Warner Huh, MD (Host): Hello, everyone. This is Dr. Warner Huh, the Chair of Obstetrics and Gynecology here at the University of Alabama at Birmingham and UAB Medicine, and I want to welcome you to this monthly episode of Women's Health with Dr. Huh. So with me today is Dr. Hurd, who is a Professor in the Department of OB GYN and the Division of Reproductive Endocrinology and Infertility.

He's been in practice for over 40 years and has held numerous leadership positions in women's including reproductive endocrinology and infertility, was previously at Duke University before he came here and held the leadership position at the American Society of Reproductive Medicine, who has an office here in Birmingham.

And what we're going to talk about today is Hormone Replacement Therapy in Women, A Critical Appraisal of the Benefits and Risks. I'm really excited about this one. It's something that I've been thinking about doing for a long, long time. And what triggered me to do it now is actually we got a request from someone in the public who really wanted us to talk about this topic.

But I think this is such a critically important topic and so important in fact that Dr. Hurd and I were talking about this earlier and we're probably going to need to do this in two parts, which I'm totally fine with. I think it's, this is one of those things in women's health that markedly impacts their quality of life. So welcome Dr. Hurd to the podcast. I'm really excited to have you today.

William Hurd, MD: Hey, thank you so much for having me.

Host: So let's dive right into it. Again, for our listeners let's just talk about menopause and a little bit of why this happens to all women. So maybe you can just talk about what menopause is and sort of the natural physiologic aspect of menopause.

William Hurd, MD: Menopause actually refers to stopping periods and is something that all women do as their ovaries stop working. The average age is 50, but the process really starts for most women in their forties. If it happens before 40, it's known as premature menopause, and there's multiple causes of that too.

Host: And what are some of the symptoms that women experience when they go through menopause, commonly known as the quote unquote change of life here in the South?

William Hurd, MD: It really varies from no symptoms at all to fairly severe hot flashes, or hot flushes as the formal name, which can either be irritating if they happen during the day, or cause some real sleep disturbances in the evening. As it progresses and your estrogen level drops, some people have significant vaginal dryness and actually to the point of atrophy.

Host: And so I think most women figure out they're going through the change of life when either they have some menstrual irregularities or like you said, they start having these vasomotor symptoms, which are these hot flashes and vaginal atrophy or dryness. Are there any other longer term, more significant consequences of going through menopause for a woman?

William Hurd, MD: There certainly are. The tricky part of it is, is it happens at the time that women and men are aging and there's a lot of age related problems as we all know. So they're mixed in with that. It's taken us a long time to understand which ones are estrogen deficiency related and which are just age related.

Host: Yeah, I mean, I think that we've learned a lot related to the consequences of estrogen deprivation. Usually, you know, in this case, through menopause. And that has obviously led to at least in the 80s and 90s, the widespread use of hormone replacement therapy, specifically estrogen, to address some of these symptoms.

But what I want to really talk about, is an interesting period of time, particularly in the 2000s and the 2010s and now, where after a major study known as the Women's Health Initiative, that the use of hormone replacement therapy radically changed. So I think for our listeners, they probably don't know what the WHI is, and so maybe we need to spend just a little bit of time talking about that. So I thought maybe you can just dive into that and we can take it from there.

William Hurd, MD: Yeah, in, the 80s, we started using a lot of estrogen mainly for menopausal symptoms of hot flashes and also vaginal dryness. And we thought that maybe it would help other things because women have less heart attacks and strokes until they start getting into the menopause and their heart attacks and strokes risk increased.

So, what happened is the pharmaceutical company decided to do a massive study comparing women who got estrogen with progesterone, which we can talk about later, compared to those women who didn't. They picked women who the average age was 60, which was about a decade after menopause, who had had cardiovascular disease already, and they wanted to see if it would prevent that.

Surprisingly enough, the people who got estrogen and progesterone had more cardiovascular disease. And even more surprising is the women who got estrogen plus progesterone had an increase in breast cancer risk as well.

Host: Yeah, and that's the, and I think after that, I think you would probably agree with me, is that the practice of prescribing HRT changed radically, and radically is probably an understatement. Like, my understanding is that in the decade that followed the WHI, that there was almost an 80 percent reduction in the prescribing of HRT because of this fear of breast cancer.

William Hurd, MD: That and heart disease both. So it was, it basically, the, the study was a little overinterpreted, but it scared everyone so much that family practice and OBGYN doctors quit giving out estrogen.

Host: Yeah, I think, I think over interpreted is actually a nice way to put that, Dr. Hurd, but no, I think you're exactly right. You know, so again, my understanding is that the average age in the Women's Health Initiative study was, I think, 63. So we're already looking at an older cohort of women, not women that are going through the change of menopause.

And you know, I think we were commonly prescribing women that were on HRT that were going through menopause. And I think there have been some inappropriate extrapolations of data in older women to younger women. I think that's created this huge disservice to women in general for the last two decades.

William Hurd, MD: I totally agree.

Host: Yeah. And again, for the listeners, I want to highlight this. The WHI study was done with the end point being what are you interested in studying and what kind of difference you're going to make in really cardiac outcomes because the hypothesis at that time was that HRT could be used to reduce significant cardiac events.

And I think breast cancer, as we talked about, was another end point as well. Can you just comment a little bit on the hormone replacement therapy that was used in that trial? Because, A, I think it's mainly of a historical importance, but just so that they're aware of what they were prescribed, so.

William Hurd, MD: Sure. At that time, the only thing available for oral therapy was conjugated equine estrogen. And if you can understand the words there, that was horse estrogen. And we also used that with synthetic progestin called medroxyprogesterone. So those were the standard things available and that's what was studied. It really is historical. We don't often use that therapy today.

Host: Yeah. And so can you comment again on why the progesterone? Because without getting too much into the weeds, the WHI was split into two studies, one with estrogen, one with estrogen and progesterone. We're talking about almost 27, 000 women, which is actually amazing in aggregate. But why would we prescribe progesterone to some and not to others?

William Hurd, MD: Yeah, estrogen has a whole lot of known good benefits but one of the less good benefits is that it stimulates the endometrium, the lining of the uterus. Every month when a woman ovulates, she makes progesterone and sheds her lining, that's menstruation, and that protects the lining from pre cancer and cancer. So it was well known that if you just give estrogen alone, it will increase the risk of endometrial cancer. If you give it with progesterone or progestin, the cancer risk was actually less than women who've never been on progestins. So when you have a uterus, progestins are given. At that time, they were only given orally, systemically, and now we have several different ways to give progestins.

Host: Yeah. And I think that's an important point because you and I were talking before we started this podcast. It was like, it's funny 20 years later. I mean, we don't use these drugs really anymore, which then begs the question is, you know, as we talk about risks and benefits in this podcast, can they be applied equally to these new formulations and in the interest of being succinct, I think we don't know the answer to that question, unfortunately. But yeah.

William Hurd, MD: Some we do and some we don't. The first question is, if you give it through your skin transdermally rather than orally, is that better? It turns out that's a much lower risk of blood clots and cardiovascular disease. Is it better to give bioidentical estrogen and progesterone rather than synthetic or horse estrogen?

We hope so, but the study, the big studies have not been done yet to prove that it's better or not.

Host: Right. Let's talk a little bit about the breast cancer risk. I think that most women in the community, when they think of HRT, I would bet you that the number one thing that they think about risk is breast cancer.

William Hurd, MD: Yeah, that, and as they get older, cardiovascular disease, but you're right, breast cancer, the most common cancer in women, it really worries for women for a very good reason.

Host: Right. You know, and I was a fellow at the time and a very young faculty member when the WHI was published, but I think that that was much of where the sensationalism revolved around was this reported 25 to 30 percent increased risk of getting breast cancer.

And if you break that down, it's a little bit less risk than you would think. Basically, how much risk of there is a woman getting breast cancer per age? Well, it goes up with age, but overall, it's about 0.5%, a half percent. That's five women in a thousand. Well, if you give estrogen and progesterone together, that risk goes up at least 20 or 25%.

That's six women in a thousand. So basically per year, one woman in a thousand more will have a breast cancer if they're taking estrogen and progesterone, systemically. So that's what scared people, but they weren't thinking of the absolute risk of one in a thousand, they were thinking of the relative risk, which is 25%, which is pretty scary.

Yeah. And you know, you already, you already answered the next question for me. And this is, I think, a good educational takeaway point for our listeners is understanding the difference of what we call absolute risk and relative risk, right? And, so it bothers me when, you know, we read articles in the lay press that says X causes cancer and increases it by 20 percent because it really doesn't put that risk into context.

And I think for the person is either uninformed or misinformed, it sounds really scary, but in reality, what you said just earlier is people who are taking HRT, specifically estrogen and progesterone, that amounts to a .1 percent increase in their risk, 1 in 1000 essentially. And the more important thing is, and I think when we look at this, my understanding is it had zero impact or little impact on mortality related to breast cancer.

And that's where I think we did a disservice. We didn't really contextually put this data out there for not only for patients to understand, but I think providers didn't understand it as well. I will profess that I don't think I quite understood it until I started diving deep into the trial. But the one thing I thought would be interesting is, what was the effect of breast cancer or the risk of breast cancer in the estrogen only arm?

William Hurd, MD: Yeah, and not only did that study show a difference, but subsequent studies have really shown a big difference, not only in the estrogen alone, but also when estrogen started. But the bottom line is, people who start estrogen, had estrogen alone, had no risk in that study. And now we know people who start estrogen at the time of menopause actually have a decreased risk of breast cancer.

So it's amazing how that kind of works is, the estrogen alone is part of the important part or what we're doing in some people now giving them local progesterone in the form of an IUD and then systemic estrogen. And then part of it is the timing of when you start it.

Host: So I think if you look at the effect of estrogen and progesterone versus estrogen by itself. I mean, I think we can probably agree that they're diametrically opposite effects or observations as it relates to a breast cancer risk. You would by deduction think then is the obviously the progestin, the cause right there. And I think that a lot of people have recognized, Hmm, maybe the progestin is really what is contributing to the increased risk and just to kind of recapitulate what you just said, that's why I think we look at the use of progesterone very differently now, than we did previously, but it's just surprising to me that you can have such a strikingly different effect in regards to breast cancer between two hormones versus one hormone, that one hormone being estrogen, basically.

William Hurd, MD: I totally agree. We really didn't suspect progesterone, which was such a benefit to the endometrial lining as a problem with breast cancer until that study.

Host: Yeah, yeah. And I think, you know, going back again there are millions of women in this country, unfortunately, that were never given HRT because of this over raised risk of breast cancer. I think it's gratifying to me, to see that the needle is coming back towards the middle. I think there's some practices that I'm a little bit concerned about, but I think for the goal for this podcast and our public is to really understand what that risk of breast cancer is.

Now, obviously, if you have a woman that's on HRT for many years and is in her 70s and 80s, yeah, I would say that probably the risk of breast cancer is going to go up purely because as they get older, their risk increases as well. But also to recognize that if you take a younger woman, a woman in her late forties, early fifties, considering that they are hopefully low risk or average risk and don't have a family history of breast cancer or a personal history, I don't think that we should be having a conversation that withholding HRT because of this quote unquote risk of breast cancer. I don't know if you'd agree with that or disagree with that. So, yeah.

William Hurd, MD: There's no treatment, medical or surgery that we have that has no risk. So, we just have to make sure that the benefit outweighs the risk. And consider that again every year as, their age changes, and their risks change and we get more information.

Host: Yeah. And, for the listeners, I know this is true for Dr. Hurd because he and I have shared this offline, but for me, as I get older, I'm in, I'm in my 50s. And, as we get older, we realize that maintaining your quality of life is so important. I think this is one of the things that we do in women's health where we have such a dramatic impact improving the quality of life for women, particularly when they go through this period, right?

And it's, you know, I don't know. I'm personally on a mission to make sure that we set the record straight and we provide the best care possible, but we have a genuine balance risk versus benefit ratio discussion with our patients about HRT. So anyway, it's for me, this is incredibly important. So, Stepping away from breast cancer risk, and you know, briefly we talked about the fact that we didn't see any real benefit related to cardiac risk reduction, what about some of the other stuff putatively that HRT helps or doesn't help? Specifically, for like dementia and fracture reduction. Do you have any thoughts about the benefits in that area?

William Hurd, MD: Yeah. Now, first off, one thing to remember is it's all about timing and studies now have pretty much shown that if you start estrogen at around the time of menopause, it delays and decreases the risk of heart attacks and strokes. So it has a big plus if you start it later in the 60s, it at least temporarily increases it because the blood vessels have already been perhaps damaged by age and by low estrogen.

So it really is a plus even for heart attacks and strokes. The biggest obvious one, health wise is bone health. Everybody, men and women, lose about 2 percent of bone mass a year their entire life. And women, when they lose their estrogen, it goes up to about 5%. So in some people with very thick bones or many women, that's not a big deal, but if people at high risk for thin bones, family history, being thin, smokers, we still see those occasionally, those women really lose a lot of bone quickly and are at risk for osteoporosis, which is thin bones and fractures associated with them. Estrogen doesn't build bones, but it decreases the loss back to the average 2%, which makes a giant difference.

Host: Yeah, no, that's a great point. And to kind of put that in a broader context, and this is the reason I'm asking the question is the mortality and the morbidity related to a hip or spine fracture in older women is huge. It's, and I don't, and it sometimes, more individuals die from complications related to a hip fracture than, than I care to, to acknowledge, but it's an enormous number. But to your point, Dr. Hurd, I think that the listeners should understand, if you take a woman who is not on HRT and they go through menopause, their bone density is, goes, it drops like a cliff, basically.

And I don't know how you feel about this, but I think estrogen is one of those few agents that we give that has such a profound effect on bone remodeling, to your point, that it mitigates that bone loss, that two percent bone loss, which is huge over time. Right?

William Hurd, MD: 5 percent is really tremendous. Yeah, absolutely. And basically it's a very gentle kind physiologic way to prevent bone loss. We now have modern ways to build bone back up but they're a little more difficult for patients to do. It's really important because as you mentioned things like vertebrae collapse and things like that have a big effect on patient health and well being, but of a hip fracture, in general, half the people who have a hip fracture don't live another six months. So it's a giant problem. Nowadays, we look for it and recognize it earlier. So hopefully we can build the bone up before that happens, but we can't always.

Host: No, you're exactly right. Couldn't agree with you more. So, one of the things I want to talk to you about, and this is probably going to require a subsequent podcast between you and me because we can spend an entire 30 minutes talking about this, is so what's available to women today? So obviously we mentioned earlier that the eight, the hormone replacement therapy and the WHI study, we don't use that much anymore.

They're pretty much historical drugs. But what is available to women? And it's a broad question, I acknowledge that because there are lots of things out there, but if you could maybe summarize that for our listeners, that would be great.

William Hurd, MD: Yeah, the short answer is there's oral estrogen. We most commonly use bioidentical now, which is estradiol. There's topical estrogen, which it actually seems to be a little bit safer in some ways, and those are estrogen patches or actually creams you can rub in. And there's vaginal estrogen, which we can use for vaginal atrophy without having to worry about any systemic effects of it.

Progestins are a little bit trickier. Bioidentical progesterone is available orally, but it's not as potent as the synthetic progestins, so there isn't really a topical progestin that's been shown to be effective. There are multiple progestins though, so we have a lot of different choices. In general, we tend to use bioidentical estrogen and progesterone because we're not sure yet, but we were hoping that is what your body's used to is a little safer.

Host: And so just not to put you on the spot, like, so for a woman that is low or average risk, I mean, what do you normally prescribe as your first line agents for HRT, assuming they have a uterus?

William Hurd, MD: Right. So, yeah. It really depends on their age and what they want to do. We see some people who, for medical reasons, have had their ovaries removed even in their 20s or sometimes 30s and 40s.

That's one group and those people often want to use estrogen orally because it's just more acceptable in their age group and it's exquisitely safe in that age group. Heart, you know, again, if the heart attack and stroke risk is slightly higher, the heart attack and stroke risk before the age of menopause is really low in women.

So the, absolute risk of making any problem there is the same or less than birth control pills. As women age in the peri, we see a lot of perimenopausal women who are in their 40s. They're, haven't stopped having periods yet. And often we give those women the choice, would you like to use oral estrogen or would you like to use transdermal estrogen. And then finally, as women age, if they stay on estrogen, we strongly encourage them to use transdermal because it certainly decreases the risk of blood clots and cardiovascular disease.

Host: Yeah. So, one question that I know that this gets asked of you and it's a hard question. If you have a woman that starts on hormone replacement therapy in their 50s and they're well controlled and their symptoms are well controlled, how long do you leave them on it? How do you counsel your patients about when they come off?

William Hurd, MD: There is no right answer for everybody. So every year you talk about the relative risk and the relative benefits. And when people have medical conditions that make it riskier, those people have to come off. As they get older, because the increase in breast cancer is time related, if they still have their uterus, we're now starting to switch people to progestin IUDs so they don't have any progesterone effect on their breasts that we know about.

The studies show the progesterone IUDs really protect their endometrial lining. They haven't had big enough studies yet to be sure that it minimizes or decreases the risk of increased breast cancer because it's such a small absolute risk, it takes very large studies to show that. So basically it's different for everybody. But some women stay on it through their 60s, a few in their 70s, and most women just choose not to stay on it after that because of the ongoing risks.

Host: Yeah. And I know it's a tough question, right? But it's like everyone wants to know, like, how long do we need to stay on? And I think to your point, it's individualized. And I think that's, there's no clear cut. You stop at this age point. I think that's the take home message for this group, right?

William Hurd, MD: The tricky part is why did you start it? The people who started it for menopause, those terrible symptoms that really could be terrible in some people, they're never going to have those symptoms again. But whenever they stop estrogen, they're going to have some hot flashes increase. So we have to taper off. So those people, that's one thing. Other people are using it because they have thin bones or risk for it. And those people stay on it much longer.

Host: Yup. Last question. Do you have any thoughts about how women should get proper counseling on this topic, right? So one of the reasons why we're doing this, obviously, is to get the message out there, to level set what we really know and the truth behind hormone replacement therapy, and for us to contribute, in a small way, that risk benefit ratio. But do you have any personal thoughts about, listeners to this, how do they seek accurate counseling about HRT?

William Hurd, MD: Yeah, that is right now a difficult problem and what I tell most people about any medical problem is first go to your primary care doctor, family practice, or OBGYN and ask for a referral because they know who the people are that are credible and can help you. Unfortunately, there's not many people out there now that are well trained in hormone therapy. Probably the place not to go is, there are a whole group of people giving out hormone therapy at kind of unregulated higher doses. So I would depend on your gynecologist or family practice doctor to guide you to the right people that are going to do it safely and in the up to date way.

Host: Yeah, and I know there's the North American Menopausal Society. I think they have something on their website about people who at least are credible individuals and providers and is is that a site, that you use or?

William Hurd, MD: That's one and they're probably the leaders in that area and the other one is the American Society for Reproductive Medicine. So, because many of the members of that are interested in this area as well.

Host: Okay.

William Hurd, MD: The American College of OBGYN would be a good help too.

Host: Great. Yeah, I think that they all have good websites and so I think our listeners can check that out. But well, I appreciate your coming on Dr. Hurd. I think if it's okay with you, maybe in the near future, you and I can have a separate podcast about, just again, the different formulations and maybe get into the details of transdermal versus bioidentical.

The one thing that we haven't even talked about is testosterone, right? So that's something obviously women are very interested in. But I, want to make sure we do that topic justice and maybe carve out some future time to talk about that.

William Hurd, MD: Well, thank you very much for inviting me and it'd be a pleasure to come back.

Host: So again, I want to thank Dr. Hurd for giving us an awesome discussion and introduction to hormone replacement therapy in women, a critical appraisal of the benefits and risks. And again this topic was pushed forward by one of our listeners and I'm really thankful for that individual to suggest this and it's something that I've been wanting to do for a long time. And as always, please rate this podcast and we welcome any comments, particularly on topics that you may all want to be learning more about. And so for more information on our OBGYN care, including menopausal care services and other clinical services that UAB provides, please check out uabmedicine.org. And until next time, I hope you guys are doing well. Spring is basically here and I hope you guys have a great day. Take care. Peace out.