Forskolin: Friend or Foe? Stories and Studies About Fat Loss, Lean Gains, Topical Cellulite Treatment, Testosterone, Cancer, Hepatotoxicity, Drug Interactions & More

There is a single human study that would suggest that forskolin would make you get closer to this classic physique w/out tons of salad (who said that's necessary anyway?).

Since Maxim asked in one of his more recent comments about the usefulness and/or downsides of forskolin, I dediced to dedicate this Sunday (finally again?) to answering a user question and am going to briefly sum up some older and the few novel findings on forskolin I am aware of.

For those of you who find that boring: Don't blame Maxim alone, another reason for this decision was that I have seen discussions on forskolin resurface elsewhere on the Internet. By the way, I write re-surfaced, because forskolin has once been hailed as a testbooster and fat loss adjuvant, but as the prices increased and people came out with faked or low-quality products that did not yield results, the market collapsed.

What is forskolin and where does it originate from?

As usually there is more than a single answer to this question. The most straight forward general ones are probably (a) it is a white to white with yellow cast powder, or (b) a labdane diterpenoid with antihypertensive, positive inotropic, platelet aggregation inhibitory and adenylate cyclase activating properties. Moreover, forskolin is able to activate the adenylate cyclase and thus increase the intracellular cyclic AMP levels in most tissues and cells. And hat  it's called forskolin, because it is derived from the Indiant plan Coleus forskohlii is probably something 99% of you knew already.

The reason I suppose that Maxim got interested in it, is that it is commonly used in cell studies to raise the levels of cyclic AMP (cAMP; cf. Alasbahi. 2012) and did a pretty impressive job in the recently discussed PGC-1a study. On the other hand, it did also increase the expression of the aromatase enzyme in the Yang study mentioned in the "Natural Sildenafil & Testosterone Alternative" post on which Maxim replied with the initially mentioned comment.

"Wait, wasn't it supposed to be a testbooster and now it also inhibits myostatin and increases estrogen? What does this stuff not do?" - Well, forskolin is, above all, a cAMP modulator

Forskolins chemical structure. Sometimes it's also referred to as Colforsin; 7-beta-acetoxy-8, 13-epoxy-1-alpha, 6-beta, 9-alpha-trihydroxylabd-14-en-11-one; or Coleonol (img. from Sigma-Aldrich's product database)

I know that sounds confusing, but in essence forskolin does nothing but increasing cAMP levels in almost all types of cells. cAMP a breakdown product of ATP (=> cAMP => AMP) in turn is one of those molecules which exert most their effects as intracellular signal transducer. In that, it is involved in the activation of protein kinases and regulates the effects of adrenaline and glucagon. It also modulates the calcium channels and contributes to growth hormone release; unfortunately, cAMP has also been implicated in the proliferation of not very beneficial cell growth aka cancer. The same ion-flux mediation has recently been implicated in the etiology of ADHD, as well (Arnsten. 2012).

Still, it's not all about c-AMP. Probably cAMP unrelated downsides of coleus forkohlii are for example:

• forskolin induces hepatic CYP2C enzymes and coleus forskohlii extract and thus attenuates the anticoagulant action of warfarin. (Yokotan. 2012) 
• even more than isolated forskolin, coleus forskohlii  messes with the hepatic enzyme cascade (P450) and has even been shown to be hepatoxic in a study published in the July issue of the Journal of Toxicology (Virgona. 2012)

On the other hand there are a handful of benefits, e.g.

• 

  Figure 1: Effects of 12 weeks on 2x250mg (10%) forskolin on testosterone (free and total) and lean & fat mass (Godard. 2005)

  In a 2005 study (Godard. 2005), which caused quite a stir in the health and fitness community back then, Godard et al. observed profound beneficial effects of testosterone and body composition (cf. figure 1) after the ingestion of 2x250mg of a 10% standardized forskolin (Forslean).
  
  Now, the unfortunate truth is that the15 subjects (average age, BMI, and body fat percent were 24.4 +/- 5.9 years, 32.5 +/- 4.1 kg/m2 , and 35.2 +/- 8.3%) who had been randomized to the active arm of the study, and the 15 participants in the placebo arm (28.7 +/- 8.6 years, 32.6 +/- 3.8 kg/m2 , and 35.0 +/- 7.3%) were non-active sedentary overweight/obese (BMI 26 kg/m2 or more) individuals. Add the funding by Sabinsa (Forslean producer) to the equation and decide for yourself how relevant you think the results are going to be for you...

• In several in-vitro studies, forskolin has been used as a positive control to compare the effects of other compounds on the testosterone release in leydig cells. Lin et al. for example used it in 2001 as a comparison for lactate and found a ~3x increase in testosterone release in incubated leydig cells (Lin. 2001). A similar study by Yu et al. showed that the addition of green tea catechins lead to an additional stimulation of forskolin induced testosterone production in cell cultures (Yu. 2010).

• 

  Figure 2: Results of 12-week intervention w/ forskolin containing topical cream (Roure. 2011)

  As part of a topical cosmetic slimming product combining tetrahydroxypropyl ethylenediamine, caffeine, carnitine, retinol and, obviously, forskolin it has shown some promise as a topical anti-cellulite and toning agent (Roure. 2011). The clinical study was however financed by Johnson & Johnson and I am not sure how much of the effects were actually brought about by forskolin (the placebo was a basic gel with the same texture containing mainly water, gelifying and preservative systems). So take the data in figure 2 with a grain of salt, ladies - I bet 12 weeks on this product are not going to be exactly inexpensive.

• The administration of forskolin in conjunction with rutin (the glycoside between the flavonol quercetin and the disaccharide rutinose), vitamin B1 & B2 in a 2010 study by Pescosolido et. al. lead to a significant reduction in intra-ocular pressure in 15 glaucoma patients after 40 days (Pescosolido. 2010). Similar results were observed in a 2012 study for forskolin and rutin alone (Vetrugno. 2012)

• An in-vitro study by Cristobal et al. provides first evidence for the ability of forskolin to restore PPA2 in acute myeloid leukemia. That would make it a potential candidate for the treatment of this type of cancer, but to my knowledge there is as of yet not even a rodent study that would support these in-vitro results. Moreover, previous studies have suggested that Forskolin may even favor the proliferation of other types of leukemia (Kobayashi. 1994)

Time to weigh the "established" benefits and downsides

Figure 3: Effect of different doses of forskolin with and w/out epinephrine on FFA release from rat adipocytes - watch out this is from yet another in-vitro study with rodent cells (Litosch. 1982)

 In view of the fact that the aforementioned study by Godard is the only human study is only backed up by in-vitro data from rodent studies (Litosch. 1982, cf. figure 3), the fat loss benefits are as  Jeukendrup et al. point out in their 2011 review of purported fat burners...

"[...] promising, there is [yet] only one study at the present time and more work is required before forskolin can be recommended as a fat metabolism-enhancing substance." (Jeukendrup. 2011)

If you add to this the host of wanted and unwanted, known and unknown side effects that occur in response to the coleus foskohlii induced cytochrome P450 modulation (e.g. the mice in the aforementioned study by Virgona lost some visceral fat, but the costs were increased fat deposition in the liver and elevated transaminase levels).

With the questionable "fat loss" benefits (remember stress is also a powerful lypolitic and the problem is not to get the fat out of the cell, but rather to burn it), and the almost non-existant human data on the purported testosterone boosting effects, this should be reason enough not to buy more than one bottle for a test-run. After which I highly suggest to do some lab work to see if whatever good or bad you believe you are feeling is an actual boost in T (check T-levels) or hepatic side effects (check ALT, AST & ALP).

Note (update in response to comments): As far as the hepatoxicity is concerned the suggested dosage of 2x 250mg coleus forskholii most supplements come with may be higher than the medium dose in the study by Virgona, but is still probably "liver save" if you double dose on that, you are however landing in the no-man's land (=not tested for) gray zone between the medium dosage and the "danger zone" of  ~49mg/kg per day (human dose equivalent) that was tested in the study. Don't freak out, if you did that in the past, the levels return to normal afterwards and temporarily elevated ALT + AST or ALP levels do not necessarily mean that your liver is whacked forever ;-)

References:

• Alasbahi RH, Melzig MF. Forskolin and derivatives as tools for studying the role of cAMP. Pharmazie. 2012 Jan;67(1):5-13.
• Arnsten AF, Jin LE. Guanfacine for the treatment of cognitive disorders: a century of discoveries at Yale. Yale J Biol Med. 2012 Mar;85(1):45-58. Epub 2012 Mar 29.
• Godard MP, Johnson BA, Richmond SR. Body composition and hormonal adaptations associated with forskolin consumption in overweight and obese men. Obes Res. 2005 Aug;13(8):1335-43. 
• Jeukendrup AE, Randell R. Fat burners: nutrition supplements that increase fat metabolism. Obes Rev. 2011 Oct;12(10):841-51. 
• Kobayashi K, Nishikawa M, Omay SB, Toyoda H, Deguchi K, Shirakawa S. Forskolin potentiates G-CSF-induced proliferation of a murine myeloblastic leukemia cell line. Leuk Res. 1994 Feb;18(2):111-7.
• Lin H, Wang SW, Wang RY, Wang PS. Stimulatory effect of lactate on testosterone production by rat Leydig cells. J Cell Biochem. 2001 Jun 26-Jul 25;83(1):147-54.
• Pescosolido N, Librando A. Oral administration of an association of forskolin, rutin and vitamins B1 and B2 potentiates the hypotonising effects of pharmacological treatments in POAG patients. Clin Ter. 2010;161(3):e81-5. 
• Roure R, Oddos T, Rossi A, Vial F, Bertin C. Evaluation of the efficacy of a topical cosmetic slimming product combining tetrahydroxypropyl ethylenediamine, caffeine, carnitine, forskolin and retinol, In vitro, ex vivo and in vivo studies. Int J Cosmet Sci. 2011 Dec;33(6):519-26.
• Vetrugno M, Uva MG, Russo V, Iester M, Ciancaglini M, Brusini P, Centofanti M, Rossetti LM. Oral administration of forskolin and rutin contributes to intraocular pressure control in primary open angle glaucoma patients under maximum tolerated medical therapy. J Ocul Pharmacol Ther. 2012 Oct;28(5):536-41.
• Virgona N, Taki Y, Yamada S, Umegaki K. Dietary Coleus forskohlii extract generates dose-related hepatotoxicity in mice. J Appl Toxicol. 2012 Jun 22.
• Yokotani K, Chiba T, Sato Y, Taki Y, Yamada S, Shinozuka K, Murata M, Umegaki K. Hepatic cytochrome P450 mediates interaction between warfarin and Coleus forskohlii extract in vivo and in vitro. J Pharm Pharmacol. 2012 Dec;64(12):1793-801.
• Yu PL, Pu HF, Chen SY, Wang SW, Wang PS. Effects of catechin, epicatechin and epigallocatechin gallate on testosterone production in rat leydig cells. J Cell Biochem. 2010 May 15;110(2):333-42.

SVSR: Supplement-Drug Interactions, Exercise & Your Pysche, Running vs. O-Lifting vs. Heart Health, N3-to-N6 Ratios, CYP Enzymes, Cannabinoids & Telomeres

The SuppVersity Science Round-Up every Thursday live on Carl Lanore's Super Human Radio -- tune in live at 1PM (EST=  6PM GMT)!

I hope that most of you have already had a chance to listen to yesterday's installment of the SuppVersity Science Round Up on Super Human Radio. In case you didn't, or have been waiting for me to post the link to the podcast (just a reminder: you can always download the latest show, from the navigation bar on the right, where it says: "Physical Culture for your Ears"), I'd suggest you go and download the podcast either now, or after going through today's SuppVersity Science Round Up Seconds.

The "Seconds" are as the name implies no "leftovers", but actually yet another selection from the selection of god knows how many interesting newsbits I usually pile up for the short 1h show, Carl and I are doing every Thursday. I would therefore encourage everyone to do both, listen to the podcast and read the "Seconds" one day later. After all, the things Carl and I discuss on the air won't reappear here, they are "SHR exclusives", so to say ;-)

Apropos, in yesterday's show, the topics we did cover were

• premature ejaculation, and how only two hormones seem to make a difference,  
• peptides as prostate cancer vaccine, and how Harvard scientists build them from scratch,
• supps vs. medications, and how fatal commonly overlooked interactions can be, and
• copper, and why it may well matter than raw milk has 2-3x more than pasteurized milk

and before we go on with the actual "seconds", I must acquit myself of a promise -- the promise to provide you with more information on #3 on the above list.

Supplemental data: Supplement vs. drug interactions

Figure 1: Important supplement drug interactions based on Tsai (2012)

Those of you who have already listened to the podcast will probably be waiting eagerly for the supplemental material with more information about the potential pitfalls with supplement-drug interactions, Carl and I have been talking about on yesterday's show. With some digging, typing, searching, excerpting and formatting on my part, I have actually come up with a quite comprehensive and for people who are not familiar with all the funky drug names, probably even more understandable version (see figure 1) of the tabular overview H.H. Tsai and colleagues from the China Medical University Hospital and the College of Pharmacy at the University of Illinois at Chicago have included in their latest review of the literature (Tsai. 2012).

What I left out are the two pages (!) part on St. John's wort. With 147 drug (!) interaction ranging from "A" as in "amiodarone" to "W" as in "warfarin" and covering almost every drug type from anti-depressants, protease inhibotors, calcium channel blockers, PDE-5 inhibitors (viagra & co), SERMs, proton pump inhibitors, etc.. In view of the fact that these are only the known interactions, it would be easier to list those drugs with which St John's does not conflict, anyway. So, unless you have a study at hand which conclusively shows that St. John's is no problem, I would rather err on the side of caution, than end up in the ER.

Top 5 of the most frequent interactions observed with medication that act on (ranked by frequency, figure in brackets indicates percentage of all drugs in the study; based on Lin. 2012):

1. nervous system (19.6%)
2. cardiovascular system (17.7%)
3. antiinfectives for systemic use (14.7%)
4. alimentary tract and and immunomodulating agents (12.2%)
5. musko-skeletal system (6.4%)

As far as the supplement list in figure 1 goes, the most frequent potential side effect due to supplement-drug interactions affected drugs / supplements that play a role in blood coagulation. Danshen, evening primrose, gingko, glucosamine, white willow bark, garlic, vitamin E, fish oil to name only the most common ones, they all can increase the risk of bleeding not only, but specifically in patients who are taking warfarin (aspirin, ibuprofen, heparin and others were on the list, as well).

"What’s wrong with telling a patient, 'If you don’t hear from us with your lab results a few days, give us a call'? The answer is plenty, if that patient is receiving warfarin therapy. Because warfarin has a narrow therapeutic range and complex pharmacology, insufficient monitoring or errors in dosing can lead to severe and possibly life-threatening bleeding and clotting in patients receiving it." (Bush. 2002)

In view of the "top 5" above, this certainly sounds counter-intuitive, but we are dealing with a practical research bias here. As I mentioned on the air, there is simply an overabundance of research on potential interaction with warfarin, because finding the right dosage and adapting it appropriately is already hard even when there are no confounding variables, so that a sudden supplement-drug interaction and subsequent increase in the risk of bleeding can potentially be fatal (see the quote in the red box to the right)!

Regardless of what medication you may be on, rules that apply for a healthy individual that does not take any medication chronically (not even 'harmless' NSAIDs), don't apply to you! So please for one, follow the recommendation you find on each and every supplement to "talk to your medical practitioner" before you add another 'harmless' supplement on top of the 'harmless' over-the-counter or prescription drugs you are taking.

The Seconds: Interesting news that have been missing from yesterday's show

After this pretty lengthy addendum, let's get to three other items I had actually planned to have on the show, two of them are exercise, while the third one is a health and supplementation... and, when I come to think about it, obviously also diet related news-item:

• Exercise makes you happy and puts an end to the greed for money! That's not exactly the result of a recently conducted study from the Charité in Berlin (Bothe. 2012), but it is more or less what follows from the differential response Bothe et al. observed in their untrained and highly trained subjects to monetary stimuli after they had completed a standardized running exercise (30 min at 60-70 % VO2max, T) or placebo (P).
  

  

  Who would have thought that: Exercise reduces the anticipatory response to monitary incentive delay (MIT) test (Bothe. 2012)

  "Acute exercise was found to influence gain anticipation. In the P compared to the T group a more pronounced anticipation-related BOLD response was found in mesolimbic and mesocortical dopamine-innervated regions like the VS, hippocampus (Hipp) and subgenual anterior cingulate cortex (sgACC). [...] Additionally, several brain structures potentially associated with motor preparation (primary and supplementary motor areas) as well as structures belonging to the ventral (lingual gyrus) and dorsal (cuneus, precuneus) visual pathway showed stronger BOLD responses to gain anticipation in the P group compared with the T group." (Bothe. 2012)

  Moreover, according to the paper which is going to be published in one of the upcoming issues of Medicine and Science in Sports and Exercise, all 43 healthy men between the age of  20 - 32 years who participated in the study showed similar increases in mood (effect size F=11.70).
  
  With both, the beneficial outcome of the positive and negative affect schedule and the decrease in anticipatory signalling (= the greedy "I am about to win!") in the psychological testing session (the so-called monetary incentive delay) in an fMRI brain scanner, being identical it becomes evident that you don't have to be an athlete to monetize (all puns intended ;-) on the beneficial psychological effects of exercise.

• 

  Figure 1: Changes in total lean mass, aerobic fitness, strength (mind the scaling with x10!), right ventricular mass and end-diastolic volume in subjects in the endurance (runners) and strength training arm (O-lifting) of the 24-week study (based on Spence. 2012)

  Changes to the heart (right ventricular) due to exercise are mild, and if anything more pronounced in response to endurance than resistance training! " Left ventricular (LV) adaptation to exercise training has been the focus of 'athlete's heart' research to-date, information regarding right ventricular (RV) adaptation is sparse, due to its complex structure and imaging technique limitations." (Spence. 2012) So scarce, in fact, that this recent study that has been conducted by researchers form the The University of Western Australia, the University of Leeds, a and the Liverpool John Moore's University is the first to take a closer look at the impact endurance or resistance training have on the morphology of the RV.
  
  For their randomized trial, the researchers recruited twenty-three young untrained men.. The men were assigned to either
  
  • endurance training (E; n = 10)  - consisting of a progressively overloaded program of walking/jogging/running, divided into three training phases over the 24-week period, or
  • resistance training (R; n = 13) - with a focus on periodised R program was Olympic weightlifting with incorporated assistance exercises (e.g. deadlift, squat, bench press, overhead press) to develop overall strength and technique
  for a total timespan of 6 months, in the course of which body composition, aerobic fitness, muscular strength, RV morphology (MRI) and function (speckle tracking echocardiography) were continously monitored.
  
  The results Spence et al. are going to publish in one of the future issues of Medicine and Science in Sports and Exercise refute even two pieces of common "knowledge". Firstly, a still totally benign, right ventricular hypertrophy was exclusively observed in the endurance training group, yet not in the heavy lifters who were doing their squats, deadlifts and military presses (by 2.7g following E and by 1.4 g  following R training). Secondly, both strength and size gains were no prerogative of the lifting weight group. Contrary to the increase in total lean mass (+1.3 kg vs. +2.1 kg), the strength increase of +53.8 kg vs. +35.3 kg was yet much significantly more pronounced in the weight lifters.
  
  On the other hand only the endurance training group saw significant statistically improvements in their aerobic fitness level. This correspondence of endurance exercise, mild ventricular hypertrophy and increased fitness levels is unquestionably telling in terms of "how bad" a physiologically enlarged heart where the ratio of left-to-right ventricular  mass remains intact (which was the case in the study at hand), don't you think so?
• Omega-3s, omega-6s, telomere length, CYP enzymes, endogenous cannabinoid and the liver you need all of them to see the complete picture While the epidemiologists are still debating who will and who won't benefit from omega-3 supplementation, those who still care about how our bodies works and why their colleagues over at the epidemiology department are still debating, have made quite some progress as far as the underlying health benefits of rectifying the omega-3 to omega-6 balance are concerned.
  
  
  Why are endocannabinoids problematic? One of the answers is: "They will make you fat!" Basically we have known that forever, but a recent study which tracked the conversion of dietary linolic acid (n-6) to it's endocannabinoid metabolits, 2-AG and anandamide has recently confirmed not just that, but also that the provision of no more than 1% of the total energy of the diet in form of eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) can already make a huge difference (Alvhem. 2012). With the addition of the long-chain omega-3s, the rodents in the study had a 8:1 ratio of linolic acid (LA) to long-chain omega-3 fatty acids in their diets. Still much higher than what you will hear is necessary, but sufficient to reverse the overabundance of arachidonic acid, in the phospholipids of liver and erythroctes, and the +200% increase in endocannabinoid levels that had been brought about, when the researchers had increased the linolic acid content of the diet from 1% to 8% of the total energy intake. In view of the fact that the same goes for the increased food intake, feed efficiency, and adiposity the mice had developed on the 60% fat (total) diet with a high linolic acid content, this study - despite being done on rodents - clearly shows that it does not necessarily have to be a 1:1 ratio to grasp major health benefits.
  
  If you get down from  30:1 to 8:1 you've come a tremendous way, already; and guess what: The easiest way to achieve that is to just cut out all seed and vegetable oils as well as processed foods that contain them.
  In a recent review on the differential effects of fatty acids on human metabolism in the Italian journal Medical and surgical pediatrics G. Caramia emphasizes the role of omega-6 derived endocannabinoids:
  

  "[E]ndocannabinoids like anandamide (N-arachidonoylethanolamine) and 2-arachidonoylglycerol [that arise from the enzymatic conversion of linolic acid by enzymes from the cytochrome P450 family at the liver are] capable of mimicking the pharmacological actions of the active principle of Cannabis sativa preparations such as hashish and marijuana (-)-Delta9-tetrahydrocannabinol. They act as true 'endogenous cannabinoids' by binding and functionally activating one or both [of the] cannabinoid receptor present on nervous and peripheral cell membranes." (Caramia. 2012; my emphases)

  Unfortunately, the same enzymes which are responsible for the generation of those endocannabinoids, are also responsible for the conversion of n-3 PUFAs into more potent metabolites of EPA and DHA, which will actually do most of the the vascular- and cardioprotective magic that is commonly ascribed to "fish oil".
  
  And how does all that relate to telomeres?
  
  These competitive effects in turn segue directly into the observations of a double-blind 4-month trial that involved 106 healthy sedentary overweight middle-aged and older adults. The participants supplemented their diets with capsules containing either (1) 2.5 g/day n-3 PUFAs, (2) 1.25 g/day n-3 PUFAs, or (3) a placebo that mirrored the proportions of fatty acids in the typical American diet.
  
  Now, it's not news that this led to decreases in inflammatory markers. I am not going to bore you with those, don't worry!
  
  What is news, and in my eyes very important, is that neither the provision nor the dosage of additional long-chain omega-3s had an effect on telomere length, the only variable that mattered was were the changes in the n-6:n-3 PUFA plasma ratios, which "helped clarify the intervention’s impact: telomere length increased with decreasing n-6:n-3 ratios (p= 0.02)" (Kiecolt-Glaser. 2012).

That's it as far as today's seconds go... you want more? Man, I could certainly give you more, but you know that gluttony was once considered a sin, right? Tomorrow is another day, and if you can't wait, just head over to the SuppVersity Facebook wall, which is always bursting from the seems with the latest tidbits from the realms of health, exercise and nutrition sciences.  

References:

• Alvheim AR, Malde MK, Osei-Hyiaman D, Hong Lin Y, Pawlosky RJ, Madsen L, Kristiansen K, Frøyland L, Hibbeln JR. Dietary Linoleic Acid Elevates Endogenous 2-AG and Anandamide and Induces Obesity. Obesity (Silver Spring). 2012 Oct;20(10):1984-94.
• Bothe N, Zschucke E, Dimeo F, Heinz A, Wüstenberg T, Ströhle A. Acute Exercise Influences Reward Processing in Highly Trained and Untrained Men. Med Sci Sports Exerc. 2012 Oct 10.
• Bush J. Preventing errors in your practice. Reducing risks for patients receiving warfarin. Fam Pract Manag. 2002 Jul-Aug;9(7):35-38.
• Caramia G. [Essential fatty acids and lipid mediators. Endocannabinoids]. Pediatr Med Chir. 2012 Mar-Apr;34(2):65-72.
• Kiecolt-Glaser JK, Epel ES, Belury MA, Andridge R, Lin J, Glaser R, Malarkey WB, Hwang BS, Blackburn E. Omega-3 fatty acids, oxidative stress, and leukocyte telomere length: A randomized controlled trial. Brain Behav Immun. 2012 Sep 23. pii: S0889-1591(12)00431-X.
• Spence AL, Carter HH, Murray CP, Oxborough D, Naylor LH, George KP, Green DJ. MRI-derived Right Ventricular Adaptations to Endurance versus Resistance Training. Med Sci Sports Exerc. 2012 Oct 15.
• Tsai HH, Lin HW, Simon Pickard A, Tsai HY, Mahady GB. Evaluation of documented drug interactions and contraindications associated with herbs and dietary supplements: a systematic literature review. Int J Clin Pract. 2012 Nov;66(11):1056-1078.

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.