Wisconsin National Primate Research Center, University of Wisconsin, Madison, USA.
Am J Physiol Endocrinol Metab. 2010 Nov;299(5):E741-51. doi: 10.1152/ajpendo.00058.2010. Epub 2010 Aug 3.
Discrete fetal androgen excess during early gestation in rhesus monkeys (Macaca mulatta) promotes endocrine antecedents of adult polycystic ovary syndrome (PCOS)-like traits in female offspring. Because developmental changes promoting such PCOS-like metabolic dysfunction remain unclear, the present study examined time-mated, gravid rhesus monkeys with female fetuses, of which nine gravid females received 15 mg of testosterone propionate (TP) subcutaneously daily from 40 to 80 days (first to second trimesters) of gestation [term, mean (range): 165 (155-175) days], whereas an additional six such females received oil vehicle injections over the same time interval. During gestation, ultrasonography quantified fetal growth measures and was used as an adjunct for fetal blood collections. At term, all fetuses were delivered by cesarean section for postnatal studies. Blood samples were collected from dams and infants for glucose, insulin, and total free fatty acid (FFA) determinations. TP injections transiently accelerated maternal weight gain in dams, very modestly increased head diameter of prenatally androgenized (PA) fetuses, and modestly increased weight gain in infancy compared with concurrent controls. Mild to moderate glucose intolerance, with increased area-under-the-curve circulating insulin values, occurred in TP-injected dams during an intravenous glucose tolerance test in the early second trimester. Moreover, reduced circulating FFA levels occurred in PA fetuses during a third trimester intravenous glucagon-tolbutamide challenge (140 days gestation), whereas excessive insulin sensitivity and increased insulin secretion relative to insulin sensitivity occurred in PA infants during an intravenous glucose-tolbutamide test at ∼1.5 mo postnatal age. Data from these studies suggest that experimentally induced fetal androgen excess may result in transient hyperglycemic episodes in the intrauterine environment that are sufficient to induce relative increases in pancreatic function in PA infants, suggesting in this nonhuman primate model that differential programming of insulin action and secretion may precede adult metabolic dysfunction.
在恒河猴（Macaca mulatta）中，妊娠早期胎儿雄激素的离散性增加会促进雌性后代成年多囊卵巢综合征（PCOS）样特征的内分泌前体。由于促进这种 PCOS 样代谢功能障碍的发育变化尚不清楚，本研究检查了经时间匹配、怀有雌性胎儿的妊娠恒河猴，其中 9 只妊娠雌性从妊娠 40 至 80 天（第一至第二 trimester）每天接受 15 毫克的丙酸睾酮（TP）皮下注射[足月，均值（范围）：165（155-175）天]，而另外 6 只此类雌性在相同的时间间隔内接受油载体注射。在妊娠期间，超声检查量化了胎儿的生长指标，并作为胎儿血液采集的辅助手段。足月时，所有胎儿均通过剖宫产分娩进行产后研究。从母代和婴儿中采集血液样本，用于葡萄糖、胰岛素和总游离脂肪酸（FFA）测定。TP 注射在母代中短暂加速了体重增加，对产前雄激素化（PA）胎儿的头直径略有增加，并且与同期对照相比，婴儿期的体重增加适度增加。TP 注射的母代在第二 trimester 早期进行静脉葡萄糖耐量试验时出现轻度至中度葡萄糖不耐受，循环胰岛素值的曲线下面积增加。此外，在第三 trimester 静脉给予胰高血糖素-甲苯磺丁脲挑战（妊娠 140 天）时，PA 胎儿的循环 FFA 水平降低，而 PA 婴儿在约 1.5 月龄时进行静脉葡萄糖-甲苯磺丁脲试验时，胰岛素敏感性相对增加，胰岛素分泌增加。这些研究的数据表明，实验性诱导的胎儿雄激素过多可能导致宫内环境中的短暂高血糖发作，足以诱导 PA 婴儿的胰腺功能相对增加，这表明在这种非人类灵长类动物模型中，胰岛素作用和分泌的差异编程可能先于成年代谢功能障碍。
