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Endocrine Section, Laboratory of Clinical Investigation, National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, Maryland 20892
Address all correspondence and requests for reprints to: Dr. Julia T. Arnold, Endocrine Section, Laboratory of Clinical Investigation, National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, Maryland 20892. E-mail: jarnold{at}mail.nih.gov.
Dehydroepiandrosterone (DHEA) is produced by the adrenal cortex and is the most abundant steroid in humans. Serum levels of DHEA and its sulfated conjugation product, DHEA sulfate (DHEAS), peak in men and women in the third decade and decrease progressively and profoundly with age (1). In the United States, DHEA is widely available as an over-the-counter dietary supplement and is increasingly self-prescribed for its alleged anabolic and antiaging effects, with unsubstantiated claims of beneficial effects on body composition, cardiometabolic, immune, and neurobiological functions, as well as uncertain long-term safety, in the elderly (2). Humans and other primates are unique among animal species in that their adrenal glands secrete large amounts of DHEA and DHEAS (3). To date, no cognate nuclear or membrane receptor for DHEA has been identified, and its mechanisms of action remain a subject of active investigation. DHEA has been shown to exert many of its effects via the androgen receptor (AR) and/or estrogen receptor (ER) after its enzymatic conversion to androgen or estrogen (4), although direct effects of DHEA on the AR and ER have also been demonstrated (5, 6). Moreover, DHEA can act via non-steroid-receptor nongenomic pathways, as shown in vascular endothelial cells (7). In aged adults, the use of DHEA as a dietary supplement is of potential concern in that its androgenic or estrogenic actions may stimulate proliferation of, and other adverse effects on, cancer cells within the prostate or breast. Controversy remains as to whether DHEA enhances or reduces the risk of prostate and breast cancer (8).
In this issue of Endocrinology, Chen et al. (9) report their studies on the direct agonistic and antagonistic effects of DHEA on AR, ER
, and ERß in human prostate cancer and other cells. Using competitive receptor binding assays, the investigators found that DHEA exhibited a higher affinity for ERß than for AR (mutant or wild-type receptors) or ER. These effects were noteworthy, in that they resulted from the actions of DHEA as a direct ligand in a cell-free system, so that conversion of DHEA to androgenic or estrogenic metabolites was nonexistent. In further evaluating the possible influence of DHEA as a weak androgen, it was found to exert both agonistic and antagonistic effects on the AR. DHEA administration in micromolar doses elicited a small agonistic effect on the AR to induce proliferation of human LNCaP prostate cancer cells. Whether this effect resulted from metabolic conversion of DHEA to dihydrotestosterone (DHT) by LNCaP cells, or from direct binding of DHEA to the AR of these cells (which harbor a mutation in the ligand-binding region resulting in a broadening of ligand specificity), or both, was not evaluated. Of particular note was the finding that, at relatively high concentrations (5 µM), DHEA antagonized DHT-induced AR transcription in both mouse mammary tumor virus and prostate-specific antigen (PSA) promoters, similar to the effects of the known AR antagonist, bicalutamide. Consequently, DHEA administration resulted in a 75% inhibition of DHT-induced PSA expression in LNCaP cells.
DHEA activated transcription of the ERß in more physiologically relevant range of 500 nM in contrast to the micromolar concentrations required to antagonize the AR. Chen et al. (9) observed that DHEA exerted clear-cut agonistic effects on ERß. DHEA strongly activated transcriptional activity in a construct containing ERß, which was 50% higher than that elicited by estradiol (E2). Moreover, DHEA administration elicited greater transcriptional activation of ERß vs. ER and no detectable activation of AR, suggesting that ERß is the preferred target for the transcriptional effects of DHEA. Additionally, the ER antagonist ICI-182,780 antagonized DHEA-induced transcription, consonant with an effect of DHEA mediated via its direct binding to ERß. The authors speculated that DHEA, at concentrations known to occur in the prostate (90 nM), alone and together with E2, could activate ERß transcription in humans. The direct consequence of activating ERß and delineating the downstream signaling effects in the prostate remain an area of active investigation. Additionally, the relevance of these in vitro effects of DHEA on AR at micromolar concentrations, or on ERß at mid-nanomolar concentrations, remains to be determined in appropriate in vivo models of prostate cancer.
Taken together, the data of Chen et al. (9) are consistent with the notion that DHEA can exert a direct, physiologically relevant, agonistic effect on ERß, a lesser antagonistic effect on the AR, and a modest effect on ER, in addition to its role as a precursor for androgens and estrogens. What, then, might be the effects of DHEA on cancer prevention or promotion? Although DHEA and DHEAS have been reported to increase mammary cancer cell proliferation via the AR (10), multiple other in vivo and in vitro studies conducted in rodents, or their cells, suggest that DHEA prevents cancer progression (11, 12, 13, 14, 15), whether by inhibition of glucose-6-phosphate dehydrogenase (14) or other carcinogen-metabolizing enzymes (15), or by other mechanisms. The relevance of these studies to human biology is uncertain, however, as the amounts of DHEA and DHEAS are much lower in rodents than in humans, and the physiological importance of these adrenal steroids are unknown in rodents.
Epidemiological data in men and women are inconclusive. Some studies indicate that the age-related declines in DHEA, testosterone, and estrogens protect against the increasing occurrence of hormone-sensitive cancers that occur with aging (16), whereas others reveal that elevated serum levels of DHEA and DHEAS are associated with decreased cancer rates (17), suggesting a protective effect.
Although retrospective clinical studies suggest that adrenal androgens alone do not promote normal prostatic growth in humans (18), the effects of DHEA on preneoplastic cells or prostate cancer cells have been less well studied. DHEAS is known to be present in high levels in the human prostate, as is the sulfatase that converts DHEAS to DHEA (19). Prostate cells also contain 3ß- and 17ß-hydroxysteroid dehydrogenase and can metabolize DHEA to DHT (20), which accounts for as much as one sixth of total prostatic DHT (21).
Several laboratory studies demonstrated various agonistic effects of DHEA in human LNCaP prostate cancer cells, which are known to be androgen responsive and to contain a mutant AR that binds DHEA (5, 22, 23). In one of these studies, DHEA and E2, like DHT and testosterone, stimulated LNCaP cell proliferation and modulated cellular PSA, AR, ERß, and IGF axis gene and protein expression, although the effects of DHEA and E2 were of lesser magnitude and were delayed in comparison with those of DHT and testosterone (23). The latter findings suggest that DHEA may be a prostate cancer-promoting factor in men who use it as a dietary supplement and harbor an occult or known prostate cancer containing a mutant AR. Further studies are warranted to evaluate DHEA effects on prostate cancer cells containing wild-type vs. mutant AR, as well as DHEA-induced stromal influences on prostate cancer (i.e. epithelial) cells.
Are DHEA effects in the prostate mediated partly via ERß agonistic actions, and, if so, are they cancer promoting or protective? Estrogens have been used historically in prostate cancer therapy and, in part, act indirectly on cancer cell growth by suppressing endogenous androgens. Estrogenic effects on the prostate, as mediated directly through ER and ERß, have been reviewed more recently (24). ERß expression has been reported to be down-regulated (25) and methylated (26) in prostate cancer cells, whereas ERß is reexpressed (or unmethylated) in metastatic prostate cancer lesions (27). Uncertainty remains as to the precise role of estrogens and ERs in the prostate. ERß is increasingly recognized as an important regulator of prostate function (28), especially as a potential "brake" to androgen-driven proliferation (29). In ERß knockout mice, the prostatic epithelial cells become hyperproliferative (30, 31). Prior studies have revealed that, in the presence of CYP7B, DHEA is metabolized to 7-hydroxy-DHEA, which can directly interact with ERß (6). Moreover, ER ligands can inhibit DHT induction of PSA gene expression and prostate tumor cell growth (32). Thus, intraprostatic DHEA can function as a direct or indirect ER ligand and can potentially influence prostatic cancer pathogenesis independently and/or by modulating androgenic effects.
DHEA effects in the prostate may be further influenced by endocrine-immune interactions. For example, sulfatase activity is present in macrophages, thus allowing for the conversion of DHEAS to DHEA (33). Additionally, the cytokines IL-4 and IL-13 induce 3ß-hydroxysteroid dehydrogenase activity in normal prostate epithelial cells, thus promoting conversion of DHEA into testosterone and estrogen metabolites (34). Thus, the effects of the enzymatic microenvironment may underlie immune system-aggravated cancer progression and contribute to prostatic inflammatory atrophy (35), the earliest lesion of prostate cancer, wherein resident inflammatory cells might induce metabolism of endogenous DHEAS and DHEA to DHT, increasing androgenic activity and a proproliferative microenvironment. The growth vs. quiescence of prostatic tissue is presumed to result from complex signaling between epithelial and stromal cells, along with resident and infiltrating immune cells, all within the local hormonal and growth factor milieu. In many tissues, hormonally induced stromal cells provide secondary factors, mediating the hormonal effect to epithelial cells (36). The precise roles of stromal and immune cell factors in modulating DHEA effects on normal and malignant prostate cell functions remain to be elucidated.
The use and regulation of DHEA are topics of considerable interest. In the early 1980s, DHEA was sold in the United States as a nonprescription drug for its alleged antiaging, anticancer, antiobesity, and other properties. In 1985, the U.S. Food and Drug Administration reclassified DHEA as a prescription drug based on unknown potential long-term risks and following the banning of DHEA by the International Olympic Committee. In October, 1994, the U.S. Congress enacted the Dietary Supplement Health and Education Act, which made DHEA available as an over-the-counter dietary supplement. More recently (May 2005) bill S. 1137 has been submitted to Congress "To include dehydroepiandrosterone as an anabolic steroid." This was in response to the potential use (abuse) of DHEA as an anabolic steroid.
The studies by Chen et al. (9), and others, highlight the need for further well-designed laboratory, translational, and clinical investigations of the mechanisms of action, efficacy, and safety of DHEA, so that questions regarding its potential for improving or compromising human health can finally be answered.
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Received July 19, 2005.
Accepted for publication September 8, 2005.
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-fluoro-5-androsten-17-one. Carcinogenesis 18:989–994 and the androgen receptor in normal human prostate glands, dysplasia, and in primary and metastatic carcinoma. Am J Pathol 159:79–92This article has been cited by other articles:
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  N. E. Gray, X. Liu, R. Choi, M. R. Blackman, and J. T. Arnold Endocrine-Immune-Paracrine Interactions in Prostate Cells as Targeted by Phytomedicines Cancer Prevention Research, February 1, 2009; 2(2): 134 - 142. [Abstract] [Full Text] [PDF]
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