Age of natural menopause in BRCA1/2 mutation carriers

Abstract

OBJECTIVE: Germline mutations in BRCA1 and BRCA2 are related to increased lifetime risk of breast cancer and ovarian cancer. While risk reducing salpingo-oophorectomy has been demonstrated to reduce the risk for both cancers, loss of fertility is a major concern. A recent study suggested an association of BRCA1 mutation with occult primary ovarian insufficiency. The aim of this study is to test the hypothesis that BRCA mutation carriers will have earlier onset of menopause, implying a diminished ovarian capacity compared with normal cycling control women. DESIGN: Retrospective study with historical control. MATERIALS AND METHODS: Within the UCSF Cancer Risk Program registry, 537 BRCA mutation carriers were identified and sent a questionnaire regarding cancer surveillance strategies and follow-up; the response rate was over 80%. The information was cross-checked with chart review of admission records and operation reports. The mean age of natural menopause for carriers was compared to the presumed population mean of 51.4 years, as reported by the Study of Women's Health Across the Nation(SWAN), a large multicenter study with more than 3000 women included. RESULTS: Any carriers undergone surgical menopause (risk reducing salpingo-oophorectomy, n=169, 31.4%; oophorectomy for cancer or benign indications, n=62, 11.6%) or chemotherapy-induced menopause(n=32, 6.0%) were excluded, and a total of 99 carriers (18.4%) with natural menopause were included. The mean age of menopause in BRCA 1/2 mutation carriers was 48.7, significantly lower than the normative data 51.4 (n=99, 95%CI 48.0∼49.4, p<0.001); while comparing individually, BRCA1, 48.5 (n=44, 95%CI 47.5∼49.4, p<0.001), and BRCA2, 48.9 (n=55, 95%CI 47.9∼49.9, p<0.001). CONCLUSION: BRCA1/2 mutations may be associated with earlier onset of menopause. If confirmed, this information has important implications in counseling BRCA1/2 mutation carriers when making the already complex decisions regarding family building. The mechanism underlying this association should be investigated.