International Union of Pharmacology. LXV. The Pharmacology and Classification of the Nuclear Receptor Superfamily: Glucocorticoid, Mineralocorticoid, Progesterone, and Androgen Receptors

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International Union of Pharmacology. LXV. The
Pharmacology and Classification of the Nuclear
Receptor Superfamily: Glucocorticoid,
Mineralocorticoid, Progesterone, and Androgen
Molecular Endocrinology Group, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National
Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina (N.Z.L., J.A.C.); Pharmacology
and Cancer Biology, Duke University Medical Center, Durham, North Carolina (S.E.W., D.P.M.); Department of Molecular and Cellular
Pharmacology, University of Miami Miller School of Medicine, Miami, Florida (K.L.B.); University of Pittsburgh School of Medicine,
Department of Pharmacology, Pittsburgh, Pennsylvania (D.D.); Prince Henry’s Institute of Medical Research, Clayton, Victoria, Australia
(P.J.F.); Royal Victoria Hospital, Molecular Oncology Group, Montreal, Quebec, Canada (V.G.); Yale University School of Medicine, New
Haven, Connecticut (R.B.H.); Bristol-Myers Squibb, Immune Cell Function Group, Princeton, New Jersey (L.M.); Universite´ Paris Sud,
Unite´ Mixte de Recherche, Centre National de la Recherche Scientifique 8612, Chatenay-Malabry, France (J.-M.R.); Department of
Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas (N.L.W.); and Departments of Pediatrics and Biochemistry
and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (E.M.W.)
The glucocorticoid receptor (GR
), mineralocorticoid
receptor (MR), progesterone receptor (PR), and andro-
gen receptor (AR) are classic members of the nuclear
receptor superfamily, composing subfamily 3C. Mem-
bers of this subfamily are among those receptors that
were cloned the earliest, with the GR being cloned in
1985 and the MR, PR, and AR shortly thereafter (Hol-
lenberg et al., 1985; Arriza et al., 1987; Misrahi et al.,
1987; Chang et al., 1988; Lubahn et al., 1988). Individ-
ually and in combination, these four receptors play piv-
otal roles in some of the most fundamental aspects of
physiology such as the stress response, metabolism, im-
mune function, electrolyte homeostasis, growth, devel-
opment, and reproduction.
Multiple signaling pathways have been established
for all four receptors, and several common mechanisms
have been revealed (Mangelsdorf et al., 1995). One main
signaling pathway is via direct DNA binding and tran-
scriptional regulation of responsive genes. Another is via
protein-protein interactions, mainly with other tran-
scription factors such as nuclear factor-
B, activator
protein-1, or signal transducer and activator of tran-
scriptions, to regulate gene expression patterns. Both
pathways can up-regulate or down-regulate gene ex-
pression. Both pathways require ligand activation of the
receptor and interplay with multiple protein factors
such as chaperone proteins and coregulator proteins
(Lonard and O’Malley, 2005).
These four steroid hormone receptors also exemplify
the tremendous capacity and precision of endocrine
modulatory mechanisms. Patients carrying mutated
receptors frequently experience severe complications,
and transgenic animals lacking individual receptors
frequently cannot reproduce and/or survive (Cole et
al., 1995, 2001; Lydon et al., 1995; Quigley et al., 1995;
Berger et al., 1998; Tajima et al., 2000; Bray and
Cotton, 2003; Sato et al., 2003; Sartorato et al., 2004;
Lin et al., 2005; Matsumoto et al., 2005). Temporally
controlled tissue distribution patterns during devel-
opmental stages, reproductive phases, and disease
states contribute to the diverse activities of these re-
ceptors. Recently, exciting new information has
emerged regarding these receptors, such as their
structures, domain interactions, coregulatory part-
Address correspondence to: Dr. John Cidlowski, Laboratory of
Signal Transduction, National Institute of Environmental Health
Sciences, National Institutes of Health, Department of Health and
Human Services, 111 TW Alexander Dr., P.O. Box 12233, Research
Triangle Park, NC 27709. E-mail:
Abbreviations: GR, glucocorticoid receptor; MR, mineralocorti
coid receptor; PR, progesterone receptor; AR, androgen receptor;
DBD, DNA-binding domain; LBD, ligand-binding domain; GRE, glu-
cocorticoid response element; AF, activation function; SRC-1, steroid
receptor coactivator 1; ACTH, corticotropin; CBG, corticosteroid-
binding globulin; CNS, central nervous system; SHBG, sex hormone-
binding globulin; HSP, heat shock protein; NCoR, nuclear receptor
Article, publication date, and citation information can be found at
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ners, multiple isoforms, post-translational modifica-
tions, and synthetic selective modulator ligands,
which show promise for new effective therapeutic ap-
The GR, MR, PR, and AR share structural similari-
ties, with all containing three functional domains, i.e.,
the N-terminal transactivation domain followed by the
DNA-binding domain (DBD) and the C-terminal ligand-
binding domain (LBD) (Mangelsdorf et al., 1995). A
hinge region links the DBD and the LBD. Compared
with the GR, the sequence identities of the N-terminal
domains of the MR, PR, and AR are 38, 24, and 16%, of
the DBDs are 94, 91, and 79%, and of the LBDs are 57,
54, and 51%, respectively (Hollenberg et al., 1985; Arriza
et al., 1987; Misrahi et al., 1987; Chang et al., 1988).
Overall sequence identities for each receptor among dif-
ferent species (human, rat, and mouse) are between 81
and 97%.
The crystal structure of the DBD was solved for the
GR (Luisi et al., 1991). The structures of the DBDs for
other receptors can be inferred on the basis of the high
degree of similarity of this domain among this group of
receptors. Several unique features contribute to the abil-
ity of the GR DBD to bind specifically to its target DNA
recognition sequences, termed glucocorticoid-response
elements (GREs). The GR DBD has a single globular
domain containing two perpendicular
helices, one of
which is responsible for specific DNA recognition and
together with the other
helix forms the cross-shaped
hydrophobic core of the DBD. At the N terminus of each
helix, a zinc ion coordinated by four cysteine residues in
a tetrahedral geometry holds the peptide loops. The
DBD, which is monomeric and unstructured in solution,
dimerizes in a head-to-head orientation when it binds to
DNA with the recognition helices of each DBD in adja-
cent major grooves of the DNA. This accounts for the
cooperative binding of two DBD domains to the GRE.
The precise chemistry of the protein-protein and the
protein-DNA interfaces has also been elucidated (Luisi
et al., 1991). The protein is anchored to the phosphate
backbone with seven contacts on either side of the major
groove. The DNA-recognition helix makes three van der
Waals contacts between a valine and the methyl group of
a thymine. Classic GREs consist of two hexameric in-
verted repeat half-sites separated by a 3-base pair
spacer. The sequence of the half-sites determines which
receptor can be recognized specifically. In nonspecific
binding, the contacts made between the receptor and
DNA are rearranged and fewer in number. In addition,
gene-specific GR-GRE interactions have been reported.
For example, it has been reported that a GR trimer
binds to the pro-opiomelanocortin promoter and exerts
transcription repression (Drouin et al., 1993); composite
GREs recruit additional transcription factors that deter-
mine the direction of GR-mediated transcription of the
proliferin gene (Diamond et al., 1990); GR forms a het-
erodimer with other steroid hormone receptors such as
MR (Calle et al., 2003; Funder, 1993; Trapp and Hols-
boer, 1996) and AR (Chen et al., 1997) on some other
The crystal structures for the LBD of the GR, MR, PR,
and AR have been made available through work from
several groups (Williams and Sigler, 1998; Matias et al.,
2000; Bledsoe et al., 2002, 2005; Kauppi et al., 2003;
Fagart et al., 2005; Li et al., 2005). Remarkable similar-
ities as well as some unique features have been identi-
fied, providing strong evidence for several important
aspects of receptor function including ligand selectivity,
receptor dimerization, and coactivator recruitment. One
of the common features of the LBDs of the GR, MR, PR,
and AR is the structural composition and organization.
Each LBD contains 11
helices (designated helix 1, 3, 4,
5, 6, 7, 8, 9, 10, 11, and 12) and four small
strands that
fold into a three-layer helical sandwich. The region be-
tween helices 1 and 3 is unstructured in the steroid
receptors, in contrast to the other nuclear receptors from
which the nomenclature derives. Helices 1 and 3 form
one side of the sandwich, and helices 7 and 10 form the
other side. The middle layer (helices 4, 5, 8, and 9) is
arranged at the upper half of the LBD, delimiting a
hydrophobic cavity underneath where the steroid mole-
cule is bound. Toward the C terminus, the activation
function (AF)-2 helix, helix 12 packs against helices 3, 4,
and 10 as an integrated part of the domain structure.
Following helix 12 is an extended
strand that forms a
sheet together with a
strand between helices 8 and 9.
Thus, the ligand-binding pocket has a scaffold framed by
multiple helices and the first two
strands. The cognate
steroid ligand for each receptor is completely buried
within the ligand-binding pocket. Three structural fea-
tures ensure ligand selectivity. First, the unique hydro-
gen bond network between the receptor and the bound
ligand establishes specific recognition between the cog-
nate ligand and receptor. For example, the MR ligand-
binding pocket contains a unique polar surface absent in
the other receptors, which is critical for specific binding
of aldosterone. Second, the shape of the steroid and the
topology inside the binding pocket enhance selectivity.
The GR ligand-binding pocket contains a branched side
pocket due to a proline residue in the linker between
helices 6 and 7, which is critical for high-affinity binding
of glucocorticoids to the GR. Third, the relative position
of the binding pocket within the receptor LBD plays a
role in ligand selectivity. Compared with the other re-
ceptors, the AR ligand-binding pocket seems to be
shifted up toward helices 1 and 3, which contributes to
selectivity of the AR for androgens. The relative position
of the ligand-binding pocket provides a structural basis
for the importance of residues outside of the pocket,
which are critical for the integrity of the LBD (Rogerson
et al., 1999).
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Another common feature of the LBD among steroid
receptors is the presence of the coactivator-binding cleft
on the surface of the LBD above the ligand-binding
pocket (Williams and Sigler, 1998; Matias et al., 2000;
Bledsoe et al., 2002; Li et al., 2005). This AF-2 binding
site is essential for the ligand-dependent recruitment of
a wide variety of coactivators that determine transcrip-
tional activity of the receptor. Specific charged residues
termed charge clamps and intermolecular interactions
facilitate relative cofactor selectivity by each receptor. A
common motif among the coactivators that interacts
with these charge clamp residues is the leucine-rich
LxxLL motif (Lonard and O’Malley, 2005). The AR, how-
ever, prefers FxxLF motifs and interacts with lower
binding affinity with the LxxLL-containing cofactors
such as steroid receptor coactivator 1 (SRC-1) (He et al.,
2002, 2004).
Structures of the N-terminal variable regions are not
available to date for any of the receptors in this subfam-
ily. Recent work from several laboratories suggests that
this domain possibly folds into an organized structure
and interacts with the C terminus of the receptor
through specific intra- and intermolecular interactions
(Langley et al., 1998; He et al., 1999; Tetel et al., 1999;
Rogerson and Fuller, 2003). A glutamine-rich region in
the AR N terminus is necessary and sufficient for re-
cruiting coactivators such as SRC-1 (Bevan et al., 1999).
Polymorphisms such as glutamine-rich tracts of abnor-
mal length in the AR result in molecular changes and
neurological disease (Poletti, 2004). Further work is
needed to shed light on the molecular organization of
this important domain that contributes to the transcrip-
tional activity of the receptor.
Endogenous Ligands and Their Functions
The major glucocorticoid in the human is cortisol, also
called hydrocortisone, whereas in rodents the major glu-
cocorticoid is corticosterone. The synthesis and secretion
of glucocorticoids by the adrenal cortex are tightly reg-
ulated by the hypothalamo-pituitary-adrenal axis,
which is sensitive to negative feedback by circulating
hormones and exogenous glucocorticoids. Healthy indi-
viduals secrete 10 to 20 mg of cortisol daily (Katzung,
2004; Goodman et al., 2006). The rate of secretion fol-
lows a circadian rhythm governed by pulses of pituitary
hormone corticotropin (ACTH). In plasma, cortisol is
bound to circulating proteins, such as corticosteroid-
binding globulin (CBG) that binds 90% of the circulating
hormone under normal circumstances. The remaining
cortisol is free or loosely bound to albumin and is avail-
able to exert its effects on target cells. CBG is increased
in pregnancy, by estrogen administration, and in hyper-
thyroidism. Synthetic glucocorticoids such as dexameth-
asone are largely bound to albumin rather than CBG.
GR is expressed in almost all tissues although tissue-
and cell cycle-specific regulation of GR levels have been
reported (Cidlowski et al., 1990; Oakley et al., 1996; Lu
and Cidlowski, 2005). Glucocorticoids exert a vast array
of physiological functions via the GR. Glucocorticoids are
important regulators of carbohydrate, protein, and fat
metabolism (Katzung, 2004; Goodman et al., 2006). In
the fasting state, glucocorticoids stimulate gluconeogen-
esis and glycogen synthesis via a variety of mechanisms
including increasing the production of enzymes critical
in gluconeogenesis, stimulating the release of amino
acids from muscles, promoting insulin resistance in the
peripheral tissues, and inhibiting adipokines such as
adiponectin. These processes protect glucose-dependent
tissues such as the brain and heart during starvation.
Glucocorticoids also profoundly modulate immune re-
sponses by regulating the activity of peripheral leuko-
cytes, by suppressing the production of cytokines and
chemokines, and by changing the life span of immune
cells. In addition, glucocorticoids are critical for the func-
tions of the central nervous system (CNS), digestive,
hematopoietic, renal, and reproductive systems. The de-
velopment of fetal lung is dependent on glucocorticoids.
The most physiologically important mineralocorticoid
is aldosterone. Aldosterone is synthesized in the adrenal
cortex primarily under the regulation of the renin-an-
giotensin system, potassium status, and ACTH. Aldoste-
rone is secreted at the rate of 100 to 200
g/day in
normal individuals with a moderate dietary salt intake
and does not seem to be tightly bound to serum proteins
(Katzung, 2004; Goodman et al., 2006). MR is expressed
in epithelial tissues, such as the distal nephron or colon
(Krozowski and Funder, 1983). Vectorial sodium reab-
sorption is driven by a mechanism coupling the apical
epithelial sodium channel to sodium-potassium ATPase,
the basolateral sodium pump. Both the epithelial so-
dium channel and Na
-ATPase subunit genes are
differentially regulated by aldosterone (Verrey et al.,
1987; Kolla et al., 1999; Amasheh et al., 2000; Epple et
al., 2000; Kolla and Litwack, 2000). Consequently, aldo-
sterone promotes the reabsorption of sodium from the
distal convoluted and cortical collecting renal tubules.
Sodium reabsorption in the sweat glands, salivary
glands, and gastrointestinal mucosa can also be in-
creased by aldosterone. Thus, aldosterone is a critical
regulator of serum sodium and other electrolytes and of
cardiovascular tone. Interestingly, MR expression and
function extend to nonepithelial cells such as hippocam-
pal and hypothalamic neurons, cardiomyocytes, the vas-
culature, and adipocytes, with studies reporting both
physiological and pathophysiological roles of MRs at
these additional sites emerging (de Kloet et al., 2000;
Funder, 2004). The MR is unique in that it is the recep-
tor for two physiological ligands, aldosterone and corti-
sol (or corticosterone in rodents). Both have a similar
affinity for MRs and, therefore, given the much higher
circulating concentration, cortisol might be expected to
exclusively occupy MRs. In epithelial and vascular tis-
sues this occupation is prevented by the presence of the
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enzyme 11
-hydroxysteroid dehydrogenase 2, which
converts cortisol to the inactive metabolite, cortisone.
Inhibition of this enzyme by mutation or ingestion of
inhibitors such as licorice or carbenoxolone results in
inappropriate MR activation and hypertension. In other
tissues such as the heart and selected areas in the CNS,
the MR may act as a receptor for cortisol.
Progesterone is the most important progestin in hu-
mans. It is synthesized in the ovary, testis, and adrenal
gland from circulating cholesterol. Large amounts are
also synthesized and released by the placenta during
pregnancy. In the ovary, progesterone is produced pri-
marily by the corpus luteum. In addition to having im-
portant hormonal effects, progesterone serves as a pre-
cursor in the synthesis of estrogens, androgens, and
adrenocortical steroids. Normal males seem to secrete 1
to 5 mg of progesterone daily (Katzung, 2004; Goodman
et al., 2006). The progesterone level is only slightly
higher in the female during the follicular phase of the
menstrual cycle. During the luteal phase of the cycle and
in the third trimester of pregnancy, the rate of proges-
terone secretion increases to 10 to 20 mg/day and to
several hundred milligrams during the latter part of
pregnancy. In plasma, 90% or more of total progesterone
is bound by albumin and CBG. PR is expressed in the
female reproductive tract, mammary gland, brain, and
pituitary gland (Mangal et al., 1997; Soyal et al., 2005).
In many cells, estrogens induce expression of PR, and its
presence is a common marker for estrogen action in both
research and clinical settings. In many biological sys-
tems, progestins enhance differentiation and oppose the
cell proliferation action of estrogens. The unequivocal
roles of progesterone in a variety of events such as ovu-
lation, implantation, mammary gland development,
maintenance of pregnancy, and behavior are well estab-
lished. Progesterone also increases the ventilatory re-
sponse of the respiratory centers to carbon dioxide and
decreases arterial and alveolar P
in the luteal phase
of the menstrual cycle and during pregnancy. Progester-
one has depressant and hypnotic actions in the CNS,
which may be mediated via inhibitory neurotransmitter
receptors. Accumulating data indicate a role for proges-
terone in male reproductive events (Gadkar-Sable et al.,
In humans, the predominant androgen secreted by the
testis is testosterone. In men, 8 mg of testosterone is
produced daily (Katzung, 2004; Goodman et al., 2006).
In women, 0.25 mg of testosterone is synthesized by the
ovary and by peripheral conversion of androstenedione
produced by the adrenal gland. Alterations in plasma
concentrations of testosterone and androstenedione oc-
cur during the menstrual cycle. In some ovarian disor-
ders, androgens secreted by the ovary can be elevated,
resulting in partial virilization. The concentration of
testosterone in the plasma of males is relatively high
during three periods of life: during embryonic develop-
ment, during the neonatal period, and from puberty
throughout adult life. The androgen concentration starts
to rise in male embryos in approximately the 8th week of
development and declines before birth. Androgen rises
again during the neonatal period and then falls to typi-
cal prepubertal values within the first year of life.
Plasma testosterone increases again at the time of male
puberty and is maintained at the adult level until it
declines gradually in senescence. Approximately 40 to
65% of circulating testosterone is bound to sex hormone-
binding globulin (SHBG). SHBG is increased in plasma
in response to estrogen and thyroid hormone and in
patients with cirrhosis of the liver. SHBG levels are
decreased by androgen and growth hormone and are
lower in obese individuals. Most of the remaining tes-
tosterone is bound to albumin. Approximately 2% re-
mains free and available to enter cells and bind to in-
tracellular AR. In AR-target tissues such as prostate
and skin, testosterone is reduced at the 5
position to
5-dihydrotestosterone, which serves as the active hor-
mone (Auchus, 2004). Unlike other steroid receptors, AR
is stabilized by high-affinity binding of testosterone or
5-dihydrotestosterone that induces the N-terminal
FxxLF motif binding to the AF-2 in the LBD (Langley et
al., 1998; He et al., 1999). 5-Dihydrotestosterone disso-
ciates more slowly than testosterone from AR and
thereby more effectively stabilizes the AR complex.
Androgens serve critical functions at different stages
of life in the male (Katzung, 2004; Goodman et al., 2006).
During embryonic life, androgens virilize the urogenital
tract of the male embryo, and their action is thus essen-
tial for the development of the male phenotype. Lack of
a fully functioning AR due to naturally occurring muta-
tions in the male fetus results in incomplete male geni-
tal development or a female external phenotype (Quigley
et al., 1995). The role of the neonatal surge of androgen
secretion is not well defined, but it may contribute to
developmental functions within the CNS. At puberty,
androgens stimulate the development of secondary sex-
ual characteristics. The growth-promoting properties of
androgen increase height and the development of the
skeletal musculature. In addition to stimulating and
maintaining sexual function in men, androgens may also
be responsible in part for aggressive behaviors. Andro-
gens have critical physiological roles in women as well.
Testosterone and androstenedione are precursors for es-
trogen biosynthesis; testosterone and 5-dihydrotester-
one also produce androgenic effects via the AR.
Therapeutic Uses and Limitations
For several years, compounds targeting GR functions
have been among the most frequently prescribed drugs.
This is mainly due to immunomodulatory actions of glu-
cocorticoids and their use in infections, allergies, eye
diseases, hematological disorders, pulmonary diseases,
skin diseases, inflammatory conditions of bones and
joints, and acute respiratory distress syndrome (Kat-
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zung, 2004; Goodman et al., 2006). In addition, glucocor-
ticoids are a key to treating certain leukemias and are
frequently included in chemotherapy regimens for their
antiemetic, antiedema, and palliative properties. GR
agonists are also the mainstay in the management of
congenital adrenal hyperplasia and Addison’s disease
(adrenal insufficiency), in diagnostic tests for Cushing’s
syndrome (adrenal hyperfunction), and in certain psy-
chiatric conditions. Furthermore, glucocorticoids are the
treatment of choice for impending premature parturi-
tion to accelerate neonatal lung maturation. RU-486, a
potent GR antagonist, causes generalized glucocorticoid
resistance. In Cushing’s syndrome caused by ectopic
ACTH production or adrenal carcinoma, RU-486 can
reverse the symptoms, ameliorate glucose intolerance,
and normalize blood pressure. Multiple mechanisms
contribute to the antagonistic actions of RU-486 with the
GR (Rhen and Cidlowski, 2005). Binding of RU-486 with
GR stabilizes the heat shock protein (HSP)-GR complex
and alters the interaction of GR with coregulators,
which together result in the formation of transcription-
ally inactive GR molecules.
Prolonged glucocorticoid therapy causes serious side
effects (Rhen and Cidlowski, 2005). Osteoporosis, meta-
bolic syndrome, impaired development, and blunted
growth all limit chronic use of glucocorticoids. Patients
receiving long-term glucocorticoid treatment experience
redistribution of body fat from the extremities to the
trunk and face. Neural and psychological disturbances,
such as psychosis, depression, and euphoria, can occur.
To reduce these untoward actions of glucocorticoids, the
lowest dosage with therapeutic efficacy, intermittent ad-
ministration, and localized routes of administration
have been implemented with some success (Buttgereit et
al., 2005).
Dysregulation of the MR-aldosterone system reveals
its importance in various human pathological conditions
such as mineralocorticoid resistance, disorders of the
CNS, hypertension, and cardiac failure (Katzung, 2004;
Goodman et al., 2006). MR agonists such as fludrocorti-
sone are used in the treatment of adrenal insufficiency.
MR antagonists such as spironolactone and eplerenone
are used for the treatment of hypertension, excess urine
protein excretion, and heart failure. The potassium-
sparing properties of spironolactone and eplerenone can
be life-threatening if hyperkalemia develops (Sica,
The two most frequent uses of progestins are for con-
traception, either alone or with an estrogen in oral con-
traceptives, and for hormone replacement therapy when
combined with estrogen in postmenopausal women (Kat-
zung, 2004; Goodman et al., 2006). Progestins are also
used in several settings for ovarian suppression, e.g.,
dysmenorrhea, endometriosis, hirsutism, and uterine
bleeding. In addition, progesterone can be used diagnos-
tically to test for estrogen secretion and for responsive-
ness of the endometrium. Progestins have been used as
a palliative measure for metastatic endometrial carci-
noma and in the treatment of renal and breast carci-
noma. The presence of the PR is considered a useful
prognostic marker in breast cancer irrespective of the
patient’s progestational status. Contraception with pro-
gestins is useful in patients with hepatic disease, hyper-
tension, psychosis, or mental retardation. The side ef-
fects include headache, dizziness, weight gain, and
glucose intolerance. Recent studies suggest that certain
progestin plus estrogen replacement regimens in post-
menopausal women may increase the incidence of breast
cancer, a finding that may promote the development of
improved hormone replacement therapy (Rossouw et al.,
The GR antagonist RU-486 is also a potent PR antag-
onist. RU-486 binds to PR with high affinity and can
terminate pregnancy (Schreiber and Creinin, 2005). RU-
486 has effects on ovulation as well. If given acutely in
the mid to late follicular phase of the menstrual cycle,
RU-486 delays follicle maturation and the luteinizing
hormone surge, and ovulation occurs later than normal.
If the drug is given intermittently or continuously, ovu-
lation is prevented in most but not all cases. These
effects are largely due to actions on the hypothalamus
and pituitary rather than the ovary. RU-486 may pro-
duce effects on the cervix, myometrium, ectopic endome-
trial tissue (i.e., endometriosis), certain types of breast
cancer, and meningiomas via its antiprogestin activity.
RU-486 has been used as a postcoital contraceptive, and
it may be slightly more effective than high-dose estro-
gen-progestin combinations. The mechanism of action in
this case is thought to be prevention of implantation.
Other investigational or potential uses for RU-486 in-
clude the induction of labor after fetal death or at the
end of the third trimester and treatment of endometri-
osis, leiomyoma, breast cancer, and meningioma. The
antiprogestin activity of RU-486 is mediated by binding
to the PR (Wardell and Edwards, 2005). Binding of RU-
486 induces a conformational change in the PR LBD
that facilitates the dissociation from heat shock protein
complexes, dimerization of the receptor, and cooperative
binding to hormone response elements in target genes
(Gass et al., 1998). The distinct conformational changes
in the receptor LBD induced by RU-486 inhibit coacti-
vator recruitment but facilitate receptor interaction
with corepressors including nuclear receptor corepressor
(NCoR) and silencing mediator of retinoic acid and thy-
roid receptors (Wagner et al., 1998). RU-486 binding to
PR also disrupts an intramolecular interaction between
the N and C domains that has been shown to be required
for maximal activity of the agonist-occupied receptor
(Tetel et al., 1999). Detailed structure-function studies
have also revealed that RU-486 binding may recruit
RU-486-specific corepressors to specific residues in the
receptor C-terminal tail (Vegeto et al., 1992; Xu et al.,
1996). In addition, RU-486-bound receptors counteract
agonist-bound receptors via formation of inactive het-
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erodimers (Meyer et al., 1990; Leonhardt et al., 1998).
Via these mechanisms, RU-486 acts as a potent antag-
onist for PR. RU-486 can also be a partial agonist for
both PR and GR when selective coregulators are re-
cruited (Jackson et al., 1997; Schulz et al., 2002). Other
PR antagonists such as ZK 98299 have been developed.
However, none of these compounds has been used exten-
sively in the clinical setting because of toxicity.
Androgen therapy is primarily used in male hypogo-
nadism, in aging, and in attempts to reverse protein loss
after trauma, surgery, or prolonged immobilization
(Katzung, 2004; Goodman et al., 2006). Androgens are
also used in boys with delayed puberty, and the weak
androgen danazol is used in women with endometriosis.
The principal clinical application of AR antagonists such
as flutamide, nilutamide, or bicalutamide is in the treat-
ment of prostate cancer, usually in conjunction with
long-acting luteinizing hormone-releasing hormone an-
alogs. Androgen blockade usually decreases the volume
of the primary and metastatic lesions by inducing apo-
ptosis (Kyprianou et al., 1990). Despite the initial re-
sponse to antiandrogen therapy, however, an androgen-
refractory status with a fatal outcome frequently
develops (Isaacs, 1999). Recurrent prostate cancer
seems to result from increased AR signaling caused by
increased AR expression in the presence or absence of
AR gene amplifications (Koivisto et al., 1997), increased
expression of enzymes that convert adrenal androgens
to testosterone (Stanbrough et al., 2006), AR mutations
(Tan et al., 1997; Taplin et al., 1999; Marcelli et al.,
2000; Feldman and Feldman, 2001; Gregory et al.,
2001), or AR activation in a ligand-independent manner
(Craft et al., 1999). The onset of recurrent prostate can-
cer seems to involve increased AR-dependent growth
factor signaling that overcomes apoptosis induced by
androgen depletion (Ruijter et al., 1999; Feldman and
Feldman, 2001). The aim of continued research in this
area is to improve the prognosis for patients with pros-
tate cancer.
Adverse effects of androgen treatment in women in-
clude hirsutism, acne, amenorrhea, clitoral enlarge-
ment, and deepening of the voice (Katzung, 2004;
Goodman et al., 2006). Androgen replacement or perfor-
mance-enhancing steroid use in men may cause sleep
apnea, polycythemia, azoospermia, a decrease in testic-
ular size, aggression, and psychosis. On the other hand,
androgen blockade used in treating prostate cancer can
be accompanied by hot flushes, loss of libido and sexual
potency, and bone loss and osteoporosis (Labrie et al.,
In 1849, Berthold showed that the transplantation of
gonads into castrated roosters prevents the typical signs
of castration and published the first experimental evi-
dence for the effect of an endocrine gland (Klein, 1968).
More than a century later, the first steroid receptor was
cloned (Hollenberg et al., 1985). In the past 20 years,
tremendous progress has been made in our understand-
ing of the fundamental mechanisms of the intracellular
steroid hormone receptors. Continued effort by research-
ers in the field is paving the way for more efficient and
specific therapeutic approaches via modulation of the
GR, MR, PR, and AR. Although each of these receptors is
encoded by a single gene, recent evidence suggests that
multiple GR, MR, and PR receptor isoforms are pro-
duced (Kastner et al., 1990; Pascual-Le Tallec et al.,
2004; Lu and Cidlowski, 2005). Via both transcriptional
and translational mechanisms, the GR gene, for in-
stance, produces a minimum of 16 GR proteins with
distinct functions and tissue distribution patterns (Lu
and Cidlowski, 2005). These receptor isoforms increase
the number of molecular targets underlying diseases. In
addition, alternative signaling pathways of steroid hor-
mone receptors are being investigated. The ability of the
GR to change the half-lives of certain mRNAs, notably
via interaction with specific signals in the untranslated
regions, has been recognized as a potentially important
anti-inflammatory mechanism (Mozo et al., 1998; New-
ton et al., 1998). Steroid receptors localized on cell mem-
branes, such as the PR on spermatozoa, can also trigger
multiple signaling pathways to affect cell function (Gad-
kar-Sable et al., 2005). Another important aspect of con-
tinuing research is the development of selective modu-
lators of these receptors that are capable of maintaining
the beneficial responses mediated by each receptor while
reducing unwanted side effects (Chang and McDonnell,
2005). For example, an ideal selective GR modulator
would have therapeutic actions in specific tissues or
would have the ability to dissociate transactivation and
transrepression effects of GR, an ideal selective PR mod-
ulator would have antiproliferative effects on the endo-
metrium and breast but would not oppose the protective
effects of estrogen on bones and the cardiovascular sys-
tem (Smith and O’Malley, 2004; Chwalisz et al., 2005),
and selective AR modulators could be effective therapies
in treating prostate cancer. Thus, exciting new avenues
are being discovered by studies of the classic steroid
hormone receptors.
Tables 1 through 4 summarize the functions, biologic
activities, structural properties, and ligands of GR, MR,
PR, and AR, respectively.
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Receptor nomenclature NR3C1
Receptor code 4.10.1:GC:3:C1
Other names GCCR, GCR, GRL
Molecular information Hs: 777aa, P04150, chr. 5q31-q32
Rn: 795aa, P06536, chr. 18p12
Mm: 783aa, P06537, chr. 18 B3
DNA binding
Structure Homodimer
HRE core sequence GGTACANNNTGTTCT (GRE, half-site, palindrome)
Partners HSP90 (physical, functional): cellular localization
; HMGB (physical, functional): DNA
; AP-1 (physical, functional): transactivation
; NF-
B (physical, functional):
; 14-3-3
(physical, functional): cellular localization, transactivation
Agonists Dexamethasone (1–8 nM),* triamcinolone acetonide (6 nM),* prednisolone (15 nM),
triamcinolone (20 nM), cortisol (10–50 nM),* corticosterone (60 nM),* desoxycorticosterone
(70 nM) IC
Antagonists RU-486 (0.4 nM)* K
Corepressor BAG1
Biologically important isoforms GR
{Hs, Mm, Rn}: main isoform
{Hs}: widely expressed alternative splicing variant
lacking ligand binding, associated with several diseases
; GR-A, B, C, D {Hs, Mm, Rn}:
alternative translation initiation isoforms with distinct transcriptional activities and tissue
distribution patterns
Tissue distribution Ubiquitous {Hs, Mm, Rn} Northern blot, Q-PCR, in situ hybridization, Western blot
Functional assay Suppression of endogenous cortisol level by exogenous dexamethasone {Hs}
; apoptosis of
thymocytes in the thymus {Rn}
; elevated blood glucose level by intravenous injection of
glucocorticoids {Hs}
Main target genes Activated: PEPCK-C {Hs},
MKP-1 {Mm},
lipocortin-1 {Hs},
; repressed: PEPCK-C {Hs},
IL-8 {Hs},
Mutant phenotype GR
mice die within hours because of respiratory failure; they have atelectatic lungs,
impaired liver function, impaired HPA axis, increased plasma levels of ACTH and
corticosterone and enlarged adrenal glands that produce no adrenaline {Mm} knockout
mice expressing type II GR antisense RNA exhibit impaired T-cell function, disrupted HPA
axis, increased plasma levels of ACTH and corticosterone, reduced GR binding, and
alterations in thymocyte migration {Mm} antisense oligonucleotide
Human disease Glucocorticoid resistance: due to various SNPs
; glucocorticoid hypersensitivity: due to an
N363 polymorphism
; asthma: due to a receptor mutation
; acute childhood
lymphoblastic leukemia: due to a receptor mutation
aa, amino acids; chr., chromosome; HRE, hormone response element; RXR, retinoid X receptor; HMGB, chromosomal high-mobility group B; NK-
B, nuclear factor-
PPARBP, peroxisome proliferator-activated receptor binding protein; Q-PCR, quantitative polymerase chain reaction; HPA, hypothalamo-pituitary-adrenal; ACTH, adre-
nocorticotropin; SNP, single-nucleotide polymorphism; GRE, glucocorticoid response element; CREBBP, cAMP response element binding protein binding protein.
* Radioligand.
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Receptor nomenclature NR3C2
Receptor code 4.10.1:MC:3:C2
Other names MR, MCR, MLR, aldosterone receptor
Molecular information Hs: 984aa, P08235, chr. 4q31.1
Rn: 981aa, P22199, chr. 19q11
Mm: 978aa, Q8VII8, chr. 8 C1
DNA binding
Structure Homodimer, heterodimer
HRE core sequence ACAAGANNNTGTTCT (GRE, half-site, palindrome)
Partners HSP90 (physical, functional): cellular localization
; HMGB (physical, functional): DNA
-HSD2 (functional): tissue specificity
Agonists Desoxycorticosterone (1 10
M), progesterone (1 10
M),* fludrocortisone (1.2 10
M), cortisol (1.1–1.5 10
M), dexamethasone (1 10
M)* IC
; aldosterone (1–1.5
)* K
Antagonists Drospirenone (1 10
M), spironolactone (1.4 10
M), eplerenone (1 10
Coactivator NCOA1, PGC-1
Corepressor NCOR1, NCOR2, PIAS1
Biologically important isoforms MR-A {Hs, Mm, Rn}: main isoform
; MR-B {Hs, Mm, Rn}: truncated N terminus
; various
splice variants also exist resulting in either altered DNA or ligand binding {Hs, Rn}
Tissue distribution Liver, brain, heart, kidney, colon, aorta, hippocampus, hypothalamus, adrenal fasciculate,
epidermal keratinocytes, neurons of the CNS, cardiac myocytes, endothelial and smooth
muscle cells of the vasculature {Hs,Mm,Rn} Northern blot, Q-PCR, in situ hybridization,
Western blot, immunohistology
Functional assay Renal clearance {Mm}
; colonic transepithelial Na
reabsorption {Mm}
Main target genes Activated: Enac {Hs},
Mutant phenotype Homozygous MR-deficient mice have a normal prenatal development; during the 1st week of
life, these animals develop symptoms of pseudohypoaldosteronism, lose weight, and
eventually die at around day 10 due to kidney failure {Mm} knockout
; a conditional
knockout model expressing solely in the heart an antisense mRNA directed against the
murine MR; within 2–3 months, mice develop severe heart failure in the absence of
hypertension or chronic hyperaldosteronism {Mm} antisense oligonucleotide
Human disease Hypertension: Ser
3 Ile SNP causes gain of function
; pseudohypoaldosteronism type 1:
various polymorphisms cause loss of activity; autosomal-dominant; haploinsufficiency seems
to be the predominant mechanism
aa, amino acids; chr., chromosome; HRE, hormone response element; ELL, eleven-nineteen lysine-rich leukemia; HMGB, chromosomal high-mobility group B; 11
-hydroxysteroid dehydrogenase 2; Q-PCR, quantitative polymerase chain reaction; SNP, single-nucleotide polymorphism; GRE, glucocorticoid response element.
* Radioligand.
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