Aromatase in the dock

Gynecomastia - feminine look of the male breast, lipomastia - the excessive accumulation of fat around the nipples, breast cancer, prostate hypertrophy and cancer - all of these problems can have a common reason which is called: aromatase.

In sickness and in health ...

Aromatase is an enzyme (actually - an enzyme complex) converting the male sex hormones to the female ones, androgens - to estrogen, testosterone and androstenedione - respectively - to estradiol and estrone.

Through these activities a woman's body produces the most distinctive group of sex hormones. However, the same estrogens which determine the characteristics of physiognomy and reproductive also expose women to breast cancer and promote the development of breast cancer.

In certain ranges of values ​​- aromatase and estrogens are also necessary to maintain adequate male health and form. Their excess, however, causes many problems - both medical as well as aesthetic. For example, it can lead to the prostate disorder, testicular atrophy, decrease of testosterone level, hyperplasia of mammary glands surrounding tissue (gynecology and lipomastia) and their exposure to tumor changes, accumulation of fat around the thighs and buttocks and water under the skin and joints.

Aromatase inhibitors

A significant excess of estrogens appears most of all during the 'steroid treatment', when athletes take high doses of testosterone and its derivatives - mostly synthetic androgens - the so-called anabolic-androgenic steroids. In such cases aromatase converts them collectively to monstrous portions of estrogen. Now estrogens negatively affect the hypothalamus and pituitary gland, reducing the production and release of pituitary hormones (gonadotropins), which is called a negative feedback effect and which ultimately inhibits vital functions of testicles, reduces the weight of their tissue and blocks the production of testosterone. They also negatively affect other tissues, causing the above-mentioned health and aesthetic problems.

And at this point we encounter the first situation justifying the use of an aromatase inhibitor (AI) - an agent inhibiting the activity of this enzyme - by the athlete: meatheads include similar drugs to strong 'steroid treatment' to avoid health problems and to prevent the accumulation of subcutaneous fat and water, which make it difficult to achieve the effect of shaped body.

They also employ AI after the end of the treatment, in order to unlock the axis hypothalamic-pituitary-gonad, to restore the weight and functions of testicles and to resume the production of their own testosterone, and such a process is called 'unblocking' or PCT - post cycle therapy.

The excess of estrogens also occurs during the men’s so-called 'hormone storm' associated with puberty, the elderly, in the case of obesity, as is sometimes the result of specific genetic predisposition.

In the first case, once again the excess of testosterone, collectively converted to estradiol, is to blame.

In the second - the situation is more problematic, especially due to the fact that in this case generally we deal with the testosterone deficiency ... Probably with age the activity of aromatase increases, which increases the conversion of testosterone to estradiol, which - as we know - inhibits the production of testosterone.

Obesity promotes the overproduction of estradiol, as aromatase is an enzyme particularly active inside fat tissues. The more fat - the more aromatase and increased conversion of androgens to estrogens. The more estrogen - the more fat - this may a kind of a “vicious circle”. The high expression of the aromatase gene for some men is an innate feature. Such men possess a large reserve of aromatase, convert more androgens to estrogens and accumulate a lot of fat around the nipples, thighs and buttocks. It is said that they have gynoidal (female) features of constitution, and in the meathead’s slang they are defined as 'gynomen' - 'butches’ - in a free translation.

Let us leave aside youths and juniors, as they are unlikely to use AI, unless prescribed by a doctor when well developed gynecomastia causes problems with self-acceptance and environment acceptance. They are willingly employed by oldboys and amateur of bodybuilding with a tendency to gain weight or gynoidal accumulation of fat. What is more (!), in meathead’s environment You can even face an opinion that one cannot - with this type of problem or steroid treatments - get perfect burn fat, without a good aromatase inhibitor.

Sometimes athletes also use aromatase inhibitors as testoboosters - agents increasing testosterone level. When we lower the estrogens levels, they do not suppress the hypothalamus, pituitary and gonadotropins, so the testicles produce more testosterone. The increase of your own testosterone level imitates then the effects of its administration from the outside - we get faster increase in strength and muscle mass, I do not have to remind You that testosterone is one of the most powerful anabolic hormones - developing muscles.

From the oncology - to sport We can take for granted that the history of aromatase inhibitors began in 1967 - the date of publication of Cash's work, in which the author suggested the validity of the aminoglutethymide in the treatment of breast cancer. Then it was observed that the use of this drug brought improvement for women with this disease, but this effect was associated with the inhibition of the synthesis of adrenal hormones. Aminoglutethimide was a drug used for years with good results with hyperactivity of these glands - in the so-called Cushing's disease. It was known that estrogens promote the development of breast cancer, and adrenal glands produce (apart from cortisol and aldosterone) DHEA - a hormone converted in stages to estrogen. It turned out, however, that with the effective blockade of enzymes producing steroid hormones from cholesterol, aminoglutethimide is at the same time, an additional potent inhibitor of aromatase.

Since the major disadvantage of aminoglutethymide, in the context of its anti-estrogens properties, was the blocking of the vital cortisol production, attempts were taken to obtain better inhibitors of aromatase - selective ones - abolishing the activity of only one enzyme. One of the first, not very successful test was based on the synthesis of aminoglutethymide derivative - roglethimid - the drug that has not won wide recognition among oncologists. Then another molecules were studied and introduced (or not) to the treatment. Many of them remained in the standards of pharmacological treatment in oncology, while some have been used only in sports doping.

The simplest distribution of aromatase inhibitors runs along the lines of chemical structure, usually they are divided into non-steroidal and steroidal ones.

Until now, in medicine or doping the following compounds are used (or were used):

non-steroids - aminoglutethimide, roglethimid, letrozole, anastrozole, fadrozole, vorozole;

steroid - formestane, eksmestan, testolactone, mesterolone, androstentrion, androstatriendion and hydroksyandrostentrion (the last three - just in sports).

The ones that are used by most of the athletes for doping practices, I discussed in detail in the article in No.16 of magazine Perfect Body, so here I will remind only their drawbacks ...

Disadvantages of inhibitors

AI do not belong to safety drugs. In addition to adverse effects resulting from the specific nature of each of them individually, they also generate health problems generally associated with lowered level of estrogen, the most important of which are muscle and joint pain, osteoporosis, atherosclerosis, depression and impotence. Deep estrogen deficiency also limits the rate of muscles development, even at an elevated level of testosterone. In a study that evaluated the impact of AI on men, although a significant increase in the level of testosterone was observed, no increase of muscle mass and improvement in strength test results were noted. All this is caused by the fact, that estrogens are the hormones no less important for men as for women. Recently some propose to treat them, even not as female sex hormones, but only as unisex hormones.

Estrogens contribute to maintain the health of the man, as well as participate in the development of his muscles. Estradiol is an anabolic more potent than testosterone. It is not used as an anabolic drug merely because it significantly deregulates both male and female hormones. It stimulates the synthesis of the most important, tissue hormone - IGF-1 in the muscle cells. It also stimulates myogenesis - maturing young satellite cells to adult muscle cells. In the muscles it activates androgen receptors and sensitizes them to the androgen activity, it was found out that testosterone - to establish the maximum anabolic potential - should be in the following proportion to estradiol, 80:1. For example - a drastic shortage of estrogen in the male body, with which we deal in hereditary deficiency of aromatase, is manifested, among others, by shaping of the so called eunuchoidal body build - the tall height, unnaturally long, skinny limbs and poor muscle mass (symptoms of the disorder withdraw after administration of 1 mg of estradiol per day). Estradiol also activates its own estrogen receptors in muscle cells.

It was demonstrated that trainings increase the number of estrogen receptors in the muscle tissue, and that this increase is a prerequisite for adaptation of muscles to effort.

So maybe it is worth to look for something milder - less decreasing estrogen, something which will not generate any adverse effects, but at the same time will implement all objectives set by the athletes.

Polyphenols - Nature's wonders

Many natural, plant micro-nutrient elements from the group of polyphenols show structural similarity to the aromatase product - estradiol. Owning to the above fact, the compounds of this type are called even phyto-estrogens and are often tested for aromatase inhibition potential, since the products of the given enzyme (in this case - estrogens) are usually its inhibitors. Of course, these works are not carried out with the eye to the athletes, but rather to people suffering from cancer. Athletes can naturally use these results - in a reasonable and safe manner and in accordance with the provisions of anti-doping - to fight against estrogen and aromatase. As during the last 30 years, ​​a lot of similar studies have been conducted - not just on polyphenols, but also on other food ingredients - below I will focus only on those that may have practical significance for us ...

Several studies have demonstrated Kelles - 1984, Campbell - 1993, Kao - 1998, Jeong - 1999, Edmunds - 2005, Sanderson - 2005), that a relatively potent inhibitor of aromatase (only twice weaker than formestane and comparable with aminoglutethimide) is the most important flavonoid (subgroup of polyphenols) of propolis - chrysin. The second most important flavonoid of propolis - apigenin - turned out to be AI even slightly stronger than chrysin (Jeong, 1999). In turn, the extract of propolis reduces aromatase activity by more than 50 percent (Journal Supportive Oncology, 2005). The problem is that these compounds poorly infiltrate the body, but works to improve their bioavailability are carried out. The assimilability of these both flavonoids is supposedly increased by piperine. So you can try: at a meal - 40-50 drops of propolis tincture with a teaspoon of minced black pepper. This can have a profound meaning also owning to the fact that piperine itself blocks aromatase (Balunas, 2008).

In almost all the works mentioned above, a naringin potential was also assessed. This flavonoid only slightly weaker than chrysin inhibited aromatase. On the other hand, Jeong showed that hesperetin is a AI even stronger than chrysin. Since both compounds are the main polyphenols of citrus fruit (hesperetin - orange, naringin - grapefruit), that is why they are common in a patented extracts of citruses - Sinetrol. Aromatase activity is also reduced by grapefruit and orange juice (Chen, 2002), but wekaer - respectively - 3 and 4 times from the juice of black grapes, about which I will write later ...

However, in 2003, Goodin studied the impact of the green tea polyphenols on aromatase.

One of them - EGCG - administered for 7 days at a dose of 12.5 mg per kilogram of body weight, decreased aromatase activity by 56 per cent. This creates a viable alternative to synthetic AI, taking into account that such a strong dose, per an adult man, constitutes only 4 capsules of Olimp supplement - Green Tea. On the other hand, Way in 2004 compared directed against aromatase EGCG activity, with the same activity of theaflavins - polyphenols characteristic only for black tea. It turned out that they are on average 4 times more active than EGCG, so at lower doses they contribute to the inhibition of the enzyme. In this research model - with the concentration at which EGCG decreased aromatase activity in the range between 50 and 70, theaflavins inhibited enzyme by nearly 95 percent.

That is why, while burning fat, reduction supplements with citrus and tea extracts are a good choice - also owning to the inhibition of aromatase.

It is worth to mention, that among other caffeinated drinks, except tea, the ability to inhibit aromatase was also showed by: coffee and cocoa (Osawa, 1990). Though, it must be pointed out that the first beverage is about 50% stronger than the other.

Wang proved in 2006 that a relatively potent inhibitor of aromatase (more than 3 times stronger than naringins) is resveratrol - the most active polyphenol of dark grapes and red wine. Some ability to inhibit aromatase is also showed by pigments of dark grapevines and red fruit - anthocyanidins (Neves, 2007).

Various black grape preserves are characterized by the strong inhibition feature of this enzyme... For example a juice, as demonstrated by Chen in 1998. However, the record holder is here undoubtedly Cabernet Sauvignon (a type of red wine) - almost ten times stronger than grape juice (Eng - 2001, 2002, 2003). In Eng’s studies not much worse fared other red wines - Merlot, Pinot Noir and Zinfandel. Dried grapes also inhibit aromatase, but 3 times less than grape juice (Balunas - 2008). Nevertheless, the main researchers’ focus is attracted by grape seed extract, as these - as shown by Kijima in 2006 - decrease the activity of aromatase in the range between 70 and 80 percent, depending on the concentration of the extract. What's interesting, author of the study noted that the inhibition was here mainly the effect of blocking, by the active ingredients of seed, the glucocorticoids receptors - transcription factors through which cortisol acts in cells stimulating genes for the production of aromatase protein. This finding seems to be important owning to the fact that cortisol is a hormone which at the same time destroys muscle and develops fat tissue. The inhabitation of its activity not only helps to fight against aromatase and estrogen, but in general - against the fat, the so-called metabolic syndrome (occurring at the same time: obesity, diabetes and hypertension) and sarcopenia (age-related, progressive loss of muscle mass and strength), and also promotes athletes’ muscle growth.

Recently some researches discussed the influence of pomegranate juices and extracts, because they - as evidenced by the studies - possess broad health properties (particularly anti cancer ones), and what is more - strengthen muscles, reduce cortisol and increase testosterone. At this point we are particularly attracted by the Adam’s work from 2010, which examined the impact of urolithins - very metabolically active compounds - on the aromatase. These compounds occur from the transformation of the consumed pomegranate polyphenols which takes place in the intestinal flora. As it turned out - almost all of these compounds blocked our enzyme to a lesser or greater extent, but methyl-urolithin B (MUB) decreased aromatase activity by about 70 percent ... That probably explains why - in the study of Kim in 2002 - pomegranate juice inhibited the enzyme at 51 percent.

Strawberry juice was only twice weaker aromatase blocker than black grape juice (Chen, 2002). This is probably caused by the fact that, in turn, the main strawberries flavonoid - fisetin - is relatively strong AI, about 8 times weaker than chrysin (Leong, 1999).

Aromatase is also inhibited by juices of other fruits from the rosaceae family, which includes strawberry, peach, apple, blackberry and plum juice (Chen - 2002, Balunas - 2008). All - about three times weaker than the grape juice. Although cherry juice was not examined in this light, it is the most important cherry flavonoid - prunetin - that inhibits aromatase only 7 times weaker than chrysin. Probably not without significance is the fact that the fruits from the rosaceae family contain ellagic and ursolic acid. The first of these compounds is responsible for the above mentioned pomegranate activity, and as far as the second is concerned, I will write about it later ...

Quercetin - a substance characteristic for onions and related to this plant vegetables from the lily family, turned out to be another flavonoid inhibiting aromatase activity (Kelles - 1984, Ducrey - 1997, Moochhala - 1988, Pelissero - 1996, Saarinen - 2001). Although the activity of quercetin was 10 times lower than chrysin and apigenin, it is sufficient to block aromatase - at the appropriate concentration - 85 percent (Eng, 2002). However, water extract of onion inhibited aromatase only 3 times weaker than the grape juice (Grube, 2001).

In 2004 Wang studied, the activity of chalcones - polyphenols being the flavonoids precursor. Several of the compounds had the ability to block our enzyme, though butein turned out to be the most potent inhibitor, which decreased the aromatase activity by 90 percent. And now we must praise our countrymen: the world's first butein supplement - InhAR - was launched by a Polish company Megabol!

One more chalcone - xanthohumol is an aromatase inhibitor with an activity similar to butein and only 3 times weaker than chrysin (Monteiro, 2006). As this polyphenol is a part of the active compounds of hops, its considerable amounts were found in a variety of beers. Owning to the presence of xanthohumol, dark beers possess the ability to inhibit aromatase almost equal to black grapes juices, while light ones to the grapefruit ones (Monteiro, 2006).

Ligants are also a group of polyphenols of a relatively high capacity of aromatase inhibition.. From the food we usually aspire secoisolariciresinol and matairezinol, found in tea, olives, various seeds and grains (although their most abundant food source is linseed), converted by the intestinal flora to enterolactone and enterodiol. All four lignans inhibit aromatase10 times weaker than chrisin (Saarinen, 2003), but one of their metabolite - dihydroxyenterolacton - only about 5 times (Adlercreutz, 1993).

Recently discovered group of relatively rare in nature polyphenols with strong anticancer properties is the group of xanthones. The greatest wealth of these compounds was found in the very tasty exotic fruit - mangosteen. Its preparations showed a half times higher aromatase inhibition capacity than black grapes juice (Balunas, 2008). However, one of the mangosteen xanthones - gamma mangostin - was nearly 12 times more potent than EGCG AI (Balunas - 2008).

Researchers have high hopes on the mangosteen, especially in the treatment of breast and prostate cancer. I see in it a future especially for young men, athletes, and older men to whom the excess estrogen interferes with the maintenance of full health and obtaining starting or simply aesthetic silhouette.

Not only polyphenols ... In the search for ways to fight against aromatase, the researchers examined not only polyphenols, but also a variety of natural compounds from other chemical groups.

For example Angwafor noted in 2008 a significant decrease in the level of estradiol in 42 men treated for 14 days with astaxanthin - carotenoid pigment of sea alga, which gives color to salmon meat. Referring to previous research, he suggested that this was due to the blocking effect of this compound on aromatase.

As I mentioned above - a compound similar to the product of the enzyme may be its inhibitor. Thus, similar to estrogens, polyphenols tend to be aromatase inhibitors. Moreover, plant steroids and triterpenoids are all similar to estrogens. These compounds are at the same time similar to the aromatase substrates, i.e. androgens. Compounds similar to the substrates can block the enzyme either. Though, it is no wonder that steroids and triterpenoids aroused the interest of scientists. Nevertheless, from so far examined types of food compounds, only two possess so strong inhibitory activity, to talk about them as AI in a practical meaning - spinasterol and ursolic acid. Water extract from spinach showed the ability to inhibit aromatase perhaps thanks to the spinasterol content, but this inhibition was more than 3 times weaker than grape juice (Grube, 2001). Ursolic acid turned out to be the AI about 14 times weaker than that chrisin or apigenin (Jeong, 2000), blocking aromatase - at the appropriate concentration - in more than 30 percent (Gansser, 1995). Because much of this compound is contained in all blueberries and rosaceae fruits, that is why it can contribute - together with polyphenols - to the above mentioned, a relatively high inhibitory activity of the juices derived from these fruits.

Potentially high biological activity, directed against aromatase, demonstrate also some fatty acids. One of the typical for fish omega 3 acids - DHA - works twice stronger than grape juice, and the second - EPA - at the level comparable to the juice. The main component of olive - oleic acid - is a bit stronger than grape juice. More than four times weaker activity than oleic acid, was showed by stearic acid - the main fat compound of chocolate. On the other hand, characteristic acid of coconut oil - myristic acid - worked only 3 times weaker than the oleic one (Balunas, 2006). Record holder here, however, is probably linoleic acid, working more than 3 times more potent than grape juice (Balunas, 2008). However, the strongest AI are its derivatives - CLA and 9-oxo-ODA. The first decreased the aromatase activity by 84, and the second - about 95 percent (Kraus, 1991).

Since linoleic acid is a fatty compound, characteristic for tomatoes, probably because of that and owning to the substantial content of narigenin, tomato products inhibit aromatase (some do not show here the activity) only twice weaker than coffee (Osawa, 1990).

Conjugated derivatives of linoleic acid (CLA) are, in turn, fatty compounds present in substantial quantities in many fungi, but especially - in meadow mushrooms. As indicated by Grube in 2001 and by Balunas in 2008, the meadow mushrooms are very strong AI - for example, a water extract from these fungi worked here about 15% stronger than grape juice.

As it was shown in the studies - some ability to inhibit aromatase possess also (other than those already mentioned: onions, spinach and tomato) other vegetables - celery, parsley, carrots, cabbage (including its seeds, i.e. mustard and sinapis), broccoli, chicory, endive and pepper. Aromatase inhibitors in soup vegetables are compounds from the group of furanocoumarins, similar to psolaren (McDermott, 2005). However, in brassica vegetables - probably indole derivatives, such as indole-3-carbinol (Shilling, 1999).

On the other hand, as far as spices are concerned, turmeric - reducing aromatase activity by more than 50%, works here the best (JSO, 2005). If we were to discuss popular herbs - then willow bark, licorice and cat's claw reduce aromatase activity by more than 50% (JSO, 2005), and mistletoe - about 94 percent (Kowalska, 1990).

How to use it ...? In theory everything looks fine, in practice, however, it is not so colorful ... Most of the studies cited here were carried out on isolated cell contents, or on isolated cells - mainly cancer ones. Generally, however, in vitro, i.e. outside a living organism. Moreover, chrysin provides us with the best example, that many polyphenols - particularly flavonoids - infiltrate with difficulty the interior of the human body. Of course attempts have been taken to improve their bioavailability - the solution here may be micronization (maximum fragmentation) or supplementation with the compounds enhancing the absorption, such as piperine. Therefore, in this situation, in the fight practice against aromatase, we especially must appreciate those substances which were described as those lowering the level of estrogen in a living organism - EGCG and astaxanthin. One can bear a credit risk on resveratrol and pomegranate, because these compounds increased testosterone levels in living organisms, and the increased level of this hormone - as we know - may indirectly indicate the inhibition of aromatase.

Alcoholic drinks - wine and beer - are difficult to use in real life, the reason of which I do not have to explain carefully. It is better not to be crazy about caffeine drinks too ...! Consumption of coffee, depending on the amount, raised or lowered estrogen level in the body. The point is that caffeine increases the level of cellular messenger cAMP, which stimulates the synthesis of aromatase. That is the reason why, the excess caffeine can be fatal here. So it is better for example to reach decaffeinated green tea extract in capsules, than to drink large amounts of strong tea.

The translation of the article by Slawomir Ambroziak (2012) a sports journalist and pharmacist, from the information portal (translation and boldface by the service