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  • Nancy Mullan, MD

MTHFR Mutations and Estrogen Balance

Updated: Jan 23, 2020

Estrogen is a major hormone in female physiology that influences many factors including your energy, mood, and quality of life. Many women have hormone imbalances that produce symptoms, and while estrogen is not the only hormone in your body, it is a major player in symptom production. For example, either too much or too little estrogen in your body can cause mood disorder, PMS, abdominal or pelvic pain, and water retention, to mention only a few symptoms.

Estrogen's most obvious and predominant roles are its function in the production of secondary sex characteristics and its impact on the female reproductive cycle, including ovulation and endometrial tissue proliferation. It stimulates breast development and supports gestation and lactation. It prepares and matures the centers in your brain that incline you to impregnation and child rearing. Plus, it impacts the maturation of your uterus and endometrial lining, so that you can carry a baby.

There are three primary estrogens: Estrone (E1) is mostly seen in post menopausal women; Estradiol (E2) is the most potent estrogen and predominates in cycling females; and Estriol (3) is a weak estrogen which is present during pregnancy. There are also many secondary estrogens that form during the breakdown of these three primary estrogens that continue to have estrogenic activity.

Estradiol (E2) is primarily involved with the reproductive cycle. Follicle stimulating hormone stimulates the growth and maturation of a follicle from your ovary and the egg inside of it. The inside walls of the follicle produce estradiol. As the follicle matures, it produces more and more estradiol, until finally there comes an estradiol surge. This estradiol surge induces another hormone called luteinizing hormone to peak. The peaking of luteinizing hormone results in the release of the egg from the follicle. The egg is now free to be fertilized by sperm. This fertilized egg, things going as nature intended, ultimately grows into a baby. 

The graph below shows you the estradiol peak during a menstrual cycle. It shows you the upper limit of normal estradiol production, a median level and the lower limit of normal level. In all three cases, it is this mid-cycle peak that produces a surge in luteinizing hormone that releases the egg for fertilization.

The important thing about estradiol is its fluctuation. It needs to peak and then be rapidly deactivated so the predominant hormone of the second half of the cycle, progesterone, can take over. If estradiol is not optimally deactivated, a condition called 'estrogen dominance' occurs. There is too much estrogen relative to progesterone in your body and you get symptoms. This spells trouble for you like overstimulated breast tissue, painful periods, endometriosis and infertility. Women whose estradiol levels are similar to the 'Upper limit' curve in the second half of their cycles are more likely to have symptoms from periods.

An MTHFR mutation slows down the deactivation of estradiol. The MTHFR gene produces the MTHFR enzyme. If you have a mutation in your MTHFR gene, you make less active MTHFR enzyme, and less active MTHFR enzyme means that you make fewer methyl groups. If you have a mutation in two MTHFR genes, you make many fewer methyl groups.

Estradiol needs a methyl group to attach to it in order to deactivate. If you have too few methyl groups to do this step, estradiol and the breakdown metabolites of estradiol that still have estrogenic activity remain high in your body.  This is not optimal for the estradiol fluctuation that must occur for a normal cycle and conception.

It also happens that Estrone (E1) needs a methyl group to attach to it to deactivate. Estrone has less estrogenic activity than estradiol, but it is still a potent estrogen. So now you have two different kinds of estrogen with their hormonally active metabolic breakdown products still present when they should have been cleared for optimal hormone function.

Specialists in obstetrics know to check the MTHFR gene for mutations if you can't conceive. If they find one, they will tell you to take 5-methyl folate, the kind of folate that the MTHFR enzyme makes. This is the kind of folate that helps you make methyl groups. They may also tell you to take methyl B12. B12 works with 5-methyl folate and you get some extra methyl groups from the methylated form of B12.

It is great when this works. But the pathway that makes methyl groups is attached to a pathway that clears toxins and also to a pathway that makes neurotransmitters. There may be other gene mutations surrounding the MTHFR mutation that may make getting the methyl group producing pathway and your body to function the way you need it to really complex.

Beyond that, MTHFR mutations impair immunity because your immune system needs methyl groups to function. You may have chronic infections in your body particularly in your gastrointestinal tract. So it may not be as simple for you as taking 5-methyl folate and methyl B12.

If it has not been simple for you, you are the person I am talking to here. You need to take your health or your conceiving a baby into your own hands. While obstetricians may know enough about the MTHFR mutation to test for it and to give you 5-methyl folate and B12, that's usually about all they know. Most other mainstream PCPs and specialists know nothing about MTHFR at all. They are not going to help you here. That's the bad news.

The good news is this: the methyl group producing pathway and the other pathways attached to it are nutritional pathways. You really can get them to work with dietary intervention and appropriate supplementation. To do this you have to know your genetics for the whole methyl group producing pathway, not just MTHFR. You have to get some background in how the pathway works and specifically how yours is working. It is difficult, but not impossible, to learn about it and fix it. It is way less burdensome than in vitro fertilization or spending half your month in pain and depressed. I help women with this all the time.

I have a downloadable, no-cost ebook on my website that explains methyl groups and methylation. Click here to download your free ebook.

If you have any questions about how your methylation mutations are being handled, you can get an Exploratory Conversation with me. It is a 30-minute conversation in which I will listen to your health issues, review your recent test results, and make recommendations about what  you should do. The fee for this service is $129.

It is easy to set a time for this conversation, and it can save you weeks or months of doing the wrong thing, lurching around in the dark with a clinician who doesn’t know anything about the genetics or molecular biology of MTHFR. You may be dealing with conditions in your body that are confusing and difficult to understand. I can help you cut through all of that and give you clarifying input that moves you in the right direction. I look forward to being able to help you, Dr. Mullan

What people like you are saying about Dr. Mullan’s work:

I shudder at the thought of what my family would be like without Dr. Mullan. Thankfully, with her help, we have stopped my husband's chronic 30 year battle with kidney stones. He is no longer forming them and is stone free. My thyroid is now working normally, my body temperature is almost normal and my hair has grown back. My oldest daughter's Autism is in the process of being reversed and her hair pulling has stopped. The greatest blessing from our good health is the birth of my second daughter Ava, now one-year-old. At 50 years old I carried her to term. One of my doctors commented to me saying “ you are carrying this baby like a 22-year-old.” Yes, I am because of Dr. Mullan and working on my methylation pathway. One by one she is knocking off symptoms and bringing us back to health. The future is bright! Thank you, Dr. Mullan, for the work you do.


Wow. I feel great. Thank you for your help. It's amazing really. Like a light turned on. Curious to see what the next tests show. To ride this peak indefinitely is my goal. Ha. I have energy again. Yay!

Really grateful,


I am so relieved. My daughter is doing SO WELL since we started with you! We have been to so many doctors and tried so many things.Now I can start working on my own program with you....


So excellent! I literally learn something every single time and I get clarification on things that have been lingering in my mind… VB

You are giving people a huge gift by empowering them… It’s about helping the patient become their own healer by taking them to a higher level of consciousness… AL

Thank you so much, Dr. Mullan. Thank you so, so much for everything you do. MS

Wow! I have to tell you, this was such an uplifting session. It’s so nice to hear good news, especially about a child. Anxiety, OCD and a host of other mental/psychiatric symptoms have been a huge hurdle for me. So to hear this story of all those awful symptoms totally going away is such a bright light for me!!!! TR

Fantastic, caring, smart, savvy doc. I worked with Dr. Mullan for a couple of years to help MTHFR mutations and their associating expressions! To say the least! She's brilliant. At that time she had weekly calls for her patients - free - where we could ask questions and she would reply. What doctors do this? She does. She's also an animal lover and is right on about the way she practices medicine. I highly recommend her. In good health!


"Dr. Nancy Mullan is a beautiful person. She is an expert in her field and has helped our family so much. I am very grateful to her. She came highly recommended and I know why. I would recommend her and her website for information re: healing from a genetic point of view. Thank you, Dr. Mullan, for everything.”


"Dr.Mullan has helped me with issues that I have struggled with for years. She is knowledgable and practical. I would recommend her to others.”


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