High Intensity Training + Mesterolone Yield Muscle- and Fiber-Type Specific Size Gains Of Up To 100% & More

Want to learn more about fiber types? ➫ review past SuppVersity articles

I am not telling you a secret, when I say that testosterone alone - in the absence of training - will lead to significant increases in skeletal muscle mass (if you think that sounds like a secret you must have missed my previous article from the "Intermittent Thoughts on Building Muscle" series | read more). To a certain extend, the same is true for DHT (learn more), and - as a recent 6-week rodent study by Karina Fontana, Gerson E. R. Campos, Robert S. Staron and Maria Alice da Cruz-Höfling shows even by the structurally similar, orally bioavailable derivative Mesterolone (aka Proviron), which produces pretty drastic, fiber-type specific increases in muscle size, when it is administered in super-physiological doses for 6 weeks (Fontana. 2013).

AAS +/- HIT = ?

Basically the question the researchers from the universities of Campinas (Brazil) and Ohio had in mind, when they came up with their study protocol was: Do anabolic steroids exert direct effects on the fiber type composition and cross-sectional area of skeletal muscle fibers of sedentary and high-intensity, aerobically-exercised transgenic mice.

DHT & T ⇔ fat & muscle Comp | more

Why did the researchers select 1 alpha-methyl-17 beta-hydroxy-5 alpha-androstan-3-on (Mesterolone), not testosterone? At first sight it may seem stupid not to go for straight testosterone, but Fontana et al. deliberately chose "DHT", for two reasons: (1) oral bioavailability and (2) no hepatoxicity ➫ no injection induced wound-formation or liver damage that would skew the results.

As the scientists point out, the aim of the study was thus "to investigate the role of mesterolone in a supposed catabolic environment" (Fontana. 2013) and answer the following detail questions:

• Does the interaction of anabolic hormone treatment and high-intensity aerobic exercise produce an increase in muscle mass and redistribution of skeletal muscle fiber types? 
• Are muscles with distinct metabolic and contractile properties (i.e., fast/glycolytic vs. slow/oxidative) differently modulated by the anabolic androgenic steroid treatment combined with a high-intensity, endurance-type training program? 
• As such, three skeletal muscles were studied under these experimental conditions: soleus (SOL), tibialis anterior (TA) and gastrocnemius (GAS). 

To be able to do so, assigned their transgenic mice (these mice have been "modified" so that they have a lipid metabolism that's closer to the one of human beings) to four different groups, i.e.

Table 1: Overview of the incremental exercise program the rodents in the "EX-" (=exercise) groups performed on a treadmill 5x per week

• Sed-C - sedentary control
• Sed-M - sedentary + 3x2mg/kg* Mesterolone per week
• Ex-C -5x/week HIT exercise + gum arabic placebo
• Ex-M - 5x/week HIT exercise + 3x2mg/kg* M per week

*Note: The scientists claim to administer "supraphysiological" against that background we must assume that we are talking about 2mg/kg for a human (if that was the rodent dose, the human equivalent) would be 12-15mg and that's clearly not "supra-physiological" - 3 doses of 150-200mg of Mesterolone which comes in 25mg pills, on the other hand, would be "supra-phyiological".

After 6 weeks, the animals were sacrificed, their muscles harvested and an analysis of the entire range of pure and hybrid fiber types was conducted.

Mesterolone is not DHT: Anonymous was kind enough to remind me that the original version of this article did not make a clear distinction between DHT and 1-alpha-methyl-DHT aka Mesterolone (or Proviron). He did however mix his facts up, because contrary to A.'s claim Mesterolone has a 3x higher binding affinity for the androgen receptor in skeletal muscle than "regular" DHT (Saartok. 1984). With a 4x higher affinity for SHBG, it is however difficult to predict the real-world differences. This is particularly true in view of the fact that the growth response could be triggered by non-receptor mediated mechanisms, as well.

Just in case you don't remember all the details you've learned about the different fiber types in previous SuppVersity articles, keep in mind that type I fibers are mainly oxidative, they use fat as a "preferred" substrate and will get you from A to B when you walk or jog. The type II fibers, on the other hand are "glycolytic", this means, that they rely heavily on glucose. Their prerogative are explosive / fast contractions and they carry the lions share of the weight you through around at the gym.

Figure 1: Muscle weight and body weight (in g) at the end of the study (Fontana. 2013)

Against that background it's quite telling that the tibialis, the muscle with the largest amount of Type IIA and Type II AD fibers, fast twitch fibers that can use both, glucose and fat as fuel, is the only muscle where we don't see the following relation between the muscle weight: EX-M > EX-C > SED-M > SED-C.

Figure 2: Detailed analysis of the changes in fiber type composition of soleus, tibialis and gastrocnemius muscle; all data expressed relative to sedentary control (Fontana. 2013)

If you take a closer look at the detailed fiber type analysis the researchers conducted (Figure 2), you will see that a similar trend can be observed in the "intermediate" muscle, the gastrocnemius (see grey arrow). The effects the DHT clone had on the "oxidative" soleus, on the other hand, were in no instance more pronounced than those of the 20-60min treadmill running regimen (see Table 1, for details).

Suggested: "Serum & Intramuscular Testosterone, DHT and Androgen Receptor Response to High vs. Low Volume Training" | more

So what can we learn from this study? (1) Contrary to the common believe that muscle building was a prerogative of testosterone, Mesterolone (Proviron, DHT) can obviously build muscle, as well - at least, when it is administered at supra-physiological doses (see comment above; plus: don't do that at home ;-). (2) Despite the fact that the orally bioavailable DHT derivative does build muscle, even in the absence of physical activity, the changes are really pronounced only, when it is combined with intensive exercise. (3) Astonishingly, even running, i.e. a simple endurance exercise has significant anabolic effects on both oxidative (this is what you would expect) and glycolytic (this is actually surprising) muscle fibers. (4) This effect is highly amplified by Mesterolone - particularly in the Type IIA + IIAD fibers of the gastrocnemius, which has a particularly high content of "glycolytic only" Type IIB fibers (>50% in the exercise groups).  

This fourth and point, is actually the most interesting one. It does after all confirm what I mentioned only casually in previous articles about DHT, the true androgen, which is rapidly deactivated in the muscle and does still appear to play an important role in the structural changes your musculature undergoes, when you exercise. Speaking of changes, I guess you will already have realized that the highly pronounced increase in muscle fiber size of the type II fibers stands in line with the often-touted "strength building" effects of designer steroids with structural resemblance to DHT. The overall mass gains - and this is something you may have heard about said AAS, as well, on the other hand, are rather mediocre (see Figure 1).

References:

• Fontana, Karina, et al. "Effects of Anabolic Steroids and High-Intensity Aerobic Exercise on Skeletal Muscle of Transgenic Mice." PloS one 8.11 (2013): e80909. 
• Itil, Turan M., et al. "Male hormones in the treatment of depression: effects of mesterolone." Progress In Neuro-Psychopharmacology 2.4 (1978): 457-467. 
• Ly, Lam P., et al. "A double-blind, placebo-controlled, randomized clinical trial of transdermal dihydrotestosterone gel on muscular strength, mobility, and quality of life in older men with partial androgen deficiency." Journal of Clinical Endocrinology & Metabolism 86.9 (2001): 4078-4088. 
• Saartok, Tönu, Erik Dahlberg, And Jan-Åke Gustafsson. "Relative binding affinity of anabolic-androgenic steroids: comparison of the binding to the androgen receptors in skeletal muscle and in prostate, as well as to sex hormone-binding globulin." Endocrinology 114.6 (1984): 2100-2106.
• Singh, Keerti, Asha Singh, and A. K. Sarada. "Assessment of mesterolone therapy in oligospermic males." www.ijpsi.org Volume 2 Issue 3 March 2013.

Creatine, DHT, Hair Loss & Prostate Cancer - Bro-Scientific Old Wives' Tales or Possible Side Effect? Plus: (Non-)Sense Creatine Loading, Exercise Induced 5-α Reduction & More

Poor guy! Must have taken too much creatine and treated his hair for muscle ;-) Ok, seriously, creatine may have helped a little that he was able to build this impressive physique, but the hair? Come on, seriously!?

If you have been around the bulletin boards of the fitness and bodybuilding community, I am pretty sure you will have heard about creatine induced increases in dehydrotestosterone (DHT). Probably you will also have had someone chime in who claimed that his hair started to fall out, when he started to use creatine supplements - right? Well, I guess in that case you will probably also remember how another guy chimed in and said: "Hold on does that mean that creatine will cause prostate cancer?"

Never heard something like that? I suggest you trust my word, then; and in case you want "scientific evidence" head over to www.pubmed.com and type in "creatine D" it will offer you "creatine DHT" as one of the typical search phrases people are looking for.

Cock-and-bull - right?

It is true that there is a study that supports the concept of increased DHT levels in athletes (20 collegiate rugby players to be precise) in response to 21 days of creatine supplementation. The athletes who participated in the said trial came from a Rugby Institute situated near Stellenbosch University in South Africa. None of the subjects had taken any supplements with their normal diet for 6 weeks before the trial in the course of which all had been randomized to one of the following groups:

• creatine: 25g creatine + 25g glucose for 7 days; 5g crea + 25g glucose for 14 days
• placebo: 50g glucose for 7 days; 30g glucose for 14 days
  

The subjects underwent standardized training, albeit for different player positions, during the whole study period. All subjects were residents at the institute and the ate the same food at the cafeteria. Moreover, all 20 were just coming back from a winter break and were "in similar condition as the start of the study and not fatigued from consecutive weeks of match play" (van der Merwe. 2009).

Instead of simply taking more you may rather want to "Super Charge Creatine W/ Baking Soda" | learn more

Creatine loading is neither necessary nor useful for the majority of athletes. Unless you have a meet close ahead there is no need to gobble down 25g+ doses of creatine - specifically not in one sitting. While the typical creatine supplementation protocol consists of a loading phase of 20 g creatine/d or 0.3 g creatine/kg/d that's followed by a 3-5 g/day (or 0.03g/kg) maintenance phase (Buford. 2007), it is also possible to use daily doses of ~3–6 g or between 0.03 to 0.1 g/kg per day (Willoughby. 2001; Hickner. 2010).

All subjects were lean (13-14% body fat and muscular 75kg muscle of 86-87kg total body weight) and thus way more representative of the average creatine guzzling gymrat than untrained average Joes whose beer bellies may well have messed up their endocrine system to an extend that could explain the DHT increases from 0.98 nmol/L to 1.53 nmol/L. The fact that the DHT levels in the control group did not change significantly in the course of the 7-day loading phase (in fact they dropped, but due to the high standard deviation the drop from 1.26 nmol/L to 1.09 nmol/L was non-significant), lends further support that the changes, the researchers observed must have been the result of the 25g of creatine the 10 subjects in the active arm of the trial had to swallow on during the first seven days of the study period.

Figure 1: Serum DHT levels total (left) and expressed relative to baseline levels in control group (right); data calculated based on van der Merwe et al. 2009

As you will probably already have read in-between the lines, I am not exactly impressed - let alone scared - by these results. Why? Well, the initial 56% increase in DHT was not only followed by a -10% decline during the maintenance phase, but this decline brought the DHT levels of the young men in the creatine group pretty close to where they had been in the placebo group at T0 (1.38nmol/L vs. 1.26 nmol/L for creatine vs. placebo, respectively).

The high DHT levels observed in the study at hand, were only midrange

If that does not comfort you, maybe it will help, if I tell you that the reference range for adult men ranges from 0.8-3.4 nmol/L (NHS Pathology. 2013 - please note that these reference ranges vary from lab to lab, in ng/dL the upper limit usually is 85ng/dL, which is 2.93nmol/L). Accordingly, the total DHT level of the subjects in the van der Merwe study did not even scratch the 50% mark on the reference range, when they maxed out at the end of the 7-day loading phase.

With a meager 9% difference to the baseline levels in the control group and a total DHT level of 1.38nmol/L in the "low DHT" zone of the reference range, I wouldn't say it is necessary (from a mere safety perspective) to investigate, as Green suggested it in a 2010 letter to the editor, whether the creatine supplement that has been used in the study may have been contaminated with androgenic compounds (Green. 2010). To answer the question about the why, i.e. "Why did the DHT levels in the creatine group go up, while those in the control group remained the same?",  it would yet in fact be nice to know if we were dealing with the side effects of androgenic compounds in the creatine supplement or the physiological effects of exercise, which has repeatedly been shown to be able to increase both intra-muscular and systemic DHT levels in men and rodent models (see the bottom line for selected references).

Want to learn how to modulate your DHT levels naturally? Rice, safflower, sorghum & Co. can help! learn more

In view of the fact that these increases are intensity dependent, but limited by the androgen suppressive effects of overtraining, The increased DHT levels may eventually have been a secondary response to increased training loads and the ameliorative effect creatine exerts on the androgen suppressive effects of overreaching (Volek. 2004).

And while I cannot tell you if this actually was the reason for the increase in DHT, I can tell you that the scientists assertion that what they observed was a "large increase in DHT rather than a marginal (possibly physiologically insignificant)"  (van de Merwe. 2009) is (at best) warranted if we look at the intra-group effect. In view of the broad "normal" range and the low baseline DHT levels in the creatine group, this relevance of this relative increase is yet more than questionable.

And the increasing DHT:Testosterone ratio?

Even at the risk of sounding like a smart ass, I do not want to forgot to mention that the "oh so dangerous" increase in DHT/T levels the scientists emphasize in their conclusion was found to be associated with a reduced risk of hair loss (-35% risk reduction) in 315 male subjects who were stratified with regard to age, race, and case-control (Demark-Wahnefried. 1997).

This and similar observations which have been made by Nomura et al. (1988), Hsing (1993) Shaneyfelt (2000) with respect to the non-significant impact of high(er) serum DHT levels on the occurance of prostate cancer and, more importantly, the increased risk that comes with higher T:DHT ratios, I seriously doubt that you have to be concerned about either your superb head of hair or your hitherto still pain and cancer free prostate when you are downing your daily dose of 3-5g creatine monohydrate.

No! Physical activity does not cause prostate cancer. I guess you will be surprised that I even address this issue, but due to several major shortcomings in previous prospective and epidemiological studies, you will easily find studies such as the one by Cerhan et al. which claims that men with a high physical activity have a 90%(!) increased risk of prostate cancer. What the abstract does not tell you, though, is that the researchers "forgot" to conduct a time lagged analysis to overcome the "I started to exercise yesterday, so I exercise vigorously every day" effect and did thus fail to measure consistent physical activity. Edward et al. did just that over a 4 year period and observed a -53% risk reduction for men aged 65+ to develop advanced prostate cancer.

Take home message: Despite being statistically relevant the absolute changes in the DHT levels van der Merwe et al. observed in the study at hand were neither physiologically relevant (DHT remained well within the reference range), nor totally inexplicable. Being afraid of hair loss, let alone prostate cancer, in response to the consumption of (untainted) creatine supplements is thus totally unwarranted.

And just in case you still want to freak out, I suggest you keep sitting on your ass for the rest of your life and refrain from ever playing football or any other sport again... why? Well according to Lupo et al., your DHT levels will double during a single football match. This and similar observations by Hawkins in a middle aged men on a 12-months aerobic exercise program (14.5% increase with moderate intensity cardio 6x per week; cf. Hawkins. 2008), as well as the results from Aizawa et al. who were able to demonstrate "that acute exercise enhances the local bioactive androgen metabolism in the skeletal muscle of both sexes" and not just men, do as bro-logic dictates suggest that any kind of physical activity will make you hair fall out and your prostate grow... now tell me how realistic is that?

References:

• Aizawa K, Iemitsu M, Maeda S, Otsuki T, Sato K, Ushida T, Mesaki N, Akimoto T. Acute exercise activates local bioactive androgen metabolism in skeletal muscle. Steroids. 2010 Mar;75(3):219-23.
• Buford T, Kreider R, Stout J, Greenwood M, Campbell B, Spano M, Ziegenfuss T, Lopez H, Landis J, Antonio J:International Society of Sports Nutrition position stand: creatine supplementation and exercise.J Int Soc Sports Nutr. 2007;4.
• Cerhan JR, Torner JC, Lynch CF, Rubenstein LM, Lemke JH, Cohen MB, Lubaroff DM, Wallace RB. Association of smoking, body mass, and physical activity with risk of prostate cancer in the Iowa 65+ Rural Health Study (United States). Cancer Causes Control. 1997 Mar;8(2):229-38. 
• Demark-Wahnefried W, Lesko SM, Conaway MR, Robertson CN, Clark RV, Lobaugh B,
  Mathias BJ, Strigo TS, Paulson DF. Serum androgens: associations with prostate
  cancer risk and hair patterning. J Androl. 1997 Sep-Oct;18(5):495-500. 
• Giovannucci EL, Liu Y, Leitzmann MF, Stampfer MJ, Willett WC. A prospective study of physical activity and incident and fatal prostate cancer. Arch Intern Med. 2005 May 9;165(9):1005-10.
• Hawkins VN, Foster-Schubert K, Chubak J, Sorensen B, Ulrich CM, Stancyzk FZ, Plymate S, Stanford J, White E, Potter JD, McTiernan A. Effect of exercise on serum sex hormones in men: a 12-month randomized clinical trial. Med Sci Sports Exerc. 2008 Feb;40(2):223-33
• Hickner R, Dyck D, Sklar J, Hatley H, Byrd P:Effect of 28 days of creatine ingestion on muscle metabolism and performance of a simulated cycling road race.J Int Soc Sports Nutr 2010;7:26.
• Hsing AW, Comstock GW. Serological precursors of cancer: serum hormones and risk of subsequent prostate cancer. Cancer Epidemiol Biomarkers Prev. 1993 Jan-Feb;2(1):27-32.
• van der Merwe J, Brooks NE, Myburgh KH. Three weeks of creatine monohydrate supplementation affects dihydrotestosterone to testosterone ratio in college-aged rugby players. Clin J Sport Med. 2009 Sep;19(5):399-404.
• Nomura A, Heilbrun LK, Stemmermann GN, Judd HL. Prediagnostic serum hormones and the risk of prostate cancer. Cancer Res. 1988 Jun 15;48(12):3515-7.
• Shaneyfelt T, Husein R, Bubley G, Mantzoros CS. Hormonal predictors of prostate cancer: a meta-analysis. J Clin Oncol. 2000 Feb;18(4):847-53.
• Van der Merwe J, Brooks NE, Myburgh KH. Three weeks of creatine monohydrate supplementation affects DHT to testosterone ratio in college-aged rugby players.Clin J Sports Med. 2009;19:399–404.
• Volek JS, Ratamess NA, Rubin MR, Gómez AL, French DN, McGuigan MM, Scheett TP, Sharman MJ, Häkkinen K, Kraemer WJ. The effects of creatine supplementation on muscular performance and body composition responses to short-term resistance training overreaching. Eur J Appl Physiol. 2004 May;91(5-6):628-37.
• Willoughby DS, Rosene J:Effects of oral creatine and resistance training on myosin heavy chain expression.Med Sci Sports Exerc2001,33:1674–1681.

DHT Safer Than Previously Thought: High Blood DHT does not Induce Prostate Cancer

Regular visitors of the SuppVersity will know that the stigmatization of DHT goes without reasonable and conclusive scientific research. In their editorial to the Annals of Internal Medicine Swerloff & Wang (Swerloff. 2010) conclude from the results of more recent studies into the various effects of DHT on different tissues:

In normal men, serum DHT levels are approximately 10% of the serum testosterone levels, whereas intraprostatic DHT levels are much higher than serum levels, with the intraprostatic DHT–testosterone ratio being 7 to 8 (12). Although the authors did not measure DHT levels in
the prostate after DHT administration, Page and coworkers (13) recently reported that prostatic DHT levels did not increase when pharmacologic doses of DHT were administered (Page S. Personal communication.). These findings are consistent with those of Marks and colleagues (12), which demonstrated that administration of testosterone to mildly testosterone-deficient men increased serum testosterone levels but did not increase either prostatic DHT or testosterone concentrations. Thus, it seems that the amplifying 5alpha-reductase system is so efficient in regulating intraprostatic DHT levels that substrate (for example, testosterone) concentrations are limiting only at very low levels. Furthermore, the ability of the 5alpha-reductase system to produce high tissue levels of DHT in organs, such as the prostate, indicates that even high levels of DHT in the blood remain much lower than the levels reached in the prostate and thus have little influence on prostate growth. In contrast, high levels of DHT in the blood will act as a hormone and thus produce real effects in tissues with less dominant testosterone to DHT-amplifying systems, such as muscle, fat, and bone marrow. Although the present study was not adequately powered to definitively answer the question of long-term safety of testosterone use, these data do show that a 10-fold increase in serum DHT levels had no significant effects on prostate size, serum DHT, and International Prostate Symptom Score, suggesting that the modest increases of serum DHT seen after testosterone treatment may not have a clinically significant effect on prostate health.

So after all, this means that

1. you do not have to take Finasterid or other side-effect-loaden bullsh* if you are on TRT
2. you may benefit from the positive effects on libido, alpha-male feeling and probably muscle growth of reasonably elevated DHT-levels without having to worry about your prostate
3. you better not believe every "scientific fact" that is covered in mainstream media

Is DHT Really the 'Bad and the Ugly'?

Fellow men, common (bro-)science tells us that dihydrotestosterone (DHT, molecular structure see image on the right. HMDB) will make your hair fall out and trigger cancerous growth of your prostate. Current research, however, suggests that Estrogen might just as well be the real culprit when it comes to unwanted growth a few inches above your testes. This is, as Williams (2010) phrases it, part of a "controversial break-through" achieved by scientists in the course of the last months and the results of which he sums up as follows:

"The synergistic action of unopposed oestrogen and leptin, compounded by increasing insulin, cortisol and xeno-oestrogen exposure directly initiate, promote and exacerbate obesity, type 2 diabetes, uterine overgrowth, prostatic enlargement, prostate cancer and breast cancer."

It was thus certainly no bodily injury caused by negligence, when Konnelius et.al. 2002 administered 125-250mg transdermal DHT to 60 subjects (age range, 50–70y) and found:

"Early morning erections improved transiently in the DHT group at 3 months of treatment (P < 0.003), and the ability to maintain erection improved in the DHT group compared with the placebo group (P < 0.04). No significant changes were observed in general well-being between the placebo and the DHT group. Serum concentrations of LH, FSH, E2, T, and SHBG decreased significantly during DHT treatment. Treatment with DHT did not affect liver function or the lipid profile. Hemoglobin concentrations increased from 146.0 ± 8.2 to 154.8 ± 11.4 g/liter, and hematocrit from 43.5 ± 2.5% to 45.8 ± 3.4% (P < 0.001). Prostate weight and prostate-specific antigen levels did not change during the treatment. No major adverse events were observed."