Una Lee, A. Marcus Gustilo-Ashby, Nanette Kleinman, Firouz Daneshgari, Tiansen Li, Margot Damaser, Cleveland Clinic, Cleveland VA, Case Western University, Cleveland, OH, Harvard University, Boston, MA

Introduction and Objectives: Parity and its frequency are among the recognized risk factors for Pelvic Organ Prolapse (POP) in humans. Mice lacking the Lysl oxidase-like 1 (Loxl1) protein have been reported to develop POP by 1-2 days post partum. Our objective was to describe the incidence, variability, and severity of the manifestation of POP during the post partum period and as it relates to parity in the Loxl1-deficient mice and in comparison to the incidence of POP in a large colony of mice at an academic institution.

Methods: Loxl1-/- mice on a mixed Sv129 and C57Bl/6 background were maintained in the Cleveland Wade Park VA animal research facility. Breeding was conducted with single male-female pairs of Loxl1-/- mice and harem breeding of two females and one male. Evidence of prolapse was observed over a nine month period. POP was graded on a scale of 0-4 for perineal bulge (0 none, 1 mild perineal bulge, 2 moderate perineal bulge, 3 severe perineal bulge, and 4 for overt external uterine prolapse) using a recently described MOPQ Scale. Rectal prolapse was also noted, and graded on a scale from 0-2 (0 none, 1 mild, 2 severe). In addition, a review of the veterinarian morbidity and mortality records at the Case Western University animal facility was conducted for a 6 month period (March to September 2006). This facility examines over 20,000 mouse cages which consist of over 50,000 mice.

Results: Nulliparous Loxl-/- mice had no evidence of POP from birth until 12-16 weeks (n=16). Loxl-/- mice with Ceasarean section (C/S) did not have any evidence of POP by post partum day 4 (n=4). C/S was not ultimately protective of POP development as in one Loxl-/- mouse which had shown no evidence of POP during 3 months post partum of the first C/S. This mouse developed grade 1 POP and grade 1 rectal prolapse 2 weeks post partum and progressed to grade 2 POP and grade 2 rectal prolaspe 4 weeks post partum after her spontaneous vaginal delivery of the second pregnancy. We have noted further variation in POP development as demonstrated in 15 parous Loxl1-/- mice. Seven have no current evidence of POP: 3 have no POP after 1 delivery, 1 has no POP after 2 deliveries, 2 have no POP after 3 deliveries, and 1 has no POP after 4 deliveries. Eight Loxl1-/- mice have developed POP: 2 after the 1^st delivery, 4 after the 2^nd delivery, 1 after the 3^rd delivery, and 1 after the 4^th delivery. No mice have had more than 4 deliveries.

We observed that once POP develops, the grade of perineal bulge becomes more severe with age and parity. Mice are able to get pregnant and deliver with rectal prolapse (grade 1-2) and mild uterine prolapse (grade 1-2), but not with severe POP (Grade 3). No cervical descent was noted in our Loxl1-/- colony. All uterine prolapsed mice had concurrent rectal prolapse. Often, rectal prolapse preceded uterine prolapse, otherwise they appeared concurrently. Rectal prolapse also became more severe with time and age.

No POP was observed in our colony of C57Bl/6 control mice with one exception. One C57Bl/6 mice developed grade 4 prolapse after delivery of her third litter. The POP subsequently regressed and no bulge was visible. She became pregnant again, and was euthanized for a post-mortum examination. This compares to an incidence of two uterine prolapses confirmed by the animal facility records; of which one was in a C57Bl/6 mouse and one was in a BDNF related mouse. Normal mice develop pelvic organ prolapse, although the incidence is quite rare.

Conclusion: Although variable, the incidence of POP in Loxl1-/- mice is higher than in a normal mouse population. Development of POP in Loxl1 deficient mice varies according to the status of their parentage (with or without prolapse); their genetic background (C57Bl/6, Sv129), and frequency of parity. Such variability in the manifestation of POP is representative of the clinical situation in which the influence of environmental factors (frequency of parity, mode of delivery) likely impacts upon a potentially genetically vulnerable background (altered elastin homeostasis). The Loxl1 deficient mice are a promising model for investigation of the clinical phenomena of pelvic organ prolapse in women.

Acknowledgements: Cleveland Clinic and Wade Park VAMC

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