Department of Clinical Genetics, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands.
GROW - School for Oncology and Developmental Biology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
J Assist Reprod Genet. 2017 Nov;34(11):1475-1482. doi: 10.1007/s10815-017-1014-3. Epub 2017 Aug 22.
The aim of this study was to determine whether BRCA1/2 mutation carriers produce fewer mature oocytes after ovarian stimulation for in vitro fertilization (IVF) with preimplantation genetic diagnosis (PGD), in comparison to a PGD control group.
A retrospective, international, multicenter cohort study was performed on data of first PGD cycles performed between January 2006 and September 2015. Data were extracted from medical files. The study was performed in one PGD center and three affiliated IVF centers in the Netherlands and one PGD center in Belgium. Exposed couples underwent PGD because of a pathogenic BRCA1/2 mutation, controls for other monogenic conditions. Only couples treated in a long gonadotropin-releasing hormone (GnRH) agonist-suppressive protocol, stimulated with at least 150 IU follicle stimulating hormone (FSH), were included. Women suspected to have a diminished ovarian reserve status due to chemotherapy, auto-immune disorders, or genetic conditions (other than BRCA1/2 mutations) were excluded. A total of 106 BRCA1/2 mutation carriers underwent PGD in this period, of which 43 (20 BRCA1 and 23 BRCA2 mutation carriers) met the inclusion criteria. They were compared to 174 controls selected by frequency matching.
Thirty-eight BRCA1/2 mutation carriers (18 BRCA1 and 20 BRCA2 mutation carriers) and 154 controls proceeded to oocyte pickup. The median number of mature oocytes was 7.0 (interquartile range (IQR) 4.0-9.0) in the BRCA group as a whole, 6.5 (IQR 4.0-8.0) in BRCA1 mutation carriers, 7.5 (IQR 5.5-9.0) in BRCA2 mutation carriers, and 8.0 (IQR 6.0-11.0) in controls. Multiple linear regression analysis with the number of mature oocytes as a dependent variable and adjustment for treatment center, female age, female body mass index (BMI), type of gonadotropin used, and the total dose of gonadotropins administered revealed a significantly lower yield of mature oocytes in the BRCA group as compared to controls (p = 0.04). This finding could be fully accounted for by the BRCA1 subgroup (BRCA1 mutation carriers versus controls p = 0.02, BRCA2 mutation carriers versus controls p = 0.50).
Ovarian response to stimulation, expressed as the number of mature oocytes, was reduced in BRCA1 but not in BRCA2 mutation carriers. Although oocyte yield was in correspondence to a normal response in all subgroups, this finding points to a possible negative influence of the BRCA1 gene on ovarian reserve.
本研究旨在比较携带 BRCA1/2 突变的患者与进行植入前遗传学诊断（PGD）的 PGD 对照组患者，在接受体外受精（IVF）卵巢刺激后产生的成熟卵母细胞数量是否存在差异。
这是一项回顾性、国际、多中心队列研究，对 2006 年 1 月至 2015 年 9 月期间进行的首次 PGD 周期的数据进行了分析。数据从医疗档案中提取。该研究在荷兰的一个 PGD 中心和三个附属的 IVF 中心以及比利时的一个 PGD 中心进行。接受 PGD 的夫妇是因为存在致病性 BRCA1/2 突变，而对照组则是因为其他单基因疾病。仅纳入接受长 GnRH 激动剂抑制方案治疗、至少接受 150IU 卵泡刺激素（FSH）刺激的夫妇。由于化疗、自身免疫性疾病或遗传疾病（BRCA1/2 突变除外）而怀疑卵巢储备功能下降的女性被排除在外。在此期间，共有 106 名携带 BRCA1/2 突变的患者接受了 PGD，其中 43 名（20 名 BRCA1 突变携带者和 23 名 BRCA2 突变携带者）符合纳入标准。将他们与通过频数匹配选择的 174 名对照组进行比较。
共有 38 名携带 BRCA1/2 突变的患者（18 名 BRCA1 突变携带者和 20 名 BRCA2 突变携带者）和 154 名对照组患者进行了卵母细胞采集。BRCA 组的成熟卵母细胞中位数为 7.0（四分位距（IQR）4.0-9.0），BRCA1 突变携带者为 6.5（IQR 4.0-8.0），BRCA2 突变携带者为 7.5（IQR 5.5-9.0），对照组为 8.0（IQR 6.0-11.0）。将成熟卵母细胞数量作为因变量进行多元线性回归分析，并对治疗中心、女性年龄、女性体重指数（BMI）、使用的促性腺激素类型以及给予的促性腺激素总量进行调整，结果显示 BRCA 组的成熟卵母细胞产量明显低于对照组（p=0.04）。这一发现可以完全由 BRCA1 亚组来解释（BRCA1 突变携带者与对照组相比 p=0.02，BRCA2 突变携带者与对照组相比 p=0.50）。
BRCA1 但不是 BRCA2 突变携带者的卵巢刺激反应，表现为成熟卵母细胞数量减少。尽管所有亚组的卵母细胞产量与正常反应相符，但这一发现表明 BRCA1 基因可能对卵巢储备有负面影响。
