BRCA 2 mutation contributes to ovarian aging even with normal ovarian reserve

NEW ORLEANS — Researchers observed increased ovarian aging among women with BRCA1 and BRCA2 mutations, compared with women without the genetic alterations, but decreased ovarian reserve only among those with BRCA1, according to a speaker.

Ovarian reserve — measured by follicle density — was reduced among women with BRCA1, but not among those with BRCA2. Both mutations were associated with multiple markers of follicle DNA damage, which indicates ovarian aging, Karine Matevossian, DO, a reproductive endocrinology and infertility fellow at Warren Alpert Medical School of Brown University and the department of obstetrics and gynecology at Women & Infants Hospital in Providence, Rhode Island, said during a presentation at the ASRM Scientific Congress & Expo.

Matevossian and colleagues compared follicle count and density in ovarian tissue from premenopausal women aged 18 to 40 years with BRCA1 (n = 11) or BRCA2 (n = 9) who had undergone salpingo-oophorectomy to reduce their risk for ovarian cancer with that from a control group of 13 age-matched women who were not BRCA carriers. None of the women had ovarian cancer, chemotherapy or radiation, endometriosis or other ovarian pathology, or infertility. The researchers assessed DNA damage with phosphorylated histone H2AX (gamma H2AX) and phospho-ATM (p-ATM) analysis, and assessed oocyte apoptosis with the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay.

Researchers observed a statistically significantly lower density of primordial follicles among BRCA1 carriers, but not BRCA2 carriers, compared with the control group, Matevossian said. Primary follicle density was similar across the groups.

Gamma H2AX staining showed that BRCA1 carriers (54.2%; P < .0001) and BRCA2 carriers (50.3%; P = .0004) had a greater percentage of damaged oocytes compared with controls (31%). On p-ATM analysis, BRCA1 carriers (61.6%; P = .01), but not BRCA2 carriers (57.9%; P = .06), had a greater percentage of damaged oocytes compared with controls (42.6%). TUNEL staining, an indicator of cell apoptosis, showed BRCA1 carriers (61.5%; P = .008) and BRCA2 carriers (57.9%; P = .05) had a greater percentage of damaged oocytes compared with controls (42.6%).

“Our study can help BRCA1 and [BRCA]2 patients as they consider fertility preservation and childbearing,” Matevossian told Healio. “For BRCA1 carriers, they should be aware that they have below average follicular density and thus may have a shorter reproductive life span. For BRCA2 carriers, they may have reassuring ovarian reserve testing — ultrasounds, bloodwork — but their oocyte quality is affected by increased DNA damage, which may affect their reproductive potential.”