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Clinical Interpretation of Oestrogen Metabolites with Beth Bundy

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Clinical Interpretation of Oestrogen Metabolites with Beth Bundy

We are well aware of the normal, beneficial actions of oestrogens for both women and men, but what about negative actions? And is this a component of their normal biochemistry? Or are the negative actions more to do with aberrations in how we biotransform these vital hormones?

Firstly, notice there's PLURAL when referring to oestrogens. They are not a single entity and the various oestrogens have multiple, even contradictory actions. Moreover, how does the body handle these powerful hormonal messengers once their job is done? Certainly, the evidence on oestrogen metabolism with relation to hormonally-driven cancers is far from unambiguous!

Today, we speak with Beth Bundy, our regular guest on FX Medicine Podcast, to discuss just what's going on with oestrogens, what the evidence suggests may be going wrong with their metabolism, what this means for patients whose risk may be elevated, and how we can best help patients to minimise this risk.

Listen in as Beth takes us into the tangled web of oestrogen metabolism and unravels some of the controversial research pointing to, and away from, oestrogen metabolites and cancer risk. 

Covered in this episode

[01:11] Welcoming back Beth Bundy
[02:12] Types of oestrogen and their roles in the body
[06:43] Oestrogen metabolites and how they are metabolised by the liver
[12:15] How genetic testing factors in
[14:24] Functions and actions of the oestrogen metabolites
[18:01] Breast cancer and 4-hydroxy metabolites
[22:30] The 2:16 hydroxy ratio and cancer risk
[27:13] Testing for oestrogen metabolites
[31:51] Therapeutics to modify oestrogen metabolism
[44:01] Additional resources and closing remarks



Andrew: This is FX Medicine. I'm Andrew Whitfield-Cook. Joining us on the line again today is Beth Bundy. She's a qualified naturopath of over 19 years, specialising in integrative and functional medicine. Beth worked previously as technical consultant with PathLabs, one of Australia's original functional pathology companies and currently trains health practitioners nationally as a clinical consultant at NutriPATH Integrative Pathology Services. Beth also works as a functional medicine practitioner in a busy and highly successful integrated medical practice. Welcome back to FX Medicine. Beth, how are you?

Beth: I'm very good. I'm back again.

Andrew: We're back again, and we're talking about hormones. We're talking about oestrogen metabolites this time, clinical interpretation. 

Beth: Yes.

Andrew: I’m going to warn our listeners right from the get-go, we are going to be scratching the surface of this. There is so much more to this. It's intertwined with so many other hormones and interlinked.

Beth: That's right. And once I get started, hang on to your hats, guys. There's a lot to say.

Andrew: Well, first, let's define and differentiate oestrogens from their metabolites, because I remember myself getting caught up with 17-beta-estradiol because that's all I knew. And I argued back and forth because I was coming from this reference point which was incorrect.

Beth: Well, we'll talk like lay-people, or not lay-people, but just how ordinary people speak. And let's just boil it down to, okay, so what's easier to remember, simple words. So let's just remember that we have three main oestrogens: oestradiol, which forevermore we shall call E2; oestrone, E1; as well as oestriol, E3. So I'm just going to call them E1, E2, and E3, if everyone's okay with that. 

Now, we know that oestrogen play an important role in our productive tissues, healthy bones, they also help with neurotransmitters in the brain and keeping our cardiovascular system healthy, so that's all lovely. But then they also have different nuances of what those main three do.

And I want people to remember that E3 is the major oestrogen in pregnant women, and it's also usually the most abundant oestrogen in the urine of women when we measure them. But predominantly, you should see that more elevated with pregnancy, more than the others. It's also been examined for its role in bone and lipid metabolism as well as a, they call it a neurosteroid, which just basically regulates neurotransmission and it is neuroprotective. And it's also considered less oestrogenic than the other, E1s and E2s.

And E2 is seen as the more biologically active oestrogen, and that comes from ovarian cells and is regulated by FSH. Now, in men, because remember that men do have oestrogen as well. So in blokes and prepubescent...

Andrew: Pubescent.

Beth: ...children. Yeah, thank you. E2 comes mainly from androgens. In menstruating women... So we've got our pre and post-women when we're talking about oestrogen. So in our premenopausal women, E2 comes predominately from testosterone, metabolised from testosterone, with other conversions of testosterone in peripheral tissue. 

And the concentration of this peaks around mid-cycle, around ovulation of course. Then they decline. There's a small or little rise in the luteal phase, but then in postmenopausal women, most of the E2 that is still made comes from E1. So E1 and E2 can kind of cross-pollinate from each other. We really need pictures again. Can everyone see me cross-pollinating E2 and E1? I'm drawing a diagram for people.

Andrew: I'm going to put some diagrams up on the FX Medicine website for people.

Beth: Yeah. It's a flow. It's a pathway that this becomes this, becomes this, sort of thing. And then E1, again, is reversibly converted to E2 through a 17 beta-hydroxysteroid dehydrogenase. Let's just say it's an enzyme. 

Now, circulating E1 levels are relatively high when we're born in both men and women. It decreases postnatally and then increases again during puberty. In pre-menopausal women, E1 is predominantly produced by the conversion of androstenedione in the ovary, which androstenedione is another hormone above testosterone in our pathway. 

And these concentrations peak before ovulation, similar to E2. And in post-menopausal women, E1 becomes the predominant oestrogen. So E2 more in the menstruating women and E1 post-menopause. And in these ladies and men and children, E1 is largely produced, again, by the conversion of androstenedione in peripheral tissue, all right? So not the ovary.

So then, regarding the oestrogen metabolites, which come from E1, E2, and E3, these are metabolised by three competitive pathways involving irreversible hydroxylation by the cytochrome P450 or your CYP genes, or CYP enzymes, sorry. You've got CYP1A1, 1B1, 1A2. They're a bit like bananas in pyjamas. 

And then we have...E1 and E2 are converted to catechol oestrogen, which are your hydroxy, your 2-hydroxy-E1, your 4-hydroxy-E1, the 2-hydroxy-E2, and your 4-hydroxy-E2. So oestrone, and oestradiol get the 2 and 4-hydroxy version. And then we have the 16α-hydroxy, which is then moved on to make E3, which we talked about before. 

So the catechol oestrogens, which from here on out, I will call the hydroxys are further metabolised and methylated by the COMT enzyme, the Catechol-O-methyltransferase to your methoxyoestrogen. So now, you're 2, and 4's become to 2-methoxy and 4-methoxy E1 and E2. So there's a lot of, you know, kids in the house when it comes to, you know, oestrogen metabolites.

So what we have to remember, too, is these hydroxy oestrogens are constantly being formed and inactivated by methylation via COMT, so this is one reason why it's important to have good methylation, good COMT processes. The hydroxys and the methoxys are then sulphated and glucuronidated in the liver, which then increases their solubility in the blood, their clearance rate, and elimination in the urine and the stool. All right? So I want people to remember it doesn't just come out of urine. It comes out in the stool as well.

Now, the liver's ability to properly metabolise is what's really been found to affect the risk of breast cancer or cancers in ladies, and this is because it depends on which metabolic pathway predominates. Too much of a certain oestrogen metabolites, say the 4-hydroxys, can build up and high levels of the 4-hydroxy - and to a lesser extent, sometimes the 2s, especially if they have decreased methylation - this is highly associated with increased breast cancer risk, as those hydroxy oestrogens can oxidise to highly reactive quinones. And these, especially with predefined levels alone, can bind to DNA and cause mutations that can lead to cancer.

Andrew: Okay. We've spoken, you know, majorly about the liver. Is the conversion only done in the liver?

Beth: No. So oestrogens are metabolised in two phases: phase one, which is your hydroxylation, and phase two, your methylation. In addition to methylation, the parent oestrogen… So when we talk about parent oestrogen, that's when we're talking E1, E2, E3. And hydroxys, as I said, are conjugated to make them more soluble and excreted in your poo. 

But the first metabolism of oestrogen, which is the hydroxylation by the CYP1A1 and 1B1, they're mainly expressed in liver and in breast tissue. But ultimately, since most CYP enzymes are expressed in the liver, the majority of the metabolism of oestrogens is in the liver. But we have to remember that it does happen in other tissue.

But also I want to say the major metabolite of E2 or 2-hydroxy-E2 is mainly catalysed by CYP1A2 and 3A4 in the liver. But the banana and pyjama 1A1 is an extrahepatic tissue. 1B1, the other banana, is highly expressed in oestrogen target tissue, so that's where, like I mentioned, breast, but also ovary and uterus and that one specifically catalyses 4-hydroxy. And when 4-hydroxy is properly methylated... So again, just reiterating that we need to have those methylation pathways up to scratch or we need to assess those when we're also looking at aberrant oestrogen metabolites.

So if 4-hydroxy is properly methylated to 4-methoxy, it's relatively benign because it's easily eliminated and the risks are low. The problem is when methylation is inadequate, and there becomes a buildup of this 4-hydroxy. And interestingly, equine-based oestrogens, so your replacement therapies, do increase this metabolism into 4-hydroxy, so that's, again, something to be mindful of when you're treating women on that. And the 4-hydroxy, remember we said that's the problem that can move into the quinone forms, which increase risk for breast and endometrial cancer risk.

Andrew: Yeah. And hyperplasia. I mean, this is the whole issue of Tamoxifen, is that it's a selective oestrogen receptor modifier in the breast. But unfortunately, you have a runaway effect in the uterus, and this is where the further issues come down the line. It's activated. It's a 4-hydroxylation issue. So we'll get to that later when we're talking about how we can intercede, how we can help people with this. 

But I think it's really interesting, this interplay with our genomics. That this is one area where further research can lead to helping people who are in a subset. And this might also explain why when you look at population studies, some of these oestrogen metabolites studies, they don't have a really strong story. And so medicine will go, "Therefore, it doesn't exist." Well no, it does exist, but only in this sort of population who have got the issues.

Beth: Yeah. There's quite a lot of subgroups that it is positive for and then larger groups that it's not. So, yeah, it all gets a bit messy, and it's all a bit confusing...

Andrew: Oh, absolutely.

Beth: ...when we talk about the metabolites.

Andrew: Yeah. To me, I was so sceptical at the beginning about, you know, having your gene SNPs tested and what that was going to mean, and people going down paranoid pathways, that they've got a real issue. But now I just see it as it's a tool. It's a clinical tool that's like a background baseline, that if there's another issue surfacing, you might want to look at that and go, "Hmm."

Beth: Yeah. Absolutely. And this is where it's not just the COMT, you know?

Andrew: Yes.

Beth: That can make..."Oh, it's your CYP genes, too," so when we talk CYP enzymes or the bananas in pyjamas, but it's also their genes that are potentiating that. So this is why it's not so easy, and even when people do a test on metabolites, and then they treat it and then they don't get the results they want, it's not just as easy as throw DIM at something, and everything will be better...

Andrew: No.

Beth: ...because of all these other things that we're talking about. Yeah. So maybe we should go back into the metabolites a little bit more so.

Andrew: Let's do that. So let's look at the functions and the actions of the, mainly the E2 metabolites.

Beth: So, as we said before, or as I said before, the 16 and the 4 are relatively more oestrogenic and have more toxic potential than the 2-hydroxy, which I'd consider to have little oestrogenic or even anti-oestrogen properties in some parts. 

So there's actually some evidence from cell studies using oestrogen receptor-positive breast cancer cells, that 2-hydroxy-E1 and E2 inhibits cell growth and proliferation. And that the 2-hydroxy metabolites have been associated with normal cell differentiation and apoptosis. So this is probably where this whole "2-hydroxy is a good oestrogen" has come from. 

And a high rate of clearance, if you've got a good COMT enzyme, leads to a lower potency in the oestrogen target tissue, your breast, uterus, etc., and then going through the methoxys. So if all that works well, that has been shown to also inhibit cancer production by suppressing cell proliferation and angiogenesis, which is great.

With the 4-hydroxy, that has…mainly is the big baddie for the cancer potential because it has this ability to cause DNA damage by forming these depurinating adducts, which cause oxidative damage and can initiate cancer. It has also shown that ratios of the DNA adducts to their parent oestrogens, so the E1, E2, E3 were significantly higher in women with breast cancer. And obviously, if the COMT enzyme is inhibited, then you're going to have more 4-hydroxy as well. So we've got to make sure the methylation is pushing that 4-hydroxy group to the 4-methoxy, so it's inactive, so to speak.

Your 16α-hydroxy is another potential tumour initiator. Animal studies have shown that high urinary concentrations of the 16α-hydroxy increased proliferation of the memory cells, oncogenic expression, and breast tumour incidence. And another study on human breast tissue found that 16α-hydroxy levels were eight-fold higher in breast cancer of the lobular duct, than nearby fat tissue in the breast. 

And these sorts of things can be elevated through obesity, hypothyroidism, pesticide toxicity, or any kind of...most environmental toxicities, excess omega-6 fatty acids, and general inflammatory cytokines branching around the body. So the 2 is considered safer, 4 not so much because of the DNA mutation potential, and the 16, we don't want that high.

Andrew: How strong is the evidence for cancer causation and conversely, protection when you're looking at the supplements and the various ways that we can protect against for 4-hydroxylation, for instance?

Beth: There's quite a bit of... It was when I started digging around studies. There are quite a lot of studies, and they are somewhat contradictory, or… It's a bit mixed, yeah? 

But firstly before I say that, I want to say that most of the research on breast cancer and the oestrogen metabolites on pre- and post- women really can't be extrapolated to women on any form of oestrogen replacement. Most of this, the way we interpret any results of testing these metabolites is on women not taking oestrogen therapy, right? 

Andrew: Yes.

Beth: Because it's more about how on a baseline, how that directly or indirectly affects oestrogen metabolites. So most of these studies are on people not on stuff, yeah?

Andrew: So the caveat there is, "Don't necessarily use this for women taking oestrogen replacement therapy. This is not necessarily going to protect them."

Beth: No, because it’s…then we bring in sex hormone-binding globulin and all those, you know. It changes those of quantities of what we're producing and excreting. 

Andrew: Yes.

Beth: So, now, it's known that women not supplementing with oestrogen with high level of 4-hydroxys are associated with breast cancer. But the controversy is still persisting regarding that the 16α-hydroxy and its relationship to the 2, so this 2:16 hydroxy ratio. 

So previously, some previous research decided that a low 2:16 ratio was associated with increased breast cancer risk. So having a low 2 and a high 16. However, more recently, researchers said that a high 16, which gives you your low 2:16, is associated with a slight increase in breast cancer risk in premenopausal woman, but a lower risk in postmenopausal. 

So practitioners need to be aware when they're reading results, they need to interpret it depending on the menopausal status, yeah? 

Andrew: Oh, yeah.

Beth: Because it is going to change what that may mean.

Andrew: And also, when you're looking at breast cancer in totality, which fraction of breast cancer are we looking at? What about the oestrogen-negative-receptor? And what about the oestrogen and progesterone negative receptor cancers?

Beth: There's actually been a positive association of the 2-hydroxy and the ratio among women with the oestrogen or progesterone-negative...

Andrew: Negative? Okay.

Beth: ...tumours. Yeah. So high numbers for either of the 2:16 ratio were associated with triple the relative risk for this subgroup. So when we're talking about the subgroups of breast cancer patients, because they use...that study was from one using blood samples, so blood samples not urine, blood samples from the nurses' health study. 

And so, they compared 2:16 levels in breast cancer patients and controls. And at that time, neither oestrogen metabolite appeared to change breast cancer risk. Nor did the ratio between the two metabolites make a difference. However, the oestrogen or progesterone-negative tumours, it did have a...

Andrew: Oh, that's interesting.

Beth: ...an association. So, yeah, this is why it's all kind of, oh, you know, tricky. So...

Andrew: We certainly haven't got to the end of it. We're really at the beginning of discovering, or let's say midway through, discovering what these metabolites do in their function. 

But I think what we've got to be mindful of as practitioners is that we're dealing with a patient who has a personal history. And in all cases, the family history and a relevant medical history are the dominant things that we've got to take into consideration.

Beth: Yes, very much so. That's...

Andrew: Can't treat a test.

Beth: Exactly. And I think this is where this whole just 2:16 is missing a large part of the story. So, you know, another study tested this, "2 is good, 16 is bad" hypothesis, but they studied this in relation to endometrial cancer. And, they found that there was no association observed for the 2:16 ratio in endometrial cancer, which was interesting. 

And another meta-analysis, and I think they had like 1,100 cancer patients and 1,800 controls. They had a non-significant association, suggesting a possibly weak protective effect in premenopausal, but not in postmenopausal.

Andrew: Got you.

Beth: And again, this is studying bloods. So in a lot of these studies, they look at blood. Basically, they were saying the circulating metabolites are not associated with breast cancer risk.

Andrew: I think part of this story is that it also disses, once and for all, the myth of E2 dominance, of oestrogen dominance. We've just got to get rid of that term because you can see risk in people who have, in women especially, who have lower oestrogen levels relative to progesterone, which is normally what they're talking about, but it can still cause a problem. So it's not necessarily an oestrogen-dominant issue, but it certainly can be an oestrogen-driven issue. 

What about more recent evidence with regards to these oestrogen metabolites?

Beth: Well, I found one from earlier this year, so in March 2018 and they studied over 1,800 pre- and post-menopause ladies, and their final wash-up of this was that higher 2:16 ratio in premenopausal women was suggestive of reduced breast cancer risk overall, even for oestrogen-receptor-negative.

Andrew: Wow. Okay.

Beth: Yeah. And in postmenopausal women, 2:16 was unrelated to breast cancer risk. However, the association between 2-hydroxy and risk varied by body mass, so, you know, weight comes into it here, clearly. And their final comments were that premenopausal urinary 2-hydroxy to 16α-hydroxy oestrogen may play a role in breast cancer. However, larger studies are needed, more studies, and it says then “our findings do not support reduced breast cancer risk with higher postmenopausal 2:16 hydroxy oestrogen overall, although obesity may modify associations with 2-hydroxy.”

Andrew: Right.

Beth: So the association between the circulating oestrogens and breast cancer has been pretty well established as the oestrogens with their whole, but it's the oestrogen metabolite investigations that seem to be mixed from what we have kind of done in the past.

Andrew: What about colorectal cancer? I read some research, I think it's from 2013 that said that oestrogen and oestrogen metabolites, having been initially protective against colorectal cancer, might increase proliferation of colorectal cancer once it is set up, once it's developed. So there's an initial protection, and then it says, "Well, to hell with you." What's your opinion of this, though?

Beth: Well, one I found from 2015, and that was done on over 15,000 postmenopausal women, so postmenopausal. We always have to differentiate that. And they came to the conclusion that circulating oestrogens and their metabolites were unrelated to colorectal cancer.

Andrew: This is certainly not the end of it. There's so much more to delve into, isn't it? Pre and post, what sort of cancer?

Beth: Yeah. Absolutely. And, you know...

Andrew: And what else is going on. Like, I think this paints a perfect picture that there's multiple factors with regards to initiation of any cancer. But when we're thinking about this issue of colorectal cancer, we've got to take into account their diet, their lifestyle, their methylation, are they obese? You know, you can't just look at oestrogen metabolites in its singularity and expect to get a clear picture.

Beth: Absolutely.

Andrew: Given that it's one piece of the jigsaw, how do we test for these oestrogen metabolites? And you were mentioning blood earlier, what about blood and how accurate is urine testing versus blood?

Beth: Right. So, good question. So oestrogen and its metabolites are present in the blood, in free, unbound form or bound form to your steroid-binding proteins like SHBG, as well as your conjugate. And concentrations of the free form in blood, especially like in postmenopausal women, is in the centigram per millilitre range. 

Now, I had to look up centigram because I'd never heard of it, and it is the...it puts them in the lowest concentration of an analyte that can be determined with any accuracy. And to put it into context, you need 1,000 centigrams to make a picogram, and you need 1,000 picograms to make a nanogram. Or let us just say, we need 1 billion centigrams to make 1 microgram. So you can see it's...

Andrew: Small.

Beth: ...not even a smidge or a tad. It's an infinitesimal amount to measure in blood, but... So a lot of studies that we can read about are about blood, but they're done in research situations. And studies on urinary oestrogen and metabolites in breast cancer risk on premenopausal women have even suggested that urine is not as relevant as blood to breast tissue exposure. 

So this is the other thing we have to think about when we're just measuring urine, is how is that relevant to what's going on in the body? You know? So they're saying, "Well, it's not as relevant... Urine is not as relevant as blood when we're thinking about what's happening in the breast.”

And another study showed that average levels of E1 and E2 were significantly higher in breast tissue, than it was in urine, and that both the 2 and 16α- hydroxy pathways were less represented in breast tissue than in urine. So, you know, there's more in urine than in breast about your hydroxys. And there wasn't much of the 4-hydroxy detected in breast tissue, but it was in the urine. So we have to be careful here that we're not getting, you know, swayed by a result, which is not necessarily reflective of what's happening in the breast tissue.

Andrew: In the target tissue. Yeah. Yeah.

Beth: Yeah. Yeah. But they did find that the 2:16 ratio was similar in urine and breast tissue. So the ratio may be useful to have some idea rather than harping on the 2, 4, and 16 as separate entities, yeah?

Andrew: Right.

Beth: But ultimately, urine is the best and easiest for metabolites mainly because it's really the only commercial test available. Because the blood is more, for research purposes. So urine is beneficial for some part of the story, but, of course, we can't use it as the only piece of the puzzle. 

Andrew: Yeah, yeah.

Beth: None of these tests are the be-all and end-all. And the other thing is when they did a study on, when do you collect this? When do you collect the urine...?

So they did a study where they tested early follicular, mid follicular, periovulation, and mid-luteal, and this is in premenopausal women, obviously. And they found that the 2:16 ratio and the 2:4 ratio were significantly increased during around periovulation, so after ovulation and mid-luteal. So, you know, that's going to give us our strongest reading then around the luteal phase. 

So, you know, generally, you would say, "Well, if you want the biggest number to read...," which is helpful because sometimes, they don't really say much, then you do want around that luteal phase of menstruating women. And with menopause, you can do it anytime, clearly, because they don't have a cycle.

Andrew: Okay. So when we're talking, given that we want to intercede and we want to modify the metabolism of oestrogen, the ratios, what agents do you use? What agents do you advocate? What have you seen results with?

Beth: Because of all the studies that are random, you know, I went swimming in them to talk to you today, there doesn't seem to be enough data to confirm the role of oestrogen metabolites as true predictors of breast cancer. But we can say that any intervention which helps reduce circulating levels of the primary oestrogens is something to consider because they then become hydroxy and methoxy and this is going to help lower risk. 

So, first and foremost, I think we need to remember that we need to look at the parent oestrogen as well as the metabolites, not just go for the metabolites and that's your answer, which I know that, you know, people do, practitioners do. But there are some things we can certainly look at.

2-hydroxy levels are affected by genetics and lifestyle factors, including smoking and weight. We mentioned weight before. And increased adiposity has been associated with a reduced 2-hydroxy whereas a higher 2-hydroxy has been found in lean women, including those with anorexia, interestingly, or those who do a lot of frequent strenuous exercise. 

However, exercise generally doesn't increase the 2:16 ratio except in women with very low initial 2:16 ratios. So, losing weight and exercising does seem to shift the production towards the 2-hydroxy. I have got some bad news though regarding wine and caffeine. Like, everyone, take your...

Andrew: No.

Beth: Exactly. So depending on what time you're listening to this, take your last sip of your...finish that glass and finish that mug. Coffee intake has been associated with a higher 2-hydroxyoestrone and hydroxyoestradiol. Decaffeinated coffee was not associated with the 2-hydroxy pathway, but more so with the 16 and E3, which I thought was interesting. Progesterone, iodine, and vitamin D have all been shown to increase the 2-hydroxys and decrease the relative concentration of 4-hydroxy.

Remembering that our 2-hydroxys are created by the CYP1A1 banana, and this is activated by the phytochemicals down in the cruciferous vegetables, you know, your cauliflower, your broccoli, your cabbage, and kale. And also, iodine, progesterone, and vitamin D, you know, is worth considering, if the 2 is low or relatively low to the 4, yeah? So you can either assess those levels or just suggest people eat more leafy greens, which is always a good start. 

Also, fibre, soluble fibre, more specifically, has found to help with the 16α-hydroxy levels. And we mentioned before about COMT. We need to make sure that there's enough co-factors for your COMT enzymes to work, so that's your B6, B12, folate, betaine, and the likes.

And remembering glutathione, right? Because that's so important in the detox pathways, especially the quinone oestrogen. And, you know, a lot of our patients might be on numerous medications, hormone therapy, they've all got exposure to environmental toxins, they might be smoking, all of these things affect glutathione. Vitamin C is necessary to help glutathione, as is selenium. So all of these things need to be put into the mix when we're talking about metabolites. 

And also, because the 2:16, you know, has been talked about with breast cancer risk and what have you, and many people know about the cruciferous vegetables because they have things like the indole-3-carbinol and Diindolylmethane, which is your DIM. But now the quandary is, well, because the 2:16 and the metabolite is so controversial, I don't know what that means for IC3 and DIM. You know, I don't know if you've got any thoughts on that, Andrew.

Andrew: So, my issue is with indole-3-carbinol as a controlled agent. One, when you take I3C orally, you don't measure I3C in the blood. So the actual activation of I3C is what you're hoping can control the metabolites with. And the problem is, depending on the stomach acid, depending on digestion and a number of other factors, you can't necessarily control what it condenses to, because I3C is a monomer. It wants to condense. 

What you want it to condense to is DIM, and that's the major in vivo by-product that's measured. The problem is, and this was illustrated in a very old study by, I remember the authors, Zhu and Conner, in, I think it was 1998, and what they were talking about is, the problem is indolocarbazole. If you get that up-regulated, condensation product, then you're going to increase the four series of oestrogens, depending on the research that was cited, dogs or humans, you know, between 4 and 10-fold. That's bad.

So I remember talking...or there was a...this is a blog that I did sort of...and Christine Horton chimed in, and she said this is why she prefers broccoli sprout extract, because she prefers that it's a controlled thing, a balanced thing with other beneficial agents in there, not just one knife, if you like, of DIM versus I3C. 

So my product, and, sorry, my other problem with indole-3-carbinol is that it up-regulates CYP3A4, and therefore, you've got multiple drug detoxification issues. So, in what patient are you going to use this? Now, if you're sure, fine. But if you're not… I think the be-all and end-all with all of this is, you've got to do a test if you're going to use these agents at baseline and at, say, two, three months to show a treatment difference. And if you can't show a treatment difference or if it's going the wrong way, then for goodness sake, stop. But in no case should you be resting on either of these agents as the magic agent to go with. They're never the magic agent.

Beth: Yeah. And that's what I find that when I'm talking to practitioners, that seems to be the go-to. Soon as you say, oestrogen metabolites, it's I3C and DIM. And I agree totally with that, the conversion of I3C, we can't measure it in the blood, and it does turn to that indolocarbazole, which is...it's a dioxin-like molecule and dioxin is poison, you know. So, yeah, it is problematic, and so I personally don't jump to that as my first port of call.

Andrew: The first port of call should always be things like exercise and diet. What about, you mentioned vitamin D before, what about midday sun exposure for 5 to 15 minutes? I mean, yeah, what about, as you said, fibre? I mean, these should be the go-to things.

Beth: Yeah. And like you say, they're not the be-all and end-all, and that's not going to fix all your problems. And this is probably when people are using I3C, why sometimes they do a baseline and treat and then are saying, "Oh, the results are worse or haven't moved," and it could be because, well, you're not converting to DIM, your converting to the other...

Andrew: What about COMT?

Beth: ...the by-products.

Andrew: What about your methylation issues? What about...? We're not even talking about these today, but there's so many other... You mentioned the neurotransmitter sort of action. 

Beth: Yeah.

Andrew: I think the whole thing with any hormone is it's not a hormone in isolation. It's a hormone in a complicated network of interplay, and you've got to think really seriously about that when you're going to upset it.

Beth: Yeah. And bottom line, good, old practitioners love the gut. You know, this is the other thing we've got to consider is...

Andrew: I think this is... Yeah.

Beth: ...apart from what they're eating, is the microbiome because, again, they've done some studies and found that the levels of urine oestrogens and metabolites in men, and postmenopausal women was strongly associated with faecal microbiome richness and diversity.

Andrew: Yeah. So, there's another issue, what then influences that? Exercise, sleep, vegetables.

Beth: Yeah. Exactly. But interestingly, when they measured the premenopausal women, so the menstruating ladies, because they were collected across various times of the menstrual cycle and were highly variable, they've come up and said, "Well, that's unrelated to, their oestrogen levels are unrelated to the microbiome."

Andrew: Oh, really?

Beth: Yeah.

Andrew: Unrelated?

Beth: Unrelated. It was all too hard. It was all too variable so...which we know the microbiome varies, you know, it can vary...

Andrew: Dramatically.

Beth: ...on a day-to-day basis so... Yeah. But it's... All of those things need to be put in, too. And it is a bit like when people say that, you know, sometimes the way we're going with our supplements, we are just a natural doctor who is still prescribing pills and forgetting the tenets of, like you said, sleep, diet, laughter, sunshine, all those sorts of things.

Andrew: And the naturopathic axiom of "treat the gut and the liver."

Beth: Yeah. Absolutely. And I think we have to remember too, that as naturopathic practitioners we're often ahead of the curve in translating new theories or scientific literature and we can be an early adopter, which has merits, and sometimes we find help...to help our patients when regular medicine has yet to develop a drug or a treatment. And because we limit our intervention to relatively non-toxic, low-risk therapies, sometimes I think we have a low requirement of proof before experimenting with new ideas. So it's sort of like, "Oh, well, it might help. It won't hurt you. Let's have a go."

But what we need to do is we can be an early adopter with a new idea, but if it doesn't pan out… So if you keep using I3C and you're not getting changes, maybe you need to let it go, and see what else. And especially I think, today we have shown that there's not an absolute, linear decision about cancer risk and these hormones, oestrogen metabolites. 

So it's a lot more complex than we first thought. So I think we need to kind of step away a little bit about a test result equalling cancer or not, and kind of look at all the other things that play a part in how that result came to be.

Andrew: Well, we've spoken about a heap of resources and papers, which, you know, are still controversial and sometimes contradictory. What other further resources are there, Beth?

Beth: Well, I can pass on all the study papers that I looked at and that I mentioned today, and we can put that up on the website.

Andrew: We'll definitely put those up on the website.

Beth: So people can read, you know, keep themselves awake at night reading about it.

Andrew: Or put themselves to sleep and get some...

Beth: And put themselves to sleep. Yeah.

Andrew: And benefit their oestrogen metabolism.

Beth: Yes, and maybe they should just have their last sneaky wine and coffee before they get stuck into their party cruciferous vegetable.

Andrew: Well, we've certainly covered a lot. We've covered, you know, morning exercise and diet are, obviously, the givers of health. We should get some vitamin D, preferably at midday, only for a short amount of time, though. And we should include those naturopathic axioms of treating the gut and the liver and making sure that we're getting adequate fibre, which is a lot, and that we should also be cautious of bananas. Thanks very much, Beth.

Beth: Absolutely. Thanks, guys. Thanks for listening.

Andrew: This is FX Medicine. I'm Andrew Whitfield-Cook.



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Beth Bundy
Beth Bundy is a qualified Naturopath with over 15 years specialising in integrative and functional medicine. She plays a role in the clinical training programs and educational initiatives to offer the most advanced clinical tools available to prevent and treat the underlying causes of disease. Beth obtained her Bachelor of Health Science at the Southern School of Natural Therapies and lectured in both Nutrition and Food as Medicine for several years at the Australian College of Natural Medicine (now Endeavour College). She has worked as Technical and Practitioner Consultant with one of Australia’s top functional pathology companies where she was mentor here and overseas by some of integrative and anti-ageing medicines foremost speakers. She has operated her own business and currently also works in a busy and highly successful integrative medical practice which specialises in adrenal and hormonal issues, along with weight management and heavy metal detoxification, with a strong emphasis on functional pathology to assist clinical treatment. Additionally, she is a Clinical Consultant at NutriPATH Integrative Pathology Services. Beth provides friendly and expert clinical training and support to assist practitioners in choosing the most appropriate test profiles, interpreting test results, and offering guidance on treatment approaches.