Sex differences in anxiety and depression: role of testosterone

Abstract

Compelling evidence exists for pervasive sex differences in pathological conditions, including anxiety and depressive disorders, with females more than twice as likely to be afflicted. Gonadal hormones may be a major factor in this disparity, given that women are more likely to experience mood disturbances during times of hormonal flux, and testosterone may have protective benefits against anxiety and depression. In this review we focus on the effects of testosterone in males and females, revealed in both human and animal studies. We also present possible neurobiological mechanisms underlying testosterone's mostly protective benefits, including the brain regions, neural circuits, and cellular and molecular pathways involved. While the precise underlying mechanisms remain unclear, both activational and organizational effects of testosterone appear to contribute to these effects. Future clinical studies are necessary in order to better understand when and how testosterone therapy may be effective in both sexes.

Keywords: Anxiety; Aromatization; Depression; Dihydrotestosterone; Estradiol; Sex differences; Testosterone.

Figure 1. Steroidogenesis

Cholesterol is the precursor of all steroid hormones. The synthesis of testosterone involves a series of enzymatic steps and can occur through a number of disparate routes. Testosterone can then be aromatized to estradiol or reduced to dihydrotestosterone by the aromatase 5α-reductase.

Figure 2. Testosterone’s genomic and nongenomic effects

Testosterone exerts slower genomic actions by diffusing through the plasma membrane and binding with intracellular androgen receptors to form complexes. These complexes can then homodimerize and translocate to the nucleus and act as transcription factors at androgen response element (ARE) DNA sequences to enhance or repress transcription. Testosterone can also exert a number of rapid nongenomic effects through actions at membrane bound receptors (shown as examples, G protein coupled receptor and epidermal growth factor receptor). Rapid effects of androgens can induce a number of intracellular events such as stimulation of the MAPK-ERK pathway.