TReaTing Diabesity With Testosterone!? If You Keep DHT in Check + Stay Away From Aromatase Inhibitors, It May Work

It probably won't turn an overweight pre-diabetic into a fitness model, but a getting a TRT script has the potential of changing a man's physical and psychological health for the better.

Despite the fact that more and more men recognize the benefits of supervised testosterone replacement therapy (TRT) and the bodybuilding and fitness community cherishes 'their BIG T' as the be-all-and-end-all, many medical practitioners look at the administration of exogenous androgens as a potential health hazard. I would even bet that it won't be difficult to find one or two MDs who would say that Patricia S. Juang et al.'s idea to administer testosterone to obese men with normal, but low baseline testosterone levels to improve their body composition and insulin sensitivity borders physical injury - and that irrespective of adjuvant 5α-reductase (dutasteride) or aromatase (anastrazole) inhibitor administration.

TRT w/ or w/out aromatase or 5α-reductase inhibitor?

It goes without saying that the bodybuilding enthusiasts will think very differently about the usefulness of the 10 g testosterone gel (Testim) the fifty-seven 24–51-year old men with free testosterone levels in the lower 25% of normal range (<0.33 nmol/L) and a body mass index of ≥30.0 kg/m² in this recent  98-day randomized, double-blind, parallel group, placebo-controlled trial from the Universities of California and the Boston University Medical Center (Juang. 2013). In fact, I am pretty sure that, contrary to the scientists who put their subjects on either

• + subjects received a gonadotropin releasing-hormone antagonist to suppress endogenous T production
  10g Testim per day,
• 10g Testim + 1mg Arimidex (anastrazole) per day, or
• 10g Testim + 2.5 mg Avodart (dustasteride),

some of the physical culturists may even have suggested to use both, the aromatase inhibitor Arimidex and the 5α-reductase inhibitor Avodart to make absolutely sure that the T remains T and is not converted to estrogen or DHT.

Figure 1: Change in hormone levels (left) and body composition (right) after 98 days on 10g t-gel (Testim) with / without aromatase (Arimidex) or 5α-reductase (Avodart) inhibitor (Juang. 2013)

If they looked at the data in Figure 1, the estrogen-phobic bodybuilding enthusiasts would yet have to admit that the "bad estrogen" cannot be so bad as broscience would have it. Only minimal decreases in body fat, and significantly lower increases in fat free mass in the presence of a 5cm! (+4%) increase in waist circumference is certainly not what the bros are looking for.

Looking for natural ways to boost your testosterone levels? Look no further! You can learn about 10 ways to up your testosterone levels in my previous article "Natural Hormone Optimization Made Simple & Cheap: Avoid These 10 Anti-Androgens to Boost Testosterone & DHT" | read more

As surprising as the magnitude of the 'waist gain' may be, I personally have been more surprised by the effects the 10g of Testim had on the DHT levels of the overweight subjects. In both, the T-only and the T + Arimidex group the DHT level literally exploded and blunted the 25%, respectively 30% increase in glucose disposal during  minutes 120–180 and 240–300 of the euglycemic hyperinsulinemic glucose clamp test the scientists performed before and after the intervention period (Juang. 2013).

Despite a -40% decrease in PSA (vs. +9% in the T-only group), the 5α-reductase inhibitor dustasteride did not prevent the ~10% increase in prostate size that occurred in both the T-only (12%; +9% PSA) and T + Acodart (10%; -40% PSA) group. Other safety markers, such as AST (liver) or haemoglbin (iron overload) did not change.

The fact that dustasteride does not blunt testosterone induced lean mass gains is something you may have read in a previous article | more

Bottom line: I guess there are three things we can take away from this study:

1. TRT can help overweight men with impaired insulin resistance improve their body composition.
2. The administration of an aromatase inhibitor blunts the beneficial effects and causes a surprisingly pronounced increase in waist circumference.
3. The glucose sensitivity increases only, when the excessive reduction of testosterone to DHT is blocked by dustasteride.

In other words, if you want the T accept the E, but watch your DHT; but remember: Don't do it without blood work!

References:

• Juang, P. S., Peng, S., Allehmazedeh, K., Shah, A., Coviello, A. D. and Herbst, K. L. (2013), Testosterone with Dutasteride, but Not Anastrazole, Improves Insulin Sensitivity in Young Obese Men: A Randomized Controlled Trial. Journal of Sexual Medicine.

T-Gel with or Without an Aromatase Inhibitor? If You Are Healthy & Lean and Want to Stay This Way, There is Only One Answer: T-Gel Without Aromatase Inhibitor!

Don't let her talk you into participating in studies that risk your manliness ;-)

Would you be willing to participate in a study, where you could end up without testosterone? No? Well me neither... strangely Joel S. Finkelstein et al. were able to find 198 healthy men between 20 and 50 years who were stupid enough to participate in an experiment, where they were randomized to placebo, or testosterone gel (1.25, 2.5, 5, or 10g per day) while being on gosererelin acetate, which did suppress their natural testosterone production.

With additional 202 subjects receiving an identical "treatment", but in this case alongside a whoppy dose of the aromatase inhibitor anastrazol as a bonus, the study design leaves us with plenty of groups and tons of subjects. To "determine the relative degree of testosterone deficiency, estradiol defi­ciency, or both at which undesirable changes in body composition, strength, and sexual function begin to occur." (Finkelstein 2013)

Yep, that is the study you don't not want to be part of, but....

I bet you will still be interested in the results. Am I right? Ok, let's see then. In men receiving goserelin acetate (kills the natural testosterone production) and 0 g (pla­cebo), 1.25 g, 2.5 g, 5 g, or 10 g of testosterone gel daily (cohort 1), the mean testosterone levels were

• 0g testosterone: 44±13 ng per deciliter, 
• 1.25g testosterone: 191±78 ng per deci­liter
• 2.5g testosterone: 337±173 ng per deciliter, 
• 5g testosterone 470±201 ng per, and
• 10g testosterone 805±355 ng per deciliter

With 1.4 pg per milliliter, 7.9±2.9 pg per mil­liliter, 11.9±5.7 pg per milliliter, 18.2±10.2 pg per milliliter, and 33.3±15.3 pg per milliliter the estrogen levels of all participants were all well within the normal range (<55pg/ml).

Update: As Dr. Crisler (www.allthingsmale.com) just told me the accuracy of the information about estrogen may be questionable, because the essay the scientists used is not reliable in adult men. Instead, he suggest you use a "sensitive" essay like LabCorp (#500108), which uses the "cutting edge" LC/MS technology, Mayo Clinic's "Enhanced Estradiol" (#81816) or LabCorp's "Sensitive Estradiol (#140244), which is less expensive and thus probably a good choice for those without insurance. Dr. Crisler also pointed out that the wide variations you see in T-levels are actually a "very good thing, since this more closely mimics the serum profile of young healthy men". I do not deny that, but I still thought that it was wise to point out that the difference between 805ng/dl and 924ng/dl is absolutely non-significant when you have a range of ±521ng/dl.

Now the latter was obviously true for the guys on the aromatase inhibitor as well, with 1-2pg/ml their levels were however pathologically low and considering the high standard deviations, their T-levels were not that much higher:

Figure 1: Testosterone (ng/dl) and estrogen (pg/ml x10) in healthy men on 0, 1.25, 2.5, 5 and 10g (T0-T10) of testosterone gel with and without an additional aromatase inhibitor (Finkelstein. 2013)

"In men who also received anastrozole (cohort 2), the corresponding mean testosterone levels were 41±13 ng per deciliter, 231±171 ng per deciliter, 367±248 ng per deciliter, 485±240 ng per deci­liter, and 924±521 ng per deciliter and the corresponding mean estradiol levels were 1.0±0.4 pg per milliliter, 1.2±0.4 pg per milliliter, 2.0±2.3 pg per milliliter, 2.1±1.9 pg per millili­ter, and 2.8±1.8 pg per milliliter." (Finkelstein 2003)

[*please note the high (up to 50%!) standard deviations which tell you that the response to transdermal testosterone may vary profoundly from one men to another]

If you take a closer look at the data in Figure 1 and keep in mind that I had to multiply the estrogen levels by x10 in order to fit them into the same graph, it becomes all the more evident that the men in the non-AI group all had normal (<55pg/ml) estrogen levels. Their peers in the anastrazole group, on the other hand, had basically no estrogen at all and correspondingly high testosterone to estrogen ratios. In the worst case (yep, that is something bad!), namely 10g of t-gel + A,I the latter was as high as 335, which is almost 12x higher than in the 2.5g testosterone group without anastrazole (cohort 1).

No T, but tons of body fat

Apropos, cohort 1, in this group of men those who received the anti-androgen goserelin alongside a low(ish) doses of T-gel, i.e. either 0 g, 1.25 g, or 2.5 g of testosterone, daily, had significantly higher body fat levels and those in the 0 and 1.25g of T-gel significantly lower levels of lean mass compared to their peers in the 5g T-gel per day group.

Just a reminder: The testosterone level of the guys in the 5g group was only 470ng/dl and thus still rock bottom - the age adjusted normal levels for men are after all (I highlighted the group, where most of the subjects were in):

• 

  Effects of high and low testosterone on body composition (learn more)

  14-15 yr: 33-585 ng/dL
• 16-17 yr: 185-886 ng/dL
• 18-39 yr: 400-1080 ng/dL
• 40-59 yr: 350-890 ng/dL
• > 60 yr: 350-720 ng/dL

Those on the highest dose of T-gel (10g) ended up at the top (remember the standard deviations) of the normal range for testosterone and right in the happy medium for estrogen (normal range is 14-55pg/ml). These guys  experienced a significant decrease in body fat and increases in tigh muscle area and leg press strength.

Interestingly, both the decrease and increase in body in response to high and low testosterone levels occurred almost exclusively in the "benign" subcutaneous adipose tissue. The intra-abdominal­ fat area, on the other hand did not change significantly in any group. If we follow the standard interpretation of the health effects of the different body fat stores, the conclusion would thus be that low T is not so much of a problem, after all it's all "healthy fat" that you will gain... to bad that too much of that "healthy fat" will make you just as insulin resistance as the visceral fat - it just takes longer for the negative effects to occur.

Now what did the AI do?

Suggested read explaining why the annihilation of E2 has negative effects on your body comp: "Estrogen, Friend or Foe of Muscle Hypertrophy? Plus: Are You 'SERMing' Away Your Satellite Cells?" | more

I know, the most intriguing question has not been answered yet: What was the role of anastrazole in all this? And how did the subjects in cohort 2 fare compared to their "high" (remember even the 10g guys had normal estrogen levels) estrogen counterparts. Well,...

"In cohort 2, the percentage of body fat increased in all groups when the aromatization of testosterone to estradiol was inhibited. The magni­tudes of these increases were similar with doses of 0 g, 1.25 g, 2.5 g, and 5 g of testosterone daily, a finding that suggests a predominantly estro­genic effect" (Finkelstein. 2013)

Yep, I deliberately quoted this, because I know that you've been brain-washed to believe the opposite would happen. The big bad estrogen is what keeps you lean... good that you have been taking natural AIs for years, right? Well, no obviously not. Probably rather the reason that you still don't have the cover-model look you are aspiring.

---

Did you know that (a) the endogenous production of estrogens has significant protective effects on your heard cardiovascular health (Sudhir. 1999) and that (b) aromatase is neuroprotective and low levels of it have been associated with the occurance + progression of neurological diseases such as dementia, Alzheimer's and Parkinsons as well as an inability to recover from mechanic (trauma) or chemical (intlammation) damage to the brain (Azcoitia. 2001)? No? Well, let's hope that this is because you've never heard it and not because you've been abusing AIs for the past decade ;-)

So, to use an AI or not - is that even a question? A direct comparison of all the data from cohort 1 (no aromatase inhibitor) and cohort 2 (using anastrazole), informs us that

"The cohort–testosterone dose interaction was significant for the percentage of body fat (P = 0.001), intraabdominal­fat area (P = 0.021), subcutaneous ­fat area (P = 0.029), sexual desire (P = 0.045), and erectile function (P = 0.032)" (Finkelstein. 2013)

Or, to put it another way: The study shows us that estradiol exerts an inde­pendent effect on body fat, sexual desire and erectile function. So you better don't ignore the real world implications you are about to suffer, when you put too much faith in hearsay instead of looking at your actual blood levels:

"In the groups that received testosterone, inhibi­tion of estrogen synthesis (cohort 2), as com­pared with intact estrogen synthesis (cohort 1), was associated with significant increases in the percentage of body fat (P<0.001), subcutaneous­ fat area (P<0.001), and intraabdominal­fat area (P = 0.002) and with significant decreases in sexual desire (P<0.001) and erectile function (P = 0.022)" (Finkelstein. 2013)

Yes, you heard the scientists right. Suppressing your estrogen levels is going to make you fat, rob you of your sexual desire and render you unable to perform the deed.

At the same time it had no beneficial effect on the increases in lean body mass or strength or any other positive outcome the subjects got from using T-gel. On the contrary, the low estrogen levels on in the 10g T-gel group did actually blunt reduce the lean mass gains and the fat loss the men in cohort 1 (no anastrozole) experienced, when they used 10g of T-gel per day was effectively reversed by the AI.

Figure 2: Fat gain, lower lean mass gain, less sexual desire & lower sexual function (not shown) and the list goes on... there really is nothing remotely beneficial about low estrogen (figures from Finkelstein. 2013).

It should thus be absolutely obvious that the only reason you should use an aromatase inhibitor with your testosterone replacement therapy is blood work that indicates that you have serious issues with over-aromatization. In many cases those can be reduced if not solved by (a) reducing inflammation and (b) getting rid of your belly.

To deliberately annihilate your estrogen levels, on the other hand, is simply stupid - irrespective of whether you are on TRT or not and even if you don't care about the negative long-term effects on your brain and heart health.

References:

• Azcoitia I, Sierra A, Veiga S, Honda S, Harada N, Garcia-Segura LM. Brain aromatase is neuroprotective. J Neurobiol. 2001 Jun 15;47(4):318-29.
• Sudhir K, Komesaroff PA. Clinical review 110: Cardiovascular actions of estrogens in men. J Clin Endocrinol Metab. 1999 Oct;84(10):3411-5. Review.

SuppVersity Science Round-Up Seconds: All About DHEA. Plus: In Practice - Supplementation Benefits & Dosages?

A lack of libido appears - if at all - treatable w/ DHEA only in peri-menopausal women (Maggi. 2013; Pucchino. 2013); there are however a lot of other things DHEA can do for you.

The power of electricity made it possible. Yesterday's show went really smoothly, but despite the fact that I really tried hard to cover all the most interesting topics, there was simply too much for a 1h show. That being said, I still suggest you first download and listen to the podcast before you go ahead and read the Seconds with further basic information about dehydroepiandrosterone aka DHEA, its specific effects, its clinically investigated areas of application, a handful of surprising studies, its (non-excessive) conversion to estrogen, other things you may consider interesting and - as promised - a short-list of "candidates for DHEA supplementation" that may help you to find out whether you can benefit or not.

On a related note: Downloading the podcast is also well worth it, because you get Chris Masterjohn's interview on vitamin D as a "free goodie". Well worth it, I promise (download the podcast).

Let's not waste time, but get straight to the point

As you have heard DHEA is the most abundant steroid hormone in your body, it is produced in the mainly in the adrenal gland (~31mg in men and 18mg in women). In women specifically, DHEA is also the main precursor to androgens (testosterone, DHT & metabolites). For both men and women DHEA and DHEA-S the most abundant, sulfur-bound stable transport form of DHEA. It acts as a neurosteroid the age-induced decline of which has long been implicated as one, if not the main hormonal underpinnings of the cognitive decline we experience as we age.

Figure 1: Age-induced decline in DHEA, effects of oral contraceptice use, hormonal cascade that leads to the formation of DHEA (enzymes to the side) and overview of reasons for DHEA decline.

Looking at the data in Figure 1 (upper left hand) this would actually appear logical. After all DHEA is on a steady decline that starts as early as in our late twenties. As with "paleo logic", the "naked ape hypothesis" and the vitamin D craze (listen to the previously mentioned interview with Dr. Masterjohn and you'll know what I am talking about, here), not everything that appears to be perfectly logic is also correct. So, it should not come as a suprise that corresponding studies involving healthy individuals aged 60 years and over who were treated with (near) physiological doses of DHEA (50-100 mg/day) have yielded very few positive results (Hildreth. 2013).

Fitness is rewarded: Did you know that men who exercise regularly have 2x higher DHEA-S levels than sedentary slobs? they also have 41% lower body fat %-ages (Tissandier. 2001) - coincidence? Probably not! Being fat lowers DHEA and low DHEA increases fat gain (Pritchard. 1998). The beneficial effects of DHEA on body comp, on the other hand, are mediated by the modulation of the effects of cortisol (listen to the show) and direct lipolytic effects on subcutaneous (women) and visceral (men) fat (Hernández-Morante. 2008; more evidence).

Specifically with respect to the cognitive effects, or rather their absence in corresponding trials, it may yet well be that our problem is administration specific and/or of pharmacokinetic nature and thus a mere result of the fact that you cannot replace the endogenously produced DHEA in the central nervous system (which is next to the gonads #2 of the non-adrenal tissues that is capable of synthesizing DHEA from pregnenolone; Dong. 2012). The short-lived pronociceptive (=pain reducing) effects (<150min) of oral DHEA supplementation at 10mg/kg in rodents would furthermore suggest that we are not so much suffering from low systemic levels as we are from our bodies inability to regulate DHEA levels on demand (Gąsińska. 2012).

Apropos regulating DHEA levels "on demand"

Actually DHEA is supposed to increase in response to stress. When stress is becoming "normal", however, the stress-induced DHEA release becomes blunted (Lennartsson. 2013). This process is actually characteristic of the early stages of "adrenal fatique" - I deliberately use the term in quotation marks, because there is no "fatigue" involved here, it's a "simple" deregulation of the up and down that should be characteristic of our stress natural and health response; see "Science Round-Up Seconds: All About Cortisol, Fat Loss, Body Composition and the Efficacy & Safety of 7-Keto & Co" | read more.

And while it may make some sense to supplement with DHEA in the early stages of "adrenal fatigue" (high cortisol, minimally decreased DHEA) its "anti-cortisol" effects are going to do more harm than good, once the initially high cortisol levels are breaking away, and dropping from high to rock bottom. In these latter stages of adrenal fatigue DHEA only treatments could actually make you believe that life sucks even more than it does already.

Figure 2: Elevetated DHEA levels in the AM and PM and a low DHEA / cortisol ratio in the AM (8h) are characteristic of patients with major depression (Assies. 2004)

Life sucks? Yeah, right that reminds me of something else I could not squeeze into the life show: Did you know that the level of DHEA in the cerebrospinal fluid of suicide attempters is elevated (Chatzittofis. 2013)? No, well what about its association with regular depression, then (see Figure 2)?

"DHEA-S was significantly elevated, in conjunction with normal cortisol levels. Based on DHEA-S at 22:00 h only, 77% of the subjects were correctly classified in a discriminant analysis as depressed or control. When simultaneously entered in a multiple regression analysis, DHEA-S (morning and evening) and cortisol (evening only) predicted symptom severity in depressed patients. These preliminary results suggest that DHEA-S may be a more sensitive indicator of depression and symptom severity than cortisol in medicated but still clinically depressed patients." (Assies. 2004)

Surprised? You shouldn't be. At least as a regular here at the SuppVersity you should by now be aware that more of a good thing is not necessarily better.

Too much of a good thing is probably also the reason for most side effects

I actually went into pretty much detail on the connection between dosing schemes and ranges, on the one hand, and potential side effects, on the other hand during the live show, already. I will therefore stick to a reminder here: The more DHEA you take, and the higher the individual dosages, the greater the hard-to-predict conversion to androgens and estrogens.

Figure 3: These hormone levels (expressed relative to placebo control at baseline) do not look exactly as if they would be able to induce a -31% reduction in body fat within one month. Plus: They do by no means look like the results of 1,600mg of DHEA per day - that would be ~53x more than your body produces on a daily basis (data adapted from Nestler. 1988)

Against that background it is all the more surprising to read that Johne E. Nestler et al. claim to have supplied their subjects with 1,600mg DHEA per day (no typo I had a mistake in my show notes and said 1,800mg during the live show - sorry for that, but the general notion is the same - that's a totally crazy! dosage).

"The men then took orally, in a double blind fashion, capsules containing either placebo or 400mg(138.7mmol) DHEA four times daily [total daily DHEA dose, 1600mg or 28days]." (Nestler. 1988)

The data in the study at hand is even less credible, if we look at the results of a more recent study which showed age- dependent increases of 100-300% in testosterone, when young(er), middle aged and older men took 50mg of DHEA the night before they undertook a HIIT regimen (learn more)... but hey, maybe the guys trained once during the 30 day study period and hat a 3000% T-boost

Without changes in activity levels or dietary intake this insane (don't to this at home or anywhere else ;o) DHEA protocol lead to a 31% reduction in body fat within one month. If you listened to the show, already, you will know that I am pretty skeptical, though,

1. whether these results are accurate or simply the result of faulty measurements
2. if more than 10% of the ingested DHEA actually was absorbed

I mean let's face it: With statistical significant increases only for DHEA (280%) and androstenedione (+100%) but in the absence of significant increases in testosterone, estrogen (neither E2, nor E1), decreases in SHBG or blood sugar and insulin resistance this result is simply incredible (in the most literal sense of the word)... ah, you do remember: Don't give it a try! Right?

High estrogen is not a regular side effect

No, no and no. Look at the data from the Nestler study. 1,600mg per day and NO (=ZERO) change in estrogen. This is however not the norm - the norm is a proportional increase in estrogen and testosterone which tends to leave healthy men with a higher testosterone to estrogen ratio than before. Examples? Here you go:

Figure 4: Effects of 50mg DHEA for 36 months in 70yr old men (left) and 100mg of DHEA for 6 months in men and women (Müller. 2006; Morales. 1998)

As you can see the results may be very different: Increases in estrogen and testosterone in the Müller study with 50mg for 36 months in 100 nonhospitalized, nondiseased, independently living men, aged 70 yr and over with low scores on strength test, on the one hand; and no effects in the male participants of the study by Morales et al. (1998), on the other hand.

The Morales study should by the way remind us of one of the most important functions of DHEA in women - it's the main precursor to male sex hormones (here testosterone Figure 4, right-top and DHT Figure 4, right-bottom); as discussed further down, DHEA can thus in fact be used as a "HRT"-like treatment in women, but not in men.

So who can benefit?

Actually the previously mentioned sex difference segues nicely into my here's who benefits list, Carl and I did not really have the time to cover, yesterday... so let's see:

• 

  DHEA increases Testosterone & Blunts Muscle Damage (read more)

  people with low (age-corrected) DHEA levels - in this case DHEA is like any other hormone replacement therapy and should be monitored by a medical professional of whom you should make sure that he controls for confounding factors that would point towards confounding and causal factors
• people in their late 40s or later - as discussed in the show, the changes in hormonal levels, body comp and quality of life questionnaires may not be significant, but if you compare them to the control groups there is usually a benefical trend (gaining muscle and losing fat is better than the other way around, even if its only in the 500g range; cf. Müller. 2006; also discussed in the live show); still in view of the fact that you really don't know what you will get - get tested (must: DHEA-S, testosterone, DHT, estrogen (E2); optional: SHBG, free testosterone, E1, insulin, cholesterol panel, PSA (addition as per Daria's suggestion) - the latter two may in fact improve, by the way) after 1-2 months and every 6 months thereafter

• 

  DHEA blunts fat deposition more effectively than testosterone; for both the effects are mediated via PPAR-gamma (read more)

  men and women with low androgens - though (esp. for men) "real HRT" is probably the better way to go, you can try what I outlined for 40+ agers to bump up your androgens, as well
• women in early menopause - benefits have been observed for both the Kupperman score (index to quantify menopause symptoms) and vasomotor symptoms of menopause (Stomati. 2000).
  
  Some authors even consider it an adequate hormone replacement alternative for women (both studies used "only" 50mg/day!):
  

  

  Suggested read: "Carnitine as Repartitioning Agent? IGF-1, p-AKT & mTOR Up, Catabolic Proteins Down + 7% Improvement in Lean- to Total Mass Ratio" | read more

  "Administration of DHEA significantly affects several endocrine parameters in early and late postmenopausal women independently from body mass index. Our data support the hypothesis that DHEA treatment acts similarly to estrogen-progestin replacement therapy on the GHRH-GH-IGF-1 axis. This suggests that DHEA is more than a more than a simple "diet supplement" or "antiaging product"; rather it should be considered an effective hormonal replacement treatment." (Genazzani. 2001)

  another pro-argument is certainly the increase bone mineral density, which is and will probably always remain one of the major issues in menopause.
• Other things worth mentioning: Actually I have a couple of pages of additional notes, but I guess these are the most interesting points → DHEA increases intramuscular DHT, which is associated with increased insulin sensitivity (Sato. 2011) → DHEA improves both GLUT-4 and Akt (could also increase protein synthesis) in diabetic rodents (Sato. 2009) → DHEA improves the levels of the master anti-oxidant GSH in aging (or sick) livers (Jacob. 2011) → DHEA slows the development of type II diabetes (Byrne. 2001; rodent model) → Salivary cortisol and DHEA-S concentrations reflect the activity of the HPA axis (Ghiciuc. 2011) → DHEA opposes the immune suppressive effects of cortisol (Chen. 2004) → DHEA has thermogenic effects (Lardy. 1995) → DHEA is on the WADA list of prohibited substances, but doping researchers say its effect / side effect profile is not worth it anyway (Hahner. 2010) → DHEA has anti-breast cancer effect in rodent model of developing mammary cancer (via conversion to androgens; Labrie. 2001)
  men and women with hyperthyroidism - the increased thyroid activity "burns" through all adrenal hormones, so that backup (of both DHEA and cortisol) can become necessary (Agbaht. 2013)
• patients on glucocorticoids (e.g. for inflammatory or immune diseases) - cortisol and synthetic glucocorticoids suppress DHEA production - it's thus logical that backfilling the missing hormones can help
• people on severe chronic stress - the military, for example has conducted a handful of interesting studies; two of the most recent studies were conducted by Taylor et al. (2012) and Taylor (2013) - the researchers report neuroprotective and anabolic effects with 50mg/day (classroom phase) and 75mg/day (training in the field), respectively
• people using non-aromatizing steroids - DHEA can provide a precursor for a baseline estrogen level even on suppressive non-aromatizing drugs (listen to the show for more details)
• patients suffering from lupus erythematosus ["syndrome like" = very unspecific autoimmune disease usually with sever joint pain and arthritis, ca. 5 mio people world-wide suffer; every year 100,000 new cases in the US / constantly increasing (Buvat. 2003); honestly I suspect this leaves more cortisol to get the inflammation under control, but hey what do I know; usually women, often African American or latino] proven benefit from 200mg/day
• women with diminished ovarian reserve - while the latest review says the evidence was not there, I consider the results of a study by Gleicher (2009), alone, worth giving it a try: The researchers observed a restoration of the rate of miscarriages to normal levels in the 73 cases they evaluated – that’s a reduction of -51% risk of having a miscarriage and direct effect on the occurrence of genetic disorders like "Trisomy 21" [= down syndrome] in women with diminished ovarian reserve (Gleicher. 2010) - still: don't even think about messing with your hormones, when you are healthy and wand to become pregnant!

The worst candidate for benefits are the intended costumers of the recently released DHEA-derivates from various producers - young men in the prime of their life. Chances they will benefit are slim, but not impossible. Whether one of the DHEA based alternatives deliver is yet questionable.

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Suggested read for those who cannot get enough of DHEA stories: "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" | read more, expect similar, but not 1:1 identical results in humans

Bottom line: I guess I would have to go on for at least 10,000 additional words (now we are at ~2,300 words, by the way ;-) to give you at least a 25% "complete" image of all you could know about DHEA, but that's not really the intention of this summary. I would be happy if you felt that listening to the podcast and reading the "Seconds" improved your understanding and you remember that 2x25mg/day are probably the best way to boost DHEA-S, while 1x50 - 2x50mg per day is more of a "hormonal" booster including a higher risk for a hardly controllable conversion to downstream metabolites.

Whether the latter will or won't have beneficial effects will vary from person to person and makes testing all the more important. If you remember that and the fact that the fairy tales on the bulletin boards all over the Internet don't provide an adequate picture of what works, what sucks and what you side effects will or won't occur (listen to the podcast for additional details), I'd say you know plenty about DHEA... and if you disagree, just check out what I previously wrote about DHEA, here.

References:

• Agbaht K, Gullu S. Adrenocortical reserves in hyperthyroidism. Endocrine. 2013 Mar 27.
• Assies J, Visser I, Nicolson NA, Eggelte TA, Wekking EM, Huyser J, Lieverse R, Schene AH. Elevated salivary dehydroepiandrosterone-sulfate but normal cortisol levels in medicated depressed patients: preliminary findings. Psychiatry Res. 2004 Sep 30;128(2):117-22.
• Buvat J. Androgen therapy with dehydroepiandrosterone. World J Urol. 2003 Nov;21(5):346-55. Epub 2003 Oct 10. Review.
• Byrne JJ, Bradlow HL. DHEA-PC slows the progression of type 2 diabetes (non-insulin-dependent diabetes mellitus) in the ZDF/Gmi-fa/fa rat. Diabetes Technol Ther. 2001 Summer;3(2):211-9.
• Chatzittofis A, Nordström P, Hellström C, Arver S, Asberg M, Jokinen J. CSF 5-HIAA, cortisol and DHEAS levels in suicide attempters. Eur Neuropsychopharmacol. 2013 Feb 28. 
• Chen CC, Parker CR Jr. Adrenal androgens and the immune system. Semin Reprod Med. 2004 Nov;22(4):369-77.
• Dong Y, Zheng P. Dehydroepiandrosterone sulphate: action and mechanism in the brain. J Neuroendocrinol. 2012 Jan;24(1):215-24. 
• Gąsińska E, Bujalska-Zadrożny M, Sar M, Makulska-Nowak H. Influence of acute and subchronic oral administration of dehydroepiandrosterone (DHEA) on nociceptive threshold in rats. Pharmacol Rep. 2012 Jul;64(4):965-9. 
• Genazzani AD, Stomati M, Strucchi C, Puccetti S, Luisi S, Genazzani AR. Oral dehydroepiandrosterone supplementation modulates spontaneous and growth hormone-releasing hormone-induced growth hormone and insulin-like growth factor-1 secretion in early and late postmenopausal women. Fertil Steril. 2001 Aug;76(2):241-8. 
• Ghiciuc CM, Cozma-Dima CL, Pasquali V, Renzi P, Simeoni S, Lupusoru CE, Patacchioli FR. Awakening responses and diurnal fluctuations of salivary cortisol, DHEA-S and α-amylase in healthy male subjects. Neuro Endocrinol Lett. 2011;32(4):475-80.
• Gleicher N, Ryan E, Weghofer A, Blanco-Mejia S, Barad DH. Miscarriage rates after dehydroepiandrosterone (DHEA) supplementation in women with diminished ovarian reserve: a case control study. Reprod Biol Endocrinol. 2009 Oct 7;7:108.
• Gleicher N, Weghofer A, Barad DH. Dehydroepiandrosterone (DHEA) reduces embryo aneuploidy: direct evidence from preimplantation genetic screening (PGS). Reprod Biol Endocrinol. 2010 Nov 10;8:140. 
• Hahner S, Allolio B. Dehydroepiandrosterone to enhance physical performance: myth and reality. Endocrinol Metab Clin North Am. 2010 Mar;39(1):127-39, x.
• Hildreth KL, Gozansky WS, Jankowski CM, Grigsby J, Wolfe P, Kohrt WM. Association of serum dehydroepiandrosterone sulfate and cognition in older adults: sex steroid, inflammatory, and metabolic mechanisms. Neuropsychology. 2013 May;27(3):356-63. 
• Jacob MH, Janner Dda R, Araújo AS, Jahn MP, Kucharski LC, Moraes TB, Dutra Filho CS, Ribeiro MF, Belló-Klein A. Dehydroepiandrosterone improves hepatic antioxidant reserve and stimulates Akt signaling in young and old rats. J Steroid Biochem Mol Biol. 2011 Nov; 127(3-5):331-6. 
• Labrie F, Luu-The V, Labrie C, Simard J. DHEA and its transformation into androgens and estrogens in peripheral target tissues: intracrinology. Front Neuroendocrinol. 2001 Jul;22(3):185-212. Review.
• Lardy H, Kneer N, Bellei M, Bobyleva V. Induction of thermogenic enzymes by DHEA and its metabolites. Ann N Y Acad Sci. 1995 Dec 29;774:171-9.
• Lennartsson AK, Theorell T, Kushnir MM, Bergquist J, Jonsdottir IH. Perceived stress at work is associated with attenuated DHEA-S response during acute psychosocial stress. Psychoneuroendocrinology. 2013 Sep;38(9):1650-7.
• Maggi M, Buvat J, Corona G, Guay A, Torres LO. Hormonal causes of male sexual dysfunctions and their management (hyperprolactinemia, thyroid disorders, GH disorders, and DHEA). J Sex Med. 2013 Mar;10(3):661-77.
• Morales AJ, Haubrich RH, Hwang JY, Asakura H, Yen SS. The effect of six months treatment with a 100 mg daily dose of dehydroepiandrosterone (DHEA) on circulating sex steroids, body composition and muscle strength in age-advanced men and women. Clin Endocrinol (Oxf). 1998 Oct;49(4):421-32.
• Muller M, van den Beld AW, van der Schouw YT, Grobbee DE, Lamberts SW. Effects of dehydroepiandrosterone and atamestane supplementation on frailty in elderly men. J Clin Endocrinol Metab. 2006 Oct;91(10):3988-91.
• Nestler JE, Barlascini CO, Clore JN, Blackard WG. Dehydroepiandrosterone reduces serum low density lipoprotein levels and body fat but does not alter insulin sensitivity in normal men. J Clin Endocrinol Metab. 1988 Jan;66(1):57-61.
• Pluchino N, Carmignani A, Cubeddu A, Santoro A, Cela V, Alcalà TE. Androgen therapy in women: for whom and when. Arch Gynecol Obstet. 2013 Aug 3.
• Pritchard J, Després JP, Gagnon J, Tchernof A, Nadeau A, Tremblay A, Bouchard C. Plasma adrenal, gonadal, and conjugated steroids before and after long-term overfeeding in identical twins. J Clin Endocrinol Metab. 1998 Sep;83(9):3277-84.
• Sato K, Iemitsu M, Aizawa K, Ajisaka R. DHEA improves impaired activation of Akt and PKC zeta/lambda-GLUT4 pathway in skeletal muscle and improves hyperglycaemia in streptozotocin-induced diabetes rats. Acta Physiol (Oxf). 2009 Nov;197(3):217-25. 
• Sato K, Iemitsu M, Aizawa K, Mesaki N, Fujita S. Increased muscular dehydroepiandrosterone levels are associated with improved hyperglycemia in obese rats. Am J Physiol Endocrinol Metab. 2011 Aug;301(2):E274-80.
• Stomati M, Monteleone P, Casarosa E, Quirici B, Puccetti S, Bernardi F, Genazzani AD, Rovati L, Luisi M, Genazzani AR. Six-month oral dehydroepiandrosterone supplementation in early and late postmenopause. Gynecol Endocrinol. 2000 Oct;14(5):342-63. 
• Taylor MK, Padilla GA, Stanfill KE, Markham AE, Khosravi JY, Ward MD, Koehler MM. Effects of dehydroepiandrosterone supplementation during stressful military training: a randomized, controlled, double-blind field study. Stress. 2012 Jan;15(1):85-96. 
• Taylor MK. Dehydroepiandrosterone and dehydroepiandrosterone sulfate: anabolic, neuroprotective, and neuroexcitatory properties in military men. Mil Med. 2013 Jan;178(1):100-6.
• Tissandier O, Péres G, Fiet J, Piette F. Testosterone, dehydroepiandrosterone, insulin-like growth factor 1, and insulin in sedentary and physically trained aged men. Eur J Appl Physiol. 2001 Jul;85(1-2):177-84.

SuppVersity Cellulite Special: The Etiology of Cellulite, Genetical and Behavioural Risk Factors? Physical and Supplemental Treatment Strategies & Their Efficacy

This photo of a 37-year old woman some of you may already have seen Facebook testifies to the success of 12 weeks on 333U/cc retinol cream + high intensity laser pulses (Fink. 2006)

I guess, or should I say, I'd hope (?) that some of you have already been waiting eagerly for the write-up of yesterday's Special Installment of the SuppVersity Science Round-Up on the Super Human Network and all the details and obviously the supps, Carl and I could not squeeze into this 1h+ show.

Before you go over this huge (and this is also why it took me so long to post this) serving of the "Seconds", I do yet highly recommend that you download and listen to the podcast, first. You can grap the MP3, right here.  It's free and if you don't like the ads, just skip forward, but please come to terms with the fact that a daily 2h radio has to be financed one way or another!

Let's dig right into this lumpy-bumby skin condition, now!

Despite the fact that they did not identify the underlying reasons for the development of cellulite correctly, Alquier and Paviot (1920), who described cellulite as a non-inflammatory complex cellular dystrophy of the mesenchymal tissue caused by a disorder of water metabolism, which produced saturation of adjacent tissues by interstitial liquids that was brought about by a reaction to traumatic, topical, infectious or glandular stimuli, already had a pretty decent understanding of the structural characteristics of cellulite (cf. Rossi. 2000).

Figure 1: Overview of the four main stages in the development of cellulite. If you take closer look they actually reflect much of what Alquier & Paviot (1920) already suspected: a disorder in water metabolism and a complex tissue dystrophy, which can yet become inflammatory in the late stages

The fact that cellulite is nothing but the highly visible manifestation of the messed up structural grid that holds the skin (epidermis) and the underlying fat layer in place is also important in view of the fact that up to today, way too many people look at cellulite as if it was something like a transient allergic reactions you could get rid of, once you stop eating things high GI carbs or whatever the contemporary dietary villain may be.

Unfortunately, this is not the case so that Nürnber et al. are not totally off, when they write a a 1978 paper about the ..

“[…] the essential normality and inevitability of [cellulite] in women, the supervention of it in hormonally feminized men, and the near futility of treating the non-disease” (Review by Nürnberger. 1978)

It is, and this is something that was completely missing from the previously cited first description of the “disease”, in fact partly Mother Nature who is to blame for the

• abnormal hyperpolymerization of the connective tissue,
• primary alterations in the fatty tissue,
• microcirculatory alterations

with genetic and hormonal factors determining the basic risk profile and inactivity, a messed up diet, obesity, medication etc. being nothing but corroborating factors.

If you will, the X-chromosome and is myriad downstream effects that make a man a men could even be perceived as a genetic factor – a highly protective one that is.

Figure 2: Relative contribution of perpendicular, tilted and parallel septae to the "structural part" of the dermis (left; Querleux. 2002); comparison female vs. male skin (Rosenbaum. 1998), note: the comparison misses the important parallel structures esp. in the male skin, but I guess it still conveys the basic idea

As you can see in figure 2 (right), the mere fact that the upper most parts of the skin, the Epidermis and the Corium is much thicker in men than in women would already conceal major parts of the pumpy structure in a man. In women, on the other hand, the sclerotic macronodules that form during step four in the etiology of cellulite are highly visible through the “thin skin” of a woman.

Female skin with and without cellulite – what are the differences?

Figure 3: Photos of patients with grade II-IV cellulite. Mind the extreme difference between the contracted and uncontrated state in grade II (top vs. bottom; Rossi. 2002)

In addition to the general sex differences, Querleux et al. (2002) observed that women who suffer from cellulite have a 4x higher fat volume in the dermis, than normal women (note: the total amount of fat in men and women is not significantly different).

It goes without saying that this increase in volume would actually require an increase in strength or the number of stabilizing elements in the flexible structure that holds the fat, liquids and other components of the skin in place.In conjunction with the increased interstitial pressure that is a result of the microcirculatory alterations and the defect in collagen synthesis this increase in fat volume is however more than the comparatively unorganized fibrous structure of the female skin can hold.

If you think of the skin as three-dimensional grid that is filled with balls and lacks the structural components that separate the balls in the 1st row from those in the 2nd, 3rd, … etc. row, it should be obvious that any endogenously (interstitial pressure) or exogenously applied pressure (from within = muscle; or from outside = pinching) will push the balls or rather fat cells against the top-layer that's covering the grid (the uppermost parts of the skin) and cause pumps to appear at the surface.

A very similar mechanism is responsible for the appearance of the bumps and the valleys you see through the thin layer that’s covering the underlying fluid and fat-filled part of the dermis in women with cellulite.

Cold, not valsodilated & "lumpy-bumpy"

The presence of the sclerotic perpendicular macronodules in-between the pumps and dentures, only contribute to the nasty appearance and do little to maintain the structural integrity of the tissue that’s actually supposed to be pervaded by numerous small & flexible, randomly but highly crosslinked septae that keep the fat cells in place.

Figure 4: I assume you would not have needed this thermograph to tell me that cellulite ain't exactly hot ;-)

If you look at the thermograph to the right of this paragraph you will also notice that the metabolic activity of the tissue is similarly irregular and (don’t get fooled by the colors) overall much lower in women with cellulite compared to their “healthy” counterparts.

This is both a contributing factor, as well as a results of the decreased micro-circulation in the dermis (see cold green areas) and contributes to the increased water retention in the skin. The latter will increase the pressure and worsen the condition… it is a self-perpetuating viscous cycle, yet one that opens therapeutic doors not to reverse, but at least to halt the progress of the ongoing dystrophic processes.

Estrogen drives cellulite development

And while we are going to deal with the "therapeutic" options in just a minute, let's briefly recapitulate, what I said about the causes / confounding factors during yesterday's show (listen to the podcast for details):

• genes and sex - simply being a women predisposes you to develop cellulite; I know it's not fair, but that's how it is; the same goes for the genes: if your mother and grandmother had it, chances are you will develop it, as well 

• 

  Figure 5: The influence of estrogen on the pathophysiology of cellulite (Rossi. 2002); easy to see, estrogen is the motor of cellulite development

  high estrogen, low progesterone (e.g. puberty, pregnancy, birth control, PMS; partial revision in menopause possible) - estrogen (E2) increases the accumulation of fat, spec. in the areas that are typically affected by cellulite, it renders the fibroblasts more hydrophobic and predisposes to water retention and edema, it increases the permeability and thus the leakage from the cells and promotes the formation of sclerotic tissue (figure 5)
• insulin resistance / diabetes - does not only accelerate fat gain (at least as long as there is still some insulin around), but will also increase the production of glycosaminoglycans which will draw even more water into the tissue (Lotti. 1990)
• obesity (and obesogenic diets) - the faster the fat accumulates and the larger the cells become the greater the demand on the structural components of the dermis and the more likely it will give in and the bumps and start to appear (remember: cellulite is not about having too much body fat, if it is acquired slowly and you are not genetically pre-dispositioned to cellulite you can accumulate quite an amount of fat without developing cellulite)
• hypothyroidism - thyroid hormone increases hyaluronic acid and chondroitin sulphate production, low levels will thus hamper the formation and renewal of the structural parts of the dermis
• stress / corticosteroids - if you are not taking exogenous corticosteroids like prednisone, stress and high corticosteroid levels are actually identical and have similar effects as low thyroid hormone (by the way, stress, even "eu-stress" such as exercise, will also have thyroid hormone levels plummet; learn more)
• lack of exercise - decreased vasodilation, increased weight gain, increased water retention, increased risk of diabetes... I don't have to enumerate all of them, right?
• low potassium, zinc, copper and selenium intake - while the former will help your body regulate the water balance, zinc and copper are important for the formation of the net that keeps the fat in place and have, just as selenium anti-oxidant properties as part of Copper/Zinc Superoxide Dismutase
• smoking and boozing - both will promote the decline in micro-circulation

Now that you know what you cannot change and / or should not do, let's take a look at what you can do as far as physical treatments and supplements / drugs are concerned.

Currently available physical "treatment" options

I highly encourage you to also listen to the podcast, as I am going to keep this short in view of the fact that Carl went through all the items, anyway:

• Iontophoresis: Applies a galvanic current on the surface of the skin to depolarize it and alllow drugs pass through the dermis; it is also used to increase the vasomotor action (vasoconstriction, followed by vasodilation) of which practitioners of this method believe that it may have a positive effect on the compromised metabolism in cellulite skin
• Acoustic wave therapy / ultrasound: Uses high frequency vibrations, which have a thermic and vasodilator effect; is also used as an adjunct to "hammer" drugs into the skin; there is some evidence that it can provoke lipolysis and is thus used during liposculpture procedures. Russe-Wifingseder et al. reported only recently that the use of ultrasaund that acts only on the subcutaneous tissue produced "improvement in number and depth of dimples, skin firmness and texture, in shape and in reduction of circumference" (Russe-Wifingseder. 2013) in placebo-controlled trial.
• Thermotherapy: The heat is suppose to increase vasodilation. Experts say that its effectiveness is questionable, as some reports suggest that it did actually aggravated cellulite, maybe in consequent protein denaturation due to the high temperature. 
• Pressotherapy / Massage therapy: Either done by hand or with a pneumatic massager, the intention is to help the skin to release the liquid that's accumulating in the tissue and activate the venous return; it is also used to to treat lymphatic, venous or mixed oedema of the limbs, so that you can expect cosmetic effects of unknown (probably short ;-) duration
• Lymphatic drainage: While it has been used since 1936, the pumping movements using gentle and rhythmic pressures will stimulate the lymphatic flux, but have no proven and above all persistent effect on cellulite
• Laser therapy Low‐level, dual‐beam laser energy, as well as high intensity pulsed laser that are commonly used for "body-contouring" have been reported in several studies to "help" with cellulite. Most of those do yet only report reductions in subcutaneous fat and results like "increased well-being" among the particpants.
• Elecrolipophyresis: Unlike with the #1 on the list the electric current is not applied to the surface of the skin, but rather to several pairs of thin (0.3 mm) long (5–15 cm) needles which are connected to a low frequency current generator. This generates an electromagnetic field which is supposed to modify the interstitial tissue and aid in the circulatory drainage, as well as lipolytic processes. High quality evidence for its usefulness is absent.
• Mesotherapy – This is the well known injections of "solvents" into the adipose tissues. While there are various protocols available most involve phosphatidylcholine. What they all have in common is a highly questionable safety profile and the fact that they yield very ambiguous (mainly negative in peer-reviewed studies) results. Aside from that, dissolving the fat cells within an already corrupted structure is not exactly what I would deem helpful...

Before we go on to the supplements, let me briefly mention that a meta-analysis of cosmetic products marketed for cellulite reduction did show an overall effect, with respect to the thigh circumference (-0.46cm, analysis of 21 original papers; cf. Turati. 2013), while there was no consistent improvement in the nasty look of the skin.

Supplements & drugs for cellulite prevention (and reduction!?)

As mentioned on the show, most of the supplements in the following list are going to help mitigate some of the symptoms, reduce the fat load (literally) on the weak structure of improve the micro-circulation. Aside from retinol and maybe silicon, of which esp. the former appears to have a direct effect on what's going on beneath the surface of the skin, most don't hold much promise for getting rid of the underlying problems.

• 

  Suggested read: "Brown Algae Extract Reduces Body Fat Without Dieting or Exercise. Ecklonia Cava Polyphenols Help Shed Weight Even in The Presence of a Slight Caloric Surplus." | read more...

  Supplements to burn the fat - Methylxanthines (theobromine, theophylline, aminophylline, caffeine), which act through phosphodiesterase inhibition, isoproterenol and adrenaline which are beta-adrenergic agonists, and yohimbine, piperoxan, phentolamine and dihydroergotamine which are alpha-antagonists and will "encourage" the fat cells in this "stubborn fat area" to release more of the fat that's stored in them -- just pick the next best fat-burner from your local supplement story invent something that will have it pass through the stratum corneum and you got your "topical fat burner", of which I can only repeat that it will not get rid of the bumps - if anything it will reduce the severity.
  
  In view of the importance of Co-enzyme A in this process, adequate vitamin B5 and cysteine, which are used for its synthesis and maybe even carnitine, which helps to transport and burn the fat that's actually released from the fat traps on your thighs can enhance the effects of the previously mentioned agents. This is important because free fatty acids may saturate the system, leading to negative feedback of lipolysis (Di Salvo. 1995).

• 

  Suggested read: "How Working Out Changes the Morphology of Your Body Fat" | read more...

  Supplements to increase micro-circulation: Ivy and Indian chestnut extracts, ginkgo biloba and rutin, maybe pycegnol and the pharmacological agent Pentoxifylline, which is a drug commonly sold by Aventis under the brand name Trental it improves microcirculatory perfusion through its effect on haemorrheological factors, including erythrocyte shape, platelet aggregation and plasma fibrinogen concentration. While Pentoxifylline has been used to treat chronic venous insufficiency, stasis ulcers in controlled studies, its efficacy wrt to cellulite has not been proven.

• Antioxidant and immune modulatory supplements: Vitis Vinifera, borage oil, fucus. The latter is a common type of brown algae, that will also enhance the metabolism and reduce the oedema and intestinal inflammation.  

• Asiatic centella extract aka guta cola: The main reason this is a standalone is the frequency with which it is mentioned in the literature. Centella has a vegetable origin and consists of asiaticosideo (40%), madecassic acid (30%) and Asiatic acid (30%), triterpenic derivatives which act in vitro on fibroblasts, stimulating collagen and mucopolysaccharide synthesis.
  
  

  

  Chronic overtraining is no solution and the stress could in fact cause your to your cellulite problems. In addition, it is also the cause of chronic injuries, which persist even, when you finally realized that your own ambition is about to ruin your health (learn more).

  It has been used in the past both topically and systemically, and reported benefits of the oral administration route must probably be ascribed to its beneficial effects on the micro-circulation. According to Hausen (1993) it does neither lead to cutaneous hypersensitivity, nor does it have a toxic effect, when it is ingested.
  
  In a histopathological, double-blind study by Hachem & Borgoin from the late seventies it the administration of 60 mg of dry Asiatic centella extract orally once a day for 90 days brought about a significant reduction in the diameter of adipocytes in both the deltaoid and gluteofemoral regions in the patients who received centella compared to those who received placebo. Interestingly, this reduction was more apparent on the gluteofemoral region and went in hand with a decrease in interadipocyte fibrosis. 
  
  If it were not for the missing placebo control in most of the hitherto published studies, this could actually be a supplement worth trying.

• 

  Suggested read: "Evidence From the Metabolic Ward: 1.6-2.4g/kg Protein Turn Short Term Weight Loss Intervention into a Fat Loss Diet" 2x-3x higher than RDA protein intakes work equally well for men and women, to get and stay lean and lose fat and build / maintain muscle - it does not always take supplements, you see (learn more)?

  Sillicium: While you probably never thought about it, sillicium (organic) is present in celery, peppers, carrots, potatoes, unrefined grains and cereals and beets, all sorts of veggies and fruits, basically everything that growth on earth that has silica in it. The maximum daily recommended dose is 10.5 mg Si/day; and being a structural element of the connective tissue, it is actually not surprising that studies (mostly in vitro or rodent, unfortunately) have demonstrated that silanols (groups of hydrogen and sillicium compounds, similar to the hydrocarbides) provoke the formation of bridges between the hydroxylated amino acids of the elastic fibres and collagen fibres protecting them from non-enzymatic glycolysation and decreasing their degradation rate.
  
  Sillicum also acts as a coenzyme during interstitial matrix macromolecule synthesis. As such it helps reorganize structural glycoproteins and proteoglycans by stimulating polar amino acid grouping and normalizing hydrophilic capacity. Both effects which would obviously be highly desirable for someone suffering from a compromised dermal glycoprotein matrix. 
  
  In view of the fact that it has also been reported to increase microcirculation by modifying venous capillary and lymphatic permeability and has even been shown to stimulates cAMP synthesis as well as triglyceride hydrolysis and thus promote the release of fatty acids from the stored fat cells, it appears to be the perfect nutrient for any woman suffering from cellulite... in view of this fact it is surprising that I could not find a single reputable study proving its effects (note: I did not find one showing the opposite either) 

Actually, the next and last item on the list would be retinol,  but instead of just adding it to the bottom I want to briefly recapitulate that it was a 12-week treatment with weekly applications of intense pulsed light (the equipment used was a Quadra Q4 IPL) with a wavelength of 585-nm and nightly applications of a compounded retinyl-based cream (330 U/cc) that was applied after the ladies had used some aceton to remove the protecive layer of the skin 5x / week (Fink. 2006).

Some more details on the retinol / retinyl palmitat studies

In that it is interesting to note that the scientists picked retinyl palmitate not just for its better safety profile (compared to all-trans-retinoic acid) but also due to its short half-life, its well-known ability to stimulate type I collagen, and its ability to resist air oxidation.

Figure 6: Increase in blood flow in 20 women with moderate cellulite of the thighs treated twice daily on one side for 6 months with a 0.3% stabilized retinol cream while the opposite side was treated with the vehicle (Kligman. 1999)

In a previous study by Kligman et al. (1999) a similar cream containing 0.3% stabilized retinol did lead to marked increases in the blood flow as well as the synthesis of glycosaminoglycans and collagen in a group of 20 women with moderate cellulite on the thighs. Moreover, ...

"[t]here was also a marked reduction in the density of hypoechogenic areas on the retinol sides, from 53% to 18% of black pixels on image analysis. Blood flow measurements were unchanged on the vehicle sides but increased significantly on the retinol sides. Thickness measurements by ultrasound scan were unchanged on the vehicle sides but increased significantly on the retinol sides, from 1.44 to 1.60 mm." (Kligman. 1999)

In their study, Fink et al. observed responses in both the patients who received the combination treatment with the pulsed laser and retinol, as well as in those who received only the laser therapy; and with 60% (9) of their patients having a ≥ 50% improvement in cellulite at 3 months that lasted for 7 of the women up to the 8-months follow up, the overall results are pretty impressive.

Visible not just measurable improvements most likely due to vitamin A

Before and after pictures of the second, 50 year old patient in the vitamin A + pulsed laser study (Fink. 2006)

As I already mentioned on the show, though, the actual reason I picked this study to anchor the show were the two before and after pictures. The first set of which (see top of the page) is the one I already published on the SuppVersity Facebook Wall as a sneak preview, the other one that was taken from a 50 year-old patient (see image to the right) shows similar improvements. Due to the fact that she started out with a higher grade of cellulite, the end-result is yet not as astonishing as the one of the 37 year-old women you "know" already. Both women were in the combined treatment group and in all honesty, I personally consider the retinol the more promising therapeutic agent of the two.

As I told Carl on the show it cannot be excluded that the combination of tissue breakdown from the laser and the "collagen-anabolic" effects of retinol are perfect synergists. Similarly, it is difficult to say, whether the use of aceton only rendered the 2x/day application that was used in the Kligman study unnecessary or whether it was the removal of the stratum corneum that made the treatment so effective.

---

Bottom line: I would hope to see ongoing research in particular with regards to topical based retinol treatments for cellulite. And if respective results are published outside of the bazillion of small scale "studies" that come with the endless (and endlessly hilarious) amount of patents for all sorts of snake oil, I can guarantee that they will be part of the regular SuppVersity news (NO, I am not going to write another special, I am exhausted any you can keep all typos and worse mistakes for yourself ;-)


References:

• Di Salvo RM. Controlling the appearance of cellulite: surveying the cellulite reduction effectiveness of xanthines, silanes, CoA, 1-carnitine and herbal extracts. Cosm Toil 1995; 110: 50–59.
• Fink JS, Mermelstein H, Thomas A, Trow R. Use of intense pulsed light and a retinyl-based cream as a potential treatment for cellulite: a pilot study. J Cosmet Dermatol. 2006 Sep;5(3):254-62.
• Hachem A, Borgoin JY. Étude anatomo – clinique des effets de l’extrait titré de centella asiatica dans la lipodystrophie localisée. La Méd Prat 1979; 12(4): 17–21.
• Hausen BM. Centella asiatica (indian pennywort), an effective therapeutic but a weak Sensitizer. Contact Dermatitis. 1993; 29(4): 175–179. 
• Kligman AM, Pagnoni A, Stoudemayer T. Topical retinol improves cellulite. Journal of Dermatological Treatment. 1999; 10: 119–25
• Lotti T, Ghersetich I, Grappone C, Dini G. Proteoglycans in so-called cellulite. Int J Dermatol. 1990 May;29(4):272-4.
• Querleux B, Cornillon C, Jolivet O, Bittoun J. Anatomy and physiology of subcutaneous adipose tissue by in vivo magnetic resonance imaging and spectroscopy: relationships with sex and presence of cellulite. Skin Res Technol. 2002 May;8(2):118-24.
• Rosenbaum M, Prieto V, Hellmer J, Boschmann M, Krueger J, Leibel RL, Ship AG. An exploratory investigation of the morphology and biochemistry of cellulite. Plast Reconstr Surg. 1998 Jun;101(7):1934-9.
• Rossi AB, Vergnanini AL. Cellulite: a review. J Eur Acad Dermatol Venereol. 2000 Jul;14(4):251-62.
• Russe-Wilflingseder K, Russe E, Vester JC, Haller G, Novak P, Krotz A. Placebo controlled, prospectively randomized, double-blinded study for the investigation of the effectiveness and safety of the acoustic wave therapy (AWT(®)) for cellulite treatment. J Cosmet Laser Ther. 2013 Jun;15(3):155-62.
• Turati F, Pelucchi C, Marzatico F, Ferraroni M, Decarli A, Gallus S, La Vecchia C, Galeone C. Efficacy of cosmetic products in cellulite reduction: systematic review and meta-analysis. J Eur Acad Dermatol Venereol. 2013 Jun 14.

BPA & Phtalate News for the Plasti-Nation. The Endocrine Contribution to Muscle Growth. Magnesium & Testosterone Increase in Parallel. Anabolic Vibes on the Lat Pull & More

You still have a couple of milli- or centimeter too much on your waistline? Let's hope this spring will provide ample time to work out in the sun, after all that's the energizing way to work out, something even virtual reality indoor exercise cannot compete with (Plante. 2006)

The SuppVersity figure of the week is "90". That was the average total amount of sunshine hours we got here in North-Rhine-Westphalia within the winter months (DWD. 2013; and there were places with only 40h!). A pretty depressing figure, in the literal sense. If you listened to the last installment of the Science Round Up (click here to download the podcast), you may remember that I was actually somewhat surprised to hear that this was the darkest Winter ever since the sunshine hours have been recorded - after all, I got my 45min of "artificial sunshine" in, every morning. So, just in case you are still wondering how it's possible to write a blogpost everyday, the data from a 2012 series of studies in Dutch schools would support that it's all about the right lighting (Sleeges. 2012).

Apropos news, here is your weekly serving of short news on all sorts of things... you are missing the exercise related news? Well, I saved those for a round-up and one or two individual posts in the course of the next week ;-)

• Fiber renders mammalian guts colon proof (Nagy-Szakal. 2013) -- As a recent rodent study from the Baylor University suggest, it can hardly be too early to keep an eye on fiber intake. The mice in the pertinent study that had been randomly assigned to a low-cellulose (indigestible fiber that's present in fruits, veggies, whole grains etc.) diet had little to no protection against experimentally induced cholitis.
  
  

  

  Semisynthetic non-fermentable viscous fiber Hydroxpropyl-Methylcellulose is imported pound-wise from China and ends up as E464 from in all sorts of food - obviously at too low dosages to do the anti-obesity trick, though (learn more).

  Murine pediatric cellulose supplementation, on other hand, induces transient trophic and  anticolitic effects, which is - and that's important (!) - dependent on a continuous supply of adequate amounts of dietary fiber. The same goes for the benefifical changes in the diversity of the gut microbiome which did largely  decline after only 10 days.
  
  The protective effect on the epithelial cell lining and the increase in surface area in response to cellulose supplementation should also facilitate the uptake of those vitally important nutrients, people with Crohn's etc. are lacking - a result that may well be significant for those of you who are trying to make the most of the nutrients and not just the energy in their diets.
  
  Edit: As George Henderson rightly said, the study at hand does not talk about cancer protection, I simply inferred that from previous human studies such as Mendez (2007), Terry (2001) or Roth (2001), without mentioning that, my mistake, sorry for that. I still changed the headline to reflect the contents of the study and want to point out that George also makes a valid point stating that (a) fiber often replaces other less healthy nutrients in the diet and (b) that (my addition) "once the baby has been thrown out with the bathtub" and you already have Crohn's and co different rules may apply.

• The diabesity syndrome - Is it the soda, or the bottle it's packaged in? (Indumathi. 2013) I am well aware that the doses of BPA we are supposed to get from our "diets" is way below those that are uses in rodent studies like the one by Indumathi et al., but don't you think that it is still remarkable that the same plastic poison aka BPA that leaches so readily into the acidic brown soup 50% of the US citizens guzzle on a daily basis, induces exactly the same nasty reductions in insulin receptor and GLUT-4 transporter expression, as well as glucose oxidation and the phosphorylation of Akt which are currently still ascribed exclusively to the soda itself (see figure 1).

  

  Figure 2: Effects of 20 or 200mg/kg body weight of BPA on insulin receptor and Akt phosphorylation, GLUT-4 expression in skeletal muscle and systemic insulin and testosterone levels (Indumathi. 2013)

  Now what's worst is that these pathological changes are not likely to be observed, because it happens "silently"; i.e. in the absence of elevated blood glucose levels.
  Did you know that the amount of BPA that leaches from plastics increases by x40, when you dishwash and reuse them (Brede. 2003)? And worst of all, these figures were observed in baby bottles and thus objects those of us get in contact for whom the otherwise probably harmless exposure could actually be dangerous (DiVall. 2013). Exposure to higher temperatures of liquids in plastic containers in the summer (>40°C) is another factor which contributes to an increased leakage of BPA from the container into the liquid (Makris.2013)
  With the latter being the only blood parameters that are evaluated on a regular basis within at least a reasonably large cross section of the population it's no wonder that many of us don't see how the diabetic beast and the BPA castrator are sneaking up on them before it's already too late. Obviously no reason for the FDA or any other governmental body to even bother. Aside from the U.S. Environmental Protection Agency which has published a reference dose of 0.05 mg/kg/day for BPA in 1993 (IRIS. 1993) an official acceptable daily reference intake for BPA is still lacking. Even if the current research does not suggest that our daily exposure is high enough to actually do any harm, I would expect the reference levels to reflect that - what about you?

• 

  In 1998 the Consumer Union wrote a letter to the FDA compaining about "endocrine disrupting chemicals" in cheese and dairy in plastics wrappings. I wonder if they knew about the masked phtalates in hygiene products, as well.

  More news for the"Plasti-Nations" (various): A couple of days ago Wu et el. published a paper on the TSH and estrogen suppressive effects of phtalates in Taiwanese children. With >40% lower TSH levels and estrogen levels the changes, in the 4-5 year olds with the highest (500ppm) phtalate exposure from food stuff is alarming. The only good news is that it these changes appear to be reversible, when further exposure is avoided (Wu.2013).
  
  Apropos good news, in December 2012, Fierens et al. investigated the effects of cooking at home on the phtalate content of foods and found that, except for veggies, the phtalate content of almost all foods decline after cooking (Fierens. 2012). I guess, I don't have to mention that this is not going to happen in a crock pot unless you pour away the brew.
  
  What you should also keep in mind is that your diet is by far not the only way you are exposed to phtalates, as a group of scientists working at a University right around my corner elucidated (Koch. 2013). The "pro-breast cancer" monoethyl carboxylpentyl phthalates (MEPs) for example usually come from personal hygiene products (it's the stuff thats called "fragrance"). The dosage, by the way, was high enough for the scientists to be able to actually measure rises in MEP concentrations after people (esp. men, by the way) took a shower. Ah, and not to forget a non-negligible amount of the low molecular weight phtalates is simply with ubiquitous sources including dust and indoor air. Up to now convincing evidence for the role of this constant assault in any of the ailments our society is suffering from is not conclusive.

• Don't like oats? Buckwheat has similar benefits (Stringer. 2013) -- In a recently published paper in the scientific journal Metabolism, a group of researchers from the University of Manitoba in Winnipeg, Canada, reports that the consumption of buckwheat cracker either instead of rice crackers or simply on their own could help both diabetics and non-diabetics maintain a healthy weight.
  
  

  

  4x more iron, 3x more calcium, >9 times more magnesium, ~6x more potassium and about twice as much zinc, copper and manganese that's what buckwheat flour has to offer compared to wheat (de Francischi. 1994). If you like those figures, what about havin' one of the pancakes you see above (recipe)

  Yet, despite an increased satiety effect and improvements (increases / decreases) in the corresponding hormones glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP) and pancreatic polypeptide (PPY) the glucose response to the buckwheat crackers was not significantly different from the one the scientists observed after the consumption of rice crackers.
  
  What's intriguing, though is that it appears as if these effects were not exclusively fiber-specific. After all, the rice crackers had almost as much fiber as the buckwheat. Moreover, a 2003 study Kawa et al. confirmed that even fiber-free buckwheat extracts exert potent anti-diabetic effects, the researchers ascribed to the presence of d-chiro-inositol in the extracts (Kawa. 2003).

• Anabolic vibes - Vibrate your way to higher testosterone levels (Couto.2013) -- If you still believe vibrators were for women only you got to check out the latest issue of the International Journal of Sports Medicine, in which a group of Brazilian scientists reports that the use of one of those fancy vibration devices (20-Hz and 12-mm) during the lat pulldown induced greater increases in testosterone and lactate concentrations. Dunno if that will also work if you just swipe your girlfriends vibrator and honestly, I don't even want to know that ;-)

• Does the testosterone  and overall hormonal response to workouts even count, or are we still chasing a hormonal ghost? (Schoenfeld. 2013) -- In his latest review of the literature, Brad Schoenfeld who has been busy writing reviews on everything muscle heads are interested in within the last couple of weeks, picks the role of the endocrine response to exercise apart. In that, Schoenfeld points out that it is important to look close before you can tell whether or not a certain "hormone" will effect or even drive skeletal muscle hypertrophy.
  
  

  

  Check out this previous analysis of post-workout anabolism here at the SuppVersity (read more)

  There is for example ample evidence for the involvement of the muscle specific IGF-1 isoform IGF-1Ec, or its locally expressed splice-variant MGF and the presence of high and low responders (cf. West. 2012). Studies using its parent growth hormone, which used injections of the artificially produced recombinant growth hormone are of questionable value, since they lack the natural diversity of "growth hormones" (different GH peptides). Schoenfeld also points out that the evidence that testosterone is anabolic "is inconvertible" (Schoenfeld. 2013) and that the debate would thus have to center around its influence in the vicinity of a workout, where - and this is interesting - we actually know that the effects should occur only after the initial repression of androgen receptors is reversed.
  
  In accordance with what I have pointed out in the Intermittent Thoughts on Building Muscle Series Schoenfeld comes to the conclusion that it would be inappropriate to totally discard the importance of the endocrine response to workouts (IGF-1 & Co, in particular), just because it does not promote the (imho totally overrated) short term protein synthetic response to exercise:

  "Based on limited cellular signaling data, it is conceivable that the primary effect of post-exercise hormonal elevations is to increase satellite cell activity as opposed to mediating acute increases in muscle protein synthesis. If so, this could favor greater long-term increases in muscle hypertrophy without significantly impacting short-term gains." (Schoenfeld. 2013)

  Obviously (and rightly so) Schoenfeld concludes this paragraph of the discussion of this excellent review with the sentence "This hypothesis requires further study." -- And you bet, I will keep an eye on the topic in order to let you know whether the 8% of which West and Phillips say that it's the upper limit of the contribution the transient increases in endocrine hormones have on skeletal muscle hypertrophy (West. 2012) is an over- or underestimation.

• Excess magnesium is good for your testosterone levels, bad for your prostate and could potentially become fatal for your heart (Chandra. 2013) -- According to the latest results from a rodent study, it appears as if an excess intake of magnesium, ingested not as supplement but in form of magnesium sulfate in the chow, can boost testosterone levels by almost 30% (figure 1):

  

  Figure 1: Testosterone  levels prostate weight, luteinizing hormone and serum magnesium levels (all data expressed relative to baseline) after 15 or 29 days on diets with different magnesium content.
  

  The increase in testosterone does yet not come without downsides in the form of slight, but significant increases in prostate size as well as a profound increase in magnesium levels, which would - if they were observed in human beings already mark the early stages of hypermagnesemia. So, as important an adequate amount of magnesium in your diet may be, it should be obvious that 1.5% of the diet or ~350mg/kg magnesium sulfate and thus 35mg elemental magnesium per kilogramm body weight (the HED of the dosage that was administered to the rodents; ) is simply too much - honestly, I am surprised that the rodents did not get chronic diarrhea, anyway ;-)

Since a wise man facebooked me earlier today to keep the SuppVersity posts short on this weekend, spending some time idling around, in order to avoid ending up totally burned out (I wonder if that really was an all altruistic advice of him ;-), I will now do just that - cut it short; yet not without pointing you towards the SuppVersity Facebook Wall, which does - as every day - hold 6-10 new short news for you to read up on.
 

+++ Have a nice weekend, everyone! +++

References:

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• Chandra AK, Sengupta P, Goswami H, Sarkar M. Effects of dietary magnesium on testicular histology, steroidogenesis, spermatogenesis and oxidative stress markers in adult rats. Indian J Exp Biol. 2013 Jan;51(1):37-47.
• Couto BP, Silva HR, Filho AG, da Silveira Neves SR, Ramos MG, Szmuchrowski LA, Barbosa MP. Acute Effects of Resistance Training with Local Vibration. Int J Sports Med. 2013 Feb 26.
• de Francischi ML, Salgado JM, Leitão RF. Chemical, nutritional and technological characteristics of buckwheat and non-prolamine buckwheat flours in comparison of wheat flour. Plant Foods Hum Nutr. 1994 Dec;46(4):323-9.
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• Integrated Risk Information System (IRIS). Reference Dose (RfD): Description and use in health risk assessments. 1993 < http://www.epa.gov/ncea/iris/subst/0356.htm > 
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• Makris Kc, Andra S, Jia A, Herrick L, Christophi C, Snyder Sa, Hauser R. The Association Between Water Consumption From Polycarbonate Containers And Bisphenol-A Intake During Harsh Environmental Conditions in Summer. Environ Sci Technol. 2013 Feb 28.
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