PROJECT 2: OVARIAN AND UTERINE RESPONSES TO ANDROGEN AND DIET

与高雄激素血症和肥胖相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规律通常与高雄激素血症相关（特别是在多囊卵巢综合征，PCOS），但目前尚不清楚雄激素作用的因果关系。最近的研究表明，肥胖相关的因素，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（长期睾酮、睾酮暴露和西式饮食、wsd治疗的猴子）的验证，对雌性恒猴进行了从青春期到年轻的纵向研究，以验证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，这些假设联合起来会进一步损害生殖潜力。具体目的是评估慢性（从初潮前开始到青年期；资助期1-4年）T暴露和WSD单独或联合对卵巢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卵泡形成的特定阶段（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）。纵向研究将使用循环模式和激素水平，复杂的成像（3-D多普勒和增强对比的“微泡”超声，核磁共振成像）以及卵泡和子宫活检来监测卵巢和子宫结构功能。卵巢也将用于雄激素和脂素作用的急性（卵丘-卵母细胞复合物）和长期（3-D海藻酸包膜卵泡）研究。项目小组将与NHP核心密切合作，该核心将在四组（对照组、T组、WSD组和T + WSD组）中分别饲养猴子（n=12/组），并在第5年评估治疗效果的可逆性之前，最终测试治疗动物的生育能力。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/肝脏功能的观察结果结合起来，并将我们的发现与临床情景联系起来。重要的是，雄激素和肥胖相关因素对卵巢和子宫结构功能的作用将获得新的信息，这与临床疾病（如多囊卵巢综合征和相关不孕）的病因和治疗有关。

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.