PROJECT 2: OVARIAN AND UTERINE RESPONSES TO ANDROGEN AND DIET

项目 2：卵巢和子宫对雄激素和饮食的反应

• 批准号: 8510087
• 负责人: RICHARD L STOUFFER
• 金额: $ 21.85万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8510087
• 关键词: 3-Dimensional; Acute; Adipose tissue; Adolescent; Affect; Alginates; Amenorrhea; Androgen Receptor; Androgens; Animal Model; Animals; Anovulation; Antral; Attention; Biopsy; Characteristics; Chronic; Clinical; Clinical Protocols; Clinical Treatment; Complex; Consult; Consultations; Control Groups; Cyst; Data; Development; Diagnosis; Diet; Disease; Embryo; Encapsulated; Endometrial; Etiology; Evaluation; Exposure to; Fatty acid glycerol esters; Female; Fertility; Functional disorder; Goals; Grant; Hormones; Hyperandrogenism; Hypothalamic structure; Image; In Vitro; Infertility; Inflammatory; Instruction; Insulin; Irregular Menstruation; Lead; Leptin; Life; Lipids; Longitudinal Studies; Macaca; Macaca mulatta; Magnetic Resonance Imaging; Menarche; Menstrual cycle; Metabolic; Microbubbles; Modeling; Monitor; Monkeys; Mutant Strains Mice; Obesity; Oocytes; Ovarian; Ovary; Pattern; Periodicity; Phenotype; Pituitary Gland; Polycystic Ovary Syndrome; Primates; Process; Protocols documentation; Puberty; Reproductive Health; Research Personnel; Risk; Role; Scientist; Signal Transduction; Specialist; Staging; Structure; Syndrome; Techniques; Testing; Testosterone; Time; Toxic effect; Ultrasonography; Uterus; Validation; Woman; Women' s Health; Work; adipokines; adiponectin; base; cytokine; design; fetal; folliculogenesis; glucose metabolism; improved; in vitro testing; in vivo; indexing; liver function; nonhuman primate; novel; reproductive; research study; response; species difference; sugar; treatment effect; young adult; young woman

Diseases associated with hyperandrogenemia and obesity profoundly impact women's health, including fertility. Ovarian dysfunction and menstrual irregularity are commonly associated with hyperandrogenemia (notably in polycystic ovarian syndrome, PCOS), but it remains unclear which alterations are a cause versus effect of androgen action. Recent studies suggest that obesity-related factors, such as adipokines and inflammatory cytokines, also impair ovarian function, but direct evidence from primates is limited. Based on preliminary data, and the validation of primate models (chronically testosterone, T-exposed, and western style diet, WSD-treated monkeys), longitudinal studies on peri-pubertal to young adult, female rhesus macaques are designed to test the hypothesis that hyperandrogenemia or diet alone leads to abnormalities in follicular/oocyte development and uterine structure-function, which when combined will further impair reproductive potential. The specific aims are to evaluate the effects of chronic (beginning just prior to menarche through young adulthood; years 1-4 of grant) T exposure and WSD, alone and in combination, on ovarian folliculogenesis and oocyte/embryo quality (AIM 1), plus menstrual cyclicity and uterine structure function (AIM 2); to identify the direct actions of androgen and adipokines on the primate follicle and oocyte at specific stages (preantral, small antral, preovulatory) of folliculogenesis (AIM 3); and to determine if the effects of T exposure, and/or WSD, on ovarian and uterine structure-function are reversible (AIM 4). Longitudinal studies will use circulating patterns and levels of hormones, sophisticated imaging (3-D Doppler and contrast-enhanced "microbubble" ultrasound, MRI) plus follicular and uterine biopsies to monitor ovarian and uterine structure-function. Ovaries will also be obtained for acute (cumulus-oocyte complexes) and longterm (3-D alginate-encapsulated follicles) studies of androgen and lipokine actions. The project group will work closely with the NHP Core, which will maintain monkeys (n=12/grp) in each of the four groups (Control, T, WSD, and T + WSD treatment), and ultimately test the fertility of treated animals, prior to evaluation of reversibility of treatment effects in year 5. We will interact with Projects I and III (primate studies) and Project IV (clinical protocols) to integrate our observations with those on macaque hypothalamus-pituitary and adipose/liver function, and to relate our findings to clinical scenarios. Important, new information will accrue on the actions of androgen and obesity-related factors on ovarian and uterine structure-function, relevant to the etiology and treatment of clinical disorders, e.g., PCOS, and associated infertility.

与高雄激素血症和肥胖相关的疾病深刻影响女性的健康，包括生育能力。卵巢功能障碍和月经不规律通常与高雄激素血症有关（尤其是多囊卵巢综合征，PCOS），但尚不清楚哪些改变是雄激素作用的原因和影响。最近的研究表明，肥胖相关因素，如脂肪因子和炎症细胞因子，也会损害卵巢功能，但来自灵长类动物的直接证据有限。基于初步数据和灵长类动物模型的验证（长期睾酮、T暴露和西式饮食、WSD治疗的猴子），对青春期到年轻成年的雌性恒河猴进行纵向研究，旨在检验以下假设：高雄激素血症或单独饮食会导致卵泡/卵母细胞发育和子宫结构功能异常，两者结合将进一步损害生殖潜力。具体目标是评估慢性（从月经初潮前开始到青年期；授予的第 1-4 年）T 暴露和 WSD（单独或组合）对卵巢卵泡发生和卵母细胞/胚胎质量的影响 (AIM 1)，加上月经周期和子宫结构功能（AIM 2）；确定雄激素和脂肪因子在卵泡发生的特定阶段（窦前、小窦、排卵前）对灵长类卵泡和卵母细胞的直接作用（AIM 3）；并确定 T 暴露和/或 WSD 对卵巢和子宫结构功能的影响是否可逆（AIM 4）。纵向研究将使用激素的循环模式和水平、复杂的成像（3-D 多普勒和对比增强的“微泡”超声、MRI）以及卵泡和子宫活检来监测卵巢和子宫的结构功能。还将获取卵巢用于雄激素和脂因子作用的急性（卵丘-卵母细胞复合物）和长期（3-D 藻酸盐封装的卵泡）研究。该项目组将与 NHP 核心密切合作，该核心将在四个组（对照组、T、WSD 和 T + WSD 治疗组）中饲养猴子（n=12/grp），并最终测试接受治疗的动物的生育能力，在第 5 年评估治疗效果的可逆性之前。我们将与项目 I 和 III（灵长类动物研究）和项目 IV（临床方案）进行互动，将我们的观察结果与猕猴下丘脑-垂体和脂肪/肝功能，并将我们的发现与临床情况联系起来。关于雄激素和肥胖相关因素对卵巢和子宫结构功能的作用，将产生重要的新信息，这些信息与临床疾病（例如多囊卵巢综合症和相关不孕症）的病因和治疗相关。