“Unzip Your Genes” To Pleasure

Carolyn Ledowsky

Hi, Diane! It’s so nice to be here. I can’t wait to get stuck on this topic.

Diane Mueller, ND, DAOM, LAc

Yes. Me too. We already had a fun conversation offline that’s making me so excited about everything that’s coming and our time together. Before we jump into all the juiciness of it, let’s start by giving everybody a sense of how you got into research. Research is always so interesting to me as far as how people identify something that they’re so passionate about and go so deep into a topic like you are with genetics, MTHFR, and folate. Can you walk us through the journey of just how you got involved in your work for us?

Carolyn Ledowsky

Yes, thank you. When I first started, I had a mentor who was a real stickler for understanding blood work. I used to do the blood work, and I do my analysis. I came across this little thing that kept bugging me: that half of the people had high folate in their blood and the other half didn’t. I thought that was weird. Why would you have high folate? When I called the lab and asked them why someone would have high folate, they said, “That’s a good thing. They’re having a lot of leafy green vegetables.” I thought, No, they’re not. These people are sitting in front of me, and I know they’re not having a lot of leafy green vegetables. I thought, “Okay, that’s not the answer I wanted.” I kept searching and could not find the answer. Everybody gave me that same answer, and I was at a conference in Melbourne about 13 years ago, a bit longer now. A doctor said, “Well, MTHFR is associated with disturbed blood levels of folate.” I went, “What? Oh, my goodness, that’s what I want.” I made a beeline for and said, What is this MTHFR gene? She said, “Oh, it’s a gene that regulates you, folate.” I said, “How do I find out more?” She said, “Just Google.” I then became obsessed with this gene, and I read every paper I could read. I read everything. I used to sit until 3:00 in the morning and just read. My husband thought I was going crazy, and I started to experiment with different folate levels. When I saw the high folate in the blood, it made me want to check MTHFR. I checked intake, and sure enough, it was always the polymorphism, so then I thought, So, these people have a family history of anxiety, depression, cardiovascular disease, and multiple miscarriages. At the time, methylfolate wasn’t available in Australia.

I used to bring it in and give samples to my patients to see if they had a good reaction. Sure enough, the folate level in the blood came down, and they started to feel better. I thought, “Hang on, there is something in this.” That thing got me on the fertility side of things because I kept seeing these women who had recurrent miscarriages, and they were just being told, “Go home; there is nothing you can do; keep trying. It’s a numbers game.” I thought, “No, it’s not. Because when I changed the form of folate and increased the dose of folate, we had success.” I then did my first research degree, which was with honors, and I looked at women within fertility. I did a case series of women with infertility who had MTHFR. These women presented with multiple miscarriages, failed IVF, and were diagnosed with unexplained infertility. We took them all off folate and put them on methylfolate, and we had a 91.3% success rate at live birth. Then my supervisor said, “Oh, okay, you need to go on and do a PhD,” which is what I’m currently doing. We’re doing a pilot study for a randomized clinical trial to test a prenatal multivitamin with folic acid versus methylfolate in women with recurrent miscarriages.

Diane Mueller, ND, DAOM, LAc

Thank you so much for all of that. I want to first mention what you said about that whole thing. Folate ties must be the dark leafy greens. just how often I feel like that comes up in medicine in general. It’s not a big deal. Just ignore that. I’m sure it’s just this weird thing somebody’s doing. Or maybe it’s good, like your example, and how amazing it is to watch the pattern and be just that interested in understanding. This isn’t making sense. This isn’t adding up. I feel like we see that in clinical practice and bloodwork all the time. People coming in with very basic things around like you’re just dehydrated is another example of one that’s all here. Talk to us a little bit more. You mentioned the link between what you’re already noticing in some of your research and studies around fertility, lowering miscarriage rates, and methylfolate. I want to talk more about genetics and hormones in more detail related to sexual dysfunction. But let’s take a step back for a second just to make sure that everybody’s on the same page. I know a lot of people know about MTHFR, and it’s called the mother of our genes. I hear a lot of people call it passionately sometimes, but I know people are listening who have not heard of this. I just want to get everybody on the same page. We’re talking about methylfolate and this genetic anomaly. Can you just set the foundation for us?

Carolyn Ledowsky

Yes. We have a folate pathway that makes our biologically active folate, which is methylfolate. When we say biologically active folate, it’s the folate that the body uses to do everything it needs to do. particularly methylation of DNA, which is incredibly important for the quality of DNA for fertility. We also need this methylfolate to make a product called SAMe, which is what we call the universal methyl donor in the body. What that means is that it acts like a cofactor and an on-off switch for so many important metabolic processes. For example, for us to make phosphatidylcholine for our brain to work well, we need SAMe for the detoxification of our estrogens. We need this serum to make creatine. We need creatinine for our muscles and our brain energy.

There are so many important, what we call methyltransferase, pathways that are important biochemical pathways that the starting ingredient to make those work is methylfolate. What MTHFR does is the last step in that folate pathway to convert non-activated folates into methylfolate. So it’s a gene that can be downregulated. If someone has a polymorphism, or what we used to call a mutation, we don’t say that anymore. But just so it’s easy if someone has a mutation, it downregulates the efficiency of that enzyme. If you have two copies of this one gene, you can be downregulated by 70%. You can imagine then that if all these things are important for your hormones, your mood, your DNA, and your immune function, all of these things need them. If they’re downregulated by 70%, that’s going to have a big impact. So where we see the majority of people suffering from this downregulation, it can be particularly mood, anxiety, and depression. Those people who don’t particularly cope with stress seem to react to stress more than others, where we have hormones and particularly toxic estrogens building up in the body. There are so many different aspects we might say recurrent miscarriage, family history of cardiovascular disease, and family history of varicose veins. These are all areas where we say, “Oh, hang on, is there an MTHFR polymorphism possible?

Diane Mueller, ND, DAOM, LAc

Yes. Thank you. That helps a lot. It’s important to just say how widespread it is. We’re talking about these widespread impacts, which is probably one of the reasons why it does not get looked at as much as it perhaps should, because of the inability sometimes to think about that, because so many different things can be impacted. Let’s talk about hormones, as we’re talking about sexual health and libido at the summit. You mentioned estrogen, so maybe we can start there. How is this gene involved and is the activation of folate involved in estrogen, estrogen clearance, and estrogen metabolism in the body?

Carolyn Ledowsky

As I said, we have this MTHFR that makes cell-activated folate, and methylfolate, and then that gets brought into the cycle that makes SEMe. Now, the way that we break down estrogens is primarily through an enzyme called COMT catechol-O-methyltransferase. What happens is that this COMT gene is incredibly important in getting rid of toxic estrogens. We know that our four hydroxy estrogens, which are the more dangerous ones that need to be methylated to not be dangerous, contain and support each other. If this COMT enzyme is lacking activity because the methylfolate is low and we don’t have enough selenium to support it, then estrogen will build up. There are other key genes involved in estrogen metabolism.

So, phase one: detox genes. CYP1B1, that is an upregulation. If someone has a polymorphism, it’s because the enzyme works too fast, and what happens in phase one is that this is a toxin. Its job is to break it apart. Now, you end up with this big toxin that needs to be eradicated by phase two. So what happens is that if COMT is slow and it can’t do the job, you’ve got a lot more of these toxic elements sitting in the blood, and you can’t get rid of them. This is why we need our phase one and phase two detox enzymes to work together. COMT is important. CYP1B1 is important, and one of the others is our glucuronidation gene.

UGT genes. These are genes that not only help us break down estrogens, but they’re incredibly important for most chemicals in our body. It’s more important than glutathione. So, when we have these glucuronidations, they are jammed up by a lot of environmental things. But if glucuronidation is downregulated, you’re going to see someone holding on to more estrogens. What happens when that happens? Well, you get a whole range of things: polycystic ovaries, fibrous cystic breasts, endometriosis, cancer, breast cancer, and prostate cancer in men. Environmentally, there are so many estrogenic things that we need those pathways to work well. The last one is glutathione. Glutathione alone helps us get rid of some of these dangerous byproducts that the other enzymes are creating. There are a lot of different genes that are involved, predominantly the liver and detox and clearance genes that are supporting us. This COMT gene that we talked about and that’s so important is also incredibly important in dopamine and the way that we break dopamine down and clear dopamine.

Diane Mueller, ND, DAOM, LAc

So it’s clear what you said about the methyl donors needed for the COMT. What about phase-one and phase-two processes? Are those requiring the methyl donors as well?

Carolyn Ledowsky

Well, all detox needs the MTHFR to work optimally because of the processes by which the MTHFR makes methylfolate. Methylfolate goes into the methylene cycle, which then goes into our cystathionine beta-synthase pathway, our detox pathway. So it all leads in the direction of supporting detoxification. That’s why a lot of people will read that the MTHFR chapter means we don’t detox as well, and that’s because we haven’t gotten good input into that detox pathway.

Diane Mueller, ND, DAOM, LAc

Perfect.  Then what is the topic of epigenetic expression so people can get these genetic polymorphisms measured? We can test for these things. What do you advise people, and what have you seen in your research? Okay, we have these polymorphisms. Have they been expressed? Do we need to be concerned that just because somebody tests and they are positive for them, they are expressed and it needs to be treated appropriately? What do you think about that?

Carolyn Ledowsky

That’s such a good question, Diane. My analogy that I like to use, which explains it well, is: Imagine driving down a freeway and having a lot of potholes in your lane. It doesn’t matter how old or how new the car is; it’s going to be damaged because you’re going to take a wheel off the axle. Something’s going to happen, and it’s going to be damaged. If you’ve got rain, hail, and snow, that pothole is going to get bigger and bigger. That’s what I liken genetics to. Everybody has potholes. Some of them are big potholes. For example, if your hole is the MTHFR and you have a 70% down-regulation, I consider that a big pothole.

I also consider your B12 genes to be big potholes because, if you’ve got those genes, you have a susceptibility for that pothole to get bigger and bigger and bigger. Every time there is an environmental influence, yes, you hear people say that genes are not as important, but it’s all about the environment. To some degree, that is true. But who nowadays doesn’t have an environmental influence? Just the very presence of COVID was one of the biggest environmental influences on our genetics that we’ve ever had in the history of this planet, because we were all hit with a viral load that a lot of people had a predisposition to having high inflammation, or, particularly, those interleukin-6 and inflammatory genes. We just couldn’t control it. How I see that is that if I come and plug that culturally into your lane, it doesn’t matter how old your car is; your turtle alone does quite well. As long as you put petrol in it and look after it. I like to think of your genetics.

Some don’t matter until you’ve got an environmental insult, but some will always matter because they’re so fundamental to your biochemistry. Even the slightest bit of stress can set you off-kilter. We need to look at the ones that we go to. Yes, look, that’s interesting to know; it’s not a quote now. Will you consider that if and when anything happens? Now that you’ve got two or three, we need to plug them up because we believe you will improve significantly going forward.

Diane Mueller, ND, DAOM, LAc

I love that analogy, and it’s so true. None of us get out of this world toxin-free. It’s just not possible. Probably what some of our listeners are wondering now is: if they have this particular polymorphism, whether it’s heterozygous or homozygous, if they have it at all, do they wind up with any certain environmental toxins that are particularly important to avoid? Or do you look at this like a lot of us do clinically around almost the bucket example: you just want to make sure that you are largely avoiding as many as possible and lowering the amount of exposure as much as possible, or define it to be more specific than that?

Carolyn Ledowsky

Well, where do you start with toxicity? When talking about hormones, the two biggest environmental influences are mold exposure and estrogenic environmental impact. Credit card receipts, plastic bottles, plastic containers, and plastic cling wrap. All these things that we have are made of plastic. This is why we’re seeing such a huge increase in male prostate cancer because men are exposed to estrogen as much as women are. They still have the same genes that women have, yet they’re not considered to have an estrogenic problem, which doesn’t make any sense. The mold is huge for us. I mean, we’ve just had two years of rain. We had an El Nino, whatever it was, and we just had rain after rain. Houses were getting flooded.

When I say flooded to their roofline three times in two years, and these people are going back and living in them now, what people don’t understand is that mold exposure and mycotoxins from these molds completely wreck your hormones. So, predominantly, what they’re doing is jamming up the glucuronidation pathway, which does not allow us to clear these toxic hormones. So we’re seeing thyroid disorders. We’re seeing polycystic ovaries, we’re seeing estrogen dominance, and we’re seeing cancer. So I would say that if anyone is living in a moldy house, they have to do something about it because there is no sure way to ruin your hormones and live in a moldy house.

Diane Mueller, ND, DAOM, LAc

Yes. Thank you for saying that. It resonates so much with that. I have two different branches of my practice: one is libido, and the other is lyme and mold.

Carolyn Ledowsky

Oh, they do.

Diane Mueller, ND, DAOM, LAc

Yes. People will say to me, How are you doing this? Like, how are these things related? It’s exactly what you just said around like they’re branded differently. I do different, slightly different work, but it’s largely exactly what you said around, like sexual health and hormonal imbalances, and all that dysfunction so commonly is rooted in environmental toxicity, and I see that too, like mold being one of the top toxins. I’m so glad you said that. I want to also talk about treatment. People are coming out, and the big thing with this is that a lot of people are using methylfolate. What do you think about the uses of methylfolate? What about other supplements such as SAMe or creatine, like you mentioned? My other question with that is that I’ve read somewhere that B2 is due to a co-factor of the MTHFR of our enzyme that can help with that conversion. Do you find that your research could also be a useful nutrient in these scenarios?

Carolyn Ledowsky

Now, that is a multimillion-dollar question. Part of the analysis needs to be that we always do the genetic test. We do an organic acid test, we do a blood test, and then we do a thorough case history. What you’re trying to evaluate when you’re looking at treatments is: What are the pieces of the puzzle that need to be put down first? Where do you start? A lot of the problems that we found, particularly when people were first introduced to methylfolate, were thought to be caused by MTHFR methylfolate. I need lots of it. Let’s dive in, and they were having serious, significant reactions. Some people used to ring it. they were having, that was suicidal. We’ve got to be careful, and methylfolate is usually one of the last things that we introduce because methionine synthase is this key enzyme that takes the methylfolate and puts it into that semi-cycle. Now if you’ve got a block, it could be that your B12 is low, you’ve got exposure to yeast, you’ve got low glutathione, you’ve got heavy metals, you’ve got inflammation, and you’ve got high nitric oxide.

I mean, there are so many things that could sit there that are all low in zinc. If you’ve got any of those things happening, then that methylfolate can’t be taken up, and people will react to it. So I say to the practitioners that I teach that if that happens, you don’t just take Folinic and go, Oh, well, that’s great, let’s have Folinic because they don’t react to methylfolate. That’s not the answer. The answer is that you have to answer the question: Why did they react to the methylfolate? You have to find out what was causing that reaction. You’ve got to unpack it and then come back and try it later on once you’ve done your job. This is the thing you shouldn’t get into the habit of saying: I have this thing; therefore, I need this supplement because everybody’s completely different. Yes, in some instances, that might be the case, and you might feel better, and you might feel the best you’ve ever felt. But in a lot of cases, that’s not the way it works. You need to do it on an individual basis and say, “Okay, this person has mold exposure. I’m not going to give them methylfolate, and this person has serious adverse reactions to anything I give them.”

Therefore, I’ve got to start very gently with a pre-tox or someone who has depression, but it’s not serotonin-based; it’s dopamine-based. Yes, I’ll give them a lot of methylfolate and C-low tyrosine, and they’re going to feel great. I know that some people want to hear that it’s individual, but it’s because everybody’s different and everybody’s got a different environmental influence. Some people will react to wifi because of mold exposure. So that’s going to be a much more important conversation. You’re going to go with completely different supplements that, if someone doesn’t, and end to answer that question about environmental, it’s getting harder and harder for us to be clean and our water supply, everything we eat, the pesticides you’ll get phosphates, the glyphosate, I mean, where does it end?

We can only do what we can and be as clean as we possibly can and avoid, like particularly those estrogenic things for as far as hormones go; carry a water bottle with you; make sure you don’t take a credit card receipt; say, no, I don’t want the receipt. If you’re working in a supermarket with gloves and don’t have them, allow those things to touch you because of all these and all your personal care products. I was so alarmed when I heard this thing that said a woman gets dressed for work, and by the time she gets up and walks out of the house, she’s been exposed to 300 toxic chemicals. thinking about everything that you put on around your body, making sure you’re changing them to more natural ingredients, and cooking from scratch as much as you possibly can. I try not to buy things in packets because, again, you’re going to have folic acid. In Australia and in the US, you can fortify foods with folic acid.

Can we just say one thing about folic acid? I’ve been talking nonstop, but I thought it was important at this point when I mentioned packets. I believe, based on my research, that we have reached a limit on how much folic acid we should be having. The research says that the enzyme that deals with folic acid and makes it into methylfolate only copes with 200 micrograms a day. Now, the research we’ve just done says every single woman in pregnancy who is taking a folic acid-based prenatal is exceeding the output toxicity level deemed safe by the Institute of Medicine in the United States. We’ve got to be wary that we are having too much folic acid and that we’re inhibiting the way that this important methylfolate is working. It is going to affect our hormones, our mental health, and our children’s health. packets, try to get rid of them and try to avoid folic acid in foods. When you’re taking a supplement, don’t take it with folic acid. Take it with methyl glutamate.

Diane Mueller, ND, DAOM, LAc

Yes. Thank you. It’s exciting research we’re doing like we talked about, and I can’t wait to see what comes out of that. Another thing I just wanted to add quickly about what you’re saying about the 300 different types of chemicals that oftentimes women are exposed to before they leave the house is that another thing that I’ve seen is that even in natural product lines when we analyze them, there’ll be some things in a natural product line that are clean, and then the same product line could have some products that are not clean at all. That’s also a component that can be maddening sometimes. There is a great app out there called Yuka. I don’t know if you’ve seen it. It’s the Yuk A.

Carolyn Ledowsky

I’ll have a look.

Diane Mueller, ND, DAOM, LAc

It’s very cool. I would love your opinion on it when you look at it, but it’s very cool. You can put on your phone and start scanning products, like the barcode, and then it will list all the chemicals and their rates, according to where they’re pulling their research and the severity. But it’s very interesting to see.

Carolyn Ledowsky

 That’s user-friendly.

Diane Mueller, ND, DAOM, LAc

Yes, it’s user-friendly, and that’s how I’ve been telling people: just go through your home stuff one at a time as you’re replacing stuff; just start learning because some of it’s just some; sometimes if it says natural, it may or may not be more or less toxic; then, you think, it’s just good to do our due diligence. Is there anything else when it comes to genes, hormones, and treatments in this conversation that you think is important that we’ve got to say today?

Carolyn Ledowsky

Well, I mean, I was thinking when you were talking, one of the things we haven’t said is that we’ve talked about toxic estrogen, but why is that important? An important thing to mention is that when your estrogen levels are low and you have toxic levels of estrogen, they’re not being cleared, reducing the good levels of your estrogen and causing a reduction in testosterone. You’re talking about libido; you’re talking about sexual function. This is critical because you’re getting a displacement of your good estrogen, your DHEA. That’s the other thing we haven’t talked about; the sulfation of DHEA is important. These sulfur pathways and make sure that the so-called sulfation in phase two is working.

If you’ve got something out of balance, particularly toxic estrogen, it is going to affect all your other hormones. Often, people will say, “Oh, yes, but my estrogen is high in my blood.” We go. “Well, that’s not what we want.” That’s saying that there is possibly some toxic estrogen. When you do the metabolites, you see the metabolites, and they’ve got low testosterone or low-hydroxy estrogen, which is what we want. doing Dutch tests and particularly if you want to look at sexual function, one of the biggest genes to look out for in men for libido, where not so much libido but sexual function and erection is the nitric oxide synthase. I don’t know if anyone’s spoken about that yet, but nitric oxide synthase is an enzyme that helps you make what we call endothelial or nitric oxide, and that’s what helps an erection.

That’s the exact mechanism of Viagra. It helps with endothelial nitric oxide. Now, why wouldn’t you have good endothelial nitric oxide? Well, it may be that you’ve got inflammation that is shutting that enzyme down, or maybe you have polymorphisms in that gene that are not working as well as they should. Although Viagra is helping you do what you need to do, it’s not addressing the root cause. You could find that by doing your genetics and getting inflammation under control, you can get that erection issue under control. There are so many aspects of this that can be due to genes, but they can also be due to environmental influences.

Diane Mueller, ND, DAOM, LAc

Yes, I’m glad you brought that up because we did. We do have another interview here. We talk about how erections and erectile dysfunction are sometimes early signs of cardiovascular disease. We talked about that. But true cardiovascular standpoint and OS, but not from the genetic component. That’s an important addition to add to that conversation. It’s like there could be a genetic reason why that whole endothelial dysfunction is happening to begin with. Inflammatory causes from toxins and those sorts of things not being detoxed correctly are playing a role. We could go on and on and on and on here because one of the biggest things, too, with this genetic component of things is the web. We’re in a big web of interconnectivity. The only way to get to the root is by testing and figuring out where somebody’s imbalances are. As you said, doing proper testing to get those estrogen metabolites to look at some of those more unique and specific markers versus just total estrogen is very important. I want to make sure that we mention your giveaway. You are giving away a guide about how genes impact hormones. You guys, make sure you go around to the speaker information on Carolyn’s page to get that particular downloadable guide because it’s going to give you a lot more information and help you synthesize some of what we talked about here today. What else do you want to leave people with? I want to make sure they know how to get a hold of you and that thing as well.

Carolyn Ledowsky

Yes, our website is mthfrsupport.com.au. We see patients all around the world because we’re predominantly 100% online, which was great through COVID. Here, we’ve had people think, “Oh, I need to do something.” But I would say that if you have a long-standing condition that just has not been helped by going to see multiple practitioners, it might be time to look at your genetics and see if there is something that we would call a big pothole that’s probably standing in your way. Because what it means essentially is that you’ll probably ban dating well. People with significant potholes do Band-Aid, and they self-medicate without realizing they’re self-medicating. But they might, for example, go and live on a farm away from all the stress and environmental influences because that’s the only way they can survive. That’s great, but that’s not the way we want to live. If there are long-standing issues, don’t be afraid of the genetics, the genetic reports that we do, which is the smart DNA advanced pathways test. There are no disease SNPs in there. I mean, there are none. We’re not talking about the bracket gene.

We’re not talking about something that’s going to be scary. We’re just talking about genes that affect your metabolism—how you make B12, how you make folate, how you detox—which are biochemical SNPs. I know a lot of people say, Oh, I don’t want to do that, but they don’t need to be scared because it’s very enlightening. When you’ve got the other tests, as you say around them, it can be the most exciting thing you’ve ever done.

Diane Mueller, ND, DAOM, LAc

Yes, thank you for that. I appreciate you orienting and living, leaving us with hope and not fear. This is exciting. We’re going to get so much information. Thank you so much for being here. That will have everything she needs to get a hold of Carolyn in her speaker bio to work with her and keep her team up to date on her research. I know I will be. Thank you again for a great interview and for your time.

Carolyn Ledowsky

Thanks, Diane. It’s a pleasure.

Diane Mueller, ND, DAOM, LAc

We’ll see you all in the next interview.