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 goodfriend and colleague, Professor Franck Mauvais-Jarvis from US. He's a professorof Endocrinology with a special interest in metabolism. So, we talk a lot aboutthe role of hormones, oestradiol, especially, but also testosterone inmetabolism, in reducing incidents of diabetes, and we talk about mitochondria,the powerhouse of our cells, and how that can improve in the presence of oestradiol.So, enjoy it. So, Frank. It's really exciting. I feel like I've known you forquite a long time, but I can't remember when I first, I think I reached out toyou, 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 theother night, and I was - I read it out to my husband the line because it wassaying, there is good evidence that oestrogen protected people from COVID. AndI was saying to him, why wasn't anyone listening at the time? Like it was sofrustrating. But what, what I love about your work is that you're interested inthe metabolic processes that occur in the body. And there are very few people,really, I think, that understand the importance of hormones, oestradiol, progesteroneand testosterone, on improving our metabolism and reducing inflammation. So canyou 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 medicineand endocrinology in the hospitals of Paris and France. It's a complicatedstory. 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 withRon Khan, was actually one of the best lab to go at the time, but let's sayright now, I am endocrinologist. I take care of menopausal women andtestosterone deficient men at the Veterans Medical Center in New Orleans. ButI'm also leading a research lab on oestrogen, progesterone and testosterone inmetabolism. I'm also director of an NIH-supported centre of excellence in sex-basedprecision medicine at Tulane University School of Medicine and I'm professor ofmedicine 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. Myfather, when I was a kid, was a reproductive endocrinologist in France. Heactually was one of those who helped develop Oestrogel, the gel that women puton their skin. And the story, and nobody knows, is that he was working on thepercutaneous absorption of steroids, and he used oestradiol, tritiated, youknow, radioactive oestradiol. Brought the cream home one night, and he put iton the skin of my mother, and then he collected her urine, and he foundradioactivity. 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 goingthrough the skin.

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

Dr Franck Mauvais-Jarvis [00:04:34] Well, it was in 1969 that he did thisexperiment, that Oestrogel 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 myclinical training in endocrinology in Paris, I’d never heard of conjugatedequine oestrogens. We were, we were prescribing body identical hormones, youknow, oestradiol, progesterone and testosterone. And I actually heard the firsttime about, I mean, I heard I knew what it was, but I heard the first timeabout 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, thehysterical report of the WHI. You know, me, I was not surprised. I was notsurprised. 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 ablanket decision that all hormones were bad. And I was reading the reportrecently where they decided that they should label hormones as carcinogens, soall types of oestrogen were labelled, then as carcinogenic, so as in causingcancer as a result of that study. But that wasn't the same as oestradiol orprogesterone. I mean, the biggest concern really, from the WHI, the Women'sHealth Initiative study, was the medroxyprogesterone acetate, which is thesynthetic progestogen, wasn't it?

Dr Franck Mauvais-Jarvis [00:06:32] First of all, oestrogen 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 oestrogenalone, there was already a 30% decreased risk of breast cancer. And today, weknow because there are lots of studies that have been done, and there's arecent meta-analysis showing that CEE or oestradiol alone in women without auterus clearly significantly protect from breast cancer, when you add a progestogen,and especially a synthetic progestogen like medroxyprogesterone acetate, thenat the time of the WHI, that's when you had a signal a small increased risk ofbreast cancer. But if you think about the absolute risk, it was one or twowomen out of 10,000, so that's a very minimal risk. And first of all, it wasnot even significant. But today, if we look at the data, there is still a minorincreased risk. It's not always significant when a progestogen is added to anytype of oestrogen, and there is especially a minor risk if it's a synthetic progestogen.And probably the reason is that oestradiol increases the expression of theprogesterone receptor, and when you add progestogen on that, it may, in certaincircumstances, increase the risk. But this is a very, very minor increasedrisk, you know, if you compare it with what happens when you don't takehormones.

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, youknow, I'm a physician, not a gynaecologist, as you know, and I'm veryinterested in the immune regulating effects of hormones, so how we can reduceinflammation 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 farmore prevalent than ever before, really, but we've know even from the WHIactually looking at diabetes, there's a lower instance of diabetes in women whotake hormones, and there's a better sugar glucose control as well. And I'veseen quite a few patients who have type one or type two diabetes, and theirdiabetes control has just become haywire when they become perimenopausal, andthen they have the hormones back. But it's all three hormones can affectmetabolism in a beneficial way. But I don't know why we're not shouting fromthe rooftops about this, because to have a simple medicine that's a naturalhormone reducing risk of diabetes as well as breast cancer. But you know, justlooking 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 ofthe poorly reported effects of oestrogens in the Women's Health Initiative, ifyou look at the data, there was at five years, a 25% decreased risk ofdiabetes. And if you continued after the follow up, 13 years, there was even agreater decreased risk of diabetes. So, the decreased risk of diabetes with oestrogenalone, and even oestrogen with progestin, was as powerful as the effect inpreventing fractures, nobody speaks about that, and it's been reproduced a lotof other trials. Because oestradiol has several beneficial effects. It improvesinsulin sensitivity,it decreases visceral fat, it improves insulin production.And like you said before, it decreases inflammation and all that is veryimportant for glucose homeostasis. Overall, the insulin resistance, when youmeasure 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 diabeticwomen, of course, but the improvement in insulin sensitivity and the preventionof diabetes works in non-diabetic women, and the effect is stronger with oral oestradiol,because than transdermal, because of the first-pass liver metabolism. So, whenyou give oral oestradiol, you have a greater - so you shower the liver througha portal vein, and you have a greater suppression of hepatic glucoseproduction. It's the same reason why oral oestradiol has a greater effect onlowering LDL cholesterol and increasing HDL cholesterol than transdermalbecause of that first-pass liver metabolism.

Dr Louise Newson [00:11:55] And this is very interesting, and I just wantto sort of elaborate a little bit, because there's a lot of confusion betweentablet oestrogen, because people think about risks with tablet but it's verydifferent. When you ingest ethinylestradiol to oestradiol, because ethinylestradiolis a chemical, it's got an ethaniol bit added to it, and so when it goes intothe 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 inthe 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 riskof blood clot, deep venous thrombosis with oral oestradiol is very minimal inany women without, without taking any oestrogen. The risk is about between oneand three out of 100,000. And on oral oestrogen, whatever the oestrogen 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 oestrogens.The risk with oral oestradiol is very minimal, and especially, you know, it'salways the same thing. People mix all, all, women in the same bag. But it'snot, 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 cantake oral oestrogen without a problem. Of course, if somebody has a history ofblood clots, is obese, is sedentary, and has hypertension, or things that youwould, you would pay more attention. But still, the rich with, the risk withCEE, compared with conjugated oestrogen, compared with, ethinylestradiol is 100times more potent than oestradiol. It's not the same molecule.

Dr Louise Newson [00:14:17] Yeah, it's very important to distinguishbetween 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 theevidence and the science, but I want to individualise care for patients. Andwe've known for decades that different women often need different doses toimprove 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 theclinic working out the best formulation, the best dose, but also whetherpatches, gels, tablets, or sometimes a combination. And that really, really canvary between patients, can't it?

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

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

Dr Franck Mauvais-Jarvis [00:16:14] So why would we not measure oestradiol levelto 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'stwo 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 aswell. I saw someone yesterday in my clinic whose level of oestradiol was reallyhigh, and it didn't fit in with the clinical situation. And I said to her, didyou use your gel in the morning of the test? She said, oh, yes, I rubbed it alldown my arm. Oh, perhaps I shouldn't have done that. So it was probably acontaminated sample, and we'll just do it again when she hasn't rubbed it overwhere 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 patchesaren't sticking on very well. And so, one of my patients has been very worriedabout her mental health. She's taken a real dip in her mental health. And Ispoke 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. Andtaking a clearer history, she was also having some urinary symptoms. She washaving some muscle and joint pains, and she was having some palpitations, butshe 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 oestradiol wastriggering 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. Andas you know, a lot of people have worsening symptoms when their hormones arechanging and fluctuating. It's not just the absolute levels, so we really needto think about that. But the other part, when you talk about testosteronelevels in men, it absolutely makes sense, and the same in women. But I justwanted to ask you something, because I don't want to be rude about your ageFranck, but you know, we're both quite old, and we would have done our medicaltraining basing all the studies on the treatment we give on men. It usually wasa 70kg man, wasn't it, that the research was done when we think aboutmedication for diabetes, for hypertension, for antibiotic dosing, everything isalways based on a 70kg man. Luckily, the year, actually, I graduated in ‘94 wasthe first year that people started to realise women should be included instudies, 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 testosteronecan reduce incidence of diabetes, hypertension, cardiovascular disease,dementia, because we have good evidence for men, I'm told, but Louise, we don'thave the studies of women, therefore we can't use it for women and tell themabout these benefits, and it feels a bit not fair, really, because it's onemedicine 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 forhyposexual desire, but testosterone at any time in a woman's life, especially,you know during reproductive years, is 50 times more abundant than oestradiol. So,do you think that a hormone that is 50 times most abundant, it's actually themost abundant active sex steroid. I don't think it's only for libido or sexualdesire. It is for metabolism. It is an important metabolic hormone. Andactually there are studies, there are studies, small, randomised trial andother type of interventional studies that show that, first of all, it increasedlean mass in women. Second, it increased bone mass on top studies that weredone in menopausal women. It increases bone mass on top of oestradiol effect,and it even helped women with cardiac failure to have a better oxygenation. Soyes, I think it's clear that testosterone is important to women, and actuallyanimal studies, it's always important to look at animal studies to confirm andunderstand what we cannot go deep enough in humans, but in animal studies, itclearly shows that both oestrogen via oestrogen receptor alpha and testosteroneand DHT via the androgen receptor are necessary for bone. You know they don'twork on the same thing. One works on cortical bone, the other works on atrabecular bone. So, they are both, they are both synergising. I personallygive testosterone to any women that I see, if she wants it, I measure theconcentration in the serum, and I try to put it at the upper limit of thefemale 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 avery severely hypogonadal man. And I have, I think I follow about 100 women ontestosterone. I haven't heard about any woman tell me that she developed abeard, that her voice changed, that she had acne, or that her clitoris wasincreasing in size. Never heard of that.

Dr Louise Newson [00:22:32] No. I mean, we have thousands of women usetestosterone, and we've got data for nearly 10 years now, and we do not havebearded patients. You know, they don't shave their faces, but actually, even ifit 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 continueworking, it's enabled me to exercise, it's enabled me to sleep, it's enabled meto just be an independent person, so even if I was getting side effects as apatient, 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 wrongreasons, and they're often given antidepressants or antipsychotics, and we seea lot of women on antipsychotics that have actually very negative metabolicconsequences. We know antipsychotics can increase risk of hypertension,diabetes, osteoporosis, and, you know, reduce sexual function as well. So, it'seven 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 whytestosterone is important is that by increasing muscle mass, it actuallydecreases fat mass.

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

Dr Franck Mauvais-Jarvis [00:24:04] So the effect on fat is probably dependent onthe 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 beable to write about the role of the immune system, but also mitochondria, andhow important mitochondrial function is for our health, but how our hormones,all three, oestradiol, progesterone, testosterone, have really key roles inmitochondrial function. So, the book is written more for doctors and healthcareprofessionals, but I think there's a lot of public people, as in, non-healthcareprofessionals that will really enjoy it, because it's very evidence based. It'svery well referenced, and there's a lot of information that people will want toread and understand from it I think.

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

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

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

Dr Louise Newson [00:29:38] Yeah, it's so important. I could listen to youforever, 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 oestradiol canimprove metabolism in men and women. What are the three key things that youthink are most important about the metabolic effects of oestradiol?

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 improvemetabolism, and you prevent metabolic dysfunction. So, I think it's the mostimportant thing. Then there is, like you said, the very important effect on theimmune system and the prevention of inflammation. And then if I had to choose athird one, I think it would be the brain cognition. But there are lots of othereffects. Basically, oestradiol 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.