Science Round Up Seconds: 30-60% More Testosterone w/ 2.5g D-Aspartic Acid in Fertility Trial and Nicotine Amplifies Cardiotoxic Effects of ECA. Plus: Data on DHEA & Estrogen & Breast Cancer, Fermented Teas, AMPK, AKT & Co

DAA is probably not going to hurt your heart, but it's more likely to father a child than to build those abs. Ephedrine & Caffeine on the other hand, could help you get there, but esp. if you are also smoking you are increasing the risk that the kids you fathered using DAA will soon be without their begetter.

I guess most of all will have listened to the podcast of yesterday's installment of the SuppVersity Science Round Up already. If you didn't you have been missing Carl and me discuss new on the pro-carcinogenic effects of aspartame, the never-ending story of the fattening artificial sweeteners, the benefits of oat beta-glucans for weightloss, -maintenance and gut health, the way sorghum proanthocyanidins can lower the GI of carbohydrates and make them less susceptible to enzymatic breakdown in the small intestine, and more.

Actually this more, i.e. the news on DHEA, its metabolits and their proliferative effect on breast cancer cells, as well as the information about the beneficial effects of fermented teas on blood glucose management, reminded me of the fact that as how like the SuppVersity Science Round Up is a very good place discuss and explain things, but not exactly the place to present detailed data. Therefore, I decided to prelude the Seconds by adding a couple of graphs which illustrate what has been said on the last show. Thus, you can look at the figures while listening to the podcast.

Supportive material for the DHEA and fermented tea news

For this first installment of the Seconds I did, you guessed it, pick the aformentioned news on DHEA and the different fermented teas (see figure 1) that are  based on studies by Miller (2013) and Yamashita  (2013), respectively.

Effect of 7 days of oolong tea, black tea, pu-erh tea, instead of water on Δglucose AUC (left), AMPK, AKT and PI3K expression in skeletal muscle  of male mice (Yamashita. 2013)

Effect of estradiol (E2), DHEA and its metabolits 7-OXO,  androstenediol, and androstenedione on breast cancer cell proliferation (based on Miller 2013)

So much for the additions to visuals for the podcast, let's get to the new stuff... or actually the seconds. Of course, the seconds ;-)

• How to brew your own sodium d-aspartic acid The best thing about this study actually is that the scientists disclose how you can easily make your own PH stable sodium-d-aspartate from the cheap stuff you buy at your favorite bulk supplier: Take 2.66 g of D-aspartic acid neutralize it with 0.46 g of NaOH in 10 ml distilled water and you get a final pH of 6.5 - 7-0 - that's it, you are good to go.
  New study on d-aspartic acid confirms - 30-60% increase in testosterone and LH in infertile men (D’Aniello. 2013) Despite the fact that this is a non-sponsored study by researchers from the Hospital “S. Luca” in Vallo della Lucania, Italy, I am about as 'unpsyched' about the data the scientists present, as I am about the real world results of d-aspartic acid (DAA) supplementation in young weight training men.
  
  It's already telling that D'Aniello et al. mention the increase in testosterone and luteinizing hormone (LH) only as an aside and consider it as a "save", or I guess you better say "tolerable" side effect of a treatment  that did effectively double the amount of D-aspartic acid in the seminal plasma and did thus (at least the scientists belive in a mechanism here) increase the fertility in both, patients with reduced sperm motility and sperm count, and those who suffered only from reduced motility.
  
  The actual 'success rate' in terms of pregnancy rates after 2-3 months of treatment with 2.66g/day of DAA per day was however not exactly really earth-shattering, either. Of the patients with both low sperm count and sperm motility (oligo-asthenozoospermia) 4% fathered a child; of those who suffered 'only' from a low sperm motility (asthenozoospermia) 33% eventually managed to become daddy.
  
  Without baseline testosterone levels, of which I would not be surprised if they had been rock bottom (both oligo-asthenozoospermia and asthenozoospermia usually go hand in hand with increased oxidation and that in turn is associated with low testosterone and suppressed LH levels), this study is however about as worthless in terms of the purported ergogenic effects of DAA, as all previous human trials. That said, you could obviously mix yourself the above concussion in case you and your significant other are planning to start a new or to expand your existing family in the near future. I guess, it's unlikely that it's going to hurt.
  
  Suggested read: All About the Role of Androgens & Co in Building Muscle
   
• Putting an "N" as in "nicotine" into "EC" amplifies the negative effects of ephedrine and caffeine on your heart and may well be the reason for many of the (few) deadly side effects that occurred in the day before the ban (Brown. 2013) When a group of researchers from the Arkansas State University tried to get to the bottom of the (in some cases) fatal cardiovascular side-effects, which were the main reason for the FDA to pull ephedra-containing supplements from the market, Christopher E. Brown and his colleagues observed ...

  "[...] a synergistic effect on the rat cardiac morphology [...] as a result of intera tions between nicotine, caffeine, and Ephedra. The cardiotoxicity caused by combination dosing of Ephedra and caffeine has already been shown; however, the present study revealed an enhancement of cardiotoxicity when nicotine was administered in combination with Ephedra and caffeine." (Brown. 2013)

  The scientists had exposed male Sprague-Dawley rats to (1) synthetic combinations of nicotine (0.2 mg/kg/day), ephedrine (0–30 mg/kg/day), and/or caffeine (0–24 mg/kg/day) as well as (2) an extract from a caffeine-containing Ephedra supplement (Metabolife 356). The relatively high dose treatments were administered for only 3 days either in the full or half dose and with and without nicotine pre-treatment to model the effects of different dosing regimen on smokers and non-smokers.
  
  

  

  Figure 1: Light micrograph of representative nuclear pro-files (background, red = atypical, green = normal nuclei; my emphasis) and volume (%) of atypical cardiac cells in anterior left ventricle of the rodents (Brown. 2013)

  As far as the results go, a a brief glance on the exemplary data in figure 1 should actually suffice to see, that a baseline "N" + "EC"  stack (as in any smoker who would take ephedrine + caffeine to lose weight or psyche himself up) could eventually pave the way to the emergency room.
  
  While the data from the anterior left ventricle and anterior interventricular septum (not shown) would suggest that the identically dosed synthetic versions of caffeine and ephedrine were slightly more detrimental, than the herbal supplement  in which the Ephedra came from a standardized Ma Huang extract and part of the caffeine from Guarana, this effect was not present in either the posterior left or the anterior right or posterior right ventricle (data not shown).
  
  Apropos interventricular septum (IVS), with increases in atypical cardiac cell volume of up to 1.5% in the anterior IVS even without nicotine pre-treatment, the stout wall that separates the lower chambers was most susceptible to the effects of caffeine and ephedrine:
  

  "In the anterior section of this region, both caffeine + ephedrine combination as well as the multicomponent supplement Metabolife 356 resulted in larger numbers of atypical cells compared to water controls, in both saline- and nicotine-pretreated rats. However, only rats pretreated with nicotine responded negatively to supplements in the posterior region of the IVS. " (Brown. 2013)

  If you consider the high-pressure forces it must sustain for proper ejection volume to the arterial vasculature it should be obvious that "these changes to the ventricular tissue could be particularly detrimental to overall cardiovascular health" (Brown. 2013). Bad news? Why? At least you do now have another good reason to stop smoking... what, oh yeah, I forgot: This is irrelevant because Ephedra has been banned anyway ;-)

While I do have a couple of other Seconds I am a bit pressed on time, today. Don't worry sooner or later they will appear ither on the SuppVersity Facebook Wall, where I am posting at least half a dozen of exclusive links and mini-items, comments and more you won't find on www.suppversity.com. So, I'd suggest you do now first listen to the podcast (if you have not already done so), then check out the latest SuppVersity Facebook News and when you are done with that wait till tomorrow for this weeks installment of On Short Notice.  

References

• Brown CE, Trauth SE, Grippo RS, Gurley BJ, Grippo AA. Combined Effects of Ephedrine-Containing Dietary Supplements, Caffeine, and Nicotine on Morphology and Ultrastructure of Rat Hearts. Journal of Caffeine Research. 2013; 2(3).
• D’Aniello G, Ronsini S, Notari T, et al. D-Aspartate, a Key Element for the Improvement of Sperm Quality. Advances in Sexual Medicine, 2013, 2, 47-53.
• Miller KKM, Al-Rayyan N, Ivanova MM, Mattingly KA, Ripp SL, Klinge CM, Prough RA. DHEA metabolites activate estrogen receptors alpha and beta. Sterespectivelyroids. November 01, 2013. Ahead of print.
• Yamashita Y, Wang L, Tinshun Z, Nakamura T, Ashida H. Fermented Tea Improves Glucose Intolerance in Mice by Enhancing Translocation of Glucose Transporter 4 in Skeletal Muscle. J Agric Food Chem. 2013 Nov 5.

Reishi Protects Against Cancer & Contains Anti-Androgen; Adrenalin Rejuvenates Brown Fat; Mild Stress Normalizes Cortisol / DHEA Ratio in Elderly; DHEA, Aromatase Inhibitors & BPA vs. Joint & Brain Health; Vitamin E Battles Lymphoma

I am not happy with how the short news on Facebook simply disappear into oblivion.

The SuppVersity figure of the week is "920"! "920" as in "920 published posts" here at the SuppVersity. The reason that's the figure of the week is that I have been thinking about ways to reorganize the archive, but am a bit lost on how to structure things in a better way using blogger. This beast simply isn't made for anything that goes beyond a weekly classic blogpost a la "last week I did this and that, read about..." *yawn*

What's yet even more enervating is that despite having the huge advantage of being easily posted and directly accessible for all of you, the tons of short news items I post on a daily basis on the SuppVersity Facebook Wall simply disappear into the 'Facebook nirvana'. I currently cannot spend any time on those technical / organizational matters, but in the course of 2013 things are going to change.

In the mean time, follow the SuppVersity on Facebook and read the news, right when I post them + use google to find articles you are looking for. You will be laughing, but that's the way I dig through those 920 posts, as well ;-) Simply type whatever you look for and add a "+site:suppversity.blogspot.com" to it.

Chinese fungi are laden with cancer-protective molecules and 5a-reductase (DHT) inhibitors

In view of a recent paper from the Universitat de Valencia (Rios. 2013) it appears that it would actually be hard not to decrease your risk of developing cancer if you include extracts from Ganoderma lucidum and other related fungi, such as Poria cocos, Laetiporus sulphureus, Inonotus obliquus, Antrodia camphorata, Daedalea dickinsii, and Elfvingia applanata in your supplement regimen. With a total of 81 compounds from Ganoderma lucidum and other species from this genus, as well as 96 compounds isolated from other fungi, principally Poria cocos. It appears that these creatures (fungi are no plants, neither are they animals, but still sort of living beings) could hold the key to hundreds o natural anti-cancer agents.

Ganoderma lucidum better known as Rheishi mushroom may have cancer protective effects, but does not taste so bitter that no sane human being would eat it for a reason (photo by Eric Steinert)

I guess, I don't have to tell you that Chinese Medicine, of course, knew about the powerful anti-inflammatory and anti-proliferative effects of the lanostanes in these fungi, all along. Intuitively and probably by trial and error, the Chinese have found the tetracyclic triterpenoids that are derived from lanosterols in these fungi to be effective in the treatment of various diseases including different types of cancer. As of late the mostly anecdotal effects are backed by more and more research. A preliminary study by Sliva et al. (Sliva. 2002), for example, found that a hot water extract of both spores and the dried fruiting body of G. lucidum inhibited the progression of cancerous growth by reducing the expression of constitutively active growth and inflammation promoting transcription factors AP-1 and NF-κB: 

"The extracts also inhibited the secretion of uPA, thereby suppressing the migration of breast cancer MDA-MB-231 and prostate PC-3 cells. [...] High levels of both uPA and uPAR are associated with advanced tumors and decreased survival time in different malignant human cancers." (Rios. 2013)

These benefits do however come with a downside. At least in vitro, some of the fungi, particularly G. lucidum, obviously exert their effects via anti-androgenic pathways (Liu. 2007). A compound in Reishi that goes by the name ganoderol B, for example, does not just have inhibitory activity against 5α-reductase, but can also bind to the androgen receptor directly (if you will you could say it acts like an anti-anabolic SARM). Now, this was good news in a study that has been conducted by Liu et al., because it inhibited androgen-induced cell growth in an LNCaP cell line while suppressing testosterone-induced regrowth of the ventral prostate in rats. If those effects are however non-selective, you are about to run into problems once the molecules bind to receptors outside the prostate -- epression for example, if they block the androgen effects in the brain, etc.

That reminds me: What did Carl say on Thursday's installment of the SuppVersity Science Round Up? "The good thing about supplements is that they work, the bad thing about them is that they work!" I guess you can basically say the same about Reishi. Good that you as a SuppVersity reader always know about both, the good and the bad sides of supplements!

More short news

With me posting stuff on the fly on facebook, I am actally 'wasting' many of the very short news items, but nevertheless, here are a couple of relatively short news to round things up.

• 

  If you missed Monday's new on the quasi non-existent thermogenic effects of ephedrine, this would be a good time to read that post.

  Stress-induced browning of the fat? Chronic overexpression of noradrenaline (re-)generates wasted brown fat! In a way this is a follow up on the ephedrine post "Fat Burners Don't Work" as well as an addendum to a news on the role of GABA and brown fat in obesity, I just posted on facebook. According to an allegedly old study in the International Jornal of Obesity (Lee. 1986),  the chronic overexpression of noradrenaline as it is observed in humans with a certain form of adrenal tumor known as phaeochromocytoma can actually reactivate the intra-abdominal fat of human adults, including the omental fat, which is brown adipose tissue in infancy.
  
  Lee et al. see this as one of the main contributing factors to the weight loss which is typically seen with phaeochromocytoma. Sounds, logical, since the same stimulus that rejuvenates the Brown fat will also have it burn energy continuously - the overexpression of noradrenaline.
  
  
  Symptoms of overtly high noradrenaline levels include abdominal pain, chest pain, irritability, nervousness, pallor, palpitations, rapid heart rate, severe headache, sweating, hand tremor, high blood pressure, sleeping difficulties, and also weight loss.
  Even patients with Cushing's syndrome (hypercortisolemia) there is an increase in brown fat compared to healthy individuals. That the latter is not as profound is probably due to the ameliorative effect of cortisol on nor-adrenaline. After all, cortisol comes into play, when the stress becomes chronic and the acute nor-adrenaline response to stress, when it was prlonged any further would actually pose a direct threat to your health (just as phaeochromocytoma does, by the way; see red box on the right)
• Repeated moderate stress exposure increases DHEA production and normalizes corticosteriod levels in old apes (Goncharova. 2013). Yep, you are reading right we are not just talking about no rodent studies (although macacs are not exactly very human either ;-), but also about the role of repeated moderate stress in the normalization of aged induced abnormalities in the expression of adrenal hormones.
  

  

  Figure 2: Cortisol/DHEA ratio before and after 2h/day of immobilization stress.

  "In old monkeys the basal DHEAS levels were lower, while the [cortisol]/DHEAS ratio was higher than in young animals. Repeated immobilizations inhibited [cortisol] elevation on day 3, caused no changes in DHEAS reaction, led to increase of basal DHEAS levels and to a reduction of [cortisol]/DHEAS ratio on days 2, 3, 4, 10, 11." (Goncharova. 2013)

  In figure 2 you can see how profound the differences between acute, subchronic (3-day) and chronic responses actually are and that after 10 days of daily stress exposure in the form of daily 2-h immobilization stress actually are. Since I assume you don't want to be bound or enchained (well, maybe you want?), I suppose a viable alternative could be a shorter not too intense workout, although the acute responses to the latter vary with age as well (cf. Lennartsson. 2007).
• Monitor your DHEA levels closely, if you are concerned about joint degeneration According to a study that's about to be published in the next issue of the Journal of Steroid Biochemistry and Molecular Biology, DHEA, or the estradiol your body generates from it via local aromatization, exerts major protective effects against osteoarthritis (Li. 2013).
  
  
  An additional note of caution with respect to the abuse of aromatase inhibitors, natural or not. Since they have the potential to reduce the expression of estrogen at the neuronal level in the brain they can precipitate  Alzheimer's dementia. While estrogen appears to decrease the MMP-3 & 13 expression in the cartilage reasearch by Merlo et al. suggests that it will increase others, namely namely MMP-2 and MMP-9  in the brain and thus facilitate the clearance of the ameloid beta plague that's rendering the brains of AD patients more and more dysfunctional (Merlo. 2013). You see, it's no chance that pre-menopausal women are protected from Alzheimer's yet more susceptible to multiple sclerosis (MS). After all, high MMPs 7 & 9 have only been observed in kids with MS, as well (Unsal. 2013).
  In their experiments on a rabbit model of osteoarthritis the scientists from the Zheejiang University in China tried to nail down the beneficial effects of DHEA on chrondocites and cartilage to estrogen by co-administering DHEA with the aromatase inhibitor letrozole, and/or the estrogen receptor inhibitor fulvestrant and observed that the
  

  "[e]xpression of MMP-3 and MMP-13 increased in both DHEA-treated chondrocytes and cartilage in the presence of letrozole and/or fulvestrant, while the expression of TIMP-1 and collagen type II (Col-II) decreased." (Li. 2013)

  With the former metalloproteinases (MMPs) being proteolytic enzymes, which break down cartilage and the latter, i.e. the tissue inhibitors of metalloproteinases (TIMPs), acting as their antagonists, it appears clear why both patients on testosterone replacement therapy who use too high of a dose of aromatase inhibitors and athletes who abuse respective products on cycle or during PCT often suffer from severe cartilage degeneration - I mean, combine the endogenous cartilage destruction due to high MMPs and low TIMP levels with the wear and tear of weight lifting... what good could come out of that?
  
  Note: A very similar effect has been reported for bisphenol A by Wang et al. in 2010, already (Wang. 2010). No wonder, after all BPA decreases the local expression of aromatization in joints and cartilage so that less estrogen will be floating around to keep the MMP levels in check and TIMP up (Watanabe. 2013).
• Alpha tocopherol to prevent lymphoma Regular vitamin E, i.e. the alpha-version of the tocopherols is no longer the star at the supplement sky it has once been hailed to be. A recent study by Renu Sharma Manjula Vinaya that's been published ahead of print in the journal Molecular Biology Reports shows however that this does not mean that it's outdated and useless (ask Ray Peat about it ;-).
  
  

  

  Figure 3: Lifespan (top) and ascite volume (=water accumulation in the abdominal area) of lymphoma carrying mice treated with what would be in human terms ~325, 650 and 975 IU/day of an alpha tocopherol only supplement  (Sharma. 2013)

  In order to test the hypothesis that the ROS scavenging abilities of vitamin E should help with cancer prevention (as a student of the SuppVersity you know that respective data from epidemiological studies are equivocal, some suggesting the exact opposite; read more), the researchers initially induced the growth of lymphomas in 10-15 week old male mice and subsequently treated them with either 1.5 mg (50 mg/kg bw), 3 mg (100 mg/kg bw) or 4.5 mg (150 mg/kg bw) of alpha-tocopherol for 14 days.
  
  As the data in figure 1 goes to show you, the treatment increased the lifespan of the rodents by 25% and reduced the ascite fluid volme (see image in figure 1) by ~46%. This was accompanied by reductions in protein carbonylation and increases in the "master anti-oxidant" GSH, as well as several other markers showing that vitamin E exerted profound anti-inflammatory effects in this rodent model of lymphoma.
  
  At least in my humble opinion that does not change the fact that your best sources of vitamin E are natural and that's smart to stay away from alpha-tocopherol only supplements and prefer a whole spectrum tocopherol + tocotrienol supplement. Remember: More is not better, when the one thing that counts are the ratios (read more about vitamin E)!
  

That's it for this week's installment of On Short Notice. As mentioned in the introduction, there are more and even shorter news on the SuppVersity Facebook Wall, which usually gets updated 3+ times per day with I would guess 9-12 items total - depending on whether it's a slow news day or not and the time I have to skim studies and popular science mags and repost summaries and links of and to the latter. Let's see what did we have today, already? Ah, yeah: "Review concludes: Just being patented makes Kinesio® no better than conventional taping" (more), "Interesting stupid science finds that GABA directly mediates energy expenditure." (more), or maybe you are interested in "If rapamycin blocks seizures in model of epilepsy. Is mTOR to blame for both?" (more)?

References:

• Goncharova ND, Vengerin AA, Chigarova OA. Repeated Moderate Stress Stimulates the Production of Dehydroepiandrosterone Sulfate (DHEAS) and Reduces Corticosteroid Imbalance in Old Macaca Mulatta.  Bulletin of Experimental Biology and Medicine Volume 153, Number 5 (2013), 750-753. 
• Lean ME, James WP, Jennings G, Trayhurn P. Brown adipose tissue in patients with phaeochromocytoma. Int J Obes. 1986;10(3):219-27. 
• Lennartsson AK, Kushnir MM, Bergquist J, Jonsdottir IH. DHEA and DHEA-S response to acute psychosocial stress in healthy men and women. Biol Psychol. 2013 May;90(2):143-9.  
• Li WJ, Tang LP, Xiong Y, Zhou XD, Wu LD. The chondroprotective effects of dehydroepiandrosterone probably exerted by its conversion to estradiol. J Steroid Biochem Mol Biol. 2013 Oct 18. 
• Liu J, Shimizu K, Konishi F, Kumamoto S, Kondo R. The anti-androgen effect of ganoderol B isolated from the fruiting body of Ganoderma lucidum. Bioorg Med Chem. 2007 Jul 15;15(14):4966-72. 
• Merlo S, Sortino MA. Estrogen activates matrix metalloproteinases-2 and -9 to increase beta amyloid degradation. Mol Cell Neurosci. 2013 Apr;49(4):423-9.
• Ríos JL, Andújar I, Recio MC, Giner RM. Lanostanoids from Fungi: A Group of Potential Anticancer Compounds. J Nat Prod. 2013 Oct 23.
• Sharma R, Vinayak M. α-Tocopherol prevents lymphoma by improving antioxidant defence system of mice. Mol Biol Rep. 2013 Oct 14.
• Sliva, D.; Labarrere, C.; Slivova, V.; Sedlak, M.; Lloyd, F. P., Jr.; Ho, N. W. Biochem. Biophys. Res. Commun. 2002, 298, 603– 612.
• Unsal Y, Kıvılcım G, Ayşegül A, Arzu A, Esra G, Ercan D, Ayşe S. Matrix metalloproteinase-7 and matrix metalloproteinase-9 in pediatric multiple sclerosis. Pediatr Neurol. 2013 Sep;47(3):171-6.
• Wang KC, Lin YF, Qin CH, Chen TL, Chen CH. Bisphenol-A interferes with estradiol-mediated protection in osteoarthritic chondrocytes. Toxicol Lett. 2010 Oct 5;198(2):127-33. 
• Watanabe M, Ohno S, Nakajin S. Effects of bisphenol A on the expression of cytochrome P450 aromatase (CYP19) in human fetal osteoblastic and granulosa cell-like cell lines. Toxicol Lett. 2013 Apr 5;210(1):95-9.

Study Finds 17x Elevated Estrogen, High Progesterone + Reduced DHEA Levels in 65% of Ecdysteroid, Tribulus, Phytoestrogen, Phytosterol and / or Soy Protein Users!

Image 1 (Oliver Knöbel aka "Olivia Jones"): Not sure, but maybe the famous German drag artist Oilver Knöbel  aka "Olivia Jones" would be willing to buy some of your "all natural ergogenics"?

Tekin and Kravitz estimate the number of currently available "nutritional supplements" to be 30,000+ and if you want my personal estimate, roughly 30 of those are useful (Tekin. 2013). And while many of the other 29,970 supplements are often just dispensable, some are downright harmful or, as we have recently seen for alpha lipoic acid and zinc only beneficial for a certain, often sick, obese and diabetic part of the population (see "You are better of without alpha lipoic acid" and "Zinc supplements may cause insulin resistance & diabetes") and can - if taken in high doses or for long periods of time - become downright harmful for active physical culturists like you and me. The data Paolo Borrione and his colleagues from the Department of Health Sciences at the University of Rome present in a recently published paper does now confirm that ALA and zinc are probably still the most benign among the "potent ergogenics" and "all natural", "plant-derived nutritional supplements" that are specifically marketed to fitness enthusiasts all around the globe (Borrione. 2013).

Believe it or not: "Natural" and "non-hormonal" can be worse than synthetic and hormonal

Image 2: In view of the fact that ecdysteroids are meant to turn the guy on the left into the nasty bastard on the right, the guys in this study should be happy that they got away with hormonal imbalances ;-)

In their peer-reviewed observational pilot-study (I am already looking forward to the follow up ;-) the scientists queried 740 trained subjects (420 body builders, 70 cyclists, and 250 fitness athletes) over a 6-months period on their use of "commercially available plant-derived nutritional supplements", which contained any or several of the following ingredients

• ecdysteroids, 
• phytoestrogens, 
• phytosterols and/or
• tribulus terrestris

To my surprise only 26 of those 740 experienced trainees (all subjects have been training regularly for at least 1 year, 1–2 hours per day, 3–6 days per week) declared that they were currently using respective products, with

• In defense of at least some of the ingredients mentioned in this list to the left, it should be mentioned that it is not clear, if the observed effects were due to a single component of the supplements, due to several of the ingredients of an individual product or the highly undesirable and based on studies on isolated compounds non-predictable interactions. Personally, I would bet money that all three of these were involved, though.
  6 subjects consuming products that contained Caffeine, Citrus A., Zingiber, Guggul, Cacao, Naringine and Bioperine. 
• 6 subsect consuming products based on 5-Methyl-7Methoxyisoflavone, 7-Iso- propoxyisoflavone, 20-Hydroxyecdysone, Secretagogues, Triboxybol, Saw Palmetto extract, Beta Sitosterol, Pygeum extract, Guarana extract and Cordyceps extract. 
• 4 subjects consuming different dosages of a commercially available product containing Rhaponticum Carthamoides extract and (in one case) Ajuga Turkestanica and Rhaponticum Carthamoides root extract

for 6-12 months. The rest got at least a daily dose of phytoestrogens from soy protein products, some of which were enriched with Muira Puama and/or Guta Kola extracts - with highly detrimental consequences on the endocrine milieu for 15 (65%) of them.

Figure 1: Progesterone (ng/ml), estrogen (pg/ml) and DHEA (ng/ml) levels in users vs. non-users of "plant-derived nutritional supplements"; the bars for lower and upper indicate the lower and upper limit of the normal range, the figures on top of the blue bars are relative to the group average of the non-users (based on Borrione. 2013)

If your brain is not already malfunctioning due to too many "all natural ergogenics", it should be plain obvious that neither the 16x increase in estrogen, nor the 3x increase in progesterone are something you would be willing to pay money for. And that goes irrespective of whether you are a man or a women. After all,  these profound "hormonal alterations" (esp. the hyperestrogenism) could, as the scientists point out, lead to "severe health problems" such as

• gynecomastia, hypogonadism and reduced fertility in men, and 
• macromastia, enlarged uterus, menstrual irregularities and breast cancer in women.

In addition, hyperestrogenism represents a major risk factor for the female and male breast cancer (Heinig. 2002; Martin. 2003; Cederroth. 2010).

Taking DHEA or an "all natural" aromatase inhibitor will only exasperate the mess!

Image 2: Actually this post only confirms what I have been written in my previous post on "hormone optimization made simple and cheap". Avoiding all the natural and unnatural hormonal disruptors is the less expensive and healthiest way to optimize your endocrine system.

And while you could try to counter the reduced DHEA levels and the increase in estrogen by simply swallowing another pill (or a whole "stack"), I would suggest you better avoid all those totally natural, but by no means harmless test- or whatever boosters and suppressors of which Paolo Borrione et al. rightly state that they "have not been studied for long-term safety".

Contrary to the users in Berrione's study, of whom 45% did not even know all of the substances on the label of their supplement of choice you are now aware that the phytoestrogens, vegetal sterols and ecdysteroids are not simply not worth their money, they are more importantly not worth your health and should, just like the soy protein, which happens to be the one supplement that was on the list of every subject with abnormally elevated estrogen levels(!) never make it onto your supplement shopping list.

References:

1. Borrione P, Rizzo M, Quaranta F, Ciminelli E, Fagnani F, Parisi A, Pigozzi F. Consumption and biochemical impact of commercially available plant-derived nutritional supplements. An observational pilot-study on recreational athletes. J Int Soc Sports Nutr. 2013 Jun 19;9(1):28.
2. Cederroth CR, Auger J, Zimmermann C, Eustache F, Nef S: Soy, phyto-oestrogens and male reproductive function: a review. Int J Androl 2010, 33:304–316
3. Heinig J, Jackisch C, Rody A, Koch O, Buechter D, Schneider HP: Clinical management of breast concer in males: a report of four cases. Eur J Obstet Gynecol Reprod Biol 2002, 102:67–73.
4. Martin RM, Lin CJ, Nishi MY, Billerbeck AE, Latronico AC, Russell DW, Mendonca BB: Familial hyperestrogenism in both sexes: clinical, hormonal, and molecular studies of two siblings. J Clin Endocrinol Metab 2003, 88:3027–3034.
5. Tekin KA, Kravitz L: The growing trend of ergogenic drugs and supplements. ACSM’s Health Fitness J 2004, 8:15–18.

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. 2013)

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). 2013 May 30;9(1):47. [Epub ahead of print]

Age-Dependent 100-300% Increase in Testosterone With 50mg of DHEA the Night Before HIIT Training. But is it Still Side Effect Free & Ergogenic When Taken Chronically?

Don't be fooled. DHEA won't allow you to train forever day in and day out the study at hand does yet add to previous results which already suggested that it could have its merits whenever intensity and workloads are high (learn more)

I don't know if you have noticed, but as of late, there has been a definitive testosterone deficiency as far as the topics of the daily SuppVersity news are concerned. With today's article on the use of 50 mg of dehydroepiandrosterone aka DHEA "pre-workout" this will change dramatically (read all previous articles on DHEA). Why? Well, the protocol the researchers from the Taipei Physical Education College, the China Medical University, the Asia University and their overseas colleague from the University of Texas at Austin describe in their recently published paper will yield age-dependent increases in free testosterone ranging from +100%, for the twens, to +300% for the men in their prime of their lives (~49 years).

I see, guys, I got your full attention, now! And for the ladies, ...

... who may now believe that this article wasn't for them, I have a 2008 study from Steroids, one of the journals dealing with endocrine issues, which shows that DHEA is an important player in subcutaneous fat reduction in women (Hernandez-Morante. 2008), as well as a study in hypoadrenal women (any one suffering from the athlete's triad probably qualifies for self-induced hypoadrenalism, learn more) from Diabetes the journal of the American diabetes association showing profound improvements in insulin sensitivity after 12-weeks on 50mg/day DHEA. So don't click this article away, thoughtlessly, ladies!

5x 1 min is obviously not the only sensible HIIT protocol. Read the SuppVersity Series on Making HIIT a HIT and find out which HIIT-style would be right for you (learn more)

50mg that was, as mentioned in the introduction also the dosage Liu et al. gave their sedentary young (aged 21.4±0.3 years, N=8) and middle-aged (aged 49.3±2.4 years, N=8) male participants 12 h before the exercise challenge under supervision of staff personnel. This exercise challenge was a standardized High Intensity Interval Training (HIIT) comprising 5x2min of cycling at 100% VO2max with 1 min rest between each cycling interval. The exercise was perfomed at 9:00AM and in a fasted state. The latter is probably significant, as the hormonal response of the adrenal gland - albeit only that of cortisol (cf. Labsy. 2013) - depends on the time of the day with a 2-3x higher response in the morning compared to the afternoon (cf. Thuma. 1995; Oskis. 2013).

This protocol was meant to shed some light unto the hitherto unknown effects of DHEA supplementation on testosterone levels during the recovery period after a bout of vigorous exercise. Interestingly, enough, you as a Suppersity addict (or soon to be addict ;-) will be aware that DHEA's beneficial effects on recovery in general have actually been proven - even in a scenario of temporary overreachig (=strategic overtaining for a short time period to elicit a maximal training stimulus; see figure 1 and read all the details in my May 2013 article).

Figure 1: Changes in DHEA-S serum levels and exercise induced elevations of creatine kinase =marker of muscle damage) in 16 healthy untrained college aged men receiving 100mg/day DHEA or placebo during a 5-day "mixed-type exercise" regimen (this graph was originally discussed on May 27, 2013 and is based on Liao. 2013)

While the dosage in the study at hand was 2x lower than in the Liao study and administered only once, it could still give us some insights into whether or not the decrease in creatine kinase (and thus muscle damage) Liao et al. observed in 2013 (the study was officially published only 1 month ago) was accompanied by an increase in total and/or free testosterone. Aside from the DHEA-S levels and the amount of luteinizing hormone (LH), the latter were the two main study outcomes in the Liu study (see figures 2 & 3):

Figure 2: Dehydroepiandrosterone (DHEA-S) and total testosterone levels (TT) during the interention; the asterisk (*) over the TT bars signifies significantly different from placebo in the same age group (Liu. 2013)

If you take a closer look at the data in figure 2 you will realize that there were increases in total testosterone in both groups. Contrary to the very unsurprising increase in DHEA sulfate, the latter were yet only significant in the middle-aged study participants (mean age 49 years).

"Nice, but where's the data on cortisol and what about free test & LH?"

What is not shown in figure 1 are the cortisol levels of the study participants, which were not significantly different at baseline. After the exercise intervention, the levels did yet increase significantly - irrespective of whether or not the participants were young or middle aged or received the placebo or the actual DHEA pills. Intriguingly, the drop that occured after 24h in both age groups was much more pronounced in the middle-aged guys.

Figure 3: Free testosterone and luteinizing hormone levels during the intervention (Liu. 2013)

Contrary to the total testosterone levels, the amount of free testosterone increased significantly in both, the young and old study participants (see figure 3), it actually goes without saying that

"[...] the free testosterone to cortisol [FT/C] ratio increased significantly during the training recovery for both the middle-aged and young control groups." (Liu. 2013)

Now all that is good news, but what's even better news is that, at least in the short run, these profound elevations in free testosterone did not lead to lower levels of the "testosterone production trigger" luteinizig hormone (LH), which is released by your hypothalamus and tells your testes to produce more sex hormones. Now why is that important? Well, the answer is simple, a reduction in LH is not just a sign of the dreaded HTPA shut-down, it is the shutdown - or I should say the mechanistic cause of being "shut down" (=not producing any or too little sex hormones on your own).

Ok, higher T levels, lower testosterone to cortisol ratio, but what about estrogen?

A note on performance and estrogenic side-effects: An 8-week exercise intervention by Brown et al. which used 50mg DHEA /day combined with 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. reported that 4 weeks of 100mg 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). It is still noteworthy that the DHEA induced "estrogen dominance", which is one of the most frequenly heardt arguments against DHEA supplementation was not observed in either of the two studies.

If the above is the question that's just praying on your mind, then this is probably not the first article on DHEA administration you've read and what's more, the other ones were probably not published on the SuppVersity. While it is true that a handful of previous studies have in fact shown an increase of estrogen in response to the administration of DHEA, the important ratio of testosterone to estrogen was maintained even in the majority of those studies, where this effect was observed (for more details read the text in the red box on the right).

Regardless of how "real" the danger of elevated estrogen levels may be, there is actually another way more important question to be answered, which pertains to the sustainability of the results. In view of the fact that the DHEA was only administered once, it is way more likely that the unquestionably beneficial effects the scientists observed could be of very transient / short-lived nature. The minimal changes in luteinizing hormone for example could well become significant (and negative) in the long run. After all a +100% increase in free testosterone is nothing your body is going to ignore for weeks. It's more likely that it will slowly bounce back to the former steady state by either reducing the production of testosterone or that of DHEA.

So even if it's unlikely that the small dosage of 50 mg would eventually shut you down, you may well lose the benefits after one months of continuous supplementation.

That being said, you could also argue that the exogenous DHEA has,  just as TRT or performance enhancing drugs, the advantage of not being subject to diet-, training- and obviously age-induced reductions in their endogenous production. If any of the latter reminds of a situation / period of your life you are in, your chances of seeing benefits would at least be higher - whether they would be high enough to actually manifest in beneficial training outcomes remains questionable, though.

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It is unfortunate that science gave up on DHEA, when it became clear that it's not the fountain of youth. I mean, greater fat-inhibition effects than testosterone are nice, no (learn more about those)?

Bottom line: The new information the Liu study has to provide does actually go hand in hand with what the data from the Liao study already suggested. The purported "fountain of youth" hormone has potent ergogenic effects in training scenarios, which focus on vigorous physical activity.

Unfortunately, the evidence from these short-term interventions does not tell us anything about the beneficial and detrimental effect the low and high dose protocols from the Liuand the Liao studies will have. Personally I would assume that the benefits will wane off, but in the absence of corresponding studies, this is mere guesswork. After all, 99% of the previous research on DHEA has been done in sedentary old men and women. Few trials investigated the effects on young or middle aged subjects and less than a handful did that in an exercise scenario with any resemblances to yours or mine.

So there is probably need for at least another SuppVersity article (obviously based on a novel study), before you will hear me recommend the use of DHEA as an ergogenic supplement. Now, if you want to make sure, you don't miss that, I suggest you start following the SuppVersity on Facebook, Twitter or simply with your favorite RSS reader (click here to get to the channel ;-)

References:

• 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.  
• Hernández-Morante JJ, Pérez-de-Heredia F, Luján JA, Zamora S, Garaulet M. Role of DHEA-S on body fat distribution: gender- and depot-specific stimulation of adipose tissue lipolysis. Steroids. 2008 Feb;73(2):209-15.
• Labsy Z, Prieur F, Le Panse B, Do MC, Gagey O, Lasne F, Collomp K. The diurnal patterns of cortisol and dehydroepiandrosterone in relation to intense aerobic exercise in recreationally trained soccer players. Stress. 2013 Mar;16(2):261-5. 
• 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. 2013 Jan;113(1):99-107.
• Liu TC, Lin CH, Huang CY, Ivy JL, Kuo CH. Effect of acute DHEA administration on free testosterone in middle-aged and young men following high-intensity interval training. Eur J Appl Physiol. 2013 Feb 17.
• Oskis A, Clow A, Thorn L, Loveday C, Hucklebridge F. Differences between diurnal patterns of salivary cortisol and dehydroepiandrosterone in healthy female adolescents. Stress. 2013 Jan;15(1):110-4. 
• 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.
• Thuma JR, Gilders R, Verdun M, Loucks AB. Circadian rhythm of cortisol confounds cortisol responses to exercise: implications for future research. J Appl Physiol. 1995 May;78(5):1657-64.