Oral Presentation Annual Meetings of the Endocrine Society of Australia and Society for Reproductive Biology and Australia and New Zealand Bone and Mineral Society 2016

mTOR and endometrial aging: Hyperactivation of mTOR signalling contributes to the age-associated changes in uterine epithelium (#247)

Preety Bajwa 1 , Pradeep Tanwar 1
  1. Gynaecology Oncology group, School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan 2308, NSW, Australia

Uterus plays a critical role in pregnancy and child birth. Delaying child bearing is quite common in developed world leading to a decline in reproductive potential.  Age related changes in ovary account for most of this loss of reproductive function. However, uterine factors such as inadequate endometrial receptivity also significantly contribute to pregnancy failure in women undergoing assisted reproduction.  Aging also increases the risk of developing various gynaecological disorders such as endometrial hyperplasia and cancer leading to further impairment of fertility.  mTOR signalling pathway is one of the major regulator of aging as suppression of this pathway extends lifespan in model organisms.  However, the exact mechanism through which mTOR signalling contributes to the functional and morphological changes in uterus of aged women is currently unclear.  This study examined the role of mTOR signalling in uterine aging.

Histological examination of uteri from aged mice revealed abnormal expansion and hyperplasia as compared to young controls.  The hyperplastic endometrium of both postmenopausal women and aged mice exhibited elevated mTOR activity as seen with increased expression of pS6 protein.  Analysis of uteri from Pten heterozygous and transgenic mice further confirmed that over-activation of mTOR signalling leads to  endometrial hyperplasia and glandular crowding.  To test if inhibition of mTOR signalling will suppress hyperplastic changes in aged uterus, 9-month old mice (N=28) were treated with three different doses of rapamycin, an mTOR inhibitor, for 13 months.  We observed reduction in hyperplastic lesions in uterus of aged mice treated with rapamycin compared to controls. Furthermore, treatment with mTOR inhibitors reduced colony size and proliferation of endometrial cancer cells in 3D culture.  Collectively, we have shown that hyperactivation of mTOR pathway is responsible for diminished uterine function in aged women and therapeutic targeting of this pathway might be an effective strategy for women seeking pregnancy at advanced reproductive age.