Ovarian Reserve Diminished in Women With BRCA 1/2 Mutations
BRCA mutations with deficient DSB repair can lead to depleted primordial follicles.
Women who carry BRCA1 and BRCA2 mutations, both of which are associated with breast cancer susceptibility, are more likely to have diminished ovarian reserve, according to research presented at the American Society for Reproductive Medicine (ASRM) Annual Meeting.
Previous studies have associated BRCA mutations with earlier natural menopause, lower serum anti-Müllerian hormone, and low response to ovarian stimulation. BRCA mutations can also cause deficient DNA double strand break (DSB) repairs, which could lead to increased DNA DSBs and result in premature depletion of primordial follicles, Wayne Lin, MD, MPH, of Brigham & Women's Hospital in Boston, and colleagues wrote in an abstract.
The researchers conducted the controlled study using donated, healthy, disease-free ovaries and ovarian tissue from women aged younger than 40 years with and without BRCA mutations. The study cohort with BRCA mutations included 17 carriers with BRCA 1 and 8 carriers with BRCA 2 mutations. The carriers had their ovaries removed to reduce the risk for ovarian cancer, and the control ovaries were taken from age-matched organ donor cadavers.
The researchers sectioned the ovaries and stained them with hematoxylin and eosin to calculate primordial follicle density. They took 10 50-mcm sections from each ovary to evaluate the follicles.
The data showed that women with BRCA mutations had significantly lower densities of primordial follicles in their ovaries compared with the control group. The mean primordial follicle density was 11 vs 23 primordial follicles/mm3of ovarian cortex (P<.05).
The ovaries from BRCA carriers also had increased percentages of DNA DSBs in primordial follicles, as compared with the control group (average, 62% vs 22%; P<.05).
The researchers found no differences between BRCA 1 and BRCA 2 mutation carriers.
The results support the idea that ovarian reserve is diminished in BRCA 1/2 carriers, according to the researchers. They also suggest that DNA DSB reserve plays a vital role in maintaining ovarian reserve and that primordial follicle density may be reduced by premature attrition brought on by lethal DNA damage.
These data may be useful in fertility planning for BRCA 1/ 2 carriers, the researchers concluded
“This novel finding not only increases our knowledge of the ways ovarian function may break down, but provides us with important information to share with women who have a BRCA mutations,” ASRM President-Elect Owen Davis, MD, said during a press conference.
“It appears that a BRCA mutation may accelerate ovarian aging or the loss of primordial follicles; this is information women may need to plan their lives and families.”
- Lin W, Titus S, Ginsburg E, Oktay KH. Abstract O-17. Gene Mutations Are Associated with Diminished Primordial Follicle Density and Increased Oocyte DNA Damage in the Human Ovary. Presented at: ASRM Annual Meeting; Oct. 17-21, 2015; Baltimore.