Ovarian Aging in Women With BRCA Germline Mutations
| Autor: | Kutluk Oktay, Elizabeth S. Ginsburg, Fred Moy, Wayne Lin, Shiny Titus |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Adult medicine.medical_specialty Aging animal structures endocrine system diseases DNA damage Endocrinology Diabetes and Metabolism Biopsy Clinical Biochemistry Context (language use) Biology Biochemistry 03 medical and health sciences Follicle Young Adult 0302 clinical medicine Endocrinology Germline mutation Ovarian Follicle Internal medicine medicine Cadaver Humans Ovarian reserve skin and connective tissue diseases Ovarian Reserve Germ-Line Mutation Clinical Research Articles 030219 obstetrics & reproductive medicine BRCA1 Protein Genetic Carrier Screening Biochemistry (medical) BRCA mutation Ovary Oocyte female genital diseases and pregnancy complications 030104 developmental biology medicine.anatomical_structure Case-Control Studies Oocytes Female Folliculogenesis DNA Damage |
| Zdroj: | The Journal of clinical endocrinology and metabolism. 102(10) |
| ISSN: | 1945-7197 |
| Popis: | 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/mm3; 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 (R2 = 0.74; P = 0.0001) and DNA DSB accumulation (R2 = 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. |
| Databáze: | OpenAIRE |
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