Virtual Presentation SRB Virtual Awards 2020

Radiotherapy directly damages the uterus causing uterine artery endothelial dysfunction and pregnancy loss (#9)

Meaghan Griffiths 1 , Amy Winship 1 , Sarah Marshall 2 , Fiona Cousins 3 , Alison Care 4 , Karla Hutt 1
  1. Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
  2. Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia
  3. The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia
  4. Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia

As cancer survivorship improves, it has become increasingly important to address the long-term off-target impacts of cancer therapies, including infertility. Clinical data demonstrate that cancer treatment is associated with lower pregnancy rates and increased prevalence of pregnancy complications, suggesting damage to the uterus, but this possibility has not been investigated. The aim of this study was to determine if and how radiation exposure impairs the uterus and compromises fertility.

Adolescent (4-week old) C57BL6/CBA(F1) female mice were untreated, or exposed to whole body γ-irradiation (7Gy), then ovariectomised. Within 24 hours of irradiation, DNA damage (yH2AX) and apoptosis (Puma/TUNEL) were elevated in uteri (n=4/group). When receptivity was hormonally induced, uterine weight was decreased in irradiated mice (45.7±2.2mg) versus controls (53.5±1.3mg; p<0.01; n=7/group). Irradiated mice that received embryos from untreated donors had similar numbers of implantation sites 3-days post-transfer versus controls, however uteri were pale and atrophic, suggesting impaired vascularisation (n=11-13/group). By 10-days post-transfer, implantation sites in irradiated mice were resorbing (control 4.0±1.0 vs. 7Gy 0.3±0.2; p<0.01), although uterine artery Doppler ultrasound measurements demonstrated no change in pulsatility or resistance indices (n=8-10/group). To investigate uterine damage in the absence of an embryo, decidualisation was artificially induced. In this experiment, uterine weights in irradiated mice were significantly lower than controls (control 446.0±59.4mg vs. 7Gy 147.3±34.8mg; p<0.01; n=7-8/group), indicating impaired decidualisation and reduced capacity to adapt to pregnancy. Additionally, wire myography performed on uterine arteries demonstrated endothelial dysfunction in irradiated mice (area under the curve, control 303.7±9.91 vs 7Gy 227.4±10.55, p<0.01; n=9-10/group).

In summary, the uterus sustained permanent damage following radiotherapy, leading to pregnancy loss, likely resulting from uterine artery endothelial dysfunction, and impaired endometrial stromal cell decidualisation. These findings indicate that uterine damage contributes to infertility in cancer survivors and highlights the need for new strategies to protect the uterus during cancer treatment.