Rescue of the Ovarian Reserve after Chemotherapy

Significant advances in CTx have led to a continuous increase in survival rates of cancer patients. However, in female cancer survivors, one of the most significant secondary effects of CTx is premature ovarian failure (POF) and consequent infertility. The current approach to combating this problem is cryopreservation of oocytes or embryos prior to CTx treatment. However, POF also leads to disruption of the endocrine function of the ovary, resulting in early-onset menopause and many health risks associated with loss of estrogen. These problems highlight the necessity to identify alternative strategies that focus on preserving or rescuing both reproductive and endocrine functions in patients who receive CTx. Regenerative repair of the CTx-damaged ovary is one potential strategy. We developed a model of CTx-induced infertility in mice that leads to degeneration of the ovary and irreversible infertility. We have used this model to test approaches to rescue both fertility and endocrine functions of the ovary. However, when a fragment of a normal ovary from a mouse carrying a ubiquitous fluorescent transgene (to distinguish donor cells from host cells and donor offspring from host offspring) is grafted onto the left ovary within 10 days after CTx treatment, fertility is rescued. In fact, grafted females produce multiple litters over the next 5 months, with normal offspring derived not only from the donor but also, surprisingly, from the treated host. Our work suggests that CTx does not primarily affect oocytes, but instead leads to rapid activation and subsequent apoptosis of granulosa cells, resulting in the collapse of follicles, in accord with the “Follicle Burn-Out” hyothesis. Histological examination 4 months after grafting revealed that the grafted left ovary contained follicles in all stages of development, whereas the ungrafted right ovary had completely degenerated. Very few graft-derived cells had migrated into the host ovary, suggesting that the donor graft provides molecular signals that trigger the regenerative repair of the host ovary in a paracrine manner.