Estradiol inhibits glutamate mediated influx of calcium and thus cell death in cell line. Glutamate, the principle excitatory neurotransmitter, is involved in neurodegeneration through activation of calcium channels. This study of cell line cultures found that Estradiol inhibits this process. I question whether this is applicable to both men and women. Time will tell.
Low endogenous bioavailable testosterone levels have been shown to be associated with higher rates
of all‐cause and cardiovascular‐related mortality.39,41,46–47 Patients suffering from CAD,13–18 CHF,137 T2DM,25–26 and obesity27–28
have all been shown to have lower levels of endogenous testosterone compared with those in healthy controls. In addition,
the severity of CAD15,17,29–30 and CHF137 correlates with the degree of testosterone deficiency
In patients with CHF, testosterone replacement therapy has been shown to significantly improve exercise tolerance while having
no effect on LVEF
testosterone therapy causes a shift in the skeletal muscle of CHF patients toward a higher concentration
of type I muscle fibers
Testosterone replacement therapy has also been shown to improve the homeostatic model of insulin resistance and hemoglobin
A1c in diabetics26,68–69 and to lower the BMI in obese patients.
Lower levels of endogenous testosterone have been associated with longer duration of the QTc
interval
testosterone replacement has been shown to shorten the QTc interval
negative correlation has been demonstrated between endogenous testosterone levels and IMT of the carotid arteries,
abdominal aorta, and thoracic aorta
These findings suggest that men with lower levels of endogenous testosterone may be at a higher risk of developing atherosclerosis.
Current guidelines from the Endocrine Society make no recommendations on whether patients with heart
disease should be screened for hypogonadism and do not recommend supplementing patients with heart disease to improve survival.
The Massachusetts Male Aging Study also projects ≈481 000 new cases of hypogonadism annually in US men within the same age
group
since 1993 prescriptions for testosterone, regardless of the formulation, have increased nearly 500%
Testosterone levels are lower in patients with chronic illnesses
such as end‐stage renal disease, human immunodeficiency virus, chronic obstructive pulmonary disease, type 2 diabetes mellitus
(T2DM), obesity, and several genetic conditions such as Klinefelter syndrome
A growing body of evidence suggests that men with lower levels of endogenous testosterone are more prone to develop CAD during
their lifetimes
There are 2 major potential confounding factors that the older studies generally failed to account for. These factors are
the subfraction of testosterone used to perform the analysis and the method used to account for subclinical CAD.
The biologically inactive form of testosterone is tightly bound to SHBG and is therefore unable to bind to androgen receptors
The biologically inactive fraction of testosterone comprises nearly 68% of the total testosterone in human serum
The biologically active subfraction of testosterone, also referred to as bioavailable testosterone, is either loosely bound
to albumin or circulates freely in the blood, the latter referred to as free testosterone
It is estimated that ≈30% of total serum testosterone is bound to albumin, whereas the remaining 1% to 3% circulates as free
testosterone
it can be argued that using the biologically active
form of testosterone to evaluate the association with CAD will produce the most reliable results
English et al14 found statistically significant lower levels of bioavailable testosterone, free testosterone, and free androgen index in
patients with catheterization‐proven CAD compared with controls with normal coronary arteries
patients with catheterization‐proven CAD had statistically significant lower levels of bioavailable
testosterone
In conclusion, existing evidence suggests that men with CAD have lower levels of endogenous testosterone,13–18 and more specifically lower levels of bioavailable testosterone
low testosterone levels are associated with risk factors for CAD such as T2DM25–26 and obesity
In a meta‐analysis of these 7 population‐based studies, Araujo et al41 showed a trend toward increased cardiovascular mortality associated with lower levels of total testosterone, but statistical
significance was not achieved (RR, 1.25
the authors showed that a decrease of 2.1 standard deviations in levels of total testosterone was associated
with a 25% increase in the risk of cardiovascular mortality
the relative risk of all‐cause mortality in men
with lower levels of total testosterone was calculated to be 1.35
higher risk of cardiovascular mortality is associated with lower levels of bioavailable testosterone
Existing evidence seems to suggest that lower levels of endogenous testosterone are associated with higher rates of all‐cause
mortality and cardiovascular mortality
studies have shown that lower levels of endogenous bioavailable testosterone are associated with higher rates
of all‐cause and cardiovascular mortality
It may be possible that using bioavailable testosterone to perform mortality analysis will yield more accurate results because
it prevents the biologically inactive subfraction of testosterone from playing a potential confounding role in the analysis
The earliest published material
on this matter dates to the late 1930s
the concept that testosterone replacement therapy improves angina has yet to be proven wrong
In more
recent studies, 3 randomized, placebo‐controlled trials demonstrated that administration of testosterone improves myocardial
ischemia in men with CAD
The improvement in myocardial ischemia was shown to occur in response to both acute and chronic
testosterone therapy and seemed to be independent of whether an intravenous or transdermal formulation of testosterone was
used.
testosterone had no effect on endothelial nitric oxide activity
There is growing evidence from in
vivo animal models and in vitro models that testosterone induces coronary vasodilation by modulating the activity of ion channels,
such as potassium and calcium channels, on the surface of vascular smooth muscle cells
Experimental studies suggest that
the most likely mechanism of action for testosterone on vascular smooth muscle cells is via modulation of action of non‐ATP‐sensitive
potassium ion channels, calcium‐activated potassium ion channels, voltage‐sensitive potassium ion channels, and finally L‐type
calcium ion channels
Corona et al confirmed those results by demonstrating that not only total testosterone levels are lower among diabetics,
but also the levels of free testosterone and SHBG are lower in diabetic patients
Laaksonen et al65 followed 702 Finnish men for 11 years and demonstrated that men in the lowest quartile of total testosterone, free testosterone,
and SHBG were more likely to develop T2DM and metabolic syndrome.
Vikan et al followed 1454 Swedish men for 11
years and discovered that men in the highest quartile of total testosterone were significantly less likely to develop T2DM
authors demonstrated a statistically significant increase in the incidence of T2DM in subjects receiving gonadotropin‐releasing
hormone antagonist therapy. In addition, a significant increase in the rate of myocardial infarction, stroke, sudden cardiac
death, and development of cardiovascular disease was noted in patients receiving antiandrogen therapy.67
Several authors have demonstrated
that the administration of testosterone in diabetic men improves the homeostatic model of insulin resistance, hemoglobin A1c,
and fasting plasma glucose
Existing evidence strongly suggests that the levels of total and free testosterone are lower among diabetic patients compared
with those in nondiabetics
insulin seems to be acting as a stimulant for the hypothalamus to secret gonadotropin‐releasing
hormone, which consequently results in increased testosterone production. It can be argued that decreased stimulation of the
hypothalamus in diabetics secondary to insulin deficiency could result in hypogonadotropic hypogonadism
BMI has been shown to be inversely associated with testosterone levels
This interaction may be a result
of the promotion of lipolysis in abdominal adipose tissue by testosterone, which may in turn cause reduced abdominal adiposity.
On the other hand, given that adipose tissue has a higher concentration of the enzyme aromatase, it could be that increased
adipose tissue results in more testosterone being converted to estrogen, thereby causing hypogonadism. Third, increased abdominal
obesity may cause reduced testosterone secretion by negatively affecting the hypothalamus‐pituitary‐testicular axis. Finally,
testosterone may be the key factor in activating the enzyme 11‐hydroxysteroid dehydrogenase in adipose tissue, which transforms
glucocorticoids into their inactive form.
increasing age may alter the association between testosterone and CRP. Another possible explanation
for the association between testosterone level and CRP is central obesity and waist circumference
Bai et al
have provided convincing evidence that testosterone might be able to shorten the QTc interval by augmenting the activity of
slowly activating delayed rectifier potassium channels while simultaneously slowing the activity of L‐type calcium channels
consistent evidence
that supplemental testosterone shortens the QTc interval.
Intima‐media thickness (IMT) of the carotid artery is considered a marker for preclinical atherosclerosis
Studies have shown that levels of endogenous testosterone are inversely
associated with IMT of the carotid artery,126–128,32,129–130 as well as both the thoracic134 and the abdominal aorta
1 study has demonstrated that lower levels of free testosterone are associated with accelerated progression
of carotid artery IMT
another study has reported that decreased levels of total and bioavailable testosterone are associated with progression
of atherosclerosis in the abdominal aorta
These findings suggest that normal physiologic testosterone levels may help to protect men from the development of atherosclerosis
Czesla et al successfully demonstrated that the muscle specimens that were exposed to metenolone had a significant shift
in their composition toward type I muscle fibers
Type I muscle fibers, also known as slow‐twitch or oxidative fibers, are
associated with enhanced strength and physical capability
It has been shown
that those with advanced CHF have a higher percentage of type II muscle fibers, based on muscle biopsy
Studies have
shown that men with CHF suffer from reduced levels of total and free testosterone.137 It has also been shown that reduced testosterone levels in men with CHF portends a poor prognosis and is associated with
increased CHF mortality.138 Reduced testosterone has also been shown to correlate negatively with exercise capacity in CHF patients.
Testosterone replacement therapy has been shown to significantly improve exercise capacity, without affecting LVEF
the results of the 3 meta‐analyses seem to indicate that testosterone replacement therapy does not cause an increase
in the rate of adverse cardiovascular events
Data from 3 meta‐analyses seem to contradict the commonly
held belief that testosterone administration may increase the risk of developing prostate cancer
One meta‐analysis reported
an increase in all prostate‐related adverse events with testosterone administration.146 However, when each prostate‐related event, including prostate cancer and a rise in PSA, was analyzed separately, no differences
were observed between the testosterone group and the placebo group
the existing data from the 3 meta‐analyses seem to indicate that testosterone replacement therapy does not increase
the risk of adverse cardiovascular events
the authors correctly
point out the weaknesses of their study which include retrospective study design and lack of randomization, small sample size
at extremes of follow‐up, lack of outcome validation by chart review and poor generalizability of the results given that only
male veterans with CAD were included in this study
the studies that failed to find an association
between testosterone and CRP used an older population group
low testosterone may influence the severity of CAD by adversely affecting
the mediators of the inflammatory response such as high‐sensitivity C‐reactive protein, interleukin‐6, and tumor necrosis
factor–α
Good review of Testosterone and CHD. Low T is associated with increased all cause mortality and cardiovascular mortality, CAD, CHF, type II diabetes, obesity, increased IMT, increased severity of CAD and CHF. Testosterone replacement in men with low T has been shown to improve exercise tolerance in CHF, improve insulin resistance, improve HgbA1c and lower BMI in the obese.
vitamin D plus calcium in those with Diabetes and low vitamin D four to improve insulin resistance, HDL, LDL, beta cell function, and HgbA1c. This was a short course study of 8 weeks. Only abstract available.
Testosterone has beneficial
effects on several cardiovascular risk factors, which include cholesterol, endothelial dysfunction and inflammation
In clinical studies, acute and chronic testosterone administration increases coronary artery diameter and flow, improves
cardiac ischaemia and symptoms in men with chronic stable angina and reduces peripheral vascular resistance in chronic heart
failure.
testosterone is an L-calcium channel blocker and induces potassium
channel activation in vascular smooth muscle cells
Animal studies have consistently demonstrated that testosterone is atheroprotective,
whereas testosterone deficiency promotes the early stages of atherogenesis
there is no compelling evidence that testosterone replacement to levels within the normal healthy range contributes
adversely to the pathogenesis of CVD (Carson & Rosano 2011) or prostate cancer (Morgentaler & Schulman 2009)
bidirectional effect between decreased testosterone
concentrations and disease pathology exists as concomitant cardiovascular risk factors (including inflammation, obesity and
insulin resistance) are known to reduce testosterone levels and that testosterone confers beneficial effects on these cardiovascular
risk factors
Achieving a normal physiological testosterone concentration through the administration
of testosterone replacement therapy (TRT) has been shown to improve risk factors for atherosclerosis including reducing central
adiposity and insulin resistance and improving lipid profiles (in particular, lowering cholesterol), clotting and inflammatory
profiles and vascular function
It is well known that impaired erectile function and CVD are closely
related in that ED can be the first clinical manifestation of atherosclerosis often preceding a cardiovascular event by 3–5
years
no decrease in the response (i.e. no tachyphylaxis) of testosterone and that patient benefit persists in the long term.
free testosterone
levels within the physiological range, has been shown to result in a marked increase in both flow- and nitroglycerin-mediated
brachial artery vasodilation in men with CAD
Clinical studies, however, have revealed either small reductions of 2–3 mm in diastolic pressure or no significant effects
when testosterone is replaced within normal physiological limits in humans
Endothelium-independent mechanisms of testosterone
are considered to occur primarily via the inhibition of voltage-operated Ca2+ channels (VOCCs) and/or activation of K+ channels (KCs) on smooth muscle cells (SMCs)
Testosterone shares the same molecular binding site as nifedipine
Testosterone increases the expression of endothelial nitric oxide synthase (eNOS)
and enhances nitric oxide (NO) production
Testosterone also inhibited
the Ca2+ influx response to PGF2α
one of the major actions of testosterone is on NO and its signalling pathways
In addition to direct effects on NOS expression, testosterone may also affect phosphodiesterase type 5 (PDE5 (PDE5A)) gene expression, an enzyme controlling the degradation of cGMP, which acts as a vasodilatory second messenger
the significance of the action of testosterone on VSMC apoptosis and proliferation in atherosclerosis is difficult
to delineate and may be dependent upon the stage of plaque development
Several human studies have shown that carotid IMT (CIMT) and aortic calcification negatively correlate
with serum testosterone
t long-term testosterone treatment reduced CIMT in men with low testosterone levels
and angina
neither intracellular nor membrane-associated
ARs are required for the rapid vasodilator effect
acute responses appear to be AR independent, long-term AR-mediated effects on the vasculature have also been described,
primarily in the context of vascular tone regulation via the modulation of gene transcription
Testosterone and DHT increased the expression of eNOS in HUVECs
oestrogens have been shown to activate eNOS and stimulate NO production in an ERα-dependent manner
Several studies, however, have demonstrated that the vasodilatory actions of testosterone are not reduced by aromatase
inhibition
non-aromatisable DHT elicited similar vasodilation to testosterone treatment in arterial smooth muscle
increased endothelial NOS (eNOS) expression and phosphorylation were observed in testosterone- and DHT-treated
human umbilical vein endothelial cells
Androgen deprivation leads to a reduction in neuronal NOS expression associated with a decrease of intracavernosal pressure
in penile arteries during erection, an effect that is promptly reversed by androgen replacement therapy
Observational evidence suggests that several pro-inflammatory cytokines (including interleukin 1β (IL1β), IL6, tumour necrosis
factor α (TNFα), and highly sensitive CRP) and serum testosterone levels are inversely associated in patients with CAD, T2DM
and/or hypogonadism
patients with the
highest IL1β concentrations had lower endogenous testosterone levels
TRT has been reported to significantly
reduce TNFα and elevate the circulating anti-inflammatory IL10 in hypogonadal men with CVD
testosterone treatment to normalise levels in hypogonadal men with the MetS
resulted in a significant reduction in the circulating CRP, IL1β and TNFα, with a trend towards lower IL6 compared with placebo
parenteral testosterone undecanoate, CRP decreased significantly in hypogonadal elderly
men
Higher levels of serum adiponectin have been shown to lower cardiovascular risk
Research suggests that the expression of VCAM-1, as induced by pro-inflammatory cytokines such as TNFα or interferon γ (IFNγ
(IFNG)) in endothelial cells, can be attenuated by treatment with testosterone
Testosterone also inhibits the production of pro-inflammatory cytokines such as IL6, IL1β and TNFα in a range of cell types
including human endothelial cells
decreased inflammatory response to TNFα and lipopolysaccharide (LPS) in
human endothelial cells when treated with DHT
The key to unravelling the link between testosterone
and its role in atherosclerosis may lay in the understanding of testosterone signalling and the cross-talk between receptors
and intracellular events that result in pro- and/or anti-inflammatory actions in athero-sensitive cells.
testosterone
functions through the AR to modulate adhesion molecule expression
pre-treatment with DHT reduced the cytokine-stimulated inflammatory response
DHT inhibited NFκB activation
DHT could inhibit an LPS-induced upregulation of MCP1
Both NFκB and
AR act at the transcriptional level and have been experimentally found to be antagonistic to each other
As the AR and NFκB are mutual antagonists, their interaction and influence on functions can be bidirectional, with inflammatory
agents that activate NFκB interfering with normal androgen signalling as well as the AR interrupting NFκB inflammatory transcription
prolonged exposure of vascular cells to the inflammatory activation of NFκB associated with atherosclerosis
may reduce or alter any potentially protective effects of testosterone
DHT and IFNγ also modulate each other's signalling through interaction at the transcriptional
level, suggesting that androgens down-regulate IFN-induced genes
(Simoncini et al. 2000a,b). Norata et al. (2010) suggest that part of the testosterone-mediated atheroprotective effects could depend on ER activation mediated by the testosterone/DHT
3β-derivative, 3β-Adiol
TNFα-induced induction of ICAM-1, VCAM-1 and E-selectin as well as MCP1 and IL6 was significantly
reduced by a pre-incubation with 3β-Adiol in HUVECs
3β-Adiol also reduced LPS-induced gene expression
of IL6, TNFα, cyclooxygenase 2 (COX2 (PTGS2)), CD40, CX3CR1, plasminogen activator inhibitor-1, MMP9, resistin, pentraxin-3 and MCP1 in the monocytic cell line U937 (Norata et al. 2010)
This study suggests that testosterone metabolites, other than those generated through aromatisation, could exert anti-inflammatory
effects that are mediated by ER activation.
The authors suggest that DHT differentially
effects COX2 levels under physiological and pathophysiological conditions in human coronary artery smooth muscle cells and
via AR-dependent and -independent mechanisms influenced by the physiological state of the cell
There are, however, a number of systematic meta-analyses of clinical trials of TRT that have not demonstrated
an increased risk of adverse cardiovascular events or mortality
The TOM trial, which was designed to investigate the effect of TRT on frailty in elderly men, was terminated prematurely
as a result of an increased incidence of cardiovascular-related events after 6 months in the treatment arm
trials of TRT in men with either chronic stable angina or chronic cardiac failure have also found no increase
in either cardiovascular events or mortality in studies up to 12 months
Evidence may therefore suggest that low testosterone levels and testosterone levels above the normal range have an adverse
effect on CVD, whereas testosterone levels titrated to within the mid- to upper-normal range have at least a neutral effect
or, taking into account the knowledge of the beneficial effects of testosterone on a series of cardiovascular risk factors,
there may possibly be a cardioprotective action
The effect of testosterone on human vascular function is a complex issue and may be dependent upon the underlying androgen
and/or disease status.
the majority of studies suggest that testosterone may display both acute and
chronic vasodilatory effects upon various vascular beds at both physiological and supraphysiological concentrations and via
endothelium-dependent and -independent mechanisms
administered zoledronic acid (4 mg). Prednisolone (1 mg/kg/day) was started and simultaneously, she was administered first cycle of ABVD (Adriamycin: 25 mg/m2, Bleomycin: 10 U/m2, Vinblastine: 6 mg/m2 and Dacarbazine: 375 mg/m2), which led to normalisation of serum calcium levels over 4 days and improvement in her hemoglobin levels
Etiology of anemia in Hodgkin’s lymphoma is multifactorial. Anemia of chronic disease, decreased red cell survival, infiltration of bone marrow by tumor and marrow suppression by chemotherapy/radiotherapy are the common mechanisms
Our case had only a transient response to steroids and chemotherapy. Therefore, she was treated with Rituximab which brought hemolysis under control
Mechanism of hypercalcemia in HL has long been suggested to involve extra-renal activation of 1α-hydroxylase leading to production of 1, 25(OD)2 Vitamin D3 or Calcitriol, an active metabolite of Vitamin D, which leads to increased re-absorption of calcium and phosphate from intestine, increased osteoclast activation and bone resorption as well as increased phosphate re-absorption in renal tubules
Hypercalcemia of malignancy involves three mechanisms: 1. Humoral hypercalcemia mediated by PTHrP—seen in solid tumors like breast cancer and adult T cell leukemia/lymphoma (ATLL), 2. Direct osteoclast mediated bone resorption due to bony metastasis—seen in solid tumors and multiple myeloma, 3. Calcitriol mediated hypercalcemia—seen in Hodgkin’s and non-Hodgkin’s lymphoma as well as granulomatous disorders like tuberculosis, sarcoidosis, leprosy and disseminated Candidiasis
Hypercalcemia in HL is rare and its incidence has been reported as 0.9, 1.6 and 5.4 % in different series
The source of 1α-hydroxylase in HL has been postulated as monocytes and macrophages infiltrating the tumor akin to tuberculosis or sarcoidosis and is stimulated by IFN-γ secreted by T-lymphocytes
Like sarcoidosis, patients with HL exhibit increased sensitivity to Vitamin D supplements and sunlight, which have been found to precipitate hypercalcemia in these patients
Classical biochemical profile in Calcitriol mediated hypercalcemia include: an elevated calcium, normal/slightly elevated phosphate, normal 25(OH) Vitamin D, suppressed PTHrP and PTH, elevated Calcitriol and a normal/increased tubular reabsorption of phosphate
not been associated with a poorer prognosis and tends to subside after treatment of the underlying disease
Study finds that 57% of study participants saw a 14% reduction in coronary calcium score with combined EDTA plus tetracycline. The reduction may seem modest, and it is, but the delivery method of the EDTA is going to limit the effects. EDTA should be given IV.
steroid hormones typically interact with their cognate receptor in the cytoplasm for AR, glucocorticoid receptor (GR) and PR, but may also bind receptor in the nucleus as appears to often be the case for ERα and ERβ
This ligand binding results in a conformational change in the cytoplasmic NRs that leads to the dissociation of HSPs, translocation of the ligand-bound receptor to the nucleus
In the nucleus, the ligand-bound receptor dimerizes and then binds to DNA at specific HREs to regulate gene transcription
some steroid hormone-induced nuclear events can occur in minutes
the genomic effects of steroid hormones take longer, with changes in gene expression occurring on the timescale of hours
Classical steroid hormone signaling occurs when hormone binds nuclear receptors (NR) in the cytoplasm, setting off a chain of genomic events that results in, among other changes, dimerization and translocation to the nucleus where the ligand-bound receptor forms a complex with coregulators to modulate gene transcription through direct interactions with a hormone response element (HRE)
NRs have been found at the plasma membrane of cells, where they can propagate signal transduction often through kinase pathways
Membrane-localized ER, PR and AR have been reported to modulate the activity of MAPK/ERK, phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), nitric oxide (NO), PKC, calcium flux and increase inositol triphosphate (IP3) levels to promote cell processes including autophagy, proliferation, apoptosis, survival, differentiation, and vasodilation
ERα36, a 36kDa truncated form of ERα that lacks the transcriptional activation domains of the full-length protein. Membrane-localized ERα36 can activate pathways including protein kinase C (PKC) and/or mitogen activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) to promote the progression of various cancers
G protein-coupled receptor 30 (GPR30), also referred to as G protein-coupled estrogen receptor (GPER), is a membrane-localized receptor that has been observed to respond to estrogen to activate rapid signaling
hormone-responsive G protein coupled receptor is Zip9, which androgens can activate
GPRC6A is another G protein-coupled membrane receptor that is responsive to androgen
androgen-mediated non-genomic signaling through this GPCR can modulate male fertility, hormone secretion and prostate cancer progression
non-NR proteins located at the cell surface can bind to steroid hormones and respond by eliciting rapid signaling events
Estrogens have been shown to induce rapid (i.e. seconds) calcium flux via membrane-localized ER (mER)
ER-calcium dynamics lead to activation of kinase pathways such as MAPK/ERK which can result in cellular effects like migration and proliferation
17β-estradiol (E2) has been reported to promote angiogenesis through the activation of GPER
Membrane NRs may also mediate rapid signaling through crosstalk with growth factor receptors (GFR)
A similar crosstalk occurs between the receptor tyrosine kinase insulin-related growth factor-1 receptor (IGF-IR) and ERα. Not only does IGF-IR activate ERα, but inhibition of IGF-IR downregulates estrogen-mediated ERα activity, suggesting that IGF-IR is essential for maximal ERα signaling
This is a bombshell that shatters the current right brain approach to ER. It completely shatters the concept of eat sugar, whatever you want, with cancer treatment in ER+ or hormonally responsive cancer!
Further, ER activates IGF-IR pathways including MAPK
GPER is involved in the transactivation of the EGFR independent of classical ER
tight interconnection between genomic and non-genomic effects of NRs.
non-genomic pathways can also lead to genomic effects
androgen-bound AR associates with the kinase Src at the plasma membrane, activating Src which then leads to a signaling cascade through MAPK/ERK
However, Src can also increase the expression of AR target genes by the ligand-independent transactivation of AR
extranuclear steroid hormone actions can potentially reprogram nuclear NR events
estrogen modulated the expression of several genes including endothelial nitric oxide synthase (eNOS) via rapid signaling pathways
epigenetic changes can then mediate genomic events in uterine tissue and breast cancer cells