by Thomas Incledon, PhD(c), RD, LD/LN, RPT, NSCA-CPT, CSCS
Ever since TC and Dan Duchaine mentioned aromatase in the pages of Muscle Media, lots of copycat, no-brain-writers have talked about how to inhibit this enzyme. Here in Florida, we have a couple of local muscle rags put out by guys trying to sell supplements. You see page after page of BS about how to inhibit the aromatase enzyme from these clowns with no education or brains. They actually refer to themselves as “Gurus,” but of course, there’s only one DD. Anyway, since my last article covered testosterone production and specifically free testosterone, it now seems like a good time to discuss aromatase inhibitors. I won’t describe the synthetic kind that you need a prescription for, but I will give you all the information you need about the kind that occur in food and the kind that you can buy as a dietary supplement.
Background
Aromatase is the enzyme that converts testosterone into estradiol and androstenedione into estrone. The significance of this point is that when testosterone increases in the blood, some of it can be converted to estradiol, and then the estradiol can inhibit future production of testosterone [1]. From my last article you should know that the body has many safety valves or system checks. Inhibiting the conversion of testosterone into estradiol will only work to a point. Testosterone levels won’t go soaring through the roof because at some point testosterone will be so high that it will inhibit it’s own production, thereby bringing blood levels back down [2]. It would certainly be higher than normal though, and it’s this increase in circulating levels that could lead to better gains down the road. Now, you’re probably thinking, “If I lower estrogen and increase testosterone, I’m gonna grow.” Being a muscle head myself, I found this approach very interesting. While most of us do just want to get bigger and stronger, there also may be some other advantages to inhibiting aromatase.
Most of the research on these aromatase inhibitors addresses the treatment of a clinical or sub-clinical condition. The research has focused mainly on these special populations because they have an illness or a problem. Clinically there are a variety of reasons why doctors would prescribe an aromatase inhibitor. Low sperm count, prostate cancer, benign prostatic hypertrophy (BPH), breast cancer, elevated estrogen levels, and low testosterone levels are some of the reasons. Unfortunately, we can’t just open up a book and see just how aromatase inhibitors work best for muscle growth. This means that there is room for some speculation and extrapolation, but on the other hand, some things don’t happen in the body, no matter what. With that said, let’s check out some of the latest substances claimed to inhibit aromatase.
Ascorbic Acid
We all know ascorbic acid by its common name of Vitamin C. The fact that it has been shown to inhibit aromatase may be a bit surprising to some of you [3]. I’ve already seen some articles where the writers try to convince you that more C will boost your testosterone. If that were only the case! In the only study I found on this interaction, some research guys took placental microsomes containing aromatase and exposed them to different concentrations of ascorbic acid. At this point you have to be wondering what the heck are placental microsome preparations? Check this out, cause I know you will love it. After a woman gives birth, the placental tissue is removed. For this study, the fetal membranes, chorionic plate, connective tissue, and large blood vessels were removed from the placental tissue. The remaining tissue is cut up into small pieces and homogenized (sort of a blenderized placenta). The result is a product called the homogenate. The homogenate is spun around in a centrifuge. From here the science guys separate out the microsomal preparations (think of them as cellular storage sheds) and then place them in a little petri dish or some other container with the right amount of nutrients and tender loving care that only a scientist could have for microsomes! This incubation is then used to study the aromatase within the microsomes.
So now we have these little microsomes containing aromatase being exposed to different concentrations of ascorbic acid. At very high concentrations of ascorbic acid, there was a strong inhibition of aromatase. Now at this point you’re probably placing an online order for those super-mega-size Vitamin C pills. Hold off, because we have to look at how the ascorbic acid inhibited the aromatase enzyme. It turns out that the inhibition was not due to the direct effects of ascorbic acid on the enzyme, rather it was due to the fact that the extra Vitamin C lowered the pH of the incubation medium. Applying this in vitro study to humans simply means that there is no way that ascorbic acid will inhibit aromatase in us. Our blood maintains a pH around 7.4 and the optimal pH for aromatase activity is pretty close, about 7.5 or so. The ascorbic acid that was shown to inhibit aromatase the most dropped the pH down to around 4.0. If your blood pH gets that low, the last thing you will be worried about is your aromatase activity! You’ll be standing at the Pearly Gates worrying if that one night in Las Vegas will keep you from entering eternal peace! Looking at some real world data on humans lifting weights, we find as expected that ascorbic acid at 1 gram per day does not effect testosterone levels in male weightlifters [4]. The bottom line is that ascorbic acid has some potential as an antioxidant, but not for increasing testosterone.
Cactus Flower
European countries have been using phytotherapeutic preparations for some time. It’s only the last several years that these things have caught on in the mainstream US. The United States Pharmacopoeia does not have standards established for many of these herbs, and this could present a problem. Cactus flower is listed in the British Herbal Pharmacopoeia under the name Opuntia. The extract is listed as a medicine and claims to have astringent and antihemorragic effects, and is also indicated for the treatment of colitis, diarrhea, and prostatic hypertrophy. No listing was found in the US Pharmacopoeia or the Herbal PDR.
A recent study examined the inhibitory effects of cactus flower extracts on the aromatase and 5-alpha reductase (5AR) enzymes [5]. 5AR converts testosterone into dihydrotestosterone. Lately evidence implicates dihydrotestosterone, estradiol, and alpha receptors as playing a role in the etiology of BPH and possibly prostate cancer. So you can see why from a clinical perspective researchers are interested in products that could inhibit 5AR and aromatase. The value of these inhibitory products to athletes who want to increase their own testosterone levels, either naturally or synthetically, is that by inhibiting these enzymes, they may have fewer side effects from the increase in testosterone. On the other hand, researchers don’t know if other problems may develop from using aromatase inhibitors to decrease the potential for gynecomastia (from excess estradiol production) and BPH (from the extra reduction of testosterone). So getting back to this recent study, cactus flowers were obtained from Herbamed (Rehovot, Israel), dried and then prepared into extracts. The researchers prepared extracts of three different concentrations and then tested the extracts on tissue samples from human placentas, cultured foreskin cells, and prostatic tissue removed from prostatic hypertrophy patients. The more concentrated extract had the greatest inhibitory effects on both enzymes for all three tissue types. About 80% of the enzyme activity was inhibited by the weakest cactus flower extract. This seem like a bodybuilder’s dream come true. Inhibition of both these enzymes is a great thing, right? Well, you should be asking yourself, “At what concentrations were these extracts tested at?” It turns out they were in the microgram to milligram per milliliter range. We don’t know if blood levels of this product can get that high, or if we even need to get them that high to have an effect.
I think this product has potential, but I do have some concerns. First, we have no pharmacokinetic data on humans, meaning how much gets from your GI tract into your blood, and how long does it stay there before the body metabolizes or excretes it. Second, the fact that the extract can inhibit two different enzymes means that it lacks specificity. In other words, what good is inhibiting aromatase and 5AR if the extract also inhibits other key enzymes? I’m thinking of 17-beta hydroxysteroid dehydrogenase (which converts androstenedione into testosterone and to a smaller degree, DHEA into androstenediol) or 3-beta hydroxysteroid dehydrogenase (which converts DHEA into androstenedione and androstenediol into testosterone), enzymes that convert precursor hormones into testosterone, but it could be other enzymes, as well. Third, but not last, as I am sure that there are other issues, it may not always be a good idea to inhibit aromatase and 5AR at the same time. These researchers found out that when they inhibited 5AR in foreskin cells, more of the androgens were aromatized or converted into an estrogen. So while this extract may have possible therapeutic potential for the prostate, what about breast tissue? Putting this into perspective, it’s conceivable that by protecting the prostate using a product that blocks the reduction of testosterone, you could develop gynecomastia, because all that extra hormone has to go somewhere. Clinical trials with humans are underway and as soon as I get some more info, I’ll get it out to you.
Chrysin, Flavonoids and Phytoestrogens
Well here we are, where it all began. Remember the mysterious Flavone X? Later on we all found out it was chrysin. Let’s check out what these compounds are all about. Flavones or flavonoids are a large group of compounds found throughout the plant kingdom and in many foods. Also included in this group are isoflavones and phytoestrogens (plant substance mimicking estrogen function and/or structure). They have been used as drugs and food supplements and are reported to have antioxidant, antibacterial, and antiviral properties [6, 7]. Studies are pouring out all the time about foods containing flavonoids that are beneficial in some way to human health. Eat plenty of fruits and vegetables and you are sure to get lots of different flavonoids. Even though they are involved in a variety of biological actions, for now we’ll just focus on their ability to inhibit aromatase.
In one study, chrysin (a specific flavonoid) was compared to other synthetic and natural flavones in their ability to inhibit human placental microsome aromatase (jeez, we can’t get away from these things!). Out of the seven flavones tested, chrysin was number two in its ability to inhibit aromatase. Two doesn’t sound bad. I mean if you came in second in a bench press contest that would be considered a significant accomplishment. But second is a relative placing, meaning all that it really indicates is that you were not as good as number one, but better than everyone else was. Suppose your friends come along and ask about the results. They find out that the third place winner in this bench contest was your dad and fourth place was your mom. Now you can’t show your face in the gym anymore. Understand what I mean by relative number? So applying this to the chrysin study, we find that while chrysin was the second best inhibitor, it only had a relative potency of 13, while number one (a synthetic flavone) had a relative potency of 83. That’s a big difference. So from this one study we found out that chrysin is an inhibitor of aromatase, but it could be considered weak or strong, depending what you’re comparing it to.
Other studies have examined the inhibitory effects of various flavonoids on aromatase [8-18]. The results vary because the researchers involved used different methods to determine the inhibitory effectiveness of the flavones. In some cases adipocytes (fat cells) were used, in other cases placental microsomes were used. After looking at all these studies we come to a similar conclusion as before, that any given flavone could be considered a weak or strong inhibitor, depending on what you are comparing it to. In general most of the naturally occurring flavones are significantly weaker than the synthetic flavones.
Now lets deal with some practical and applied issues. These studies were all in vitro. In other words, they tested chrysin or other flavones on cells isolated outside the body. We still don’t know if these same effects take place in vivo (inside of us). We also don’t know what the proper dosages are to get an inhibitory effect on aromatase. Would you need milligrams or grams per day to see an effect? In vitro studies on chrysin indicate that intestinal absorption will not be that good [19]. If this holds true for in vivo results, you would need about several grams of this stuff. Studies on ingestion of flax seed meal at doses of 13.5 g per day for six weeks demonstrated an increase in plasma of the weak aromatase inhibitors enterolactone and enterodiol [20]. In addition, a recent study has shown that 16 grams of flax seed meal per day does increase urinary levels of the weak aromatase inhibitors enterolactone and enterodiol [21]. Taking all these different studies into account, it is certainly possible that flavonoids get into the body in sufficient amounts to exert biological effects that could possibly influence health. Most bodybuilders aren’t thinking health though, they are thinking muscle growth. Could you ingest enough flavonoids that would exert an inhibitory effect on aromatase, which would lead to higher testosterone levels and then lead to muscle growth? I would say at this point, no way. In support of this, I found a recent study where they put some rats on a high phytoestrogen diet and found no difference in testosterone levels or brain aromatase levels [22]. Since rats can absorb more of these flavonoids from the diet than people can, you would expect to see some hormonal changes if flavonoids inhibit the aromatase enzyme.
Like with the cactus flower, these plant compounds are not always specific for one enzyme. Let’s say that you load up on chrysin or some other flavone and enough does get into your blood to exert a strong inhibitory effect on aromatase. It may also inhibit enzymes involved in testosterone production. A recent study confirms that some flavones may exert inhibitory effects on both aromatase and 17-beta hydroxysteroid dehydrogenase [15]. Therefore, at this point, most natural flavones for aromatase inhibition appear to be a waste of money. So next time you see your buddy that sold you the Chysin product that was supposed to inhibit aromatase, ask him about it inhibiting other enzymes, or if you really want to burst his bubble, ask him why the chrysin in Andro –6 didn’t prevent estradiol levels from increasing [23]?
Nicotine, Cotinine and Tobacco
A few studies have shown that derivatives from tobacco inhibit aromatase directly or indirectly through one of their metabolites [24-28]. It certainly doesn’t make sense to start smoking just to inhibit an enzyme, but the idea of taking nicotine as a supplement may interest some people. Like the flavonoids, most of the studies on aromatase inhibition are in vitro. The tobacco alkaloids nicotine and anabasine inhibit aromatase but not 17-beta hydroxysteroid dehydrogenase [28]. The metabolite of nicotine, cotinine, also inhibits aromatase. Based on in vitro studies its seems that these tobacco alkaloids and metabolites may be more specific for aromatase than flavonoids. The next logical step would be to see what human studies on nicotine consumption or perhaps cigarette smoking have shown. Results are varied with data indicating that cigarettes decrease androgens in men [29], or when salivary levels of cotinine are controlled for, cigarette smoking is associated with elevated salivary testosterone levels in men [30]. However, men that smoked cigarettes and later switched to chewing nicotine gum (which would maintain their levels of nicotine and cotinine) experienced a decrease in androstenedione levels [30]. Moving on to some animal data, we find that nicotine and cotinine may inhibit steroidogenesis [31, 32]. Maybe these tobacco derivatives inhibit the aromatase enzyme, but then you can’t synthesize any more testosterone. Doesn’t sound like a fair trade off to me.
Cycads
Cycads are plants that have been used for food and medicine after removing toxic components. The key thing to note is that these plants can contain toxic compounds. If the extraction is not done correctly, you can get a nice big dose of toxic stuff. Extracts from five different species of cycads were found to exert inhibitory effects on aromatase in good old placental microsomes [33]. The inhibitory activity for some of these extracts was quite impressive, ranging as high as 97%. The plants Dioon spinulosum Dyer and Encephalartos ferox Bertol were extracted first with methanol and then extracted again with ethyl acetate. This was an in vitro study, so we don’t have any idea how much would be needed in the body, and we don’t know what the active ingredients are that impart inhibitory activity to the extracts. For now, keep an eye out for research on cycad extracts. I believe that the active compounds will be isolated very soon. Once that is done, the effects of the compounds on other enzymes could be studied to verify they are selective inhibitors of aromatase. Then dosage response studies can be conducted and in a short time, we’ll have a much better understanding of the potential applications of these plant extracts.
Epilobium and Ellagitannins
You may not have heard of the Epilobium genus of plants. In my experience, not many people have. Like the cycads, extracts from these plants have been used for medicinal purposes. Fortunately, the active components of the plants have also been isolated. With this information, researchers have been able to concentrate the compounds oenothein A and oenothein B in the extracts and test them on the aromatase enzyme [34]. Of the two, oenothein A was found to have the greater inhibitory effect. In addition, it appears to be selective, as it did not inhibit another steroidogenic enzyme. More research on other enzymes needs to be done to verify the selectivity of this compound for aromatase. There is also a lack of data on intestinal absorption of the compound. This is another plant compound that you should keep an eye out for as far as new research. There is a pretty reliable history on the use of the Epilobium plants. It would not surprise me to find that there are some active ingredients that some day prove useful in clinical conditions and maybe even for the progressive bodybuilding types. For now though, it makes little sense to try taking it.
So Many Products, So Few Work
Ascorbic acid, cactus flower extracts, chrysin, flavonoids, phytoestrogens, nicotine, cotinine, tobacco, cycads, and oenothein A. That’s one heck of a mouthful. Out of all of these, the cactus flower extracts, cycads, and oenothein A have the most potential to inhibit aromatase. I know you guys want dosages and timing schedules and all that, but the information is just not there to support any recommendations. Hopefully, what you got out of this article is that most of the stuff supplement companies are selling to inhibit aromatase is bogus. Researchers are involved in testing and analyzing a large variety of plants for their potential in treating the clinical conditions mentioned earlier in this article. There are most likely other plant extracts and compounds that have the ability to inhibit aromatase. When you catch wind of a new product that inhibits aromatase, remember to ask to see legitimate studies that tested this product and then ask yourself these questions: Did it inhibit enzymes inside the body or outside in some cell cultures? What dosages were required to exert the inhibitory effect? Was the study set up to verify that only aromatase was inhibited? If it is an in vitro study, is there any evidence that the product can be absorbed? Is there any animal data that examines the toxic potential of the product? Or keep reading Testosterone and I’ll be sure to keep you up on all of the latest news.
References
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