Creating Orally Active Prohormones
If you haven’t heard, there is a new technology in prohormones.
Lipophilic ester and ethers have hit the market, and are being touted as the
first truly effective solutions to the poor oral bioavailability of many such
supplements. And indeed there is a tremendous amount of promise with this
technology if properly applied. When I first realized supplement manufacturers,
my company Molecular Nutrition included, would be able to market steroidal
ethers and esters I became very excited. We in the industry have been looking
for a solution to problems with oral dosing for some time, and I knew we had a
true advance on our hands here. I became even more excited when I began
suspecting that other companies would be dropping the ball, so to speak, by not
making proper use of this technology. As they began releasing their products, I
worked quietly in the background. I went through great lengths not to just drop
powder into a capsule, but to develop a series of ether-modified,
oil-solubilized, softgel-encapsulated prohormones. In light of the very unique
design of my Ethergelsä series I thought it would be good to explain in greater
detail my reasoning in creating such a line, and why they are not the same as
many of my competitors’ products.
Traditional Oral
Prohormones
When androstenedione capsules first hit the
market in 1996, hopes were high that the first legal product for massively
elevated testosterone levels (and similarly the first true replacement for
illegal steroids) had been uncovered. It did not take long, however, for
athletes to realize that we did not quite have what we thought we did. “Andro”
caps just didn’t work the way we were expecting them to. Studies eventually
showed us what was happening with this supplement, demonstrating that large
doses would be needed for even the slightest elevations in blood testosterone
levels[i]. And even then our “legal testosterone elevator” turns out to increase
estrogen levels better that the target hormone of our interest. Initial failings
with androstenedione, at least as an increaser of serum testosterone, were
repeated with its lauded successor androstenediol[ii]. Again, relatively high
oral doses of this prohormone were shown to cause little or no elevations in
blood testosterone.
We have come to understand, of course, that this is
due to rapid metabolism of natural steroids during the harsh first-pass through
the liver. During this, most of the prohormone compound is readied for excretion
from the body long before it reaches the blood stream as an active steroid. We
should have expected this problem though. Scientists realized as early as 1939,
the same decade that testosterone was first synthesized, that this hormone was
ineffective when taken orally[iii], precluding its use as an oral medication.
Likewise no such “un-modified” testosterone product had ever been sold
commercially. Drug developers found out early on that if they wanted to make an
effective oral medication out of testosterone they must protect the steroid from
metabolism by the liver. The same holds true, even more so perhaps, for our
traditional prohormone compounds. They simply don’t work well as oral
supplements because, and I must emphasize this, we have been relying on a
practice ruled out as ineffective over 60 years ago!
17-Alpha Alkylation
During the peak years of
steroid research several effective methods were devised to create steroids
capable of passing through the liver intact, the most prominent of which
centered around protecting the hormone with the addition of a methyl or ethyl
group at the 17th carbon position (which inhibits a major path of metabolism).
Methyltestosterone was the first such steroid to be developed, followed soon by
a number of other oral steroids including ethylnandrolone (norethandrolone),
fluoxymesterone, oxandrolone and methandrostenolone. Although all of these drugs
are extremely effective oral steroids, they can also have an adverse effect on
liver function[iv], and are therefore not ideal solutions. Today they are used
very sparingly in medicine for this same reason. Additionally, for the purposes
of making a natural and legal supplement we could not use this technology, as
the compounds it creates would no longer be considered “naturally occurring”.
This would leave us in the prohormone market where we started; with plain
powder-filled capsules, most of which are unable to provide much of an anabolic
effect.
Lymphatic Delivery
But
as late as the 1960’s and 70’s the push was still on to develop effective oral
steroids that were not 17-alpha alkylated and did not carry the same unwanted
risks of liver toxicity. One concept that was successfully pursued was the
notion of bypassing the liver altogether. To do this we need to change the way
the steroid is absorbed by the body, so that it will enter circulation through
the lymphatic system and not by its normal route. The lymphatic system is
responsible for the absorption and distribution of dietary fats, and shuttles
these nutrients from the intestines to the lymph nodes so that they can reach
peripheral tissues without having to first pass through the liver. To
effectively do this however we need to increase the fat solubility of the
compound considerably, either by additioning a carboxylic acid ester (normally
used to create injectable compounds) or an ether group. For our purposes we can
look at esters and ethers as essentially the same thing. The key point with both
structural additions is that they increase the lipid solubility of the steroid,
and therefore the likelihood it will be absorbed by the lymphatic system with
dietary fat, yet later break off in circulation (via esterase enzymes) to yield
an intact active hormone.
Two lymph-delivered anabolic/androgenic
steroids were ultimately developed and marketed by pharmaceutical companies. The
first was Anabolicum Vister, which contains boldenone modified with enol ether
(quinbolone), and the second Andriol, which uses the undecanoate ester of
testosterone. Data is difficult to find on quinbolone, as it was an Italian
steroid, however Andriol has been well studied and documented in English text
medical journals. The studies are consistent, with Andriol proving to be the
only orally effective testosterone product ever developed and commercially sold.
Those who question the validity of this technology need only look at a study
published in Acta Endocrinologica in 1975[v]. Here investigators compared the
testosterone response from 100mg of orally administered testosterone
undecanoate, dissolved in oil, with the effects of an equivalent dose (63mg) of
free testosterone. The free testosterone had no noticeable effect on serum
levels of testosterone at all, while there was a 2.3 fold increase reported with
the single dose of testosterone undecanoate.
Making
it work with Prohormones
Now in the eyes of the FDA,
prohormones modified with ethers and esters are just as legal to sell as the
original compounds. They consider such modifications as technologies to enhance
the delivery of the nutrient, and not the equivalent of creating a new synthetic
hormone. We finally have the technology, and legal freedom, to create orally
active prohormones. But we can’t just jump the gun applying this to prohormones
without fully understanding the technology at hand. The two lymphatically
delivered steroids mentioned above have one very important thing in common aside
from their increased oil-solubility. Both are made in soft gelatin capsules and
use oil as carrier for the steroid. It was realized early on that dissolving the
steroid directly into oil, which will be taken up by the lymph system, is the
best way to ensure maximum absorption and oral bioavailability. In fact, it is
absolutely essential to this type of product.
To see roughly how much of
a difference it makes we can look at studies comparing the effects of different
carriers on the absorption of the ether modified anti-estrogen mepitiostane[vi].
Here we note that lymphatic absorption was about 5 ½ times greater (41.2% as
opposed to 7.5%) when the compound was dissolved in sesame oil instead of a
plain water-based solution. In fact, the tremendously poor absorption of
mepitiostane without oil makes us question whether or not ether modification
offers any real benefits at all without the use of such a carrier. One thing is
certain, ether-modified and ester-modified prohormones in plain capsules and
tablets are not made in the true design of lymphatically-delivered steroids,
which likewise makes them far less effective oral supplements than they could be
otherwise.
In Closing
As you can
see, the great time and expense I put into our Ethergelsä line of softgels,
which includes ether-modified forms of 1-testosterone, 4-androstenediol, and
19-norandrostenediol, was not to create a gimmicky packaging to market, but to
take full advantage of the technology at hand (although I must admit those
little amber caps do look pretty neat). I wanted to do it right, which meant
adhering to the true design of lymphatically delivered steroid, or I wasn’t
going to do it at all. Let there be no argument that I have accomplished this
goal, with the creation of the most orally active line of prohormones, by far,
ever to be introduced to the sports supplement market.
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