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Optimizing methylation pathways means going further than just deciding how much B12 or folate a person needs. Seeking to optimize methylation pathways means you must go far beyond just looking at MTHFR and see all the genes and biochemicals that are impacting our health. And we cannot optimize genes without understanding how our sex hormones can impact our genetic pathways. This article will provide you with new insights into how our hormones impact our genetic pathways, while offering diet and nutritional ideas to properly support those pathways.

As we all know the differences between men and women are more than just skin deep. Our differences exist on a physical, genetic, emotional and hormonal level. In fact, our sex hormones are so powerful they don’t just change the size and shape of our bodies, they change how we respond to stress in our environment. An important thing about sex hormones is that not only do they influence how our bodies look; they also influence our brain and behavior! And you will soon see just how these sex hormones can influence brain function by altering the body’s COMT and MAO pathways.


Overview of Sex Hormones, COMT and MAO

Many of you reading this article may have already performed a genetic test and are aware of your COMT and MAO status – and if you haven’t done that yet no worries. Some of you may have inherited COMT and MAO genes which are slowed compared to the normal or “wild-type”. And at first blush these genes seem like they are going to ruin your life. But as I often tell my patients the genes you inherit from your parents are not your destiny, but they are your tendency. At the end of the day the body’s environment has the biggest impact on how our genes influence our lives. With that in mind let’s look at how the hormonal environment shapes our body’s genetic tendencies.

Women have higher estrogen levels and men have higher testosterone levels – this fact cannot be disputed.  What isn’t as well known is how these two hormones impact the metabolism of our neurotransmitters by altering the speed of the COMT and MAO pathways.  You will remember from my previous post that the COMT breakdown of dopamine has a major influence on how we react to stress. And you are about to learn that our sex hormones play a major role in determining our brain neurotransmitter levels.

Studies now show that sex hormones also play a critical role in how much dopamine we have in our brain.  So logically it makes sense that men and women will react to stress differently. Because sex hormones have such a strong influence on our COMT and MAO pathways, men and women will have different COMT and MAO speeds, even if the genes and SNPs are identical.

In other words, the hormones have an epigenetic effect on the methylation of neurotransmitters that is occurring independently of the individual’s genetics – apart from that person’s genotype. A woman can be born with a fast COMT -/- genotype and yet experience all the symptoms of someone who is COMT +/+ when she is overly estrogen dominant. She experiences the symptoms not because of her genotype, but because the environment is interfering with her methylation pathways. Confused yet? Well keep reading it will all make sense shortly.

To help clarify this point I would like to ask you a question. And by asking this question I am not intending to offend anyone, but this question helps to illustrate an important point:

If you were to interview randomly 100 men and 100 women off the street, who would you expect to describe themselves as more anxious? Men or Women? And who would you expect to describe themselves as more angry or grumpy?

While I haven’t performed this study yet, I can assure you what the answers will be. More women will describe themselves as feeling anxious; and more men will describe themselves as feeling grumpy and angry. At first blush this information may not seem fair and it may sound like I am picking on one group or another. However that is far from the truth!

What this idea illustrates is that women have more anxiety and men have more anger – and you will soon see why.  Because of recent research showing how sex hormones influence brain chemistry and methylation-related pathways, we have a new level of understanding WHY women and men react differently to stress.  The answer to why women and men react to stress differently has everything to do with how estrogen and testosterone influence the methylation and breakdown of neurotransmitters.  Figure 1 shows how our sex hormones interfere with key methylation

COMT and MAO Estrogen Slows

Figure 1 – Estrogen and testosterone both influence the methylation and breakdown of neurotransmitters.


Estrogen, COMT and MAO

Compared to a healthy man, a healthy pre-menopausal woman should have much higher levels of estrogen and much lower levels of testosterone.  This elevated estrogen is a natural consequence of being female and of having the ability to conceive children.  In fact when a woman becomes pregnant her estrogen levels rise approx. 30-fold, providing the hormones her body needs to feed a growing baby. But that is only one type of estrogen, and in our environment estrogens come in many different flavors.

In addition to the estrogen made by the body, many women and men are exposed to toxic estrogens from chemicals like birth control, heavy metals, fire retardants, BPA, etc. which further increase the estrogen load. Many people are aware of the dangers of estrogenic toxins like BPA, but fewer people know that pesticides, herbicides, and fire retardants act like estrogen as well. In fact, science has now confirmed that heavy metals such as aluminum, arsenic, cadmium, lead, and mercury also activate estrogen receptors in our cells.1  These metalloestrogens as they are called create yet another burden for our detoxification systems and alter our hormone balance even more. Ultimately all this estrogen (both natural and man-made) causes problems for the COMT and MAO systems in the brain.

Key Concepts for COMT and Estrogen

Estrogen is broken down by the COMT gene – this reaction produces a calming, anti-cancer type of estrogen called 2-OH methoxy estrogen.2  2-OH methoxy estrogen is very important for health and it helps to prevent other symptoms of estrogen dominance such as PMS, heavy bleeding, fibroids, endometriosis, etc.

Even though the COMT gene breaks down estrogen, it is also epigenetically slowed down by estrogen. Meaning the more estrogen a woman or man has, the slower the COMT system will be working as cells will produce fewer copies of the enzyme. A research article from 2003 describes how hormonal therapy can be effective for dopamine-related diseases like Parkinson’s Disease. Because estrogen slows COMT pathways it may be of therapeutic value in Parkinson’s patients who need a more steady supply of dopamine in their brain.3

A recent review article published in 2015 shows how through environmental and epigenetic mechanisms, estrogen inhibits COMT pathways by about 30%. The researchers suggest this is why many women have a predisposition towards a phenotype of high anxiety and a lower tolerance for stress.4  So even if you aren’t born with a SNP in your COMT pathway, just being female or having too much estrogen can make it feel like you do have a +/- or +/+ SNP.

In addition to the epigenetic effects that estrogen has on COMT pathways, it also greatly impacts the MAO system. Because estrogen impacts both COMT and MAO pathways, it is capable of having a major impact on the levels of frontal-lobe dopamine and stress hormones throughout the body. Research has clarified that a woman’s mood is largely a reflection of how fast or slow her MAO-A system is working.

Key Concepts for MAO and Estrogen

In a study from the 1970’s, perimenopausal women with adrenal fatigue and depression were found to have a sped-up MAO system, leading to faster breakdown of dopamine and serotonin. When given oral estrogen replacement, the women were relieved of their depression symptoms.5  Menopause and adrenal fatigue both lower estrogen levels, so oral estrogen therapy helped slow down the MAO system, allowing the women to benefit from increased neurotransmitter levels.  While most women have too much estrogen and too much anxiety, women can experience the opposite problem of depression when their estrogen levels drop too low.

Interestingly a very recent study published in 2015 showed that post-partum depression is caused by a surge in the expression of MAO-A. Immediately after delivering a baby, a woman’s body goes through a profound decline in estrogen. This rapid loss of estrogen, no longer necessary since pregnancy has ended, causes a reflexive increase in the speed of MAO-A.6  As MAO-A speeds up it detoxifies neurotransmitters much faster leading to depression and other signs of post-partum depression such as apathy and excessive crying.

Another slightly older study published in 1995 confirms the relationship between estrogen levels and MAO pathways. When analyzing the effects of sex hormones the researchers found that estrogen inhibited the monoamine oxidase (MAO) pathway in brain cells.7  They concluded that this inhibition, this slowing down of the MAO system, was how estrogen creates its anti-depressant effect.  Remember a depressed woman might just be low in estrogen, while an anxious woman might have way too much.

These studies help to explain scientifically why women have a tendency towards anxiety and worry – more estrogen leads to more dopamine, adrenalin and catecholamines in the brain. And men (as you will see below) have a tendency towards anger and depression – since more testosterone leads to lower catecholamines. Estrogen has an anti-depressant effect, but too much of it can cause a woman to be unable to relax and calm down, and too little can lead to excessive crying and depression. The body doesn’t want too much and it doesn’t want too little – it wants a balanced amount!  Figure 2 below illustrates the many problems associated with unbalanced estrogen levels:

Estrogen Curve

Figure 2 – Bell curve showing reduced COMT/MAO activity with elevated levels of estrogen.

If you are born with or are exposed to more estrogen in your body (both natural and man-made) then you will have a tendency to have more dopamine in your brain because your COMT/MAO pathway has been slowed. This elevation of dopamine and catecholamines makes you much more likely to experience anxiety, worry, insomnia, chronic pain and other conditions associated with a slow COMT/MAO system.  A woman with too much estrogen may wake up and feel like she cannot handle another stressful thing at all.  And this woman with excess estrogen will also have a slowed COMT and MAO system that will tend to make her more sensitive to stress. 

Based on the information I have shared with you so far, we can see how being estrogen dominant will make it more difficult to deal with stressful life situations like a new job, new child, new relationship, relocating to a new town, etc. Excess estrogen will literally slow down your methylation pathways making you less able to tolerate even the slightest increase in stress. And if estrogen does one thing, you can bet that testosterone will probably do the opposite. So let’s now take a look at the testosterone research to see if that holds true.


Testosterone, COMT and MAO

In terms of the COMT and MAO pathways, the male sex hormone testosterone has the opposite effect of estrogen. Testosterone increases the genetic expression of COMT and MAO enzymes in the body leading to lower levels of dopamine, norepinephrine and epinephrine. If you are a man with healthy levels of testosterone in your body, you will tend to have a deficit of dopamine because your COMT and MAO enzymes are going faster.  This means men will gravitate towards activities which raise the catecholamine neurotransmitters, since these chemicals will help balance the brain and have a calming, soothing effect on the nervous system.

For many men, doing things labeled “stressful” or “risky” actually helps to balance their brain function. This is why men tend to feel a relaxed after going to the shooting range, attending a martial arts class, or riding a motorcycle at high speeds. Since men are supposed to have higher testosterone and lower estrogen, they tend to need more stress in their life in order to feel balanced and calm. Thus men often seek a riskier path in life due to the need for more dopamine and catecholamines in the brain.

If you look at our society objectively, you will notice that men tend to get into fist-fights, drive fast cars, shoot guns, rock climb, BASE jump, and do all kinds of other dangerous activities more frequently than women.  One big reason men are drawn to things which are dangerous is that these activities raise catecholamines, dopamine and adrenaline.  And when you become aware of how testosterone impacts brain function you will understand why.

Key Concepts for COMT, MAO and Testosterone

A recent study published in 2014 highlights how androgens like testosterone and DHT increase the speed of the MAO and COMT pathway in the substantia nigra and striatum where much of our brain dopamine is produced.This effect of testosterone helps to explain why men have a tendency to have lower dopamine and catecholamines; and why men seek risky behaviors in an effort to raise them. Since men have a tendency to breakdown dopamine and norepinephrine faster, they have developed an attraction for activities which are guaranteed to increase those neurochemicals.

In another related study from 2012, it was shown that testosterone increases the brain’s expression of estrogen receptor beta, the protective, calming type of estrogen receptor. Estrogen receptor beta is an important part of our hormone system because it helps to protect tissues like the breast, ovaries, uterus and prostate from the toxic effects of estrogens.  ER Beta as it is called acts like a toxic estrogen anti-dote in many tissues, including the brain. Thus testosterone not only speeds up a slow COMT and MAO system, it has many other benefits we are just beginning to learn about.

At the end of the day, men will compensate for lower dopamine by seeking behaviors which are higher risk.  I’m not saying all men do this, I’m just saying that as men we all have a tendency to behave this way.  And this tendency drives a lot of our behaviors.  Because testosterone increases the speed of COMT and MAO system, men spend a good deal of time being angry and grumpy. And to cure that persistent grumpiness and anger men seek out experiences which are stressful in order to raise dopamine/adrenalin. By raising their dopamine and adrenalin quickly, a man will actually calm down and be happy. This is self-medication at its best!


Diet and Supplement Recommendations

Now that it is clear how sex hormones influence our neurotransmitter and methylation cycle, we need to look at natural solutions for preventing and correcting these problems. In general, women need programs that help them to lower estrogen and raise progesterone. Men need programs that help them remove estrogen and raise testosterone. There are many safe, natural, and effective means for accomplishing this task. I have written down my favorite healing protocols for healthy detoxification of estrogen and estrogen-like toxins. You will find my detailed diet and supplementation protocols for men and women with hormone imbalance here.



What I see every day in my clinic is that estrogen dominance, toxins and hormone imbalances are a major cause of anxiety in both men and women. This fact doesn’t make sense until you understand how estrogen slows down the COMT and MAO pathways while testosterone speeds them up. Whether it is due to adrenal fatigue, birth control, hormone replacement, chemical toxins, etc. estrogen dominance will tend to cause imbalances in the brain and the methylation cycle. This also helps to explain why men and women deal with and react to stress so differently. Clearly when our hormones are imbalanced, our brain and methylation cycle will also become imbalanced. But it doesn’t have to be that way!

For those of you who are searching for answers to the root causes of your health problem, you are on the right track. But just learning about MTHFR genes is not enough.  To create lasting health we must understand how the environment talks to our genes. Only then will we have the opportunity to change the environment to promote a proper healing response. That road is challenging, but very rewarding. Yet, it is a hard road to travel alone.

If you would like assistance in your healing efforts please don’t hesitate to contact my office.   Working with our team of functional medicine and methylation experts will help you get better results in less time.



For more videos and learning about COMT, MAO and Methylation I recommend:

Treating COMT and MAO: How COMT Influences the Brain

How Blood Sugar Influences Dopamine/Adrenalin Levels – COMT and MAO

A Genetic Cause of Pain and Anxiety – COMT, MAO and MTHFR


In Health,

Dr. Rostenberg


By studying the current peer-reviewed research, Dr. Rostenberg has discovered powerful, natural strategies to optimize brain function and heal your body.  Using his knowledge of methylation and optimum health, he has helped patients from all over the world overcome their genetic imbalances.  He can help you uncover the genetic or root causes of your health problem and find a natural solution!  If you would like help with optimizing your genes to improve your methylation and reduce/eliminate your symptoms, please contact Dr. Rostenberg at Red Mountain Natural Medicine today. Phone 208-322-7755. Email Website



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