PROJECT 3 - THECA CELL FUNCTION IN POLYCYSTIC OVARY SYNDROME

多囊卵巢综合征（PCOS）影响5-10%的育龄妇女。基本上所有人都在遭受 从卵巢雄激素过多的生产，导致多毛症，并可能延续多个 与疾病相关的生殖和代谢紊乱，包括垂体促性腺激素改变 分泌、卵巢形态和功能异常、脂肪分布改变、胰岛素抵抗， 和血脂异常。然而，全面了解决定雄激素的机制， 缺乏过量生产，这可能是雄激素过量测量之间不一致的原因。 和临床表现。详细的翻译研究的必要性是强调， 这些患者对雄激素过多治疗的反应有限。我们假设在PCOS中， 细胞（TC）雄激素的产生受到多种卵巢内外因素的影响，尽管 这些因素之间的关系还没有得到很好的理解。因此，我们将详细评估 LH分泌增加的影响，颗粒细胞（GC）的体内和体外旁分泌影响，以及 高胰岛素血症对TC功能的影响。此外，考虑改变类固醇生成途径， 高雄激素血症将探讨GC功能的完整性，肾上腺雄激素 生产和胰岛素分泌，所有这些都与PCOS中的雄激素过度生产有关。起初， 将测定hCG刺激的TC反应的ED 50，随后用于测试LH的作用 分泌，包括脉冲释放，FSH刺激的GC旁分泌因子，和增加（胰岛素输注） 和降低的（二氮嗪）胰岛素水平。将在PCOS患者中评估Delta-4和-5类固醇途径 相对于GC的贡献（FSH刺激），对hCG表现出高和正常的17 OHP反应的妇女， 肾上腺雄激素（促肾上腺皮质激素输注）和胰岛素（二氮嗪）可能是造成这种差异的原因。 在体外，我们将评估分子和细胞旁分泌机制，通过这些机制， kit配体使用人TC/GC原代共培养系统增强TC雄激素产生。拟议 研究将开始来描述驱动卵巢雄激素过量产生的多种影响因素 并希望为患有PCOS的妇女提供新的有针对性的治疗方式。

Polycystic ovary syndrome (PCOS) affects 5-10% of reproductive-aged women. Essentially all suffer rom excess ovarian androgen production which causes hirsutism and likely perpetuates multiple eproductive and metabolic disruptions associated with the disorder, including altered pituitary gonadotropin secretion, morphologic and functional ovarian abnormalities, altered adipose distribution, insulin resistance, and dyslipidemia. However, a comprehensive understanding of the mechanisms that dictate androgen overproduction is lacking, which may account for inconsistencies between measures of androgen excess and clinical presentation in individual cases. The need for detailed translational studies is underscored by the limited response to treatment of androgen excess in these patients. We hypothesize that in PCOS theca cell (TC) androgen production is influenced by a variety of extra- as well as intra-ovarian factors, although the relationships among these factors are not well understood. Accordingly, we will assess in detail the mpact of increased LH secretion, in vivo and in vitro paracrine influences by the granulosa cell (GC), and the role of hyperinsulinemia on TC function. In addition, consideration of altered steroidogenic pathways to hyperandrogenemia will be explored with respect to the integrity of GC function, adrenal androgen production, and insulin secretion, all of which are implicated in androgen overproduction in PCOS. Initially, the ED5o for hCG-stimulated TC response will be determined and subsequently used to test the roles of LH secretion including pulsatile release, FSH-stimulated GC paracrine factors, and increased (insulin infusion) and decreased (diazoxide) insulin levels. Delta-4 and -5 steroid pathways will be assessed among PCOS women that exhibit high and normal 17OHP responses to hCG relative to contributions of GCs (FSH stimulation), adrenal androgens (ACTH infusion), and insulin (diazoxide) that may be responsible of this disparity. In vitro, we will assess the molecular and cellular paracrine mechanisms by which GC-derived inhibin and kit ligand enhance TC androgen production using the human TC/GC primary co-culture system. The proposed studies will begin to delineate the multiple influences that drive excess ovarian androgen production and, hopefully, provide insight into novel and targeted treatment modalities for women suffering from PCOS.