Do BRCA1/2 mutation carriers have an earlier onset of natural menopause?
It has been hypothesized that BRCA1/2 mutation carriers have an earlier age at natural menopause (ANM), although to date findings are inconclusive. This study assessed the influence of BRCA mutation status on ANM, and aimed to explore the reasons of inconsistency in the literature.



Cross-sectional assessment from an ongoing nationwide cohort study among members of BRCA1/2 mutated families. Information was obtained by a standardized questionnaire. Kaplan-Meier curves were constructed, and Cox regression was used to assess the association between BRCA1/2 mutation status and ANM. Adjustments were made for birth cohort, family, smoking, use of hormonal contraceptives, and parity.



A total of 1,208 BRCA1/2 mutation carriers and 2,211 proven noncarriers were included. Overall, no association was found between BRCA1/2 mutation status and ANM (adjusted hazard ratio [HR] = 1.06 [95% CI, 0.87-1.30]). We examined if the null finding was due to informative censoring by uptake of risk-reducing salpingo-oophorectomy. Indeed, within the oldest birth cohort, in which the percentage of surgical menopause events was lowest and comparable between carriers and noncarriers, the HR for earlier natural menopause in carriers was 1.45 (95% CI, 1.09-1.94). The second oldest birth cohort, however, demonstrated a decreased HR (0.67 [95% CI, 0.46-0.98]), and thus no trend over birth cohorts was found.



Various types of selection bias hamper the comparison of ANM between BRCA1/2 mutation carriers and noncarriers, genetically tested in the clinic.
1Department of Reproductive Medicine 2Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands 3Department of Epidemiology 4Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, The Netherlands 5Department of Genetics, Groningen University, University Medical Center, Groningen, The Netherlands 6Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands 7GROW, School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands 8Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands 9Department of Clinical Genetics, VU University Medical Centre, Amsterdam, The Netherlands 10Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands 11Department of Obstetrics and Gynaecology, Division of Gynaecology Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands 12Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
Theodora C
TC
van Tilborg
Frank J
FJ
Broekmans
Anouk
A
Pijpe
Lieske H
LH
Schrijver
Thea M
TM
Mooij
Jan C
JC
Oosterwijk
Senno
S
Verhoef
Encarna B
EB
Gómez Garcia
Wendy A
WA
van Zelst-Stams
Muriel A
MA
Adank
Christi J
CJ
van Asperen
Helena C
HC
van Doorn
Theo A
TA
van Os
Anna M
AM
Bos
Matti A
MA
Rookus
Margreet G
MG
Ausems
D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D003430:Cross-Sectional Studies; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006579:Heterozygote; D006801:Humans; D053208:Kaplan-Meier Estimate; D008593:Menopause / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D016016:Proportional Hazards Models; D012044:Regression Analysis; D055815:Young Adult