Brain Estradiol Content in Newborn Rats: Sex Differences, Regional Heterogeneity, and Possible de Novo Synthesis by the Female Telencephalon

Abstract

Accurate assessment of gonadal steroid levels in the developing brain is critical for understanding naturally occurring steroid-mediated sexual differentiation as well as determining the physiological relevance of exogenous steroid treatments commonly used in the study of this phenomenon. Using RIA, we measured the estradiol (E(2)) content of six regions of the developing brain immediately post partum, 1 d post partum, and after injection of exogenous estradiol benzoate, testosterone propionate, or the aromatase inhibitor formestane. We found sexually dimorphic E(2) content in several regions of the newborn brain. At 2 h of life, there was significantly higher E(2) content in males vs. females in the frontal cortex, hypothalamus and preoptic area but not in the hippocampus, brainstem, or cerebellum. Surprisingly, the female hippocampus had significantly higher E(2) content than all other female regions examined. By d 1 post partum, E(2) levels had decreased precipitously in most brain regions, and only the hypothalamus maintained a sex difference. Injection of female pups with estradiol benzoate raised tissue levels to that of the male in the hypothalamus but 2- to 3-fold higher in the other five regions. Testosterone administration increased E(2) content exclusively in the preoptic area, suggesting local variation in aromatase activity and/or substrate availability. Central administration of formestane decreased estrogen content in the male cortex, hypothalamus, and preoptic area. Formestane treatment also decreased endogenous E(2) in female cortex and hippocampus, suggesting de novo synthesis selectively in these brain regions. These data corroborate and extend previous findings of sex differences in brain E(2) levels perinatally and reveal an unexpected regional heterogeneity in E(2) synthesis and/or metabolism.

Steroids, sex and the cerebellar cortex: implications for human disease

“…Moreover, in the hippocampus estradiol levels are similar between the sexes during development. This has led to the hypothesis that, rather than relying on gonadally produced steroids, the hippocampus produces its own estradiol de novo resulting in a reduction rather than a production of sex differences (36).…”

17β-Estradiol protects the neonatal brain from hypoxia–ischemia

“…Therefore, the treatment regiment used in the present study may be applicable not only to other animal models of postnatal brain injury, but may also be appropriate for human infants at risk for traumatic events such as H/I. The paradigm of 50μg 17β-estradiol treatment every other day ensures maintained elevated estradiol levels that are in the high physiologic range (Nuñez and McCarthy, 2003;Amateau et al, 2004). However promising, much more research is needed prior to taking this lab bench research to the bedside.…”

“…Administration of the 50μg dose of 17β-estradiol on postnatal day one and two has previously been shown to elevate hippocampal tissue levels of estradiol (when collected on postnatal day two) to 53.5% greater than vehicle treated animals at the same time point. The estradiol concentration on postnatal day two is only 32% higher than the peak hippocampal tissue levels of estradiol observed on postnatal day one (Amateau et al, 2004). Vehicle treated animals received a 0.05ml injection of sesame oil (n=5 total for all groups).…”

“…The developmental production of steroid hormones (i.e. testosterone, progesterone and estradiol), comes from four distinct sources: 1) originating from the fetus, produced by the gonads or adrenal glands (Gerall et al, 1991), 2) originating from the mother, produced by her gonads and the placenta (Weisz and Ward, 1980), 3) locally converted from a biochemical precursor via the activity of an enzyme such as neuronal aromatase within rat pups (George and Ojeda, 1982), and 4) de novo synthesis in rat pups (Amateau et al, 2004).…”

Cellular and Molecular Mechanisms of the Effects of Sex Hormones on the Nervous System

“…In the developing male rat, testosterone secreted from the testes is not bound by α-fetoprotein and freely enters the brain where it is locally converted into estradiol in specific nuclei. Consequently, neonatal males have more than double the levels of estradiol than females in brain regions subject to sexual differentiation [43]. High levels of the ER are concentrated in the same brain regions and ER is essential for transducing the steroid signal [44].…”