BRCA mutations and fertility: do not push the envelope!
2013; Elsevier BV; Volume: 99; Issue: 6 Linguagem: Inglês
10.1016/j.fertnstert.2013.01.091
ISSN1556-5653
Autores Tópico(s)Reproductive Biology and Fertility
ResumoIn this issue of Fertility and Sterility, Finch et al. (1Finch A. Valentini A. Greenblatt E. Lynch H.T. Ghadirian P. Armel S. et al.members of the Hereditary Breast Cancer Study GroupFrequency of premature menopause in women who carry a BRCA1 or BRCA2 mutation.Fertil Steril. 2013; 99: 1724-1728Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar) describe the findings of their case-control study of the age at natural menopause in US and Canadian women who are carriers of the BRCA1 or BRCA2 mutation. Although their principal findings appear to be overall reassuring, a closer look at the data ought to inspire a heightened level of clinical concern for the fertility of women who carry these mutations.Finch et al. (1Finch A. Valentini A. Greenblatt E. Lynch H.T. Ghadirian P. Armel S. et al.members of the Hereditary Breast Cancer Study GroupFrequency of premature menopause in women who carry a BRCA1 or BRCA2 mutation.Fertil Steril. 2013; 99: 1724-1728Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar) report a mean age of natural menopause of 48.8 years for BRCA1 carriers, 49.2 years for BRCA2 carriers, and 50.3 years for controls. This magnitude of difference is similar to the earlier age at menopause that is associated with cigarette smoking (2Gold E.B. The timing of the age at which natural menopause occurs.Obstet Gynecol Clin North Am. 2011; 38: 425-440Abstract Full Text Full Text PDF PubMed Scopus (381) Google Scholar). On the face of it, a mean of 1.1- to 1.5-year difference in the age at menopause seems quite innocuous, and the observation that women with BRCA mutations had similar parity to those without mutations appears reassuring. In addition, similar proportions of women with and without mutations reported fertility problems or took fertility medications.Now let us take a closer look at the data. The investigators performed a survey study, recruiting women diagnosed with BRCA between 1995 and 2012. This means that the data obtained reflect a population of women who were of reproductive age in the 1960s to the 1980s. This timing reflects an era where age at first birth was younger for women than it is at present. In 1970, US women had their first child at a mean age of 21.4 years, by 2006 this age advanced to 25.0 years (3Mathews T.J. Hamilton B.E. Delayed childbearing: more women are having their first child later in life. NCHS Data Brief, 21. National Center for Health Statistics, Hyattsville, MD2009Google Scholar), and in the latest available statistics, the mean age has advanced further to 25.1 years. The phenomenon of delayed childbearing displays significant geographic variation. Women in coastal US states have had even sharper increases in age at first birth, by as much as 2 years more than the national mean. Canadian women displayed an even sharper increase in age at first birth between 1970 and 2006—from 23.7–28.0 years. This means that the underlying distribution of age at first birth is shifting. In addition, births to older mothers, those aged 35 years and older, were almost four times as frequent in Canada as they were a generation earlier, based on a 2006 report. These mothers accounted for 17.2% of births in 2004, nearly four times the proportion of only 4.6% a quarter century earlier (4Statistics Canada. Births, 2004. Monday, July 31, 2006. Available at: http://www.statcan.gc.ca/daily-quotidien/060731/dq060731b-eng.htm. Last accessed January 31, 2013.Google Scholar). Based on the data from Finch et al. (1Finch A. Valentini A. Greenblatt E. Lynch H.T. Ghadirian P. Armel S. et al.members of the Hereditary Breast Cancer Study GroupFrequency of premature menopause in women who carry a BRCA1 or BRCA2 mutation.Fertil Steril. 2013; 99: 1724-1728Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar), there was no difference in the mean age at last birth, and family sizes were similar between the women with and without BRCA mutations. Yet the range of ages at which women had their first birth was 16–49 years in the controls and 16–47 years in the cases. This very wide scatter implies that relying on the meaned data may be hazardous. Similar to age at first birth, the mean age at menopause in women with and without BRCA mutations demonstrated wide variation, with a range of 38–65 years in the controls and 30–62 years in the cases.Can we use these data to allay the concerns of newly diagnosed women with BRCA mutations? Although on the mean, the answer to this clinically important question is yes, the variation in the age at menopause is so wide that other predictors of menopause and premature menopause (e.g., smoking behavior, race/ethnicity, family history, and socioeconomic status [2]) should be taken into consideration by the careful clinician. There are also further nuances to consider. The prevalence of premature menopause (before age 40 years) was almost four times higher in BRCA carriers than in controls. Thus, a woman with a BRCA mutation runs a higher risk of irreversible infertility at an inappropriately early age, especially if she chooses to delay childbearing. To be sure, for most women, this issue will likely not rear its head; however, considering the demographics of one’s patients, it makes sense to be cautious about future fertility if it is going to be significantly delayed, especially if the worldwide trend toward later age at first birth continues.Finch et al. (1Finch A. Valentini A. Greenblatt E. Lynch H.T. Ghadirian P. Armel S. et al.members of the Hereditary Breast Cancer Study GroupFrequency of premature menopause in women who carry a BRCA1 or BRCA2 mutation.Fertil Steril. 2013; 99: 1724-1728Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar) have performed a valuable, well-controlled investigation of age at menopause and the information obtained will be useful to clinicians and their patients with BRCA mutations. The data point out the importance of individualizing information based on the issues that each of our patients bring to the table. Women with BRCA mutations appear to have normal fertility as a group, but it is our job to help identify the outliers and point out when women may be taking risks with their fertility. In this issue of Fertility and Sterility, Finch et al. (1Finch A. Valentini A. Greenblatt E. Lynch H.T. Ghadirian P. Armel S. et al.members of the Hereditary Breast Cancer Study GroupFrequency of premature menopause in women who carry a BRCA1 or BRCA2 mutation.Fertil Steril. 2013; 99: 1724-1728Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar) describe the findings of their case-control study of the age at natural menopause in US and Canadian women who are carriers of the BRCA1 or BRCA2 mutation. Although their principal findings appear to be overall reassuring, a closer look at the data ought to inspire a heightened level of clinical concern for the fertility of women who carry these mutations. Finch et al. (1Finch A. Valentini A. Greenblatt E. Lynch H.T. Ghadirian P. Armel S. et al.members of the Hereditary Breast Cancer Study GroupFrequency of premature menopause in women who carry a BRCA1 or BRCA2 mutation.Fertil Steril. 2013; 99: 1724-1728Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar) report a mean age of natural menopause of 48.8 years for BRCA1 carriers, 49.2 years for BRCA2 carriers, and 50.3 years for controls. This magnitude of difference is similar to the earlier age at menopause that is associated with cigarette smoking (2Gold E.B. The timing of the age at which natural menopause occurs.Obstet Gynecol Clin North Am. 2011; 38: 425-440Abstract Full Text Full Text PDF PubMed Scopus (381) Google Scholar). On the face of it, a mean of 1.1- to 1.5-year difference in the age at menopause seems quite innocuous, and the observation that women with BRCA mutations had similar parity to those without mutations appears reassuring. In addition, similar proportions of women with and without mutations reported fertility problems or took fertility medications. Now let us take a closer look at the data. The investigators performed a survey study, recruiting women diagnosed with BRCA between 1995 and 2012. This means that the data obtained reflect a population of women who were of reproductive age in the 1960s to the 1980s. This timing reflects an era where age at first birth was younger for women than it is at present. In 1970, US women had their first child at a mean age of 21.4 years, by 2006 this age advanced to 25.0 years (3Mathews T.J. Hamilton B.E. Delayed childbearing: more women are having their first child later in life. NCHS Data Brief, 21. National Center for Health Statistics, Hyattsville, MD2009Google Scholar), and in the latest available statistics, the mean age has advanced further to 25.1 years. The phenomenon of delayed childbearing displays significant geographic variation. Women in coastal US states have had even sharper increases in age at first birth, by as much as 2 years more than the national mean. Canadian women displayed an even sharper increase in age at first birth between 1970 and 2006—from 23.7–28.0 years. This means that the underlying distribution of age at first birth is shifting. In addition, births to older mothers, those aged 35 years and older, were almost four times as frequent in Canada as they were a generation earlier, based on a 2006 report. These mothers accounted for 17.2% of births in 2004, nearly four times the proportion of only 4.6% a quarter century earlier (4Statistics Canada. Births, 2004. Monday, July 31, 2006. Available at: http://www.statcan.gc.ca/daily-quotidien/060731/dq060731b-eng.htm. Last accessed January 31, 2013.Google Scholar). Based on the data from Finch et al. (1Finch A. Valentini A. Greenblatt E. Lynch H.T. Ghadirian P. Armel S. et al.members of the Hereditary Breast Cancer Study GroupFrequency of premature menopause in women who carry a BRCA1 or BRCA2 mutation.Fertil Steril. 2013; 99: 1724-1728Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar), there was no difference in the mean age at last birth, and family sizes were similar between the women with and without BRCA mutations. Yet the range of ages at which women had their first birth was 16–49 years in the controls and 16–47 years in the cases. This very wide scatter implies that relying on the meaned data may be hazardous. Similar to age at first birth, the mean age at menopause in women with and without BRCA mutations demonstrated wide variation, with a range of 38–65 years in the controls and 30–62 years in the cases. Can we use these data to allay the concerns of newly diagnosed women with BRCA mutations? Although on the mean, the answer to this clinically important question is yes, the variation in the age at menopause is so wide that other predictors of menopause and premature menopause (e.g., smoking behavior, race/ethnicity, family history, and socioeconomic status [2]) should be taken into consideration by the careful clinician. There are also further nuances to consider. The prevalence of premature menopause (before age 40 years) was almost four times higher in BRCA carriers than in controls. Thus, a woman with a BRCA mutation runs a higher risk of irreversible infertility at an inappropriately early age, especially if she chooses to delay childbearing. To be sure, for most women, this issue will likely not rear its head; however, considering the demographics of one’s patients, it makes sense to be cautious about future fertility if it is going to be significantly delayed, especially if the worldwide trend toward later age at first birth continues. Finch et al. (1Finch A. Valentini A. Greenblatt E. Lynch H.T. Ghadirian P. Armel S. et al.members of the Hereditary Breast Cancer Study GroupFrequency of premature menopause in women who carry a BRCA1 or BRCA2 mutation.Fertil Steril. 2013; 99: 1724-1728Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar) have performed a valuable, well-controlled investigation of age at menopause and the information obtained will be useful to clinicians and their patients with BRCA mutations. The data point out the importance of individualizing information based on the issues that each of our patients bring to the table. Women with BRCA mutations appear to have normal fertility as a group, but it is our job to help identify the outliers and point out when women may be taking risks with their fertility. Frequency of premature menopause in women who carry a BRCA1 or BRCA2 mutationFertility and SterilityVol. 99Issue 6PreviewTo evaluate the impact of carrying a BRCA1 or BRCA2 mutation on the probability of experiencing premature natural menopause. Full-Text PDF
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