Hypertension and anabolic steroids. A new pathway?
By
Patrick Arnold
People familiar with the use of anabolic steroids know that water retention and
hypertension (high blood pressure) are potential side effects. This is due to
the fact that all androgenic hormones have the capacity to cause some sodium
retention (and hence water retention) through direct action via androgen
receptors in the kidneys. Furthermore, anabolic steroids that are estrogenic or can
convert to estrogens can cause even more sodium retention via additional
interaction with renal (kidney) estrogen receptors. So it’s often thought that
an anabolic steroids propensity for water retention is
related to its potency both as an androgen and as an estrogen (manifested via
aromatization to estrogenic metabolites).
Confusion has often arisen
however when people have noticed that some steroids– which traditional thinking
tells us should not result in extraordinary water retention – end up doing just
that. steroids that should not aromatize to
estrogens such as oxymetholone (anadrol) and methyl-1-testosterone are known to
result in extreme water retention in some individuals. A recent paper* suggests
a heretofore unmentioned explanation for this.
There is an enzyme that is
localized primarily in the kidneys whose function is to protect the kidneys from
circulating cortisol. The kidneys have receptors called mineralcorticoid
receptors (MR’s) which are meant to bind to specific adrenal hormones (called
mineralcorticoids) in the body such as aldosterone. The result of this binding
is a signal to increase sodium and water retention in the body, while
stimulating the excretion of potassium. This is an important mechanism to
maintain fluid and electrolyte balance in the body.
A problem exists
though in that cortisol can also bind activate these receptors. Cortisol is a
widely circulating hormone and serves a multitude of functions throughout the
body. However its intended biological functions do not include mineralcorticoid
action in the kidneys, so to prevent this from happening the kidneys are rich in
the enzyme 11b-hydroxysteroid dehydrogenase 2 (11b-HSD2). This enzyme
deactivates cortisol by converting it into cortisone before it can bind to the
renal MRs.
Certain substances can block 11b-HSD2, and that can lead to
problems. One example is a constituent of black licorice known as glycyrrhetinic
acid. This enzyme inhibition potential is precisely why people that consume a
lot of black licorice are known to retain water and experience high blood
pressure and electrolyte disturbances. Interestingly, legend has it that Genghis
Khan had his armies ingest licorice while on the march to prevent thirst and
dehydration. Of course Genghis Khan had no idea that 11b-HSD2 inhibition was
responsible for these effects, and today many have been similarly unaware that
this property might be responsible for some of the salt/water effects of
anabolic steroids.
The study I referred to
earlier found that many anabolic steroids indeed do share the ability to
block this enzyme, and some of them are as powerful as glycyrrhetinic acid.
Fluoxymesterone (halotestin) in particular was shown to be about as potent as
glycyrrhetinic acid in this regard. This makes sense, since fluoxymesterone
shares the same 11b-OH group as cortisol and can be oxidatively metabolized by
11b-HSD2 in an analogous manner.
The
fact that fluoxymesterone serves as a substrate for 11b-HSD2 in this manner
makes it a competitive inhibitor of the enzyme. Other anabolic steroids were also found to be potent
inhibitors of the enzyme as well, although the mechanisms for these are not
clear as they do not share the 11b-OH group.
In addition to
fluoxymesterone other 11b-HSD2 inhibitor steroids of interest are oxymetholone
(anadrol), oxymesterone, and testosterone. The question arises as to how
relevant this enzyme inhibiton is in the real world. Fluoxymesterone is
generally not associated excess water retention, but then again doses used are
relatively low (20mg or less per day). In contrast, oxymetholone is well
associated with excess water retention and the doses used of that are often high
(50-150mg per day). So this may be a dose related phenomenon. Another question
that I have is what sort of inhibition might methyl-1-testosterone have, since
it seems to be the worst water retaining and hypertensive steroid ever made. Few have had decent
explanations for this and perhaps 11b-HSD2 inhibition is a culprit (the study
did not test this steroid).
A final point of interest
to mention here is the intriguing fact that 11-ketofluoxymesterone (the
metabolite formed in the kidneys as mentioned previously) is actually a stronger
anabolic steroid than fluoxymesterone according to
animal tests. I find that interesting because one would also expect it to
generally lack the troublesome enzyme inhibition that can lead to
mineralcorticoid related disturbances. Maybe if the inventors of fluoxymesterone
had decided to just simply oxidize the 11b-OH group they would have ended up
with a more healthy and effective steroid to sell.
By
Patrick Arnold
People familiar with the use of anabolic steroids know that water retention and
hypertension (high blood pressure) are potential side effects. This is due to
the fact that all androgenic hormones have the capacity to cause some sodium
retention (and hence water retention) through direct action via androgen
receptors in the kidneys. Furthermore, anabolic steroids that are estrogenic or can
convert to estrogens can cause even more sodium retention via additional
interaction with renal (kidney) estrogen receptors. So it’s often thought that
an anabolic steroids propensity for water retention is
related to its potency both as an androgen and as an estrogen (manifested via
aromatization to estrogenic metabolites).
Confusion has often arisen
however when people have noticed that some steroids– which traditional thinking
tells us should not result in extraordinary water retention – end up doing just
that. steroids that should not aromatize to
estrogens such as oxymetholone (anadrol) and methyl-1-testosterone are known to
result in extreme water retention in some individuals. A recent paper* suggests
a heretofore unmentioned explanation for this.
There is an enzyme that is
localized primarily in the kidneys whose function is to protect the kidneys from
circulating cortisol. The kidneys have receptors called mineralcorticoid
receptors (MR’s) which are meant to bind to specific adrenal hormones (called
mineralcorticoids) in the body such as aldosterone. The result of this binding
is a signal to increase sodium and water retention in the body, while
stimulating the excretion of potassium. This is an important mechanism to
maintain fluid and electrolyte balance in the body.
A problem exists
though in that cortisol can also bind activate these receptors. Cortisol is a
widely circulating hormone and serves a multitude of functions throughout the
body. However its intended biological functions do not include mineralcorticoid
action in the kidneys, so to prevent this from happening the kidneys are rich in
the enzyme 11b-hydroxysteroid dehydrogenase 2 (11b-HSD2). This enzyme
deactivates cortisol by converting it into cortisone before it can bind to the
renal MRs.
Certain substances can block 11b-HSD2, and that can lead to
problems. One example is a constituent of black licorice known as glycyrrhetinic
acid. This enzyme inhibition potential is precisely why people that consume a
lot of black licorice are known to retain water and experience high blood
pressure and electrolyte disturbances. Interestingly, legend has it that Genghis
Khan had his armies ingest licorice while on the march to prevent thirst and
dehydration. Of course Genghis Khan had no idea that 11b-HSD2 inhibition was
responsible for these effects, and today many have been similarly unaware that
this property might be responsible for some of the salt/water effects of
anabolic steroids.
The study I referred to
earlier found that many anabolic steroids indeed do share the ability to
block this enzyme, and some of them are as powerful as glycyrrhetinic acid.
Fluoxymesterone (halotestin) in particular was shown to be about as potent as
glycyrrhetinic acid in this regard. This makes sense, since fluoxymesterone
shares the same 11b-OH group as cortisol and can be oxidatively metabolized by
11b-HSD2 in an analogous manner.
The
fact that fluoxymesterone serves as a substrate for 11b-HSD2 in this manner
makes it a competitive inhibitor of the enzyme. Other anabolic steroids were also found to be potent
inhibitors of the enzyme as well, although the mechanisms for these are not
clear as they do not share the 11b-OH group.
In addition to
fluoxymesterone other 11b-HSD2 inhibitor steroids of interest are oxymetholone
(anadrol), oxymesterone, and testosterone. The question arises as to how
relevant this enzyme inhibiton is in the real world. Fluoxymesterone is
generally not associated excess water retention, but then again doses used are
relatively low (20mg or less per day). In contrast, oxymetholone is well
associated with excess water retention and the doses used of that are often high
(50-150mg per day). So this may be a dose related phenomenon. Another question
that I have is what sort of inhibition might methyl-1-testosterone have, since
it seems to be the worst water retaining and hypertensive steroid ever made. Few have had decent
explanations for this and perhaps 11b-HSD2 inhibition is a culprit (the study
did not test this steroid).
A final point of interest
to mention here is the intriguing fact that 11-ketofluoxymesterone (the
metabolite formed in the kidneys as mentioned previously) is actually a stronger
anabolic steroid than fluoxymesterone according to
animal tests. I find that interesting because one would also expect it to
generally lack the troublesome enzyme inhibition that can lead to
mineralcorticoid related disturbances. Maybe if the inventors of fluoxymesterone
had decided to just simply oxidize the 11b-OH group they would have ended up
with a more healthy and effective steroid to sell.
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