|Image 1: The ancient Greek ideal of the male body has probably more to do with DHT than the freaky physiques of today's IFBB Pro bodybuilders.|
DHT the hormone to which testosterone is just another prohormone
Similar to estrogen, DHT (exact name 17β-hydroxy-5α-androstan-3-one) is a testosterone metabolite. The process by which your body (male and female, btw.) generates this powerful androgen, the receptor-affinity of which is about 3x-10x higher than that of testosterone (depending on which source you cite and which assay the researchers used; for more detailed data on receptor binding, check out my previous blogpost "Beyond Vida's Book") is called 5-alpha reductase (5-ar). In the course of the "reduction" process one of hitherto three identified mammalian isoforms of the 5-alpha reductase enzyme (3-oxo-steroid-4-ene dehydrogenase). Of these three isoforms, which catalyze the reduction process, type III (predominantly) and type I (to a lesser extend) are expressed in human skeletal muscle (cf. Yarrow. 2011)...
"DHT makes you strong bro!" - correct!
At least for those of you who have been on some of the bulletin boards, where people discuss the effects of various androgenic compounds, the first statements that pop into your mind, when you hear the three letters D, H and T, could be "brutal strength gains", "hit new personal records on each lift" or "doubled my bench within 2 weeks". And although I suppose that statements such as the latter lack any empirical basis, the broscientitific evidence that DHT and DHT-like designer steroids exert profound effects on muscle strength cannot be denied.
In this context, the results of a 2010 study from the Biomedical and Clinical Sciences Research Institute at the School of Medicine, Health Policy and Practice of the University of East Anglia in Norwich, UK, is of particular significance (Hamdi. 2010). Using isolated extensor digitorum longus (EDL, a mainly fast twitch muscle in adult mice) and extensor digitorum longus (EDL, a mainly fast twitch muscle in adult mice) muscles from male and female mice, M.M. Hamdi and G. Mutungi established that the strength promoting effects of DHT are mediated mainly via the ERK, i.e. the extracellular signal-regulating kinase (also known as MAPK), pathway and thusly in a non-androgen receptor mediated way.
|Figure 1: Maximal isometric force production in slow an fast twitch fibers after incubation with 630pg/ml DHT; data expressed relative to initial isometric force production P0 (data calculated based on Hamdi. 2010)|
DHT works via the MAPK pathway and not via the androgen receptor
Without the "pro"-aspect of science we would yet not know that it this is neither a androgen receptor mediated action (as the use of a DHT-inhibitor did not block the effects) nor a downstream effect of IGF-1 (the inhibition of which by co-incubation with an IGR-R inhibitor left the effects similarly unchanged), but a direct effect of the DHT induced increase in ERK-1/2 phosphorylation and the subsequent accumulation of myosin light chain in the DHT treated rodent muscle:
Our hypothesis is that DHT activates the epidermal growth factor receptor (EGFR), either directly or indirectly, and this leads to an increase in the phosphorylation of ERK1/2. The activated ERK1/2 then phosphorylates MLCK which in turn phosphorylates the 20 kDa RMLCs and this increases force production in fast twitch ﬁbres but decreases it in slow twitch ﬁbres. (Hamdi. 2010)In that, it is not really important that you understand all the intermediate steps which eventually lead to the increase in force production. What is important though is the hypothesis that the changes, you are seeing in figure 2 are not mediated via the androgen receptor, which were equally distributed in both the slow- and fast-twitch fibers in the study at hand - this is particularly noteworthy, because after all DHT is the androgen per se.
|Figure 2: Changes (a.u.) in phosphorylated ERK-1/2 and myosin light chain content of slow twitch and fast twitch muscle fiber treated with either DHT or testosterone propionate; * p < 0.05 (data calculated based on Hamdi. 2010)|
Against that background it is actually quite astonishing that a series of rodent studies which were conducted by scientists from Japan (Aizawa. 2010; 2011) found statistically significant increases in intra-muscular DHT in response to an endurance type of exercise. If you add to that the results of a 2008 human study by Hawkins et al. (Hawkins. 2008), which found a similar increase in systemic DHT (and SHBG) levels in 102 sedentary men (ages 40-75 yr) who were randomly assigned to a 12-month aerobic exercise intervention, while DHT levels did not budge in a 2008 study by Vingren et al. (Vingren. 2008), which used a resistance training protocol, this raises the question whether our current understanding of the strength promoting intracrine effects of DHT is not only part of a larger picture, which would be characterized by distinct intra-, auto-, para- and endocrine effects of DHT on skeletal muscle and other exercise related physiological functions.
The litmus test: Does DHT "build muscle"?
The absence of increased levels of DHT in response to strength training as well as the fact that the increase in myosin light chain is at best "facilitative" to building bigger already suggest that, with respect to its "muscle-building effect", your most potent androgen is somewhat of a non-starter... let me give you a three of the rare examples, where scientists even dared to administer DHT to their study participants, to substantiate (not prove) this hypothesis:
- in 1992, Marin et al. found that 3 months of transdermal DHT
administration to middle-aged obese men increased muscle strength and diameter of type II muscle fibers,
albeit to a lesser extent than
testosterone administration (Marin. 1992);
- in a 3 month trial using transdermal DHT
Ly et al found a reduction in body
fat mass and improved isokinetic knee flexion strength of the
dominant leg, but no improvements in lean body mass, knee extension strength, or shoulder
flexion/extension strength in hypogonadal elderly men (Ly. 2001);
- in 2010, Idan et al. conducted a trial on the effects of DHT administration on prostate growth in 114 healthy men over 50 and found neither beneficial nor negative effects on prostate growth (please understand that I will not address the prostate issue in detail, as it is not directly related to the topic at hand and would require a whole installment of its own) and a very modest increase in lean mass (2.4%) in response to 70mg DHT gel for 2 years (!)
Note: Contrary to finasteride, which is highly selective for the type II isoform of the 5-ar enzyme, dustasteride, which has been found to reduce circulating DHT levels by >90% is a pan-5-ar inhibitor. It is thusly no wonder that 0.5mg/day of dustasteride prevented the increase in lean mass in female-to-male transsexuals who were treated with 1,000mg testosterone-undeconate for 54 weeks (Meriggiola. 2008).Although testosterone and not DHT appears to be the major hormonal driving force of actual increases in muscular size (not strength!), the results of the Meriggiola study, where the total (>90%) blockade of all three of the 5-ar isoforms by dustasteride (see red box, above) inhibited the muscle-building effects of 1,000mg testosterone-undeconate clearly suggest that the reduction of at least small amounts of testosterone to dihydrotestosterone is a necessary prerequisite for the testosterone-induced increases in lean muscle mass. Whether a critical threshold as for circulating DHT levels exists, or whether it was the dustasteride induced blockade of the local reduction of testosterone to DHT by 5-ar type III right in the skeletal muscle that was responsible for this effect will yet have to be established in future studies.
High serum DHT = lower chance of alopecia! High local 5-ar = hair loss, though.
|Image 2: Is your hair line receding? Could be DHT, but local not systemic! In young men high DHT levels correlate with full hair, in older men the local increase in 5-ar or the and the reduction in SHBG can elevate DHT beyond a healthy threshold.|
Now, how can that be? Is it testosterone that is "shaving your head from within?" - well, in a way it is, but most probably due to its local conversion to DHT (I hope by now you understand, why I stressed this factor in the introduction). Contrary to bound testosterone, which cannot be reduced by the 5-ar reductase enzymes in your scalp, the free testosterone can and will thusly - as a prohormone - do its bit to the thinning of your hairline:
[...] DHT in the hair follicle is thought to lead to hypoplasia of the scalp follicle, and a higher formation of testosterone metabolites was observed in the scalp of bald men as compared to hair obtained from nonbalding men. Yet we found a relationship, not between the disposition to balding and the ratio DHT/T, but between the diposition to balding and T_free/T_total. An elevated rate of dissociation from the binding globulin fits in well with the findings of Cipriani et al. (1983) that men with androgenic alopecia exhibit a significant reduction in sex hormone binding globulin (the same is true for bald-headed women). (Knussmann. 1992)The overall increase in both aromatization and 5-a reduction with age, as well as the tissue specific expression of those enzymes thusly explains why your men begin losing their hair, as they get older although their total androgen levels begin to decline. A similar pattern, i.e. decreased SHBG levels and consequently increases in local 5-a reduction are implicated in female androgenic alopecia, as well (De Villez. 1986).
Note: If you want to judge your serum DHT levels by your body hair, the most prudent way to do so would be look at your legs. While the correlation (r = .16) Knussmann et al. found for DHT, alone, was not statistically significant, it was still the best indicator for "high" DHT levels.Now, if we assume you have full hair and your legs have some resemblance to those of a bear (an unrealiable indicative of "high" DHT levels), does that predispose you to an increase in visceral body fat, as some sources on the Internet would have it? I mean, designer steroids that are structurally related to DHT are not particularly known for their obesogenic effect. They rather seem help their (ab-)users to lean out pretty rapidly, so the last question I will address in this installment of the Intermittent Thoughts will be ...
If testosterone helps you to lean out, will DHT make you fat?
To answer that I want to go back to the study, I presented in Friday's SuppVersity post on how eccentric training is able to recruit mesenchymal stem cells for muscular repair / hypertrophy. From either this post or the discussion of the underlying mechanisms by which testosterone works its muscle building, fat burning magic (cf. "Understanding the Big T"), you should remember that those pluripotent stem cells are unfortunately capable of becoming fat cells, as well. Luckily, dihydrotestosterone, the "big brother" of the "big T" shares testosterones anti-differential effect on pre-adipocytes (Singh. 2003).
Unfortunately, though, DHT does not prevent their proliferation (i.e. the generation of new pre-adipocytes; cf. Gupta. 2008). Instead, gene assays suggest that it stimulates all aspects of adipocyte metabolism, i.e. the beneficial ones like glycolosis (helps blood sugar management) and lipolysis (helps getting the fat out of the adipose tissue) and not (generally) beneficial ones as the production of fatty acids and triacylglyceroles, cell proliferation and differentiation (Bolduc. 2004).
Whether there is an overall negative effect of "normal" DHT levels on visceral fat, as it is sometimes suggested (esp. in the "lay press" = Internet ;-) appears however questionable. After all, Vandenput et al. (Vandenput. 2007) have shown that not DHT, but rather androstane-3 α,17-β-diol-17-glucuronide (17G), one of its metabolites correlates with visceral adiposity in healthy young men (r = 0.16; p < 0.05).
|Figure 3: Correlation of the bioactive androgens (total and free testosterone and DHT) with DXA-measurements of body fat in different compartments; data obtained from n = 1068 young men (data adapted from Vandenput. 2007)|
Serum DHT levels, on the other hand, showed the strongest negative correlation with total body fat, total body fat (% total mass), arm fat, leg fat and trunk fat of all three measured androgens (cf. figure 3) and was a close second to total testosterone as far as its negative, i.e. diminishing, effects on central fat distribution is concerned (r = -0.07; p <0.05).
Note: In view of the fact that, as of late, leptin has become a focus of attention even for the average person trying to lose weight, it might be of interest that there were statistically significant negative correlations (r = -0.23 and r = -0.25; young vs. elderly) in both study groups.Interestingly, things look somewhat different for the 1001 elderly study participants. The pattern that emerges here should remind you of the previously discussed allopecia issue. While there are still negative correlations for the total and relative amount of body fat in all compartments for serum DHT, there is a statistically yet not significant positive correlation between free testosterone and the central fat distribution in the elderly (mean age 75y) subjects that was not present in their young (mean age 19) counterparts. Moreover, the overall correlation between 17G and central obesity and the 17G/DHT ratio and central obesity raises from 0.08 and 0.20 (p < 0.05) in young men to 0.14 and 0.34 (p < 0.05) in elderly men.
Lean, mean, strong... are these "all things male"?
If we discard the important role of DHT in the brain, which would explain the "mean" (not necessarily defined as mean in aggressive, but rather as "alpha-male mean") in "lean, mean, strong" and expand "strong" to the established bone-building effects of DHT, which apparently surpass those of testosterone (eg. Capur. 1989), being as muscular as Mr. Olympia obviously is not one of the "things male". As, contrary to some of its synthetic cousins, the current research suggests that the original father of all androgens may be an indispensable bystander, when its precursor testosterone is blowing up your muscles, its immediate effects do yet appear to be restricted to strength and body composition.
Collectively, this as well as the previous installments on testosterone (Part 1, Part 2, Part 3) and estrogen should have made it quite clear that even the ostensibly straight forward role of the sex steroids in the concert of skeletal muscle hypertophy is way more complex than the commonly accepted notion that "you just inject your weekly test and become Mr. O" would suggest. It is in fact so complex that I will devote the next installment of the Thoughts to revamp the main ideas and to try to connect the dots between mTOR, myostatin, IGF, inflammation, testosterone, estrogen, DHT and co...