Primordial Follicle Survival and Changes in Ovarian Vasculature May Be Independently Regulated During Chemotherapy.

Abstract

Chemotherapeutic agents induce irreversible gonadotoxic side effects, resulting in endocrine dysfunction and infertility in female cancer survivors. In the current study, we investigated strategies to protect ovarian function from chemotherapy-induced toxicity by evaluating the effects of cisplatin, doxorubicin, or cyclophosphamide on ovarian vasculature and primordial follicle survival. This investigation was conducted using adult CD-1, PDs 5-7 CD-1, and oocyte-specific Trp63 conditional knockout (Trp63 cKO) mice that demonstrated primordial follicles survived following chemotherapy. In control ovaries, vasculature typically surrounds primordial and primary follicles, is in the theca layer as secondary follicles develop, and is distributed among stromal cells. Our findings revealed that the expression pattern of CD31/PECAM-1 (platelet endothelial adhesion molecule-1) was significantly altered in ovaries treated with chemotherapeutic agents compared with controls. The data demonstrate that these agents not only caused the loss of ovarian follicles but also damaged the ovarian vasculature. Using Trp63 cKO mice and CK2II, an inhibitor of checkpoint kinase 2, we demonstrated that vascular damage can occur independently of primordial follicle loss, and VEGFA165 was unable to prevent either outcome. This indicates that the mechanisms governing the death of primordial follicles and vascular damage may not directly affect each other. Long-term ex vivo culture and in vivo experiments demonstrated the ability of ovarian vasculature to recover from cisplatin-induced damage. In conclusion, our study suggests that ovarian follicle survival and vascular integrity may be independently regulated as independent processes, governed by distinct signaling pathway or mechanisms.