PROJECT 1: METABOLIC AND NEUROENDOCRINE RESPONSES TO ANDROGEN AND DIET

项目摘要（参见说明）：我们最近发现，青春期前雌性猴子睾酮（T）水平的轻度升高导致LH脉冲分泌频率的显著增加，以及LH对GnRH的反应增加，并得出结论，在青春期长期暴露于轻度高雄激素血症会引发生殖轴神经驱动的变化，类似于患有PCOS在成年早期随后，当猴子5岁时，我们给它们喂食西式饮食（WSD），14个月后，T处理和对照动物在卵泡早期的脉冲频率都比正常快，LH脉冲幅度也降低。与对照动物相比，T治疗的动物还显示胰岛素敏感性显着降低（低2.6倍），以及卵巢结构功能的变化，如项目II中所述。这些初步研究表明，T+WSD的组合可导致临床上与高雄激素血症和肥胖相关的神经内分泌、卵巢和代谢异常。然而，T和WSD在这些异常的发展中发挥的具体作用尚不清楚，因为该初步研究不包括单独的T组，也不包括正常的猴饲料组。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与（4）对照条件相比，青春期和早期成年（1）T、（2）WSD和（3）T+ WSD治疗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，代谢室中代谢率的测量，高胰岛素/正常血糖钳夹，地塞米松和活动。睡眠障碍以双向方式与T升高和肥胖相关，并且可能是与PCOS相关的代谢病理学的部分原因。目的2将检查治疗对生殖神经内分泌（LH、FSH和对GnRH的反应性）以及基底下丘脑中KNDy（Kisspeptin、神经激肽8、强啡肽）神经元中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/或恢复低热量、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.