Connecting the Dots Between Cardiovascular Disease, Inflammation, and Hormones

In this first Heart Health webinar during American Heart Month, Doreen Saltiel, MD, JD, investigated the connection between inflammation and cardiovascular disease. Providers who aren't considering cortisol and stress in their cardiovascular disease risk assessments may be chasing the wrong targets.

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Full Transcript and Time Stamps

0:00 Webinar Begins

1:55 What do we know already?

10:20 The role of Functional Medicine and the DUTCH Test

17:44 How do we translate this into clinical practice?

29:33 Sex Hormones: One More Right Target

42:28 Females, E2, and Cardiovascular Disease

47:12 What about menopause, E2, and Cardiovascular Disease?

57:23 Next Week's Heart Health Webinar Preview

59:29 Q&A

0:00 - Webinar Begins

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All righty. So, here we go.

0:03

Here's a disclaimer that we now put in every lecture. Here are our objectives for today. At the end of the presentation, my hope is, you'll all understand that cardiovascular disease is a chronic inflammatory disease that traditional risk factors are important and they're inflammatory triggers. And we're also going to talk about the role of sex hormones in cardiovascular disease.

0:34

What are our goals when we talk about cardiovascular disease? Well, we want to prevent cardiovascular events in those at risk and in those with what we'll call subclinical cardiovascular disease and that's typically called primary prevention.

0:49

And we want to prevent secondary events in those who've had a prior event.

0:53

Now, this is a patient of mine who presented to the Emergency Department in 2010 on Christmas day after a large Christmas meal. And while he was being, you know, triaged into the, you know, heart room, he had ventricular fibrillation and sudden cardiac death. He was resuscitated, taken to the Cath Lab, and here is his right coronary artery with what you see train tracking, here, as you could see the shadow along the outside, that's all thrombosis in there. And after we put a stint in, he has a nice wide open with what's called TIMI, low risk slope.

1:33

Some of you may say, Doreen, why did you put such a long stint in there? Well, the bypass surgeon, if he ever needed bypass, doesn't see this part. This is intro myocardial, and the surgeon actually only sees the distill right coronary artery, the ongoing right coronary artery, and the PDE, the posterior descending order, so, he still has an adequate bypass target.

1:55 What do we know already?

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So, let's start with what we know.

1:58

As Noah said, it is still the number one killer in both men and women.

2:03

Even though the incidence is going down, it is not a lipid storage disease. Years ago

2:10

it was thought that if you decrease the lipids to, like, negative zero, you will decrease cardiovascular events. And what they found is no matter how low you decrease somebody's cholesterol, their LDL cholesterol, 50, 40, 30, it didn't decrease events.

2:29

What they found was that it was a chronic inflammatory disease, and Peter Libby discovered this in the 90s.

2:36

And what he noted was that inflammation is the key driver during all stages of the ascosporic process, from initiation through progression to ultimately end organ damage.

2:49

Yes, risk factors matter, their laboratory triggers and they impact cardiovascular risk. So, how does cardiovascular disease happen? Well, the first step is actually glycocalyx degradation The endothelial glycocalyx, which we'll talk about in a little bit, gets degraded.

3:10

And what happens is, that is what leads to endothelial dysfunction and to feel a little dysfunction leads to what we call leaky blood vessels, leaky blood vessels lead to LPS translocation. Right?

3:23

Just like a leaky gut does, LPS-induced LDL oxidation occurs, you get oxidative stress. You get immune activation, and you get ascosporic plaque formation.

3:35

Now, vascular inflammation occurs at the same time as lipid accumulation occurs. You get lipid oxidation, you get inflammatory cells, you get monocytes proliferating, they become macrophages, which are insatiable. They continue to uptake LDL. They become foam cells. And eventually they develop a fibrous cap.

3:58

And really what you want is a thick fibrous cap.

4:01

And if you think about one of those cordial cherries, if the dark chocolate on a cordial cherry is really thin and you put it between your forefinger and your thumb and just, you know, tap it, it will probably crack and all that liquid will come out.

4:20

And that's what happens when you have a thin fibrous cap on a coronary lesion, it typically ruptures at the angles because it's not thick enough, as a, as the fibrous cap thickens and becomes calcified. It becomes, quote, unquote, more progressive.

4:39

And, of course, you've all heard about functioning LDL, it's important to reverse transport.

4:46

But one thing we don't think a lot about is the fact that HDL transports anti-oxidant enzymes into the interim, which breaks down oxidized lipids neutralizing all the pro inflammatory effect.

5:02

Now inflammation mediates hypertension, and hypertension mediates inflammation, activation of the RAS increases reactive oxygen species.

5:14

You get increased expression of oxidized LDL receptors. You get increased adhesion molecules, chemotactic factors, and pro inflammatory cytokines.

5:27

Hyperglycemia and even prolonged hyperglycemia, not just diabetes, leads to increased pro inflammatory cytokines and up regulation of pro inflammatory pathways.

5:41

And now we add obesity to this equation and what you get is, of course, as you know, adipose tissue is an endocrine organ. It's proinflammatory, it gets synthesis of pro inflammatory cytokines, more inflammation.

5:58

You get more anthogenesis and this has not changed.

6:03

Even though Peter Libby published this in 2005, this is the reduction in vascular events that you get with aggressive lipid lowering.

6:14

And here's your residual risk, and really despite all the advances in lipid lowering, diabetes, hypertension, there still remains a significant residual risk. So, I'm going to ask the question:

6:31

Are we chasing the wrong targets? And the answer is yes. And inflammation is one right target, I've already told you that, but to prove that you let's look at the Jupiter Trial. It was a primary prevention trial, a large, long term, double blind, placebo-controlled trial, and they wanted to look at Crestor 20 milligrams a day.

6:55

And they wanted to see that in apparently, healthy people with normal LDL's, an elevated hs-CRP, whether that would decrease events. And the reason there are quotes in the, apparently, quote, unquote, healthy people, is because 41% of them have metabolic syndrome, and there was a large number of women in this study.

7:18

What they found was that there was a 44% decrease in cardiovascular events, despite no significant change in lipid.

7:27

So, the conclusion, they came to was, regardless of your LDL,

7:31

patients with elevated hs-CRP will benefit from statin therapy, with reduced cardiovascular event rates. Now I'm not telling you to give statins to all of your patients.

7:43

I'm just trying to show you that statins, which are immune modulators, will decrease C reactive protein, decrease inflammation, and decrease events.

7:54

And when we look at a secondary prevention trial, which these were essentially MI patients, and most of them had had revascularization, and they were randomized to three doses of this IL-1B inhibitor every three months.

8:17

And these patients were an optimum medical therapy. So they were on ace inhibitors, they were on beta blockers,

8:23

they were on optimum statin therapy need, they were on aspirin, they were on anti-platelet, you know, ages like Plavix.

8:32

And so, what they found was that after 3.5 years, there was a modest, but significant, 40% relative risk reduction in inflammatory markers and 15% relative risk reduction in MI stroke or cardiovascular deaths.

8:48

These are modest reductions, but I want to point out to you, what I found to be the most significant part of it was that the placebo group that had an LDL of approximately 80 on optimal medical therapy had a 25% five year event rate.

9:11

That's significant.

9:13

And they concluded that an immune modulator like the IL-1B inhibitor significantly decreased cardiovascular event rates, independent, again, of lipid lowering.

9:23

The problem with this drug is that the infection rate was high, the death rate was high, and it was very, very expensive, so it never went any further.

9:33

And so here are some key points that, you know, you can, you know, if you just want to look at key points, it's a chronic inflammatory disease and decreasing inflammation in the absence of lipid lowering. So, it's not about lipids, it's about inflammation, will decrease cardiovascular event rates.

9:50

Risk factors, remember, are inflammatory triggers that if not addressed, increase cardiovascular adverse outcomes, and decreasing the inflammatory burden will decrease vascular events.

10:04

And so, clinicians should continue to do what our traditional peers do, which is risk factor prevention and treatment, and we're going to add to this, prevent, and treat all niches of inflammation.

10:20 - The role of Functional Medicine and the DUTCH Test

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And here's where functional medicine and the DUTCH test come in.

10:25

Well, HPA axis is one right target.

10:29

And cortisol drives inflammation and cardiovascular disease.

10:34

It leads to oxidative stress, you'll get endothelial glycocalyx and endothelial dysfunction, in all blood vessels, not just in coronary blood vessels, in cerebrovascular vessels, in Reno vessels. But we're going to start with what the HPA axis tells us about cortisol and cardiovascular disease. And then how do we measure these risks?

11:00

I'm going to just point out, for studies, there are tons of them. These are four firsts, so we'll end the full references for you are at the end.

11:09

The Interheart Study was really a case controlled study. It was the largest study to assess long term stress coronary artery.

11:17

This was based on questionnaires, this was not based on actually looking at salivary or urinary cortisol.

11:25

There were 15,000 MI patients and there were about 14,820 controls and they wanted to determine, really, the strength of the association between cardiac risk factors and acute MI.

11:41

And what they found was that the odds ratio of an MI, having an MI, was more than doubled in individuals with chronic stress in addition to conventional risk factors when they compare them to stress free individuals.

11:58

And so, they concluded that psychosocial stressors are significantly related to acute MI for all populations. And here's a graphic of what I just told you. Here's the odds ratio of having an MI. And as you add the number of risk factors, look how it jumps when you add obesity to diabetes hypertension. And then look what happens when you add psychosocial factors. So, stress matters, cortisol matters.

12:28

And this was the first study, the cardiac study linking cortisol patterns and coronary artery disease, they use salivary casting.

12:37

This was 718 young participants when they were enrolled.

12:40

So, when they enrolled, you wouldn't expect them to have a lot of calcium, but it was a 15 year follow-up.

12:46

And really, what they wanted to see is, if coronary artery calcium, a, surrogate cardiovascular marker, was associated with average daily cortisol levels and the diurnal slope.

12:58

And what they found was that a flat diurnal cortisol curve was associated with coronary artery calcium.

13:05

And when they compared the group with the steepest slope here to the group with the flattest slope, the group with the flatter slope were 3.33 more likely to have coronary artery calcium, and they concluded that HPA axis dysfunction may indeed affect coronary artery disease risk. Now, let's talk about mortality.

13:30

The Whitehall study was the first study to document that daily salivary diurnal patterns are predictive of subsequent cardiovascular mortality.

13:40

Over 4000 men and women, their average age was 61. So, these were middle aged individuals. And the follow up was about six years.

13:49

They wanted to determine or examine the association between cortisol patterns, cardiovascular and non-cardiovascular mortality, and what they found was a flattened, cortisol curve was statistically significantly associated with increased cardiovascular mortality, but that wasn't all, an elevated PM

14:10

cortisol was an independent predictor of subsequent cardiovascular mortality, there was no association with waking cortisol or CAR, so they concluded that a flattened curve and elevated PM cortisol levels are robust, cardiovascular mortality predictors in middle age, adult men and women.

14:32

Here's a urine study. This was the first urine study to document that 24-hour urinary free cortisol levels, predict cardiovascular mortality.

14:43

This was 862 older individuals. Their mean age was 74. There was a significant number of women enrolled.

14:52

This study went on for six years, and they took the urine samples at baseline and they divided the urinary free cortisol into 3 terciles.

15:02

Low urinary cortisol, moderate urinary cortisol, and high urinary court, so they wanted to determine whether the 24 hour urinary report is all levels would predict all cause and cardiovascular mortality.

15:16

And what they found was a strong predictor of cardiovascular mortality, in fact, those in the highest turnstile, whether they had no baseline cardiovascular disease or baseline cardiovascular disease had an increased cardiovascular mortality.

15:33

If they started out with no baseline cardiovascular disease. They had a six times increased risk of dying from cardiovascular disease.

15:43

If they had baseline cardiovascular disease, they had 9.2 times increased risk.

15:49

So along with salivary cortisol, urinary free cortisol is a strong cardiovascular mortality predictor in persons with and without baseline cardiovascular disease. What about inflammatory markers, I told you it's an inflammatory disease?

16:08

So, the Mesa study looked at cortisol patterns, cortisol curves over three days, and they want they asked two questions, was there a relationship between diurnal cortisol curves, and IL-6, IL-10, TNF alpha? And was there an association between total cortisol output measured by area under the curve, and IL-6, IL-10 TNF Alpha?

16:33

And the, this was a sub study of the large Mesa study, there was 869 adults.

16:40

And what they found is in those individuals who had a higher IL-6,

16:46

this was statistically significantly associated with a lower cortisol awakening response, a flatter slope, greater area under the curve,

16:57

higher TNF alpha, with lower waking cortisol, higher IL-10, nothing statistically significant.

17:04

So, HPA axis dysfunction basically may mediate associations between stress and inflammation.

17:12

So, here are some key points. Cortisol is an acute chronic stress marker; Chronic stress is significantly associated with them areas, cortisol is a strong predictor of cardiovascular risk events and mortality, you can use salivary cortisol, you can use urinary cortisol.

17:32

They'll both tell you a story, and so what does the literature tell us? It tells us that chronic stress and HPA axis dysfunction increased inflammation, cardiovascular disease risk events, and mortality.

17:44 How do we translate this into clinical practice?

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Now, how do we measure this risk?

17:49

Well, saliva is the gold standard for HPA axis testing.

17:56

And before you choose your tests, other than what's considered the gold standard, and we're going to talk about more about this next week, in this case, it's saliva testing.

18:06

This test should be validated against the gold standard, or studied, in document, to improve clinical outcomes. And, so, you can use urine. This is a commercially available, validated urine test that was published in Peer-Reviewed Journal by Newman et al.

18:24

Yes, this is the DUTCH Test, whereby they want to determine the utility of dried urine to measure cortisol and cortisol metabolites and because liquid urine is the gold standard for urine, they looked at liquid urine. And can a during a diurnal pattern could be observed in urine?

18:46

This was 68 people who the urine and saliva on the same day and the light green is salivary cortisol. The dark green is urine.

18:59

Now I need to point out to you that this, which is saliva. Is a cortisol awakening response when you, when you sense waking. Not when you're awake, when you first since waking, you do your swab. And then 30 minutes later, you do your second points.

19:18

And that the cortisol awakening response, a test of resiliency and Responsiveness, this is the first point on the urine tests, which is all the urine in your bladder from the night before and the early morning.

19:38

The CAR is somewhere in here.

19:41

But this second point, oh, let's see, how many hours later is not a CAR.

19:49

So, if you are looking for a CAR, you need to do salivary testing ,which we offer, and you need, if you're not looking for a CAR, then I would start with the DUTCH Complete, which has the urinary diurnal pattern and the cortisol metabolites. And they concluded, you all can read thi,s that it was a good surrogate for the salivary dietary pattern. So, yes, you can use this.

20:21

Now let's look at some examples, and so this is urine.

20:26

And the first thing you see is, this is a, let me orient you, this is the lower end and the reference range. This is that per into the reference range.

20:35

And what you see is, this first point is really high.

20:39

So, this individual was, didn't sleep well and really, their brain had a hamster on a wheel in it. And the hamster was running all night long.

20:54

And as you see this, after this point, this point should come down, right? Here. It's a little flat, but here, it's definitely flat. So, you have increased coronary calcium. You have increased aisle six, and here you have increased cardiovascular mortality.

21:12

Here from the In chianti study. You see a high 24-hour free urinary cortisol increase cardiovascular mortality.

21:23

When here you have saliva.

21:25

you see this lowish first morning point, hmm, elevated, TNF alpha inflammation. You don't have to remember which pro inflammatory cytokine is associated with, what. Just remember, inflammation.

21:41

Here you have a flattened curve.

21:43

Inflammation, Increased cardiovascular mortality.

21:47

And then here, again, IL-6, TNF Alpha, flattened curve.

21:55

I nighttime cortisol associated with increased cardiovascular mortality. So, you, when you order your DUTCH Test on your patient, will get lots of information about inflammation and cardiovascular risk from looking at a DUTCH test.

22:14

Let's talk a little bit about blood sugar. Now, we don't measure blood sugar on the DUTCH Test, but I think this is really, really important.

22:22

two of the, under the most undertreated, cardiovascular risk factors, are hypertension and insulin resistance, under diagnosed is obstructive sleep apnea.

22:38

If we get these things right, we may be able to decrease your risk.

22:44

But the reason I bring up blood sugar, because I mentioned the endothelial gleich, OK.

22:49

And what is it? It's a microscopically finagle negatively charged. I think of this thing as a gel, like sugary coding, that really blankets the endothelial side.

23:04

And you see its makeup and its thickness will vary. So, you really can have in the field dysfunction until you have endothelial, like a calix degradation, is really very important and provides the first line of defense.

23:21

It acts as a barrier. It helps with filtration. It allows for active endothelial cell to cell communication, and it's responsible for vascular tone.

23:32

But what's really important is that it is exquisitely sensitive to shear stress, in other words, its thickness. So, you have a uniform blood vessel, a straight tube.

23:46

You will have a thicker, endothelial, glycol calix. It'll be healthy. It should maximally protect the end of the Lehman optimum conditions. You'll get up regulation of the enzyme, responsible for converting origin into nitric oxide, which is responsible, not only for Basal Dilatation, but it has value inflammatory properties.

24:09

In areas of low shear stress bifurcations, curvatures live the ascending aorta as curves around, to become the descending aorta. At the bifurcation of the descending aorta into the feral vessels.

24:25

There is none laminar flow, think of it as oscillatory, and it kind of is turbulent. This is where the endothelial black haw.

24:35

Katelyn assisted, it predisposes to osteosclerosis and I don't know whether you've ever heard of the term.

24:41

Atherosclerosis occurs at Branch point in blood vessels.

24:46

This is why, the endothelial like, OK, let's provides anti-inflammatory and anti-thrombolytic effects by Dunking major proteins that are synthesized by the endothelial cells.

25:00

And I ... co factors the really potent anti-oxidant superoxide Dismutase and here is, what it's made up of. And, just so you can get a picture in your mind of the endothelial Gallick, OK. So here's your endothelial cells.

25:18

This is looking down the barrel of the Beslan. The here are these little Hairlike projections, and there's your endothelial cells. And here it is, if you've opened it up and are looking at it, look at these. You know, hairlike projection during the Thiel cells are here.

25:34

So, it should make sense to you that you are not going to get the theory of cell damage until you get in the field, like aw calix damage, and we'll talk about treatments for this a little bit this week, but more next week, now, hyperglycemia, even when levels or increase for a short period of time.

25:57

Damage the endothelial growth, OK.

26:00

They decreased nitric oxide.

26:03

And so, if you have diabetes or if you have insulin resistance with long term hyperglycemia, you get significant endothelial light, OK, It looks thinning, degradation and vascular vulnerabilities. How can you tell do a urine analysis, cheat test? If you see ..., this is one way of noting that you indeed, having the fuel gripe OK looks dysfunction. I'll show you a couple more here in a little bit. You don't need a fancy test.

26:33

And I'll also tell you that anybody who has risk factors, any risk factors, they are prone and, indeed, probably have, in the field, like, OK, which dysfunction?

26:45

Let me show you just a study. one study by New dwarf that was published in 2006. So, this has been around for awhile. These are healthy volunteers. There's their baseline, like, OK, let's volume.

26:58

And there's there in the Iliad function, by flow mediated basal Dilatation, something like the path, when they did a glucose infusion and raise blood sugar, look how the endothelial got thin and in the feel, your function decreases. So yeah, and the feel like, OK, let's degradation, which indeed caused endothelial dysfunction.

27:24

Now, Magnetar was used as a control, because Manigault isn't as easily absorbed, as straight up glucose is until it doesn't raise blood sugar and insulin as much. But I want to see here that when they added ...

27:39

to the glucose mixture, it mitigated the reactive oxygen species in induction of, like, OK, Luxe Degradation.

27:53

And you can see that better here, this is a component of the endothelial ... Pro Thrombin fragments. And this is pure glucose. This is Manoj tall, and this is glucose added.

28:07

initial cysteine added too to the glucose mixture, and you see the mitigation of the degradation of the end of Felix. And so, what they concluded was that hyperglycemia induce reactive oxygen species up regulate up regulation, meaning, increase reaction, reactive oxygen species, increase, oxidative stress, increased inflammation leads to endothelial black OK, looks degradation in shedding, decreased in the field.

28:38

Your function will decrease nitric oxide increased pro thrombin potential, and if you give them and instead assisting and next week, we're going to talk about our tour.

28:47

So, which has recently been patented or coronary calcification reverso.

28:58

It will mitigate hyperglycemia induced endothelial, like aw calix degradation.

29:05

It's actually plaque reduction, not calcium reduction. I apologize for that.

29:10

So, again, optimum glucose regulation is key to endothelial, like, OK, investigates feel your function.

29:17

And by adding in a shuttle cysteine, you will mitigate the damage. That's done, but the real key here is a bulldog about glucose regulation. It really is important.

29:33 - Sex Hormones: One More Right Target

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And so now let's talk about sex hormones, which is really an important target.

29:40

As individuals, age, men and women, it's associated with a chronic inflammatory state you get inquiries from inflammatory cytokines.

29:49

You get increase from rad of co-production and decreased redox potential decrease, and I inflammatory potential to balance, or mitigate that, those pro inflammatory cytokines, estrogen, progesterone testosterone, are immune modulators and anti-inflammatory hormones. They inhibit pro inflammatory cytokines and stimulate anti-inflammatory cytokines.

30:16

And as you can see here, there are receptors which are expressed in immune cells, endothelial cells and vascular smooth muscle cells.

30:25

So, as you, it should make sense to you that aging, which is associated with a decline in sex hormones, both, influence immune competence, and disease susceptibility.

30:38

So, let's start with male's, testosterone, and cardiovascular disease.

30:43

We all know that testosterone gradually decreases 1% per year in men.

30:49

After the third decade, testosterone is an independent determiner of endothelial function.

30:55

Testosterone deficiency leads to endothelial dysfunction.

30:59

You have decreased nitric oxide have increased expression of a DNA, which is asymmetric di, methyl arginine, which competitively It's a competitive inhibitor of Enos which is responsible for converting our Janine to nitric oxide.

31:17

So, you don't get nitric oxide now. What increases ADMA? You name it. It increases it.

31:24

Anything that increases inflammation is going to increase ADMA pretention, hyperloop edema. Tobacco use. You name it. It happens.

31:35

It also testosterone deficiency decreases what are called endothelial progenitor cells, which are involved in the endothelial repair process.

31:45

It increases pro inflammatory cytokines, and replacing testosterone, decreases problem inflammatory cytokines and increases anti-inflammatory cytokines.

31:57

And this is a very nice article, the full references for you in the back, which I would recommend reading, and this goes for both men and women.

32:05

Aging, in conjunction with testosterone deficiency, increases all the bad stuff, which leads to endothelial blight, OK, endothelial dysfunction, large artery stiffening, which leads to increased blood pressure, increased at the lower left ventricular hypertrophy, diastolic dysfunction, endothelial injury, and increased risk for cardiovascular disease.

32:30

Now, let's look at a study, by, this is out of Cary Murrow's Lab, and what they did, they wanted to determine if middle, aged or older men with low total testosterone would have greater age associated in the field of dysfunction related to inflammation oxidative stress.

32:50

They looked from guys with different testosterone levels, 58 healthy men, 20 younger, 20 middle aged, and 20 middle-aged with lower testosterone and here are your testosterone levels, and so let's come over here and look at what happened.

33:08

They used vitamin C as an antioxidant to see if it mitigated endothelial.

33:17

Dysfunction, here's your young guys, which are an essential control. They infuse sailing.

33:23

There's their baseline and when they infuse vitamin C on hundred CC's there was really no change.

33:31

This is all the men together, all the middle aged and older men not separated based on their testosterone levels, and what they found.

33:41

They had lower baseline endothelial function and when they gave them, vitamin C, and compare it to their baseline, it was statistically significantly better. But it was still statistically significantly worse.

33:58

Then the young guys, who really had no change, and then when they divided the group based on their testosterone levels, what they found is that in the middle aged or older men with higher testosterone, there was a statistically significant difference in endothelial function.

34:18

When compared to the younger guys, You're here.

34:23

That was no longer statistically significant when they infused vitamin C.

34:31

So, it mitigated some of the oxidative stress and improve their endothelial function.

34:37

Now, when they looked at the middle-aged and older guys, with lower testosterone levels, what they found was that, at baseline, they were statistically significantly lower than their middle-aged peers with higher testosterone and certainly, statistically significantly lower than the young guys.

34:59

When they gave them vitamin C, if they were no longer statistically significantly different from their peers, they significantly improved over their own baseline, but were statistically significantly different than the young guys. And so, they summarize that, by saying middle-aged older men with lower total testosterone levels may have accelerated vascular aging as a result of age associated in the field, dysfunction compared with their match peers. And they felt that was due to increased inflammation and oxidative stress, which was, as I showed you, mitigated by vitamin C.

35:41

So, they concluded that physiologic total testosterone levels, which are greater than 500, but less than a thousand with the goal of greater than 500 to 800 may attenuate the age-related decline in the C allele function.

35:56

This is independent of symptoms and independent of traditional risk factors.

36:01

And this is by decreasing inflammation oxidative stress. So you can make an argument any symptomatic guys who have low testosterone levels. Typically, they're not going to be asymptomatic, testosterone of 260 amino 269, you can make an argument for cardiovascular protection.

36:21

So, testosterone improves endothelial function and TD leads to end the dysfunction, inflammation oxidative stress.

36:27

So, why I ask you, is there a black box warning on all the testosterone prescriptions?

36:35

that breed, there's a possible increase in cardiovascular disease?

36:40

Well, four studies, accuracy, validity, and credibility. Today, yes. No question by experts, they want them removed from the literature.

36:47

The FDA questioning the, even though they found no reason to put a black box warning on, all testosterone prescriptions, actually mandated the warning. and here are the four studies. The time trial by ...

37:03

wasn't a cardiovascular study. They wanted to see if testosterone gel inquiry strengthens physical function, elderly frail men. And it didn't do that.

37:12

But they stopped the study early because, I quote, unquote, cardiovascular events and these events were palpitations, ABC's, specific EKG, changes, and people with demons. So, they really weren't cardiovascular events.

37:26

However, there were four events that were significant that occurred in men, whose testosterone levels were greater than a thousand, and were given then higher than recommended doses. So, the moral of the story is kept them within the recommended ranges.

37:42

...

37:42

did a retrospective study looking at men who underwent coronary angiography, and receive testosterone prescriptions, their initial results said three areas to F angiography that think prescriptions were associated with increased cardiovascular event.

37:58

However, the data was floored.

38:00

10% of the participants were women, and when they did a re-analysis of the study, what they found was that those who received testosterone had a 10.1% absolute rate, while those who did not had a 21.1 percent of it.

38:17

And then the Finkel study compare post prescription rates to pre prescription MI rates, which are really studying different things. There was no validation of actual events. They, aside from no control group, they never measured testosterone levels. They didn't look at risk factors of these individuals, and really when they, when you look at the data with a fine-tooth comb, what, what is there is that T related events were lower than the, than what we would expect in the general population.

38:48

And then, so, look that published a meta-analysis and two other studies.

38:57

Composed 35% of events, one was this serious study, and the other one is just in an unusual study was the Copenhagen Study, where they gave high dose oral methyl testosterone which resulted in super physiological levels.

39:14

Command with cirrhosis, not sure why somebody would do that.

39:17

Levels went up as high as 20,000, and the most common cardiovascular event was this Apigee or viruses, and Verso Bleating. I'm not really sure that's a cardiovascular event.

39:30

When those two studies were removed, there was no statistically significant difference in evaporates between teat treated men and not.

39:37

So, these four studies are what prompted.

39:41

The, uh, black box warning here are a bunch of studies for you that documented no increase in CI emptier coronary artery calcium, documented decrease mortality, MI, and stroke reduction when you gave testosterone.

40:00

So there's lots of data out there that support the use of testosterone in men and not to worry about cardiovascular disease. So, should there be a black box warning? Probably not.

40:16

The traverse trial is ongoing now, and my dear friend, Mohit Chiara is a principal investigator.

40:25

And all he could tell me is that this study, things are looking good, and what that means to me, they haven't stopped the study early, and it is looking at testosterone and cardiovascular risk.

40:41

And I look forward to the publications so we can clear all this mess up.

40:48

And so, here are some key points in men.

40:50

Serum is the gold standard, and we'll talk about that next week, But regardless of the dose or the delivery, you want to keep serum testosterone levels greater than 500 to less than two hours.

41:03

And that should be your goal that will optimally improve clinical outcomes, Because in one of the studies here, what they found was that in men who receive testosterone, but had lower testosterone levels, then what would consider optimal didn't have as great, a mortality reduction or MI reduction, as those who had normal levels. So, the key takeaway is maintain testosterone in the therapeutic range.

41:38

And you want to make sure that no guy has a testosterone level that's less than 200.

41:44

You need a level greater than 200 with Intact Romanization to prevent market, insignificant bone loss. An extra die, or is very important in men for bones for sexual function, as well as for cognition.

42:00

And remember, you're going to use an LC-MS/MS assay, when you are going to measure E two levels, because at the lower end of the reference range, any immunoassay is not as reliable.

42:12

And remember, that serum testosterone levels are generally higher with gels, then frames. And you may need up to two times the pre dose to achieve similar total testosterone levels in clinical outcomes.

42:28 Females, E2, and Cardiovascular Disease

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And so what about women?

42:30

Extra dial is similar to testosterone. It increases in the field of nitric oxide production decreases: inflammatory peptides it as direct anti-oxidant effect increases mitochondrial, anti-oxidant defenses.

42:45

And what has been found is that if you don't have an off estrogen, estrogen receptors will decrease, and estrogen receptor signaling will decrease your alpha is the key determinant and E to modulate endothelial cell expression, which impacts receptor signaling, sensitivity and function. Let me show you what I mean.

43:09

This was a study done, again out of carry Murrow's Lab, which looked at this is a small study, vascular endothelial your alpha expression, and wanted to see whether it was influenced by E two status, and whether it was related to endothelial function.

43:29

They did immune-fluorescence staining of peripheral, Danish in the fuel cells, and they use brachial artery flow mediated. Basically, the location, something like the end.

43:40

So remember these Levels one at ALC, MSMS levels, But pre-menopausal, in the early follicular phase was similar to the post-menopausal phase, and in the late follicular phase, they were higher, and when you look at the immune-fluorescence staining, you see the fluorescence staining is about 30 and 33% less than in the late follicular phase.

44:04

And what they found was that your alpha expression was positively associated with two levels in X expression and activation.

44:13

Now, let's look at actually endothelial function. And what they found is that, as your alpha density increased IE Scheer and mister dial levels went up, and you're out the density increased.

44:26

There was improved the allele function.

44:29

So they concluded that Jeremy to re may regulate your alpha expression, which influenced endothelial function by modulating us.

44:41

So we talked about post-menopausal women and pre-menopausal women, but we have to ask the question, do the hormone changes that occur during the menopause transition, which a lot of clinicians don't pay close attention to accelerate vascular aging and contribute to endothelial dysfunction.

45:02

So this is the modified straw criteria. And here's where they define the early menopause transition. And this is the late menopause transition, which is really a mental raya for more than two months.

45:17

And so, again, this is at a carry Moros lab, and they wanted to determine whether the menopause transition affected endothelial function is measured by brachial artery flow mediated.

45:29

Visual dilatation, this was a study that included 132 healthy women. None of them were on board.

45:37

And here are the definitions. According to the modified straw criteria, early was greater than two cycles would cycle length greater than seven days. Late aime in Rio breathe in two months, but less than 12. And there's your menopause and you all remember that menopause is defined by no cycle for 12 months.

45:55

And what they found is the menopause transition was associated with endothelial dysfunction, independent of risk factor.

46:02

So, here's your pre menopausal women.

46:05

Early perimenopause late during menopause early post-menopause late Post-menopause will all statistically significantly had less endothelial function or more in the field dysfunction, then you are Pre-menopausal women.

46:21

But this statistical significance was not as robust as the others. And they thought that then, that these women may have enough more mown available to provide some endothelial protection.

46:35

But once you got to believe peri menopausal stage, and again, this is not using LC MS MS, what they found was you had accelerated vascular aging.

46:46

But what was very interesting is that there was no statistically significant difference in endothelial function between late Barry Menopause and the Post-menopause period. So, here is your timeframe to pay attention to.

47:01

This is when you get accelerated vascular aging.

47:05

So, the menopause transition is associated with a significant decline in the function.

47:12 What about menopause, E2, and Cardiovascular Disease?

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So, is the menopause transition is a critical period during which CVD risk accelerates.

47:21

And so, the answer to our question is yes, but what about menopause extra die all? And cardiovascular disease, Lots and lots of studies, which I have for you in the back. We're going to focus on two.

47:35

The elite trial was a study done using oral esker dial one milligram and vaginal progesterone gel, 45 milligram, days 1 through 10. They never got the message there.

47:46

Use it for at least 12 days. But they had no endometrial complications.

47:52

And so, what they found was that so, let me come up here for you. And there were two study groups. one was less than six years was defined as the early group and then the late post-menopausal, who were menopausal for greater than 10 years. Most of these women had some degree of subclinical atherosclerosis, Dad, abnormal, CI EMTs, which put them in that category.

48:21

And what they found when they looked at the whole group together, is that more or less, for dial in the early post-menopausal boot slowed COMT progression compared to placebo, but it was only present at five years. And that shouldn't surprise you is coronary disease is a slowly progressive disease. And that may be why, and when you look at the keeps trial, there was no statistically significant difference in COMT between the treatment arm and the placebo arm, and that was only a three year, try it.

48:54

But when they did sub study analysis, looking at ... levels, here's where the groups kind of diverge.

49:03

In the early post-menopausal will, the higher the treatment, Jeremy to level the slower COMT progression.

49:12

And there's two levels, kind of mean, or 48.

49:15

Late post-menopausal women, the higher the ceremony two levels, COMT progression rate was increased, and their mean was 40.

49:27

So the moral of the story is, if you use serum, you want to keep them probably between 20 and 30 to 35, and we'll talk about the urine equivalent to earn a second deduct your equivalent.

49:37

And in a, early to post-menopausal women, you can take them out to 40, no somewhere between 40 and 60, and you'll get the IMTs flowing.

49:50

Now let's look at the finished trial, which, why I pulled out the finished trial, was because they use not only oral extra dial, but they use patches which we use. They use gels. They didn't use creams and fortunately, they use produced, but even despite losing progestin in all extra dial, coronary artery disease related death.

50:13

Mortality was reduced by up to 54% in a time dependent manner, meaning the longer a woman was prescribed a news, extra dial based hormone therapy, the greater the risk reduction.

50:28

And this is important because the guidelines say something different.

50:32

All risk reductions were comparable in women initiating hormone therapy, below the age of 60 and women initiating therapy greater than or equal to 60 years old.

50:47

And so, here is a summary.

50:50

Extra dial's cardiovascular mortality reduction is positively related to Ito exposure.

50:56

Patches, gel oreilles have been associated with decreased cardiovascular mortality.

51:01

Treat women as early as possible.

51:04

It's OK to initiate therapy later, and treatment may be continued for greater than 10 years. So long as you initially were stratified the individual, and you continue with ongoing risk stratification.

51:20

Don't forget women with the uterus at ... progesterone, or bad or vaginal progesterone. It doesn't increase cardiovascular risk. It may provide some cardiovascular benefits, while protecting the endometrium and improving bone mineral density, and I'll throw this in here.

51:38

When you add testosterone therapy to transdermal extra ..., progesterone and vaginal progesterone, you will get an improvement in the field of function and bone mineral density that is greater than E two and progesterone alone.

51:57

Then just summarizing what we just talked about with the elite trial, recently, menopausal women, depending on their cardiovascular risk, may require higher serum levels. And remember, we validated that the DUTCH Test is validated.

52:13

And so, that 40 to 60 is a dried urine equivalent, or about 1.8 to 2, and all the post-menopausal women 20 the left. The 40, which is equivalent to zero point seven, to approximately 1.3 to 5 on the DUTCH Test. And this is my current list of cardiovascular risk, or post-menopausal women do not need extra levels. Of 60, 80, 100, they don't need it.

52:41

They're not going to have babies.

52:43

They need to protect their heart.

52:45

And they're bones the data on replacing extra down and card cognition is mixed, and again, time since menopause an age greater than 60 should definitely cause pause.

52:59

But it shouldn't prevent you from initiating hormone therapy or continuing it.

53:04

Ongoing risk stratification, and follow-up testing is a must in all women as well as men.

53:11

So when you counsel patients, remind them that extra dial is not indicated to prevent adverse cardiovascular outcomes in either men or women.

53:20

However, the data suggests that will improve cardiovascular outcomes. And the earlier you initiate therapy, the greater the benefits.

53:30

So why isn't E two indicated?

53:33

Adverse outcomes, while the guidelines got it wrong, they base their recommendations on synthetic.

53:41

This is the position statement out of 27 from 2007 came from the North American Menopause Society, but women who initiate menopause hormone therapy more than 10 to 20 years from menopause onset.

53:55

Already six year old, the benefit risk ratio appears less favorable.

53:59

Because of the greater absolute risk of coronary artery disease, stroke venous thromboembolism N dimension, this statement is based on the WHA data, which aren't relevant. Nobody should be using oral estrogens.

54:13

They don't care, even if it's orally to they up regulate inflammatory markers as it gets to the liver.

54:20

In fact, the guidelines do remind us that we're all ..., progesterone, and ******, and vaginal microbiome progesterone, that a progestin's the treatment of choice. They also say that T D two may be preferred, especially in certain high risk populations, which is what we're talking about.

54:37

But I will tell you that prior to initiating hormone therapy in all women, especially old risk stratify.

54:47

Look at their endometrial help.

54:48

Think about their breast health, their bone health, their cardiovascular disease risk factors, as well as cognition.

54:55

You want to do ongoing surveillance. And this is not one size fits all individualized care.

55:02

And here's just some practice points. Initiate menopause is close. Initiate hormone therapy is close to menopause continue as long as appropriate with ongoing risk stratification, surveillance and bow of testing. This is the stuff I've already told you and those women who can't tolerate a patch, which is what I would start with, which we'll talk about next week T to gel products are reasonable options, however, they're not FDA approved for bone mineral density.

55:30

And the reason is when they compare gel products, they compare it to what the standard was, which was a pack. And what they found is you need higher doses and higher serum levels to get bone mineral density of ....

55:46

And that was the reason it wasn't compounded products, probably work. I use them at times, but they have no outcome data.

55:55

So you just need to document, in the medical record, why you're using a compound, the product, instead of a, if the boot product.

56:06

And remember to test, don't guess. Include metabolomics which are necessary for successful hormone practice. I can't practice without it. It tells me about tissue exposure.

56:17

It gives me hints as to up regulation of inflammation. It adds a lot to my practice.

56:25

So final thought, cardiovascular diseases of chronic inflammatory disease, it's an Olympic storage disease.

56:32

It is not enough to treat an optimized for conditional risk to optimally mitigate cardiovascular risk.

56:40

We should address all inflammatory triggers, the HPA axis, and you are an ohmic nervous system, I didn't talk about the autonomic nervous system.

56:49

The gut and T A O T, and they always an independent, prognostic indicators in individuals with and without cardiovascular disease. How does one get high levels of PML? They eat a high hospital polling, or Pauline and quantity diet, and they have this ..., which makes TMA and TMA gets sent to deliver, and it becomes ....

57:14

And remember that poor detoxification increases inflammation and hormone matters, or inflammatory modulators.

57:23 Next Week's Heart Health Webinar Preview

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Hormone deficiencies are associated with increased cardiovascular risk, adverse, cardiovascular outcomes, test, don't guess, and let's give you a little preview to next week, we're going to use case studies, and we're going to talk about an approach to the patient.

57:38

Key things you should look for in the history: what laboratory test you should be doing?

57:44

Then, I'll highlight some treatments and, my hope is, I will give you an algorithm for cardiovascular risk stratification that will be useful to you.

57:56

And, I can't leave today without talking a little bit about laboratory testing, depending on delivery.

58:06

and green is yes, which is go ex. Red is no, And yellow is maybe, think.

58:15

And this will be very, very helpful for you regarding when to optimize, when to optimally use the DUTCH ..., when the DUTCH Test may be helpful, and when not to use the DUTCH Test.

58:30

And with that, I will show my little puppies, which always make me smile, and open this up to new to questions, and let me remind you, about the new provider, 50% off, And I just need to ask you, guys, if you are a DUTCH provider, why not?

58:53

It is a great test.

58:56

It is validated, it has serum equivalence, and it's evidence based, in addition to giving you a ton of information. So, the link is in that little chat thing, below, not below here, but in the chat box.

59:15

And I will be more than happy to answer any questions and just know there are additional references for you of all that I've talked about. And Noah, you are on.

59:29 Q&A

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Thank you, doctor ..., we do have a few good questions from the audience already in the chat, and won't be able to get to all of them with the time we have left, but let's dive into what we can. And remember, doctor ... is a doctor, but she may not be your doctor. The contents of this webinar are intended to be for educational, informational purposes only. Please consult with your primary care physician before starting any new treatment plans. So doctor Saltier, the first question is, and we're gonna go really easy on you here and start back where you ended.

1:00:03

For those in Peri Menopause, it is very difficult to figure out when to do the DUTCH tests, any tips on when to do the DUTCH Test in perimenopause.

1:00:13

Well, if women aren't having regular cycles and they don't know when they abdulla because a lot of women's know when they obviously you can get an oscillation kit which Noah can talk about. There are a number of ways to determine when a woman ..., whether it be body temperature going up by a certain number of degrees.

1:00:36

But if all of those things fail or you choose not to do those, pick a day and just do the test.

1:00:46

All right, perfect.

1:00:48

Do you use hard terrorist cell? And, if so, when do you use it for cardiovascular disease patients?

1:00:55

Yes, and Arturo ..., we're going to talk about that next week.

1:00:59

But, yes, I use Arcturus shell in any individual, I think, has endothelial dysfunction, which means, if they have cortisol dysregulation, they have endothelial dysfunction if an end, and the feel of like, OK, looks dysfunction. Because remember, you gotta get through that in the ... glycol, Caitlin.

1:01:20

Anybody with cardiovascular risk factors, any body with any degree of insulin resistance?

1:01:27

Now, even though it's not approved for the gut, right, the Godhead endothelial cells.

1:01:34

And so if individuals have inflammatory bowel disease, if they have significant despite OSHA's irritable bau, I'll give it to them.

1:01:46

So anybody who, I think has endothelial dysfunction and endothelial like, OK, looks dysfunction, if they have elevated triglycerides if they have elevated lippitt. You know, it's really who wouldn't like it.

1:02:02

Are there any other supplements that, that, you believe, would help endothelial Glencoe Calix That's the only one that's been approved for plaque reduction. There are other ones out there on the market.

1:02:16

But, they have not been, uh, approved for this purpose Sticking with my new favorite word endothelial glycol Calix, How high of glucose does the endothelial glycol, calix damage start at?

1:02:35

I would, just so, you know, I would say it's probably at 70 80, and why do I say that I didn't talk about ... dysfunction?

1:02:45

But as blood sugar goes up, heart rate, recovery time, which is a marker of sudden cardiac death, decreases.

1:02:58

And when you get a decreased heart rate recovery time in individuals with blood sugars, that would be considered normal, especially if their heart rate is greater than E that baseline heart rate greater than E, they're going to have significant endothelial dysfunction.

1:03:18

Could induce ... Lego calix degradation be implicated in ...

1:03:24

disease, Yes.

1:03:28

If a female's starts testosterone, will they be on testosterone like men forever?

1:03:34

Yes.

1:03:37

There on all the easy ones, these are just softball for you, right? Does lowering cholesterol with statins inherently lower testosterone?

1:03:46

No.

1:03:49

two, those two are not together.

1:03:53

Do you have any suggestions for men with a history of prostate cancer who are given meds to decrease testosterone?

1:04:02

Well, if they are actively being treated four prostate cancer, the answer is, there's nothing to do.

1:04:15

When they get further out from prostate cancer, consult with your urologists most of them.

1:04:24

Know, that testosterone does not cause prostate cancer, that's been well proven, So unique clearance from the urologists, and then at some point, you could probably initiate testosterone therapy, that's not with metastatic prostate cancer.

1:04:43

I'm talking of people who are disease free for anywhere from 1 to 3 years, depending on the urologist.

1:04:55

Would you still prescribe ester dial to a post-menopausal woman with some cardiovascular risks even if they had a history of estrogen positive breast cancer?

1:05:06

Yes.

1:05:07

It depends on how far out they are from breast cancer number one. And the answer is yes. Estrogen decreases breast cancer. Ashford dial decreases breast cancer.

1:05:17

So there's no reason not to.

1:05:20

And Irish stratify, everybody.

1:05:25

What are some of the tools that you use for risk stratification, yeah. Let me spell our terrorism, a R T E R, O S IO. That's how you spell our terrorism.

1:05:36

Thank you.

1:05:37

And what are the tools I use? Very interesting, and I'm going to talk a little bit about this next week.

1:05:42

But you really can't use any of those calculators because they don't take any of the things we just talked about today into account, But if you start there, and I think somebody has increased cardiovascular risk.

1:05:59

I either do a CMT and, or, depending on the person at coronary artery calcium scan, which is typically where I go.

1:06:13

Would testosterone be recommended for someone with intermittent a-fib?

1:06:20

Um, well, its effects on the conduction system have not been well studied.

1:06:25

So if somebody had, you got to ask the why they have intermittent a-fib, is it they have hypertension?

1:06:33

That's not, well, is it a schema a-fib? So you're gonna really find the etiology of the atrial fibrillation.

1:06:41

And then you do the same thing as you would do with any guy, which is you order the litany of tests, which we're going to talk about next week. You evaluate their symptoms. And then we decide whether they are a candidate for testosterone.

1:06:59

I'm gonna send you down a rabbit hole with this one. When someone is on the birth control pill, is it accurate to check their hormonal status with the DUTCH Test?

1:07:10

Oh.

1:07:15

You're gonna get all these bizarre readings. And so my answer would be no, but the bigger question is, why are they on oral birth control pills? That should be the question.

1:07:27

No body should be on an oral contraceptive, partially because it is a progestin and progestin's increased breast cancer.

1:07:39

Progestin's increased cardiovascular.

1:07:42

So what you want to do is get them on a natty, I would say, a, I'm di that's an odd hormonal.

1:07:53

Because even though they say it doesn't get into the circulation when you use a Morena, it does.

1:08:01

And those are not bio-identical hormones, either.

1:08:05

So my my ideal contraceptive is a non hormonal IUD.

1:08:17

And if a patient is looking for a baseline, how long should they be off birth control to be able to look at that in in any testing?

1:08:24

Well, everybody's different, right?

1:08:27

And I've had women who, after three months, their DUTCH Test looks fabulous.

1:08:33

I've had women after six months, and then after three months, the DUTCH Test looks like, what if you're still on birth control pills, you didn't stop?

1:08:43

No, no, no, I stopped them.

1:08:46

Some people, you have to wait six months, so it's going to be a trial and error, there's no one size fits all.

1:08:55

Do you believe there's a limit to how much oreille progesterone to use at night to help with sleep?

1:09:01

Well, it depends on their pathway predominant, right?

1:09:06

So if you go down heavily during that alpha pathway, if you predominantly go down the Alpha Pathway and their alpha metabolites are already high giving them more oral progesterone is not going to help you.

1:09:22

And there is some data in vitro studies that going down that alpha pathway may increase the risk of breast cancer when you use an oral, even Owen P but in all the studies on oral progesterone, it did not increase breast cancer.

1:09:39

So, those were in vitro studies done by John wheat, so it really is dependent on your metabolomics.

1:09:51

My favorite, that's my favorite word, Noah.

1:09:54

Metabolomics, I know, it's, it's, it's, it's my second favorite word, Atha after my new favorite word today. Is there any way to detox from progestin that has been taken from an estrogen dominant patient with fibroids?

1:10:11

Yeah, we do a liver detox.

1:10:14

I would do a 30 day liver detox, you can use ... which is very gentle.

1:10:21

And then I put them on a detoxifying diet that they would eat along with that eating lots of detoxifying foods.

1:10:29

What are some of the foods in that detoxifying diet, Percent fruits, vegetables, beets And when I talk about cruciferous vegetables, I'm talking about broccoli, cauliflower, brussel, Sprouts.

1:10:43

You know, onions and garlic.

1:10:45

If you can eat those those are all detoxifying vegetables and fruit. You want to eat berries, berries, and more berries.

1:10:54

The more colorful your diet is the more detoxifying deities eat the rainbow and we're not talking about skittles, right?

1:11:03

Yes. Oh, can you?

1:11:07

Can you possibly discuss the inflammatory risk of low estrogen levels, specifically in pre menopausal women?

1:11:15

Oh, yeah, you know, women typically shouldn't have low unless they're, you know, fluctuating up and down or they are an athlete and their Their their H PG access has been turned off. And stresses the most common cause of an oscillation and EPA Act at HP G Access down regulation. Yeah, they're risk.

1:11:44

You know, the risk is the risk and it depends on how long they are estrogens are a low floor.

1:11:55

So test, evaluate, and in a young, Pershing, you're not going to give them hormones just like a young guy.

1:12:01

That's not going to be your first go to you are going to address all the underlying etiology or the stressors. Are they toxic? You're gonna look at heavy metals.

1:12:10

You're gonna look at all those things before you go anywhere, near hormones.

1:12:17

And you gotta figure out if it's a primary hormonal abnormality or a secondary hormonal abnormality emotion women who have, um, reached puberty and had a cycle.

1:12:29

And they continue to have cycles and all of a sudden they sat and they stop is not going to be a primary hormonal abnormalities typically said.

1:12:40

Do you have any recommendations to improve detoxification when someone has the M T H F R gene? Yet depends on if you're a double snip or a single snip.

1:12:53

And you really want to make sure your B vitamins and Foley, and everything in that methyl folate pathway is optimized.

1:13:07

In patients with menstrual migraine, is there any evidence for using bio identical hormone therapy instead of ...?

1:13:16

Yes. There is.

1:13:20

I don't know that data offhand but that would be an interesting Blok topic.

1:13:28

Just like peri menopausal, or Just luteal phase, depression, women who get depression based on their cycles, a lot of times it may not be the absolute value. It may be the up and down patterns and it may be the relative hormone levels. And so again, that's where you would do a sacrament.

1:13:55

It's going to be really, really important because you just don't want to give warmup. You want to see when it's happening and why.

1:14:03

And you also want to look at their HBA access.

1:14:07

No, nothing is just one thing.

1:14:12

It's all inter-related.

1:14:17

By the patterns are so important on the DUTCH Test, right? Little little plug there. Can you explain why someone would have very low E two, but maybe have high E three when they're looking at their DUTCH Test?

1:14:31

Well, I'd have to see the DUTCH Test. and remember, E three is a metabolite.

1:14:36

It's not A primary hormone. It's essentially a metabolite.

1:14:41

So I would have to see what their metabolomics look like and how they're metabolizing 16 Hydroxy 2 E 3.

1:14:53

Even though it visually it may look like a hormone, it is actually a estrogen metabolite.

1:15:04

And why is there too low, or they are.

1:15:07

They inflamed and their inflammatory pathways are up regulated in all their employment and all of their metabolites are no higher than you would expect from a low E two or allele one.

1:15:19

And remember, what we're looking at on the DUTCH Test is E 1 to 16 Hydroxy 4 Hydroxy and two Hydroxy.

1:15:29

And, remember, E two does the same thing into metabolite, but we don't, which we don't show the E two metabolites.

1:15:38

And so, remember, E three is coming, you know, from primarily E one, but there is some contribution from.

1:15:48

Someone asked a question that may be on one of the slides that that you might want to pull back up when progesterone is taken vaginally. How do you measure improvements?

1:15:59

Vaginal progesterone is the only hormone, the only progesterone that can be measured in shear.

1:16:08

Remember if you use the DUTCH Test it's going to underestimate systemic exposure.

1:16:15

Because the vaginal mucosa does not have five alpha and Beta Reductive .... Enzymes. So, you're not going to see progesterone go into its five alpha and beta metabolite. Which is what we look at on that test.

1:16:26

But you can measure Shirin levels and you can look at Serum to see what your level is. It in pre-menopausal women. you'll want to get into the lower end of the. You want to get into the ludo range.

1:16:41

And the, and depending on whether they have and this is really complicated, know, whether they have depression. You're going to want to be either super high or you don't want to be too high. It's very, very complicated, pre-menopausal depression and post-partum depression.

1:16:58

But if we're looking at post-menopausal women, you'll want to keep them towards that lower end of the luteal range, and this is plausibility argument I'm making for bone health.

1:17:10

There's no research on vaginal progesterone looking at bone Health and what we know that in pre-menopausal women, they need blood levels of progesterone or optimum bone production.

1:17:27

So what I do with my women is I get them to that lower end of the lawyering.

1:17:33

You throw the beach R T matrix back up on the screen for me.

1:17:37

What, we have a couple of people asking questions about that specifically.

1:17:44

No washing my puppies. Alright, yes, those, too.

1:17:49

All right. We'll just leave that There. Have been a couple of couple of questions about that. So, if you had questions about that, we'll leave it there for a little bit of a little bit of time for you to read through that.

1:18:00

You can see, again, the green check marks or when to use DUTCH red checkmark will be no and then kind of give you some different options below their doctor cell TO would you recommend doing a DUTCH Test on someone who is actively exercising the day that they're doing the tests?

1:18:16

And if so, their cortisol higher being during that day. Is that normal for the situation? Or, what would you be looking at?

1:18:24

Well, I like to take people when they're in their normal state, right? What are their normal activities on what they're doing now?

1:18:35

I don't recommend they do vigorous exercise when they're doing their DUTCH Tests, because I'm not going to get a good reflection of their Bazel cortisol levels.

1:18:46

What I'm going to get is exercise cortisol levels, and then how do I interpret that? I'd ask the question, other than in an exercise state.

1:18:56

So, I would recommend that the day of their DUTCH Test, they can certainly walk.

1:19:02

But I wouldn't be brisk walking, where they get their heart rate up and all of that, I would just kind of do schroll.

1:19:10

So, the answer is no, I try and have them not do vigorous activity.

1:19:17

This will be our last question. Is vaginal progesterone safer than oral progesterone or a Marina and which is better to use for each her tea?

1:19:28

It depends on the patient. Well, vaginal progesterone is not a birth control.

1:19:34

So you have to remember bio-identical hormones.

1:19:37

Oh, I've never been studied in the birth control setting, and why is that? If you randomize two groups to 300 milligrams of oral progesterone or, you know, I don't know, 200 milligrams of angina, Progesterone and neither group of women want to get pregnant and one group of women get pregnant. What happens?

1:20:04

So, that's why it's never been studied as birth control, um, and so it depends on the patient.

1:20:15

Typically are women who are having sleep difficulties.

1:20:18

My first will be oral progesterone, but I do a DUTCH Test before I start. And you'll see why in a post-menopausal woman would you do a DUTCH Test first. Well, even though the levels may be low, I look at trends, and I want to see trends and pathway predominance.

1:20:35

And then I'll give them 200 milligrams of all ... progesterone.

1:20:40

And then I will retests in, say, three months or after three months of treatment.

1:20:48

I use vaginal progesterone primarily in my reproductive women, who are trying to get pregnant.

1:20:56

If women have no sleep issues, initially been just great.

1:21:00

I give them the option back and progesterone oral progesterone.

1:21:05

But the goal is endometrial protection.

1:21:09

200 milligrams is the only dose that's been studied in randomized controlled trial. So I start with 200 milligrams.

1:21:18

If you apply it directly to the vaginal mucosa, you are bypassing first pass Metabolism and in essence, you're bathing the endometrium with progesterone.

1:21:34

Should you know, you're getting protection.

1:21:37

But a lot of women don't like to use hormones.

1:21:41

They just don't.

1:21:44

Well, thank you so much for all of your thoughts and sticking around for the additional questions. For everyone joining us, thank you for joining today. Please be sure to register for next week's follow-up conversation, where doctors don't till will be going further into detail on some of the topics that we've been going over today.

1:22:01

If you have any additional questions about today's content or general questions about the DUTCH Test, please e-mail our customer support team at , or call us at (503) 687-2050 and we will get you in touch with the right people. Again, thank you so much for joining us today, and thank you to Dr. Saltiel. We look forward to seeing you next week.

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