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Monash University Department of Medicine Alfred Hospital Prahran, Victoria 3181 Australia
Address all correspondence and requests for reprints to: Paul A Komesaroff, Professor, Monash University, Department of Medicine, The Alfred Hospital, Commercial Road, Prahran, Victoria 3181, Australia. E-mail: paul.komesaroff{at}med.monash.edu.au.
Dehydroepiandrosterone (DHEA) is a controversial hormone. There is debate about its physiological roles, its mechanisms of action, its relationships to health and disease, indeed, whether it is a hormone at all (1, 2). Despite uncertainty about its status, it is widely promoted and sold as a complementary medicine. Even here, there are controversies and discrepancies: whereas in the United States it is freely available as a harmless health food, in Australia and elsewhere it is regarded as an anabolic steroid and its distribution is strictly controlled. In the midst of this uncertainty the article by Liu et al. (3) in this issue contributes important new evidence about the physiological actions of DHEA and the intracellular signaling pathways by which they are controlled.
DHEA and its sulfated prohormone, DHEA sulfate (DHEAS) are quantitatively the most abundant circulating adrenal steroid hormones in humans. Circulating DHEAS serves as a reservoir for DHEA, with conversion by sulfotransferases occurring in a wide range of tissues. There is also extensive metabolism to estrogens and androgens, giving rise to the view that many of its effects are mediated by these hormones or other metabolites (4). Plasma DHEAS levels decline with age and vary with sex, ethnicity, and environmental factors (5).
DHEA has been linked, usually controversially, to many diseases, including malignancies (6), neurological dysfunction (7), and systemic lupus erythematosus and other immune disorders (8), and claims have been made that DHEA deficiency contributes to the symptoms associated with adrenal insufficiency (9), ageing (10, 11), menopause (12), and disorders of sexual function (13). However, the major interest in the hormone stems from epidemiological studies that have been said to show an inverse relationship between cardiovascular mortality and plasma DHEA(S) levels in men (14). Although these data too are hotly contested (15, 16), over the last few years, evidence has steadily mounted in support of a physiological role for DHEA in cardiovascular tissues.
Animal studies have shown anti-atherogenic actions in several models of vascular dysfunction (17, 18, 19). In vitro data have shown actions on vascular endothelium and smooth muscle (20, 21, 22, 23) and on key mediators of atherogenesis. DHEA(S) influences proliferation of vascular endothelial cells and smooth muscle cells independently of androgen and estrogen receptors (22, 23, 24). In endothelial cells, it increases expression of nitric oxide synthase (NOS) and thereby secretion of NO, an important regulator of vascular function, and protects these cells against apoptosis (25, 26). DHEA administration to humans improves vascular endothelial function (22, 27), reduces known cardiovascular risk markers (28, 29), and appears to inhibit atherosclerosis (17, 18, 19). The effects on endothelial cells are mediated, at least in part, through the activation of the MAPK ERK1/2 (22, 30).
Progress has been made in elucidating the receptors through which DHEA acts. Although the best characterized steroid receptors are nuclear transcription factors, it is now recognized that steroids can in some cases also activate plasma membrane receptors and thereby initiate cytosolic kinase cascades (26, 31, 32, 33). In fact, in a landmark paper in 2002, Liu et al. (34) reported a membrane-bound, G protein-coupled receptor for DHEA identified in bovine vascular endothelial cells. The binding of ligand was of high affinity (Kd = 48.7 pM) and saturable. These authors have since shown that the receptor is maximally activated by 1–10 nM DHEA to stimulate endothelial NOS and enhance NO production (35).
In separate studies, it has been shown that the release of NO depends on activation of ERK1/2 (26). Activation of ERK1/2 is a crucial signaling event in a number of cellular functions, including proliferation, migration, cell growth, angiogenesis, survival, and apoptosis (36). In vascular endothelial cells, ERK1/2 contributes to stimulation of endothelial NOS and is activated in response to a range of extracellular stimuli, including growth factors, estrogens, shear stress (37, 38), and DHEA (39).
In their current study, Liu et al. (3) put these various insights together to show that the effect of DHEA on endothelium occurs via activation of ERK1/2. They provide evidence linking DHEA effects at the endothelial plasma membrane with cellular proliferation and angiogenesis by a process mediated by pertussis toxin-sensitive G proteins and ERK1/2. In these experiments, pertussis toxin completely blocked DHEA-induced ERK1/2 activation, endothelial cell proliferation and migration, and vascular tube formation, suggesting that Gi proteins link DHEA effects with the endothelial cell processes. The authors also show rapid nuclear translocation of activated ERK1/2, a critical step in the transcriptional and cell proliferative effects of this kinase.
As a result of the work of Liu et al. (3) and others, we can now confidently accept that DHEA(S) is biologically active in its own right in cardiovascular tissue, acts through specific, membrane-bound, G protein-coupled, receptors, increases production of NOS and NO, and contributes to intracellular signaling through activation of ERK1/2 and other messengers.
This is a significant achievement. However, it leaves many questions still to be answered. Uncertainty remains about the control of the biological events, given the high circulating concentrations of DHEA. As the authors themselves point out, based on in vitro pharmacokinetic studies, human plasma concentrations of DHEA are such that the putative receptor would be fully saturated. It is possible that the specificity of DHEA action is established through control of hormone delivery to tissues by yet to be characterized binding proteins, tissue-specific DHEA receptor expression, regulation of the expression and activity of the receptor, expression of coreceptors, or other mechanisms.
Whether the receptor mechanism elaborated here is either necessary or sufficient to explain the cellular effects of DHEA remains to be determined. The time courses and dose-response characteristics of the effects of the hormone in these experiments and those from other laboratories vary widely, suggesting that the actions may occur via more than one receptor and effector pathway. It is known that DHEA and its metabolites can activate estrogen receptors (especially estrogen receptor-β), the peroxisome proliferators-activated receptor-
, and the pregnane X receptor, and the existence of several other membrane-associated receptors has also been suggested (40). It is even possible that a specific nuclear receptor will be identified that mediates actions via other transcription factors to regulate cell proliferation, in addition to the plasma membrane-initiated kinase signaling effects.
The full range of biologically active forms of DHEA remain to be elucidated. DHEA is metabolized intracellularly to other steroids, including estradiol, which also induces vascular endothelial proliferation by activation of MAPKs (41, 42), androstenediol (43), and other substances. It is possible that complex actions are mediated through different metabolites and different receptors, including differential effects on estrogen receptor- and -β.
Most importantly, how these data translate into clinical outcomes remains to be determined. Whether DHEA is a key player in cardiovascular disease, whether deficiencies or excesses are beneficial or harmful, whether administration or withholding of the hormones is appropriate in defined clinical settings—all of these questions remain to be answered. However, what we can say is that the time is at last approaching when we will be able to design the studies to address them.
In conclusion, the new science of DHEA has yielded important knowledge about this enigmatic hormone and its actions. We have come a long way, but there is still a long way to go before we can feel confident that we understand its physiological and therapeutic roles.
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Footnotes |
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Abbreviations: DHEA, Dehydroepiandrosterone; DHEAS, DHEA sulfate; NOS, nitric oxide synthase.
Received December 27, 2007.
Accepted for publication January 2, 2008.
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1) receptor: biochemical and physiological evidences, consequences in neuroprotection. Pharmacol Biochem Behav 84:581–597[CrossRef][Medline] localized in caveolae. Biochem Biophys Res Commun 263:257–262[CrossRef][Medline]i2,3. J Biol Chem 277:21379–21388
-dependent signaling pathways. J Biol Chem 272:1395–1401
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