Answer:
Much of the confusion about the wide range of side effects of steroids comes
from their various non-genomic actions. As the term non-genomic doesnt seem
to come up very often in locker room steroid conversations let me explain
Most people know that there is only one typical, or sometimes called
classical , androgen receptor (AR). The AR is an intracellular receptor,
meaning that it resides within cells (as apposed to the membrane surface) and
once bound to an androgen, travels to the nucleus of the cell and binds to the
DNA where it initiates the expression of various proteins.
The AR exerts a wide range of effects even though there is only one typical AR.
Testosterone (Test) is able to exert different effects in different tissues by
virtue of it acting as is in some tissues, and acting as its 5-alpha reduced
counterpart dihydrotestosterone (DHT) in the same and/or other tissues.
DHT has different binding properties than Test. DHT binds stronger, and stays
bound longer than Test. This subtle difference in the strength and duration of
binding is able to produce a tremendous range of different actions in the body
from the time youre a fetus to a full grown adult.
Some synthetic steroids are more like Test, and others are more like DHT. But
this still doesnt explain all the differences seen among synthetic androgens.
The differences beyond binding properties can then be explained by these
non-genomic properties mentioned earlier.
Within the last 5 years or so, more attention has been drawn to the non-genomic
effects of steroids and trying to understand them. They are called non-genomic
because they dont directly involve the steroid bound to the AR acting directly
on the cells DNA.
It is now understood that steroids can act on the cell membrane to bring about
various second messenger effects. These second messenger pathways involve kinase
pathways driven by classical receptors (MAPk, ERK, MEK, etc), as well as cyclic
AMP, lipase and other kinase pathways (PI3K, PKA, PKC, etc), including ion
fluxes (Ca++), which are driven by atypical receptors. All in all, steroids
affect cells through several different pathways and at least one atypical
steroid receptor, none of which involve what most people consider the true
intracellular mechanism of steroid action.
Most all of these non-genomic affects of steroids are acute, or immediate
Meaning, they occur within seconds or minutes of the steroid interacting with
the cell. This helps to explain why so many different organs have androgen
receptors or are sensitive to androgen levels. For example, in tissues taken
from rats, (in order of sensitivity):
Hypothalamus
Adrenal gland
Epididymis
Thyroid gland
Pituitary gland
Quadriceps muscle
Kidney
Seminal vesicle
Testis
Liver
Submaxillary gland
Bulbocavernosus muscle (penis)
Vagina
Heart
Ovary
Uterus
The hypothalamus, part of the CNS, has a higher concentration of ARs than even
the quads. That is an interesting fact. Of course this is from rats but humans
would no doubt show more or less similar distributions.
One question that has recently been brought to my attention deals with how
steroids increase strength. Aside from increases in contractile proteins,
strength is largely a product of the nervous system. The involvement of the
nervous system in generating strength starts in the brain (which can show
fatigue believe it or not) and finishes with the structures involved in
excitation contraction coupling.
It is perfectly reasonable that androgens act as a direct CNS stimulant through
non-genomic pathways by increasing cAMP activity and enhancing Ca++ flux from
the sarcoplasmic reticulum. Keep in mind that these are the same second
messenger pathways utilized by catecholamines and like drugs including
adrenaline, noradrenaline, ephedrine, and caffeine.
It is time for bodybuilders and steroid gurus alike to update their knowledge of
the mechanism of action of the drugs the use and direct the use of. There is
plenty of research available (see below) so no one claiming to be an expert has
an excuse not to be well informed about the non-genomic actions of steroids.
Sample References: (There are many, many, more like these)
1. Losel R, Wehling
M. Nongenomic actions of steroid hormones. Nat Rev Mol Cell Biol. 2003
Jan;4(1):46-55.
2: Schmidt BM, Christ M, Falkenstein E, Wehling M. Nongenomic
steroid actions: completing the puzzle. Aldosterone as an example. Exp Clin
Endocrinol Diabetes. 1998;106(6):441-5.
3: Cato AC, Nestl A, Mink S. Rapid actions of steroid receptors in cellular
signaling pathways. Sci STKE. 2002 Jun 25;2002(138):RE9.
4: Christ M, Haseroth
K, Falkenstein E, Wehling M. Nongenomic steroid actions: fact or fantasy? Vitam
Horm. 1999;57:325-73.
5: Falkenstein E, Tillmann HC, Christ M, Feuring M, Wehling M. Multiple actions
of steroid hormones--a focus on rapid, nongenomic effects. Pharmacol Rev. 2000
Dec;52(4):513-56.
6: Wehling M. Specific, nongenomic actions of steroid
hormones. Annu Rev Physiol. 1997;59:365-93.
7: Schmidt BM, Gerdes D, Feuring M, Falkenstein E, Christ M, Wehling M. Rapid,
nongenomic steroid actions: A new age? Front Neuroendocrinol. 2000
Jan;21(1):57-94.
8: Gerdes D, Christ M, Haseroth K, Notzon A, Falkenstein E, Wehling M.
Nongenomic actions of steroids--from the laboratory to clinical implications. J
Pediatr Endocrinol Metab. 2000 Jul-Aug;13(7):853-78.
9: Joels M. Modulatory actions of steroid hormones and neuropeptides on
electrical activity in brain. Eur J Pharmacol. 2000 Sep 29;405(1-3):207-16.
10:
Spindler KD. Interactions between steroid hormones and the nervous system
Neurotoxicology. 1997;18(3):745-54.
