Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Psychoneuroendocrinology. 2019 Apr;102:84-94. doi: 10.1016/j.psyneuen.2018.11.037. Epub 2018 Dec 1.
Estrogens play important roles in regulating brain development, brain function, and behavior. Many studies have evaluated these effects using ovariectomized (OVX) rats or mice with different doses of estrogen replacement, assuming that estradiol levels in all regions of the brain are the same as levels achieved in the serum. It is well known, however, that the brain contains all the enzymes necessary to produce estrogens, and that estrogen levels in the brain are determined by both systemic and local production and are region-specific. The present study conducted a detailed analysis of the relationship between systemic levels of 17-β-estradiol (E2) achieved by estrogen replacement and levels achieved in specific regions of the brain. Levels of E2 were measured in both brain and serum in OVX rats treated with different doses of estradiol benzoate (EB) using a novel and recently validated UPLC-MS/MS method. Results confirmed significantly higher levels of E2 in the brain than in serum in brain regions known to contain aromatase (ARO) activity, both in OVX controls and in rats treated with physiological doses of EB. Additional studies compared the level of E2 and testosterone (T) in the brain and serum between testosterone propionate (TP) treated OVX and male. This demonstrated higher levels of E2 in certain brain regions of males than in TP treated OVX females even though T levels in the brain and serum were similar between the two groups. Studies also demonstrated that the differences between serum and brain levels of E2 can be eliminated by letrozole (ARO inhibitor) treatment, which indicates that the differences are due to local ARO activity. Collectively the results provide a detailed analysis of brain region-specific E2 concentrations in OVX, E2-, and T-treated rats and demonstrate the degree to which these concentrations are ARO-dependent.
雌激素在调节大脑发育、大脑功能和行为方面发挥着重要作用。许多研究使用去卵巢（OVX）大鼠或接受不同剂量雌激素替代治疗的小鼠来评估这些作用，假设大脑所有区域的雌二醇水平与血清中的水平相同。然而，众所周知，大脑包含产生雌激素所需的所有酶，并且大脑中的雌激素水平取决于全身和局部产生，并且具有区域特异性。本研究详细分析了通过雌激素替代治疗实现的全身 17-β-雌二醇（E2）水平与大脑特定区域达到的水平之间的关系。使用最近验证的新型 UPLC-MS/MS 方法，在接受不同剂量苯甲酸雌二醇（EB）治疗的 OVX 大鼠的大脑和血清中测量 E2 水平。结果证实，在包含芳香酶（ARO）活性的大脑区域中，无论是 OVX 对照大鼠还是接受生理剂量 EB 治疗的大鼠，大脑中的 E2 水平均明显高于血清中的 E2 水平。其他研究比较了丙酸睾酮（TP）处理的 OVX 和雄性大鼠的大脑和血清中的 E2 和睾酮（T）水平。这表明，即使两组之间大脑和血清中的 T 水平相似，雄性某些大脑区域中的 E2 水平也高于接受 TP 治疗的 OVX 雌性大鼠。研究还表明，通过来曲唑（ARO 抑制剂）治疗可以消除 E2 血清和大脑水平之间的差异，这表明差异是由于局部 ARO 活性所致。总的来说，这些结果提供了 OVX、E2 和 T 处理大鼠大脑特定区域 E2 浓度的详细分析，并表明了这些浓度在多大程度上依赖于 ARO。
