背景:350名女性中估计有1名携带种系BRCA1/2突变,这增加了患乳腺癌和卵巢癌的风险,也可能导致不孕。都成熟了,产生性类固醇的卵巢卵泡是从不可再生的原始卵泡池中提取的,称为“卵巢储备”。早期卵巢储备功能衰竭的临床意义超越了不孕症,包括内分泌功能丧失和过早绝经的长期不良健康后果。我们的目的是确定卵母细胞中Brca1的条件性丢失是否会影响卵泡数量,随着母亲年龄的增长,小鼠的卵母细胞质量和生育力。我们还旨在确定AMH作为卵巢功能标志物的实用性,通过评估BRCA1/2突变的小鼠和女性的循环AMH水平,并将其与卵巢卵泡计数相关联。
方法:在本研究中,我们解决了该领域中一个长期存在的问题,即卵母细胞中BRCA1失活的功能后果。为了概述卵母细胞中BRCA1蛋白功能的丧失,我们使用Gdf9-Cre重组酶(WT:Brca1fl/flGdf9/+;cKO:Brca1fl/flGdf9cre/)在卵母细胞中产生了条件基因缺失的小鼠。
结果:在综合育种试验后,两组之间的可育寿命没有改变,卵母细胞中Brca1的条件性丢失导致雌性小鼠的产仔数减少。与WT动物相比,Brca1cKO动物的卵巢储备减少,并且在出生后(PN)300天的母亲年龄较高,卵母细胞成熟受损。血清抗苗勒管激素(AMH)浓度(临床实践中使用的卵巢储备的金标准间接标记)不能预测Brca1cKO小鼠与WT相比原始卵泡数量的减少。此外,我们发现,在一小部分有BRCA1/2突变的绝经前女性队列的配对样本中,卵泡数量或密度与血清AMH浓度之间无相关性.
结论:一起,我们的数据表明,BRCA1是女性卵母细胞数量和质量的关键调节因子,提示在这种情况下,应谨慎使用AMH作为卵巢储备的可靠标志物.
背景:这项工作是通过维多利亚州政府运营基础设施支持和澳大利亚政府NHMRCIRIISS实现的。这项工作得到了澳大利亚研究理事会(ALW-DE21010037和KJH-FT190100265)的资助,以及国家乳腺癌基金会(IIRS-22-092)授予ALW和KJH。上帝军,YML,LT,EOKS和MG得到了澳大利亚政府研究培训计划奖学金的支持。上帝军,YML和LT也得到了莫纳什研究生卓越奖学金的支持。YC,SG和XC得到了莫纳什生物医学发现研究所博士奖学金的支持。LRA还得到了莫纳什大学ECPF24-6809920940奖学金的支持。JMS得到了NHMRC资助(2011299)的支持。MH得到了NHMRC调查员赠款(1193838)的支持。
BACKGROUND: An estimated 1 in 350 women carry germline BRCA1/2 mutations, which confer an increased risk of developing breast and ovarian cancer, and may also contribute to subfertility. All mature, sex steroid-producing ovarian follicles are drawn from the pool of non-renewable primordial follicles, termed the \'ovarian reserve\'. The clinical implications of early ovarian reserve exhaustion extend beyond infertility, to include the long-term adverse health consequences of loss of endocrine function and premature menopause. We aimed to determine whether conditional loss of Brca1 in oocytes impacts ovarian follicle numbers,
oocyte quality and fertility in mice with advancing maternal age. We also aimed to determine the utility of AMH as a marker of ovarian function, by assessing circulating AMH levels in mice and women with BRCA1/2 mutations, and correlating this with ovarian follicle counts.
METHODS: In this study, we addressed a longstanding question in the field regarding the functional consequences of BRCA1 inactivation in oocytes. To recapitulate loss of BRCA1 protein function in oocytes, we generated mice with conditional gene deletion of Brca1 in oocytes using Gdf9-Cre recombinase (WT: Brca1fl/flGdf9+/+; cKO: Brca1fl/flGdf9cre/+).
RESULTS: While the length of the fertile lifespan was not altered between groups after a comprehensive breeding trial, conditional loss of Brca1 in oocytes led to reduced litter size in female mice. Brca1 cKO animals had a reduced ovarian reserve and
oocyte maturation was impaired with advanced maternal age at postnatal day (PN)300, compared to WT animals. Serum anti-Müllerian hormone (AMH) concentrations (the gold-standard indirect marker of the ovarian reserve used in clinical practice) were not predictive of reduced primordial follicle number in Brca1 cKO mice versus WT. Furthermore, we found no correlation between follicle number or density and serum AMH concentrations in matched samples from a small cohort of premenopausal women with BRCA1/2 mutations.
CONCLUSIONS: Together, our data demonstrate that BRCA1 is a key regulator of
oocyte number and quality in females and suggest that caution should be used in relying on AMH as a reliable marker of the ovarian reserve in this context.
BACKGROUND: This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. This work was supported by funding from the Australian Research Council (ALW - DE21010037 and KJH - FT190100265), as well as the National Breast Cancer Foundation (IIRS-22-092) awarded to ALW and KJH. LRA, YML, LT, EOKS and MG were supported by Australian Government Research Training Program Scholarships. LRA, YML and LT were also supported by a Monash Graduate Excellence Scholarship. YC, SG and XC were supported by Monash Biomedicine Discovery Institute PhD Scholarships. LRA was also supported by a Monash University ECPF24-6809920940 Fellowship. JMS was supported by NHMRC funding (2011299). MH was supported by an NHMRC Investigator Grant (1193838).