Dehydroepiandrosterone: A neuroactive steroid

https://doi.org/10.1016/j.jsbmb.2014.03.008Get rights and content

Highlights

  • Dehydroepiandrosterone and its sulfate are formed mainly in the adrenals, the gonads and the brain.

  • In the brain dehydroepiandrosterone and its sulfate exert a handful of effects on the control of brain functions.

  • There are several types of the mechanisms of action of these steroids.

  • An important part of these effects is mediated by metabolites of dehydroepiandrosterone.

  • The present paper brings a short outline of dehydroepiandrosterone dependent events in the brain.

Abstract

Dehydroepiandrosterone (DHEA) and its sulfate bound form (DHEAS) are important steroids of mainly adrenal origin. They are produced also in gonads and in the brain. Dehydroepiandrosterone easily crosses the brain–blood barrier and in part is also produced locally in the brain tissue. In the brain, DHEA exerts its effects after conversion to either testosterone and dihydrotestosterone or estradiol via androgen and estrogen receptors present in the most parts of the human brain, through mainly non-genomic mechanisms, or eventually indirectly via the effects of its metabolites formed locally in the brain. As a neuroactive hormone, DHEA in co-operation with other hormones and transmitters significantly affects some aspects of human mood, and modifies some features of human emotions and behavior. It has been reported that its administration can increase feelings of well-being and is useful in ameliorating atypical depressive disorders. It has neuroprotective and antiglucocorticoid activity and modifies immune reactions, and some authors have also reported its role in degenerative brain diseases.

Here we present a short overview of the possible actions of dehydroepiandrosterone and its sulfate in the brain, calling attention to various mechanisms of their action as neurosteroids and to prospects for the knowledge of their role in brain disorders.

Introduction

In 1934, Butenandt and Dannenbaum [1] isolated dehydroepiandrosterone (3β-hydroxy-5-androsten-17-one, DHEA) from urine and designated to be a physiologically inactive product. In 1944, Munson and colleagues identified its 3β-sulfate (DHEAS). Nowadays, 80 years later, we still have many uncertainties about the physiological function and the importance that DHEA plays in human life. DHEA reaches serum concentrations of about 30 nmol/l in young healthy men. DHEAS, on the other hand, is found in concentrations of more than 10 μmol/l. This makes DHEA and its sulfate-bound form the most abundant steroids in humans.

It was recognized early on that DHEA is mainly of adrenal origin, and that it is a substrate for testosterone formation and secondary to estrogen production. The metabolic pathways leading to androstenedione and further to androgens and estrogens [2], [3], its oxidoreduction on C3 and C17 and/or reduction of the double bound at C5 leading to isomeric androstanediols, androstenediol and androstanedione [4] were also shown to take place in the brain [5].

A non-negligible portion of DHEA is hydroxylated at C7 and C16 to 7α-, 7β- [5], [6], [7] and 16α- and 16β- [8] hydroxyderivatives. Recently, an alternative metabolic pathway, from DHEA to dihydrotestosterone omitting testosterone as an intermediate product, has attracted interest [9], [10].

For a long time DHEA, DHEAS and their metabolites were considered biologically unimportant degradation products of steroid metabolism. Presently, however, DHEA is a matter of intensive interest, as a compound with many functions in the human brain as well as other reasons. For very detailed information on DHEA/S as a neurosteroid with complete citations of original sources until 2009, see the review by Maninger et al. [11].

Section snippets

Synthesis and metabolism of DHEA(S) in periphery

The primary organ producing DHEA (primarily in the sulfated form) and further adrenal precursors of androgens is the inner layer of the adrenal cortex, zona reticularis. The key enzymes participating in adrenal synthesis of DHEA are encoded by genes for steroidogenic acute regulatory protein (StAR) controlling cholesterol transport within the mitochondria, cholesterol side-chain cleavage enzyme (CYP11A1) providing conversion of cholesterol(S) to pregnenolone(S), 17α-hydroxylase/17,20

DHEA(S) synthesis

Adrenal steroidogenesis in mammals is species specific. Only adrenal of humans and higher primates synthesize substantial quantities of C19 steroids mostly in the sulfated form. These substances are further converted to effective androgens. While rats primarily convert pregnenolone to androstenedione in the sequence: pregnenolone  progesterone  17-hydroxyprogesterone  androstenedione (Δ4 pathway), humans, primates, and ruminants use almost entirely the Δ5 pathway: pregnenolone  

DHEA in health and disease

Dehydroepiandrosterone was long considered as to have limited value for human health, though some [48] already a half century ago drew attention to low DHEA or DHEAS levels in diseases such as diabetes, hypertension, arteriosclerosis, gout and obesity. The proposed mechanism of action in these disorders focused on the role of DHEA in the pentose cycle as an uncompetitive inhibitor of glucose-6-phosphate dehydrogenase [48], [49]. The associations of abnormal DHEA and the so-called diseases of

Mechanisms of DHEA action in the brain

DHEA mediates its action via multiple signaling pathways involving specific membrane receptors and via metabolic transformation into physiologically active steroid compounds (e.g., testosterone, dihydrotestosterone, estradiol, 7α-hydroxy- and 7β-hydroxy-DHEA, or 7α- and 7β-hydroxy-epiandrosterone) acting through their specific receptors. These pathways include: nitric oxide synthase activation, modulation of γ-amino butyric acid receptors (GABA-R), N-methyl-d-aspartate receptors (NMDA-R), sigma

Conclusion

Dehydroepiandrosterone and dehydroepiandrosterone sulfate are indeed true neurosteroids, differing in their influence on brain functions and modulating them in a variety of ways through multitude of different mechanisms.

Acknowledgement

Supported by a grant project NT/13980-4 and NT 12340-5 of the Internal Grant Agency of the Ministery of Health, Czech Republic.

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