| Popis: |
Ten-year survival rates from paediatric cancer now exceeds 75%. Survival from cancer in females of reproductive age is also improving. An understanding of the impact of radiotherapy, chemotherapy and therapy with novel biological agents is required in order to allow appropriate counselling of these patients so that they can make important life decisions with the knowledge of how their future fertility may be compromised. Irradiation of the ovaries, uterus or cranium can all cause premature ovarian insufficiency (POI). Threshold doses above which fertility rates decrease significantly are 30 Gy for the hypothalamus/pituitary and 5 Gy for the ovaries, although there is some loss of fertility below these levels. The impact of direct ovarian irradiation results from primordial oocyte loss and is dependent upon patient age, radiotherapy field and fractionation schedule. The impact of chemotherapy on incidence of POI depends upon class of cytotoxic agent, dose and patient age at time of treatment. Alkylating agents (such as cyclophosphamide and thiotepa) appear to cause a much higher incidence of POI than non-alkylating agent chemotherapy, particularly if given as part of a high-dose chemotherapy regime supported by stem cell or bone marrow transplantation. These agents crosslink DNA and have an effect on mitochondria. It has been postulated that it is their effect on the most metabolically active cells in the ovary (granulosa cells) that results in the high incidence of POI. Some classes of cytotoxic agents (e.g., antimetabolites, antitumour antibiotics and mitotic inhibitors) by virtue of their mechanism of action mainly affect mitotically active cells and it is postulated that these agents also predominantly affect granulosa cells rather than oocytes. For other chemotherapy agents (e.g., topoisomerase inhibitors), it is unclear which ovarian cells are predominantly affected. The duration of targeted therapy use has been too short to allow comprehensive assessment of impact on fertility, but there is a suggestion that the addition of bevacizumab (a monoclonal antibody targeting vascular endothelial growth factor A) to chemotherapy may increase the incidence of POI. Here we describe the impact of radiotherapy and chemotherapy on future female fertility and then summarize the mechanisms of action of different classes of chemotherapy drugs in order to form the context for the subsequent discussion of the specific effects of these agents on the ovary. |
