Cooperative Multicenter Reproductive Medicine Network (U10)

描述(由申请者提供)：加州大学旧金山分校(UCSF)生殖健康中心(CRN)是参与合作多中心生殖医学网络(RMN)的独特机构。CRN对患者护理采取多学科方法，并将受益于旧金山凯撒永久医院和旧金山综合医院(SFGH)的社区参与。这种伙伴关系允许强大的实践量，这将促进受试者的登记，而我们患者的不同种族、民族和社会人口特征将增加 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，可以确保成功。临床研究是将基础科学转化为床边的关键一步，这项研究的应用直接影响到患者的护理。在过去的40年里，发达国家的女性推迟了生育。生育率随着年龄的增长而下降，35岁以上女性的活产率低于年轻女性。活出生率的下降反映了卵母细胞非整倍体的增加，导致植入失败，并增加了流产和出生缺陷的风险。老年不孕症患者卵母细胞线粒体活性异常，三磷酸腺苷生成减少，限制了正常卵母细胞染色体分离和胚胎发育。如果没有足够的ATP，对正常染色体分离至关重要的减数分裂纺锤体可能不会正确形成，纺锤体的改变会导致非整倍体胚胎。在老年妇女中，原始卵泡中的卵丘卵母细胞复合体(COC)几十年来暴露在线粒体呼吸产生的低水平活性氧种(ROS)中。由此产生的对线粒体DNA和参与辅酶Q10合成的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的可用性随着年龄的增长而减少。如果我们的假设是正确的，我们可能能够通过给予辅酶Q10来增加ATP的产生和抗氧化活性，从而减少对COC的损害，从而部分逆转卵母细胞的衰老。为了验证这一假设，我们提出了一项多中心、安慰剂对照的随机试验，目的如下：1)确定补充CoQ10是否缩短了卵巢刺激和宫腔内授精后体外受精(IVF)/卵母细胞浆内单精子注射(ICSI)后的分娩时间；2)确定补充CoQ10是否影响卵母细胞的发育能力、卵泡内的氧化应激和线粒体功能；以及3)确定卵泡中的氧化应激是否与卵巢/时间老化以及卵母细胞的发育能力有关。我们的研究在方法上是创新的-将CoQ10的大型多中心随机安慰剂对照试验与卵巢卵泡的实验室评估相结合，以表征氧化应激(OS)和CoQ10在卵巢老化中的作用。此外，阳性结果将为女性提供第一种治疗方法，以克服老化对卵母细胞的影响，以及由此导致的怀孕潜力下降。

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.