Estrogen – The Good, The Bad and The Ugly

Part 1 of 5

Most people associated estrogen with women however we are beginning to see a serious impact that estrogen has on overall health. 

What is Estrogen?
Is a hormone that primarily functions to stimulate tissue growth such as in the restoration of the endometrium and during pregnancy in the expansion of breast tissue.The latest research has shown that different tissue having varying numbers of each estrogen receptor type α, β, and ϒ. 

The Ugly – Too Much Estrogen

How is Estrogen Produced?
Estrogen is produced from cholesterol from the ovaries as shown below.  Redundant pathways

From pregnenolone and progesterone precursors assure routes of synthesis.  Testosterone is aromatized to estradiol (E2), which is reduced to form estrone (E1) in a reversible reaction.  Estradiol can be reconverted to estrone or further hydroxylated to form estriol (E3). 

FSH stimulates estradiol secretion in the ovaries.  All three forms have varying levels of activity.

Estradiol – most active estrogen
Estratriol – intermediate acting estrogen
Estrone – least active form of estrogen

Synthesis of Estradiol



Metabolites of Estrone

Estrone metabolites include 2-hydroxyestrone, 4-hydroxyestrone, and 16α-hydroxyestrone.  Research has found that 2-hydroxyestrone formation is catalyzed predominantly by CYP1A2, CYP1A1 and CYP1B1 enzymes; 4-hydroxyestrone formation is catalyzed predominantly by CYP1B1, CYP1A2, and CYP 1A1 enzymes respectively; and 16α-hydroxyestrone formation is catalyzed predominantly by CYP2C19, CYP1A1 and CYP3A5.

Pathways that Compete for Estrone


Estrone has three key fates.  It may undergo reduction to estradiol or hydroxylation at the 2 or 16α positions.  Reduction of the keto group of 16α-hydroxyestrone produces estriol.  The 2- and 16α-hydroxyestrones are major excretory products, appearing in ratios above 2:1 in healthy states.  Small fractions of these two derivatives are also methylated by catechol-O-methyl transferase and SAMe to form methoxy derivatives.  A further hydroxylation at the 4 position (not shown) occurs to only small extents, but 4-hydroxyestrone has estrogenic activity and carcinogenic activity.

Estrogen Clearance
Estrogen is cleared by Phase I and II hepatic detoxification reactions.  Phase I consists of three major pathways via the cytochrome P450 enzyme system; Phase II, sulfation, methylation and glucuronidation help to further detoxify Phase I products. 

So How Do You Clinically Assess Yourself for Estrogen
Part 2 of 5

So the majority of guys out there are probably scared to death of having high levels of estrogen.  High levels of estrogen like anything else has it bad and ugly effects.  High levels of estrogen are characterized by symptoms such as increased anxiety, difficulty sleeping and an increase in irritability. High levels are also associated with increased risk of cancer and highly proliferative breast tissue, resulting in fibroids or cysts as well as an increased growth of prostate cancer cells.  Ironically, many of these symptoms are experienced during menopause when estrogen levels fall.
Research has shown that estrogen responses are bimodal with levels that are too high resulting in dysfunctions similar to levels that are too low.  However estrogen is not all bad…research has found that appropriate levels of estradiol reduce oxygen reactive species, increase coronary blood flow and decrease bladder disorders by reducing neurogenic inflammation.
The testing of estrogen levels is recommended due to the potential adverse effects associated with both elevated and depressed levels.

FEMALE CYCLE SERUM REFERENCE VALUES

 

Follicular

Luteal

Post-Menopause

CONCENTRATION

pg/mL

 

pg/mL

Progesterone

 

5-25 ng/mL

 

Estrone (E1)

10-150

16-170 pg/mL

 

Estradiol (E2)

50-300

200-400 pg/mL

 

Estriol (E3)

5-50

10-60 pg/mL

 

Total Estrogen

70-400

70-700 pg/mL

 


Considerable attention should be given to downstream estrogen metabolites that result as a consequence of supplementing with synthetic estrogen. 

Estrogen Metabolites
Phase I estrogen metabolism occurs via a number of CYP 450 pathways, including 1A1, 1B1 and 3A4 which yield 2-hydroxytrogens (2-OHE), 4-hydroxyestrogens (4-OHE) and 16α-hydroxyestrone (16α-OHE1).

2-OHE and 4-OHE are further metabolized via catechol-O-methyltransferase (COMT) to 2-methoxyestrone (2-OMeE1) and 4-methoxyestrone (4-OMeE1).  2-OMeE, 4-OMeE and 16α-OHE1 metabolites may also be conjugated via sulfation and glucuronidation. 

Individual Analytes


Analyte

High

Low

2-OHE1 ~ Good Estrogen

If both 2-OHE1 and 16α-OHE1 are high, consider methods to better excrete estrogens or decrease HRT

If 2-OHE1 and 16α-OHE1 are both low, total estrogen production may be low.  Address underlying causes of low hormone production

16α-OHE1 ~ Bad Estrogen

If both 2-OHE1 and 16α-OHE1 are high consider methods to better excrete estrogen or decrease HRT

If 2-OHE1 and 16α-OHE1 are both low, total estrogen production may be low.  Address underlying causes of low hormone production

2-OMeE1

Produced from 2-OHE via COMT; 2-OMeE1 has shown anti-proliferative effects
Generally no treatment recommended
Ensure adequate Phase II detoxification

May be due to poor methylation
If 2/16 ratio is also low may indicate a CYP imbalance
If total estrogen metabolite production is low, consider direct assessment of estrogen levels

4-OHE1 ~ Bad Estrogen

Considered a bad estrogen
Produced via CYP1B! and deactivated via COMT to non-carcinogenic 4-OMeE
Consider testing of COMT and CYP1B1
Reduce stress: COMT also involved in metabolism of epinephrine
Increase inhibitors of CYP1B1
Grapefruit, Ginseng
Avoidance of CYP1B! inducers
Polycyclic aromatic hydrocarbons
Evaluate methylation activity
Can be converted to DNA damaging estrogen quinines
Glutathione (reduces quinones)
Resveratrol (prevents quinones)
Selenium, zinc, magnesium

Low levels of the “bad” estrogen
Generally no treatment recommended

4-OMeE1

Generally no treatment recommended

Improve methylation for high 2-OHE1:2-OMeE1 Ratio


So What Does This All Mean?

Well in a nut shell we have to look at the ratios of these analytes in order to detect any abnormalities in the detoxification and biotransformation of Phase I and II metabolism.  Imbalances in the ratios of the above analytes has been associated with an increased risk for certain cancers, including breast, prostate and colon.

How to Develop the Optimum Estrogen Cleanse Protocol for a Healthier Body but also a Better Physique
Part 3 of 5

The Estronex Test
The Estronex test measures urinary estrogen metabolites  and is an easy test which involves collecting the first urine in the morning making no blood draw necessary.  The Estronex profile is primarily used to in breast cancer prevention programs, and ideal for men to evaluate the risk of breast and prostate cancer.

However we are going to use it to assist us in designing the optimum program to assist in losing bodyfat.

2/16 Ratio (2-OHE1 + 2-OHE2/16α-OHE1)
The 2-OHE is associated with reduced cancer growth and referred to as the good estrogen metabolite
The 16α-OHE1 is a powerful estrogen receptor agonist shown to encourage tumor development

If 2/16 Ratio is Low
Increased risk of estrogen sensitive cancers:
Oral contraceptive users may have significantly lower 2/16 ratios

Treatment
Lower an elevated BMI
Increase cruciferous vegetables, including: broccoli, cabbage and brusselsprouts
Supplement with dried organic brussel sprouts or kale
Supplement with di-indolemethane (DIM)
Stimulate hepatic P450-1A1 biosynthesis
Increase ground flax seed intake
Increase intake of omega 3 fatty acids
Increase fruit and vegetable intake
Ensure adequate estrogen receptor functions:
Evaluate markers for oxidative stress such as p-hydroxyphenyllactate, 8-hydroxy-2-deoxyguanosine and lipid peroxides
Ensure adequate estrogen detoxification and biotransformation
Ensure proper gut function to avoid entero-hepatic recirculation and to encourage proper elimination

If 2/16 Ratio is High
Most but not all epidemiological studies have found that women with a high urinary 2/16 ratio are at reduced risk for breast cancer. However, excessive reduction of 16α-hydroxyestrone (leading to an increase in the 2/16 ratio) may reduce bone formation due to its role in osteogenesis
Smoking stimulates CYP1A1 and may therefore  cause a higher 2/16 ratio

Treatment
Evaluate the methylation activity of 2-OHE1 (homocysteine, B12, folic acid status).  Since metabolism of 2-OHE1 is dependent on SAMe, accumulation of 2-OHE1 may demonstrate poor methylation activity
Increase intake of antioxidants

Methylation Ratio
2-Hydroxyestrone and 4-Hydroxyestrone are methylated in Phase II to produce 2-methoxyestrone (2-OMeE1) and 4-methoxyestrone (4-OMeE1) via the COMT enzyme.  2-OMeE1 has been referred to as a good estrogen
4-OMeE1 is considered a non-carcinogenic metabolite of 4-OHE1
Methylation is important to properly clear the estrogens
High COMT activity has been associated with reduced risk of certain cancers

If 2-OHE1/2-OMeE1 Ratio is High
Means there is an imbalance in the metabolism of estrogen
It is necessary to evaluate the activity of methylation

  1. Serum homocysteine
  2. Serum B12 or urinary methylmalonate
  3. Urinary FIGLU
  4. Urinary xanthurenate
  5. Genetic testing; COMT, MTHFR, CYP1A1

Reduce stress:

  1. COMT is involved in the metabolism of epinephrine, reducing availability for estrogen metabolism

Support methylation

The Nuts and Bolts of Putting Together the Estrogen Cleanse
Part 4 of 5

The amount of estrogen needed by men to support general health function is very small and today men on average have excessive amounts of estrogen in their system for several reasons.  The first is that the enzyme aromatase which converts testosterone to estrogen is elevated and tends to be higher in fatter guys because aromatase resides in the fat tissue.  Second, men today are exposed to high amounts of chemical estrogens in the environment such as BPA and phthalates.  BPA is a petroleum based chemical that mimics the structure of estrogen and has been shown to affect the endocrine response in the body in humans and animals.  Phthalates are another chemical estrogen that are used in plastics and many personal care products such as shampoo and skincare lotion.  They contribute to excess estrogen levels and need to be detoxified as safely and quickly as possible in order to minimize the damage they have on tissues in the body.  Third, estrogen is cleared  by undergoing phase I detoxification in the liver which contains the Cytochrome P450 dependent hydroxylases enzymes (CYP1A1, CYP1B1 and CYP3A4/CYP2E); basically there are three potential pathways for estrogen to be converted via the hydroxylase pathway. 

Three pathways, the key to remember is that the production of 16αOHE1 via the CYP3A4/CYP2E pathway produces a compound that is an estrogen agonist which predisposes us to higher rate of cancer.  Obviously we don’t want that to happen, when we look the CYP1B1 pathway there is the production of 4OHE1 which is another bad estrogen.  Therefore we only have one pathway left.   The CYP1A1 which produces 2OHE1 (estrogen agonist) which is healthier and our strategy will be to support the conversion of estrogen along the 2OHE1 pathway.

Get Your Estronex Profile Completed
After closely reviewing the results, this middle age male who was experiencing typical symptoms of estrogen toxic overload, simply put this guy is swimming in a sea of estrogens.  The development of this program will be broken into 2 phases: identification of problematic areas and secondly how to treat the excessive estrogen in order to minimize the health effects and risks that come from too much estrogen. 

View Lab Results

This patient is characteristic of males today who have elevated levels of estradiol which is unbound floating freely in the blood allowing it to bind with cellular receptors resulting in some pretty deleterious effects on his physique such as elevated body fat, low libido and predisposes him to a number of health conditions such as prostate cancer.

Interpretation of Results

High 2/16 Hydroxyestrogen Ratio (2-OHE1 + 2-OHE2)/16a-OHE1
Causes: poor methylation activity which is part of Phase II Detox which converted the quinones to methoxyestrogens. 
Action: need to test for homocysteine, folate and B12 to assess methylation status

High 4-Hydroxyestrone and Methylation Ratio
High 4-Hydroxyestrone (4-OHE1)
Causes: produced by CYP1B1 and deactivated by COMT
Action: reduce stress, increase CYP1B1 inhibition, evaluate methylation activity, reduce build-up of DNA damaging estrogen quinines

High 2-OHE1/2-OMeE1
Causes: imbalanced estrogen metabolism
Action: need to assess methylation activity (serum homocysteine, serum B12 or urinary methylmalonate, urinary FIGLU, urinary xanthurenate, genetic testing (COMT, MTHFR, CYP1A1)

Time to Take the War to Estrogen

General Tips

  1. Improve gastrointestinal Health
  2. Improve diet with low carbohydrates, high protein and omega 3 fatty acids
  3. Decrease body fat
  4. Use phytoestrogens to promote the C2 pathway
  5. Block aromatase and stop testosterone from turning into estrogen
  6. Keep estrogen bound to sex hormone binding globulin (SHBG)
  7. Improve estrogen metabolism by promoting the C2 pathway
  8. Ensure complete elimination of estrogen
  9. Supplement with essential nutrients
  10. Watch what you drink
  11. Limit chemical estrogen exposure

The Specifics to Designing the Right Estrogen Cleanse Program
Part 5 of 5

For sake of simplicity, we are going to put everything in a table format which is easier to follow.

Goal

Instructions

Recommendation

Improve Methylation to Drive Phase II Detox

Assess methylation activity (serum homocysteine, serum B12 or urinary methylmalonate, urinary FIGLU, urinary xanthurenate, genetic testing (COMT, MTHFR, CYP1A1)

Support Methylation

Folic Acid
Tetrahydrofolate
B12
B6
SAMe
Increase antioxidants – eg. limonene
Magnesium

Reduce Stress

 

 

Drive Phase I Detox Pathway (C2 Pathway)

C-2 Pathway produces very weak estrogenic activity

Phytoestrogens
Fish Oils
DIM
Increase intake of cruciferous vegetables: broccoli, cabbage, and brussel sprouts
Supplement with DIM
Stimulate hepatic P450 1A1 synthesis
Increase intake of flax seed lignans
Reduce inflammation

Improve Gastrointestinal Health

To improve excretion of unwanted estrogen from the body

Increase dietary fiber (lignans such as flaxseeds) can bind to estrogen in the digestive tract so it will be excreted from the body
Dietary fiber will also reduce B-glucoronidase that breaks apart bound estrogen
Pre and Probiotic

Improve Diet with low carbs, high protein and omega 3 fatty acids

Help detoxify estrogens and provide adequate fiber. 
Improve insulin sensitivity will improve lean body mass composition and reduce the amount of body fat ultimately improving estrogen detoxification

 

Decrease body fat

More body fat the higher the levels of aromatase  enzyme that turns testosterone to estrogen

 

Block Aromatase from Converting Testosterone to Estrogen

Blocking aromatase is key to reducing the buildup of estrogen in the body

Selenium, melatonin, zinc, green tea and citrus flavones such as oranges and grapefruits are effective at inhibiting aromatase

Increasing the Amount of Estrogen Bound to SHBG

Increase intake of flaxseed hulls will help increase SHBG as well as aromatase preventing estrogen from floating freely in the blood acting on receptors

Flaxseed lignans

Promote Complete Elimination of Estrogen

Avoid the production of quinones
Reduce B-glucoronidase to prevent enterohepatic recirculation of estrogen

Use D-Glucurate to inhibit beta-glucuronidase
Reserveratrol, Gluthathione can help block the production of damaging quinones

Eliminate Alcohol

Alcohol increases estrogen levels in men and women

If you drink consume wine rich in either resveratrol or trans-resveratrol

Limit Chemical Estrogen Exposure

Plastics contain BPA which mimics estrogen

Avoid plastic containers for food and water
Use glass and get a stainless steel water bottle. 


I have personally used an estrogen cleanse once per year and have noticed dramatic results in the amount of body fat I was storing within 7 days and suggest that you employ this as another strategy to improve lean body composition.