Detection of estradiol in rat brain tissues: Contribution of local versus systemic production.

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.