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J Appl Physiol
91: 1854–1859, 2001.
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Genome and Hormones: Gender Differences in Physiology
Historical Perspectives: An abridged history
of sex steroid hormone receptor action
STACEY A. FANNON, REGINA M. VIDAVER, AND SHERRY A. MARTS
Society for Women’s Health Research, Washington, District of Columbia 20036
Received 1 June 2001; accepted in final form 25 July 2001
estrogen; progesterone; androgen; coactivators; corepressors
in various aspects of
growth, development, differentiation, reproduction,
and homeostasis. They exert their effects by means of
steroid hormone receptors, such as estrogen (ER), progesterone (PR), androgen (AR), glucocorticoid (GR),
and mineralocorticoid receptors. Steroid hormone receptors belong to the steroid/thyroid hormone receptor
superfamily, which includes thyroid hormone (TR),
retinoic acid (RAR), and vitamin D3 receptors, as well
as “orphan” receptors [e.g., ER-related-1 (ERR-1),
ERR-2, and chicken ovalbumin upstream promoterSTEROID HORMONES ARE INVOLVED
Address for reprint requests and other correspondence: R. M. Videaver, Society for Women’s Health Research, 1828 L St. NW, Suite 625
Washington, DC 20036 (E-mail: [email protected]).
1854
transcription factor], for which no ligands have yet
been found.
All members of the steroid and thyroid hormone
receptor superfamily share similar structure consisting of modular domains A through F (from NH2 to
COOH terminus; Ref. 38). Each receptor contains a
unique A/B region, which is variable in length and
sequence between the receptors. The A/B region allows
for protein-protein interactions and transcriptional activation of target genes. The cysteine-rich C region
contains two zinc fingers important for DNA binding
and receptor dimerization. In some receptors, region D
contains the nuclear localization signal and/or a transactivation domain. The E region is responsible for
several functions, including ligand binding, heat shock
protein (HSP) association, receptor dimerization, nuclear localization, hormone-dependent transactivation,
and, in some cases, transcriptional repression. The F
region is present in few receptors and exhibits minimal
regulatory function (38).
This brief historical perspective on steroid hormone
action focuses on the discovery and elucidation of the
mechanism by which the sex steroid hormones (estrogens, progesterone, and androgens) affect gene expression through direct interaction with nuclear DNA and
transcription machinery by means of steroid hormone
receptors. We have chosen to limit discussion to the sex
steroid hormones because they are the significant players in the development of female- and male-specific
traits. Although much research on the sex steroid hormones has focused on their role in reproduction, a
recent report issued by the National Academy of Sciences Institute of Medicine (IOM; 40) found that differences between the sexes go well beyond the reproductive system and secondary sex characteristics, to
include nearly every tissue and organ in the body. For
example, men and women often exhibit different symptoms when having a heart attack, women are more
likely than men to recover language abilities after a
left-hemisphere stroke, and women are more likely to
suffer from autoimmune diseases in general (40).
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Fannon, Stacey A., Regina M. Vidaver, and Sherry A.
Marts. Historical Perspectives: An abridged history of sex
steroid hormone receptor action. J Appl Physiol 91:
1854–1859, 2001.—The field of steroid hormone action is well
established, although it is barely more than four decades old.
Pivotal experiments in the late 1950s and 1960s showed that
hormone-binding components exist within nuclei of target
tissues and that steroid hormones act by regulating gene
expression, rather than directly influencing enzymatic processes. The understanding that steroid hormone receptors
interact with the general transcription machinery and alter
chromatin structure came in the 1970s and 1980s, and details of this mechanism continue to be elucidated. In addition, the discovery of rapid cellular responses to steroid
hormones has led to the identification of putative membranebound steroid receptors that act without affecting gene transcription. As noted in the recent Institute of Medicine report
Exploring the Biological Contributions to Human Health:
Does Sex Matter?, the effects of steroid hormones and defects
in steroid hormone receptor action have a profound impact on
human health and disease. Future research directives include the development of potent, selective steroid receptor
modulators, the elucidation of nongenomic steroid hormone
effects, and further exploration of hormone-genome interactions.
HISTORICAL PERSPECTIVES
1855
Moreover, the effects of sex steroid hormones begin
during embryonic development and continue through
the life span, from “womb to tomb,” as the IOM report
describes it. Thus understanding the roles of the sex
steroid hormones during development, in normal physiological processes, and in the etiology and progression
of diseases is essential to advancing human (and animal) health. This historical perspective provides a general overview and abridged history of the burgeoning
field of steroid receptor action. Because of space limitations, reviews are predominantly cited instead of
primary references. The reader is urged to refer to
these reviews for more detailed accounts.
The late 1960s and early 1970s brought an explosion
of research on steroid hormone receptors. In 1972,
O’Malley’s laboratory was the first to purify a steroid
hormone receptor, PR from chicken, to near homogeneity. Interestingly, they discovered two isoforms,
PR-A and PR-B. PR-B is ⬎100 amino acids longer (NH2
terminus) than PR-A, but otherwise the two isoforms
are identical. This finding is consistent between species, with the exception of rabbit, in which PR exists as
a single form (35). Soon after the purification of PR,
ER and AR were purified, although it was not until
1996 that a second form of ER, ER-␤, was discovered
(11, 23).
THE BIRTH OF THE FIELD OF STEROID
HORMONE ACTION
THE MOLECULAR BIOLOGY REVOLUTION
J Appl Physiol • VOL
Molecular elucidation. With the advent of recombinant DNA and DNA sequencing technologies in the
mid 1970s came the ability to characterize the steroid
hormone receptors and their target genes in more detail. O’Malley’s laboratory was the first to clone (1977)
and sequence (1978) a target gene for steroid hormones, ovalbumin from chicken, and soon after came
the discovery by Pierre Chambon’s laboratory that the
gene contains exons and introns (25). Cloning of the
first steroid hormone receptor (GR) occurred in 1985
through a collaboration between Ronald Evans’, Michael Rosenfeld’s, and Brad Thompson’s laboratories.
Shortly after this milestone, the receptors for estrogen
(1986; now known to be ER-␣), progesterone (1987),
and androgen (1988) were cloned. In humans, the ER-␣
gene resides on chromosome 6, whereas ER-␤ is on
chromosome 14 (11). Human PR localizes to chromosome 11 (18), and the AR gene resides on the X chromosome, underscoring its necessity for female, as well
as male, development (28).
Cloning of PR also allowed for the understanding of
how the A and B isoforms are derived from the same
gene. Interestingly, different species accomplish this
feat via different methods, with the chicken isoforms
arising as a result of different translation start sites
within the same transcript, and the human isoforms
occurring via different transcription start sites (35).
A model emerges. Through the work of a number of
laboratories in the 1980s and early 1990s, a model for
steroid receptor action at the level of the gene began to
emerge. In 1983, Keith Yamamoto’s and Jan-Åke
Gustaffson’s laboratories demonstrated for the first
time that a steroid hormone receptor (GR) binds DNA
in a sequence-specific manner. The receptor binding
site, now termed the steroid response element (SRE), is
located upstream of steroid hormone-regulated promoters. In general, SREs are 15-base pair consensus
sequences consisting of two half sites, arranged as
6-base pair inverted repeats separated by a few random base pairs. The SREs for various receptors exhibit
significant sequence similarity, with SREs for GR, PR,
and AR oftentimes being identical (26). In 1988,
O’Malley’s laboratory was able to show that receptors
bind the SREs cooperatively as dimers, with one receptor molecule at each half site (26). In vitro experiments
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Pivotal experiments performed in the late 1950s and
early 1960s, primarily in the laboratories of Gerald
Mueller and Elwood Jensen, set the stage for the development of the field of steroid hormone action. Jensen’s laboratory showed that tritiated estradiol was
specifically taken up and retained in the immature rat
uterus, indicating the presence of an “estrogen-binding
component” or “estrophilin,” later termed “estrogen
receptor” by Jensen (14, 25). This was the first time
that target tissue specificity was observed for a natural
hormone. Also during this period, Mueller’s laboratory
reported that estrogen treatment induced RNA and
protein synthesis. Later, Mueller was able to show that
all known uterine responses to estradiol were blocked
when either RNA or protein synthesis was inhibited,
showing that transcription and translation were required for estradiol’s effects (14).
In the mid 1960s, Jack Gorski’s laboratory showed
that tritiated estradiol bound to the estrogen-binding
component and that this complex could be solubilized
from rat uterus cell nuclei. Jensen, Gorski, and others
then showed that, after estradiol treatment, estradiol
traveled from the cytosol to the nucleus (14, 25). For
many years, it was thought that ER bound estrogen in
the cytoplasm and was then translocated to the nucleus. However, it is now known that ER is a nuclear
factor that initiates interaction with estrogen in the
nucleus (20). The same holds true for PR, although
other members of the steroid/thyroid hormone receptor
superfamily appear to have both nuclear and cytoplasmic localization (4).
In the mid to late 1960s, researchers concluded that
steroid hormones regulate gene expression (through
interaction with cognate receptors), rather than influencing enzymatic metabolism. In 1966, Gorski and
Angelo Notides collaborated to show that estradiol
treatment resulted in the synthesis of a specific uterine
protein (24). Subsequently, Bert O’Malley’s laboratory
demonstrated steroid-mediated mRNA induction of
ovalbumin in response to estrogen and of avidin in
response to progesterone (25). The 1960s culminated
with the first Gordon Conference on Hormone Action,
establishing steroid hormone action as a legitimate
and growing field of research (25).
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HISTORICAL PERSPECTIVES
REFINING THE MODEL
Coactivators. In 1989, experiments performed in the
laboratories of both O’Malley and Hinrich Gronemeyer
showed that overexpression of one steroid hormone
receptor results in the inhibition of itself or other
steroid hormone receptors. These experiments suggested that other limiting factors, termed “coactivators,” might modulate transactivation by steroid hormones. These coactivators are thought to function as
bridging factors that, directly or indirectly, facilitate
the crucial protein-protein interactions between the
steroid hormone receptor and the general transcription
J Appl Physiol • VOL
machinery to ensure efficient transcription of target
genes (38). In addition, several coactivators have been
shown to either possess, or interact with proteins that
possess, histone acetyltransferase (HAT) activity (31).
By facilitating chromatin remodeling, HAT proteins
may enhance the formation of stable preinitiation complexes and thus increase transcription of target genes.
Both general coactivators, as well as receptor-specific coactivators exist. Two general coactivators, steroid receptor coactivator-1 (SRC-1) and cAMP response
element binding protein-binding protein (CBP), enhance the transcriptional activities of several steroid/
thyroid hormone receptors (38). SRC-1 was identified
in 1995 by O’Malley’s laboratory and was shown to
enhance the transcriptional activity of all steroid hormone receptors tested, without altering basal promoter
activity. In 1996, William Chin’s laboratory showed
that SRC-1 interacts with a variety of steroid and
thyroid hormone receptors in a ligand-dependent manner, as well as with TATA-binding protein and TFIIB.
Subsequently, O’Malley’s laboratory discovered that
SRC-1 not only has intrinsic HAT activity but also
interacts with an additional HAT protein, p300/CBPassociated factor (PCAF), thus giving it a role in chromatin remodeling (31). RU-486, an antagonist of PR,
prevents the interaction of SRC-1 with PR, thus discouraging transcription of PR target genes (31). CBP,
which was first described by Richard Goodman’s laboratory in 1993, interacts with SRC-1 and TFIIB, as
well as with PCAF. Receptor-specific coactivators do
exist, such as the androgen receptor-associated protein
70, first described by Chawnshang Chang’s laboratory
in 1996 (38).
Corepressors. Not only can the steroid/thyroid hormone receptors activate transcription in the presence
of hormone but also they can silence basal promoter
activity of target genes in the absence of hormone or in
the presence of antagonist. This phenomenon was first
observed with TR and RAR, which have been shown to
bind cognate DNA response elements in the absence of
hormone and repress basal transcription (38). Competition experiments suggested that this silencing activity requires binding of a “corepressor.” The corepressors silencing mediator for RAR and TR (SMRT) and
nuclear receptor corepressor (N-CoR) were cloned in
1995 (38). These proteins are thought to act by recruiting additional proteins with histone deacetylase activity, thus inhibiting transcription complex formation
(8). Agonists, but not antagonists, are able to dislodge
corepressors bound to unliganded receptors, thus relieving the silencing function. In the case of a mixed
agonist and antagonist, such as tamoxifen (for ER),
relief of the silencing functions may depend on the
relative ratio of coactivators to corepressors (10, 38).
Evidence for corepressor interaction with the classic
steroid hormones is also emerging. Recently, ER has
been shown to interact with N-CoR (10). In addition,
the surprising observation that human PR-A acts as a
transdominant transcriptional inhibitor appears to be
due to its interaction with the corepressor SMRT and
its inability to interact with coactivators (8). As recep-
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performed in the mid 1990s demonstrated that receptor binding to DNA is not hormone dependent (22).
In the mid 1980s, Etienne-Emile Baulieu’s, David
Toft’s, and William Pratt’s laboratories discovered that
inactive steroid hormone receptors interact with a nonhormone protein, later identified as a HSP (HSP90;
Refs. 15, 34). HSPs likely stabilize unliganded steroid
hormone receptors by preventing folding, aggregation,
and DNA binding (13). Steroid hormone receptors are
the only members of the steroid/thyroid superfamily
known to bind HSPs (1). Experiments performed by the
Pratt and Toft laboratories in the late 1980s demonstrated that the dissociation of HSPs from receptors is
hormone-dependent (33).
In the mid 1980s, steroid hormone receptors were
shown to be phosphorylated in a hormone-dependent
manner. Edwin Milgrom’s laboratory showed that PR
is phosphorylated, and with hormone administration,
becomes hyperphosphorylated (35). These experiments
suggested that steroid hormone receptor action is dependent on phosphorylation status.
In the late 1980s and early 1990s, O’Malley’s laboratory showed that steroid hormone receptors interact
with transcription factor IIB (TFIIB), leading to the
hypothesis that steroid hormone receptors facilitate
transactivation via protein-protein interactions with
general transcription factors. This hypothesis was soon
validated when they successfully reconstructed the entire pathway of steroid hormone action in a liganddependent, receptor-mediated, cell-free transcription
system (25). They showed that ligand-bound receptor
(PR) binds the SRE and stabilizes the association of
general transcription factors, including TFIIB. This
interaction between receptor and general transcription
factors allows for the successful recruitment of the
polymerase to the promoter and subsequent transcription of the target gene.
These discoveries were the culmination of the previous three decades of research and led to a well-supported model for steroid hormone receptor action: ligand binding induces a conformational change in the
receptor, releasing HSPs. The receptor undergoes hormone- and DNA-dependent hyperphosphorylation,
dimerizes, and binds its target DNA. The binding of the
receptor to the SRE allows for the recruitment of general transcription factors and, subsequently, RNA
polymerase to begin efficient transcription (13, 35).
HISTORICAL PERSPECTIVES
tor specific coactivators and corepressors continue to be
discovered, researchers can better understand how steroid hormone receptors alternate between gene silencing and transactivation functions.
The interesting biology of steroid hormone receptor
action on gene expression is dependent on several
factors, including the nature of the ligand (agonist or
antagonist), the isoform or subtype of receptor, the
nature of the steroid response element, and the character and balance of coactivators and corepressors.
These factors confer tissue and gene specificity and
begin to explain the complexity and diverse cellular
roles of steroid hormone receptors.
STEROID HORMONE RECEPTOR DEFECTS
J Appl Physiol • VOL
Mutations in genes regulated by and whose products
regulate ER-␣ and ER-␤ are associated with breast and
ovarian cancer (6, 7), and estrogen deficiencies contribute to osteoporosis and cardiovascular disease (16, 40).
Selective estrogen receptor modulators (SERMs), such
as tamoxifen and raloxifene, which have mixed estrogenic and antiestrogenic properties, have been developed to treat and prevent these diseases, and more are
in development. Tamoxifen was developed in the late
1970s to treat breast cancer via its antiestrogenic properties. In addition, tamoxifen has been shown to be
chemoprotective, reducing the risk of breast cancer by
almost 50% in women at high risk of getting the disease (30). Tamoxifen also produces beneficial estrogenic effects in other target tissues, such as bone, thus
preventing postmenopausal osteoporosis. However, the
estrogenic properties of tamoxifen are not limited to
the bone and thus cause unwanted side effects such as
increased risk of endometrial cancer. Raloxifene, a
second-generation SERM developed in the 1980s, exhibits bone-beneficial actions without the toxic side
effects caused by tamoxifen (5, 20, 27). Clinical trials
have also demonstrated that raloxifene has beneficial
estrogenic effects on the cardiovascular system, including reducing low-density-lipoprotein and total cholesterol levels (32). In addition, the ongoing Study of
Tamoxifen and Raloxifene trial is attempting to determine whether raloxifene will also be useful as a breast
cancer chemoprotective agent (30). The future of SERM
development relies on the further elucidation of ER
action, and the understanding of how drugs work in
each target tissue.
PR defects. The mid to late 1970s and early 1980s
brought the discoveries that abnormal action of PR
played a role in disease, specifically breast cancer,
uterine fibroids, and endometriosis (3). Subsequently,
antiprogestins, notably RU-486, began being synthesized to treat PR-related diseases. During the early
1980s, it was discovered that RU-468 binds to the rat
ovary PR, and its direct antiprogesterone action on the
uterus was thought to induce menstruation and early
abortion (37). The antiprogestin activity of RU-486 has
been used for the treatment for meningiomas and endometriosis and as a postcoital contraceptive (3).
The mid 1990s brought the development of PR
knockout mice. Because PR is induced by estrogen via
ER, it was unclear which reproductive effects are due
to PR or ER. By knocking out PR, it became clear that
this molecule is necessary for proper development of
the reproductive organs and mammary glands, as well
as induction of the sexual response in females. Males
show no observable effects (19). The development of the
SRC-1 knockout mouse later in the decade showed the
importance of this molecule in progesterone action,
because the animals exhibit partial hormone resistance in the uterus, mammary gland, prostate, and
testis (31).
AR defects. Androgens, primarily testosterone and
its active metabolite dihydrotestosterone (DHT), play
crucial roles in development and maintenance of male
phenotype (2), and evidence is accumulating for a cru-
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Much has been learned about the functions of steroid
hormone receptors by studying gene knockouts and
naturally occurring mutations. These studies allow researchers to gain insight into the causes of many diseases, such as cancer (breast, endometrial, prostate),
osteoporosis, and androgen insensitivity, to name a
few. By understanding the mechanism of action of
steroid hormone receptors and their structure-function
relationships, researchers can better design drugs
(e.g., tamoxifen, raloxifene, RU-486) to treat debilitating diseases caused by defects in steroid hormone receptor action.
ER defects. In 1993, Oliver Smithies’ and Kenneth
Korach’s laboratories collaborated to create ER-␣
knockout mice. Female ER-␣ knockout mice exhibit
severe reproductive and behavioral phenotypes, including complete infertility, absence of breast tissue
development, and absence of sexual response. Male
mice exhibit a significant reduction in fertility, and
both female and male mice have altered bone densities
(39).
No ER mutations were known in humans until 1994,
when a 28-yr-old male patient with an ER-␣ mutation
was described as exhibiting estrogen resistance, tall
stature, low bone mineral density, unfused epiphyses,
insulin resistance, and abnormal gonadotropin secretion. Taken together, these phenotypes suggest ER-␣ is
important for bone maturation and mineralization,
normal reproduction, and sexual behavior (39).
In 1998, the Smithies, Gustafsson, and Korach laboratories collaborated to create ER-␤ knockout
(BERKO) mice. Female BERKO mice are fertile and
exhibit normal sexual behavior but have fewer and
smaller litters than wild-type mice due to reduced
ovarian efficiency. Older male BERKO mice display
signs of prostate and bladder hyperplasia. Both male
and female BERKO mice display abnormal breast epithelial growth and develop severe cystic breast disease
as they age. Also, mice lacking both ER-␣ and ER-␤
have been generated and survive, although both sexes
are infertile. On the basis of these results, it can be
concluded that ER-␤ is of importance for normal reproduction and ovarian function, prostate growth control,
and may have a protective role in the breast (11).
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HISTORICAL PERSPECTIVES
FUTURE DIRECTIONS
Despite the great deal of information about steroid
hormone action now known, many questions remain
unanswered relating to receptor activation, regulation,
and protein interactions. Since the early 1990s, it has
been known that ligand-independent activation of PR
and ER can occur (25). However, the full implications
of these observations are not yet understood, although
researchers have suggested that this type of activation
may be associated with breast and uterine cancers and
may have ramifications for learning, memory, and behavior. In addition, multiple interactions have been
observed between steroid hormone receptors and other
superfamily members, growth factors, and protein kinases (17). Further elucidating how these diverse interactions are involved in the regulation of gene expression and cell proliferation will aid in the detection
and treatment of various diseases and conditions.
Yet another question deserving of further attention
is how rapid cellular responses to steroid hormones,
which cannot be explained by classic hormone transacJ Appl Physiol • VOL
tivation, occur. This “nongenomic” mechanism was
proposed as early as 1975 by Richard Pietras and Clara
Szego to involve membrane-bound steroid receptorinduced increases in intracellular second messengers
(36). In recent years, evidence has accumulated for the
presence of classic ERs (both ER-␣ and ER-␤) at the
membrane of specific types of cells (29, 36). In addition,
a putative nonnuclear, membrane form of PR has been
cloned (36). Understanding how membrane-bound and
classic steroid hormone receptors interact to govern
complex hormone-mediated cellular responses promises to yield therapeutic options for diverse conditions
such as cancer and neurodegenerative and cardiovascular diseases.
The understanding that sex steroid hormones exhibit effects on tissues outside the reproductive tract,
such as bone, heart, and brain, underscores the necessity of including both male and female animals and
humans in research studies and of analyzing resulting
data by sex. Such analyses are imperative to elucidating important physiological differences and similarities between the sexes. Forums such as the Journal of
Applied Physiology’s miniseries on Genome and Hormones: Gender Differences in Physiology will surely
advance the understanding of the relationships between the molecules that affect and are affected by
steroid hormones and animal and human health.
We thank Carol Sartorius, Ulla Hansen, and Paul Bertics for
critical comments on the manuscript.
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cial role for testosterone in female biology. A single AR
appears to bind both testosterone and DHT (2). Testosterone is rapidly converted to DHT by 5␣-reductase in
androgen-sensitive tissues such as the prostate (28),
and the AR binds DHT with higher affinity than testosterone.
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the treatment of androgen-dependent prostate cancer
(3).
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