Estrogen: How it is made and how we get rid of it

genetics and estrogen metabolism

Estrogen is usually thought of as the female hormone. While it is true that women produce more estrogen than men, this is a topic that applies to all of us. Estrogen – from how much is made to how it is broken down – is dependent on both genetics and lifestyle factors and affects both men and women.

If you’re like me, you probably think “I know what estrogen is”, but do you? really? I’ll be honest and admit that I hadn’t really thought about how estrogen works within a cell and what exactly it is doing.

This article explains (from a genetic point of view):

  • how estrogen is made
  • how that estrogen is broken down – and –
  • how this influences the risk of breast cancer, prostate cancer, and uterine fibroids

Disclaimer: Everything written here is for informational purposes. Talk with your doc, read through the referenced literature before making any decisions – especially in relation to cancer or cancer prevention. 

Estrogen creation and metabolism

When you look up estrogen online, it is usually defined as ‘a female sex hormone’… which really tells you nothing. There are actually several different types of estrogen, and it is a hormone important in both males and females.

Types of estrogen:

There are several forms of estrogen in the body, and the amounts of each type become important for hormone-related cancer risk and uterine fibroids. [ref]

  • Estradiol (E2) or 17β-Estradiol – primary form in women prior to menopause
  • Estriol (E3) – main type of estrogen during pregnancy
  • Estrone (E1)  -primarily made after menopause
  • Estretrol (E4) – only during pregnancy, made by the fetus

How is estrogen made?

Estrogen is made in the ovaries (major source, women), testes (males), brain, liver, pancreas, fat cells, intestines, and adrenals. [ref] The precursor for estrogen is cholesterol.

Cholesterol is first converted (using CYP11A1) into progesterone, which is then converted (using CYP17A1) into androstenedione.

Androstenedione can be converted into testosterone, dihydrotestosterone, or estrogen.

If it goes the estrogen route, androstenedione is converted (using CYP19A1) first to estrone, which is then converted (using 17β-HSD) into estradiol. [ref]

This definitely needs a flow chart!

how estrogen is made from cholesterol

Within follicle cells in the ovary, the conversion of the steroid hormone precursor into estrogen is controlled by follicle stimulating hormone (FSH) levels. FSH is produced in the pituitary gland, and, along with luteinizing hormone, controls the menstrual cycle.

Estrogen Sulfate:

If you ever get a hormone panel done, you will probably see estrogen sulfate listed. Estrogen sulfate is the most abundant form of estrogen, but it is also not very active.  It can be considered as a storage form of estrogen that can be converted by HSD17B1 (17β-Hydroxysteroid dehydrogenase) into estradiol.  High levels of estrogen sulfate can be a risk factor for breast cancer.

What does estrogen do in the body?

Estrogen regulates the menstrual cycle and is imperative for reproduction. The ‘primary and secondary sexual characteristics’ of women (breasts, wider hips, lack of facial hair, etc) are due to estrogen.

For everyone, estrogen is also important in maintaining bone density. Low estrogen is linked to osteoporosis. It is also important in brain function and controlling inflammation. 

In men, estrogen is also necessary (at low levels) in the production of sperm. Loss of the estrogen receptor in the testes results in abnormal sperm. On the other hand, too much estrogen can also be bad. [ref][ref]

What happens when you have too much estrogen?

Signs of excess estrogen in women include:

  • weight gain
  • heavy periods
  • fibroids
  • PMS
  • fibrocystic breasts
  • loss of sex drive
  • fatigue, depression, anxiety

For men, too much estrogen leads to:

  • gynecomastia (a.k.a. man boobs)
  • sexual dysfunction
  • loss of muscle mass
  • fatigue, depression, anxiety

Digging deeper – estrogen receptors:

So we know that estrogen does a lot in the body – but exactly how does this work? Estrogen is transported all over the body via the bloodstream and then enters into cells.

So what exactly does estrogen do in cells?  It binds to estrogen receptors in the nucleus causing them to turn on and off the transcription of a number of different genes. Thus, the different estrogen receptors can control whether a gene gets transcribed into a protein that is used in the cell.

There are several different estrogen receptors:

  • ERα is encoded by the gene ESR1 gene.
  • ERβ is encoded by the ESR2 gene.
  • G protein-coupled estrogen receptor 1 is encoded by the GPER1 gene.

The estrogen receptors can bind to and turn on hundreds of different genes. Some that are important include the LDL receptor, progesterone receptor, IGF-1, and many more. These genes are related to hormones, cholesterol, and growth within the body.[ref]

In a nutshell, estrogen causes the body to increase the production of other hormones, growth factors, and metabolic factors. 

Getting rid of estrogen (metabolism):

To control the level of estrogen in the body, we have to have a way to break it down and eliminate it. This is a multi-step process.

In the liver, the CYP450 enzymes can metabolize estrogen. Specifically, this is done by the CYP1B1, CYP1A1, or CYP1A2 enzyme.  This process creates metabolites known as 2-OHE1 (E2), 4-OHE1(E2), and 16α-OHE1, all of which are also known as catechol estrogens.

These catechol estrogens can be metabolized by COMT (catechol-O-methyltransferase) or through glucuronidation (UGT genes) This makes them water-soluble and able to be excreted. [ref]

Essentially, this is a two-step process that needs to work in tandem:

  • Phase I, the CYP1B1 or CYP1A1 breaks down estradiol into the catechol estrogen metabolites.
  • Phase II, they need to be made into water-soluble substances (by COMT, UGTs).

Why is it so important that both phases happen in sync? Because some of the metabolites, such as 16α-OHE1, are also able to activate the estrogen receptors — and are implicated, big time, in breast cancer.[ref] So you don’t want certain Phase I metabolite hanging around in the body.

To recap: estrogen is broken down in two phases. The different phase I options can cause ‘good’ or ‘bad’ metabolites. Phase II then needs to make those metabolites water-soluble, so that they can be pooped or peed out.

Estrogen metabolites linked to breast, ovarian, and prostate cancer:

For breast cancer, the 4-OHE1(E2) and 16α-OHE1 metabolites are implicated in increasing the risk. Higher amounts of 2-OHE1(E2) or a better ratio of 2-OHE1:4-OHE1 decreases breast cancer risk. Additionally, you don’t want too much estrogen (E1 or E2), in general, hanging around (Goldilocks here- just the right amount is needed).  [ref][ref]

Prostate cancer risk is increased with 4-HOE1(E2) metabolites also. [ref]

In general – the estrogen metabolites that start with “2” are good and the ones that start with “4” or “16” need to be limited.  But this, in part, depends on your phase II metabolism as well.

So let’s take a look at how these catechol estrogen metabolites are formed and then processed out of the body with a nifty diagram:

As you can see, upregulating the CYP1A1 enzyme is going to increase the 2-OHE1 path.

Too much estrogen being metabolized through CYP1B1 into 4-OHE1(E2) and the estrogen quinones can potentially be bad if your body has slower phase II  (COMT, GSTP1, GSTM1, NQO1) enzymes. [ref][ref]

The connection between smoking and estrogen-related cancers:

Smoking increases the risk of breast cancer and prostate cancer. I had always assumed that this is simply because smoking is bad… and I had never thought about why those specific cancers would be connected to smoking.  Part of the ‘why’ is because cigarette smoke causes DNA damage – it’s bad :-).

But the specific of ‘why breast cancer‘ is that components of cigarette smoke increase the CYP1B1 and CYP1A1 enzymes. If that increase is tipped towards the CYP1B1 path (due to genetic variants) and you can’t get rid of the estrogen metabolites fast enough (due to phase II genes, diet, lifestyle), then cigarette smoking is going to increase the ‘bad’ estrogen metabolites. Smoking also may impair the phase II metabolites, thus creating more estrogen quinone metabolites with a decreased ability to eliminate them. [ref][ref]

Therefore, combining some of the phase I and phase II genetic variants (below) with smoking causes a fairly large increase in the risk of cervical, breast, or prostate cancer.

Estrogen Elimination:

Let’s go one step further and make the two-step process of estrogen metabolism into a three-step process…  because once the catechol estrogen metabolites have been metabolized (COMT), they have to be excreted (yep – urine or feces).  And this becomes important as well when it comes to the gut microbiome…

The estrogen that has been metabolized and is ready to be eliminated through feces can actually be recycled back into circulation due to an interaction with certain bacteria in your gut microbiome. Beta-glucuronidase, produced by the gut microbiome, can reverse the reaction that the UGT enzymes did to make the estrogen metabolites more water-soluble. This can cause the estrogen metabolites to be reabsorbed from the intestines and go back into circulation.[ref]

Calcium d-glucarate can suppress the beta-glucuronidase activity in the gut, thus increasing the amount of estrogen metabolites that are excreted (which is a good thing!).[ref]

Estrogen Mimics:

There are several environmental toxicants that act similarly to estrogen in the body.  Among these, phthalates and BPA are ubiquitous and found in almost everyone’s body these days. These chemicals can bind to the estrogen receptors. [ref][ref]

Phthalates are used in vinyl, plastics, adhesives, artificial fragrances (laundry detergent, air freshener), personal care products, and more.  [ref]

BPA is also found in plastics and we are exposed through food and drinks being stored in plastic containers or cans with linings that contain BPA. Even the paperboard used in food packaging (especially if it is recycled cardboard) can contain BPA which is transferred to food.[ref]

These estrogen mimics (at the levels found in people every day) have been linked to increased risk of:

  • endometriosis [ref]
  • enlarged prostate [ref]
  • almost 2-fold increase in breast cancer for higher phthalate exposure (estrogen receptor-positive) [ref]
  • BPA exposure at low levels is linked to increased breast and prostate cancer[ref]
  • uterine fibroids[ref][ref]

 


Genetic variants:

I’ve thrown a lot of terms and gene names at you.  Let’s get specific in how this applies to you and your genetic variants.

Most of these are really common genetic variants, so don’t freak out if you have one or all of the variants and they are linked to cancer. Lots of things are linked to cancer… The variants interact with each other as well as with your diet and lifestyle when it comes to various conditions associated with them. The point here is to use the information to make changes – dietary, lifestyle – to minimize your risk factors.

Here is the nifty diagram again so that you don’t have to scroll back up:

Estrogen metabolism genes:

Phase 1 metabolism:

CYP1A1 gene:
phase I detoxification of estrogen into 2-OHE1(E2)

Check your genetic data for rs1048943 (23andMe v4 only):

  • T/T: most common type, normal function
  • C/T: increased risk of cervical cancer; increased risk of fibroids
  • C/C: increased risk of cervical cancer[ref], especially in smokers (8-10-fold increase in risk for active smokers)[ref] increased risk of uterine fibroids [ref][ref]

CYP1B1 gene:
phase I detoxification of estrogen into 4-OHE1(E2)

Check your genetic data for rs1056836 Leu432Val (23andMe v4, v5; AncestryDNA):*

  • G/G: (Leu/Leu – slower); decreased estradiol metabolism [ref] increased hot flashes, especially in smokers [ref]
  • C/G: intermediate/decreased estradiol metabolism [ref]
  • C/C: (Val/Val – faster); decreased risk of prostate cancer [ref][ref]

*Note that these are referred to in the plus orientation to match 23andMe data. This variant is prone to confusion because the variant is very common and the orientation is often switched in studies.

Check your genetic data for rs1056827 A119S (23andMe v4 only):

  • C/C: normal
  • A/C: somewhat increased risk of uterine fibroids
  • A/A: increased risk of breast cancer [ref] increased risk of uterine fibroids [ref]

CYP3A4 gene:
converts estrogen into 16a-OHE1 (higher levels linked to breast cancer)

Check your genetic data for rs2740574 (23andMe v4, v5; AncestryDNA):

  • T/T: normal
  • C/T: somewhat increased risk of ovarian cancer
  • C/C: increased risk of ovarian cancer, prostate cancer [ref]; increased CYP3A4 activity [ref]

Phase II estrogen metabolism genes:

COMT gene:
phase II detoxification of estrogen metabolites

Check your genetic data for rs4680 (23andMe v.4 and v.5):

  • G/G: (Val/Val) higher COMT activity
  • A/G: intermediate COMT activity
  • A/A: (Met/Met) lower COMT activity; increased risk of hot flashes, especially in smokers[ref] increased risk of breast cancer [ref]

GSTP1 gene:
another phase II detoxification enzyme important for reducing estrogen quinones

Check your genetic data for rs1695 (23andMe v4, v5; AncestryDNA):

  • A/A: normal
  • A/G: normal risk of breast cancer
  • G/G: reduced function, increased risk of breast cancer [ref] increased risk of prostate cancer[ref]

GSTM1 gene: another phase II detoxification enzyme important for reducing estrogen quinones

Check your genetic data for rs366631 (23andMe v4 only):

  • A/A: deletion (null) GSTM1 gene. GSTM1 deletion is associated with 2x increased risk of breast cancer [ref]  This is actually the most common genotype in most populations.
  • A/G: GSTM1 present
  • G/G: GSTM1 present

UGT1A1/6 gene:
phase II detoxification gene for reducing estrogen metabolites

Check your genetic data for rs2070959 (23andMe v4, v5; AncestryDNA):

  • A/A: normal
  • A/G: normal
  • G/G:  lower enzyme activity [ref] possibly increased breast cancer risk[ref]

NQO1 gene: phase II detoxification enzyme

Check your genetic data for rs1800566 (23andMe v4, v5; AncestryDNA):

  • A/A: slightly increased cancer risk [ref] [ref] very low NQO1 enzyme activity [ref] increased prostate cancer risk [ref]
  • A/G: slightly increased cancer risk, reduced NQO1 enzyme activity
  • G/G: normal

While each of these genetic variants individually increases the risk of estrogen-related cancer by a bit, the combo of variants and the interaction with lifestyle factors can be large. Faster phase I metabolism combined with slower phase II metabolism can be a problem.[ref]

A combo of CYP1B1 rs1056836 CC (Val/Val – faster) and COMT rs4680 AA (Met/Met – slower) increases the risk of ovarian cancer significantly (2 – 5-fold). Smoking interacts here to also dramatically increase the risk of ovarian cancer in these women. [ref][ref]

The combo of CYP1B1 rs1056836 CC and COMT rs4680 AA also increases (somewhat) the risk of prostate cancer. [ref] This combo also doubles the risk of breast cancer.[ref]

Other studies simply note that a number of combos of the higher risk alleles in all these genes increase the risk of breast cancer.[ref]

Genes involved in making estrogen:

Here is the estrogen creation diagram again:

how estrogen is made from cholesterol

CYP19A1 gene (aromatase): converts androstenedione and testosterone into estrogen

Check your genetic data for rs4646 (23andMe v4, v5; AncestryDNA):

  • A/A: less common genotype, lower estrogen levels;  longer breast cancer survival in premenopausal women but shorter survival in postmenopausal women [ref]
  • A/C: intermediate
  • C/C: most common genotype, higher estrogen levels [ref]

Check your genetic data for rs700518 (23andMe v4, v5; AncestryDNA):

  • T/T: increased risk of benign prostate hyperplasia[ref]; higher estrogen levels (men)[ref]
  • C/T: intermediate
  • C/C: lower estrogen levels (men)

CYP17A1 gene: converts progesterone into androstenedione

Check your genetic data for rs743572 (23andMe v4 only; AncestryDNA):

  • A/A: normal
  • A/G: decreased risk of breast cancer
  • G/G: decreased risk of breast cancer [ref]

 


Lifehacks:

Most of these life hacks are geared towards getting rid of excess estrogen. Keep in mind that you may not want to get rid of estrogen, depending on your age and estrogen levels. There is no one size fits all here!

Testing is the only way to actually know your estrogen levels. You can order your own hormone test panels online (UltaLabs Estrogen Panel) or go to a doctor. Honestly, this is one area that even if you don’t like to go to the doctor, you may want to find a qualified person to help with interpreting the test results.

Phase I enzymes:

CYP1A1:
Diindolylmethane (DIM) is a compound found in cruciferous vegetables. DIM upregulates CYP1A1.[ref] For someone who has a slower CYP1A1 variant or a faster CYP1B1 variant, this may be a really good thing.  DIM may also decrease CYP19A1 (aromatase), thus decreasing the production of estrogen, to begin with.

You could eat a ton of cruciferous vegetables to get your DIM, or it is available as a supplement. Cabbage is the cruciferous vegetable highest in DIM.

Studies show that DIM increases the ratio of 2-OHE1:16α-OHE1 — which may be beneficial for preventing cancer.[ref][ref] There is some good evidence that it may be beneficial for prostate cancer as well[ref][ref], but not all studies agree [ref]. Read the studies, talk with your doctor.

If you decide to supplement with DIM, a lot of clinicians recommend combining it with calcium d-glucarate (which helps with estrogen elimination). Jarrow sells a combo of DIM and calcium d-glucarate, or you can get them as separate supplements if you want to take them at different times of the day.

One more layer to add into the complexity here:  Circadian Rhythm.
The CYP1A1 enzyme levels rise and fall over the course of a day along with the core circadian gene, CLOCK. [ref] If I understand the research correctly, taking DIM in the morning may be more effective than taking DIM at night.

CYP3A4:
CYP3A4 is the enzyme needed for converting estradiol into 16α-OHE1.

Grapefruit juice and bergamot (both contain bergamottin) inhibit CYP3A4. You may think (like I did) that inhibiting the production of 16α-OHE1 would decrease breast cancer risk. On the other hand, inhibiting CYP3A4 may also increase the overall amount of estrogen in the body.  Studies on grapefruit show mixed results:  Drinking grapefruit juice has been shown to lower estradiol in postmenopausal women.[ref] One study did find that eating grapefruit increased the risk of breast cancer a little bit.[ref] Another study found no effect from eating grapefruit.[ref] None of the studies looked at the ratio of 2-OHE1:16α-OHE1…

Just make sure that you don’t drink grapefruit juice while taking a medication that needs the CYP3A4 enzyme! The effects of a 6 oz glass of grapefruit juice can last for 24 hours.[ref]

St. John’s wort increases CYP3A4.[ref][ref]  I can’t find any research studies, though, that show that this could increase breast or prostate cancer risk. It may have benefits, such as inhibiting CYP1B1, that outweigh any possible negatives from the increase in CYP3A4.[ref]

Increasing Phase II enzymes:

You want to avoid 4-OHE1/2 hanging around, and if you have a slow COMT gene, the 4-OHE1 can be turned into estrogen quinones, which could be bad…

To get rid of the quinones, you need the phase II enzymes, GST’s or NQO1, both of which are controlled by Nrf2 and increased by cruciferous vegetable intake. (Check your genetic variants for the Nrf2 pathway.)

Sulforaphane and/or cruciferous vegetable intake increase GST and NQO1. You can get sulforaphane from eating broccoli sprouts or via a supplement.  Cruciferous vegetables are available in your grocery store :-) Cruciferous veggies include cabbage, broccoli, cauliflower, kale, collards,  and Brussels sprouts.

One study specifically found that women with the GSTP1 rs1695 G/G genotype overall were at a slightly greater risk of breast cancer — but that was because cancer risk increased quite a bit when the women had a low cruciferous vegetable intake. [ref] Eating plenty of cruciferous vegetables should mitigate the risk from this variant.

N-acetyl cysteine (NAC) and resveratrol have been shown to reduce the catechol estrogen quinones (bad stuff).  [ref]  These work by increasing the expression of NQO1,  which reduces the quinones to catechols [refNAC and resveratrol are both available as supplements on Amazon and at your local health food store.  (Note that if you carry the NQO1 rs1800566 TT genotype which has very low enzyme activity, this may not be as effective for you.)

Getting rid of estrogen mimics:

Both phthalates and BPA are thought to mimic estrogen in the body and have been shown to bind to the estrogen receptors.

The question of how to get rid of these ubiquitous chemicals, though, is a tough one… most studies find that 90 – 100% of people have them in their body on any given day.

Personal care products that contain phthalates have been shown to significantly increase phthalate levels in the body.  Go read the labels and see what you are using each day (shampoo, body wash, lotions, etc). Look for the big long chemical words that contain ‘phthalate’ in there somewhere. For example, dibutyl phthalate or di-2-ethylhexyl phthalate.

Perfumes and fragrances often contain phthalates.[ref] Cosmetics and perfume sales clerks were found to have higher phthalate levels after their shift at work. [ref] Synthetic air fresheners and laundry detergent fragrances can be another source.[ref]

A new study just came out this month showing that skin exposure to phthalates from clothing is actually the largest source for babies (Chinese study). [ref] Other studies, though, point to inhaling phthalates through dust particles.[ref]  This would be a good reason to go dust and vacuum your house today.

BPA is found in plastics (don’t microwave your food in plastic) and plastic water bottles. Most people know this…  get a glass water bottle and some glass containers for storing your leftovers.

Canned foods have high levels of BPA due to the can linings containing PVC.[ref] So switching to eating fresh vegetables should help decrease BPA exposure somewhat. (A recent study of people in NC found that BPA in food only explained about 20% of the daily dose, but older studies show it being more significant.[ref])

But what a lot of people don’t realize is that BPA or BPS is also used on thermal cash register receipts.[ref][ref] One study found that using hand sanitizer and then holding a cash register receipt for a couple of minutes increased BPA levels considerably. This was done with people holding a cash register receipt after using hand sanitizer and then eating french fries. (This is such a real-world scenario for any germaphobe stopping for a fast-food lunch.) Wet hands were found to have a 100-fold increase in BPA transfer from the thermal printed receipt paper.  There was also a huge increase in serum BPA (both transdermal and transfer to the french fries, although they only ate 10 french fries…).

More to read:

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4 Comments on “Estrogen: How it is made and how we get rid of it

  1. Thank you for this! For the fellas out there who are TT for CYP19A1 gene (aromatase): converts androstenedione and testosterone into estrogen- rs700518 – would aromatase inhibition be a good idea here, if I understand this correctly? Thanks!

    • If I understand it correctly, theoretically yes.
      A quick search, though, didn’t turn up any studies that show any studies on that for men. If you are thinking about dietary interventions to lower aromatase for men, it seems like that would be a good idea. I have no idea, though, if a prescription aromatase inhibitor would be a good idea.
      For women with metastatic breast cancer, carriers of the rs700518 variant had a ‘higher clinical benefit’ from an aromatase inhibitor (Femera) (study). But the side effects may be greater — another study of women with breast cancer found that the aromatase inhibitor caused women with the rs700518 variant to have greater bone loss. (study).
      Thanks for reading and commenting.
      Debbie

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