Ovarian Aging in Women With BRCA Germline Mutations

Context: Recent clinical and laboratory studies suggested that women with BRCA mutations have lower ovarian reserve and their primordial follicle oocytes may be more prone to DNA damage; however, direct proof is lacking. Objective: To determine whether women with germline BRCA mutations have reduced primordial follicle reserve and increased oocyte DNA damage. Design: A comparative laboratory study of ovarian tissue obtained from unaffected BRCA mutation carriers (BMCs) vs age-matched organ donor cadavers. Setting: Two academic centers. Patients or Other Participants: Of the 230 ovarian specimens from BMCs, 18 met the study inclusion criteria. Healthy ovaries from 12 organ donor cadavers served as controls. Intervention: Histology and immunohistochemical analysis on paraffin-embedded ovarian sections. Main Outcome Measure(s): Primordial follicle density and the percentage of DNA double-strand break (DSB)-positive primordial follicle oocytes. Results: Ovaries from BMCs had significantly lower primordial follicle densities than those of controls (11.2 +/- 2.0 vs 44.2 +/- 6.2 follicles/mm(3); P = 0.0002). BRCA mutations were associated with increased DNA DSBs in primordial follicle oocytes (62% +/- 5.2% vs 36% +/- 3.4%; P = 0.0005). In subgroup analyses, both BRCA1 and BRCA2 mutations were associated with lower primordial follicle density (P = 0.0001 and 0.0030, respectively), and BRCA1 mutations were associated with higher DNA DSBs (P = 0.0003) than controls. The rates of follicle decline (R-2 = 0.74; P = 0.0001) and DNA DSB accumulation (R-2 = 0.70; P = 0.0001) appeared to be accelerated, particularly in primordial follicle oocytes of BMCs over age 30 years. Conclusions: We provide direct evidence of diminished ovarian reserve as well as accelerated primordial follicle loss and oocyte DNA damage in women with BRCA mutations. These findings may further our understanding of ovarian aging, and be useful when counseling BMCs.