Women with BRCA1 mutations may be at risk of low ovarian reserve

Women who carry a BRCA1 mutation, a gene mutation that predisposes women to developing breast cancer, may also experience premature loss of eggs, according to a British study. The study analyzed the levels of anti-Müllerian hormone (AMH) in women who are carriers of BRCA1 mutation and those who are not. AMH levels are used to determine the level of ovarian reserve–each woman’s ability to produce good-quality eggs, which declines naturally with age. The British researchers found that women with BRCA1 mutations were on average about 2 years “older” in ovarian age, compared to women who don’t carry the mutation. So, a 35-year-old woman who carry a BRCA1 mutation may have eggs that are equivalent to those from a 37-year-old without the mutation.

Association of BRCA1 mutations and ovarian reserve was a topic that CHR investigators explored a while ago, so we asked Norbert Gleicher, MD, CHR’s Medical Director and Chief Scientist (below), to give us a background:

norbert_gleicher_mdThe suspicion that the BRCA gene may be associated with low functional ovarian reserve (LFOR, or more commonly known as DOR, diminished ovarian reserve) was “born” at CHR when Kutluk Oktay, MD, was a member of CHR’s physician team in 2008 and 2009. Indeed, CHR investigators were the first to publish an abstract reporting that BRCA1, but not BRCA2, was associated with LFOR and low egg yields.

The idea arose from observing IVF outcomes in breast cancer patients at CHR. Breast cancer, because of lower egg numbers in these patients, always appeared associated with low functional ovarian reserve. CHR was at the time actively researching the effects of the FMR1 gene on ovarian reserve, and CHR’s clinicians noticed that the ovaries of BRCA1 patients behaved more like those of patients with certain types of FMR1 mutations that had been associated with low FOR.

CHR investigators then followed up on a potential BRCA/FMR1 connection in a number of studies, while, after leaving CHR, Dr. Kutluk further expanded his research on the association of BRCA1 with low FOR. This association, however, remained controversial. A number of other investigators published studies which were unable to confirm associations between BRCA1 and low FOR.

This history makes the new British study even more important: It confirms the initial CHR report of the BRCA1-LFOR linkage with a relatively large patient base. The study’s weaknesses are that it is a cross-sectional study and not a longitudinal study, and that the study does not define individual BRCA1 mutations. What we learned in our BRCA/FMR1 work is that different BRCA mutations can behave very differently. The next question to be answered is, therefore, which specific BRCA1 mutations are associated with low FOR.

Our British colleagues are to be congratulated on an excellent piece of work. Considering the size of patient population they have available for research, we would hope to see a follow up manuscript with these data in the near future.