Disturbed estrogen and progesterone action in ovarian endometriosis.

Endometriosis is a very common disease in pre-menopausal women, where defective metabolism of steroid hormones plays an important role in its development and promotion. In the present study, we have examined the expression of 11 estrogen and progesterone metabolizing enzymes and their corresponding receptors in samples of ovarian endometriomas and control endometrium. Expression analysis revealed significant up-regulation of enzymes involved in estradiol formation (aromatase, sulfatase and all reductive 17beta-hydroxysteroid dehydrogenases) and in progesterone inactivation (AKR1C1 and AKR1C3). Among the estrogen and progesterone receptors, ERalpha was down-regulated, ERbeta was up-regulated, and there was no significant difference in expression of progesterone receptors A and B (PRAB). Our data indicate that several enzymes of estrogen and progesterone metabolism are aberrantly expressed in endometriosis, which can lead to increased local levels of mitogenic estradiol and decreased levels of protective progesterone. Changes in estrogen receptor expression suggest that estradiol may also act via non-estrogen receptor-mediated pathways, while expression of progesterone receptors still needs further investigation.

Surgical treatment of adnexal masses in pregnancy: indications, surgical approach and pregnancy outcome.

OBJECTIVE: To analyze the indications, surgical approach and pregnancy outcome in women undergoing surgical treatment of adnexal masses in pregnancy. STUDY DESIGN: In this retrospective study, 51 women were enrolled. Preoperative sonographic appearance, the size of the tumor, patient's age, gestational age at the time of surgery and pregnancy outcome following a laparoscopic and/or laparotomy approach were evaluated. The data were obtained from the National Perinatal Informational System, National Cancer Registry, inpatient records, operative reports and pathology records, and responses to a questionnaire on pregnancy outcome mailed to all the patients. RESULTS: Of the 51 pregnant women with adnexal masses, 27 were treated laparoscopically and 24 through laparotomy. Acute symptoms were the indication in 14 (27.4%) and tumor > 5 cm or sonographic appearance in 37 (72.6%). There were 44 (86.4%) benign and 7 (13.6%) malignant masses (4 borderline and 3 cancers). There were no differences in pregnancy outcome between emergency and planned surgery or between laparoscopy and laparotomy. CONCLUSION: Surgical treatment of persistent adnexal masses in pregnancy, particularly those with a sonographic appearance of a complex tumor, is justified because of the high risk of torsion, rupture and malignancy. Immediate treatment of symptomatic masses permits conservative, fertility-preserving surgery and has no adverse effect on pregnancy outcome. Laparoscopic surgery and surgery in the first trimester do not impair pregnancy outcome.

Altered levels of acylcarnitines, phosphatidylcholines, and sphingomyelins in peritoneal fluid from ovarian endometriosis patients.

Endometriosis is a complex, polygenic, and estrogen-dependent disease that affects 6% to 10% of women of reproductive age, and 30% to 50% of women with infertility and/or pelvic pain. Surgical diagnosis of endometriosis is still the gold standard, as there are currently no diagnostic biomarkers available. Due to the invasive diagnostics, it can take up to 11 years before affected women are diagnosed and receive the appropriate treatment. We performed a targeted metabolomics study to search for potential semi-invasive biomarkers in peritoneal fluid from endometriosis patients. Our case-control study comprised 29 ovarian endometriosis patients and 36 healthy control women. The 148 metabolites included acylcarnitines, glycerophospholipids, and sphingolipids, which were quantified by electrospray ionization tandem mass spectrometry. The strength of association between the metabolites and the metabolite ratios and disease was assessed using crude and adjusted odds ratios. The best combination of biomarkers was then selected by performing step-wise logistic regression. Our analysis reveals significantly decreased concentrations of 10 metabolites, of carnitine and acylcarnitines (C0, C8:1, C6C4:1 DC, C10:1), phosphatidylcholines (PC aa C38:3, PC aa C38:4, PC aa C40:4, PC aa C40:5), and sphingomyelins (SM C16:1, SM C18:1), and 125 significantly altered metabolite ratios in patients versus control women. The best model includes two ratios: a carnitine to a phosphatidylcholine (C0/PC ae C36:0); and between two phosphatidylcholines (PC aa C30:0/PC ae C32:2). When adjusted for age, this provides sensitivity of 82.8% and specificity of 94.4%, with AUC of 0.944. Our study supports the importance of carnitine, phosphatidylcholine, and sphingomyelin metabolites in the pathophysiology of endometriosis, and confirms the potential for the combination of individual metabolite ratios to provide biomarkers for semi-invasive diagnostics.

Disturbed balance between phase I and II metabolizing enzymes in ovarian endometriosis: a source of excessive hydroxy-estrogens and ROS?

Oxidative metabolism of estrogens was studied in 31 ovarian endometriosis and 29 normal endometrium samples, by qPCR. Expression was monitored for genes encoding five estrogen hydroxylating, five hydroxy (OH)-estrogen conjugating, and three estrogen quinone detoxifying enzymes. CYP1B1, COMT, NQO1, and GSTP1 protein levels were determined using Western blotting and immunohistochemistry staining. Increased expression of CYP1A1, CYP3A7 and COMT, and higher levels of MB-COMT were seen in endometriosis, as compared to normal endometrium. Expression of CYP1B1, CYP3A5, SULT1A1 and NQO2 was unchanged, with comparable CYP1B1 protein levels. Expression of SULT1E1, SULT2B1, UGT2B7, NQO1, and GSTP1 was decreased. Three NQO1 isoforms were detected; NQO1c appears to be endometriosis-specific. Our data indicate a disturbed balance between phase I and II metabolizing enzymes in endometriosis, potentially leading to excessive OH-estrogen and altered ROS formation, and stimulation of proliferation of ectopic endometrium. This is the first report on disturbed expression of estrogen oxidative metabolism genes in ovarian endometriosis.

Laparoscopic rectal resection of deep infiltrating endometriosis.

PURPOSE: Deep infiltrating endometriosis with colorectal involvement is a complex disorder, often requiring segmental bowel resection. Complete removal of all visible lesions is considered the adequate treatment of infiltrating endometriosis in order to reduce recurrence. In this article, we describe our experience with laparoscopic management of deep infiltrating endometriosis with involvement of the rectum. METHODS: A retrospective analysis of data from patients with deep infiltrating endometriosis with rectal involvement who underwent a laparoscopic surgery in the years 2002-2009 at the Department of Obstetrics and Gynecology at our institution was done. RESULTS: Between 2002 and 2009, a laparoscopic partial rectal resection was performed in 52 patients, and laparoscopic disk resection was performed in 4 cases with deep infiltrating endometriosis. The mean age of patients was 34.4 years (range, 22-62 years). Preoperative symptoms included dysmenorrhea, dyspareunia, chronic pelvic pain, and infertility. The laparoscopic procedure was converted to formal laparotomy in 3 patients (5.4%). The mean duration of surgery was 145 minutes. Postoperative complications included 3 cases of anastomotic leakage with rectovaginal fistula in two cases and intraabdominal bleeding in 1 case. The mean hospital stay was 7 days. Postoperatively, nine patients had a normal delivery, two of them after in vitro fertilization treatment. CONCLUSION: Laparoscopic rectal resection for deep infiltrating endometriosis is a relatively safe procedure, when performed by a surgeon and a gynecologist with sufficient experience in laparoscopic colorectal surgery.

Novel estrogen-related genes and potential biomarkers of ovarian endometriosis identified by differential expression analysis.

In the search for novel biomarkers of endometriosis, we selected 152 genes from the GeneLogic database based on results of genome-wide expression analysis of ovarian endometriosis, plus 20 genes related to estrogen metabolism and action. We then performed low-density array analysis of these 172 genes on 11 ovarian endometriosis samples and 9 control endometrium samples. Principal component analysis of the gene expression levels showed clear separation between the endometriosis and control groups. We identified 78 genes as differentially expressed. Based on Ingenuity pathway analysis, these differentially expressed genes were arranged into groups according to biological function. These analyses revealed that 32 differentially expressed genes are estrogen related, 23 of which have not been reported previously in connection with endometriosis. Functional annotation showed that 25 and 22 genes are associated with the biological terms "secreted" and "extracellular region", respectively. Differential expression of 4 out of 5 genes related to estrogen metabolism and action (ESR1, ESR2, PGR and BGN) was also confirmed by immunohistochemistry. Our study thus reveals differential expression of several genes that have not previously been associated with endometriosis and that encode potential novel biomarkers and drug targets.