DHEA Revives Liver of Aged Rats and Improves Antioxidant Reserves and Akt Signaling in Young and Old Rats.

Image 1:  I don't think celebrities realize it, but there is more to anti-aging than an unlined face. New studies show that DHEA could after all help with all sorts of age related diseases (img. antiagingpossible.com)

It's been a while since DHEA was in the news. While I have posted a handfull of mostly beneficial findings related to dehydroepitestosterone (DHEA), the hype that sourrounded its purported anti-aging effect in the late 1990s has completely abated. In view of DHEA's implication  (or rather the lack of the latter) in age-related autoimmune disease, sexual disfunction, osteoporisis, deteroiations of lipid metabolism, type 2 diabetes and cardiovascular and liver disease (Basci. 2007- ignificance of  dehydroepiandrosterone  and  dehydroepiandrosterone  sulfate  in  different  diseases), it is questionable how people beyond the age of 40, when DHEA production declines by 2% per year(!) could not benefit from a carefully planned and monitored DHEA treatment. A group of scientists from Brazil obviously thought the same and decided to take a fresh look at what happens on a molecular level, when 3 (young rats) and 24 months (old rats) old male Wistar-rats are given 10mg/kg deyhdroepitestosterone [human equivalent: 1.62mg/kg; 80kg human: 130mg/day] subcutaneously per day for 5 weeks (Jacob 2011).

Figure 1: Relative changes in total, reduced and oxidized glutathione in young and old rats after 5 weeks on 10mg/kg DHEA (data adapted from Jacob 2011)

As you can see in figure 1, the treatment induced profound increases in total and reduced glutathione and age-dependendly increased (young) or decreased the absolute level of oxidized glutathione (GSSG). Despite the absolute increase in GSSG, usually a marker of oxidative stress, the more important GSH / GSSG ratio, i.e. the ratio of reduced to oxidized glutathion, a more comprehensive marker of the balance of pro- vs. anti-oxidant metabolic processes, improved even more in the twelve young rats, (+6% GSH/GSSG) than in their older companions (+1% GSH/GSSG).

Figure 2: p-Akt levels in young and old rats with and without DHEA supplementation (data adapted from Jacob 2011)

As a faithful student of the SuppVersity, the serine/threonine kinase Akt should not be a stranger to you, after all, mTOR and p706SK (the "muscle builders", you've read about in the context of BCAAs, leucine and exercise-induced protein synthesis), are among its intracellular substrates. In agreement with previous studies, chronic administration of DHEA increased p-Akt-expression in the study at hand (cf. figure 2). The scientists speculate "that the Akt activation in this organ [the liver] is a protective answer" and could, after all, be the underlying reason for the preservation / restauration of hepatic function in the old rats.

Image 2: Oral DHEA supplements are sold for a few bucks over-the-counter (at least in the USA). Yet,
esp. for people under the age of 35, it probably does not make sense to buy and use those. At least, for
as long as it takes for the results of the study at hand to be confirmed in humans. And the allegedly benign 7-Keto DHEA could wreak havoc on your natural corticosteroid metabolism.

So how much DHEA should I take? Given the fact that the name of this blog is SuppVersity, I should have apprehended DeDeRa's question on which form and how much DHEA I would suggest you take. My answer is quite simple: NONE! Why? Well, this is a rodent study done with injectable DHEA. Not only would it be imprudent to extrapolate any dosing suggestions for oral DHEA supplements in humans, without clinical tests, we cannot even be sure that the effects would be identical, even if we hit the right dosage. Thus, while I am convinced that DHEA is probably more benign than many other OTC "supplements", especially people under the age of 30-35 should think twice or better thrice before popping any DHEA supplement - this includes 7-keto, the cortisol-suppressant effects of which can wreak havoc on your natural corticosteroid balance, make you feel tired and sluggish and deprive your body of an important anti-inflammatory pathway.

Most importantly, however, the study does away with the longstanding prejudice that DHEA (at the given dosage) "represent[s] a toxic potential to [the] liver". The isolated finding that endogenous DHEA lead to increased oxidation in the liver (it still does, but the overall pro- vs. anti-oxidant balance still improves!), as well as insufficient funding by the pharmaceutical industry, who obviously is not interested in naturally occuring and thus non-patentable treatment methods, had been one of the primary reasons many scientists decided not to dig deeper into the ameliorative, preventive and restaurative effects of DHEA in the context of age-related diseases. Personally, I hope that the few new studies that have been published, lately, will encourage other researchers to have another look at a hormone with profound yet complex and complicated effects on numerable aspects of the mammalian metabolism.

Less Than 15mg of DHEA Exert Identical Beneficial Effects on Insulin Sensitivity as 1h of Cardio 5x Per Week. Both Effects Mediated Via Increases in Intra-Muscular DHT

Image 1: It has long been established that diabetics have particularly low DHEA levels (Loviselli. 1994), but what's the chicken and what's the egg here?

It is quite funny, sometimes you don't hear about certain supplements, (pro-)hormones, exercise-modalities etc. in years and then, all of a sudden, there are two studies on the respective topic in one week; and moreover, two pretty interesting ones! Last Friday, exactly 7 days ago, you've read here at the SuppVersity about the muscle-protective effects of low-dose dehydroepiandrosterone (DHEA) supplementation during a 5-day intense multiple-type exercise protocol (cf. "DHEA Blunts Muscle Damage During 5 Days of Combined Endurance, Strength and HIIT Training in Young Men"). Today, I have another interesting set of data for you - data which could not just shed some light onto the underlying mechanisms of the said protective effects against skeletal muscle damage, but also on DHEA's beneficial effects on insulin sensitivity.

Not younger, but leaner with a minimalist dose of DHEA?

In a 6 week trial, and thus over a more than eight times longer timespan than in the previously mentioned human study on skelatal muscle damage, Koji Sato and his (or her?) colleagues from the Ritsumeikan University, the Senshu University and the University of Tsukuba (all in Japan, as you probably already suspected) investigated the effects a low dose of DHEA (human equivalent: 0.16mg/kg per day => 10-15mg/day) supplementation on the insulin, QUICKI (=quantitative insulin-sensitivity check index) and intramuscular DHEA and DHT (dihydrotestosterone) levels in sedentary or exercised dietary obese male rodents.

Figure 1: Relative insulin levels, QUICKI, intramuscular DHEA and DHT content in obese male rodents after 6 weeks of DHEA or combined DHEA + exercise (1h, 5days/week) treatment (data adapted from Sato. 2012)

As you can see in figure 1 the effects of both 5x/week running on a treadmill (ETA: 1h) and orally administered DHEA were profound. If you compare the "exercise only" group (red) to the two DHEA groups (green and violet), you will yet notice interesting parallels. Not only were the decreases in serum insulin and the increases (=improvements of insulin sensitivity) in the QUICKI test very similar, the exercise regimen alone yielded a +56% increase skeletal muscle DHEA content and a +71% increase in DHT.

Exercise increases intramuscular DHEA & DHT...
 

Figure 2: Hormonal cascade from DHEA to DHT; all enzymatic conversions can take place on a systemic and intra-cellular level!)

At least the latter, i.e. the increase in DHT should not be news to you if you have been following the in-depth articles at SuppVersity over the past couple of months. From the Intermittent Thoughts on DHT you know that exercise in general and HIT endurance exercise in particular has been found to boost intramuscular dihydrotestosterone levels, as well. The bros, or friends of bros among you, will probably also have heard the horrific stories about creatine monohydrate leading to increased levels of DHT (van der Merve. 2009), of which every reasonable person must actually assume that they are nothing but a downstream effect of increased training loads and/or improved adaptation... I mean, think about it "paleo style": Why would the mammalian body (rodent and human appear to react alike here) increase the DHEA and, via 5-alpha reductase (cf. figure 2), the dihydrotestosterone levels in response to high volume exercise, if not as a means of adaptation?

Oral DHEA + exercise = double-whammy against obesity

The combined treatment, or I should say the exogenous support of the exercise induced changes had - and this is not visible from the data in figure 1, astonishingly profound effects on the diet induced weight gain of the lab animals. While all other rodents became fatter, those in the exercise + DHEA group remained at a steady body weight level; an observation the researchers comment as follows:

Although DHEA administration and exercise training each produced beneficial effects, 6-weeks of combination treatment were more effective for obesity. The precise mechanisms that reduced abdominal fat weight in the combination group remain unclear, yet we can propose several plausible hypotheses. 2 weeks of DHEA administration has been shown to activate fatty acid metabolism-related enzymes, such as long-chain fatty acyl-coenzyme A synthase, and to increase free CoA levels in liver (Mohan. 1998; Mohan. 1990). In addition, exercise training is  known to reduce adipogenesis via upregulation of fatty acid metabolism and increased energy expenditure (Hou. 2003). Therefore, 6-weeks of combination treatment may have promoted additive reductions in abdominal fat volume.

In other words, while DHEA increases the efficacy of fatty acid oxidation, exercise takes care of the increase in energy expenditure which is - all convictions wrt to "calories don't count" and the "calories in vs. calories out"-hypothesis aside - still a fundamental prerequisite that the fatty acids do actually get burned and are not released into circulation to be restored or replaced a couple of hours later.

"Ok, I am just ordering some DHEA, how much should I take?"

Before you head over to the online vendor of your choice to make sure you get your share of DHEA before the FDA hears that it could hamper the sales of diabetes drugs and removes it from the OTC market, I would like to remind you that despite the fact that Sato et al. rightly claim that a "combination treatment [with DHEA and DHT] may be more beneficial than either therapy alone", a cursory glance on the data in figure 1 should suffice to tell you that those additional benefits as statistically significant as they may be are just that "additional" and that exercise alone yielded about equal results, is free of negative and full of beneficial side effects (update: as long as you don't overtrain; thanks Stapedius for this important note) and does not have the same host of studies refuting its efficacy as DHEA has (Clore. 1995).

It is nevertheless intriguing that a hormone the medical orthodoxy has, more or less all of a sudden, dropped like a hot potato and declared "questionable" and "ineffective" is now, roughly 15-20 years being rediscovered... and I am pretty sure that this was not the last DHEA study you will see and read about here at the SuppVersity ;-)

References:

1. Clore JN. Dehydroepiandrosterone and body fat. Obes Res. 1995 Nov;3 Suppl 4:613S-616S. Review.
2. Hou CW, Chou SW, Ho HY, Lee WC, Lin CH, Kuo CH. Interactive effect of exercise training and growth hormone administration on glucose tolerance and muscle GLUT4 protein expression in rats. J Biomed Sci. 2003 Nov-Dec;10(6 Pt 2):689-96.
3. Loviselli A, Pisanu P, Cossu E, Caradonna A, Massa GM, Cirillo R, Balestrieri A. [Low levels of dehydroepiandrosterone sulfate in adult males with insulin-dependent diabetes mellitus]. Minerva Endocrinol. 1994 Sep;19(3):113-9.
4. van der Merwe J, Brooks NE, Myburgh KH. Three weeks of creatine monohydrate  supplementation affects dihydrotestosterone to testosterone ratio in college-aged rugby players. Clin J Sport Med. 2009 Sep;19(5):399-404.
5. Mohan PF, Cleary MP. Effect of short-term DHEA administration on liver metabolism of lean and obese rats. Am J Physiol. 1988 Jul;255(1 Pt 1):E1-8.
6. Mohan PF, Ihnen JS, Levin BE, Cleary MP. Effects of dehydroepiandrosterone treatment in rats with diet-induced obesity. J Nutr. 1990 Sep;120(9):1103-14.
7. Sato K, Iemitsu M, Aizawa K, Ajisaka R. Testosterone and DHEA activate the glucose metabolism-related signaling pathway in skeletal muscle. Am J Physiol Endocrinol Metab. 2008 May;294(5):E961-8. Epub 2008 Mar 18.
8. Sato K, Iemitsu M, Aizawa K, Mesaki N, Ajisaka R, Fujita S. DHEA administration and exercise training improves insulin resistance in obese rats. Nutr Metab (Lond). 2012 May 30;9(1):47. [Epub ahead of print]

DHEA Blunts Muscle Damage During 5 Days of Combined Endurance, Strength and HIIT Training in Young Men

Image 1: Who would have thought that? Dehydroepiandrosterone (DHEA), a demystified anti-aging agent, turns out to be a potent muscle protectant in young men

In the past couple of days you have learned all those "boring" things about regeneration. Taking a hot bath, training lightly, posing, isometric contractions, ... and what about supplements? The basics, which are. protein, creatine and baking soda *rofl*, are probably already part of your regimen, but would you have thought that dehydroepiandrosterone, short DHEA (not to be confused with DHA in fish oil), the touted vitality and longevity hormone, of which the medical establishment has long concluded that there is, as in the case of most antioxidants "little evidence to suggest that DHEA replacement or supplementation prolongs life or prevents disease" (Kamel. 2008) could make a valuable addition to the supplement regimen of young athletes who constantly train at the narrow margin between over-reaching and overtraining? No? Then you will be interested in the results of a recently published study from William J. Kraemer's group at the Department of Kinesiology and Health Education at the University of Texas at Austin (Liao. 2012).

5 days of successive "mixed-type exercise" + 100mg/day DHEA

Figure 1: Graphical illustration of the 5-day exercise regimen

The 16 healthy male college students (age 19.2; BMI 22.5 kg/m²) who volunteered for the study had unfortunately not performed "any types of exercise training for at least 3 months before the experiment" (which is a pitty, because it obviously reduces the significance of the results for you, someone who would never take 3 months off ;-), in the course of which they had to complete a 5-day exercise training regimen (cf. figure 1).

While the subjects in the control group received 2x50mg caps with flour, the participants in the active arm of the study supplemented  2x50mg of DHEA at breakfast and dinner. Serum insulin, DHEA-S, and testosterone levels, as well as creatine kinase and delayed-onset muscle soreness were measured every 24h.

300% less creatine kinase (=muscle damage) with DHEA

As you can see in figure 1 the supplemental DHEA lead to a rapid yet not fully sustained increase in DHEA-S levels which was accompanied by a statistically significant increase in total testosterone only within the first 2 days of treatment.

Figure 2: Changes in DHEA-S serum levels and exercise induced elevations of creatine kinase in 16 healthy untrained college aged subjects receiving 100mg/day DHEA or placebo during a 5-day "mixed-type exercise" regimen (data adapted from Liao. 2012)

And while I leave it up to you to decide how likely it is that the drop in DHEA-S on day 3 was a consequence of the additional shuttle run, of which Liao et al. state that it was incorporated to "increase the magnitude of muscle damage" (Liao. 2012), it should be obvious that the blunted increase in blood creatine kinase levels on day 4, i.e. ~48h after the HIIT-esque 5000m shuttle run on day 2, must be related to the DHEA supplement. On the other hand, the ...

[f]asting glucose levels were unaffected by Placebo and DHEA supplementation. [...] The [exercise induced] improvement of glucose tolerance following exercise training did not differ between the Placebo and DHEA groups

and neither the fasting insulin levels, nor the insulin response during the oral glucose tolerance test were affected.

Practical implications & limitations

Figure 3: DHEA levels peak during puberty and begin to decline in your late twenties (Labrie. 2005). Against that background it would be interesting to see the very same study in a group of say "best-agers" or "baby-boomers", who could potentially derive much greater benefits from a boost in DHEA levels - although studies without exercise intervention yielded very conflicting and mostly disappointing results.

Earlier this week, I have argued that you have to limit (not necessarily minimize) muscle damage to maximize the exercise induced net skeletal muscle protein accrual in the immediate vicinity (48h) of a workout (cf. "48h to Your Next Workout? Time to Take a Bath"). What I did not mention before is that the corresponding decrease in exercise induced inflammation should actually lead to an increase (or rather the absence of a decrease) in whole body insulin action, as it has been observed in response to eccentric muscle damage in previous studies (Costill. 1990; Asp. 1997). That this was not the case, here, could simply be a consequence of the timepoint at which the oral glucose tolerance test (OGGT) was conducted. After all, the data in figure 2 indicates that on day 6, the day of the second OGGT the CK levels had already returned to baseline. It is thus still likely that we would have seen a pronounced difference in insulin induced glucose clearance in the DHEA group on day 3 (post workout), day 4 and probably even day 5.

A note on performance and estrogenic side-effects: An 8-week exercise intervention by Brown et al. which used only 50mg supplemental DHEA per day and a significantly lower workload, as well as longer recovery periods (3x total body workouts per week) did not produce significant changes in any of the study parameters. Neither beneficial ones, such as greater strength increases or hypertrophy, nor negative ones such as increases in estrogen or deteriorations of the lipid profile (Brown. 1999). In 2010, on the other hand, Ostojic et al. report in the Chinese Journal of Physiology that 4 weeks of 100mg supplemental DHEA, despite having no effects on the body composition of the 19-21 year-old soccer players who participated in the study, led to statistically significant increases in total testosterone (+37%), DHEA-S (+197%) and estradiol (+21% compared to the subjects in the placebo group; Ostojic. 2010). The overall significance of these results is yet questionable, since both studies were pretty underpowered (N=10 and N=20 for Brown and Ostojic, respectively) and employed comparatively low-volume / low-intensity exercise protocols with sufficient rest between workouts. It should still be mentioned that the DHEA induced "estrogen dominance", which is one of the most frequent arguments against DHEA supplementation you will hear on pertinent bulletin boards, was not observed in either of the two.

Whether long-term (e.g. year-long) supplementation with DHEA at a dosage of 100mg+ per day is a safe undertaking, does yet likewise remain to be determined as the real-world impact and effect size of the reduced muscle damage and the purported improvements / absence of impairments of glucose tolerance during periods of intense training (more intense than the 3x per week whole body workouts in the Brown study, see red box). That all these effects could help you to train more frequently, gain more strength, build more muscle (less damage) and stay leaner on a bulk (insulin sensitivity), should be obvious. If they don't produce real world results and come at a probably overrated yet certainly existent risk of hormonal imbalances, it is probably safer to stick to what you have learned earlier this week and resort to the 42°C hot tub and some posing (=max. isometric contractions) on your off days, to keep the muscle damage during the next workout at bay.

References:

1. Asp S, Rohde T, Richter EA. Impaired muscle glycogen resynthesis after a marathon is not caused by decreased muscle GLUT-4 content. J Appl Physiol. 1997 Nov;83(5):1482-5. 
2. Brown GA, Vukovich MD, Sharp RL, Reifenrath TA, Parsons KA, King DS. Effect of oral DHEA on serum testosterone and adaptations to resistance training in young men. J Appl Physiol. 1999 Dec;87(6):2274-83.
3. Costill DL, Pascoe DD, Fink WJ, Robergs RA, Barr SI, Pearson D. Impaired muscle glycogen resynthesis after eccentric exercise. J Appl Physiol. 1990 Jul;69(1):46-50.
4. Kamel NS, Gammack J, Cepeda O, Flaherty JH. Antioxidants and hormones as antiaging therapies: high hopes, disappointing results. Cleve Clin J Med. 2006 Dec;73(12):1049-56, 1058.
5. Labrie F, Luu-The V, Bélanger A, Lin SX, Simard J, Pelletier G, Labrie C. Is dehydroepiandrosterone a hormone? J Endocrinol. 2005 Nov;187(2):169-96. Review. 
6. Ostojic SM, Calleja J, Jourkesh M. Effects of short-term dehydroepiandrosterone supplementation on body composition in young athletes. Chin J Physiol. 2010 Feb 28;53(1):19-25.
7. Liao YH, Liao KF, Kao CL, Chen CY, Huang CY, Chang WH, Ivy JL, Bernard JR, Lee SD, Kuo CH. Effect of dehydroepiandrosterone administration on recovery from mix-type exercise training-induced muscle damage. Eur J Appl Physiol. 2012 May 16. [Epub ahead of print]

Longterm DHEA Supplementation Improves Suboptimal Insulin Sensitivity and Induces Beneficial Changes in Body Composition and Inflammatory Markers TNF-Alpha & IL-6 in Elderly Subjects

It has long been established that after peaking at the end of puberty, the production of dehydroepiandrosterone (DHEA) steadily declines with age and approaches levels of approximately 80% in the elderly (>75y). In the late 20th century, initial studies investigating the "anti-aging" effect of the adrenal hormone DHEA provided results that appeared to confirm the hypothesis that the restauration of DHEA to youthful levels would have beneficial cognitive and metabolic effects. Many of the findings could yet not be reproduced in follow-up studies and the pharmaceutical industry soon lost interest in spending money into research on a naturally occurring and thus non-patentable compound. Consequently, expensive long-term studies such as the one (Weiss. 2011) recently been published in the medical journal AGING are scarce and thus well-worth being mentioned on the SuppVersity.

Figure 1: Changes in Body Weight and Body Composition Before and After 12 months of DHEA
(data adapted from Weiss. 2011)

In 2004, already, Villareal, Weiss et al. had published the encouraging results of a short term intervention with DHEA on abdominal fat and insulin action in elderly women and me. The study at hand is a follow up on these results intended to evaluate the longterm efficacy and safety of 50mg supplemental DHEA in a study cohort of 136 men and women who were randomized to either DHEA or placebo treatment for 12 months. The outcomes of the first 12 month (114 subjects decided to either begin or continue treatment with DHEA for a second year) showed minor, but statistically improvements in body composition in the male subjects (cf. figure 1) and a normalization of insulin sensitivity in patients with previously impaired glucose metabolism.

The DHEA replacement resulted in small but significant decreases in body fat percentage and total fat mass in the male participants, while the men in the placebo group had small but significant increases. Trunk and appendicular fat masses showed a similar reduction. Abdominal visceral fat, evaluated using MRI, underwent a very small, but statistically significant, decrease in the men in the DHEA group; however, the difference between the changes in visceral fat between the DHEA and placebo groups was not significant. There were no significant changes in body weight in the women in either the DHEA or placebo group. The only significant change in body composition in the women was a small increase in fat free mass in the DHEA group. 
[...] improvements in glucose tolerance in response to DHEA occurred only in those participants who had abnormal glucose tolerance.

These results, along with the finding that other than minor increments in both testosterone and estradiol in the male subjects, would suggest that the bodies of the subjects "used" the supplemental DHEA to replenish their age-relatedly low DHEA-sulfate levels and the ensuing effects on previously impaired glucose tolerance and the reduction of inflammatory cytokines TNF-Alpha (-30%) and IL-6 (-31%) could be directly related to the restauration(!) of youthful DHEA levels in the 65 to 75 year-old study participants. The improvements in body composition, which were observed exclusively in the male participants, on the other hand, could be intricately related to the downstream metabolism of DHEA into testosterone. At least, this would explain the lack of significant effects in women, who, nevertheless, gained a small, yet measurable amount of lean body mass in the course of the first 12 month on DHEA (cf. figure 1).

DHEA the Slimming Hormone? Study Finds: Dehydroepiandrosterone Directly Inhibits Cortisol Synthesis in Rodent Adipocytes

After initially being hailed as the fountain of youth, the pharma-financed medical sciences dropped DHEA, when investors realized that a naturally occurring hormone would not be patentable. This and some discouraging and/or inconclusive results from long-term studies had DHEA literally disappear from the research scene for quite some time. Therefore, I am positively surprised that on the forthcoming European Congress of Endocrinology 2011 researchers from the Kobe University in Japan are going to present a paper (Tagawa. 2011) that shows that there may in fact be more to the initial findings of DHEA induced weight loss than follow-up studies would have it.

Tagawa et al. investigated the possible mechanism behind the weight loss effects of DHEA and found that there is a direct inhibitory effect of DHEA on glucocorticoid (re-)synthesis in adipose tissue:

Using differentiated 3T3-L1 adipocytes, we demonstrated that DHEA inhibited 11β-HSD1 activity at a concentration of 1 μM within 10 min. Inhibition was also observed in a cell-free system comprised of microsomes prepared from rat adipose tissue and NADPH, a coenzyme of 11β-HSD1. A kinetic study revealed that DHEA acted as a non-competitive inhibitor of 11β-HSD1. Further, DHEA did not inhibit 11β-HSD type 2, which inactivates cortisol or corticosterone in tissues involved in water and electrolyte metabolism, in rat kidney microsomes at a concentration <25 μM. Moreover, no conversion from DHEA to other sex steroid hormones or their precursors was observed under the present experimental conditions.

These are three significant observations. Firstly, the presence of DHEA inhibits the synthesis of cortisol via 11Beta-HSD1. Secondly, it does not prevent exogenous cortisol to be converted to the "inactive" cortisone via 11Beta-HSD2 and thirdly, the dreaded conversion into estrogen, testosterone or DHT does not take place. All this would make the naturally occurring hormone DHEA a perfect selective 11β-HSD1 inhibitor, of which Stewart et al. from the University of Birmingham write (Stewart. 2011):

Selective 11β-HSD1 inhibitors lower blood glucose, improve insulin sensitivity and cause weight loss in animal models. Biomarkers have been validated to confirm target inhibition in primate and human studies. Recent clinical trials show reduction in HbA1c and blood pressure in obese patients with diabetes mellitus who have failed on metformin therapy. Potentially the therapy offers a ‘magic bullet’ for patients with Metabolic syndrome with reduced blood glucose accompanying improved insulin sensitivity, lower lipids and blood pressure and reversal of hepatic steatosis secondary to reduced autocrine generation of cortisol in liver, adipose tissue, pancreas and muscle. Liabilities include activation of the HPA axis secondary to increased cortisol clearance with hyperandrogenism, though the extent and significance of this is debated.

One thing, though, before you now go about eradicating cortisol to zero. Your body needs a healthy level of cortisol to function. It goes hand in hand with thyroid hormone, helps you manage stress, perform in the gym and is even necessary to "burn" body fat. Again, moderation is key and you certainly want to know where you stand before you start tweaking your cortisol levels into the wrong direction.

DHEA Inhibits Fat Gain More Effectively Than Testosterone. Both Work by Reducing PPAR-γ and Thusly Lipid Storage

Image 1: This is the "Fountain of Youth" in Karlsruhe, Germany. I have never been there, but I guess I should take the next train and check whether water contains 0.4% or 0.8% DHEA ;-)

Outside of the medical practices of some anti-aging docs nobody appears to care about the "good old" dehydroepiandrosterone (DHEA), these days. As a diligent student of the SuppVersity, you are yet well aware of the reviving effects DHEA has on the liver (cf. August, 26, 2011), pancreas & insulin sensitivity (cf. May, 15, 2011) and adipocyte metabolism (cf. April, 8, 2011) in "older" people or everyone with suboptimal DHEA levels. You will also be aware that the adrenal steroid hormone which can be converted to testosterone (and thusly DHT or estrogen) at the target tissue exerted pretty astonishing effects on body composition in a handful of initial (very) high-dose trials. Follow up studies in the late 1990s were yet mostly unable to reproduce these encouraging results and with the increasing concerns about potential side-effects and the lack of funding from the pharmaceutical industry, who did not have an interest in finding out that a non-patentable substance would ameliorate or even cure some of of the ailments they were and still are making a fortune on.

DHEA a Weapon in the War Against Diabesity?

The most widespread of these ailments certainly is diabetes; a pathology the management of which (not it's treatment!) has generated a $42 billion dollar market (data from 2010) that is estimated to grow to $114.3 billion dollar by 2016 (inverstorplace.com). It is thusly no wonder that the recently published study by Kei Fujioka and his colleagues from the Departments of General Internal Medicine and Parasitology at the Gifu University Graduate School of Medicine in Gifu, Japan, was not funded by a Japanese (let alone US ;-) pharmaceutical company, but by a research grant from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Fujioka. 2012).

Figure 1: Simplified illustration of the adrenal hormone production cascade

Based on the scattered conglomerate of previous results the researchers speculated that feeding Otsuka Long-Evans Tokushima fatty rats chow with 0.4% dehydroepiandrosterone (DHEA) in it would ameliorate if not totally prevent the development of type II diabetes and / or related pathologies to which this rodent strain, which is also one of the standard models for type II diabetes, is particularly prone.

Figure 2: Relative differences in epdidymal fat pad weights, serum glucose, triglyceride, total cholesterol and free fatty acid levels in LETO and OLETF rats after 52weeks on chow with 0.4% DHEA (=100mg/day; human equivalent: 16mg/day); data expressed relative to rats on control diet (data adapted from Fujioka. 2012)

As you can see in figure 1 rodents don't have to be genetically disposed to get type II diabetes to benefit from a human equivalent of ~16mg/day. The ever-hungry (=polyphagic) LETO rats, the scientists put on the same 0.4% DHEA diet for 52 weeks has similarly reduced visceral fat depots (epididymal fat - LETO: -50%; OLETF: -33% vs. control), triglycerides and free fatty acids. The improved glucose levels were yet only statistically significant in the otherwise diabetic OLETF rats and the increase in total cholesterol in the LETO group is difficult to judge without at least some additional data on the ratio of "good" HDL to "bad" LDL.

DHEA vs. Testostosterone - Who is the "King" of Metabolic Hormones

Luckily, the Fujioka et al. were not satisfied with these results and conducted another experiment. This time with normal rats (Wistar strain) and with a second group which received 0.4% testosterone in their chow.

Figure 3: Fat weight, triglyceride content of liver and gastrocnemius muscle, body temperature and adipocyte diameter in male wistar rats after 4 weeks on DHEA (0.4%) or testosterone (0.4%) containing chow; data expressed relative to control on standard chow (data adapted from Fujioka. 2012)

Compared to the poor critters in the control group, who had to content themselves with the "non-anabolic" standard chow, both the rats in the DHEA and the testosterone groups had reduced body fat levels (remember the control rats were "normal", not fat!), reduced triglyceride deposition in both liver and muscle tissue, an increased body temperature and a statistically highly significantly decreased adipocyte size (cf. figure 3) - and believe it or not, all these beneficial effects were more pronounced in the DHEA group.

Figure 4: DHEA-S (µg/dL), testosterone (ng/dL) and PPAR-γ expression in control, DHEA and testosterone group at the end of the study period (data adapted from Fujioka. 2012)

In view of the initially mentioned role of dehydroepiandrosterone as a precursor to testosterone (cf. figure 1) and its own yet negligible ability to interact with the androgen receptor (Tan. 1997), it should not surprise you that the purported mechanism behind their beneficial effects on "all things fatty" is identical: a reduced expression of the "triglyceride storage receptor" PPAR-γ, the same receptor the smart business men from the pharmaceutical industry target with their lipid and blood glucose lowering drugs to treat high blood glucose and/or lipid levels for increased obesity, and subsequently another increase in glucose and lipid levels which will "unfortunately" require either more of the old or even better less of the more expensive "next generation" drugs... *clever, right?*

Similar Effects in Healthy, Young Human Beings are Highly Questionable

Image 2: Neither Drogba (l) nor Ronaldo (r) are candidates for DHEA supplementation (img VanityFair WC special edition).

Assuming that you are not already on your way to your local supp store to make sure you get the last bottles of DHEA before the FDA comes up with another horror story based on which this "dangerous supplement" has to be added to the banlist, I want to caution you that a 2010 study from the PA University of Novi Sad (Ostojic. 2010), in Serbia did not find any beneficial effects on body composition in 20 young soccer players who received an oral DHEA supplement (100mg/day) for 4 weeks - and that, despite +40% increases in total testosterone (free testosterone unchanged), +27% increases in estrogen and 197% increases in DHEA. As an active non-sedentary, non-obese, non-metabolically deranged individual, like the 19-22 year old soccer players in the Ostojic study, it is unlikely that your six-pack will show overnight, just by popping grams of DHEA per day.

Before we do not know why in some trials (rodents and humans) oral DHEA supplements yield phenomenal results (in the study at hand, both the lower dosage, as well as the "chronic" administration in very low doses spread across the day could be decisive factors), while they totally suck in others, the "specificity rule" from the Three Simple Rules of Sensible Supplementation would preclude anyone under the age of 35+ (DHEA levels begin to decline ~30y) from supplementing with DHEA, unless this someone knows (not just guesses!) from bloodwork that his/her DHEA levels are at least borderline low. And don't forget, even then DHEA or rather its downstream metabolites (estrogen in particular) can be similar suppressive on your own natural hormone production as "real gear" or the reputed OTC "pro-hormones" 90% of which are active steroids, anyway.