can result from anatomic abnormalities as well proinflammatory cellular and immune factors. Treatment options for women seeking pregnancy include surgical removal and/or in vitro fertilization. The aim of this study was to review current literature on the pathogenesis of endometriosis and treatment options for infertility. METHODS: Recent published articles regarding infertility and endometriosis have been reviewed analyzing PubMed and Cochrane databases. RESULTS: In vitro fertilization (IVF) is a valid option for patients after surgical management has not restored fertility. IVF may be offered sooner to older patients or to those with more severe disease. It is unclear if prior surgical treatment has deleterious effects on IVF outcomes. It does appear, however, that surgical removal of endometriomas may lead to decreased ovarian reserve. This may not affect fertility outcomes. CONCLUSION: Endometriosis is a leading cause of pelvic pain and infertility. The most accepted theory of how endometriosis develops is the retrograde transplant theory by Sampson, but a constellation of numerous other factors are involved. The gold standard for diagnosis is operative; therefore, the true prevalence of this disease is uncertain. Many women with endometriosis will seek fertility treatment. In this case if endometriosis is found, it should be treated.     

Minimal and mild endometriosis. Nd:YAG laser treatment and changes in prostaglandin concentrations in peritoneal fluid

Among many patients, infertility originates with minimal and mild endometriosis. Recently, peritoneal fluid factors have come to be associated with infertility in minimal and mild endometriosis patients, and prostaglandin (PG) is suspected of being one of those factors. We use the Nd:YAG laser for treatment of endometriosis; a total of 52 cases of minimal and mild endometriosis have been treated so far with the laser under laparoscopy in our clinic. At the same time we measured the peritoneal fluid volume and PG concentration in peritoneal fluid. Peritoneal fluid volume and PGE2 concentrations were found to be significantly higher than those in the control group (tubal obstruction patients). Seven of 52 patients received second-look laparoscopy three months after Nd:YAG laser treatment; the PG concentration showed a tendency to decrease in many patients, and the PGE2 concentration turned out to be insignificant. Within one year, 30 patients achieved pregnancy. In minimal and mild endometriosis patients Nd:YAG laser treatment may alter the PG concentration in peritoneal fluid, thereby increasing the change of pregnancy.     

Early endometriosis invades the extracellular matrix.

OBJECTIVES: To investigate whether the aminoterminal propeptides of type III procollagen are increased in patients with early endometriosis and to demonstrate that the subtle lesion of endometriosis is an active stage of the disease. DESIGN: Aminoterminal propeptide of type III procollagen was determined in serum and peritoneal fluid (PF) of 100 consecutive patients undergoing laparoscopy. SETTING: Academisch Ziekenhuis Maastricht, The Netherlands, a tertiary care center. RESULTS: Aminoterminal propeptide PF levels were significantly higher in women with early lesions of endometriosis compared with levels in two groups of controls, i.e., fertile, cycling, women without the disease (P = 0.019) and women on oral contraceptives without the disease (P = 0.036). No difference was found in aminoterminal propeptide PF levels when comparing patients with early lesions of endometriosis and patients with unexplained infertility, the third control group. Aminoterminal propeptide PF levels of patients with endometriosis without early lesions were not different from PF levels in controls. CONCLUSION: The early lesion is an active stage of endometriosis, invading the extracellular matrix. In women with unexplained infertility active, microscopic endometriosis may be present.     

Increased nitric oxide in peritoneal fluid from women with idiopathic infertility and endometriosis.

OBJECTIVE: To verify whether nitric oxide in peritoneal fluid is associated with endometriosis and infertility. STUDY DESIGN: Twenty-five women with idiopathic infertility and 38 with endometriosis were recruited, and 18 cases of uterine myomata and 2 cases of ovarian cyst served as controls. Peritoneal fluid samples were aspirated from the pouch of Douglas during laparoscopy or laparotomy. Metabolites of nitric oxide (nitrite and nitrate) in peritoneal fluid were determined by a method using nitrate reductase and the Griess reaction. RESULTS: Peritoneal concentrations of nitrate/nitrite in both infertile women (42.02 +/- 12.98 mmol/L) and patients with endometriosis (41.75 +/- 16.42 mmol/L) were significantly higher than that in controls (33.96 +/- 13.07, P < .05 for both). No significant difference in peritoneal nitrate/nitrite level was found between infertile women and patients with endometriosis (P > .5). Peritoneal levels of nitrate/nitrite were comparable among patients with endometriosis at different stages (P > .5). Patients with endometriosis had more peritoneal fluid than controls and idiopathic infertile women, while controls and idiopathic infertile women had comparable amounts of peritoneal fluid. CONCLUSION: An increased peritoneal level of nitric oxide is a common alteration in endometriosis, endometriosis-associated infertility and idiopathic infertility and may be associated with the pathogenesis of these diseases.     

Occult and minimal forms of endometriosis: therapeutic strategies

The hidden forms of endometriosis, especially the microscopic or non visible endometriosis, are entities presenting difficult problems for the diagnosis and sometimes the selection of a treatment; non visible endometriosis seems to be more of an interesting theoretical concept as long as its existence and clinical significance will not have been better documented and confirmed. Minimal endometriosis (Stage I of the AFS-1985 classification) is frequent in infertility cases and its incidence is probably underestimated because of atypical aspects better known today. Its relationship with infertility still seems hypothetical, even if new data seem to implicate it to a greater degree. Numerous disorders have been found to explain the harmful effect of endometriosis on sterility. All the usual means of treatment of endometriosis may be selected; however, coelioscopic destruction at the time of the diagnosis seems most appropriate in case of pain or infertility; in the latter group, secondarily, a short medical treatment may be used before resorting to Fertilization in vitro of GIFT, which will be preferred if the patient is older and there is a long history of infertility.     

子宫内膜异位症患者腹腔液白细胞介素17水平的变化及其意义

目的探讨白细胞介素17(IL17)与子宫内膜异位症(内异症)发病的关系。方法应用酶联免疫吸附(ELISA)法检测36例不同期别内异症患者(内异症组)和26例非内异症患者(对照组)腹腔液中的IL17水平。结果内异症组和对照组腹腔液IL17水平分别为(5.7±1.9)ng/L和(5.3±1.4)ng/L,两组比较,差异无统计学意义(P>0.05)。按1985年美国生育学会内异症分期标准(rAFS)进行分期,Ⅰ～Ⅱ期内异症患者(16例)腹腔液IL17水平为(6.4±1.7)ng/L,Ⅲ～Ⅳ期内异症患者(20例)为(5.1±1.8)ng/L,两者比较,差异有统计学意义(P<0.05)。卵泡期和黄体期腹腔液IL17水平在两组间比较,差异均无统计学意义(P>0.05)。内异症不孕患者腹腔液IL17水平为(6.4±1.8)ng/L,内异症未合并不孕患者为(5.1±1.8)ng/L,两者比较,差异有统计学意义(P<0.05)。结论IL17水平变化可能与早期内异症及内异症不孕的发病有关。     

Glutathione peroxidase concentration in the peritoneal fluid from infertile women

OBJECTIVES: To assess the concentration of Plasma Glutathione Peroxidase (plGPx) in the peritoneal fluid (PF) of patients with unexplained infertility and infertile women with minimal and mild endometriosis. MATERIALS AND METHODS: 33 women were studied, including 8 infertile women with minimal or mild endometriosis, 15 patients with unexplained infertility and 10 patients with tubal occlusion (a reference group). Concentration of plGPx was measured in the PF using a commercially available ELISA kit (Oxis Inc.). RESULTS: The plGPx concentration was significantly (p = 0.04) lower in PF from women with unexplained infertility (846 +/- 177 ng/ml) compared to the reference group (1023 +/- 238 ng/ml), but did not differ significantly (p = 0.25) between women with endometriosis (918 +/- 81 ng/ml) and patients with tubal infertility. CONCLUSIONS: Our results suggest that low peritoneal plGPx concentration may play a role in the pathogenesis of infertility.     

Prolactin hyperstimulation in response to thyrotropin-releasing hormone in patients with endometriosis

In order to clarify the role of hyperprolactinemia as a possible cause of infertility in patients with endometriosis, baseline serum prolactin (PRL) concentrations and the PRL response to thyrotropin-releasing hormone (TRH) stimulation were measured in 14 infertile women with endometriosis and in 13 normal, fertile women. Baseline PRL concentrations were 2-fold greater in the endometriosis group than in normal subjects, but the mean values did not differ significantly. Following TRH administration, a significant increase in peak PRL concentrations was observed in patients with endometriosis (211.5 +/- 34.9 ng/ml) when compared with corresponding values in control subjects (117.1 +/- 14.9 ng/ml, P less than 0.05). This hypersecretory state was selective for PRL because no significant differences between the baseline and TRH-stimulated thyroid-stimulating hormone (TSH) concentrations or total serum thyroxine concentrations were observed. In summary, some infertile women with endometriosis exhibit a greater capacity for PRL secretion than normal women. These results suggest that relative hyperprolactinemia may be responsible for the infertility associated with endometriosis, and that PRL suppression may be indicated in these patients.     

Total antioxidant status of peritoneal fluid in infertile women

OBJECTIVE: To determine whether impairment of the antioxidant systems of peritoneal fluid might be a factor responsible for infertility. STUDY DESIGN: Total antioxidant status was measured in peritoneal fluid obtained from 18 infertile women suffering from minimal or mild endometriosis, 23 patients with unexplained infertility, 12 women with tubal infertility and 13 fertile women. RESULTS: Total antioxidant status was significantly lower in peritoneal fluid from women with unexplained infertility (0.49+/-0.21 mmol/l) compared to both fertile patients (0.67+/-0.24 mmol/l, P=0.02) and women with tubal infertility (0.76+/-0.26 mmol/l, P=0.001). Peritoneal fluid total antioxidant status did not differ significantly between patients with endometriosis (0.61+/-0.2 mmol/l), tubal infertility and the fertile group (P>0.05). CONCLUSIONS: Our results suggest that low antioxidant status in peritoneal fluid may play a role in the pathogenesis of infertility.     

Role of cytokines in endometriosis-associated infertility

Endometriosis, which is common in women of reproductive age, may affect fertility. It is also clear that mechanical disruption of the pelvic anatomy may cause infertility. However, our understanding of the association between the early stage of endometriosis and infertility remains incomplete. Bloody peritoneal fluid (PF) is frequently observed in the cul-de-sac of endometriosis patients and contains various biologically active factors. We found that the concentrations of tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) in PF from patients with endometriosis were significantly higher than that of patients with endometriosis. There were significantly positive correlations between the levels of TNF-alpha and IL-6. We compared the levels of these cytokines with regard to the R-AFS stages and scores, but no differences were observed. In contrast, these cytokines correlate with the number and extent of red color peritoneal endometriosis. TNF-alpha increased the expression of IL-6 messenger RNA and protein in endometriotic stromal cells derived from chocolate cyst in a dose-dependent manner. The addition of IL-6 inhibited the development of mouse preimplantation embryo and impaired sperm function. We concluded that increased levels of IL-6 in peritoneal fluid of patients with active red endometriosis might be related to endometriosis-associated fertility.