11. Genistein

[00:00:00.330] - Dr. Gordon
Should all older women on hormone replacement therapy also be on genestein so that it blocks too much estrogen going to their breasts or their uterus? That's my question number one, which inspired question number two? Should it be used as an antiaging intervention for everybody?

[00:00:24.610] - Dr. Lemanne
You you have found your way to the Lemanne Gordon podcast where Docs talk shop. Happy Eavesdropping. I'm Dr. Dawn Lemanne. I treat cancer patients.

 [00:00:43.850] - Dr. Gordon
I'm Dr. Deborah Gordon. I work with aging patients.

 [00:00:47.570] - Dr. Lemanne
We've been in practice a long time.

 [00:00:50.030] - Dr. Gordon
A very long time.

 [00:00:51.630] - Dr. Lemanne
We learn so much talking to each other.

 [00:00:53.860] - Dr. Gordon
We do. What if we'd let people listen?

 In today's episode, Dr. Lamont and I start to sort through something that will likely be an ongoing topic of interest, namely the role of genestein, a phyto- or plant-sourced estrogen in both of our worlds. We explore its use in both estrogen mimicking and estrogen blocking for certain conditions of aging, bone and brain health, as well as cancer prevention and cancer survival. We'll touch on blue zones and some of the risks and benefits of various other members of the legume family. Let's listen in as Dr. Lemanne explains the role of a Catholic nun in all of this discussion.

 [00:01:50.450] - Dr. Lemanne
We're going to talk about a nun today.

 [00:01:52.870] - Dr. Gordon
We're going to talk about a nun?

 [00:01:55.130] - Dr. Lemanne
Yes. She's somewhat of a public figure in cancer research. Are we rolling? Yes, we are. Okay. Yeah, I'm going to talk about a nun today. Do you want to hear about a nun?

[00:02:09.230] - Dr. Gordon
I do want to hear about a nun.

 [00:02:10.950] - Dr. Lemanne
So she's a public figure. She's a public figure now, but she's not around. She was a 69 year old woman in 1970 when the cancer that she had metastasized to her pleura, her name was Sister Catherine Francis and she lived in Michigan and she was a nun in the convent of, according to Wikipedia, the Immaculate Heart of Mary. And some of the cells from her breast cancer, specifically from the pleural or lining of the covering of the lung, some of her breast cancer had spread to the covering of the lung and made some fluid there. Some of this fluid was removed and the breast cancer cells that were found in this fluid from around her lungs was cultured and it was cultured by the Michigan Cancer Foundation. And her cells are still in use in breast cancer research, in cell line research, meaning not in human beings, but in culture and in animal studies. So her cells were called are called MCF-7 standing for Michigan Cancer Foundation-Seven. And I just wanted to bring that up because we're going to be talking today, I think, about genestein. And I'll bet that both of us are going to have come across studies involving mice and possibly cell cultures that will have used Mary Sister Catherine Francis's cells or Michigan Cancer Foundation-7 or excuse me, MCF-7 breast cancer cells.

 [00:04:06.320] - Dr. Gordon
So that is good to know because that is one of the stumbling points of my understanding, all the ways I might use or not use genestein, which is indeed yes, you're right. What I want to talk about today, and in homage to you and our sound engineer, it even relates to coffee.

 [00:04:30.150] - Dr. Lemanne
Well, genestein. Tell us what genestein is. It sounds like some weird, unusual chemical that's made in a lab. Is that what we're talking about here?

 [00:04:40.010] - Dr. Gordon
Well, actually, yes. Now, but really, genestein is a natural compound. It was found and identified in a flowering plant in 1899 in a family of plants. I think it was Fabaceae. It was a lesser family of flowering plants to my familiarity.

 [00:05:02.600] - Dr. Lemanne
Fabaceae.

 [00:05:03.730] - Dr. Gordon
Fabaceae. But it is much more prevalent in Fabaceae.

 [00:05:08.600] - Dr. Lemanne
That's beans, right?

 [00:05:10.200] - Dr. Gordon
No, that's the leguminosae, which is where it's mostly found. So legume—legumes—are also flowering plants and that's where it's primarily identified and accessed now, but it was originally found in a different family of plants. It's in the class of isoflavones, which is just the way they describe what the molecule looks like, like a protein or a fat or an isoflavone. And leaving nature aside, we've been able to isolate it and synthesize it for over 100 years from the early 1920s.

 [00:05:54.040] - Dr. Lemanne
Deborah, you are one of the smartest people I know. However, I am looking at something that's at least smarter than me. It's Wikipedia, and it says the fabacier or leguminoseae commonly known as the legume or bean family. Could we be talking about the same thing?

 [00:06:20.010] - Dr. Gordon
We are talking about the same thing, and I am not really I'm being.

 [00:06:25.230] - Dr. Lemanne
A jerk about this. I agree, I agree. But the reason looking at this is because I am not a big fan of legumes for everyone. And I think what you're about to talk about is going to kind of spill over into something I really love to talk about, which is the evils of beans. Okay, I'm going to turn it back over to you. Okay.

 [00:06:55.740] - Dr. Gordon
So I believe that the original family is not a complete overlap with the legumes, which are indeed beans, but for your mind to have a rest easily in this topic of genestein, it is also found in wait for it coffee.

 [00:07:13.760] - Dr. Lemanne
Oh, really?

 [00:07:14.940] - Dr. Gordon
It's found in the coffee

 [00:07:16.070] - Dr. Lemanne
Well, coffees are beans, right? Coffee beans, yes, but they are different.

 [00:07:19.500] - Dr. Gordon
From the legumes that grow in pods.

 [00:07:22.710] - Dr. Lemanne
And forgive me, coffee, something that I worship for saying that I hate beans. I love coffee beans, I love cocoa beans. And now I'm the one that's not being precise enough.

 [00:07:35.710] - Dr. Gordon
Yeah, we can figure out the botany of this if we want to in a show note. But I want to talk about Genestein, because if you just look like in Wikipedia, it says, oh, it has two main functions. It inhibits angiogenesis, which is the growth of new blood vessels. We need angiogenesis when we're children and we're growing, but if we have too much angiogenesis when we're older, that is one of the things that can feed is growing cancer cells, as I would understand it.

 [00:08:15.040] - Dr. Lemanne
So that's really interesting, and I do agree there certainly has to be a balance between angiogenesis and not too much angiogenesis. Now, angiogenesis is good when you're old, too, for physical conditioning. So when you go out for a nice run and you have a stimulus to improve your physical condition, one of those stimuli is to increase blood flow to the heart via increased capillary numbers and thickness in the myocardium. So you want to have right. Your heart healthy angiogenesis. Yeah.

 [00:08:47.530] - Dr. Gordon
Your heart and all your exercising muscles really good, but you don't particularly want it in your breast tissue.

 [00:08:56.810] - Dr. Lemanne
Agreed. Yes.

 [00:08:58.060] - Dr. Gordon
And so what's interesting, in addition to inhibiting angiogenesis, and I'm sure there's stronger agents than genestein, genestein is also a phytoestrogen, meaning a plant that acts like an estrogen. And here's where I want to do a Maya culpa for any oversimplifying I've done before and try and go into a little more detail when I just say it acts like estrogen.

[00:09:28.670] - Dr. Lemanne
Okay, I think that sounds fine. Okay.

 [00:09:33.400] - Dr. Gordon
Yes.

 [00:09:34.180] - Dr. Lemanne
All the Mea culpas we can produce are probably good. Yeah.

 [00:09:39.720] - Dr. Gordon
In homage to the nun. Thank you.

 [00:09:42.080] - Dr. Lemanne
Yes. Oh, is that a Latin phrase in the I believe it is Roman Catholic tradition.

 [00:09:47.790] - Dr. Gordon
I believe it is. So interestingly. We all think of estrogen as a hormone, but in fact, there is no such hormone as estrogen. It's a class of hormones that activates estrogen receptors, but you can have all different kinds of estrogens and they behave differently.

 [00:10:10.870] - Dr. Lemanne
Oh, I love that explanation. That's beautiful. Go on.

 [00:10:14.780] - Dr. Gordon
Which is so useful when you think of some of the debates about hormone replacement therapy, because they say, didn't the estrogen they were giving women in 2001 cause breast cancer? And I would say, well, first of all, do you really think the estrogen in your body is the same as that found in the urine of a pregnant horse? And I think most reasonable people would say, well, I don't really know very much, but I got to assume they're going to be different.

[00:10:41.070] - Dr. Lemanne
Are they? Yes, they're different.

 [00:10:43.790] - Dr. Gordon
And it's different the estrogen that your body makes from one time of your life to another, it's different. The kind of estrogen that your body makes versus what's in birth control pills and the big advent of modern chemistry, big pharma, to which I am grateful for this, is they have been able to synthesize the most powerful human estrogen, estradiol. And now it is available as a pharmaceutical. It really is a human estrogen.

[00:11:16.720] - Dr. Lemanne
Well, that's good news. Something you said just now. I've just got to go back to it. So we make different types of estrogen at different periods of our life. Can you talk a little bit more about that? What's the difference between pre puberty, puberty, reproductive era and menopause?

 [00:11:35.090] - Dr. Gordon
Right. So all our lives, men and women make three different kinds of estrogen. And they are numbered in this very handy way of e one, E two and e three.

[00:11:49.510] - Dr. Lemanne
Oh, that's good. Yes.

[00:11:51.300] - Dr. Gordon
And women in general, when they're not in their reproductive years, a ten year old girl and a ten year old boy might have very similar levels of estrogen. But at that age, it's going to be estriol. It's going to be a mixture of all three estrogens e one, E two and E three. And they're not going to be very numerous or abundant in the reproductive years. Women go crazy making E two, lots of e two. And that's the one that is responsible for us growing into adult women able to reproduce and women with their curves and all that. But remember I said men have estrogen too and is there a risk of them developing curves and things like that? And the answer to that is really lying in one more categorization I want you to indulge me in, which is that estrogen, when you spill it into the body, has very little initial effect all on its own. What it does is as a molecule travel to the cells of your body and in the nucleus of the cells it binds to an estrogen receptor.

 [00:13:08.510] - Dr. Lemanne
Okay?

 [00:13:09.230] - Dr. Gordon
And the estrogen receptor triggers protein synthesis. And those proteins are what work the magic that we attribute to estrogen, which is really primarily E two, but the others that has traveled into the nucleus of the cell and activated estrogen receptors now very handily for men. The estrogen receptors that estrogen does amazing things in the body. It helps us, our bones, maintain their sturdiness so we don't demineralize our bones. It helps our brain grow new brain cells and clean up garbage, particularly amyloid beta. As we get older, which we all have, not just Alzheimer's people. We have estrogen receptors in our heart and in our intestines. And we know that estrogen has been identified as having beneficial effect in a lot of those areas. There's also estrogen receptors of this same category estrogen receptor beta in men's prostate. But the estrogen receptor that.

 [00:14:19.410] - Dr. Lemanne
So we've been talking about different types of estrogen estrogen one, estrogen two and estrogen three. And now you're talking about estrogen receptors. And there are different estrogen receptors as well.

 [00:14:29.850] - Dr. Gordon
Exactly. So estrogen receptor alpha is the one that more enters into your discipline because it is found primarily in the lining of the uterus and the breasts where estrogen yes, is necessary. I need to have estrogen in those different organs if I want them to do the things they do. But it's also associated with an increased risk of cancer. And that's a completely different receptor than the one that does so many of the good things that we attribute to estrogen throughout the other parts of the body. And different people individually and different genders have different amounts of estrogen receptors in different parts of their body.

 [00:15:17.270] - Dr. Lemanne
So estrogen receptors come in two flavors, alpha and beta.

 [00:15:20.930] - Dr. Gordon
That's right.

 [00:15:21.420] - Dr. Lemanne
And estrogen itself comes in three types?

 [00:15:24.400] - Dr. Gordon
Yes.

 [00:15:24.780] - Dr. Lemanne
One, two, and three. Okay. So there are a lot of interactions that you can have. There three binding moieties and two different types of binding sites. So there's a lot of different configurations.

 [00:15:39.270] - Dr. Gordon
Do yeah, there's actually one more estrogen receptor, but it's not that important. So we're just going to leave that aside. We're going to primarily say there's two alpha and beta estrogen. All the different forms of estrogen that our body makes binds to both alpha and beta receptors. But genestein does not does not bind to alpha bind equally.

 [00:16:04.730] - Dr. Lemanne
Does not bind equally to alpha and beta receptors.

 [00:16:08.210] - Dr. Gordon
That's right.

 [00:16:09.350] - Dr. Lemanne
Tell me a little bit more. So I'm sure about what you were saying about men.

 [00:16:16.970] - Dr. Gordon
Men have breast tissue as well as.

 [00:16:19.600] - Dr. Lemanne
We do, but they have more of the estrogen beta receptors.

 [00:16:25.600] - Dr. Gordon
Well, they don't have as many estrogen alpha receptors in their region of their body that could grow to a breast. They have some. So when an overly abdominally obese man starts developing breast tissue, that's because he does have some estrogen receptor alphas in his breast and breast area. And now he's making more estrogen because of aromatase, turning his testosterone, because of the obesity. That's right.

 [00:17:01.030] - Dr. Lemanne
Okay, so getting fat in a male can lead to the production of what's called man boobing.

 [00:17:12.080] - Dr. Gordon
I was thinking you were going to say gynecomastia, Dr. Lamont.

 [00:17:15.350] - Dr. Lemanne
Okay. So gynecomastia the growth of breast tissue in males, which we do see in obese, and can that be reversed with weight loss or is that permanent? Are the is that breast tissue permanently enlarged in those men, even if they become thin?

 [00:17:34.220] - Dr. Gordon
I've definitely seen low level man boobs regress, but I've seen some man boobs walking around in the general public that I wonder that same question. What do you think?

 [00:17:48.950] - Dr. Lemanne
I don't know the answer, and I think it's concerning. So especially when you see it in very young men and even boys, adolescent boys, it's concerning. You definitely want to try to address that if it's possible.

 [00:18:05.290] - Dr. Gordon
And sometimes young boys go through a tiny phase of it that's primarily around the nipple that is absolutely regressive. It's just their body having their estrogen sensitivity because they make estrogen, too, because they need it in their bones, brain, heart, intestines, other places that's getting a little bit ahead of their testosterone production.

 [00:18:27.080] - Dr. Lemanne
So this is right at the moment of puberty, then. Yeah.

 [00:18:29.670] - Dr. Gordon
Getting those little tiny man buds, as opposed to man boobs, which are less attractive. So this all got started swimming around in my mind when I recently had a patient who had an endometrial cancer, and she had a hysterectomy, so she no longer had her endometrium, the lining of the uterus, and she was being treated to make sure her endometrial cancers didn't spread to whatever extent they might have still been around her body. And I was a little concerned and I don't think they were using an estrogen blocker. I'm not really sure what they were using. I should have looked that up. But I was thinking either with that or instead of that. I just wondered, would genestein help? Because here's the interesting thing. It doesn't bind similarly in degree. So estrogen, you throw it in, it attaches to all the estrogen receptors you throw in genestein. It likes beta receptors a lot more than it likes alpha receptors. So it keeps our bone and brains not as strong as estrogen, but it's pretty good. But at the alpha receptors, it can either stimulate them to work like estrogen, or it works as an antagonist and protects those alpha receptors that look like they're in the endometrium, which could be her endometrial cancer.

 [00:20:00.870] - Dr. Gordon
I'm imagining traveling around her body and block any feeding those might get from the natural estrogen she still has in her body.

 [00:20:11.120] - Dr. Lemanne
So this is a competitive inhibition situation, then, you're saying, so the genestein looks like estrogen. The alpha receptors think it's estrogen and go ahead and bind to it, and that prevents the real estrogen from having any interaction with the alpha receptor. Is that what's going on here?

[00:20:28.670] - Dr. Gordon
That's what is presumed from my minimal oncology reading is going on because it has been a helpful adjunct to chemotherapy in endometrial cancer, at least in a couple of articles I found, which I don't have handy. And so I thought you should just take this. It's going to be good for your bones, good for your brain, which your estrogen had been helping, and it'll go well with your chemotherapy. And I asked her to talk to her oncologist about it, but it made me think, and this is where I really wanted to pick your brain. Should all older women on hormone replacement therapy also be on genestein so that it blocks too much estrogen going to their breasts or their uterus? That's my question number one, which inspired question number two? Should it be used as an anti aging intervention for everybody there? So those are my questions. Will you just please answer them?

 [00:21:35.970] - Dr. Lemanne
Well, I will say with question one, it's really a beautiful question, and it tells me what a great doctor you are. What you're doing here is you're playing the symphony of metabolism, and you're having the horns come in here, and then you're pointing to the violins, and you're trying to blend them together into a harmonic whole. And I don't think anyone can answer this question in a blanket way, but what happened with your patient? Did you actually start her on genestein, and how did she do?

[00:22:10.350] - Dr. Gordon
I told her to check with her oncologist.

 [00:22:14.970] - Dr. Lemanne
Was that me? No. Okay.

 [00:22:18.940] - Dr. Gordon
It was another local oncologist. I asked her to check, and I have not seen her back. And I thought I needed to explore this a little more before I perhaps engaged in a conversation with her oncologist. But since then I've recommended it to women who, on estrogen, had a little bit of endometrial hyperplasia, or to women who I had my first mammogram in 30 years this last month.

 [00:22:48.550] - Dr. Lemanne
Oh, congratulations. Yeah.

 [00:22:49.830] - Dr. Gordon
She said, oh, your last mammogram was 30 years ago? I said yeah. Anyway, when you have a mammogram, at least at our local facility, they are obligated--So they say in the letter to tell you--if they think you have dense breast tissue.

 [00:23:06.550] - Dr. Lemanne
Right.

 [00:23:07.470] - Dr. Gordon
So I think all of us with dense breast tissue should be on genestein.

 [00:23:13.550] - Dr. Lemanne
That's very interesting. I'm not going to ask you if you have dense breast tissue, but you can tell us if you want to. But I will tell you that in Japan, young women wishing to preserve fertility are treated with genestein if they have endometrial cancer. And the reason is that genestein is believed, at least in some studies, to upregulate the progesterone receptor, so it increases progesteronic activity. Is that a word I'd say?

 [00:23:41.050] - Dr. Gordon
Progestogenic.

 [00:23:42.190] - Dr. Lemanne
Progestogenic. Okay, thank you. It increases well, I'll just say progesterone receptor expression in the endometrial tissue and in endometrial cancers. And so it's used as a treatment. In Japan, they're a little bit more interested in natural compounds than we are here, and they use them a lot in oncology, and they study them. Unfortunately, a lot of the literature is published in Japanese, so we don't get to read it very often. But this study is actually published in 2022 out of the Graduate School of Medical Science, department of Obstetrics and Gynecology in Kyoto School of Medicine. So that's a really interesting idea that you've come up with. It sounds like independently, because you are truly a brilliant doctor. And I really mean that, and I really like that idea. I think this is what people really need and want from their physician, someone who can think broadly and also deeply and in really effective ways about how can we better treat some of these conditions that have a lot of overlapping needs. So now you're thinking about treating everyone with it. You want to put it in the water? I want to say no, you've left out something.

 [00:25:00.020] - Dr. Lemanne
You have left out something that I think is really important. You mentioned fabacier, and I argued that I think that's the same as legumes, and I could be wrong, but my major point is, why have you left out where most people get genestein in their daily diet? Is there something you want to say or not say about that?

 [00:25:27.590] - Dr. Gordon
Well, I think that is a really good point, and also, I don't want it in the water because of some things which we'll get to, you know, the reason they study it primarily in Southeast Asia is because in the food supply, although traces may be found in the coffee plant, it's primarily found in soy.

 [00:25:49.310] - Dr. Lemanne
Now, you said that with an odd tone. I mean, what's wrong with soy?

 [00:25:54.210] - Dr. Gordon
Well, you were just saying that you were telling people not to eat legumes. And I must say, well, soy is allergenic for many people. It's in the top five, I think, of most allergenic foods with gluten, dairy, corn, soy, one other. And so I think we have to be a little bit careful with soy. They make it differently in Asia. So even the tofu in Asia, like our tempeh here has been fermented.

 [00:26:25.060] - Dr. Lemanne
Oh, really? I didn't know.

 [00:26:27.870] - Dr. Gordon
Just they have an easier manufacturing process here, but the fermenting process makes the soy a little bit more human, digestible, absorbable less allergenic less gut upsetting. Why don't we make it that way here?

 [00:26:44.350] - Dr. Lemanne
Well, and I want to clarify, I don't tell my patients never to eat beans. And some studies, epidemiologic studies in particular, have suggested that eating legumes may be associated with longevity. The Blue Zones, those kinds of things that have looked at that tend to come to that conclusion. I'm not sure about that, but I can be corrected if that's incorrect at some point in the future. I don't think we really know at this point. I'll say that I think one of the reasons that people in the Blue Zone live a long time is not because of necessarily of their diet, although I'm sure that has something to do with it. But I think it's the amount of food. A lot of the people in the Blue Zones are very, very short. So the shorter you are, the longer you're going to live, because the longer IGF one you've had in childhood, possibly because of food restriction, caloric restriction of some sort. I think there's a lot to still look at in studies of overall longevity, especially if they're done in an epidemiologic way, which is kind of a clumsy way, but it's one of the only ways we have.

 [00:27:49.980] - Dr. Gordon
But back but I just have to.

 [00:27:52.630] - Dr. Lemanne
You'Ve got to say something. Okay.

 [00:27:53.530] - Dr. Gordon
You've got to say something. Two other thoughts that are so different and not controlled for about why some of Asian communities may have longevity versus American or Western communities. They have a stronger sense of community and family in general, but more uniquely and more consistently. They don't sit on chairs all the time. They are down and up from the floor dozens of times every day late in life.

 [00:28:26.530] - Dr. Lemanne
Well, I have long legs. And so I think being short, it would make it a lot easier for me to get up and down off the floor all day. I have a hard time with that because I have these big long legs to fold up every time.

 [00:28:38.950] - Dr. Gordon
But it would make you a great rower. I've got this idea, dr. Lamont.

 [00:28:46.070] - Dr. Lemanne
I've tried rowing. I kept falling out of the boat. But I think rowing is a beautiful sport. It is a beautiful sport.

 [00:28:55.780] - Dr. Gordon
But okay, back to my coming back from my little aside about I think there's really many theories about why the Blue Zones are associated with longevity, but some of it might be the legumes they eat.

 [00:29:08.580] - Dr. Lemanne
Might be it might be the sunshine. So the one community in the blue zones in the United States, I think was 7th day Adventists in Loma Linda, California. Very nicely sunny place, okinawa in Japan, where there's a blue zone. Not all of Japan, just Okinawa. And that turns out to have a rather tropical climate more akin to the Philippines than the rest of Japan. And then, of course, there's a South American blue zone, I believe, maybe in Ecuador, vilkabamba. And then there's one or two in the Mediterranean area. Of course, we're talking sunshine in all of these areas. There's some vitamin D going on.

 [00:29:49.050] - Dr. Gordon
Yeah. And you get up into the latitudes, such as the one at which we live, which is up near the top of most of the United States. We are really better known for vitamin D deficiency diseases like multiple sclerosis, which is and cancer, which is higher in the northern latitudes. And that can shorten some people's lives. Definitely.

 [00:30:13.010] - Dr. Lemanne
Well, back to soy or genestein. Excuse me. We're carefully avoiding the word soy, although I can tell you that there is an interesting small group of studies carried out in Chicago that purport to associate early soy consumption in African American babies with later development of uterine fibroids.

 [00:30:39.040] - Dr. Gordon
Exactly. I did see that.

[00:30:42.030] - Dr. Lemanne
And so I don't know if that's going to hold up. It's only one group that studied it, as far as I know, and I think it's an interesting proposition. Certainly soy formula has been used in babies that aren't able to take animal based formulas or breast milk.

 [00:30:57.790] - Dr. Gordon
You're right.

 [00:30:58.550] - Dr. Lemanne
And there is some possible estrogenic activity in both males and females in that situation, in those infants.

 [00:31:07.190] - Dr. Gordon
I think this study has been duplicated in an animal model. I believe that's what I came across. I didn't see it in a population observation. That is amazing because when I was picking a supplemental formula for my daughter, the dairy ones seemed more synthetic. The soy ones seemed they were advertised and maybe actually even produced as simpler formulas. And they never suggested that that might promote later growth of fibroids. And I wonder if in the population that you said where it was observed, if that was a soy exposure early in life, so would genestein or soy. And I do have to say there are other sources of genestein now that are from more compatible legume. Did you know? I think this is true. Please correct me if I'm wrong. I think actually pomegranates are a legume.

 [00:32:17.690] - Dr. Lemanne
Oh, I am a horrible botanist. I have no comment on that.

 [00:32:21.700] - Dr. Gordon
We're going to check that. That's interesting because they're the other source of gen.

 [00:32:26.100] - Dr. Lemanne
I love pomegranates.

 [00:32:27.530] - Dr. Gordon
Well, I think you're I'm sorry, legume family.

 [00:32:31.010] - Dr. Lemanne
If pomegranates are one of your own, I apologize from the bottom of my heart.

 [00:32:36.440] - Dr. Gordon
Pomegranates are fantastic, and they are what's used in some of the non soy based, because I do have a patient over the years whose I've really convinced her from all the soapboxing I do in general in life, that women should give hormone replacement therapy a try. And she's given it a college try half a dozen times, and we could never really make it acceptable to her for just side effects of it. And so I suggested she tried genestein, and at the time, it was only available as a soy derivative, and she was reactive to that as well. So she's doing better. Too soon to say on a pomegranate based soy. Very pomegranate based genestein.

 [00:33:21.270] - Dr. Lemanne
Very, very interesting. Yeah. Okay. Well, so what kinds of things are you using genestein for? And then I'm going to chime in about my concerns in cancer specifically, but there's arguments both ways.

 [00:33:40.070] - Dr. Gordon
Okay. And that's what I really want to hear, because from a cursory reading, which is that it oh, gee. It blocks estrogen. Let's see. In general, estradiol reduces the risk of breast cancer. One of the greatest contributors to it.

 [00:33:55.930] - Dr. Lemanne
No, go back there's. Estrogen one, estrogen two, and estrogen three. I'm going to see if I'm correct. Estrogen one, estradiol no. Okay. All right. Flunked that.

 [00:34:09.600] - Dr. Gordon
Keep going.

 [00:34:10.320] - Dr. Lemanne
Estrogen two, estrone no.

 [00:34:13.760] - Dr. Gordon
Switch those around.

 [00:34:15.200] - Dr. Lemanne
Okay, so estrogen one is estrone, which.

 [00:34:18.770] - Dr. Gordon
Is primarily the estrogen that we continue to make as we age.

 [00:34:22.790] - Dr. Lemanne
Okay. And estrogen two is estradiol, which is the yes, and I have no idea what estrogen three is.

 [00:34:28.620] - Dr. Gordon
It's estriol, which is the predominant estrogen that emerges from the shadows in pregnancy. And it's also an important part of how we metabolize all estrogens in our liver to prepare them for excretion. They pass through a stage of being estriol.

 [00:34:49.560] - Dr. Lemanne
Okay, let me review just so I'm sure. Estrogen one is estrone. Yes. All right. And that's the one that well, I won't go there. I'll be wrong. Estrogen two is estradiol. Yes. All right. And that's the one that we make at puberty, and that turns us into full fledged menstruating, reproductively ready persons. Okay. And estrogen three is estriol, and that's the one that most estrogens pass through in the liver, and that's the one that we can then remove from the body. Is that correct?

 [00:35:31.260] - Dr. Gordon
Well, it's conjugated, so it becomes two hydroxy estrone or two hydroxy estriol. It's conjugated, but yes. So we can remove estrogen from the body. E two doesn't have a good elimination pathway, but both e one and E three do.

 [00:35:49.460] - Dr. Lemanne

And then the estrogen receptors alpha, that's the one that we find in the breast and reproductive tract of females when they're of reproductive age. And the other estrogen receptor beta, is found in a whole host of other tissues, like bone, brain, et cetera. And both men and women have those, but men have a higher ratio of estrogen receptor beta to alpha than women do. Yes. Okay. All right.

 [00:36:27.580] - Dr. Gordon
Very good.

 [00:36:28.240] - Dr. Lemanne
Did I get a C minus? Here?

 [00:36:29.760] - Dr. Gordon
No, you got an. A plus for organizational skill while my mind is still swimming in complexity.

 [00:36:36.260] - Dr. Lemanne
Well, I think this is important for me to understand exactly what the different categories are, although it's a little bit of a nerdy thing to do, but I think it'll be of interest to our listeners, too, to kind of have that organization. So the three estrogens and the two receptors and the various interactions between the estrogens and the receptors. Yes. And that's what you are a virtuoso at. You are playing the interactions and turning them up and down, turning the dials as needed to address various conditions.

 [00:37:09.190] - Dr. Gordon
Right. So how I was introduced to this is I became aware when we did our Precision Medicine Approach to Alzheimer's study that we published last summer, that when we did genetics on people, the estrogen receptor beta in the brain not only is good when estrogen sits on it because it helps it make new brain cells better neurotransmission clean up amyloid beta, which go back to saying we all have so estrogen receptor beta in the brain. Our brains are very happy when estrogen sits there. The thing that's unusual about these particular receptors, particularly in the brain, is when estrogen is not sitting there, they have a hissy fit and an empty estrogen receptor beta in the brain raises inflammation in the brain.

 [00:38:19.550] - Dr. Lemanne
Wow.

 [00:38:21.650] - Dr. Gordon
So that's okay, that's fixed. If I, as a woman, am taking estradiol and it's one of the reasons that estradiol used after menopause well, certainly during our fertile years and then used after menopause seems to reduce the otherwise high incidence of Alzheimer's in women, which would be caused by the lack of estrogen sitting in that receptor, which then causes a hissy fit and causes inflammation. So great estrogen can silence that. Two issues arise, though. What are men going to do? I'm not going to give men estradiol if they have estrogen receptor betas in their brain that aren't getting properly fed with estrogen. And so what has emerged as a therapeutic modality for them is to give them genestein.

[00:39:14.210] - Dr. Lemanne
Very interesting. All right. And that activates estrogen receptor beta in the brain. In the brain of the male.

 [00:39:20.790] - Dr. Gordon
And as a good side effect, it does it in the bones as well and helps maintain bone integrity.

 [00:39:26.050] - Dr. Lemanne
So I'm assuming it does this in males and females.

 [00:39:28.460] - Dr. Gordon
That's right.

 [00:39:29.000] - Dr. Lemanne
Okay. And it's great for males because it doesn't activate the reproductive tissue, breast. And of course, men don't have uterine tissue, but it doesn't activate anything that might cause them some trouble.

 [00:39:41.840] - Dr. Gordon
And helpful for women, too, because I was saying that estradiol, if you really look at the literature from the Women's Health International study, it was the estradiol component that actually reduces the risk of breast cancer. When they gave it to women without an opposing progestin, they had actually less breast cancer by taking estradiol at menopause.

 [00:40:08.310] - Dr. Lemanne
All right. Does estradiol have particular affinity for estrogen receptor beta or do all the estrogens.

 [00:40:15.260] - Dr. Gordon

All the estrogens like all the receptors.

 [00:40:17.690] - Dr. Lemanne
Okay. So really you activate different estrogens and the receptor part of things is more passive. Is that one way of thinking about it? When the body wants to play a certain tune, it increases the amount of the correct one of the three estrogens.

 [00:40:39.410] - Dr. Gordon
It does. And the estrogen receptor distribution is determined more genetically than temporarily. So how the different production of the different estrogens at different times is orchestrated, I'm not really sure about. But what I want to say about genestein. So that while it totally makes the estrogen receptor beta very happy and feel as if it's full of estrogen, it doesn't do that when it gets to estrogen receptor alpha, it is weaker in alpha in general. So you could take genestein till the cows come home as a pubescent male and you're not going to develop breasts like you would if you took estradiol, say, in a gender reassignment operation. You would never just use genestein to grow breasts in a male because it does sit in the receptors that are in the breasts, but not as strongly as estradiol does. And in some cases it actually blocks the activity that otherwise that receptor would stimulate.

 [00:42:01.680] - Dr. Lemanne
Very interesting.

 [00:42:04.390] - Dr. Gordon
Which is why I think it's been an adjuvant in some chemotherapy. So my patients, as they age and I want to keep them on estrogen estradiol. But just by advancing age, doesn't each advancing year mildly increase our risk of all sorts of cancers?

 [00:42:26.570] - Dr. Lemanne
Absolutely. So age is a risk factor for cancer. Yes.

 [00:42:31.020] - Dr. Gordon
So even though she's on estradiol, which in the studies reduces her risk of cancer, some older women are still eventually going to get. And I think I have had several of these, and I've talked to you about them, and you've seen at least one of them. They had estrogen receptor positive breast cancer on hormone replacement therapy past the age of 70 or 75.

 [00:42:55.830] - Dr. Lemanne
Well, it's interesting too, because women who come to me who have been on hormone replacement therapy after menopause and then are diagnosed with breast cancer actually have a better prognosis than women who develop breast cancer while not on hormone replacement therapy. Very few women who develop breast cancer while on hormone replacement therapy actually die of breast cancer. Now, there are some I'm not going to make a blanket statement that hormone replacement therapy is slam dunk for absolutely curable breast cancer. So you don't even have to think about it. But it does make me think, well, there's something about the hormone replacement therapy that has turned this breast cancer possibly into a milder situation. And I don't think we understand that. But it's an interesting thing to think about.

 [00:43:49.520] - Dr. Gordon
It is. And I guess I wonder if it isn't in those cases, the less nefarious ones where genestein might have just made that not happen.

 [00:43:59.230] - Dr. Lemanne
That's an interesting yeah, very interesting idea. That's one of the ways that we try to prevent breast cancer. We try to use things like tamoxifen and related drugs in women who don't have breast cancer but who are at high risk of breast cancer for various reasons to try to decrease the incidence of breast cancer in those patients because.

 [00:44:21.270] - Dr. Gordon
Tamoxifen blocks estrogen receptors. Both, I mean, throughout the body. Tell us a little bit about how tamoxifen works.

 [00:44:30.100] - Dr. Lemanne
So tamoxifen looks a lot like estrogen to the estrogen receptors and it sits in the estrogen receptors and prevents real estrogen from getting into the estrogen receptors and stimulating the growth of the production of certain hormones that drive the growth of in our case, what we're most interested in is breast tissue. It also actually stimulates through the estrogen receptor beta in a good way positively the growth of bony tissue, among other things, which isn't actually a wonderful thing because it can actually increase bone density at the same time as it's decreasing the risk of breast cancer recurrence or the initial diagnosis of breast cancer. Genestein has been looked at with several breast cancer drugs and it's thought that genestein might interfere with the effectiveness of tamoxifen by competing with tamoxifen for that estrogen receptor. So now we've got a really a three body problem here. We've got real estrogen trying to get onto that receptor and then we've got tamoxifen and genestein competing to get in there. And there was a 2002 study, I think, looking at the interaction between tamoxifen and genestein in breast cancer cells. And again, I believe this was the MCF seven cells.

 [00:46:08.480] - Dr. Lemanne
So all we can say is that in that particular situation mary Catherine mary Catherine Francis I can't remember her name, I'm sorry, but MCF cells from a nun with very advanced breast cancer this interfered with tamoxifen's effect with genestein, interfered in that particular situation. There are some other studies that suggest that that could be the case. But again, I think all we can really say is that in that particular set of cells and in the mice that were injected with these cells, which were what are called Athymic mice, mice mice who've been bred to have their thymus gland non functioning. Meaning they have very, very poor ability to reject human cells which is necessary for testing for testing in this way. Exactly. In that particular model, we see an effect between tamoxifen and genestein in which genestein might block the effectiveness of tamoxifen. But I think that's all we can say in this very artificial model that's very far removed from reality and using only one patient's breast cancer cells, we saw an interaction.

 [00:47:30.500] - Dr. Gordon
So I have one little seemingly parallel comment about estrogen receptor beta in the bones and the brain. So in general, if you are treating a postmenopausal woman for this is my understanding for estrogen receptor positive breast cancer and she's not been on hormone replacement therapy. You give her tamoxifen and it doesn't cause any cognitive impairment. However, tamoxifen either sits on the receptors in the brain or it must sit on the receptors in the brain. It doesn't antagonize them. They don't get worse when they've started taking tamoxifen and menopause. But in my little group of brain doctors with whom I was discussing this recently, the women who were on estrogen replacement therapy for the benefit of their brains and developed a cancer for which their estrogen was stopped and tamoxifen was substituted or tamoxifen was just given for their bone density. Their brains did suffer as if either estrogen was doing better for their brain than tamoxifen, or tamoxifen actually took down a notch. A brain that had been improved with estrogen. So it has some attachment to estrogen receptor beta beyond just the bones, where it seems beneficial in the brains, it's not as good as estrogen.

 [00:49:16.230] - Dr. Gordon
And I don't think in the bones, I don't think it's as good as estrogen. 

[00:49:18.940] - Dr. Lemanne
I totally agree. And I know that my patients tell me I don't think as sharply now that I'm on tamoxifen.

 [00:49:25.730] - Dr. Gordon
Oh, they do.

 [00:49:26.500] - Dr. Lemanne
And especially the ones who've previously been on a hormone replacement therapy, there is a definite antagonistic effect of tamoxifen on brain health, and I wish it weren't so. And it is a difficult problem, and I think it's one that we definitely want to believe our patients when they say, I'm not thinking as well, and to try to discuss what we might be able to do to help that so that they can get their breast cancer treatment if they need it. And I think it's a difficult problem.

 [00:49:56.610] - Dr. Gordon
It is.

 [00:49:58.030] - Dr. Lemanne
But genestein actually one way, especially in postmenopausal treatment patients with breast cancer, we can treat those patients with drugs called aromatase inhibitors. So there are three different aromatase inhibitors. Two of them are interfered with with genestein, and those are Letrosol and aromacin. The third one, called exomestain, actually has its efficacy increased if the patient also takes genestein, at least based on studies in mice with no thymus glands who are injected with MCF, seven breast cancer cells, again from the Nun in Michigan from the 1960s. So I think that's really an interesting finding. And if a patient doesn't tolerate tamoxifen because they have cognitive issues, we certainly could try exomestane with genestein and see.

 [00:50:56.870] - Dr. Gordon
If they feel better with the two of those together. That's very interesting because that's one of the cases where genestein binds less strongly to estrogen receptor alpha in the uterus and the breast, except if it can be an antagonist. This is circular, and my brain is swimming in circles about this. And that's a good differentiation to know because, of course, aromatase inhibitors in and of themselves can very frequently cause cognitive impairment in older women.

 [00:51:38.220] - Dr. Lemanne
Absolutely.

 [00:51:38.960] - Dr. Gordon
Yeah.

 [00:51:39.700] - Dr. Lemanne
So there's a chemotherapy drug that's very famous, and our patients will have heard of it if they've ever had chemotherapy. It's called adriamycin.

 [00:51:47.020] - Dr. Gordon
Oh, yes, I've heard of that. Affects the heart, doesn't it?

 [00:51:49.330] - Dr. Lemanne
It can have terrible side effects in the heart. Although we can protect against that fasting exercise. Coq ten there are a lot of things that can actually protect the heart from Adriamycin, so we can talk about that at some point.

 [00:52:00.300] - Dr. Gordon
I'd like to hear that.

 [00:52:01.180] - Dr. Lemanne
But Adriamycin and genestein are synergistic against breast cancer cells in culture and I think that that's really important for people to know. Also, genestein acts synergistically with EPA Icosapenta INOIC acid, fish oil in what setting in breast cancer cell culture. So it helps kill breast cancer cells to take genestein along with fish oil, especially the moiedian fish oil called EPA. So I think that those are two important things that patients can know and discuss with their doctors, of course, whether they want to use them or not. But it's encouraging to know that there are some simple things that are inexpensive that you can do to protect yourself from side effects of Adriamycin. And possibly some of these other drugs like Exomestane and genestein may be one of them.

 [00:52:59.450] - Dr. Gordon
So I am going to experiment with proper informed consent, some of my older patients, the women who are in hormone replacement therapy, and also going to think, because it's so good for our bones and our brains, whether we're worried about breast cancer a lot, a little or none, perhaps all older patients. Which raises the question for us to talk about perhaps next time, what are the interventions, besides caloric restriction, that show benefit for people who just want to extend, not just the length of their life? Because modern medicine does that great, but how do we extend the quality of our life? And should genestein be a part of that? Whether or not you're balancing out HRT in an older woman or just giving it to a person interested in longevity.

 [00:53:56.810] - Dr. Lemanne
I think that'd be a wonderful topic. So you're talking about the health span.

[00:54:01.090] - Dr. Gordon
The health.

 [00:54:03.870] - Dr. Lemanne
So who doesn't want that?

 [00:54:07.230] - Dr. Gordon
So genistein!  well, this has been still a mind swimming discussion, which I would say is somewhat inspired by my conversation that I was having with this brain docs. And one of them said, is there any chance you could tap the brain power of Dr. Don Le Mon on this question? So the surprise to me was she doesn't even know we have a podcast, number one. But number two, I can't wait to ask Dr. Lamont about this.

 [00:54:39.050] - Dr. Lemanne
Well, I hope I've at least partially answered and hemmed and hawed about the pros and cons of genestein in cancer. But certainly soy has been associated with improved survival of lots of cancers, including kidney cancer, breast cancer, just a lot of different types of cancer. So it's an interesting topic, it's very complex. I do want to point out to our listeners that when you look at breast cancer studies, one of the things to look for is, is this a cell culture study or an animal study in which certain breast cancer cells from one patient from 60 years ago were injected into mice with no immune systems. And if that's the case, you want to take some of those findings with a grain of salt. They're not necessarily going to translate to, benefit for or harm to any particular patient who's not that particular unfortunate nun from the 1960s who had a very advanced case of breast cancer. A very particular type of breast cancer. It was hormone receptor positive and who had liquid taken from around her lungs and cells cultured from that liquid. It's a very specific situation.

 [00:56:01.010] - Dr. Gordon
It strikes me that cancer research is very challenging, and the idea of the moonshot to the moon very hard. Let's cure cancer. Well, every cancer is different, and even breast cancer is completely different. There's at least half a dozen kinds, probably a breast cancer. We think of the different combos, but it seems as if, in general, breast cancer, human therapeutics have massively improved over the last couple of decades. Is that right? Over the mastectomy that someone might have had 40 years ago?

 [00:56:36.400] - Dr. Lemanne
You know what's? 50 years, when you look at statistics, you can look at statistics up, down, and sideways and come up with different interpretations. The improvement in survival for certain cancers has increased over several decades. There are some cancers for which there's really been very little or almost no improvement. For instance, colorectal cancer, esophageal cancer, pancreatic cancer, glioblastoma, and there are others. These have dismal survival statistics, and they haven't changed over the past many. So, you know, I don't think Elon Musk listens to this podcast, but if he did, I would tell him. Here's what I would say to Elon Musk you think going to Mars is hard? Try looking at cancer.

 [00:57:31.060] - Dr. Gordon
Try looking at cancer so much harder.

 [00:57:33.050] - Dr. Lemanne
Yeah, so much know we can figure out how to get to Mars. Trying to figure out cancer is one or two orders of magnitude more complex, maybe three orders.

 [00:57:45.510] - Dr. Gordon

We'll have to flag him on this podcast, make sure he listens up. Well, this has been great, and my mind is still swimming, but I do want to go into some of the topics we've touched on today, such as longevity, health, span enhancers, and some of the chemotherapy side effects that can be mitigated by powers of doityourself medicine that people can take into their own hands.

 [00:58:16.540] - Dr. Lemanne
Oh, you want to do DIY chemotherapy side effect mitigation?

 [00:58:21.900] - Dr. Gordon
Exactly.

 [00:58:23.090] - Dr. Lemanne
All right, you're on.

 [00:58:24.200] - Dr. Gordon
Okay, see you next time.

 [00:58:25.650] - Dr. Lemanne
That's great. 

[00:58:26.400] - Dr. Gordon
Bye bye. You have been listening to the Lamont Gordon podcast, where docs talk shop.

 [00:58:34.900] - Dr Lemanne
For podcast, transcripts, episode notes and links, and more, please visit the podcast website@docstalkshop.com .. Happy eavesdropping. 

[00:58:54.330] - Dr Lemanne

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 [00:59:11.240] - Dr. Gordon
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 [00:59:23.250] - Dr.Lemanne
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 [00:59:37.810] - Dr. Gordon
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 [00:59:44.560] - Dr. Lemanne
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 [00:59:53.210] - Dr. Lemanne
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