Genes Involved in Estrogen Metabolism

Key takeaways:
~ Estrogen is a hormone that turns on or off the transcription of estrogen-responsive genes, many of which are involved in cell growth.
~ The synthesis of estrogen and the breakdown of estrogen are tightly regulated.
~ Genetic variants in the estrogen metabolism pathways impact the risk of breast or prostate cancer.
~ Environmental estrogen mimics, such as from plastics, can also interact with the way your body metabolizes and balances estrogen levels.

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Estrogen creation and metabolism

Estrogen is a steroid hormone that is synthesized from cholesterol and is important in reproduction, bone density, heart health, and brain health.

There are several different types of estrogen, and it is a hormone important in both males and females, although at different levels. Estrogen – from how much is made to how it is broken down – is dependent on both genetics and lifestyle factors affecting both men and women.

Let’s get started by looking at the types of estrogen and how it is created, including the genes involved. Then we will dive into the research on estrogen metabolites and how they can affect your health. Genetic variants in the estrogen metabolism genes can affect cancer risk and your body’s tolerance for estrogen-mimicking chemicals.

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 – the primary form in women before menopause
Estrone (E1) -primarily made after menopause, primary form in men
Estriol (E3) – the main type of estrogen during pregnancy
Estretrol (E4) – only during pregnancy, made by the fetus

For the most part, we will focus here on estradiol (E2) and estriol. In addition to these types of estrogen, there are also estrogen metabolites created from the breakdown of estrogen, which we will cover below.

How is estrogen created in the body?

Estrogen is synthesized in the following tissues:[ref]

ovaries (major source in women, E2)
testes (males)
fat cells (E1, especially post-menopause)
brain
liver
pancreas
intestines
adrenals

The precursor for estrogen is cholesterol, which 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 (E1), which is then converted (using 17β-HSD) into estradiol.[ref]

Here is a flow chart to give you a better idea of the conversion of cholesterol into estrogen, including the genes that are involved.

Estrogen Sulfate: Storage form of estrogen
On a hormone lab panel test, you will likely 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.

Driving estrogen production: FSH
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 (LH), controls the menstrual cycle.

Estrogen Receptors: Controlling Genes

So what exactly does estrogen do in cells?
Estrogen is transported throughout the body and can bind to estrogen receptors in the cell nucleus controlling the transcription of many 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 receptor is encoded by the gene ESR1 gene.
ERβ receptor is encoded by the ESR2 gene.
GPER1 (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 important targets of estrogen include the LDL receptor, progesterone receptor, IGF-1, and many more. These genes are related to hormones, cholesterol, and growth within the body.[ref]

Estrogen receptors (ERs) are present in a wide variety of tissues in the body. For example, ERs are important in vascular endothelial cells, which line blood vessels. Estrogen receptors are found in cardiomyocytes (heart muscle cells), neurons, airway cells, muscles, the uterus, testes, fat tissue, bone, breast, kidneys, and more.

Estrogen receptors can also cause rapid activation of signaling pathways, or immediate changes, in certain cells. Estrogen can also impact mitochondrial biogensis, function, and regulation of ATP production.[ref]

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

What does estrogen do in the body?

For women, 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 production starting in puberty.

For men and women, estrogen is also important in maintaining bone density and cognitive function. Low estrogen is linked to osteoporosis. It is also important in brain function and controlling inflammation.[ref]

In men, estrogen is also necessary at low levels in the production of sperm. The loss of the estrogen receptor in the testes results in abnormal sperm. On the other hand, too much estrogen can also be detrimental to male reproductive health.[ref] Balance is key.

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
sexual dysfunction
loss of muscle mass
fatigue, depression, anxiety

Outside of estrogen’s essential role in reproduction, estrogen plays a key role in the control of energy metabolism.[ref]

Getting rid of estrogen (metabolism or breakdown and elimination):

The level of estrogen in the body needs to be at the right level for the individual’s age and sex. To control the level of estrogen in the body, we have to have multiple ways to break it down and eliminate it. This is a multi-step process involving what are known as phase I and phase II detoxification enzymes.

Phase I and Phase II estrogen metabolism:

In the liver, the CYP450 enzymes can metabolize estrogen. Specifically, this is done by the CYP1B1, CYP1A1, or CYP1A2 enzymes.

This process creates metabolites known as 2-OHE1 (E2), 4-OHE1(E2), and 16α-OHE₁, all of which are also known as catechol estrogen metabolites.

These catechol estrogen metabolites can be further changed by the COMT (catechol-O-methyltransferase) enzyme or through glucuronidation (UGT genes) This makes them water-soluble and able to be excreted through urine or feces.[ref]

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

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

It is important that the two phases of estrogen metabolism act in sync.

Some of the metabolites, such as 16α-OHE_1,are also able to activate the estrogen receptors. These specific estrogen metabolites increase the risk of breast cancer.[ref] Thus, you don’t want certain Phase I metabolites hanging around in the body.

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 relative risk of cancer.

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. Everything needs to be in balance.[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 or at least eliminated quickly from the body.[ref]

Here is a diagram of how these metabolites go together:

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 significantly increases the risk of breast cancer and prostate cancer.

Part of the smoking increases cancer risk in general is that it can cause DNA damage. However, smoking specifically increases the risk of breast cancer through upregulating the CYP1B1 and CYP1A1 enzymes. For people with genetic variants that cause more of an impact on CYP1B1 upregulation – combined with an inability to eliminate the estrogen metabolites fast enough (due to phase II genes, diet, and lifestyle) – then cigarette smoking is going to significantly 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 phase I and phase II genetic variants (see the genotype report below) with smoking causes a fairly large increase in the risk of cervical, breast, or prostate cancer.

Estrogen Elimination: Phase III

Let’s go one step further and make the two-step process of estrogen metabolism into a three-step process…

Once the catechol estrogen metabolites have been metabolized (COMT), they have to be excreted (urine or feces).

The gut microbiome comes into play here in making sure that the metabolites are excreted and not reabsorbed. 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, an enzyme 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 number of estrogen metabolites that are excreted.[ref]

Estrogen Mimics: BPA, Phthalates, and Other Toxicants

There are several environmental toxicants that act similarly to estrogen in the body. Among these, phthalates and BPA are ubiquitous, with research showing that almost everyone has them in their bodies. These estrogen-mimicking chemicals can bind to the estrogen receptors, similarly to the way that estrogen binds.[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 containing BPA. Even the paperboard used in food packaging (especially if it is recycled cardboard) can contain BPA, which is then transferred to the food we eat.[ref]

These estrogen mimics (at the levels found in people every day) have been linked to increased risk of several estrogen-related conditions, including:

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]

We will cover more on how to avoid and eliminate these estrogen mimics in the Lifehacks section. First, though, let’s cover how your genes interact with estrogen metabolism (phase I and phase II) and how your genes impact estrogen creation.

Estrogen Genotype Report:

This section shows how your genes make you unique when it comes to estrogen metabolism and estrogen synthesis. Most are common genetic variants, and almost everyone will have a few of the variants. Do not be overly worried if you have a variant that increases the relative risk of breast or prostate cancer. The goal is to use the information to make changes – dietary, and lifestyle – to minimize your risk factors.

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Lifehacks for estrogen balance:

Testing is the only way to truly know your estrogen levels. You can order your own hormone test panels online (e.g. UltaLabs Estrogen Panel) or go through your doctor. A qualified professional can help you with making sense of your hormone test results.

The lifehacks below are based on natural supplements and lifestyle changes for reducing estrogen and shifting towards the less-risky estrogen metabolites. Please also talk with your doctor about prescription-based options and be sure to discuss any supplement interactions if you are on medications.

Optimizing Phase I detoxification for estrogen metabolism:

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Related Articles and Topics

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Fibroids: Genes, root causes, and solutions

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PMS, Genetics, and Solutions

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