Cooperative Multicenter Reproductive Medicine Network (U10)

描述（由申请人提供）：加州大学弗朗西斯科分校（UCSF）的生殖健康中心（CRN）是唯一能够参与多中心生殖医学合作网络（RMN）的机构。CRN采用多学科方法进行患者护理，并将受益于Kaiser Permanente San弗朗西斯科和San弗朗西斯科总医院（SFGH）的社区参与。这种伙伴关系允许强大的实践量，这将促进受试者的招募，并且我们患者的不同种族，民族和社会人口统计学特征将增加 治疗方案。同样重要的是，我们在临床试验方面拥有领导力和经验，以确保成功。临床研究是将基础科学转化为临床研究的关键步骤，该研究的应用直接影响患者护理。在过去的四十年里，发达国家的妇女推迟了生育。生育率随着年龄的增长而下降，35岁以上妇女的活产率低于年轻妇女。活产率的下降反映了卵母细胞非整倍体的增加，导致植入失败和流产和出生缺陷的风险增加。老年不孕症患者的卵母细胞中线粒体活性异常，ATP的产生减少，这限制了正常的卵母细胞染色体分离和胚胎发育。如果没有足够的ATP，减数分裂纺锤体，这是至关重要的正常染色体分离，可能无法正确形成，和改变纺锤体的结果在非整倍体胚胎。在老年女性中，原始卵泡中的卵丘卵母细胞复合体（COC）暴露于低水平的活性氧（ROS），这些活性氧是由线粒体呼吸产生的。对线粒体DNA和辅酶Q10合成相关酶的累积损伤将减少线粒体产生ATP的底物。我们假设卵母细胞线粒体功能的改变反映了辅酶Q10随年龄增长而减少。如果我们的假设是正确的，我们可能能够通过给予辅酶Q10来部分逆转卵母细胞老化，以增加ATP的产生并增加抗氧化活性，从而减少对COC的损伤。为了验证这一假设，我们提出了一项多中心、安慰剂对照、随机试验，其目的如下：1）确定补充辅酶Q10是否减少卵巢刺激和宫腔内授精后体外受精（IVF）/卵胞浆内单精子注射（ICSI）的分娩时间; 2）确定补充辅酶Q10是否影响卵母细胞发育能力、卵泡内氧化应激和线粒体功能; 3）确定卵泡中的氧化应激是否与卵巢/时间老化和卵母细胞的发育能力有关。我们的研究在方法上是创新的-它结合了coQ 10的大型多中心随机安慰剂对照试验，以及对卵巢卵泡的实验室评估，以表征氧化应激（OS）和coQ 10在卵巢衰老中的作用。此外，阳性结果将为女性提供第一种治疗方法，以克服衰老对卵母细胞的影响以及由此导致的怀孕潜力降低。

DESCRIPTION (provided by applicant): The Center for Reproductive Health (CRN) at the University of California, San Francisco (UCSF) is uniquely positioned to participate in the Cooperative Multicenter Reproductive Medicine Network (RMN). The CRN takes a multi-disciplinary approach to patient care and will benefit from community involvement of Kaiser-Permanente San Francisco and San Francisco General Hospital (SFGH). This partnership allows a robust practice volume that will facilitate subject enrollment, and the diverse racial, ethnic, and socio-demographic characteristics of our patients will increase the generalizability of treatment protocols. Equally important, we have the leadership and experience in clinical trials to ensure success. Clinical research is a key step in translating basic science to the bedside, and the application of this research directly affects patient care. Over the last four decades, women in the developed world have delayed childbirth. Fertility decreases with age, and live birth rates are lower in women over 35 than in younger women. The decline in live birth rate reflects an increase in oocyte aneuploidy, leading to failure of implantation and increased risk for miscarriages and birth defects. Older infertility patients appear to have abnormal mitochondrial activity in oocytes and reduced production of ATP, which limits normal oocyte chromosomal disjunction and embryo development. Without sufficient ATP, the meiotic spindle, which is crucial for normal chromosome segregation, may not form properly, and altered spindles result in aneuploid embryos. In older women, the cumulus oocyte complex (COC) in primordial follicles is exposed to low levels of reactive oxygen species (ROS) produced by mitochondrial respiration over decades. The resultant cumulative damage to mtDNA and enzymes involved in coQ10 synthesis would reduce the substrate for ATP production by the mitochondria. We hypothesize that altered mitochondrial function in oocytes reflects diminished availability of coQ10 with age. If our hypothesis is correct, we may be able to partially reverse oocyte aging by giving coQ10 to increase ATP production and increase anti-oxidant activity, thereby reducing damage to the COC. To test this hypothesis, we propose a multicenter, placebo-controlled, randomized trial with the following aims: 1) Determine if coQ10 supplementation reduces time to delivery after ovarian stimulation and intrauterine insemination followed by in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI); 2) Determine if coQ10 supplementation affects oocyte developmental competence, intrafollicular oxidative stress, and mitochondrial function; and 3) Determine if oxidative stress in the follicle is relatedto ovarian/chronological aging and to the developmental competence of oocytes. Our study is innovative in its approach - which combines a large multicenter randomized placebo-controlled trial of coQ10, with laboratory evaluation of ovarian follicles, to characterize the role of oxidatve stress (OS) and coQ10 in ovarian aging. Additionally, a positive result would offer women the first treatment to overcome the impact of aging on the oocyte and the resultant lowered pregnancy potential.