Science Round-Up Seconds: Nicotine's Effect on Brain Aromatase & the Consequences, 2D:4D Digit Ratio Predicts Testosterone Response to Sprinting and All the Anti-Obesity & Pro-Brain Effects W/ Just 2 Cups of Coffee per Week?

Wallaby Lachie Turner (left), Greg Inglis (centre) & Jarryd Hayne (Stuff.co.nz) - who would have thought that the relative length of their 2nd and 4th digit could predict their testosterone response after the sprint? Not you? Well, then you got to check out the first of the short-items at the bottom.

Those of you who have listened to yesterday's installment of the SuppVersity Science Round-Up on Super Human Radio, will have realized that the show did - as usual - take a somewhat different direction than originally planned. Before I get to the actual SuppVersity Round-Up Seconds, of which there actually weren't all too many I consider absolutely newsworthy and appropriate for a written format, I thought I would briefly mention the paper on which I based the hypothesis (remember: this is nothing certain) that there may be a link between the calcium-influx into the muscle and the strength and hypertrophy effects of performance enhancing drugs (spec. those with a high anabolic : androgenic effect ratio) - for those of you who may want to follow up on this hypothesis or think Carl and I were just making things up ;-) 

The study I refer to shortly after the last break (download the podcast), was conducted by a group of researchers from the Instituto de Ciencias Biomedicas at the Universidad de Chile in Santiago de Chile, dealt with the modulatory effects of testosterone (and aldosterone) on intracellular calcium response in skeletal muscle cell cultures and not the subsequent consequences on contractile force of hypertrophy and could thus only serve as a point of departure for future investigations to either confirm or refute this idea (Estrada. 2010).

Nicotine exposure, brain aromatase and gender-specific implications

With the advent of new technologies, esp. the direct observation of aromatase activity in primate brains (Lidstrom, 1998; Kim, 2009; Biegon, 2010), our understanding of the peripheral effects of certain substances on hormone metabolism, one of the latest such insights pertains to the effects of nicotine exposure on the expression of the aromatase enzyme in the brain.

Figure 1: Effect of nicotine on brain aromatase availability in the female baboon. Representative baseline PET image coregistered with MRI at baseline and following injection of low dose (0.015 mg/kg) or high dose (0.03 mg/kg) nicotine. PET images show averaged frames acquired between 52.5 and 90 min after tracer injection, pseudocolored using the rainbow spectrum, with purple indicating the lowest density and red indicating the highest density of radioactivity (from Biegon, 2010).

In a recently published paper scientists from the Brookhaven National Laboratory Upton in New York did now connect the dots between the previously observed direct inhibitory effects on the central expression of the CYP19a mediated expression of the aromatase enzyme of nicotine and (potentially) other tobacco alkaloids. Thus, Anat Biegon, Nelly Alia-Klein and Joanna S. Fowler are not only able to explain, why women are more susceptible to the addictive effects of the nicotinic acetylcholine receptor agonist, which accumulates in the leaves of several members of the Solanaceae (nightshade) family, than men, but observations such as the early onset of menopause and lower plasma estrogen levels and correspondingly higher osteoporosis risk in female smokers compared to their non-smoking peers, as well (Daniell. 1972; MacMahon. 1982; Nusbaum. 2000; Pant. 2008; Korkor. 2009).

Table 1: Comparison of the effects of nicotine exposure and the effects of an aromatase inhibitor (at different time points in life) on sexual behavior, anxiety and depression, hot flashes, and weight gain in men and women (Biegon. 2012)

The scientists also list a couple of other ascertained side-effects pertaining which are equally important to men and women: The sexual behavior for example has been shown to drop both in response to prenatal, as well as acute nicotine exposure in male mammals - something those of you who happen to have a prescription for an aromatase inhibitor as an adjunct to their TRT regimen and did not hit the sweet spot between too much and too little estrogen, will certainly be aware of. While anecdotal evidence clearly points into that direction the scientific consensus on the negative impact of aromatase inhibitors on male libido in men (not male rodents), is however not yet clear. Personally, I believe this is partly due to the fact that pertinent studies usually deal with subjects who reduce their estrogen levels to normal, which could in fact lead to increased testosterone and DHT level in the absence of any negative side effects on the patients' libido.

If you take a look at the overview in table 1, you will however realize that other effects as the anxiolytic effects of acute nicotine exposure in adult women or the weight loss effect (which is certainly another reason women like to smoke) stand in direct opposition to the hypothesis that the majority of nicotines beneficial and negative side-effects were mediated by its effects on the aromatase enzyme. Fortunately, for most smokers, this appears to apply to the pro-Alzheimer's effects of low brain aromatase (Hiltunen. 2006), as well - at least, if we go by the conflicting results of the latest epidemiological studies, which contradict earlier findings that did even suggest that smokers would have a lower risk of Alzheimer's disease.

Alzheimer's, dementia, etc. are yet only examples of the far reaching effects brain aromatase and its regulation by nicotine and other substances such as aromatase inhibiting drugs, but also all sorts of environmental toxins with endocrine side-effects could have - so you can easily expect more interesting study results in the future.

Other news that did not make it into the show

As I have mentioned in the introduction, we did cover a hell lot of ground, so that most of the other studies are directly related to the luteinizing hormone negative feedback and thus no real "news" - I skipped discussing those, since I though that everyone listening will get the main message and did not want to bore those of you who are not interested in this topic with a show solely on the effects of nutrient deprivation and exercise on the endocrine milieu. But enough of the excuses, there is still more:

• Right-left digit ratio (2D:4D) predicts testosterone response to exercise in 79 professional Rubgy players (Kilduff. 2012) - In the analysis, researchers from the Swansea University at the Sports Science, Talbot Building in Singleton Park,  Swansea, UK, found that despite significant differences in basal testosterone levels, the 2D:4D ratio, which is generally regarded as an indicator of in-utero androgen exposure was significantly associated with a lower testosterone response to repeated sprint-agility tests in the 25 subjects who participated in the active arm of the study.

• Caffeine prevents weight gain and cognitive impairment by high fat diet (Moy. 2012) - This is not news? Just read on, you will soon realize that it is news! Firstly, the scientists from the University of Albany identified an ameliorative effect of caffeine on the diet-induced reduction of hippocampal expression of the brain-derived neurotrophic factor (BDNF) as the underlying mechanism behind it's neuroprotective effect (the same stuff that's also increased by exercise, by the way).
  
  

  

  Figure 2: Assuming this is not a mistake in the study caffeine once a week would be enough to boost the BDNF levels of junk-food and normal eaters alike (Moy. 2012)

  And secondly, the rodents received only a single, weekly intraperitoneal injection that would be equivalent to ~250mg in a human being (I double checked, the study says: "All animals received either caffeine (20 mg/kg) or saline (volume-matched), i.p., once weekly."; my emphasis in Moy. 2012). If that's not a mistake, chronic caffeine consumption may not even be necessary to see a hell-lot of the anti-diabetes and anti-neurological damage effects of coffee - just 2 cups once per week that's it!
  
  And if you look closely at the data in figure 2 you see that even "normal" people may benefit from this regimen.

Since tomorrow is an official installment of "On Short Notice" due, I will leave you on that flabbergast caffeine study and just remind you that there is - as everyday (guaranteed even on Christmas ;-) tons of interesting new stuff on the SuppVersity Facebook Wall, as well - let's see what we have today:

• Insulin has anti-Alzheimer's effect - Yeah you read me right. It reduces the formation of ameliod beta plague (read more)
• Yet more plant extracts with natural anti-cancer activity: Chamaejasmenin B and neochamaejasmin C isolated from the root of Stellera chamaejasme L known in TCM as Rui Xiang Lang D (read more)
• Want to father a Nobel Laureate and in your early to late 30s? Than its about time you procreate! Study finds U-shaped curve for father's age and intellectual abilities of the offspring peaking at 32-37 years or so (read more) 
   
• ...plus the rest I did not mention (read all)

I guess with the podcast to listen to and some food for thought on once-weekly caffeine administration (on a side note, injecting into the intraperitoneal cavity is, for most substances, only minimally different from oral ingestion and done only to assure that the animals don't spit whatever you want them to ingest back out) you will survive the next couple of hours until the facebook news will receive another update and the next installment of "On Short Notice" is going to be published? If not, complain in the comment area ;-)
 
References:

• Biegon A, Kim SW, Alexoff DL, Jayne M, Carter P, Hubbard B, King P, Logan J, Muench L, Pareto D, Schlyer D, Shea C, Telang F, Wang GJ, Xu Y, Fowler JS. Unique distribution of aromatase in the human brain: in vivo studies with PET and [N-methyl-11C]vorozole. Synapse. 2010 Nov; 64(11):801-7. 
• Biegon A, Alia-Klein N, Fowler JS. Potential contribution of aromatase inhibition to the effects of nicotine and related compounds on the brain. Front Pharmacol. 2012;3:185.
• Daniell HW. Osteoporosis and smoking. JAMA. 1972 Jul 31;221(5):509.
• Estrada M, Liberona JL, Miranda M, Jaimovich E. Aldosterone- and testosterone-mediated intracellular calcium response in skeletal muscle cell cultures. Am J Physiol Endocrinol Metab. 2000 Jul;279(1):E132-9.
• Hiltunen M, Iivonen S, Soininen H. Aromatase enzyme and Alzheimer's disease. Minerva Endocrinol. 2006 Mar;31(1):61-73.
• Korkor AB, Eastwood D, Bretzmann C. Effects of gender, alcohol, smoking, and dairy consumption on bone mass in Wisconsin adolescents. WMJ. 2009 Jul;108(4):181-8.
• MacMahon B, Trichopoulos D, Cole P, Brown J. Cigarette smoking and urinary estrogens. N Engl J Med. 1982 Oct 21;307(17):1062-5.
• Moy GA, McNay EC. Caffeine prevents weight gain and cognitive impairment caused by a high-fat diet while elevating hippocampal BDNF. Physiol Behav. 2012 Dec 6.
• Nusbaum ML, Gordon M, Nusbaum D, McCarthy MA, Vasilakis D. Smoke alarm: a review of the clinical impact of smoking on women. Prim Care Update Ob Gyns. 2000 Sep 1;7(5):207-214.
• Pant S, Shapiro CL. Aromatase inhibitor-associated bone loss: clinical considerations. Drugs. 2008;68(18):2591-600.
• Roselli CE, Abdelgadir SE, Ronnekleiv OK, Klosterman SA. Anatomic distribution and regulation of aromatase gene expression in the rat brain. Biol. Reprod. 1998; 58, 79–87.
• Roselli CE, Resko JA. Cytochrome P450 aromatase (CYP19) in the non-human primate brain: distribution, regulation, and functional significance. J. Steroid Biochem. Mol. Biol. 2001; 79, 247–253.

 

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.

1.3g of Grape-Seed Extract Could Protect You From Oxidative Damage, Viral Infections, Obesity and Insulin Resistance, Reduce Your Heart Rate and Blood Pressure and Increase Your Nitric Oxide Production by >25%

Image 1: Bought in bulk, grape-seed extract is actually reasonably cheap... and it does not even taste as awful as some other herb / seed extracts ;-)

After initially being hailed as the yet another anti-oxidant panaceum, grape-seed extract (GSE) has been displaced by newer, fancier "superfoods" from the headlines of the major health and wellness newscasters. Therefore, even you, as a highly self-educated student of the SuppVersity could have missed out on a handful of recently released studies which reported antiviral effects of GSE (Su. 2011) and confirmed its ameliorative effect on diet-induced obesity (Ohyama. 2011) and (high) fructose-induced insulin resistance (Meeprom. 2011). Moreover, a meta-analysis of nine controlled with more than 300 human subjects and daily doses ranging from 250mg to 2,000mg of GSE, which was published in the Journal of the American Dietetic Association (Feringa. 2011), found that ...

[b]ased on the currently available literature, grape seed extract appears to significantly lower systolic blood pressure and heart rate, with no effect on lipid or CRP levels.

These results suggest that we (at least some of) the beneficial health effects that have been observed in rodent studies actually translate to human beings - something  we cannot (yet?) say for some of the next generation "panacea" ;-) This is also important in view of the significance of the results GSE-administration had on exercise-induced oxidative stress in a more recent study by scientists from the universities of Konya and Dicle in Turkey (Belviranli. 2011), which was published in the latest issue of the British Journal of Nutrition.

The experiments were carried out with 64 adult male Sprague Dawley rats who were randomly assigned to one of the following six groups:

• sedentary control (C, n=10), 
• chronic exercise control (CEC, n=11), 
• acute exercise control (AEC, n=11), 
• GSE-supplemented control (GC, n=10), 
• GSE-supplemented chronic exercise (GCE, n=11), and 
• GSE-supplemented acute exercise (GAE, n=11)

The rats in the treatment groups received a standardized GSE extract containing 54% dimeric, 13% trimeric, 7% tetrameric and <5% monomeric proanthocyanidines and undisclosed amounts of cathechines and oligomeric proanthocyanidines, at a daily dose of 100mg/kg body weight in their drinking water for 6 weeks.

Image 2: Click here to learn how to calculate human equivalent doses (HED)

Rat to human equivalent dosage calculation: If you have already read my dissertation on how to calculate the so-called human-equivalent-dose (HED), you will probably already have whipped out your calculator and are just about to type "100mg times the K-value for rats, which is 6; divided by the K-value for humans, which is 37" ... and what does your calculator tell you? Correct! The HED of 100mg/kg GSE in rats is 16.33mg/kg - in other words, if you weigh 80kg you will have to take roughly 1,300mg of grape-seed extract per day to mimic the dosage that was used in the study.

The dosage, according to the scientists, was chosen because it had elicited beneficial anti-oxidant effects in previous studies on alloxan induced diabetes (El-Alfy. 2005) and age-related oxidative damage (Balu. 2006). And, as Belviranli et al. had suspected, it exhibited similar protective effects against the oxidative stress triggered by both chronic, 5x a week treadmill exercise at 25m/min for 45 minutes, as well as, acute running on the treadmill at 30m/min until exhaustion.

Figure 1: Effects of acute or chronic exercise and grape seed extract (GSE) supplementation on plasma malondialdehyde (MDA) levels (data calculated based on Belviranli. 2011).

As you can see in figure 1, administration of 100mg/kg grape-seed extract per day augmented the beneficial effect of 6 weeks of chronic exercise on muscle MDA levels (-37% vs. -18% in the control group) and ameliorated the acute +22% increase in MDA levels due to increased lipid peroxidation during exhaustive treadmill running.

Figure 2: Effects of acute or chronic exercise and grape seed extract (GSE) supplementation on plasma nitric oxide (NO) levels (data calculated based on Belviranli. 2011).

GSE supplementation also increased the expression of nitric oxide (NO in  plasma; on average +25%) in all animals (cf. figure 2). Moreover, GSE ameliorated the increase in xanthine oxidase and adenosine deaminase activities due to acute exercise and triggered an overall increase in antioxidant enzyme activities.

So, even if your favorite anti-aging and health (onilne-)magazine or vendor appears to have forgotten about grape-seed extract. For a physical culturist like you and me, it may yet well be worth to (re-)include the extract from the seeds of the fruits of Vitis vinifera, which are a particularly rich source of vitamin E, linoleic acid and, most importantly, oligomeric proanthocyanidins, into our supplement regimen. And if the current study does not convince you, it may help, if I remind you of the 2006 study by Kijima et al. who were able to show that GSE due to its anti-aromatase activity can suppress tumor growth in a breast cancer model (Kijima. 2006) ... ah, and before I forget: don't be stupid and buy over-priced caps. Use google and find yourself a source of bulk grape-seed extract - don't worry the taste is not all too bad ;-)

T-Gel with or Without an Aromatase Inhibitor? If You Are Healthy & Lean and Want to Stay This Way, There is Only One Answer: T-Gel Without Aromatase Inhibitor!

Don't let her talk you into participating in studies that risk your manliness ;-)

Would you be willing to participate in a study, where you could end up without testosterone? No? Well me neither... strangely Joel S. Finkelstein et al. were able to find 198 healthy men between 20 and 50 years who were stupid enough to participate in an experiment, where they were randomized to placebo, or testosterone gel (1.25, 2.5, 5, or 10g per day) while being on gosererelin acetate, which did suppress their natural testosterone production.

With additional 202 subjects receiving an identical "treatment", but in this case alongside a whoppy dose of the aromatase inhibitor anastrazol as a bonus, the study design leaves us with plenty of groups and tons of subjects. To "determine the relative degree of testosterone deficiency, estradiol defi­ciency, or both at which undesirable changes in body composition, strength, and sexual function begin to occur." (Finkelstein 2013)

Yep, that is the study you don't not want to be part of, but....

I bet you will still be interested in the results. Am I right? Ok, let's see then. In men receiving goserelin acetate (kills the natural testosterone production) and 0 g (pla­cebo), 1.25 g, 2.5 g, 5 g, or 10 g of testosterone gel daily (cohort 1), the mean testosterone levels were

• 0g testosterone: 44±13 ng per deciliter, 
• 1.25g testosterone: 191±78 ng per deci­liter
• 2.5g testosterone: 337±173 ng per deciliter, 
• 5g testosterone 470±201 ng per, and
• 10g testosterone 805±355 ng per deciliter

With 1.4 pg per milliliter, 7.9±2.9 pg per mil­liliter, 11.9±5.7 pg per milliliter, 18.2±10.2 pg per milliliter, and 33.3±15.3 pg per milliliter the estrogen levels of all participants were all well within the normal range (<55pg/ml).

Update: As Dr. Crisler (www.allthingsmale.com) just told me the accuracy of the information about estrogen may be questionable, because the essay the scientists used is not reliable in adult men. Instead, he suggest you use a "sensitive" essay like LabCorp (#500108), which uses the "cutting edge" LC/MS technology, Mayo Clinic's "Enhanced Estradiol" (#81816) or LabCorp's "Sensitive Estradiol (#140244), which is less expensive and thus probably a good choice for those without insurance. Dr. Crisler also pointed out that the wide variations you see in T-levels are actually a "very good thing, since this more closely mimics the serum profile of young healthy men". I do not deny that, but I still thought that it was wise to point out that the difference between 805ng/dl and 924ng/dl is absolutely non-significant when you have a range of ±521ng/dl.

Now the latter was obviously true for the guys on the aromatase inhibitor as well, with 1-2pg/ml their levels were however pathologically low and considering the high standard deviations, their T-levels were not that much higher:

Figure 1: Testosterone (ng/dl) and estrogen (pg/ml x10) in healthy men on 0, 1.25, 2.5, 5 and 10g (T0-T10) of testosterone gel with and without an additional aromatase inhibitor (Finkelstein. 2013)

"In men who also received anastrozole (cohort 2), the corresponding mean testosterone levels were 41±13 ng per deciliter, 231±171 ng per deciliter, 367±248 ng per deciliter, 485±240 ng per deci­liter, and 924±521 ng per deciliter and the corresponding mean estradiol levels were 1.0±0.4 pg per milliliter, 1.2±0.4 pg per milliliter, 2.0±2.3 pg per milliliter, 2.1±1.9 pg per millili­ter, and 2.8±1.8 pg per milliliter." (Finkelstein 2003)

[*please note the high (up to 50%!) standard deviations which tell you that the response to transdermal testosterone may vary profoundly from one men to another]

If you take a closer look at the data in Figure 1 and keep in mind that I had to multiply the estrogen levels by x10 in order to fit them into the same graph, it becomes all the more evident that the men in the non-AI group all had normal (<55pg/ml) estrogen levels. Their peers in the anastrazole group, on the other hand, had basically no estrogen at all and correspondingly high testosterone to estrogen ratios. In the worst case (yep, that is something bad!), namely 10g of t-gel + A,I the latter was as high as 335, which is almost 12x higher than in the 2.5g testosterone group without anastrazole (cohort 1).

No T, but tons of body fat

Apropos, cohort 1, in this group of men those who received the anti-androgen goserelin alongside a low(ish) doses of T-gel, i.e. either 0 g, 1.25 g, or 2.5 g of testosterone, daily, had significantly higher body fat levels and those in the 0 and 1.25g of T-gel significantly lower levels of lean mass compared to their peers in the 5g T-gel per day group.

Just a reminder: The testosterone level of the guys in the 5g group was only 470ng/dl and thus still rock bottom - the age adjusted normal levels for men are after all (I highlighted the group, where most of the subjects were in):

• 

  Effects of high and low testosterone on body composition (learn more)

  14-15 yr: 33-585 ng/dL
• 16-17 yr: 185-886 ng/dL
• 18-39 yr: 400-1080 ng/dL
• 40-59 yr: 350-890 ng/dL
• > 60 yr: 350-720 ng/dL

Those on the highest dose of T-gel (10g) ended up at the top (remember the standard deviations) of the normal range for testosterone and right in the happy medium for estrogen (normal range is 14-55pg/ml). These guys  experienced a significant decrease in body fat and increases in tigh muscle area and leg press strength.

Interestingly, both the decrease and increase in body in response to high and low testosterone levels occurred almost exclusively in the "benign" subcutaneous adipose tissue. The intra-abdominal­ fat area, on the other hand did not change significantly in any group. If we follow the standard interpretation of the health effects of the different body fat stores, the conclusion would thus be that low T is not so much of a problem, after all it's all "healthy fat" that you will gain... to bad that too much of that "healthy fat" will make you just as insulin resistance as the visceral fat - it just takes longer for the negative effects to occur.

Now what did the AI do?

Suggested read explaining why the annihilation of E2 has negative effects on your body comp: "Estrogen, Friend or Foe of Muscle Hypertrophy? Plus: Are You 'SERMing' Away Your Satellite Cells?" | more

I know, the most intriguing question has not been answered yet: What was the role of anastrazole in all this? And how did the subjects in cohort 2 fare compared to their "high" (remember even the 10g guys had normal estrogen levels) estrogen counterparts. Well,...

"In cohort 2, the percentage of body fat increased in all groups when the aromatization of testosterone to estradiol was inhibited. The magni­tudes of these increases were similar with doses of 0 g, 1.25 g, 2.5 g, and 5 g of testosterone daily, a finding that suggests a predominantly estro­genic effect" (Finkelstein. 2013)

Yep, I deliberately quoted this, because I know that you've been brain-washed to believe the opposite would happen. The big bad estrogen is what keeps you lean... good that you have been taking natural AIs for years, right? Well, no obviously not. Probably rather the reason that you still don't have the cover-model look you are aspiring.

---

Did you know that (a) the endogenous production of estrogens has significant protective effects on your heard cardiovascular health (Sudhir. 1999) and that (b) aromatase is neuroprotective and low levels of it have been associated with the occurance + progression of neurological diseases such as dementia, Alzheimer's and Parkinsons as well as an inability to recover from mechanic (trauma) or chemical (intlammation) damage to the brain (Azcoitia. 2001)? No? Well, let's hope that this is because you've never heard it and not because you've been abusing AIs for the past decade ;-)

So, to use an AI or not - is that even a question? A direct comparison of all the data from cohort 1 (no aromatase inhibitor) and cohort 2 (using anastrazole), informs us that

"The cohort–testosterone dose interaction was significant for the percentage of body fat (P = 0.001), intraabdominal­fat area (P = 0.021), subcutaneous ­fat area (P = 0.029), sexual desire (P = 0.045), and erectile function (P = 0.032)" (Finkelstein. 2013)

Or, to put it another way: The study shows us that estradiol exerts an inde­pendent effect on body fat, sexual desire and erectile function. So you better don't ignore the real world implications you are about to suffer, when you put too much faith in hearsay instead of looking at your actual blood levels:

"In the groups that received testosterone, inhibi­tion of estrogen synthesis (cohort 2), as com­pared with intact estrogen synthesis (cohort 1), was associated with significant increases in the percentage of body fat (P<0.001), subcutaneous­ fat area (P<0.001), and intraabdominal­fat area (P = 0.002) and with significant decreases in sexual desire (P<0.001) and erectile function (P = 0.022)" (Finkelstein. 2013)

Yes, you heard the scientists right. Suppressing your estrogen levels is going to make you fat, rob you of your sexual desire and render you unable to perform the deed.

At the same time it had no beneficial effect on the increases in lean body mass or strength or any other positive outcome the subjects got from using T-gel. On the contrary, the low estrogen levels on in the 10g T-gel group did actually blunt reduce the lean mass gains and the fat loss the men in cohort 1 (no anastrozole) experienced, when they used 10g of T-gel per day was effectively reversed by the AI.

Figure 2: Fat gain, lower lean mass gain, less sexual desire & lower sexual function (not shown) and the list goes on... there really is nothing remotely beneficial about low estrogen (figures from Finkelstein. 2013).

It should thus be absolutely obvious that the only reason you should use an aromatase inhibitor with your testosterone replacement therapy is blood work that indicates that you have serious issues with over-aromatization. In many cases those can be reduced if not solved by (a) reducing inflammation and (b) getting rid of your belly.

To deliberately annihilate your estrogen levels, on the other hand, is simply stupid - irrespective of whether you are on TRT or not and even if you don't care about the negative long-term effects on your brain and heart health.

References:

• Azcoitia I, Sierra A, Veiga S, Honda S, Harada N, Garcia-Segura LM. Brain aromatase is neuroprotective. J Neurobiol. 2001 Jun 15;47(4):318-29.
• Sudhir K, Komesaroff PA. Clinical review 110: Cardiovascular actions of estrogens in men. J Clin Endocrinol Metab. 1999 Oct;84(10):3411-5. Review.

Melatonin As Potent as Letrozole in Inhibiting Aromatization of Testosterone to Estrogen - This Raises the Question: Is a Lack of / Bad Sleep to Blame for Breast Cancer?!

Sleeping for 7-8h w/out interruption in a pitch black room to max. your melatonin is the best breast cancer prevention.

It may sound hilarious to the next best average Joe, but the study results Suthat Chottanap and colleagues from the Chulabhorn Graduate Institute are about to present in one of the next issues of Toxicology in Vitro confirm what SuppVersity readers already knew: It's more than likely that there is a direct link between a lack of quality sleep as people who are working shift works have it and the risk of breast cancer.

The latter increases in women who do not sleep during the period of the night when melatonin levels are typically at their highest by ~14% (Davis. 2011), an observation that appears only logical in view of what I am about to tell you today.

You can learn more about sleep and the circadian rhythm at the SuppVersity

Sunlight, Bluelight, Backlight and Your Clock

Sunlight a La Carte: "Hack" Your Rhythm

Breaking the Fast to Synchronize the Clock

Fasting (Re-)Sets the Peripheral Clock

Vitamin A & Caffeine Set the Clock

Pre-Workout Supps Could Ruin Your Sleep

Among various naturally occurring, biologically active compounds, resveratrol and melatonin have been suggested to act as aromatase inhibitors, which make them potential candi-dates in hormonal treatment of breast cancer.

These previous observations were the actual reason why Suthat Chottanap and colleages set up a handful of petri-dishes in which they a co-culture model primary human breast adipose fibroblasts (BAFs) with testosterone and melatonin or resveratrol. It has long been known that these fat cells from the breast tissue can convert testosterone to estradiol, and do thus contribute to the estrogen receptor-mediated growth and proliferation of of breast cancer T47D cell proliferation.

Figure 1: Anti-aromatase effect of resveratrol vs. melatonin (1000x lower dosage; left) and anti-proliferative (=anti-growth) effects of melatonin in breast cancer cells (Chottanapund. 2014)

As the data in Figure 1 shows, this nasty side effect of the presence of testosterone and the fat aromatase factories, the BAFs, was countered by both melatonin and resveratrol, albeit at different levels of the "drug".

• for resvertrol the scientists needed a concentration of 20µM, i.e. 20 microMol = 0.000002 Mol and thus 1000x more(!) than for melatonin
• for meltonin a concentration of 20nM, i.e. 20 nanoMol = 0.000000002 Mol was sufficient

Now that alone is pretty astonishing. In the end, you could argue, however, that it would only confirm what we already knew: Resveratrol is a much less potent "wonderdrug" than the hype in mainstream media makes it look like.

What really makes the results outstanding, though, is that melatonin was as potent as letrozole, the most potent antiaromatase inhibitor the publicly available pharmaceutical arsenal knows in suppressing cell proliferation, estradiol (E2) production and gene expression of CYP19A1, pS2andKi-67. No wonder that the Thai authors of the paper at hand are convinced that "melatonin clearly offers potential advantages for breast cancer treatment". And this assumption is supported by both the often-reported association between increased breast cancer risk and shift work and the inverse correlation between the risk of breast cancer and urinary melatonin levels Eva S. Schernhammer and Susan E. Hankinson report in a 2005 paper - a correlation, which remained significant even when the women who had a history of night-shift were excluded!

Learn how light synchronizes your circadian rhythm and protects you against breast cancer & obesity.

Bottom line: It's too early to tell anyone to consume melatonin supplements as an effective means to counter the development of breast cancer. The results of the study at hand do yet confirm that sleep and in that sleep during a time of maximal melatonin production, which is at night or in a pitch black room is of paramount importance to your health.

While we are waiting for the first rodent and human studies to confirm a systemic anti-aromatase effect of melatonin, I would thus suggest that you take another look at the SuppVersity Circadian Rhythm Series, all the articles of which you can find @ http://suppversity.blogspot.com/feeds/posts/summary/-/crs/?max-results=9999 if you are using an RSS compatbile browser or a plugin for chrome.

References:

• Chottanapund, Suthat, et al. "Anti-aromatase effect of resveratrol and melatonin on hormonal positive breast cancer cells co-cultured with breast adipose fibroblasts." Toxicology in Vitro (2014).
• Davis, Scott, Dana K. Mirick, and Richard G. Stevens. "Night shift work, light at night, and risk of breast cancer." Journal of the national cancer institute 93.20 (2001): 1557-1562.
• Schernhammer, Eva S., and Susan E. Hankinson. "Urinary melatonin levels and breast cancer risk." Journal of the National Cancer Institute 97.14 (2005): 1084-1087.

Andropause? Low Testosterone? At Risk of Developing Diabetes? Get a Free Hormonal Panel and Access Your Personal Health Risks With an Old-Fashioned Measuring Tape.

Image 1: Not as realiable as bloodwork,
but a valid first indicator of testosterone
levels and metabolic health in general
(image from Millionlineincome)

I have been writing about getting hormones tested before. And if you listened to Thursday's episode of Super Human Radio and tuned in even before I was on, you will have heard Dr. Crisler from "All Things Male" talk about the paramount importance of optimal testosterone and free testosterone levels on physiological and pyschological health of the purportedly "stronger" sex (yeah, I am talking about us, guys ;-) If that got you interested or you suspect, for whatever reason, to have low testosterone levels, but are unwilling or unable to spend money on a blood test, you may well be interested in the results of a study that was published in the May issue of the Asian Journal of Andrology (Alan. 2011).

Alan et al. who investigated the relationship of age, adiposity and testosterone levels in 207 otherwise healthy aging men (>= 54 year) with symptoms of hypoandrogenism found a significant correlation of both total and free testosterone levels and the waist-to-height (WHt) ratio of their subjects:

[...] WHt ratio was more strongly correlated with TT and cFT than either WC [waist circumference] or BMI. Furthermore, in models of TT and cFT, the addition of Ht to WC resulted in an increase in the magnitude of the regression coefficients for both WC (inverse correlate) and Ht (positive correlate), with the contributions of both WC and Ht both being significant (P<0.05 for all).

Table 1: Waist-to-height ratio corresponding
to increased risk of high blood pressure,
elevated blood glucose and high triglyceride
levels (data adapted from Leitzmann. 2010)

Or in other words, if your tall and lean chances are your erectile dysfunction or whatever possibly androgen-related problem is plaguing you, is not a result of low testosterone levels. While this does not exclude the possibility that overtly high estrogen levels or low 5a-reductase activity and consequently low DHT levels (I have written about the importance of DHT in the context of "all things male" before) are at the bottom of your problems, you will at least know that checking testosterone alone probably won't provide the answer to your question.

On the other hand, these results exemplify the viscous circle of how low, or as many family physicians like to refer to them, "age appropriate", androgen levels, predispose to (predominantly visceral) adiposity, which - apart from its direct detrimental effects on metabolic health (cf. table 1) - in turn increases aromatization of testosterone to estrogen and thus further reduce the availability of the primary male sex steroid. While it appears that this is another instance of the "chicken and the egg, who was first?"-question, I would argue that chances are that the "age appropriate" decline in androgen levels goes hand in hand with increasing obesity and should thus also be addressed by a multi-faceted approach constituting of professionally* supervised hormone replacement therapy and appropriate life-style changes, in other words, the incorporation of regular exercise and healthy eating habits into your daily routine.

* the attribute "professional" obviously excludes your average family Dr. who considers your testosterone level "age appropriate" and refuses to measure estrogen, DHT, DHEA and all the other endocrine parameters without which you will never get the full picture

Will Sex Before a Competition Hamper Your Performance? Plus: How Can Estrogen, Cortisol, Quail and Muhammad Ali Help Us Answer This Important Question

Image 1: At least in his later life, Muhammad Ali could hardly be considered a "bro". Notwithstanding, he was 100% convinced that having sex the night before a fight was a total no-go.

I you are a bro, or frequent one or many of the pertinent boards, the question whether or not sexual intercourse with yourself or your partner will have beneficial, neutral or negative effects on your performance in the gym, and more importantly your gains and endocrine system probably is not news to you. Even in case you do not belong to either of the former categories, I am sure you will have heard about Olympians or other athletes refraining from the previously mentioned exchange of bodily fluids on the day, if not during the whole week, let alone weeks before a competition. Now, as chance would have it, I stumbled across an interesting study that was conducted by a group of researchers at the University of Liege in Belgium (it goes without saying that Liege is in Wallonia, the French-speaking part of Belgium, right? ;-) that may not be able to provide direct evidence for or against pre-competition sex, but could at least help us to shed some allegedly dim light on the hormonal changes that occur in your brain, when birds and bees finally meet (Dickens. 2012).

Of the birds and the bees and how stressing the best things in life can become

To study the effects of stress and sexual intercourse on neural aromatase (remember: the enzyme that converts testosterone into estrogen) and circulating stress hormones Molly J. Dickens and her colleagues from the Research Group in Behavioural Neuroendocrinology picked a very exotic model: The common quail. Now, despite the undeniable differences that (hopefully) exist between your sexual partner of choice and these shrunken chickens, birds, in general, and quails in particular have a long history as a supposedly accurate model for systemic effects of hormonal changes at the cerebral level and have been used, among other things to elucidate hormonal effects on appetite and food intake (Balthazard. 1998).

Significant other advisory: Don't take today's news so serious that you ruin your partnership. This is one of the SuppVersity posts with at least as much entertainment as informative value ;-)

The researches tested the nuclei-specific aromatase activity changes, the corresponding observable behavior, subsequent fertilisation rates and corticosterone (cortisol) concentrations of quail in a relaxed, non-stressed or an acutely stressed (15 min restraint) immediately prior to sexual interaction (5 min) with stressed or non-stressed partners. Quite a complex undertaking, and in all honesty nothing I want to think about for longer than by any means necessary, so let's get straight down to the nitty gritty ;-)

Figure 1: Cortisol levels in stressed and non-stressed male and female quail before (baseline) and after intercourse with a stressed or non-stressed partner (data adapted from Dickens. 2012)

As you can see in figure 1 the cortisol response of birds and bees, ah... pardon, male and female quail in stressed + non-stressed, stressed + stressed, non-stressed + non-stressed and non-stressed + stressed pairings was very differential. let's briefly go through some very realistic *rofl* scenarios, say you are a...

• Male weight lifter right before competition - In this case your baseline cortisol would be high (stressed), what would you do to keep that in check? Right you would have sexual intercourse with your hopefully totally relaxed girlfriend / wife. The stress reduction would be meager, but alas... there are different reasons to engage in this utterly human act (and did I mention that it is 100% paleo?)
• Male student who trains just for fun - Assuming that you are one of the slackers whose parents finance their studies (don't deny it, I know you, guys!) and who spend most of their time in the gym hitting on the girls, you better stick to just hitting on them, if you don't want to quintuple your stress levels. Although, let's be honest, the reasons you are not seeing any gains are probably not related to high cortisol levels, anyways ;-)
• Female 200m runner right before competition - With the big day right ahead your cortisol levels are skyrocketing, the worst thing you could do now, is make out with one of your male colleagues who is likewise totally stressed out. You better go home to your loving boyfriend or husband and spend some cozy hours with him to reduce your stress levels by -44% and decrease your not chance to jump the gun.
• Female leisure time gymrat: You are calm, you know you are sexy and have no reason to be stressed out other than your boring, non-stressed boyfriend or husband at home. And  while you would be way better off with the hectic postman (obviously only in terms of stress increases ;-), I am not sure if that could not have very enervating and thus stressing consequences *rofl*

I see, you are questioning the value of the practical advice I am putting out here? Well, let's see what others have to say on the issue, let's take Samantha McGlone and Ian Shrier, for example, in their review of the literature they explicitly mention that despite the fact that (McGlone. 2000):

[...] the results of these studies [there were obviously only three scientific ones published between 1975 and 1989], one might conclude that sexual activity the night before competition would not affect performance. However, each of the above-mentioned studies focused on the physiological effects of precompetition sex, which would only be expected to decrease performance if the activity led to exhaustion. Considering that normal sexual intercourse between married partners expends only 25-50 calories (the energy equivalent of walking up two flights of stairs), it is doubtful that sex the previous night would affect laboratory physiological performance tests. Remembering that the original hypothesis suggested that performance would only be affected through a change in aggression, researchers really should have measured variables that are affected by aggression (e.g., motivation, alertness, and attitude toward competition).

Now this is where brain aromatase activities come into play of which Trainor et al. report in a detailed review of the pertinent literature that "in most cases estrogen [in the brain!] increases the probability and intensity that males will engage in aggressive behavior" (Trainor. 2006) - surprised, right?

Brain aromatase, estrogen and the crunch question: "Sex or no sex before a competition?"

Now, what does that mean in view of the finding that the stress induced increase in aromatase activity was immediately reversed in the male quail (the changes in the female quail were less consistent)? I guess, it means Muhammad Ali who always insisted that sexual abstinence before an event was an absolute must was right - at least in a sport such as boxing which certainly depends on a decent level of aggression you do not want to compromise that by dumping down brain aromatase activity, would you? What? Oh, you would? Well, I guess me, too ;-)

References:

1. Balthazart J, Ball GF. The Japanese quail as a model system for the investigation of steroid-catecholamine interactions mediating appetitive and consummatory aspects of male sexual behavior. Annu Rev Sex Res. 1998;9:96-176.
2. Dickens MJ, Balthazart J, Cornil CA. Brain aromatase and circulating corticosterone are rapidly regulated by combined acute stress and sexual interaction in a sex specific manner. Journal of Neuroendocrinology. 2012. [Epub ahead of print] DOI: 10.1111/j.1365-2826.2012.02340.x
3. McGlone S, Shrier I. Does sex the night before competition decrease performance? Clin J Sport Med. 2000 Oct;10(4):233-4.
4. Trainor BC, Kyomen HH, Marler CA. Estrogenic encounters: how interactions between aromatase and the environment modulate aggression. Front Neuroendocrinol. 2006 Jul;27(2):170-9. Epub 2006 Jan 10.

Vitamin D and Testosterone. Sunshine Vitamin Not So Manly, After all? Vitamin D Increases Aromatase Activity in Sertoli Cells

Vitamin D is all the rave. Even mainstream nutritionists are now jumping on the vitamin D bandwagon and the hype is spilling over from the Internet to newspapers and TV stations. "Take your Vitamin D!" is what children and adults, men and women, couch-potatoes and top-level athletes are told. Recently discovered problems related to the accurate measurement of actual vitamin D levels aside (e.g. Shah. 2011), a recent investigation into the immediate effects of vitamin D on aromatase activity in Sertoli cells of rat testes, suggests that we have to reevaluate whether this advice, which is hitherto largely based on epidemiological data, is not overgeneralizing, to say the least.

Image 1: Transverse section of a tubule of the testis of a rat. X 250. (Wikipedia)

After all, the results of the aforementioned study, which has been published in the Journal of Vertebrate Reproduktive Science & Technology (Zanatta. 2011), clearly indicate that, contrary to common believe, your testosterone levels will not benefit from high vitamin D levels. On the contrary, in their in-vitro study Zanatta et al. found that incubation of Sertoli cells with 100nm 1,25D "increased the amount of aromatase transcript [...] in [Sertoli cells of] 30-day-old rats". Additionally, the scientists were also able to show that the increased aromatase activity was not exclusively due to a genomic effect, but was mediated via a "non-genomic activation of the membrane-bound vitamin D receptor involving the PKA pathway". Whether this is a tissue-, rat- or even age-specific effect does yet still warrant further investigation.
The latter is especially true in view of conflicting data on the effects of vitamin D on aromatase activity in especially in view of previous studies such as Lundgvist 2011 et al. (Lundgvist. 2011) who found that

In breast cancer MCF-7 cells, aromatase gene expression and estradiol production were decreased, while production of androgens was markedly increased. In NCI-H295R cells, 1α,25-dihydroxyvitamin D(3) stimulated aromatase expression and decreased dihydrotestosterone production. In prostate cancer LNCaP cells, aromatase expression increased after the same treatment, as did production of testosterone and dihydrotestosterone. In summary, our data show that 1α,25-dihydroxyvitamin D(3) exerts tissue-specific effects on estrogen and androgen production and metabolism.

So, will taking supplemental Vitamin D3 (1,25D) transform you into a hermaphrodite? Will you get rid of gynecomastia (gyno), but develop testicular cancer? The answer to both questions is probably "NO" And I am by no means suggesting that you extrapolate the rat data from isolated sertoli cells to human beings, but In view of these findings, it is nevertheless becoming increasingly questionable whether the correlations between testosterone and vitamin D that have been observed in epidemiological studies have not been misinterpreted as causative, where in fact, both, higher testosterone, as well as vitamin D levels, are a mere results of confounding variables such as an overall healthier, more active lifestyle. After all, our previous understanding of the connection between vitamin D and testosterone could have been as misleading as the idea that firetrucks cause fire, because an "epidemiological" investigation of fires would show that they are present whenever ones breaks out.

Video 1: Clifford L. Johnson, MSPH (CDC):

"The Importance of Monitoring Vitamin D Status in the U.S.",

Thursday, August 19, 2010, at 9 a.m. (EDT)

A pros pos epidemiological studies: A recent report from the Centers for Disease Control and Prevention National Center for Health Statistics in Maryland (see video above) states that in the US...

[t]he risk of vitamin D deficiency increased between 1988-1994 and 2001-2002 in both sexes but did not change between 2001-2002 and 2005-2006.

With two-thirds of the population having, what the National Center for Disease Control and Prevention considers "sufficient vitamin D" levels, you probably better follow my previous advice and just get your level tested before starting on any kind of supplementation regime. If you want to do me a favor, you also check how taking additional D affects your testosterone levels. I promise to publish your results - anonymously, of course ;-)

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!