MicroRNA-30d and microRNA-181a regulate HOXA11 expression in the uterosacral ligaments and are overexpressed in pelvic organ prolapse.

The balanced turnover of collagen is necessary to maintain the mechanical strength of pelvic supportive connective tissues. Homeobox (HOX) A11 is a key transcriptional factor that controls collagen metabolism and homoeostasis in the uterosacral ligaments (USLs), and the deficient HOXA11 signalling may contribute to alterations in the biochemical strength of the USLs, leading to pelvic organ prolapse (POP). However, it is unknown how HOXA11 transcripts are regulated in the USLs. In this study, we found that microRNA (miRNA)-30d and 181a were overexpressed in women with POP, and their expression was inversely correlated with HOXA11 mRNA levels. The overexpression of miR-30d or 181a suppressed HOXA11 mRNA and protein levels in 293T cells, whereas the knockdown of these miRNAs enhanced HOXA11 levels and collagen production. Cotransfection of a luciferase reporter plasmid containing the 3'-untranslated region of HOXA11 with miR-30d or 181a mimic resulted in decreased relative luciferase activity. Conversely, cotransfection with anti-miR-30d or 181a increased luciferase activity. Taken together, these results indicate that both miR-30d and 181a are important posttranscriptional regulators of HOXA11 in the USLs and could be a potential therapeutic target for POP.

NGF and HB-EGF: potential biomarkers that reflect the effects of fesoterodine in patients with overactive bladder syndrome.

PURPOSE: To determine whether levels of nerve growth factor (NGF) and heparin-binding epidermal growth factor-like growth factor (HB-EGF) can be used to objectively assess overactive bladder syndrome (OAB) treatment outcome and to evaluate the effects of fixed-dose fesoterodine on OAB symptoms. MATERIALS AND METHODS: This study included 124 participants (62 patients with OAB and 62 controls) in Severance Hospital between 2010 and 2012. In patients with OAB, 4 mg fesoterodine was administered once daily. Repeated evaluations of putative biomarker levels, urine creatinine (Cr) levels, and questionnaire responses, including the Overactive Bladder Symptom Score (OABSS) and the Overactive Bladder Questionnaire (OAB q), were performed from baseline to 16 weeks. RESULTS: Urinary levels of NGF/Cr (OAB: 1.13±0.9 pg/mg; control: 0.5±0.29 pg/mg) and HB-EGF/Cr (OAB: 8.73±6.55 pg/mg; control: 4.45±2.93 pg/mg) were significantly higher in subjects with OAB than in controls (p<0.001). After 16 weeks of fixed-dose fesoterodine treatment, urinary NGF/Cr levels (baseline: 1.13±0.08 pg/mg; 16 weeks: 0.60±0.4 pg/mg; p=0.02) and HB-EGF/Cr levels significantly decreased (baseline: 8.73±6.55 pg/mg; 16 weeks: 4.72±2.69 pg/mg; p=0.03, respectively). Both the OABSS and OAB q scores improved (p<0.001). However, there were no a statistically significant correlations between these urinary markers and symptomatic scores. CONCLUSION: Urinary levels of NGF and HB-EGF may be potential biomarkers for evaluating outcome of OAB treatment. Fixed-dose fesoterodine improved OAB symptoms. Future studies are needed to further examine the significance of urinary NGF and HB-EGF levels as therapeutic markers for OAB.

Two-year urinary outcomes of sacrocolpopexy with or without transobturator tape: results of a prolapse-reduction stress test-based approach.

INTRODUCTION AND HYPOTHESIS: Women undergoing sacrocolpopexy (SCP) are at risk for postoperative stress urinary incontinence (SUI). However, the optimal management for this condition remains debatable. The aim of this study was to evaluate urinary outcomes 2 years after SCP with or without transobturator tape (TOT) based on the results of a prolapse-reduction stress test. METHODS: A prospective, observational study was conducted assessing a cohort of women undergoing SCP. Patients were assigned to the TOT or non-TOT group based on results of a prolapse-reduction stress test. The primary outcome was SUI (defined as a positive cough stress test or bothersome symptoms) or additional surgery for this condition. RESULTS: Among the 247 women enrolled, 223 (90 %) received surgery per assignment and completed the follow-up. Two years after surgery, 5.4 % of women in the TOT group and 28.6 % in the non-TOT group had SUI or received additional anti-incontinence surgery (p < 0.01). In the non-TOT group, more women with symptoms of SUI prior to surgery had postoperative SUI or received additional anti-incontinence surgery than those without symptoms (42.9 % vs. 20.0 %, p = 0.01). CONCLUSIONS: A preoperative prolapse-reduction stress test alone is not sufficient to determine the need for anti-incontinence surgery at the time of SCP. In particular, women with symptoms of SUI despite a negative prolapse-reduction stress test are more likely to experience postoperative SUI or additional anti-incontinence surgery.

Changes in sexual function and comparison of questionnaires following surgery for pelvic organ prolapse.

PURPOSE: The aim of this study was to evaluate the effect of surgical repair of pelvic organ prolapse on female sexual function and to assess correlations between the two using two current standardized questionnaires. MATERIALS AND METHODS: From October 2009 to September 2010, 143 patients with posterior compartment or combined vaginal prolapse were included. We assessed surgical outcomes according to anatomical change in the vagina and results of the Female Sexual Function Index (FSFI) and Pelvic Organ Prolapse/Urinary Incontinence Sexual Function questionnaire (PISQ-12) both pre- and postoperatively. RESULTS: Among the 143 preoperative patients, 99 and 84 patients responded to the PISQ-12 and FSFI, respectively. The mean PISQ-12 score increased after surgery (p<0.001). Specifically, postoperative scores for questions 8 and 12 were higher than their respective preoperative scores (p<0.001). Postoperatively, mean FSFI score changed only slightly (p=0.76), and only the score for the satisfaction domain was improved (p=0.023). In regards to vaginal anatomy, vaginal length was significantly greater postoperatively (6.99±0.18 vs. 7.56±1.08, p<0.001), and postoperative vaginal caliber was narrowed to a two-finger width. CONCLUSION: In this study, surgery for pelvic organ prolapse was shown to affect female sexual function. Moreover, menopause was associated with a change in postoperative sexual function.

Association between the poly(ADP-ribose) polymerase-1 gene polymorphism and advanced pelvic organ prolapse.

OBJECTIVE: Apoptotic cell death, probably induced by oxidative stress, contributes to the development of pelvic organ prolapse. Because poly(ADP-ribose) polymerase-1 is an important mediator of cellular response to oxidative stress, genetic variations in the poly(ADP-ribose) polymerase-1 gene may play a role in the pathogenesis of pelvic organ prolapse. This study aimed to determine the association between advanced pelvic organ prolapse and Val762Ala polymorphism in the poly(ADP-ribose) polymerase-1 gene. METHODS: A total of 340 women were enrolled in the study. The pelvic organ prolapse group consisted of 185 women with stage III or IV pelvic organ prolapse, whereas the control group consisted of 155 postmenopausal women with stage 0 or I pelvic organ prolapse who visited the hospital for treatment of benign gynecologic disease or routine gynecologic checkup. Genotyping of the poly(ADP-ribose) polymerase-1 Val762Ala polymorphism was performed by real-time polymerase chain reaction analysis using a TaqMan assay. RESULTS: Genotype distribution in the pelvic organ prolapse group was different from that in the control group (P = 0.024). Furthermore, C-allele frequency was lower in the pelvic organ prolapse group than in the control group (P = 0.029). Women with the CC genotype had a 0.461-fold lower risk of developing advanced pelvic organ prolapse than women with the TT genotype (95% CI, 0.245-0.870; P = 0.017), and women with the C-allele had a 0.716-fold lower risk of developing advanced pelvic organ prolapse than women with the T-allele (95% CI, 0.527-0.973; P = 0.033). CONCLUSIONS: These findings suggest that the poly(ADP-ribose) polymerase-1 Val762Ala polymorphism is associated with a decreased risk of advanced pelvic organ prolapse.

Estrogen-related genome-based expression profiling study of uterosacral ligaments in women with pelvic organ prolapse.

INTRODUCTION AND HYPOTHESIS: The aim of the study was to identify the differential expression of estrogen-related genes that may be involved in the menopause and pelvic organ prolapse (POP) using microarray analysis. METHODS: An age, parity, and menopausal status-matched case-control study with 12 POP patients and 5 non-POP patients was carried out. The study was conducted from January to December 2010 at Yonsei University, Severance Hospital. We examined microarray gene expression profiles in uterosacral ligaments (USLs) from POP and non-POP patients. Total RNA was extracted from USL samples to generate labeled cDNA, which was hybridized to microarrays and analyzed for the expression of 44,049 genes. We identified differentially expressed genes and performed functional clustering. After clustering, we focused on transcriptional response and signal transduction gene clusters, which are associated with estrogen, and then validated the changes of gene expression levels observed with the microarray analysis using quantitative polymerase chain reaction (qPCR). RESULTS: The data from the microarray analysis using more than a 1.5-fold change with p value <0.05 resulted in 143 upregulated genes and 87 downregulated genes. Of 59 genes identified to be associated with signal transduction and transcription, 4 genes were chosen for qPCR that have been classified to be associated with estrogen. We found that estrogen receptor-related receptor-α (ERRα) was downregulated and that the expression of death-associated protein kinase 2 (DAPK 2), signal-transducing adaptor protein-2 (STAP-2), and interleukin (IL)-15 were upregulated. CONCLUSIONS: We found four differentially expressed genes by microarray analysis that may account for the way in which changes in estrogen level affect POP pathophysiology.

Alteration of elastin metabolism in women with pelvic organ prolapse.

PURPOSE: Although there are many studies about the effects of vaginal birth, the effects of menopause on pelvic floor support have not been identified. We compared elastin metabolism in the uterosacral ligament of women with and without pelvic organ prolapse, and defined the menopausal regulation of this process. MATERIALS AND METHODS: The study group consisted of 35 women who underwent hysterectomy for pelvic organ prolapse. The control group consisted of 39 women without pelvic organ prolapse. A questionnaire was administered to assess age, parity, body mass index, and menopausal status. Expression levels of mRNA, and protein for neutrophil elastase, matrix metalloproteinase-2, and matrix metalloproteinase-9 were determined by real-time quantitative polymerase chain reaction and ELISA, respectively, using uterosacral ligament samples from each patient. Expression of alpha-1-antitrypsin, an inhibitor of neutrophil elastase, was also determined. ANOVA, the Kruskal-Wallis test and multivariate linear regression were used for statistical analysis. RESULTS: Expression of neutrophil elastase and matrix metalloproteinase-2 mRNA was higher in women with pelvic organ prolapse than in those without pelvic organ prolapse. Compared to before menopause, neutrophil elastase and matrix metalloproteinase-2 showed a significant decrease in postmenopausal women without pelvic organ prolapse, although these remained increased in postmenopausal women with pelvic organ prolapse. Alpha-1-antitrypsin was significantly less in postmenopausal women with pelvic organ prolapse than in postmenopausal women without pelvic organ prolapse. The activities of neutrophil elastase, matrix metalloproteinase-2 and matrix metalloproteinase-9 were increased in women with pelvic organ prolapse, and these trends were similar to neutrophil elastase and matrix metalloproteinase-2 expression even after adjustment for age, parity and menopausal status. CONCLUSIONS: After menopause increased elastolytic protease has a significant role in the development of pelvic organ prolapse.

Comparison of Burch colposuspension and transobturator tape when combined with abdominal sacrocolpopexy.

OBJECTIVE: To compare the treatment outcomes of Burch colposuspension and transobturator tape (TOT) when each is combined with abdominal sacrocolpopexy (ASC) to treat stress urinary incontinence (SUI) with pelvic organ prolapse (POP). METHODS: Consecutive cases of Burch colposuspension and TOT combined with ASC were retrospectively reviewed. Patients with SUI and POP beyond stage III--according to the POP-quantification system--were included. RESULTS: Mean hospital stay was longer in the Burch group (n=49) than in the TOT group (n=60) (11.3 vs 7.8 days; P<0.001), as was operation time (202.7 vs 170.1 minutes; P<0.001); furthermore, there were higher rates of urinary retention (53.1% vs 11.7%; P<0.001), de novo urgency (18.4% vs 3.3%; P=0.01), and recurrent SUI (18.4% vs 1.7%; P=0.003) in the Burch group. The cure rate was significantly higher in the TOT group than in the Burch group (98.3% vs 69.7%; P<0.001). CONCLUSION: The use of TOT with ASC resulted in higher cure rates and better functional outcomes than did Burch colposuspension with ASC.

Risk factors associated with voiding dysfunction after anti-incontinence surgery.

INTRODUCTION AND HYPOTHESIS: The aim of this study is to investigate the risk factors of voiding dysfunction occurring within 1 month after surgical treatment of urinary incontinence. METHODS: Medical records of 903 women who underwent anti-incontinence surgery at Yonsei Medical Health System from January 1999 to April 2007 were reviewed. The patient demographics, urodynamic parameters, pelvic organ prolapse stage, surgical procedures, and concomitant surgery were retrospectively evaluated. Postoperative voiding dysfunction was defined as post-void residual urine measuring greater than 100 cc at two or more successive trials. RESULTS: Age, menopausal status, maximum flow rate, average flow rate, post-void residual, anti-incontinence surgery type, stage of pelvic organ prolapse, and concomitant prolapse surgery were associated predictors of voiding dysfunction after anti-incontinence surgery. In multivariate analysis, concomitant anterior colporrhaphy (OR 2.4; 95% CI 1.38-4.11) was the only independent risk factor. CONCLUSIONS: The most important risk factor associated with voiding dysfunction was concomitant anterior colporrhaphy.

A long-term treatment outcome of abdominal sacrocolpopexy.

PURPOSE: The aim of this study was to evaluate the long-term treatment outcome and major complication rates of abdominal sacrocolpopexy (ASC). MATERIALS AND METHODS: This retrospective study included 57 Korean women who underwent ASC with mesh for symptomatic uterine or vault prolapse and attended follow-up visits for at least 5 years. Forty-seven women with urodynamic stress incontinence concomitantly received a modified Burch colposuspension. The long-term anatomical and functional outcomes and complication rates were assessed. RESULTS: The median follow-up was 66 months (range 60-108). Overall anatomical success rates (no recurrence of any prolapse >or= stage II according to the pelvic organ prolapse-quantification system) were 86.0%. Urinary urgency and voiding dysfunction were significantly improved after surgery, however, recurrent stress urinary incontinence developed in 44.7% (21/47) of cases and half of them developed within 1-3 months post-op. Bowel function (constipation and fecal incontinence) and sexual function (sexual activity and dyspareunia) did not significantly change after surgery. Major complication requiring reoperation or intensive care developed in 12 (21.0%) cases. CONCLUSIONS: ASC provides durable pelvic support, however, it may be ineffective for alleviating pelvic floor dysfunction except for urinary urgency and voiding dysfunction, and it contains major complication risk that cannot be overlooked.