Estrogen Receptors, Estrogenics, And The Rise of Western Disease (Part 1)

The Story Of A Hormone That Gets All The Blame

Should estrogen really get the bad rep it has, or is there something else missing we haven't fully looked at?

I'll let you decide.

In this post, we are going to be discussing estrogen receptors and how estrogen affects the body.

In the next post, we will discuss what "fake" estrogens (estrogenics) do to the body, and how you can protect yourself from the dangers of estrogenics.

 
 

Introduction To Estrogen

When people hear estrogen they think mostly of women and menstrual cycles. R

Well, it does play a part in those, so that's not wrong, but it also does play a in many other aspects of creating a healthy body. R

It acts directly on the hypothalamus (the part of the brain that regulates metabolism) to control food intake, energy usage, and how the body should store or burn fat. R 

Estrogen also works on muscle, the liver, fat (as an organ - more about this later), and the immune system. R

It is also involved in regulating inflammation in the body. R

Basics Of Estrogen

 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660717/figure/F4/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660717/figure/F4/

 

Estrogens are one of 3 sex hormones (the others being androgens/anabolic steroids like testosterone and progestogens like progesterone). R

There are 4 major naturally occurring forms of estrogen:

  1. Estrone (E1) - predominant during menopause R
  2. Estradiol (E2) - predominant reproductive years (most potent and prevalent in the body) R
  3. Estriol (E3) - most prominent in the body, but the weakest of the 4 R
  4. Estetrol (E4) - produced only during pregnancy R

Benefits Of Estrogen

  • Anti-Aging
  • Decreases Risk of Dementia, Alzheimer's and Parkinson's Disease
  • Decreases Risk of Diabetes
  • Enhances Mood
  • Improves Bone Density
  • Improves Cognition
  • Improves Hair, Skin, and Wound Healing
  • Increases Energy Levels
  • Protects Against Leaky Gut
  • Protects the Heart
  • Suppresses Food Intake

Downsides Of Estrogen

  • Accelerates the Storage of Fat
  • Causes Brain Fog
  • Causes Constipation
  • Decreases Muscle Tone
  • Increases Chance of Cancer
  • Increases Likelihood of Developing Gallstones
  • Makes You More Sensitive To Pain
  • May Induce Schizophrenia

This next part of the post now gets a little bit technical, so click here if you want to skip to toxic xenoestrogens (I won't get offended). 

Click here if you want to skip to menopause and loss of estrogen in the body. 

Estrogen Receptors

Where Are Estrogen Receptors

Estrogen receptors are found in: R R

  • Bladder
  • Bones
  • Brain
  • Breasts
  • Esophagus
  • Eyes
  • Fat (adipocytes)
  • Gut Lining
  • Immune cells (mast cells, macrophages, monocytes, dendritic, T and B cells)
  • Kidneys
  • Liver
  • Lungs
  • Lymph nodes
  • Mitochondria
  • Muscle
  • Ovaries
  • Pancreas
  • Prostate
  • Skin
  • Spleen
  • Stem cells
  • Thyroid
  • Tonsils
  • Trachea
  • Uterus

We covered most of these receptors (along with PCOS and menopause) in my interview with Felice Gersh.

Estrogen Receptor Alpha (ERalpha/ERα) is expressed in and regulates:

  • Brain: hypothalamus and amygdala
  • Gonadal organs: uterus, ovary, prostate, testes, and breast
  • Regulates functions: Reproduction, feeding, gonadotropin-releasing hormone (GnRH), LH and FSH
  • Contributes to: Autoimmune conditions R

Estrogen Receptor Beta (ERbeta/ERβ) is expressed in and regulates:

  • Brain: hippocampus, claustrum, and cerebral cortex
  • Non-gonadal organs: colon, bone barrow, vascular endothelium, lung, and bladder
  • Regulates functions: Mood, cognition/cognitive performance and anxiety

There are greater levels of ERα expression in women, but levels of ERβ expression do not differ. R

ERalpha and ERbeta regulate gene expression, while G-protein coupled, membrane localized estrogen receptors (GPR30) mediate non-genomic actions of estrogen. R

Metabolites of testosterone (similar to estrogen) can also activated ERs. R

How Estrogen Affects The Body

This part is also technical, so it's cool if you go onto the next section (but this time I'll get offended - jk).

I've bolded the most important parts for easier reading.

1. Estrogen And Mitochondrial Function

 
https://longevityandhealthspan.biomedcentral.com/articles/10.1186/2046-2395-3-2

https://longevityandhealthspan.biomedcentral.com/articles/10.1186/2046-2395-3-2

 

Mitochondria are parts of the cell that produce energy (ATP) for the body. R

Estrogen regulates homeostasis (normal balance) of mitochondria.

One way estrogen does this is by binding to estrogen receptors in mitochondria to turn on a genetic pathway called Nuclear Respiratory Factor-1 (NRF-1). R

NRF1 controls genes that create new mitochondria (for more energy), oxygen consumption, and programmed cell death (protecting against cancer. R

Estrogen can turn on other gene pathways as well such as mitogen-activated protein kinase (MAPK), phosphatidylinositol-3-kinase (PI3K), G protein regulated signaling, c-fos, protein kinase C (PKC) and calcium (Ca2+) influx.

Each of these pathways regulate cellular function and survival. R

For example, estrogen's ability to regulate calcium (Ca2+) channels helps controls cellular respiration (the metabolism of cells). R

Ca2+ homeostasis is critical for healthy neurons and decreases the chances of developing many metabolic disorders, such as Alzheimer's disease. R

Estrogen can also bind to estrogen receptors in mitochondria can also increase manganese-superoxide dismutase (MnSOD) and glutathione peroxidase (GPx). R

MnSOD (aka SOD) and GPx are two very strong anti-oxidants that clean up free radicals in the cell and help keep cellular homeostasis. R

They do this by converting free radicals into hydrogen peroxide (H2O2), which is more readily available to cross out of the cell. R

2. Estrogen And The Brain

 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1778460/figure/F6/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1778460/figure/F6/

 

Estrogen in the brain can protect against neurotoxicity and excitotoxic neuronal loss. R

This means that estrogen protects the brain from too much neuronal signaling in the brainR

One mechanism for this is that estrogen receptors on neurons co-express GABA (an inhibitory/calming neurotransmitter) and neuropeptide Y (NPY). R

NPY (which estrogen can activate) increases food intake and storage of energy as fat, reduces anxiety and stress, reduces pain perception, affects the circadian rhythm, reduces alcohol intake, lowers blood pressure, and controls epileptic seizures (which all of these will be discussed more in depth below). R R R

The way NPY works in your brain is determined by the ratio of which types of estrogen receptor you have in your brain (that's all for NPY now, there will be more on NPY later in this post).

Estrogen is able to protect against myelin (the protective coating around neurons) degradation, a common problem seen in the pathology of multiple sclerosis. R

Estrogen receptors are found in myelin in both the brain and spinal cord. R

Estrogen also acts similarly to brain-derived neurotrophic factor (BDNF). R

BDNF is a factor that creates new brain and neuronal connections. R

For example, in the hippocampus (long term memory center of the brain) and in other parts of the brain as well, similarly to BDNF, estrogen can enhance learning, spacial memory and long term potentiation (LTP). R

Estrogen can induce the expression of BDNF as well and enhance synaptic plasticity (creating more connections between neurons). R R

Not only that, but estrogen can improve memory consolidation in the hippocampus (within minutes). R

Also, estrogen has been shown to prevent Alzheimer's Disease (AD) and cognitive decline in post-menopausal women. R R R

One way it helps is that estrogen has shown to reduce amyloid beta (plaques that build up in the brain of AD patients) in the brain. R

Another way is that estrogen reactivates glucose transports (GLUT), which allow the brain to use glucose again instead of ketone bodies (we will discuss this further below). R

This is because there is a loss of estrogen during menopause (more on this below). R

Estrogen has shown to have anti-inflammatory properties on the brain and spine. R 

For example, estrogen can prevent excess inflammation after spinal cord injuries (SCI). R

Estrogen can also prevent the development of parkinson disease (PD), which is characterized by a loss of dopamine in the brain. R

PD is characterized by loss of dopamine in the brain and estrogen helps maintain healthy dopamine levels. R R

Estrogen also increases acetylcholine in the brain, which is helpful for learning and memory retention. R

It is important to note that estrogen receptors in the prefrontal cortex (front part of the brain) when activated by Selective Estrogen Receptor Modulators (SERMs) can induce schizophrenic like symptoms in those genetically predisposed. R

In the brain, estrogen can induce mast cell-derived brain fog. R

When mast cells (regulatory immune modulators) are active (specifically in a pro-inflammatory state), they can cause brain fog. R

Mast cells have estrogen receptors and when they are activated by estrogen, they can act increase inflammation. R

On example of this is estrogen's ability to make mast cells release histamine (which can contribute to histamine intolerance). R

Progesterone can inhibit estrogen-induced mast cell degranulation. R 

3. Estrogen And Metabolism 

 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660717/figure/F2/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660717/figure/F2/

 

Estrogen improves inflammation related to metabolic dysfunction in many ways. R

For example, estrogen can enhance the way glucose is used in the body. R

Glucose is very important for the body because it is required by mitochondria to create ATP. R

One example is that estrogen can enhance glucose transporters (GLUT) function. R

GLUTs  are necessary for transporting glucose (and other sugar molecules) to all the organs in the body (including the brain). R

Declined function of GLUT is commonly seen in Alzheimer's disease (AD), diabetes, and other metabolic diseases. R

For example, in AD GLUT can become impaired, which makes the brain unavailable to use glucose as its energy source. R

So, people will turn to the ketogenic diet (high fat, low carb) to enhance ketone bodies (beta hydroxybutyrate), which is an alternate source of energy for the brain. R

This is great but doesn't fix the problem if GLUT impairment is from low estrogen levels. R

Estrogen also potentiates cholecystokinin (CCK), which suppresses food intakeR

CCK makes you less hungry and satiated. R

Estrogen also increases leptin sensitivity. R

Leptin is a powerful signal in the brain that inhibits food intake and increases energy expenditure. R

Leptin resistance (LR - the inability for the brain to recognize leptin signaling) is commonly seen in people who are inflamed. R

Neuropeptide Y (NPY) can be activated by estrogen and LR. R

Increased NPY can increase hunger, food intake, and fat accumulation while decreasing energy output. R R

This (LR and NPY) is what signals estrogen to tell the body to fat directly store more fat. R

Signaling to fat?

Yes fat is your largest organ (I bet you thought it was your skin). R

This is because fat has neuroendocrine receptors and the ability to cross communicate with the other organs in the body. R

When estrogen tells the body to store more fat, it does it by activating peroxisome proliferator-activated receptor (PPAR-γ) .R

PPARgamma is a mechanism that tells the body to specifically store glucose into fat. R

Estrogen also works on insulin receptors. R

For example, estrogen can improve insulin sensitivity by fixing expression of insulin in the liver. R

It also helps with insulin resistance by decreasing the oxidative stress of insulin (since insulin is an inflammatory molecule). R

Estrogen also stimulates AMPK. R

AMPK is a central regulator of many cellular processes (including cell growth, mitochondrial creation, and management of free radicals). R

Estrogen directly and indirectly affects the thyroid and production of growth hormones (GH). R

For example, estrogen deficiency (along with thyroid hormones) inhibits the release of GH after exercise, stopping many of the benefits of exercise. R

4. Estrogen And Circadian Function

Your circadian clock (24 hour clock cycle) is controlled by the suprachiasmatic nucleus (SCN), located in the brain. R

It has both estrogen and testosterone receptors. R

These receptors help synchronize the body with the external environment (like light and food). R R

Estrogen modulates sleepR

For example, estrogen lengthens the secretion of adrenocorticotropic hormone (ACH), which regulates cortisol production and circadian rhythms. R

This can make stress worse and it is one reason why stress alters sleep. R

In women, estrogen decreases non-rapid eye movement (NREM) and rapid eye movement (REM) sleep, while in men estrogen increases REM sleep. R

5. Estrogen And Mood Disorders

As seen with postpartum, perimenopause, and postmenopause depression, withdrawal of estrogen is correlated with significant mood lowering. R R R

The gene Catechol-O-methyl transferase (COMT) heavily influences estrogen in mood disorders. 

COMT is an enzyme that breaks down catecholamines (such as dopamine, epinephrine, and norepinephrine). R

For example, protein levels of COMT in the hypothalamus (responsible for certain metabolic processes and other activities of the autonomic nervous system) enhances estrogens ability to control obsessive compulsive disorder (OCD). R

In some cases with depression, estrogen receptors and BDNF receptors have been shown to be inactive in parts of the amygdala (a part of the brain that processes memory, decision-making, and emotional reactions). R

Estrogen in the brain can also act like a selective serotonin reuptake inhibitor (SSRI), by estrogen's ability to inhibit the re-uptake of serotonin. R

Also, estrogen can increase dopamine (D2) receptors (necessary for a positive mood, although too much could induce schizophrenia). R

Estrogen can increase pain sensitivity. R

Low levels of estrogen have also been linked to increased anxiety. R

6. Estrogen And Cancer

Estrogen can increase superoxide, a free radical that can destroy cancerous cells. R

Estrogen activation of receptors have shown to help against:

  • Brain Cancer R
  • Breast Cancer R R
  • Colon Cancer R
  • Melanoma Cancer R
  • Non-Melanoma Cancers R
  • Prostate Cancer R 

It should be noted that estrogen has shown to inhibit apoptosis (programmed cell death), which may progress tumor formation and replication.  R

Here are a few supplements that can directly help estrogen influenced cancer:

  • Blocking Blue Light has shown to protect against breast cancer. R
  • EGCG (from green tea) acts as a histone deacetylase inhibitor (HDACi) and may be able to protect against breast cancer. R
  • Melatonin decreases binding of estrogen to receptors in breast cancer stem cells. R

Decreasing leptin resistance also helps with breast cancer. R

7. Estrogen And The Vascular System

 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2274006/figure/F1/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2274006/figure/F1/

 

The heart (as well as the ovaries and the brain) has the most mitochondria in the body. R

Estrogen can protect the mitochondria in the heart, allowing the heart to have good amounts of energy. 

Estrogen protects against atherosclerosis (hardening of the arteries), which is why the rate of heart disease for women is low until after menopause. R

First, estrogen increases nitric oxide (NO). R

NO relaxes arteries and promotes healthy blood pressureR

Second, estrogen works on vasopressin (VP - also known as antidiuretic hormone) in substantially different ways in each part of the body (this is dependent on what kind of estrogen receptor is being activated). R

Vasopressin controls blood pressure and urine excretion. R

Since estrogen can inhibit some the effects of VP, it helps lower blood pressure. R

This effect of estrogen on VP is different in males than females, and chances throughout the cycle and during pregnancy. R

This is why water retention is so common during pregnancy. R

It is important to note that testosterone and dihydrotestosterone (DHT - testosterone's androgenic metabolite) have similar effects on VP as estrogen does. R  

Estrogen promotes lung function as well by supporting alveoli (the sacs in the lungs that absorb and release oxygen). R

Estrogen has also shown to decrease low density lipoprotein (LDL) particle size, and smaller LDL particles (which are commonly associated with atherosclerosis). R

8. Estrogen And The Gut

 
https://academic.oup.com/jnci/article/doi/10.1093/jnci/djw029/2457487/The-Intestinal-Microbiome-and-Estrogen-Receptor

https://academic.oup.com/jnci/article/doi/10.1093/jnci/djw029/2457487/The-Intestinal-Microbiome-and-Estrogen-Receptor

 

Estrogen can reduce bowel motility (how fast food goes through the gut), fixing diarrhea or causing constipation. R

Estrogen can also increase the risk of developing gallbladder stones. R

Estrogen can prevent the development of stomach ulcers. R 

Estrogen can also protect against developing leaky gut (intestinal permeability) by downregulating inflammatory cytokines (chemical messengers) in the gut. R

The microbiome plays a huge role on how the estrogen works on the gut.

For example, dysfunction in the way estrogens are metabolized in the gut (also know as the "estrobolome"), may increases chances of developing breast cancer. R

9. Estrogen And The Immune System

Estrogen affects many immune and inflammatory conditions including autoimmune diseases and the immune's response to parasites and bacterial infections. R

Estrogen can reduce a TH1 cytokines (pro inflammatory chemical messengers). R

For example, when rats were injected with lipopolysacharide (LPS - bacteria fragments made to stimulate an immune response), estrogen was able to strengthen the inflammatory response to fight the pathogen. R

Estrogen also helps fight infections that would cause buildup of plaque. R

Estrogen has anti-microbial properties in that it can inhibit or protect against:

  • Ebola R
  • Hepatitis C Virus R R
  • HIV R
  • Infections in Bone R 
  • Malaria R
  • Puumala virus infection R
  • Urinary Tract Infections (UTIs - when estrogen is taken vaginally) R R R

One reason for why estrogen is great at fighting infections and inflammation is that it helps mobilize white blood cells and neutrophils (immune cells needed to fight foreign invaders). R

10. Estrogen And Sex Organs/Sexual Drive

In women, estrogen:

  • Increases breast size during puberty and pregnancy (along with GH and IGF-1, which can be repressed by testosterone) R R
  • Induces lordosis (wanting to have sex) behavior - this is controlled by the ventromedial nucleus of the hypothalamus R R
  • Increases uterine growth R
  • Increases vaginal lubrication R
  • Promotes sexual receptivity  - testosterone without free estrogen actually decreases sex drive R R
  • Stimulates endometrial growth R
  • Thickens the vaginal wall R

In men,  estrogen:

  • Promotes a healthy libido R
  • Regulates healthy production of sperm R

11. Estrogen And Pregnancy/Cycles In Women

Estrogen regulates a healthy pregnancy and menstrual cycles in women. 

Every cycle, a surge in estrogen levels induce the release of luteinizing hormone. R

This then triggers ovulation by releasing the egg from the Graafian follicle in the ovary. R

Estrogen together with progesterone (another sex hormone) promotes and maintains the uterus lining in preparation for insemination of the egg. R

During pregnancy there is an increase in breast size because of an increase in estrogen, growth hormone (GH) and insulin-like growth factor 1 (IGF-1). R R

Estrogen, progesterone and prolactin (an inhibitor neurotransmitter and hormone) also help maintain and create the connective tissue found in breast tissue. R R

The increase of the breast tissue helps with lactation (milk production) for the upcoming baby. R R

Estrogen also upregulates oxytocin receptor in myometrium (making the mother fall in love with her child). R

Interestingly, it has been shown that estrogen levels in men who are fathers are higher than non-fathers. R

12. Estrogen and Human Development

Estrogen is very important for proper brain development and cognitionR

For example, alterations in estrogen receptors are commonly found in Autism Spectrum disorders (ASD). R

High levels of testosterone and low levels of estrogen during pregnancy also contribute ASD development. R

Faulty development of estrogen receptors may also contribute to Attention Deficit Hyperactivity Disorder (ADHD), schizophrenia, Tourette’s Syndrome, Fragile X syndrome (FXS), Bipolar Disorder, and other neurological disorders. R

Estrogen also plays a role in the sexual orientation and gender identity of the child. R

For example, estrogen has masculinizing effects on the brain of baby boys while in the womb. R

Oxytocin (the bonding hormone/neurotransmitter) also regulates sexual orientation during development. R

The microbiome (bacteria) from semen in the vagina can also influence estrogen receptors, thus influencing the development of the child. R

13. Estrogen And Muscles, Bones and Wound Healing

 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660717/figure/F3/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660717/figure/F3/

 

Estrogen helps protect muscles from oxidative stress. R

For example, estrogen is able to help men use carbohydrates efficiently when doing endurance exercises by decreasing carbohydrate oxidation. R

Estrogen deficiency in women is commonly associated with bone loss and osteoporosis. R

Even in men, estrogen (along with preptin) is the main regulator of bone. R

Estrogen prevents bone resorption (the breakdown of bone tissue being released into the blood causing calcification of the body). R

It does this by inhibiting NF-kB (a pro-inflammatory pathway) in osteoblasts (bone cells), by reducing osteoblast cell death, and by increasing the lifespan of osteoblasts. R

Estrogen-related receptor gamma (ERR-gamma) activation, can actually do the opposite (can be activated by BPA, discussed in the next post). R R

Estrogen can also enhance wound healingR

Estrogen is anti-inflammatory, enhancing skin repair. R R

Estrogen also signals to keratinocytes (skin cells) to increase collagen production and reduce matrix metalloproteinases  (such as MMP2 and MMP9), which are elevated in chronic wounds. R

14. Estrogen And Aging

Estrogen makes the skin look younger (less wrinkles, better elasticity) and prevents skin aging. R R

Estrogen protects against the aging effects of the sun (from both UVA and UVB). R

Estrogen can increase melanin (pigment in hair and skin) production, which is beneficial for vitiligo. R

Estrogen also makes hair look youngerR

In women it can increase melanin in hair, but in men it does the opposite. R

In case studies, estrogen can also help with hair regrowth in alopecia (patches of hair loss). R

Estrogen can also increase longevity in both men and women. R R R

For example, estrogen therapy has shown to lower all-cause mortality in older women. R

Estrogen, Menopause, and Hysterectomy

Menopause (put simply) is when a women has depleted levels of estrogen. R

After menopause, circulating estrogen levels significantly decrease and is produced locally in tissues, (this is similar to a man as men make non-circulating estrogen synthesized in the breast, brain, muscle, bone, and fat tissues). R

This can cause devastating metabolic problems such as developing Alzheimer's Disease, dementia, cardiovasuclar disease, and weight gain (and pretty much all the points seen above in this post). R R R

Having a hysterectomy or ovariectomy warrant the same effects. R

After menopause, estrogen therapy should be begin promptly, as there is evidence that there is a window to when hormone replacement therapy will work. R

For example, elderly women who were treated with hormone replacement therapy had no effects, but those who started hormone therapy right after menopause had effects from the therapy. R

I will repeat, estrogen has very little effect on memory if administered years after menopause. R

Also, collagen can help with obesity in menopause, hysterectomy and ovariectomy. R

Atrophic vaginitis (AV) is common in postmenopausal women. R

Hormonal therapy (HT helps with this (as HT increased in Lactobacillus strains in the vagina). R

Supplementing with lactobacillus strains (vaginally) may produce the same effect, but I'd like to see more research on this. R

Supplements That Raise Or Lower Estrogen

Testing Estrogen Levels

Estradiol in blood should normally be:

  • Male: 15-25pg/mL
  • Female: Day 3: <80pg/mL and Day 14: 150-350pg/mL

In urine:

  • Male: 0-6 μg/24hrs
  • Female: Follicular phase: 0-3μg/24hrs, Ovulatory peak: 4-14μg/24hrs, Luteal phase: 4-10μg/24hrs, Postmenopausal: 0-4μg/24hrs

You can test your estrogen levels here.

The next part of this post is in Part 2 where we will be discussing what "fake" estrogens (estrogenics) do to the body, and how you can protect yourself from the dangers of estrogenics.

Estrogen's Mechanism Of Action

https://www.hindawi.com/journals/mi/2014/615917/fig1/

https://www.hindawi.com/journals/mi/2014/615917/fig1/

https://www.hindawi.com/journals/mi/2014/615917/fig2/

https://www.hindawi.com/journals/mi/2014/615917/fig2/

Simple:

  • Estrogen regulates the immune system and protects cells from over activation.
  • It also enhances hormetic antioxidant systems, making cellular processes and mitochondrial output even stronger.
  • Estrogen relaxes the arteries, protects the heart and brain, and is a key player in creating neurotransmitters and neurotrophic factors. 

Advanced:

  • Other endogenous estrogens, the biosyntheses of which do not involve aromatase, include 27-hydroxycholesterol, dehydroepiandrosterone (DHEA), 7-oxo-DHEA, 7α-hydroxy-DHEA, 16α-hydroxy-DHEA, 7β-hydroxyepiandrosterone, 4-androstenedione, 5-androstenediol, 3α-androstanediol, and 3β-androstanediol, and may have important endogenous functions as estrogens. R
  • Some estrogen metabolites, such as the catechol estrogens 2-hydroxyestradiol, 2-hydroxyestrone, 4-hydroxyestradiol, and 4-hydroxyestrone, as well as 16α-hydroxyestrone, are also estrogens with varying degrees of activity. R
  • Estrogen directly stimulates IL-1 production by macrophages. R
  • E2 increases IFN-γ and IL-10, but decreases IL-18, and caspase-1. R R
  • In the hippocampus estrogen activates MAPK, ERK, PI3K/Akt, CaMKII, CREB, and Src/Fyn. R
  • Estrogens bind to and activate rapid-signaling membrane estrogen receptors (mERs), such as GPER (GPR30). R
  • Estrogen enhances calcium homeostasis. 
  • Estrogen turns on NRF-1 via ERalpha and subsequently promotes transcription of mitochondrial transcription factor Tfam (mtDNA maintenance factor, also called mtTFA) and then Tfam targets mtDNA-encoded genes. R
  • ERα and ERβ interact with NF-κB to inhibit transcription. R
  • When ERα is occupied by the selective ER modulator (SERM) 4-hydroxytamoxifen (4-OHT), the conformation of a critical α-helix (helix 12) within the LBD, is altered such that the coactivator binding groove is unavailable and corepressors. R
  • For example, silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) and nuclear receptor corepressor (NCoR), interact with the LBD and recruit histone deacetylase (HDAC) complexes to suppress gene transcription in a cell type- and gene- dependent manner. R
  • E2 rapidly increases intracellular cAMP, inhibits Ca+2 influx, stimulates Ca+2 release from internal stores, stimulates nitric oxide (NO) production, and activate MAPK. R
  • Also, phytoestrogens that bind ERβ and ERα can activate sirtuin 1 (SIRT1) which in turn deacetylates and activates PGC-1α. R
  • PGC-1α is considered a master regulator of mitochondrial biogenesis in mammals. R
  • Phytoestrogens can decrease H2O2, leading to ER-activation of the MAPK pathway leading to NFκB activation and increased MnSOD expression.  R
  • E2 increases mitochondrial respiration, superoxide production, O2 uptake, and intracellular ATP levels. R
  • E2 prevents the UV-stimulated cytochrome c release. R
  • E2 increases anti-apoptotic Bcl-2 and mtDNA-encoded MRC expression. R
  • Estrogen also works similarly to DPP4 inhibitors. R
  • E2 activates Src and ERK/MAP kinases and enhances NMDA receptor phosphorylation and function. R
  • Estrogen has an inhibitory effect on NMDA-stimulated VP secretion. R
  • Testosterone and dihydrotestosterone (DHT) are as effective as estradiol in inhibiting both NMDA- and osmotically-stimulated VP release. R 
  • Estrogen can increase vasoactive intestinal peptide (VIP) in the pituitary, but not the hypothalamus. R
  • Estrone is can protect against kainate, haemoglobin, FeCl2, NMDA, serum deprivatio, glutamate, glucose privation, FeSO4, -amyloid peptide and H2O2 toxicities. R
  • Estriol can protect against several toxicities such as NMDA , glutamate, glucose privation, FeSO4 and -amyloid peptide. R
  • Estrogen inhibits RANKL-stimulated osteoclastic differentiation of human monocytes by inducing ERa binding to a scaffolding protein, BCAR1; the ERa/BCAR1 complex then sequesters TNF receptor-associated factor 6 (TRAF6), leading to decreased activation of NFkB and impaired RANKL-induced osteoclastogenesis. R
  • In wound healing, estrogen increases circulating level of factors 2, 7, 9, 10, plasminogen, decreases antithrombin III, increases platelet adhesiveness, and downregulates macrophage migration inhibitory factor (MIF). R R
  • Estrogen deficiency can also increase TGF-B1 in bones. R
  • Estrogen can decrease IL-1β, IL-6, IFNγ in the cervix, while increasing IL-8, via modulation of TLR2 and TLR4. R
  • Estrogen receptor alpha activation, but not beta, increases the risk of developing gallstones. R