A French cohort study of 1,109 female survivors of childhood solid cancer identified the following as risk factors for nonsurgical menopause: exposure to and dose of alkylating agents, especially during adolescence; radiation dose to the ovaries; and oophorectomy. Women treated with alkylating agents after the onset of puberty, either alone (RR, 9; 95% CI, 2.7-28, P = .0003) or associated with even a low dose of radiation to the ovaries (RR, 29; 95% CI, 8-108, P < .0001), had the highest risk ratio for nonsurgical menopause. Exposure to unilateral oophorectomy was associated with a 7-year-earlier age at menopause. The overall rate of nonsurgical menopause by age 40 years was only 2.1% and substantially lower than the CCSS and European Organization for Research and Treatment of Cancer cohort studies that include survivors of hematological malignancies.
Fertility was evaluated among the 6,224 male CCSS participants aged 15 to 44 years who were not surgically sterile. They were less likely to sire a pregnancy than siblings (hazard ratio [HR] 0.56; 95% CI, 0.49-0.63). Among survivors, the HR of siring a pregnancy was decreased by radiation therapy greater than 750 cGy to the testes (HR, 0.12; 95% CI, 0.02-0.64), higher summed alkylating agent dose score or treatment with cyclophosphamide (third tertile - HR, 0.42; 95% CI, 0.31-0.57) or procarbazine (second tertile - HR, 0.48; 95% CI, 0.26-0.87; third tertile - HR, 0.17; 95% CI, 0.07-0.41). The HR of siring a pregnancy was inversely related to the summed alkylating agent dose score (P -value for linear trend = <.001). Those who had a summed alkylating agent dose score of 2 (HR, 0.67; 95% CI, 0.51-0.88; P = .004), 3 (HR, 0.48; 95% CI, 0.36-0.65; P <.001), 4 (HR, 0.34; 95% CI, 0.22-0.52; P <.001), 5 (HR, 0.38; 95% CI, 0.22-0.66; P <.001), or 6 to 11 (HR, 0.16; 95% CI, 0.08-0.32; P <.001) were also less likely to ever sire a pregnancy compared with those who did not receive any alkylating agents. Compared with siblings, the HR for ever siring a pregnancy for survivors who had an alkylating agent dose score of 0 and a hypothalamic/pituitary radiation dose of 0 cGy and a testes radiation dose of 0 cGy was 0.91 (95% CI, 0.73-1.14; P = .41).