Impact of smoking on the age at natural menopause in BRCA1/2 mutation carriers in northern california

Abstract

Timing of fertility preservation and risk-reducing salpingo-oophorectomy is of great concern for BRCA1 and BRCA2 mutation (BRCA1/2) carriers. Our preliminary analyses suggested BRCA1/2 carriers may have an earlier age at natural menopause, consistent with findings from a recent study relating BRCA1 to occult primary ovarian insufficiency. The aim of this study was to examine the association of BRCA1/2 and age at natural menopause, and possible effect modification of smoking,a possible exogenous modifiable risk factor. Retrospective study with historical control. 166 Caucasian BRCA1/2 carriers in Northern California with natural menopause or still menstruating were identified within UCSF Cancer Risk Program registry and compared to 765 Caucasian women in Northern California included in the Study of Women's Health Across the Nation(SWAN) cohort. We compared median age at natural menopause and any effect modification of smoking,using the Kaplan-Meier approach for unadjusted analyses and Cox proportional hazards regression analyses to adjust for confounding factors. The median age at natural menopause in BRCA1/2 carriers was statistically significantly earlier than normal population (48 vs 53years,log-rank p-value <0.0001). The unadjusted hazard ratio of natural menopause was 3.94 (95% confidence interval 2.34,6.65), 4.05 (2.30,7.12) after adjusting for smoking. For BRCA1/2 carriers who were current heavy smokers (≥20cigarettes/day), the median age at natural menopause was45.5, significantly earlier than never or past smokers or current light smokers (<10,10-19cigarettes/day) (log-rank p-value = 0.0021). BRCA1/2 is associated with significantly earlier age at natural menopause, and heavy smoking poses additional risk for even earlier menopause. As the relationship between menopause and end of natural fertility is considered fixed, this finding of earlier menopause and the impact of smoking is important for counseling BRCA1/2 carriers and is suggestive of the underlying mechanism.