ReviewNeurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS)
Section snippets
1. Introduction
Dehydroepiandrosterone (DHEA) and its sulfate ester, DHEAS, together represent the most abundant steroid hormones in the human body. Nonetheless, their physiological significance, their mechanisms of action and their possible roles in human disease are not well understood. Highlighting the potential health significance of DHEA and DHEAS, concentrations of these hormones in humans typically decrease steadily with age, approaching a nadir at about the time many diseases of aging become markedly
2. DHEA(S) secretion changes across the lifespan
During human gestation, high concentrations of DHEAS are secreted by the fetal zone of the adrenal gland [199]. After birth, DHEA(S) concentrations decline over the first six months and remain low until adrenarche starts at six to eight years in both boys and girls, at which point DHEA(S) is synthesized and secreted from the zona reticularis layer of the adrenal cortex and circulating concentrations begin to rise [120], [234]. Adult humans secrete both DHEA and DHEAS from the zona reticularis
3. Biosynthesis of DHEA(S)
Dehydroepiandrosterone, 5-androsten-3 beta-ol-17-one, is a 19 carbon steroid that is synthesized from cholesterol by two steroid metabolizing enzymes (see Fig. 1, for more details about the biochemistry of steroid synthesis of DHEA see [16], [201]). The first, rate-limiting, and hormonally regulated step in the synthesis of all steroid hormones is the conversion of cholesterol into pregnenolone by the mitochondrial enzyme cholesterol side chain cleavage P450scc. Pregnenolone is converted into
4. Relative DHEA(S) concentrations in brain vs. plasma vs. CSF in humans
Higher concentrations of DHEA are found in the brain compared to plasma. In a study of ten postmortem human brains, DHEA concentrations were 29.4 nmol/kg in prefrontal lobe, 16.3 nmol/kg in parietal lobe, 13.1 nmol/kg in temporal cortex, 16.9 nmol/kg in cerebellum, and 18.7 nmol/kg in corpus callosum [164]. These data were derived from nine women and one man (76–93 years old), and it is worth noting that large individual differences in DHEA brain concentrations were observed, with prefrontal lobe
5. Species differences—humans vs. rodents
Humans and rodents (rats and mice) differ in the pathways through which sex steroids are synthesized. Whereas the Δ4 pathway predominates with rodents, the 17,20-lyase activity of the human P450c17 enzyme strongly prefers the Δ5 pathway [95] (see Fig. 1). Subsequent conversion of DHEA into androstenedione by 3β-hydroxysteroid dehydrogenase (3βHSD) is the only pathway by which humans produce androstenedione [67]. In rodents, conversion of cholesterol to androstenedione can occur through two
6. DHEA(S) as a neurosteroid
Important actions in the central nervous system (CNS) were initially inferred from observations that DHEA and DHEAS were synthesized de novo in brain, as brain concentrations were higher than plasma concentrations and brain concentrations remained high after adrenalectomy and gonadectomy of rats [68], [69]. Indeed, they have been termed “neurosteroids” for this reason [27], [28]. DHEA and DHEAS were among the first neurosteroids identified in rat brains [68], [69]. Cytochrome P450c17 was found
7. Mechanisms of action for DHEA(S)
Steroid hormones affect gene transcription by binding to specific cytoplasmic receptors, and then translocating into the nucleus, or binding to receptors that are resident in the nucleus, where they bind to steroid responsive elements on DNA. To date, no nuclear steroid receptor with high affinity for either DHEA or DHEAS has been found [326], [328]. The mechanisms by which DHEA(S) operate are not fully understood [326]. DHEA(S) may mediate some of its actions through conversion into more
8. Neurobiological actions of DHEA(S)
In this section, we focus on reported neurobiological actions of DHEA(S) and their proposed mechanisms of action, which may or may not be mediated by some of the receptors discussed above. The focus of this review is on the possible mechanisms of action of DHEAS, DHEA and its more immediate metabolites (e.g., 7α-hydroxy-DHEA) in the brain, rather than the possible effects due to conversion of DHEA(S) into sex steroids (e.g., estradiol and testosterone). Neurobiological actions of estradiol and
9. Methodological issues
Some of the contradictory findings between studies may be due to methodological differences. As more studies demonstrating the effects of DHEA(S) on neuroprotection are published, we will gain a better understanding of the important factors involved in the process. In reviewing the previously published studies, it has become clear that three of the important methodological issues that account for some of the variability in results between studies are: (1) the timing of DHEA(S) administration,
10. Implications of DHEA(S) mechanisms and actions for health and neuropsychiatric illnesses
Preclinical findings such as those reviewed above were largely influential in kindling interest in human applications of DHEA(S) for neuropsychiatric indications. In the remainder of this paper, we review data in humans showing relationships between circulating endogenous DHEA(S) concentrations and neuropsychiatric illness and function, as well as DHEA treatment data derived from double-blind, controlled clinical trials.
In humans, DHEA(S) concentrations in blood, urine, saliva, and
11. DHEA(S) concentrations and neuropsychiatric illnesses
Correlational studies have suggested a relationship between endogenous concentrations of DHEA(S) and depression, anxiety spectrum disorders, post-traumatic stress disorder (PTSD), schizophrenia, and dementia as well as mood, memory, and functional abilities in healthy aging individuals. However, numerous caveats (outlined more fully elsewhere [337]) are important to consider before ascribing causality in these relationships. For example, DHEA(S) concentrations often decrease non-specifically
12. DHEA(S) treatment effects
Whether or not endogenous concentrations of DHEA(S) are abnormal in various neuropsychiatric illnesses, it is possible that exogenous DHEA supplementation could have therapeutic benefits. Several studies have examined the possibility that pharmacotherapy with DHEA might have beneficial effects, although the majority were either small-scale or short-term, so definitive conclusions are lacking. These studies will be examined in the next section.
13. Summary
Considerable ambiguity remains regarding the role of DHEA(S) in human neuropsychiatric illness and the potential therapeutic applications of DHEA. There is intriguing but conflictual support for the use of DHEA (in addition to glucocorticoids and mineralocorticoids) in treating patients with Addison’s disease or hypopituitarism. Beneficial effects of DHEA have been consistently reported in individuals with major depression, dysthymia and schizophrenia, but these findings are based on a
14. Future research directions
In reviewing the preclinical and clinical data regarding DHEA, one is struck by the inconsistency in the clinical findings, despite preclinical findings that DHEA and DHEAS have many biological actions. Much of this incongruity undoubtedly lies in the methodological differences on which we have commented. Alternatively, the failure to replicate uniformly the benefits seen in preclinical studies in clinical studies may lie in the nature of neuropsychiatric diagnoses. Many clinical ante mortem
Acknowledgments
This research was partially funded by grants from the O’Shaughnessy Foundation, the National Alliance for Research in Schizophrenia and Affective Disorders, the Stanley Foundation and the Alzheimer’s Association to O.M.W.; by NIH Grant (NS049462) and March of Dimes Grant (07-554) to S.H.M.; and N.M. was funded by an NIMH T32 training Grant (MH09391).
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