As cancer survivorship rises, addressing the off-target impacts of cancer therapies has become increasingly important. Clinically, previous radiotherapy exposure is associated with reduced pregnancy rates and pregnancy complications. However, specific impacts on the uterus have not been investigated. Here, we aimed to determine if radiotherapy exposure damages 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 to distinguish uterine from ovarian damage. Within 24 hours, DNA damage (yH2AX) and Puma-mediated apoptosis were elevated in uteri (n=4/group), demonstrating immediate, direct uterine damage post-irradiation.
Implantation rates were unchanged between groups after healthy donor embryo transfer (3-days post-transfer; n=11-13/group), although pale, atrophic uteri suggested radiation may impair vascularisation. By 10-days post-transfer, all irradiated mice experienced resorption (control 4.0±1.0 vs. 7Gy 0.3±0.2 viable sites; p<0.01), though ultrasound did not detect changes in uterine artery pulsatility or resistance (n=8-10/group). 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).
Endometrial receptivity and decidualisation were artificially induced to investigate adaptation to pregnancy. Irradiated mice demonstrated normal receptivity, but lower decidualised uterine:body weight ratio (control 446.0±59.4mg vs. 7Gy 147.3±34.8mg; p<0.01; n=7-8/group). Similarly, primary human endometrial stromal cell decidualisation was lower in vitro post-irradiation (prolactin secretion; control 278±42.5pg/mL vs. 7Gy 79.39±42.5pg/mL, n=2/group). Apoptosis-resistant Puma-null mice (n=4-5/group) decidualised normally post-irradiation compared to wild-type controls, demonstrating Puma-mediated apoptosis post-irradiation contributes to impaired decidualisation, limiting maternal adaptation to pregnancy and leading to pregnancy loss in vivo.
These data demonstrate that direct radiotherapy-mediated damage to the uterus persists long-term, impairing uterine adaptations to pregnancy via a multimodal mechanism. This includes uterine artery endothelial dysfunction, impaired decidualisation, and Puma-mediated apoptosis. Critically, Puma deletion rescues this phenotype, highlighting Puma blockade as a potential therapeutic intervention for improving fertility preservation.