Biomarkers Tests

Estrogens and Metabolites (Urine) – DUTCH — Interpretation of DUTCH test (Dried Urine Test) from Precision Analytics (PART 2)

Here is a full list of the Estrogens and Metabolites:

https://healthmatters.io/biomarker-category/estrogens-and-metabolites-urine-dutch

estrogens metabolites estrone estradiol estril 2-oh-e1 2-methoy-e1

Estrogen’s basic biological function is as an anabolic hormone. There are three primary forms of estrogen: estrone (E1); estradiol (E2); and estriol (E3). All three forms have varying levels of activity and specificity for different tissues. E2 is the most active of the estrogens and is responsible for most of the actions attributed to the estrogens.

Where is estrogen made?

Estrogen is made primarily in the ovaries of cycling women while smaller amounts can be converted from testosterone through a process called aromatization. In menopause estrogen production shifts almost completely to aromatization. The enzyme responsible for aromatization is found in fat tissue, the brain, gonads, blood vessels, skin, and bone.

In Men: 

Men need far less estrogen than women and it is aromatized primarily from testosterone. Women who are still cycling have much greater quantities of estradiol than men, but it is important to note that men do make estrogen. In fact, the level of estrogen in men is actually higher than the level in a post-menopausal woman!  

What does estrogen do?

– Growth and development of female secondary sex characteristics

– Thickens the uterus for implantation, increases vaginal acidity to protect against infection, important for vaginal lubrication (particularly E3)

– Necessary for bone health

– In the brain helps maintain body temperature, protects against memory loss, increases serotonin and serotonin receptors

– Important for collagen production, skin thickness and getting blood supply to the skin

– Helps protect against atherosclerosis

What is a metabolite?

When the body makes a hormone such as estrogen it must be processed by the body in the liver through the process of phase 1 and phase 2 detoxification before it can be excreted out the other end. This is known as hormone metabolism. As a hormone is undergoing that process, it gets changed into other forms known as metabolites.

Phase 1 metabolism:

In the liver, estrone and estradiol are converted into the phase 1 metabolites known as 2-OH-E1, 4-OH-E1 or 16-OH-E1. These metabolites can go back out into circulation before going through phase 2 detoxification where they are then excreted out of the body. The phase 1 metabolites can be more damaging to the body by causing estrogen- dominant symptoms or increasing the risk for cancer in both men and women.

Generally speaking, the 2-OH-E1 is considered the safer metabolite as it only weakly induces cell proliferation and might even inhibit it, the 4-OH-E1 can damage DNA and may be more cancer inducing.

You can assess phase 1 metabolism by looking at the relative amounts of these hormones.

The normal estrogen metabolism ratio of the three (2-OH-E1 + 4OH-E1 + 16OH-E1) is as follows:

– 70% of the total usually makes up the 2-OH-E1 fraction

– 10% comes from the 4-OH-E1

– 20% from 16-OH-E1

Phase 2 metabolism (methylation):

After estrogens go through phase 1 detoxification, they move on to methylation which is part of phase 2 detoxification. Methylation, in essence, “neutralizes” the phase 1 metabolites and prepares them to be excreted out of the body instead of shuttling them back into circulation. Only 2-OH and 4-OH estrogens are methylated. 16-OH-E1 is not.

A healthy result should fall into the range 12 – 26 ng/mg.

– A moderately potent estrogen. Binds primarily to Estrogen Receptor Alpha (ERα).

– Estrone is metabolized into 2-OH E1 (“good”)16-OH-E1 (“bad”), and 4-OH-E1 (“bad”).

Produced by the ovaries, the estrone hormone is one of three types of estrogen, and it is one of the major hormones found in the bodies of postmenopausal women. While research into estrone function is still ongoing, largely due to the fact that it is the least powerful of the three types of estrogen, women should still understand this hormone and its known effects on the body.

Specifically, estrone (also called oestrone) is an estrogen like estradiol and estriol. Unlike the other two, estrone comes from the ovaries, as well as the adipose tissue and adrenal glands.

It is a weaker estrogen, commonly found in higher quantities in postmenopausal women.

How Does Estrone Function?
As an estrogen, estrone is responsible for female sexual development and function. Because it is less powerful than the other estrogens, estrone can sometimes serve as a repository for estrogens, and the body can convert it to estrogen when needed.

Possible Problems with Estrone
The effects of low Estrone or high Estrone levels are not yet well known. Women who have breast cancer or men who are being treated to reduce testosterone levels — such as in prostate cancer treatment — may need to have their estrone levels monitored, because estrone levels can increase in these cases. Women who are obese will produce more estrone from fatty tissue. Too much estrone has been linked to breast and endometrial cancer growth. Besides this potential outcome, other results of increased estrone levels are not yet known.

Women who have too little estrogen hormones, including oestrone, may develop osteoporosis. Low estrogen levels can also cause the symptoms of menopause, including hot flashes, fatigue, poor sex drive and depression. For women who are postmenopausal and who are still struggling with these symptoms, low oestrone levels may be the reason. However, research has not yet found a definite link between the ovary hormone and these symptoms.

Estrone (E1), estradiol (E2), and estriol (E3) are three endogenously produced estrogens.

– Made via aromatization in several tissues like fat and muscle

– Weaker compared to Estradiol (Research says the estrogenic activity is about 4% of estradiol’s activity)

– Most abundant in menopause

– Converts into estradiol (E2)

What does Estrogen do?

1. Growth and development of female secondary sex characteristics

2. Thickens the uterus for implantation, increases vaginal acidity to protect against infection, important for vaginal lubrication (particularly E3)

3. Necessary for bone health

4. In the brain helps maintain body temperature, protects against memory loss, increases serotonin and serotonin receptors

5. Important for collagen production, skin thickness and getting blood supply to the skin

6. Helps protect against atherosclerosis

7. Estrogen through the ER helps induce or upregulate the expression of the PR

What does it mean if your Estrone (E1) result is too low?

Women who have too little estrogen hormones, including oestrone, may develop osteoporosis. Low estrogen levels can also cause the symptoms of menopause, including hot flashes, fatigue, poor sex drive and depression. For women who are postmenopausal and who are still struggling with these symptoms, low oestrone levels may be the reason. However, research has not yet found a definite link between the ovary hormone and these symptoms.

Why does estrogen decrease?

– Age (peri-menopause and menopause)

– Irregular cycles/skipped cycles/anovulation

– Hysterectomy with ovaries removed

– Anorexia

– Low cholesterol (backbone to hormones)

– Extreme exercise or training

– Extreme stress resulting in skipped menses

– Under appropriate body weight percentage for height/age

• Mixed research: suggested <15% body fat = amenorrhea

– Hypogonadism (ovaries fail)

– Hypopituitarism (pituitary not communicating)

– Decreased blood flow to the ovaries

– Ex. Surgery or smokers

– Breast feeding

– Hypothyroidism

– PCOS

– Fertility medications

– Opioid pain medications (in last 6 months)

– Hormonal birth control – pill, patch, ring, implant, injection

What does it mean if your Estrone (E1) result is too high?

Why do Estrogen levels increase?

1. Overweight/obesity

2. Peri-menopause = surges of estrogen

3. Diabetes

4. PCOS

5. Estrogen supplementation

6. Steroid medications

7. Poor liver clearance so estrogens build up

8. Dysbiosis/Estrobolome problems

9. Over aromatization from testosterone

10. Environmental estrogens (difficult to test however)

11. Alcohol (2 or more glasses/day shown to increase E)

12. Ovarian cysts

A healthy result should fall into the range 1.8 – 4.5 ng/mg.

As the strongest of the three estrogens, estradiol (E2) is an important player in the female reproductive system. Understanding this hormone will help women take better control of their reproductive health.

Estradiol is one of three estrogen hormones naturally produced in the body. While men and women have estradiol, and it has a role in both of their bodies, women have much higher levels of the hormone than men.

Functions:

Estradiol has several functions in the female body. Its main function is to mature and then maintain the reproductive system. During menstruation, increased estradiol levels cause the maturation and release of the egg, as well as the thickening of the uterus lining to allow a fertilized egg to implant. The hormone is made primarily in the ovaries, so levels decline as women age and decrease significantly during menopause.

In men, proper estradiol levels help with bone maintenance, nitric oxide production, and brain function. While men need lower levels than women, they still require this important hormone to function well.

In women, too much estradiol has been linked to acne, constipation, loss of sex drive, and depression. If the levels are extremely high they can cause uterine and breast cancer. Women with high estradiol levels may experience weight gain and cardiovascular disease. For men, it can lead to the development of female characteristics, and loss of sexual function or muscle tone.

If the body does not have enough estradiol, bone growth and development is hindered, and adults can develop osteoporosis. Girls may experience delayed puberty with low estradiol levels. Mood swings have also been connected to low estradiol levels.

Estradiol (E2) is about 10 times as potent as E1 and about 80 times as potent as E3 in its estrogenic effect.

Except during the early follicular phase of the menstrual cycle, its serum levels are somewhat higher than that of E1 during the reproductive years of females. Thus it is the predominant estrogen during reproductive years both in terms of serum levels and estrogenic activity. E2 to E1 conversion is generally favoured and the metabolites in the Dutch test tell you whether this occurring correctly. Incorrect conversion greatly increases the risk factors for certain reproductive cancers.

Estradiol and Menopause:

The effects of estradiol are clearly seen in women experiencing menopause. During this process, women naturally have lower levels of estradiol as the ovaries stop ovulating. This change often causes mood swings, vaginal dryness, hot flashes, and night sweats — the symptoms commonly associated with menopause. Over time, lower estradiol levels can lead to osteoporosis.

What does it mean if your Estradiol (E2) result is too low?

If the body does not have enough estradiol, bone growth and development is hindered, and adults can develop osteoporosis. Girls may experience delayed puberty with low estradiol levels. Mood swings have also been connected to low estradiol levels.

Why does estrogen decrease?

– Age (peri-menopause and menopause)

– Irregular cycles/skipped cycles/anovulation

– Hysterectomy with ovaries removed

– Anorexia

– Low cholesterol (backbone to hormones)

– Extreme exercise or training

– Extreme stress resulting in skipped menses

– Under appropriate body weight percentage for height/age (Mixed research: suggested <15% body fat = amenorrhea)

– Hypogonadism (ovaries fail)

– Hypopituitarism (pituitary not communicating)

– Decreased blood flow to the ovaries (Ex. Surgery or smokers)

– Breast feeding

– Hypothyroidism

– PCOS

– Fertility medications

– Opioid pain medications (in last 6 months)

– Hormonal birth control – pill, patch, ring, implant, injection

Common symptoms of low estrogen:

– In women – fatigue, depression, hot flashes, night sweats, vaginal dryness, pain with intercourse, low libido, joint pain, brain fog, migraines/headaches, fertility issues, dry skin

– In men – not generally considered symptomatic, but in very extreme cases men may have similar symptoms as in the list above for women

Common ways to raise estrogen:

In women – address the cause, phytoestrogens such as Red Clover, Dong Quai, Kudzu, soy, diosgenin, genistein, fennel, and Black Cohosh (although studies are mixed on whether it acts as a phytoestrogen or not), Maca, and bioidentical estrogen replacement

What does it mean if your Estradiol (E2) result is too high?

In women, too much estradiol has been linked to acne, constipation, loss of sex drive, and depression. If the levels are extremely high they can cause uterine and breast cancer. Women with high estradiol levels may experience weight gain and cardiovascular disease. For men, it can lead to the development of female characteristics, and loss of sexual function or muscle tone.

Why do Estrogen levels increase?

– Overweight/obesity

– Peri-menopause = surges of estrogen

– Diabetes

– PCOS

– Estrogen supplementation

– Steroid medications

– Poor liver clearance so estrogens build up

– Dysbiosis/Estrobolome problems

– Over aromatization from testosterone

– Environmental estrogens (difficult to test however)

– Alcohol (2 or more glasses/day shown to increase estrogen)

– Ovarian cysts

– Having elevated testosterone levels – testosterone gets converted to estrogen through the aromatase enzyme. Therefore, having Polycystic Ovarian Syndrome (PCOS), over supplementing with testosterone or DHEA or generally having a high production of this hormone, can lead to more estrogen being produced as a byproduct.

In men – over aromatization from testosterone to estrogen due to inflammation and blood sugar/insulin issues, environmental/xenoestrogen exposure (this does not show up on DUTCH testing, but they can cause symptoms), moderate alcohol use, and obesity

Common symptoms of elevated estrogen:

– In women – mood swings, weight gain, breast tenderness, fibrocystic breasts, heavy menses, fibroid/polyp development.

– In men – breast development, weight gain, and mood swings.

Common ways to lower estrogen:

Please consult with your health care provider about advice/treatment/diagnosis. The following statements are general informational statements.

– In women – address the cause, avoid alcohol, avoid environmental/xenoestrogens, DIM/I3C supplementation, calcium-d-glucurate, increased fiber (especially ground flax seeds), increased detoxification support, and weight loss

– In men – address the cause, avoid alcohol, avoid environmental/xenoestrogens, DIM/I3C supplementation, calcium-d-glucurate, increased fiber, decrease blood sugar and insulin, increased detoxification support, weight loss, and things that block aromatase (Chrysin, Damiana, Zinc and pharmaceutical aromatase inhibitors)

Other general interventions to keep in mind that can be beneficial for everyone if you don’t know the status of your hormones includes:

– Avoiding xenoestrogen exposure. Here is a great link to the top endocrine disruptors to avoid your environment [L]:

– Eat more cruciferous vegetables from the Brassica family- broccoli, kale, Brussels sprouts, cauliflower, cabbage, kale, etc.

– Support your liver on-goingly – from the basic lemon water to increasing consumption of dandelion or dandelion tea, doing a liver cleanse twice a year and reducing consumption of sugar and alcohol.

– Make sure your bowels are going – lots of fluids and high fiber in your diet will help regulate your bowel movements and make sure your hormones are properly detoxified rather than sitting in your body and recirculating back in the system.

A healthy result should fall into the range 5 – 18 ng/mg.

– The ‘end product’ of estradiol/estrone metabolism

– 16-OH-E1 can convert into estriol

– Not made in the ovaries

– Very weak estrogen

– Elevated in pregnancy due to placental production 

The third estrogen is known as Estriol (E3) and is produced in significant amounts during pregnancy. In men and women, Estriol is irreversibly produced by estradiol (estriol cannot make estradiol) or from estrone through 16-OH-Estrone which makes it the largest circulating estrogen because both Estrone and Estradiol can make it. Despite this, estriol is not nearly as potent as estradiol (Estradiol is 80x more potent!). The least potent of the estrogens, Estriol (E3) levels are traditionally used clinically to gauge the viability of pregnancies. In the context of this profile, estriol is least likely to be associated with high-estrogen problems (e.g. breast cancer), and is generally viewed as a “protective” estrogen. Conversion of 16alpha-hydroxyestrone to estriol is important to consider.

Note: If one is taking a “Bi-Est” or “Tri-Est” preparation, an elevated estriol is not unusual.

References:

https://www.mayocliniclabs.com/test-catalog/Clinical+and+Interpretive/81711

What does it mean if your Estriol (E3) result is too low?

Doctors usually test E3 during pregnancy, when it temporarily becomes the main estrogen. Abnormal levels of estriol may be a sign of problems with the baby’s health — but you’d get a lot more tests to find out for sure. You might need several tests to track changes in your estrogen levels over time.

What does it mean if your Estriol (E3) result is too high?

High estriol implies a potential for elevated 16alpha-hydroxyestrone (16-OH-E1), a very potent estrogen that is associated with increased risk of breast cancer. There appears to be an association of elevated estriol and elevated 16alpha-hydroxyestrone in patients with systemic lupus erythematosus, implying shifted metabolism in that condition.

A healthy result should fall into the range 5.1 – 13.1 ng/mg.

Most consider 2-OH-E1 favorable – In women not on hormonereplacement therapy, 2-OH-E1 is considered a “good” estrogen because it is associated with reduced cancer growth.

Estrogen is metabolized (primarily by the liver) down three phase I pathways. The 2-OH pathway is considered the safest because of the anti-cancer properties of 2-OH metabolites. Conversely, the 4-OH pathway is considered the most genotoxic as its metabolites can create reactive products that damage DNA. The third pathway, 16-OH creates the most estrogenic of the metabolites (although still considerably less estrogenic than estradiol). 16-OH-E1 has been shown to encourage tumor development.

2-Hydroxyestrone is an endogenous biomarker and major urinary metabolite of estrone and estradiol. Along with 16α-Hydroxyestrone, 2-Hydroxyestrone is used as an indicator for increased risk of breast cancer.

This metabolite of Estrone is considered protective. A comparison with 2-Methoxyestrone, its Phase II liver metabolite, may help with assessing adequacy of methylation processes.

There are numerous modifiers of this value, most of which induce changes in the level of 2-OH-E1. These include intake of indole-3-carbinols from cruciferous vegetables, flaxseed, soy, omega-3 fatty acids, and vigorous exercise. All are shown to improve the levels of 2-OH-E1 in most individuals. It is to be emphasized that some individuals in clinical studies have exhibited a paradoxical response to treatments that would typically raise the 2-OH-E1 levels. Therefore, follow-up testing after treatment is strongly suggested. There may be an increased likelihood of osteoporosis with excessive 2-OH-E1 production. It is important to note that the ideal upper limit of 2-OH-E1 is not apparent from the existing literature.

Attention to bone loss processes in the urine is perhaps warranted in individuals with a very high 2:16alpha-hydroxyestrone ratio.

What does it mean if your 2-OH-E1 result is too low?

If low your health professional can work with you to address this in a few different ways, such as:

– Cruciferous vegetables like broccoli contain I3C

– I3C (=Indole-3-carbinol) gets metabolized to DIM

– DIM (=diindolylmethane) increases the conversion of estrogen to 2-OH-Estrogens

– Some health care professionals promote DIM, some I3C, and some providers promote a combination to help estrogens move down the 2-OH pathway.

What does it mean if your 2-OH-E1 result is too high?

– High levels of the “good estrogen” are typically considered beneficial; however, when coupled with a low 2-Methoxy-E1, it may indicate poor methylation activity.

– If both 2-OH-E1 and 16-OH-E1 are high, then total estrogen load may be high. Consider methods to better clear the estrogens from the body or HRT dosing may need revision if only 2-OH-E1 is very high.

– In post-menopausal women on hormone-replacement therapy, a very high 2-OH-E1 can result from high doses of estradiol. Thus, elevated levels of 2-OH-E1 are associated with increased cancer risk. The prescribing doctor should be consulted about dosing when such very high 2-OH-E1 are found.

The 2 pathway is the most favourable and we want to see it used more. It excretes estradiol and estrone. Estrone is converted into 2-Hydroxyestrone (2-OH-E1) as part of Phase 1 detox which is known as hydroxylation. 2-OH-E1 is a ‘good’ estrogen because it doesn’t stimulate cell growth. When it is methylated into the 2-Methoxy-E1 in Phase 2 it becomes cancer protective. Enough exercise, cruciferous veggies like broccoli, and specific supplements can raise 2-OH-E1 levels.

A healthy result should fall into the range 0 – 1.8 ng/mg.

– The 4-OH pathway is considered the most genotoxic as its metabolites can create reactive products that damage DNA.

– Estrone is hydroxylated through Phase 1 detox to form 4-OH-E1. In Phase 2 it is methylation to form 4-MeE1. When 4-OH-E1 is properly methylated to 4-MeE1 it is relatively benign as the 4-MeE1 is easily eliminated and risks are low.

– When it is not methylated 4-OH-E1 builds up. Then it converts to 3,4-Quinones which are carcinogenic similarly to the 16 pathway. Women with uterine fibroids may have increased levels of 4-OH-E1. High levels of estrogen across the board are associated with heavy cycles.

4-OH-E1 is referred to as the “bad” estrogen, along with 16-OH-E1.

– It is a minor pathway of estrogen metabolism.

– It may also enhance cancer development.

– It may directly damage DNA by causing breaks in the molecular strands of DNA.

Human breast cancer tissue produces much higher levels of 4-OH-E1 than 2-OH-E1, while normal breast tissue produces approximately equal amounts of the two metabolites. Women taking hormone therapy with a polymorphism in CYP1B1 had twice the risk of developing breast cancer compared to other HRT users.

Furthermore, the 4-Hydroxyestrones have the ability to convert to metabolites that react with DNA and cause mutations that can be carcinogenic. It is also present in greater quantities in patients deficient in methionine and folic acid. Women who have uterine fibroids also may have increased levels of 4-Hydroxyestrones.

References:

– Spink BC, Fasco MJ, Gierthy JF, Spink DC. 12-O-tetradecanoylphorbol-13-acetate upregulates the Ah receptor and differentially alters CYP1B1 and CYP1A1 expression in MCF-7 breast cancer cells. J Cell Biochem. Sep 1 1998;70(3):289- 296.

– Hayes CL, Spink DC, Spink BC, Cao JQ, Walker NJ, Sutter TR. 17 beta-estradiol hydroxylation catalyzed by human cytochrome P450 1B1. Proc Natl Acad Sci USA. Sep 3 1996;93(18):9776-9781.

– Yang L, Gaikwad NW, Meza J, et al. Novel biomarkers for risk of prostate cancer: results from a case-control study. Prostate. Jan 1 2009;69(1):41-48.

– Castagnetta LA, Granata OM, Traina A, et al. Tissue content of hydroxyestrogens in relation to survival of breast cancer patients. Clin Cancer Res. Oct 2002;8(10):3146-3155.

What does it mean if your 4-OH-E1 result is too low?

– Low levels of the “bad estrogen”

– Generally no treatment recommended

What does it mean if your 4-OH-E1 result is too high?

The bad news may be that you are making too much of the 4-hydroxyestrogens and not methylating them well. The good news is that you know this is happening and can do things to change how your body metabolizes estrogens, and in doing so decrease your breast cancer risk. Nutritional intervention (e.g., foods rich in DIM or indole-3-carbinol) can be used to shift estrogens in the direction of 2-hydroxylation, which is safer. Additionally, methylation of estrogen metabolites can be supported nutritionally (e.g., methyl donors such as vitamin B12, folic acid, SAM-e, and foods such as onions, garlic and beets). And the effectiveness of this intervention can be evaluated by measuring the ratio of 2- and 4-methoxyestrone to 2- and 4-hydroxyestrone.

– Improve methylation by adding cofactors (B12, folate) or methyl donors (betaine, dimethyl glycine)

– Consider genetic testing for COMT and CYP1B1 activity, particularly if positive family history

– Reduce stress: COMT is involved in the metabolism of epinephrine, reducing availability for estrogen metabolism

– Increase inhibitors of CYP1B1 (Grapefruit, Ginseng)

– Avoidance of CYP1B1 inducers (Polycyclic aromatic hydrocarbons)

Evaluate methylation activity:

– Serum Homocysteine

– Serum B12 or methylation

– Urinary FIGLU

– Urinary xanthurenate

Other potential protective factors:

– Glutathione (reduction of estrogen quinones)

– Resveratrol (prevents estrogen quinone formation)

– Selenium, zinc, magnesium

A healthy result should fall into the range 0.7 – 2.6 ng/mg.

Both 16a-OHE1 and 4-OHE1 have been referred to as the “bad” estrogens.

– This estrogen metabolite is a more potent estrogen than the other two (2-OH and 4-OH). If this value is elevated, we may see estrogen dominance. 

– Estrogen is also metabolized through the ’16’ pathway. We need this route however it should be used significantly less than the 2-OH pathway. Phase 1 in the 16-Hydroxyestrone pathway is also hydroxylation. Phase 2 is a reduction phase that produces Estriol which is a weak estrogen.

16α-Hydroxyestrone (16α-OH-E1), or hydroxyestrone, also known as estra-1,3,5(10)-trien-3,16α-diol-17-one, is an endogenous steroidal estrogen and a major metabolite of estrone, as well as an intermediate in the biosynthesis of estriol. It is a potent estrogen similarly to estrone, and it has been suggested that the ratio of 16α-hydroxyestrone to 2-OH-E1, the latter being much less estrogenic in comparison and even antiestrogenic in the presence of more potent estrogens like estradiol, may be involved in the pathophysiology of breast cancer. Conversely, 16α-hydroxyestrone may help to protect against osteoporosis.

Synthetic and Natural Estrogens:

Estrone (E1), estradiol (E2) and estriol (E3) are the three estrogens. Synthetic estrogen (premarin) is made up of E1 and E2 estrogen. E1 is the main estrogen that the body makes post menopausally, and most researchers believe that high E1 levels increase the risk of breast cancer.

Estrogen Metabolism:

The metabolism of estrogen in women changes after menopause. The body metabolizes estrogen into two major pathways and one minor. The two major are 2 and 16-hydroxyeone (2-OH and 16 OH, respectively). The minor pathway is 4-hydroxyestrone (4-OH). 2-OH is the good metabolite. 2-OH does not stimulate cell growth and it blocks the action of stronger estrogens that may be carcinogenic.

16-OH has a significantly stronger estrogenic activity, and studies show that it may increase the risk of breast cancer.

4-OH is also not desirable as it may directly damage DNA and cause mutations, thus it is thought to promote cancer development. Premarin breaks down exclusively into 4-hydroxyestrogen.

What does it mean if your 16-OH-E1 result is too low?

Low levels of the “bad estrogen” are typically considered beneficial.

16-OH-E1 is the immediate precursor to the weak estrogen, estriol (E3). Please also note that 16-OH-E1 is important for maintaining bone mineral density. Excessive reduction of 16-OH-E1 may reduce bone formation and increase oxidant stress.

If 16-OH-E1 is low and 2-OH-E1 is low, then total estrogen production may be low. Address underlying causes of low hormone production, as needed.

 

What does it mean if your 16-OH-E1 result is too high?

– Higher levels of the 16 pathway are associated with breast cancer, obesity, hypothyroidism, pesticide toxicity (organochlorines), high Omega-6 fatty acids, and inflammatory cytokines.

– 16-OH-E1 has been shown to encourage tumor development

Lowering levels of 16aOH-E1 have been achieved via indole-3-carbinol or one of its metabolites, di-indol methane (DIM). Soy and flax meal have also been shown to lower 16aOH-E1 levels.

A healthy result should fall into the range 2.5 – 6.5 ng/mg.

The biomarker 2-Methoxy-E1 is part of the phase 2 metabolism.

2-Methoxy-E1 is produced from 2-OH-E1 through the COMT enzyme. Anti-cancerogenic effects have been ascribed to 2-OH-E1and particularly 2-Methoxy-E1.

2-Methoxy-E1 has shown antiproliferative effects in both hormone-dependent and hormone-independent breast cancer cells. These studies have shown that urinary 2-Methoxy-E1 levels were lower in breast cancer patients than controls.

As an example: The average woman usually turns her 2-OH-E1 with a value of 10 into 2-Methoxy-E1 with a value of 5. So it’s usually a 2:1 relationship. So look at your 2-OH-E1 value and your 2-Methoxy-E1 value and see if you have a 2:1 ratio.

The 2-Methoxy Estrogens are considered to be protective. Low levels are usually a reflection of overall low estrogens and may be improved with supplemental estrogen. Metabolized from 2-OH-E1. A comparison of 2-Methoxy-E1 with 2-OH-E1 allows insight into methylation pathways. If the 2-Methoxy-E1 value is at least 25% of 2-OH-E1 value, methylation is probably adequate. If <25% consider adding methyl donors.

Phase 2 metabolism (methylation):

After estrogens go through phase 1 detoxification, they move on to methylation which is part of phase 2 detoxification. Methylation, in essence, “neutralizes” the phase 1 metabolites and prepares them to be excreted out of the body instead of shuttling them back into circulation. Only 2-OH and 4-OH estrogens are methylated. 16-OH-E1 is not.

What does it mean if your 2-Methoxy-E1 result is too low?

Identify cause:

If 2-OH-E1 and 4-OH-E1 are high, then low 2-Methoxy-E1 is likely the result of poor methylation. Follow methylation treatment recommendations.

– Ensure adequate COMT function via methyl donors such as SAMe, B12, folic acid, and B6.

– Poor cancer protection

– Associated with preeclampsia

Possible reasons for poor conversion to 2-Methoxy-E1:

– Nutrient deficiency

– Genetic defects in methylation (MTHFR, COMT). These genes are involved in methylation.

If someone has poor methylation, they may be at higher risk for estrogen dominance and estrogenic cancers.

– It is important to note that methylation is not the only phase II option for these hormones. Technically every estrogen measured in the DUTCH profile is a Phase 2 metabolite because they only exist in urine as phase 2 conjugates like glucuronides. For example, all of the estradiol in urine is in one of three different forms of estradiol-glucuronide.

– It is also important to note that methylation is an important detoxification step for catecholamines (like adrenaline) and other compounds. Compromised methylation can affect overall health in multiple ways and the methylation index on the DUTCH results can give insight into overall methylation efficiency.

– Poor methylation can be caused by nutrient deficiencies or genetic defects in enzymes (namely MTHFR and COMT). Magnesium and methyl donors (SAMe, B Vitamins, TMG, Choline, Folate, Methionine) are cofactors needed for methylation to work properly.

It’s important however not to rush to supplement with all of these or just one of the nutrients listed above but to do proper testing to assess whether the issue is elevated estrogen levels only, poor phase I, poor phase II or all of the above! Supporting the system only partly, or supporting only phase I when phase II may be sluggish, may only exacerbate your symptoms or not be nearly as effective.

Note: When levels of 2-OH-E1 and the methylated 2-Methoxy-E1 are very low (<0.5), ratios of the metabolites are more approximate as the individual values are somewhat less reproducible. 

What does it mean if your 2-Methoxy-E1 result is too high?

– Generally no treatment recommended

– Ensure adequate phase II detoxification

A healthy result should fall into the range 0 – 1.2 ng/mg.

Research and clinical studies show that the 2-hydroxylated estrogens (2-OH E2 and 2-OH E1) are a safer pathway of hydroxylation than the 4-hydroxyestrogens (4-OH E2 and 4-OH E1), which bind to and damage DNA, leading to mutations that are associated with increased breast cancer risk. If either 4-OH-E2 or 4-OH-E1 are higher than reference range, and not well methylated, this may indicate higher risk for DNA damage, mutations, and risk for developing breast cancer.

Hydroxylation of estrogens in the 2-position of estradiol (2-OH-E2) and estrone (2-OH-E1) is considered a safer pathway for metabolism than the 4-position hydroxylations of these estrogens. The 2-position hydroxylations (considered safer) are increased with cruciferous vegetables (and extracts of them) as well as iodine. The most commonly used are indole-3-carbinol (I3C) and its metabolite diindolylmethane (DIM). Iodine also increases the 2-hydroxylation of estrogens, with a slight increase in 4-hydroxylation. The more dangerous 4-hydroxylated estrogen metabolism is enhanced by exposure to environmental toxins, mostly petrochemical-based products but also heavy metals, that induce 4-hydroxylation pathway enzymes, and cause formation of Reactive Oxygen Species (ROS) that co-oxidize the catechol estrogens to more dangerous estrogen quinones.

A healthy result should fall into the range 0 – 0.5 ng/mg.

4-OHE1and 4-OH-E2 are referred to as the “bad” estrogens, along with 16a-OHE1. They are primarily produced by CYP1B1 and CYP34A, respectively, enzymes localized in tissues, including breast and prostate as well as liver. Some have suggested that increased expression of CYP1B1 and 4-hydroxylation of estradiol are biomarkers of tumorigenesis.

Human breast cancer tissue produces much higher levels of 4-OH than 2-OH, while normal breast tissue produces approximately equal amounts of the two metabolites. Women taking hormone therapy with a polymorphism in CYP1B1 had twice the risk of developing breast cancer compared to other HRT users.

References:

http://www.ncbi.nlm.nih.gov/pubmed/16411670

http://www.pnas.org/content/94/20/10937.long

http://www.ncbi.nlm.nih.gov/pubmed/14749240

https://www.ncbi.nlm.nih.gov/pubmed/25048790

http://www.cqzb.cn/references.htm

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4632771/

https://www.sciencedirect.com/science/article/pii/S1658077X16300960

What does it mean if your 4-OH-E2 result is too low?

Generally no treatment recommended

What does it mean if your 4-OH-E2 result is too high?

The bad news may be that you are making too much of the 4-hydroxyestrogens and not methylating them well. The good news is that you know this is happening and can do things to change how your body metabolizes estrogens, and in doing so decrease your breast cancer risk. Nutritional intervention (e.g., foods rich in DIM or indole-3-carbinol) can be used to shift estrogens in the direction of 2-hydroxylation, which is safer. Additionally, methylation of estrogen metabolites can be supported nutritionally (e.g., methyl donors such as vitamin B12, folic acid, SAM-e, and foods such as onions, garlic and beets). And the effectiveness of this intervention can be evaluated by measuring the ratio of 2- and 4-methoxyestrone to 2- and 4-hydroxyestrone.

– Improve methylation by adding cofactors (B12, folate) or methyl donors (betaine, dimethyl glycine)

– Consider genetic testing for COMT and CYP1B1 activity, particularly if positive family history

– Reduce stress: COMT is involved in the metabolism of epinephrine, reducing availability for estrogen metabolism

– Increase inhibitors of CYP1B1 (Grapefruit, Ginseng)

– Avoidance of CYP1B1 inducers (Polycyclic aromatic hydrocarbons)

Evaluate methylation activity:

– Serum Homocysteine

– Serum B12 or methylation

– Urinary FIGLU

– Urinary xanthurenate

Other potential protective factors:

– Glutathione (reduction of estrogen quinones)

– Resveratrol (prevents estrogen quinone formation)

– Selenium, zinc, magnesium

High levels of 4-hydroxylated estrogens (4-OH-E2 and 4-OH-E1) and/or low levels of their methylated forms are associated with increased breast cancer risk.

Lifestyle modifications help reduce excessive levels of the parent estrogens (estradiol, estrone) and their down-stream hydroxylated metabolites.

Some of these lifestyle modifications include:

– maintaining a healthy weight,

– exercising,

– eating green leafy vegetables

– avoiding excess red meat,

-assuring that iodine and selenium are within healthy ranges that protect the breast epithelium, using bioidentical hormones (particularly natural progesterone),

– avoiding toxic foods and chemicals as much as possible.

EAT FIBER:

Try to consume 40 to 60 grams of fiber every day. Fiber helps to bind excessive hormones and metabolites that are excreted in your stool. The addition of fiber will also help to bind and excrete excessive fats.

EAT FLAX SEEDS:

Flax seeds – Flax seeds are a promoter of CYP1A1 and an inhibitor of CYP1B1. Thus, flax seeds are promoters of 2 hydroxylation (neutral estrogen), and inhibitors of 4 hydroxylation (potentially undesirable). Flax also has shown to inhibit CYP3a4 and reduce the excretion of 16OHE1, another potentially problematic estrogen.

EAT GREEN VEGGIES:

Eat raw organic broccoli, Brussels sprouts, kale, or cauliflower three times per week. A recent clinical trial found that these vegetables produce the substances indole – 3 – carbinol (I3C) and diindolymethane (DIM). They help to stimulate or make more CYP1A1, which is responsible for making more 2-OHE1. Increased ratios of 2-OHE1 to 16a-OHE1 are thought to be protective against breast cancer formation.

EAT BERRIES:

Numerous types of berries (blackberries, raspberries, grapes, blueberries) are a rich source of polyphenolic compounds, including ellagic acid. Ellagic acid is a promoter of glutathione transferase (GSTM) as well as NQO1 (quinone reductase). These 2 enzymes are important in the detoxification of 3,4 semi-quinones. Additionally, ellagic acid has been shown to increase DNA repair genes, as well as reduce DNA adducts that have been formed by carcinogens.

GRAPEFRUIT AND CITRUS PEEL:

Grapefruit & Citrus peel are sources of hesperidin. Hesperidin at high doses inhibits CYP1B1 and also CYP3a4. Grapefruit is notorious for inhibiting CYP3a4. Citrus peel contains a considerable amount of hesperidin, that is especially true of dried tangerine peel. An assortment of studies done on hesperidin have found an overall increase in blood flow and circulation, reduction in blood pressure, and reduction in symptoms of cell adhesion factors, which may disrupt cancer activities.

DHA:

Take 600 – 800 mg of DHA omega 3 fatty acids per day. The easiest way to do this is through supplementation. This helps to prevent overall inflammation in the body.

MULTIVITAMIN:

Take a good multivitamin in order to ingest adequate amounts of nutrients necessary to convert estrogen metabolites to the protective methyl forms such as 2-MeOHE1. Specifically you want adequate amounts of methyl folic acid, methyl cobalamin, and vitamin B6. (Consult your health care practitioner prior to taking a multivitamin).

AVOID PROCESSED SUGARS:

Avoid processed sugars or excessive amounts of natural sugars. Excess sugar is stored as fat in humans. Estrogen loves to store itself in fat cells. These stored estrogens can be released or converted, causing more effects of estrogen dominance. This can increase a person’s risk of estrogen-induced cancers.

EXERCISE:

Exercise 5 times per week for 30 minutes each time, including 3 days of resistance training. This helps to control excessive body weight and increases natural regulation of sex hormones.

AVOID CHEMICALS:

Avoid contact or ingestion of pesticides and/or chemical irritants. Many common chemical products cause DNA damage in cells, making them more susceptible to developing cancers.

AVOID GENETICALLY MODIFIED FOODS:

Avoid genetically modified foods or foods with chemical preservatives. Many of these types of foods have been shown to cause cellular damage.

AVOID EXCESS CONSUMPTION OF SOY PRODUCTS:

Avoid excess consumption of processed soy products as they may increase your risk of estrogen metabolite production.

LOWER STRESS LEVELS:

Keep your stress levels as low as possible.

A healthy result should fall into the range 0 – 0.7 ng/mg.

The biomarker 2-Methoxy-E2 is part of the phase 2 metabolism.

2-Methoxy estrogens is produced from 2-OH estrogens through the COMT enzyme. Anti-cancerogenic effects have been ascribed to 2-OH estrogensand particularly 2-Methoxy estrogens.

2-Methoxy-estrogen has shown antiproliferative effects in both hormone-dependent and hormone-independent breast cancer cells. These studies have shown that urinary 2-Methoxy estrogen levels were lower in breast cancer patients than controls.

Phase 2 metabolism (methylation):

After estrogens go through phase 1 detoxification, they move on to methylation which is part of phase 2 detoxification. Methylation, in essence, “neutralizes” the phase 1 metabolites and prepares them to be excreted out of the body instead of shuttling them back into circulation. Only 2-OH and 4-OH estrogens are methylated. 16-OH-E1 is not.

What does it mean if your 2-Methoxy-E2 result is too low?

Identify cause:

– If 2-OH and 4-OH estrogens are high, then low 2-Methoxy estrogen is likely the result of poor methylation.

– Follow your doctors methylation treatment recommendations.

– If 2/16 ratio is also low, then low 2-Methoxy estrogen may be indicating a CYP imbalance.

– Follow your doctors recommendations for improving a low 2/16 ratio.

– If total estrogen metabolite production is low, then consider direct assessment of estrogen levels.

– Ensure adequate COMT function via methyl donors such as SAMe, B12, folic acid, and B6.

– Poor cancer protection

– Associated with preeclampsia

What does it mean if your 2-Methoxy-E2 result is too high?

– Generally no treatment recommended

– Ensure adequate phase II detoxification

A healthy result should fall into the range 35 – 70 ng/mg.

Where is estrogen made?

Estrogen is made primarily in the ovaries of cycling women while smaller amounts can be converted from testosterone through a process called aromatization. In menopause estrogen production shifts almost completely to aromatization. The enzyme responsible for aromatization is found in fat tissue, the brain, gonads, blood vessels, skin, and bone.

In Men:

Men need far less estrogen than women and it is aromatized primarily from testosterone. Women who are still cycling have much greater quantities of estradiol than men, but it is important to note that men do make estrogen. In fact, the level of estrogen in men is actually higher than the level in a post-menopausal woman!  

What does estrogen do?

– Growth and development of female secondary sex characteristics

– Thickens the uterus for implantation, increases vaginal acidity to protect against infection, important for vaginal lubrication (particularly E3)

– Necessary for bone health

– In the brain helps maintain body temperature, protects against memory loss, increases serotonin and serotonin receptors

– Important for collagen production, skin thickness and getting blood supply to the skin

– Helps protect against atherosclerosis

The three primary estrogens:

Estrone (E1):

– Weaker compared to Estradiol

– Research says the estrogenic activity is about 4% of estradiol’s activity

– Most abundant in menopause

– Made via aromatization in several tissues like fat and muscle

– Converts into estradiol (E2)

Estrone (E1) is also made by the ovary but in fat tissue in lesser quantities. While not as abundant in circulation as estradiol, estrone excess can still increase the risk for estrogen dominant cancers as well as estrogen dominant symptoms such as breast tenderness, heavy menstrual cycles, headaches, and erectile dysfunction and breast development in men just like estradiol. Estrone is commonly thought to be more abundant during menopause.

Estradiol and estrone can interconvert into each other.

Estradiol (E2):

– Most potent

– Made primarily in the ovaries

The main and most potent estrogen is known as Estradiol (E2). It is made primarily in the ovaries or testes but also the fat, liver, and neural tissue.

Expected values for E2:

– 1.8 – 4.5 Premenopausal (days 19-22), not on birth control

– 1.0 – 2.0 Collecting right after menstruation

– 4.0 – 12.0 Collecting close to ovulation

– 0.2 – 0.7 Postmenopausal (and not supplementing) or on birth control

Estriol (E3):

– The ‘end product’ of estradiol/estrone metabolism

– 16-OH-E1 can convert into estriol

– Not made in the ovaries

– Very weak estrogen

– Elevated in pregnancy due to placental production

The third estrogen is known as Estriol (E3) and is produced in significant amounts during pregnancy. In men and women, Estriol is irreversibly produced by estradiol (estriol cannot make estradiol) or from estrone through 16-OH-Estrone which makes it the largest circulating estrogen because both Estrone and Estradiol can make it. Despite this, estriol is not nearly as potent as estradiol (Estradiol is 80x more potent!).

What does it mean if your Total Estrogen result is too low?

Why does estrogen decrease?

– Age (peri-menopause and menopause)

– Irregular cycles/skipped cycles/anovulation

– Hysterectomy with ovaries removed

– Anorexia

– Low cholesterol (backbone to hormones)

– Extreme exercise or training

– Extreme stress resulting in skipped menses

– Under appropriate body weight percentage for height/age (Mixed research: suggested <15% body fat = amenorrhea)

– Hypogonadism (ovaries fail)

– Hypopituitarism (pituitary not communicating)

– Decreased blood flow to the ovaries (Ex. Surgery or smokers)

– Breast feeding

– Hypothyroidism

– PCOS

– Fertility medications

– Opioid pain medications (in last 6 months)

– Hormonal birth control – pill, patch, ring, implant, injection

Common symptoms of low estrogen:

– In women – fatigue, depression, hot flashes, night sweats, vaginal dryness, pain with intercourse, low libido, joint pain, brain fog, migraines/headaches, fertility issues, dry skin

– In men – not generally considered symptomatic, but in very extreme cases men may have similar symptoms as in the list above for women

Common ways to raise estrogen:

In women – address the cause, phytoestrogens such as Red Clover, Dong Quai, Kudzu, soy, diosgenin, genistein, fennel, and Black Cohosh (although studies are mixed on whether it acts as a phytoestrogen or not), Maca, and bioidentical estrogen replacement

What does it mean if your Total Estrogen result is too high?

Why do Estrogen levels increase?

– Overweight/obesity

– Peri-menopause = surges of estrogen

– Diabetes

– PCOS

– Estrogen supplementation

– Steroid medications

– Poor liver clearance so estrogens build up

– Dysbiosis/Estrobolome problems

– Over aromatization from testosterone

– Environmental estrogens (difficult to test however)

– Alcohol (2 or more glasses/day shown to increase estrogen)

– Ovarian cysts

– Having elevated testosterone levels – testosterone gets converted to estrogen through the aromatase enzyme. Therefore, having Polycystic Ovarian Syndrome (PCOS), over supplementing with testosterone or DHEA or generally having a high production of this hormone, can lead to more estrogen being produced as a byproduct.

In men – over aromatization from testosterone to estrogen due to inflammation and blood sugar/insulin issues, environmental/xenoestrogen exposure (this does not show up on DUTCH testing, but they can cause symptoms), moderate alcohol use, and obesity

Common symptoms of elevated estrogen:

– In women – mood swings, weight gain, breast tenderness, fibrocystic breasts, heavy menses, fibroid/polyp development.

– In men – breast development, weight gain, and mood swings.

Common ways to lower estrogen:

Please consult with your health care provider about advice/treatment/diagnosis. The following statements are general informational statements.

– In women – address the cause, avoid alcohol, avoid environmental/xenoestrogens, DIM/I3C supplementation, calcium-d-glucurate, increased fiber (especially ground flax seeds), increased detoxification support, and weight loss

– In men – address the cause, avoid alcohol, avoid environmental/xenoestrogens, DIM/I3C supplementation, calcium-d-glucurate, increased fiber, decrease blood sugar and insulin, increased detoxification support, weight loss, and things that block aromatase (Chrysin, Damiana, Zinc and pharmaceutical aromatase inhibitors)

Other general interventions to keep in mind that can be beneficial for everyone if you don’t know the status of your hormones includes:

– Avoiding xenoestrogen exposure. Here is a great link to the top endocrine disruptors to avoid your environment [L]:

– Eat more cruciferous vegetables from the Brassica family- broccoli, kale, Brussels sprouts, cauliflower, cabbage, kale, etc.

– Support your liver on-goingly – from the basic lemon water to increasing consumption of dandelion or dandelion tea, doing a liver cleanse twice a year and reducing consumption of sugar and alcohol.

– Make sure your bowels are going – lots of fluids and high fiber in your diet will help regulate your bowel movements and make sure your hormones are properly detoxified rather than sitting in your body and recirculating back in the system.


Disclaimer:

Test results may vary depending on your age, gender, health history, the method used for the test, and other things. Your test results may not mean you have a problem. Ask your healthcare provider what your test results mean for you.

The information on healthmatters.io is NOT intended to replace a one-on-one relationship with a qualified health care professional and is not intended as medical advice.

2 comments

  1. Great time to post this because low estrogen can make someone prone to viral infection. Very good information and must have taken you a long time to put this together. I really appreciate the work you do and how in depth you cover things. Keep up the good work.

    Like

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