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Sites
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Receptor subtypes
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ERα
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ERβ
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Other receptors
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Brain
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Cholinergic neuron , GABAergic neuron , Pro-opiomelanocortin neuron
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GnRH neurons , Subiculum neuron Ammon
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GPER1 (glial cell, rat), GPER1
(GABAergic neuron,
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Fat
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Adipocyte
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Adipocyte
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GPER
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Bone
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Osteoblast , Osteocyte .
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Liver
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Hepatocyte
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Blood vessel
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Smooth muscle cell , Vascular endothelial cell
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Endothelial cell
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GPR30 (endothelial cell, )
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Intestine
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Epithelial
cell , Parietal cell , Myenteric neuron
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Epithelial
cell , Parietal cell
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GPER
(colonic epithelia,
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Skin
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Keratinocyte
, Mast cell Sebocyte
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Keratinocyte
, Mast cell
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Adrenal
gland
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Adrenal
cortex
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Adrenal
cortex
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GPER1
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Muscle
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Satellite
cell
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Satellite
cell
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Kidney
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Mesangial
cells
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Mesangial
cells
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Pancreas
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β-cell
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β-cell
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Adipose tissues, where estradiol stimulates the
production of high density lipoprotein cholesterol (HDL) and triglycerides
while decreasing LDL production and and fat deposition , are the
most extensively studied sites of extra-gonadal estrogen synthesis. Both male and female
aromatase-deficient (Cyp19KO) mice exhibit obesity and
dyslipidemia , proving that estradiol plays a beneficial role in the
lipogenesis. However, an adverse effect of adipose tissue-driven estradiol is
also indicated in the pathogenesis of breast cancer. For instance, in a breast
with a tumor, adipose tissues proximal to the tumor exhibit higher aromatase
activity than those distal to the tumor
What are the good effects and ill effects of
extra gonadal androgens on the Bone?
Aromatase expression in
human bone has been demonstrated in osteoblasts, chondrocytes, and fibroblasts,
where they convert circulating androgens into estrogens . In the bone of
prepubertal children, the locally synthesized estradiol stimulates epiphyseal
maturation during the growth phase. However, in both males and females, the
massive pubertal increase of estradiol leads to increased apoptosis of
chondrocytes in the epiphyseal plate, causing chondrocyte depletion and hence,
ossification and growth slow-down. In adults, estradiol increases bone
formation and mineralization and reduces bone resorption, thus reducing the
risk of osteoporosis. Therefore, it is not surprising that the incidence of
osteoporosis increases in postmenopausal women as their ovaries lose estradiol
synthetic capacity.
What are the good
effects and ill effects of extra gonadal
androgens on the Skin?
Aromatase expression in
the skin occurs mainly in hair follicles and sebaceous glands. Glucocorticoids,
cAMP analogs, growth factors, and cytokines modulate aromatase expression in
these cells and therefore, local estrogene synthesis . Estradiol enhances
collagen synthesis, increases skin thickness, and stimulates blood flow in the
skin. Therefore, in situ estrogen synthesis in the skin is vital for
maintaining healthy skin. Estradiol also prolongs the anagen phase of the hair
cycle and therefore enhances hair growth by increasing the synthesis of
essential growth factors stimulating the proliferation of hair follicle cells.
What are
the good effects and ill effects of extra gonadal androgens on the Liver?
In the liver, estradiol
regulates protein synthesis, including lipoprotein and proteins responsible for
blood clotting (factors II, VII, IX, X, plasminogen) . Estrogen signaling
is also essential in regulating glucose homeostasis, thus improving glucose
tolerance and insulin sensitivity. Recent research has explored the possibility
that postmenopausal women with nonalcoholic fatty liver disease and with long
durations of estrogen deficiency could have a higher risk of having severe
fibrosis than premenopausal women . Estrogen receptor beta (ERβ) is
implicated in mediating the protective role that estradiol plays under
pathogenic condition in the liver as it shows potent anti-proliferative and
anti-inflammatory properties. As such, chronic disease is linked to elevated ERβ expression in the
liver. ERβ is also known to mediate the anti-tumor action of estrogens in
intrahepatic cholangiocarcinoma.
What are the good effects and ill effects of
extra gonadal androgens on the Brain?
High levels of estrogen receptors are expressed during brain
development. During this period, sex hormones determine apoptosis, neuronal
migration, neurogenesis, axonal guidance, and synaptogenesis. Estradiol induces
sexual differentiation in the developing brain. Aromatase mRNA expression in
the hypothalamus of males peaks before and after birth, inducing sexual
differentiation of the brain. In the brains of both males and females,
estradiol provides a neuroprotective effect. Estradiol’s prevention of
neurodegeneration in brain tissues is proven in both the Cyp19KO mouse model
and the aromatase inhibitor-treated mouse
. Inhibition or null
mutation of aromatase, a key enzyme for estradiol synthesis, results in
accelerated neurodegeneration. Estradiol effects in the brain also include
regulating mood, pain sensitivity, motor control, and cognitive behavior.
Estradiol regulates neuronal metabolism by modulating the expression of
metabolic enzymes such as GLUT (glucose-transporter), glycolytic enzyme
hexokinase, pyruvate dehydrogenase (PDH), aconitase, and ATP synthase .
What are the good effects and ill effects of
extra gonadal androgens on the Adrenal gland?
Estrogens stimulate adrenal cortex growth during development by
promoting cell proliferation and enhancing steroidogenic activity by increasing
StAR and SF-1 expression in the adrenal gland. In the fetal adrenal gland,
estradiol and ACTH form as a positive regulatory loop in which estradiol
increases ACTH secretion from adrenal cortex while ACTH increase estradiol in
the ovary.
What are the good effects and ill effects of
extra gonadal androgens on the Pancreas?
Estradiol increases insulin gene expression and insulin content in
β-cells , increases β-cell proliferation during pancreatic development and
recovery from injury, and prevents apoptosis of β-cells upon inflammatory
insult via ERα- and ERβ-mediated pathways.
What are the good effects and ill effects of
extra gonadal androgens on Other female organs ?
In the blood vessel, estradiol positively impacts vascular
function by preventing the oxidation of LDL cholesterol, stimulating nitric
oxide synthesis and release, and inhibiting fibroblast transition to
myofibroblast, preventing cardiac fibrosis and atherosclerosis
development. In the muscle, estradiol increases muscle mass and strength, alleviating
disuse-induced muscle atrophy and promoting regrowth after reloading. It also
stimulates muscle repair by stimulating satellite cell proliferation. Estradiol
replacement on ovariectomized mice shows that estradiol can reduce stiffness in
muscle as well as stimulate muscle regeneration. In the kidney, estradiol has a
role of protecting kidney functions during progressive glomerulosclerosis in
the female rat remnant kidney model. In the intestine, to maintain the
intestinal epithelium, estrogens are necessary. Estrogens improve epithelial
barriers and reduce intestinal permeability, preventing chronic mucosal
inflammation in animals and humans
What are the good and bad effects on inflammatory response in
different areas on the body.
Estrogens play an important role in the inflammatory response by
regulating development, proliferation, migration, and apoptosis of immune
cells . Lymphocytes have been shown to express estrogen receptors (ERα and
ERβ), but the expression levels of both receptors vary among cell types. CD4＋ T-lymphocytes express
ERα whereas B-lymphocytes express ERβ. In contrast, CD8＋ T-lymphocytes express
both receptors at low but equivalent levels. Regardless of subcellular
differences, estrogens appear to exert a suppressive effect on both B- and
T-lymphopoiesis. In support, B-lymphocyte formation is selectively reduced with
estradiol treatment , and ovariectomy results in increased
B-lymphopoiesis . In addition to the inhibitory effect on lymphopoiesis,
estradiol has been shown to influence T helper (Th) responses; inhibit the
production of Th1 cytokines such as IL-12, TNF-α, and IFN-γ; and stimulate Th2
anti-inflammatory cytokine production such as IL-10, IL-4, and TGF-β. Estradiol
has also been shown to modulate the main activities (maturation, differentiation,
and migration) of myeloid cells, including monocytes, macrophages, and
dendritic cells. Thus, estradiol has an important impact on immune cells and
affects both the innate and the adaptive immune systems, which may account for
its contribution in diseases associated with immune disorder.
ESTROGEN AND ESTROGEN RECEPTORS IN THE GUT
In an effort to identify extra-gonadal sites of de novo estradiol
synthesis, we generated a double transgenic mouse line in which a transgenic
aromatase promoter induces the expression of a red fluorescent protein (RFP)
(un-published). In this animal, RFP signal is strongly expressed in the Peyer's
patch (Pp), a secondary lymphoid organ in the intestine. Pp have an
organizational structure similar to lymph nodes consisting of multiple
follicles and interfollicular areas. A follicle is made of a germinal center
that is filled with proliferating B-lymphocytes, follicular dendritic cells,
and macrophages; the interfollicular area is populated with T-lymphocytes as
well as B-lymphocytes, macrophages, and dendritic cells. As part of the
gut-associated lymphoid tissue, Pp are known as inductive sites of intestinal
immune responses . The induction process in the Pp starts with sensing
antigens or microbes in the gut lumen by M-cells located in a monolayer of
specialized intestinal epithelial cells known as the follicle-associated
epithelium. M-cells transport antigens to antigen-presenting cells,
specifically dendritic cells (DCs), within the underlying sub-epithelial dome
through transcytosis. Dendritic cells then further present antigens to T-and
B-lymphocytes, triggering priming and proliferation of lymphocytes to complete
the immune response. A well-known effect of the Pp’s induction function is
generating antigen-specific intestinal IgA responses, which is critical for
maintaining host-microbiota interaction, generating immune tolerance, and
preventing infection Interestingly, estrogens plays a significant role in
the gastrointestinal tract. In this section, we will describe some of the
lesser known roles for estrogen in the gastrointestinal system.
Napoleon Bonaparte was not aware of the true importance of his
words when he said “An army marches on its stomach.” Technically, an
army marches on its intestines. The gastrointestinal tract (GIT) is a unique
environment colonized by a remarkable variety of bacteria as well as other
organisms including fungi and viruses. This superorganism, the microbiome, is
not a simple spectator in biological processes but is an active component of
the biochemical and metabolic health of the host. The microbiome is capable of
digesting large molecules into simpler ones that can be efficiently reabsorbed
by the host. The importance of a healthy microbiome has been well
published , and multiple pathologies have been correlated with poor
diversity of the microbiome, including irritable bowel (IBS) ,
osteoporosis , and gluten intolerance. Therefore, controlling the
microbiome is paramount to maintaining an optimally functioning GIT. The
mucosal epithelium is perfectly adapted to monitor both microbial and nutrient
composition. The release of antimicrobial peptides or anti-inflammatory
molecules maintains the optimal microbial ecology depending on the current GIT
contents.
What are the good effects and ill effects of
extra gonadal androgens on the Appetite?
Researchers have noted a correlation between estradiol levels and
appetite. Food intake is significantly decreased during the preovulatory period
when estradiol levels are increasing. These actions are attributed to estradiol
inhibiting appetite indirectly through cannabinoid receptors. Further, blocking
estrogen receptors with ICI182,270 ablates any action of estradiol on
appetite . What is more interesting is that appetite is influenced by the
microbiome present in the GIT. Bacterial peptides signal hunger or satiation;
in essence, the bacteria control our desire to eat. Locally synthesized
estrogen produced in response to microbiome composition in turn may influence
immune responses, bringing us back to control of microbiome composition.
Immune function. Estrogenic compounds in the gut lumen suppress
immune function through targeted apoptosis and inhibition of cell proliferation
in the germinal centers of ileal Pp . The Pp are important in generating
protective immune responses to pathogens through both innate and cell medicated
responses and are also key in tolerizing the host to food antigens.
The mucosal surfaces of the gut must maintain homeostasis, allowing sufficient
function of Pp to prevent immune responses to food antigens yet not responding
prolifically to commensal bacteria in the gut. Abnormal Pp function through
estrogenic compounds is responsible for initializing autoimmune responses and
impaired innate responses. Again, we see the constituents of the gut signaling
control of the microbiome composition. This leads into the next topic of
estrogens and cancer.
What are the good effects and ill effects of
extra gonadal androgens on the formation
of Cancer?
The small intestine is the main absorptive area of the
gastrointestinal tract. To maximize absorption, the epithelial layer is covered
with invaginations or crypts of Lieberkühn and exists as a sheet of single
cells. These cells are prone to injury and are therefore replaced every 3-5
days. To facilitate this replacement, the base of the crypts is populated with
stem cells that differentiate into the mature epithelium as they migrate
towards the crest of the crypt. ERα and ERβ are both expressed in the crypt
cells. However, they are distributed such that ERα is predominantly expressed
in the cells at the base of crypts and ERβ is expressed in the cells towards
the crest. ERα signaling stimulates proliferation and ERβ signaling
opposes this action, and the net signaling from the two receptors controls
proliferation. To further support the role of estrogen receptors in tumor
development, ERβ-deficient mice demonstrate a hyper-proliferation of the
colonic epithelium with progression to colon carcinoma . More than 30
years ago, it was established that there is an associative risk between reduced
estrogen levels and colorectal cancer in menopausal women and that hormone
(estrogen) replacement therapy reduces the incidence of colorectal cancer .
Recent literature on estrogen and colorectal cancer confirms an
anti-tumorigenic role for estrogen signaling in the gut due to preferential ERβ
signaling .
However, estrogen in the gut is not always good. A recent review
by Kwa et al. associated the “estrobolome”, bacteria
with the capacity to metabolize estrogens, with level of risk for breast
cancer. A phylogenetic diverse microbiome favors metabolism of conjugated
estrogens. Once metabolized, the free estrogens are more easily reabsorbed
increasing systemic estrogen levels. Increased circulating estrogens levels
increases relative risk for hormone dependent malignancies such as breast
cancer. As described above, our recent unpublished work has demonstrated that
not only are Pp able to respond to estrogens, but they are also a significant
site of estradiol synthesis. Thus, Pp are able to monitor the bacterial
diversity of the gut lumen and secrete estradiol. This estradiol then regulates
immune responses locally and ultimately alters the diversity of the microbiome.
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