MTHFR Testing and Estrogen
A large percentage of the population carries a gene anomaly which interferes with the body's ability to use vitamin B-12, a vitamin critical to our ability to metabolize hemocysteine to process folate. The National Library of Medicine article on the methylenetetrahydrofolate reductase enzyme (MTHFR) outlines the many different ways this gene works in our metabolism and how the deficiencies in genes affect the body's ability to metabolize vitamin B-12. Recently Dr. Jen Gunter wrote a Substack article emphasizing that there is no connection between MTHFR and estrogen.
Dr. Gunter uses the general term estrogen. There are several forms of estrogen, so when she’s talking about “toxic estrogen” it’s hard to know whether she’s means estradiol (E2), estrone (E1), estriol (E3), Premarin, or some derivative of estrogen.
I have certainly never ordered an MTHFR test to assess for “estrogen” treatment or for neural tube defects. However, in the process of learning about the MTHFR gene, I discovered, as did everybody else, that between 20 percent and 40 percent of the population have some version of the deficient MTHFR gene. For me, the concern then with the MTHFR gene was in relation to pregnancy-related problems which can include difficulty getting and staying pregnant. But we also learned that there was a small percentage of the population with MTHFR who had serious problems associated with this gene anomaly, which included DVTs, pulmonary emboli, atherosclerosis, strokes, and heart attacks.
Back in 2013 the American College of Medical Genetics and Genomics came out recommending against testing for MTHFR because the variants were so common. Most of us in medicine understand that the practice of medicine is a series of looking for degrees and options. The recognition of degree in medicine is well documented. For example, we measure hemoglobin, electrolytes, cancer in its stages, all in terms of degree because degree of disease or illness is associated with degree of recovery, which every doctor and every patient want to know. So why should measuring and treating MTHFR associated with homocysteine elevation be treated any differently?
I have had many patients who had two genes for the troublemaker C677T variant. For them, this enzyme defect turned out to be a very serious cardiovascular issue. Elevated levels of homocysteine have been associated with increasing incidence of cardiovascular disease—a matter of life and death. These events have nothing to do with the concept of MTHFR deficiency and “toxic estrogen” or neural-tube defects.
Three of my patients who had serious health issues with MTFHR stand out in my memory. In 2007, a 23-year-old woman came to me. She was already on Lovenox (a shot like heparin) prescribed by her hematologist oncologist. She was pregnant at 10 weeks, had two C677T genes, and had previously had an unprovoked deep vein thrombosis (DVT) while on the birth control pill. Although you might say that the pill is a form of provocation for her DVT, there are many women taking oral contraceptive pills who do not get DVTs or blood clots in their lungs (pulmonary emboli/ PEs).
We have traditionally thought that unprovoked DVTs are more serious than provoked DVTs, and therefore the duration of anticoagulant treatment is much longer with the unprovoked DVT than with the provoked ones. This patient's pregnancy was totally unremarkable, and she delivered her baby (her first) by C-section. Mom, dad, and baby did well postpartum and she returned pregnant with her second baby three years later, still on Lovenox. Again, her postpartum course was completely unremarkable.
Another of my patients, a newly married Caucasian woman on oral contraceptives, presented to labor and delivery with a backache on her right side. I could have called this muscle strain, but I didn’t. When I asked, she denied having shortness of breath. I remained concerned that the patient may possibly have a PE. So, I rephrased the question and asked her whether she had shortness of breath when she was walking up the steps. She said, “Yes.” So I ordered a CT angiogram. As is typical for PEs, there were several showers of clots noted on the CT angio of her chest. These PEs hardly ever happen only one time. The radiologist who read the CT angio said, “If your patient had had any more pulmonary emboli, she probably would have died.” Her MTHFR testing revealed two C677T genes. She was given Lovenox, and later coumadin, and finished college with a radiology tech degree.
With another patient, a 54-year-old lady who came to visit me in my clinic, her husband indicated that she had many seizures while she slept at night, but she was unaware of them. I ordered an MRI of her brain which revealed multiple small strokes. In those days, we could still order MTHFR testing without a lot of hocus-pocus. This patient tested positive for two sets of C677T genes. Of the three patients described here, this lady was the most complicated because she had no insurance and no ability to pay for her treatment.
Because of the complexity of her diagnosis, I called Mayo and was informed after several hours on the phone that they had what they called a charity function, which would became available to this patient in six months. Our problem was what to do with these multiple strokes in the meantime.
The continual strokes took a toll on this patient. She worked as a housekeeper, but she eventually had to stop working because she became confused and had a hard time performing duties which had been familiar to her for 30 years. Eventually, she couldn’t drive the car because she couldn’t make decisions. She reported that one day as she was driving down the street, a dog appeared on the road. She couldn’t decide what to do. She finally got the car stopped and sat crying. From that time on, she refused to drive anymore because of the deterioration she was having in her judgment.
She arrived at the Mayo clinic after six months and had several stents placed in some cerebral arteries. On the drive home she began having more strokes, so Mayo was called again and sent a helicopter to bring her back to Mayo where she had more stents placed.
When she arrived home after the second Mayo visit, she seemed to be all right for a few months and then begin having more strokes. She remained on Coumadin. Remembering the six-month wait for Mayo clinic charity I decided to try North Dakota Medicaid, which is extremely problematic because they really insist on in-state care even if the level and quality of care needed isn't available in the state. The last thing this patient needed was six more months of having frequent small strokes. Sometimes fate shines on us. I arranged for her to have another procedure done but this time in state, in Fargo, North Dakota. To my surprise, the doctor who had done her stent placement at Mayo had moved to Fargo, so, in spite of all the other differences, she had the same doctor in Fargo as she had had at Mayo.
When she woke up post-operatively she said she knew her surgery had gone well because she could see the ceiling. She could count the ceiling tiles. She remained on Coumadin and had no more strokes.
In summary, I agree with the American College of Medical Genetics and Genomics, as well as Dr. Jen Gunter, that the majority of people with MTHFR variants do not share the kind of risks that these three patients did, but certainly, these three patients had life threatening issues which I believe were directly related to the two C677T genes. Moreover, there are many people who fall in between normal genes and the various combinations of the C677T. I believe these people have symptoms including more and earlier myocardial infarctions (heart attacks), and strokes of various kinds, including strokes to the brain as well as small and large bowel. If we never check for MTHFR with patients who have family histories of these diseases, we will never know.
Again, life in general as well as medicine in particular, is more likely to lie in shades of gray, degrees of health or illness, rather than yes or no decisions. Simply pretending that reality and diagnosis are a process of either/or, we miss providing needed care to those who go without MTHFR testing only to develop serious health problems later. The people with this C677T gene deserve to have effective treatment as well as do all the people in between, the real shades of gray.