(125) The PTEN/PI3K/AKT signaling pathway exacerbates endometriosis and its associated pain.

Harriet Omenge, Dinh Nam Tran, Tae Hoon Kim and Jae-Wook Jeong

Department of Obstetrics, Gynecology and Women’s Health, University of Missouri, Columbia, MO 65211, USA

Abstract Text:

Endometriosis is a benign gynecological condition in which endometrial-like tissue grows outside of the uterus. It affects 190 million women across the world. Chronic pelvic pain and infertility are some of the debilitating symptoms that diminish the patient’s quality of life. However, the pathogenesis and mechanism that promotes the establishment and survival of endometriotic lesions is unclear. PTEN/PI3K/AKT signaling pathway is critical regulating cell survival and apoptosis. To determine the effect of the PTEN/PI3K/AKT signaling pathway in endometriosis, mice with a uterine-specific Pik3ca^H1047R mutation were developed to activate this signaling pathway using Pgr^cre/+Rosa26^mTmG/+ and Rosa26-Pik3ca^H1047R/+ mice (Pgr^cre/+Rosa26^{mTmG/Pik3ca H1047R}; Pik3ca^act). Endometriosis was surgically induced in control (Pgr^cre/+Rosa26^mTmG/+) and Pik3ca^act mice at 8 weeks of age. One month after endometriosis induction, the number of endometriotic lesions significantly (p < 0.05) increased in Pik3ca^act mice (12.00 ± 1.30) compared to the control group (6.80 ± 1.24). To evaluate the effect of hyperactive PTEN/PI3K/AKT signaling on endometriosis-associated pain, we applied non-reflexive tests based on the decrease or absence of natural behavior in rodents. The non-reflexive tests used were the burrowing and nesting tests. In the burrowing test, 200 g of food was placed into a burrow within a mouse cage, a single mouse was left in the cage for 12 hours. The amount of burrowed food was measured by subtracting the remaining food from the original amount. One month after endometriosis induction, food burrowing was significantly (p < 0.05) decreased in Pik3ca^act mice (99.00 ± 18.25) compared to control mice (154.64 ± 14.45).  For the nesting test, a single nest was placed in a clean cage, where only one mouse was housed for 12 hours. We observed a significant (p < 0.005) decrease in nesting behavior in Pik3ca^act mice (2.88 ± 0.35) compared to control mice (4.38 ± 0.26). The behavioral nesting and burrowing test results demonstrated that endometriosis-associated pain is significantly increased in the hyperactivated PTEN/PI3K/AKT signaling. The results of the burrowing and nesting tests demonstrate that the aberrant activation of PTEN/PI3K/AKT signaling increases the number of endometriotic lesions in endometriosis and exacerbates endometriosis-associated pain. This study contributes to the understanding of the pathophysiology of endometriosis and suggests PTEN/PI3K/AKT signaling as a potential therapeutic target for endometriosis and its associated pain. This work was supported by NIH R01HD108895.