In Vivo Models of Ovarian Toxicity

5.1 Introduction

The success of cancer treatment creates a growing population of female cancer survivors who wrestle with long-term side effects of chemotherapy, including primary ovarian insufficiency (POI). This growing survivorship presents researchers and clinicians with the challenging mandate to develop therapeutics that improve ovarian function post-chemotherapy. Continuing research is therefore devoted to developing non-invasive, drug-based ovarian shields and ovarian-regenerative technology. An ideal ovoprotective drug would be easily administered in conjunction with traditional chemotherapy, and preserve both long-term endocrine function and fertility by preventing chemotherapy toxicity to the ovary. Developing ovoprotective drugs requires detailed understanding the mechanism(s) of chemotherapy ovarian insult in order to identify potential targets to achieve the ultimate balancing act: shield the healthy ovary from chemotherapy, but kill cancer. Key parameters include identifying the ovarian cell type(s) and follicles affected by each chemotherapy agent, and temporal resolution of primary insult and subsequent cell death. In vivo animal models are required to understand systemic effects of chemotherapy as they provide native cellular interactions, the dynamic intrafollicular communication and allow assessment of fertility and the health of subsequent generations.

5.2 Rodent Models of Chemotherapy-Induced Follicular Depletion and Ovoprotection

The most common in vivo model for ovotoxicity is the mouse. Rodents provide short lifespans with rapid progression from birth through reproductive maturity (weeks) and short intergenerational times (months), allowing comprehensive studies from acute insult through the birth of multiple generations. While not currently standard in ovotoxicity studies, transgenic mouse cancer models of leukaemia, breast cancer and sarcomas will be key in determining whether chemotherapy remains effective when administered with ovoprotective agents by providing simultaneous assessment of cancer remission rates and ovoprotection. Despite these advantages, large differences remain compared to human reproductive physiology; rodents are multi-ovulatory and typically do not experience natural menopause. Rodents are more sensitive to chemotherapy than humans, limiting cumulative chemotherapy doses and impeding recapitulation of multi-dose chemotherapy regimens. Proof-of-concept oncofertility rodent studies therefore require confirmation in non-human primates more closely related to humans.

5.2.1 Chemotherapy-Induced Follicular Depletion

Foundational chemotherapy studies measured ovotoxicity as follicle loss, leading to three models describing follicular depletion. In the first model, chemotherapy directly destroys primordial follicles, depleting the ovarian reserve. For example, cisplatin depletes primordial and primary follicles in mice treated at postnatal day (PND)5 (i.e., paediatric mice). Secondary follicle counts are unchanged at PND9, however, demonstrating relative resistance.

In the second model, chemotherapy induces apoptosis only in follicles containing actively dividing granulosa cells. Doxorubicin (DXR) induces widespread apoptosis in granulosa cells of growing follicles within 12 hours, but primordial follicles do not exhibit apoptosis until 48 hours post-treatment, and then only in small numbers consistent with the primordial follicle recruitment rate in mice.

The third, not mutually exclusive, “burnout” model postulates that cyclophosphamide first depletes growing follicles, which promotes primordial follicle recruitment, explaining the observed time-dependent follicular depletion followed by restoration of growing follicle numbers. This model predicts that consecutive chemotherapy treatments compound depletion as primordial follicles prematurely activated by the first round of chemotherapy become the growing follicle pool destroyed by the following chemotherapy dose. Future studies tagging chemotherapy-injured follicles to quantify growth and atresia in vivo may allow clear delineation of ovarian remodelling.

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