Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS)

Abstract

DHEA and DHEAS are steroids synthesized in human adrenals, but their function is unclear. In addition to adrenal synthesis, evidence also indicates that DHEA and DHEAS are synthesized in the brain, further suggesting a role of these hormones in brain function and development. Despite intensifying research into the biology of DHEA and DHEAS, many questions concerning their mechanisms of action and their potential involvement in neuropsychiatric illnesses remain unanswered. We review and distill the preclinical and clinical data on DHEA and DHEAS, focusing on (i) biological actions and putative mechanisms of action, (ii) differences in endogenous circulating concentrations in normal subjects and patients with neuropsychiatric diseases, and (iii) the therapeutic potential of DHEA in treating these conditions. Biological actions of DHEA and DHEAS include neuroprotection, neurite growth, and antagonistic effects on oxidants and glucocorticoids. Accumulating data suggest abnormal DHEA and/or DHEAS concentrations in several neuropsychiatric conditions. The evidence that DHEA and DHEAS may be fruitful targets for pharmacotherapy in some conditions is reviewed.

Figure 1

The Δ5 and Δ4 pathways of steroid hormone synthesis. The chemical names of the enzymes are shown for each reaction. P450scc, cholesterol side chain cleavage; 3βHSD, 3β-hydroxysteroid dehydrogenase; P450c17, 17α-hydroxylase/c17,20-lyase. The dotted arrow refers to the 17,20-lyase reaction that does not occur in human beings.

Figure 2

Mechanisms of action of DHEA and DHEAS in neurons. This cartoon summarizes many of the actions of DHEA and DHEAS described in detail in the text. DHEA and DHEAS have inhibitory effects (red blocking arrow) at the GABA_A receptor (section 6 and 7.1). DHEA and DHEAS act as agonists (green arrow) at the σ₁ receptor (section 6 and 7.1), which subsequently may activate the NMDA receptor. DHEA inhibits Ca²⁺ influx (red blocking arrow) into the mitochondria (section 7.1). DHEA influences embryonic neurite growth through stimulation (green arrow) of the NMDA receptor (section 7.2). DHEA increases (green arrow) kinase activity of Akt and decreases apoptosis, while DHEAS decreases (red blocking arrow) Akt and increases apoptosis (section 7.4). DHEAS increases (green arrows) TH mRNA and TH protein abundance (section 7.5) leading to increased catecholamine synthesis. DHEA and DHEAS stimulate (green arrows) actin depolymerization and submembrane actin filament disassembly and (green arrows), increasing secretion of catecholamines (“da” and “ne”) from secretory vesicles (section 7.5). DHEA and DHEAS inhibit (red blocking arrow) reactive oxygen species (ROS) activation of transcription mediated by NF-κB (section 7.6 and 7.7). DHEA inhibits (red blocking arrow) nuclear translocation of the glucocorticoid receptor (GR) (section 7.8). Mechanisms of action not pictured in this graph are: alterations of brain derived neurotrophic factor (BDNF) synthesis, inhibition of stress-activated protein kinase 3 (SAPK3) translocation, and inhibition of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSDl) activity. Abbreviations: σ₁, sigma 1 receptor; Akt, serine-threonine protein kinase Akt; Ca²⁺, calcium; da, dopamine; GABA_A, γ-aminobutyric acid type A receptor; GR, glucocorticoid receptor; ne, norepinephrine; NF-κB, nuclear factor kappa B; NMDA, N-methyl-D-aspartate receptor; ROS, reactive oxygen species; TH, tyrosine hydroxylase.