Cisplatin and Doxorubicin Induce Distinct Mechanisms of Ovarian Follicle Loss; Imatinib Provides Selective Protection Only against Cisplatin

Abstract

PurposeChemotherapy treatment in premenopausal women has been linked to ovarian follicle loss and premature ovarian failure; the exact mechanism by which this occurs is uncertain. Here, two commonly used chemotherapeutic agents (cisplatin and doxorubicin) were added to a mouse ovary culture system, to compare the sequence of events that leads to germ cell loss. The ability of imatinib mesylate to protect the ovary against cisplatin or doxorubicin-induced ovarian damage was also examined.Experimental designNewborn mouse ovaries were cultured for a total of six days, exposed to a chemotherapeutic agent on the second day: this allowed for the examination of the earliest stages of follicle development. Cleaved PARP and TUNEL were used to assess apoptosis following drug treatment. Imatinib was added to cultures with cisplatin and doxorubicin to determine any protective effect.ResultsHistological analysis of ovaries treated with cisplatin showed oocyte-specific damage; in comparison doxorubicin preferentially caused damage to the granulosa cells. Cleaved PARP expression significantly increased for cisplatin (16 fold, p<0.001) and doxorubicin (3 fold, p<0.01). TUNEL staining gave little evidence of primordial follicle damage with either drug. Imatinib had a significant protective effect against cisplatin-induced follicle damage (p<0.01) but not against doxorubicin treatment.ConclusionCisplatin and doxorubicin both induced ovarian damage, but in a markedly different pattern, with imatinib protecting the ovary against damage by cisplatin but not doxorubicin. Any treatment designed to block the effects of chemotherapeutic agents on the ovary may need to be specific to the drug(s) the patient is exposed to.

AMH/MIS as a contraceptive that protects the ovarian reserve during chemotherapy

“…To test these hypotheses, we used gene therapy with MIS, or rhMIS parenteral protein administration, to create a complete arrest in primordial follicle activation concurrently with chemotherapy cycles. As a proof of concept we chose three commonly used chemotherapeutic classes with well-described gonadotoxicities: platinums (54), anthracyclins (55), and alkylating agents (56). Both platinums (such as CBP) and anthracyclins (DOX) interfere with DNA replication and as such are particularly toxic to dividing granulosa cells of secondary and antral follicles, albeit with distinct toxicity profiles (55), and thus represent ideal targets for an MIS oncofertility intervention.…”

“…As a proof of concept we chose three commonly used chemotherapeutic classes with well-described gonadotoxicities: platinums (54), anthracyclins (55), and alkylating agents (56). Both platinums (such as CBP) and anthracyclins (DOX) interfere with DNA replication and as such are particularly toxic to dividing granulosa cells of secondary and antral follicles, albeit with distinct toxicity profiles (55), and thus represent ideal targets for an MIS oncofertility intervention. CPA is an alkylating agent, a class that is particularly damaging to germ cells, and is the most problematic gonadotoxic chemotherapeutic in the clinic, particularly because it is often used in young girls with hematological cancers (57).…”

Chemotherapy-Induced Oxidative Stress and Infertility

“…Cancer treatment with DNA alkylating agents, such as cyclophosphamide (CP) and Ifosfamide (IFO) and Cisplatin can lead to gonadotoxicity, impaired fertility, ovarian failure, resulting in premature menopause (1)(2)(3).…”

“…Mitochondria which function to generate energy by oxidative phosphorylation, are known as one of the main endogenous sources of ROS. Studies reported that exposure to cisplatin leads to a significant increase in intracellular ROS (3). A few others reported that treatment with antioxidants attenuates the cytotoxic effects of cisplatin on different organs, suggesting an involvement of oxidative stress in the pathogenesis of cisplatin-induced cytotoxicity which also seen in reproductive system (7).…”

Protective Effects of Cistanches Herba Aqueous Extract on Cisplatin-Induced Premature Ovarian Failure in Mice

“…Chemotherapeutic agents can also lead to POF in women during their reproductive years, and can therefore affect their future fertility. The risk for developing POF appears to be dependent upon the exact nature of the chemotherapeutic regimen, and includes factors such as drug dosage and patient age (Morgan et al, 2013). Recent studies have documented the induction of ovarian dysfunction as a result of cisplatin, including menstrual disorders, premature menopause, and infertility (Chen et al, 2015；Li et al, 2013.…”