How do chemotherapeutic agents damage the ovary?
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Chemotherapy treatment in premenopausal women has been linked to premature ovarian failure (POF), and hence infertility, through ovarian follicle loss. The exact mechanisms that lie behind this loss are unclear and so the action of two commonly used chemotherapeutic agents were compared here. Cisplatin is a DNA cross-linking agent commonly used in the treatment of ovarian, lung and bladder cancers, while the anthracycline doxorubicin is commonly used to treat leukaemia and breast cancer. Neonatal mouse ovaries were cultured in vitro and exposed to cisplatin or doxorubicin in order to determine their effects on primordial and early growing follicles. Both drugs caused a dose dependant follicle loss but targeted different cell types. Cisplatin caused a significant increase in follicles with unhealthy oocytes; furthermore primary stage follicles were the follicle class most affected (up to 98% classified as unhealthy compared with 13% in control, p<0.001). In contrast, doxorubicin caused a significant increase in follicles with unhealthy granulosa cells and affected all follicle stages present. When the mechanism of cell death was further investigated, apoptosis was the main pathway through which these drugs cause ovarian cell death. Doxorubicin in particular caused a significant increase in apoptosis of ovarian somatic cells including the granulosa cells and stroma. Imatinib mesylate, a tyrosine kinase inhibitor which is also used as a chemotherapeutic agent, has been implicated as a potential therapy to block the ovotoxic effects of cisplatin. Results here confirm this finding (29% of follicles classified as unhealthy in the cisplatin only group compared to 8% in the cisplatin and imatinib co-treatment group, p<0.001) and found further, that imatinib was unable to protect against doxorubicin-induced damage (28% of follicles classified as unhealthy in the doxorubicin treated group compared to 19% in the doxorubicin and imatinib cotreatment group). Imatinib treatment alone in newborn ovaries caused a significant increase in the number of follicles present at the end of culture compared to control (402±43 in the imatinib group compared to 188±34 in control, p<0.001), which is likely due to an effect on follicle formation. In conclusion, the work presented in this thesis demonstrates drug specific actions of cisplatin and doxorubicin on the mouse ovary. This suggests that any therapy designed to confer ovarian protection in the future may have to be tailored to be drug specific.