Identifying precursor phenotypes of pelvic organ prolapse by quantifying pelvic floor functional reserve: a novel approach to advancing prevention efforts - ABSTRACT Up to 1 in 5 women undergo surgical treatment for pelvic organ prolapse (POP) yet we know little about its pathogenesis; thus, women receive interventions for POP only once they have reached end-stage disease. Identification of early markers of POP (precursor phenotypes) is needed to identify women at risk of end-stage POP and to develop effective preventative strategies, which currently do not exist. Our long-term goal is to change the status quo from treatment of end-stage POP to prevention of early POP through screening and early detection. Well-established risk factors for POP include aging, VD, and family history (FH). The Lifespan Model posits that maximal pelvic floor functional reserve (PF reserve), or its capacity to function optimally at full growth based on each person’s unique structural properties, is largely predetermined. PF reserve declines throughout life, due primarily to VD and aging. End-stage POP develops once PF reserve is impaired below a specific threshold and those who begin with a lower PF reserve will reach this threshold sooner. Women who undergo POP surgery before they reach 45 years are 5-fold more likely to have a FH of POP, supporting the concept that PF reserve is heritable. Childbirth induced levator ani muscle (LAM) avulsion, where the pelvic floor muscle is torn, is a major risk factor for POP, but is only present in ~50% of POP cases. An understanding of PF reserve will fill in critical knowledge gaps about the pathogenesis of POP, why effects of VD and aging differ amongst women according to their FH risk, and ultimately will provide avenues to identify prevention and early therapeutic strategies based on phenotypes of PF reserve. Using MRI, clinical measures, and RNA sequencing of the LAM, we plan to quantify structural, functional, and cellular & molecular domains of PF reserve in women without LAM avulsion and prior to the onset of age- related changes. Four groups of women, 18-30 yo, will be selected based on FH and VD risk. The objective of Aim 1 is to quantify the effect of FH risk on baseline PF reserve prior to VD. The objective of Aim 2 is to quantify the effect of FH risk on PF reserve after the first VD. Using Aims 1&2 data, we will determine, for the first time in humans, correlations between primary cellular/molecular pathways and structural/functional pelvic floor parameters. In Aim 3, we will apply these PF reserve results to a validated biomechanical platform (POP- SIM) to quantify PF reserve and identify parameters with the greatest impact on POP development. Our overall objective is to test the hypothesis that FH risk, defined as ≥1 first-degree relative with POP, impairs PF reserve and that VD increases the magnitude of that effect in the absence of well-established risk factors of LAM avulsion and aging. At the end of this project, we expect to have identified POP precursor phenotypes that can be validated in future studies and used to develop a new domain of research in the area of POP prevention.
