Age at menopause and its influencing factors in a cohort of survivors of childhood cancer: earlier but rarely premature

Is the age at menopause in a cohort of childhood cancer survivors earlier and what are the risk factors associated with earlier age at menopause? Menopause occurred at a median age of 44 years in this cohort which is earlier than in the general population, but premature menopause was uncommon. Main risk factors for non-surgical menopause were exposure to and dose of alkylating agents, especially during adolescence, radiation dose to the ovaries and oophorectomy. While survivors of childhood cancer are known to be at increased risk for developing premature menopause, data on its risk factors are limited. A cohort study of 1109 still-living female survivors of childhood solid cancer treated between 1945 and 1985, of whom 863 (78) returned a follow-up questionnaire. Of them, 157 were excluded. Seven hundred and six women, among whom 32 have attained 40 years of age, were included in this study. A Cox regression model was used to determine risk factors influencing the age at menopause. Ninety seven women have reached menopause at a median age of 44 years. Menopause has been surgically induced in 36 of women. In multivariate analysis, risk factors for non-surgical menopause included exposure to alkylating agents, increasing radiation dose to the ovaries, procarbazine dose, cyclophosphamide dose and unilateral oophorectomy. The highest risk ratio for non-surgical menopause was observed for women treated after the onset of puberty with alkylating agents, either alone (RR 9, 95 CI: 2.728, P 0.0003) or associated with even a low dose of radiation to the ovaries (RR 29, 95 CI: 8108, P 0.0001). Exposure to unilateral oophorectomy is associated with a 7-year earlier age at menopause. By the age of 40, only 2.1 had non-surgical premature menopause and its main risk factors were age at diagnosis, cyclophosphamide dose, exposure to melphalan and radiation dose to the ovaries. The information on menopause was based on self-reported data without confirmation by FSH levels. Participants to this study have been treated for cancer from 1945 to 1985 and one can expect an increase in premature menopause incidence with more recent protocols using high-dose alkylating agents. This study provides data on risk factors for a reduced fertility window in order to inform survivors at risk and help oncologists to design new therapeutic protocols avoiding this risk. This study does not confirm the high rate of premature menopause reported by the Childhood Cancer Survivor Study, but this population differs from theirs (no leukemia and a lower percentage of lymphoma). EDF, Ligue Nationale contre le cancer, IRESP, PHRC, AFSSAPS, Fondation Pfizer. No conflict of interest.