January 12, 2001
Issue #29

ORAL ACTIVATION OF STEROIDS
by Pat Arnold

The subject of androgenic / anabolic steroids, and the different ways that have been found to make them orally active, has been tossed around lately on the internet mags.  This is an interesting topic to the science minded out there, but beyond that, it also has potential utility to the prohormone supplements.  The following is my take on the subject, including scientific references and conjecture on my part.
 

The problem with natural androgens

Testosterone is the primary androgen in the human, and is the golden standard by which all other steroids are compared.  Unfortunately, testosterone has very poor activity when taken orally.  This necessitates that testosterone be administered by extra-oral means such by injection, subcutaneous pellet implant, and transdermal gel or patch.

17alpha alkylated steroids

Scientists have developed several synthetic testosterone derivatives that have increased oral bioavailability.  The first synthetic alteration that scientists utilized is known as 17 alpha alkylation.  17a alkylation involves the addition of an alkyl group (methyl or ethyl) to the alpha position of the 17 carbon of the steroid backbone.   The alkylation at this position prevents the major route of androgen deactivaton – oxidation to a 17-keto steroid - from taking place.  This allows a large part of the steroid to avoid liver first pass metabolic degradation.  Examples of 17a alkylated steroids are methyltestosterone and Norethandrolone (Nilevar) 

While 17a alkylation is a very effective means of rendering steroids orally active, it suffers from a serious drawback.  These steroids are all to some extent toxic to the liver.  Some are more toxic than others, but they all have been associated with this problem.  Jaundice is not completely uncommon with the usage of this stuff, although this condition is generally confined to individuals who are predisposed to liver problems.  Several cases of liver cancer have supposedly been linked to 17a alkylated steroids, however, nothing definitive has been established in this regard.  On the other hand, it is somewhat common to observe increases in blood test indicators of liver stress such as BSP retention, and intrahepatic cholestasis (a condition where bile clogs up and stops flowing from the liver).

While the dangers of 17a alkylated steroids are not trivial, they still comprise some of the most potent anabolic agents available, and therefore their use continues.  Most smart bodybuilders are aware of the potential toxicities of these steroids, and therefore they are judicious with their use of them.

Lipophilic steroid derivatives

After ingestion, most steroids make their way to the intestines where they are absorbed into the portal circulation.  The portal circulation carries the steroid directly to the liver, which is the workhouse of destructive metabolism and inactivation of drugs.  As a result, if the steroid is not protected in some way, very little will make it through the liver and into the rest of the body where it can do its magic.

In addition to the portal route, there is another route through which substances can be absorbed into the body from the intestine.  If a substance is lipophilic (fat like) enough it will be absorbed in the same manner that dietary fat is.  Dietary fat is incorporated into chylomicra, which are small fat globules composed of protein and fat.  These chylomicra are absorbed into the lymphatic circulation, which by passes the liver.   If you make a steroid lipophilic enough by altering its structure, then it too will incorporate into chylomicra and absorb into the lymphatic system.  Once in the lymphatic system it can cross over into the general blood circulation, making it there without being subjected to the massive metabolic breakdown in the liver. 

Scientists have found that by adding lipophilic side chains to steroids, they will to some extent be absorbed into the lymphatic system.   If the side chain is linked on in such a way that it can hydrolyze (break apart) easily after being absorbed, the steroid is essentially rendered orally active.   Two side chains that have been utilized to increase the oral bioavailability of steroids through increased hepatic absorption are long chain alkyl ester groups, such as is seen with testosterone undecanoate (andriol), and enyl ether groups, such as is seen with quinbolone (anabolicum vaster).

The term “orally active” is of course a relative term.   Lipophilically modified steroids are more orally active than the free parent steroids, however, they are nowhere near as active as the 17alpha-alkylated steroids.  Testosterone undecanoate (TU) is probably the most commonly known lipophilically modified androgen, and it is not considered a very potent compound (its recommended daily dosage is about 240mg).   In fact, one study found the oral administration of testosterone undecanoate led only to an absolute testosterone bioavailability of 6.83 +/- 3.32%.  That is very slight, especially considering the fact that in the same study they found the bioavailability of straight testosterone to be 3.56 +/- 2.45% (Eur J Drug Metab Pharmacokinet 1986 Apr-Jun;11(2):145-9).  That means TU is just a little less than twice as orally active as free testosterone, which is unimpressive to say the least.

The other problem with lipophilic steroid preparations is the high variability in absorption from one person to another.  In other words, one guy might absorb the stuff very well while the other guy might absorb very little.  There is also high variation within individuals themselves, depending on their gastrointestinal condition when they take the stuff.   In another study, ten post-menopausal women were given 40 mg of TU and their peak blood values were recorded.  The values varied widely - more than ten fold (range: 5.8-64.0 nmol/L) - amongst the subjects (J Clin Endocrinol Metab 1998 Nov;83(11): 3920-4).

There is no specific data I can find on the bioavailabilty of enyl ether compounds, but since their mode of action is identical to long chain alkyl ester compounds like TU, it is a fair assumption that they too are not outstandingly high in oral bioavailability, or in consistency of absorption.  What I do know is that the one and only enyl ether oral steroid on the market today (quinbolone) is generally regarded by European bodybuilders / athletes as too weak to even  bother taking.


Ring A modified steroids

There is one more class of anabolic / androgenic steroids that are orally active.  These have unique structural modifications in the steroid A ring.  What these modifications do is help preserve the steroids 17beta hydroxyl group, and minimize oxidation to the inactive 17-keto form.

Androgens such as testosterone exist in the body in equilibrium between their active 17beta hydroxyl form and the inactive 17-keto form.

Normally, the equilibrium lies pretty far to the right (formation of inactive 17 keto steroid), however some steroids have certain modifications made in the A ring that alter this equilibrium by shifting it heavily to the left (towards the formation of active 17beta hydroxyl steroid).

The most common A-ring modifications that shift the 17beta hydroxyl / 17-keto equilibrium to the left are methylation at the 1alpha position, and unsaturation (double bond) in the 1(2) position (Acta Endocr, 41, (1962) 494).  Examples of orally active steroids that contain one or more these modifications include methenolone (primobolan), mesterolone (proviron), and 1-testosterone.

You probably have heard of mesterolone and methenolone, but it is doubtful you have ever heard of 1-testosterone.  1-testosterone is a very interesting compound, not just because it is orally active but also because it is very anabolic.  It has been reported to be over 7 times as anabolic as testosterone in a study funded by the pharmaceutical giant Searle (J Org Chem, 27 (1962) 248).  Furthermore, being a 5alpha reduced steroid, it should not aromatize to estrogens.