Description): Pelvic floor dysfunction including urinary incontinence and pelvic organ prolapse is a major health issue for women resulting in an 11 percent lifetime risk of requiring surgery. The cost of urinary incontinence alone in 1995 alone was estimated at $26 billion in the United States. Several studies have identified pregnancy related risk factors for pelvic floor dysfunction including vaginal parity, increased infant birth weight, forceps and vacuum assisted vaginal delivery, episiotomy and prolonged second stage of labor. However, vaginal delivery fails to fully explain the genesis and progression of pelvic floor dysfunction since severe pelvic organ prolapse has been observed in nulliparous women and most women who deliver vaginally do not develop prolapse. Pelvic organ prolapse and urinary incontinence result from failure of the support mechanism derived from pelvic fascia and muscles. Many researchers have hypothesized that a parturition-related denervation injury to the female pelvic floor leads to weakness of the levator ani muscles which in turn results in marked stress placed on the uterosacral cardinal ligaments and endopelvic fascia, ultimately leading to secondary failure of the fascia and development of prolapse. Other studies suggest a primary failure of the fascia. Associations have been reported between prolapse, joint hypermobility and abdominal striac suggesting a generalized connective tissue defect affecting pelvic organ support, joints and skin. One explanation is a defect in collagen biosynthesis. Such a generalized connective tissue disorder might affect collagen's biomechanical strength and be explained at the genetic level. The long-term objective, therefore, is to gain insight into the mechanisms of pelvic floor dysfunction through the study of collagen at the molecular and biochemical levels. Collagen cross-linking is critical for the stability and mechanical strength of the collagen molecule and for the cohesiveness of the collagen fibrils. Hydroxylation of lysine is critical for the cross-linking process and the level of hydroxylation varies among tissues, Lysyl oxidase and lysyl hydroxylase are two enzymes involved in the early steps of the cross-linking process. We hypothesize that alterations in the intermolecular cross-linking may result in weakened connective tissue which may lead to pelvic floor dysfunction. Few studies have examined the biochemical nature of connective tissue or genetic differences in women with pelvic floor dysfunction.
The specific aims are to compare: 1. total collagen content, 2. the six characterized collagen cross-links, 3. the ratio of Type I/III collagen, 4. the level of lysine hydroxylation, 5. collagen solubility, and 6. the genes coding for lysyl oxidase and the three isoforms of lysyl hydroxylase (LH1, LH2, LH3), in patients with advanced-stage pelvic organ prolapse and age and parity matched controls. This study would be the first large-scale comprehensive description of collagen cross-linking, lysine hydroxylation, and of genes coding for enzymes involved in the cross-linking process, in patients with pelvic organ prolapse.
|Hundley, Andrew F; Yuan, Lingwen; Visco, Anthony G (2008) Gene expression in the rectus abdominus muscle of patients with and without pelvic organ prolapse. Am J Obstet Gynecol 198:220.e1-7|
|Hundley, Andrew F; Yuan, Lingwen; Visco, Anthony G (2006) Skeletal muscle heavy-chain polypeptide 3 and myosin binding protein H in the pubococcygeus muscle in patients with and without pelvic organ prolapse. Am J Obstet Gynecol 194:1404-10|
|Visco, Anthony G; Yuan, Lingwen (2003) Differential gene expression in pubococcygeus muscle from patients with pelvic organ prolapse. Am J Obstet Gynecol 189:102-12|