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. 2025 May 21;27(1):87.
doi: 10.1186/s13058-025-02030-9.

Distribution of age at natural menopause, age at menarche, menstrual cycle length, height and BMI in BRCA1 and BRCA2 pathogenic variant carriers and non-carriers: results from EMBRACE

Nasim Mavaddat  1 , Debra Frost  2 , Emily Zhao  2 , Daniel R Barnes  2 , Munaza Ahmed  3 , Julian Barwell  4 , Angela F Brady  5 , Paul Brennan  6 , Hector Conti  7 , Jackie Cook  8 , Harriet Copeland  9 , Rosemarie Davidson  10 , Alan Donaldson  11 , Emma Douglas  12 , David Gallagher  13 , Rachel Hart  14 , Louise Izatt  15 , Zoe Kemp  16 , Fiona Lalloo  17 , Zosia Miedzybrodzka  18 , Patrick J Morrison  19 , Jennie E Murray  20 , Alex Murray  21 , Hannah Musgrave  22 , Claire Searle  23 , Lucy Side  24 , Katie Snape  25 , Vishakha Tripathi  15 , Lisa Walker  26 , Stephanie Archer  2   27 , D Gareth Evans  28 , Marc Tischkowitz  29 , Antonis C Antoniou  2 , Douglas F Easton  2   30
Affiliations

Distribution of age at natural menopause, age at menarche, menstrual cycle length, height and BMI in BRCA1 and BRCA2 pathogenic variant carriers and non-carriers: results from EMBRACE

Nasim Mavaddat et al. Breast Cancer Res. .

Abstract

Background: Carriers of germline pathogenic variants (PVs) in the BRCA1 and BRCA2 genes are at higher risk of developing breast and ovarian cancer than the general population. It is unclear if these PVs influence other breast or ovarian cancer risk factors, including age at menopause (ANM), age at menarche (AAM), menstrual cycle length, BMI or height. There is a biological rationale for associations between BRCA1 and BRCA2 PVs and reproductive traits, for example involving DNA damage and repair mechanisms. The evidence for or against such associations is limited.

Methods: We used data on 3,046 BRCA1 and 3,264 BRCA2 PV carriers, and 2,857 non-carrier female relatives of PV carriers from the Epidemiological Study of Familial Breast Cancer (EMBRACE). Associations between ANM and PV carrier status was evaluated using linear regression models allowing for censoring. AAM, menstrual cycle length, BMI, and height in carriers and non-carriers were compared using linear and multinomial logistic regression. Analyses were adjusted for potential confounders, and weighted analyses carried out to account for non-random sampling with respect to cancer status.

Results: No statistically significant difference in ANM between carriers and non-carriers was observed in analyses accounting for censoring. Linear regression effect sizes for ANM were -0.002 (95%CI: -0.401, 0.397) and -0.172 (95%CI: -0.531, 0.188), for BRCA1 and BRCA2 PV carriers respectively, compared with non-carrier women. The distributions of AAM, menstrual cycle length and BMI were similar between PV carriers and non-carriers, but BRCA1 PV carriers were slightly taller on average than non-carriers (0.5 cm difference, p = 0.003).

Conclusion: Information on the distribution of cancer risk factors in PV carriers is needed for incorporating these factors into multifactorial cancer risk prediction algorithms. Contrary to previous reports, we found no evidence that BRCA1 or BRCA2 PV are associated with hormonal or anthropometric factors, except for a weak association with height. We highlight methodological considerations and data limitations inherent in studies aiming to address this question.

Keywords: BRCA1; BRCA2; Body mass index; Cancer; Height; Menarche; Menopause.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The EMBRACE study was approved by the East of England – Cambridge South Ethics Committee (ref 98/5/026, IRAS 20971). All participants gave written informed consent. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

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