PROJECT 2: OVARIAN AND UTERINE RESPONSES TO ANDROGEN AND DIET

与高雄激素血症和肥胖症有关的疾病严重影响妇女的健康，包括生育能力。卵巢功能障碍和月经不调通常与高雄激素血症（特别是在多囊卵巢综合征，PCOS）有关，但目前尚不清楚哪些改变是雄激素作用的原因与影响。最近的研究表明，肥胖相关的因素，如脂肪因子和炎性细胞因子，也损害卵巢功能，但从灵长类动物的直接证据是有限的。基于初步数据和灵长类动物模型（长期睾酮、T暴露和西式饮食、WSD治疗猴）的验证，设计了对青春期至年轻成年雌性恒河猴的纵向研究，以检验高雄激素血症或饮食单独导致卵泡/卵母细胞发育和子宫结构-功能异常的假设，当两者结合时，将进一步损害生殖潜力。具体目标是评估慢性（从初潮前开始到成年早期;资助的第1-4年）T暴露和WSD单独和联合对卵泡发生和卵母细胞/胚胎质量（AIM 1）以及月经周期和子宫结构功能（AIM 2）的影响;确定雄激素和脂肪因子在特定阶段对灵长类卵泡和卵母细胞的直接作用（窦前、小窦、排卵前）的卵泡发生（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（三维多普勒和对比增强的“微泡”超声，MRI）加上卵泡和子宫活检来监测卵巢和子宫的结构-功能。还将获得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藻酸盐包封卵泡）研究。项目组将与NHP核心密切合作，NHP核心将在四个组（对照组、T组、WSD组和T + WSD组）中饲养猴（n=12只/组），并在第5年评价治疗效应的可逆性之前，最终检测治疗动物的生育力。我们将与项目I和III（灵长类动物研究）以及项目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/肝功能的观察结果相结合，并将我们的发现与临床情景相关联。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，与临床疾病的病因学和治疗相关，例如，多囊卵巢综合征及相关不孕症。

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.