Friday, March 29, 2013

Science Round-Up Seconds: All About Cortisol, Fat Loss, Body Composition and the Efficacy & Safety of 7-Keto & Co

Believe it or not. High dose hydrocortisone can decrease body fat levels (Babikian. 1962; see further down) and the acute administration of prednisolone has repeatedly been shown to have pronounced endurance performance (e.g. +61%; Arlettaz. 2007).
It's not like the Science Round Up was a request show, but I still want to start the Seconds to yesterday's installment of the show (download the podcast) with an honest an sincere apology to one of our listeners. Yeah, there is no debating, Carl and I had promised to talk about the "cortisol blockers can cause necrosis of the liver" study (Zou. 2013) and then simply forgot about it. I guess this was due to the unplanned "copper + HFCS = arrhythmia" excursion at the beginning of the show, but I don't want to give the impression I was looking for excuses here. Instead, I decided to make up for our negligence by taking the opportunity to go beyond simply answering the question whether the recently published data on the pro-necrotic effects of 11beta HSD reductase inhibition is a reason of concern for those of you have been taking respective products in the past and - as a bonus - discuss the effects of cortisol and cortisol inhibitors on body composition, in general.

All clear-signal - You are not going to die!

Let me answer the health related question first: I don't think there is reason to be concerned even if you've been using the 7-oxo's, -keto's and all the other caps and creams that are supposed to annihilate the "bad, bad" cortisol in the past. Due to the fact that Zou and colleagues did not use any of the common OTC supplements, but genetic ablation or UE2316, another 11beta-HSD that's commonly used in pertinent studies, it is not even certain that the DHEA-metabolites you can buy at every supplement store will produce identical / identically pronounced negative side effects.

From a previous installment of the Seconds (go back): Effect of estradiol (E2), DHEA and its metabolites 7-OXO & co on breast cancer cell proliferation (based on Miller 2012)
Since both the genetic ablation and the research drug the scientists used are working by inhibiting the same enzyme as the DHEA-metabolites that are sold as "cortisol blockers", it is yet almost sure that they would have the potential to do so.

That being said, the mere potential of hepatic necrosis, or even liver failure which would yet require the liver to be thoroughly beat up already,  should not be a problem for smart SuppVersity readers like yourself, anyway. After all, you do know about the janus-faced nature of cortisol, as well as its physiological importance and would therefore never try and annihilate this powerful fat solvent, right?

"Cortisol a fat solvent? What are you talking about?"

I know, for those of you for whom this is the first visit to the SuppVersity after years of being bamboozled by  conventional wisdom, it will probably sound crazy to call cortisol, "the fattening hormone" that's to blame for your belly and your skinny arms at the same time as a "fat solvent". So let's briefly take a look at what cortisol actually does.

Suggested read for the SuppVersity Freshmen (and -women ;-): Scientists cover 6 months contest prep of natural body builder who loses almost exlusively fat despite (or should I say due to?) +100% elevated cortisol and tanking testosterone levels (read more).
Firstly, cortisol is a profound anti-inflammatory. It does not cause inflammation, but rises in response to inflammation (the downside obviously are it's immuno-supressive effects). Secondly, cortisol is a glucocorticoid and makes sure that there is alway enough glucose floating around in your system by (a) digging into the fat and protein stores of your body to fuel your acute energy demands and (b) decreasing insulin release and sensitivity to spare glucose (Andrews. 1999).

While those of you who have already been "on" a cortisol inhibitor may have felt the negative sides of function #1 in their joints, few people acknowledge that the inhibition of cortisol and it's ability to increase the lypolytic rate (=release of fat) in adipocytes by 50% and more (Djurhuus. 2002; Cambell. 2011) could actually hamper, not accelerate weight loss while you are dieting.

There is no debating: Cortisol can be a mean bitch, but...

Now, the last four words of the previous paragraph are in fact what's making all the difference here. As long as you give your body the chance to actually burn off the fat that's getting pushed out of the fat cells by cortisol, the "beneficial" effects cortisol has on adipogenesis are nothing to be afraid of (Campbell. 2011). In the unfortunate case you are constantly stressed, overeating and chronically inflamed, however, the chronically elevated cortisol + insulin levels will however create a "perfect" obesogenic storm.

There is no conclusive evidence for the beneficial effects of OTC 11beta HSD inhibitors as fat loss adjuvants: Even in obese subjects and sponsored studies published in "author pays" journals such as Current Therapeutic Research, neither the body fat loss (p=0.41), nor the change in basal metabolic rate (p=0.86; not change in T3), or the fat free mass changes (p=0.39) were different between those subjects who dieted and exercised with a placebo and those who consumed a commercially available 7-keto supplement (Zenk. 2002). Against that background I was surprised when I was lectured earlier today by someone whose opinion I really respect that for him the use of the current #1 seller made a huge difference. How come? Well, if we also imply the results of the follow-up study by Zenk (Zenk. 2005), this time sponsored by iSatori where the multi-ingredient product Lean System 7 did prevent the drop in metabolic rate in obese (BMI ~33kg/m²) subjects, it would appear that the reason for the benefits are brought about by one or all of the additional ingredients, of which coleus forskohlii and piper nigrum are also part of the proprietary blend of the previously mentioned product. That the maintenance of a higher metabolic rate did yet not translate into increased fat loss and the subjects in the active arm actually los lean mass, while those in the placebo arm did not puts yet another question mark behind the "7-keto promotes body recomposition" hypothesis.
This storm is self-perpetuating as the chronically inflamed and ever growing visceral adipose organ, which contributes "approximately two-thirds [...] to splanchnic cortisol production in healthy men" (Andrew. 2005; the rest is produced in the liver), will spill out more and more cortisol. The cortisol, in turn will increase lipolysis and have the free fatty acid and triglyceride levels skyrocket. This, on the other hand, worsens the pre-existing insulin resistance, ... It's a vicious cycle and to my mind the only scenario where the interventional use of an 11beta-HSD reductase inhibitor like 7-keto & co could be a promising strategy.

If we do however take into account that the underlying cause of the pathological upregulation of the 11beta HSD reductase activity and cortisol production in the adipose organ is nothing but the well-known inflammation of the visceral fat stores that's not a consequence, but a in fact the cause of chronically elevated cortisol levels (Lee. 2013), it does not really seem to be prudent to manage the disease by targeting the well-meant (since anti-inflammatory) increase in cortisol. Any promising treatment (vs. management) strategy should thus aim at eliminating the underlying reasons of the inflammation, which are in 90% of the cases an obesogenic diet and a lack of exercise. And instead of supressing the downstream reaction to increased levels of TNF-alpha and its pro-inflammatory cousins with 11beta-HSD inhibitors, anti-inflammatory agents like curcumin, green tea and the like could be used to keep the inflammation while the underlying reasons are taken care of.

... cortisol also drives fat loss on a diet
I guess I don't have to remind you of the recently published SuppVersity article with the title "Scientific BB Contest Prep Coverage" (read more) and the skyrocketing cortisol levels of the subject in the pertinent study. What I guess may be worth mentioning again, though, is the fact that the impressive reduction of body fat to the sub-5% range did not take place despite, but at least in part due to this increase in our bodies' most powerful long-acting fat liberator (the catecholamines are the short-acting ones). A hormone, by the way, which supplied the body of the "starving" athlete with all the fats it needed to keep going in a situation the subject's body must have interpreted as a bad harvest that was accompanied by the disappearance of major parts of the local fauna. A situation which would have left our ancestors "looking for food" (=spending energy working out) all day, while still being rewarded with ~25% less than they would actually need to maintain their unaesthetic, but live-saving energy depots (=body fat).

So, if caloric deficit + diet + training + adequate protein + high natural cortisol = fat loss, you could suspect that using the synthetic glucocorticoids like hydrocortisone, prednisone & co should be a neat way to lose  body fat, right? Now, as surprising as this may sound this is in fact exactly what Levon G. Babikian did observe back in the 1960s, when he was able to show that medium and high dosages of 0.12mg and 0.18mg hydrocortisone per day lead to significant increases (medium dose), respetively decreases (high dose) in total and visceral body fat of mature male albino mice (a low dose of 0.09mg of hydrocortisone did not have any effect). And with a -30% total and -40% reduction in visceral body fat mass (not percentage!) those changes were not just statistically, but also physiologically highly significant. After all, the rodents in the high dose arm did thus have 2.4% less body fat than those in the control group (7.4% body fat vs. 10%).

"So does that mean that an increase in cortisol will get you ripped?"

Even if it were not for all the other nasty side effects (high blood pressure, immune suppression, loss of potassium, etc.), a high dose of hydrocortisone certainly ain't the "weight loss adjuvant of choice" for physical culturists who do not have a weight class as a ceiling to his / her overall body mass. After all, the impressive figures from the Babikian cannot hide the fact that it's not all fat mass you'd lose - despite statistically significant improvement in body fat percentage.

What about testosterone? Contrary to a Sep. 2003 1-week trial by Armani et al., where 7g of licorice lead to significant reductions in total (but not free!) testosterone, a larger scale 4-week trial with 100g/day of licorice containing 0.15% glycyrrhizic acid could not find any significant changes in sex steroid hormones (Sigurjonsdottir. 2005)
Against that background, it is somewhat surprising that the consumption of the 3g/day of licorice, a purported testosterone antagonist (see figure) and proven inhibitor of the oxidase of cortisol to cortisone and potentiator of glucocorticoid function (Whorwood. 1993; Asl. 2008), for 4 weeks lead to a ~2% reduction in body fat in 15 normal-weight subjects (7 males, age 22-26 yr, and 8 females, age 21-26 yr)  - and that in the absence of of prescribed or voluntary dietary restriction, exercise or overall weight loss (Armani. July 2003). Major side effect were not observed. The increase in extracellular water (5% in men and 1% in women) could yet obscure at least some of the beneficial effects, while you are actually "on" the glycyrrhizinic acid containing herb (whether the effects can be avoided if you keep an eye on adequate potassium intake has, afaik not been studied).

Promising fat loss results (2mm reduction in superficial tigh fat) have also been observed upon topical application of glycyrrhetinic acid, the main active ingredient in licorice, to the tighs of 18 healthy women (20-33 years) in a 2005 by the same Italian researchers. Still, despite the fact that this study used a glycyrrhetinic acid concentrate, we cannot exclude that part of the previously observed weight loss effects are brought about by non-cortisol amplifying components in licorice or the synergism of the latter with the inhibitory effects glycyrrhetinic acid exerts on the inactivation of cortisol.

Bottom line: As I already hinted at towards the end of the last paragraph on licorice, it's beneficial effects on fat loss, as statistical significant as they may be are about as dubious as the meager weight loss (not fat loss) effects in the sponsored 7-keto studies in obese individuals. Aside from the initial message that you probably won't whack your liver, if you use DHEA metabolites as cortisol blockers, the "bottom line" of the above treatise would be: In normalweight, healthy individuals, the use of agents DHEA metabolits to inhibit and skew the natural glucocorticoid metabolism for fat loss or body recomposition purposes is not supported by the currently available literature.

I did decide not to bore you with the issue of transient exercise induced cortisol and testosterone spikes in this article. If you want to learn more about that take a look at this, this (middle) and this (bottom) article. Without giving away too much in advance - this is another instance where the bad guy ain't necessarily as bad as you may have been told.
From a mechanistic perspective, it would even seem counter-indicated, especially in the context of low calorie and low carbohydrate diets, where the skyrocketing cortisol levels, the increase in lipolysis and the decrease in insulin release and sensitivity are actually necessary to maintain stable blood glucose levels by sparing the available glucose and providing enough fat as a substrate to fuel your daily energy demands. If this energy source ain't available any longer, the result is profound fatique (aka adrenal fatique) that will - regardless of all other metabolic effects certainly not help you shed body fat.

I don't want to exclude that certain individuals with whatever pre-existing cortisol issues can benefit from the use of these products, but as it was the case with Isatori's 7-keto product it is not unlikely that additional ingredients (for Lean System 7 these were yerba mate, guarana, citrus aurantium, coleus forskohlii, dandelion leaf, and piper nigrum) and/or the use of other supplements, as well as the concomitant diet and exercise programs people are following are responsible for the rave N=1 reviews some of these products get on the pertinent bulletin boards.

I mean, how will the authors of those reviews know they would not have seen the same effects without 7-keto and co. Everyone who is serious about improving his physique, will tell you that no two diets are the same and comparisons to previous diets are not necessarily objective. And finally, we don't want to forget the influence of sponsored logs, the "rep system" and the "brocebo effect" have on a trainees motivation (if you spend money, you want to make sure you made it right, after all it worked magically for X, Y & Z) and the perceived contribution the ingestion of a couple of pills had to his success, do we?

  • Andrew R, Westerbacka J, Wahren J, Yki-Järvinen H, Walker BR. The contribution of visceral adipose tissue to splanchnic cortisol production in healthy humans. Diabetes. 2005 May;54(5):1364-70.
  • Andrews RC, Walker BR. Glucocorticoids and insulin resistance: old hormones, new targets. Clin Sci (Lond). 1999; 96:513–523
  • Arlettaz A, Portier H, Lecoq AM, Rieth N, De Ceaurriz J, Collomp K. Effects of short-term prednisolone intake during submaximal exercise. Med Sci Sports Exerc. 2007 Sep;39(9):1672-8. 
  • Armanini D, De Palo CB, Mattarello MJ, Spinella P, Zaccaria M, Ermolao A, Palermo M, Fiore C, Sartorato P, Francini-Pesenti F, Karbowiak I. Effect of licorice on the reduction of body fat mass in healthy subjects. J Endocrinol Invest. 2003 Jul;26(7):646-50.
  • Armanini D, Bonanni G, Mattarello MJ, Fiore C, Sartorato P, Palermo M. Licorice consumption and serum testosterone in healthy man. Exp Clin Endocrinol Diabetes. 2003 Sep;111(6):341-3.
  • Armanini D, Nacamulli D, Francini-Pesenti F, Battagin G, Ragazzi E, Fiore C. Glycyrrhetinic acid, the active principle of licorice, can reduce the thickness of subcutaneous thigh fat through topical application. Steroids. 2005 Jul;70(8):538-42. Epub 2005 Apr 12.
  • Asl MN, Hosseinzadeh H. Review of pharmacological effects of Glycyrrhiza sp. and its bioactive compounds. Phytother Res. 2008 Jun;22(6):709-24. doi: 10.1002/ptr.2362. Review.
  • Babikian LG. Effect of Hydrocortisone, Corticosterone, and Cortisone on Visceral and Total Body Fat in Albino Mice Physiological Zoology. 1962; 35(4):314-322.
  • Lee JH, Gao Z, Ye J. Regulation of 11β-HSD1 Expression during Adipose Tissue Expansion by Hypoxia through Different Activities of NF-kB and HIF-1α. Am J Physiol Endocrinol Metab. 2013 Mar 19.
  • Kerstens MN, Riemens SC, Sluiter WJ, Pratt JJ, Wolthers BG, Dullaart RP. Lack of relationship between 11beta-hydroxysteroid dehydrogenase setpoint and insulin sensitivity in the basal state and after 24h of insulin infusion in healthy subjects and type 2 diabetic patients. Clin Endocrinol (Oxf). 2000 Apr;52(4):403-11.
  • Sigurjonsdottir HA, Axelson M, Johannsson G, Manhem K, Nystrom E, Wallerstedt S. Liquorice in moderate doses does not affect sex steroid hormones of biological importance although the effect differs between the genders. Horm Res. 2006;65(2):106-10.
  • Whorwood CB, Sheppard MC, Stewart PM. Licorice inhibits 11 beta-hydroxysteroid dehydrogenase messenger ribonucleic acid levels and potentiates glucocorticoid hormone action. Endocrinology. 1993 Jun;132(6):2287-92.
  • Zenk, JL, Tami RH, Laurie JK, and Michael AK. The effect of 7-Keto Naturalean™ on weight loss: A randomized, double-blind, placebo-controlled trial. Current therapeutic research. 2002; 63(2): 263-272.
  • Zenk JL, Leikam SA, Kassen LJ, Kuskowski MA. Effect of lean system 7 on metabolic rate and body composition. Nutrition. 2005 Feb;21(2):179-85.
  • Zou X, Pellicoro A, Aucott R, Ramachandran P, Clarkson M, Webster1 SP, Iredale JP, Walker BR, Michailidou Z. 11βHSD1 deficiency increases susceptibility to liver fibrosis by activating hepatic stellate cells. Endocrine Abstracts. 2013; 31(P315)