Pathophysiology Of Pelvic Organ Prolapse Research Articles

An Improved Understanding of the Pathophysiology of Pelvic Organ Prolapse: A 3D In Vitro Model under Static and Mechanical Loading Conditions.

The suboptimal outcomes of pelvic organ prolapse (POP) surgery illustrate the demand for improved therapies. However, their development is hampered by the limited knowledge on the cellular pathophysiology of POP. Current investigations, that are limited to tissues and 2D in vitro models, provide highly inconclusive results on how the extracellular matrix (ECM) metabolism and fibroblasts are affected in POP. This study uses a physiologically relevant 3D in vitro model to investigate the cellular pathophysiology of POP by determining the differences between POP and non-POP fibroblasts on ECM metabolism, proliferation, and fibroblast-to-myofibroblast (FMT) transition. This model, based on the synthetic and biomimetic polyisocyanide hydrogel, enables the incorporation of mechanical loading, which simulates the forces exerted on the pelvic floor. Under static conditions, 3D cultured POP fibroblasts are less proliferative, undergo FMT, and exhibit lower collagen and elastin contents compared to non-POP fibroblasts. However, under mechanical loading, the differences between POP and non-POP fibroblasts are less pronounced. This study contributes to the development of more comprehensive models that can accurately mimic the POP pathophysiology, which will aid in an enhanced understanding and may contribute to improved therapies in the future.

Is there an association between pelvic organ prolapse and oxidative stress? A systematic review.

Introduction and hypothesisThe pathophysiology of pelvic organ prolapse (POP) has not been fully elucidated, although accumulating evidence suggests that oxidative stress is involved. The present systematic review comprehensively discusses this topic.MethodsThe PubMed/Medline, Scopus, and Web of Science databases were searched for relevant studies published up to May 2021. This systematic review was registered in the PROSPERO database (registration number CRD42021242240). Two independent researchers screened and selected articles that fulfilled predefined inclusion criteria, performed a quality assessment, and extracted the relevant data. Of 901 original articles retrieved, 8 fulfilled the selection criteria and were included in the review.ResultsElevated levels of markers of oxidative stress, such as advanced glycation end products, hydroxynonenal and hydroxydeoxyguanosine, were found in various parts of the pelvic floor of patients with POP. Accordingly, the levels of glutathione peroxidase and superoxide dismutase, known as major antioxidant enzymes, were reduced, compared to those in healthy controls. Levels of two other markers (mitofusin 2 and nuclear factor erythroid derived 2) also support hypotheses suggesting the involvement of oxidative stress in POP.ConclusionsIn the literature available, an association between oxidative stress and pelvic organ prolapse was confirmed.

MRI biomarker of muscle composition is associated with severity of pelvic organ prolapse

The pathophysiology of pelvic organ prolapse is largely unknown. We hypothesized that reduced muscle mass on magnetic resonance defecography (MRD) is associated with increased pelvic floor laxity. The aim of this study was to compare the psoas and puborectalis muscle mass composition and cross-sectional area among patients with or without pelvic laxity. An observational retrospective study was conducted on women > age 18years old who had undergone MRD for pelvic floor complaints from January 2020 to December 2020 at Stanford Pelvic Health Center. Pelvic floor laxity, pelvic organ descent, and rectal prolapse were characterized by standard measurements on MRD and compared to the psoas (L4 level) and puborectalis muscle index (cross-sectional area adjusted by height) and relative fat fraction, quantified by utilizing a 2-point Dixon technique. Regression analysis was used to quantify the association between muscle characteristics and pelvic organ measurements. The psoas fat fraction was significantly elevated in patients with abnormally increased resting and strain H and M lines (p < 0.05) and increased with rising grades of Oxford rectal prolapse (p = 0.0001), uterovaginal descent (p = 0.001) and bladder descent (p = 0.0005). In multivariate regression analysis, adjusted for age and body mass index, the psoas fat fraction (not muscle index) was an independent risk factor for abnormal strain H and M line; odds ratio (95% confidence interval) of 17.8 (2-155.4) and 18.5 (1.3-258.3) respectively, and rising Oxford grade of rectal prolapse 153.9 (4.4-5383) and bladder descent 12.4 (1.5-106). Puborectalis fat fraction was increased by rising grades of Oxford rectal prolapse (p = 0.0002). Severity of pelvic organ prolapse appears to be associated with increasing psoas muscle fat fraction, a biomarker for reduced skeletal muscle mass. Future prospective research is needed to determine if sarcopenia may predict postsurgical outcomes after pelvic organ prolapse repair.

International Urogynecological Consultation (IUC): pathophysiology of pelvic organ prolapse (POP)

This manuscript is the International Urogynecology Consultation (IUC) on pelvic organ prolapse (POP) chapter one, committee three, on the Pathophysiology of Pelvic Organ Prolapse assessing genetics, pregnancy, labor and delivery, age and menopause and animal models. An international group of urogynecologists and basic scientists performed comprehensive literature searches using pre-specified terms in selected biomedical databases to summarize the current knowledge on the pathophysiology of the development of POP, exploring specificallyfactors including (1) genetics, (2) pregnancy, labor and delivery, (3) age and menopause and (4) non-genetic animal models. This manuscript represents the summary of three systematic reviews with meta-analyses and one narrative review, to which a basic scientific comment on the current understanding of pathophysiologic mechanisms was added. The original searches revealed over 15,000 manuscripts and abstracts which were screened, resulting in 202 manuscripts that were ultimately used. In the area of genetics the DNA polymorphisms rs2228480 at the ESR1 gene, rs12589592 at the FBLN5 gene, rs1036819 at the PGR gene and rs1800215 at the COL1A1 gene are significantly associated to POP. In the area of pregnancy, labor and delivery, the analysis confirmed a strong etiologic link between vaginal birth and symptoms of POP, with the first vaginal delivery (OR: 2.65; 95% CI: 1.81-3.88) and forceps delivery (OR: 2.51; 95% CI: 1.24-3.83) being the main determinants. Regarding age and menopause, only age was identified as a risk factor (OR : 1.102; 95% CI: 1.02-1.19) but current data do not identify postmenopausal status as being statistically associated with POP. In several animal models, there are measurable effects of pregnancy, delivery and iatrogenic menopause on the structure/function of vaginal support components, though not on the development of POP. Genetics, vaginal birth and age all have a strong etiologic link to the development of POP, to which other factors may add or protect against the risk.

Role of Fibroblasts and Myofibroblasts on the Pathogenesis and Treatment of Pelvic Organ Prolapse.

Pelvic organ prolapse (POP) is a multifactorial connective tissue disorder caused by damage to the supportive structures of the pelvic floor, leading to the descent of pelvic organs in the vagina. In women with POP, fibroblast function is disturbed or altered, which causes impaired collagen metabolism that affects the mechanical properties of the tissue. Ideal surgical repair, either native tissue repair or POP surgery using an implant, aims to create a functional pelvic floor that is load-bearing, activating fibroblasts to regulate collagen metabolism without creating fibrotic tissue. Fibroblast function plays a crucial role in the pathophysiology of POP by directly affecting the connective tissue quality. On the other hand, fibroblasts determine the success of the POP treatment, as the fibroblast-to-(myo)fibroblast transition is the key event during wound healing and tissue repair. In this review, we aim to resolve the question of “cause and result” for the fibroblasts in the development and treatment of POP. This review may contribute to preventing the development and progress of anatomical abnormalities involved in POP and to optimizing surgical outcomes.

The polymorphisms of extracellular matrix-remodeling genes are associated with pelvic organ prolapse

Introduction and hypothesisExtracellular matrix (ECM) synthesis and metabolism abnormalities may influence the pelvic supporting system and lead to the occurrence and development of pelvic organ prolapse (POP). Genetic polymorphisms of such related genes have been increasingly studied. This study aims to explore the association between the single-nucleotide polymorphisms (SNPs) of genes encoding ECM processing enzymes (a disintegrin and metalloproteinase with thrombospondin motifs [ADAMTSs]), ECM degrading enzymes (matrix metalloproteinases [MMPs]) and their tissue inhibitors of metalloproteinase (TIMPs), and POP.MethodsWe conducted an association study including 48 women with POP at stages III and IV and 48 women without prolapse in Chinese groups. SNPs were identified using the target region sequencing technique. We performed Fisher’s exact tests to assess the association between SNPs and POP in the unadjusted model and logistic regression analysis in the adjusted model, adjusting for delivery and pregnancy.ResultsThere was a significant association between TIMP2 SNP rs2277698 (odds ratio [OR], 0.37; 95% confidence interval [CI], 0.16–0.82; P = 0.015), ADAMTS13 SNP rs149586801 (OR, 0.18; 95% CI, 0.05–0.69; P = 0.012), and ADAMTS1 SNPs rs370850 and rs422803 (OR, 3.71; 95% CI, 1.35–10.15; P = 0.011 for both), rs402007, rs428785, rs434857, and rs445784 (OR, 2.18; 95% CI, 1.05–4.56; P = 0.038 for the four), and POP in the adjusted model.ConclusionTIMP2, ADAMTS13, and ADAMTS1 might be candidate genes for POP. Our results provide preliminarily new evidence for future investigation of these genes in the pathophysiology of POP.

Fibrous components of extracellular matrix and smooth muscle of the vaginal wall in young and postmenopausal women: Stereological analysis

The anterior vaginal wall is subject to many diseases, such as pelvic organ prolapse. The pathophysiology of this illness is multifactorial, and as such, structural components of the vagina are involved. Furthermore, it is more prevalent in older women. There is a lack of data in the literature regarding the extracellular matrix components of the vaginal wall and its changes with aging. The work presented herein aims to perform a stereological study of the extracellular matrix in young and old women. It was observed a decrease of the volumetric density of smooth muscle (45.5 ± 3.2 % and 32.8 ± 5.8 % for the G1 and G2 samples, respectively) and an increase of collagen and elastic fibers with age (35.9 ± 2.1 % and 54.1 ± 5.9 % for the G1 and G2, respectively) in the mucosa of the vaginal wall. These results could help to better understand the pathophysiology of pelvic organ prolapse concerning the aging process.

Core-Shell Poly(l-lactic acid)-Hyaluronic Acid Nanofibers for Cell Culture and Pelvic Ligament Tissue Engineering.

Pelvic organ prolapse (POP) has become one of the most common serious diseases affecting parous women. Weakening of pelvic ligaments plays an essential role in the pathophysiology of POP. Currently, synthetic materials are widely applied for pelvic reconstructive surgery. However, synthetic nondegradable meshes for POP therapy cannot meet the clinical requirements due to its poor biocompatibility. Herein, we fabricated electrospun core-shell nanofibers of poly(l-lactic acid)-hyaluronic acid (PLLA/HA). After that, we combined them with mouse bone marrow-derived mesenchymal stem cells (mBMSCs) to assess the cellular response and pelvic ligament tissue engineering in vitro. The cellular responses on the composite nanofibers showed that the core-shell structure nanofibers displayed with excellent biocompatibility and enhanced cellular activity without cytotoxicity. Moreover, compared with PLLA nanofibers seeded with mBMSCs, PLLA/HA nanofibers exhibited more cellular function, as revealed by the quantitative real-time polymerase chain reaction (RT-qPCR) for pelvic ligament-related gene markers including Col1a1, Col1a3 and Tnc. These features suggested that this novel core-shell nanofiber is promising in stem cell-based tissue engineering for pelvic reconstruction.

Narrative review of the epidemiology, diagnosis and pathophysiology of pelvic organ prolapse.

ABSTRACTThe exact prevalence of pelvic organ prolapse is difficult to establish. The anatomical changes do not always consist with the severity or the symptoms associated with prolapse. There are many risk factors associated with pelvic organ prolapse and this review aims to identify the epidemiology and pathophysiology while looking at the known risk factors for pelvic organ prolapse. PubMed search involved a number of terms including: epidemiology, risk factors, reoccurrence indicators, management and evaluation. Several risk factors have been associated with pelvic organ prolapse, all contribute to weakening of the pelvic floor connective tissue/collagen, allowing the pelvic organs to prolapse through the vaginal walls. Among the risk factors are genetic background, childbirth and mode of delivery, previous hysterectomy, menopausal state and the ratio between Estrogen receptors. The “Integral theory” of Petros and the “Levels of Support” model of Delancey enable us to locate the defect, diagnose and treat pelvic organ prolapse.The currently available demographic data is not reliable enough to properly estimate the true extent of pelvic organ prolapse in the population. However, standardization of the diagnosis and treatment may significantly improve our ability to estimate the true incidence and prevalence of this condition in the coming years.

Metabolomics study of serum and urine samples reveals metabolic pathways and biomarkers associated with pelvic organ prolapse

Pelvic organ prolapse (POP) is a common medical condition among women and involves complicated diagnostics and controversial surgical management. The exact molecular mechanism underlying POP is poorly understood, especially at the metabolism level. To explore the metabolic mechanism underlying POP and discover potential biomarkers for POP diagnosis, we applied a non-targeted metabolomics approach using ultra-high performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF-MS). Metabolomics study of serum samples from patients with POP (n = 24) and controls (n = 22) revealed a total of 59 metabolites that are significantly different (VIP ≥ 1 and p ≤ 0.05) between the two groups. Between urine samples from POP patients (n = 45) and controls (n = 59), 33 metabolites differed significantly (VIP ≥ 1 and p ≤ 0.05). Metabolic pathways affected by these differentially expressed metabolites were analyzed. In both serum and urine samples, three pathways including arginine biosynthesis and purine metabolism were found to be significantly related to POP. Six metabolites including GPC, 1-methyladenosine, maleic acid, L-pyroglutamic acid, inosine, and citrate are significantly changed (VIP ≥ 1 and p ≤ 0.05) in both serum and urine samples from patients with POP. Receiver operating characteristics (ROC) curve analysis showed that using these six metabolites as a biomarker could distinguish patients with POP from controls with good accuracy in both serum (AUC = 1) and urine samples (AUC = 0.854). Collectively, these results further extended our understanding of key regulatory metabolic pathways involved in the pathophysiology of POP, as well as provided some promising biomarkers for effective POP diagnosis.

Management of Occult Urinary Incontinence with Prolapse Surgery.

The purpose of this paper is to review (1) the epidemiology and pathophysiology of pelvic organ prolapse (POP) and occult stress urinary incontinence (SUI), (2) examine the data on combined operative management of POP and occult SUI, (3) discuss the approaches to clinical decision making, and (4) present future therapies. Prospective data on many approaches to concomitant treatment of prolapse and occult stress urinary incontinence, such as minimally invasive sacrocolpopexy and midurethral sling, or older approaches that have regained favor among patients and clinicians wishing to avoid synthetic mesh, such as native tissue prolapse repair and pubovaginal sling, are limited. Safe durable treatments with absorbable graft materials that promote a beneficial host response are intriguing but may be far from clinical implementation. Stem cell therapy for the treatment of stress urinary incontinence has demonstrated benefit in phase I/II trials but has not been studied in the setting of concomitant treatment of occult SUI with POP surgery and remains in the preclinical phase for the treatment of POP. A personalized approach to concomitant SUI surgery that incorporates individual risk assessment as well as informed patient preferences likely optimizes the risk/benefit ratio and patient satisfaction. Novel therapies, including graft materials and cellular therapies that stimulate a regenerative response, may improve or maintain continence outcomes while mitigating risk and alter the approach to both POP and SUI surgery.

Expressions of homeobox, collagen and estrogen genes in women with uterine prolapse

ObjectiveGenetic contribution is thought to be involved in the pathophysiology of pelvic organ prolapse (POP). We aimed to study the gene expression profiles of the genes HomeoboxA11 (HOXA11), HomeoboxA13 (HOXA13), Collagen Type I (COL1A), Collagen Type III (COL3A), estrogen receptor genes (ESR1 and ESR2) of round (RL) and uterosacral ligaments (USL) in postmenopausal women with uterine prolapse. Study designGene expressions of 32 postmenopausal women with prolapse were analysed according to gene expressions of 8 postmenopausal women without prolapse. Quantitative real-time PCR (qRT-PCR) method was used for the detection of expression levels of the genes. Student’s t-Test and Mann–Whitney U test were used for statistical analysis. ResultsIn the USL specimens of all women with uterine prolapse HOXA13 and ESR1 gene expressions were decreased compared to controls (0.5 fold, p = 0.04 and 0.82 fold, p = 0.04, respectively). In the RL specimens, ESR2 gene expression was decreased 0.7 fold in women with prolapse when compared to controls (p = 0.04).In the USL specimens of women with advanced stages of prolapse (stage ≥3), HOXA13 and COL3A gene expressions were decreased compared to controls (0.44 fold, p = 0.043 and 0.39 fold, p = 0.045, respectively). In the RL specimens, ESR2 gene expression was decreased 0.65 fold in women with prolapse when compared to controls (p = 0.052). ConclusionThe significant decrease in the expression of the genes HOXA13, COL3A in the USL and ESR2 in the RL especially in advanced stages of prolapse, implicate that these gene expressions may play a role in the development of uterine prolapse.

Immunolocalization of Advanced Glycation End Products, Mitogen Activated Protein Kinases, and Transforming Growth Factor-β/Smads in Pelvic Organ Prolapse.

Collagen and matrix metalloproteinases (MMP) play a pivotal role in the pathophysiology of Pelvic Organ Prolapse (POP) as a switch between type I and III collagen together with a simultaneous activation of MMPs have been observed in the vaginal wall. The aim of this study was to evaluate the Advanced Glycation End (AGE) products, ERK1/2 and transforming growth factor (TGF)-β/Smad pathway expression in muscularis propria in women with POP compared with control patients. We examined 20 patients with POP and 10 control patients treated for uterine fibromatosis. Immunohistochemical analysis using AGE, RAGE, ERK1/2, Smads-2/3, Smad-7, MMP-3, and collagen I-III, TIMP, and α-SMA were performed. Smad-2/3, Smad-7, AGE, ERK1/2, p-ERK, and p-Smad3 were also evaluated using Western-blot analysis. POP samples from the anterior vaginal wall showed disorganization of the normal muscularis architecture. In POP samples, AGE, ERK1/2, Smad-2/3, MMP-3, and collagen III were upregulated in muscularis whereas in controls, Smad-7 and collagen I were increased. The receptor for AGEs (RAGE) was mild or absent both in controls and prolapse. We demonstrated the involvement of these markers in women with POP but further studies are required to elucidate if the overexpression of these molecules could play a crucial role in the pathophysiology of POP disease.

Biomechanical Mapping of the Female Pelvic Floor: Prolapse versus Normal Conditions.

Background:Quantitative biomechanical characterization of pelvic supportive structures and functions in vivo is thought to provide insight into pathophysiology of pelvic organ prolapse (POP). An innovative approach—vaginal tactile imaging—allows biomechanical mapping of the female pelvic floor to quantify tissue elasticity, pelvic support, and pelvic muscle functions. The Vaginal Tactile Imager (VTI) records high definition pressure patterns from vaginal walls under an applied tissue deformation and during pelvic floor muscle contractions.Objective:To explore an extended set of 52 biomechanical parameters for differentiation and characterization of POP relative to normal pelvic floor conditions.Methods:96 subjects with normal and POP conditions were included in the data analysis from multi-site observational, case-controlled studies; 42 subjects had normal pelvic floor conditions and 54 subjects had POP. The VTI, model 2S, was used with an analytical software package to calculate automatically 52 biomechanical parameters for 8 VTI test procedures (probe insertion, elevation, rotation, Valsalva maneuver, voluntary muscle contractions in 2 planes, relaxation, and reflex contraction). The groups were equalized for subject age and parity.Results:The ranges, mean values, and standard deviations for all 52 VTI parameters were established. 33 of 52 parameters were identified as statistically sensitive (p < 0.05; t-test) to the POP development. Among these 33 parameters, 11 parameters show changes (decrease) in tissue elasticity, 8 parameters show deteriorations in pelvic support and 14 parameters show weakness in muscle functions for POP versus normal conditions.Conclusions:The biomechanical mapping of the female pelvic floor with the VTI provides a unique set of parameters characterizing POP versus normal conditions. These objectively measurable biomechanical transformations of pelvic tissues, support structures, and functions under POP may be used in future research and practical applications.

Transcriptional Regulation of Connective Tissue Metabolism Genes in Women With Pelvic Organ Prolapse.

The aim of this study was to compare differences in expressions and relationships between key genes involved in extracellular matrix metabolism and tissue cellularity in women with and without pelvic organ prolapse (POP). A total of 80 biopsies (anterior cuff, posterior cuff, and/or leading edge) were obtained from 30 women: n = 10 premenopausal without POP (controls), n = 10 premenopausal with POP, and n = 10 postmenopausal with POP. Quantitative reverse-transcriptase polymerase chain reaction was used to assess gene expression of bone morphogenetic protein 1 (BMP1), collagen types I (COL1) and III (COL3), relaxin family peptide receptor 1 (RXFP1), matrix metallopeptidase 2, and TIMP metallopeptidase inhibitors 2 and 3. Hematoxylin and eosin staining was used to assess cellularity of the connective tissue layer. Kruskal-Wallis test, Mann-Whitney U test, Pearson correlation, or linear regression analyses were used, as appropriate. Bone morphogenetic protein 1 expression was significantly up-regulated in patients with POP compared with controls. Bone morphogenetic protein 1 expression was correlated with COL1 expression in all groups but only correlated with TIMP metallopeptidase inhibitor 3 expression in controls. Similarly, COL3 expression was correlated with RXFP1 expression in women with POP but not in controls. The degree of dependence (slope of the regression line) between COL1 and COL3 expressions was significantly elevated in premenopausal women with POP compared with the other 2 groups. The slopes between COL1-COL3, COL3-matrix metallopeptidase 2, COL1-RXFP1, and COL3-RXFP1 expressions were significantly lower in postmenopausal women compared with premenopausal women with POP. No differences were found in overall tissue cellularity. Bone morphogenetic protein 1 expression may play a significant role in the pathophysiology of POP. The finding that BMP1 expression was correlated with COL1 expression in all groups suggests a conserved association between BMP1 and collagen synthesis in the vaginal wall. The elevated slope between COL1 and COL3 expressions may be associated with early (premenopausal) development of POP. The expression of RXFP1 in postmenopausal women and its altered intergene regulation suggests a role for RXFP1 in connective tissue metabolism outside pregnancy.

How common is ballooning? Hiatal area on 3D transperineal ultrasound in urogynecological patients and its association with lower urinary tract symptoms.

Pelvic floor ultrasound plays a major role in urogynecologic diagnostics. Using 3D ultrasound we can identify integrity of levator ani and measure hiatal area in the axial plane. The main goal of our study was to measure hiatal area on Valsalva in a cohort of urogynecological patients. Furthermore, we aimed to correlate hiatal area with urogynecological symptoms, levator integrity and evaluate cut-off values for pelvic organ prolapse. In a retrospective analysis, we included 246 patients seen for urogynecological problems in our tertiary urogynecological unit. After a standardized interview and physical examination, a 3D pelvic floor ultrasound was performed. According to the cardinal urogynecological symptoms and signs, patients were categorized into three groups: pelvic organ prolapse, stress urinary incontinence and overactive bladder symptoms. Median age of our study population was 66 (range 29-94) years, median parity was 2.1 (range 0-9) with 17 (6.9%) nulliparous women. Symptoms of overactive bladder in 71.1% were most common, followed by 54.5% symptoms of stress incontinence and 32.1% symptoms of prolapse. On examination 49.2% showed signs of prolapse. Levator avulsions on 3D ultrasound were detected in 20.7%. Hiatal area was normally distributed with a median of 28.7cm2 (range 10.4-50.0cm2). Patients with levator avulsion had a significantly larger hiatal area (p<0.001). Also patients with signs of prolapse had a significantly larger hiatal area (p<0.001). There was no correlation between hiatal area and symptoms of overactive bladder (p=0.374). Although not reaching statistical significance there was evidence of a smaller hiatal area for patients with stress incontinence (p=0.016). In our cohort there were 33.7% (83) women without ballooning, 27.2% (67) showed mild, 18.3% (45) moderate, 12.3% (30) marked and 8.5% (21) severe ballooning. The ROC curve analysis for hiatal area on patients with prolapse yielded an AUC of 0.755 [95% CI (0.696-0.814)]. Using the Youden-Index we obtained 27.53cm2 as a cut-off with a sensitivity of 0.70 and a specificity of 0.69. Hiatal area is a new repeatable diagnostic parameter. Its clinical application could improve our understanding of the pathophysiology of pelvic organ prolapse as a form of hiatal hernia.

The Epi-No(®) birth trainer does not prevent birth trauma.

I Kamisan Atan and co-authors are to be congratulated for their rigorously designed and performed randomised controlled trial (RCT) of an interesting and clinically important question: can progressive vaginal distension, by use of an inflated vaginal balloon device in late pregnancy, decrease the occurrence of birth trauma? Unfortunately, the answer appears to be ‘no’. The pathophysiology of pelvic organ prolapse is becoming better understood, particularly with adva-nces in multidimensional magnetic resonance imaging (MRI) and ultrasound imaging (Singh et al. Am J Obstet Gynecol 2003;188:910–5) that detect subclinical pelvic changes related to vaginal birth, which has long been recognised as an important risk factor for prolapse. To allow passage of the evolutionarily large fetal head through a woman's pelvis, the pelvic muscles must undergo dramatic deformation, so it is not surprising that pelvic muscle damage, either avulsion or over-distension, occurs in as many as one-third of women having their first vaginal birth (Dietz et al. BJOG 2008;115:979–84). Similarly, results of this RCT found pelvic muscle damage in 27% of women, with levator avulsion in 13.1% and over-distension (termed microtrauma in this trial) in 13.8%. In contrast to the results of a small observational study that reported a significantly higher chance of delivery with an intact perineum in women who used the Epi-No device, compared with standard practice (Kovacs et al. Aust NZ J Obstet Gynaecol 2004;44:347–48), perineal outcomes in this trial did not differ between groups. Overall, approximately three-quarters of women achieved vaginal delivery, with half delivering over an intact perineum and about one-quarter undergoing episiotomy. The trial results confirmed the under-diagnosis of obstetric anal sphincter damage, which was clinically recognised in only 5–7% of women, equally in both groups, versus 17.6% found by ultrasound. Overall, the RCT results were reassuring regarding safety: the use of the birth trainer did not seem to cause pelvic damage, with the possible exception of an increased risk of ultrasound-diagnosed external anal sphincter defect, which was marginally statistically significant in the intention-to-treat analysis (21% in the intervention group versus 14% in the control group; risk ratio, RR, 1.44; P = 0.07), and statistically significant in the treatment-received analysis (22 versus 12%, respectively; RR 1.76; P = 0.007). Is it possible, then, to alter the biomechanical properties of the pelvic muscles to protect them from damage during vaginal birth? This trial was not designed to answer that specific question; however, I believe the authors appropriately chose to study the clinical impact of their intervention. If any impact had been observed, it would then be possible to establish the mechanism by which the impact occurred. Negative results may seem disappointing, but they are an important contribution to the growing body of knowledge about birth trauma and later consequences for pelvic floor function. Birth-related pelvic damage cannot currently be predicted and, at least for levator avulsion, once such damage has occurred, it appears to be irreversible. Thus, ideally, the results of further research will inform changes in prenatal, obstetric, and postnatal practices to improve pelvic health, and its related quality-of-life impact, for women. None declared. Completed disclosure of interests form available to view online as supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Collagen metabolic disorder induced by oxidative stress in human uterosacral ligament‑derived fibroblasts: A possible pathophysiological mechanism in pelvic organ prolapse.

Pelvic organ prolapse (POP) is a global health problem, for which the pathophysiological mechanism remains to be fully elucidated. The loss of extracellular matrix protein has been considered to be the most important molecular basis facilitating the development of POP. Oxidative stress (OS) is a well-recognized mechanism involved in fiber metabolic disorders. The present study aimed to clarify whether OS exists in the uterosacral ligament (USL) with POP, and to investigate the precise role of OS in collagen metabolism in human USL fibroblasts (hUSLFs). In the present study, 8-hydroxyguanosine (8-OHdG) and 4 hydroxynonenal (4-HNE), as oxidative biomarkers, were examined by immunohistochemistry to evaluate oxidative injury in USL sections in POP (n=20) and non-POP (n=20) groups. The primary cultured hUSLFs were treated with exogenous H2O2 to establish an original OS cell model, in which the expression levels of collagen, type 1, α1 (COL1A1), matrix metalloproteinase (MMP)-2, tissue inhibitor of metalloproteinase (TIMP)-2 and transforming growth factor (TGF)-β1 were evaluated by western blot and reverse transcription-quantitative polymerase chain reaction analyses. The results showed that the expression levels of 8-OHdG and 4-HNE in the POP group were significantly higher, compared with those in the control group. Collagen metabolism was regulated by H2O2 exposure in a concentration-dependent manner, in which lower concentrations of H2O2 (0.1–0.2 mM) stimulated the anabolism of COL1A1, whereas a higher concentration (0.4 mM) promoted catabolism. The expression levels of MMP-2, TIMP-2 and TGF-β1 exhibited corresponding changes with the OS levels. These results suggested that OS may be involved in the pathophysiology of POP by contributing to collagen metabolic disorder in a severity-dependent manner in hUSLFs, possibly through the regulation of MMPs, TIMPs and TGF-β1 indirectly.

Fibulin-5 (FBLN5) gene polymorphism is associated with pelvic organ prolapse

ObjectiveFBLN5 encodes a key protein of elastic fiber matrix assembly and function that contributes to maintaining pelvic support and plays the important role in the pathophysiology of pelvic organ prolapse (POP). The aim of the study was to investigate whether there is an association between common single-nucleotide polymorphisms (SNPs) of the FBLN5 gene and POP. Study designA total of eleven tag SNPs of the FBLN5 gene were genotyped using the polymerase chain reaction with confronting two-pair primers (PCR-CTPP) in 210 patients with POP (stages III–IV) and 292 controls with no even minimal POP. ResultsWe revealed significant associations of tag SNPs rs2018736 and rs12589592 with POP. The top association signal was found for SNP rs2018736 (protective effect for the minor allele A) in the entire set: p=0.0026, OR=0.42, 95% CI: 0.24–0.75; in the stratum with pelvic floor trauma: p=0.0018, OR=0.27, 95% CI: 0.11–0.64; and in the stratum with fetal macrosomia: p=0.013, OR=0.14, 95% CI: 0.03–0.71. The results of the haplotype analyses were consistent with the single SNP analysis. In the strata without perineal trauma and fetal macrosomia effects were non-significant, possibly, due to the smaller effect sizes. ConclusionsCurrent data provide, for the first time, strong evidence that common SNPs of the FBLN5 gene are associated with POP especially after pelvic floor injury.

UVA-Photoactivated Riboflavin Treatment of Vaginal Cells Derived from Pelvic Organ Prolapse Cases

Background: The pathophysiology of pelvic organ prolapse (POP) involves vaginal collagen degradation. Strengthening collagen by UVA-photoactivated cross-linking has been demonstrated and suggested target applications include the vaginal wall. Aim: To identify UVA irradiation and riboflavin effects on vaginal cells. Materials and Methods: Vaginal cells were incubated for 24 h (DMEM/F-12 Ham's media) and were exposed to riboflavin (0, 0.1 and 10%) for 30 min before UVA photoactivation. Percentages of live, apoptotic and necrotic cells were determined by propidium iodide/Hoechst 33342 stains. Results: UVA decreased vaginal cell viability [mean ± standard error of the mean: 26.2 ± 0.5% vs. control (43.9 ± 3.8%)], but riboflavin blocked UVA-induced damage (57.9 ± 2.7 and 56.7 ± 2.1% at 0.1 and 10% riboflavin, respectively). Cells treated with low- and high-dose riboflavin had lower apoptosis (32.9 ± 1.0 and 35.5 ± 0.9%, respectively). Furthermore, riboflavin-treated cells had reduced necrosis (9.3 ± 1.7, 7.8 ± 3.0%) versus UVA-only (32.4 ± 5.5%) or control (17.1 ± 2.8%). Viability was similar for cells from the cervical and hymenal segments. Conclusion: The results demonstrated that riboflavin attenuated UVA damage in vaginal cells by inhibiting necrosis. Cervical and hymenal end vaginal cells were equally affected by UVA. UVA phototoxicity was reduced by the presence of riboflavin.