Low libido, estrogen dominance and high cholesterol are experienced by many people. To understand what could be happening, let’s take a look at a few genetic variants that can play a part. We will also discuss the role of estrogen in women and men and how estrogen is metabolized and detoxified in the body. We will also look at what estrogen dominance is and the possible causes.

Liver detoxification

To understand how estrogen dominance happens, we first need to understand how estrogen (and other substances) are detoxified in the body. Estrogen is detoxified in three phases. The first phase is in the liver, the second in the gut and the third phase is through excretion by stools, urine and sweat. When your liver is and gut are not detoxifying estrogens correctly or adequately, estrogen is reabsorbed and recirculates where it creates estrogen dominance symptoms (which I will get into in a moment.)

Phase 1: The liver (CYP450 activators)

In order to detox compounds, these enzymes have to turn them from fat soluble into water soluble so that they can be excreted via urine and stools. Phase 1 enzymes are known as activators. The CYP450 enzymes identify toxins and flag them.

Estrogen metabolism occurs in the liver via the Cyptochrome P-450 enzymes. There are three main pathways for metabolism of estrogen leading to elimination: 2-Oh, 4-OH and 6-OH.

How you metabolise and eliminate estrogen depends on how efficient your CYP450 enzymes are and the load of everything else your liver needs to metabolise as well as your gut estrobolome (a collection of bacteria involved in estrogen regulation, either allowing it to be excreted or recirculated.)

The 2-OH metabolite causes the least DNA damage that leads to cancer and has a mild estrogenic effect. It is deactivated by methylation and leaves the body through the stool.

The 4-OH estrone metabolite forms after the liver enzymes process it. It is detoxified by glutathione, an antioxidant. Research shows it increases cancer by damaging DNA. It is considered the harmful type of estrogen.

The 16-OH metabolite is considered the bad estrogen. High levels are associated with heavy periods, breast tenderness, breast cancer, obesity, inflammation and thyroid problems. It damaged DNA, binds strongly to estrogen receptors and prevents cell death, allowing abnormal cells to grow.

We need to support estrogen metabolism to help it eliminate quickly and safely before it can be reabsorbed and recirculated whereby it can cause damage. We do this by supporting our liver and gut.

Intermediate Phase

Once the compounds have been identified and activated they sit in a holding cell where they wait processing by the enzymes in phase 2. Activated toxins need to be neutralized to be made less harmful and reactive. Phase 1 enzymes generate a lot of free radicals which are an unstable atom and the by-products of normal metabolism. However, they can damage cells causing illness and aging. We need the help of antioxidants from nutrients to neutralize free radical damage. Antioxidants help prevent damage to healthy cells.

Phase 2 : GST enzymes (excretors)

After the toxins have been processed in the intermediate phase, they are sent to phase 2 where the GST enzymes take over to neutralize these volatile compounds and make them ready for excretion.

Other processors are involved in this phase such as sulfation, glutathione conjugation, methylation, glucuronidation acetylation and amino acid conjugation.

Phase 3 : Excretion

Phase 3 relies on the gallbladder and intestines. Your liver packages waste products into bile, stores them in the gallbladder and releases them into the intestines upon fat consumption, eventually exiting the body via stool.

Waste is also removed by sweat and urine. Although the liver is thought of as the primary detoxification organ, it it requires a huge amount of nutrients that must be absorbed via the gut in order to function optimally. The gut is also the initial site of exposure to orally digested toxins.

What can go wrong

Things can go wrong in the detoxification pathway when there is an increased exposure to environmental toxins, genetic mutations and inadequate intake of nutrients to support this pathway.

What would cause estrogen to not be detoxified correctly?

Epigenetic factors such as not eating the right foods that help break down estrogen in the body, eating meats that contains antibiotics and hormones, being overweight (estrogen is stored in fat cells, the more fat cells you have, the more estrogen you will have), certain medications that increase estrogen such as birth control pills and HRT, xenoestrogenes (synthetic estrogens that mimic real estrogen, the body cannot tell theses apart), gut dysbiosis, lack of ovulation, stress and genetic variants that are getting influenced by all these epigenetic factors.

Genetics

COMT

COMT (catecol-O-methyltransferase) is a gene involved in the methyaltion pathway. COMT is responsible for breaking down estrogens as well as various neurotransmitters. The COMT enzyme accounts for more than 60% of the dopamine degradation in the prefrontal cortex,but for less than 15% in the striatum.

Depending on what variant you have, this can go three ways:

• Fast COMT (V158M val/val GG) can break down estrogen quite quickly, leading to lower levels of estrogen, dopamine, neuroepinephrine and epinephrine
• Slow COMT (V158M met/met AA) can break it down slowly, which can lead to higher levels of estrogen,dopamine, neuroepinephrine and epinephrine 
• Intermediate COMT (val/met, AG) which can be pulled either way according to other factors we won’t discuss here today

This is NOT only dependent on your variant but more so on what is happening epigenetically. In other words, what is going on in your actual life:  what you are eating, your lifestyle, and your environment, which all influence your genes.

It gets complicated too, because often hormone issues are as a result of multiple things going wrong: incorrect diet, poor nutrition (such as untreated nutritional deficiencies)  lifestyle habits (smoking, drinking alcohol, exposure to xenoestrogens, stress, gut issues, etc) and other genetic pathways that play a part too like detoxification. (estrogen is detoxified in the liver and gut)  All this can cause an imbalance in hormones and slow COMT down.

Often estrogen imbalance can be as a result of:

• an imbalance in progesterone to estrogen
• the body is creating too much estrogen
• the body is having trouble breaking down estrogen and not excreting it properly
• your body is not making enough progesterone
• epigenetic factors influence genetic variants
• genetic variants responding to all the above

MAO

MAO(monamine oxidase) is an enzyme that plays a role in the degradation process of various monamines such as dopamine, serotonin, norepinephrine and epinephrine.

• Slow MAO-A (rs6323) T allele
• Fast MAO-A (rs6323) G allele

MAO either too fast or too slow affects neurotransmitters which affect mood. With estrogen levels being too high, it can lead to anxiety, and with estrogen being too low, it can lead to depression. Estrogen slows down MAO, reducing the speed at which the body breaks down serotonin, resulting in higher brain serotonin levels, but can lead to lower dopamine levels, thus causing an imbalance.

MAO-A is slowed down by high estrogen, and high estrogen can further slow COMT.

PEMT : Estrogen and cholesterol

PEMT (phosphatidylethanolamine N-methyltransferase) is an enzyme in methylation. It uses SAMe to methylate phosphatidylethanolamine producing phosphatidylecholine, a vital component of cell membranes. PEMT is involved in the consumption of SAMe in the synthesis of phospholipids, linking the methylation cycle to lipid metabolism.

Estrogen boosts PEMT activity in the liver. When estrogen levels are low, it lowers the responsiveness of PEMT to produce phosphatidylcholine. When we don’t have enough choline from diet sources, it can make you more susceptible to Non-alchoholic fatty liver disease. When women go through perimenopause and menopause, and estrogen levels drop, this effects choline levels. So if your LDL cholesterol levels start to go up, it can be an indication you need more estrogen as well as choline. (Just a note that in the methylation cycle, a deficiency in choline reduces the capacity to handle a methionine load, resulting in elevated homocysteine)

Since PEMT is part of the methylation cycle, it requires folate further up the chain to get to choline. As far as diet goes, make sure you get folate, choline and betaine. Resveratol also stimulates PEMT in the liver and can increase HDL and lower LDL cholesterol.

COMT and Estrogen in women

The COMT enzyme activity is reduced epigenetically by estrogen with the enzyme activity being 30% lower in
females than in males.

Estrogen naturally declines in a woman as she ages. So, if you already have variants impacting COMT, this can further impact your levels according to your epigenetic factors. A woman with fast COMT can still have estrogen dominance in perimenopause/menopause if she is not supporting her health through diet, exercise, lifestyle, and environment factors that are driving excess estrogen levels up. Low Estrogen levels can be caused by genetic variants, diet and lifestyle factors, a low-functioning pituitary gland, autoimmune conditions and naturally declining levels as seen in perimenopause and menopause.

Certain variants involved in estrogen biosynthesis, estrogen metabolism, and phase I and phase II detoxification affect estrogen, too. Estrogen needs to be metabolized safely and relies on methylation. Otherwise, it produces harmful metabolites that increase the risk of certain estrogen related cancers. This is especially true if you have variants in COMT, SULT1A1, and CYP17A.

Symptoms of estrogen dominance in women include:

• irregular cycles, blood clots in
• heavy or painful periods – PMDD
• breast tenderness and fibrocystic breasts
• uterine fibroids
• endometriosis
• weight gain especially around the tummy,hips and thighs
• loss of libido
• fatigue
• mood swings, depression and anxiety
• insomnia
• hair loss
• brain fog, poor memory

High estrogen comes with risks for CVD, certain cancers such as breast, ovarian, endometrial; blood clots

Low Estrogen symptoms:

• hot flashes
• heart palpitations
• excessive sweat
• insomnia
• anxiety, depression
• forgetfulness
• low libido**
• dry skin
• Irregular periods or no periods (amenorrhea)
• tender breasts
• weight gain especially on the stomach

Low Estrogen can lead to osteoporosis, high cholesterol levels, CVD Risk

**Low libido can be a symptom of BOTH low and high estrogen. This is why it is super important to pay attention to what you are doing in your life, rather than rely solely on which genetic variants you have.

How Testosterone/estrogen impacts men

Both men and women produce estrogen, although for men, they have more testosterone than estrogen. However, men can also suffer from estrogen dominance as a result of epigenetic factors such as diet, nutritional deficiencies, lifestyle factors (stress) and environment factors (such as exposure to xenoestrogens through chemicals and hormones in food such as red meat)

Estrogen dominance in men can lead to estrogen related cancers such as prostrate cancer. Some symptoms of estrogen dominance in men are:

• erectile dysfunction
• weight gain*
• decrease in libido
• enlargement of the breast tissue
• depression, anxiety
  
• loss of energy/fatigue
• decrease in muscle mass
• infertility
• insomnia

For men, as they age, testosterone declines just as estrogen declines in women.

*Being overweight can increase estrogen is men because fat cells contain an enzyme called Aromatase which converts testosterone into more estrogen, depleting testosterone.

What to do next

1.  Diet and nutrition: Eating a diet high in whole foods and reducing your consumption of saturated fats, sugars, highly processed foods containing preservatives, additives, colorants as well as avoiding meat that is not pasture-fed and organic (Free from hormones and antibiotics) Diet and nutrition is about avoiding the bad, but incorporating the good as well as checking for any nutritional deficiencies you may have and correcting those.
2. Lifestyle: limiting alcohol, avoiding smoking and making sure you get plenty of sunshine and exercise can help your liver detoxify and reduce the load of xenoestrogens.
3. Environment: limit your exposure to harsh chemicals, toxic compounds in household cleaning products, body and face products and the use of plastics.
4. Get DNA testing done. Contact me for more information

You do not have to sit with estrogen dominant conditions and high cholesterol. Both of these conditions can be managed successfully through modifiable factors as mentioned above that in turn lead to better gene expression.

References:

1. Sex-dichotomous effects of functional COMT genetic variations on cognitive functions disappear after menopause in both health and schizophrenia, European Neuropsychopharmacology, Volume 25, Issue 12, 2015, Pages 2349-2363,https://www.sciencedirect.com/science/article/pii/S0924977X15003302

2. Catechol-O-methyltransferase, dopamine, and sleep-wake regulation, November 2014 Sleep Medicine, https://www.researchgate.net/publication/268760342_Catechol-O-methyltransferase_dopamine_and_sleep-wake_regulation
3. Schulster M, Bernie AM, Ramasamy R. The role of estradiol in male reproductive function. Asian J Androl. 2016 May-Jun;18(3):435-40. doi: 10.4103/1008-682X.173932. PMID: 26908066; PMCID: PMC4854098.
4. Hammes SR, Levin ER. Impact of estrogens in males and androgens in females. J Clin Invest. 2019 May 1;129(5):1818-1826. doi: 10.1172/JCI125755. Epub 2019 May 1. PMID: 31042159; PMCID: PMC6486327.
5. Resseguie M, Song J, Niculescu MD, da Costa KA, Randall TA, Zeisel SH. Phosphatidylethanolamine N-methyltransferase (PEMT) gene expression is induced by estrogen in human and mouse primary hepatocytes. FASEB J. 2007 Aug;21(10):2622-32. doi: 10.1096/fj.07-8227com. Epub 2007 Apr 24. PMID: 17456783; PMCID: PMC2430895.
6. Fischer LM, da Costa KA, Kwock L, Galanko J, Zeisel SH. Dietary choline requirements of women: effects of estrogen and genetic variation. Am J Clin Nutr. 2010 Nov;92(5):1113-9. doi: 10.3945/ajcn.2010.30064. Epub 2010 Sep 22. PMID: 20861172; PMCID: PMC2954445.
7. Al Rajabi A, Castro GS, da Silva RP, Nelson RC, Thiesen A, Vannucchi H, Vine DF, Proctor SD, Field CJ, Curtis JM, Jacobs RL. Choline supplementation protects against liver damage by normalizing cholesterol metabolism in Pemt/Ldlr knockout mice fed a high-fat diet. J Nutr. 2014 Mar;144(3):252-7. doi: 10.3945/jn.113.185389. Epub 2013 Dec 24. PMID: 24368431.