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Division of Endocrinology and Metabolism (S.C.M., S.K.) Center for Osteoporosis and Metabolic Bone Diseases University of Arkansas for Medical Sciences, and The Central Arkansas Veterans Health Care System (S.C.M.) Little Rock, Arkansas 72205
Address all correspondence and requests for reprints to: Stavros C. Manolagas, M.D., Ph.D., 4301 West Markham Street, Mail Slot 587, Little Rock, Arkansas 72205. E-mail: manolagasstavros{at}uams.edu
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Introduction |
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 Top Introduction Skeletal, cardiovascular, and...Low levels of receptor...Relaxed gender specificity of...Nongenotropic actions, membrane...Summary and conclusionsReferences |
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During the last decade, there have been significant advances in our understanding of the mechanism of action of sex steroids on the skeleton, the cardiovascular system, and the central nervous system. The purpose of this perspective is to provide a brief outline of these advances with an emphasis on the emergence of several thematic similarities in the action of sex steroids on nonreproductive tissues. For more thorough discussion of this topic, the reader is referred to recent review articles (1, 2, 3, 4, 5).
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Skeletal, cardiovascular, and central nervous system (CNS) effects of sex steroids |
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TopIntroductionSkeletal, cardiovascular, and...Low levels of receptor...Relaxed gender specificity of...Nongenotropic actions, membrane...Summary and conclusionsReferences |
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Although two recent clinical trials have failed to show a protective effect of HRT in postmenopausal women with preexisting coronary heart disease (11, 12), an extensive body of evidence indicates that estrogens do have atheroprotective properties that result from a variety of actions. Such actions include favorable changes in lipoprotein metabolism and oxidation, modulation of endothelial permeability to low density lipoprotein, as well as regulation of the expression of cytokines and cell adhesion molecules, vascular smooth muscle cell and neointimal proliferation and migration, calcification and platelet adhesion, and aggregation. Evidence from animal and human studies has strongly suggested that estrogens, at physiological levels, also cause vasodilatation (3). This effect is shared by androgens. This finding is consistent with reports that normotensive men have higher plasma testosterone than hypertensive and that angina pectoris can be successfully treated with acute injections of testosterone (13, 14). In the case of either class of sex steroids, the effect on vasodilatation is mediated by activation of endothelial nitric oxide synthase (eNOS), as well as through increased expression of the eNOS and prostacyclin synthase genes, which regulate vascular tone (15, 16). Dihydrotestosterone, on the other hand, has been shown to increase human monocyte adhesion to endothelial cells, a proatherogenic effect that is mediated at least in part by increased endothelial cell-surface expression of vascular cell adhesion molecule 1 (17); this is perhaps one of several reasons for the higher incidence of coronary artery disease in men compared with premenopausal women.
In the CNS, besides regulating gonadotropin and PRL secretion and sexual behavior, estrogens influence verbal fluency and memory, fine motor skills, coordination of movement as well as mood (4, 5, 18). In addition, they seem to decrease the risk of neurodegenerative diseases and attenuate injury by suppressing the effects of neurotoxic or ischemic stimuli or increasing the resilience of the brain to injury (19, 20). Several mechanisms may account for these effects. Estrogens selectively enhance the growth and differentiation of axons and dendrites (neurites) in the developing brain, an effect that may be recapitulated following injury later in life. Estrogens also exert antiapopotic effects on neuronal cells that are mediated by activation of mitogen-actived protein (MAP) kinases or protein kinase A and protein kinase C, down-regulation of the expression of neurotrophin receptors, or by altering free radical production or free radical action on cells. Estrogens may also regulate the cholinergic system by inducing acetylcholinesterase and its activity or the receptor for nerve growth factor (NGF), reduce the tone of dopaminergic neurons, and have antinociceptive and analgesic actions. Androgens protect neuronal cells from oxidative stress, and also alter the expression of the opioid receptor (21, 22). In addition, aromatizable as well as nonaromatizable androgens alter the morphology, survival, and axonal regeneration of lower motor neurons (23); and, androgen receptor dysfunction causes degeneration of spinal and bulbar motor neurons (Kennedy’s disease) (24).
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Low levels of receptor expression and little or no variation by gender, compared with reproductive tissues |
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TopIntroductionSkeletal, cardiovascular, and...Low levels of receptor...Relaxed gender specificity of...Nongenotropic actions, membrane...Summary and conclusionsReferences |
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Consistent with the effects of sex steroids on skeletal growth and
remodeling, receptors for estrogens (ER
and ERß) or androgens (AR)
are present in chondrocytes, osteoblasts, and bone marrow stromal cells
as well as in osteoclasts and their progenitors. Remarkably, however,
the level of expression of ER, ERß, or AR in bone cells is at
least 10-fold lower compared with reproductive tissues. In addition,
the distribution of the receptors in bone cells does not vary by
gender, as similar levels of ER and AR have been found in bone cells
from males and females.
ER and ERß, as well as AR, have been identified in vascular
endothelial and smooth muscle cells (including cells from the coronary
arteries, aorta and peripheral veins) as well as myocardial cells and
macrophages. Nonetheless, as is the case with bone cells, the
concentration of the estrogen receptors in cells of the cardiovascular
system is very small—as little as 50-fold less compared with cells of
reproductive tissues (25). Moreover, there does not seem
to be different distribution of the ER in cells from males or females.
The atheroprotective effects of estrogen are mediated to a large extent
through the ER, but ER-independent mechanisms may be also
involved (26).
Receptors for ER, ERß, or AR have been demonstrated in the
pituitary and hypothalamus as well as in nonhypothalamic brain regions
such as the hippocampus, basal forebrain, brain stem, the
causate-putamen and substantia nigra, the olfactory lobe, amygdala,
cortex, midbrain, central brain, cerebellum and cholinergic,
serotonergic, and catecholaminergic neurons. The level of estrogen
receptor expression varies among different regions of the brain, but by
and large, with the exception of the pituitary that exhibits moderate
to high levels, ER or ERß expression in neuronal cells such as
glial, is very low or undetectable. The levels of the expression of
these receptors in brain may also vary at different stages of life, as
indicated by the transient expression of ER in the cerebral cortex
during neonatal development—a period of dramatic neurogenesis and
differentiation—but the receptors virtually disappear thereafter
(20).
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Relaxed gender specificity of nonreproductive tissue responsiveness to estrogens or androgens |
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TopIntroductionSkeletal, cardiovascular, and...Low levels of receptor...Relaxed gender specificity of...Nongenotropic actions, membrane...Summary and conclusionsReferences |
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Until recently it was thought that low doses of estrogens are
responsible for the pubertal growth spurt in both boys and girls.
Nonetheless, from the case of a man with estrogen resistance due to a
mutation of the ER gene (27) and two men with aromatase
deficiency (28, 29), it has become clear that androgens,
if nonaromatized to estrogen, can also stimulate growth directly at the
level of the epiphyseal chondrocyte. Indeed, all three men achieved
their genetic potential for height at a normal age of 16–17 yr, rather
that at a later age, as could be expected with hypogonadism. On the
other hand, high doses of estrogens inhibit growth by inhibiting cell
proliferation at the hypertrophic zone or by inducing terminal
differentiation of proliferating chondrocytes, apoptosis of
hypertrophic chondrocytes, and vascular and osteoblast invasion into
the growth plate. Because estrogen-resistant men in their mid to late
twenties have tall stature and continued linear growth as a
result of delayed skeletal maturation, androgens may be ineffective in
inducing epiphyseal maturation and closure. Consequently, estrogens
must be responsible for the closing of the epiphyses in both sexes
(30).
The decreased bone mass in the male with the mutant estrogen receptor and increased bone mass after treatment with estrogens in the two males with aromatase deficiency have also suggested that estrogens derived by peripheral aromatization of androgens are critical for the maintenance of bone mass in postpubertal life in men (31). However, in all three cases, the decreased bone mass and the increased levels of bone markers in young males with estrogen deficiency, in the face of androgen sufficiency, could well be the result of failure to achieve peak bone mass because of defective skeletal growth during development as well as the fact that these individuals never underwent puberty—not to loss of bone mass, as is the case with the common forms of osteoporosis. In support of this contention, humans with complete androgen insensitivity, due to mutations in the androgen receptor gene on the X-chromosome, have decreased bone mass, in spite of the elevated estrogen levels (32); and women with androgen insensitivity syndrome had decreased bone mineral density even when fully complying with estrogen therapy (33). Moreover, androgens, including nonaromatizable ones, like dihydrotestosterone, have identical effects to those of estrogens on the biosynthetic activity and the birth as well as the death of bone cells in vitro and in vivo, at least in rodents (7, 34). Even more importantly, androgens can prevent bone loss in ovariectomized rodents (35, 36, 37, 38). However, in a recent study of elderly men estrogen loss seemed to be more critical for a short-term increase in bone resorption markers than loss of androgens; whereas both estrogen and androgen loss were needed to elicit a short-term decrease in bone formation markers (39); these quick changes probably reflect the pro- and antiapoptotic effects of sex steroids on osteoclasts and osteoblasts.
Heretofore, there has been no explanation for the puzzling
efficacy of either class of sex steroids in females and males.
Nonetheless, recent studies from our group have elucidated a potent
antiapoptotic effect of estrogens or androgens on osteoblasts and
osteocytes, which can be transmitted by the ER, ERß, or the AR
with similar efficiency irrespective of whether the ligand is an
estrogen or an androgen (10). We suspect that these
findings are relevant to the efficacy of either class of sex steroids
in females and males. We also speculate that our findings may account
for the weak and puzzling skeletal phenotype of the deletion of the
ER or ERß genes in mice (40). Indeed, these mice
exhibit a decrease in the length and diameter of the femur in both
females and males as well as low bone turnover, which are diametrically
opposite to the increased length of long bones and the high turnover of
patients with hypogonadism, or the humans with the ER or the
aromatase mutations. An equivocal bone phenotype has been also observed
in aromatase-deficient (ArKO) mice (41). While possible
that the minor phenotypic changes in these mutant mice may be due to
loss of estrogenic effects on skeletal development or compensatory
changes in the production of estrogens or androgens, an alternative
explanation is that the difference between the receptor deficient
vs. the hormone deficient mice might be due, in part, to the
ability of the AR to transmit bone protective effects of estrogens.
The effect of estrogens in vascular smooth muscle cells from
males and females also appears to be gender independent. Indeed,
estrogen administration improves vascular reactivity in men, produces a
significant increase in the response to the endothelial vasodilator
acetylcholine (Ach), prevents carotid injury in castrated male rats,
and reduces plaque formation in transgenic male mice expressing low
levels of apoE (16, 42, 43, 44). Furthermore, the man with the
homozygous mutation of the ER gene also has abnormal vascular
reactivity (45). Like estrogens, administration of
testosterone produces dose-dependent relaxation of the thoracic aorta
of rats and rabbits and attenuates the contractile response of the
aorta to phenylephrine (13, 16). Remarkably, the effects
of testosterone occur in both males and females in a gender-independent
fashion. Furthermore, the effects of testosterone persist in the mouse
model of testicular feminization (tfm); and, are demonstrable in the
presence of an androgen receptor antagonist or an aromatase inhibitor
(13). This evidence raises the possibility that the
vasodilating effects of androgen may be mediated by a sex-nonspecific
mechanism, perhaps through the ER.
In some regions of the brain, the male and female response to estrogens differs, but in others, estrogens can regulate similarly gene expression in males and females. Moreover, administration of estrogens and progestins improves the outcome after cerebral ischemia and traumatic brain injury in experimental models. This neuroprotective effect of estrogen administration extends to males as well (46).
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Nongenotropic actions, membrane receptors, and MAP kinases |
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TopIntroductionSkeletal, cardiovascular, and...Low levels of receptor...Relaxed gender specificity of...Nongenotropic actions, membrane...Summary and conclusionsReferences |
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), the actions of estrogens on the
skeleton and the CNS seem to result primarily either from
protein-protein interaction between the estrogen receptor and other
transcription factors such as NF-
B, AP-1, or C/EBP (49)
(Fig. 1B), or via rapid nongenotropic mechanisms (Fig. 1C). The same
seems true for the cardiovascular system. Some direct effects of
estrogen on the blood vessels may be exerted through ERE-independent
genomic actions, but the vast majority of the effects of estrogen on
the vasculature, including relaxation of coronary arteries,
vasodilatation and protection of blood vessel injury to hypoxic
insults, occur via rapid nongenotropic actions.
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, by activation of the
PI3-kinase-Akt pathway. Remarkably, it was demonstrated that this
effect results from direct interaction of the receptor protein with the
p85 regulatory subunit of the PI3-kinase (50). The
relaxation of the rat thoracic aorta by testosterone is also mediated
via NO release (16).
The antiapoptotic effect of estrogens and androgens on osteoblast and
osteocytes is mediated via a Src/Shc/ERK signaling cascade and a region
of the classical receptor that is distinct from the one responsible for
the genotropic actions of the ligand-activated protein
(10). Indeed, using ER as a paradigm, we determined
that this effect requires only the ligand binding domain and is
eliminated by nuclear targeting of the receptor protein. Interestingly,
expression of constitutively active Src or stimulation of the
endogenous Src/JNK pathway enhances transcriptional activation of the
estrogen-ER complex and strongly stimulates the otherwise weak
activation by the unliganded ER, through a Raf/MEK/ERK and a
MEKK/JNKK/JNK signaling cascades (51, 52). Thus, Src may
be a pivotal protein for the function of the ER both in its genotropic
and nongenotropic modes of action.
Estrogens phosphorylate Src within seconds in mammary tumor
cells, and ER or AR coimmunoprecipitate with Src in prostate cancer
cells (53, 54). This evidence taken together with the
finding that the antiapoptotic signal of the ligand binding domain of
the ER is preserved when targeting this protein to the membrane, but it
is lost when targeting it to the nucleus (10), suggests
strongly that these actions are mediated via the whole, or a fraction,
of the classical receptor that is associated with the plasma membrane
(Fig. 1C
). In support of this notion, Razandi et al.
(55, 56) have shown that both ER and ERß can be
detected in the cell membrane and that a membrane impermeable form of
estrogen (E2BSA) protects endothelial cells from
hypoxia-induced apoptosis and preserves their function via rapid
activation of the p38ß MAP kinase.
Several members of the MAP kinase signaling pathway, including Src,
Shc, and ERKs, are clustered in caveolae—specialized membrane
invaginations that are enriched in the scaffolding protein caveolin-1
and compartmentalize signal transduction (57). Caveolae
are found in a variety of cell types including neuronal, endothelial,
and osteoblastic cells (5, 58). ER has been shown
recently to coimmunoprecipitate with caveolin-1 (59).
Furthermore, a subpopulation of ER has been colocalized in caveolae
with both caveolin and eNOS in human endothelial cells
(15). Hence, it is very likely that nongenotropic
activation of signaling pathways by sex steroids is mediated via the
classical receptors, or perhaps a shortened spliced variant, that is
localized in the membrane and in particular within caveolae.
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Summary and conclusions |
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TopIntroductionSkeletal, cardiovascular, and...Low levels of receptor...Relaxed gender specificity of...Nongenotropic actions, membrane...Summary and conclusionsReferences |
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The nongenotropic effects of sex steroids on cells from nonreproductive tissues like bone can be readily demonstrated in vitro with physiologic concentrations (10-11, 10-10 M), in spite of the relatively low levels of receptor expression in such cells. This is in sharp contrast to genotropic effects that if at all, are extremely hard to elicit even with supraphysiologic concentrations of the steroids in nonreproductive tissues. This apparent dichotomy suggests that the "relatively low" receptor expression in nonreproductive tissues may be sufficient for accommodating nongenotropic actions of sex steroids but insufficient for genotropic actions. Hence, it is possible that the low receptor expression in cells from nonreproductive tissues is nature’s design of protecting these tissues from the fluctuating sex hormones during pregnancy and the menstrual cycle, while preserving their ability to respond continuously to the beneficial effects of sex steroids.
In closing, we propose that better understanding of the differences and similarities of the mechanism of action of sex steroids in nonreproductive vs. reproductive tissues, together with evidence that one can dissociate nongenotropic from genotropic activities of the sex steroid receptors with synthetic ligands (10), may provide novel means of preserving the beneficial effects of sex steroids on nonreproductive tissues during postreproductive life, while minimizing or eliminating effects that are no longer needed (and are often harmful) on the reproductive tissues.
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Footnotes |
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Received March 2, 2001.
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References |
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TopIntroductionSkeletal, cardiovascular, and...Low levels of receptor...Relaxed gender specificity of...Nongenotropic actions, membrane...Summary and conclusionsReferences |
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is a major mediator of
17ß-estradiol’s atheroprotective effects on lesion size in Apoe
-/- mice. J Clin Invest 107:333–340[Medline]
-reductase deficiency and complete androgen insenstitivity:
natural models to suggest a direct role for androgens on bone density
in men. Program of the 81st Annual Meeting of The Endocrine Society,
San Diego, CA, 1999, p 93 (Abstract)
-dihydrotestosterone partially restores cancellous bone volume in
osteopenic ovariectomized rats. Am J Physiol Endocrinol Metab
267:E853–E859
and ERß expressed in Chinese hamster
ovary cells. Mol Endocrinol 13:307–319
(ER) signaling. caveolin-1 drives ligand-independent nuclear
translocation and activation of ER. J Biol Chem 274:33551–33556This article has been cited by other articles:
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