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How Genes Impact Hormones with Dr Denise Furness

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How Genes Impact Hormones with Dr Denise Furness

How do our genes influence our hormones? We often view our genetic make-up as static and unchangeable, but in actual fact they are dynamic and constantly evolving in direct response to our environment, diet and lifestyles. For instance, hormonal secretion, metabolism and excretion are all swayed by both our nutritional status and the many enzymes systems that may be up, or down-regulated as a result of our unique single nucleotide polymorphisms (SNPs).

In today's podcast we're joined by Dr Denise Furness who takes us through the relevant genomic factors affecting our hormones, the intimate interplay that our diet and lifestyle can have on our hormonal health, and how natural health practitioners can positively modify effects with judicious use of specific supplementation.

Covered in this episode

[00:42] Welcoming back Dr Denise Furness
[05:22] Genetic factors in sex hormone metabolism
[08:59] The epigenetic impact of dietary behaviours
[11:16] When is genetic testing relevant?
[14:16] What hormones are affected by what genes?
[33:39] Combining genetics with functional testing
[43:28] With thanks to Denise

Andrew: This is FX Medicine, I'm Andrew Whitfield-Cook. Joining us on the line again today is Dr Denise Furness. A molecular geneticist and nutritionist with over 16 years' experience who conducted her PhD in nutritional genomics and genomic health at CSIRO Human Nutrition under the mentorship of the famed Prof. Michael Fenech. 

She's been involved in genetics and nutrition, health research for over 13 years and was principal investigator in predicting adverse pregnancy study at the Women's and Children's Hospital, Adelaide and was involved in the SCOPE studies. You can find out more about them at scopestudy.net. 
Her interests include the diagnosis and treatment of underlying triggers such as detoxification, inflammation, oxidative stress and methylation. Denise works closely with integrative practitioners in order to apply this knowledge and address the possible underlying issues associated with various health concerns, including fertility, gastrointestinal disorders, and mental health.  
Warmly, I welcome you back to FX Medicine. How are you, Denise? 
Denise: I'm well, thank you. Thank you for that lovely introduction. 
Andrew: Well, I've got to say you've earned it. I don't know how you stop. Like, you just go, go, go. 
Denise: It feels like a long time ago that I was, you know, writing grants and running those studies back in the hospital days. I've sort of been in the clinical practice world now for about 5 years, but it's nice to have you mention it because that's where it all began. 
Andrew: Do you still keep in contact with those other investigators and find out what's transpired since those studies finished? Or, indeed is the SCOPE finished?  
Denise: Absolutely. So, well, SCOPE…it was a huge study. That was a sort of a global effort with people in Manchester, and Ireland, and New Zealand. A lot of that has been written up. The PAPO study was a small study. That was mine. I ran that in my post doc. To be honest, we didn't end up writing it all up. I sort of moved on and had babies. But I do stay in contact with all of those people, including Michael Fenech, and I actually…even though I'm in clinical practice now, I am doing a bit of research around genetics, and someone that I used to work with at CSIRO is helping me with some of the research I'm doing now. So we do all stay in touch.  
And, interestingly I was just over in New York last week at the Integrative Healthcare Symposium, and it was amazing to see Jeff Bland get up and present research that was done around about 15 years ago at CSIRO. It was not my research around pregnancy and fertility but it was Alzheimer's research. It was actually Phil Thomas and Michael Fenech, but I was there with them while Phil was doing his PhD. We're in the same lab together, and it really was the same work I was doing – DNA damage, and nutrigenomics, methylation but in relation to Alzheimer's, not pregnancy. And he was saying that this is crucial the way with the future, and that was so exciting. I ran up to Jeffrey and said, "Guess what? You know, that's the lab I worked in. I worked with those people," and I said, "I have left research and I'm doing it in the clinic." And he was so excited because, you know, he and others were sort of saying this is the way of the future – genetics, epigenetics…

Andrew: Oh, for sure. 

Denise: You know, preventative medicine. And really that's why I left research and moved into this more clinical role because I do believe we really can help people when we are addressing these underlying factors. 
Andrew: Oh, yeah. You know, in the past, there were pharmaceutical companies. I remember one, in particular, that got dragged across the coals for using research in India. So they used women from India and smothered, if you like, the important point that they have a different response to hormonal interventions. So they were dragged across the cold because the results were glowing but they may not glow so much in other cultures. So this whole thing about personalised medicine really does come down to our genes. 
Denise: Exactly. So you've got your pharmacogenomics that does play a huge role in the way that people can metabolise different medications and pharmaceuticals. And then we've got the nutrigenomics which is obviously where I come into, doing a lot of genetic testing in relation to how well people may metabolise nutrients or how sensitive they are to particular toxins. Or, for example, today, you know, I think the topic is really…we want to talk about hormones and fertility. We know that genetic variations can play a role in how well someone will produce oestrogens, or break them down, how well they can actually eliminate them from the body. 
Andrew: Let's talk about that. the topic is how genes affect our sex hormones. Why are we seeing so many sex hormone metabolism issues so much more than before? Polycystic ovarian syndrome was a rare thing in my day. Despite the fact that it may be better reported now and there was a lot of effort into bringing it into the limelight. What other factors are involved in sex hormone metabolism issues? 
Denise: Well, firstly I'll say that it's not our genetics that are driving this, because our genes really haven't changed in that short amount of time. But what has changed is our environment. 

So, you know, we are exposed to all these things called xenoestrogens. They're found in plastics and, you know, particularly people that are heating plastic in the microwave, please don't because these chemicals can leak into your food. And when we say ‘xenoestrogens’, these are things that act like estrogen in the body. They combine to the oestrogen receptors and cause these oestrogen-like effects. 
So, the chemicals in the environment play a role. Our food plays a role. I mean we think about farming and agriculture, a lot of animals are given hormones. We then ingest these meats. Particularly, you know, younger children are more sensitive to some of these chemicals and possibly hormones in the food chain. I mean for those that this is a new area, you can even get onto books such as One Bite at a Time. Some of you may know Tabitha McIntosh

Andrew: Ahh, yes. 

Denise: The other author, yeah, Sarah Lantz. So, there's a lot of information that is becoming available now that we can learn about these things in our environment. And I do think the environment is the biggest factor in this.  
But also when we're thinking about these hormone-related disorders, particularly around oestrogens, we know that fat mass is directly correlated with the amount of oestrogen. So when we think about girls that are going through puberty, or when the onset menstruation is it's due to the amount of oestrogen. And that occurs when these females or younger girls have enough fat really, on their body, that triggers the body to say, "All right, we're going to produce more oestrogen and that's going to result in stimulating the growth of reproductive organs, breast tissue, etc.” And a lot of younger girls now are a lot heavier. They do have an increased fat mass and that's going to increase the oestrogen circulating in their bodies and then bringing on the menstrual cycle earlier. And we know a lot of these hormone-related disorders are associated with exposure. So an increased exposure to hormones and increased exposure to estrogens and estrogen metabolites. So if someone is menstruating earlier, then obviously that's going to increase, and because of the hormones, that's going to increase the exposure to the hormones. 
So I would say the environment is the biggest factor. But there are definitely genetic predispositions. 

Andrew: Right. 

Denise: So some of us will be able to tolerate a higher amount of oestrogen. We’ll convert it into the metabolites at a faster rate. And also then we’ll metabolise it perhaps down down a safer pathway to 2-hydroxy metabolism, and then we can get rid of that through methylation, which is, you know, with the COMT enzyme, or glucuronidation, or sulfation, or even the conjugation of glutathione.  
So, when you're thinking about hormones, you really want to think about detoxification. It's similar, phase 1 and phase 2 pathways that help excrete these hormones from the body. 
Andrew: And indeed when you're talking about women being heavier, I should say girls being heavier nowadays, and so there's a greater likelihood that they're overweight. We've got to be really careful here with body image and the whole anorexia issue and all of this thing…what do you call it? Body shaming, that sort of thing. However, facts are facts. We are all… 
Denise: I'm not saying girls should be skinnier. You're exactly right, but we need to be realistic. Facts are facts, and a lot of us are heavier than we should be. We want a healthy weight, yes.  
Andrew: That's right, with healthy activity. But, it's really interesting when you look at the reasons for that increased weight. That's, you know, very largely diet, and certainly there's activity there as well. But when you're talking about the dietary components, what can you eat that would decrease the recirculation of oestrogen metabolites? Fibre. Well, they're not eating that because they're eating fats and carbs and they're not eating the fibre. So it's really interesting how there's a self-propagation almost of the, you know, "fat begets fat" concept. 
Denise: And I mentioned I guess that direct association with the possibility of hormones coming through the food chain. But as you mentioned, there's fibre but also eating real food, eating plenty of, you know, cruciferous vegetables. We know that can help with, you know, oestrogen metabolism and the metabolism of toxins in the body. 

But also just having a good, healthy, balanced diet with real food is going to support that gut microbiota. And the healthier your gut is, the better you are at dealing with hormones. Because we know that dysbiosis can also affect hormones being, you know, recirculated back into the system. So it really comes down to a lot of those basics of, you know, like you said, exercise is important for maintaining weight. But also breaking down other, sort of, stress hormones and things that links in with COMT so there is a bit of a direct relationship between breaking down catechol oestrogens and catecholamines. Exercise can help stimulate that. Also, you know, sleep and things like that. 
So, getting back to the basics can improve people's hormonal balance, which then will obviously help with, you know, hormonal-related disorders.  
Andrew: So, it's really interesting you say that, because how often do we bang on about getting rid of the bright screens at night and having a restful sleep, getting enough hours of sleep? 

And we're talking about, you know, coming into the teenage years here, the formative age, you know, for body type, if not coping mechanisms and stress. But you also have things like family relationships. I was very interested to learn…there was a really interesting story with regards to, you know, psychosocial stressors from family breakdown affecting early menarche, early menstruation.  
Denise: Really? That's fascinating. 
Andrew: Yeah, fascinating. So when you think about stress, sleep, diet, exercise, ring a bell for every sort of condition known to man?  
Denise: Absolutely and I'm glad you brought that up because the social and stress, you know, interactions are also something that comes into play here. 

And people might be listening, thinking, "Well, why do we care about genetics with everything they've just said?" And, yes, they could make sense if someone comes in. If you're a practitioner listening to this, and someone does come in, and they do have serious problems with their sleep, they're not sleeping well, they are overweight, they're not eating well, you definitely want go there first. You're probably not going to jump into genetic testing. 

But often the patients…nearly all the patients I see have already started working at these things. They've already made changes to their diet. Many of them may be gluten or dairy-free. They know that impacts with inflammation or they might have food sensitivities. And they've tried to get a lot of these steps in order. And the genetics is something that you'd come to when people have made changes but perhaps they're not getting the results that they were expecting.

Andrew: Right. 

Denise: Or they're still having hormonal problems. You then may want to dig a little deeper and say, you know, "Why do you have…?" Let's just say they've measured their oestrogen metabolites and they've got high levels of 4-hydroxy, which we know that's the one that… 
Andrew: It's really propagative.  
Denise: …can cause quinones. Yeah, quinones, DNA damage, possibly even cancer. So, someone might come to you and say, "Well, I've made these changes, but I still have “oestrogen dominance," or, "I've got high oestrogen," or, "I've got issues with metabolites," you then may want to say, "Well, let's dig a little deeper and find out why. You know, do we need to start doing some functional testing or some genetics to understand what's going on in your body?"  
And the other thing with genetics, too, is often people are confused with why these things are happening to them, and it allows you to be able to explain things, "Well, this is your predisposition or your risk." And you then go from there and say, "Well, what can we do about that?" And you can focus on, well, is it likely to be, say, phase 1 or is it phase 2? Is it oxidative stress? Things like that.  
Andrew: So let's talk about which hormones are affected by which genes? Because this sort of ties into what you would do on a clinical level, what you just mentioned with regards to detoxification phase 1, phase 2, and what genes affect those processes. Can we get through a few of the… 
Denise: I'd love to, I'd love to. 
Andrew: …genetic impacts? 
Denise: Of course I would. That's the thing I want to talk about the most.  
Andrew: All right, so the obvious one is CYP. There must be a myriad of genes. I know of a couple with regards to medications. 
Denise: Yeah. So, the ‘cytochrome P450s’ or some people call them the CYP or the CYP genes, the genes that code for phase 1 detoxification enzymes. And we know the CYP enzymes can often metabolise multiple things. Some of you may be aware of them in relation to pharmacogenomics. So breaking down the drugs but they're also important for breaking down hormones, and chemicals, and toxins we're exposed to. 

If for those that know a bit about hormone metabolism, if I sort of start at the beginning. For those that don't, you'll still be interested or you could always listen to this again and pull out a picture or Google hormone or oestrogen metabolism and then sort of follow through.  
But the first one I would mention would be the CYP or the CYP17A1. CYP17A1 is something that converts progesterone or pregnenolone into the androgens. And there's a genetic variation that can increase enzyme activity. So that would mean that progesterone could get pushed over to the androgens. Therefore that person might be at risk of having a little lower oestrogen levels, more of the androgens. 

And then the next step, I'm sure many of the listeners would have heard about this one, is the CYP19A1, commonly known as aromatase. So, aromatase can then come in, or is the next step, that converts those androgens into oestrogens. And again it's a genetic variation that we can test for. But there's also a lot of lifestyle factors that influence aromatase and that's why we hear a lot about it.  
So visceral adiposity, so those that have got increased belly fat. We know now that fat isn't just a storage molecule of energy or a storage…not really a molecule but a storage, you know, organ or storage tissue. Now we really think of it like an endocrine organ or endocrine tissue. Because it does have the ability to produce hormones such as oestrogen but also inflammatory compounds so, you know, cytokines that stimulate the immune system and can lead to chronic inflammation. 

So for those that have extra fat mass or even those that are drinking alcohol, alcohol can upregulate or switch on aromatase. So for guys that don't want their testosterone being converted to oestrogen a little quicker, maybe lay off the alcohol. Plus, there's a genetic variation as I mentioned. 
So they’re a couple of steps in sort of producing oestrogen in the pathway. And then we have some more cytochrome P450s. They're CYP1A1, CYP1B1 and others that are involved in converting the oestrogen… so, you know, the estradiol, you know, your E1, your E2 down into those oestrogen metabolites. That first sort of step in breaking down the oestrogens. And we can have either the 2-hydroxy, which is thought to be the safest. Some call it the ‘beneficial oestrogen,’ but reality is it's still a metabolite. 

Andrew: Yeah. 

Denise: It can be reactive. So I do say to people “it's still an active metabolite that needs to be broken down.” Though it is a safer option than the 4-hydroxy or the 16-hydroxy. 
So, the 4-hydroxy estrogen comes from the conversion using cytochrome P450 1B1. Now there's a lot of research around 1B1 and we know that the genetic variation that increases activity can make people more susceptible to having more of those 4-hydroxy metabolites in comparison to the 2-hydroxy which comes from CYP1A1. 

CYP1B1, CYP1A1, both of these are actually involved in not just hormone metabolism but also breaking down or metabolising what are known as PAHs, or polycyclic aromatic hydrocarbons. These are things found in combustion fuels, so think about car exhaust fumes, also cigarette smoke. Even not they're the main players but even a bit of breaking down caffeine. It's really CYP1A2 that's the main player in caffeine. But if you are consuming all of these things or exposed to a lot of these chemicals, that can also influence the metabolism of these oestrogens.  
So we can test for these SNPs and say to someone, "Well, you are more at risk of having this 4-hydroxy estrogen. That could be part of the reason why you've got higher levels of this particular metabolite." Or, if they haven't had testing done, it might then trigger you to say, "Well, you do have high oestrogen. You have a genetic variation that makes you more susceptible to the 4-hydroxy. We want to test this and find out do you actually have high levels, because if you do, we want to start to treat that or try to manage that as quick as possible." Because the 4-hydroxy as well as the 16 but particularly the 4-hydroxy can cause the quinones which leads to DNA damage and then, you know, DNA damage as we know can cause a number of outcomes including cancers. 

Andrew: Yeah.
Denise: So, the testing can also help you determine if you want to then go and do, you know, other testing because remember the genetics will only tell us about risk and predisposition. You're talking to the patient about the likelihood of something happening within them based on the genes they've inherited from their parents. You obviously have to measure levels to find out if that gene is expressing or having an impact on the individual. 
So that's, sort of, phase 1, which I've gone through but then there's the phase 2 detoxification enzymes as well. And, one of the big players is COMT, catechol O-methyltransferase. Many of the listeners probably know COMT because it's linked with stress and anxiety. Some associations possibly with mental health because it does break down the catecholamines. So your dopamine, adrenaline, and noradrenaline. 

But it also breaks down catechol oestrogens. And when I just mentioned these oestrogen metabolites, the 2-hydroxy, the 4-hydroxy, and the 16-hydroxy, they are actually catechol oestrogens. So it's that same enzyme that breaks those down. And we know there's a genetic variation that significantly impacts on how well COMT can function. So some people will be slower or that they're not as efficient as breaking down these metabolites. And in addition to having a genetic variation, we know that nutrition plays a big role here, too. Because the cofactor is magnesium. And being a methyl transferase, you obviously need to have plenty of your folate and B vitamins to make those methyl groups. So you can talk to people there about, you know, nutrition and their ability or likelihood of breaking down these things at a faster or slower rate.  
And then you've got genetic variations in our glutathione transferases, which is also another important mechanism for breaking down or safely excreting hormones and other chemicals. So there's our GSTP1, which is particularly relevant when we think about hormones. So glutathione transferase P1. For the listeners, I remember P1 as peripheral. Because most of your phase 2 and your glutathione transferase enzymes are in the liver, so you've got your GST1, M1. There's a whole family of them. But the P1 is what's found predominantly in other tissues like breast. So if you're thinking about getting rid of catechol oestrogens in the breast tissue, you've got your GSTP1 but also in the brain, the lungs, and things like that. So there are genetic variations that can affect how well that GSTP1 can clear catechol oestrogens and chemicals from the body.  
And there's one more I probably want to mention that listeners may or may not have heard of, and that's the NQO1 or quinone reductase. And the reason I want to mention that one is because if someone does have high oestrogen metabolites and are producing quinones, or are likely to be producing these quinones that are quite dangerous. It's quinone reductase along with the glutathione transferases that help neutralise, I guess, or break down those quinones so they can't go and cause cellular damage and DNA damage. And the genetic variation within NQO1 actually has a huge impact on how well that enzyme can work. So depending on the research papers you read, some will say that there is actually no activity at all if you inherit the homozygous, so meaning two variants. 
Andrew: So therefore high-risk? 
Denise: Hugely high-risk. So these people don't have the ability or the same ability as someone that has a fully functioning NQO1. 

Now that doesn't mean they can't breakdown quinones at all. There are other pathways and mechanisms in the body. But the NQO1 does play a big role. So these people that have inherited the normal or so-called normal genotype definitely have a better ability to get rid of those quinones, reduce oxidative stress and help with that. 

And the NQO1 interestingly, too, is what regenerates CoQ10 into the active form as well as vitamin E. So it acts as a phase 2 detox enzyme with quinones. Even benzoquinones, people are more sensitive to benzene if they've got the genetic variation. But it also acts as an antioxidant by helping to regenerate our antioxidants once they become oxidised. So that's a really interesting one that I love looking at with the patients as well. 
Andrew: That's really interesting you say that about the CoQ10 and the benzenes because that's a metabolic pathway from tyrosine where… 
Denise: Oh, you're about to teach me something. 
Andrew: Well, I actually found this when I was looking at the actions of statins, and why would some people get myositis and others not. Sorry, forgive me. If you've got an HMG coenzyme A reductase inhibitor, a statin, and they're really effective, then why aren't all patients getting muscle pains? There must be an accessory pathway, and that's through tyrosine and phenylalanine. You make CoQ10 through tyrosine and phenylalanine... 
Denise: So I think phenylalanine, tyrosine, L-DOPA, dopamine, I'm thinking that way. Which way is the CoQ10 coming from?  
Andrew: That's the way. That is. 
Denise: Okay. 
Andrew: Yeah. It's an accessory pathway and along that pathway is the benzoates. So, it just rings so true when you're talking about this.  
Denise: Isn't it exciting when you put it all together? 
Andrew: Yeah. 
Denise: It's really cool when you start looking at the pathways, and that's why I said to the listeners, for those that are familiar with the area, you're probably following me, going, "Wow." For those that aren't, you probably just thought, "My goodness she spoke about so many things. What is it that…?" 

Go and have a look at something with, you know, phase 1 and phase 2 detox and hormones. Because you'll be able to follow and go, "Oh, okay." And then when you start to think about, "Well, what is the area for that patient? Is it phase 1?" you know, "Do we want to do something to support that or is it phase 2 or is it oxidative stress?"  
You know, if they do have genetic variations, NQO1, and think about all those important endogenous antioxidants you can test for, too. So SOD2 or MnSOD. Superoxide dismutase is a very powerful endogenous antioxidant. Again, there’s a genetic variation that has a huge impact on how well that enzyme can work. If someone's got that, they need the cofactor manganese and so many of us are deficient in some of these trace elements and minerals. So that might, you know, stimulate you to say, "Well, I'm going to test manganese," or, "I'm going to give them a tiny bit of manganese," if you think their diet is deficient.  
So, yeah, there's a lot that you can look at that can help you then I guess tailor specific nutrients or, you know, foods or lifestyle changes to help that person sort of optimise their health more from a mechanistic point of view like detoxification or methylation or, you know, managing inflammation and then working their way up for them to get well rather than sort of coming from the top-down and saying, "Well, I might just give you this hormone." Of course, some people will need hormones. I'm not saying don't do that, but addressing some of these issues can really help people get to those underlying causes and start to balance these things. 
Andrew: The big thing for me though was you can try and learn a pathway or, you know, muscles, the nerves, you know, the 12 cranial nerves by mnemonics and you can learn these things by route. I get that. And they'll last in your memory a certain period of time and then they'll fade if you don't use them. But the real trick for me was having a meaning for a patient. That's where I remember something because it now has a reason to help somebody. 
Denise: And often the patients will resonate with what you're saying. You start talking about say, let's say, the antioxidant enzymes, and you say to them, "Well, you know, there's a number of things we can do if you are at increased risk for oxidative stress. Let's talk about the exercise you've done in the past. How have you responded?" And if they say, "I tried to do some HIIT training. I pushed myself to the maximum, and I was wiped out for days," well, we can say to them, "Well, actually your capacity to deal with oxidative stress, which is produced, you know, from ATP, the mitochondria, when you're exercising, is maybe not as good as your friend who did the HIIT training with you and coped really well. You want to start to have incremental changes in your exercise at a slower pace and then your body will adapt. Because you can upregulate or switch on these antioxidant enzymes through physical activity." 

And particularly the patients that I work with are often unwell so, you know, it does put a big burden on them if they have got issues with oxidative stress or inflammation, and they do push themselves. But it's being able to put all that stuff in context and then guide people with, you know, some lifestyle changes or diet. And, I mean I think, I'm obviously biased with genetics but, you know, they love it. They start to go, "Well, this stuff makes sense," or, "Oh, I've noticed that," or you talked to them about caffeine metabolism. For example, you know, CYP1A2 and they're like, "You're right. I drink coffee and I get palpitations or I get a bit jittery." And they'll be like, "That's why I can't drink coffee." I'm like, "Yes, because you are a slow metaboliser, your body doesn't break it down. Plus, you're exposed to this, this, and this, and the enzyme's busy trying to break down these environmental pollutants that you can't necessarily control your exposure to.” 
Andrew: What other genetic impacts? So we've mentioned COMT, the various CYP enzymes, glutathione transferase P1. Can I ask, by the by, P1, what does that stand for? 
Denise: So I think it's…are they Greek? You might be able to tell me. It's theta, mu, and pi, because there's no… 
Andrew: Ahh, pi one, right. 
Denise: Yeah, so it's pi 1 and, as I said, I gave the listeners my little trick, which I don't need it anymore, but once I started in genetics, what made me remember the ‘P’ was peripheral because most of these are predominantly found in the liver. 

Andrew: Got you. 

Denise: Whereas the P1, which is why it's particularly interesting when we're thinking about hormone metabolism because it is more in those reproductive organs compared to the liver. So you have mu, theta, and pi.  
Andrew: Yep. And the manganese SOD, MnSOD? What else? 
Denise: It’s also called SOD2. There are other genetic variations in antioxidant enzymes. There's catalase, glutathione peroxidase. Even from a nutrient perspective, you can come at this in relation to methylation, which is an important way of dealing with some of these…or, particularly the oestrogen metabolism. 

So thinking about the ones that most people know, MTHFR, you know, MTR, things like that that influence methylation homocysteine metabolism. Even PEMT. If you want to talk about methylation, one of my new favourite genes is PEMT, phosphatidylethanolamine methyltransferase. 

Andrew: Right?

Denise: You know PEMT? 
Andrew: Nope. 
Denise: It's my new favourite? So PEMT is my new favourite because I think it was last year a great review came out looking at PEMT with BHMT and MTHFD1. All of them influence choline which is a methyl donor as well. And when people are low in folate, they often turn to choline for supporting methylation which can be a problem if the choline is taken from your cell membranes where we have that phosphatidyl, the choline so we know that's important for the lipid membranes.  
So PEMT converts ethanolamine into phosphatidylcholine, and there's a genetic variation within PEMT that means that people don't produce that endogenous phosphatidylcholine as well. And therefore they rely moreso on choline from the diet, and choline comes… one of the best sources is egg yolks.  
Andrew: Right, and what about things like as a supplement? Would they benefit more from the use of things like phosphatidylserine or indeed phosphatidylcholine? 
Denise: Yeah, that's why it's my new favourite. because I can actually do something about it, and I'm just, you know… 
Andrew: How very interesting. 
Denise: This is probably only an N5, mind you, so I've really sort of been doing this since the end of last year. We're now in March 2018. So at the end of last year, when I read about this review, I really started paying attention to PEMT particularly in association with MTHFD1 and BMHT because I don't often look at genes in isolation. And all of them are linked with that choline metabolism. 

Andrew: Wow. 

Denise: But, particularly PEMT has a stronger influence. So I've actually done research on MTHFD1. I’ve published a paper linking that with fertility things. I wish I knew about PEMT 15 years ago, but I think PEMT has a stronger impact.  
And, what I did is I started putting these patients that, particularly if they had a sensitivity to eggs and I didn't think they were getting enough phosphatidylcholine in their diet, on the phosphatidylcholine. And as I said, this is not published. This is my clinical observation but these patients I've put on the phosphatidylcholine have reported they feel better.

And those of you out there would know with nutritional medicine, often we don't get quick results. I mean some people can have some B12 and feel great. But I had people coming back for different reasons with mental health stuff, whether it was gut things or fertility that there definitely seems to be an improvement. Mind you it might just this new, exciting wave. I might put the next five people on it and not get such good results. But at the moment, I am putting the genes together with the diet, and giving phosphatidylcholine and getting good results. So it's my new favorite. You got my information on my new favorite at the moment. Hopefully, it works for those out there that do this as well. 
Andrew: Just following on from what you spoke about earlier that you can have your genetic test, and that's static. Genes don't change. But you need to know a measurement of what the function of those organs or tissues are. What do you say about measurement? How should we be measuring and when?  
Denise: That is a great question. As I say to most people, the genetics aren't a standalone test. And if you do do them on their own, you really can only talk about risk or predisposition or susceptibility. 

So if someone comes to you and they say, "Well, you know, I think I'm oestrogen-dominant," and you might say to them, you know, "Why do you think that?" They might have already done testing. But if they haven't, you actually want to test and if you want to talk about why they might be oestrogen-dominant or you want to get to underlying factors that we've already discussed, you'll do the genetics.  
But, you actually want to be looking at hormone levels or, you know, if you think there is some kind of inflammatory thing going on or oxidative stress because these are the drivers of things like PCOS or endometriosis, or fertility issues. Then you would want to look for these things. You can do hormone testing obviously in the blood, the urine, and then even look for…you can do simple things like CRP to determine if someone has some systemic inflammation and there are even a lot of functional tests you can do looking at oxidative stress.  
So it really depends on the patient. But having those supporting tests really helps you determine if those genes are expressing what you may be concerned about. Or helping you have I guess a marker because what I love about doing that kind of testing is you've then got something to go back to. So the patient will come to you. You've done your genetics, and you say, "Well, you're at risk of this," or, "Your genetics have helped you target your treatment," and you say, "Well, I'm going to focus here first because this seems to be, you know, a genetic weakness." Perhaps let's say it's oxidative stress or one of those areas, or it's a nutrient area. We've mentioned about, you know, the choline. There's also a lot of genes related to vitamin D and things like that. 

So you might say, "Well, I'm going to focus here." And you've got some testing and you can say, "Well, this is your vitamin D level now," or, "This is your oxidative stress level," or, "This is your level of hormone metabolites." And then depending on the treatment and how far along that patient is, by the way, if they need to change diet and lifestyle, it can be a longer process. But if they've already done that, you might say, "Well, you know, I want you to introduce some of these supplements." Obviously, diet is first but we're assuming they've done a lot of that. So we're going to come in with, say, some of these supplements, and personally I don't give a lot of supplements at once because you don't know what's working and not working. So, it'll be sort of one thing, monitor how you feel.  
I'll give you an example. If someone comes to you and I haven't had a lot of these patients, but let's just say someone's healthy, they're not overweight, they're sleeping well, their diet's in order but for whatever reason, they've got, you know, high-oestrogen and in particular, the 4-hydroxy metabolites. Well, we might say, "Okay, you've worked on your gut. You've worked on diet. Let's really focus on the oestrogen. So we're further down the track with their health journey. I might say, "Well, let's look at something, you know, a supplement like calcium D-glucarate or something to help them excrete that oestrogen and then perhaps a supplement to encourage that CYP1A1. So something that's going to push that estrogen down the 2-hydroxy pathway."  
So you can start to really support that system, and then we'll say to the patient, "Well, I want to measure that again in 3 months to see if the treatment is working." So, having other tests allows you to measure and determine if your treatment is working. 

Often when it is working, the patients might...depending on financial situations, some of these things can be expensive. They may not want to do testing. They might just say, "Well, I feel better," or "I'm getting the results. I had a little … because of perhaps the oestrogen. I'm losing weight," or, "I'm not getting the mood swings," or, "I'm not getting, you know, sore and lumpy breasts." So, you can go on symptoms.  
I am a scientist. That's how I entered the field of functional medicine, so I do love to test. So I do a lot of testing with my patients, and most of them understand that. But you've obviously got to think about what that patient can afford and what's important for them. So I like doing a lot of testing because it allows you to have a baseline and allows you to actually have a record of things that are improving. Or it's not always easy, sometimes we don't get the results we're looking for. Then you can say, "Well, why didn't we? Why didn't this happen?" We need to start looking somewhere else because actually I didn't get it right and I don't always get it right. That's part of functional medicine. You know, the person is probably still getting better and improving their health, but you didn't get the result you wanted. Well, why not? What else is going on? And then that makes you put your thinking cap on, start asking more questions. Did we miss something in the history? Have we not addressed something?  
So I do do a lot of testing and that helps me then develop my treatment protocols. And as I said at the beginning, there's always the diet and exercise and lifestyle first, but then I do support that with all the supplements, and the genetics and the testing is really what guides those supplements.  
Andrew: Yeah, I'll add my own little caveat with regards to measurement because you have mentioned the 2:16 ratio plus the four series of oestrogens. And if you are going to employ supplements which sway the 2:16 ratio, please everybody test for the four series. They are a separate risk. And you may be lulled into a false sense of security by thinking that you're positively swaying the 2:16 ratio. But if you don't measure the four series, you may be doing really catastrophic damage to your patients. So always measure the four series of hydroxy and, if you can, methyl oestrogens as well. 
Denise: Great, great comment there. The testing that I use actually does look at the 2, the 4, the 16, and it gives me a level of the methylated oestrogen. 

Andrew: Yeah. 

Denise: So I can actually see which pathway it's going down, which will help me guide the treatment. But then also what's the methylation like. Now don't be confused. I've had some people say, "Oh, you know, I'm an under or over methylated based on some of this hormone testing." This is specific for the catechol oestrogens. It doesn't refer to methylation as a whole in the body.

Andrew: No. 

Denise: But if it is low, you do need to speak to them about, "All right, what's the folate you take? What's the B vitamin? Is there some sort of toxic load or stress that's, you know, pulling on that methylation pathway?" So that's really important.  
And I'm not sure if there's time, but I think you and I when we initially mentioned having this topic or this discussion, you told me about some research around DIM and I3C. And I have to admit I didn't read those papers you sent me but you mentioned some really important information about that because I do sometimes use these supplements. Do we have time to share that? 
Andrew: Well, look, my issue is with I3C is around A) stability of supplements. That's been shown to be an issue. People tend to try and say that there's something as well, you know, added into it to ensure stability, without any proof of that. 

But, once you take it in your body, you then got to look at condensation products. And I am…  there is research to show that I3C has A) effects on certain drug metabolism enzymes, the 3A4 in particular. So if somebody's taking a concomitant medication, let's say the OCP, and you have a pregnancy, where do you sit ethically, or medically, or medicolegally with that?  
So, it's more to do with the induction and control, but I stress the big thing is measurement. If you can prove that you're swaying the 2:16 in a favorable thing as well as the four series, then go along with whatever you're doing with my blessing. But if you can't or you don't know, then you're doing the wrong test. 
Denise: You may have noticed that I didn't say what I was using for the CYP1A1 because I couldn't remember our conversation. I thought, "Hmm, Andrew has some strong information on that and good research papers I haven't looked at." But I'm glad that you shared that with me. I will go back to those papers. 

I don't often give those supplements. I think hopefully I stressed it throughout the talk that, you know, I think if people really are working on the gut, and nutrition, and the basics, all the stuff we spoke about at the beginning of this. People will start to get well, and it's not just about their hormones. You know, it's reducing inflammation. It's really getting them well from the ground up. But there will be times where, you know, with certain patients, and I have had a few, they had done all these things and then you do really need to get in there and target particular supplements. So that's really interesting. 
Andrew: I should also add there, there is a… you can also give the sulforaphane from broccoli sprout extract. But again it's got to be a stable product which will release glucoraphanin. So it’s got to be… stability is a real big issue. 
Denise: And the good thing with the sulforaphane is it upregulates or switches on a lot of these detoxification enzymes. 

Andrew: That’s right. 

Denise: Yes, very powerful when you do get the right supplement when that is what is needed in that patient. 
Andrew: Denise, I love the expansive knowledge that you have and how you bring it back down to a practical level with patients. You know, it's obvious that you've treated a heck of a lot of patients and seeing what works and what doesn't but also seeing the natural variation of our genes and what lies within. So, I thank you just from the bottom of my heart for taking us through a tiny snip of our genetic play with regards sex hormones. Thanks so much for joining us on FX Medicine today. 
Denise: Thank you for your time. I hope that everyone enjoys that as much as I did, and I hope to hear from you soon. Bye. 
Andrew: This is FX Medicine, I'm Andrew Whitfield-Cook.  

Additional Resources

Dr Denise Furness
The SCOPE Study
The PAPO Study

Research explored in this episode

Aggarwal BB, Ichikawa H. Molecular Targets and Anticancer Potential of Indole-3-Carbinol and Its Derivatives. Cell Cycle. 2005 Sep;4(9):1201-1215
Bradlow HL. Indole-3-carbinol as a Chemoprotective Agent in Breast and Prostate Cancer. in vivo. 2008;22:441-446

Rogan EG. The Natural Chemopreventive Compound Indole-3-carbinol: State of the Science. in vivo. 2006;20:221-228

Reed GA, Arneson DW, Putnam WC, et al. Single-dose and multiple-dose administration of indole-3-carbinol to women: pharmacokinetics based on 3,3'-diindolylmethane. Cancer Epidemiol Biomarkers Prev. 2006 Dec;15(12):2477-81

Anderton MJ, Manson MM, Verschoyle RD, et al. Pharmacokinetics and tissue disposition of indole-3-carbinol and its acid condensation products after oral administration to mice. Clin Cancer Res. 2004 Aug 1;10(15):5233-41

Crowell JA, Page JG, Levine BS, et al. Indole-3-carbinol, but not its major digestive product 3,3'-diindolylmethane, induces reversible hepatocyte hypertrophy and cytochromes P450. Toxicol Appl Pharmacol. 2006 Mar 1;211(2):115-23. Epub 2005 Jul 25

Gao X, Petroff BK, Oluola O, et al. Endocrine disruption by indole-3-carbinol and tamoxifen: blockage of ovulation. Toxicol Appl Pharmacol. 2002 Sep 15;183(3):179-88

Other podcasts with Denise include:


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