Intermittent Thoughts on Building Muscle: IGF-1 and its Splice Variants MGF, IGF-IEa & Co - Master Regulators or a Bunch of Cogs in the Wheel of Muscle Hypertrophy?

Image 1: With regard to IGF-1 and its splice-variants like MGF, there is probably 10x-100x more bro- than pro-scientific data out there - this does not help us, though, since you never know which of the bro-reports is bogus and which is not.

In view of the fact that we have not covered much ground with the last installment (we did build a pretty solid foundation, though ;-), I will try my very best to steer a middle course between presenting impressive amounts of facts and explaining the complex and in part not even completely elucidated physiological underpinnings of skeletal muscle hypertrophy, or, as the bros would say, getting big and buffed! A pros pros Bro, you will unquestionably have read on one of the myriads of bodybuilding-related bulletin boards how the injection of X amounts of IGF-1 right into the muscle made BigGuns, or whatever the poster's pseudonym may have been, grow "3 inches in 2 weeks"... ok, his profile picture looks impressive, but is that credible? Does IGF-1 really have such profound effects on muscle growth? And about what type of growth are we talking here? The myostatin-negative "ballooning up" of the muscle, which leaves you with overblown myogenic domains and dysfunctional muscles?

IGF-1: Insulin, growth hormone, or what?

To be able to answer these and related question we will first have to understand what exactly this "insulin-like growth factor 1" actually is. From a (bio-)chemical perspective it is nothing but a bond of 70 amino acids which are entangled into a specific peptide structure that is characteristic for somatomedin C, as IGF-1 is also called. Both the "growth" in IGF-1, as well as the "somato" in its old-fashioned appellation already suggest that what we are dealing with, here, is a "growth hormone related" polypeptide. And in fact, the synthesis of IFG-1, which, in the case of the systemically available fraction, takes place primarily in the liver, and is triggered by systemic growth hormone (somatotropin) levels.

Figure 1: Changes in systemic IGF-1 levels after 5-weeks on either a "normal" (=55:15:30 carbs:protein:fats) or a low carb "high protein" (=20:30:50) diet in 8 men with untreated type II diabetes (data adapted from Nuttal. 2006)

The "insulin" in its name, however, is pretty misleading... or I should say people mislead themselves, by not reading  the name correctly: It's not "insulin-growth factor", but "insulin-like growth factor" and the "like" refers to the structure of the molecule and does not imply that it is released in response to insulin spikes, as you may have read it on one of the aforementioned bulletin boards. If you do take a look at the growth hormone and IGF-1 levels of eight male subjects in a 2006 study on the metabolic of 5-weeks on what the scientists call a "high protein, low carbohydrate diet" (Nuttall. 2006), you will see that an increase in protein and fat from 15% to 30% and 30% to 50%, respectively elicited an 34% increase in serum IGF-1 levels over the treatment period, a finding that is corroborated by the recently published results of Matthew B. Cooke and his colleages from the Department of Health, Human Recreation and Performance at Baylor University.

Figure 2: Serum IGF-1 levels in response to whey vs. maltodextrin supplementation and subsequent lower body resistance training (data adapted from Cooke. 2011)

In their randomized double-blinded cross-over study, Cooke et al. had a group of 10 recreationally active men (2-3 non-resistance training exercise sessions per week) perform a lower body exercise program (leg presses and knee extensions, 4 sets, 8-10 reps at 80% of the individual 1RM) with either 10g of maltodextrose or 10g of whey 30 minutes before the exercise bout (Cooke. 2011). The results of the study (equal IGF-1 response regardless of whey or carbohydrate supplementation) imply that even in the short term, in healthy subjects and in conjunction with exercise the ingestion of carbohydrates is not superior to the provision of fast acting protein sources as a means to either increase or maintain systemic IGF-1 levels.

On a side note: The insulin-mediated induction of Akt, which subsequently triggers the phosphorylation of the mammalian target of rapamycin (mTOR) and thusly does its bit to elevate protein synthesis, has no direct relation to IGF-1, which - I cannot emphasize that enough - has a structure resemblance to insulin, nothing more, nothing less. And what's more, the insulin response in the aforementioned study by Cooke et al. was identical in the whey vs. maltodextrin arm of the study.

Systemic vs. local IGF-1 expression: A crucial distinction

If you have been following the daily research updates here at the SuppVersity over the last months, you may now be wondering why I am even caring about those growth hormones (after all you should, after reading the first paragraph, realize that IGF-1 is something like the active incarnation of somatotropin), when Stuart Phillips lab has quite conclusively shown that even the exercise induced elevation of testosterone does not correlate with subsequent increases in muscle protein synthesis. Certainly a good question, but nevertheless not difficult to answer:

1. The previous installments of the Hypertrophy 101 (Part 1, Part 2) should have made it quite clear that protein synthesis alone is not sufficient to grow. Without intra-muscular restructuring / reorganization and the recruitement of new myonuclei from satellite cells, you would sooner or later grow beyond the maximally allowed myonuclear domain sizes (assuming that by whatever means you block the healthy upregulation of mystatin that will prevent that) and end up as an over-muscled but completely dysfunctional wrack.
2. In a very recently published study, the results of which I have actually been holding back, because I thought I would get to them much earlier in this series, the very same Stuart Phillips whose studies are "responsible" (in fact it is the way they are discussed by the lay-press and abused by the supp-companies that is actually "responsible") for the current over-emphasis on acute increases in the protein synthetic response to exercise and/or supplements, reports that there actually was a statistically significant correlation between exercise induced growth hormone release and increases in mean type I fiber (p<0.06) and type II (p<0.04) cross-sectional area (CSA) in 56 healthy previously non-resistance trained healthy young men in response to a 12-week, 5-day per week resistance training regimen (West & Phillips. 2011).
3. While we have hitherto been talking about systemic IGF-1, it has become evident in the course of the last decade that the hepatic IGF-1 output, which is the main determinant of circulating IGF-1 levels, has little to no impact on the IGF-1 induced increases in skeletal muscle mass and remodeling of muscle tissue that has been previously studies in Petri dishes. In fact, recent research suggests that, just like the liver produces IGF-1 for "the whole body", muscles produce their own IGF-1, or I should say, their own IGFs-1, whenever they are challenged to grow and/or repair (Velloso. 2010), and that the decline of muscle mass with age is at least in parts attributable to a defect / reduction in the expression of local IGF-1 splice variants (for an explanation of what this is, see red box below).

If we now count 2. and 3. together the result is not 5. but rather that it is the growth hormone mediated, exercised-induced local expression of IGF-1 splice variants, which drives the repair and restructuring process that allows for continuous (healthy) muscle growth.

Did you know that the intra-muscular (=autocrine, meaning directly in the tissue where it is supposed to work) "construction process" of the mature 70 amino acid polypeptide IGF-1 gives rise to three different splice variants of insulin-like growth factor (note: the structure of IGF-1 gene does theoretically allow for 6 variants)? And though we are just beginning to understand the physiological roles of IGF-IEa, IGF-IEb and IGF-IEc, also known as MGF (mechano-growth factor), their distinctly timed expression in response to physical overload appears to constitute one of the major driving forces of myocellular hypertophy.

In order to fully understand the role "the" insulin-like growth factor 1 plays in the physiology of muscle growth, it is thusly important to realize that the common perception of IGF-1 as a systemic hormone is, at best, incomplete - I would even venture to say that it is totally flawed.

MGF?! Yeah, I have heard of that one!

Figure 3: Stained myocyte migration (top) and infiltration (bottom) essays for IGF-1 and MGF; more stains = greater effect (taken from Mills. 2007).

Of the three primary splice variants that are expressed in skeletal muscle, IGF-IEc, or MGF (Mechano-Growth Factor) has probably received the greatest attention - so much attention that even the aforementioned bros, will probably have grasped the notion that this is somewhat of a local isoform of IGF-1 which is expressed in response to exercise induced muscle damage and could potentially be the magic bullet to grow beyond what we have hitherto believed to be possible... and, guess what, in essence this appears to be correct.

In one of the earlier studies on the cellular effect of MGF, Yang et al. were able to show that MGF stops the IGF-1 mediated cell differentiation process (in practice this means that it stops the satellite cells from differentiating = specializing and becoming muscle cells) and increases their proliferation. Or put more simply: While in vitro exposition to IGF would suffice to build muscle, as long as there are enough progenitor cells (satellite cells) available, MGF is necessary to replenishes the satellite cell pool of which you have learned in the previous installments that it is necessary to a) repair damaged muscle tissue and b) increase the number of myonuclei in order to grow beyond the physiological growth limit that arises due to the muscle-type-specific upper limit to the myonuclear domain size (cf. previous installments).

Figure 4: Cell proliferation data in response to MGF treatment after blocking the IGF-I receptor.

As the data in figure 4 goes to show the effects of the complete polypeptide IGF-1 and its splice variant MGF appear to be mediated, at least partly via distinct receptors. And while recent research suggest that MGF also exerts similar effects on tendon (Olesen. 2006), brain (Dluzniewska. 2005) and nervous tissue (Aperghis. 2004), our primary concern here, is its pivotal role in muscle repair, which involves the activation of satellite cells, their proliferation (Yang. 2002) and migration (Mills. 2007).

A series of studies by Hammad et al., which was originally intended to investigate the effects of age on the expression of the different IGF splice variants, goes to show that the "muscle (re-)building effects" of MGF are not restricted to the test tube. In their 2002 study (Hamed. 2002), the researchers were able to show profound increases in the MGF expression in the quadriceps muscles of 8 healthy young men (age 29.5 ± 1.5 years, body mass 81.1 ± 2.4 kg, height 179.3 ± 1.8 cm) 2.5h after a single muscle-damaging leg-extension exercise (10 sets of 6 repetitions at 80% 1-RM, 2 min rest between sets):

Figure 5: MGF (ng mRNA / 10^8 µg RNA) and IGF-IEa ng mRNA / 10^5 µg RNA) expresion in quadriceps muscle of young subjects before and 2.5h after 10 sets of 6 repetitions at 80% 1-RM on a leg-extension machine with 2min rest between sets (data adapted from Hamed. 2002)

If you take a closer look at the data in figure, you will probably notice that there was one subject with an extreme MGF response, the scientists explain by a particularly high type-IIx fiber content of the quadriceps of this individual. If you remember the mouse studies and the analysis of the muscle composition of bodybuilders from the previous installments, you will be aware that the shift from type IIb to type IIx muscle fibers is one of the main characteristics of "getting real big". The extreme MGF response (>10x higher than the mean MGF expression across the other subjects) in this subject thusly suggests the increased growth capacity of type IIx muscle fibers is in part due to their ability to release MGF in response to strenuous exercise and thusly multiply / replenish their satellite cell pool to prepare for future growth.

Figure 6: MGF (ng mRNA / 10^8 µg RNA) and IGF-IEa ng mRNA / 10^5 µg RNA) expresion in quadriceps muscle of young subjects after eccentric HIIT exercise on cycle ergometer (data adapted from Hamed. 2008)

Interestingly, a 2008 follow up study (this time involving nine healthy young men aged 20–27 years, cf. Hamed. 2008) with a completely different training protocol that consisted of

60min of opposing the rotation of the pedals down to 60 r.p.m. Subjects performed the following program of six working intervals: six working intervals: 0–6min at 50%, 6–12min at 75%, 12–20min at 100%, 20–25min at 130%, 25–40min at 100% and 40–60min at 75% of the load  eliciting concentric VO2max

illicited surprisingly similar results (cf. figure 6). And in both cases, it appears to be the MGF splice variant not the IGF-IEa variety that drives the short term (hours to days) response to strenuous exercise.

HIIT and resistance training a dynamic duo for MGF expression

Assuming that you are following each and every post here at the SuppVersity (you know you should be ;-), this should remind you of a previous blogpost of mine (cf. "HIT Your Satellite Cells to Increase Your Gains!"), in which I explained that one of the many advantages of high intensity training (not even interval) over classic "cardio" training is that it can increase satellite cell proliferation. Now, with this installment of the Intermittent Thoughts you finally understand, why this is the case.

Image 2: This is not the kind of muscle damage you should be aiming for in the gym.

Now, while protein synthesis and increases in domain size are partly mediated via nutrition, the intra-muscular expression of the IGF-IE splice variants appears (at least based on the current research) to depend solely on exercise, or I should say the wear and tear that goes hand in hand with heavy exercise. In that it seems to be less important, whether you are "pumping away" or "cycling like maniac", as long as its "hard" - to put that into perspective, in the 2008 study by Hamed et al. the subjects underwent ~3600 eccentric muscle contractions in only 1 h, their creatine kinase (CK) levels (marker of muscle damage) increased by +183% and all subjects reported profound muscle soreness.

This controlled amount of muscle damage ties in nicely with the topic of next week's installment which will center around the the intricate relation of the inflammatory response to exercise, the expression of the well-known and less known inflammatory cytokines, TNF-alpha, IL-6 and IL-15 (sorry, Trevor, I have already gone overtime, so your question will have to wait till next week ;-) and the muscle (re-)building effects of IGF-1 and its intra-muscular children.

Milk Thistle in PCT - Tamoxifen (Nolvadex) Still a Liver Killer, Despite Hepatoprotective Effect of Silymarin or Ziziphus

Image 1: Silybum marianum, a medical plant that has been used to treat liver disease for >2,000 years and is a staple in many "post cycle therapy" supplements you can current purchase at your favorite supplement store.

Whether or not you are into "performance enhancing drugs" does not really matter. If you have browsed through the range of one of the myriad of on-line supplement vendors, you will have seen them: the "liver protectors", "supplements for liver health", or simply "post-cycle recovery" supplements. The most common ingredient, you will see on the labels of supplements listed in these or similar categories, is silymarin, a flavonoid complex consisting of silybin (the most active component), silydanianin and silychristin, which is either extracted or simply contained in a crude extract of the seeds of Silybum marianum, a flowering plant of the daisy family, the manufacturers put into their capsules. While scientists still debate whether and for which type of liver disease(s) the use of the obviously non-patentable (you know that this means that no big pharma company will be willing to acknowledge that it works ;-) flavonoid would be an appropriate treatment option (Loguercio. 2011), generations of bodybuilders may actually have saved their live(rs) from the toxic effect of a highly "underrated" liver-killer, the "bros" know as "Tamox" - the Selective Estrogen Receptor Modulator (SERM), Tamoxifen, which is the active ingredient in the "anti-breast-cancer drugs" Nolvadex, Istubal, and Valodex.

In a mouse model (using 60 male Balb/c mice), scientists from Malaysia and the Middle-East conducted a 4-week study on the toxicity of orally administered tamoxifen (20mg/kg; HED ~1.2mg/kg) and the potential protective effect of milk thistle or jujube (Ziziphus, a tree from the buckthorn family, and the 'silymarin of the middle' east; Shahat. 2011) extracts at 300mg/kg (HED ~24mg/kg; ~2g for an 80kg human). To this ends, the animals were randomly assigned to one out of four 6 groups (Al-Jassabi. 2011):

1. control - no tamoxifen, no silymarin extract, no ziziphus
2. silymarin control (SC) - no tamoxifen, 300mg/kg silymarin extract, no ziziphus
3. ziziphus control (ZC) - no tamoxifen, no silymarin extract, 300mg/kg ziziphus
4. tamoxifen control (TC) - 20mg/kg tamoxifen, no silymarin extract, no ziziphus
5. tamoxifen silymarin (TS) - 20mg/kg tamoxifen, 300mg/kg silymarin extract, no ziziphus
6. tamoxifen ziziphus (TZ) - 20mg/kg tamoxifen, no silymarin extract, 300mg/kg ziziphus

Now, if you look at the actual effects the admittedly high dose of tamoxifen that was administered to the animals (note: while a 100kg bodybuilder would have to take 160mg to achive the same exposure I have seen obviously idiotic recommendations on various boards which suggest starting off your PCT with doses in the 80mg+ range!), I suppose that those of you who have (for whatever reasons) already used Nolvadex & Co. will probably be shocked.

Figure 1: Changes in transaminase enzymes, lipid peroxidation and anti-oxidant enzymes in male mice after 4 weeks treatment with 20mg/kg tamoxifen per day (data calculated based on Al-Jassabi. 2011).

7-12x elevations in transaminase levels (ALT, GPT, GOT), >70% reductions in antioxidant enzymes (SOD, CAT, GSHpx), on average, and the incredible 68x elevation in lipid peroxidation after "only" four weeks of treatment should make every steroid user reconsider, whether a tamoxifen-based post-cycle protocol does not do more harm than good. After all, one of the most common causes of gynecomastia is liver cirrhosis (Swerdloff. 2011), and you will probably agree that taking a drug to "protect" yourself from the estrogen rebound after (or even in the course of a cycle) which has gynecomastia as a possible side-effect of a side-effect does not really make sense.

Moreover, scientific data on the efficiacy of tamoxifen in the treatment of male hypogonadism (which is basically what steroid users will experience at the end of a "cycle") is pretty scarce, if not non-existent and from a "scientific point of view" clomifene citrate (clomid) would appear to be the SERM of choice, here (cf. Katz. 2011).

I hope that you notice the stupidity of the typical bro-scientific approach to taking B to counter the side-effects A, C to counter the side-effect B, D to counter the side-effects of C... and so on and so forth..., because, after all, even if C or D were silymarin or ziziphus, the use of these potent liver-protectants would still leave you with profoundly elevated transaminase levels and reduced anti-oxidant capacity (cf. figure 2):

Figure 2: Changes in transaminase enzymes, lipid peroxidation and anti-oxidant enzymes in male mice after 4 weeks treatment with 20mg/kg tamoxifen + 300mg/kg silymarin or ziziphus per day (data calculated based on Al-Jassabi. 2011).

And what's more the lipid peroxidation would be significantly ameliorated by the use of 2g of silymarin (HED) per day, but still 13x over normal. If that is what you want, go ahead and terminate a harsh cycle with a harsher PCT, if not - select another method to get your HPTA (hypothalamic-pituitary-thyroid-axes) back in shape and use the milk thistle to counter potentially hepatoxic effects of the cycle itself.

Ah, and I don't know if you have even remotely considered that: Not taking steroids would make any PCT and potential on- or off-cycle liver toxicity obsolete. The use of milk thistle extracts could yet nevertheless make sense! After all, the staff at ScienceDaily posted a short news-item on the anti-lung-cancer effects of silymarin, just this morning - so if your "drug of choice" is nicotine (not AAS), don't forget to take your milk thistle ;-)

Cardio, Fat and IGF-1: Study Investigates Modulatory Effect of Endurance Exercise and High Fat Meals on IGF1 Binding Protein Levels in Obese Human Subjects

Image 2: 3D structural model of the IGF1 protein (rendered by Emw)

It's probably less than 24h ago, that you read about growth hormone (GH) here, at the SuppVersity. Its increase during fasts was one of the points, I addressed in yesterday's installment of the Intermittent Thoughts on Intermittent Fasting series. In fact it has been known for quite some time now, that fasting does increase the release of the 191-amino acid, single-chain polypeptide from the anterior pituitary gland, which in turn facilitates the (mostly) desirable switch to non protein-catabolic metabolic state, where fat becomes the major energy substrate. GH's growth promoting magic, on the other hand is believed to be largely mediated by the growth hormone induced production and release of insulin like growth factor 1 (IGF-1) in the liver, as well as directly at the level of target tissues. Apart from the sheer amount of IGF that is produced, its binding to respective carrier proteins, so called insulin like growth factor binding proteins, or IGFBPs, is yet another major determinant of the half-life and more importantly the mode of interaction of the IGF peptides with their target receptors at the cell surfaces.

From previous studies into the effects of exercise on IGF-1 levels activity, we already know that trained endurance athletes exhibit higher levels of IGFBP-1 (insulin like growth factor binding protein 1) than their sedentary counterparts (Manetta. 2003). Other studies have shown that after acute (vs. chronic) bouts of aerobic exercise the levels of IGFBP-1 return to baseline within 12-24h (Nindl. 2009; Berg. 2008; Koistinen. 1996) In that, the IGF-binding effect of exercise appears to be restricted to endurance type of exercises, as a more recent study by Nindl et al.found no increase in IGFBP-1 levels in young lean women after 8 weeks of strength training (Nindl. 2010).

Image 2: Ronny Coleman's belly is recurrent topic on various bulletin boards. This image was part of a discussion on the muscular development forum. Is it s imply fat or the results of the false(?) belief in "the muscle building magic" of IGF-1? (photo by Dan Ray for MuscularDevelopment.com)

The results from the Nindl study are also important in view of the interpretation of "increased" or "reduced" endogenous (i.e. produced by the body) IGF-1 levels in terms of their purported anabolic effect on muscle tissue, as Nindl. et al. point out...

[...] increased lean mass, aerobic fitness, and upper and lower body strength resulting from an 8-wk exercise training programs can occur without concomitant increases in either circulating bioactive or immunoreactive IGF-I, as well as associated IGFBPs. In terms of reflecting positive anabolic neuromuscular outcomes, these data do not support a role for endocrine-derived IGF-I. (Nindl. 2010)

All horror stories about GH-guts aside, you may want to keep that in mind before you condemn all aerobic exercise as being anti-anabolic and pay a shitload of money for supplements that "have been shown in clinical trials" (why are you laughing? ;-) to increase IGF-1 levels.

From epidemiological studies (Heald. 2003; 2005), we also "know" (you are probably familiar with my antipathy against epidemiology) that high fat diets are associated with lower levels of IGFBP-1. It has also been implicated as more or less reliable predictor of cardiometabolic diseases in longitudinal studies (Heald. 2001). Reason enough for Prior et al. to probe the combined effect, or I should say, the interference of 6 months of potentially IGFBP-1 lowering aerobic exercise ("3 weekly sessions of 20 minutes at 50% of heart rate reserve and gradually increased to 3 weekly sessions of 40 minutes at 70% of heart rate reserve"), on the one hand, and IGFBP-1 suppressing high fat meals (84% was derived from fat, 13.7% from carbohydrates, and 2.7% from protein), on the other hand, in a group of 10 overweight (bodymass index = 28.7 ± 0.9 kg/m²), older (61± 2 years) men and women.

Figure 1: Effect of 6 month of aerobic exercise on serum free glucose, free insulin, HOMA-IR and IGFBP-1 levels in obese subjects (data calculated based on Prior. 2011).

As the data in figure 1 goes to show, the exercise regimen had profound beneficial effects on insulin sensitivity - evidenced by the increase in serum free insulin levels and HOMA-IR (considered a "reliable" long-term marker of insulin resistance). As previous research had suggested, these changes were accompanied by a major increase in IGFBP-1 (and thus presumably a decrease in IGF-1 receptor activity). The increase in IGFBP-1 was however (almost completely, cf. figure 2) 4h after the study participants consumed a single high fat meal.

Figure 2: Effect of high fat meal (84% fat, 13.7% carbohydrates, and 2.7% protein) on IGFBP-1 levels (data calculated based on Prior. 2011)

This negative effect of high fat feeding on IGFBP-1, as can be seen in figure 2, was almost identical before and after the 6-month exercise intervention, which led the scientists to conclude that despite the fact that ...

[...] aerobic exercise training has a potentially beneficial effect to increase fasting plasma IGFBP-1 concentrations in previously sedentary middle-aged to older adults  [..., a]erobic exercise training did not attenuate the adverse effect of a high-fat meal on plasma IGFBP-1 concentrations

Image 3: Germany's former foreign minister Joschka Fischer is a famous "victim" of the "low-fat-marathon-style-endurance-training" fat loss myth with built in YoYo-effect - I guess you will have your own celebrities with similar impressive "transformations" ;-)

and (you probably expected this) use this as a welcome opportunity for repeating the good (I should rather say "bad") old mantra of the benefits of chronic endurance exercise and low fat dieting.... I mean, come on. Look at our (Germany's) former foreign minister, Joschka Fischer (cf. image 3) - don't we all know that low-fat cereals and marathon running are no solution.

It would be nice to see some scientists going beyond this illusive paradigm, in order to gain insights into the underlying mechanisms or, even more fundamentally, to answer the question whether high(er) levels of free IGF-1 are causative or just corollary to cardiovascular disease, cancer and all the other maladies IGF-1 is currently held responsible for and which role all the healthy low-fat grains we are supposed to eat play in the etiology of these diseases... in case that is going to happen within my life-time, you can be dead-certain (pun intended) that the SuppVersity is the place, where you will read about it first.

Beyond Vida's Book, Part 2/2: Androgen, Progesterone, Estrogen & Corticosteroid Receptor Activities of ALLmost All Anabolic Steroids - Metabolits, Progestins & More

Image 1: Tetrahydrogestrinone aka THG,
aka "The Clear" and the bone of contention
in the "BALCO Scandal" could probably
have been identified years before, if the
WADA detectives already had the new
 mammalian androgen responsive reporter
gene assays at their disposal.

As mentioned in part 1 of this post (cf. Beyond Vida's Book, Part 1/2), Houtman and the other scientists from BioDetection Systems B.V. and the Institute of Public Health and the Environment in the Netherlands, did not exactly want to provide juicers with data on which steroids may cause unexpected side-effects, when they conducted their study in 2008. The original idea was to demonstrate that their technology would be able to identify even those androgens, which have hitherto not been classified as illegal substances - so called "designer steroids", which would not turn up in the chemical–analytical approaches combining gas chromatography (GC) or liquid chromatography (LC) separations with mass spectrometry (MS) or tandem mass spectrometry (MS/MS) simply because their molecular structure is hitherto unknown (you cannot find what you ain't looking for ;-).

This is the second part of a two part series, click here to read more about nandrolone, trenbolone, testosterone and all the androgens on the list of prohibited substances of the World Anti Doping Agency.

If this method had been available back in the day, when Patrick Arnold developed THG (tetrahydrogestrinone aka "The Clear") for BALCO, the detectives from the World Anti Doping Agency (WADA) would probably have been able to identify Marion Jones and other athletes who used this highly performance-enhancing drug, even before baseball star Berry Bonds blew the whistle in 2001.

Figure 1: Relative potency at the androgen (compared to testosterone), progesterone (compared to progesterone) and estrogen alpha and beta receptors (compared to estrogen) of "The Clear" (THG), trenbolone and nandrolone
(calculated based on data from Houtman. 2008)

Now, more than 10 years later, THG is on the list of WADA prohibited compounds and we know that "The Clear" is 0.25x as androgenic as dihydrotestosterone and 1.15x more androgenic than testosterone. We also know that THG is a powerful progestin, with 91% of the receptor activity of "real" progesterone (trenbolone has 35%), but hardly any translational activity at the level of the estrogen (0.0017% for estrogen-beta) and corticosteroid receptor.

Figure 2: Relative potency (new reference:
progesterone!) of steroids not on the
WADA list at the progesterone receptor
(data calculated base on Houtman. 2008)

A few notes on the graphs: Houtman et al. did not measure the relative potency at the progesterone receptor for all of the "other exogenous androgens". Instead of meshing androgen and progesterone activity into a single graph, I thus decided to seperate the two, because otherwise it would have been difficult to identify which of the steroids actually have "zero" transcriptional activity at the progesterone receptor and which just have not been analyzed by the scientists. Additionally I recalculated the references using testosterone and progesterone instead of DHT and the over-potent progestin ORG2085.

Among the better known other (I am sticking to Houtman et al.'s nomenclature, here) exegenous androgens, the Dutch scientists analyzed, trestolone, or 7a-methyl-19-nor-T (MENT), is certainly the "meanest bitch". It's androgenic activity is almost 10x higher than that testosterone (and thus 3x more potant than nandrolone!) and its potency as a transcriptional activator at the level of the progesterone receptor is still 29% of that of progesterone and thus more than 9x higher than that of nandrolone aka "Deca".

Figure 2: Relative potency at of steroids
not on the WADA list at the androgen
receptor; note that I re-calculated the
values relative to testosterone as a new
reference, this means that you have to
divide the values by 4.68 to get DHT as
a reference, as in Part 1, fig. 2 (data
calculated base on Houtman. 2008)

The major offenders, as far as chances of immediate (cf. red box in part 1 of this article) progesterone-related side effects are concerned, are yet the norethisterone derivatives (relative potencies compared to progesteron)

1. 11b-ethynyl-NET - 880%
2. delta-15-NET - 290%
3. 11b-ethenyl-NET - 262%
4. 6a-methyl-NET - 253%
5. 11b-I37ethyl-NET - 139%

I guess, you probably already suspect that these are agents in progesterone-only or combined contraceptive pills. So, in essence nothing athletes will be using.

The 7-alpha-methylated derivate of the progestin nethisterone, 7a-methyl-NET, however, has an androgen/progesterone activity ratio of 427/8. Now, although the respective values for trenbolone and nandrolone are only 442/35 and 327/7 this does not necessarily go to tell you that it would make a powerful mass builder, especially in view of the results of previous studies using CHO-AR reporter gene assays, according to which nandrolone (I do not have data on trenbolone, here) has a 1.6x higher androgen receptor binding affinity than the aforementioned nethisterone derivate.

Image 2: The dissection of the
prostate (image by Gray. 2005) is
an unsavory, yet obligatory part
of the Hershberger assay, an in-
vivo method to evaluate the
androgenic activity of steroids
that was developed by
T.V. Hershberger in the 1960s.

Different tests, different results: Most of the data you will currently find on message-boards and certain webpages is based on the "old" CHO-AR reporter gene assays, the results of which often contradict relative activity levels measured by AR CALUX. According to the CHO-AR gene assay, for example the nandrolone would be the more potent androgen receptor agonist (2.65x more potent, Sonneveld. 2005). According to the Chemical Activated Luciferase gene eXpression test, on the other hand, its almost the other way around. Lastly, according to the good old Hershberger-test, which was developed in the 1960 and '70s as an in-vivo procedure to evaluate the androgenic activity of steroids in rats, 7a-methyl-NET has 6.25x the androgenic activity of nandrolone. While it is likely that the CALUX assay is the most reliable method, when it comes to the exact cellular mechanisms, the good old Hershberger-tests, Julius Vida (the "Vida" from "Vida's Book") used, as well, still have their merit, as they provide some insight into what may happen when the compound is administered to an actual living organism.

Similar to the WADA-prohibited compounds, where with the exception of 4-chloro-19-nor-T, 19-norclostebol (4%) and 19-nor-androstenediol (1%) most of the compounds that have been tested exhibited &lt;1% of the receptor activity of estradiol at both the estrogen beta and alpha receptors, compared to estradiol none of the tested (estrogen receptor transcriptional activity was measured for only 10 out of 36 androgens) compounds had significant estrogenic activity. 7a-methyl-NET, the progestin discussed in the previous paragraph, for example has a relative potency of 0.038%, which is more than 4x higher than the 0.009% potency of nandrolone, yet still less than half of the activity of DHEA (0.081%).

Figure 3: Relative potency of steroid metabolits at the androgen receptor, note that I re-calculated the values relative to testosterone as a new reference, this means that you have to divide the values by 4.68 to get DHT as a reference, as in Part 1, fig. 2 (data calculated base on Houtman. 2008)

Similarly, out of the less-androgenic (cf. figure 3) metabolites and isomers Houtman et al. actually tested, only 5a-androstane-3b,17b-diol (0.543%) and 4-androstenediol (4-AD) (0.125%) presented significant interactions with the estrogen beta receptor (0.039% and 0.012% at the alpha receptor).

If I may remind you of the the high transcriptional activity of nandrolone and trenbolone, I've discussed in the first part of this article, which corresponds well with the progesterone related side-effects many athletes complain about, the relatively high activity of 4-AD at the estrogen receptor (25x higher than testosterone) in the CALUX assay is yet another sign for the real-world relevance of the luciferase assay data (cf. red box "Different tests, different results"). After all, androst-4-ene-3b,17b-diol, which happens to be one of the pro-hormones that has lately re-appeared on the "supplement" market, is well-known to be one of the "wetter" compounds.

Figure 4: Relative potency of several natural and synthetic steroids at the corticosteroid receptor with cortisol as a reference (data calculated based on Houtman. 2008)

Finally, we will have a brief look at those steroids which mess with the glucocorticoid receptor. Other than the usual suspects in figure 4, only fluoxymesterone (0.27%), 5a-hydrogen-11b-methyl-NET (0.52%), 11b-methyl-19-nor-T (1.97%), 7a-methyl-19-nor-T aka "Trestolone" or "MENT" (1.56%) and progesterone (0.65%) exhibit any notable corticosteroid activity (expressed relative to the potency of cortisol). However, nandrolone, trenbolone and other anabolics with progestational activity appear to exert indirect effects on the mammalian corticosteroid metabolism (Moor. 1971) and may thus induce downstream effects the CALUX assay obviously cannot detect (suggested read: red box on DHEA and aromatization in part 1 of this article).

With the issue of literal "side-effects", i.e. effects not related to direct transcriptional activity at the receptor sites, I want to conclude this two part series on the immediate effects of a broad range of androgens on androgen, progesterone, estrogen and corticosteroid receptors by reminding you of the fact that despite an ever-increasing accuracy and the constant development of even more sophisticated analytical methods, there still is (and probably never will be) a machine, where you insert a certain molecule, press a few buttons and get a print out that says: "Person A; age: 25, sex: male; training: 5x a week; nutrition: [...] will gain Xlbs of lean mass and shed Ylbs of fat on a Z-week cycle of XYZmg of compound ALPHA".

Beyond Vida's Book, Part 1/2: Androgen, Progesterone, Estrogen & Corticosteroid Receptor Activities of ALLmost All Anabolic Steroids - WADA Prohibited Compounds.

Image 1: Data on the interaction of androgens
with the progesterone receptor is scarce,
this study has it!

This is only blogpost #499, yet at the same time, its a premiere! It's the first time that I am aware of that something you read at the SuppVersity has been covered by the "competition" before. Kudos to my dutch friends from ergogenics.org, who dug up a 2008 paper by Corine J. Houtman et al. (Houtman. 2008) with extensive CALUX(R) bioassay data on the androgen, progesterone, estrogen and corticosteroid receptor response to allmost all popular steroids - it would probable be the "A", as in 4-androstenediol (the "good old 4-AD"), to "Z", if there actually was a common androgen with a "z" as its first character.

Note! Due to the fact that the sheer amount of data from this study exceeds the time I can spend on analyzing and compiling it for you, today, this is going to be a two part series, with the second part on what the authors describe as "potential" AAS (among these are such illustrious names as 7a-methyl-19-nor-T aka Trestolone or MENT) will follow tomorrow. And don't get mad at me for that, at least it does have the advantage that you can comment / pose questions today and have them answered in detail, by tomorrow ;-)

Update: click here for part 2!

The original intention of the study obviously was to demonstrate that by the means of the mammalian androgen receptor responsive reporter gene assay (AR CALUX® bioassay), the anti-doping agency would be able to identify hitherto unknown "designer steroids", which would not show up in the usual tests, where the chemical structure of the substance you are looking for must be known beforehand. The CALUX bioassay, on the other hand, directly measures the transcriptional activity of a specific steroid receptor when it is exposed to a given substance and is thus a very reliable measure of the biological effect a certain anabolic will have on the cellular level.

Figure 1: Enzymes, their cellular location,
substrates and products in human
steroidogenesis; DHEA is the first
compound in the left androgen column
(figure by Slashme and Mikael Häggström)

While it is of course grandiose to be able to measure receptor activity directly, a non-negligible weakness of these bioassays is that they do not provide any insight into the effects of downstream-metabolits of the tested androgen. Let's take dehydroepiteandrosterone (DHEA) as an example. It is well known that after several enzymatic reactions DHEA can eventually be converted to estrogen (cf. figure 1), if however you measure the transcriptional activity of DHEA at the estrogen receptor it turns out to be 0.0813% of 17β-Estradiol (E2). This example clearly shows that, at least in the case of aromatizeable steroids such as DHEA, CALUX provides only part of the overall picture. Keep that in mind, when you are trying to interpret the data!

Other than "Vida" in his famous rat studies, these assays obviously do not provide any information about the "anabolic" value of the respective compounds. Oxandrolone, for example, is known as a highly anabolic steroid, which has about 6x the anabolic activity of testosterone. Nevertheless, its activity at the androgen receptor is only 1% of that of dihydro-testosterone (DHT) and thus no more than 1/20 of the androgen receptor activity of testosterone (cf. figure 2). Accordingly, the following data will not really tell you how much muscle an athlete will be able to accrue whilst taking a certain steroid, but rather which androgen, progesterone, and estrogen related side-effects he or she may experience in the course of that cycle.

Figure 2: Relative potency at the
androgen (reference: DHT) and
progesterone (reference: ORG2085)
receptor of androgens that are
officially prohibited by WADA
(based on Houtman. 2008)

If you have a look at the androgens from the WADA's list of prohibited compounds in figure 2, you will notice that compared to the synthetic progestin 16a-ethyl-21-hydroxy-19nor-4-pregnene-3,20-dione (ORG2085) only a handful of compounds exhibits a significant transcriptional activity at the progesterone receptor:

• 17a-ethyl-19-nor-T (norethandrolone) - 24%
• norbolethone - 21%
• tetrahydrogestrinone (THG) - 7%
• gestrinone - 5%
• 17b-trenbolone - 3%

If the occurrence of trenbolone as the last item on the list of androgens with a high activity at the level of the progesterone receptor puzzled you, you obviously have not heard of the dreaded "progestin-gyno" this powerful steroid is supposed to induce!? While 3% of the activity of a synthetic progestin does not sound much, trenbolone is a 6423x more potent activator of the progesterone receptor than testosterone and it is still 525x more active than nandrolone aka "deca", another of the commonly used mass and strength agents the use of which is rumored to have induced gynecomastia in a non-negligible number of drug using athletes.

Only 4-chloro-19-nor-T, 19-norclostebol (4%), 19-nor-androstenediol and methyl-androstenediol (0.1%) exhibit transcriptional activity >0.1% of that elicited by estradiol at the estrogen alpha and beta receptors and none of the tested androgens from the WADA list has an activity >0.002% (this is fluoxymesterone) of that of dexamethasone at the corticosteroid receptor. In order not to overcomplicate things, I have decided to exclude this additional data from figure 2.

This is only part 1! Don't forget to check back tomorrow for more information on metabolites and isomers, such as 4AD & Co., other exogenous androgens that are not yet on the WADA anti-doping list, such as 7a-methyl-19-nor-T (Trestolone,  MENT) and other steroids!

Update: click here for part 2!

Amino Acids for Super Humans. Part IV: Purported Ergogenics - Beta Alanine, Carnitine, Glutamine

This relevant for all of you - regardless of whether you can or cannot spare the time: Tune in live and listen to me @ Carl Lenore's Super Human Radio to learn that amino acids are far more than just the building blocks of the proteins of your body...

Listen live to SHR @ 12:00PM ET

Amino Acids for Super Humans. Part IV
Purported Ergogenics - Beta Alanine, Carnitine, Glutamine

In the fourth installment of the show, we are going to look at three of those amino acids everyone interested in fitness and body building knows: Beta Alanine, Carnitine and Glutamine. Will the increase performance, fat loss and muscle gains, as some supplement companies would have it, or will they mostly cost your hard earned money or even make you sick? Tune in live @ 1pm ET and learn more!

Androstenedione, Grand Daddy of All Prohormones: Carcinogenic Poison or Non-Toxic Muscle Builder?

I suspect you have already read statements like "prohormones will kill your liver", "prohormones will give you gyno" and/or "prohormones will induce prostate cancer", haven't you? Well, Androstenedione is not methylated, so bro-science would tell you that your liver won't take a beating. Yet, all gynecomastia issues aside, what if its not the methyl-group but the prohormone itself that is liver toxic or carcinogenic? A recent study published in the journal of Food and Chemical Toxicology on May 30 2011 (Blystone. 2011) sheds some light onto potential side effects of the "grand daddy of all prohormones".

Chard R. Blystone and his colleagues administered  "subchronic" doses of androstenedione @ 10, 20, or 50 mg/kg body weight to male and @ 2, 10, or 50 female mice. And they did that for two years.

Figure 1: Cancer risk of male F344/N rats after 2 years of chronic exposure to androstenedione at 10, 20, or 50mg/kg body weight relative to 0mg control (data adapted from Blystone. 2011)

To put that into perspective, an average androstenedione cycle lasts anywhere from 4-8 weeks and dosages range from 100-600mg/day, considering the fact that the average laboratory rat weighs about 300g and the human equivalent dose of the highest, 50mg/kg dose, is 8.1mg/kg (this would equal a 650mg daily dose for a 80kg human being), the rats receiving 50mg/kg androstenedione per day for two years were exposed to the equivalent of 473513.51mg or roughly 440g of androstenedione. In their abstract the scientists summarize their observations as follows:

Increased incidences of lung alveolar/bronchiolar adenoma and carcinoma occurred in the 20 mg/kg male rats and increases in mononuclear cell leukemia occurred in the 20 and 50 mg/kg female rats, [...]. In male and female mice, androstenedione was carcinogenic based upon a significant increase in hepatocellular tumors [cancerous growth in the liver]. A marginal increase in pancreatic islet cell adenomas in male (50 mg/kg) and female (2, 10, 50 mg/kg) mice was considered to be related to androstenedione administration.

While this does sound pretty dangerous looking beyond the abstract and at the actual data, part of which I plotted for you in figure 1, does yet speak a very different language. Although the scientists also mention that to their own surprise androstenedione decreased "incidences of male rat Leydig cell adenomas and female rat mammary gland fibroadenomas", they did not mention that it did so (if not always in a statistically significant manner) in mononuclear cell leukemia and interstitial cell adenoma, as well (cf. figure 1). While the situation is somewhat different in female rats (who would have suspected that supra-physiological doses of testosterone //this is what andro will initially convert to// would be bad for female mice ;-), this is another incidence, where someone who relied solely on the abstract, would be fooled into overestimating the negative and to underestimate unexpected positive effects of a drug that has been vilified like very few compounds before it.

In view of these results, some bros may now argue that taking androstenedione could actually be beneficial for your health, "protecting" you from several types of cancer! Well, before you jump on that bandwagon, remember that these are probably the same bros of whom you will read on various boards, that they use androstenedione or similar "mild" prohormones to fill the gaps between cycles of much harder steroids... As a reader of the SuppVersity, you get the facts, the interpretations and, even more importantly, the real world choices you make are up to you.

Amino Acids for Super Humans. Part III - Sulfur, More Than Just Rotten Eggs.

This relevant for all of you - regardless of whether you can or cannot spare the time: Tune in live and listen to me @ Carl Lenore's Super Human Radio to learn that amino acids are far more than just the building blocks of the proteins of your body...

Listen live to SHR @ 12:00PM ET

Amino Acids for Super Humans. Part III
Sulfur, More Than Just Rotten Eggs
update: Episode available for download, now!

In the third installment of the show, we are going to look at the commonly overlooked. yet vitally important sulfur-containing amino acid methionine, its "children" and "grand children", cysteine, n-acetyl-cysteine (NAC) and the purported "cell volumizer" taurine.

As usual, I will do my best to provide relevant examples and relate the theory to practical advice. The magic of individual amino acids will be tackled in the shows to come.

update: Episode available for download, now!

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

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

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


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

Why does my chest look like that, god damnit?

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

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

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

A necessarily incomplete overview of the worst offenders

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

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

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

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

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

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

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

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

Prevention is #1, but sometimes treatment is inevitable

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

Antioxidant Gear: Anabolic Steroid Stanozolol Decreases Mitochondrial ROS Generation and Oxidative Stress Induced by Acute Exercise in Rat Skeletal Muscle

Figure 1: Molecular structure of Stanozolol
(from Wikipedia)

Oswaldosalcedo, a member of the Mind&Muscle forum came up with a recent study (Saborido. 2011) that found some surprisingly healthy "side-effects" of Stanozolol, a synthetic anabolic orally available steroid derived from testosterone, also known as Winstrol.

The scientists tested the effect of Stanozolol administration on markers of mitochondrial oxidative stress in rats after an acute bout of exhaustive exercise and found: 

Stanozolol treatment markedly reduced the extent of exercise-induced oxidative damage to mitochondrial proteins, as indicated by the lower levels of the specific markers of protein oxidation, glycoxidation, and lipoxidation, and the preservation of the activity of the superoxide-sensitive enzyme aconitase. This effect was not due to an enhancement of antioxidant enzyme activities. Acute exercise provoked changes in mitochondrial membrane fatty acid composition characterized by an increased content in docosahexaenoic acid. In contrast, the postexercise mitochondrial fatty acid composition was not altered in stanozolol-treated rats.

Those of you who frequent the Mind & Muscle Forum, may already have read my comment on the changes in plasma fatty acid composition of the cell membranes in the respective thread: These changes vaguely remind me of a recent study on the effects of fish oil supplementation in elite athletes (Omega-3 Fatty Acids PRO(!)-Inflammatory in Athletes) where an increase in DHA (docosahexaenoic acid) also increased oxidative stress in the participants. The finding that Winstrol (Stanozolol) protects against acute exercise-induced oxidative stress by reducing mitochondrial ROS production, in association with a preservation of mitochondrial membrane properties by inhibiting the increase in DHA in the cell membrane may thus also be of relevance in view of the benefits / pitfalls of fish oil supplementation. Since (manageable) structural damage and super-compensatory repairs are also a prerequisite at the heart of training adaptation and muscle growth, the decrease in cellular integrity induced by increases in long-chain PUFAs in the cell membranes could also explain the "anabolic" effect of fish oil that has been observed in a handful of studies.