Clear Chemist By Patrick Arnold: EPO Wannabes
Q: Patrick, I am an endurance athlete and I was wondering if you knew any supplements that act like erythropoietin (EPO). Is there anything out there that is not a drug that can boost the oxygen-carrying capacity of my blood?
A: I studied this area quite a bit in the past, because I knew there was a market for a natural blood booster. A “natural EPO” would definitely be a good seller, but on the other hand it would probably garner me a lot of negative attention from the drug-testing folk and their political and media lackeys. Because of this, I knew I had to be careful and not sell something that had too many potential downsides (i.e., toxicity), but at the same time I wanted to make sure that the stuff actually had a measurable effect on athletes.
There were two ideas in particular I studied with interest. The first involved a category of testosterone metabolites called 5beta-androstanes. 5beta-androstanes are less known than the “DHT” class of testosterone metabolites, which are known of course as 5alpha-androstanes. The major difference between 5alpha-androstanes and 5beta-androstanes are the fact that all of the latter are hormonally inactive, while the 5alpha-androstanes are often very active.
Now while it is known that androgens can increase red blood cell production via increases in erythropoietin (EPO) production, this is not how the 5beta-androstanes metabolites work. 5beta-androstanes appear to stimulate the production of erythrocytes (red blood cells) by a post-EPO pathway…perhaps by stimulating the synthesis and incorporation of hemoglobin into differentiated erythrocyte progenitor cells. Gardner and Juneja, two medical researchers, had success using the 5beta-androstane alpha-etiocholanolone in aplastic anemia patients. They had to administer prednisone along with the alpha-etiocholanolone, because this steroid metabolite is highly pyrogenic (it produces fever and pain at the injection site).
It was later found by researchers working for a company called SuperGen that the pyrogenesis problem associated with alpha-etiocholanolone administration can be avoided by the use of its direct precursor etiocholandione. Etiocholandione is an interesting compound that also has been studied for anti-obesity properties. The company SuperGen holds the patents on the use of etiocholandione for both anti-obesity and for usage as an erythropoietic agent. Being a steroid compound, I was familiar with the chemistry of etiocholandione and I knew I could probably synthesize it efficiently and economically. So around nine or 10 years ago, I visited with the SuperGen people in California to discuss the possibility of licensing the compound for one of these uses. What they had to tell me was a big letdown, as they informed me that the clinical trials on the compound were very dissapointing and they gave up on the stuff pretty much. So I gave up on it, too. I don’t wanna sell something that sucks, even if you can tell a great marketing story using some published literature.
The next idea for an EPO-like supplement I explored was not something that suffered from a lack of efficacy, but rather I had other reasons for deciding not to pursue it. Before recombinant EPO was available, there were not a lot of effective treatments available for treating anemic patients. If your anemia was not respondent to nutritional interverntions such as iron, vitamin B-12, or folic acid supplementation, then there wasn’t much left other than perhaps anabolic steroids (which can have unwanted side effects, especially for women and children). So scientists took notice when they discovered that excessive exposure to the common metallic element cobalt was responsible for a disorder called polycythemia— which is nothing more than excessive production of red blood cells.
Cobalt is a common element that is in the same periodic table group as iron and nickel.
We consume very small amounts of cobalt every day, mostly in the form of vitamin B-12, which is a complex molecule called a coordination compound that has an atom of cobalt in the center. In larger amounts, cobalt ingestion has been associated with conditions such as asthma and pneumonia. After studying cobalt administration (as cobaltous chloride) in animals and then humans, medical researchers discovered that doses can be given that result in marked increases in hematocrit (percentage of red blood cells in blood) in patients with anemic diseases (usually patients on dialysis). Doses as low as 30mg a day given for several weeks were sufficient. Since cobalt is rapidly eliminated, there was minimal buildup in the system, so blood levels were not too hard to control.
The mechanism by which cobalt stimulates erythropoeisis is by creating in the body what is essentially a “false hypoxic state,” which basically means it tricks your body into thinking it is not getting enough oxygen. Your body responds to hypoxic conditions by increasing the efficiency of energy production through anaerobic glycolysis, production of new blood vessels (angiogenesis) and of course the production of more red blood cells (erythropoeisis). These events are mediated by a group of biochemical messengers known as hypoxia-inducible factors (HIFs). These are released in response to low blood oxygen conditions and regulate the genes responsible for the metabolic events I just previously mentioned.
OK, so it all sounds great. Cobaltous chloride is dirt-cheap and works remarkably well. So why didn’t I market it as a supplement? Well even though the toxicity of cobalt at the dosages used for this purpose are not unreasonable, the potential for problems is still there. Stomach issues including nausea are not uncommon and cardiomyopathy (damage to the heart muscle) has been reported with its usage. Hypothyroidism is also a potential concern, as is interference with the absorption and utilization of dietary iron. But even with toxicity put aside, just the nature of its intended effect is troublesome to me. Raising your hematocrit for performance benefits is not something that is a game. If you misjudge and raise it too high (hematocrit over 54 or so) you run the risk of all kinds of cardiovascular dangers, such as stroke and congestive heart failure. Since supplements are often distributed haphazardly to just about anyone, it’s just not worth the risk. Plus, we live in a very litigious society and I seem to be an especially fun target for the ambulance chasers. I don’t need the stress or the guilt.
Q: Patrick, I heard they are going to be implementing a test for growth hormone at the 2008 Beijing Olympics. Is this true? And do you have any idea how they might go about doing such a thing?
A: Yes, I have been hearing in the news lately that the World Anti-Doping Agency (WADA) plans on doing that. I believe it’s entirely possible that they will, however they said the same thing back in the 2004 Athens Olympics and it turned out it was a hoax. Don’t put it past the doping testers to make up a story just to scare athletes away from using. Kind of like how the teachers in elementary school would tell us kids that the principal had a spanking machine in his office. I know that definitely kept my ass in line.
Anyway, there has been a lot of progress toward an effective GH test. They have been working on this for many years. It’s not an easy task to detect growth hormone use. The exogenous growth hormone that people inject is exactly the same thing that your body produces, so you just can’t look for its presence in the blood, or its metabolites in your urine. Furthermore, GH production fluctuates so widely from person to person, and even throughout the day for any one individual, that looking for evidence of large amounts of GH is not going to work.
One approach that has been explored and might be used in Beijing deals with the detection of what are known as GH-responsive proteins. The most well-known of these proteins is IGF-1, which is produced in the liver in response to increased levels of circulating GH. There are some other GH-responsive proteins as well, such as the collagen peptides. The advantage of this test is that these GH-responsive proteins tend to have long half-lives. For example, most of the IGF-1 circulating in the blood is bound as a complex to IGF1-BP3, and this complex has a half-life of 15 hours. The downside to this test (as I see it) is that there still are wide variations in the levels of GH-responsive proteins such as IGF-1 amongst individuals. People with acromegaly, for example have enormous amounts of IGF-1 in their bodies. I suppose the way to compensate for this disadvantage would be to establish an “endocrine profile” of a particular athlete by keeping records of results from numerous past tests. Then if an inordinately high level of one or more of these GH-responsive proteins shows up in one test, a very good case for a positive can be made. In fact, endocrine profiling is something that WADA has already started implementing, so my hunch is probably right, here.
The other major approach that is being examined is somewhat reminiscent of the testosterone test, which looks at the ratio of testosterone to epitestosterone. Epitestosterone is an isomer of testosterone that is always produced in the testes along with testosterone in a fixed ratio. When urinary excretion of testosterone and epitestosterone produce a ratio outside of a specific range, that athlete is considered to be taking exogenous testosterone and is given a drug positive. Well, like epitestosterone and testosterone in the testes, there are other GH like peptides produced side-by-side with growth hormone in the pituitary. These strange peptides are called GH isoforms, and are structurally quite similar to GH, but with minor chemical alterations. They are produced in around 5 percent to 10 percent the amount of regular GH and their physiological significance is poorly understood. As a marker for GH doping, they can come in handy, and immunoassays specific for them have been developed that can detect them with good precision. So this test has the potential to be as useful as the Test/Epi assay has been for many years. The only drawback I can see is that GH is in and out of the body very fast, so unless the athlete is tested within 24-48 hours after his last shot, the test will probably be useless.
Bottom line, though, is tested athletes are not going to be able to use GH as freely as they used to. Does that mean the testers have solved the GH problem? I don’t think so. As long as it’s only the GH isoform test, an athlete can just use a bioidentical GH secretagogue like GHRH or Ghrelin, or even IGF-1 itself. Yeah, the doping wars are the never-ending cat and mouse game. It’s about as sensible as the nuclear arms race was, not to mention increasingly expensive and personally intrusive.