Naturally Occurring Aromatase Inhibitors
by Thomas Incledon
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, where I live, 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 written by these clowns with no education or brains. They actually refer to themselves as "gurus" but, of course, there's only one DD.
Since my Elevating Free Testosterone article covered testosterone production, 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 that you can buy as a dietary supplement.
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 the estradiol can inhibit future production of testosterone by its own elegant little feedback system.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 its own production, thereby bringing blood levels back down.2 It would certainly be higher than normal, though, and it's this increase in circulating T 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 musclehead myself, I found this approach very interesting. While most of us 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's 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.
We all know ascorbic acid by its common name of vitamin C. The fact that it's 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 that I found on this supposed 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, because I know that you'll love it. After a woman gave birth, they nabbed some placental tissue. The fetal membranes, chorionic plate, connective tissue, and large blood vessels were removed from the placental tissue for this study. The remaining tissue was then cut up into small pieces and homogenized (sort of a blenderized placenta). The result was a product called the homogenate. The homogenate was spun around in a centrifuge. From here, the science guys separated out the microsomal preparations (think of them as cellular storage sheds) and placed 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 was 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, but rather 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's no way for ascorbic acid to inhibit aromatase in the human body.
Our blood maintains a pH of 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 that you'll be worried about is your aromatase activity. You'll be standing at the Pearly Gates worrying if that one night of debauchery 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 one gram per day doesn't 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.
European countries have been using phytotherapeutic preparations for some time. It's only in the last several years that these things have caught on in the mainstream US. However, the United States Pharmacopoeia doesn't have standards established for many of these herbs, and this could present a problem. Of course, 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 it's 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 (5-AR) enzymes,5 which convert 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 5-AR 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 seems 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?" It turns out that they were in the microgram to milligram per milliliter range. We don't know if blood levels of this product can even get that high, or if we even need to get them that high to have an effect.
I think that this product has potential, but I do have some concerns. First, we have no pharmacokinetic data on humans, meaning that we don't know how much gets from your GI tract into your blood or how long it stays 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 5-AR 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 other enzymes could be affected, as well.
Third, but not last (as I am sure that there are other issues involved), it may not always be a good idea to inhibit aromatase and 5-AR at the same time. These researchers found out that when they inhibited 5-AR in foreskin cells, more of the androgens were aromatized or converted into estrogen. So, while this extract may have possible therapeutic potential for the prostate, it could affect breast tissue, too.
Putting this into perspective, it's conceivable that by using a product which blocks the reduction of testosterone to protect the prostate, you could develop gynecomastia because all of 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 that 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 substances mimicking estrogen function and/or structure). They've 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're sure to get lots of different flavonoids. Even though they're involved in a variety of biological actions, for now we'll just focus on their ability to inhibit aromatase.
In one study, chrysin 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 — all it really indicates is that you weren't as good as number one, but better than everyone else. Suppose that your friends come along asking about the results, and they find out that the third place winner in this bench contest was your dad and fourth place went to your mom. Now you can't show your face in the gym anymore. Understand what I mean by relative number?
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 numero uno (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 can only be considered weak or strong depending on 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, while placental microsomes were used in others. After looking at all of these studies, we come to a similar conclusion as before — 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 let's 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 of the body. We still don't know if these same effects take place in vivo (inside of us) or what the proper dosages are to get an inhibitory effect on aromatase. Would you need milligrams or grams per day to see an effect? Furthermore, in vitro studies on chrysin indicate that intestinal absorption isn't all that good.19 If this holds true for in vivo results, you'd need several grams of this stuff, unless the delivery system that I hear Tim and the boys are working on comes through.
Studies on the ingestion of flaxseed meal at doses of 13.5 grams 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 flaxseed meal per day does increase urinary levels of the weak aromatase inhibitors enterolactone and enterodiol.21 Taking all of these different studies into account, it's certainly possible that flavonoids get into the body in sufficient amounts to exert biological effects which could possibly influence health. Most bodybuilders aren't thinking health, though — they're thinking muscle growth.
Could you ingest enough flavonoids to get an inhibitory effect on aromatase, leading to higher testosterone levels and additional muscle growth? I would say, at this point, no way. In support of this, I found a recent study in which they put some rats on a high-phytoestrogen diet and found no difference in testosterone or brain aromatase levels.22 Since rats can absorb more of these flavonoids from the diet than people, you'd expect to see some hormonal changes if flavonoids, indeed, inhibit the aromatase enzyme.
Like with the cactus flower, these plant compounds aren't 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. Unfortunately, they 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.
Therefore, at this point, most natural flavones for aromatase inhibition appear to be a waste of money. So the next time you see your buddy who sold you the chrysin product that was supposed to inhibit aromatase, ask him about it inhibiting other enzymes or, if you really want to burst his bubble, 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 were done in vitro. The tobacco alkaloids nicotine and anabasine do, indeed, inhibit aromatase, but not 17-beta hydroxysteroid dehydrogenase.
Cotinine, the metabolite of nicotine, also inhibits aromatase. Based on in vitro studies, its seems that these tobacco alkaloids and metabolites may be more specific for aromatase than the flavonoids. The next logical step would be to see what human studies on nicotine consumption or, perhaps, cigarette smoking have shown, and that's just what I did.
Results are varied, with data indicating that cigarettes decrease androgens in men29 but, when salivary levels of cotinine are controlled, cigarette smoking is associated with elevated salivary testosterone levels in men.30 However, men who smoked cigarettes and later switched to chewing nicotine gum (which would maintain their levels of nicotine and cotinine) experienced a decrease in androstenedione levels. 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 tradeoff to me.
Cycads are plants that have been used for food and medicine after their toxic components were removed. If the extraction of toxins isn't done correctly, though, 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 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 or what the active ingredients are that impart inhibitory activity to the extracts.
Keep an eye out for research on cycad extracts, though. I believe that the active compounds will be isolated very soon. Once that's done, the effects of the compounds on other enzymes could be studied to verify that they're 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. That's okay. 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 isolate 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 didn't inhibit another steroidogenic enzyme. More research on other enzymes needs to be done to verify the selectivity of this compound for aromatase. There's also a lack of data on intestinal absorption of the compound, but this is another plant compound that you should keep an eye out for as far as new research. There is, however, a pretty reliable history on the use of the Epilobium plants.
It wouldn't surprise me to find that there are some active ingredients in the Epilobium genus which, some day, prove useful in clinical conditions, and maybe even for those progressive bodybuilding types out there. 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 that you guys want dosages, timing schedules, and all that, but the information just isn't there to support any recommendations.
Hopefully, what you got out of this article is that most of the stuff that 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 and, most likely, there are 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. 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's 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.
About the author
Tom has been involved in scientific research, lecturing, and writing about performance enhancement for over ten years. He regularly speaks at national conferences and conducts seminars across the country. For private consultation, email [email protected] or call Human Performance Specialists, Inc. at 954-577-0689.
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