Age of natural menopause onset in BRCA1/2 carriers – systematic review and meta-analysis
Łukasz Kępczyński†1,2, Katarzyna Połatyńska3, Jordan Sałamunia4, Tadeusz Kałużewski4, Andrzej Kużawczyk5, Agnieszka Gach1
1Department of Genetics, Polish Mother’s Memorial Hospital Research Institute (Łódź, Poland); 2Laboratory of Molecular Biology, Department of Internal Medicine, Kidney and Diabetes, Medical University of Łódź (Łódź, Poland); 3Department of Neurology, Polish Mother’s Memorial Hospital Research Institute (Łódź, Poland); 4Laboratory of Medical Genetics of the “Genos” Partnership R&D Division (Łódź, Poland). 5Institute IurisMed – Independent Medical Examiners (Kutno, Poland);
The influence of germinal BRCA1 and BRCA2 on age of natural menopause remains inconclusive and controversial. 4 studies and our original, unpublished data from families, affected by BRCA1 or BRCA2 mutations, consisted of at least two postmenopausal female siblings with differing mutation status, combining data from 1535 germinal BRCA1 and BRCA2 mutation carriers and 3191 control individuals, does not support the hypothesis of association between germinal mutation of “breast cancer genes” and premature menopause.
„Breast cancer genes” BRCA1 and BRCA2 are by far the most widely studied human genes, and consequences of germline mutations of both genes for cancer risk are very well described . Non-oncological implications of germline BRCA1 and BRCA2 genes, complicating reproductive health, including early natural menopause, reduced ovarian reserve and unresolved association between BRCA1 and BRCA2 mutation, premature ovarian failure and CGG repeat number in FMR1 gene, are far less described [2, 3, 4, 5, 6].
Woman’s reproductive lifespan is limited by the age of menarche and age of natural menopause (ANM). Timing of both events are determined by genetic and environmental factors, with relatively high heritability for ANM, estimated on around 50% . At least intragenic 3 loci (SYCP2L, UIMC1, and MCM8) and a least 1 intergenic locus (13q34) are associated with ANM across different ethnic populations , and can be treated as quantitative trait loci (QTL) for ANM. Loci for premature menopause were also identified, with most widely studied association between premature ovarian failure (POF) and number of CGG repeats in FMR1 gene .
The influence of germinal BRCA1 and BRCA2 on AMN remains inconclusive and controversial. Hence, we conducted a comprehensive systematic review and meta-analysis of BRCA1 and BRCA2 mutation on ANM.
Material and Methods
PubMed database was searched for abstracts by two reviewers (ŁK and KP) using the keywords: (“BRCA1” OR “BRCA2” OR “hereditary breast cancer”) AND (“menopause”). We identified 193 citation; both reviewers independently reviewed potentially relevant studies subsequently excluded studies which were not case-control, cohort or cross-sectional studies. Additionally, reference lists from systematic reviews or meta-analyses, dealing with the topic of menopause and BRCA1 and BRCA2 germinal mutations, were also checked to identify eligible studies. Studies dealing only with risk-reducing salpingo-oophrectomy (RRSO) and influence of ANM on breast and/or ovary cancer risk were excluded. Two studies (see Table 1) not reporting dispersion measures and not reporting ANM in control group were left in tabular summary, yet were excluded from meta-analysis. Discrepancies in retrieved list were resolved by consensus. We also included our original, unpublished data from families, affected by BRCA1 or BRCA2 mutations, consisted of at least two postmenopausal female siblings with differing mutation status (Table 2). As most of the data reported median and range for ANM, we estimated mean and standard deviation using Hozo et al. approach . Meta-analysis was done using random effects model on standardized mean differences. Statistical analysis was conducted using R (version 3.6.1. The R Foundation for Statistical Computing).
Results and Discussion
Our database search retrieved 193 articles by initial strategy, and 6 studies, combining data from 2121 germinal BRCA1 and BRCA2 mutation carriers and 3741 control subjects [11, 12, 13, 14, 15, 16]. Four of the studies used Kaplan-Meier approach to asses the differences between carriers and non-carriers [12, 13, 16], two studies were excluded from meta-analysis, as they reported no dispersion measures (and we were unable unambiguously derive those data from Figures)  or did not report data from control group . We also included original data from 7 mutation carriers and 9 non-carrier siblings, summarized in Table 2. Studies included in presented meta-analysis combined data from 1535 germinal BRCA1 and BRCA2 mutation carriers and 3191 control individuals. Results of preformed meta-analysis are presented in Figure 1. Results only from group affected with BRCA1 mutation was similar to group combining carriers of either mutations (data not shown). Shortage of data from carriers of germinal BRCA2 mutation did not enabled draw significant conclusions.
Three studies reported association BRCA1 and BRCA2 with premature menopause [11, 12, 14], two studies reported no evidence of that association [13, 16]. Meta-analysis results does not support the hypothesis of association between germinal mutation of “breast cancer genes” and premature menopause. Nevertheless, data from all included studies are prone to selection biases as cessation of observation due to RRSO or cancer-related and treatment-related menopause. Only carefully designed prospective study may resolve the true association between BRCA1 and BRCA2 and early menopause.
|Study||BRCA1/2 Positive||BRCA1 Positive||BRCA2 Positive||Controls||Geographical region|
|Rzepka-Górska et al., 2006||Median = 45.5 
(Range: 39 – 52)
|Median = 45.5 
(Range: 39 – 52)
|NA||Median = 48.2 
(Range: 43 – 53)
|Lin et al., 2012||Median = 49 
(Range: 26 – 55)
|Median = 48 
(Range: 26 – 55)
|Median = 49 
(Range: 28 – 53)
|Median = 53 
(Range: 18 – 53)
|United States (California)|
|Collins et al., 2013||NA||Median = 51.||Median = 51 ||Median = 52 
Median = 51 
|Australia and New Zeland|
|Finch et al., 2013||Mean = 50.3 
(Range: 38 – 53)
|Mean = 49.9 
(Range: 39 – 65)
|Mean = 50.8 
(Range: 38 – 59)
|Mean = 49.0 
(Range: 30 – 63)
Mean = 48.8 
(Range: 30 – 57)
Mean = 49.2 
(Range: 36 – 62)
|Canada and United States|
|Tea et al., 2013||NA||Mean = 40.7 ||Mean = 46.8 ||NA||Austria|
|van Tilborg et al., 2016||Median = 53 
(Range: 28 – 59)
|NA||NA||Median = 53 
(Range: 35 – 62)
|Kępczyński et al., 2020
|Mean = 48.4 
(Range: 43 – 52)
|Mean = 48.4 
(Range: 43 – 52)
|NA||Mean = 46.2 
(Range: 41 – 52)
 All cases were attributed to BRCA1 mutations
 Range derived from Figures 3 and 4
 No dispersion measure nor range was given – excluded from analysis
 Controls for BRCA1 positive group
 Controls for BRCA2 positive group
 Mean calculated as mean of menarche in whole group + mean reproductive lifespan, no actual data nor dispersion measure was given – excluded from analysis
 Only one family with BRCA2 mutation
|Family||BRCA1 mutation||Age of natural menopause|
|NM_007294.4||BRCA1/2(+) sister(s)||BRCA1/2(–) sister(s)|
- Kuchenbaecker KB, Hopper JL, Barnes DR, et al. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. JAMA. 2017; 317(23): 2402-2416.
- de la Noval BD. Potential implications on female fertility and reproductive lifespan in BRCA germline mutation women. Arch Gynecol Obstet. 2016; 294(5): 1099-1103.
- Oktay K, Kim JY, Barad D, Babayev SN. Association of BRCA1 mutations with occult primary ovarian insufficiency: a possible explanation for the link between infertility and breast/ovarian cancer risks. J Clin Oncol. 2010; 28(2): 240-244.
- Cordeiro Mitchell CN, McGuinness B, Fine E, et al. Navigating the body of literature assessing BRCA1/2 mutations and markers of ovarian function: a systematic review and meta-analysis. J Assist Reprod Genet. 2020.
- Weghofer A, Tea MK, Barad DH, et al. BRCA1/2 mutations appear embryo-lethal unless rescued by low (CGG n<26) FMR1 sub-genotypes: explanation for the „BRCA paradox”?. PLoS One. 2012; 7(9): e44753.
- Laitman Y, Ries-Levavi L, Berkensdadt M, et al. FMR1 CGG allele length in Israeli BRCA1/BRCA2 mutation carriers and the general population display distinct distribution patterns. Genet Res (Camb). 2014; 96: e11.
- Murabito JM, Yang Q, Fox C, et al. Heritability of age at natural menopause in the Framingham Heart Study. J Clin Endocrinol Metab. 2005; 90(6): 3427-30.
- Carty CL, Spencer KL, Setiawan VW, et al. Replication of genetic loci for ages at menarche and menopause in the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) study. Hum Reprod. 2013; 28(6): 1695-706.
- Noto V, Harrity C, Walsh D, Marron K. The impact of FMR1 gene mutations on human reproduction and development: a systematic review. J Assist Reprod Genet. 2016; 33(9): 1135-1147.
- Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol. 2005; 5: 13.
- Rzepka-Górska I, Tarnowski B, Chudecka-Głaz A, et al. Premature menopause in patients with BRCA1 gene mutation. Breast Cancer Res Treat. 2006; 100(1): 59-63.
- Lin WT, Beattie M, Chen LM, et al. Comparison of age at natural menopause in BRCA1/2 mutation carriers with a non-clinic-based sample of women in northern California. Cancer. 2013; 119(9): 1652-9.
- Collins IM, Milne RL, McLachlan SA, et al. Do BRCA1 and BRCA2 mutation carriers have earlier natural menopause than their noncarrier relatives? Results from the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer. J Clin Oncol. 2013; 31(31): 3920-3925.
- Finch A1, Valentini A, Greenblatt E, et al. Frequency of premature menopause in women who carry a BRCA1 or BRCA2 mutation. Fertil Steril. 2013; 99(6) :1724-1728.
- Tea MK, Weghofer A, Wagner K, Singer CF. Association of BRCA1/2 mutations with FMR1 genotypes: effects on menarcheal and menopausal age. Maturitas. 2013; 75(2): 148-51.
- van Tilborg TC1, Broekmans FJ, Pijpe A, et al. Do BRCA1/2 mutation carriers have an earlier onset of natural menopause? Menopause. 2016; 23(8): 903-910.