Ovarian function may be impaired following treatment with combination chemotherapy that includes an alkylating agent and procarbazine such as MOPP; MVPP (nitrogen mustard [mechlorethamine], vinblastine, procarbazine, and prednisone); ChlVPP (chlorambucil, vinblastine, procarbazine, and prednisone); MDP (doxorubicin, prednisone, procarbazine, vincristine, and cyclophosphamide); or the combination of COP (cyclophosphamide, vincristine, and procarbazine) with ABVD (Adriamycin [doxorubicin], bleomycin, vinblastine, and dacarbazine). Amenorrhea was reported in 11% after MOPP (2 of 18 girls treated at age 2 to 15 years), 31% after MDP (10 of 31 girls treated at age 9.0 to 15.2 years), and 13% after ChIVPP (3 of 23 girls treated at age 6.1 to 20.0 years),[16,36,37] but in 0% after COP/ABVD (0 of 17 girls treated at age 4 to 20 years).
Ovarian function was evaluated in women treated with drug combinations that did not include procarbazine. Ovarian function was normal in all of six women treated for non-Hodgkin lymphoma with a cyclophosphamide containing drug combination. Others reported that pubertal progression was adversely affected in 5.8% of 17 patients treated before puberty compared with 33.3% of 18 patients treated during puberty or after menarche. However, the administration of cyclophosphamide did not correlate with the abnormal pubertal progression observed in these patients. Administration of ifosfamide 27 g/m2 to 90 g/m2 to 13 females resulted in evidence of impaired estrogen production in only one patient. Cisplatin administration resulted in amenorrhea in 14% of seven patients.
All women who received high-dose (50 mg/kg/day x 4 days) cyclophosphamide prior to BMT for aplastic anemia developed amenorrhea following transplantation. In one series, 36 of 43 women had recovery of normal ovarian function 3 to 42 months after transplantation, including all of the 27 patients who were between ages 13 and 25 years at the time of BMT. Most postpubertal women who receive TBI prior to BMT develop amenorrhea. In one series, recovery of normal ovarian function occurred in only 9 of 144 patients and was highly correlated with age at irradiation in patients younger than 25 years. In a series restricted to patients who were prepubertal at the time of BMT, 44% (7 of 16) had clinical and biochemical evidence of ovarian failure.
Of 3,390 eligible participants in the Childhood Cancer Survivor Study (CCSS), 215 (6.3%) developed acute ovarian failure. Survivors with acute ovarian failure were older (aged 13–20 years vs. aged 0–12 years) at cancer diagnosis and more likely to have been diagnosed with Hodgkin lymphoma or to have received abdominal or pelvic radiation therapy than survivors without acute ovarian failure. Of survivors who developed acute ovarian failure, 75% had received abdominal-pelvic irradiation. Radiation doses to the ovary of at least 2,000 cGy were associated with the highest rate of acute ovarian failure with over 70% of such patients developing acute ovarian failure. In a multivariable logistic regression model, increasing doses of ovarian irradiation, exposure to procarbazine at any age, and exposure to cyclophosphamide at ages 13 to 20 years were independent risk factors for acute ovarian failure.