Dr. Nanette Santoro on Treatments for Vasomotor Symptoms

Transcript: Dr. Nanette Santoro on Vasomotor Symptoms

Nina: Welcome to our interviews with expert series. Today our topic is the treatment of vasomotor symptoms, and I am thrilled that we have the expertise of Dr. Nanette Santoro to discuss this topic with, I will let Dr. Santoro introduce herself and then we will dive in.

Hello, I’m Nanette Santoro, professor and chair of OB-GYN at the University of Colorado School of Medicine. I have spent most of my career involved in menopause research as initially a recruiter and then a clinical gynecologist for the Women’s Health Initiative, an investigator in the SWAN study (Study of Women’s Health Across the Nation), a principal investigator at one of the sites for the KEEPS study (Kronos Early Estrogen Prevention Study) and have had a long-term interest in menopausal symptoms.

Nina: Wonderful. Do you have any guess at how many perimenopausal and menopausal patients you’ve treated over the years?

Dr. Santoro: Oh, hard to know. Probably in the thousands. 

Nina: That was going to be my guess. I didn’t want to do the math. So, while we’re laying some groundwork, can you just do a quick definition of vasomotor symptoms so that everybody’s on the same page? What do we mean when we say vasomotor symptoms?

Defining Vasomotor Symptoms (1:16)

The experience of a flash or flush 

Dr. Santoro: Sure. I mean, the typical experience that someone will report, and I can say this as a vasomotor symptom survivor myself, is a head-to-toe sensation of heat that comes almost unbidden. Some women will notice that there are triggers and that’s always helpful because one can then avoid those triggers, but not all the time. And what’s really happening physiologically in the body is that there’s a sensation of, there’s a vasoconstriction that happens. So almost as if there’s a sensation of cold that precedes that, followed by an opening of the blood vessels, a vasodilatation, which causes the heat sensation. Some people will turn red as a beet, others will have profound sweating, and they have all different severities. So some women will notice a very mild thing that may not even be clear to them, whereas others will have really severe hot flashes, drenching sweats. Typically, they’re worse at night and women will report night sweats that may even make them have to get up and change their bedsheets or their pajamas. Some women rarely report it going from toe to head.  

The underlying physiology of why hot flashes/flushes happen

And we think and now have more insight that this all originates in where the body’s thermostat is, which is in the hypothalamus, in the midbrain, which governs some very basic bodily functions. So, the body’s thermostat is thrown off and we now know that this is mediated through at least one pathway is the neurokinin pathway in the brain. And when estrogen levels are down or variable as they are in perimenopause, neurokinin receptors go up and they start triggering this pathway that activates hot flashes. So, estrogen is related to it, but it’s part of a different type of pathway.

Are hot flashes and night sweats that occur in perimenopause the same as in menopause? (3:05)

Nina: So just while we’re on the laying groundwork, and you just sort of raised this, are hot flashes and night sweats in perimenopause the same sort of physiologically or biologically as they are in menopause after you’ve had your final menstrual period?

Dr. Santoro: To the extent that the underlying physiology is the same, I would say probably yes, because we know that they respond to the same treatments, but what’s happening in the perimenopause is that hormones are up and down. So, the maddening thing about perimenopausal hot flashes is that they can be terrible for a couple of months and then the ovary will just of its own bidding on its own clock will start to make hormones again and they’ll go away. So, this can be confusing.

At what point, do you consider treating hot flashes and night sweats? (3:47)

Nina: When a patient comes into your office and has hot flashes, night sweats, at what point, what severity, what level of bother, how do you think about when to suggest treatment? And then among the treatments, if you could sort of walk us through how do you think through the various treatments that are available?

Dr. Santoro: A lot of it is really up to the patient and her willingness to take a prescription medication and how bad they [the hot flashes] are. And in some cases, I will suggest to patients that they strongly consider it because the level of disruption is following a certain pathway. And one of the pathways that I think it’s good to be aware of is that the hot flashes can sort of cascade into sleep disturbance. The sleep disturbance starts to wear someone down, then the patient starts to feel tired in the daytime, having daytime sleepiness. And that can also in turn then impact on mood. So, when I see that sort of a cascade happening, I tend to be a little more nudgy about maybe you should try something because we can roll a lot of that back and you’re really going to feel much better.

What are the treatment options for vasomotor symptoms? (4:96)

Nina: Then you sort of come to a point where you’re, okay, we’re going to treat this. Then, how do you think about the range of treatments and just again, based on your clinical experience, what’s most effective, what’s also effective, what works?

Dr. Santoro: Yeah, there’s not a lot of behavioral treatments that are out there that make a difference. 

Some women will have triggers. Alcohol can be a trigger. Caffeine can be a trigger. Many women will drink to help them sleep, but alcohol actually makes you a little more vasospastic so it can make hot flashes worse. And someone will notice since I became menopausal, red wine does not do it for me. It gives me trouble. So if you notice those triggers, it’s good to avoid them. 

There’s some evidence that for sleep, cognitive behavioral therapy (CBT) can give some improvements. The usual things that doctors recommend generically like exercise don’t really improve hot flashes, but for some reason exercisers seem to be less impacted, they’re less bothersome. And maybe that’s because they’re used to sweating more, but we don’t really know. 

Dietary interventions have been tried. Omega 3s no improvement. And all of the herbal supplements that are out there have really not stood up to rigorous scientific testing. On the other hand, they are pretty low cost and they are low harm, in most cases. I do recommend that patients tell their doctors if they’re taking any of those things because sometimes monitoring is necessary and interactions should happen, but for the most part, they don’t work that well or consistently.

Nina: Okay. On that note, on supplements, are you mostly referring to sort of black cohosh supplements? There are a whole bunch more out there now. There’s French maritime bark. I mean, I’m seeing all different things in the hot flash, sleep better, roll it together, supplements. Are they all generally low cost and pretty safe? 

Dr. Santoro: And I do think a lot of this is buyer beware. So, I do recommend that if people take supplements, they use ones that have GMP good manufacturing practices on the label [bottle should have GMP or cGMP marked on it]. It’s probably an indicator of improved quality, but there is virtually no regulation. And these are not FDA regulated products, so they’re not required to prove to what’s called proof of claim, and they’re not held to the safety and efficacy standards that FDA-approved medications are held to. 

So, they can have downside risks. And I agree with you, Nina, there’s a ton of these out there, and there’s more almost on a weekly basis. Because if you do enough studies, one of them is going to look like it works and that one is the one that shows up in the advertising. So, I would say for the most part, buyer beware, the best tested has been black cohosh.

And in one really big trial that was very well done and reported in the Journal of the American Medical Association [correction: in Annals of Internal Medicine], both perimenopausal and menopausal women were included. It ultimately didn’t show effectiveness. I wonder, because I do know some patients that say they feel that it helps them if part of that was the perimenopausal women were included and their hot flashes came and went anyway, so it’s not clear. Of all of the ones out there, that’s the one that I think is probably worth a try. 

And there’s also a well-known placebo effect in hot flash studies. So, women taking the inactive drug in a randomized trial have a pretty big response rate. So, there’s a certain cognitive input, there’s a measure of belief that it’s going to help. It seems to help, which is fascinating.

Prescription treatment options (8:35)

Nina: It is fascinating. Let’s move on to the prescription options then.

Dr. Santoro: When I have a patient who has vasomotor symptoms that are treatable that we’ve decided we need to do something, the next thing I ask for is are there other symptoms related to estrogen changes that we might be able to get, kill two birds with one stone. Because if there’s multiple symptoms, that makes a pretty good case for hormone therapy. It’s economical. We don’t have to treat multiple things. There are fewer things to have to remember to take. 

So, for most women, and I would say that 75% of women are candidates for hormone therapy to get through the worst period of their vasomotor symptoms. This can be a median duration of up to seven years. And we know that in different populations, they vary a little bit differently. So, women that get them early are going to have them for longer. Those that get them later, they have a shorter duration. And there’s some racial and ethnic differences that black women tend to have worse and longer duration of hot flashes. So, we try to forecast, is this going to be a long-term thing for you? It’s probably not a good idea to try to tough it out.

Options for people who should not take hormone therapy (9:45)

Nina: And so, you say 75%, so the 25%, what do you offer there? And then we could talk in a minute about who they are that aren’t candidates.

Dr. Santoro: And there are some women who are just high risk for breast cancer, history of a blood clot, liver disease, other hormone sensitive cancers that they are cancer survivors of. These are people who really should not take hormones. So, we then need to go to the non-hormonal options. 

And up until recently, we have only had drugs that were discovered pretty much in patients with breast cancer because the breast cancer survival has increased, but largely because we give medications that reduce estrogen levels in the body to very, very low levels, the aromatase inhibitors. So that takes any estrogen that you have and just — it’s not created. 

So, these women have the lowest of the low estrogen levels and they have ferocious hot flashes, and of course they could never take estrogen. But often they would come back to their doctors and say, you gave me this antidepressant, or you gave me this medication for pain and my hot flashes got better. So that between the patients and doctors, they began to rigorously test some of these things and figured out, hey, they have some effectiveness. 

None of those medications are as good as hormones, but for individual people, that can make them [hot flashes] tolerable and for some they’ll go away. So that’s how we backed into gabapentin, which is really a good medication for nighttime hot flashes especially. It’s got the side effect of making you sleepy. And some women get dizzy from it, which limits its use. 

Anti-depressants as a viable treatment for hot flashes/night sweats (11:23)

And the whole SSRI/SNRI class of antidepressants of those, in my opinion, venlafaxine [Effexor] is one of the most effective ones. There have been well-done clinical trials through the MS Flash clinical trial network that has shown that escitalopram [Lexapro] and citalopram [Celexa] are also pretty effective in that you can combine these with a low dose of estrogen in some cases and get even better relief. [Link here, see Figure 1] So those have all really withstood, I think rigorous scientific testing. There’s not a lot of contraindications to these medications, but they have off-target effects. And when you give them to non-depressed people, the off-target effects can be annoying enough to limit their use. Many women are also averse to being offered an antidepressant [for hot flashes] because they think they’re being told this is all in your head. That’s not true. It seems to work on a different biological basis, but it’s not well understood. 

And we now, for the first time since May [2023], and in the EU since December, have access to an entirely new class of drugs. And I talked before about the neurokinin-3 receptor, so that was determined to be one of the pathways that mediates hot flashes. And if you can interrupt that receptor, you actually bypass estrogen completely and you eliminate hot flashes. Those medications look like they have efficacy on a par with estrogen. They are not hormones, and they seem to have very few, if any, off-target effects. So, they’re just out in the market. They’ve been tested in thousands of women to date, but we’re going to learn more as it gets in more widespread use.

Nina: Are you already able to use them with your patients now?

Dr. Santoro: Yes. I have been prescribing it from the day it got approved because I have a practice that has many people that can’t take hormones or that won’t take them.

WHI (Women’s Health Initiative) Findings: Was there a breast cancer risk finding or not? (13:21)

Nina: Interesting. So, to this point about can’t or won’t, and breast cancer, there was a recent article, and there have been many, the people point out something to the effect that the WHI (Women’s Health Initiative) was either wrong or the data was misinterpreted and that there really is no breast cancer risk. 

Can you talk about that a little bit? I think this is really without us getting really into the details about the WHI. This is one thing I see a lot on Instagram and I just feel like it’s important information for women to have. It’s confusing for sure.

Dr. Santoro: Yeah, no, I think it’s very important. I think there’s two points that I want to make about it. First of all, is that hormone therapy is so fraught with worry over the breast cancer issue that the whole concept of benefit is completely drowned out, that the level of fear is so great that there’s no appreciation of the benefit that it may have. 

So, for women that are reticent to try hormones, my clinical pearl is really that I tell them, you are not committing to 10 years of hormone therapy or 15 years of hormone therapy. You’re committing just commit to three months. Try it for three months. Let’s meet again. Let’s see how you feel. And if you feel much better, on a number of different measures, you may want to continue. And then we can have the conversation about breast cancer risk because having that conversation before you start the hormones, it weights it unfairly in a negative way.

Once someone says, now I understand the benefit, let’s talk about the risks. The risks of venous
thromboembolisms exist for hormones. There’s also a small increased risk of gallbladder disease, but the gorilla in the room is always breast cancer. And the Women’s Health Initiative (WHI) remains 20 plus years later, the best data that we have now, it did only look at one type of hormone. But the body doesn’t have a PremarinÒ  or ProveraÒ  receptor, it has an estrogen and a progesterone receptor. [Here Dr. Santoro is referring to the specific products used in this large trial. They were brand names PremarinÒ and ProveraÒ. See our WLB hormone therapy chart for an overview of the different forms of estrogen and progestogens. There remain questions about how these different forms work in our bodies.] So, until we know more, I think that you need to consider that these drugs all have the similar class effects. And the WHI showed that over time breast cancer risk goes up. And what makes me convinced that this is a real risk and not a fake risk is that the degree that it goes up is the same as if a woman were to have a delayed menopause.

So, for example, if I had menopause at 50, my final period was at 50, I would have a certain breast cancer risk based on that. Because that’s when my hormones, my estrogen drop down to basal levels. If I had menopause at age 54, I have a slightly higher breast cancer risk — goes up maybe a percent or less per year. And if I took hormones up till age 54, I would have the same breast cancer risk as a woman who had menopause at age 54. So physiologically that tells me that this all makes sense. 

So, I think that saying that there is no risk is a little bit of denial. And there is a saying that if you torture data enough, it will tell you what you want to hear. So, I don’t think that it’s responsible to say there is no risk. You can look at the data in a couple of different ways and parse it. 

Women who had never taken hormones before and who went into the WHI did not seem to show that breast cancer risk. But what you do see when you look at breast cancer risk is you see two curves that diverge and they diverge significantly over time. So, I do think that it’s really a matter of hormone use and length of time. So that by five years in the Women’s Health Initiative, the women who took hormones had a higher breast cancer risk than those who did not.

And so, five to seven years is really the sort of window that many of us thought, gee, that’s fine. It’s short-term use. You’re not really going to have a big impact on breast cancer, but there may be some impact. The other piece of data that I think we cannot ignore when we get into this debate is that in the overall population, breast cancer risk or breast cancers went down in the years after the WHI was published, and many women flushed their hormones down the toilet. 

So, it does seem to indicate that there is an increased risk. And basically, it stands to reason. Pre-pubertal girls don’t get breast cancer. People who are never exposed to estrogen don’t get breast cancer. Men who are exposed to more estrogen than normal have a higher risk of breast cancer. So, saying that estrogen has no relationship to breast cancer does not make sense to me as a reproductive endocrinologist.

Nina: Gotcha. And just on the WHI, the other thing that I think has happened is there’s this kind of window hypothesis, right? They reanalyzed the data in the women 50 to 59, and that is also a better picture in terms of risk. Is that correct? 

Dr. Santoro: Yes, yes. And it’s not one of the pre-specified endpoints, but when you look at the age buckets, it looked like women aged 50 to 59, whether they took estrogen only or estrogen plus progesterone that is with or without a uterus had better overall mortality outcomes. So that’s one of the few groups that did better when you followed them up 17 years later. For most other groups, there was just a null effect of hormones.

Nina: And I think that’s part of the message out there too. And so I just wanted to put that out there. It is confusing and there’s so many ways to parse the data, and there’s many studies, and you referred to it before, you made a funny remark about we don’t have Provera receptors. But just so that we’re clear, the products that were used in the WHI, there are more available today. And so that’s another kind of point that people raise, that there are different drugs and they may bind to the receptors differently than the ones that were used.

Dr. Santoro: And they may have some different effects. And the surprising to me, the most surprising finding in the WHI is that women who had a hysterectomy and who took estrogen alone in the form of Premarin [Premarin is conjugated equine estrogen, not estradiol which is a naturally occurring estradiol, the more often used product today] had a consistently lower risk of breast cancer over the entire study. And after 17 years of follow-up. So Premarin may in itself be different and have some slightly different effects. And in the Kronos [KEEPS] study, we had much smaller groups of women that we looked at for four years. We did see some differences [the KEEPS study looked compared various products used]. So likely there are some differences with naturally occurring estrogen and progesterone, which is what is now the preferred way to give these hormones may have some different target effects. But I think that you cannot ignore these data [WHI]. We’re not going to be able to do another WHI with naturally occurring estradiol and progesterone. It was a gazillion dollar study and very unlikely to be repeated. So, we need to live with the data we have and make responsible decisions.

Nina: Yeah. Well, I love you’re, I’m so glad you said it. I think I also have it on the Women Living Better site. When you said, I’m not asking you to marry hormones, I’m asking you to date them for three months and see how you feel. Right. And any medication we take has benefits and risks, and that is a good way to weigh what the benefits are and then discussing the very unique, to a person of one, risks for each woman. So, I’m so glad you brought that up. 

And I also just want to reiterate the point about SSRIs that they have been tested and they’re not equal to hormone therapy, but they are close. And I think I have the MS Flash Data or a reference to that paper also on the site because so many women who don’t get the explanation that they’ve been tested for hot flashes do think that, oh, my provider thinks that I’m depressed, and they don’t understand that connection. So, I think that’s really important. [Link here, see Figure 1]

Well, this has been excellent. Are there any other things that you’d like to, you think it’s important that lay women know as they kind of move into this phase of life and the hot flashes crop up and any other pearls of wisdom? 

Dr. Santoro: Well, I think the most important thing is that this isn’t the natural childbirth of your fifties, and you don’t have to struggle through it. It really can erode wellbeing over time in a way that you may not notice and it’s not necessary to suffer. There may be some very simple low risk things that can be done. And many of my patients come into the office thinking I’m a hormone doctor and I’m going to give them hormones. And they’re bracing for a struggle, an intellectual struggle. And there’s so many options out there so that women need to appreciate there isn’t any one single best way to do this, but there are actually a number of good ways to try.

Concerns with non-FDA approved products (22:23)

Nina: Super. Any other, I know the other topic that comes up with this are other non-FDA approved hormones that are out there, and it seems like increasingly more providers offering them. In your experience, what any, again, buyer beware there from you?

Dr. Santoro: Yes. And it’s the most costly and the most consumptive of resources way of taking hormones. Number one, it causes more downstream side effects. That’s been shown by studies from a group in Pennsylvania and the levels are not really well controlled. So the National Academy of Medicine looked at this a few years ago, and their report came out right in the middle of the pandemic. So, it was met with crickets, but they came out very clearly against using these compounded medications. [WLB covered this in a 3-part blog post]. There is no really logical reason to use them, other than the fact other than you’re allergic to everything else, you just cannot take the FDA-approved medications, which is the reason that we use compounding.

In other instances, some patients simply don’t tolerate them. They have adverse side effects; they can’t deal with the carrier substance. And in those cases, sure it makes sense to do it, but that’s a tiny fraction of the people taking it. It’s estimated that almost a third of the hormone market are in the form of these pellets. The pellets are advertised in a misleading way. They are not FDA-approved. They are not FDA regulated. So just like the herbal medications, they don’t have to have the same level of proof of claim. They’re also not required to list the same side effects. So, if I were to give a patient a naturally occurring estradiol, she gets a package insert that wallops her with a lot of scary stuff, that this may increase your risk of cancer, it may increase your risk of blood clots, it may increase.

And my favorite part of the package inserts as probable dementia. What the FDA meant to say was it probably increases the risk of dementia, which was seen in the WHI study, but many of my patients interpret that and as I’m probably going to get dementia. 

So, the package insert is horrific. And if I were a compounder, and I was advertising on the web my fabulous, compounded hormones, I could say all kinds of stuff and don’t have to include any of that black box package labeling [the package insert], which really ought to be the same thing. So, it’s very illogical. But because these hormones are considered dietary supplements, they fall under this ancient DSHEA act, The Dietary Supplement Health and Education Act, and they are exempt from these regulations. That has led to making many people very wealthy. 

And a lot of the pellet people harken from Texas, they have almost what’s a pyramid scheme where you make more money if you sell more pellets. Patients are encouraged to refer a friend. The pellets can sometimes contain testosterone. And I, and my colleagues in endocrinology, have seen absolutely wacky hormone levels. Patients can feel very good when the hormone soar, and then as they come crashing down, they feel desperate. So, there’s a process also called tachyphylaxis where your receptors get reduced in your brain when you get a big slug of a certain substance because it kind of gets eaten up and the receptors can’t recycle fast enough. And that may be happening in these cases, but we just know virtually nothing about it. And because they have not undergone any testing, the absence of evidence is not the same thing as evidence of absence. But many websites will claim you can’t show me any systematic evidence that these are harmful. You can’t because no one does those studies.

Nina: Right. And they’re not required to track them like an FDA approved product. Right, exactly. No post-marketing surveillance. So, you’re not going to find out.

Dr. Santoro: Most appalling to me is that these companies advertise. They kind of come across as these sort of mom and pop like hippie dippy shops, like the Celestial Seasonings of hormones. And that is not true. Many of them are big conglomerates. I will use anything I can to try to steer patients away from this.

Nina: And I think you used the word “levels” a couple of times, and what you’re talking about is unpredictable amounts of the hormones in the products and then causing unpredictable amounts in the patients. Right? Both. 

Dr. Santoro: Exactly. 

Nina: I know you’ve told me that you’ve seen that. And all of my other collaborators that are also healthcare providers see the same things, patients that come afterwards with these really crazy high, sometimes unhealthy levels. 

Well, this was super, thank you so much for taking the time. I’m so glad that more people in the world are going to get the Nanette Santoro wisdom, and I’m excited to get this up and out there. Thanks so very much. 

Dr. Santoro: Great. Thanks