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PubMed2004

Familial risk among Japanese patients with endometriosis.

OBJECTIVES: This study was designed to examine the prevalence of endometriosis among female siblings of patients with endometriosis in Japan. METHODS: A total of 339 patients with endometriosis were questioned about endometriosis in their sisters. The control group consisted of 284 Japanese healthy fertile women with no history of endometriosis. Similarly, the controls were interviewed about their sisters. RESULTS: We detected sisters with endometriosis in 8.8% of cases and 1.5% of the control population. The relative risk of endometriosis in female siblings was 5.7. However, a significant difference was not seen in age at diagnosis and clinical stage between patients with or without a family history of endometriosis. CONCLUSIONS: These data demonstrate a familial tendency for endometriosis and suggest that endometriosis has a genetic factor in the pathogenesis.

Adolescent↗
PubMed1998

Reproducibility of the revised American Fertility Society classification of endometriosis using laparoscopy or laparotomy.

OBJECTIVE: To assess the discrepancy between laparoscopic and laparotomic scoring methods using the revised American Fertility Society (AFS) classification of endometriosis. METHOD: In this prospective study, 84 patients with endometriosis were scored twice (laparoscopically and laparotomically) by the same subspecialty-certified reproductive endocrinologist. The magnitude of inter-method variability was reported quantitatively by the S.D. of the differences in scores between the pairs. The differences in the mean endometriosis scores between the two methods were assessed by the paired Student's t-test. P < 0.05 was considered as statistically significant. Discrepancy between the two methods in the staging of endometriosis patients was presented by kappa measure of agreement. RESULT: There was considerable variability in the scores between the two scoring methods by the same observer. Among individual components of the scoring system, the greatest variability occurred in the ovarian endometriosis and cul-de-sac obliteration subscores, with the least variability observed for peritoneum endometriosis. The inter-method variation in score was sufficient to alter the endometriosis staging in 34.5% of patients, including a difference of two stages in 3.6% of patients. The kappa coefficient was 0.49, indicating fair-to-good agreement between the two scoring methods. CONCLUSION: Inter-method variability between laparoscopic and laparotomic scoring methods was high for ovarian endometriosis subscore using the revised AFS classification of endometriosis. Agreement in endometriosis staging between the two methods was fair to good.

Endometriosis↗
PubMed2002

Ovarian and extraovarian endometriosis-associated cancer.

OBJECTIVE: To determine clinical characteristics of women with endometriosis-associated intraperitoneal cancers, to assess differences based on the relationship of the cancer to the endometriosis, and to assess factors associated with survival. METHODS: A search of medical records at The University of Texas M. D. Anderson Cancer Center from 1970 to 1999 identified patients who had synchronous endometriosis and intraperitoneal cancer. Demographic and clinicopathologic characteristics were evaluated for differences based on the relationship of the cancer to the endometriosis and for correlation with survival. RESULTS: One hundred fifteen patients were identified: 25 patients with ovarian cancer arising in endometriosis, 21 with an extraovarian cancer arising in endometriosis, 33 patients with endometriosis and ovarian cancer in the same location but without a definite transition point, and 36 patients with ovarian cancer and incidental endometriosis. Women with extraovarian cancers arising in endometriosis were more likely to be postmenopausal (P <.001) and use hormone replacement (P <.001). The median age was 47 years, the most common histological tumor types were clear cell and endometrioid (23% each), and the most common stage was stage I (31%). The median survival was 35 months. Univariate survival analysis revealed that gravidity (P <.038), grade (P <.001), stage (P <.001), histology (P <.01), and type of chemotherapy (P <.011) correlated with survival. Multivariable analysis revealed that stage and gravidity independently predicted survival. CONCLUSION: Women with endometriosis-associated cancers are typically premenopausal, have a high incidence of endometrioid and clear cell histologies, and have early stage disease. Stage and gravidity independently predicted survival.

Adenocarcinoma, Clear Cell↗
PubMed1996

Growth-regulated alpha expression in the peritoneal environment with endometriosis.

OBJECTIVE: To investigate the presence and modulation of growth-regulated alpha, a member of the chemokine family with neutrophil chemotactic activity, in the peritoneal fluid of women with or without endometriosis. METHODS: Peritoneal fluid samples were obtained at laparoscopy from 63 women with endometriosis and 19 fertile women without endometriosis. Endometrial tissue was obtained from uteri after hysterectomy for reasons other than endometrial disease or from endometrial biopsies of reproductive-age women. Cellular RNA was extracted and northern blots were hybridized with an oligonucleotide probe complementary to a specific sequence of growth-regulated alpha messenger RNA. Growth-regulated alpha in peritoneal fluid and culture supernatant was quantified using enzyme-linked immunosorbent assay. Statistical analyses were performed using Kruskal-Wallis and Mann-Whitney tests. RESULTS: The median (range) concentration of growth-regulated alpha in peritoneal fluid samples from 19 normal fertile women was 27 pg/mL (0-108), from 24 women with moderate endometriosis 34 pg/mL (8-150), and from seven with severe endometriosis was 73 pg/mL (10-221) (P = .04, P = .01, respectively). In the moderate and severe endometriosis groups, the levels of growth-regulated alpha were significantly higher in the peritoneal fluid of women with untreated endometriosis (73 pg/mL [10-221]) than in women with medically treated endometriosis (25 pg/mL [8-47]). In mesothelial and endometrial stromal cells in culture, growth-regulated alpha messenger RNA and protein were detectable constitutively; however, both interleukin-1 alpha and tumor necrosis factor-alpha induced higher levels of growth-regulated alpha messenger RNA and protein in a dose- and time-dependent manner. CONCLUSIONS: Growth-regulated alpha levels are elevated in the peritoneal fluid of women with moderate and severe endometriosis. This chemotactic factor, which acts via the interleukin-8 receptor, may play a role in the pathogenesis of endometriosis.

Adult↗
PubMed2003

Future directions in endometriosis research.

Future research in endometriosis must focus on pathogenesis studies in the baboon model, the early interactions between endometrial and peritoneal cells in the pelvic cavity at the time of menstruation, and potential differences between eutopic endometrium and myometrium in women with and without endometriosis. More integration is needed between the areas of epidemiology and genetics. Pelvic inflammation in women with endometriosis could be the target for new diagnostic and therapeutic approaches. Important questions remain regarding the relationship between endometriosis and environmental factors. Systemic and extrapelvic manifestations of endometriosis must be analyzed carefully, and better tools are needed to measure quality of life in women with chronic pain caused by endometriosis. Most current evidence supports a causal relationship between endometriosis and subfertility, and the spontaneous progressive nature of endometriosis has been demonstrated in 30% to 60% of patients. Recurrence of endometriosis after classic medical and surgical therapy is a major and underestimated problem, especially in women with advanced disease. Integrated clinical and research teams are needed that combine expert medical, surgical, and holistic care with state-of-the-art research expertise in immunology, endocrinology, and genetics to discover new diagnostic methods and medical treatments for endometriosis.

Animals↗
PubMed2006

Expression of hepatocyte nuclear factor-1beta (HNF-1beta) in clear cell tumors and endometriosis of the ovary.

Clear cell tumors of the ovary are frequently associated with ovarian endometriosis. Clinicopathologically, it has been suggested that clear cell tumors develop from endometriosis, but there has been little molecular evidence supporting this speculation. Microarray analysis revealed recently that hepatocyte nuclear factor-1beta (HNF-1beta) was significantly upregulated in clear cell carcinoma of the ovary. In the present study, we examined 30 clear cell tumors (26 malignant, three borderline, and one benign) and 40 endometriotic cysts to clarify if differentiation into the clear cell lineage already begins in ovarian endometriosis. All of the 30 clear cell tumors, including borderline and benign ones, showed immunohistochemical expression of HNF-1beta in the nucleus, while other types of ovarian epithelial tumors (endometrioid, serous, mucinous, and Brenner tumors) rarely expressed it. Among 30 clear cell tumors, 17 (56%) cases were associated with endometriosis, and endometriotic epithelium was identified in 12 cases. In nine of the 12 cases, distinct nuclear immunostaining for HNF-1beta was detected in the endometriotic epithelium, as well as in the clear cell tumor. HNF-1beta expression was observed either in atypical endometriosis (four cases), or in endometriosis of a reactive nature (five cases). Furthermore, 16 of 40 (40%) endometriotic cysts without a neoplasm also expressed HNF-1beta, and the expression was almost exclusively observed in the epithelium showing inflammatory atypia. Our results indicate that HNF-1beta is an excellent molecular marker for ovarian clear cell tumors, including benign, borderline and malignant lesions. Early differentiation into the clear cell lineage takes place in ovarian endometriosis, not only in atypical endometriosis, but also in endometriosis with degenerative and regenerative changes, and this is probably responsible for the frequent occurrence of clear cell carcinoma in ovarian endometriosis.

Adenocarcinoma, Clear Cell↗
PubMed2001

Hyperprolactinemia and luteal insufficiency in infertile patients with mild and minimal endometriosis.

The objective of the present paper was to assess the presence of hormonal alterations in infertile women with stage I or II endometriosis (Group III, n = 20) compared to fertile women without endometriosis (Group I, n = 14) and to fertile women with endometriosis (Group II, n = 7). Serum levels of FSH, LH, estradiol, TSH, and PRL were measured between days 1 and 5 of the early follicular phase; in the luteal phase, three serum samples were collected for progesterone measurement, and endometrial biopsies were performed. Serum estradiol levels were lower (p = 0.035) in infertile patients with endometriosis than in fertile patients without endometriosis. Six infertile patients with endometriosis presented prolactin levels above 20 ng/ml. This was not observed in the other groups. Luteal insufficiency was more frequent in infertile patients with endometriosis (78.9%) than in fertile patients with (42.9%) or without endometriosis (0%). In a multiple logistic regression analysis, only the presence of endometriosis and infertility was significantly associated with luteal insufficiency. The serum levels of LH, FSH, and TSH were not significantly different among the groups. Luteal insufficiency and altered prolactin secretion were associated with endometriosis, and could be important mechanisms causing infertility in this group of patients.

Adult↗
PubMed2003

Endometriosis: interaction of immune and endocrine systems.

Endometriosis is a common gynecologic disorder characterized by the presence of endometrial tissue outside the uterine cavity. Although no single theory can explain all cases of endometriosis, the most commonly accepted theory is Sampson's theory of retrograde menstruation. Retrograde menstruation occurs in 76 to 90% of women. The much lower prevalence of endometriosis suggests that additional factors determine susceptibility to endometriosis. Endometriosis is associated with changes in both cell-mediated and humoral immunity. Impaired natural killer cell activity resulting in inadequate removal of refluxed menstrual debris may play a role in the development of endometriotic implants. Moreover, although the peritoneal fluid of women with endometriosis contains increased numbers of immune cells, these seem to facilitate rather than inhibit the development of endometriosis. Macrophages that would be expected to clear endometrial cells from the peritoneal cavity appear to enhance their proliferation by secreting growth factors and cytokines. Although it is unclear whether these immunologic alterations induce endometriosis or are a consequence of its presence, they appear to play an important role in allowing endometriosis implants to persist and progress and contribute to the development of associated infertility and pelvic pain. Danazol and gonadotropin-releasing hormone (GnRH) agonists are commonly used for the medical treatment of endometriosis. These medications seem to down-regulate cellular and humoral immune responses concomitant with their effect on endometriotic implants. Immunomodulatory effects of danazol and GnRH agonists are likely to contribute to the observed clinical improvement associated with their use.

Antibody Formation↗
PubMed2003

Endometriosis and subfertility: is the relationship resolved?

There are many arguments to support the hypothesis that there is a causal relationship between the presence of endometriosis and subfertility. These arguments are reviewed in this article and include: (1) an increased prevalence of endometriosis in subfertile women compared with women of proven fertility; (2) a reduced monthly fecundity rate (MFR) in baboons with mild to severe (spontaneous or induced) endometriosis compared with those with minimal endometriosis or a normal pelvis; (3) a trend toward a reduced MFR in infertile women with minimal to mild endometriosis compared with women with unexplained infertility; (4) a dose-effect relationship: a negative correlation between the r-AFS stage of endometriosis and the monthly fecundity rate and crude pregnancy rate; (5) a reduced monthly fecundity rate and cumulative pregnancy rate after donor sperm insemination in women with minimal-mild endometriosis compared with those with a normal pelvis; (6) a reduced MFR after husband sperm insemination in women with minimal to mild endometriosis compared with those with a normal pelvis; (7) a reduced implantation rate per embryo after IVF in women with moderate to severe endometriosis compared with women with a normal pelvis; and (8) an increased monthly fecundity rate and cumulative pregnancy rate after surgical removal of minimal to mild endometriosis.

Animals↗
PubMed2004

Interferon-gamma gene dinucleotide (CA) repeat and interleukin-4 promoter region (-590C/T) polymorphisms in Japanese patients with endometriosis.

BACKGROUND: Endometriosis is a multifactorial disease with possible genetic predisposition and involvement of environmental factors in its pathogenesis. Cytokines may play important roles in the pathogenesis of endometriosis. The aim of this study was to investigate whether the interferon-gamma gene (IFNG) CA-repeat and interleukin-4 (IL-4) promoter region (-590C/T) polymorphisms may be responsible in part for genetic susceptibility to endometriosis. METHODS: IFNG CA-repeat and IL-4 -590C/T polymorphisms were determined for 185 patients with endometriosis and 176 healthy fertile women by quantitative genescan technology and PCR-restriction fragment length polymorphism analysis, respectively. Patients with endometriosis were analysed further according to their stage of disease, the presence or absence of chocolate cysts and whether or not their disease was associated with adenomyosis and/or lyomyomata. RESULTS: The global IFNG allele frequencies in the patients with endometriosis were significantly different from those in the control women (chi2 = 12.964, 6 df, P = 0.0436). The difference was due to an increase of the a13 (114 bp) allele in patients with endometriosis (chi2 = 10.222, P = 0.0088, corrected P = 0.0352, odds ratio = 1.48, 95% confidence interval = 1.10-1.98). There were no differences in IL-4 -590C/T genotypes and allele frequencies between control women and all patients with endometriosis or between control women and each subgroup of patients with endometriosis. CONCLUSION: The results suggest that the IFNG CA-repeat polymorphism is associated with susceptibility to endometriosis in a Japanese population.

Adult↗
PubMed2005

Regulation of hepatocyte growth factor by basal and stimulated macrophages in women with endometriosis.

BACKGROUND: The different macromolecules as secreted by macrophages in the pelvic environment are believed to enhance the growth of endometriosis. However, the possible mediator that stimulates macrophages for the production of different growth factors is not well described. Therefore, we investigated the possible production of hepatocyte growth factor (HGF) by the basal and lipopolysaccharide (LPS)-stimulated macrophages derived from women with or without endometriosis. METHODS: Using primary culture and 4-well chamber slides, adherent macrophages immunoreactive to CD68 were isolated from the peritoneal fluid (PF) of 20 infertile women with endometriosis and 12 women without endometriosis. The proliferation of basal and LPS-treated macrophages was investigated by the dimethylthiazole tetrazolioum bromide (MTT) assay. The production of HGF in the culture media of basal and LPS-stimulated macrophages was examined by enzyme-linked immunosorbent assay. The expression of mRNA for HGF and its receptor, c-Met, in the macrophages was investigated by RT-PCR. The effect of HGF on the growth of endometrial cells and macrophages was analysed by bromodeoxyuridine (BrdU) incorporation. RESULTS: A >100% increase in the proliferation of peritoneal macrophages derived from women with endometriosis, and particularly of those harbouring dominant red lesions, was observed after treatment with LPS (P<0.05). A 4- and 3-fold increase in the production of HGF was observed by the LPS-treated macrophages derived from women with stage I-II endometriosis and stage III-IV endometriosis, respectively, when compared with non-LPS-treated macrophages (P<0.001). At the transcriptional level, we found a 5-fold increase in HGF mRNA expression in LPS-treated macrophages versus basal macrophages in women with endometriosis (P<0.001). The BrdU incorporation study indicates that 10-100 ng/ml of HGF enhanced the growth of endometrial epithelial cells, stroma and macrophages (approximately 50% increase) derived from women with endometriosis (all P<0.05). CONCLUSION: LPS could be an inflammatory mediator of macrophage stimulation in the pelvic microenvironment. Besides mesenchymal cells, HGF is also produced by peritoneal macrophages and is possibly involved in the growth of endometriosis.

Adult↗
PubMed2005

Estrogen and progesterone receptor expression in macrophages and regulation of hepatocyte growth factor by ovarian steroids in women with endometriosis.

BACKGROUND: Information regarding macrophage-mediated regulation of hepatocyte growth factor (HGF) by ovarian steroid hormones in women with endometriosis is limited. Therefore, we investigated the regulation of HGF by steroid hormones in isolated macrophages and stromal cells derived from women with or without endometriosis. METHODS: We isolated CD68 immunoreactive adherent macrophages in vitro from 46 women with endometriosis and 30 women without endometriosis. Estrogen receptor (ER) and progesterone receptor (PR) expression in macrophages was demonstrated by immunohistochemistry and RT-PCR. Production of HGF in the culture media of basal and ovarian steroid-stimulated macrophages was examined by enzyme-linked immunosorbent assay. Expression of mRNA for HGF and its receptor, c-Met in macrophages and stromal cells in response to ovarian steroid was investigated by RT-PCR. The single and combined effect of HGF and estrogen on the growth of macrophages and stromal cells was analysed by bromodeoxyuridine (BrdU) incorporation. RESULTS: ER and PR were expressed in isolated macrophages and intact tissue at the protein and mRNA levels. Macrophages derived from women with endometriosis produced significantly higher concentration of HGF (352.2 +/- 4.9 pg/ml) in conditioned media after treatment with estradiol (10(-8) mol/l) than that of basal macrophages (221.5 +/- 32.8 pg/ml, P<0.05) or women without endometriosis (170.6 +/- 2.6 pg/ml, P<0.05). These effects were less evident after treatment with progesterone. Treatment with tamoxifen (10(-6) mol/l) reversed the production of HGF and other macromolecules. Secretion of HGF in response to ovarian steroids was further enhanced after activation with lipopolysaccharide. The mRNA expressions of HGF and its receptor, c-Met, were also detected in macrophages and stroma in response to estrogen, suggesting an autocrine regulation. HGF mRNA expression was higher in cells of women with endometriosis than non-endometriosis women. Bromodeoxyuridine incorporation indicated that exogenous stimulation with HGF and estrogen, either alone or in combination, significantly increased the cell proliferation of both endometrial stroma and macrophages compared to that of non-endometriosis or non-treated cells. CONCLUSION: These results suggest that besides other inflammatory mediators, ovarian steroids also participate in the production of HGF by peritoneal macrophages which may be involved in the growth of endometriosis either alone or in combination with estrogen.

Adult↗
PubMed2004

Analysis of the codon 72 polymorphism of the TP53 gene in patients with endometriosis.

Endometriosis is a benign gynaecologic disease that is associated with a certain risk for malignant degeneration. The disease has a genetic background, but the locations of possible genomic aberrations are still poorly clarified. In this context, the proline form of TP53 codon 72 polymorphism has been recently associated with the risk of developing endometriosis. In this case-control study, we aimed to investigate further the potential association between endometriosis and this polymorphism in order to evaluate whether this genetic variant may influence the susceptibility to the disease. Genomic DNA was obtained from a consecutive series of 303 Italian Caucasian women of reproductive age who underwent laparoscopy for benign gynaecological pathologies. Endometriosis was defined according to the criteria of Holt and Weiss [Holt V and Weiss NS (2000) Recommendations for the design of epidemiologic studies of endometriosis. Epidemiol 11,654-659] for the definite disease. Subjects of similar age without laparoscopic evidence of the disease served as control group. Molecular analysis of TP53 codon 72 polymorphism was performed by PCR amplification. Endometriosis was documented in 151 women. We found no statistically significant difference in the distribution of TP53 codon 72 polymorphism genotypes between patients with and without endometriosis. The respective proportions of arginine homozygotes, heterozygotes and proline homozygotes were 55.6, 39.7 and 4.6% in the group with endometriosis and 59.9, 30.9 and 9.2% in the control group. Moreover, no statistically significant association was demonstrated between TP53 codon 72 polymorphism and the various clinical manifestations of the disease, although a non-significant tendency towards an increased frequency of the proline allele was observed in association with specific manifestations of the disease reflecting a more severe form. Our results suggest that the TP53 codon 72 polymorphism does not confer genetic susceptibility to endometriosis in the Italian population. However, a possible susceptibility role of this polymorphism in endometriosis development towards very severe forms cannot be ruled out.

Adult↗
PubMed2006

Angiopoietin-1, angiopoietin-2 and Tie-2 expression in eutopic endometrium in advanced endometriosis.

Endometriosis is one of the most common gynaecological disorders, but its aetiology and pathogenesis remain obscure. The refluxed menstrual debris in women with endometriosis may be more prone to implantation, invasion and growth in the peritoneum or ovary through the actions of extracellular proteolysis and angiogenesis. It has been hypothesized that the endometrium from women with endometriosis has higher angiogenic activity and expresses more angiogenic factors. Using quantitative competitive PCR (QC-PCR) combined with the reverse transcription of total RNA into cDNA, we investigated the expression of angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2) and Tie-2 in the eutopic endometrium from 56 women with severe endometriosis and that from 64 women without endometriosis during the follicular and luteal cycles. The protein expression from the eutopic endometrium was analysed by western blotting. Results were analysed statistically by Kruskal-Wallis and Mann-Whitney U tests. The eutopic endometrium from women with endometriosis expressed higher levels of mRNA and protein of Ang-1 (P < 0.05) and higher levels of mRNA of Ang-2 than the endometrium from normal women (P < 0.05). Tie-2 mRNA and protein expression from the eutopic endometrium did not differ significantly between endometriosis patients and normal controls. These results suggest that the eutopic endometrium from endometriosis patients is more angiogenic and prone to growth because of greater Ang-1 mRNA and protein expression and higher Ang-2 mRNA expression than the endometrium from women without endometriosis. Thus, increased angiogenic activity may be responsible for the pathogenesis of endometriosis.

Adult↗
PubMed2001

Malignancy in endometriosis: frequency and comparison of ovarian and extraovarian types.

One thousand consecutive cases of surgically proven endometriosis were reviewed to evaluate the frequency and types of pelvic cancers that were associated with ovarian and extraovarian endometriosis. The frequency and types of histologic abnormalities present in the eutopic endometrium when cancers were noted in endometriosis were also evaluated. In the large subset of cases for which the authors were the primary pathologists and all foci of endometriosis were recorded, the frequency of malignancy was 10.8%. In contrast, the frequency was only 3.2% in cases diagnosed by others previously in our institution. Cancers were more commonly found in ovaries when endometriosis was present in that ovary (5%) compared to when endometriosis was present at other sites (1%). Clear cell and endometrioid carcinomas were the malignancies most commonly seen in ovaries containing endometriosis, while clear cell adenocarcinoma and adenosarcoma were most commonly seen in conjunction with extraovarian endometriosis. The association of endometriosis with endometrioid and clear cell carcinoma was much stronger than that of serous and mucinous tumors (p < .01). Concurrent endometrial pathology was commonly seen in cases of malignant transformation of endometriosis (32% of cases).

Adenocarcinoma, Clear Cell↗
PubMed2025

Identification and Validation of Novel Combinatorial Genetic Risk Factors for Endometriosis across Multiple UK and US Patient Cohorts.

BACKGROUND: Endometriosis affects about 10% of women usually of reproductive age. It often has severe negative impacts on patients' quality of life, but the average time to a definitive diagnosis remains 7-9 years, and there are few effective therapeutic options. Relatively little is known about the genetic drivers of the disease even though its heritability is fairly high. A recent large genome wide association study (GWAS) meta-analysis identified 42 genomic loci associated with risk of endometriosis, but together these explain only 5% of disease variance. METHODS: We used the PrecisionLife&#xae; combinatorial analytics platform to identify multi-SNP disease signatures significantly associated with endometriosis in a white European UK Biobank (UKB) cohort. We assessed the reproducibility of these multi-SNP disease signatures as well as 35 of the 42 meta-GWAS SNPs in a multi-ancestry American endometriosis cohort from All of Us (AoU) after controlling for population structure. RESULTS: We identified 1,709 disease signatures, comprising 2,957 unique SNPs in combinations of 2-5 SNPs, that were associated with increased prevalence of endometriosis in UKB. Pathways enriched in the disease signatures included cell adhesion, proliferation and migration, cytoskeleton remodeling, angiogenesis as well as biological processes involved in fibrosis and neuropathic pain.We observed a significant enrichment of these signatures (58-88%, p<0.04) that are also positively associated with endometriosis in the AoU cohort, including one 2-SNP signature that is individually significant. Reproducibility rates were greatest for higher frequency signatures, ranging from 80-88% for signatures with greater than 9% frequency (p<0.01) in AoU. Encouragingly, the disease signatures also show high reproducibility rates in non-white European AoU sub-cohorts (66-76%, p<0.04 for signatures with greater than 4% frequency).A total of 195 unique SNPs mapping to 98 genes were identified in the high frequency reproducing signatures (>9%). Of these, 7 genes were previously identified in the endometriosis meta-GWAS study and 16 genes have a previous association with endometriosis. 75 novel genes were identified in this study.We characterized 9 novel genes that occur at the highest frequency in reproducing signatures and that do not contain any SNPs linked to known GWAS genes, providing new evidence for links between endometriosis and autophagy and macrophage biology. Reproducibility rates, ranging between 73% to 85%. are especially strong for the signatures that contain these 9 genes independently of any SNPs mapping to the meta-GWAS genes. CONCLUSION: Although using much smaller, less well-characterized datasets than the previous whole genome meta-GWAS study, combinatorial analysis has provided important new insights into the genetics and biology of endometriosis including reproducible biologically relevant genes that are overlooked by GWAS approaches.The 75 novel gene associations provide new insights and routes for study of the disease and potential new therapies. Several of the novel genes identified are credible targets for drug discovery, repurposing and/or repositioning. Using the disease signatures identified as genetic biomarkers in trials of candidates drugs targeting specific mechanisms will enable precision medicine-based approaches. We hope this will encourage new targeted therapy discovery efforts.

Endometriosis↗
PubMed1994

Macrophage activation factors and cytokines in peritoneal fluid from patients with endometriosis.

Endometriosis is often associated with infertility, which might be a consequence of intraperitoneal macrophage activation and various immunological events related to it. To determine what triggers macrophage activation and what immunologic conditions occur in the peritoneal cavity of a patient with endometriosis, we measured the amounts of phospholipase A2, cholesterol fractions (HDL, LDL, and VLDL), interleukins (IL)-1 and 6, granulocyte-macrophage-colony stimulating factor (GM-CSF), and phosphatidylserine in peritoneal fluid. Peritoneal-fluid samples were collected during laparoscopy or laparotomy from 14 patients with endometriosis and from 11 patients with other diseases (5 with myoma uteri, 5 with benign ovarian cysts and 1 with a double uterus) as controls. With regard to phospholipase A2, there were no significant differences between the endometriosis group and the control group. LDL was significantly lower in the endometriosis group than in the control (p < 0.05). The levels of IL-1 and GM-CSF were similar in both groups; IL-6, however, was higher in 7 endometriosis patients with associated infertility than in the 9 non-endometriosis fertile patients. These findings suggest that inflammatory tissues are not related to the activation of intraperitoneal macrophages in endometriosis patients. Cholesterol fractions (HDL or LDL) might participate in macrophage activation in these patients, but this remains to be clarified. The high IL-6 levels observed in infertile endometriosis suggest that some immunological events that prevent patients from becoming pregnant take place in women with endometriosis-associated infertility.

Adult↗
PubMed2002

Endometriosis and infertility: a cause-effect relationship?

Two major methodological problems that impact clinical research in endometriosis are the absence of a low-cost, highly reliable method for diagnosing endometriosis and the possibility that endometriosis is actually multiple different diseases that we have not yet been able to differentiate. Animal models of endometriosis clearly demonstrate that advanced endometriosis causes reduced fertility. In humans, endometriosis and infertility are commonly associated. However, few data from high-quality clinical trials demonstrate that endometriosis causes infertility in humans. Future research should focus on the implications of the observation that, in ovarian endometriosis cysts, the epithelium is monoclonal. This observation suggests that nonrandom somatic mutations cause ovarian endometriosis cysts. If somatic mutations cause ovarian endometriosis cysts, it is likely that a small number of genes can be identified that play a central role in pathogenesis of this disease.

Animals↗