Latest / The Dr Louise Newson Podcast / 20 - Hormones and metabolism: Unlocking the science with Professor Franck Mauvais-Jarvis

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20 - Hormones and metabolism: Unlocking the science with Professor Franck Mauvais-Jarvis · The Dr Louise Newson Podcast

0:00
Some of you might know already, but this podcast has been
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Thank you so much. So in this podcast, I've got a
0:25
really good friend and colleague, Professor Frank Movey
0:28
Jarvis from US. He's a professor of
0:31
endocrinology with a special interest in metabolism.
0:35
So we talk a lot about the role of hormones, estradiol
0:39
especially, but also testosterone in metabolism, in
0:42
reducing incidence of diabetes. And we talk about mitochondria,
0:47
the powerhouse of ourselves, and how that can improve in the
0:50
presence of estradiol. So enjoy it.
0:55
So Frank, it's really exciting. I feel like I've known you for
0:59
quite a long time, but I can't remember when I first, I think I
1:02
reached out to you, didn't I? Because I'd read one of your
1:05
great papers. Was at the beginning of COVID.
1:08
Yeah. And in fact, I was reading a
1:10
paper the other night and I was, I read it out to my husband, the
1:13
line, because it was saying there is good evidence that
1:17
estrogen protected people from COVID.
1:20
And I was saying to him, why wasn't anyone listening at the
1:23
time? Like it was so frustrating.
1:26
But what what I love about your work is that you're interested
1:29
in the metabolic processes that occur in the body.
1:32
And there are very few people really, I think that understand
1:36
the importance of hormones, estradiol, progesterone and
1:39
testosterone on improving our metabolism and reducing
1:44
inflammation. So can you just tell me a bit
1:47
about your background and why you're doing what you're doing,
1:52
a bit about the research that you've done for so many years?
1:55
I'm an endocrinologist. I trained in internal medicine
2:01
and endocrinology in hospitals of Paris in France.
2:07
It's a complicated story. I moved to the US to do a post
2:10
doctoral fellowship to study metabolism, you know, and I was
2:14
at the Jostling Diabetes Centre and Harvard Medical School with
2:19
Ron Khan was actually one of the best lab to go at the time.
2:23
But let's say right now I am endocrinologist.
2:26
I take care of menopausal women and testosterone deficient men
2:31
at the Veterans Medical Center in New Orleans.
2:35
But I'm also leading a research lab on estrogen, progesterone
2:44
and testosterone in metabolism. I'm also a director of an NIH
2:52
supported Center of Excellence in Sex based Precision medicine
2:57
at Tulane University School of Medicine.
3:01
And I'm professor of medicine at, at, at at Tulane.
3:05
So that's where that's where we stand now.
3:08
Now you ask me, why did they got interested into that?
3:11
You know, it's a very long story.
3:12
My father, when I was a kid with a reproductive and
3:16
doctrinologist in in France, he actually was one of those who
3:23
helped develop estro gel, the gel a woman put on their skin.
3:28
And the story of Nobody Knows is that it was working on the
3:33
percutaneous absorption of steroids.
3:36
And he used estradiol, triciaated, you know,
3:42
radioactive estradiol, brought the cream home one night and he
3:46
put it on the skin of my mother. And then he collected her urine
3:51
and he found radioactivity. That's what a in 1969. 1969.
3:58
One of the first evidence that steroid hormone were going
4:03
through the skin. Amazing but I'm confused because
4:09
that's 1969 and that was Easter dial but around that time it was
4:14
all conjugated equine estrogens. It was the pregnant horses urine
4:19
or it was ethanol Easter dial. So certainly in the UK and US
4:24
that was the go to prescription for HRTI know it was slightly
4:28
different in the continent, but why were people not thinking
4:31
more about Easter dial? Well, it was in 1969 that he did
4:36
this experiment, but Estrogel was developed in France in 1986.
4:45
So the question why? Well, you know, when I, when I
4:49
went to medical school and when I did my clinical training and
4:55
endocrinology in, in Paris, I never heard of, of conjugated
5:01
equine estroges. We, we were, we were prescribing
5:06
body identical hormones, you know, estradiol, progesterone
5:09
and, and testosterone. And I actually heard the first
5:14
time about, I mean, I heard, I knew what it was, but I heard
5:18
the first time about CEE and, and medioxy progesterone acetate
5:24
during the earthquake of 2002. You know, the Women's Health
5:28
Initiative trial report by the, by the media and by JAMA, the
5:36
hysterical report of the WHI you know, me, I was not surprised.
5:42
I was surprised because we were prescribing other types of
5:46
hormones. And so I was.
5:48
I was incredible from the beginning.
5:54
Well, it was so wrong because then they made a blanket
5:57
decision that all hormones were bad.
6:00
And I was reading the report recently where they decided that
6:05
they should label hormones as carcinogens.
6:08
So all types of estrogen were labeled then as carcinogenic, so
6:14
as in causing cancer as a result of that study.
6:17
But that wasn't the same as estudiol or progesterone.
6:21
I mean, the biggest concern really from the WHI, the Women's
6:25
Health Initiative study was the magoxy progesterone acetate,
6:29
which is the synthetic progesterone, wasn't it?
6:31
First of all, estrogen are not carcinogen because we know today
6:37
actually they knew it from the the beginning during the WHR,
6:41
the arm without the arm in women without a uterus, the arm with
6:48
conjugated estrogen alone, there was already a 30% decreased risk
6:53
of breast cancer. And today we know because there
6:56
are lots of studies that have been done and there's there's a
6:59
recent meta analysis showing that CEE or estradiol alone in
7:06
women without uterus clearly significantly protect from
7:11
breast cancer. When you add a progesterone and
7:13
especially a synthetic progesterone like mirroxy
7:17
progesterone acetate, then at the time of the WHI that's when
7:23
you had a signal a a small increase risk of breast cancer.
7:29
But if you think about the absolute risk, it was one or two
7:34
or two women out of 10,000. So that's a very minimal risk.
7:39
And first of all, it was not even significant.
7:42
But today, if we look at the data, there was still a minor
7:48
increase risk. It's not always significant when
7:50
a progesterone gene is added to any type of estrogen.
7:57
And there is especially a minor risk if it's a synthetic
8:01
progesterone. And probably the reason is that
8:07
estradiol increases the expression of the progesterone
8:12
receptor. And when you add progesterone on
8:16
that, it may in certain circumstances increase the risk.
8:19
But this is a very, very minor increase risk, you know, if you
8:24
compare it with what happens when you don't take hormones.
8:30
Absolutely. And that is a big difference
8:31
actually when you're comparing the risks of not having
8:34
hormones. And you know, I'm a physician,
8:37
not a gynecologist, as you know, and I'm very interested in the
8:41
immune regulating effects of hormones.
8:43
So how we can reduce inflammation in our body, how we
8:46
can improve our metabolism as in our bodies and reduce future
8:51
risk of diseases, including diabetes, which we know is far
8:56
more prevalent than ever before, really.
8:59
But we've known even from the WHI actually looking at
9:02
diabetes, there's a lower incidence of diabetes in women
9:06
who take hormones and there's a better sugar, you know, glucose
9:11
control as well. And I've seen quite a few
9:14
patients who have type one or type 2 diabetes and their
9:19
diabetes control has just become haywire when they've become
9:22
perimenopausal and then they have the hormones back.
9:26
But it's all three hormones can affect metabolism in a
9:29
beneficial way. But I don't know why we're not
9:32
shouting from the rooftops about this because to have a simple
9:37
medicine that's a natural hormone reducing risk of
9:41
diabetes as well as breast cancer, but you know, just
9:45
looking at metabolic effects of diabetes, that's really
9:47
important, isn't it? It is right and in fact it's one
9:53
of the poorly reported the effect of estrogens in in the
10:00
Women's Health Initiative. If you look at the data, there
10:04
was a five years, a 25% decreased risk of diabetes and
10:08
if you continued after the the follow up 13 years, there was
10:11
even a a greater decreased risk of diabetes.
10:13
So the decreased risk of diabetes with estrogen alone and
10:18
even estrogen with progestin was as powerful as the effect in
10:25
preventing fractures. Nobody speaks about that.
10:28
And it's been reproduced a lot of other trials because
10:31
estradiol has several beneficial effects.
10:34
It improves insulin sensitivity, it decreases visceral fat, It
10:40
improves insulin production. And like you said before, it
10:44
decreases inflammation and all that is very important for
10:47
glucose hernostasis. Overall the insulin resistance
10:53
when you measure that by Houma is improved by about 30%.
11:00
But what is interesting is that it's the effect and it works in
11:05
in diabetic women of course, but the improvement in insulin
11:08
sensitivity and the prevention of diabetes works in non
11:11
diabetic women. And the effect is stronger with
11:17
oral estradiol because than transdermal because of the first
11:23
past liver metabolism. So when you give oral estradiol,
11:28
you have a greater, so you shower the liver through a
11:31
portal vein and you have a greater suppression of hepatic
11:37
glucose production. It's the same reason why oral
11:40
estradiol has a greater effect on lowering LDL cholesterol and
11:48
increasing HDL cholesterol than transdermal because of that
11:53
first pass liver metabolism. And this is very interesting and
11:56
I, I just want to sort of elaborate a little bit because
11:59
there's a lot of confusion between tablet estrogen because
12:03
people think about risks with tablet, but it's very different
12:07
when you ingest ethanol estradiol to estradiol, because
12:12
ethanol estradiol is a chemical. It's got an ethanol bit added to
12:17
it. And so when it goes into the
12:19
liver, it will activate clotting factors.
12:21
It will work very differently in the liver rather than the pure
12:25
estradiol. And I don't know what it's like
12:28
in the US, but in the UK there's only one contraceptive that
12:32
contains estradiol. All the others are ethanol,
12:35
estradiol, whereas most doctors would just say it's estrogen and
12:39
they won't know the difference. And metabolically, this is
12:43
really, really important actually.
12:45
Yes. And the, the risk DVT, you know,
12:48
the, the risk of blood clot deep venous thrombosis with oral
12:53
astrolio is very minimal in, in any women without, without
12:58
taking any estrogen, the risk is about between 1:00 and 3:00 out
13:04
of 100,000. And on oral estrogen, whatever
13:09
the estrogen is, it's about 3 to 15.
13:13
So that would be 3 times more. But it's still, it's still very,
13:17
very little, you know, but that's all over the, the, the,
13:21
the board all estrogens, the risk with our estrogen is very
13:26
minimal. And especially, you know, it's,
13:29
it's always the same thing. People mix all all women in the
13:34
same bag, But it's not, this is not precision medicine, you
13:38
know, you know, if you take women who are healthy, who are
13:44
not obese, we don't have any history of blood clots.
13:48
I mean, they can take oral estrogen.
13:49
We have a problem of course, if somebody has a history of blood
13:53
clots, he's obese, he's sedentary and has hypertension
13:57
or things that you would you would pay more attention.
14:00
But still the risk with the risk with CEE compared the conjugated
14:07
estrogen compared with estradiol ethanol, estradiol is 100 times
14:13
more potent than estradiol. It's not the same molecule.
14:16
Yeah, it's very important to distinguish between the
14:20
difference. And, you know, when you talk
14:22
about precision medicine, it's really important because as a
14:26
clinician, of course I want to use the evidence in the science.
14:29
But I went to individualized care for patients.
14:33
And we've known for decades that different women often need
14:37
different doses to improve their symptom control and also their
14:41
future health. And we've known this with oral
14:45
and transdermal medication. And we spend a lot of the time
14:49
in the clinic working out the best formulation and the best
14:53
dose, but also whether patches, gels, tablets or sometimes a
14:58
combination. And that really, really can vary
15:01
between patients concept. And actually it takes me to a
15:05
another problem of the current recommendations is that we it is
15:11
not recommended that you measure Estrada levels and and women.
15:16
I know you do because you're a forward thinking in a modern
15:21
physician, but it's now recommended that you measure
15:24
estradiol level in women. So basically what is recommended
15:27
is to consider the treatment is efficient if hot flashes are
15:32
corrected, but it doesn't tell you if you have a serum
15:37
concentration of estradiol that are therapeutic for
15:40
osteoporosis. And, and all studies have shown
15:44
that you needed about 80 to 100 picogram per ML minimum to
15:49
prevent osteoporosis 100%. And usually when you use gels or
15:55
patches, you don't know where you are and, and, and very often
16:02
you're below 60 picogram per ML. So you may protect hot flashes,
16:07
which is already good. You don't know if you have
16:09
enough estrol to prevent osteoporosis.
16:12
So why would we not measure estradiol level to supplement
16:19
women, but we measure testosterone level when we
16:23
supplement men? What does it mean?
16:26
It makes no sense, does it? And I think there's, there's,
16:29
there's two things that are really interesting in that.
16:31
Firstly is that any tests we do in medicine is a guide and it
16:36
helps us, but it has to be in clinical contexts as well.
16:39
I saw someone yesterday in my clinic whose level of estradiol
16:42
was really high and it didn't fit in with the clinical
16:46
situation. And I said to her, did you use
16:48
your gel in the morning of the test?
16:50
She said, Oh yes, I rubbed it all down my arm.
16:53
Oh, perhaps I shouldn't have done that.
16:55
So it was probably a contaminated sample and we'll
16:58
just do it again when she hasn't rubbed it over where the needle
17:01
went in. But also there was another
17:04
patient of mine over here. It's very unusual, but it's been
17:07
really warm, Frank, which and a lot of patches aren't sticking
17:11
on very well. And so one of my patients has
17:14
been very worried about her mental health.
17:16
She's taken a real dip in her mental health.
17:19
And I spoke to her and she was getting worse in migraines as
17:22
well. And she said, but I've not
17:24
changed anything. Everything is the same.
17:26
I don't understand. And taking a clearer history,
17:29
she was also having some urinary symptoms.
17:31
She was having some muscle and joint pains, and she was having
17:34
some palpitations, but she thought they weren't significant
17:38
to tell me. It was only when I asked her.
17:40
And then I got her to show me the patches and they were
17:44
bubbling and lifting. And so this inadequate or
17:48
suboptimal absorption of the estradiol was triggering her
17:51
symptoms, but it was worse actually because it was
17:54
intermittent. So I'm sure at night time when
17:57
it's cooler, they were absorbing better.
17:59
And as you know, a lot of people have worsening symptoms when
18:02
their hormones are changing and fluctuating.
18:04
It's not just the absolute levels.
18:07
So we really need to think about that.
18:09
But the other part when you talk about testosterone levels in
18:13
men, it's absolutely makes sense and the same in women.
18:17
But I just wanted to ask you something because I don't want
18:21
to be rude about your age, Frank, But you know, we're both
18:25
quite old and we would have done our medical training basing all
18:30
the studies on the treatment we give on men.
18:33
It's usually was a 70 kilogram man, wasn't it?
18:35
That the the research was done? When we think about medication
18:40
for diabetes, for hypertension, for antibiotic dosing,
18:44
everything is always based on a 70 kilogram man.
18:48
Luckily the year actually I graduated in 94 was the first
18:52
year that people started to realise women should be included
18:55
in studies, which is great. But somehow when it comes to
19:00
testosterone for women, we're not allowed to look at the male
19:05
studies. So when I say that testosterone
19:08
can reduce incidence of diabetes, hypertension,
19:11
cardiovascular disease, dementia, because we have good
19:14
evidence for men, I told. But Louise, we don't have the
19:17
studies of women, therefore we can't use it for women and tell
19:20
them about these benefits. And it feels a bit not fair
19:24
really, because it's one medicine that we're not allowed
19:26
to look at the men's data, the. Underground society say, you
19:30
know, it's, it should be approved only for a hyposexual
19:33
desire, but testosterone at any time in a woman's life,
19:40
especially, you know, during reproductive years is 50 times
19:44
more abundant than estradiol. So do you think that a hormone
19:49
that is 50 times most abundant, it's actually the most abundant
19:53
active sex steroid? I don't think it's only for
19:58
libido or sexual desire. It is for metabolism.
20:02
It is an important metabolic hormone.
20:05
And actually there are studies, there are studies small
20:09
randomized trial and and other type of interventional studies.
20:14
That show that first of all it increased lean mass in women,
20:19
second it increased bone mass on top studies that were done in
20:24
menopausal women, it increases bone mass on top of astrolio
20:29
effect and it even help women with cardiac failure to have a
20:35
better oxygenation. So yes, I think it's clear that
20:41
testosterone is important to women and actually animal
20:44
studies, it's always important to look at anymore studies to
20:48
confirm and, and and understand what we cannot go deep enough in
20:53
humans. But in animal studies it clearly
20:56
shows that both estrogen via estrogen receptor alpha and
21:02
testosterone and DHTV are the androgen receptor unnecessary
21:06
for bone. You know they don't work on the
21:09
same thing. One works on cortical bone, the
21:13
other works on a a tabicular bone.
21:15
So they are both they are both synergizing.
21:20
I personally give testosterone to any women that I see.
21:25
If she wants it, I measure the concentration in the serum and I
21:31
try to put it that the upper limit of the female
21:36
concentration, let's say testosterone in women is between
21:40
20 and 80 and and 70 nanogram per DL.
21:45
I try to put women at 8100, which would be a very severely
21:50
hypogonal men and I have I think I follow about 100 women on
21:55
testosterone. I haven't heard about any women
21:58
tell me that she developed a beard, that her voice changed,
22:04
that she had acne, or that her clitoris was increasing in size.
22:10
Never heard of that, no. I mean, we have thousands of
22:13
women use testosterone and we've got data for nearly ten years
22:16
now and we do not have bearded patients, you know, they don't
22:20
shave their faces. But actually even if it caused
22:24
side effects, I would still as a menopausal women want to take it
22:27
because testosterone has transformed my brain.
22:30
It's enabled me to continue working, it's enabled me to
22:34
exercise, it's enabled me to sleep, it's enabled me to just
22:38
be an independent person. So even if I was getting side
22:42
effects as a patient, I'm allowed to choose and and I can
22:46
balance benefits versus risks. But you know, we hear all the
22:50
time that women have just refused it for the wrong
22:53
reasons. And they're often given
22:55
antidepressants or antipsychotics.
22:57
And we see a lot of women on antipsychotics that have
23:01
actually very negative metabolic consequences.
23:04
We know antipsychotics can increase risk of hypertension,
23:08
diabetes, osteoporosis, and, you know, reduce sexual function as
23:14
well. So it's even worse actually for
23:16
a lot of these people. And probably, and, and when I
23:21
say probably, I mean what the studies suggest is that because
23:28
testosterone in women at, you know, women physiological dose,
23:33
high physiological dose for women.
23:36
The reason why testosterone is important is that by increasing
23:39
muscle mass, it actually decreases fat mass.
23:42
So the effect on fact is probably dependent on the effect
23:46
of on on muscle, Absolutely. And I really agree.
23:50
So just before we end, I just wanted to thank you publicly
23:54
actually because you invited me to co-author 2 chapters of your
23:57
book which has just come out. It's a really amazing book and I
24:01
can't wait to read the rest. You've had the pleasure of
24:04
reading it all, but just can you just tell us a little bit about
24:07
the book and why you wanted to do it?
24:11
So it's a book about precision hormone therapy, which obviously
24:17
includes a large first part on menopausal hormone therapy,
24:24
every aspect of menopausal therapy from private practice to
24:31
academic practice, breast cancer, progestogens, diabetes,
24:38
cognition, etcetera. There's also of course a very
24:41
important part on testosterone therapy, but you know, a
24:47
precision hormone therapy is also important with regard to
24:51
thyroid hormone therapy and growth hormone therapy.
24:55
So it's really about the bioidentical hormones which are
25:02
very important to maintain health span.
25:06
You know, it's not going to increase our lifespan, but it is
25:10
clearly improving the health span.
25:13
So they are, they are anti aging hormones.
25:16
Whatever they say, the data, the science is there.
25:20
They are anti aging hormones. That's why I wanted to, you
25:25
know, collect a group of experts and and edit that book.
25:29
And that's why I wanted to have you in the book.
25:31
Well, it was. Great.
25:32
And I it was lovely to be able to write about the role of the
25:37
immune system but also mitochondria and how important
25:42
mitochondrial function is for our health.
25:44
But how the hormones, all three estradiol, progesterone,
25:47
testosterone have really key roles in mitochondrial function.
25:51
So the book is written more for doctors and healthcare
25:55
professionals, but I think there's a lot of public people,
25:59
as in non healthcare professionals that will really
26:01
enjoy it because it's very evidence based.
26:04
It's very well referenced and there's a lot of information
26:07
that people will want to read and understand from it.
26:11
I think you know, you just. Said something very important
26:14
that I think we should say a few word about is the, the
26:17
importance of estrogen in mitochondria.
26:21
And you know, I think evolutionary speaking, that's
26:26
what estrogens were designed to do because the the ancestral
26:32
estrogen receptor evolved 500 million years ago approximately
26:38
before any other steroid receptor, before the stress
26:42
hormone receptor, before anything.
26:45
And it evolved in in molluscs and anilines, you know, worms
26:51
these anymore they didn't have sexual reproduction.
26:54
So the reason why there was an estrogen receptor there and
26:58
there was not even estrogen is that probably they were using
27:03
phytoestrogen, environmental estrogen to binary receptor and
27:07
to protect survival and to promote energy and to protect
27:12
the mitochondrial. Because one of the very
27:14
important thing we know today is that mitochondrial function is
27:19
geared toward women metabolism. Mitochondria in women are much
27:24
more functional, have less mitochondrial DNA damage, less
27:30
oxidative stress and better function than mitochondrial men.
27:35
And why? Because women have higher level
27:37
of estradiol, not only they transmit the mitochondria, but
27:42
they have high level of estradiol to protect the
27:44
mitochondria. So I think estrogen are very
27:46
important for mitochondria, but testosterone in men is a
27:52
reservoir of estradiol and most of the beneficial effect of
27:56
testosterone in men apart from muscle mass are mediated via
28:01
estradiol via is coercion to estradiol, including erection
28:06
and libido. Yeah.
28:08
So we should be doing more studies in men about the
28:12
importance of estradiol in the metabolism and longevity and
28:17
mitochondrial function of of men, because men get really
28:20
freaked out when I say to them that they've got more estadiol
28:23
in their body often than menopausal women who don't take
28:26
hormones. I see a lot of men who come when
28:30
I put them on testosterone and Tamil doctor, you know, I have a
28:33
high level of the female hormone.
28:36
I have to explain to them it's not a female hormone.
28:39
And I also see men who come treated by some outside doctors
28:46
in Women's Health clinic who put them on testosterone with an
28:49
aromatase inhibitor. Basically they eliminate all the
28:53
beneficial effects on testosterone, especially on
28:55
vessels because men with aromatase mutation who do not
28:59
make estradiol, they die of a heart attack soon.
29:01
Not only they have osteoporosis, but they die of heart attack.
29:05
So I have to explain to them, listen, it's not a female
29:08
hormone. Without estradiol, you wouldn't
29:11
have a hard on. I tell them exactly like this,
29:14
then they'll never ask me the question again.
29:16
They understand. Yeah.
29:18
It's so important. I could listen to you forever.
29:21
Before we end, I always ask the three sort of take home tips,
29:25
learning tips. So I'd really like to ask you
29:29
three ways that estradiol can improve metabolism in men and
29:35
women. What are the three key things
29:38
that you think are most important about the metabolic
29:41
effects of estradiol 1? One thing is the effect on
29:44
mitochondria. If you improve mitochondria, the
29:48
powerhouse of the cell, you improve metabolism and you
29:53
prevent metabolic dysfunction. So I think it's the most
29:55
important thing. Then there is, like you said,
29:58
the very important effect on the immune system and the prevention
30:04
of inflammation. And then if I had to choose a
30:09
third one, I think it would be the brain cognition.
30:15
But there are lots of other effects because basically
30:19
Estradel works on every single organ and cell.
30:24
It's amazing. It's so important, yet it's been
30:26
neglected for so long. So well, thank you so much and
30:31
hopefully I'm coming out to America at some stage soon.
30:34
But but thank you so much for your time.
30:36
I've really enjoyed it. Thank you.
30:37
It was my pleasure. To be here.