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Editors Selection IGR 9-3

Basic research: Androgen

Comment by Robert Nickells on:

13761 Androgen receptor and NFkB expression in human normal and glaucomatous optic nerve head astrocytes in vitro and in experimental glaucoma, Agapova OA; Kaufman PL; Hernandez MR, Experimental Eye Research, 2006; 82: 1053-1059

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Androgens are steroid hormones that are often linked to sex determination and prostate cancer. Historically, androgens have been identified as ligands for intracellular binding receptors that are translocated to the nucleus when activated, causing changes in transcriptional activity of target cells. In addition to their well-defined regional target of the developing reproductive system, recent studies have revealed a much more complex role for these hormones, demonstrating that not only are neurons one of the most prominent cellular targets of androgens, but also that their metabolism is much more complex than previously appreciated. For example, many androgens are processed further into forms with completely different properties.

Agapova et al. (324) published a series of experiments exploring the components of androgen ligand-receptor pathway in glaucomatous optic nerve head astrocytes. The impetus for this work was derived from earlier studies (Agapova et al., 2003) showing up-regulation of several isoforms of 3α -hydroxysteriod dehydrogenases (3β -HSD) in reactive astrocytes of glaucomatous optic nerve heads. These enzymes are involved in modifying androgens, such as dihydrotestosterone, into the neuroactive metabolites 3α -diol and 3β -diol. In vitro assays using astrocytes from normal and glaucomatous donors showed that glaucomatous cells had a much greater capacity to process dihydrotestosterone into 3α -diol. In their newer studies, Agapova and colleagues expand on these results and show increases in Androgen Receptor (AR) mRNA and protein expression in cultured astrocytes derived from human glaucoma samples (relative to cells from normal individuals) and that astrocytes in the optic nerve heads of non-human primates with experimental glaucoma exhibit more intense immunoreactivity and nuclear localization of AR, the latter being a hallmark of activation of the receptor. Consistent with this finding, they also demonstrate similar increased expression and localization of the transcription factor NFκB, which has been implicated in the transcriptional activation of the AR gene among a variety of others.

Androgen metabolism and androgen steroids may play role in astrocyte responses glaucomatous stimuli

These studies are interesting, in that they provide some initial evidence that androgen metabolism and androgen steroids may play a role in astrocyte responses to glaucomatous stimuli. Activated ARs affect gene expression directly by interacting with nuclear transcription factors, but can also bind to and affect various ion-gated channels. The authors suggest that nerve head astrocytes are androgen target cells, and this steroid hormone sensitivity may have a bearing on why some individuals are susceptible to steroid induced glaucoma. Interestingly, the evidence presented by these authors also provides something of a caveat to this hypothesis. Although astrocytes may be androgen target cells, the elevated levels of 3a-HSDs argues that these cells are actively converting androgens into 3α -diol in order to modify this ligand for other receptors. One of the principal targets of 3&alphaa-diol, for example, is not the AR but the GABA_A receptor instead.

Currently the role of steroids in the central nervous system is still poorly defined. The work of Agapova and colleagues has now provided some evidence that androgen metabolism is altered in astrocytes activated in the glaucomatous nerve head.

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