Surgical Treatment of Patients with Endometriosis in the Certified Endometriosis Centers of the DACH Region - A Subanalysis of the Quality Assurance Study QS ENDO pilot.

Introduction After puberty, at least 10% of all women and girls suffer from endometriosis. Surgery is useful for both the diagnosis and therapy. To date, quality indicators for the surgical treatment of endometriosis are lacking. QS ENDO aims to record the quality of care provided in the DACH region and to introduce quality indicators for the diagnosis and treatment of endometriosis. In the first phase of the study, QS ENDO real, the reality of care was recorded using a questionnaire. The second phase, QS ENDO pilot, investigated the treatment of patients who underwent surgery in certified endometriosis centers in a defined time-period. Material and Methods The surgical data of 10 patients from each of the 44 endometriosis centers in the DACH region was recorded using an online tool. Collected data included the approach used, the endometriosis phenotype, a description of the surgical site, resection status, histological confirmation, the use of a classification, and any complications. All operations were carried out in October 2016 as the defined time-period. The surgical approaches used were compared with the recommendations in the current guidelines. Results The data of 435 patients with a median age of 34 years were evaluated. 315 (72.4%) were nulliparous. 120 patients had given birth to at least one child and 42.5% (51) of them had delivered their child by caesarean section. About 50% of all patients also had deep infiltrating endometriosis in addition to ovarian endometriosis, and the median NAS score was 7.5. With regards to the surgical treatment, endometriomas were completely resected in 81% (94) of patients. 87.3% of patients underwent resection of peritoneal endometriosis. Forty-one patients had a hysterectomy, with a total hysterectomy carried out in 26 (63.4%) and a supracervical hysterectomy in 15 (36.6%) patients. Of the 59 patients with bowel endometriosis, half had segmental resection and half had shaving of the anterior rectal wall. Complications requiring revision occurred in 0.9% of cases. Conclusion The surgical procedures carried out in the certified endometriosis centers of the DACH region are largely in line with the recommendations for appropriate surgical approaches in the current standard guidelines.

Multicenter evaluation of blood-based biomarkers for the detection of endometriosis and adenomyosis: A prospective non-interventional study.

OBJECTIVE: To evaluate blood-based biomarkers to detect endometriosis and/or adenomyosis across nine European centers (June 2014-April 2018). METHODS: This prospective, non-interventional study assessed the diagnostic accuracy of 54 blood-based biomarker immunoassays in samples from 919 women (aged 18-45 years) with suspicion of endometriosis and/or adenomyosis versus symptomatic controls. Endometriosis was stratified by revised American Society for Reproductive Medicine stage. Symptomatic controls were "pathologic symptomatic controls" or "pathology-free symptomatic controls". The main outcome measure was receiver operating characteristic-area under the curve (ROC-AUC) and Wilcoxon P values corrected for multiple testing (q values). RESULTS: CA-125 performed best in "all endometriosis cases" versus "all symptomatic controls" (AUC 0.645, 95% confidence interval [CI] 0.600-0.690, q < 0.001) and increased (P < 0.001) with disease stage. In "all endometriosis cases" versus "pathology-free symptomatic controls", S100-A12 performed best (AUC 0.692, 95% CI 0.614-0.769, q = 0.001) followed by CA-125 (AUC 0.649, 95% CI 0.569-0.729, q = 0.021). In "adenomyosis only cases" versus "symptomatic controls" or "pathology-free symptomatic controls", respectively, the top-performing biomarkers were sFRP-4 (AUC 0.615, 95% CI 0.551-0.678, q = 0.045) and S100-A12 (AUC 0.701, 95% CI 0.611-0.792, q = 0.004). CONCLUSION: This study concluded that no biomarkers tested could diagnose or rule out endometriosis/adenomyosis with high certainty.

QS ENDO Pilot - A Study by the Stiftung Endometrioseforschung (SEF) on the Quality of Care Provided to Patients with Endometriosis in Certified Endometriosis Centers in the DACH Region.

Introduction Endometriosis significantly reduces patients' quality of life and is additionally a burden on healthcare and social security systems. There are currently no quality indicators for the treatment of endometriosis. The care of patients with endometriosis must be considered inadequate. QS ENDO aims to record the quality of care available in the DACH region and to introduce quality indicators for the diagnosis and treatment of endometriosis as part of providing quality assurance in endometriosis care. The first phase, QS ENDO Real, recorded the reality of current care using a questionnaire. The second phase, QS ENDO Pilot, investigated the treatment of 435 patients who underwent surgical treatment within a defined one month period in certified endometriosis centers. Material and Methods An online tool was used to gather information about 9 points which covered both prior patient history and the process of clinical diagnosis. Surgery reports were reviewed to obtain information about the surgical approach, the investigated sites, findings of any histological examinations, the use of classification systems, and information about resection status. Results 85.3% of patients were asked all 4 questions about their prior medical history. All 5 diagnostic steps were carried out in 34.5% of patients. The 3 areas needed to describe potential sites of disease were recorded in 67.1% of patients. Samples for histological examination were taken in 84.1% of patients. The endometriosis stage was classified in 94.7% of surgeries. A combination of the rASRM and the ENZIAN classifications, which is needed for complex cases, was used in 46.1% of patients. Complete resection was achieved in 81.6% of surgical procedures. Conclusion For the first time, the quality of care in certified endometriosis centers has been recorded using QS ENDO Pilot. Despite the high certification standards, a substantial number of required indicators were omitted.

Effects of Vitamin D Supplementation on Surrogate Markers of Fertility in PCOS Women: A Randomized Controlled Trial.

Vitamin D (VD) might play an important role in polycystic ovary syndrome (PCOS) and female fertility. However, evidence from randomized controlled trials (RCT) is sparse. We examined VD effects on anti-Müllerian hormone (AMH) and other endocrine markers in PCOS and non-PCOS women. This is a post hoc analysis of a single-center, double-blind RCT conducted between December 2011 and October 2017 at the endocrine outpatient clinic at the Medical University of Graz, Austria. We included 180 PCOS women and 150 non-PCOS women with serum 25-hydroxyvitamin D (25(OH)D) concentrations <75 nmol/L in the trial. We randomized subjects to receive 20,000 IU of VD3/week (119 PCOS, 99 non-PCOS women) or placebo (61 PCOS, 51 non-PCOS women) for 24 weeks. Outcome measures were AMH, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, dehydroepiandrosterone sulfate, and androstenedione. In PCOS women, we observed a significant treatment effect on FSH (mean treatment effect 0.94, 95% confidence interval [CI] 0.087 to 1.799, p = 0.031) and LH/FSH ratio (mean treatment effect -0.335, 95% CI -0.621 to 0.050, p = 0.022), whereas no significant effect was observed in non-PCOS women. In PCOS women, VD treatment for 24 weeks had a significant effect on FSH and LH/FSH ratio but no effect on AMH levels.

Effects of vitamin D supplementation on androgens in men with low testosterone levels: a randomized controlled trial.

PURPOSE: It has been hypothesized that vitamin D is associated with androgen levels in men. We, therefore, aimed to evaluate whether vitamin D supplementation increases serum total testosterone (TT) levels in men with low TT levels at baseline. METHODS: The Graz Vitamin D&TT-RCT is a single-center, double-blind, randomized placebo-controlled trial conducted between March 2013 and November 2017 at the endocrine outpatient clinic at the Medical University of Graz, Austria. One-hundred healthy men with serum TT levels < 10.4 nmol/l and 25-hydroxyvitamin D [25(OH)D] levels < 75 nmol/l participated in the trial. Subjects were randomized to receive 20,000 IU of vitamin D3/week (n = 50) or placebo (n = 50) for 12 weeks. Primary outcome was TT measured using mass spectrometry. Secondary outcomes were free testosterone, free androgen index, sex hormone-binding globulin, estradiol, follicle-stimulating hormone, luteinizing hormone, metabolic characteristics, and body composition. RESULTS: Ninety-four men [mean age and 25(OH)D: 47 (± 12) years and 56.3 (± 18.3) nmol/l, respectively] completed the study. We found no significant treatment effect on serum TT or on the remaining secondary outcome variables. CONCLUSION: Vitamin D treatment had no effect on serum TT levels in middle-aged healthy men with low TT levels.

Effects of vitamin D supplementation on metabolic and endocrine parameters in PCOS: a randomized-controlled trial.

PURPOSE: Vitamin D status may be associated with insulin resistance and other key features of polycystic ovary syndrome (PCOS), but data from preliminary randomized controlled trials (RCTs) are conflicting. Therefore, we aimed to investigate the effects of vitamin D supplementation on plasma glucose area under the curve (AUCgluc, primary outcome measure) and on other metabolic and endocrine parameters (secondary outcome measures). METHODS: This study was a single-center, double-blind, randomized placebo-controlled trial conducted between December 2011 and July 2017 at the Medical University of Graz, Austria. One-hundred and eighty women with PCOS and 25-hydroxyvitamin D [25(OH)D] concentrations < 75 nmol/L were randomized in a 2:1 ratio to either receive 20,000 IU of cholecalciferol weekly or placebo over 24 weeks. Primary outcome was the between-group difference in AUCgluc at study end while adjusting for baseline values. RESULTS: In total, 123 participants completed the study [age 25.9 ± 4.7 years; BMI 27.5 ± 7.3 kg/m2; baseline 25(OH)D 48.8 ± 16.9 nmol/L, baseline fasting glucose 84 ± 8 mg/dL]. Vitamin D supplementation lead to a significant increase in 25(OH)D [mean treatment effect 33.4 nmol/L; 95% confidence interval (CI) 24.5 to 42.2; p < 0.001] but had no significant effect on AUCgluc (mean treatment effect - 9.19; 95% CI - 21.40 to 3.02; p = 0.139). Regarding secondary outcome measures, we observed a significant decrease in plasma glucose at 60 min during oral glucose tolerance test (mean treatment effect - 10.2 mg/dL; 95% CI - 20.2 to - 0.3; p = 0.045). CONCLUSIONS: Vitamin D supplementation had no significant effect on metabolic and endocrine parameters in PCOS with the exception of a reduced plasma glucose during OGTT.

Altered expression of progesterone receptor isoforms A and B in human eutopic endometrium in endometriosis patients.

Recent data implicate an altered expression of progesterone receptor isoform A (PR-A) and B (PR-B) in the endometrium of endometriosis patients. This prospective exploratory study aimed to precisely determine the PR-A and PR-B expression using immunohistochemical techniques in eutopic endometrium of women with endometriosis compared with disease-free women throughout the menstrual cycle. All symptomatic patients underwent laparoscopy for the diagnosis of endometriosis and histological confirmation of the disease (EO) whereas controls were proven disease-free (CO). In CO samples (n=10) an increased expression of PR-A and PR-B during the proliferative to early secretory phase and a decreased expression of both receptor isoforms during the mid to late secretory phase was ascertained in accordance with previous studies. In patients with endometriosis (n=16) no cycle dependent pattern of PR-A and PR-B expression was identified in contrast to patients without endometriosis. Moreover, in EO samples a huge variety of inter- and intra-individual differences in PR-A and PR-B expression were detected. These data provide further evidence that dysregulation of the PR-A and PR-B expression might contribute to the pathophysiology of endometriosis.

When sex is not on fire: a prospective multicentre study evaluating the short-term effects of radical resection of endometriosis on quality of sex life and dyspareunia.

OBJECTIVE: The aim of the current study was to evaluate the effect of surgical removal of endometriosis on dyspareunia, sexual function, quality of sex life and interpersonal relationships. STUDY DESIGN: A questionnaire-based multicentre prospective study was conducted in six tertiary referral centres in Austria and Germany. Ninety-six patients with histologically proven endometriosis and dyspareunia were included. Before surgery and averagely 10 months postoperatively (range 9-12 months), the Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale (FSDS) were used to screen women's sexuality. Additionally, we evaluated psychological parameters and pain intensity during/after sexual intercourse via a self-administered questionnaire. RESULTS: Pain scores measured via NAS during/after intercourse decreased significantly after surgery. Frequencies of interrupted sexual intercourse, feelings of guilt towards the partner, being afraid of pain before/during sexual intercourse and feelings of being a burden for the relationship also decreased significantly in patients with peritoneal endometriosis and deep infiltrating endometriosis. Interestingly, sexually related personal distress did not improve in women with peritoneal endometriosis/vaginal resection, but improved in cases of deep infiltrating endometriosis (DIE). CONCLUSION: Radical laparoscopic excision of endometriosis offers an effective treatment option and offers a significant improvement in dyspareunia and quality of sex life.

Hematopoietic stem and progenitor cells acquire distinct DNA-hypermethylation during in vitro culture.

Hematopoietic stem and progenitor cells (HPCs) can be maintained in vitro, but the vast majority of their progeny loses stemness during culture. In this study, we compared DNA-methylation (DNAm) profiles of freshly isolated and culture-expanded HPCs. Culture conditions of CD34(+) cells - either with or without mesenchymal stromal cells (MSCs) - had relatively little impact on DNAm, although proliferation is greatly increased by stromal support. However, all cultured HPCs - even those which remained CD34(+) - acquired significant DNA-hypermethylation. DNA-hypermethylation occurred particularly in up-stream promoter regions, shore-regions of CpG islands, binding sites for PU.1, HOXA5 and RUNX1, and it was reflected in differential gene expression and variant transcripts of DNMT3A. Low concentrations of DNAm inhibitors slightly increased the frequency of colony-forming unit initiating cells. Our results demonstrate that HPCs acquire DNA-hypermethylation at specific sites in the genome which is relevant for the rapid loss of stemness during in vitro manipulation.

Reduced hemopexin levels in peritoneal fluid of patients with endometriosis.

OBJECTIVE: To study altered hemopexin concentrations in peritoneal fluid (PF) samples from patients with endometriosis. Recent data implicate a role of altered iron metabolism in endometriosis patients. Hemopexin is the major transport protein for heme. Like iron, heme exposure to the epithelial surface can provoke oxidative stress on the peritoneal epithelium. Therefore, altered hemopexin concentrations and heme scavenging in PF might play a role in the pathophysiology of endometriosis. DESIGN: Prospective explorative study. SETTING: Academic tertiary care center. PATIENT(S): Eighty symptomatic patients scheduled for laparoscopy for the diagnosis and/or therapy of endometriosis. INTERVENTION(S): Aspiration of PF samples during laparoscopy. MAIN OUTCOME MEASURE(S): Hemopexin and heme concentration in PF. RESULT(S): At laparoscopy, 47 of 80 (58.8%) patients exhibited endometriosis, and 33 (41.2%) were proven disease-free (CO). By means of ELISA significantly lower concentrations of hemopexin in the samples from patients with endometriosis (endometriosis 0.377 ± 0.16 mg/mL) compared with controls (disease-free 0.479 ± 0.20 mg/mL) could be demonstrated. Heme levels in the samples were not significantly different between groups (endometriosis 9.130 ± 6.124 µM and disease-free 9.990 ± 4.485 µM). There was no significant correlation between heme and hemopexin levels (Pearson's correlation coefficient r = -0.146). Demographic data between the groups were comparable. CONCLUSION(S): These data provide further evidence that hemopexin is significantly down-regulated in PF samples from patients with endometriosis compared with controls. This study confirms recent findings in two-dimensional gel electrophoresis demonstrating a down-regulation of hemopexin in PF from patients with endometriosis in a larger series of samples.

Mass spectrometry and serum pattern profiling for analyzing the individual risk for endometriosis: promising insights?

OBJECTIVE: To evaluate whether distinct patterns of serum proteins in symptomatic women are of value to predict endometriosis before laparoscopy. DESIGN: Prospective exploratory cohort study. SETTING: Tertiary care center. PATIENT(S): A total of 91 consecutive symptomatic patients suffering from dysmenorrhea, dyspareunia, chronic pelvic pain, or unexplained infertility. INTERVENTION(S): Collection of serum samples and a standardized protocol for patients' history before laparoscopic diagnosis. MAIN OUTCOME MEASURE(S): Protein expression was analyzed by mass spectrometric analysis according to surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) standards. The analysis of data was performed using a genetic algorithm (ClinProTools 2.0 software) and a rule-based decision-tree algorithm (XLminer software). RESULT(S): A total of 90 out of 91 samples were eligible for analysis. At laparoscopy, 51 of 90 patients (56.7%) exhibited endometriosis and 39 of 90 (43.3%) were disease free. Analyzing the serum samples, the software revealed a unique selection of mass peaks between 2,000 and 20,000 Da, which allowed for discrimination between patients suffering from endometriosis and control subjects. Overall recognition capacity was 70.8%, exhibiting a sensitivity of 81.3% (95% confidence interval [CI] 66.5-92.5) and a specificity of 60.3% (95% CI 46.1-74.2]) using the genetic algorithm, and a sensitivity of 78.4% and a specificity of 59.0% using the rule-based decision-tree algorithm. CONCLUSION(S): These findings provide direct evidence that screening for serum protein patterns using SELDI-TOF MS before laparoscopy might be of discriminative value in the prediction of disease and partly confirms recently published data. However, in this prospective setting, we found both low sensitivity and low specificity, which disqualifies the screening for serum protein patterns by SELDI-TOF MS as a "quick fix" diagnostic test.

Combination of CCR1 mRNA, MCP1, and CA125 measurements in peripheral blood as a diagnostic test for endometriosis.

This study investigated the possible use of CCR1 mRNA measurement in peripheral blood leukocytes in combination with measurements of monocyte chemotactic protein-1 (MCP-1) and CA125 protein in serum as a diagnostic test for endometriosis.The expression of CCR1 mRNA in peripheral blood leukocytes was measured by quantitative real-time polymerase chain reaction. MCP-1 and CA125 levels in serum were determined by ELISA and ECLIA.The ratio of CCR1/HPRT mRNA in peripheral blood of patients with endometriosis and adenomyosis was significantly elevated compared with women without endometriosis. Additionally, serum levels of MCP-1 and CA125 were significantly higher in patients with endometriosis. This method showed a sensitivity of 92.2%, a specificity of 81.6%, a negative predictive value of 83.3%, a positive predictive value of 92.3%, a likelihood ratio of a positive test result of 5.017, and a likelihood ratio of a negative test result of 0.096 to predict the presence or absence of endometriosis.The results imply the potential use of CCR1 mRNA, MCP-1, and CA125 protein measurements for the diagnosis or exclusion of endometriosis.

Relative expression of 1,25-dihydroxyvitamin D3 receptor, vitamin D 1 alpha-hydroxylase, vitamin D 24-hydroxylase, and vitamin D 25-hydroxylase in endometriosis and gynecologic cancers.

The authors demonstrate expression of the vitamin D receptor (VDR) and its hydroxylases in the endometrium and ovaries of women with and without endometriosis and endometrial or ovarian cancer. Immunohistochemistry showed strong staining of the VDR in endometriosis and endometrial cancer, with the most intense staining in epithelial cells. The VDR mRNA was significantly increased in patients with endometrial and ovarian cancer compared to the control group. There was a significantly higher 1 alpha-hydroxylase expression in the endometrium of patients with endometriosis compared to healthy controls. The observed differences in VDR and 1 alpha -hydroxylase mRNA levels were maintained at the protein level. The authors found no differences in 25-OH vitamin D levels between the serum of patients with endometriosis (25.7 +/- 2.1 ng/mL, n = 46) and healthy controls (22.6 +/- 2.0 ng/mL, n = 33, P = .31). They hypothesize that vitamin D might influence the local activity of immune cells and cytokines thought to play important pathogenic roles in the development and maintenance of endometriosis.

Impaired glucose tolerance is associated with changes in clinical and biochemical parameters in women with polycystic ovary syndrome.

BACKGROUND: To characterize the phenotype of women with polycystic ovary syndrome with and without impaired glucose tolerance by determining various polycystic ovary syndrome-associated clinical and laboratory parameters. METHODS: In a prospective clinical study, we evaluated a series of 102 Caucasian women with polycystic ovary syndrome. Women completed a detailed questionnaire and underwent a standardized oral glucose tolerance test. Various polycystic ovary syndrome-associated laboratory values such as hormonal and metabolic parameters were determined in these women and correlated to clinical data and the presence/absence of impaired glucose tolerance. Furthermore, the insulin resistance was calculated using the homeostasis model assessment index and correlated with clinical and biochemical parameters. RESULTS: Eighty-eight (86.3%) and 14 (13.7%) women were diagnosed as having non-impaired glucose tolerance and impaired glucose tolerance, respectively. Presence of impaired glucose tolerance was associated with an increased body mass index, increased body weight, elevated serum levels of bioavailable testosterone, insulin like growth factor-1, insulin, HbA1c, leucocytes, uric acid, alkaline phosphatase, hepatic C-reactive protein, and decreased serum levels of sex-hormone binding globulin. No association was ascertained with subfertility, hirsutism, and menstrual irregularities. We ascertained a positive correlation between the homeostasis model assessment index and body mass index, body weight, alkaline phosphatase, and hepatic C-reactive protein. CONCLUSIONS: Impaired glucose tolerance seems to be associated with a specific phenotype within polycystic ovary syndrome. This phenotype is more likely to present with biochemical parameters similar to an inflammatory reaction and a metabolic disorder.