Androgen Action and the Androgen Receptor
<Introductory Physiology and Pharmacology of Androgens
Endogenous androgens are well known for their many functions in promoting
sexual differentiation and the induction of the male phenotype. In the male, the
two endogenous androgens most active in promoting these effects are testosterone
(T) and dihydroxytestosterone (DHT). T is the most quantitatively important
androgen in systemic circulation while DHT is the most abundant cellular
metabolite and most potent androgen in most androgen sensitive tissues
(excluding skeletal muscle; Mainwaring 1977).
The physiological effects of androgens have been discussed since the 1930's
when several investigators observed that the injection of male urinary extracts
into dogs not only promoted androgenic effects on the canine reproductive tract
but also caused nitrogen retention or an anabolic effect (Kochakian and Mrulin
1935). Since then, much information has been gathered about the various anabolic
and androgenic effects of exogenous androgens on human physiology (Braunstien
1997). During fetal development androgens are important in the appropriate
differentiation of the internal and external male genital systems. Later, during
puberty, androgens mediate growth and functional integrity of the scrotum,
epididymis, vas deferens, seminal vesicles, prostate, and penis. During this
time androgens also stimulate skeletal muscle growth, growth of the larynx, and
stimulate the pubertal growth spurt. Both ambisexual hair growth and sexual hair
growth as well as sebaceous gland activity are regulated by androgens throughout
the life cycle. Finally, androgens also play many diverse roles in the adult
including: behavioral roles (sexuality, aggression, mood, and cognitive
function), regulation of spermatogenesis, regulation of bone metabolism,
maintenance of muscle mass and muscle function, various effects on the
cardiovascular system, and regulation of prostate cancer (Nieschlag and Behre
1998). This list is far from exhaustive as androgens most likely play roles in
nearly every organ and cell of the body. As further investigations are
conducted, additional physiological effects of endogenous androgens will surely
Although the prior brief discussion has dealt with the physiological effects
of the endogenous androgens T and DHT, it must be noted that numerous exogenous
steroids have been synthesized in attempts to alter the anabolic to androgenic
ratios relative to these two hormones (for a review see Vida 1969). In clinical
situations of hypogonadism, T replacement is necessary to replace both the
anabolic and androgenic effects of the deficient endogenous androgens. In such
situations, T therapy alone is warranted. But in other situations of anabolic
deficiency such as catabolic wasting syndromes and administration of
glucocorticoids, agents that promote anabolism (nitrogen retention) in the
absence of androgenic effects are desirable. Although these agents were
originally called "anabolic steroids", no compound has yet been synthesized that
completely dissociates anabolic from androgenic effects. Therefore these agents
are still properly termed anabolic androgenic steroids (AAS). Interestingly,
subsequent investigations of various anabolic androgenic compounds have
demonstrated that many (but not all) of the compounds with very low affinity for
the androgen receptor have a more complete dissociation of androgenic and
anabolic effects (Saartok et al 1984, Dahlberg et al 1981). Since their relative
binding affinities can be as low as 0.01, the mechanism of action of anabolic
androgenic steroids might only be directly receptor dependent in a few
situations. These situations include extensive intracellular metabolism of the
low affinity anabolic androgenic compounds to high affinity compounds or
concentration dependent displacement of receptor bound T and DHT by the anabolic
androgenic compounds (Gustafsson et al 1984). In addition, even in the absence
of viable androgen receptors, these compounds exert androgen specific or
anabolic effects in various tissues of the body (Rommerts 1998). These
observations may offer indirect evidence for distinct androgen receptor
dependent (direct) and androgen receptor independent (indirect) mechanisms of
action for the various endogenous and exogenous anabolic androgenic steroids. In
fact, Rommerts et al propose that although distinct in some tissues, direct and
indirect androgen action may be closely linked in tissues sensitive to both
effects (Rommerts 1998). As androgen research becomes more advanced and focuses
on examining the androgen receptor, nuclear androgen response elements, and
androgen signaling, researchers are getting closer to the desired dissociation
of anabolic and androgenic effects.
Androgen Action - Direct and Indirect Mechanisms
Androgen action on target cells remains only partially characterized and
understood. Original investigators believed that androgens exerted their effects
only through a cytosolic androgen receptor present only in sex-dependent tissues
of the body. Today we know the situation to be more complex as both direct or
genomic effects as well as indirect or non-genomic effects have been uncovered
in nearly every tissue of the body. In addition, androgen receptors have been
localized in many tissues not thought to be androgen sensitive. Using
radioligand binding techniques, biochemical exchange assays, and
immunohistochemical techniques, it is clear that androgen receptors are present
in both cytosolic as well as nuclear cellular compartments (Sar et al. 1990).
Although androgens possess both genomic (direct) and non-genomic (indirect)
actions, it has been thought that the majority of their action is through direct
activation of DNA transcription via high affinity interactions with
intracellular androgen receptors (AR). At least it is though so because these
interactions have been studied in the most detail. Although receptor dependent
interactions may ultimately turn out to be quantitatively most important, as
androgen receptor independent actions continue to be uncovered, the importance
of these non-genomic interactions may shed new light on androgen's effects.
It has been demonstrated that some androgen sensitive tissues do not contain
nuclear androgen response elements (ARE). In addition, other androgen sensitive
tissues do not contain viable intracellular androgen receptors due to AR
insensitivity, the absence of AR, or AR blockade. As a result, it has been
hypothesized that endogenous androgens (T and DHT for example) may act
indirectly on cells without the presence of an AR. To this end, it is thought
that androgens might can act as mediators of secondary transcription factors;
that they might act in the regulation of autocrine and paracrine mediators of
gene expression; or that they might influence the secretion of other hormones
that mediate androgen effects in distant tissues (Verhoeven and Swinnen 1999).
In addition it is thought that some of these effects may be the result of plasma
protein bound androgen interaction with extracellular receptors (Rommerts 1998).
Some of the postulated non-genomic, AR-independent effects of androgens include:
-increases in both liver derived and locally produced IGF-I and IGF-I mRNA
(Arnold et al 1996, Mauras et al 1998)
-displacement of glucocorticoids from the glucocorticoid receptor and
interference of glucocorticoid binding to glucocorticoid response elements (Hickson
et al 1990,
Danhaive and Rousseau 1986, Danhaive and Rousseau 1988)
-the release of several autocrine "andromedins" including androgen induced
factor, schwannoma-derived growth factor, keratinocyte growth factor, and
growth factor, to name a few (Tanaka et al 1992, Sonoda et al 1992, Yan et al
-transmembrane influx of extracellular calcium (Koenig et al 1989, Lieberherr
Grosse 1994, Steinsapir et al 1991)
-activation of extracellular signal-related kinase cascades via binding to a
yet unidentified extracellular receptor (Peterziel 1998)
Although the indirect androgen actions discussed above are still subject to
speculation, the evidence for androgen receptor independent action is becoming
more impressive. Direct androgen action, on the other hand, is well
There is however some ambiguity as to whether androgen binds the AR in the
cytosol or in the nuclear membrane. Regardless, the AR is typically bound to
heat shock protein 90 that maintains the AR inactive state and the AR hormone
binding affinity (Fang et al 1996). Upon binding however, direct androgen action
is initiated as inhibitory heat shock proteins are released from the androgen
receptor. The AR is then phosphorylated and undergoes a conformational change
necessary for translocation and dimerization (Grino et al. 1987). Although in
the wild-type receptor, this ligand binding is necessary for transcriptional
activity, one in vivo receptor with a deleted ligand binding domain does posess
transcriptional activity. This may indicate that the unliganded binding domain
is actually a repressor of receptor action due to conformational constraints in
the unbound receptor possessing the ligand binding domain (Jenster et al 1991).
Once in the nucleus (either by direct binding there or by translocation), the
phosphorylated receptor is dimerized and binds to a DNA androgen response
element (ARE). The hormone response element, which is also bound by other
hormone receptors from this family, is a 15 base pair sequence responsible for
transcription initiation. Once bound, other transcription regulating proteins or
co-activators may also bind the AR-ARE complex to stabilize the promoter of the
regulated gene (Shibata et al 1997, Kang 1999). Such co-activators include
proteins such as ARA 54, ARA 55, ARA 70, ARA 160 (Yeh et al 1996, Hsiao et al
1999). This binding of such co-factors ultimately results in the regulation of
transcription rate. The resultant mRNA from androgen dependent transcription is
then processed and transported to ribosomes where it is translated into proteins
that can alter cellular function. Although the above mechanism is by far the
most predominant, in some tissues there is evidence for a ligand-independent
dependent activation of transcriptional activity via the AR. As mentioned above,
an unliganded receptor with a deletion of the ligand binding domain may possess
activity. This indicates activity in the absence of ligand binding. In addition,
growth factors (insulin-like growth factor, keratinocyte growth factor, and
epidermial growth factor) as well as protein kinase A activators might be able
to induce a transcriptionally active AR in the absence of ligand binding (Culig
et al 1995, Nazareth and Weigel 1996). Some of these ligand independent
transcription activators may act via influencing the AR phosphorylation state.
The Androgen Receptor
The androgen receptor is a member of the steroid receptor family of nuclear
transcription factors. This family is a group of structurally related nuclear
transcription factors that mediate the action of steroid hormones. The steroid
receptor family includes three other receptors including the glucocorticoid
receptor, the mineralocorticoid receptor, and the progesterone receptor (Beato
1989). Although there are several regions of each receptor that are heterologous,
the ligand-binding and DNA-binding domains are surprisingly highly conserved (Sheffeild-Moore
2000). In addition to their structural homology, these receptors also are
related by their ability to activate gene transcription via the same DNA hormone
response element (Quigley et al 1995).
There are two characterized forms of the androgen receptor. The first, and
predominant form, is a 110-114 kDa protein of 910-919 amino acids (Jenster et al
1991, Wilson et al 1992, Liao et al 1989). The second is a smaller 87 kDa
protein of about 720-729 amino acids in length that makes up only about 4-26% of
the detectible androgen receptors located in varying tissues (Wilson and McPhaul
1996). The relevance of this second form of receptor is unknown, but the
full-length receptor has been well-characterized. The isolation and
characterization of this form of the human androgen receptor cDNA has allowed
for sequencing of its amino acid constituents (Chang et al 1989).
The human androgen receptor is a single polypeptide comprised of four
discrete functional domains (Quigley 1998).
The A/B region is the N-terminal domain of the AR and comprises over half of
the receptor protein (residues 1-537). Within this domain is a transcription
activation region and several regions of homopolymeric amino acid stretches that
may be important in transcriptional regulation. These amino acid stretches may
also be important in interactions with other regions of the receptor protein and
in determining the three-dimensional structure of the receptor. Among the four
members of the steroid receptor family, this region is poorly conserved both in
length and sequence similarity (Evans 1988). The C region of the AR (residues
559-624) is the DNA binding domain. This region is composed of two folded "zinc
fingers" which each binding one zinc ion. The first zinc finger is responsible
for recognition of the target DNA sequence while the second stabilizes
DNA-receptor interaction by contact with the DNA phosphate backbone (Freedman
1992, Berg 1989). Between members of the steroid receptor family, this region is
the most highly conserved. At the overlap between the between the C and D
regions, there is a nuclear targeting sequence (amino acids 617-633) that is
responsible for androgen dependent translocation from the cytosol to the nucleus
(Jenster 1993). The D region, or hinge region (residues 625-669), seems to be
responsible for androgen dependent conformational changes of the AR. In
addition, one of the AR phosphorylation sites is located in this region (Zhou et
al 1995). Finally, the E region is the C-terminal domain of the androgen
receptor and is responsible for ligand binding. This region consists of about
250 amino acids (residues 670-920) and functions in specific, high affinity
binding of androgens. This region is also thought to be the binding site for
inhibitory proteins such as the 90 kDa heat shock protein that resides on the
inactivated AR. Transcriptional co-activators may also reside here (Jenster
The AR, as described above, has been identified in a vast array of genital and
non-genital tissues using several techniques including northern and western blot
analysis as well as immunohistochemical techniques. Most recently,
immunohistochemical techniques have become the predominant method of
characterization of both cellular and subcellular distribution of the AR due to
the sensitivity, specificity, and ease of the method (Ruizeveld De Winter et al
1991, Kadi et al 1999, Sar et al 1990). Using immunohistochemical techniques,
the AR has been clearly demonstrated in nearly all tissues (Janssen et al 1994,
Kimura et al 1993, Takeda et al 1990). As mentioned earlier, despite
characterization in both the cytosol and nucleus, the exact location of ligand
binding is not yet clear. The predominant model (shown above in figure 1)
however suggests that the cytosolic AR is inactive until it binds ligand. At
this point it it undergoes an appropriate conformational change and it is
transolcated to the nucleus via the nuclear targeting sequence (residues
617-633; Grino et al 1987, Jenster et al 1993, Zhou et al 1994). At this point,
it is able to undergo binding to the androgen response element.
Based on early studies, the AR has been identified as a high affinity, low
capacity receptor. Saturation binding analyses done using the androgen receptor
radiolabelled ligands [3H]-T, [3H]-methyltrienolone (MT), and [3H]-DHT have
shown saturability and therefore have been analyzed using scatchard plots
corrected for nonspecific binding. The results of such investigations have been
difficult to interpret however due to several confounding variables. First,
since the amount of AR protein seems to be very low, small experimental errors
will translate into large statistical errors. In addition, a significant amount
of non-specific binding is found in AR experiments (Snochowski et al 1979). If
this binding is not corrected for, then experimental errors could again be
large. Also, androgens (especially T and DHT but not MT) are subject to several
metabolic enzyme systems that differ between tissues. If uncontrolled, these
metabolic pathways could also confound results. For example, measurements of
apparent DHT binding to the AR may be underestimated due to metabolic conversion
to androstanediols that do not bind to the receptor while the measures for
apparent T binding could be overestimated due to formation of DHT which will
bind strongly to the receptor (Michel and Baulieu 1980). Finally, since Kd
values and Bmax values for the AR are variable with species, sex, age, and
androgen levels, controlling all variables relevant to the AR presents a
difficult proposition (Stahl et al 1978). As a result of the potential confounds
discussed, Kd values from 0.074nM up to 6.4nM and Bmax values from 1-30 fmol/mg
protein have been reported for the AR in various tissues using different
radiolabelled ligands. With this said, close inspection of the published
literature reveals that since different radiolabelled ligands have been used in
the research, since different cytosolic preparations have been employed, and
since different populations and species have been used, it only stands to reason
that variable results have been obtained.
In this review, I will discuss binding affinity and capacity in one tissue
(skeletal muscle) to simplify the discussion. Since skeletal muscle does not
possess significant amounts of the enzyme responsible for the conversion of T to
DHT (5alpha reductase), T is the predominant AR ligand. In research examining
the skeletal muscle AR using labeled T, the lack of metabolic conversion to DHT
helps to eliminate one potential confound. Other metabolic conversions using the
3alpha- and 3beta-hydroxysteroid dehydrogenases remain and can only be
controlled by the addition of ammonium sulfate to the cytosolic preparation to
eliminate the activity of these enzymes (Michel and Baulieu 1980). These two
precautionary measures, however are incomplete and the synthesis of
methyltrienolone (17 alpha-methyl-3-oxo-estra-4,9,11-trien-17 beta-ol), which
binds to the AR with the same affinity as T yet is not metabolizable, was of
greta value to AR binding studies. The use of labeled MT therefore has added
another element of control to AR studies.
Preliminary work by Michel and Baulieu using [3H]-T and [3H]-androstanolone (DHT)
ligands in enzyme-free preparations of castrate male and female rat quadriceps
femoris yielded similar Kd values for both ligands of approximately 0.70nM
(Michel and Baulieu 1980). These values are similar to several other reports of
T affinity in skeletal muscle. In another investigation using rat thigh
homogenates prepared with [3H]-T, Kd values of approximately 1nM and Bmax values
of 15-30 fmol/mg protein were found (Michel and Baulieu 1974). The Bmax values
in this experiment are higher than those reported anywhere else in the
literature for skeletal muscle. Krieg et al, using [3H]-androstanolone (DHT) in
rat muscle homogenates found a Kd range of 1.4nM to 6.4nM and 0.8-4.2 fmol/mg
protein (Krieg 1976). Krieg et al could not explain the reason for differences
between their work and the work of Michel and Baulieu but hypothesized that such
errors could potentially arise due to the very small amount of receptors in the
cytosol as well as the fact that these receptors are very difficult to isolate.
Later work by Saatok et al, using the nonmetabolizable [3H]- MT in rabbit
skeletal muscle cytosol preparations, found Kd values of 1.25-1.66nM and Bmax
values of 2.76-5.18 fmol/mg protein, potentially confirming the work of Krieg (Saatok
1984). Finally, work by Snochowski et al also using [3H]- MT in male and female
human skeletal muscle cytosolic preparations has indicated that Kd values for
the AR were approximately 0.074-0.7nM (mean of 0.28nM) while Bmax values were
1-4fmol/mg protein (Snochowski et al 1981). From these variable data it is
obvious that although the AR is clearly a high affinity and low capacity
receptor, useful and consistent quantitative data have not been obtained
regarding affinity and capacity in muscle. The differences in this literature
again could be due to the different radioligands used in the studies, different
ages and androgen levels in the subject populations, and amplified experimental
errors due to such small levels of detectible AR protein. To discuss skeletal
muscle in relation to the prostate, although variable results have been obtained
for prostate tissue as well, Bmax values seem to be about 10fold lower (per mg
protein) while Kd values are of a similar magnitude (Ekman et al 1979).
Androgen Metabolism and AR Binding
To further elaborate on the importance of androgen metabolism in the
determination of AR levels and, more importantly, in the mechanism of action of
androgens, a brief discussion of this subject is in order. T and DHT are the two
most potent androgens in the body however their relative importance in different
tissues varies. It is known that although the prostate AR can bind both T and
DHT, the affinity of the AR for T is only 33% of that for DHT (Grover et al
1975). In contrast, in skeletal muscle and kidney fractions, the binding
affinity for T is greater than that for DHT despite affinity for both ligands (Gloyna
and Wilson 1969, Bullock et al 1974). T itself is extensively metabolized in
most androgen-sensitive tissues. The predominant metabolite in the prostate, for
example, is DHT. Important in this metabolic pathway are the relative levels of
5alpha reductase and 3alpha- and 3-beta hydroxysteroid dehydrogenases. Since DHT
is the active metabolite in most tissues, high conversion of T to DHT via the 5
alpha reductase pathway and low metabolism of DHT via the 3 hydroxysteroid
dehydrogenase pathways is necessary for optimal androgen action (Rommerts 1999).
In skeletal musle, on the other hand, 5alpha reductase activity is low while
3alpha- and 3-beta hydroxysteroid dehydrogenase activity is higher leading to a
predomination of T and other inactive metabolites. In fact, in skeletal muscle,
less than 5% of T is metabolized (Minguell and Sierralta 1975). This is optimal
due to the fact that in skeletal muscle, the AR has a higher affinity for T than
for DHT. Interestingly, despite the differences between the metabolic pathways
for T as well as the differences in affinities for various T metabolites, the AR
appears to be nearly identical in structure across androgen sensitive tissues.
The differences in androgen action between tissues is now thought to be due to
DNA response elements as well as specific co-activators or repressors present in
the different tissues.
In conclusion, this review has discussed several relevant topics in androgen
pharmacology, physiology, and receptor theory. Although much is yet to be
discovered regarding androgen mechanism of action, the androgen receptor,
regulation of androgen receptor mediated transcription, and control of the
androgenic and anabolic effects of testosterone and its metabolites, new
discoveries are rapidly being reported. With investigations currently being
conducted to examine androgen receptor co-activator proteins as well as androgen
response element functions in a wide spectrum of tissues, manipulation of some
of the diverse actions of androgens can be postulated. And these discoveries may
contribute to the holy grail of androgen research; successful dissociation of
the anabolic and androgenic affects of androgens.
John M Berardi
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