Volkan Turan1,2, Matteo Lambertini3,4, Dong-Yun Lee5, Erica Wang6, Florian Clatot7, Beth Y Karlan8, Isabelle Demeestere9, Heejung Bang10, Kutluk Oktay1. 1. Department of Obstetrics and Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT. 2. Department of Obstetrics and Gynecology, Health and Technology University School of Medicine, Istanbul, Turkey. 3. Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova, Genova, Italy. 4. Department of Medical Oncology, UOC Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy. 5. Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. 6. Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA. 7. Department of Medical Oncology, Henri Becquerel Centre, Rouen, France. 8. UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA. 9. Fertility Clinic, Research Laboratory on Human Reproduction, CUB-Erasme, and Université Libre de Bruxelles (ULB), Brussels, Belgium. 10. Division of Biostatistics, Department of Public Health Sciences, University of California, Davis, CA.
Abstract
PURPOSE: To determine whether germline BRCA (gBRCA) pathogenic variants are associated with decreased ovarian reserve. MATERIALS AND METHODS: An individual patient-level data meta-analysis was performed using five data sets on 828 evaluable women who were tested for gBRCA. Of those, 250 carried gBRCA, whereas 578 had tested negative and served as controls. Of the women with gBRCA, four centers studied those affected with breast cancer (n = 161) and one studied unaffected individuals (n = 89). The data were adjusted for the center, age, body mass index, smoking, and oral contraceptive pill use before the final analysis. Anti-Müllerian hormone (AMH) levels in affected women were drawn before presystemic therapy. RESULTS: The mean age of women with versus without gBRCA1/2 (34.1 ± 4.9 v 34.3 ± 4.8 years; P = .48) and with gBRCA1 versus gBRCA2 (33.7 ± 4.9 v 34.6 ± 4.8 years; P = .16) was similar. After the adjustments, women with gBRCA1/2 had significantly lower AMH levels compared with controls (23% lower; 95% CI, 4 to 38; P = .02). When the adjusted analysis was limited to affected women (157 with gBRCA v 524 without, after exclusions), the difference persisted (25% lower; 95% CI, 9 to 38; P = .003). The serum AMH levels were lower in women with gBRCA1 (33% lower; 95% CI, 12 to 49; P = .004) but not gBRCA2 compared with controls (7% lower; 95% CI, 31% lower to 26% higher; P = .64). CONCLUSION: Young women with gBRCA pathogenic variants, particularly those affected and with gBRCA1, have lower serum AMH levels compared with controls. They may need to be preferentially counseled about the possibility of shortened reproductive lifespan because of diminished ovarian reserve.
PURPOSE: To determine whether germline BRCA (gBRCA) pathogenic variants are associated with decreased ovarian reserve. MATERIALS AND METHODS: An individual patient-level data meta-analysis was performed using five data sets on 828 evaluable women who were tested for gBRCA. Of those, 250 carried gBRCA, whereas 578 had tested negative and served as controls. Of the women with gBRCA, four centers studied those affected with breast cancer (n = 161) and one studied unaffected individuals (n = 89). The data were adjusted for the center, age, body mass index, smoking, and oral contraceptive pill use before the final analysis. Anti-Müllerian hormone (AMH) levels in affected women were drawn before presystemic therapy. RESULTS: The mean age of women with versus without gBRCA1/2 (34.1 ± 4.9 v 34.3 ± 4.8 years; P = .48) and with gBRCA1 versus gBRCA2 (33.7 ± 4.9 v 34.6 ± 4.8 years; P = .16) was similar. After the adjustments, women with gBRCA1/2 had significantly lower AMH levels compared with controls (23% lower; 95% CI, 4 to 38; P = .02). When the adjusted analysis was limited to affected women (157 with gBRCA v 524 without, after exclusions), the difference persisted (25% lower; 95% CI, 9 to 38; P = .003). The serum AMH levels were lower in women with gBRCA1 (33% lower; 95% CI, 12 to 49; P = .004) but not gBRCA2 compared with controls (7% lower; 95% CI, 31% lower to 26% higher; P = .64). CONCLUSION: Young women with gBRCA pathogenic variants, particularly those affected and with gBRCA1, have lower serum AMH levels compared with controls. They may need to be preferentially counseled about the possibility of shortened reproductive lifespan because of diminished ovarian reserve.
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