Ovarian surgery impairs fertility and hormone production by decreasing the number of follicles present. However, the remaining ovary is typically able to compensate if no chemotherapy or radiation is given. Pelvic surgery for non-gynecologic malignancies can have a deleterious effect on folliculogenesis by cytokine production. Formation of pelvic adhesions may also affect ovulation and tubal transport.
All chemotherapeutic agents affect the mature follicle through DNA damage with subsequent apoptosis and temporary amenorrhea. If the primordial follicle pool is unaffected, folliculogenesis will proceed after completion of cancer treatment with resumption of menses. However, alkylating agents such as cyclophosphamide, busulfan and nitrogen mustard and heavy metals such as cisplatin have a deleterious effect on the primordial follicles, diminishing the reserve pool. Although patients who receive these therapies may resume menses as follicular maturation of the remaining follicles occurs, they subsequently experience accelerated folliculogenesis and apoptosis with premature ovarian insufficiency.
Radiation injury of the gonads is dose-dependent and age confers protection. Radiation doses greater than 2 Gy result in a loss of 50% of ovarian follicles. Doses greater than or equal to 15 Gy and 6 Gy in adult and pre-pubertal patients respectively result in infertility. Irreversible damage to the uterus occurs at doses greater than 30 Gy. Radiation exposure to the hypothalamus and pituitary gland affects production of gonadotropins with decreased folliculogenesis and decreased production of estrogen.
Risk to fertility is greatest with alkylating agents and radiation therefore risk stratification from chemotherapy is based on the cumulative dose of alkylating agents received. The alkylating agent dose (AAD) and the cyclophosphamide equivalent dose (CED) risk-stratification systems allow calculation of risk. Using the AAD, a score of 1, 2 or 3 is given for the cumulative dose of alkylating agent that falls within the first, second or third tertile, respectively. Patients with a score of 3 or 4 are at increased risk of infertility . Both the AAD and the CED function similarly, however the AAD was based on a specific cohort of patients from the Childhood Cancer Survivor Study whereas the CED has applicability independent of study population . Risk stratification by alkylating agent is performed prior to therapy to guide implementation of fertility preservation therapies based on risk. However, treatment regimens may change during the course of therapy and in such instances, cumulative dose and risk assessment may be re-calculated post-therapy.