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

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

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

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

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

Sunlight, Bluelight, Backlight and Your Clock

Sunlight a La Carte: "Hack" Your Rhythm

Breaking the Fast to Synchronize the Clock

Fasting (Re-)Sets the Peripheral Clock

Vitamin A & Caffeine Set the Clock

Pre-Workout Supps Could Ruin Your Sleep

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

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

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

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

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

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

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

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

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

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

References:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Getting rid of "gyno" with  aromatase inhibotors

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

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

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

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

Getting rid of "gyno" with topical DHT cream

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

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

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

Conclusion and the last resort: Surgery

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

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

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