Dr Louise Newson [00:00:00] Some of you might know already, but thispodcast has been nominated by the British Podcast Awards for the listenerschoice. So, we really need your votes, because it would be such an honor andthrill to do well in this so if you go to the show notes and click on the link,it won't take you long. Please just vote for us. Thank you so much.

Dr Louise Newson [00:00:23] So on this podcast, I've got a really good friend and colleague, Professor Franck Mauvais-Jarvis from US. He's a professor of Endocrinology with a special interest in metabolism. So, we talk a lot about the role of hormones, estradiol, especially, but also testosterone in metabolism, in reducing incidents of diabetes, and we talk about mitochondria, the powerhouse of our cells, and how that can improve in the presence of estradiol. So, enjoy it. So, Frank. It's really exciting. I feel like I've known you for quite a long time, but I can't remember when I first, I think I reached out to you, didn't I, because I'd read one of your great papers,

Dr Franck Mauvais-Jarvis [00:01:07] Was it the beginning of COVID?

Dr Louise Newson [00:01:08] Yeah. And in fact, I was reading a paper the other night, and I was - I read it out to my husband the line because it was saying, there is good evidence that estrogen protected people from COVID. And I was saying to him, why wasn't anyone listening at the time? Like it was so frustrating. But what, what I love about your work is that you're interested in the metabolic processes that occur in the body. And there are very few people, really, I think, that understand the importance of hormones, estradiol, progesterone and testosterone, on improving our metabolism and reducing inflammation. So can you just tell me a bit about your background and why you're doing what you do, and a bit about the research that you've done for so many years?

Dr Franck Mauvais-Jarvis [00:01:56] I'm an endocrinologist. I trained in internal medicine and endocrinology in the hospitals of Paris and France. It's a complicated story. I moved to the US to do a post-doctoral fellowship to study metabolism, you know. And I was at the Joslin Diabetes Center and Harvard Medical School with Ron Khan, was actually one of the best lab to go at the time, but let's say right now, I am endocrinologist. I take care of menopausal women and testosterone deficient men at the Veterans Medical Center in New Orleans. But I'm also leading a research lab on estrogen, progesterone and testosterone in metabolism. I'm also director of an NIH-supported centre of excellence in sex-based precision medicine at Tulane University School of Medicine and I'm professor of medicine at Tulane, so that's where, that's where we stand now. They asked me, why did you get interested into that? You know, it's a very long story. My father, when I was a kid, was a reproductive endocrinologist in France. He actually was one of those who helped develop Estrogel, the gel that women put on their skin. And the story, and nobody knows, is that he was working on the percutaneous absorption of steroids, and he used estradiol, tritiated, you know, radioactive estradiol. Brought the cream home one night, and he put it on the skin of my mother, and then he collected her urine, and he found radioactivity. That's what in 1969.

Dr Louise Newson [00:03:56] 1969!

Dr Franck Mauvais-Jarvis[00:03:56] One of the first evidence that steroid hormone were going through the skin.

Dr Louise Newson [00:04:06] Amazing, but I'm confused, because that's 1969 and that was estradiol. But around that time, it was all conjugated equine estrogens. It was the pregnant horse’s urine, or it was ethinylestradiol. So certainly in the UK and US, that was the go-to prescription for HRT. I know it was slightly different in the continent, but why were people not thinking more about estradiol?

Dr Franck Mauvais-Jarvis [00:04:34] Well, it was in 1969 that he did this experiment, that Estrogel was developed in France in 1986. So the question, why? Well, you know, when I when I went to medical school and when I did my clinical training in endocrinology in Paris, I’d never heard of conjugatedequine estrogens. We were, we were prescribing body identical hormones, you know, estradiol, progesterone and testosterone. And I actually heard the first time about, I mean, I heard I knew what it was, but I heard the first time about CEE and medroxyprogesterone acetate during the earthquake of 2002 you know, the Women’s Health Initiative trial report by the by the media and by JAMA, the hysterical report of the WHI. You know, me, I was not surprised. I was not surprised. I was surprised because we were prescribing other types of hormones. And so I was, I was incredulous from the beginning.

Dr Louise Newson [00:05:55] Well it was so wrong, because then they made a blanket decision that all hormones were bad. And I was reading the report recently where they decided that they should label hormones as carcinogens, so all types of estrogen were labelled, then as carcinogenic, so as in causing cancer as a result of that study. But that wasn't the same as estradiol or progesterone. I mean, the biggest concern really, from the WHI, the Women's Health Initiative study, was the medroxyprogesterone acetate, which is the synthetic progestogen, wasn't it?

Dr Franck Mauvais-Jarvis [00:06:32] First of all, estrogen are not carcinogen, because we know today. Actually, they knew it from the beginning during the WHI, the arm, without the arm in women without a uterus, the arm with conjugated estrogen alone, there was already a 30% decreased risk of breast cancer. And today, we know because there are lots of studies that have been done, and there's are cent meta-analysis showing that CEE or estradiol alone in women without auterus clearly significantly protect from breast cancer, when you add a progestogen, and especially a synthetic progestogen like medroxyprogesterone acetate, then at the time of the WHI, that's when you had a signal a small increased risk of breast cancer. But if you think about the absolute risk, it was one or two women out of 10,000, so that's a very minimal risk. And first of all, it was not even significant. But today, if we look at the data, there is still a minor increased risk. It's not always significant when a progestogen is added to any type of estrogen, and there is especially a minor risk if it's a synthetic progestogen. And probably the reason is that estradiol increases the expression of the progesterone receptor, and when you add progestogen on that, it may, in certain circumstances, increase the risk. But this is a very, very minor increased risk, you know, if you compare it with what happens when you don't take hormones.

Dr Louise Newson [00:08:30] Absolutely, and that is a big difference, actually, when you're comparing the risks of not having hormones. And, you know, I'm a physician, not a gynaecologist, as you know, and I'm very interested in the immune regulating effects of hormones, so how we can reduce inflammation in our body, how we can improve our metabolism, as in our bodies, and reduce future risk of diseases, including diabetes, which we know is far more prevalent than ever before, really, but we've know even from the WHI actually looking at diabetes, there's a lower instance of diabetes in women who take hormones, and there's a better sugar glucose control as well. And I've seen quite a few patients who have type one or type two diabetes, and their diabetes control has just become haywire when they become perimenopausal, and then they have the hormones back. But it's all three hormones can affect metabolism in a beneficial way. But I don't know why we're not shouting from the rooftops about this, because to have a simple medicine that's a natural hormone reducing risk of diabetes as well as breast cancer. But you know, just looking at metabolic effects with diabetes, that's really important, isn't it?

Dr Franck Mauvais-Jarvis [00:09:50] It is. You're right, and in fact, it's one of the poorly reported effects of estrogens in the Women's Health Initiative, if you look at the data, there was at five years, a 25% decreased risk of diabetes. And if you continued after the follow up, 13 years, there was even a greater decreased risk of diabetes. So, the decreased risk of diabetes with estrogenalone, and even estrogen with progestin, was as powerful as the effect in preventing fractures, nobody speaks about that, and it's been reproduced a lot of other trials. Because estradiol has several beneficial effects. It improves insulin sensitivity, it decreases visceral fat, it improves insulin production. And like you said before, it decreases inflammation and all that is very important for glucose homeostasis. Overall, the insulin resistance, when you measure that by HOMA [homeostatic model assessment], is improved by about 30%but what is interesting is that it's the effect, and it works in in diabetic women, of course, but the improvement in insulin sensitivity and the prevention of diabetes works in non-diabetic women, and the effect is stronger with oral estradiol, because than transdermal, because of the first-pass liver metabolism. So, when you give oral estradiol, you have a greater - so you shower the liver through a portal vein, and you have a greater suppression of hepatic glucose production. It's the same reason why oral estradiol has a greater effect on lowering LDL cholesterol and increasing HDL cholesterol than transdermal because of that first-pass liver metabolism.

Dr Louise Newson [00:11:55] And this is very interesting, and I just want to sort of elaborate a little bit, because there's a lot of confusion between tablet estrogen, because people think about risks with tablet but it's very different. When you ingest ethinylestradiol to estradiol, because ethinylestradiolis a chemical, it's got an ethaniol bit added to it, and so when it goes into the liver, it will activate clotting factors. It will work very differently inthe liver, rather than the pure oestradiol. And I don't know what it's like in the US, but in the UK, there's only one contraceptive that contains oestradiol.All the others are ethinylestradiol,whereas most doctors will just say it's oestrogen, and they won't know thedifference and metabolically, this is really, really important actually.

Dr Franck Mauvais-Jarvis [00:12:46] Yes, and the risk of DVT, you know, the risk of blood clot, deep venous thrombosis with oral estradiol is very minimal in any women without, without taking any estrogen. The risk is about between one and three out of 100,000. And on oral estrogen, whatever the estrogen is, it's about three to fifteen. So that would be three times more, but it's still, it's still very, very little, you know, but that's all over the board, all estrogens. The risk with oral estradiol is very minimal, and especially, you know, it's always the same thing. People mix all, all, women in the same bag. But it's not, this is not precision medicine, you know

Dr Louise Newson [00:13:38] Yeah

Dr Franck Mauvais-Jarvis [00:13:38] You know, if you take women who are healthy, who are not obese, we don't have any history of blood clots. I mean, they can take oral estrogen without a problem. Of course, if somebody has a history of blood clots, is obese, is sedentary, and has hypertension, or things that you would, you would pay more attention. But still, the rich with, the risk with CEE, compared with conjugated estrogen, compared with, ethinylestradiol is 100times more potent than estradiol. It's not the same molecule.

Dr Louise Newson [00:14:17] Yeah, it's very important to distinguish between the difference. And you know, when you talk about precision medicine,it's really important, because as a clinician, of course, I want to use the evidence and the science, but I want to individualise care for patients. And we've known for decades that different women often need different doses to improve their symptom control and also their future health, and we've knownthis with oral and transdermal medication, and we spend a lot of the time in the clinic working out the best formulation, the best dose, but also whetherpatches, gels, tablets, or sometimes a combination. And that really, really can vary between patients, can't it?

Dr Franck Mauvais-Jarvis [00:15:03] And actually, it takes me to another problem of the current recommendations is that we, it is not recommended that you measure estradiol levels in women. I know you do because you're a forward-thinking and modern physician, but it's not recommended that you measure estradiol level in women. So basically, what is recommended is to consider the treatment is efficient if hot flashes are corrected, but it doesn't tell you if you have aserum concentration of estradiol that are therapeutic for osteoporosis. And all studies have shown that you needed about 80 to 100 picogram per ml minimum to prevent osteoporosis, and usually when you use gels or patches, you don't know where you are and, and very often you're below 60 picogram per ml, so you may protect hot flashes, which is already good you don't know if you have enough estradiol to prevent osteoporosis.

Dr Louise Newson [00:16:14] Yeah.

Dr Franck Mauvais-Jarvis [00:16:14] So why would we not measure estradiol level to supplement women, but we measure testosterone level when we supplement men. What does it mean?

Dr Louise Newson [00:16:26] It makes no sense, does it? And I think there's two things that are really interesting in that. Firstly, is that any test we doin medicine is a guide and it helps us, but it has to be in clinical context as well. I saw someone yesterday in my clinic whose level of estradiol was really high, and it didn't fit in with the clinical situation. And I said to her, did you use your gel in the morning of the test? She said, oh, yes, I rubbed it all down my arm. Oh, perhaps I shouldn't have done that. So it was probably a contaminated sample, and we'll just do it again when she hasn't rubbed it over where the needle went in. But also, there was another patient of mine overhere. It's very unusual, but it's been warm Frank which, and a lot of patches aren't sticking on very well. And so, one of my patients has been very worried about her mental health. She's taken a real dip in her mental health. And I spoke to her, and she was getting worsening migraines as well, and she said,but I've not changed anything. Everything is the same. I don't understand. And taking a clearer history, she was also having some urinary symptoms. She was having some muscle and joint pains, and she was having some palpitations, but she thought they weren't significant to tell me, it was only when I asked her, and then I got her to show me the patches, and they were bubbling and lifting. And so, this inadequate or suboptimal absorption of the estradiol was triggering her symptoms. But it was worse actually, because it was intermittent. So, I'm sure at night time, when it's cooler, they were absorbing better. And as you know, a lot of people have worsening symptoms when their hormones are changing and fluctuating. It's not just the absolute levels, so we really need to think about that. But the other part, when you talk about testosterone levels in men, it absolutely makes sense, and the same in women. But I just wanted to ask you something, because I don't want to be rude about your age Franck, but you know, we're both quite old, and we would have done our medical training basing all the studies on the treatment we give on men. It usually was a 70kg man, wasn't it, that the research was done when we think about medication for diabetes, for hypertension, for antibiotic dosing, everything is always based on a 70kg man. Luckily, the year, actually, I graduated in ‘94 was the first year that people started to realise women should be included in studies, which is great. But somehow, when it comes to testosterone for women, we're not allowed to look at the male studies. So when I say that testosterone can reduce incidence of diabetes, hypertension, cardiovascular disease, dementia, because we have good evidence for men, I'm told, but Louise, we don't have the studies of women, therefore we can't use it for women and tell them about these benefits, and it feels a bit not fair, really, because it's one medicine that we're not allowed to look at the men's data.

Dr Franck Mauvais-Jarvis [00:19:44] And but when you think about it, so the only, the endocrine societies say, you know, say it should be approved only for hyposexual desire, but testosterone at any time in a woman's life, especially, you know during reproductive years, is 50 times more abundant than estradiol. So, do you think that a hormone that is 50 times most abundant, it's actually the most abundant active sex steroid. I don't think it's only for libido or sexual desire. It is for metabolism. It is an important metabolic hormone. And actually there are studies, there are studies, small, randomised trial and other type of interventional studies that show that, first of all, it increased lean mass in women. Second, it increased bone mass on top studies that were done in menopausal women. It increases bone mass on top of estradiol effect, and it even helped women with cardiac failure to have a better oxygenation. So yes, I think it's clear that testosterone is important to women, and actually animal studies, it's always important to look at animal studies to confirm and understand what we cannot go deep enough in humans, but in animal studies, it clearly shows that both estrogen via estrogen receptor alpha and testosterone and DHT via the androgen receptor are necessary for bone. You know they don't work on the same thing. One works on cortical bone, the other works on atrabecular bone. So, they are both, they are both synergising. I personally give testosterone to any women that I see, if she wants it, I measure the concentration in the serum, and I try to put it at the upper limit of the female concentration. Let's say testosterone in women is between 20 and 80 and70 nanogram per dl [deciliter]. I try to put women at 80-100 which would be a very severely hypogonadal man. And I have, I think I follow about 100 women on testosterone. I haven't heard about any woman tell me that she developed a beard, that her voice changed, that she had acne, or that her clitoris was increasing in size. Never heard of that.

Dr Louise Newson [00:22:32] No. I mean, we have thousands of women use testosterone, and we've got data for nearly 10 years now, and we do not have bearded patients. You know, they don't shave their faces, but actually, even if it caused side effects, I would still, as a menopausal woman, want to take it, because testosterone has transformed my brain. It's enabled me to continue working, it's enabled me to exercise, it's enabled me to sleep, it's enabled me to just be an independent person, so even if I was getting side effects as a patient, I'm allowed to choose and, and I can balance benefits versus risks. But you know, we hear all the time that women are just refused it for the wrong reasons, and they're often given antidepressants or antipsychotics, and we see a lot of women on antipsychotics that have actually very negative metabolic consequences. We know antipsychotics can increase risk of hypertension, diabetes, osteoporosis, and, you know, reduce sexual function as well. So, it's even worse, actually, for a lot of these people.

Dr Franck Mauvais-Jarvis [00:23:40] And probably, and when I say probably, I mean, what the studies suggest is that, because testosterone in women, at you know, women physiological dose, high physiological dose for women, the reason why testosterone is important is that by increasing muscle mass, it actually decreases fat mass.

Dr Louise Newson [00:24:03] Yeah.

Dr Franck Mauvais-Jarvis [00:24:04] So the effect on fat is probably dependent on the effect of on muscle.

Dr Louise Newson [00:24:09] Absolutely, and I really agree. So just beforewe end, I just wanted to thank you publicly, actually, because you invited meto co-author two chapters of your book, which has just come out. It's a reallyamazing book, and I can't wait to read the rest. You've had the pleasure ofreading it all, but just, can you just tell us a little bit about the book andwhy you wanted to do it?

Dr Franck Mauvais-Jarvis [00:24:31] So it's a book about precision hormone therapy,which obviously includes a large first part on menopausal hormone therapy,every aspect of menopausal therapy, from private practice to academic practice,breast cancer, progestogens, diabetes, cognition etc. There’s also, of course,a very important part on testosterone therapy. But you know precision hormonetherapy is also important with regard to thyroid hormone therapy and growthhormone therapy. So, it's really about the bioidentical hormones, which arevery important to maintain health span. You know, it's not going to increaseour lifespan, but it is clearly improving the health span. So they are, theyare anti-ageing hormones, whatever they say, the data, the science is there, theyare anti-ageing hormones. That's why I wanted to, you know, collect a group ofexperts and edit that book. And that's why I wanted to have you in the book.

Dr Louise Newson [00:25:52] Well, it was great, and I, it was lovely to be able to write about the role of the immune system, but also mitochondria, and how important mitochondrial function is for our health, but how our hormones, all three, estradiol, progesterone, testosterone, have really key roles in mitochondrial function. So, the book is written more for doctors and healthcare professionals, but I think there's a lot of public people, as in, non-healthcare professionals that will really enjoy it, because it's very evidence based. It's very well referenced, and there's a lot of information that people will want to read and understand from it I think.

Dr Franck Mauvais-Jarvis [00:26:33] You know, you just said something very important that I think we should say a few words about, is the importance of estrogen in mitochondria. And you know, I think evolutionary speaking, that's what estrogens were designed to do, because the ancestral estrogen receptor evolved 500million years ago, approximately, before any other steroid receptor, before the stress hormone receptor, before anything, and it evolved in in mollusks and annelids, you know, worms, these animals, they didn't have sexual reproduction. So, the reason why there was an estrogen receptor there, and there was not even estrogen is that probably they were using phytoestrogen, environmental estrogen, to bind the receptor and to protect survival and to promote energy and to protect the mitochondria, because one of the very important things we know today, is that mitochondrial function is geared toward women metabolism. Mitochondria in women are much more functional, have less mitochondrial DNA damage, less oxidative stress, and better function than mitochondria of men. And why? Because women have higher level of estradiol. Not only they transmit the mitochondria, but they have high level of estradiol to protect the mitochondria. So, I think estrogen are very important for mitochondria, but testosterone in men is a reservoir of estradiol. And most of the beneficial effect of testosterone in men, apart from muscle mass, are mediated via estradiol, via conversion to estradiol, including erection and libido.

Dr Louise Newson [00:28:28] Yeah, so we should be doing more studies in men about the importance of estradiol in the metabolism and longevity and mitochondrial function of men, because men get really freaked out when I say to them that they've got more estradiol in their body often than menopausal women who don't take hormones.

Dr Franck Mauvais-Jarvis [00:28:49] I see a lot of men who come when I put them on testosterone, oh, doctor, you know, I have a high level of the female hormone. I have to explain to them it's not a female hormone. And I also see men who come treated by some outside doctors in women's health clinic who put them on testosterone with an aromatase inhibitor. Basically, they eliminate all the beneficial effects on testosterone, especially on vessels, because men with aromatasemutation who do not make estradiol they die of a heart attack soon. Not only they have osteoporosis, but they die of heart attack. So, I have to explain to them, listen, it's not a female hormone. Without estradiol, you wouldn't have a hard on. I tell them exactly like this, they never asked me the question again. They understand.

Dr Louise Newson [00:29:38] Yeah, it's so important. I could listen to you forever, but before we end. I always ask for three sort of take-home tips, learning tips. So, I'd really like to ask you three ways that estradiol can improve metabolism in men and women. What are the three key things that you think are most important about the metabolic effects of estradiol?

Dr Franck Mauvais-Jarvis [00:30:03] One, one thing is the effect on mitochondria.

If you improve mitochondria, the powerhouse of the cell, you improve metabolism, and you prevent metabolic dysfunction. So, I think it's the most important thing. Then there is, like you said, the very important effect on the immune system and the prevention of inflammation. And then if I had to choose a third one, I think it would be the brain cognition. But there are lots of other effects. Basically, estradiol works on every single organ and cell.

Dr Louise Newson [00:30:45] It's amazing. It's so important, yet it's been neglected for so long, so well, thank you so much, and hopefully I'm coming outto America at some stage soon but thank you so much for your time. I've really enjoyed it. Thank you.

Dr Franck Mauvais-Jarvis [00:30:58] Was my pleasure to be here.