Women's health is severely impacted by pelvic organ prolapse (pop), a highly prevalent condition that results from abnormal elongation and breaks of the connective tissue of the vaginal walls and its paravaginal attachments. The functional consequences of POP include vaginal protrusion, urinary incontinence, and voiding disorders, conditions that often demand surgical treatment. The underlying causes of POP are unknown, through hormonal deprivation, multiparity, and aging are all impacted. The work proposed addresses the role of steroid hormones, aging and parity in the rhesus macaque vagina. Preliminary data indicate that this model system is a valid and clinically relevant one for the study of pelvic floor disorders. The working hypothesis is that hormonal deprivation will lead to decreases in specific measurable endpoints, including steroid receptor levels, collagen density, elastin density and extracellular matrix components in the vaginal wall, and that these changes will be associated with decreases in biomechanical strength. Further aspects of the hypothesis are that matrix metalloproteinases will be up-regulated in hormonally deficient environments and that these degradative enzymes play a role in weakening the vaginal wall. Finally it is hypothesized that the degradative changes caused by hormonal deprivation can be reversed by appropriate hormonal replacement therapy, and that the response may vary with aging and parity. To examine these hypotheses the above mentioned endpoints will be measured in the vaginal fibromuscular wall and its paravaginal attachments and will be correlated with changes in biomechanical strength in both multiparous and nulliparous macaques.
The specific aims will evaluate: 1) hormone replacement immediately after ovariectomy, 2) hormonal replacement after long term estrogen deprivation, 3) the rate of matrix metalloproteinase up-regulation after ovariectomy, and 4) properties of the vaginal wall in naturally aged macaques. Special attention will be paid to the effects of a SERM (raloxifene) as there are tow reports that experimental SERMs increase the incidence of POP. The SERM (raloxifene) as there are two reports that experimental SERMS increase the incidence of POP. The results will provide entirely novel data on the role of hormonal deprivation, parity and age on the anterior vaginal wall and its paravaginal attachments in a rigorously controlled primate model of direct clinical relevance to POP.
| Clark, Amanda L; Slayden, Ov D; Hettrich, Kevin et al. (2005) Estrogen increases collagen I and III mRNA expression in the pelvic support tissues of the rhesus macaque. Am J Obstet Gynecol 192:1523-9 |
| Slayden, Ov D; Hettrich, Kevin; Carroll, Rebecca S et al. (2004) Estrogen enhances cystatin C expression in the macaque vagina. J Clin Endocrinol Metab 89:883-91 |
| Otto, Lesley N; Slayden, Ov D; Clark, Amanda L et al. (2002) The rhesus macaque as an animal model for pelvic organ prolapse. Am J Obstet Gynecol 186:416-21 |
