Prolonging Reproductive Life after Cancer: The Need for Fertoprotective Therapies

The survival rate of reproductive-age patients with cancer is increasing, reflecting the advent of better and more efficient therapies. Cancer survivors seek the resumption of a normal and healthy life, which often includes starting a family. Unfortunately, many cancer treatments increase the risk of premature ovarian insufficiency (POI) and infertility. Assisted reproductive technologies (ART) can address infertility, but fail to preserve the natural function of the ovaries as a source of hormones that regulate many aspects of women's health. The advancement of fertoprotective technologies is hindered by our lack of understanding of oocyte biology and their sensitivity to cancer therapies. Because many cancer treatments cause DNA damage, apoptosis is thought to be the major mechanism eliminating damaged oocytes. Indeed, recent studies in mice demonstrate that targeting proteins involved in apoptosis protects oocytes and prevents infertility in females exposed to radiation. Therefore, a better appreciation of oocyte response to radiation and anticancer drugs will uncover new targets for the development of specialized therapies to prevent ovarian failure. We make a case here for the necessity of such fertoprotective treatments. We review recent findings that have significantly advanced our understanding of how cancer therapies induce apoptotic death in oocytes, and how we could use this knowledge to design better fertoprotective treatments. Trends Oncofertility bridges oncology and reproductive research in pursuit of fertility preservation options for cancer survivors. Genotoxic agents damage DNA, causing lesions that result in cell death or mutations. Many drugs commonly used in cancer therapies are genotoxic and are more harmful to ovaries than testes. Fertility preservation in men is more accessible because sperm cryopreservation is non-invasive and standardized. By contrast, most current fertility preservation methods for women require surgeries and often additional hormonal stimulation. The majority of fertility preservation treatments in women address the ability to produce biological children but fail to preserve the hormonal function of ovaries. More research is needed to understand the mechanisms of how various cancer therapies impact on ovarian function so as to develop better fertoprotective agents that also protect immature eggs that support endocrine function of the ovary. Animal models show that blocking apoptotic response saves oocytes exposed to DNA-damaging cancer treatments and keeps females fertile post-treatment. Therefore, targeting the DNA damage response and apoptosis in oocytes holds promise for new fertoprotective therapies and merits more research into the mechanisms of oocyte response to genotoxic agents.