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PubMed2002

Macrophages, oxidation, and endometriosis.

Retrograde menstruation has been suggested to be the cause for the presence of endometrial cells in the peritoneal cavity. However, little is known about the events that lead to the adhesion and growth of these cells that ultimately result in endometriosis, considering the fact that the disease occurs only in certain women despite the common occurrence of retrograde menstruation in most women. We postulate that, in normal women, the endometrial cells and tissue that arrive in the peritoneal cavity during menstruation are effectively removed by macrophages that are chemoattracted and become resident tissue macrophages in the peritoneal cavity. In contrast, the peritoneal macrophages in women with endometriosis are nonadherent and ineffectively scavenged, resulting in the sustained presence and growth of the endometrial cells. We also postulate that the peritoneal fluid is not a passive reservoir of the factors secreted by cells of the peritoneum, but actively promotes endometriosis. The peritoneal fluid is rich in lipoproteins, particularly low-density lipoprotein, which generates oxidized lipid components in a macrophage-rich inflammatory milieu. The oxidants exacerbate the growth of endometriosis by inducing chemoattractants such as MCP-1 and endometrial cell growth-promoting activity. We provide evidence for the presence of oxidative milieu in the peritoneal cavity of women with endometriosis, the nonscavenging properties of macrophages that are nonadherent, and the synergistic interaction between macrophages, oxidative stress, and the endometrial cells. For example, the peritoneal fluid lipoproteins of subjects with endometriosis have increased the propensity to undergo oxidation as compared with plasma lipoproteins, and the subjects also have increased titer of autoantibodies to oxidatively modified proteins. If the oxidative proinflammatory nature of the peritoneal fluid is an important mediator of endometriosis growth, anti-inflammatory agents and antioxidants might afford protection against endometriosis.

Ascitic Fluid↗

PubMed2000

Autoimmunity in endometriosis: relevance to infertility.

PROBLEM: Endometriosis is a complicated multi-factorial disease. Genetic and immunologic factors play a key role in its pathophysiology. We were the first to describe endometrial and ovarian autoimmunity in women with endometriosis in 1981. METHODS OF STUDY: ELISA and Western blot analysis. It is accepted that women with endometriosis have autoimmunity to endometrial, ovarian and nuclear antigens. We have now established that: 1. The endometrial autoantigens to which the endometriosis patients have autoimmune reactions are endometrial transferrin and alpha 2-HS glycoprotein. 2. Levels of antibodies to both these proteins are specifically elevated in women with endometriosis, thus making them important candidates for developing an endometrial antibody assay for a non-invasive diagnosis of endometriosis. 3. Levels of transferrin and alpha 2-HS glycoprotein are significantly elevated in the peritoneal fluid of women with endometriosis. 4. Antibodies to transferrin and alpha 2-HS glycoprotein also inhibit in vitro sperm motility. CONCLUSION: These data strongly suggest the possibility of endometrial autoantibodies playing an important role in the infertility often associated with endometriosis.

Antibodies↗

PubMed2000

Stem cell factor (SCF) concentrations in peritoneal fluid of women with or without endometriosis.

PROBLEM: In the quest for possible involvement of stem cell factor (SCF), a cytokine known to have multiple effects, in the pathogenesis of endometriosis, we evaluated concentrations of SCF in peritoneal fluid (PF) of women with or without endometriosis. METHOD OF STUDY: SCF concentrations in PF collected from women undergoing laparoscopy were measured, using a specific enzyme-linked immunosorbent assay (ELISA). Reverse transcription-polymerase chain reaction (RT-PCR) analysis to detect gene expression of c-kit, the receptor for SCF, was performed using the endometriotic tissue and the eutopic endometrium collected during the operation. RESULTS: SCF concentrations in PF of women with endometriosis were significantly higher compared to women without endometriosis. Looking at SCF concentrations in PF of women with endometriosis stratified by disease stage, women with stage I and II exhibited relatively higher SCF levels in PF, whereas SCF levels in PF with stage III and IV were comparable with those without endometriosis. The expression of mRNA for c-kit was detected in both the endometriotic tissue and the eutopic endometrium. CONCLUSION: We demonstrated an elevation in SCF levels in PF associated with endometriosis and the presence of its receptor in endometriotic tissues. Given the known pleiotropic properties of SCF, the present results suggest that SCF might play a role in the pathogenesis of endometriosis.

Adult↗

PubMed1985

Endometriosis detection by US with laparoscopic correlation.

Endometriosis is a common cause of female infertility. It may affect as many as 40% of infertile women and may be the sole contributing factor to infertility in 15%. A study was undertaken to determine the usefulness of the routine pelvic ultrasound (US) examination in the detection of endometriosis by correlating pelvic US findings with laparoscopic findings in 85 patients who underwent both examinations. Forty-eight patients (56.5%) had no laparoscopic evidence of endometriosis, and 37 patients (43.6%) had endometriosis. Eight of the patients had abnormal sonograms; of these patients, only four had sonographic abnormalities that corresponded to laparoscopically identified endometriosis. Thus, US was successful in detecting endometriosis in only four (10.8%) of 37 patients. US is neither sensitive nor specific in diagnosing endometriosis. Furthermore, we believe that US does not have a significant role in the diagnosis or management of endometriosis in patients in whom a pelvic mass or other obvious pelvic abnormality is not suspected.

Adnexal Diseases↗

PubMed2002

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.

Causality↗

PubMed2002

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.

Adult↗

PubMed1999

Pathogenesis of endometriosis: the role of peritoneal fluid.

Peritoneal fluid is a specific microenvironment. It originates mainly as an ovarian exudation product due to increased vascular permeability, and contains large amounts of macrophages and their secretion products, which include growth factors, cytokines and angiogenic factors. Similarly, within the ovary, there is also a specific microenvironment, best characterised by the follicular milieu with steroid hormone concentrations that are 1,000 times higher than in plasma. Since endometrial cells in peritoneal fluid and superficially implanted cells will be influenced by peritoneal fluid concentrations, any differences found between minimal endometriosis and eutopic endometrium could be the consequence of their different local environments, rather than inherent cellular differences. Superficial endometrial implants may be regulated by factors in peritoneal fluid, while deep endometriosis and cystic ovarian endometriosis may be under the influence of factors in blood and within the ovary, in which case minimal endometriosis may be physiologic only, while deep endometriosis and cystic ovarian endometriosis, both associated with pelvic pain and infertility, may be a pathological state. In conclusion, the local endocrine environment, that is, in blood, peritoneal fluid, and within the ovary, should be taken into account to explain the differences between superficial, deep and cystic ovarian endometriosis, together with inherent differences in the endometrial cells of women with and without endometriosis.

Animals↗

PubMed2006

Nuclear factor-kappab (NF-kappaB): an unsuspected major culprit in the pathogenesis of endometriosis that is still at large?

Endometriosis, defined as the ectopic presence of endometrial glandular and stromal cells outside the uterine cavity, is a common benign gynecological disorder with an enigmatic pathogenesis. Many genes and gene products have been reported to be altered in endometriosis, yet some of them may not be major culprits but merely unwitting accomplices or even innocent bystanders. Therefore, the identification and apprehension of major culprits in the pathogenesis of endometriosis are crucial to the understanding of the pathogenesis and would help to develop better therapeutics for endometriosis. Although so far NF-kappaB only has left few traces of incriminating fingerprints, several lines of investigation suggest that NF-kappaB, a pivotal pro-inflammatory transcription factor, could promote and maintain endometriosis. Various inflammatory agents, growth factors, and oxidative stress activate NF-kappaB. NF-kappaB proteins themselves and proteins regulated by them have been linked to cellular transformation, proliferation, apoptosis, angiogenesis, and invasion. Interestingly, all existing and nearly all investigational medications for endometriosis appear to act through suppression of NF-kappaB activation. In endometriotic cells, NF-kappaB appears to be constitutively activated, and suppression of NF-kappaB activity by NF-kappaB inhibitors or proteasome inhibitors suppresses proliferation in vitro. Viewing NF-kappaB as a major culprit, an autoregulatory loop model can be postulated, which is consistent with existing data and, more importantly, can explain several puzzling phenomena that are otherwise difficult to interpret based on prevailing theories. This view has immediate and important implications for novel ways to treat endometriosis. Further research is warranted to precisely delineate the roles of NF-kappaB in the pathogenesis of endometriosis and to indict and convict its aiders and abettors.

Endometriosis↗

PubMed1992

Decreased natural killer cell activity in women with endometriosis.

Natural killer (NK) cell activity is characterized by the spontaneous capacity of lymphoid cells derived from nonimmunized hosts to recognize and lyse certain tumor cell lines, virus-infected cells and transplanted tumor cell lines. Endometriosis is characterized by implantation and proliferation of autologous ectopic tissue in the pelvic cavity. Therefore, we focused on examining NK cell activity in women with endometriosis. NK cell activity in peripheral blood from women with endometriosis was lower than in women without endometriosis. On the basis of this finding, we analyzed also the effect of peripheral sera of women with endometriosis on NK cell activity. In the presence of peripheral sera of women with endometriosis, NK cell activity was significantly suppressed as compared with the sera of women without endometriosis. The suppressive effect of sera of women with endometriosis on NK cell activity showed dose-dependent curves. These studies provide the speculation that natural immunity mediated by NK cells may modulate the development of endometrial implants.

Cytotoxicity, Immunologic↗

PubMed2004

Endometriosis and inflammation in infertility.

A wealth of publications proposes that endometriosis and inflammation may have an unfavorable influence on fertility. A recent meta-analysis of assisted reproductive technologies demonstrated that, once confounding factors are controlled for, the pregnancy rate in women with endometriosis is approximately 50% of the rate of women with tubal factor infertility. Peritoneal fluid of women with endometriosis contains elevated amounts of macrophages and their secreted products, such as growth factors, cytokines, and angiogenic factors. Because reproductive organs are bathed in and thus will be influenced by peritoneal fluid, these proinflammatory mediators would affect various aspects of reproduction in women with endometriosis. Advanced stages of endometriosis may have easily understandable factors, such as distortion of the anatomy, causing infertility. On the other hand, in minimal or mild endometriosis mechanisms underlying reproductive failure are subtle and remain controversial. Recent reports suggest that inflammatory factors play a role in this endometriosis-associated reproductive failure. This review provides an overview of recent data on the effects of endometriosis-associated inflammation on fertility.

Endometriosis↗

PubMed2004

Antiangiogenesis therapy for endometriosis.

It is known that angiogenesis is of pivotal importance for the development of endometriosis. However, in the treatment of endometriosis patients, prevention of endometriosis lesion development only will not be sufficient as a therapy. Treatment options, aimed at interfering with established lesions, have to be developed. In this study we evaluated whether inhibition of angiogenesis by angiostatic therapy is also effective in antagonizing the sustentation of endometriosis. We evaluated the effect of the angiostatic compounds antihuman vascular endothelial growth factor, TNP-470, endostatin, and anginex on the growth of established endometriosis lesions in the nude mouse model. We show that human endometrium in the proliferative endometrium is highly angiogenic and that vascular endothelial growth factor-A is the most important angiogenesis promotory factor. The angiostatic compounds significantly decreased microvessel densities and the number of established endometriosis lesions. In the remaining lesions, the number of pericyte-protected vessels is not different in control and treated mice; however, the number of unprotected vessels was significantly reduced in the groups treated with the angiostatic agents. Our data demonstrate that inhibitors of angiogenesis effectively interfere with the maintenance and growth of endometriosis by inhibiting angiogenesis. This suggests that the use of angiostatic agents may be promising as a therapy for endometriosis.

Adult↗

PubMed1989

Reduced bone mass in reproductive-aged women with endometriosis.

Cortical and trabecular bone masses were measured by quantitative computed tomography of the distal radius in 41 women (30 +/- 1 yr) with endometriosis documented by laparoscopy and compared to those in 35 normal women (32 +/- 1 yr). Hormonal status was assessed, and a subset of 10 women with endometriosis underwent evaluation of calcium absorption and excretion. Menstrual cycles were regular in all women, and hormonal medication had not been administered during the 3 months before evaluation. Estradiol and progesterone varied as expected with the day of the cycle. Fasting calcium excretion was normal. Mean cortical and trabecular bone mass values in women with endometriosis were compared to those in the normal women. Women with endometriosis had significantly decreased cortical and trabecular bone mass. Cortical bone mass in normal subjects was 1263 +/- 11 Hounsfield units (HU), whereas in endometriosis, cortical bone mass measured 1133 +/- 16 HU (P less than 0.0001). Normal trabecular bone mass was 226 +/- 10 HU compared to a mean trabecular bone mass of 173 +/- 9 HU (P less than 0.0001) in endometriosis. Despite the decrease in bone mass documented by quantitative computed tomography, hormonal and calcium dynamics were normal and, therefore, did not appear to be significant etiological factors in regard to the bone loss. Since immunological abnormalities have been reported in association with endometriosis, immune factors may play a role in the development of bone loss in endometriosis and might be of pathogenic significance in this reproductive disorder.

Adult↗

PubMed1996

Aromatase expression in endometriosis.

The conversion of C19 steroids to estrogens occurs in a number of tissues, such as the ovary and placenta, and is catalyzed by aromatase P450 (P450arom; the product of the CYP19 gene). P450arom expression has also been detected in a number of uterine tumors, such as leiomyomas and endometrial cancer. On the other hand, P450arom expression was undetectable in normal endometrial and myometrial tissues. The present study was conducted to determine the presence or absence of aromatase expression in peritoneal endometriotic implants and in the eutopic endometrium of women with endometriosis. Endometriotic implants in pelvic peritoneum (n = 17; e.g. posterior culdesac, bladder, and anterior culdesac) and eutopic endometrial curettings (n = 11) of 14 patients with histologically documented pelvic endometriosis were obtained at the time of laparoscopy or laparotomy. Pelvic peritoneal biopsies distal to endometriotic implants as well as normal endometrial tissues (n = 7) from disease-free women were used as negative controls. We used competitive RT-PCR technology employing an internal standard to amplify P450arom transcripts in total ribonucleic acid (RNA) isolated from these tissues. P450arom transcripts were detected in all endometriotic implants and in all eutopic endometrial tissues from patients with endometriosis. P450arom messenger RNA species were not detectable in endometrial tissues from disease-free women or in endometriosis-free peritoneal tissues. The highest levels of transcripts were detected in an endometriotic implant that involved the full thickness of the anterior abdominal wall. The P450arom transcript level within the core of this endometriotic mass was 4-fold higher than that in the surrounding adipose tissue. It has been shown recently that aromatase expression in various human tissues is regulated by the use of tissue-specific promoters via alternative splicing. To analyze promoter usage, we amplified by RT-PCR the most likely promoter-specific untranslated 5'-termini of P450arom transcripts in 2 endometriotic implants. It appears that these endometriotic implants use both the adipose-type promoter I.4 and gonadal-type promoter II for aromatase expression. The use of promoter I.4 for aromatase expression in adipose tissue has been recently observed to be regulated by members of the interleukin-6 (IL-6) cytokine family. Based on these findings, we examined by RT-PCR, IL-6 and IL-11 messenger RNA expression in 5 endometriotic tissues and 1 eutopic endometrial sample from a patient with endometriosis. We detected IL-6 and IL-11 transcripts in all endometriotic tissues and in the eutopic endometrial tissue sample studied. Our findings indicate that both eutopic endometrial tissues and endometriotic implants from patients with endometriosis are biochemically different from normal endometrial tissues of disease-free women. The presence of aromatase expression in eutopic endometrial tissues from patients with endometriosis may be related to the capability of implantation of these tissues on peritoneal surfaces. Furthermore, the possibility of estrogen production in these implants may serve to promote their growth. Increased IL-6 and IL-11 expression in these tissues suggests that P450arom expression in endometriosis may be regulated in part by these cytokines.

Adult↗

PubMed1997

Immunolocalization and regulation of the chemokine RANTES in human endometrial and endometriosis tissues and cells.

Retrograde menstruation is postulated as the initiating event in the histogenesis of endometriosis; however, subsequent steps in the pathogenesis of this common disorder remain poorly characterized. The ip accumulation of activated leukocytes and the infiltration of endometriosis lesions by macrophages and T cells are cytological markers of the inflammatory nature of this syndrome. The apparent recruitment of these leukocytes prompted us to search for chemokine expression by endometriosis cells. We reported previously that pelvic fluid RANTES (regulated upon activation, normal T cell expressed and secreted) concentrations correlated with the stage of endometriosis. In the current study, RANTES messenger ribonucleic acid (mRNA) was identified in normal endometrium and endometriosis lesions, and techniques were developed to localize RANTES protein within these tissues. Using isolated endometrial and endometriosis cell cultures, we demonstrated that RANTES mRNA and protein can be induced by the proinflammatory cytokines tumor necrosis factor-alpha and interferon-gamma in endometrial stromal, but not in epithelial or adenocarcinoma cells. Immunocytochemical studies confirmed the biochemical findings. Metabolic labeling experiments verified that nascent RANTES secreted by cytokine-stimulated endometriosis stromal cells was the mature, 8-kDa protein predicted by the mRNA encoding this chemokine. The results indicate that RANTES is a normal constituent of the eutopic endometrium. We propose that secretion of RANTES by ectopic endometriosis implants provides a mechanism for peritoneal leukocyte recruitment.

Adult↗

PubMed1998

Deficient 17beta-hydroxysteroid dehydrogenase type 2 expression in endometriosis: failure to metabolize 17beta-estradiol.

Aberrant aromatase expression in stromal cells of endometriosis gives rise to conversion of circulating androstenedione to estrone in this tissue, whereas aromatase expression is absent in the eutopic endometrium. In this study, we initially demonstrated by Northern blotting transcripts of the reductive 17beta-hydroxysteroid dehydrogenase (17betaHSD) type 1, which catalyzes the conversion of estrone to 17beta-estradiol, in both eutopic endometrium and endometriosis. Thus, it follows that the product of the aromatase reaction, namely estrone, that is weakly estrogenic can be converted to the potent estrogen, 17beta-estradiol, in endometriotic tissues. It was previously demonstrated that progesterone stimulates the inactivation of 17beta-estradiol through conversion to estrone in eutopic endometrial epithelial cells. Subsequently, 17betaHSD type 2 was shown to catalyze this reaction, and its transcripts were detected in the epithelial cell component of the eutopic endometrium in secretory phase. Because 17beta-estradiol plays a critical role in the development and growth of endometriosis, we studied 17betaHSD-2 expression in endometriotic tissues and eutopic endometrium. We demonstrated, by Northern blotting, 17betaHSD-2 messenger ribonucleic acid (RNA) in all RNA samples of secretory eutopic endometrium (n=12) but not in secretory samples of endometriotic lesions (n=10), including paired samples of endometrium and endometriosis obtained simultaneously from eight patients. This messenger RNA was not detectable in any samples of proliferative eutopic endometrium or endometriosis (n=4) as expected. Next, we confirmed these findings by demonstration of immunoreactive 17betaHSD-2 in epithelial cells of secretory eutopic endometrium in 11 of 13 samples employing a monoclonal antibody against 17betaHSD-2, whereas 17betaHSD-2 was absent in paired secretory endometriotic tissues (n=4). Proliferative eutopic endometrial (n=8) and endometriotic (n=4) tissues were both negative for immunoreactive 17betaHSD-2, except for barely detectable levels in 1 eutopic endometrial sample. Finally, we sought to determine whether deficient 17betaHSD-2 expression in endometriotic tissues is due to impaired progesterone action in endometriosis. We determined by immunohistochemistry the expression of progesterone and estrogen receptors in these paired samples of secretory (n=4) and proliferative (n=4) eutopic endometrium and endometriosis, and no differences could be demonstrated. In conclusion, inactivation of 17beta-estradiol is impaired in endometriotic tissues due to deficient expression of 17betaHSD-2, which is normally expressed in eutopic endometrium in response to progesterone. The lack of 17betaHSD-2 expression in endometriosis is not due to alterations in the levels of immunoreactive progesterone or estrogen receptors in this tissue and may be related to an inhibitory aberration in the signaling pathway that regulates 17betaHSD-2 expression.

17-Hydroxysteroid Dehydrogenases↗

PubMed2000

Localization in tissues and secretion of eotaxin by cells from normal endometrium and endometriosis.

Our laboratories have focused recently on the production and localization of eotaxin, a C-C-chemokine of 8.4 kDa, whose major biological activity is the chemoattraction of eosinophils. Given evidence of autoimmune activity in the endometriosis syndrome, we hypothesized that eosinophil chemoattractants might be expressed in endometriosis. In histological sections, we observed eotaxin protein localized mainly in epithelial cells, with only very faint immunostaining in the surrounding stromal cells. Prominent eotaxin accumulation was noted in the luminal epithelium of secretory endometrium. Eotaxin distribution in endometriosis was similar to that seen in eutopic endometrium but with higher levels of eotaxin staining in the glandular epithelium. Peritoneal fluid concentrations of eotaxin were significantly higher in women with moderate or severe endometriosis than in women with minimal or mild endometriosis or no disease. The treatment of isolated human endometriosis epithelial cells with estradiol, medroxyprogesterone acetate, tumor necrosis factor-alpha, and interferon-gamma stimulated measurable eotaxin secretion into the conditioned media. The results indicate that eotaxin is produced in epithelial cells of normal endometrium and endometriosis tissues, varies across the menstrual cycle, and is elevated in women with endometriosis. We postulate that eotaxin, interacting with other known cytokines and immune cells, contributes to an inflammatory reproductive tract environment, leading to endometrial or blastocyst dysfunction.

Adult↗

PubMed2002

Dioxins and endometriosis: a plausible hypothesis.

A potential connection exists between exposure to organochlorine chemicals and the increasing prevalence of endometriosis. Evidence shows that dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin) can increase the incidence and severity of the disease in monkeys and can promote the growth or survival of endometrial tissue implanted into rodents in a surgically induced model of endometriosis. The mechanism of the connection between organochlorine chemicals and endometriosis is not clear. Effects on growth factors, cytokines, and hormones (components of the immune and endocrine systems) are potential means of mediating the possible promotion of endometriosis by dioxins. Studies on epidemiology and on structure-activity relationships of organochlorine chemicals and endometriosis have been additional approaches to this problem. In this regard, toxic equivalence (TEQ) appears to be an important determinant of the effects of organochlorine chemicals on endometriosis. In this article, we review the literature related to endometriosis and dioxins and attempt to integrate the various sources of information that bolster the hypothesis connecting dioxins and endometriosis.

Animals↗

PubMed2002

Serum dioxin concentrations and endometriosis: a cohort study in Seveso, Italy.

Dioxin, a ubiquitous contaminant of industrial combustion processes including medical waste incineration, has been implicated in the etiology of endometriosis in animals. We sought to determine whether dioxin exposure is associated with endometriosis in humans. We conducted a population-based historical cohort study 20 years after the 1976 factory explosion in Seveso, Italy, which resulted in the highest known population exposure to 2,3,7,8-tetrachlorodibenzo-(italic)p(/italic)-dioxin (TCDD). Participants were 601 female residents of the Seveso area who were (3/4) 30 years old in 1976 and had adequate stored sera. Endometriosis disease status was defined by pelvic surgery, current transvaginal ultrasound, pelvic examination, and interview (for history of infertility and pelvic pain). "Cases" were women who had surgically confirmed disease or an ultrasound consistent with endometriosis. "Nondiseased" women had surgery with no evidence of endometriosis or no signs or symptoms. Other women had uncertain status. To assess TCDD exposure, individual levels of TCDD were measured in stored sera collected soon after the accident. We identified 19 women with endometriosis and 277 nondiseased women. The relative risk ratios (RRRs) for women with serum TCDD levels of 20.1-100 ppt and >100 ppt were 1.2 [90% confidence interval (CI) = 0.3-4.5] and 2.1 (90% CI = 0.5-8.0), respectively, relative to women with TCDD levels (3/4) 20 ppt. Tests for trend using the above exposure categories and continuous log TCDD were nonsignificant. In conclusion, we report a doubled, nonsignificant risk for endometriosis among women with serum TCDD levels of 100 ppt or higher, but no clear dose response. Unavoidable disease misclassification in a population-based study may have led to an underestimate of the true risk of endometriosis.

Adult↗