Dehydroepiandrosterone: A neuroactive steroid
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.
References (106)
DHEA, important source of sex steroids in men and even more in women
Prog Brain Res
(2010)- et al.
Metabolism of dehydroepiandrosterone and delta 5-androstene-3 beta, 17 beta-diol
J Biol Chem
(1954) - et al.
Die Harnausscheidung des 7-Hydroxydehydroepi-androsteronsulfats
Clin Chim Acta
(1962) - et al.
Characterisation of microsomal dehydroepiandrosterone 7-hydroxylase from rat liver
Steroids
(1968) - et al.
The intracrine sex steroid biosynthesis pathways
Prog Brain Res
(2010) - et al.
Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS)
Front Neuroendocrinol
(2009) - et al.
Regulation of the adrenal androgen biosynthesis
J Steroid Biochem Mol Biol
(2008) - et al.
Sulfated and unsulfated steroids modulate gamma-aminobutyric acid A receptor function through distinct sites
Brain Res
(1999) - et al.
Localisation of dehydroepiandrosterone sulphotransferase in adult rat brain
Brain Res Bull
(1999) - et al.
Hydroxysteroid sulfotransferase activity in the rat brain and liver as a function of age and sex
Steroids
(1997)
Steroid sulfatase and sulfuryl transferase activity in monkey brain tissue
Steroids
Metabolism of free and sulfoconjugated DHEA in brain tissue in vivo and in vitro
Steroids
Dehydroepiandrosterone sulphate and dehydroepiandrosterone in serum: Differences related to age and sex
Maturitas
Dehydroepiandrosterone and its 7-hydroxylated metabolites do not interfere with the transactivation and cellular trafficking of the glucocorticoid receptor
J Steroid Biochem Mol Biol
In vitro metabolism of dehydroepiandrosterone (DHEA) to 7alpha-hydroxy-DHEA and Delta5-androstene-3beta,17beta-diol in specific regions of the aging brain from Alzheimer's and non-demented patients
Brain Res
Reduced brain levels of DHEAS in hepatic coma patients: Significance for increased GABAergic tone in hepatic encephalopathy
Neurochem Int
Analysis of pregnenolone and dehydroepiandrosterone in rodent brain: Cholesterol autoxidation is the key
J Lipid Res
Peripheral neuroactive steroids may be as good as the steroids in the cerebrospinal fluid for the diagnostics of CNS disturbances
J Steroid Biochem Mol Biol
Neuroactive steroids in periphery and cerebrospinal fluid
Neuroscience
Adrenal glands of mouse and rat do not synthesize androgens
Life Sci
Inhibition of glucose-6-phosphate dehydrogenase by steroids. I. Effects of 3β-hydroxy-Δ5-steroids of the C19- and C21-series upon human red blood cell glucose-6-phosphate dehydrogenase
J Steroid Biochem
DHEA and the intracrine formation of androgens and estrogens in peripheral target tissues: Its role during aging
Steroids
Role of pregnenolone, dehydroepiandrosterone and their sulfate esters on learning and memory in cognitive aging,
Brain Res Brain Res Rev
Difference in pre- and post-treatment plasma DHEA levels were significantly and positively correlated with difference in pre- and post-treatment Hamilton depression scores following successful therapy for major depression
Psychoneuroendocrinology
Actions of dehydroepiandrosteroneand its sulfate in the central nervous systemm: Effects on cognition and emotion in animals and humans
Brain Res Rev
Dehydroepiandrosterone (DHEA) – A precursor steroid or an active hormone in human physiology
J Sex Med
Selective conversion by microglia of dehydroepiandrosterone to 5-androstenediol-A steroid with inherent estrogenic properties
J Steroid Biochem Mol
Metabolism of dehydroepiandrosterone by rodent brain cell lines: Relationship between 7-hydroxylation and aromatization
J Steroid Biochem Mol
Steroid hormones and neurosteroids in normal and pathological aging of the nervous system
Prog Neurobiol
Pregnenolone and dehydroepiandrosterone as precursors of native 7-hydroxylated metabolites which increase the immune response in mice
J Steroid Biochem Mol Biol
A novel cytochrome P450 expressed primarily in brain
J Biol Chem
Studies of the enzyme complex responsible for pregnenolone and dehydroepiandrosterone 7aplha-hydroxylation in mouse tissues
Steroids
Neurosteroid 7-hydroxylation products in the brain
Int Rev Neurobiol
Involvement of steroids and cytochromes P(450) species in the triggering of immune defenses
J Steroid Biochem Mol Biol
The 7-hydroxylation of dehydroepiandrosterone in rat brain
Steroids
Dehydroepiandrosterone 7alpha-hydroxylation in human tissues: Possible interference with type 1 11beta-hydroxysteroid dehydrogenase-mediated processes
J Steroid Biochem Mol Biol
7α-Hydroxylation of dehydroepiandrosterone does not interfere with the activation of glucocorticoids by 11β-hydroxysteroid dehydrogenase in EtC cerebellar neurons
J Steroid Biochem Mol Biol
Dehydroepiandrosterone 7-hydroxylase CYP7B: Predominant expression in primate hippocampus and reduced expression in Alzheimer's disease
Neuroscience
The neurosteroid dehydroepiandrosterone sulfate is an allosteric antagonist of the GABAA receptor
Brain Res
Mnemonic effects of testosterone and its 5alpha-reduced metabolites in the conditioned fear and inhibitory avoidance tasks
Pharmacol Biochem Behav
Isolierung eines neuen, physiologisch unwirksamen Sterinderivates aus Mannerrharn, seine Verknupfung mit Dehydro-androsteron und Androsteron: ein Beitrag zur Konstitution des Androsterons
Z Physiol Chem
DHEA and peripheral androgen and estrogen formation: Intracrinology
Ann N Y Acad Sci
Characterization of the dehydroepiaandrosterone (DHEA) metabolism via oxysterol 7alpha-hydroxylase and 17-ketosteroid reducatse activity in human brain
J Neurochem
The isolation of 16α-hydroxydehydroepiandrosterone (3β,16α-dihydroxyandrost-5-en-17-one) from the urine of normal men
Biochem J
Increased activation of the alternative “backdoor” pathway in patients with 21-hydroxylase deficiency: Evidence from urinary steroid hormone analysis
J Clin Endocrinol Metab
The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders
Endocr Rev
P450 oxidoreductase deficiency: A disorder of steroidogenesis with multiple clinical manifestations
Sci Signal
The secretion of dehydroepiandrosterone and dehydroepiandrosterone sulphate in man
J Endocrinol
Expression of the steroidogenic enzyme P450scc in the central and peripheral nervous systems during rodent embryogenesis
Endocrinology
Immunoreactive cytochrome P-450(17 alpha) in rat and guinea-pig gonads, adrenal glands and brain
J Reprod Fertil
Cited by (120)
Hair cortisol and dehydroepiandrosterone and their associations with optimism and pessimism in older people
2024, Hormones and BehaviorNeuroactive steroids and Parkinson's disease: Review of human and animal studies
2024, Neuroscience and Biobehavioral ReviewsNeuroinflammation: The central enabler of postoperative cognitive dysfunction
2023, Biomedicine and PharmacotherapyAndrogens impact on psychopathological variables according to CPRS, and EDI 2 scores: In women with bulimia nervosa, and eating disorder not otherwise specified
2023, Journal of Steroid Biochemistry and Molecular Biology