DHEA: The Saga Continues

Recently, a friend asked my opinion on an article that
appeared in Life Extension magazine:  How
Congress Is Being Misled to Think That DHEA Is an “Anabolic
Steroid”.   title="Dehydroepiandrosterone">DHEA has been
a topic here before; I wrote about it ( href="http://scienceblogs.com/corpuscallosum/2006/10/tepid_water_thrown_on_a_hot_pr.php">Tepid
Water Thrown on a Hot Product: DHEA); Tara wrote about it ( href="http://scienceblogs.com/aetiology/2006/10/failure_of_alternative_med.php">The
failure of alternative medicine); and Orac wrote about it ( href="http://scienceblogs.com/insolence/2006/10/alternative_medicine_continues_to_fail_1.php">Alternative
medicine continues to fail).



Back then, we were commenting on a study that had been designed to see
if DHEA had any beneficial or detrimental effects on a population of
elderly persons.  Specifically, they wanted to see if there
was an increase in muscle mass, stamina, or bone density; whether
glucose regulation improved; or whether quality of life
improved.  They also looked for evidence of harm.



href="http://scienceblogs.com/corpuscallosum/images/DHEA_pathways.JPG">

What they found was, basically, nothing.  There
were slight improvements in a few areas, but nothing significant.
 No harm was detected, either.  



With that as background, I read the Life Extension
article.  I must say, I found it to be both informative, and
irritating...

The magazine is published by the href="http://en.wikipedia.org/wiki/Life_Extension_Foundation">Life
Extension Foundation.  Along with the article cited
above, there was an another on the same subject: Congress
Seeks to Ban DHEA, by href="http://chetday.com/lifeextensioninterview.htm">William
Faloon (not available on line).



The gist of the two articles is this: bills have been introduced in
Congress ( href="http://www.govtrack.us/congress/bill.xpd?bill=s110-762">S.
762 and href="http://www.govtrack.us/congress/bill.xpd?bill=h110-1249">H.R.
1249) that would classify DHEA as an anabolic steroid under
the Controlled Substances Act.  The result would be that the
substance could not be purchased without a prescription.  



The Senate bill was introduced by  href="http://grassley.senate.gov/index.cfm?FuseAction=Biography.Home">Chuck
Grassley, cosponsored by McCain and Durbin.  The
House bill was introduced by href="http://roskam.house.gov/Biography/">Peter Roskam,
and has no cosponsors.  As far as I could tell, Grassley is
the only one who mentions it on his website:

href="http://grassley.senate.gov/index.cfm?FuseAction=PressReleases.Detail&PressRelease_id=5292">GRASSLEY
CONTINUES EFFORTS TO CRACK DOWN ON STEROID ABUSE

Bill Adds a Common Steroid to List of Banned Substances

 

WASHINGTON – Senator Chuck Grassley today
introduced legislation that would add dehydroepiandrosterone, or DHEA,
to the list of anabolic steroids that are classified as controlled
substances under the Anabolic Steroid Control Act.  The
legislation was introduced with Senators John McCain of Ariz. and Dick
Durbin of Ill...



...Like all steroids, DHEA has a number of potential long-term physical
and psychological effects, including heart disease, cancer, stroke,
liver damage, severe acne, baldness, dramatic mood swings and
aggression. 

Life Extension took exception to that last paragraph.  They
inquired about the basis for the claims.  They were sent a
copy of a paper by Fernand Labrie, et. al.

href="http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T8X-4K7FJ9X-1&_user=10&_coverDate=07%2F31%2F2006&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=4573662e7807a50b15c0bed80b3a678f">Dehydroepiandrosterone
(DHEA) is an anabolic steroid like dihydrotestosterone (DHT), the most
potent natural androgen, and tetrahydrogestrinone (THG)

The Journal of Steroid Biochemistry and Molecular Biology

Volume 100, Issues 1-3, July 2006, Pages 52-58



We have recently taken advantage of the unique power of DNA microarrays
to compare the genomic expression profile of tetrahydrogestrinone (THG)
with that of dihydrotestosterone (DHT), the most potent natural
androgen, thus clearly demonstrating that THG is an anabolic steroid.
In 2004, the U.S. Controlled Substances Act has been modified to
include androstenedione (4-dione) as an anabolic steroid. However,
despite the common knowledge that dehydroepiandrosterone (DHEA) is the
precursor of testosterone, DHEA has been excluded from the list of
anabolic steroids. We thus used the same DNA microarray technology to
analyze the expression profile of practically all the 30 000 genes of
the mouse genome modulated by DHEA and DHT in classical
androgen-sensitive tissues. Daily subcutaneous injections of DHT (0.1
mg) or DHEA (3 mg) for 1 month in gonadectomized C57BL6/129 SV mice
increased ventral prostate, dorsal prostate, seminal vesicle and
preputial gland weight (p < 0.01 for all tissues). As early as
24 h after single injection of the two steroids, 878, 2681 and 14 probe
sets were commonly stimulated or inhibited (p < 0.01, change
≥ 30%), in the prostate (ventral + dorsal), seminal vesicles and
preputial glands, respectively, compared to tissues from gonadectomized
control animals. After 7 days of daily treatment with DHEA and DHT,
629, 919 and 562 probe sets were commonly modulated in the same tissues
while after 27 days of treatment, 1195, 5127 and 2883 probe sets were
modulated, respectively. In analogy with the data obtained with THG,
the present microarray data provide an extremely precise and
unquestionable genomic signature and proof of the androgenic/anabolic
activity of DHEA. Such data add to the literature showing that DHEA is
transformed into androgens in the human peripheral tissues as well as
in laboratory animal species, including the monkey, thus exerting
potent androgenic/anabolic activity. The present microarray approach to
identify anabolic compounds is applicable to all potential
androgenic/anabolic compounds.

The abstract indicates that study provides "proof of the
androgenic/anabolic activity of DHEA".  Never mind that tehy
used 3mg injected doses in mice, while the usual human oral doses are
about 15 to 200mg per day.  I didn't do the math, but the LEF
did:

The
numbers came in showing that the human-equivalent dose of DHEA used in
this gene expression study was 15,800 mg in the four-week arm, and an
astounding 43,910 mg in the one-week arm.

To put this in context, LEF sells DHEA in 100mg capsules, #60 for $30.
 You would have to take 158 of them at a cost of $79 per day
to get a dose comparable to what the mice got in the lower-dose arm of
the study.  That is not completely out of the question; drug
abusers, after all, have been known to do some pretty strange things to
get whatever effect they are looking for.  But the abstract
refers to "potent androgenic/anabolic activity".  Potency, of
course, refers to the magnitude of the effect per milligram of dose.
 Their own data do not show that DHEA is "potent," rather the
opposite.



The paper simply does not support the contention that DHEA should be a
controlled substance.  The paper that Orac, Tara, and I
commented upon earlier also does not show that.  If anything,
it shows that Congress can safely ignore the whole issue.



So what is going on here?  



LEF points out one possibility.  The lead author of the JSBMB
paper, Fernand Labrie, happens to hold a US patent on the medical use
ofa combination of DHEA and selective estrogen receptor modulators
(SERMs).  ( href="http://www.patentstorm.us/patents/7005428-fulltext.html">US
Patent 7,005,428)  The medical rationale for such
treatment is outlined in another of his papers:

href="http://erc.endocrinology-journals.org/cgi/content/full/13/2/335">

href="http://erc.endocrinology-journals.org/cgi/content/full/13/2/335">Future
perspectives of selective estrogen receptor modulators used alone and
in combination with DHEA

Endocrine-Related Cancer 13 (2) 335-355



...However, it is expected that a SERM alone will not meet
all the requirements of women’s health at the postmenopause
when ovarian estrogen secretion has ceased and peripheral formation of
androgens and estrogens from DHEA by intracrine mechanisms is decreased
by 60% or more. One possibility is to combine a SERM with DHEA, a
precursor of sex steroids that permits, somewhat like SERMs,
tissue-specific formation of androgens and/or estrogens according to
the level of expression of the steroidogenic and steroid-inactivating
enzymes. DHEA could thus compensate for the important loss of androgens
that accompanies aging and could also permit sex steroid formation and
action in the brain while breast cancer prevention would be achieved by
the SERM.

Tamoxifen is a SERM, and it happens to be a generic drug.
 DHEA is now available over the counter.  So if his
approach is proven to be efficacious, the patent could enable him (and
his company, Endorecherche, Inc.) to market a combination drug
at a high price, but only if DHEA is not otherwise available.
 If anyone can get it, then anyone with a prescription for
generic tamoxifen could get the same result at a much lower cost.
 



There are two sides to this issue, and there are people on both
sides who have a financial stake in the outcome.   face="Helvetica, Arial, sans-serif">Endorecherche
may be angling for patent protection for a product, while LEF wants to
be able to sell DHEA for 50 cents a capsule.   face="Helvetica, Arial, sans-serif">While that
does not
prove that they are not credible sources, it does give up good reason
to cast a critical eye toward their arguments.



It is hard to know what motivates people, but large sums of money
generally suffice.  I can't determine if the LEF's allegations
are true, that Congress is being manipulated into passing a law that
could be financially favorable to Endorecherche.  It would not
be a huge surprise, though.  Clearly, Senator Grassley, based
upon his press release, has been hoodwinked.  



On the other hand, Fernand Labrie is not the only one with scientific
credentials who advocates for making DHEA an FDA-regulated substance.
 In an href="http://content.nejm.org/cgi/content/full/355/16/1724">NEMJ
editorial (not open-access), Dr. Paul Stewart argues the same
thing:

In
light of an evidence base for the efficacy of DHEA in patients with
adrenal insufficiency, DHEA should no longer be accepted as a food
supplement and should instead be treated as a regulated drug.

Gary Wadler, M.D,
argues
the same:

In
conclusion, my own view is -- and I feel very strongly about it for the
reasons I discussed earlier -- the steroid hormones, including DHEA and
Androstenedione, should be reclassified as drugs requiring a
consultation with a physician, and the obtaining of a written
presciption for these substances, in accordance with the principles of
medical practice.

So even though Grassley and the others are citing a paper that does not
support their contentions, there are credible experts out there who
would support the legislation.  I don't happen to agree with
them, but they are out there.



You see, Dr. Stewart argues that DHEA can be used to treat adrenal
insufficiency, so it should be considered a drug.  But water
deficiency can be treated by, no big surprise, water.  Water
can be dangerous in overdose.  But nobody is arguing that
water should be a controlled substance.  Arguing that DHEA is
or is not an anabolic steroid is pointless; it is irrelevant from a
legal standpoint.  



The legal issue is this: does Government have a compelling interest
that would justify regulation of the substance?  I haven't
seen anything that demonstrates that it does, to my satisfaction.