Tongkat Ali Boosts Testosterone in Late Onset Hypogonadism: 200mg of Standardized Eurycoma Longifolia Extract Increases Total Testosterone by 47%

Image 1: Let's hope no one uproats
and steels this flowering plant from
the family Simaroubaceae after reading
about its testosterone boosting effects ;-)

Kudos to Benson, who certainly is one of the Minds on the Mind And Muscle Forums (I don't know about his muscle, though ;-). Benson dug up a very recent article on the effects of "Ali's Stick" (Tambi. 2011), which would be the literal translation of "Tongkat ali", also known as the "Malaysian ginseng", a herb that has been used by generations of men in South-East-Asia to improve their sexual performance, on testosterone levels in 76 male patients suffering from late-onset hypogonadism (LOH) and, consequently, Aging Males' Symptoms (AMS).

The study that is going to be published in the next issue of Andrologia, the first international journal of andrology, was conducted by an international team of scientists from Malaysia and South Africa. For their study Tambi et al. recruited a group of initially 350 patients, who were treated at the Wellmen Clinic at Damai Service Hospital in Kuala Lumpur for late-onset hypogonadism (LOD; mean initial testosterone levels: 5.66 nM) and Aging Males' Symptoms (AMS; mean initial score: 38.05 - higher values = more severe symptoms). The men were treated with 200 mg (two capsules with 100 mg) of a patented, highly standardized water-soluble extract of Tongkat ali (produced by Phytes Bioteks, Biotropics Malaysia, patent number: WO0217946) for 4 weeks, after which both serum testosterone tests, as well as AMS questionnaires were repeated. In the 76 patients who actually completed the trial (cf. discussion of drop out rate at the end of the post)

[...] treatment of LOH patients with this Tongkat ali extract significantly (P < 0.0001) improved the AMS score as well as the serum testosterone concentration. While before treatment only 10.5% of the patients did not show any complaint according to the AMS scale and 35.5% had normal testosterone levels, after the completed treatment 71.7% and 90.8% of the patients showed normal values, respectively.

Quite impressive results for a traditional aphrodisiac. And at first sight, the data on mean, minimal and maximal testosterone levels before and after treatment (figure 1) would corroborate this impression.

Figure 1: Mean, minimal and maximal total testosterone levels of 76 patients with late-onset hypogonadism before and after treatment with 200mg of a patented, standardized Tongkat ali extract for 4 weeks (data adapted from Tambi. 2011)

Unquestionably, Eurycoma Longifolia Jack would make a great addition to the post cycle therapy of drug using athletes and gymrats. Having shut down their natural testosterone production due to the administration of exogenous testosterone or other quasi-hormonal compounds, many steroid users find themselves in a situation of self-inflicted "early-onset" hypogonadism, when they finally come off their steroid cycles. In these circumstances, which closely resemble LOF, "Ali's stick" may well help to bring the endogenous hormone production back to "normal".

Figure 2: Illustration of the hormonal
production line (by Slashme and
Mikael Häggström; Wikipedia)

Whether the average non-steroid-using gymrat in his early to late twenties would see any benefits does yet remain to be elucidated. Notwithstanding, the results of Ali & Saad from 1993 (unpublished dissertation, cited by Tambi), which suggest that the eurypeptide, the purported active ingredients in the extract, accelarates the hormonal production line at its very beginning, by enhancing CYP17 (17 α-hyroxylase/17, 20 lyase) enzyme activity. Thus boosting "the metabolism of pregnenolone and 17-OH-pregnenolone to yield more dehyroepiandrosterone (DHEA)", progesterone and 17-OH-progesterone appropriate amounts of the alkaloids, quassinoids, quassinoid diterpenoids, eurycomaosides, eurycolactones, laurycolactones and eurycomalactons from Tongkat ali could eventually facilitate an increase in total testosterone via conversion of the former into 4-androstenedione and testosterone.

It is however more than questionable whether the total testosterone levels of otherwise healthy men would likewise increase by +45%. And even if they did - will you notice the difference? Well, do not expect too much apart from an increase in libido, for we do not know how much of this testosterone is actually free, how the accelaration of the hormonal production line will affect other hormones and binding globolins, etc. Accordingly, you can hope for beneficial effects on athletic performance and/or body composition, yet they are by no means guaranteed - I would not even say "probable".

All that being said, there is another major drawback that comes with the high dropout-rate of >76% (!) While the scientists don't comment on the reasons for the dropouts, you may well ask yourself, "Why would a guy who experiences major improvement in the sexual department stop using the very medication that is triggering these improvements?" Well, I guess he would not. So, let's play devil's advocate and assume that the testosterone level of the rest of the men did not budge at all (it could well be that due to whatever mechanisms it may even have dropped). 

Figure 3: Total testosterone levels before and after treatment for all patients who initiated treatment assuming that that the >75% dropouts did not see any benefits in testosterone (data extrapolated from Tambi. 2011)

In figure 3 I have plotted how the data would like under that assumption. There would still be an increase of 11%, 16% and 20%, for mean, minimal and maximal total testosterone levels, respectively. With a standard deviation of 1.51mM (=27%) and 2.46mM (30%), before and after treatment. Yet, these increases would hardly be significant. You better keep that in mind before you google a source for the patented Tongkat ali extract from Phytes Bioteks (using a non-standardized extract or whole stems, is not likely to work, anyway) and spent your hardly earned bucks into hopes of a jacked physique and animalistic sexual performance. If you insist on trying it, make sure you get enough cholesterol in your diet to feed the process of steroidogenesis (cf. figure 2)

Chest Fat, Bitch Tits, Chesticles, Gynecomastia, Lipomastia and Co.: Infinite Ways to Name it, 45 Ways to Prevent It

Image 1: Luckily "gyno", or in this case lipomastia, does not always look that bad. Oftentimes it is more subtle, yet still annoying a psychological burden for men suffering from it. This pictures alone should be reason enough to give all the 45+ contributing mentioned in this article a wide, wide berth (image from  cosmeticsurgerybangalore.com)

If you type "gynecomastia" into your favorite search engine, your chances to find one of the major fitness and bodybuilding forums among your first hits are about 99%. This indicates that gynecomastia, lipomastia, "bitch tits", "fat tits" and whatever else many people use to measure by the same yardstick is much more prevalent than you would think if you conducted a survey on the street. The reasons for that are manifold. Men, who frequent those bulletin boards are oftentimes more conscious about their looks than Mr. Average, they are also more prone to be exposed to exogenous hormonal agents that can contribute to the development of the aforementioned unaesthetic pathologies. Most importantly, though, gynecomastia is something you don't talk about. You have it, you suffer, but you don't talk publicly about it - after all, that would just make you even more unmanly! Right? No, false! Utterly false!


In fact, the widespread implicit understanding that the above statement was right is a damn good reason for me to do the opposite and talk, or rather write about causes (today's installment) and ways to get rid of this humiliating condition (next installment updated!).

Why does my chest look like that, god damnit?

According to the currently accepted scientific paradigm, gynecomastia is a result of hormonal imbalances; mostly an overabundance of estrogen, which stimulates the glandular tissue of the male breasts and thus contributes to its growth and, in some cases, cancerous degeneration. The underlying reasons for these imbalances, on the other hand, are manifold and only partly understood. And while we will have a closer look at numerous individual factors in the following paragraphs, exogenous estrogens and estrogen like substances, an increased metabolism of androgens and an inhibition of the degradation of estrogens in the liver are probably the worst offenders (if you are interested in male health, I highly recommend, you also last week's article on "Natural Hormone Optimization: 10 Things to Avoid for Optimal Androgen Levels").

"Prolactin gyno" - does it exist? Although I suspect that >60% of the "prolactin gynos" you read about on the pertinent bulletin boards are in fact mediated by high estrogen levels, there is scientific evidence for the occurrence of abnormal tissue growth in patients with prolactin-secreting tumors (Giminez-Roqueplo. 1999) - it thusly appears possible that compounds which either interact directly with the respective receptors or the administration of which will produce abnormally high prolactin levels, could lead to the development of gynecomastia in men. In view of the antagonistic relationship of prolactin and dopamine and the complicated interactions between dopamine and testosterone levels, it is yet well possible that this is just another instance of hypogonadism, in this case as a result of elevated prolactin and suppressed dopamine production.

These imbalance do not inevitably lead to an actual increase in breast tissue, though. Minor imbalances or chronic low exposure to synthetic or natural estrogens / estrogen-like compounds will often produce a general often subtle feminization of the male body, which is accompanied by an increased deposition of body fat in the chest area. In more severe cases, this can be a very pronounced accumulation of dense adipose tissue right under and around the nipples. And while these pseudo-gynecomastias or lipomastias may be totally benign, the humiliating "chest fat" is oftentimes just a companion or forerunner of pathological changes in the neighboring breast tissue.

A necessarily incomplete overview of the worst offenders

In the following overview that does not make any claims of being complete, I will thus not even try to make predictions like "... is more likely to cause lipomastia" or "... will rather induce gynecomastia". Moreover, you should also keep in mind that all of the pathologies, drugs and supplements can contribute to the development of gynocomastia, lipomastia and plain "chest fat", yet none of them, not even those for which a causal relationship has been established, will inevitable lead to the growth of the highly unaesthetic and potentially hazardous tissue overgrowth in the chest area!

Pathologies / diseases that are commonly associated with abnormal fat deposition, lipomastia and gynecomastia in men:

• Hypogonadism - Often but not always characterized by increased FSH, LH and SHBG levels and decreased total and free testosterone, as well as DHEAS levels; one of the most common non-environmental / drug-related reasons is Klinefelter' syndrome, a condition in which men have an extra X chromosome and which is usually associated with hypogonadism and reduced fertility (Yazici. 2010)
• Obesity - Obesity can contribute to the development of gyno- and even more lipomastia. In that it is not certain whether it is just a corollary factor with hypogonadism as the common denominator, or contributes directly to the development of unaesthetic and/or pathological changes in the breast tissue through an increased aromatization of testosterone into estrogen in the abundant adipose tissue (Wake. 2007)
• Liver cirrhosis - A cirrhotic liver (either due to alcohol or NAFLD) cannot metabolize the sex steroids properly. This does often result in low free testosterone and high estrogen levels, which can cause increases in chest fat or an enlargement and / or cancerous growth of the breast tissue (Cavanaugh. 1990). Similar effects could by the way arise from the (over-)use of supplements, such as berberine, quercitin, naringine, piperine, schisandra etc., which mess with the cytochrome P450 cascade, an enzymatic cascade that is responsible for metabolizing drugs and hormones (e.g. Gurley. 2012; Guo. 2012; Ho. 2000).

While the former were more or less "organ-related" causes of gynecomastia, the following list contains a handful of drugs that have scientifical evidence to back their causal involvement in the etiology of gynecomastia:

• Anabolic steroids & prohormones - Either due to increased estrogen levels on cycle, hormonal shut-down and hypogonadism or hormonal imbalances after the cycle, use of compounds that have the potential to induce gynecomastia in PCT (see "hormonal agents" in list below) or (possibly) direct or indirect effects on prolactin (see red box above)
• Other endocrine agents - Bicalutamide, Diethylstilbestrol, Dutasteride, Ethinylestradiol, Finasteride, GnRH, Goserelin, Leuprorelin
• Drugs for gastrointestinal disorders - Metoclopramide
• Diuretics - Spironolactone

In view of the fact, that most people will be aware of the dangers, it yet questionable in how far the commonly overlooked / largely unknown drugs and other offenders with less, but still existend scientific evidence to bolster their involvement in the development of abnormal fat deposition, lipomastia and gynecomastia in men do not pose a much greater threat. You should thus better beware of these:

• Statins - Roberto et al. report a significantly higher incidence in male gynecomastia among statin users (Roberto. 2012). Interestingly, the relative increase in risk correlated with the ability of the respective drug to inhibit HMG-CoA, or, if you will, it's potency. Intriguingly, gynecomastia is rarely mentioned as one of the myriad of potential side-effects of statin treatment, although the non-corrected incidence rate in the database records Roberto et al. analysed was 1/68 - with 25% of the US population in the 45+ age range being "on a statin", this would translate into roughly 1Mio! cases of statin unduced gynocomastia among the baby boomer generation, alone (this calculation assumes that there are ~70Mio babyboomers, which would be in accordance with data from census.gov). You should also keep in mind that if statins can do that supplements, like red yeast rice, which is actually nothing but a natural statin, are likely to be able to induce gynecomastia, as well.
• Proton pump inhibitors - Omeprazole, Ranitidine & co.
• Antineoplastic agents & Calcium channel blockers - Estramustine, Imatinib, Mandipine, Nicardipine, Nisoldipine, Nitrendipine
• Antivirals & -mycotics - Didanosine, Efavirenz, HAART, Indinavir, Ketoconazole, Nevirapin,
• Lipid modifying drugs - Bezafibrate
• Diuretics - Eplenerone, Bumetanidine
• Hormonal agents - Chlormadinone, Clomiphen, Cyproterone acetate, Follicle-stimulating hormone, HCG, Medroxyprogesterone acetate
• Immunosuppressants - Cyclosporin
• Psychoanaleptics & Psycholeptics - Fluoxetine, Haloperidol, Olanzapine, Risperidone, SSRIs, Sulpiride

Despite the fact that for many of these drugs the exact mechanisms have not yet been elucidated, it is likely that in most cases their "pro-gyno effect" is a downstream result of impairments of the HTPA (hypothalamic-thyroid-pituitary-axes), liver function or both and thus eventually mediated by the same fundamental hormonal imbalances that were discussed in the second paragraph of this article.

Prevention is #1, but sometimes treatment is inevitable

Even if you don't have a plenty of skeletons in your closet, no history of legal or illegal drug abuse, no diet-induced NAFLD, are lean, don't use truckloads of useless supplements etc., puberty and "bad genes" alone could have left you with a batch of unwanted tissue in a place where it certainly does not belong. In this case, avoiding all the 45+ aforementioned factors may help not to make things even worse, it will yet not make those ugly little bastards disappear over night; and I guess that alone should be reason enough to come back for part II of this series, in which we are going to take a look at potential treatment strategies - including, but not limited to classic surgical interventions.

Tongkat Ali - Malaysian Viagra W/ Anti-Belly Effect: More Than 30% Reduced Omental Fat Pad Size + Corresponding Increases in Testosterone W/ Human Equiv. of 4g+/Day

It's efficacy in situations like this has more scientific back-up than any of the muscle building of fat burning promises some Tongkat Ali supps come with.

By now, most of you should have read the article on the testosterone "boozing" effects of alcohol and realized that the post workout Margarita probably comes off second best, when we compare it to whey and may - at least until we don't know otherwise - actually be pathological (=the result of a disturbance of the normal hormone metabolism in the liver). That being said, we better go back the "tried(!) and proven(?)" stuff. I mean a herb that goes by the name "Long Jack" does already sound way more promising than a "Blood Mary" doesn't it?

"Long Jack? ;Malaysian viagra? Ok, I am in!"

As the popular name already implies, the root of Eurycoma longifolia Jack, an evergreen plant that belongs to the family Simaroubaceae has a long (all puns intended) tradition in folk medicine. For which purposes? Well, in Malaysia, where people obviously like it a little more explicit, it's called "Tongkat Ali" (TA) and means (literally translated) "Ali's walking stick"... if that ain't explicit enough for you, just call it the "bushman's viagra", or whatever you like.

What's interesting and important to know though is that medicinal value highly of the root extract depends on the soil the plant was grown on. Tongkat Ali from the Malaysian Peninsular, for example, has higher concentrations of phytochemical compounds, such as eurycomaride, tannins, high molecular weight polysaccharides, glycoproteins, mucopolysaccharides and alkaloids of the quassinoid group, than TA from Thailand, Vietnam or Indonesia (Jiwajinda. 2001; Miyake. 2009). This is an important fact to keep in mind, when you buy your TA and a potential reason why you (a) may require way higher dosages than science would suggest to see any effect or (b) may not experience any of the benefits you may have hoped for (e.g. raging libido, increased testosterone and, as you are about to learn in today's article, loss of belly fat).

"Did I hear fat loss?" Yeah, you did!

I have to concede, the hitherto unrecognized fat loss effects Solomon et al. report in their latest paper that's about to be publishe in the peer reviewed journal andrologia were actually the main reason the 14-day rodent experiment the South African researchers conducted eventually made it into the SuppVersity news. The meager testosterone increase of +30% alone doesn't give me a kick, at all. I mean there are way more potent natural testosterone boosters out there that don't exert any beneficial downstream effects on your physique. So why should we bother?

Figure 1: Relative (in % of pre values) body weight, testes weight, prostate weight, weight of the epididymal and omental fat pads, the gastrocnemius muscle and the testosterone levels of the rodents after 14 days on the high or low dose of the extract (

And in fact, the 5.7% reduction in body weight the rodents in both the low (200mg/kg) and high dose (800mg/kg) arm of the study experienced would be quite the opposite of what you'd usually expect as a downstream effect of increased testosterone levels in otherwise healthy rodents. With a statistically significant increase in sperm vitality in the low dose and a less pronounced statistically non-significant increase in sperm vitality in the high dose group, as well as the highly significant increases in sperm count in both groups, it is yet very unlikely that the already small amount of body weight the rodents lost in the course of the 14-day experiment was a sign of toxicity or whatever.

What's more likely is that the overall weight loss effect is simply the result of the highly significant -31.9% reduction in omental and probably other not explicitly measured body fat (not the epididymal fat, i.e. the fat around the reproductive organs, though).

"How much of this stuff do I need?"

Don't be fooled: The testosterone and libido boosting effects we see in the study at hand is something dozens of other herbs can do as well, thin of the study on Nigella Sativa from one of the past installments of "On Short Notice", for example.

Provided you can get your hands on a correspondingly potent extract, it probably would not be necessary, and certainly a waste of valuable ressources to take more than the low dose regimen (HED 4g/day) , which is, compared to what we have hitherto seen in human trials, still hilariously much.

For the fertility part of the equation, way smaller doses of as little as 300mg of a freeze dried water extract from TA (brandname Physta(R)) have shown quite astonishing results in a group of 30-55 year old male subjects who achieved a 44.4% higher sperm motility, 18.2% higher semen volume and subjectively improved erectile performance after 12-weeks on this commercially available product (Ismail. 2012).What you should at least keep in mind though is the fact that financing of the study was provided by Biotropics Malaysia Berhad, the producer of Physta.

Similar fertility related results were also reported by Tambi et al. in 2010 (another "proprietary extract" ;-) and a handful of older and in some cases non-peer reviewed studies. As far as more physical culture related effects are concerned, a recent review by Chen et al. concludes that

"Eurycoma longifolia Jack, or 'tongkat ali', has not appeared to elicit any ergogenic effect on endurance performance in a limited number of studies of these herbs. However, future studies of this herb are definitely warranted because there might be a dose-dependent response and the supplementation duration of the previous studies might have been too short." (Chen. 2012)

It would therefore appear as if TA was more of "classic" libido & testosterone booster than an ergogenic. Something like tribulus and maca and just as those two probably of very dubious usefulness for young athletic men in the prime of their reproductive years.

---

Bottom line: That being said, Long Jack could be worth a try for everyone with already (or temporarily ;-) reduced testosterone levels, at least if we trust the judgement of Tami et al. who conclude their 2012 study into the effects of 1 month on 200g of a water-soluble TA extract with the words: "The standardised water-soluble extract of Tongkat ali proved to be a suitable herbal supplement in overcoming symptoms of LOH [late onset hypogonadism]." (Tambi. 2012)

The veterans among the SuppVerity readers may remember that I also covered the 2012 study by Tambi et al. on the usefulness of TA for men hypogonadal men (learn more)

If you still insist to try it, you should keep an eye on the eurycomanone and 13α(21)-dihydroeurycomaone content of whatever product you are buying, because these are the two fractions which will increase LH and FSH production and are thus probably responsible for jacking up your testosterone and sperm production (Low. 2013).

What? You cannot find a product that's standardized for those? Not even a supplement producer losing a word about their existence? Well, that's how this business works. Cite the studies and discard all the nasty details you don't like...


References:.

• Chen CK, Muhamad AS, Ooi FK. Herbs in exercise and sports. J Physiol Anthropol. 2012 Mar 8;31:4. doi: 10.1186/1880-6805-31-4. Review.
• Ismail SB, Wan Mohammad WM, George A, Nik Hussain NH, Musthapa Kamal ZM, Liske E. Randomized Clinical Trial on the Use of PHYSTA Freeze-Dried Water Extract of Eurycoma longifolia for the Improvement of Quality of Life and Sexual Well-Being in Men. Evid Based Complement Alternat Med. 2012;2012:429268.
• Jiwajinda S, Santisopasri V, Murakami A, Hirai N, Ohigashi H. Quassinoids from Eurycoma longifoliaas plant growth inhibitors.Phytochemistry. 2001; 58:959–962
• Low BS, Das PK, Chan KL. Standardized quassinoid-rich Eurycoma longifolia extract improved spermatogenesis and fertility in male rats via the hypothalamic-pituitary-gonadal axis. J Ethnopharmacol. 2013 Feb 13;145(3):706-14.
• Miyake K, Tezuka Y, Awale S, Li F, Kadota S.Quassinoids fromEurycoma longifolia. J Nat Prod. 2009; 72:2135–2140. 
• Solomon MC, Erasmus N, Henkel RR. In vivo effects of Eurycoma longifolia Jack (Tongkat Ali) extract on reproductive functions in the rat. Andrologia. 2013 Mar 6.
• Tambi MI, Imran MK. Eurycoma longifolia Jack in managing idiopathic male infertility. Asian J Androl. 2010 May;12(3):376-80. doi: 10.1038/aja.2010.7. Epub 2010 Mar 29.
• Tambi MI, Imran MK, Henkel RR. Standardised water-soluble extract of Eurycoma longifolia, Tongkat ali, as testosterone booster for managing men with late-onset hypogonadism? Andrologia. 2012 May;44 Suppl 1:226-30.

Intermittent Thoughts on Building Muscle: Understanding the "Big T" - Testosterone Programs Stem Cells to Become Muscle not Fat + Keeps Satellite Cells & Motoneurons Alive

Image 1: Graphical summary of the probably best known function of testosterone - including who are not so "profane" as building muscle and getting ripped ;-)

In the last two installments of the Intermittent Thoughts, I have tried to convey a realistic perception of what exactly the effects of both supra- (that is below) and super- (that is above) physiological (that is "normal" in the sense that they represent the "average" male human being) levels of testosterone on body composition are. In this installment of the series I am now going to provide more information on the "exact" molecular underpinnings by which testosterone works its muscle building and fat burning magic. There is however one thing related to data I presented in the previous installments, I want to emphasize again: The use of a testosterone enanthate in the Bhasin study makes it very difficult to use the data to make prognoses with regard to the results you would see, when you use natural (or unnatural) supplements to raise the endogenous (produced by your testes) production of testosterone. And although there are certainly dozens of factors that would preclude respective inferences, I am going to address only those three, of which I believe that they are the most significant ones.

Three things to keep in mind, when you interpret the data from the last installment(s):

1. With testosterone enanthate having a ~4-5 day half-life, the testosterone levels, which, in the Bhasin study, were measured on day 7 after the injection, represent only a <50% remainder of the testosterone levels we would see within 24 hours post injection.
   

   

   Figure 1: Hypothetical serum testosterone levels in the course of the first seven days after the injection of endogenous testosterone (blue) compared to the regular diurnal rhythm (green) and the levels in response to a pretty potent (+70%) natural testosterone booster (red; all data has illustrative value, only)

   In spite of the fact that the data in figure 1 is obviously not based on "real" experimental data, I hope that by taking a brief look at the ratios of the areas under the curve of the
   
   
   • "normal" testosterone level with its ~40% daily variation (green), the...
      
   • +70% (maximally) naturally boosted testosterone level (red) and a ...
      
   • testosterone enanthate injection (blue),
      
   all of you will understand why the "muscle building / fat burning" effects of a +70% boost in testosterone from whatever OTC product you may be taking can hardly compare to injectable testosterone.
    
2. Another aspect that should be taken into account is the non-existent sex hormone binding globulin (SHBG) response in the Bhasin study, due to which the relative increases in bound and free (=unbound and purportedly "active") testosterone were identical. This can, but does not necessarily have to be the case, when you raise your testosterone levels "naturally". In that, the aromatization of testosterone to estrogen, appears to be one of the major correlates (I am deliberately not speaking of "causation" in this context) of increases in SHBG. In the worst case, you could thusly "boost" your total testosterone and end up with less free test due to a (possibly estrogen induced / related) increase in SHBG. That being said, I know a hand full of cases, where the exact opposite is the case. Especially very lean (yet still muscular) men tend to have low SHBG levels, so that despite "low-normal" total testosterone many of them have normal-high or even very high free testosterone levels.
    
3. The last factor that makes a direct quantitative comparison of the effects "naturally" and "artificially" elevated testosterone levels questionable, to say the least, is the absence of the natural diurnal rhythm with exogenous testosterone administration. In the course of 24h the testosterone levels fluctuate by +/-40% with a spike in the morning (around 6-7am) and a trough in the early evening. Contrary to the "artificially enhanced" testosterone levels, the ones on the printout from your lab thusly represent either the daily max (if the blood was drawn early in the morning), an average (blood drawn around noon) or the nadir (blood drawn in the evening) of your 24h testosterone level.
   Just as an aside: Imagine you wanted to sell a "natural test booster". What would be the best way to get a "clinically proven" rise in testosterone? Right! You just get your "study" participants tested in the evening for baseline and in the morning for post-intervention levels and *bang* you got your "clinically proven" +40% increase in testosterone ;-)
   And even if you managed (by whatever means) to "naturally" raise your testosterone to a level that you would "on average" have +200% the natural negative feedback mechanism (inhibition of luteinizing hormone (LH) release) will soon put an end to your thusly short-dated testosterone boost.

All that does yet not change the observation we have made in the first installment of this (hitherto) three-part series about the effects of testosterone on skeletal muscle hypertrophy: Testosterone builds muscle! The underlying physiological processes, however, are not fully elucidated. The brief summary I have put together in the following paragraphs is thusly a "work in progress" not only because I am still trying to figure out "how testosterone works", but also because the complex interplay of hormones, protein signalling cascades and key players of the immune system simply has not been fully elucidated, yet.

Direct effects of testosterone on muscle cells

I don't know if you have ever heard the name "Vida", if not, then you have probably not delved into the depth of bro-scientific steriodology. Julius A. Vida's book Androgens and Anabolic Agents was published in 1969 is what some people would call the "steroid bible". It contains information about the structure and biological activity of 666 different steroids.

Figure 2: Scan from Vida's book showing data on the androgenic and anabolic activity of 19-Nortestosterone (Nandronole, aka DECA) from a rodent model.

With the latter being of particular interest for roid / pro-steroid producers and consumers, scans of the tables, that make up a good part of the original book can be found on bulletin boards all over the Internet (cf. figure 2). Vida obtained the data from rodent studies and estimated the "anabolic" effect of the tested compounds based on the hypertrophy response of the levator ani muscle of his lab animals. Now, you may rightly ask yourself, how that relates to the topic at hand... well, the reason Vida (and most other researchers) chose the levator ani muscle as a benchmark is its high responsiveness to androgens, because it has a much greater androgen receptor (AR) density than the most of the skeletal muscle you are probably trying to build, when you are at the gym (well, I assume you don't train the levator ani, do you? ;-).

Image 2: The levator ani muscle is especially prone to androgen induced hypertrophy, because it has a particularly high amount of androgen receptors. Whether this is something you are particularly happy about or not, does not matter, in 99% of the cases that you read about the "anabolic activity" of a given "designer steroid", the latter is usually provided relative to the testosterone-induced hypertophy response of this muscle.

Interestingly, the areas of the muscle with the highest androgen receptor expression are the myonuclei and the satellite cells. You know both of them from previous installments of this series and will certainly remember that the recruitement of new myonuclei from satellite cells was a necessary prerequisite for continuous muscle growth, because with ever-increasing myonuclear domain sizes, the muscle will eventually become disfuctional (cf. "Growing Beyond Limits"). It is thusly likely to assume that, next to IGF-1, testosterone provides a second, secondary or complementary growth stimulus to the otherwise quiescent satellite cells. From the fact that the subjects in the Bhasin study exhibited a marked hypertrophy response in the absence of adequate training stimuli, we may also further conclude that the action of testosterone, contrary to the previously discussed locally expressed IGF-1 splice variants (cf. MGF & Co), does (at least up to a certain degree) not depend on muscle damage / strength training. The results of a 2005 study from the Human Performance Laboratory at the University of Connecticut (Kraemer. 2005), which found a -46% reduction in androgen receptor expression in response to volume (not single set, though) training, would even suggest, that testosterone takes a backseat, whenever the MGF-pathway is doing its muscle building job.

Whether the latter, i.e. testosterone's job in building muscle, is identical to the one of IGF-1 and its splice variants is debatable, anyways. After all experiments with isolated bovine satellite cells have shown that incubation with the synthetic androgen trenbolone lead to dose-dependent increases in protein synthesis and decreases in protein degradation (Kamango-Sollo. 2011). The function of testosterone could thusly be to maintain myoblasts (=progenitor cells) in the proliferate state - or, put more simply, testosterone keeps the satellite cells alive and ready to be incorporated into the muscle, whenever this becomes necessary.

Testosterone turns potential fat into muscle

Despite the fact that the muscle building effects of testosterone are at the heart of this series, I guess that you were similarly impressed by the effect the administration of graded doses of testosterone enanthate had on the body fat levels of the subjects in the Bhasin study. One possible explanation for this effect would certainly be the increased energy demands of the additional skeletal muscle mass. This alone can however hardly explain the profundity of the negative effects Bhasin et al. observed in the low and very low dose testosterone enanthate groups.

Figure 3: Relative change in lean and fat mass in response to changes in serum testosterone levels; the green area indicates "normal" = physiological testosterone levels; the asterisks (*) denote statistically significant (p < 0.05) changes vs. baseline (calculated based on Bhasin. 2001)

I mean, if you take a close look at the data, even the low-dose groups effectively gained some muscle mass (<2% and statistically non-significant). A loss of skeletal muscle mass thusly cannot explain the 18-37% increase in fat mass (cf. figure 3). In a subsequent publication Bhasin et al. thusly propose a - I may say quite exciting - alternative explanation for this and similar observations in hypogonadal men (Bhasin. 2004):

[...the] reciprocal change in lean and fat mass induced by androgens is best explained by the hypothesis that androgens promote the commitment of mesenchymal pluripotent cells into myogenic lineage and inhibit adipogenesis through an androgen receptor mediated pathway.

This priming effect testosterone has on the "universal" stem cells from connective tissue would not only result in a greater amount of stem cells that are to become muscle cells (in other words: satellite cells), testosterone would also reduce the amount of "future adipocytes" and thusly inhibit the formation of new and the replenishment of apoptotic, i.e. dead, fat cells. This hypothesis is corroborated by  recent findings of Semirale et al. who report that reduced visceral and subcutaneous fat accumulation with a reciprocal increase in lean mass in male mice with targeted androgen receptor over-expression in mesenchymal stem cells (Semirale. 2011).

The role of testosterone in the mind-muscle connection

Its effect on the actual muscle cells and their progenitors aside, testosterone also binds to the androgen receptors on the motoneurons that innervate the muscle. Interestingly, the death of these motoneurons, is considered the primary cause for sarcopenia and the associated decrease in muscle mass in the course of the aging process (Narici. 2008). Direct treatment of motoneurons with different doses of testosterone leads to increases in motoneuron size and number (Fraley. 2002; Mansouri. 2003). The physiological equivalent of the latter may thusly well be responsible for the improvements in the "mind-muscle connection" users of performance enhancing drugs frequently report. It may also facilitate a greater / optimized activation of existing muscle fibers and could thusly contribute to strength gains which would not depend on previous muscle growth. The increase in strength, in turn, would allow athletes to lift heavier weight and provide a novel growth stimulus, and so on...

Whenever there is talk of androgens and the "mind-muscle connection", someone usually mentions the three letters D, H and T and thusly invokes the role of the most potent androgen, dihydrotestosterone, to which the "Big T" is nothing but a prohormone. Whether it really is DHT, a combination of both, or if one is just more potent in inducing these androgen-related neuronal effects, will however be a topic for the next installment of this series,  in which DHT and estrogen will round out a still very sketchy portray of the complex role the "sex hormones" play in an orchestrate that is so complex that the notion that one hormone, protein, amino acid, or inflammatory cytokine alone could make your muscle grow is simply ridicolous - even if this hormone is "The Big T" ;-)