JAMA Study on Androsteindione - A Critique
By Owen R. Fonorow
On June 2 of this year the American Medical Association (AMA)
published EFFECT OF ORAL ANDROSTENEDIONE ON SERUM TESTOSTERONE AND ADAPTATIONS TO RESISTANCE TRAINING IN YOUNG MEN, a Randomized Controlled Trail, JAMA, Vol 281, No.21. King, et al. The eight week study of 20 young men reportedly is only the second published study to investigate the effect of oral androstenedione administration on the blood testosterone concentration. The previous study reported a 4- fold and 7- fold increase in 2 women.
Androstenedione occurs naturally in the human body and is the direct precursor to the hormone testosterone. Mark McGuire made this orthomolecular substance famous last year when Major League Baseball’s home run king admitted that he supplemented with it. The substance has been banned by some major league sports, including the NFL, but it is legal for purchase and has been on the market for more than a year in the U.S. The media and others have questioned the safety and efficacy of androstenedione after the McGuire admission because of its alleged similarity to other banned anaerobic steroids (hormone-like substances) known to have harmful side effects. This JAMA study clarifies some of these issues.
OVERVIEW: STUDY PURPOSE AND OBJECTIVES
The purpose of this study was to investigate the anabolic effects of oral androstenedione intake on young men without previous weight training experience. Specifically, the study clinically investigated the short term effect of a single dose of 100 mg androstenedione (phase 1) followed by a longer term investigation of 300 mg of androstenedione during an 8 week period of weight training (phase 2). The time between phase 1 and 2 is not specified, but might have been as long as three months.
Blood chemistry and muscle tissues were evaluated for the effects of androstenedione on serum ndrostenedione, Luteinizing Hormone (LH), Follicle-Stimulating hormone (FSH), free testosterone and total testosterone. In addition liver function and general blood chemistry were monitored.THE FINDINGS:
According to King et al in their paper, androstenedione was found to be an ineffective anabolic steroid with potential harmful side effects and was not found to increase either free or total serum testosterone. This conclusion is at variance with their data. According to the study data androstenedione is apparently harmless, is a weak anabolic steroid, and will increase serum
testosterone. While the data did not show anabolic gains in the androstenedione group over placebo, (both group’s muscle size increased the same amount during the resistance training), the study data did show, but the authors did not report, that oral androstenedione increased both free and total testosterone blood serum levels.
The study accurately reported increases in serum androstenedione and the estrogen’s estrone and estradiol. On the other hand, the hormones LH, FSH, liver enzymes and blood chemistry were unchanged indicating few potential harmful side effects. A variant of High Density Lipoprotein (HDL-C) was reduced by 12% during the experiment, a rather low number as earlier studies with anabolic steroids have recorded HDL reductions up to 70%. For some unexplained reason a small, limited, oral dose of androstenedione did significantly shock or stimulate the production of serum levels of testosterone without (before) resistance training.
THE MISSING FINDING
According to the data, both the placebo and androstenedione groups began the study with the same free and total serum testosterone levels. (Initially, the placebo group’s average free testosterone levels were slightly higher.)
During the course of the study, serum levels of free and total testosterone were significantly increased in the androstenedione group but remained the same in the placebo group.
According to the data, after the initial 2 doses of 100 mg androstenedione were administered, each separated by 1 week, and before the start of weight training (interval unspecified), the free testosterone levels in the androstenedione group increased from 80 to 120 pmol/L. A 50% increase! Total Testosterone increased by 33% from 24 nmol/L to 32 nmol/L.
Surprisingly, the stated conclusions, and the accompanying refrain from extensive media coverage, ignored their data. In particular, the authors claim that their study showed no significant increase in either total or free testosterone during the course of the study.
This is clearly false.
They note the higher serum testosterone in the androstenedione group, but call it a “hard to explain” fluke. Why they ignored this result is unclear.
By the end of the study, said to be four months later, the placebo group’s testosterone levels remained constant, while the androstenedione group’s free and total testosterone remained elevated.
The authors do not address the unspecified interval between phase 1 and phase 2 and merely claim that during the 8 week weight (phase 2) training interval, the relative levels of free and total testosterone remained constant. This is where their claim that serum testosterone levels were not significantly increased comes from. However, the data shows that the testosterone in the androstenedione group had already risen, and ended up, much higher than the placebo group. The unanswered question is why only one or two doses of 100 mg androstenedione was (apparently) so effective as probable “shock treatment” in elevating free and total serum testosterone? (The authors have no explanation for this finding and simply ignore it.) It would also be helpful to know the interval between phase1 and phase 2. It is possible to infer this period was over a month based on the start of the study (February1998) and the end of the 8 week study (June 1998)
SERUM ANDROSTENEDIONE FROM ORAL INGESTION
Androstenedione is produced from DHEA in the body. It is said to be a direct testosterone recursor in the metabolic pathway from cholesterol through pregnenolone to DHEA to androstenedione to testosterone. The finding that blood serum androstenedione substantially increases from oral intake as important. For example, one possible outcome from taking oral androstenedione might have been no appreciable increase in blood serum levels.
Protein-based hormones are known to break down into their constituent amino acids in the gut when taken orally. Insulin, for example, is a large molecule and does not remain intact during digestion. Oral insulin will not be effective increasing blood serum levels of insulin for this reason. Testosterone has a similar problem. The finding that serum androstenedione levels were unchanged, had it occurred, would indicate that the substance dissolves during oral supplementation and that taking it by mouth was a complete waste. On the contrary, the King et al study shows a direct and significant blood serum correlation between oral androstenedione intake and subsequent blood serum levels, peaking over 300% after 2 hours and remaining high for about 4 hours.
LUTEINIZING HORMONE (LH)
The levels of Luteinizing Hormone (LH) were studied because this hormone is thought to be involved with the body’s self production of testosterone. If LH is decreased, then the production of testosterone will also decrease. One outcome of the present study might have been a change in LH indicating a reduction in the body’s own production of testosterone. In this scenario, androstenedione might have “switched off” the body’s own production of testosterone.
According to JAMA:
“Anabolic steroid administration has previously been shown to suppress endogenous testosterone production, secondary to decreased serum levels of LH and FSH. In our study, serum concentrations were unaffected.”.
Thus, contrary to their stated conclusions, this study provides another important indicator that androstenedione is safe by finding that serum concentrations of LH and FSH were unaffected by supplementation. This finding suggests, to quote the authors, “that hypothalamic-pituitary function was not modified by androstenedione supplementation.”
The study measured both free and total serum testosterone in both study groups. Although, the JAMA author’s conclude that serum testosterone was found not to be significantly elevated during the course of this study, this is clearly wrong in the context of the entire study. In the beginning of the study the levels of the two study groups were equivalent. By the end of the study testosterone was significantly higher in the androstenedione group.
According to Jonathan V. Wright and Lane Lenard in their recent book MAXIMIZE YOUR VITALITY & POTENCY For Men Over 40, page 53:
“Testosterone circulates in the blood in two different forms: free and bound. About 70 to 80% of circulating testosterone is bound to a protein named sex hormone binding globulin (SHBG). Testosterone bound to SHBG is essentially out of action. It is locked up and can have no physiological effect on tissues. Another 20% or more of circulating testosterone is bound to another protein, albumin. Testosterone bound to albumin may be biologically available under certain conditions. Finally, only about 1 to 3% of circulating testosterone is free, which means it is completely biologically available and potentially active at testosterone target cells. When referring to testosterone levels, it is extremely important to distinguish between the free and bound varieties.”
King et al, note the significant increased free testosterone between the two study groups, then dismiss this phenomenon with the comment:
“The significantly higher serum free testosterone concentrations observed in androstenedione both before and during resistance training and supplementation [phase 2] were unexpected, and difficult to explain, given the random assignment of subjects to each treatment group.”
This statement seems to imply that the difference in testosterone levels occurred before supplementation and was therefore due to the make-up of the two study groups. One has to go back
to the charts, (figure 1 and figure 2, pg 2022). Accordingly, the difference occurred after the phase 1 (100 mg) supplementation.
So unless the 10 men who participated in phase 1 were different than the 10 men in the androstenedione group during phase 2, this statement makes no sense.
According to their own data, the placebo group began with a slightly higher average free testosterone serum levels than the androstenedione group!
MUSCLE AND STRENGTH GAINS
Gains in muscle composition and strength were equivalent for both the androstenedione and placebo groups. Significant increases were noted in both study groups. The JAMA Editor commented on these roughly equivalent gains:
“For example, of the young men enrolled, only 2 had ever engaged in resistance training, and that training had been more than 1 year earlier. Such inexperienced weight trainers generally make significant gains in the early phase of resistance training programs. These large strength gains could overshadow, statistically, any potential gains from androstenedione.”
We agree. The authors classify androstenedione as a “weak anabolic steroid”, yet the AMA would
still like to see this substance off the market. They seem to want it both ways. The substance in ineffective but should be removed from the market. Which is it?
The JAMA commentary discusses the Anabolic Steroid Control Act of 1990 and notes that testosterone and a number of derivatives as Schedule III drugs under the Controlled Substance Act.
Since androstenedione is not specifically mentioned, it can only be banned if the following criteria are met:
1) The substance must have a molecular structure related to testosterone
2) the substance must have a pharmacology related to testosterone
3) the substance cannot be an estrogen, progestin or corticosteroid, and
4) the substance must promote muscle growth.
In its commentary on the study, the JAMA editor admits that the King et al. study data show that androstenedione does not meet the fourth criterion. Incomprehensibly, JAMA based its opinion that the government intervene and remove androstenedione from the market on the hypothesis that if androstenedione, like testosterone, were administered by injection at a substantially higher dose, muscle growth would be observed. This fractured argument fails on several counts. If the moon was made of green cheese, and we could get there we might then eat it.
The moon isn’t made of green cheese and the King study shows that oral androstenedione itself increased blood serum androstenedione by 300%. And why ban a substance to be taken orally when the undesirable effects are only after an injection?
It is difficult to see how injections could do much better than oral administration, or have a more profound effect. Or how the JAMA editor can infer, with no data, that androstenedione may in fact be able to increase muscle mass. (Maybe they know something they are not telling us?)
UNWARRANTED HEALTH CONCERNS
Unnatural variants of testosterone are known to be toxic, especially to the liver because this organ can’t handle the metabolic by-products. Wright and Lenard argue in their book MAXIMIZE YOUR VITALITY & POTENCY For Men Over 40 that natural testosterone isn’t toxic. In the King et al study, liver function was monitored. According to the authors, “Serum concentrations of liver function enzymes were within normal limits for all subjects throughout the study and were unaffected by training or supplementation. Training or supplementation did not significantly affect total iron, hematocrit, and hemoglobin concentrations.”
So why were the study authors, AMA and the national media so concerned about possible health ramifications? (These concerns were expanded in the press reports.) There seem to be two reasons. The standard concerns about anabolic steroids (even in the face of their stated finding that total serum testosterone and muscle growth were not affected?!) and a concern that a reduction in so-called “good” cholesterol (HDL-C) may lead to heart disease.
CHOLESTEROL AND HEART DISEASE
The King et al paper begins with the contention that “increased concentrations of testosterone in the blood have been associated with an increased risk of cardiovascular disease.” It is almost as if making these statements more often in a prestigious medical journal makes them true. One objective of the study was to look for evidence supporting this supposition.
The study found little in the way of lipid changes in the study groups.According to the King et al, “the 8-week period of training and supplementation did not affect serum concentrations of cholesterol, HDL cholesterol, very LDL cholesterol or triglycerides.
Only serum HDL cholesterol concentration was significantly reduced.”
The JAMA authors connect the single lipid change, lowered HDL-C with future heart disease.
This assertion is tenuous at best, and the AMA knows it. Even King et al state “The serum HDL-C concentration did not reach a level typically considered to constitute a risk factor for cardiovascular isease.” From the data, we can conclude that the LDL (bad) to HDL (good) ratio remained unchanged in the androstenedione group over the 8 week [phase 2] training period. The LDL/HDL ratio varied less in the androstenedione group than the placebo group, i.e., varying from 2.25 (week0) to 2.69 (week . The placebo’s ratio declined from 3.38 (week 0) to 2.58 (week .
The ratio of good to bad cholesterol is used by physicians. This ratio may be a factor for the physician to help determine the risk of possible heart disease and heart attack in some patients, but there is no evidence that an adverse LDL to HDL ratio is the root cause of heart problems, or more specifically, that lowering HDL will by itself lead to future heart problems.
In other words, there have been no studies where HDL-C was the only factor lowered and heart disease was the outcome in a controlled experiment. For one reason, heart disease does not generally occur in animals, and such experiments are difficult to conduct on human subjects.
As Wright and Lenard’s book makes a salient point in this regard. Much evidence now indicates that decreased rather than increased testosterone elevates the risk of heart disease. If increased testosterone really was the cause of heart disease, and not the reverse, why is heart disease more prevalent in the aged — when testosterone and other hormone levels generally decline?
Even if one accepts the assertion that a drop in HDL cholesterol is dangerous, this is no reason to stop taking testosterone. It may be a reason to take action to increase your blood serum concentration of HDL. Many steroidal hormones are made from cholesterol and one can take steps to increase serum cholesterol through dietary intake and other means with an eye on improving the HDL to LDL ratio.
While this study seems to have been well run and the data seem valid, it is hard to understand how a prestigious peer-reviewed journal such as JAMA, could miss an obvious finding of significantly increased serum testosterone? It seems that one objective of publishing the King et al study was to discourage androstenedione use by teenagers. Perhaps the fear that more teenagers would be encouraged to take the supplement if the substance was shown to elevate testosterone is one reason King et al ignored its surprising outcome.
The JAMA investigators found androstenedione to be safe, but warn that this finding doesn’t rule out an adverse reaction from sustained use. The JAMA authors speculate about potential downsides from oral use, and these concerns were picked up in press reports. Extraneous inferences to potential heart disease, pancreatic and prostate cancer and liver malfunction detracted from an otherwise sound study. Little in the data supports these conjectures.
The last sentence of the accompanying JAMA editorial commentary is enlightening in the regard:
“However, if a supplement is in fact what most medical professionals consider to be a potentially armful drug, action is needed to protect the public. In the case of androstenedione, the study by King et al contributes to the evidence suggesting that the government should carefully consider intervening and remove androstenedione and its derivatives from the market.” (JAMA, Vol 281, No. 21, pg 2044)
This comment is very hard to understand in light of the study data. In fact, this study contributes no such evidence. No change in liver function was detected. No abnormal blood chemistry, save a predictable decline in High Density Lipoprotein cholesterol (so called “good” cholesterol.) No change in pituitary hormone function, e.g., LH or FSH. There was a significant increase in estrogen hormones in the androstenedione group, but the authors concede that these estrogen’s can be the by-product of testosterone metabolism during weight training. In other words, this finding may be the
inevitable result of the higher levels of testosterone.
MORE EVIDENCE : ANDROSTENEDIONE IS HARMLESS
Most of the concerns about adverse health effects are inferences based on previous experiences with anabolic steroids which the King et al study, if valid, proves have little relevance. That these inferences are even mentioned is strange. The authors do not acknowledge any change in testosterone or relative gains in muscle mass with the placebo group. They assume all the bad consequences without any supporting evidence.
We searched the Internet for reports of harmful effects from oral androstenedione. The product has been on the market for about a year. There have been no reports to the FDA. The single report found during the Internet search was in relation to a product that also contained 40 mg niacin. The man in question went to an emergency room for a severe body rash. He lived to write the report. The reported symptoms reminded me of a niacin flush. Other than this single report, no adverse reactions to androstenedione were found.
An anonymous Internet author claims to have inside knowledge of the East German research into androstenedione. He states that the reason the East Germans used the substance was not necessarily because it elevated testosterone, but because it significantly elevates estrogens. Apparently, blood tests for anabolic steroid use measure the Testosterone/Estrogen ratio.
According to this source, the East Germans used androstenedione to mask increased testosterone sage from the Olympic blood tests by normalizing the androgen:estrogen balance.
According to Wright/Lenard, this balance may be desirable regarding prostate health and important in preventing prostate cancer. On page 248 of their book they state “There is good evidence that a normal androgen:estrogen balance may actually protect against heart disease, muscle and bone loss, and both benign and cancerous prostate overgrowth.”
LIBIDO IN OLDER MEN
While the JAMA study of young men did not measure libido, the results may be good news for older men. King et al say as much. First, the JAMA data indicates that the oral administration of androstenedione may be an effective “shock treatment” for increasing blood serum levels of free testosterone over time. This result indicates that middle age men may also benefit from androstenedione by increasing their free testosterone and perhaps their libido. Second, the substance
is apparently free from toxicity or harmful side effects.
Owen R. Fonorow
PO Box 73172
Houston, Texas 77273