Evidence of cancer therapy-induced chronic inflammation in the ovary across multiple species: A potential cause of persistent tissue damage and follicle depletion

Chemotherapy and radiation treatments are known for deleterious effects on the ovary, which can result in prolonged recovery time before ovarian function resumes, including follicular growth after completion of these therapies. To better understand the protracted ovarian dysfunctions after chemotherapy and radiotherapy, we designed a comprehensive study to investigate the underlying mechanisms involved in chronic ovarian damage that prevent follicular development and/or to induce persistent follicle loss. Blood and ovarian samples were collected from reproductive age women, rhesus macaques, and mice after completion of chemotherapy and/or radiotherapy and from age-matched patients and animals without chemotherapy agent or radiation exposure to serve as controls. Serum levels of anti-Müllerian hormone and proinflammatory cytokines, monocyte chemoattractant protein 1 and IL6, were measured. Ovarian tissue was assessed for histopathology and inflammatory cell infiltration, e.g., macrophages and neutrophils, by immuohistochemistry. Serum anti-Müllerian hormone concentrations were lower, whereas proinflammatory cytokine concentrations were higher, in patients and rhesus macaques at ~1 year post-chemotherapy agent and/or radiation exposure compared with controls. The number of primordial follicles reduced in the mouse ovary > 5 weeks after a single injection of cyclophosphamide. Macrophage infiltration was observed in the ovarian cortex of humans and animals. These data suggest that chronic inflammation induced by chemotherapy agents and/or radiation treatment may be associated with persistent ovarian tissue damage, follicle depletion, and functional decline. Interventions that dampen the overactivated inflammatory response may further protect the ovary after completion of chemotherapy and radiotherapy to maintain follicle viability and support continued follicular development in female patients.