The most likely explanation for the species differences

The most likely explanation for the species differences in aromatase distribution and the unique TP-0903 distribution in humans is the unique location, size and highly elaborate organization of the human aromatase gene (e.g. Bulun et al., 2003). The human Cyp19 is a large gene located on chromosome 15 which has 10 different tissue-specific promoters under the control of distinct physiological mediators, while the mouse gene is located on chromosome 9, is much smaller and contains a smaller number of tissue specific promoters (Kamat et al., 2002, Golovine et al., 2003, Honda et al., 1994). Since other promoters besides the brain specific exon 1.f (Sasano et al., 1998) are expressed in the human brain, this heterogeneity may also provide the basis for brain region specific regulation of aromatase. Comparing in vivo and postmortem results in humans is more difficult since the methodologies used do not include autoradiography or direct binding of inhibitors, and therefore are not as comparable to PET results. Furthermore, postmortem studies in humans generally included a relatively small number of regions and subjects. With these caveats in mind, the post mortem and in vivo findings are generally compatible. Thus, aromatase gene expression was examined in postmortem samples from eight brain regions (Sasano et al., 1998). The amount of aromatase mRNA determined by RT-PCR assay in 6 cases (4 men, 2 women) was highest in pons, thalamus, hypothalamus and hippocampus. Analysis of multiple exons 1 revealed that exons I.f, considered specific for brain, as well as the fibroblast type and gonadal type (Bulun et al., 2003), were expressed in the brain. Both the gonadal and brain types tended to be utilized in hypothalamus, thalamus and amygdala. The amount of overall mRNA expression was also higher in hypothalamus, thalamus and amygdala than in other regions of the brain. There were no differences of utilization of exons 1 and mRNA expression of aromatase between female and male brain. The authors conclude that their results demonstrate that aromatase is expressed widely in human brain tissues in both men and women. The presence of aromatase transcripts in human temporal cortex, frontal cortex and hippocampus was also confirmed by Stoffel-Wagner et al. (1999). Aromatase immunoreactivity was found in hypothalamus, amygdala, preoptic area and (cholinergic) ventral forebrain nuclei by Ishunina et al. (2005). More recent studies confirmed aromatase immunoreactivity in temporal cortex, hippocampus and prefrontal cortex (Yague et al., 2006, Yague et al., 2010). Immunohistochemistry was also used to examine the cellular and subcellular distribution of aromatase in the human brain, establishing the presence of aromatase immunoreactivity in neurons as well as in glia. Thus, cortical and hippocampal aromatase was detected in pyramidal cells, granule cells and interneurons; in perikarya, dendrites, axons and axon terminals (Naftolin et al., 1996, Yague et al., 2006, Yague et al., 2010). The presence of glial aromatase was confirmed in prefrontal cortex, temporal cortex and hippocampus, where it was associated with astrocytes (Yague et al., 2006, Yague et al., 2010). Aromatase enzymatic activity was first described in the fetal human limbic system by Naftolin et al. (1971), followed by reports on activity in the adult brain and temporal cortex (Naftolin et al., 1996, Steckelbroeck et al., 1999). These findings are in broad agreement with the in vivo observations on the gross anatomical level, showing aromatase is present throughout the brain. Previous studies on postmortem brain samples (e.g. Sasano et al., 1998. Steckelbroeck et al., 1999, Stoffel-Wagner et al., 1999) did not note sex differences or age effects on brain aromatase activity and gene expression in men and women, while the results of the in vivo studies described above do suggest a small but consistent sex difference and age effects, with higher levels in men (compatible with findings in rats) and an age–dependent decrease in most brain regions. The discrepancy most likely reflects issues of statistical power since previous human studies, including published pilot data from the same series (Biegon et al., 2010a, Biegon et al., 2010b) examined a much smaller number of subjects (32 vs. less than 10).