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

基本信息

批准号：
8642541
负责人：
RICHARD L STOUFFER
金额：
$ 27.03万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8642541
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&apos 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

项目摘要

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.

与高狂力血症和肥胖有关的疾病对妇女的健康深远影响，包括生育能力。卵巢功能障碍和月经不规则性通常与高雄激素血症有关（尤其是在多囊卵巢综合征，PCOS中），但尚不清楚哪些改变是雄激素作用的原因而不是雄激素作用的原因。最近的研究表明，与肥胖相关的因素（例如脂肪因子和炎症细胞因子）也损害了卵巢功能，但灵长类动物的直接证据受到限制。 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合并将进一步损害生殖潜力。具体的目的是评估慢性（刚开始在年轻成年之前开始；授予的1-4年），单独和联合使用WSD，对卵巢卵泡发生和卵泡/胚胎/胚胎质量（AIM 1），再加上cyclicity cyclicity and Cyclicity and cyclicity and cyclicity and cyclitual and cyclicity and buitterine and etterine结构功能（AIM 2）；在特定阶段（纤毛，小砂质，卵泡前），雄激素和脂肪因子对灵长类动物卵泡和卵母细胞的直接作用（AIM 3）；并确定T暴露和/或WSD的影响是否对卵巢和子宫结构功能是可逆的（AIM 4）。纵向研究将使用循环模式和激素水平，复杂的成像（3-D多普勒和对比度增强的“微泡”超声波，MRI）以及滤泡和子宫活检来监测卵巢和子宫结构功能。还将获得有关雄激素和脂蛋白作用的急性（卵母细胞复合物）和长期（3-D藻酸盐封闭的卵泡）研究的卵巢。该项目组将与NHP核心紧密合作，NHP核心将在四组中的每个组中维持猴子（n = 12/grp）（对照，T，WSD和T + WSD治疗），并最终测试治疗动物的生育能力，然后在5年内评估治疗效应的可逆性之前，将与项目I和III（PRACTICE IIV）相互作用（我们和Project IIV）（我们的临床）。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。重要的是，与临床疾病的病因和治疗相关的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新的信息，例如PCOS和相关的不孕症。