Vitamin(S!) E, The Whole Picture: Delta Tocopherol a Rising Star in Cancer Protection

Those of you who have attentively followed my dissertation on fish oil (cf. SHR: ProfDrAndro talking on the Pros & Cons of Fish Oil) may remember that - as an aside - I mentioned that not alpha-tocopherol, which is what supplement companies add to their fish oils, but delta-tocopherol would be the anti-oxidant of choice to protect the highly oxidizable oil from going rancid.

Figure 1: Toco-8, one of the few
tocotrienol products on the market

A very recent report (Li. 2011) on findings of scientists from The State University of New Jersey is only one out of a whole line studies that imply that the real health value of "vitamin E" (we should better start writing "the vitamins E") does not lie in one, but in the combination of the tocopherols (alpha, gamma, delta) and the naturally ocuring tocotrienols, of which both the delta-tocopherol, as well as the group of tocotrienols have long been overlooked in the course of what one should probably call the "alpha-tocopherol"-hype.

According to Li et al., of the three tocopherols (alpha, gamma, delta @ a human equivalent dose of 800IU) the scientists fed to mice, which had previously been "infected" with "human lung cancer H1299 cells", the "δ-Tocopherol inhibited tumor growth most strongly" (delta > gamma > alpha). And with reference to the underlying mechanism of the observed superiority of delta-tocopherol to the two other isomers, the scientists argue:

The higher activity of δ-T in the inhibition of tumor growth corresponded well with its ability to inhibit the formation of 8-OHdG, γ-H2AX, and nitrotyrosine as well as to induce cell apoptosis.

With 8-OHdG being a marker for oxidative stress, γ-H2AX being a marker for cellular damage and nitrotyrosine being a reactive derived from nitrogen species and tyrosines in proteins, these findings suggest that delta-tocopherol protects against oxidative stress and cellular damage, and, at the same time, facilitates apoptosis of cancerous cell lines (on a side note: a characteristic feature of cancer is that the "normal" and healthy programmed cell death does not occur). Alpha-tocopherol, on the other hand, has "little or no influence" on these parameters.

If one also takes into consideration that the tocopherols appear to displace each other...

[...] dietary γ- or δ-tocopherol, however, decreased serum α-tocopherol levels, and dietary α-tocopherol decreased serum levels of γ-tocopherol.

...it is becoming more and more obvious that supplementation with isolated tocopherols, as it has been the case in many of the inconsistent studies on the effect of "vitamin E" on cancer, is not warranted.

So, if you decide to copy the study and supplement 800IU of vitamin E, make sure it comes from a source of "natural, mixed tocopherols" or even better tocopherols & tocotrienols, of which S. Wada in a very recent review (Wada. 2011) on the effects of vitamin E on cancer writes:

Vitamin E, especially tocotrienols, seems to be a potent agent for cancer prevention, however no large-scale clinical trial on the cancer prevention effect of tocotrienols has been conducted yet. Therefore it is expected that clinical trials overcoming the lower bioavailability of tocotrienols will be conducted, and it is urgently needed to assess the safety and the efficacy of the administration of the tocotrienols as a part of a cancer prevention regimen.

Ah, and don't forget: The SuppVersity is the place where you will read about these studies first ;-)

Beet Root Juice Supplementation Improves Exercise Performance. Nitrate Content of the Beets Decreases ATP Turnover in High Intensity Exercise.

Nitrates have long been decried as toxic and dangerous and I bet, before their latest appearance to the supplement market, none of you would even have remotely considered to consciously increase his/her dietary nitrate supply. Yet, recent scientific studies confirm that nitrate (in moderate doses) is not only safe, but also has, its effects on vasodilation aside, quantifiable effects on exercise performance.

A group of scientists from the UK tried to find out the underlying mechanisms of the ergodicity of supplemental nitrate (Baily. 2011). Following a six day supplementation period in the course of which seven males (aged 19-38 yr) consumed 500 mL per day of either nitrate-rich beetroot juice (~300mg nitrate content) or placebo (PL, with negligible nitrate content). What they observed is best described as a "tuning effect" that was observable both, in the course of high, as well as in the course of low intensity exercise training.

During low intensity exercise, the pulmonary VO2 amplitude and thus the oxygen need during this kind of aerobic exercise decreased by -7%. An even more profound effect of nitrate supplementation was observed during high intensity activity (knee extensor exercises) where the ATP turnover decreased by -25%. These results stand in line with an overall increase in exercise tolerance of +25% in the nitrate supplemented group over placebo.

Other than a some other researchers had speculated, Baily et al. did not find any indications of a changed phosphate vs. oxygen (P/O) ratio in the muscle. The changes in ATP turnover a 6-day loading phase with dietary nitrate from beet root juice triggers, must thus be considered the underlying mechanism of the ergogenic effect of nitrates, which, as you may have notices, appear in various forms (amino acid nitrates, creatine nitrates, etc.) in recently released supplements - not without reason, as it turns out.

Confusing Study Results: Saliva Testing "Adequate" For Free Testosterone, Yet Way Off For Cortisol!?

Many of us spend a fortune on "hormone optimization", but when it comes to actually testing our levels, most of us are pretty cheap: "200$ for labs? No way I rather buy another test booster for that money - won't hurt, I guess!" And even, if we finally decide to test our testosterone levels, we will usually choose the cheapest and most convenient testing method: saliva testing. But is this an adequate way of assessing one's hormonal status? Although these tests have been around forever, nobody appears to be sure how reliable they actually are. A recent study (Caenegem. 2011) from the University Hospital of Ghent, Belgium, attempts to provide answers.

The researchers tested two saliva collection methods, chewing on a cotton swab (Salivette, Sarstedt) and passive drooling on 30 healthy males with a median age of 27 years (range 19–65 years) and compared their findings against serum levels, which were measured on the same occasion. Here are their results:

For cortisol, we observed a mean positive bias of 65% for passive drooling versus Salivette. In addition, cortisol determined on passive drooling samples correlated much worse with calculated free cortisol than cortisol analyzed on the cotton samples (respectively r=0.34 versus r=0.70). However, for testosterone passive drooling correlated well with the calculated free fraction (r=0.66). A positive bias of 21% for testosterone collected by passive drooling versus Salivette was observed. In contrast to earlier reports, we found no artefactually high testosterone results with the cotton-based collection method.

Obviously, these results seem to indicate that saliva testing for testosterone is a good, while saliva testing for cortisol is a bad idea, BUT these results are in fact intrinsically flawed. By just calculating free serum values instead of using equilibrium dialysis to actually measure them, the scientists' control values and with them their assessment of the "appropriateness" and "inappropriateness" of salivary testosterone, respectively cortisol testing are questionable. 

From what I hear from practitioners like Dr Crisler, it is highly advisable to spend the extra cash to have measured (not calculated) serum testosterone levels as reliable baseline and 4x saliva cortisol profiles to see where your levels are at throughout a 24h period. Arguably, this is yet another case in which a questionable study design leads to results which refute common practice and aggravate a confusion around hormonal testing procedures which affects practitioners and patients, alike.

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.

Now Its Official: Propecia Drug Finasteride Kills Male Libido Permanently

Image 1: Chemical structure of finasteride

Other than the FDA some European medicine and health care agencies, such as the Swedish Medical Products Agency and the Medicines and Healthcare Products Regulatory Agency of the United Kingdom already had the guts to declare in their patient informations that "persistence of erectile dysfunction after discontinuation of treatment with Propecia has been reported in post-marketing use." While this was obviously no reason for the all-mighty FDA to correct or re-evaluate their own documents, two it did intrigue Michael S. Irwig and Swapna Kolukula, two US scientists from Washington and Baltimore, respectively.

In their study (Irwig. 2011), the scientists conducted standardized interviews with 71 otherwise healthy men (age: 21–46y), who experienced permanent (>3 months) sexual side effects after temporary use of Finasteride. Their reports are staggering:

94% developed low libido, 92% developed erectile dysfunction, 92% developed decreased arousal, and 69% developed problems with orgasm. The mean number of sexual episodes per month dropped and the total sexual dysfunction score increased for before and after finasteride use according to the Arizona Sexual Experience Scale (P < 0.0001 for both).

These sexual side effects occurred after a "mean duration of finasteride use [of] 28 months" and they were persistent up to the interview date. For the study population this meant that they had already been suffering 40 months, on average, when the interviews took place; and chances are that many of them will suffer the consequences of an insufficient (or should I say incompetent or corrupted?) drug approval process and consequent indoctrination of medical practitioners for the rest of their lives.

Note: After receiving some critical feedback via facebook, I feel that it is necessary to point out that the result of the study may not be misinterpreted as "Every Finasteride user will experience persistent decreases in libido, erectile disfunction etc.", but as "In those percentage of Finasteride users, where such side effects occur, they can potentially be permanent." So the news is neither that Finasteride will cause these effects in each and every user, nor that it may cause such side effects (that is in fact mentioned in the package insert, I suppose), but that IF side effects occur, it is possible that they are persistent.

Chrysine: 5,7-dihydroxyflavone for Bigger Balls and Higher Serum Testosterone

Polyphenols in general and flavonoids in particular are every supplement producer's favorite. Its so easy to pick up some exotic plant from somewhere deep down in the jungle, extract an exotic flavonoid, give it a fancy chemical looking name and provide some in-vitro data on his anti-oxidant omnipotence or whatever. In most cases the compounds disappear from the market within weeks, yet chrysine which is extracted from the Common Passion Flower, has been around for years. A recent study (Ciftcy. 2011) by Ciftci et al. provides further evidence that its market persistence may not be without a reason.

Over the time course of the scientists fed a group of lab rats 50 mg/kg chrysin (human equivalent ~8mg/kg) or placebo for 60 days and found:

that chrysin significantly increased GSH, CAT, GSH-Px and CuZn-SOD levels, but did not change the formation of TBARS significantly. In addition, sperm motility, sperm concentration and serum testosterone levels significantly increased, whereas abnormal sperm rate significantly decreased with chrysin treatment.

In essence the improvement in antioxidant markers (vs. placebo) went hand in hand with a measurable increase in sperm health and serum testosterone.

Figure 1: Testosterone levels of rats after 60 day intervention with 50mg/kg chrysin. (Ciftcy. 2011)

 "Great", well, maybe not so... although this is an almost 50% increase in testosterone, we do not know how other important hormonal parameters such as SHBG (binds testosterone and thus renders it basically useless), estrogen or cortisol looked like. An estimation of the "muscle building effects", the producers of respective supplements are advertising, is thus futile. And, if you asked my opinion, even if SHBG did not budge and we have an appropriate increase in free testosterone, the latter is probably too little to induce noticeable changes in strength and/or body composition.

L-Citrulline Improves Sexual Performance: 50% Chance of Improvement with just 1.5g/day

You probably receive the same amount of daily spam mails trying to refer you to dubious viagra retailers somewhere on the Cayman Islands, or wherever else in the world. In case, you ever even thought about ordering stuff like that, you may as well consider getting some l-citrulline from your local supplement store first.

Scientistsfrom the University of Foggia in Italy (Cormio. 2011) have found that supplementation with as little as 1.5g/day l-citrulline improved erection hardness in men with mild erectile dysfunction (and I always thought Italian men would not have any erection problems ;-):

Significant improvement in the EHS [erection hardness score] from 3 to 4 was reported by 2 (8.3%) of the 24 men when taking the placebo and 12 (50%) of the 24 men when taking L-citrulline (P < .01). The mean number of intercourses per month, a nonvalidated patient-reported outcome we have commonly used in patients treated for ED, was 1.37 ± 0.93 at baseline, 1.53 ± 1.00 at the end of the placebo phase (P = .57), and 2.3 ± 1.37 at the end of the treatment phase (P < .01). For treatment satisfaction, all 12 patients reporting an EHS improvement from 3 to 4 scored very satisfied, and the remaining 12 scored not satisfied and all asked for a PDE-5 inhibitor prescription at the end of the study phase. Finally, no AEs [adverse events] occurred.

So, this is a 50% chance of improvement. In view of the price of l-citrulline (as bulk-powder) it would be worth a try. I promise, I won't tell anyone ;-)

News on USP Labs' "Pink Magic": High Dose Massularia Acuminata Increases Testosterone and Makes Bucks Horny as Hell

Faithful readers of the SuppVersity will probably remember my short write-up on USP Labs Test Booster "Pink Magic". Now that the initial fuss about how "brilliant" and "unique" the product is, is over there is finally another study on the efficiency of its main ingredient, a shrub called massularia acuminata.

Two scientists from Nigeria (Yakubo. 2011) published an article on the "Effect of Aqueous Extract of Massularia acuminata Stem on Sexual Behaviour of Male Wistar Rats" in the January issue of Evidence Based Complementary Alternative Medicine. The scientists found that supplementation with 500 and 1000mg/kg body weight (equivalent to 6.8g and 13.6g) of an aqueous extract of the stem of the botanical...

... increased the frequencies of mount and intromission. In addition, the ejaculation latency was significantly prolonged (P < .05). The latencies of mount and intromission were reduced significantly whereas ejaculation frequency increased. The extract also reduced the postejaculatory interval of the animals. Computed percentages of index of libido, mounted, intromitted, ejaculated and copulatory efficiency were higher in the extract treated animals compared to the distilled water-administered control whereas the intercopulatory interval decreased significantly.

In short: the rats were horny as hell ;-) But there was more to it:

The extract also significantly (P < .05) increased the serum testosterone content of the animals except in those administered with 250mg/kg body weight on days 1 and 3.

In view of these results it is interesting to have a look at the amount of massularia in Pink Magic. Unfortunately, USP provides no data on the amount of the individual ingredients - so, we only know that there is 1.6g of a mixture of massularia and two other botanicals in one serving. Massularia is mentioned first which tells us that it should be the main ingredient. So, let's be generous and assume that there is 1.0g of massularia per serving. USP recommends 3 servings per day. This would amount to 3.0g of massularia, which has now been clinically proven to be insufficient; and what's more even with 6.8g/day (equivalent to 500mg/kg in rats) the increase in testosterone (cf. Table 1) is still almost negligible.

Table 1: Effect of aqueous extract of Massularia acuminata stem on serum testosterone concentrations of male rats. (Yakubo. 2011)

What about all the positive feedback on various message boards, then? Well, we do not know how the dosing protocol used in rats eventually translates to human beings. The above calculation is based on a standard human equivalence dose formula, the accuracy of which is certainly questionable. Thus, the results of the study are actually good news for USP Labs, as they prove that massularia which, by the way is not a USP Labs exclusive anymore, actually works.