Menopausal Hormone Therapy: Clinical Benefits and Outcome Studies

In this non-CME webinar, Dr. Doreen Saltiel reviews the limitations of hormone-related guidelines, while demonstrating how the clinical evidence guides prescribing micronized progesterone, estradiol, and testosterone therapy. She also dives deep into which delivery methods and doses improve clinical outcomes.
Since the 2002 Women’s Health Initiative (WHI) publication, menopausal hormone therapy (MHT), especially estrogen (E)/estradiol (E2) replacement therapy (ERT), has been hotly debated. The WHI’s preliminary data release changed clinician practice patterns. Since then, clinicians have struggled with weighing the benefits with the risks. Since women spend approximately 1/3 of their lives hormone insufficient/deficient, it is important to understand MHT’s benefits and risks and how they may impact your patients and practice.

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Full Transcript and Time Stamps

(0:03) Dr. Doreen Introduces The Topic

(3:38) Presentation Begins

(8:21) Progesterone

(30:30) Estradiol

(1:03:08) Estriol

(1:06:53) Testosterone

(1:16:51) Case Study

(1:30:57) End of Presentation

(1:32:37) Q&A


(0:03) Dr. Doreen Introduces the Topic
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For the next 90 minutes or so, we're going to have some fun talking about bio identical hormone replacement therapy. We're going to dig deeper into the clinical benefits, and show you some of the outcome studies, which you can use in your toolbox. I turn my webcam off due to satellite issues, and let's get started. There are my disclosures, and just so you know, I am a consultant for Precision Analytical, along with the ACC and Calroy Health Sciences.

(0:38) And so, I first wanted to share with you evidence that actually changed my practice.

(0:44) In post-menopausal women, serum or a validated DUTCH levels between the post-menopausal and luteal ranges, so the top of the post-menopausal, and the bottom of the luteal ranges can be used to monitor transdermal estradiol.

(1:00) However, DUTCH, which is a validated, peer-reviewed four-spot dried urine test, is a better option, and I will show you in a bit.

(1:09) Transdermal progesterone, non-vaginal, does not balance estradiol's endometrial proliferative effects, no matter what you've heard. And I'm going to show you that data.

(1:21) In women, transdermal testosterone doses as high as 10 milligrams per day and pellet doses of 50 to 150 milligrams that increased serum levels above the upper limit of normal, using an LC-MS/MS assay, which you must use in all women pre-menopausal, post-menopausal, adolescents for testosterone, and in all post-menopausal women for estradiol and men for estradiol are safe and do not result in adverse events.

(1:54) And saliva should not be used to monitor HRT.

(2:00) There are no available validated assays with either clinical outcome data in serum equivalent. In addition, there are no outcome studies using compounded creams.

(2:10) Now, I trained at A4M. I trained under Pam Smith, David Zava, who both claimed saliva should be used.

(2:20) However, you have to ask yourself, what are those values mean, where in that when they're in that therapeutic range. What are the serum equivalents?

(2:32) There's no outcome studies using saliva that says, you are protecting bones, you are protecting the heart. None. So, how do you know what to do with that information?

(2:48) And that's why I don't use saliva anymore, other than for cortisol, it's still the gold standard for cortisol, but I use serum and dried urine. And the fact that I use compounded creams, as well as many of you do, there are no studies.

(3:07) So, you have to, at least, explain to the patient why you're using a compounded cream, when there are FDA approved equivalence available and explain to them that there are no outcome studies.

(3:23) All right. Now for that. So, what I've learned is to extrapolate from the literature when you can, rationalize when you must, but always individualized care, and please document.

(3:38) Presentation Begins
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You need to document why you're doing what you're doing. So, now on to the presentation.

(3:46) At the end, you all should have a better understanding and gain insight into prescribing micronized progesterone, transdermal estradiol, transdermal, or all testosterone, not just transdermal, and which delivery methods and doses improve clinical outcomes. And we're going to talk a little bit about the limitations of hormone related guidelines. But before we start again, you all, for those of you who are new to this, need to become very familiar with the steroid pathway.

(4:17) And when you look at the steroid pathway, it's easy to assume that exogenous pregnenolone or progesterone, can go and make other hormones. That's not the case. Let me show you a specific example. And that example is when we're talking about cortisol. People talk about cortisol steal, pregnenolone steal, progesterone steal, there is no such thing as that concept.

(4:48) Let me show you why. The brain gets the signal. ACTH gets into the adrenal cortex cell and then triggers the star protein, binds to cholesterol, that's exogenous LDL cholesterol, which then enters the mitochondria, and it's within the mitochondria that pregnenolone is metabolized, so it's not exogenous pregnenolone, it's not circulating pregnenolone.

(5:27) It is metabolized from LDL cholesterol, de novo LDL cholesterol in the mitochondria. It then leaves the mitochondria, enters the endoplasmic reticulum, where it's then converted to progesterone.

(5:41) Progesterone is then converted to 11 deoxycortisol in the cytoplasm, which then re-enters the mitochondria and makes cortisol. That's how cortisol is made. So, when you give somebody progesterone, you don't have to worry. It's going to pregnenolone.

(5:59) I mean, excuse me. It's going to cortisone. When you give somebody pregnenolone, you don't have to worry that it's going to cortisol.

(6:07) Then cortisol leaves the adrenal cortex and gets into the systemic circulation and does its thing. So, the questions that we're going to answer today that we all should be asking ourselves, when we talk about hormones, is why do we prescribe hormones?

(6:26) What hormones should we prescribe?

(6:28) Why do we test hormones, and what tests do we do? And I don't have enough time to talk about what tests do we do. My hope is that Mark will follow up with another webinar talking about what tests we do in each of the different scenarios based on the hormone delivery that you're using.

(6:49) So, why do we prescribe hormones? Well, to improve clinical outcomes, whether we're talking about pre- and perimenopausal women who have luteal phase defects, or we're talking about post-menopausal women.

(7:01) And then, why do we test hormones? Well, to make a diagnosis to monitor efficacy of therapy, and this is very, very important, to ensure that we're in the studied ranges that are proven to be safe and improve clinical outcomes.

(7:17) Saliva doesn't have any of those, and they haven't validated against serum, so you have serum equivalence.

(7:25) And so, we're going to spend the majority of our time talking about what hormones should we prescribe and what the evidence tells us.

(7:34) And, in addition, we're going to ask, what are the patient's treatment goals? What's the most effective dose to optimize these goals? And how best to limit any and all adverse events? So, what does the literature tell us about menopausal hormone therapy, dosing delivery, and clinical outcomes, and what levels have been documented to be safe and improve clinical outcome.

(7:58) So, for each of the hormones, we're going to discuss relevant guidelines on where they fall short, discuss agreed upon benefits for each hormone, including delivery and dosing the ones that everybody agrees on, and discuss benefits that are somewhat controversial, and discuss how to use each hormone in clinical practice. All right. Let's start with progesterone.

(8:21) Progesterone
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And here is the American Association of Clinical Endocrinologists and the American College of Endocrinology's position statement: When the use of progesterone is necessary, and I say it's always necessary in menopausal women, micronized progesterone is considered safer than progestin.

(8:38) Oral micronized progesterone, 200 milligrams, protects the endometrium, and if you're using a transdermal estradiol pack, 0.025 milligrams, or 100 milligrams of vaginal micronized progesterone protects the endometrium.

(8:56) Everybody in the functional medicine community, and I think everybody in the traditional community would agree with this.

(9:04) All right. I don't have time to go through each of these. I'm going to highlight key points, and there's a bunch of references for you at the end. But what I want to tell you is progesterone is safe.

(9:17) That's number one, and number two. So, you don't have to worry about it increasing breast cancer like progestin's. You don't have to worry about the cardiovascular system. It is safe.

(9:30) We're going to start with where it is been most published and what it's mainly its primary uses, which is endometrium protection, 200 milligrams, and 100 milligrams both protect the endometrium.

(9:45) Moyer was a 1993 observational study that actually documented, if you use progesterone less than 11 days, you don't get an optimum progestogenic effect. In other words, you're not optimally protecting the endometrium.

(10:02) So, that's where if you do sequential progesterone, that 12 to 14 days, comes from the PEPI trials. The landmark trial that it's a randomized control trial that documented at 200 milligrams protects the endometrium. DeCarlo, use 200 milligrams and 100 milligrams of oral, and he also compare vaginal progesterone with a 0.05 milligram patch. All of them protected the endometrium and the KEEPS trial, which was cardiovascular study protected the endometrium at 200 milligrams.

(10:39) Now, I want to point out this Mirkin study. This was the replenished style or REPLENISHED study, where Bijuva, which is the oral micronized progesterone, 100 milligrams and one milligram of oral estradiol combination pill was studied to become FDA approved and it is. What they found was that there was a statistical, significant correlation between a woman's baseline estradiol level in their material histology. So, for women who had baseline serum estradiol levels, and this used a sensitive assay. So, it's a reliable assay of greater than 10, were more likely to have a baseline proliferative endometrium. And then a woman who had a baseline E2 of less than five, or in the 5 to 10 range, the women whose baseline E2 was than five. If you saw a spotting, it's because they had atrophic endometrium. They need more progesterone.

(11:37) If their E2 is greater than 10, and they're bleeding, they definitely need more progesterone. That's why the recommendation, by most of the guidelines, of 200 milligrams, is a very reasonable place to start.

(11:51) So, a woman's endometrial health pre-hormone initiation is really key when determining the initial oral micronized progesterone dose and transdermal estradiol dose.

(12:04) Vaginal progesterone's a little different, it bathes the endometrium in progesterone, so the doses typically don't have to be that high. Yes, they were studied at 100 and 200 milligrams, definitely protects the endometrium, but these are secretory dosages, meaning for women who are trying to reproduce. What Ross showed in 1997 is that if you use 90 milligrams every other day, and achieved a luteal level of around 6.8 nanograms, you protected the endometrium.

(12:40) He also showed that at 45 milligrams there was some degree of endometrial proliferation, no hyperplasia, but this is using 45 milligrams every other day, and I would recommend if 45 milligrams is what you're going to use, ultimately do it daily.

(12:59) I would start off with you. If you're going to start with vaginal progesterone in 100 milligrams, when all is stable, then you may consider decreasing it to 45.

(13:11) Now, De Ziegler looked at 45 milligrams and it protected the endometrium, and very interestingly, the elite trial was a cardiovascular trial that looked at oral estradiol and vaginal progesterone.

(13:24) There were no adverse endometrial effects, and here are those studies for you. The full citations are at the end.

(13:35) And so, what about transdermal, on-the-skin progesterone and the endometrium. There are people who say you can use it, it protects the endometrium. It doesn't.

(13:47) Two pilot studies, actually one pilot study on one large observational study, the pilot study, by Wren, used a 0.1 milligram patch, a hefty dose of a patch, and they use transdermal progesterone 16,21 or 64 milligrams times 14 days. And what they found, despite sky-high saliva levels that exceeded serum luteal levels, there was no endometrial protection.

(14:13) So, how valuable is saliva?

(14:17) The Vashisht study is the largest study was a four year, open-label study, and they use one milligram of an oral estrogen with estradiol and transdermal... Excuse me, is this was Oestrogel, I apologize, and transdermal progesterone, 40 milligrams, and what they found: 32% of the women had either endometrial proliferation or hyperplasia, I'm not willing to take that chance. The one study that the protagonist of transdermal progesterone site is delaying any study, where they use 20 BID, added to 0.625 of conjugated, F1 estrogen.

(15:00) And she herself said the results are encouraging.

(15:06) And in quotes, "Although the lack of endometrial hyperplasia is promising, additional longer clinical trials to ensure safety are required before transdermal progesterone cream can be offered as an alternative to standard HRT." So, even this one study, all of them agree there is not enough data to recommend transdermal progesterone to protect the endometrium.

(15:34) And so, there is some data on vasal motor symptoms in transdermal progesterone, but it does not protect the endometrium to the degree that is necessary. No data since these studies.

(15:46) In addition, there's no data on improving bone mineral density, the small amounts of data that exist on transdermal progesterone states, it doesn't improve bone mineral density.

(15:59) So, a woman's pre-treatment endometrial health is important when considering both transdermal estradiol and micronized progesterone.

(16:07) OMP 200mg is guideline recommended it and is a reasonable first choice. Oral micronized progesterone also protects the endometrium.

(16:16) Vaginal micronized progesterone, 100 milligrams daily initially is a reasonable alternative of women who don't want to take 200 milligrams for endometrium protection. Vaginal micronized progesterone, 45 milligrams daily, also protects the endometrium.

(16:32) And don't use transdermal progesterone to protect the endometrium, the evidence doesn't support it.

(16:37) And probably the most important point is that no lab test, serum, saliva, urine, tells you about progesterone's effect on the endometrium.

(16:51) None of them. An optimal level does not tell you whether you are protecting the endometrium. So, follow the clinical data. What about bone mineral density?

(17:08) You need progesterone for optimum bone mineral density, you need a normal ovulatory cycle of 12 to 16 days. Progesterone is estradiol's physiologic partner. And when the two are balanced, bone mineral density is stable.

(17:23) Adolescence, premenopausal women, and perimenopausal women commonly have clinically normal cycles with ovulatory disturbances.

(17:34) HPA axis dysfunction is thought to be at the root cause.

(17:38) Let's look at a theoretical, ideal lumbar spine areal bone mineral density lifetime. This is when bone mineral density should be increasing.

(17:48) It's balanced during the reproductive years or the premenopausal years. And during perimenopause, you have skipped cycles, so reabsorption is greater than formation, right? Because progesterone makes new bone, estrogen prevents absorption, and in menopause, you have a dramatic or rapid increase in bone loss that stabilizes over time until women become more frail. And it increases bone loss again. And it increases the risk of frailty fractures. So, what does the data say?

(18:28) This is an 1990 study done by Jerry Lin Prior. And she's written a lot about progesterone.

(18:35) It was a one-year study looking at spinal bone loss in pre-menopausal women. They use quantitative CT.

(18:42) And this is a normal luteal cycle. And they define a short cycle is less than 10 days. And there was no statistically significant difference in bone loss between those women with normal luteal phases and those women with short cycles. When these two groups were compared to women who had more than one short cycle or any at anovulatory cycles, there was a statistically significant increase in bone loss in this group. And, in fact, she found in those women, who were anovulatory, a bone loss of about 4.2% per year. So, this is in the setting of normal estradiol levels. So, in the presence of normal estradiol levels, if you have more than one short luteal cycle or any anovulatory cycles, you're at increased risk for early and possibly excess bone loss.

(19:37) And in 2014, her group did, and looked at, all the data out there and published the 2014 meta analysis of prospective studies, and what they found was that regularly menstruating women with more frequent ovulatory disturbances, we're losing approximately bone mineral density at about 1% per year. So, what does this mean?

(20:03) If a woman does not increase bone mineral density as expected, or loses it at about 1% per year over her 30 to 45 cycling years, it's possible that by the time she reaches perimenopause, she may already have lost 10 to 20% of her bone mineral density. To have a high index of suspicion, a normal cycle length doesn't necessarily equal an ovulatory cycle test using the DUTCH validated cycle-map.

(20:38) Don't guess. Again, yes, serum equivalent, and so, what about treatment?

(20:43) For reproductive aged women, adolescence, 300 milligrams, if they're oligomenorrhea, 14 through 27, if they're amenorrhea 14 days on, 14 days off, will restore the normal ovulatory cycle.

(20:58) In peri- and postmenopausal women, there were no outcome studies evaluating progesterone alone, regarding bone mineral density in fractures.

(21:07) In a 2017, published a randomized controlled trial meta analysis, which included more than a thousand women, again during prior, documented that recently post-menopausal women who were randomized to estrogen alone, mostly conjugated, equine estrogen, or CEE and mainly a progestin, that the combined group statistically significantly increased bone mineral density to a greater degree than estrogen alone. So, combined therapy was better.

(21:40) She stated in one of her review papers that, oral micronized progesterone, 200 to 300 milligrams, is thought to provide the same degree of bone mineral density protection, as 2.5 milligrams of MPA. But again, there are no studies.

(21:58) And so, progesterone is estradiol's physiologic partner in premenopausal women with luteal phase defects.

(22:06) Oral micronized progesterone 300 milligrams, is recommended in postmenopausal women, 200 milligrams, a reasonable starting dose for both endometrial protection in bone mineral density.

(22:18) All right. What about neurobiological effects? This is the plausibility argument.

(22:23) We know that progesterone is synthesized and metabolized both outside the brain and inside of the brain.

(22:30) Progesterone and it's neuroactive metabolites act within the brain and spinal cord to decrease inflammation, increase neurogenesis and increased myelin repair and the study, there are no studies really that randomized progesterone and look at progesterone, as a, and, you know, with as an outcome, as a neuroprotectant progesterone alone with cognitive impairment.

(23:00) But the study that everybody cites is the one by Allison Berent-Spillson, where they looked at oral estradiol a milligram, an oral progesterone, targeted milligram separately, and they looked at cognition and neurobiological effects. And what they found was that oral estradiol improved verbal processing. Whereas oral micronized progesterone improved verbal memory tasks, and they concluded understanding estradiol's and progesterone's effect could lead to more effective therapies that may impact cognitive performance.

(23:31) Again, this was not an outcome study. And so, how do we translate this into clinical practice?

(23:38) Let's start with, this is a DUTCH Cycle-Map again validated against serum. Let me orient you.

(23:46) The black lines are your reference range. OK? This is estradiol, estrogens on top. This is progesterones on the bottom, and again this is urine.

(23:57) So, the red is estradiol and the blue is estrone, down here, beta-pregnanediol.

(24:05) When you look at endogenous progesterone is the best marker of endogenous progesterone beta-pregnanediol is the red, and the blue is alpha pregnanediol.

(24:19) And so, what we see here is that estrogen, let's start here, the pre-ovulatory estradiol rise that triggers LH to be released occurred early.

(24:34) And then, when we look at estradiol and estrone compared to progesterone, progesterone is on the lower end. o, clearly the patient is estrogen dominant.

(24:46) And then, we come over to the progesterone and we look at the luteal phase. And we see that there's a little bump.

(24:55) Now, did the patient ovulate? Did the patient not ovulate? Nobody, it's hard to tell looking at at this, but, again, you know, estrogens are kind of on the higher side. Progesterones are on the lower side, and what we talk about we talked about HPA-axis dysfunction as a root cause. And we talked about, without adequate progesterone, the patient is a setup for increased bone loss.

(25:22) This is a young girl whose mom listened to one of these webinars, called me up, her mom's a physician. Her daughter is 18, over exercises, is on track and and soccer, and she's a 4.0 student, sleeps six hours a night. And she was concerned that, even though she has normal cycles, and sometimes she skipped cycles, that she may be a setup for abnormal bone mineral density.

(25:51) So, what did we do? Well, I didn't give her any progesterone. We addressed her HPA axis, we addressed her diet, which was kind of sad, we addressed her sleep.

(26:02) We made sure her micronutrients were all in the optimum range, and we retested her at about four and a half months.

(26:13) And here's what we see. What the first thing you should notice is that, that estradiol, ovulatory estradiol, all right, occur at the appropriate time.

(26:24) But, when we look over here, she still is relatively estrogen dominant. So, again, and look how high her estrone is relative to her estradiol. So, she does not detox well.

(26:37) We saw that over here, to some degree, now, it looks much more significant here, but now, when we look at her ovulatory peak, guess what? She definitely ovulated.

(26:52) And when we check serum using LC-MS/MS assay, her progesterone was 20, at the same. You know, on the same day that, you know, around the same time we did this, so she's definitely ovulating.

(27:05) So, you don't always need to give patients drugs to make a significant impact.

(27:13) And as I tell my cardiovascular patients, I can give you all the medicines in the world, if you don't change your lifestyle, we're not going to make a dent.

(27:24) All right. So, progesterone is important for optimum bone mineral density. You want normal length luteal cycles.

(27:31) Test, don't guess, you want to use a DUTCH validated Cycle-Map, which provides the most actionable information, and in adolescence, pre and perimenopausal women, oral 300 milligrams is a reasonable choice. Vaginal micronized progesterone. The data goes from 100 to 300 milligrams. Check, you want to check serum levels to ensure you're in the luteal range.

(27:54) Now, if you use urine, urine is going to underestimate luteal levels or levels of progesterone.

(28:09) Why? We're measuring metabolites, the vagina, the endometrium, doesn't have five alpha and beta reductase enzymes, so you're not going to get progesterone metabolites, right?

(28:28) Use serum. Check and make sure you're in the luteal range, and you can use serum to monitor vaginal progesterone.

(28:37) In all postmenopausal women, follow the clinical data, 200 milligrams is reasonable. Vaginal 100 or 45 should result in serum levels at the lower end of the luteal range. Now practice pointers.

(28:51) In premenopausal women with luteal phase defects, including PCOS, 300 milligrams or vaginal 100 to 300. Most of my young women do not want to use vaginal progesterone, so I wind up giving them 300 milligrams of oral progesterone.

(29:08) In postmenopausal women with a uterus, oral 200 or 100, and I typically, me, started 200 and I started vaginal 100, if I'm going to use vaginal, protects the endometrium, and may prevent osteoporosis. And the data is unclear whether the lower doses provide the same degree of protection of potential, in air quotes, protection, as oral 200 milligrams.

(29:37) And if you use vaginal progesterone, ensure you're in the lower end of the luteal range and that's the plausibility argument.

(29:46) If you're in the luteal range, you should, you should, be protecting bones.

(29:54) And in postmenopausal women without a uterus, the same thing above applies, 200 or 100 vaginal, 100 or 45, what you want to do, is you want to balance your transdermal estradiol to avoid estrogen dominance and approximate luteal levels to prevent osteoporosis. If a 100 milligrams and a woman without a uterus does it, great.

(30:17) If the vaginal 45, does it, great, I typically start all my patients on 200 milligrams of oral and vaginal 100. What about estradiol?

(30:30) Estradiol
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Well, there's a, there's this tug of war between allopathic medicine and functional medicine.

(30:34) You know, allopathic medicine takes time because all the data has to be based on large randomized controlled trials, for them to make recommendations.

(30:47) Whereas functional medicine looks at the totality of the data. But we sometimes get it wrong too, as we did with saliva.

(30:55) Let's look at the guidelines for estradiol. And when I talk about menopausal therapy, here I'm talking about estradiol predominantly. It is the most effective treatment for vasal motor symptoms, in general, urinary syndrome of menopause, and it prevents bone loss and fractures.

(31:15) Treatment should be individualized.

(31:17) Use the best available evidence to maximize benefits and minimize risks, and you should re-evaluate the benefits and risks and do ongoing surveillance. And everybody agrees, for women younger than 60 who are within 10 years of menopause?

(31:32) Have no contra indications, the benefits outweigh the risks. Everybody agrees. Here's where it gets sticky.

(31:39) For women who initiate hormone therapy more than 10 or 20 years from menopause, or are older than 60, the benefit risk ratio appears a little less favorable because of the greater absolute risk of coronary disease, stroke, venous thromboembolism, and dementia.

(32:00) Well, that statement above is based on the WHI data, right, which use CEM progestins, which are no longer relevant nobody should be using CEE, or any oral estrogen and a progestin.

(32:17) In fact, the guidelines remind us that oral or vaginal is the treatment of choice, and transdermal estradiol may be preferred.

(32:24) And what I, when I'm mentoring deoxy, here's what I tell me, is what I tell them prior to initiating hormone therapy, whether it be in men or women. Risk stratify.

(32:36) Make sure you know the status of the endometrium, the breast, their bones, their cardiovascular system, as well as any degree of cognitive impairment. And you must do ongoing surveillance.

(32:50) Don't just treat them, you need to continuously re-evaluate women, and men, for that matter.

(32:58) All right, let's talk about the benefits, and the goal is how do we optimize these? Well, these three, everybody agrees with, there is absolutely no arguing.

(33:08) For most women, and I say, most, all FDA approved transdermal estradiol product patches, gels, improved vasal motor symptoms, and vulva vaginal atrophy with serum or DUTCH validated dried urine levels just outside the post-menopausal women and I'll get to the exception to that.

(33:27) A patch zero point zero two five milligrams improves clinical outcomes, serum 20 to 40 PICO grams per mil using an LC-MS/MS assay or a DUTCH urine of zero point seven to 1.8 nanograms per milligram.

(33:43) Gel doses are product specific, but shoot for those same ranges, because, as you see here, a, zero point three seven five milligram estrogel is the lowest dose at four weeks that improves visual motor symptoms and vulva vaginal atrophy.

(33:59) Whereas Divigel, zero point twenty five milligrams improves only vulva vaginal atrophy. You have to go to zero point five milligrams to improve vasal motor symptoms and vulva vaginal atrophy.

(34:11) All FDA approved patches improve bone mineral density and prevent osteoporosis, the same serum or validated dried urine levels. ou don't need to get levels to 60 or 70, like they used to believe.

(34:24) FDA approved gels are not approved for osteoporosis prevention.

(34:28) And that's because when you look at a phase three study, where they compared the existing standard, which in this case was patches against the gel, it took higher doses of gels at higher serum levels to be equivalent to a low dose patch or a very low dose patch, at much lower serum levels.

(34:53) So, that's why it's not FDA approved. So, the patch which improves all of those is a reasonable starting dose when initiating therapy. And so, for most women, a low dose patch improves vasal motor symptoms, vulva vaginal atrophy, and bone mineral density. At serum or dried urine levels just outside the post-menopausal range, and why do I use dried urine, is because it averages over a 24-hour period. If you get serum, it's one point in time. That may not be the most accurate point in time to reflect a serum level. Especially when you use gels because they bounce all over the place.

(35:40) Transdermal estradiol gels are a reasonable alternative but they're not approved for osteoporosis prevention. No outcome studies using creams, and so, thus far we can say zero point zero two five milligram patch with oral 200 is where I start or 100. Or vaginal 100 or 45 typically. I may decrease the dose ultimately to 45, improves clinical outcomes

(36:07) And protects the endometrium, what about breast cancer? Both estrogen-alone and estradiol-alone decrease breast cancer incidence and breast cancer mortality. Estradiol estrogen does not increase breast cancer. OK, the WHI got it wrong, and I'll show you here.

(36:33) Here's all the studies that you, and the citations are in the back, but we're going to focus on the WHI 2020 update and the finished trial. The data was misinterpreted. You have to remember that the WHI was not a breast cancer study.

(36:52) It was a cardiovascular study where they looked to determine if the beneficial effects that were seen in young women in observational studies could be applied to older women.

(37:05) And that's why only about 10% were in the typical menopausal range where we're going to start therapy. And they use cardiovascular statistics, and applied it to breast cancer, which they shouldn't have done.

(37:19) And Hodis, in a wonderful 2018 review article stated, "Any association that may exist between menopausal hormone therapy and breast cancer appears to be rare, and really no greater than any other medications commonly used in clinical medicine, like ace inhibitors, or beta blockers."

(37:40) And what that 20-year follow-up study showed is that CEE alone decreased both breast cancer incidence and breast cancer mortality. The breast cancer mortality reduction was up to 45%.

(37:53) And the CEE and MPA, versus placebo trial, is where it got money. In the hormone naïve group versus placebo, which was 75% of the population, there was no difference in breast cancer incidence. In the prior treatment arm, meaning these women were treated with hormones before, had a washout pairing them were randomized to the treatment or placebo. They falsely reported this higher incidence of breast cancer, when actually, there was a divergence encouraged that was due to an unusually low placebo group breast cancer incidence, not an increased incidence.

(38:29) In essence, there was no effect on incidents, breast cancer incidence. And so, let me show you the data.

(38:38) The average age of these women was 63 years old, and they were more than 12 years since menopause.

(38:45) And they were stratified by prior hormone use. So when you look at this group, this is hormone naïve, you see the curves are just about identical.

(38:55) Then when you come over here, you see here is where the curves separate and what they said, oh my God, this is due to an increased breast cancer incident as opposed to an unusually low breast cancer incidence in the placebo group.

(39:13) And this has, to date, never been changed in all of the WHI interpretations. And so, is there any data to support that this was actually a lower breast cancer incidence in this placebo arm? Well, yes.

(39:35) This is the WHI Observational study, where they looked at, compared it to the CEE and MPA placebo arm versus the, there's no placebo on an observational study, then nonusers.

(39:49) And when you look at no prior hormone use, it's about identical.

(39:54) When you look at prior hormone use, it's much lower in the MPA trial, but just about identical to all the others. Hmm.

(40:05) And then, when they looked at the dietary WHI dietary modification trial and look at CEE and MPA overall, including the 75% group, look at the annualized percent event rate of breast cancer, they are identical. So, the bottom line is, as I stated earlier, there really is no increase in breast cancer incidence in this group. And if you lift this blue curve up, which is the treatment arm, and place it right on top of here, it's almost identical. Well, I just told you the WHI doesn't matter because we don't use CEE and progestins, but what about the Finnish database where they used bio identical hormones. And there was about almost 500,000 women, where they compared them to non users, they either used oral estradiol, transdermal patch, or transdermal gels. Unfortunately, they use progestins. And what they found was that any E2 based hormone therapy was associated with an up to 54% breast cancer mortality reduction.

(41:21) The greatest mortality reduction was in the women who were within 10 years in menopause 52-59, regardless of whether they were using a progestin or not.

(41:33) But there were still breast cancer mortality benefits up to the age of almost 80, and it's only when women were older than 80, and they use the combined group, that it was greater, the breast cancer mortality, was greater than the age matched controls and not by much.

(41:54) So, they concluded that all of these products, bio identical products, statistically significant decreased mortality, breast cancer mortality up to 54%.

(42:07) Even when hormone therapy was used for greater than 10 years. So, this negates that WHI, Asian initiation was not related to breast cancer mortality that sort of negates that over 60.

(42:22) And what was most important in this population, where they have a high incidence of cardiovascular disease and breast cancer, whereas one in twenty women died from breast cancer in the general population, women who used hormone therapy, all comers, at a 50% mortality reduction, only one in ten died.

(42:42) So, that's significant. And as you see here in the clinical pearls, E2 alone decreases mortality with the greatest mortality 50 to 59 years old.

(42:53) And you may consider to maximize the E2 alone effects, vaginal micronized progesterone actually may be a better option, though it's never been studied.

(43:04) There are your key points. There's substantial evidence, not only decreases breast cancer incidents, but decreases mortality.

(43:12) Even when women using combined therapy had a mortality benefit, the greatest mortality benefit occurred the the closer to menopause a woman was.

(43:23) But age at, hormone initiation and duration is not associated with increased breast cancer into 10 mortality and does decrease mortality.

(43:34) Time since menopause should cause pause, right, you should think about it.

(43:38) You should risk stratify if you council patients, but not prevent them from initiating or continuing hormone therapy.

(43:46) And so, the bottom line is: a patch or a gel decreases breast cancer incidence and mortality. Now, what about cardiovascular disease? We know that aging increases inflammation. You get all these free radicals. You get decreased redox potential, and we know that hormones are immune modulators. We also know that estrogen, progesterone and testosterone receptors are expressed in all immune cells, endothelial cells, and vascular smooth muscle cells.

(44:19) So, when you add a decline in hormones and sex hormones onto the aging process, you see how both influenced immune competence and disease susceptibility. So, when you add a decline in hormones and sex hormones onto the aging process, you see how both influenced immune competence and disease susceptibility. And here's just a summary of estradiol's endothelial effects, nitric oxide it has direct antioxidant effect, and it increases mitochondrial antioxidant defenses.

(44:46) And you know, when you talk about receptors, use it or lose it, you have to have adequate estradiol levels.

(44:42) ER alpha is more pronounced in the vascular endothelium.

(44:57) And what it's thought that E2 serum levels modulate your expression, which impacts signaling, sensitivity, and function. This is a study out of Carrie Moro's lab.

(45:13) And you are going to see lots of stuff where she's done work on estrogen here and in the menopause transition.

(45:22) This was an observational study, very small study, and what they wanted to determine was whether the vascular endothelial cell ER alpha expression was influenced by serum estradiol levels and related to endothelial function.

(45:36) There was immunofluorescence staining, peripheral endothelial cells, looking at the ER alpha receptor. And what you see here in the early follicular phase, there's some staining. So, there's some ER alpha expression in the late follicular phase. It's much, much greater, and in women who are postmenopausal, it's the least. So, this is a dynamic process during a normal cycle.

(46:04) And what was very interesting, which we're going to review here in a second, is that a premenopausal levels of about 36, and postmenopausal levels of about 30, you didn't have much ER alpha expression.

(46:19) But when you had estradiol levels of about 80 in the late luteal, excuse me, late follicular phase, you had a robust ER alpha expression. Now, this was using old technology. And so, I don't want you to say I have to shoot for a level of 80. You want to use newer technology. This is just to show you trends.

(46:46) And when they looked at ER alpha expression and flow-mediated vasodilatation, which is a validated way of looking at endothelial function, they found that the greater the ER expression, the better endothelial function was. Another way to say that, is that as serum E2 levels decrease and ER alpha expression decrease, so does endothelial function.

(47:18) So, it's very, very important that women have adequate estrogen levels. And so, what about that menopause transition. We talk a lot about pre menopausal women. We talk a lot about post-menopausal women, but does the menopause transition accelerate vascular aging and contribute to endothelial dysfunction?

(47:38) Well, let's first define the menopause transition, which is what's used in the literature. And that's the straw criteria.

(47:46) And it's amenorrhea of greater than 60 days, two months, but less than a year. And so, that's really where we're going to be focusing on. Again, this is out of Carrie Moro's lab, where they looked at the menopause transition to determine how would affect endothelial function, and what they divided these women up based on whether they were early peri-, late peri-, early post-menopausal, late post-menopausal based on the straw criteria. This had 132 women more than the other study.

(48:17) And what they found was that the menopause transition was associated with endothelial dysfunction, independent of traditional risk factors.

(48:26) So, when they compared all of these peri-, late, early, late post-menopausal, to the pre-menopausal women, they all had a statistically significant decrease in endothelial function.

(48:42) And what is really key is that when they looked at the early peri menopausal women, compared to the pre menopausal women. separately, yeah, this was statistically significant.

(48:55) But they, they felt that there was probably enough hormone around to provide enough endothelial function and look at the serum levels of about 50, again, these are not sensitive assays.

(49:09) But as women progress through the menopause transition, look at how the E2 levels fell. There was an accelerated decline in endothelial function. In other words, the late peri menopausal, early post-menopausal, and late post-menopausal women there was no statistically significant difference between endothelial function, in any of these three groups.

(49:33) So, the menopause transition, especially late peri menopause, is a critical period which CVD risk accelerates and endothelial function declines.

(49:46) So, the answer to our question is, yeah, does it impact vascular aging?

(49:52) And here are the studies, and it's no wonder that when you give women back hormones, you see an improvement in cardiovascular disease risk. Here are the studies. We're going to focus on the elite and the finished trial. Let me point out to you that the CEE alone trial in the young women, 40% had decreased MI risk and all cause mortality. That's why the WHI said less than 60 is OK, greater than 60, no.

(50:23) But again, we don't use CEE, we don't use progestin.

(50:26) Let's talk about the elite study. This was a cardiovascular study with a divided women into early post-menopausal, less than six years, and late post-menopausal women, greater than 10 years.

(50:41) They were, each group was randomized to oral estradiol, if they had no uterus, and oral estradiol plus vaginal progesterone if they did have a uterus.

(50:50) And what they found was that the women in the early group with serum levels of approximately 48, and this is using a very sensitive assay, so these are real numbers, was associated with statistically significant decrease in CIMT progression.

(51:12) When you looked at the late group, initially, they said there was no difference between the placebo and those treated regarding CIMT progression.

(51:23) But when they divided these women, based on their serum levels, they found that higher serum levels were associated with an increase in CIMT progression.

(51:35) So, the moral of the story is: keep older women at serum levels of about, you know, 20 to 30 and younger women, you may need to get them up to 40 to 60, and recently menopausal.

(51:51) Then, once again, the finished database, in all estradiol uses coronary artery disease. Related death risk was reduced by up to 54% in a time dependent manner meaning, the longer a woman was prescribed and used an estradiol-based hormone regimen, the greater the risk reduction.

(52:12) All reductions were comparable in women initiating therapy less than age 60, and in women initiating therapy, greater than or equal to 60 years of age, and duration, did not impact mortality.

(52:30) So, here's your bottom line. I threw this in here, even though I don't have time to talk about premature menopause, or premature ovarian insufficiency, and early surgical menopause. These are associated with increased cardiovascular disease risk, cognitive impairments, or hormone therapy is necessary.

(52:48) But estradiol decreases cardiovascular, morbidity, and mortality.

(52:54) Um, you know, recently menopausal women, depending on their cardiovascular disease risk, because all the women in the elite trial had subclinical vascular disease, may require higher serum levels closer to the low luteal range, or validated dried urine levels closer to 1.8 to 2 nanograms per milligram, for CIMT reduction older post-menopausal women, and women further from menopause, probably do best regardless with serum E2 levels of 20 to less than 40, and I aim for about 30, or validating dried urine of zero point seven to about 1.3 to 1.5. And this is regardless of cardiovascular disease risk. And once again, time since menopause and age should cause pause, not prevent initiation or continuation.

(53:45) And please, ongoing risk stratification, follow-up testing is a must for all women.

(53:51) So, when counseling patients, remind them that the guidelines, the traditional guideline, say it's not indicated to prevent adverse outcomes, however, the data suggests that it will improve outcomes. And the earlier you initiate therapy, the greater the benefits, and what about cognition?

(54:10) Another plausibility argument. Some studies document. It helps some document, no benefits, some document harm.

(54:18) Why is that? Different demographic populations, different formulations, and those different doses used, different study durations. And the reality is most studies were too short to discern estradiol's protective effects.

(54:33) Most studies were not designed to measure cognitive performance or Alzheimer's disease risk as a primary endpoint.

(54:42) But let's look at some of the benefits. It increases CNS antioxidants, decreases free radicals, improves cerebral blood flow.

(54:50) It promotes ATP generation, is involved in DNA repair, enhances synaptic plasticity.

(54:58) Women during the late peri menopause, during menopause, complained brain fog, decreased attention, and similar to what we saw with the menopause transition, cognitive changes are related to changing E2 levels in ER expression.

(55:13) What we also know is that higher estrone levels are associated with oral cognition, specifically working memory.

(55:23) And this is a very nice article by ..., where he outlines effects of estrogen on the brain, on cognition, and on dementia. This was the WHISCA trial, which you know, is a WHI tria,l so I just crossed it out.

(55:37) And so, the real question we have to ask: we know that estrogen has beneficial effects on the brain, but does it improve cognitive performance and prevent Alzheimer's disease?

(55:47) There are the studies, some say, you know, it increases cognitive impairments. I'm saying, no benefit, no harm. And some says, yeah, helps.

(55:56) So, the initial WHI memory studies documented an increase in dementia regardless of whether it was CEE + MPA, or CEE-alone.

(56:06) The Finnish study, interestingly, that showed a decrease in breast cancer mortality, decrease in cardiovascular disease mortality, actually showed an increase in Alzheimer's disease risk, aged initiation and treatment less than 10 year. So again, here, the closer to closer to menopause that you treat and less than 10 years is not an issue. But were you treated longer than 10 years? The risk was the same for whether you're using estradiol progestin or estradiol alone.

(56:39) So that's why the data is confusing, but both studies use progestins, which has been shown to decrease cognitive performance, these studies may not be relevant. And so then we started talking about the critical window hypothesis that says, Wait a second, if we give it to women up to the age of 60, and within 10 years of menopause, where the risk of dementia is small, it can have a positive impact.

(57:05) So, WHIMS-Young were 50 to 55 year old women who started menopausal hormone therapy. You know, close to menopause, and what they found: no benefit, no harm.

(57:18) So, there's the critical window hypothesis. KEEPS-Cog was a four year cardiovascular study, but when they looked at cognition in a sub study, there was neither cognitive benefit nor harm. They did see with a transdermal estradiol patch less amyloid B deposition, especially in EPOE E4 women.

(57:40) But there was no benefit and no harm, and the elite study, we just talked about a five year cardiovascular study, no benefit, no harm.

(57:50) Though micronized progesterone was used in the in the studies, neither study was really long enough to assess Alzheimer's disease risk.

(57:58) Then there are some short studies that did document improved cognitive performance. The two pilot studies by Asthana documented that women who have mild to moderate Alzheimer's disease, when they were placed on either a point five milligram patch or a zero point one milligram patch did document improvement in the lower dose, attention in verbal memory, and in the higher dose, semantic, verbal, and visual memory.

(58:31) But what was interesting, once the patch was taken away, cognition return to baseline as did serum levels. This was a three month study by Joffe that looked at peri and post-menopausal women baseline serum E2 levels were here, but there were no on-treatment serum results, and they found that a zero point zero five milligram patch improved executive functioning. And the most promising is the large, observational Cache County study. So, this is an ongoing longitudinal study that assessed, you know, E and E2's lifetime exposure on cognitive function.

(59:08) And the 2013 publication stated: in post-menopausal women, if menopausal hormone therapy started within five years and continued for greater than 10 years, you will see an approximate 37% decreased Alzheimer's disease risk.

(59:24) Then in 2019, a publication said, you know what, older women had a greater benefit than younger women the longer use of hormone therapy.

(59:33) The longer older woman used hormone therapy, the greater the benefit. However, timing does make a difference. There was a statistically significant association with the mini Mental Status exam.

(59:46) But those who have hormone therapy initiated within five years versus those who had it initiated greater than six years with those initiated earlier, had better scores.

(59:59) So, estradiol is not indicated to improve cognitive performance, so please, counsel patients that it may or may not improve cognition and set expectations, so the data is as clear as mud. Does it improve cognitive performance and prevent Alzheimer's disease?

(1:00:15) Yes, maybe, no. And it may be because other factors may play a real significant role. This was a KEEPS sub study where they looked at women who were within three years of menopause cardiovascular history. The Mean age was 60, this sub study, they used the patch. Or CEE 0.45 milligrams and oral micronized progesterone.

(1:00:43) What they found was that sleep quality was very, very important, and those who had improved sleep quality had less beta amyloid B deposition. Mean serum levels were 44, so serum levels are adequate, and again, this was very sensitive, I'd say. So, sleep is now a factor that we have to consider.

(1:01:08) And what they found, is that transdermal estradiol had the greatest benefit on cognitive performance and amyloid B accumulation and clearance, so it's more than just hormones. You have to look at HPA axis resiliency, inflammation, sleep quality, toxins. And I can go on and on and on, it's not all about hormones for any of these.

(1:01:39) So, transdermal estradiol should not be prescribed to improve cognitive performance.

(1:01:44) Most studies were too short, a zero point zero two five milligram patch has not been assessed regarding cognitive performance, zero point zero five patch, and of zero point one improve cognitive performance in older women with mild to moderate Alzheimer's disease. Very small studies, very short studies. Do not treat people and tell them that you may see benefit based on these studies. This is just to show you that we need studies that are targeting cognitive impairment and Alzheimer's disease.

(1:02:15) And the Cache County study is the most promising menopausal hormone therapy, when initiated within five years and continued for more than 10 years, may reduce risks. So there, initiate hormone therapy as close to menopause as possible. Continue as long as appropriate with ongoing risk stratification, surveillance, and follow up testing.

(1:02:36) A patch zero point zero two five milligrams and, either, Oral 200, 100, BMP 145 does all of these things for those post-menopausal women who cannot tolerate a patch.

(1:02:49) A gel is a reasonable option, however, it's not approved for bone mineral density, compounded products probably work.

(1:02:56) I use them, but they have no outcome data and make sure your tests include metabolomics, which are necessary for a successful normal practice.

(1:03:08) Estriol
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Now a couple of words about E3, there are no FDA approved E3 formulations.

(1:03:14) Most E3 is predominantly formed from estrone E 1, E2 is reversibly oxidized, the E1 and both can irreversibly be converted to E3. In vitro studies document that E3, when given with E2, may exert antagonistic effects. Now, let's talk about estrogen metabolism just a bit.

(1:03:36) All right, we're going to start here. E1 is metabolized down this one A1 pathway. Two Hydroxy E1 is thought to be the least damaging. The one B1 pathway is thought to be the most damaging.

(1:03:55) And the 3A4 pathway, which is the most predominant pathway, is basically barely estrogenic and is thought to protect bones, and is not as damaging as previously thought.

(1:04:09) Now, I will tell you, and it's the same here one A1, B1, A3, A4, I will tell you that if all of these don't undergo appropriate phase two metabolism, what you will see is all of these will become toxic intermediaries and can increase the risk of cancer. Certainly, this is the one we all talk about, but all three of these can be toxic intermediaries.

(1:04:39) E3's clinical utility is most studied using vaginal estriol and all improves vulva vaginal atrophy symptoms and at this higher dose you can see it improved vasal motor symptoms.

(1:04:52) When we talk about E3 in cancer it does not, vaginal estriol does not increase endometrial cancer, very interestingly, the breast cancer data is missed.

(1:05:02) In animal studies, E3 breast implantation reduced the development of chemically induced breast cancer. In vitro studies, placing estriol with breast cancer cell lines, E3 could bind to and stimulate breast cancer in tissue culture, so, not protected. In human studies, physiologic E3 levels, were not a significant breast cancer protector. It is an immune modulator.

(1:05:30) And the most studies is in multiple sclerosis, and what they, what you see is that in women who are pregnant, during the third trimester, when E3 levels are the highest, there's significant improvement in relapsing, remitting MS, and in human studies with an MS immuno-modulator drug, they found that oral E3 in both men and women reduced relapse rates and the bone mineral density data is mixed.

(1:05:59) Estriol must be compounded. Most support, it's vaginal use. Potential role in MS with either oral or transdermal, and I would use transdermal, and I'd probably use half the dose, oral for milligrams. But for both, you can use it for both men and women, no large studies documenting E3's role in breast protection. It's a plausibility arguments into binds to the ER beta, which is antiproliferative. Vaginal E3, or vaginal dryness, is a half a milligram per gram in a mucolox base, which basically sticks and increases contact time.

(1:06:43) So that you get more lasting coverage, you don't get leakiness, and you apply a gram at HS for two weeks, then two times a week, and then PRN.

(1:06:53) Testosterone
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Now, what about testosterone? Well, there's a global consensus that was published in 2019 only indicated for a hyperactive sexual desire disorder. I don't think so. Use LC- MS/MS, absolutely.

(1:07:06) Measure total testosterone, serum hormone binding globulin. Absolutely. Interestingly, there's an uncertain association between baseline T levels, NET levels, and clinical findings. And there is no cutoff that can be used to differentiate those with and without symptoms.

(1:07:23) They recommend approximating physiological levels. I agree with most of these, except this one, and probably down here, and this depends on the delivery you're using. And the reason I highlighted Susan Davis's name is because I'm going to show you some studies where she contradicts herself.

(1:07:42) And here's the most recent 2021 practice guidelines, total T not used to diagnose HSDD, but, as a baseline, serum levels don't predict efficacy treatment.

(1:07:54) However, there is some correlation between treatment and response, and some believe, if you get testosterone levels too high, sexual desire may decrease, there's this bimodal curve. Remember, women make about 0.2-0.25 and a healthy woman's mid luteal ranges anywhere from 15 to 228, with a mean of about 58.

(1:08:16) So dosing this, this guideline recommends, should be 110th to 115th a male dose. So, for example, androgen, 50 milligrams. If you use a gel, should be 3.5 to 5 milligrams per day, should maintain physiologic levels. Now, I'm not telling you to start at that, though this is what these guidelines say, you should use serum, which is the default. We all agree with that, because of nuances with urine, which I'll talk about. And you test them 4 to 6 weeks to assess efficacy, if you're looking at peak level.

(1:08:53) And then when stable, every 4-6 months, and when you test testosterone depends on the question you're asking. And I agree with most of this. And so do most of us. All right. Let's talk about androgen production.

(1:09:10) The DHEAS is 100% of produced in the adrenal glands. So, what if you see a low DHEA-S, HPA axis dysfunction, T think inflammation because solation decreases DHEA. 90% adrenal, 10% the ovaries, whereas androstenedione is 50/50, and testosterone only 25% is from the adrenal glands and the ovaries, then 50% of it is by peripheral conversion.

(1:09:39) Like in men, estradiol is from 100% peripheral conversion. So, what do we know? There's no FDA approved formulation. It's safe, effective, and does not increase cardiovascular disease, breast cancer, endometrial cancer.

(1:09:56) Most studies document, you need to be, at least, at the high end of the reference range to include improved clinical outcomes, and I have the studies at the end for you.

(1:10:04) These are the things that have been studied, studies that document clinical success, with serum T levels that were somewhat, or it's many times higher, found no significant adverse event. Serum is the gold standard.

(1:10:18) It can be monitored in urine, however, however, however, similar to testosterone monitoring in men, you must be aware of the UGT snip and other nuances. Alright? Topical needs to be compound, starting dose can range from 0.5 to 5 milligrams. I typically start, depending on the woman, between 0.5 and a milligram. Vaginal, starting dose is typically half of what you would use for topical because the vagina is a mucosa, it is not a barrier, right? It's not the skin.

(1:10:52) Pellets are an excellent option, but you must understand hormone metabolism in detoxification.

(1:10:58) Patients really require less testosterone than you think, and I monitor after 12 treatment weeks with blood and urine for comprehensiveness. Now, let's debunk some of the testosterone myth: the myth of it increases cardiovascular disease. It does. Look who's here. Susan Davis, documented was the first randomized controlled trial to assess testosterone's effect. They use the testosterone pellet 50 milligrams in women on stable estradiol, the everyday use 50 mm should be way, way, way, way, way, too much, and I'll talk a little bit about estradiol and pellets here in a bit.

(1:13:34) Women on combined therapy, so, what they concluded was that adding testosterone therapy was more effective at increasing bone mineral density than either E2 alone, or E2 and progesterone.

(1:13:49) And I think the women, the reason they don't make those recommendations, is because the studies were small. And I told you that the traditional world needs these large studies to make a recommendation, whereas we look at the totality of the data. What about breast cancer? T is antagonistic, it inhibits ER alpha expression and prevents stimulation

(1:14:11) Interestingly, breast cancers, which are AR positive or androgen receptor positive, are associated with better prognosis, and it's really that testosterone to estradiol ratio, or the balance that's breast protective.

(1:14:23) And, when you take a testosterone pellet, plus an aromatase inhibitor, combined in a pellet, it's been show not only to decrease androgen deficiency symptoms in breast cancer survivors, but decreases invasive breast cancer, and if you place the pellet in the breast near the tumor, it will decrease tumor size.

(1:14:48) And this is at a Becky Glazer's lab which, basically, she has the largest database on pellets. This was a 10 year prospective study looking at women with androgen deficiency symptoms, who they receive pellets looking at breast cancer incidence. And they compare it to this pseudo control group, as well as the SEER database. And what they found, was that there was a 39% decrease in invasive breast cancer, compared with either the age matched SEER data, or the pseudo controls. And when you come over here and look at cases per 100,000, there's Becky Glazer's date or 165, verses the WHI, E alone, which decreases breast cancer, still had a higher breast cancer incidents than her study.

(1:14:41) So, they concluded that long term treatment didn't increase invasive breast cancer and actually may decrease it, and should be investigated for hormone therapy and breast cancer prevention.

(1:14:53) So, key points, it's safe, doesn't increase endometrial cancer, breast cancer, or cardiovascular disease risk, when it's added to oral or vaginal progesterone and a patch, it improves endothelial function and bone mineral density to a greater extent than either alone. So, a transdermal estradiol patch, plus oral micronized progesterone, plus a TD transdermal testosterone cream, or a testosterone pellet, this is, typically, weight based is a nice place to start.

(1:16:30) Understand a woman's hormone metabolism prior to starting hormone therapy, especially if you're going to add testosterone. T metabolism in both men and women is complicated. It's not easy. Serum is your default, urine adds comprehensiveness, and similar estradiol, follow-up testing. And ongoing surveillance is a must.

(1:16:51) Case Study
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So, let's talk about Maggie.

(1:16:53) She is a 52 year old post-menopausal woman who seeks advice on menopausal hormone therapy. Her last cycle was 12 months ago, so, she's actually post-menopausal, and she'd been miserable for the past six months, probably during that perimenopause transition. She, has all the symptoms, her mind doesn't stop racing, she has trouble sleeping. She wakes multiple times at night. I'm not going to focus on cortisol here.

(1:17:20) Just know, must address the HPA axis, because patients will tell you, I don't feel any better for my hormones I need more hormones. Must address the HPA axis. You must address their gut, you must address toxins to get optimum benefits from hormones.

(1:17:36) Happily married. She's a physician. She's normal weight. She overexercises. She takes vitamin D and calcium and a multivitamin after a recent bone mineral density documented osteopenia. So, you wonder if she had short luteal phases when, as a young woman or was anovulatory during her earlier years, everything is unremarkable, a recent mamo- and a recent pap and pelvic exam.

(1:18:06) I'll get on my soapbox. If you are going to give hormones, it is your responsibility to make sure that the patient had a recent mammogram or whatever you use to assess breast health, a recent pap, and a pelvic exam, that were normal and documented in your records.

(1:18:24) All right, here are her baseline labs. She is insulin resistant, she has dysglycemia, look at her lipids, her lipids are abnormal, heart particle numbers elevator. Her APO-B is abnormal, she's inflamed, her oxidized LDL is elevated.

(1:18:41) Her TMAO is elevated. Interestingly, TMAO is an independent predictor of cardiovascular adverse outcomes, but it's also a marker of gut dysbiosis.

(1:18:52) People who have healthy guts and eat a predominantly plant based diet, don't make as much TMA as those who eat a sad diet or a lot of meat, colane, and eggs. And they don't have as much, regardless of their other risk factors, that then gets to the liver to be oxidized and form TMA up.

(1:19:17) Her CRP has elevated. She has an abnormal, excuse me. She has an abnormal calcium, coronary artery calcium scan. And her CIMT is abnormal. So, she has subclinical vascular disease.

(1:19:30) Her DHEA-S is on the low side, her Vitamin D is good, on vitamin D and look at her serum hormone binding globulin. It's low, because she has no hormones, right?

(1:19:40) All of her hormones are low, her prolactin is normal, or FSH and LH really high, everything else is, low. So, we have a symptomatic post-menopausal woman with osteopenia, subclinical AS CVD, HPA axis dysfunction, and gut dysbiosis, there's all her tests so far and so, what are we going to do?

(1:20;00) We're going to do a DUTCH test with cortisol and cortisol metabolites. But again, we're only going to focus on her sex hormones here. Let me orient you

(1:20:09) The purple bar is the post-menopausal range. This is that area between the post-menopausal range and the beginning of the luteal range. Here it is here, zero point seven to 1.8, estradiol.

(1:20:22) Here's your luteal range. And there is estriol, you know, we talked about the three pack waves, one A1, one B1, one A3, A4. Now, when we look at the ratios, which is helpful, you see the expected ratio up to hydroxy 60 to 80 and hers is 78.4. 4 Hydroxy should be 7.5 to 11. Hers is high, uh oh. And her 16 hydroxy should be 13 to 30 and that's low, and you may exploring why are you doing metabolism? When she has no hormones?

(1:20:57) Well, I want to see trends. I want to see how she's metabolizing the hormones that she has. This is not about absolute numbers. This is looking at a pattern.

(1:21:08) And then we looked at her methylation activity, days to detoxification, and we see her methylation activity is pretty good, here.

(1:21:19) So, what are we going to do? Now, let's look at her androgens. I want to point you here first to progesterone.

(1:21:25) Now, remember for endogenous progesterone, you can get a serum equivalent.

(1:21:30) But what we're really looking at for progesterone is metabolites. Is she going down, the five alpha or five beta pathway, five alpha pregnanediol goes on to allopregnanolone ? So, you'll get some insight in to Gabba, and sleep, if she has difficulty sleeping.

(1:21:53) Now, when we talk about DHEA, DHEA, is as we talked about sulfate, and 100% in the adrenal gland, hers is on the lower side.

(1:22:03) It's not, you know, down here, but it's not optimum, right? You want to be here, or in here, I like it to be in the 75th percentile. And then we look at testosterone here, which is low and again, it was low in serum.

(1:22:19) And now we look at these androgen metabolites, which look pretty okay. And so, when you can't just look at a DHEA-S in serum and say, I'm gonna give DHEA.

(1:22:33) These androgen metabolites come from both testosterone and DHEA, and if you don't know what's happening with DHEA metabolites, in other words, what the tissues are seeing, right, because you only get metabolites when it gets into the cell, it does its thing, and gets metabolized. This tells you about tissue exposure. This tells you what the tissues are doing.

(1:23:06) I wouldn't give her DHEA, knowing this, hard tissues are seeing plenty of DHEA, if it's not predominantly coming from testosterone, and so, how do we evaluate testosterone?

(1:23:20) Well, we have to determine if she has what's called that UGT snip, which I will talk about here in a sec. Her testosterone is at the lower end, her five alpha is within range, and her five Beta is within range. Now, this UGT snip is 2B17 glucuronide, which glucuronidase testosterone, five alpha, DHT, and five beta androstanediol. In individuals who have that deletion, these will be very low. And you'll see five alpha and epi testosterone, which are conjugated by different UGT, 2B7, being at appropriate ranges, that's how you kind of know.

(1:24:10) But in her, she doesn't have evidence of the UGT snip, but what we have found looking at DUTCH's database is that epitestosterone in women predominantly come from the ovaries, so, it's not surprising that in a post-menopausal woman, it's low.

(1:24:27) But testosterone is converted peripherally, 50% of it. But these are all within range, so are her tissues seeing enough testosterone, maybe?

(1:24:40) Maybe, she has symptoms. Now, here is androgen metabolism, I don't expect you to be able to see all of this really well, but what I wanted to point out is that an androsterone and etiocholanolone, in addition to being DHEA metabolites, are also testosterone downstream metabolites. So, it's important that you recognize it.

(1:25:06) Test androgen metabolism is complicated, as is estrogen metabolism. All right. And so what did I do? I gave her a patch and I gave a vaginal estriol.

(1:25:17) I gave her 200 milligrams and she wanted to start with a cream. She didn't want to pellet, and I was perfectly happy, and I will do that she has a uterus. She talked to me about a pellet and I told her, it wasn't in her best interest, until I understood all of what was happening with her metabolism, because her initial metabolism didn't tell us a whole lot.

(1:25:42) We gave her dim to help it go preferentially down that 1A1 pathway, multivitamin, hormones drain vitamins, especially complex B vitamins, and after we gave for other things for her adrenals, but, you know, you get these are just the basics. Four spot dried urine, after three treatment months for hormones, metabolites, cortisol, and then I will get blood to look at and calculate her free testosterone.

(1:26:14) Total testosterone serum hormone binding globulin, FSH, and LH, because you want to see the effect. You're actually having right, FSH it come down, LH should come down if the tissues are seeing adequate hormone because of the feedback loop, four months later, she feels terrific.

(1:26:30) LH should come down if the tissues are seeing adequate hormone because of the feedback loop, four months later, she feels terrific. I've asked her to do, the hardest was decreasing her exercise. he's eating healthier, more vegetables, more plant based sources. Animal proteins or grass fed inorganic, she eats about 20 to 25 grams of fiber. We're still working on that. And she's been compliant.

(1:26:46) Here's the follow up labs, testing blood sugar glycemic parameters are dramatically better. Her lipids now, I do have to tell you, I did put her on a statin.

(1:26:57) She had subclinical vascular disease, and we talked about a statin verse other options and, given she has subclinical vascular disease, the data is there, statins decrease event rates, statins decrease mortality.

(1:27:12) So, in addition, she got coQ-10.

(1:27:14) and all of the other zinc, all of the things that statin strain B vitamins. Here are her hormones, FSH came down, boom. LH came down, serum hormone binding globulin went up a little, DHEA has stayed about the same.

(1:27:24) LH came down, serum hormone binding globulin went up a little, DHEA has stayed about the same.

(1:27:31) Vitamin D stayed the same, total E came up. Now remember, she's a young woman who's recently menopausal, who has evidence of abnormal CIMT, as well as abnormal coronary calcium score. So, keeping her total estradiol using an LC-MS/MS assay at about 50 is perfectly fine, and her total testosterone was 40, and she was very happy.

(1:27:55) Now, here is her pretreatment stuff that we talked about. Let's look at a post-treatment. Her estradiol is 1.93.

(1:28:04) Her estriol all is high, probably due to conversion, as well as I gave her estriol, and again, we're now going down that 3A4 pathway, 1B1 is less so, and her 1A1 is better. Her methylation activity is high. So, things are looking pretty sweet.

(1:28:28) Now, when we look at her progesterone and remember, we're looking at metabolites, oral progesterone goes into the gut. It's metabolized both by five alpha and beta metabolism in the gut, as well as in the liver.

(1:28:40) And what you see here is she basically favors five beta pregnanediol. So, if she had sleep issues, which she doesn't, I could conceivably increase her progesterone.

(1:28:55) Now when we look at her testosterone, her testosterone looks beauteous, but when we look at her androgen metabolites, they stayed just about the same. So, most of her androgen metabolites are coming from DHEA, which stayed about the same, as did her DHEA-S.

(1:29:16) So, I would not give her DHEA. Her tissues are seeing plenty of DHEA. And so, here's our key points. All of these things you can look at for yourself. And I just want to say the compounded creams probably work, but there is no data.

(1:29:37) And my final thoughts: start MHT as close to menopause, continue for at least 10 years with ongoing risk stratification surveillance, and follow up. Start low. Go slow. Set expectations.

(1:29:50) A low dose patch, oral, plus a milligram of transdermal testosterone is a reasonable place to start, or you can use a pellet if you want. I typically start this way until I see what's going on. It's evidence based, improves clinical outcomes, and remember to check metabolomics, learn and understand metabolomics. It's essential to a successful practice.

(1:30:14) And then finally, ask yourself, are your decisions evidenced based? Are you questioning the absolutes and asking, show me the data.

(1:30:28) And remember that women spend a third of their lives hormone insufficient or deficient. So, it's important we get it right. This is something that Mark and the group recently updated.

(1:30:41) It's monitoring hormones with lab testing and it tells you where DUTCH is excellent, where DUTCH has some fallbacks, and it's a great reference for you, as well as there are others on the DUTCH website.

(1:30:57) End of Presentation
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And so, I think now I practiced interventional cardiology for a very long time, and I have more fun doing this. And those of you in the audience who know me, this is Nicky. After Nicky Arnstein, and I'm a huge Barbra Streisand fan. And so, we call him Noodle and he's five. There's my beloved Bear, who passed away after 15 years in 2013. And there's my white collie, who I made the diagnoses of Addison's disease while I was going through the A4M Fellowship.

(1:31:34) So, here's the new provider stuff. And I am more than happy to answer any questions. Tim, back to you. Thank you so much, Doreen. And, what a fantastic time to spend the last 90 minutes learning from you. Thank you for all the time and effort you put into these presentations and educating our providers, and also providers that are interested in using the DUTCH test. I know that one of my colleagues has placed a link in the chat channel, so that people can see the offers that we have for them and how they can get started with us, or, you know, utilize one of our webinar offers here for current providers, and then patients have have an option too. Okay, so now we get to answer some questions and I think we just we'll go as long as you feel comfortable, Doreen, we have some great questions here.

(1:32:37) Q&A
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The first question is: how did you think about progesterone in women with progesterone receptor positive breast cancer?

(1:32:45) Conventional oncologists are only addressing estrogen. It's the same thing. There is some data out there that talks about, and from John Wiebe's lab, that progesterone metabolites, one of the metabolites, can increase breast cancer.

(1:33:06) So, I don't give progesterone or estrogen to women with breast cancer, they have to be 10 years out for me to consider it, but I do use testosterone, and in those women I'll use testosterone pellets, let a little bit of it convert. Get their estradiol levels if they're not on tamoxifen to about, you know, 25, some at least trying to protect their bones.

(1:33:33) And if they have a uterus, I may consider using vaginal progesterone with a discussion with the oncologist, and not get into the luteal levels, because remember, the low doses are going to protect the endometrium.

(1:33:58) But I don't think with serum levels of about 25 or 30, there's much need to worry about endometrial hyperplasia and endometrial cancer. Okay, wonderful, thanks. To summarize that, in women with breast cancer, testosterone is okay. In women who have breast cancer, and are less than 10 years, no estrogen or progesterone, greater than 10 years, talk to the oncologist. In those women, I will use a patch, and I will use regular progesterone, if they have, with or without a uterus, I use it.

(1:34:36) So, greater than 10 years.

(1:34:38) Got it, thank you. How about, is oral progesterone recommended for perimenopausal women?

(1:34:44) Yes. The answer is yes, and you want to use the higher doses of, at least 200, you may want to use 300 because estradiol is bouncing all over the place. And it's during perimenopause, you know, progesterone starts to fall first.

(1:34:59) That's why they have estrogen dominant symptoms. And so, yes, you definitely want to do a cycle map. And you definitely want to replace progesterone. You want to protect their bones. They're not estrogen deficient at this point.

(1:35:12) Unless direct that latter 2 to 3 months. Okay, we know that hormones have, kind of, they escalate and they drop off.

(1:35:22) How long does progesterone last after, like, a 12 day treatment, where does it go? So, well, remember that it peaks in four hours and is gone by eight hours. And so, the data shows you can use it sequentially 12 to 14 days, I use it continuously.

(1:35:44) I don't want women with a uterus to be without progesterone. I am not a fan of sequential treatments.

(1:35:56) Got it, okay, and would you always give OMP and PMP at the same time, and what is the reason for that?

(1:36:03) Oh, no, no, no, you're either using Oral, or vaginal, one or the other, so.

(1:36:10) Right, oral micronized progesterone, if I'm using that, women have difficulty sleeping, I may start with that. Other women get to sleep beyond it. No matter what dose I use, that I've got a vaginal progesterone, which actually bays the endometrium.

(1:36:27) I don't have to worry about it, and if you want to get that estrogen alone effects of breast cancer and cardiovascular effects, then vaginal micronized progesterone may be a better option. And I offered Maggie vaginal progesterone. She said, yes. I think the latter, I would have rather used vaginal progesterone on her.

(1:36:49) I see, well, that's good. Thank you for clarifying that. When would you give estradiol therapy to a perimenopausal woman?

(1:36:59) You know, in the latter few months, if I've done a bunch of tests, and her estradiol levels are consistently low.

(1:37:09) In other words, she has been amenorrhoeic for more than six months, continuously.

(1:37:18) And is E2 only reserved for post-menopausal women?

(1:37:23) No, if you are going to give, whenever you are going to consider giving estradiol therapy, it's always estradiol, you never want to use any estrogen.

(1:37:33) And you don't want to use oral estradiol, you want to use transdermal estradiol.

(1:37:43) And, what side effects would you anticipate with optimal testosterone therapy to improve bone mineral density? None.

(1:38:01) If women are dosed appropriately, and their hormones are optimum, then you should have no side effects. Women may complain a little bit that they get a little extra chin hairs, or, you know, above the lip. Most women are willing to live with that, knowing the benefits that they're getting with, number one, libido, with strength, they lean out, there are lots and lots of benefits.

(1:38:34) I have never had a woman tell me, take me off testosterone, never in 15 years. They always say to me, can I have more? But just enough, right? Just enough to do the job. Right. Not too much. Not too little. Goldilocks.

(1:38:52) Absolutely. Is it true that there is a window of optimal opportunity to give BHRT, as one statute and receptors in the female brain shut down, they cannot be reactivated? Is this true?

(1:39:09) No, and you know, again, I said that similar to cardiovascular disease, that estrogen receptors are dynamic and so, clearly you want to treat people as early as possible. But that doesn't mean you shouldn't treat women who are approaching 60 or 60, they're still gonna get cardiovascular benefits, they're still gonna get breast cancer benefits.

(1:39:34) They may not get cognition benefits, and they may not get cognition benefits, even if they're treated early on. Based on the studies that the randomized controlled trials that have been done, no benefit, no harm.

(1:39:50) Right, okay, good to know. Then moving on, to that progesterone question. What is the goal for the serum progesterone levels when you recheck labs?

(1:40:03) Well, if you're using oral progesterone, can't check serum. You take it at night. It peaks in four hours. Gone by the next day.

(1:40:14) So, unless you're waking people up in the middle of the night, to check serum levels, oral progesterone follow the clinical data. Vaginal progesterone, get into the lower end of the luteal range.

(1:40:32) Now, what are what are the endometrial cancer risks for vaginal progesterone?

(1:40:38) None, zero. It protects the endometrium, none, zero. And frankly, even a progestin will protect the endometrial. But we're not using progestins, right? The rest of the question is: is there any harm in giving topical valvular estriol for women who are menstruating? Are we talking about vaginal estriol or on the skin-? Vaginal.

(1:41:23) Why would you give it to menstruating women, there's no reason to give it to a menstruating woman, right?

(1:41:30) They should have plenty of hormone. Got it, let's see here, we've got some more good questions coming in.

(1:41:43) Got it, let's see here, we've got some more good questions coming in.

(1:41:57) Yeah, there's not a lot of data on that. What you want to do is do a cycle map, and make sure their hormones are optimized.

(1:42:08) That's really going to be the key. I would look in that setting. If women are losing hair and it's in a male pattern, you know, I would look for PCOS, I would look for luteal phase defects, right? Because when women and PCOS is an insulin resistance syndrome, and it shifts ovarian FSH and LH activity to favor the production of androgens.

(1:42:38) And so, if somebody is losing hair in a male pattern way, then I would think insulin resistance, PCOS, and start looking for root causes, and test, don't guess. Test, and don't guess, I love that.

(1:42:57) That is a good thing to remember. In pre-menopausal women with a history of depression,

(1:43:05) Do you find micronized progesterone worsening their mental health issues or helping? How do you help women with mental health issues?

(1:43:17) The first thing is I look for, do they need any hormones, right? Right. And estrogen is more associated with depression than is progesterone or the literature is more robust with estradiol.

(1:43:35) Progesterone is common. And it depends, do they have anxiety, but I don't give any hormones unless I see a need, and in a premenopausal woman, unless she has a luteal phase defect, there's no reason to give her progesterone.

(1:43:56) Can you also comment on the use of progesterone in women with a hysterectomy that has some anxiety and sleep issues?

(1:44:07) So, I give all women progesterone for bone mineral density, regardless of whether they have a uterus or not. And so, if women are getting anxious on progesterone, the first question you have to ask. Is it a long acting progesterone or a short acting progesterone?

(1:44:26) And they should be taking oral progesterone at night, before they go to bed. Not during the day. So, those are the questions, then I look at metabolites.

(1:44:40) I ask, is there anything in the progesterone? Because if they're going predominantly down, that beta pathway and not enough alpha, they may not have enough progesterone. Right, because you want it to go down that alpha pathway into b comment. If, no matter what, then I'll then go to vaginal progesterone, and use something else if they need help with sleep.

(1:45:04) Interesting. Do you treat women with surgical menopause without uterus and ovaries the same way as you do those with? Yeah, you need progesterone for bone mineral density.

(1:45:19) You need progesterone plausibility for the brain. You know, and so yeah, there is no reason not to give progesterone to a woman, who's had a hysterectomy early on, definitely, later on, definitely, for bone mineral density. And in those women, I love vaginal progesterone.

(1:45:42) Okay, can you talk a little bit more about, and thank you so much for all the time you spent with us, and answering all these questions, they keep flooding in. The more questions you answer, the more questions come to mind for our audience, which is fantastic.

(1:46:05) Another question here. Can you define the earlier you start with hormone therapy, the better. Does this mean before menopause, during perimenopause, what's the right window?

(1:46:20) Well, actually, when we're talking about, you know, treating early, I'm talking about a post-menopausal woman. The earlier you can get her, the better off, the greater the benefits. Now, if you see a woman who's been really is in that, she's not a year because remember, menopause is defined as one year from the last menstrual period. But she hasn't had a cycle in eight months. So, she's shy four months.

(1:46:52) I will do, I actually will do a cycle map on her, as well, I'll do a cycle map plus a DUTCH Complete, so I can see what's going on, if anything, I do FSH and LH, and remember FSH now, are not really reliable.

(1:47:11) Because they bounce all over the place. And then I decide, because she's been without a cycle for eight months to start hormone therapy. That's that late perimenopause where vascular disease starts to accelerate. So, yes, I will start it then.

(1:47:28) Okay, then could you talk about the importance of, well, the question is it important to make sure that the patient is detoxifying oral progesterone, or what do you think about detoxified?

(1:47:44) Well, I make sure that when I talk about detoxification, I'm actually talking about phase two detoxification. In the optimum world, I would love to put everybody on a elimination diet or, you know, Metagenics, you know, 10 day, 12 day detox, or pure encapsulations are designed to help to kind of clear their liver.

(1:48:13) However, however, transdermal estrogen isn't really going through first fast metabolism, testosterone pellets aren't going through first pass metabolism, it's just oral progesterone

(1:48:26) And, you know, most of the metabolism occurs in the gut. So, you really want to make sure they have a healthy gut. Will I hold back hormone therapy from a woman?

(1:48:40) No, I won't, but I will- most patients don't want to do a detox. So, I'll try with an elimination diet, I clean up their diet, give them lots of detoxifying foods, you know, things like that, as I'm giving hormone therapy. Because you've got to meet the patient where they are, or you lose them.

(1:49:00) That makes total sense. Can you talk a little bit too, Dr. Saltiel, about how can DUTCH show, or does DUTCH show markers of active bone loss? And could it be used to monitor this in a case of menopausal hormone therapy for osteoporosis, as well as other hormone metabolism levels?

(1:49:25) Well, actually, you know, in 2019, Precision Analytical, I'll just say Mark, et al., published a study where they looked at the DUTCH test using a cycle map, and in post-menopausal women against serum, and they found serum equivalence.

(1:49:46) And so, we know from the data that if you keep a woman's serum estradiol level using an LC-MS/MS assay, must do that, between 20 and 40. You know, some women may need 50, up it, you know, I typically try and aim 35 around there. You will protect bones.

(1:50:08) It's from the FDA studies, and it's from other studies. And so, when you translate that to DUTCH, that's an estradiol level outside the post-menopausal range, and just into that... Let's go... So, it's just outside the post-menopausal range, to just here in the luteal range, and as we talked about with cardiovascular disease, some women may need to get in here.

(1:50:43) And that's okay, those women with subclinical disease. But the data on post-menopausal women, and bone mineral density, whether you're looking at Archer Studies, whether you're looking at naphthalene studies, whether you're looking at YC studies with all the patches, say, 20 to 40, which is zero point seven about zero point seven to 1.8. You want to be outside this post-menopausal range.

(1:51:11) You want to be, you know, one point between there and I try and aim towards this, 1.7, 1.8. Then I know I'm safe in urine. And, but for cardiovascular disease, I try and keep it about 1.5. Remember, because older women are more prone to have CIMT progression.

(1:51:36) So, as you're helping a woman keep good, healthy bone density, when do you add a bone density scan?

(1:51:46) Initially, everybody gets a bone mineral density along with their mamo, and pap, and pelvic. They get a bone mineral density scan. I follow the guidelines, and, you know, sometimes the guidelines say you've got to wait until they're 50, or whatever. They change all the time, I do it then. But I will do some urine markers for bone mineral density.

(1:52:13) That, you know, look at bone turnover, and don't ask me what those are. I'd have to think about them up for a minute off the top of my head here. N-telopeptide is one of them, but there are a bunch of others that I look at to determine bone turnover.

(1:52:38) But I always do a bone mineral density, and then I follow whatever the guideline say, because nobody's going to pay for a bone mineral density, if it's not indicated.

(1:52:48) So, do you use some of the markers in the DUTCH Tests for leading indicators for bone density health? Oh, estradiol, I look at estradiol. I look at testosterone. Absolutely. Absolutely. That's fantastic. You talked about the, how are you doing, by the way?

(1:53:08) How are you holding up? I'm fine. Okay, fantastic. You talked about the value of sleep and keeping patients healthy. What do you recommend for menopausal and insomnia? Or how did you go about thinking about addressing that in a patient?

(1:53:27) I will do a DUTCH Complete and look at progesterone metabolites, and see what I can do about alpha versus beta, and otherwise, I look at melatonin, and see what their melatonin levels are.

(1:53:44) And then I kind of addressed those, too, depending on if their mind is racing, L-theanine will reset the HPA, will reset cortisol, and decreases mind racing. Phosphatidylserine helps, you know, taurine is calming, magnesium, there's a whole bunch of nutraceuticals that you can use to address sleep.

(1:54:10) The first thing is lifestyle. Get the phone out of the room, turn the TV off, make sure the room is dark, don't eat too late. So, there's a whole bunch of lifestyle things, as well as nutraceuticals and pharmaceuticals that you can use.

(1:54:27) So, that's great. Thank you. Doctor Saltiel, for you know, just kind of helping a new provider get out of the gate for post-menopausal women. Do you recommend starting with the DUTCH Complete initially to get the first picture, or would you start with the DUTCH Plus, which adds cortisol element to it?

(1:54:49) Well, it depends on how comfortable... Well, I would start with the DUTCH Complete, um, and it really depends on your thoughts about their HPA axis. A DUTCH Plus is perfectly fine, because it'll give you the cortisol awakening response, and it'll give you the diurnal cortisol pattern, plus everything else.

(1:55:15) And so, either one, where, I like cortisol metabolites, you know, kind of helps me with what's which predominates cortisol or cortisone, and the impact of the 11 beta HSD enzymes, but that's kind of advanced. So, if people are comfortable with cortisol, I would start with the DUTCH Plus, salivary cortisol. If they want to roll their sleeves up and get the clinical team to explain to them cortisol metabolites, then I would jump in with the DUTCH Complete.

(1:55:57) Because once you get it, you won't lose it.

(1:56:02) Absolutely and what does that look like? What does the support look like from the DUTCH team from a provider to other providers? How is that a value add in your mind?

(1:56:13) Oh, my God. First of all, they're experts at the DUTCH Test, right? And so, they've looked at thousands and thousands, and they've seen patterns. And they've heard about a ton of different scenarios.

(1:56:27) And, so, for any provider, new or not so new provider, they can give you some insight. Number one, for a new provider, they'll walk you through the test.

(1:56:38) They will explain to you what the test means, how to assess the test, and where to start, and where to go. And then they, you know, as you get more experience, they'll go through the nuances of the test with you. It's absolutely valuable. Now, you have to treat the patient, so they're not going to tell you how to treat the patient because you're the treating physician, but they can help you walk through the DUTCH Test.

(1:57:10) Right, so, a brand new provider that is using the DUTCH Test for the first time shouldn't feel bad at all about calling the clinical support team and asking a bunch of questions, and just maybe even getting a start, right?

(1:57:27) Right. Absolutely. They're there to help you. Oh, my god. Hormones are complicated. Hormones are complex. This is a complicated test, because hormones are complicated

(1:57:41) Simplifying this test will take away from the tests meaning, and the truth of the matter is, I can't practice without metabolomics at all, every single patient male and female get metabolomics from me. You can't practice without it, right? You don't understand what the tissues are seeing, unless you see metabolites, all right? From serum, you get what's floating around.

(1:58:11) So, Doctor Saltiel, you have thousands and thousands of people that listen to you and your lectures, and, you know, even today, hundreds and hundreds, but thousands registered for this. What do you, for someone, who's, you know, getting into hormones, or maybe just been doing it for a little while, what should their expectations be for really, getting good at this and being able to effectively help their patients? And how would you help them think about that?

(1:58:40) Well, first, you have to decide you want to be a hormone expert and not dabble. Once you make that decision, it's really understanding the literature, so I don't expect anybody to read the literature, like I have, that's why we have white papers to help with references.

(1:59:04) And then understand the patient's HPA axis and their gut, because the bottom line is, without addressing the HPA axis, patients are going to say, do I need more hormones? Without addressing their gut, they're not going to get optimum benefits. And then, you don't have to start with toxins, you know, over time, you get better and better at these things, and the most important thing is, is to use this, use this, you know, a point oh two five, if you draw blood initially on a patient and their estradiol levels were like Maggie's, really, really low.

(1:59:50) You will be very safe and very comfortable giving her a zero point zero two five milligram patch. And if she has Dyspareunia and vaginal dryness, giving her vaginal estriol, which is where most of the literature is.

(2:00:05) And choosing whether you want to use oral progesterone or vaginal progesterone. And then, adding testosterone, if her testosterone levels like Maggie's were in the toilet, you can start with a milligram. I would do a DUTCH Test before I initiate hormone therapy.

(2:00:25) So the first thing I do, is I get serum and I get a DUTCH Test, and then I assess what I'm going to do. And all those things I gave you are very safe, evidence based, as long as you follow up the patient.

(2:00:42) Now, if you have a post-menopausal woman, and they're obese, and they are inflamed, and their serum estradiol level is 30, she doesn't need estrogen. And her serum testosterone is 40, she doesn't need testosterone. Do a DUTCH Test, she hasn't had a cycle in a year. See what it shows.

(2:01:11) So, don't just give hormones to people because they are quote unquote post-menopausal. I always live by test, don't guess, four months retest. If things are stable, I do serum and DUTCH at the, you know, six months after that four months test, and then I do it twice a year. Unless something changes, if I change a dose, I do it again at the three month mark and I start all over again.

(2:01:44) So, there's a healthy and simple way for providers that are interested in treating patients hormones to get out of the gate. They can do a serum test. They can do a DUTCH Test, they could call in, have the clinical team review, that. They should do both. You will never give up, serum, right? You gotta get thyroid or you're going to get liver function tests. You're gonna get FSH and LH in serum hormone binding globulin, you're gonna get prolactin, so you never gonna give up serum. You're gonna get, you know, some people get estradiol in testosterone just right out of the gate.

(2:02:24) And then, along with the DUTCH Test, then at my four months, I do FSH and LH, I do testosterone, I don't do estradiol. Um, and I just follow the clinical data for progesterone, unless I'm using vaginal progesterone.

(2:02:40) I want to make sure I'm in the lower luteal range. And how would you coach providers that are listening? Because a big part of our practitioners encourage the patient, right? We're getting to a new patient education, as we're starting already, investigating hormone replacement therapy there.

(2:03:06) Well, most of the time, patients come in and say, I want hormones, so, and the first thing I do is, I sit down, and I explain to them the data.

(2:03:19) Here, in a post-menopausal woman, or in a guy, you know for a guy, I look at that data. nd for a woman, we'll, because we're talking about post-menopausal women here predominantly, or late peri menopausal women, I'll explain to them that low estrogen levels, low progesterone levels cause symptoms, and will impact long term outcomes. I talk about bone mineral density and the reason I focus on bone mineral density is because most women will tell you when the vasal motor symptoms are better, they'll tell you when their vaginal dryness is better. They can't tell you about their bones.

(2:03:57) The first indication may be a fracture, and then I talk about the fears of breast cancer and I talk about the data on breast cancer.

(2:04:07) And in some women who are have higher education, I will even show them the slide that I showed here, and explain to them that the WHI was not a breast cancer study, and I go through all of that.

(2:04:20) And I talk to them about estrogen alone and whether they want vaginal progesterone or oral micronized progesterone.

(2:04:27) And then I talk about cardiovascular disease and estrogens, and then I talk about how it's not indicated, and then I talk about cognition. And how, yes, maybe, no. Nobody knows.

(2:04:42) But it's not indicated and I'm not giving it to you for that, I'm giving it to you for vasal motor symptoms, mobile vaginal atrophy, bone mineral density. I believe it protects your heart. It may or may not protect your brain.

(2:04:54) And then, I talk about testosterone, not increasing breast cancer, not increasing heart disease, and how it helps. And when it's added to those, you'll get a greater benefit. And my initial appointment with people is about two hours, and then we talk about testing and why we need to do these tests.

(2:05:15) I let them use their insurance for all the serum labs and then this test. And then, they come back and then we, I always start with, I give them something to walk out with. And typically, it's a probiotic. Typically, we talk about diet and we just try to initiate a couple of things, and improve their sleep, just doing a couple of lifestyle things until they come back.

(2:05:42) Once they come back, we talk about initiating hormone therapy. Once I initiate hormone therapy, I check in on them at six weeks. How are you doing, how are things going? And I set expectations that it may take up to three months to see maximum benefits.

(2:06:01) Especially when we're dealing with the HPA axis. If their HPA axis, if they have significant HPA axis dysfunction, they may not feel the benefits of hormone therapy for awhile, but they need to be re-assured, it's helping their bones

(2:06:18) They'll get the benefits of vaginal dryness, but they still may have vasal motor symptoms because it happens with HPA axis dysfunction also. And so, I go through all of that, and then I'd give them, you know, handouts, and I talk about the interrelationships and six weeks I check in. And then at three months, we retest after three months of treatment.

(2:06:43) That's fantastic. Thank you for laying out that plan, how you help think about a new patient, onboarding a new patient, and caring for a new patient.

(2:06:53) I know, for, I'm sure many of those who are very interested in working with patients and their hormones, that helps them know, at least, understand the lay of the land or how to get out of the gates. So, Doctor Saltiel, you've been fantastic, we can't thank you enough for the time that you spent with us today. There's a lot of thank you's coming into the chat section here, in the question section.

(2:07:22) We look forward to our next time with you and our upcoming webinars on Wednesday from Precision Analytical, makers of the DUTCH test. For all of our attendees today, we want to thank you for being a part of this time with Dr. Saltiel.

(2:07:42) We welcome you to join us every month for our Wednesday webinars, and if you have questions, which I know there's many more here, we're gonna do our best to try to address as many as possible. But you can also e-mail those to info@dutchtest.com.

(2:07:58) That's info@dutchtest.com, and we'll do our best to get back to you, or book a clinical consult, if you're a DUTCH provider. Or sign up with us and we'll help you get started in your effort to care for patients, and help them on their journey, define health and wellness, and treating hormones and many other things that providers do. So, thanks again for attending, and thank you, Dr. Saltiel, for your time and this fantastic lecture.

(2:08:33) I hope everybody has a wonderful, wonderful day, and we will see you next time. Goodbye.