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.
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 androstenedione, Luteinizing Hormone (LH), Follicle-Stimulating hormone (FSH), free testosterone and total testosterone. In addition liver function and general blood chemistry were monitored.
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.
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)
Androstenedione is produced from DHEA in the body. It is said
to be a direct testosterone precursor 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 was 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.
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!
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?)
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.
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 total cholesterol, LDL 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 disease." 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 8). The placebo's ratio declined from 3.38 (week 0) to 2.58 (week 8).
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 harmful 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.
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 usage 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."
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
fonorow@foxvalley.net
FAX: 1-630-416-1309
http://www.vitamincfoundation.org
http://www.paulingtherapy.com