As cancer survivor rates rise, understanding and preventing adverse, long-term impacts of cancer treatments, including those on fertility, have become increasingly important. Clinical data show radiotherapy stunts uteri growth and causes resistance to hormone replacement therapy in pre-pubertal girls. Female cancer survivors also experience lower clinical pregnancy rates, take a longer time to achieve pregnancy (despite normal ovarian and endocrine function), require a greater number of embryo transfers to achieve pregnancy and exhibit higher prevalence of pregnancy complications. Together, this suggests that cancer treatments damage the uterus, but this has been largely ignored by the oncofertility field. We aimed to determine the impact of radiotherapy on the uterus, independent of ovarian effects, and its ability to establish and maintain healthy pregnancy.
Adolescent (4-6-week-old) female mice exposed to whole body high dose (7 Gray) irradiation, or non-irradiated control were ovariectomised before hormonal stimulation to induce endometrial receptivity, or transfer of equal number of day 3 blastocysts from healthy, unexposed donor mice (n=6-8/group).
Within hours of irradiation, markers of DNA damage (yH2AX), cell death (CC3 and TUNEL), and the intrinsic apoptosis pathway (PUMA) localise to irradiated adolescent mouse uteri. Additionally, irradiated mice hormonally induced to become receptive had significantly decreased uteri weight (p<0.05) and myometrial area (p<0.01) versus controls, and reduced estrogen receptor alpha mRNA (p<0.05). Irradiated mice that received embryo transfers demonstrated a trend for decreased implantation site number (p<0.1), with pale, atrophic uteri suggesting vascular defects. To investigate this possibility further we are employing Doppler ultrasound to determine the effect of irradiation on uterine artery blood flow in pregnant and non-pregnant mice. Defining the extent of uterine damage caused by cancer treatments and the underlying mechanisms would be a breakthrough in understanding how cancer treatments compromise reproductive outcomes.