DHEA is one of the body's primary defense mechanisms against cortisol. Not only does DHEA act like a functional anti-glucocorticoid and protect tissues but as I posted a few month ago, DHEA blocks new cortisol synthesis by inhibiting the enzyme 11β-HSD1 in micromolar concentrations, which is achievable with 5mg-10mg dose of DHEA.
DHEA, in low doses, directly inhibits cortisol synthesis
Now, this study shows that DHEA also enhances the actvity of 11β-HSD2, and that is the enzyme responsible for de-activating cortisol by converting it into cortisone. Inhibitors of 11β-HSD1 are a holly grail of Big Pharma as a drug for treating diabetes, depression, obesity, mania, etc and activators of 11β-HSD2 can do the same. As I posted recently, niacinamide seems to be such enhancer of 11β-HSD2 and maybe also even an inhibitor of 11β-HSD1.
Niacinamide Lowers Cortisol
So, a drug that does both (DHEA + niaciamide, or emodin + niacinamide combo) would be an absolute gold nugget, so I would not be surprised if DHEA gets expeditiously declared as "anabolic steroid" and banned once FDA realizes what potential it has.
DHEA induces 11 -HSD2 by acting on CCAAT/enhancer-binding proteins. - PubMed - NCBI
"...Recently, we reported that DHEA decreases 11β-HSD1 mRNA expression in cultured cells and C57Bl/6J mice.17 Here, we tested the hypothesis that DHEA has antiglucocorticoid effects by inducing a switch from 11β-HSD1–dependent activation to 11β-HSD2–dependent inactivation of glucocorticoids. We investigated the impact of DHEA on 11β-HSD2 expression and activity in RCCD2 rat cortical collecting duct cells.21 Incubation of RCCD2 cells for 24 h with 25 μM DHEA resulted in 2.6-fold higher 11β-HSD2 gene expression (Figure 1A) and 3.5-fold increased reductase activity (Figure 1B). DHEA dosage-dependently enhanced 11β-HSD2 activity, reaching approximately 80% of maximal activation at 25 μM (EC50 approximately 15 μM; data not shown). DHEA up to 100 μM did not affect corticosterone conversion in human embryonic kidney 293 (HEK-293) cells expressing recombinant 11β-HSD2 under the control of a cytomegalovirus promoter, excluding a direct stimulatory effect of DHEA on enzyme activity (Figure 1C). We next examined whether the DHEA-mediated induction of 11β-HSD2 gene expression involves changes in mRNA stability. DHEA treatment increased 11β-HSD2 transcription in RCCD2 cells approximately three-fold (Figure 1D). Addition of the transcription inhibitor actinomycin D (10 μg/ml) after 24 h of incubation with vehicle or 25 μM DHEA resulted in a similar decay of 11β-HSD2 mRNA over the course of 4 h, with estimated half-lives of 138 and 148 min, respectively (Figure 1D). Together, these observations suggest that DHEA stimulates 11β-HSD2 activity in RCCD2 cells primarily through activation of gene transcription. In contrast to renal cortical collecting duct cells, DHEA did not affect 11β-HSD2 expression in Caco-2 and SW620 colon cells (data not shown), suggesting tissue-specific regulation."
"...To ensure that the DHEA-mediated suppression of glucocorticoid reactivation reported in a previous study with mice17 is not species specific, we measured 11β-HSD1 mRNA expression in liver, white adipose tissue (WAT), and kidney from Sprague-Dawley rats fed standard rodent chow or chow containing 0.2% DHEA. DHEA significantly lowered 11β-HSD1 mRNA expression in liver (19 ± 3% of control; P < 0.001), WAT (28 ± 5%; P < 0.001), and kidney (57 ± 10%; P < 0.01; Figure 4), in line with previous observations in C57BL/6J mice.17 DHEA treatment for a relatively short time (12 d) did not significantly alter food intake or body weight in C57BL/6J mice and Sprague-Dawley rats (data not shown)."
"...Our results from experiments with RCCD2 cells suggest that the effects of DHEA are not due to its metabolism to 17β-estradiol or testosterone with subsequent activation of estrogen receptor and androgen receptor, because neither antagonists of these receptors (Figure 7A) nor the aromatase inhibitor formestane (data not shown) had any influence. Instead, inhibition of Akt kinase prevented the DHEA-induced increase of C/EBP-β protein expression and its phosphorylation on Ser105 as well as stimulation of 11β-HSD2 activity. Recent evidence suggested that DHEA might act through G-protein–coupled membrane receptors and subsequent activation of PI3K/Akt.23 Phosphorylation of Ser105 on rat C/EBP-β has been shown to enhance its transactivation potency.24,38"
"...Impaired intracellular metabolism of glucocorticoids contributes to the development of various pathologic conditions. Here, we investigated the counteracting effects of DHEA on local glucocorticoid metabolism by 11β-HSD enzymes, a mechanism originally proposed by Homma et al.,15 who observed reduced ratios of corticosterone to 11-dehydrocorticosterone and decreased BP in spontaneously hypertensive rats. We previously reported that DHEA downregulated 11β-HSD1–dependent glucocorticoid regeneration in liver, adipose tissue, and kidneys of C57BL/6J mice.17 DHEA had the same effects in Sprague-Dawley rats in this study. Moreover, 11β-HSD2–dependent glucocorticoid inactivation was enhanced in kidneys of DHEA-treated mice and rats. The sum of the locally altered glucocorticoid metabolism (i.e., enhanced renal 11β-HSD2 activity and reduced 11β-HSD1 activity in liver and adipose tissue; Table 1) led to decreased ratios of urinary free corticosterone to 11-dehydrocorticosterone in DHEA-treated Sprague-Dawley rats, in line with Homma et al.15 Because DHEA does not compete with glucocorticoids for binding to glucocorticoid receptors,25 it may protect from excessive glucocorticoid action by means of altered glucocorticoid metabolism."
DHEA, in low doses, directly inhibits cortisol synthesis
Now, this study shows that DHEA also enhances the actvity of 11β-HSD2, and that is the enzyme responsible for de-activating cortisol by converting it into cortisone. Inhibitors of 11β-HSD1 are a holly grail of Big Pharma as a drug for treating diabetes, depression, obesity, mania, etc and activators of 11β-HSD2 can do the same. As I posted recently, niacinamide seems to be such enhancer of 11β-HSD2 and maybe also even an inhibitor of 11β-HSD1.
Niacinamide Lowers Cortisol
So, a drug that does both (DHEA + niaciamide, or emodin + niacinamide combo) would be an absolute gold nugget, so I would not be surprised if DHEA gets expeditiously declared as "anabolic steroid" and banned once FDA realizes what potential it has.
DHEA induces 11 -HSD2 by acting on CCAAT/enhancer-binding proteins. - PubMed - NCBI
"...Recently, we reported that DHEA decreases 11β-HSD1 mRNA expression in cultured cells and C57Bl/6J mice.17 Here, we tested the hypothesis that DHEA has antiglucocorticoid effects by inducing a switch from 11β-HSD1–dependent activation to 11β-HSD2–dependent inactivation of glucocorticoids. We investigated the impact of DHEA on 11β-HSD2 expression and activity in RCCD2 rat cortical collecting duct cells.21 Incubation of RCCD2 cells for 24 h with 25 μM DHEA resulted in 2.6-fold higher 11β-HSD2 gene expression (Figure 1A) and 3.5-fold increased reductase activity (Figure 1B). DHEA dosage-dependently enhanced 11β-HSD2 activity, reaching approximately 80% of maximal activation at 25 μM (EC50 approximately 15 μM; data not shown). DHEA up to 100 μM did not affect corticosterone conversion in human embryonic kidney 293 (HEK-293) cells expressing recombinant 11β-HSD2 under the control of a cytomegalovirus promoter, excluding a direct stimulatory effect of DHEA on enzyme activity (Figure 1C). We next examined whether the DHEA-mediated induction of 11β-HSD2 gene expression involves changes in mRNA stability. DHEA treatment increased 11β-HSD2 transcription in RCCD2 cells approximately three-fold (Figure 1D). Addition of the transcription inhibitor actinomycin D (10 μg/ml) after 24 h of incubation with vehicle or 25 μM DHEA resulted in a similar decay of 11β-HSD2 mRNA over the course of 4 h, with estimated half-lives of 138 and 148 min, respectively (Figure 1D). Together, these observations suggest that DHEA stimulates 11β-HSD2 activity in RCCD2 cells primarily through activation of gene transcription. In contrast to renal cortical collecting duct cells, DHEA did not affect 11β-HSD2 expression in Caco-2 and SW620 colon cells (data not shown), suggesting tissue-specific regulation."
"...To ensure that the DHEA-mediated suppression of glucocorticoid reactivation reported in a previous study with mice17 is not species specific, we measured 11β-HSD1 mRNA expression in liver, white adipose tissue (WAT), and kidney from Sprague-Dawley rats fed standard rodent chow or chow containing 0.2% DHEA. DHEA significantly lowered 11β-HSD1 mRNA expression in liver (19 ± 3% of control; P < 0.001), WAT (28 ± 5%; P < 0.001), and kidney (57 ± 10%; P < 0.01; Figure 4), in line with previous observations in C57BL/6J mice.17 DHEA treatment for a relatively short time (12 d) did not significantly alter food intake or body weight in C57BL/6J mice and Sprague-Dawley rats (data not shown)."
"...Our results from experiments with RCCD2 cells suggest that the effects of DHEA are not due to its metabolism to 17β-estradiol or testosterone with subsequent activation of estrogen receptor and androgen receptor, because neither antagonists of these receptors (Figure 7A) nor the aromatase inhibitor formestane (data not shown) had any influence. Instead, inhibition of Akt kinase prevented the DHEA-induced increase of C/EBP-β protein expression and its phosphorylation on Ser105 as well as stimulation of 11β-HSD2 activity. Recent evidence suggested that DHEA might act through G-protein–coupled membrane receptors and subsequent activation of PI3K/Akt.23 Phosphorylation of Ser105 on rat C/EBP-β has been shown to enhance its transactivation potency.24,38"
"...Impaired intracellular metabolism of glucocorticoids contributes to the development of various pathologic conditions. Here, we investigated the counteracting effects of DHEA on local glucocorticoid metabolism by 11β-HSD enzymes, a mechanism originally proposed by Homma et al.,15 who observed reduced ratios of corticosterone to 11-dehydrocorticosterone and decreased BP in spontaneously hypertensive rats. We previously reported that DHEA downregulated 11β-HSD1–dependent glucocorticoid regeneration in liver, adipose tissue, and kidneys of C57BL/6J mice.17 DHEA had the same effects in Sprague-Dawley rats in this study. Moreover, 11β-HSD2–dependent glucocorticoid inactivation was enhanced in kidneys of DHEA-treated mice and rats. The sum of the locally altered glucocorticoid metabolism (i.e., enhanced renal 11β-HSD2 activity and reduced 11β-HSD1 activity in liver and adipose tissue; Table 1) led to decreased ratios of urinary free corticosterone to 11-dehydrocorticosterone in DHEA-treated Sprague-Dawley rats, in line with Homma et al.15 Because DHEA does not compete with glucocorticoids for binding to glucocorticoid receptors,25 it may protect from excessive glucocorticoid action by means of altered glucocorticoid metabolism."