Shayzreen M. Roshanravan

Extracellular matrix proteases contribute to progression of pelvic organ prolapse in mice and humans

Pelvic organ prolapse (POP) is a common condition affecting almost half of women over the age of 50. The molecular and cellular mechanisms underlying this condition, however, remain poorly understood. Here we have reported that fibulin-5, an integrin-binding matricellular protein that is essential for elastic fiber assembly, regulated the activity of MMP-9 to maintain integrity of the vaginal wall and prevented development of POP. In murine vaginal stromal cells, fibulin-5 inhibited the β1 integrin-dependent, fibronectin-mediated upregulation of MMP-9. Mice in which the integrin-binding motif was mutated to an integrin-disrupting motif (Fbln5RGE/RGE) exhibited upregulation of MMP-9 in vaginal tissues. In contrast to fibulin-5 knockouts (Fbln5-/-), Fbln5RGE/RGE mice were able to form intact elastic fibers and did not exhibit POP. However, treatment of mice with β-aminopropionitrile (BAPN), an inhibitor of matrix cross-linking enzymes, induced subclinical POP. Conversely, deletion of Mmp9 in Fbln5-/- mice significantly attenuated POP by increasing elastic fiber density and improving collagen fibrils. Vaginal tissue samples from pre- and postmenopausal women with POP also displayed significantly increased levels of MMP-9. These results suggest that POP is an acquired disorder of extracellular matrix and that therapies targeting matrix proteases may be successful for preventing or ameliorating POP in women.

Failure of Pelvic Organ Support in Mice Deficient In Fibulin-3

Fibulin-5 is crucial for normal elastic fiber synthesis in the vaginal wall; more than 90% of fibulin-5-knockout mice develop pelvic organ prolapse by 20 weeks of age. In contrast, fibulin-1 and -2 deficiencies do not result in similar pathologies, and fibulin-4-knockout mice die shortly after birth. EFEMP1 encodes fibulin-3, an extracellular matrix protein important in the maintenance of abdominal fascia. Herein, we evaluated the role of fibulin-3 in pelvic organ support. Pelvic organ support was impaired significantly in female Efemp1 knockout mice (Fbln3(-[supi]/-)), and overt vaginal, perineal, and rectal prolapse occurred in 26.9% of animals. Prolapse severity increased with age but not parity. Fibulin-5 was up-regulated in vaginal tissues from Fbln3(-[supi]/-) mice regardless of prolapse. Despite increased expression of fibulin-5 in the vaginal wall, pelvic organ support failure occurred in Fbln3(-[supi]/-) animals, suggesting that factors related to aging led to prolapse. Elastic fiber abnormalities in vaginal tissues from young Fbln3(-[supi]/-) mice progressed to severe elastic fiber disruption with age, and vaginal matrix metalloprotease activity was increased significantly in Fbln3(-[supi]/-) animals with prolapse compared with Fbln3(-[supi]/-) mice without prolapse. Overall, these results indicate that both fibulin-3 and -5 are important in maintaining pelvic organ support in mice. We suggest that increased vaginal protease activity and abnormal elastic fibers in the vaginal wall are important components in the pathogenesis of pelvic organ prolapse.

Anterior abdominal wall nerve and vessel anatomy: clinical implications for gynecologic surgery

OBJECTIVEnWe sought to describe relationships of clinically relevant nerves and vessels of the anterior abdominal wall.nnnSTUDY DESIGNnThe ilioinguinal and iliohypogastric nerves and inferior epigastric vessels were dissected in 11 unembalmed female cadavers. Distances from surface landmarks and common incision sites were recorded. Additional surface measurements were taken in 7 other specimens with and without insufflation.nnnRESULTSnThe ilioinguinal nerve emerged through the internal oblique: mean (range), 2.5 (1.1-5.1) cm medial and 2.4 (0-5.3) cm inferior to the anterior superior iliac spine (ASIS). The iliohypogastric emerged 2.5 (0-4.6) cm medial and 2.0 (0-4.6) cm inferior. Inferior epigastric vessels were 3.7 (2.6-5.5) cm from midline at the level of the ASIS and always lateral to the rectus muscles at a level 2 cm superior to the pubic symphysis.nnnCONCLUSIONnRisk of anterior abdominal wall nerve and vessel injury is minimized when lateral trocars are placed superior to the ASISs and >6 cm from midline and low transverse fascial incisions are not extended beyond the lateral borders of the rectus muscles.

Effects of Preoperative Local Estrogen in Postmenopausal Women With Prolapse: A Randomized Trial

CONTEXTnPelvic organ prolapse (POP) increases in prevalence with age; recurrence after surgical repair is common.nnnOBJECTIVEnThe objective of the study was to determine the effects of local estrogen treatment on connective tissue synthesis and breakdown in the vaginal wall of postmenopausal women planning surgical repair of POP.nnnDESIGNnThis was a randomized trial.nnnSETTINGnThe study was conducted at an academic tertiary medical center.nnnPATIENTS OR OTHER PARTICIPANTSnPostmenopausal women with a uterus and symptomatic anterior and/or apical prolapse at stage 2 or greater participated in the study.nnnINTERVENTIONnEstrogen (Premarin) or placebo cream for 6 weeks preoperatively was the intervention.nnnMAIN OUTCOME MEASURESnFull-thickness anterior apical vaginal wall biopsies were obtained at the time of hysterectomy and analyzed for mucosa and muscularis thickness, connective tissue synthesis, and degradation. Serum levels of estrone and 17β-estradiol were analyzed at baseline and the day of surgery using highly sensitive liquid chromatography-tandem mass spectrometry.nnnRESULTSnFifteen women per group (n = 30 total) were randomized; 13 per group underwent surgery. Among drug-adherent participants (n = 8 estrogen, n = 13 placebo), epithelial and muscularis thickness was increased 1.8- and 2.7-fold (P = .002 and P =.088, respectively) by estrogen. Collagen types 1α1 and 1α2 mRNA increased 6.0- and 1.8-fold in the vaginal muscularis (P < .05 for both); collagen type Ia protein increased 9-fold in the muscularis (P = .012), whereas collagen III was not changed significantly. MMP-12 (human macrophage elastase) mRNA was suppressed in the vaginal mucosa from estrogen-treated participants (P = .011), and matrix metalloprotease-9 activity was decreased 6-fold in the mucosa and 4-fold in the muscularis (P = .02). Consistent with menopausal norms, serum estrone and 17β-estradiol were low and did not differ among the two groups.nnnCONCLUSIONSnVaginal estrogen application for 6 weeks preoperatively increased synthesis of mature collagen, decreased degradative enzyme activity, and increased thickness of the vaginal wall, suggesting this intervention improves both the substrate for suture placement at the time of surgical repair and maintenance of connective tissue integrity of the pelvic floor.

Pathophysiology of Urinary Incontinence, Voiding Dysfunction, and Overactive Bladder

Urinary incontinence and voiding dysfunction are common forms of pelvic floor dysfunction affecting women. The complex interactions between the nervous system and lower urinary tract anatomy allow for the coordinated functions of urine storage and evacuation. A thorough understanding of these components and their interactions is the foundation for the diagnosis and treatment of pathologic conditions affecting urine storage or evacuation. These components include changes in neurologic or muscular function, alterations in anatomy, and the deleterious effects of many common comorbid conditions on the lower urinary tract.