The Current Understanding of Clinical Data on Ovarian Toxicity from Cancer Treatment

4.2.1

Age

Age-related differences are most likely due to a reduction of the ovarian reserve with ageing, which increases the risk of developing POI post-chemotherapy. Females less than 40 years of age exposed to chemotherapy agents have a 22–61% risk of developing amenorrhoea, and this rate increases to 66–95% in females older than 40 years. Resumption of menstruation was higher in patients younger than 40 years compared to those older than 40 years. In the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-30 study, 708 patients diagnosed with breast cancer were treated with four cycles of doxorubicin and cyclophosphamide (AC) and four cycles of docetaxel. The resumption of menses occurred within 24 months in 45.3% of patients aged under age 40 years, 10.9% of those aged 40–50 and in 3.2% of patients aged over 50 years.

4.2.2

Type of Chemotherapy

The type of chemotherapy is a strong determinant of POI ( Figure 4.1 ). Alkylating agents carry the highest risk because these drugs are not cell cycle specific, meaning that both resting and developing follicles can be damaged. Cyclophosphamide is the most commonly utilized agent in this group; it is frequently used to treat a wide range of cancers including lymphomas, leukaemia, neuroblastoma, retinoblastoma and breast carcinoma. Other clinical uses for cyclophosphamide include immunosuppressive therapy following organ transplants or as a treatment for connective tissue disorders. Cyclophosphamide leads to major disruptions in nucleic acid function and inhibits DNA and protein synthesis. Its use is associated with DNA crosslinking in granulosa cells, stromal fibrosis and capillary changes in the female reproductive system. Gonadal toxicity with cyclophosphamide alone or in combination with other chemotherapeutics has been documented. The authors reported previously that even a single dose of cyclophosphamide resulted in a drastic reduction in human primordial follicle reserve in a xenograft model. Boumpas et al. compared the effects of short (seven doses) and long (>15 doses) courses of cyclophosphamide treatment in 39 females aged under age 40 years diagnosed with systemic lupus erythematosus to evaluate the effect of number of doses of cyclophosphamide on menstruation and the incidence of sustained amenorrhoea was found to be higher in the long-course group (12.5 vs. 39%, p=0.07).

Doxorubicin, a topoisomerase inhibitor antracyclin antibiotic, is widely integrated in a variety of cancer regimens, and acts by intercalating DNA. It is one of the most effective drugs for the treatment of solid tumours such as breast cancer. DNA damage and apoptotic cell death in human granulosa cells and primordial follicles, as well as a reduction in stromal blood flow, has been shown after in vivo administration of doxorubicin. Depending on intensity, duration, and combination with other chemotherapy agents, doxorubicin treatment may result in POI in cancer patients.

Taxanes are relatively new chemotherapeutic agents that act on the cytoskeleton to disrupt microtubule function. They are commonly used to consolidate doxorubicin- and cyclophosphamide-based treatment in breast cancer patients. Laboratory studies of taxane-induced ovarian toxicity are limited and conflicting. Tarumi et al. suggested that the ovarian toxicity of paclitaxel is mild and does not involve the primordial follicles; however, in another study in rats, primordial follicle counts decreased following the administration of paclitaxel. Recently, Lopes et al. demonstrated that docetaxel directly impairs the early stages of ovarian follicle development, but it has no direct effect on the primordial follicle reserve in mice. Though the data are limited, clinically, taxanes do not appear to have a strong ovary-damaging effect.

Cycle-specific agents – such as 5-fluorouracil, methotrexate and vinca alkaloids – appear to affect only the developing and mature follicles and hence cause transient amenorrhoea without damaging primordial follicles.