van Tilborg Theodora C, Derks-Smeets Inge A P, Bos Anna M E, Oosterwijk Jan C, van Golde Ron J, de Die-Smulders Christine E, van der Kolk Lizet E, van Zelst-Stams Wendy A G, Velthuizen Maria E, Hoek Annemieke, Eijkemans Marinus J C, Laven Joop S E, Ausems Margreet G E M, Broekmans Frank J M
Department of Reproductive Medicine, University Medical Center Utrecht, Heidelberglaan 100, Room F05.126, PO Box 85500, 3508 GA Utrecht, The Netherlands
Department of Clinical Genetics, Maastricht University Medical Center+, PO Box 5800, 6202 AZ Maastricht, The Netherlands.
Hum Reprod. 2016 Nov;31(11):2651-2659. doi: 10.1093/humrep/dew242. Epub 2016 Oct 5.
Do BRCA1/2 mutation carriers have a compromised ovarian reserve compared to proven non-carriers, based on serum anti-Müllerian hormone (AMH) levels?
BRCA1/2 mutation carriers do not show a lower serum AMH level in comparison to proven non-carriers, after adjustment for potential confounders.
It has been suggested that the BRCA genes play a role in the process of ovarian reserve depletion, although previous studies have shown inconsistent results regarding the association between serum AMH levels and BRCA mutation status. Hence, it is yet unclear whether BRCA1/2 mutation carriers may indeed be at risk of a reduced reproductive lifespan. STUDY DESIGN, SIZE, DURATION: A multicenter, cross-sectional study was performed between January 2012 and February 2015 in 255 women. We needed to include 120 BRCA1/2 mutation carriers and 120 proven non-carriers to demonstrate a difference in AMH levels of 0.40 µg/l (SD ± 0.12 µg/l, two-sided alpha-error 0.05, power 80%).
PARTICIPANTS/MATERIALS, SETTING, METHOD: Healthy women aged 18-45 years who were referred to the Clinical Genetics Department and applied for predictive BRCA1/2 testing because of a familial BRCA1/2 mutation were asked to participate. A cross-sectional assessment was performed by measuring serum AMH levels and filling out a questionnaire. Multivariate linear regression analyses adjusted for age, current smoking and current hormonal contraceptive use were performed on log-transformed serum AMH levels.
Out of 823 potentially eligible women, 421 (51.2%) were willing to participate, and of those, 166 (39%) did not meet our inclusion criteria. Two hundred and fifty-five women were available for analyses; 124 BRCA1/2 mutation carriers and 131 proven non-carriers. The median [range] AMH level in carriers was 1.90 µg/l [0.11-19.00] compared to 1.80 µg/l [0.11-10.00] in non-carriers (P = 0.34). Adjusted linear regression analysis revealed no reduction in AMH level in the carriers (relative change = 0.98 (95%CI, 0.77-1.22); P = 0.76).
LIMITATIONS, REASONS FOR CAUTION: Participants were relatively young. Power was insufficient to analyze BRCA1 and BRCA2 mutation carriers separately. AMH levels may have been influenced by the use of hormonal contraceptives, though similar proportions of carriers and non-carriers were current users and adjustments were made to correct for potential confounding in our analysis.
Limitations of the current analysis and limitations of the existing literature argue for prospective, well-controlled follow-up studies with recurrent AMH measurements to determine whether carriers might be at risk for low ovarian reserve and to definitively guide care.
STUDY FUNDING/COMPETING INTERESTS: This study was partially financially supported by a personal grant for Inge A.P. Derks-Smeets, kindly provided by the Dutch Cancer Society (Grant Number UM 2011-5249). Theodora C. van Tilborg, Inge A.P. Derks-Smeets, Anna M.E. Bos, Jan C. Oosterwijk, Christine E. de Die-Smulders, Lizet E. van der Kolk, Wendy A.G. van Zelst-Stams, Maria E. Velthuizen, Marinus J.C. Eijkemans and Margreet G.E.M. Ausems have nothing to disclose. Ron J. van Golde has received unrestricted research grants from Ferring and Merck Serono, outside the submitted work. Annemieke Hoek received an unrestricted educational grant from Ferring pharmaceutical BV, The Netherlands and a speaker's fee for post graduate education from MSD pharmaceutical company, outside the submitted work. Joop S.E. Laven has received unrestricted research grants from Ferring, Merck Serono, Merck Sharpe & Dome, Organon, and Schering Plough, outside the submitted work. Frank J.M. Broekmans is a member of the external advisory board for Merck Serono (The Netherlands), outside the submitted work.
NTR no. 4324.
基于血清抗苗勒管激素（AMH）水平，与经证实的非携带者相比，BRCA1/2突变携带者的卵巢储备是否受损？
在对潜在混杂因素进行调整后，与经证实的非携带者相比，BRCA1/2突变携带者的血清AMH水平并未降低。
尽管先前的研究表明血清AMH水平与BRCA突变状态之间的关联结果不一致，但有人提出BRCA基因在卵巢储备耗竭过程中起作用。因此，目前尚不清楚BRCA1/2突变携带者是否确实存在生殖寿命缩短的风险。
研究设计、规模、持续时间：2012年1月至2015年2月期间，对255名女性进行了一项多中心横断面研究。我们需要纳入120名BRCA1/2突变携带者和120名经证实的非携带者，以证明AMH水平差异为0.40μg/L（标准差±0.12μg/L，双侧α错误0.05，检验效能80%）。
参与者/材料、设置、方法：因家族性BRCA1/2突变而被转诊至临床遗传学部门并申请BRCA1/2预测性检测的18至45岁健康女性被邀请参与研究。通过测量血清AMH水平并填写问卷进行横断面评估。对经对数转换的血清AMH水平进行多变量线性回归分析，并对年龄、当前吸烟状况和当前激素避孕药使用情况进行调整。
在823名潜在符合条件的女性中，421名（51.2%）愿意参与，其中166名（39%）不符合纳入标准。255名女性可供分析；124名BRCA1/2突变携带者和131名经证实的非携带者。携带者的AMH水平中位数[范围]为1.90μg/L[0.11 - 19.00]，非携带者为1.80μg/L[0.11 - 10.00]（P = 0.34）。调整后的线性回归分析显示携带者的AMH水平没有降低（相对变化 = 0.98（95%CI，0.77 - 1.22）；P = 0.76）。
局限性、谨慎原因：参与者相对年轻。检验效能不足以分别分析BRCA1和BRCA2突变携带者。AMH水平可能受到激素避孕药使用的影响，尽管携带者和非携带者中当前使用者的比例相似，并且在我们的分析中进行了调整以校正潜在的混杂因素。
当前分析的局限性以及现有文献的局限性表明，需要进行前瞻性、严格对照的随访研究，并反复测量AMH，以确定携带者是否存在卵巢储备低的风险，并明确指导治疗。
研究资金/利益冲突：本研究部分得到了荷兰癌症协会（资助编号UM 2011 - 5249）提供给英格·A.P.德克斯 - 斯米茨的个人资助。西奥多拉·C.范·蒂尔堡、英格·A.P.德克斯 - 斯米茨、安娜·M.E.博斯、扬·C.奥斯特维克、克里斯汀·E.德·迪 - 斯穆尔德斯、利泽特·E.范·德·科尔克、温迪·A.G.范·泽尔斯特 - 斯坦姆斯、玛丽亚·E.韦尔特胡森·马里努斯·J.C.艾克曼斯和玛格丽特·G.E.M.奥森斯均无利益冲突需要披露。罗恩·J.范·戈尔德在提交的工作之外，从辉凌和默克雪兰诺获得了无限制的研究资助。安妮米克·赫克在提交的工作之外，从荷兰辉凌制药公司获得了无限制的教育资助，并从默克制药公司获得了研究生教育的演讲费用。乔普·S.E.拉文在提交的工作之外，从辉凌、默克雪兰诺、默克夏普&多姆、欧加农和先灵葆雅获得了无限制的研究资助。弗兰克·J.M.布罗克曼斯在提交的工作之外，是默克雪兰诺（荷兰）外部咨询委员会的成员。
NTR编号4324。
