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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

References:

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

Less Than 15mg of DHEA Exert Identical Beneficial Effects on Insulin Sensitivity as 1h of Cardio 5x Per Week. Both Effects Mediated Via Increases in Intra-Muscular DHT

Image 1: It has long been established that diabetics have particularly low DHEA levels (Loviselli. 1994), but what's the chicken and what's the egg here?

It is quite funny, sometimes you don't hear about certain supplements, (pro-)hormones, exercise-modalities etc. in years and then, all of a sudden, there are two studies on the respective topic in one week; and moreover, two pretty interesting ones! Last Friday, exactly 7 days ago, you've read here at the SuppVersity about the muscle-protective effects of low-dose dehydroepiandrosterone (DHEA) supplementation during a 5-day intense multiple-type exercise protocol (cf. "DHEA Blunts Muscle Damage During 5 Days of Combined Endurance, Strength and HIIT Training in Young Men"). Today, I have another interesting set of data for you - data which could not just shed some light onto the underlying mechanisms of the said protective effects against skeletal muscle damage, but also on DHEA's beneficial effects on insulin sensitivity.

Not younger, but leaner with a minimalist dose of DHEA?

In a 6 week trial, and thus over a more than eight times longer timespan than in the previously mentioned human study on skelatal muscle damage, Koji Sato and his (or her?) colleagues from the Ritsumeikan University, the Senshu University and the University of Tsukuba (all in Japan, as you probably already suspected) investigated the effects a low dose of DHEA (human equivalent: 0.16mg/kg per day => 10-15mg/day) supplementation on the insulin, QUICKI (=quantitative insulin-sensitivity check index) and intramuscular DHEA and DHT (dihydrotestosterone) levels in sedentary or exercised dietary obese male rodents.

Figure 1: Relative insulin levels, QUICKI, intramuscular DHEA and DHT content in obese male rodents after 6 weeks of DHEA or combined DHEA + exercise (1h, 5days/week) treatment (data adapted from Sato. 2012)

As you can see in figure 1 the effects of both 5x/week running on a treadmill (ETA: 1h) and orally administered DHEA were profound. If you compare the "exercise only" group (red) to the two DHEA groups (green and violet), you will yet notice interesting parallels. Not only were the decreases in serum insulin and the increases (=improvements of insulin sensitivity) in the QUICKI test very similar, the exercise regimen alone yielded a +56% increase skeletal muscle DHEA content and a +71% increase in DHT.

Exercise increases intramuscular DHEA & DHT...
 

Figure 2: Hormonal cascade from DHEA to DHT; all enzymatic conversions can take place on a systemic and intra-cellular level!)

At least the latter, i.e. the increase in DHT should not be news to you if you have been following the in-depth articles at SuppVersity over the past couple of months. From the Intermittent Thoughts on DHT you know that exercise in general and HIT endurance exercise in particular has been found to boost intramuscular dihydrotestosterone levels, as well. The bros, or friends of bros among you, will probably also have heard the horrific stories about creatine monohydrate leading to increased levels of DHT (van der Merve. 2009), of which every reasonable person must actually assume that they are nothing but a downstream effect of increased training loads and/or improved adaptation... I mean, think about it "paleo style": Why would the mammalian body (rodent and human appear to react alike here) increase the DHEA and, via 5-alpha reductase (cf. figure 2), the dihydrotestosterone levels in response to high volume exercise, if not as a means of adaptation?

Oral DHEA + exercise = double-whammy against obesity

The combined treatment, or I should say the exogenous support of the exercise induced changes had - and this is not visible from the data in figure 1, astonishingly profound effects on the diet induced weight gain of the lab animals. While all other rodents became fatter, those in the exercise + DHEA group remained at a steady body weight level; an observation the researchers comment as follows:

Although DHEA administration and exercise training each produced beneficial effects, 6-weeks of combination treatment were more effective for obesity. The precise mechanisms that reduced abdominal fat weight in the combination group remain unclear, yet we can propose several plausible hypotheses. 2 weeks of DHEA administration has been shown to activate fatty acid metabolism-related enzymes, such as long-chain fatty acyl-coenzyme A synthase, and to increase free CoA levels in liver (Mohan. 1998; Mohan. 1990). In addition, exercise training is  known to reduce adipogenesis via upregulation of fatty acid metabolism and increased energy expenditure (Hou. 2003). Therefore, 6-weeks of combination treatment may have promoted additive reductions in abdominal fat volume.

In other words, while DHEA increases the efficacy of fatty acid oxidation, exercise takes care of the increase in energy expenditure which is - all convictions wrt to "calories don't count" and the "calories in vs. calories out"-hypothesis aside - still a fundamental prerequisite that the fatty acids do actually get burned and are not released into circulation to be restored or replaced a couple of hours later.

"Ok, I am just ordering some DHEA, how much should I take?"

Before you head over to the online vendor of your choice to make sure you get your share of DHEA before the FDA hears that it could hamper the sales of diabetes drugs and removes it from the OTC market, I would like to remind you that despite the fact that Sato et al. rightly claim that a "combination treatment [with DHEA and DHT] may be more beneficial than either therapy alone", a cursory glance on the data in figure 1 should suffice to tell you that those additional benefits as statistically significant as they may be are just that "additional" and that exercise alone yielded about equal results, is free of negative and full of beneficial side effects (update: as long as you don't overtrain; thanks Stapedius for this important note) and does not have the same host of studies refuting its efficacy as DHEA has (Clore. 1995).

It is nevertheless intriguing that a hormone the medical orthodoxy has, more or less all of a sudden, dropped like a hot potato and declared "questionable" and "ineffective" is now, roughly 15-20 years being rediscovered... and I am pretty sure that this was not the last DHEA study you will see and read about here at the SuppVersity ;-)

References:

1. Clore JN. Dehydroepiandrosterone and body fat. Obes Res. 1995 Nov;3 Suppl 4:613S-616S. Review.
2. Hou CW, Chou SW, Ho HY, Lee WC, Lin CH, Kuo CH. Interactive effect of exercise training and growth hormone administration on glucose tolerance and muscle GLUT4 protein expression in rats. J Biomed Sci. 2003 Nov-Dec;10(6 Pt 2):689-96.
3. Loviselli A, Pisanu P, Cossu E, Caradonna A, Massa GM, Cirillo R, Balestrieri A. [Low levels of dehydroepiandrosterone sulfate in adult males with insulin-dependent diabetes mellitus]. Minerva Endocrinol. 1994 Sep;19(3):113-9.
4. 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.
5. Mohan PF, Cleary MP. Effect of short-term DHEA administration on liver metabolism of lean and obese rats. Am J Physiol. 1988 Jul;255(1 Pt 1):E1-8.
6. Mohan PF, Ihnen JS, Levin BE, Cleary MP. Effects of dehydroepiandrosterone treatment in rats with diet-induced obesity. J Nutr. 1990 Sep;120(9):1103-14.
7. Sato K, Iemitsu M, Aizawa K, Ajisaka R. Testosterone and DHEA activate the glucose metabolism-related signaling pathway in skeletal muscle. Am J Physiol Endocrinol Metab. 2008 May;294(5):E961-8. Epub 2008 Mar 18.
8. Sato K, Iemitsu M, Aizawa K, Mesaki N, Ajisaka R, Fujita S. DHEA administration and exercise training improves insulin resistance in obese rats. Nutr Metab (Lond). 2012 May 30;9(1):47. [Epub ahead of print]

Chest Fat, Bitch Tits, Chesticles, Gynecomastia, Lipomastia and Co.: Infinite Ways to Name it, Only 5 to Get Rid of It

Image 1: Is it what he eats, is it what he drinks or is it just  andropause? Whatever it may be, Jack does not have the "classic gyno".

In the last installment of this two-part series on gynecomastia, lipomastia and co. we have seen that the number of appellations this common, mostly benign enlargement of the male breast has been given, is easily outnumbered by the potential, mostly pharmacological, but also supplemental and/or dietary factors which have been implicated in its development. In a recent paper, Krysiak and Okopien estimate the incidence of mild proliferation of the glandular breast tissue to 30%-50% of the male population (Krysiak. 2012). Against that background, the universal ignorance towards the profound psychological effects, as well as the tacit acceptance that, breasts or no breasts, "men don't cry" are certainly uncalled-for.

If it's benign you got to live with it!

The idea, "if it's not cancerous", it won't hurt, is probably also the main reason for the lack of viable (N=5), let alone "proven" (N=1, surgery) treatment strategies. A couple of case-reports and small scale studies do yet suggest that its surgical removal, which is uncertainly the method of choice for non-benign or exuberantly proliferating tissue growth, is not the only option you may have to get rid of a condition of which I suspect that it has been bothering many of you for years now.

Whichever of the following strategies you may pick, your first step should always be to avoid / drop all of the 45+ offenders I mentioned in the last installment, and to avoid the 10 previously discussed anti-androgens like a plague. Yet while these "passive" treatments may suffice to stop your breasts from growing even further, it is unlikely that they will put a long lasting real gyno (not just normal fat!) in remission. If you are among these unfortunate, yet certainly not rare cases, you may have to resort to one or more of the following "alternative" (from the perspective of most MDs) but not mutual exclusive anti-gyno strategies.

Getting rid of "gyno" by losing body fat (not weight!)

Image 2: This poor boy may not know it, but he is just lying the fat foundation for embarrassing female breasts

It should actually be obvious that losing excess body fat is the logical next step following aforementioned necessity to avoid anything that could precipitate gyno. Aside from the constant assault to xeno- (BPA & co=)and purportedly healthy phyto-estrogens (soy & co), the obesity epidemic is probably the main reason for the high prevalence of enlarged breast tissue in the male part of the population, anyways. Particularly during puberty, when the natural hormonal production overshoots the increased aromatase activity in the abundant adipose tissue of today's Playstation gambling couch potatoes can be hazardous.

Puberty and the spontaneous regression of pubertal gynecomastia can yet also serve as an encouraging example that an ample increase and stabilization in the androgen to estrogen ratio, as it should occur towards the end of puberty, can send mild cases of pubertal gynecomastia and lipomastia into remission. Similar effects can be seen in adults, when

• you lose fat without starving yourself - Starvation would lead to decreased androgen production and could, if anything, help not to make things even worse; more often than not, it does yet make things worse. After all, large breasts on a skinny man look even worse than breasts of the same size on a slightly chubby guy.
• you are gradually losing fat over a long period of time - It is more than likely that the chest fat is going to be the last to go; in fact, it may take a profound reduction in total body fat shift the androgen-to-estrogen ration into the normal range before you see any improvements
• you don't resort to questionable fat burners - with herbs, tea or whatever extracts in them that will have either direct estrogenic or anti-androgenic side-effects or mess with the cytochrome P450 cascade of your liver (see previous installment)

Fat loss is a particularly good tool to get rid of "fat tits", i.e. an unbalanced deposition of regular fat tissue. It will take its time, though, and it won't help to combat "acute flare-ups" from the (obviously accidental) ingestion of certain "supplements". It is likewise unrealistic to assume that it would put a full-blown gynecomastia, i.e. the (over-)growth of glandular tissue, cancerous or not, into remission.

Getting rid of "gyno" with Tomaxifen, a selective estrogen receptor inhibitor

In view of its kinship with breast cancer, it should not surprise you that the single scientifically well-established anti-gyno agent is a selective estrogen receptor modulator, in short SERM. Tamoxifen, brand name Nolvadex, has been used in a couple of small scale trial with reasonable success (e.g. Parker. 1986; Algaratnam. 1987; McDermontt. 1990; Ting. 2000), the results of which Braunstein et al. summarize as follows (Braunstein. 2007):

[A]dministered orally at a dose of 20 mg daily for up to 3 months, has been shown to be effective in randomized and nonrandom-ized trials, resulting in partial regression of gynecomastia in approximately 80% of patients and complete regression in about 60%.

Despite the existent evidence that would support the use of Tamoxifen as the "anti-gyno" drug of choice, Daughty and Wilson, in their 2003 letter to the editor of the British Journal of Medicine, rightly state:

The evidence base for their conclusion is small (135 patients) and is certainly not derived from randomised controlled clinical trials. [...] until more evidence shows that tamoxifen is safe in this condition it should not be recommended as first line treatment, especially in pubertal boys.

If you add to that the potential hepatoxicity (cf. "Milk Thistle Against Tamoxifen Induced Liver Injury"), as well as the two documented cases of epigastric distress and the one known case of  post-traumatic deep-vein thrombois, it is self evident that you and your medical practitioner should carefully monitor your liver as well as other health parameters if you decide to give Tamoxifen or alternatively Clomiphene (cf. Plourde. 1983) a try.

Getting rid of "gyno" with  aromatase inhibotors

There is also some evidence from case reports that would support the use of 2nd generation aromatase inhibitors (AI), Letrozole, in particular, to combat gynecomastia. As Braunstein et al. point out (Braunstein. 2007), their efficiency seems yet to be limited to cases, where over-aromatization of testosterone into estrogen is the underlying reason of the the problem. If this applies to you, talk to your medical practitioner about the use of a very low dose of letrozole, like 2x per week 2.5mg, or resort to 25mg of the (in the US formerly) OTC, yet very potent aromatase inhibitor ATD (more is counter-indicated because it could start "clogging" your androgen receptor, cf. "Antiandrogen effects of ATD").

Note: In a 2004 randomized controlled trial by Plourde et al. the "standard AI", Anastrazol, was ineffective for patients with residual pubertal gynecomastia (Plourde. 2004). Similarly, Riepe et al. found no effects in pubertal boys other than a reduction in breast tenderness (Riepe. 2004). It is therefore, as Sarah L. Maidment points out not not just that "Anastrozole may not be more effective than placebo in decreasing the size or volume of breast tissue in persistent pubertal gynaecomastia", but also that "its long-term effects and safety are still unknown" (Maidment. 2010). 

If the over-aromatization is related to an increased amount of body fat, this treatment strategy should be complemented by appropriate lifestyle changes (diet + exercise; follow the SuppVersity for daily tips on what works). The effectiveness of your weight loss efforts will be largely augmented by the restoration of a normal estrogen-to-androgen ratio and will hopefully allow you to maintain the latter once you seize taking the drug.

Update: If you hesitate to use a "real" aromatase inhibitor you could also resort to melatonin (kudos to Peter Rouse for the reminder), of which a dose as low as 3mg melatonin per day taken at 5pm for 6-month can shift the testosterone-to-estrogen ratio into the desired direction (Luboshitzky. 2002)

Getting rid of "gyno" with topical DHT cream

Largely unknown in the US, but a relatively common treatment strategy in Europe, in particular in France, is the use of topical DHT cream. The available literature on this issue is scarce. The results of one of the few well-documented trials by Kuhn et al. are yet promising and stand in line with the natural "anti-estrogenic" effects of dihydrotestosterone (Kuhn. 1983):

Local administration of DHT was followed by the complete disappearance of gynaecomastia in 10 patients, partial regression in 19 and no change in 11 patients after 4 to 20 weeks of percutaneous DHT (125 mg twice daily).

This is a 33% success rate in patients with idiopathic (meaning we don't know the underlying reason) gynecomastia. That is less effective than tamoxifen  and certainly neither what you would call a "tried and proven" method, but probably better than the bro-scientific use of DHT-precursors and pro-steroids with structural resemblance to DHT. Especially in the US, it may however difficult to find a medical practitioner who would be willing to prescribe and monitor this treatment, I guess.

Conclusion and the last resort: Surgery

Image 3: Assuming that you find a surgeon who knows what he is doing, surgery is unquestionably the best - diet and exercise aside, probably also the safest treatment strategy. In cases of non-benign gynecomastia it should be the go-to treatment, anyway.

If we take a final look at the meager amount of treatment options, it stands to reason that the avoidance of anything that could exasperate the condition, as well as the reduction of body fat should have priority over all other treatment strategies. If those fail, the next step should be a comprehensive hormonal panel, on the asis of which you and your medical practitioner should decide which route to go.

In case none of the pharmacological approaches works, you can still resort to to surgery (or radio-therapy, but I guess most of you will prefer the knife, right?), the "gold standard therapy for symptomatic gynecomastia in most patients" (Johson. 2011). Just make sure you do not spoil the ship for a ha'porth of tar - or put more simply, go and seek an expert!

Natural Hormone Optimization Made Simple & Cheap: Avoid These 10 Anti-Androgens to Boost Testosterone & DHT

Image 1: I am not aware of the effect the process of making yourself up has on androgen levels, but the PCPs in many cosmetics could in fact lead to hormonal imbalances.

One of the things you hear and read increasingly often, when it comes to topics such as detoxification, the use of anti-inflammatory supplements or simply increased intakes of omega-3 fatty acids to counter the "hazardous omega-6 overload in your diet", is the analogy of somebody banging his head against a wall asking for a helmet, instead of simply stopping this stupid practice. Likewise, it does not really make sense to invest $50 into an already more or less worthless natural testosterone booster, when, at the same time, you are eating or even supplementing one of the items on the following list of proven anti-androgens:

• anti-androgenic drugs - cyproterone acetate, spirolonactone, flutamide, ketoconazole, finasteride & co.: It stands to reason that your doctor will have had good reason to prescribe you one or the other of the aforementioned drugs; and at least as far as the DHT blocker dustasteride is concerned, diligent SuppVersity students will be aware that it does not compromise testosterone-replacement-therapy induced changes in body composition. In this regard, it should however be mentioned that the pertinent study, I discussed on March 12, 2012 (cf. "Dustasteride Does Not Hamper Changes in Body Composition on Supraphysiological Doses of Testosterone") was not a training study and that, given DHT's hitherto not fully elucidated role in satellite cell recruitment and proliferation, it is well possible that we would have seen differences in weight training athletes.To use these drugs as a means to bolster up your testosterone levels is therefore not just risky and irresponsible, but plain out stupid.
• ATD (1,4,6-androstatriene-3,17-dione): Yes, surprisingly the potent anti-estrogen (aromatase inhibitor) and much-touted testosterone-booster ATD is a relatively potent anti-androgen. You can read all about ATD's anti-androgenic effects in an older blogpost here at the SuppVersity: "Anti-androgenic effect of ATD"
   
• Chaste tree (Vitex agnus-castus): Also sold to help your testosterone levels along, yet even more to counter the scientifically hitherto non-established phenomenon of "progesterone gyno", Vitex is another relatively commonly used supplement of which a 2007 study by Nasri et al. shows that it will probably reduce, not increase your luteinizing hormone (LH) and testosterone levels in parts, but not exclusively via dopaminergic pathways (Nasri. 2007)
• Green Tea (Camellia sinensis): As a diligent student of the SuppVersity you will already be aware of the differential effects of green tea and its catechins on serum testosterone levels; if you are interested, in the details you can read them up in "5 Cups of Green Tea Can Reduce Testosterone by Up to -20%"
• Licorice (Glycyrrhiza glabra): The phytoestrogens in licorice have been shown to reduce testosterone levels in women; glycyrrhizin and glycrrhetic acid exhibit anti-androgen effects in healthy (Armanini. 2003) and diabetic men (Fukui. 2003)  - there is yet also counter-evidence coming from Josephs et al., who were "unable to reproduce" previous results showing a licorice reduced reduction in the conversion of androstenedione to testosterone (Josephs. 2001), since the latter does yet reference a previous study by Armanini et al. the results of which the latter were able to repdroduce in 2003 (Armanini. 2003), it is save to assume that licorice does in fact reduce testosterone levels in diabetic and healthy men and women; and that despite the fact, that a more recent study shows that its corticosteroid (cortisol) modulating effects are probably of greater relevance than its impact on the androgens and other sex steroids (Sigurjonsdottir. 2006)
• Red clover: Extracts from red clover exhibit potent binding affinity to the androgen and progesterone receptor and "theoretical estrogenic activity expressed as equivalent E2 concentration is in the same range as recommended for synthetic estrogen" (Beck. 2003)
• Reishi (LinghZi): Red reishi is supposed to be the mushroom with the greatest anti-androgenic activity. A methanol extract from Ganoderma lucidum has been found to decrease testosterone-to-DHT conversion by up to 80% in a 2005 study by Fujita et al. (Fujita. 2005)
• Spearmint (M. spicata): At least in women spearmint tea has been shown to increase estrogen and luteinizing hormone in the follicular phase of their menstrual cycle (Aktodgan. 2007). In a 2004 study that was conducted on male rodents, on the other hand, the daily administration of peppermint tea (M. spicata) for a period of 30days lead to significant increases in luteinizing and follicle stimulating hormone and increases in serum testosterone, yet with the serious downside of "extensive degenerative changes in the germinal epithelium and spermatogenesis arrest compared with the findings in the testicular biopsies of the control group" (Aktogan. 2003)
• Soy and soy phytoestrogens: It goes without saying that you won't take your girlfriends pill, right? So why do you even remotely consider eating soy, let alone supplementing soy phytoestrogens? "I've seen soy consumption cause impotency in numerous patients." - Dr. John Crisler (male hormone expert) on my facebook wall in response to Jefferson. 2012; avoid feeding soy to your male offspring at all costs (Sherill. 2010; Leraiki. 2011; Siepmann. 2011)
• White Peony (Paeonia lactiflora): Also known as Chinese Peony, the ornamental plant has been shown to contain at least two compounds, 6'-O-galloylalbiflorin and pentagalloylglucos, which bind to the androgen receptor and thusly inhibit its activation by testosterone, DHT and weaker androgens (Washida. 2009).
• Xenoestrogens & Co - BPA (Bisphenol A as in plastics), PCPs (as in cosmetics), etc.: Can inhibit testosterone production by reducing the conversion of cholesterol to androgens (Feng. 2012) and estrogen-like effects (Nakamura. 2010); similar effects have been reported for all sorts of so-called "xenoestrogens", these are synthetic compounds that act as (mostly weak) estrogens in the human body and can induce permanent damage to the endocrine system and resproductive system, specifically in young boys and adolescents. In grown up men and women they have been linked to the development of various forms of cancer (Donovan. 2007).

I know, "avoid this... avoid that..." does not sound half as sexy as "with just three caps of our product you can boost your testosterone levels by up to 123.741%!... but you know what? Other than those red gren, blue, yellow, red and white caps in their mostly black, as of late yet often white (probably to suggest "drug-like" effects) boxes, it's totally free and, more importantly, it works!

Dustasteride Doesn't Hamper Mass & Strength Gains on TRT, but Compromises the Fat Loss Effects of Testosterone and Does Not Reduce Any of the Side Effects

Image 1: I guess after the publication of his latest study, Mr. Bhasin will have a bad standing with the pharma reps from GlaxoSmithKline & Co ;-)

What happens if you take a couple of healthy guys and put them on a cycle... ah, pardon, I mean, "put them on hormone replacement therapy"? Assuming that you have paid attention in the seminars of the Intermittent Thoughts Series on Building Muscle (cf. "Preliminary Conclusion + Summary"), particularly the part "Quantifiying the Big T", it should not be difficult for you to answer: The guys will gain a few slabs of lean muscle mass! But what would happen if you added in some finasteride, or it's uber-potent cousin dustasteride? Will you gain more or less? Will you be protected from acne and prostate growth?

The "Big T" as in "Testosterone" or as in "Taboo"?

As an MD you are not supposed to ask these questions... you are not even supposed to put your male patients on TRT. What you are yet supposed to do is to believe in all the fairy tales the reps from pharmaceutical industry are serving you up with: "Testosterone replacement is dangerous! It is irresponsible [blablabla...], but if it really is necessary, make sure you also prescribe our newest 5-alpha reductase inhibitor [...]"... hold on, I wanted to refrain from the whimpering, so let's get to a real man, who does the balls to ask these questions and the boldness to do human trials to answer them: Shalender Bhasin!

Figure 1: Dose response relationship of muscle gain (in kg) per mg of testosterone enanthate; the white line indicates a dose that would probably have produce testosterone levels identical to baseline (calculated based on Bhasin. 2001)

If the above figure does not ring a bell, I suggest you do now go back to my article "Quantifiying the Big T" and familiarize yourself with Bhasins previous work.

Testosterone + Dustasteride = More Muscle and Less Prostate Growth?

In their latest study Bhasin et al. conducted an experiment that was actually pretty similar to their previous trial (Bhasin. 2012). The subjects were once more healthy, eugonodal (= normal testosterone levels) men, this time however from a broader age-range (18-50y; mean age ~40y) than in their previous trial (18-30y). The dosing protocol was identical (50, 125, 300 or 600mg/week testosterone enanthate) and even the treatment period, 20 weeks, was (I would guess) deliberately matched to that of the 2001 study on the dose-response relationship between exogenous testosterone administration and improvements in body composition (Bhasin. 2001).  I have discussed in length in the previously cited blogpost. The single innovation in this study was thusly the administration go 2.5mg of the potent 5-alpha reductase inhibitor dustasteride to 70 of the 139 subjects.

Image 2: Natural DHT modulation therapy
with rice, safflower & sorghum

A brief reminder for the "regulars" and a heads-up for all of you who do not get their daily dose of SuppVersity news, as of yet (a huge mistake, by the way ;-): If you have only minor problems with elevated (or too low) dihydrotestosterone levels, you may be interested in the results of a 2011 study which found that rice and safflower oils can inhibit 5-alpha reductase, while sorghum appears to boost the reduction of testosterone to the 10x more potent androgen DHT by 30-40%. If you want to know more, go back to my previous blogpost "Problems with High or Low DHT? Use Rice or Safflower to Inhibit and Sorghum to Promote 5-Alpha Reductase!" (click here to be redirected)

Contrary to what you probably think, the primary objective of the study was yet not to check if the pharma rep had been lying and dustasteride (or any other 5-ar inhibitor) would help prevent prostate cancer and other maybe less life-threatening, but not exactly easy to tolerate side effects allopecia or severe acne, but - you will hardly believe that - "to determine whether 5ar-reduction of testosterone to DHT is obligatory for mediating its effects on fat-free mass."

Figure 2: Increases in fat free mass and fat mass, as well as leg press and bench press strength (all values in kg) after 20 weeks on different doses of testosterone enanthate (50, 125, 300, 600mg/week) with or without 2.5mg of dustasteride per day (data adapted from Bhasin. 2012)

A brief glance at the data in figure 2 should suffice to answer this question with a definitive "no!" The subjects gained (dose-dependently) the same amount of fat-free mass and lean body mass (not shown in figure 1), but there was a statistically significant reduction in the testosterone-induced loss of body fat in the dustasteride group (p=0.05). Interestingly this difference is the most pronounced in the 300mg/week group, which is what a "bro" would probably call a "beginner cycle"... if you were thinking about (ab-)using testosterone to get in shape there would thusly be no reason to try to counter the reduction to DHT with a potent 5-alpha reductase inhibitor like DHT. After all, the strength gains were "identical" (p way above the p = 0.05 margin of statistical relevance, cf figure 1, right), as well and...

Table 1: Incidence of side effects in the subjects of the two study arms (adapted from Bhasin. 2012)

... if you look at the number of unpleasant side effects in the two groups in table 1, you will notice that even those won't be diminished if you block the reduction of testosterone to the "all things male" hormone DHT.

"And what about my prostate and cholesterol levels?"

Although Bhasin et al. defined the effects of dustasteride administration on the "maintenance of androgen effects on sexual function, hematocrit, sebum production, bone markers, and lipid levels" as their secondary outcomes and winked at the potential increases in prostate size, they did not make themselves even more vulnerable to the attacks from the anti-TRT crowd by simply ignoring this issue and did measure the prostate sizes before and after the 20-week intervention by the means of magnetic resonance imaging and found that...

[...c]hanges in prostate volume and PSA level were not significantly related to either testosterone dose or concentration, and did not differ significantly between the placebo and dutasteride groups. The dose-adjustment mean difference in change in PSA level between participants assigned to placebo and participants assigned to dutasteride was 0.13ng/mL (95% CI, −0.05 to 0.31 ng/mL; P = .15) and the corresponding difference in changes in prostate volume was 0.91 cm³ (−0.44 to 2.25 cm³; P = .19).

The incidence of acne (sebum production) was identical (25 subjects in both groups) and the "acne scores did not differ between groups." Lastly, the levels of "hemoglobin and hematocrit increased dose dependently in the placebo and dutasteride groups" and did "not differ significantly between the groups". In view of the fact that the dose-dependent decreases in total and HDL were also identical between the groups and neither the serum NTx (collagen-type I N-telopeptides), nor the osteocalcin levels were hampered or promoted by the addition of dustasteride to the TRT regimen, there appears to be no reason for an otherwise healthy man to take a drug, which in and out of itself can produce serious and in rare cases even permanent side-effects (cf. "Finasteride Kills Male Libido Permanently").

Don't Base Your Judgement on Hearsay and the Results of Others - Get Labs Done!

That being said, there are certainly cases, where the enzymatic cascade is messed up and the more or less uncontrolled over-production of dihydrotestosterone would not only compromise the beneficial of injectable testosterone, but pose a serious health risk. Especially for those of you who are on TRT for medical reasons (and by the way, there is no such thing as a "trenbolone deficiency", bros ;-), it would thusly be prudent to base your decision for or against an 5-ar inhibitor on your individual serum levels... and, regardless of whether you decide to take or to decline your MD's offer, you better make sure that your testosterone is not shoveled to the other, the estrogenic side of the hormonal divide!

Intermittent Thoughts: Dihydrotestosterone (DHT) - Bigger, Stronger, Faster or just Balder, Fatter and Unhealthier?

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.

I guess after the revelations about the importance of estrogen in the process of skeletal muscle hypertrophy in the last installment of the Intermittent Thoughts you will probably be eager to hear what its male counterpart dihydrotestosterone (DHT), is able to do... I mean, with DHT being the male hormone par excellence it is only reasonable to assume that its effects on skeletal muscle mass and strength, two characteristic features of the male persuasion, must be significant, right? Before we are going to address this vitally important questions, let's briefly take a look at what the dihydrotestosterone actually is.

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)...

Illustration 1: (1) Testosterone (either preformed or locally formed from DHEA) arrives at the target tissue, (2) is reduced to DHT by one out of three locally expressed reductase enzymes and (3) either acts intracrine, i.e. right inside the cell, where it was formed or is released into circulation.

I do not want to lose myself in too many details at this point, but a rough grasp of the local reduction of testosterone and the subsequent intracrine (meaning right where the hormone is created, cf. illustration 1) effects of DHT is of paramount importance to understand some of the initially counter-intuitive effects of DHT, you are going to read about in the following paragraphs.

"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)

As the data in figure 1 goes to show, incubation of isolated rat myofibers with 630pg/ml androstanolone (17β-hydroxy-5α-androstan-3-one, DHT) increased the isometric force (P0 = 100%) of the fast twitch muscle fibers in the EDL from both male and female mice by ~30%. If we take a look at the SuppVersity's Motto  "Where Bro- and Pro-Science Meet in the Spirit of True Wisdom", this is thusly one of the (as of late rare) occasions, where bro- and pro-science actually "meet", not "clash", in the "Spirit of True Wisdom".

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)

The experiments also revealed that, despite the increase in p-ERK-1/2 in the slow-twitch muscle fibers, testosterone treatment did not induce similar changes in myosin light chain content like DHT. In view of the fact that the scientists have used female DGL and soleus muscle fibers for this experiment to minimize the local reduction of DHT to testosterone and isolate the effects of DHT, it should also be stated that the last-mentioned effects on slow-twitch fiber ERK-1/2 phosphorylation may well be a downstream effect of the aromatization of testosterone to estrogen (cf. "Estrogen: Friend or Foe of Skeletal Muscle Hypertrophy").

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 (!)

Now, if you take a look at these examples and compare that to what you know about the muscle-building effects of testosterone, it should be obvious why most "chemical athletes" (i.e. steroid users) take 5-ar inhibitors like finasteride when they are "on" high doses of testosterone. Since the latter will reduce the circulating levels of DHT by "only" 50% this practice allows them to keep any unwanted DHT-related androgenic side effects (which are going to occur when you reach supra-physiological DHT levels) at bay, while still having enough 5-alpha reductase activity to benefit from the highly appreciated effects on muscle strength.

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 muscle is obviously not the only thing you want... and when it comes to DHT, hair, respectively the loss of the latter, obviously is the first thing that comes to mind. Notwithstanding that it is an established fact that bathing your hair follicles in excess amounts of dihydrotestosterone will eventually kill them, you may be surprised to hear that a 1992 paper by Knussmann et al. (Knussmann. 1992) showed that contrary to common believe the correlation between allopecia and serum DHT levels in the 110 healthy young men in their study is a negative one (r = -.25, p < 0.01). Yet although the same is true for total testosterone (r = -.25, p < 0.01), the correlation between the ratio of free / total testosterone (T_free/T_total) is positive and statistical significant (r = .02; p < 0.05)!

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...

Problems with High or Low DHT? Use Rice or Safflower to Inhibit and Sorghum to Promote 5-Alpha Reductase!

Image 1: High or too low DHT levels? Nature has the cure for both. Lower your DHT levels with rice bran or safflower flower extracts or raise it with a crude extract from Sorghum bicolor seeds.

Hairloss for men, and even more so for women, is certainly one of the nastiest side effects of either naturally or artificially induced hormonal disturbances. And while the vilification of DHT as the #1 inducer of male pattern baldness and a potential cause of female hair loss may be overblown, it is a well-established fact that (over-)expression of DHT, or rather a high / over-activity of the 5a-reductase enzyme which converts testosterone to the ~10x more potent androgen dihydrotestosterone will, over time, lead to a shrinkage and gradual disappearance of affected hair follicles. In that, it is noteworthy that similar to the carcinogenic effects estrogen exerts on female (and male) breast tissue, it is mostly the local and not so much the systemic reduction of testosterone to DHT, or, in the case of estrogen, the "aromatization" of testosterone into estrogen, which causes the problems.

In view of the fact that DHT appears to play a role in the etiology of prostate cancer, as well the results of test-tube studies on the effects of rice and safflower extracts on the 5a reductase in human DU-145 prostate cells Warintorn Ruksiriwanich and his colleagues present in their latest paper in The Journal of Supercritical Fluids, could well hold the key to natural alternatives to the currently available pharmacological 5a-reductase inhibitors finasteride and dustasteride (Rukisiriwanich. 2011).

Rice and safflower extracts are potent 5a-reductase inhibitors

In their initial experiment the researchers had determined that of the 10 edible plant crude extracts they had prepared by either supercritical carbon dioxide fluid (scCO2) low temperature treatment or ethanolic maceration, the rice (Oryza Sativa L.) and the Safflower (Carthamus tinctorus L.) which had been prepared by the scCO2 method yielded the largest amount of unsaturated fatty acids (cf. figure 1):

Figure 1: Fatty acid composition (left) and total polyphenol content (right) of the ten edible plant extracts after scCO2 processing (data adapted from Rukisiriwanich. 2011).

The sorghum (Sorghum bicolor L.) extract took a close third place, but lacked the gamma-linoleic acid (GLA) content which sets the rice and the safflower extracts apart from peanuts, soybeans, flax, lotus, sesame, and, obviously, corn. The sunflower extract, on the other hand, had the highest total phenolic content, but lacked the "essential" polyunsaturated fatty acids, of which we are going to see that they are the driving forces behind the 5ar inhibition both the rice, as well as the safflower extracts exerted on the prostate cells upon incubation at 0.1mg/ml (cf. figure 2):

Figure 2: 5a-reductase activity of essential fatty acids, pharmacological agents and rice, safflower and sorghum extracts and respective fractions (data adapted from Rukisiriwanich. 2011).

If you scrutinize the results in figure 2, you will notice that further processing (fractions #1 to #4; intended to produce an even more concentrated and thusly more potent extract) did not improve the inhibitory effect of the crude rice extract and profoundly reduced the anti-5ar activity of the safflower extract. In view of the fact that, at the given dosage of 0.1mg/ml the crude rice and safflower were more potent than their pharmacological rivals, dustasteride and finasteride, this is yet another item to be added to my never-ending list of evidence for the genuine truth behind my favorite saying: Nature knows best!

Image 2: If you look like this, you better go
get some sorghum bicolor extract, right away ;-)

Sorghum increases 5a-reductase by more than 50%!

Moreover, nature appears to be similarly aware of the fact that ridicolously low levels of the male hormone par excellence are likewise undesirable for men - pseudohermaphroditism, an extreme case of which you can see in image 2 is one of the common consquences of low / lack of 5ar in men (cf. Sinnecker. 1996). I mean how else would you explain that she invented Sorghum bicolor, a grass species that originated in northern Africa, and is now cultivated widely in tropical and subtropical regions turns out to increase 5a-reductase activity by at least 54%?

How does this work? I mean is there finasteride in rice?

These astonishing results raise the question what exactly is responsible for these non-negligible effects of the plant extracts. To answer this question the scientists performed one of their "dreaded" correlation analysis (you know that is what the American Heart Health Association sponsors to then confuse correlation with causation and tell us that cholesterol causes heart disease ;-) and came up with a whole bunch of highly correlated variables (Pearson coefficients >0.9). Of the 10 tested variables, the linoleic and total unsaturated fatty acid content of the crude rice, as well as the same ingredients in fraction #3 of the crude rice extract were yet the only ones which showed a significant (p < 0.05, crude extract) and highly significant correlation (p < 0.01, fraction #3) with the 5ar activity of the respective compounds.

The fact that these statistical shenanigans did not yield significant correlations for any of the ingredients of the crude safflower extract and its inhibitory effect  (which by the way was within one standard deviation identical to the one of the rice extract!) on 5a-reductase makes me question the validity, or I should say "significance" *rofl* of this analysis. After all, their own analysis, as well as previous studies (e.g. Pham. 2002) clearly show that on a mg/ml base gamma linoleic acid (GLA) is a much more potent inhibitor of 5a-reductase activity than linoleic acid... but hey, why even bother? I mean, if nature knows best, anyway, let's just trust her and rely on the crude extracts - or should I say "nature's proprietary blends". I guess, if Oryza sativa bran or Carthamus tinctorus flower extracts prevent your hair from falling out and your prostate from carcinogenic growth, or a crude extract from Sorghum bicolor seeds effectively restores your virility, you probably won't care if it was the LA, the GLA or whatever else nature has packed into the bran, flower and seeds that was responsible for these effects - the only caveat is in vivo human data is still lacking ;-/