PROJECT 1: METABOLIC AND NEUROENDOCRINE RESPONSES TO ANDROGEN AND DIET

项目摘要(参见说明)：我们最近发现，青春期前雌性猴子的睾酮(T)水平轻微升高，导致黄体生成素(LH)脉动性分泌频率显著增加，以及对促性腺激素释放激素(GnRH)的反应增加，并得出结论，在青春期期间长期暴露于轻度高雄激素血症会触发生殖轴的神经驱动变化，类似于成年早期患有多囊卵巢综合征的女孩的情况。随后，当猕猴5岁时，我们给它们喂西式饮食(WSD)，14个月后，T组和对照组动物在卵泡早期的脉搏频率都比正常快，并且黄体生成素的脉搏幅度降低。T组动物的胰岛素敏感性也显著低于对照组(降低2.6倍)，卵巢结构功能也发生了变化，详见项目II。这些初步研究表明，T WSD的组合可导致神经内分泌、卵巢和代谢异常，临床上与高雄激素血症和肥胖症相关。然而，T和WSD在这些异常的发生中所起的具体作用尚不清楚，因为这项初步研究没有包括单独的T组，也没有正常的猴食组。项目I的总体目标是使用青春期雌性恒河猴模型进一步确定青春期和成年早期(1)T、(2)WSD和(3)T WSD治疗与(4)对照条件相比，对代谢和生殖神经内分泌轴功能的影响。目的1将检查这四种治疗方法对关键代谢系统和睡眠模式的影响，测量代谢底物和激素水平、ivGTT、ITT、代谢室代谢率的测量、高胰岛素/正血糖钳夹、葡聚糖和活动度。睡眠障碍以双向方式与T升高和肥胖有关，并可能是与多囊卵巢综合征相关的代谢病理的部分原因。目的研究不同治疗方法对大鼠生殖神经内分泌(促黄体生成素、卵泡刺激素和促性腺激素释放激素的反应性)、下丘脑基底区KNDy(Kispeptin、Neurokinin 8、Dynorphin)神经元多肽水平和基因表达的影响。目标3将测试通过移除T植入物和/或恢复低卡路里、低脂肪饮食来降低循环T水平是否会逆转高雄激素血症和WSD发生的神经内分泌和代谢变化。

PROJECT SUMMARY (See instructions): We recently discovered that a mild elevation in testosterone (T) levels in prepubertal female monkeys led to a significant increase in the frequency of pulsatile LH secretion, as well as an increase in LH response to GnRH, and concluded that chronic exposure to mild hyperandrogenemia over the course of puberty triggers changes in the neural drive to the reproductive axis that resemble those of girls with PCOS in early adulthood. Subsequently, when monkeys were 5 years of age, we fed them a Western Style Diet (WSD) and after 14 months both T-treated and control animals had a faster than normal pulse frequency in the early follicular phase, as well as decreased LH pulse amplitude. T-treated animals also showed a significant decrease in insulin sensitivity compared to control animals (2.6-fold lower), and changes in ovarian structure function, as detailed in Project II. These pilot studies demonstrate that a combination of T+WSD can lead to neuroendocrine, ovarian and metabolic abnormalities clinically associated with hyperandrogenemia and obesity. However, the specific roles that T and WSD played in the development of these abnormalities are unclear, as this pilot study did not include a T alone group, nor a normal monkey chow group. The overall goal of Project I is to use the pubertal female rhesus monkey model to further define the effects of adolescent and early adult (1) T, (2) WSD, and (3) T+ WSD treatment, compared to (4) control conditions, on function of the metabolic and reproductive neuroendocrine axes. Aim 1 will examine the effects of these four treatments on key metabolic systems and sleep patterns, measuring metabolic substrate and hormone levels, ivGTT, ITT, measurement of metabolic rate in a metabolic chamber, hyperinsulinemic/euglycemic clamps, dexascans, and activity. Sleep disorders are linked to both elevated T and obesity in a bi-directional fashion and could be partially responsible for the metabolic pathologies associated with PCOS. Aim 2 will examine the effects of treatments on reproductive neuroendocrine secretion (LH, FSH and responsiveness to GnRH), plus peptide levels and gene expression in KNDy (Kisspeptin, Neurokinin 8, Dynorphin) neurons in the basal hypothalamus. Aim 3 will test whether decreasing circulating T levels by removing T implants and/or reinstating a lower calorie, low fat diet will reverse neurendocrine and metabolic changes occurring with hyperandrogenemia and WSD.