René Wenzl

Implanon® versus medroxyprogesterone acetate: effects on pain scores in patients with symptomatic endometriosis — a pilot study ☆

BACKGROUND Implanon has been reported to be effective in the treatment of dysmenorrhea. We compared the therapeutic efficacies of depot medroxyprogesterone acetate (DMPA) and Implanon with regard to pain relief in women with endometriosis. STUDY DESIGN In a clinical research center at a university hospital, 41 patients with dysmenorrhea, nonmenstrual pelvic pain and dyspareunia associated with histologically proven endometriosis were included in an open, prospective, randomized, controlled clinical trial. Twenty-one women were assigned by computer-generated randomization to receive Implanon, and 20 women to receive DMPA. As main outcome measures of this pilot study, we evaluated pain improvement quantified according to visual analog scale score, side effects, vaginal bleeding patterns, withdrawal rate and overall degree of satisfaction. RESULTS During a follow-up period of 1 year, we ascertained a clear improvement in pain intensity for both treatment options. After 6 months, the average decrease in pain was 68% in the Implanon group and 53% in the DMPA group. The side-effects profile and the overall degree of satisfaction after study termination were comparable for both treatment options. CONCLUSION Concerning pain relief, the therapeutic efficacy of the contraceptive implant Implanon is not inferior to that of DMPA in symptomatic endometriosis.

Enhanced epithelial to mesenchymal transition (EMT) and upregulated MYC in ectopic lesions contribute independently to endometriosis

BackgroundEpithelial to mesenchymal transition (EMT) is a process in which epithelial cells lose polarity and cell-to-cell contacts and acquire the migratory and invasive abilities of mesenchymal cells. These abilities are thought to be prerequisites for the establishment of endometriotic lesions. A hallmark of EMT is the functional loss of E-cadherin (CDH1) expression in epithelial cells. TWIST1, a transcription factor that represses E-cadherin transcription, is among the EMT inducers. SNAIL, a zinc-finger transcription factor, and its close relative SLUG have similar properties to TWIST1 and are thus also EMT inducers. MYC, which is upregulated by estrogens in the uterus by an estrogen response cis-acting element (ERE) in its promoter, is associated with proliferation in endometriosis. The role of EMT and proliferation in the pathogenesis of endometriosis was evaluated by analyzing TWIST1, CDH1 and MYC expression.MethodsCDH1, TWIST1, SNAIL and SLUG mRNA expression was analyzed by qRT-PCR from 47 controls and 74 patients with endometriosis. Approximately 42 ectopic and 62 eutopic endometrial tissues, of which 30 were matched samples, were collected during the same surgical procedure. We evaluated TWIST1 and MYC protein expression by immunohistochemistry (IHC) in the epithelial and stromal tissue of 69 eutopic and 90 ectopic endometrium samples, of which 49 matched samples were analyzed from the same patient. Concordant expression of TWIST1/SNAIL/SLUG and CDH1 but also of TWIST1 and MYC was analyzed.ResultsWe found that TWIST1, SNAIL and SLUG are overexpressed (p < 0.001, p = 0.016 and p < 0.001) in endometriosis, while CDH1 expression was concordantly reduced in these samples (p < 0.001). Similar to TWIST1, the epithelial expression of MYC was also significantly enhanced in ectopic endometrium compared to eutopic tissues (p = 0.008). We found exclusive expression of either TWIST1 or MYC in the same samples (p = 0.003).ConclusionsEpithelial TWIST1 is overexpressed in endometriosis and may contribute to the formation of endometriotic lesions by inducing epithelial to mesenchymal transition, as CDH1 was reduced in ectopic lesions. We found exclusive expression of either TWIST1 or MYC in the same samples, indicating that EMT and proliferation contribute independently of each other to the formation of endometriotic lesions.

Interleukin-1 alpha but not interleukin-1 beta gene polymorphism is associated with polycystic ovary syndrome

Interleukin-1 (IL1) is a multifunctional cytokine and IL1-mediated inflammatory processes have been proposed to influence the processes of ovulation, fertilization and implantation. All these parameters are also affected in women with polycystic ovary syndrome (PCOS). This study investigated the association of common polymorphisms of the interleukin-1 genes (IL1A and IL1B) with the occurrence and clinical characteristics of PCOS. We evaluated one polymorphism of the IL1alpha gene (IL1A C[-889]T) and two of the IL1beta gene (IL1B promoter C[-511]T and IL1B exon 5 position +3953) in 105 Caucasian women with PCOS and 102 healthy Caucasian controls by polymerase chain reaction. For the mutated IL1A allele, allele frequencies in women with PCOS and controls were 60% and 46%, respectively, versus 40% and 54%, respectively, for the wild type allele. Allele frequencies in women with PCOS and controls were 59% (54%) and 61% (41%), respectively, for the mutated IL1B promoter (mutated IL1B exon 5) and 41% (46%) and 39% (59%), respectively, for the wild type alleles. Presence of a polymorphism in the interleukin-1alpha but not the interleukin-1beta gene was found to correlate with the occurrence of PCOS (p=0.04; odds ratio 1.8). The serum level of FSH and subsequent LH/FSH ratio correlated with the polymorphism of IL1A within the PCOS group (p=0.005 and 0.01, respectively). We have shown that a common polymorphism of the interleukin-1alpha but not interleukin-1beta gene is associated with the presence of PCOS and with clinical parameters of women affected by this condition.

Family incidence of endometriosis in first-, second-, and third-degree relatives: case-control study

BackgroundInitial publications examining the hereditary aspects of endometriosis appeared in the early seventies and demonstrated an up to seven-fold risk for endometriosis in first-degree relatives of endometriosis patients. The aim was to evaluate the influence of hereditary aspects on the endometriosis risk in our patient collective.MethodsIn a retrospective cohort study we evaluated the incidence of endometriosis among first-, second-, and third-degree relatives of endometriosis patients and compare it with its incidence among first-, second-, and third-degree relatives of patients without endometriosis.Result(s)Eighty patients in whom endometriosis had been confirmed laparoscopically and histologically by biopsy and 60 patients in whom no endometriosis had been found during laparoscopy were given a questionnaire about the presence of symptoms associated with endometriosis and its family incidence. Patients of both the endometriosis and the control group were 37.7 ± 6.2 and 45.9 ± 12.0 years of age at the time of the interview, respectively (p < 0.05). Information about the presence of endometriosis was more readily available for relatives of those in the endometriosis group than for those in the control group (325/749 [43.4%] vs. 239/425 [56.2%], p < 0.05). In 5/136 (3.7%) and 8/134 (6.0%) first-degree relatives of endometriosis patients and the control group, respectively, information about the presence of endometriosis was not available (p = 0.554). Endometriosis was found in 8/136 (5.9%) first-degree relatives of patients and in 4/134 (3.0%) first-degree relatives of controls in the real-case analysis (p = 0.248). When comparing endometriosis characteristics between endometriosis patients with and without a history of familial endometriosis, no significant differences were found.Conclusion(s)There is a trend toward an increased familial incidence of endometriosis. In contrast to the literature, we found a less dramatic increase in familial risk for the development of endometriosis.

Combined Hysterectomy/Salpingo-Oophorectomy and Mastectomy is a Safe and Valuable Procedure for Female-to-Male Transsexuals

INTRODUCTION Sex reassignment surgery is an important step for transsexuals, since it is known to help the patients to live more easily in their gender role and to significantly increase quality of life. AIMS To critically evaluate our experience with the combined procedure of hysterectomy, bilateral salpingo-oophorectomy, and bilateral mastectomy for female-to-male (FtM) transsexual patients. METHODS Thirty-two FtM transsexuals who underwent hysterectomy, bilateral salpingo-oophorectomy, and bilateral mastectomy in one single operative setting. MAIN OUTCOME MEASURES Operating time and complications, both intra-and postoperatively. RESULTS Patients were 30.0 ± 5.8 years of age, with a body mass index of 24.8 ± 3.5 kg/m(2). The majority of patients underwent hysterectomy and bilateral salpingo-oophorectomy by laparoscopy (31/32, 96.9%). The median operating time was 222.5 minutes (inter-quartile range [IQR] 190-270 minutes). The median postoperative stay was eight days (IQR, 7-9 days). Postoperative adverse events were found in five patients (15.6%), including breast hematomas as the most frequent complication (4/32, 12.5%). In one patient (1/32; 3.1%), conversion from laparoscopy to laparotomy was necessary, which was considered an adverse event. None of our patients required reoperation or readmission to the hospital. CONCLUSION Combined hysterectomy/salpingo-oophorectomy, and bilateral mastectomy in a single operating session seems a safe, feasible, and valuable procedure for FtM transsexuals.

Functional and anatomic results after creation of a neovagina according to Wharton-Sheares-George in patients with Mayer-Rokitansky-Küster-Hauser syndrome—long-term follow-up

OBJECTIVE To evaluate the long-term outcomes and degree of satisfaction after neovaginoplasty according to Wharton-Sheares-George in women with Mayer-Rokitansky-Küster-Hauser syndrome. DESIGN Open, monocentric follow-up study. SETTING University hospital and referral center for pediatric and adolescent gynecology. PATIENT(S) Ten patients with Mayer-Rokitansky-Küster-Hauser syndrome with neovaginas created according to Wharton-Sheares-George 3 to 77 months ago. INTERVENTION(S) Gynecologic follow-up examination, including vaginal swab, bacterial culture, Papanicolaou smear, hybrid capture test for human papillomavirus typing, biopsy, pelvic ultrasound, and 2 questionnaires concerning global quality of life and degree of sexual satisfaction. MAIN OUTCOME MEASURE(S) Satisfaction with sexual function, quality of life, length and width of neovagina, structure of vaginal epithelium, and type of bacterial colonization. RESULT(S) Functional long-term follow-up results showed a high subjective degree of general well-being and sexual satisfaction in affected women. A satisfactory neovaginal length (mean, 8.3 ± 1.06 cm; range, 7-10 cm) and width (mean, 3.3 ± 0.5 cm; range, 2.5-4 cm) was obtained. As revealed by smears and biopsy, the neovagina resembled a natural vagina with regard to type of bacterial colonization and structure of epithelium. CONCLUSION(S) The goal of any method of creating a neovagina is to provide the patient the possibility to have satisfactory sexual intercourse and to enhance well-being and quality of life. These aims can be achieved by creating a neovagina according to Wharton-Sheares-George.

Epigenetic Alterations Affecting Transcription Factors and Signaling Pathways in Stromal Cells of Endometriosis

Endometriosis is characterized by growth of endometrial-like tissue outside the uterine cavity. Since its pathogenesis may involve epigenetic changes, we used Illumina 450K Methylation Beadchips to profile CpG methylation in endometriosis stromal cells compared to stromal cells from normal endometrium. We validated and extended the Beadchip data using bisulfite sequencing (bis-seq), and analyzed differential methylation (DM) at the CpG-level and by an element-level classification for groups of CpGs in chromatin domains. Genes found to have DM included examples encoding transporters (SLC22A23), signaling components (BDNF, DAPK1, ROR1, and WNT5A) and transcription factors (GATA family, HAND2, HOXA cluster, NR5A1, OSR2, TBX3). Intriguingly, among the TF genes with DM we also found JAZF1, a proto-oncogene affected by chromosomal translocations in endometrial stromal tumors. Using RNA-Seq we identified a subset of the DM genes showing differential expression (DE), with the likelihood of DE increasing with the extent of the DM and its location in enhancer elements. Supporting functional relevance, treatment of stromal cells with the hypomethylating drug 5aza-dC led to activation of DAPK1 and SLC22A23 and repression of HAND2, JAZF1, OSR2, and ROR1 mRNA expression. We found that global 5hmC is decreased in endometriotic versus normal epithelial but not stroma cells, and for JAZF1 and BDNF examined by oxidative bis-seq, found that when 5hmC is detected, patterns of 5hmC paralleled those of 5mC. Together with prior studies, these results define a consistent epigenetic signature in endometriosis stromal cells and nominate specific transcriptional and signaling pathways as therapeutic targets.

Cytokeratin-19 as a biomarker in urine and in serum for the diagnosis of endometriosis--a prospective study.

Abstract Endometriosis compromises the quality of life of countless women worldwide and is a leading cause of disability. Clinical symptoms of endometriosis can be very heterogeneous leading to a long interval between onset of symptoms and surgical diagnosis. A noninvasive, rapid diagnostic test is urgently needed. In this prospective study, we evaluated the usefulness of Cytokeratin-19 (CK19) as a biomarker for the diagnosis of endometriosis through urine and serum ELISA. 76 reproductive-aged women undergoing laparoscopy for benign conditions were included to this study and divided into two groups by the presence (n = 44) or absence (n = 32) of endometriosis. There was no statistically significant correlation between the concentration of CK19 in urine (p = 0.51) or in serum (p = 0.77) and the diagnosis of endometriosis. Assigning the samples to the proliferative or secretory cycle stage did not sufficiently lower the p values. In this study, the promising data reported in the recent literature about CK19 serving as a sufficient biomarker for endometriosis could not be verified when tested in a larger sample size. Further studies are warranted to explore the usefulness of CK19 in the diagnosis of endometriosis.

Soluble VCAM-1/soluble ICAM-1 ratio is a promising biomarker for diagnosing endometriosis

Study question Do cell adhesion molecules play a role in endometriosis, and can they be used as a biomarker for diagnosing endometriosis? Summary answer Altered expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) in the endometrium and peritoneum may play a key role in endometriosis and the soluble VCAM-1/soluble ICAM-1 ratio is a promising biomarker. What is known already Cell adhesion molecules are cell surface proteins that mediate cellular adherence, inflammatory and immune responses, and cancer-related biological processes. Altered expression of VCAM-1 and ICAM-1 in women with endometriosis has been investigated previously; however, gene expression levels in tissues and protein levels in the serum have not been investigated in the same patients. Study design size, duration We performed a prospective, longitudinal study (the Endometriosis Marker Austria) in patients who underwent a laparoscopy for benign gynecological pathology in a university-based tertiary referral center for endometriosis. From a total of 138 women who were included in the study from July 2013 through September 2014, 97 had not received hormonal treatment for at least 3 months prior to recruitment and were included in the analysis; 49 (50.5%) of these women had endometriosis, and the 48 (49.5%) who did not have endometriosis served as a control group. Participants/materials setting methods During laparoscopy, tissue samples were obtained from ectopic and eutopic endometrium, and from normal pelvic peritoneum. In addition, serum samples were collected immediately before and 6-10 weeks after surgery. The mRNA levels of VCAM-1, ICAM-1 and epithelial cell adhesion molecule (EpCAM) were measured using quantitative real-time PCR, and serum protein levels of soluble VCAM-1 (sVCAM-1), ICAM-1 (sICAM-1) and EpCAM (sEpCAM) were measured using ELISA and correlated with endometriosis status. Main results and the role of chance The mRNA levels of both VCAM-1 and ICAM-1 were higher in ectopic endometriotic lesions than in eutopic endometrium (P < 0.001). Moreover, the mRNA levels of both VCAM-1 and ICAM-1 were higher in normal peritoneum samples obtained from women with endometriosis compared to those from controls (P = 0.038 and P = 0.009). The mRNA levels of VCAM-1 were also higher in the eutopic endometrium samples obtained from women with endometriosis compared to controls (P = 0.018). With respect to serum protein levels, compared to controls, the women with endometriosis had lower serum levels of sICAM-1 (P = 0.042) and higher levels of sVCAM-1 (P < 0.001). Our analysis revealed that the serum levels of sVCAM-1 were not affected by lesion entity, menstrual cycle phase or disease severity. An receiver operating characteristics curve, calculated to determine whether preoperative serum sVCAM-1 concentration can be used to predict endometriosis, found an AUC of 0.868 with 80% specificity and 84% sensitivity at a cutoff value of 370 pg/ml. This predictive performance can be further improved by calculation of the sVCAM-1/sICAM-1 ratio, leading to an AUC of 0.929 with 86.7% specificity and 90.3% sensitivity at a cutoff ratio value of 1.55. Large scale data Not applicable. Limitations reasons for caution The relatively small sample size in the expression analyses is a possible limitation of this study. Wider implications of the findings Our findings could contribute to an improved understanding of the pathogenesis of endometriosis and the role of cell adhesion molecules. In addition, the results may lead to the development of new, non-invasive tools for diagnosing endometriosis. The ability to diagnose patients by measuring serum sVCAM-1 levels or the sVCAM-1/sICAM-1 ratio would have considerable clinical value. Study funding/competing interest(s) The Ingrid Flick Foundation (Grant no. FA751C0801), which played no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. The authors declare no competing interests.

Prevalence and severity of cyclic leg pain in women with endometriosis and in controls - effect of laparoscopic surgery

OBJECTIVE In addition to dysmenorrhea, dyspareunia, and subfertility, pain in the lower extremities has been described to be a further complaint in women affected by endometriosis, and lysis of nerve entrapment was thought to be associated with amelioration of leg pain. Therefore, we aimed to compare the prevalence of cyclic leg pain and pain intensity between women with endometriosis and without endometriosis, and to evaluate the effect of laparoscopic surgery. STUDY DESIGN Forty-four women with endometriosis and 58 controls were included in a prospective, controlled clinical trial at a University hospital/tertiary referral center. Participants were asked to complete questionnaires the day before and six to nine weeks after laparoscopy. The prevalence and intensity of leg pain and improvement after laparoscopic surgery, quantified according to a visual analog scale (VAS) score, were evaluated. We also recorded involvement of dermatomes, the presence and intensity of dysmenorrhea, and correlations between age, stage of endometriosis (rAFS-score), and preoperative VAS scores. RESULTS Before surgery, more women were affected by leg pain in the endometriosis group, compared to the control group (45.5% and 25.9%, respectively). Preoperative VAS scores for leg pain, however, were not significantly different between the two groups. A moderate correlation in the preoperative VAS scores between leg pain and dysmenorrhea was observed. After laparoscopy, we found a significant improvement in leg pain intensity in both groups. The mean difference in the VAS score for pain reduction between the study group and the control group was 0.74 (95% CI: -0.61-2.08), which was not statistically significant. CONCLUSIONS The prevalence of leg pain is increased in endometriosis, while leg pain intensity is not, compared to women without endometriosis. Laparoscopic surgery-even without preparation and decompression of nerve tissue-is associated with an improvement in pain intensity in women with endometriosis, as well as in the group without endometriosis.