Scientists Say Menopause’s ‘Moment’ Is Long Overdue

On this episode, two leading women’s health researchers provide a wide-ranging discussion on menopause – from basic science concepts and historical perspectives to hormone therapies and other clinical implications. Our guests are Nanette Santoro, MD, professor and E. Stewart Taylor Chair in the Department of Obstetrics and Gynecology at the University of Colorado School of Medicine (SOM), and Joshua Johnson, PhD, associate professor in the SOM’s Department of Obstetrics and Gynecology. 

Transcript

Megan Lane 

Welcome to another episode of Health Science Radio where we talk with researchers at the University of Colorado Anschutz Medical Campus about the ways that they're innovating and advancing healthcare. My name is Megan Lane and I'm the communications director for research in the CU Anschutz Office of Communications. It's a pleasure to be joined by Dr. Thomas Flaig, our vice chancellor for research in our studio inside the historic Fitzsimons Building on the CU Anschutz Medical Campus. Today we'll be exploring menopause, the final reproductive stage of women's lives.

More specifically, we'll talk about the timing of menopause, research around implanting ovarian tissue back into patients to delay menopause and other topics around this pivotal transitional stage of a woman's life. Our guests today are two accomplished researchers on menopause and in the wider field of reproductive sciences, obstetrics and gynecology, Dr. Nanette Santoro, and Dr. Joshua Johnson. They're both faculty members in the Department of Obstetrics and Gynecology at the University of Colorado School of Medicine. So welcome Dr. Santoro and Dr. Johnson.

Dr. Nanette Santoro

Thank you.

Dr. Joshua Johnson 

Thank you.

Dr. Thomas Flaig 

As we start this topic, maybe we could just begin with a broad definition of  the medical situation or the medical definition of menopause to set the table for the larger discussion. 

Dr. Nanette Santoro   

So technically menopause is when a woman has gone for an entire year without a menstrual period, that kind of defines it if she's in the right age group. And it happens because the ovary kind of has a time-limited certificate. It's not going to last for a woman's entire lifespan. It has about 40, 50 years when it's going to last to be ovulating and have eggs in it. And then the follicles that are the structures that contain the eggs in the ovary slowly undergo a process of attrition over time, which my colleague, Josh, is doing a very good job of trying to define better and understand.

Dr. Thomas Flaig 

And as we think about this from a research or medical point of view, has anything changed in understanding of menopause over the last several years or maybe the ways that we approach it sort of medically?

Dr. Nanette Santoro 

I think we've learned a lot medically about what the processes, that there's a lead-in to menopause called very vaguely perimenopause. And there are cycle changes that are probably happening all through a woman's life because as people like Josh have shown the numbers of follicles and eggs in the ovary are declining throughout a woman's life, even beginning from when she's a fetus.

Megan Lane 

I've seen a lot in the media lately about delaying menopause. There was a New York Times article over the summer. The headline was, “Is Delaying Menopause the Key to Longevity?” How did this idea of delaying a natural part of aging come about initially? And what if any benefits are there to delaying menopause?

Dr. Nanette Santoro 

There's a long history, I mean menopause in itself is somewhat perplexing because why does the ovary ever stop? Is it just that people weren't meant to live this long and it just happens? Males can continue to reproduce forever. Why did the ovary have this time limit on it? Is that even fair? Men can continue to reproduce. We are living to be older than ever before. Should the ovary continue working beyond its expiration date? That's natural and it's a legitimate question to ask.

I mean, to my thinking that's been answered in a couple of different ways because the experiment of giving women ovarian hormones after menopause has already been done. It's been done several times in an effort to promote longevity. And there really isn't evidence that it promotes longevity. It doesn't seem to reduce longevity, but it doesn't seem to have any miraculous promotion of longevity.

Dr. Joshua Johnson 

And if I could jump off from there, in agreeing with Dr. Santoro, I would add that there are consequences of post-menopausal life that are quite well understood. Conditions that women experience that range from uncomfortable to also even health-threatening and life-threatening ultimately if we're talking about cardiovascular consequences. And so the longevity can be separated I think into two different areas, living longer generally and feeling healthier and also reducing the risk of certain disease states that could kill you along the way.

And so separating those two things, it's excellent to avoid dangerous disease states and some of that can be done or are extended by ovaries working longer.

Megan Lane

Dr. Santoro, I'm also interested to hear more about your research on the timing of menopause and some of the factors that  can influence when menopause begins.

Dr. Nanette Santoro 

There's a few known factors, probably the number one is smoking. There's probably environmental exposures that make a difference, but there's not ones that are well known that cause this. There's also a number of genetic factors and vulnerabilities that cause women to have menopause sooner. Being in a very deprived environment, poor nutrition, those things can cause it, but that tends to have to be pretty extreme before you see a difference.

Dr. Joshua Johnson

Something interesting that I can add is that the number of follicles that girls are born with can span in the hundreds of thousands to over a million. And what controls how many follicles girls are born with is entirely unknown or mostly entirely unknown. So that factor, how many you're born with tends to result in later menopause if you're born with very many.

Dr. Nanette Santoro 

And in fact, the most spectacular loss of follicles is when a woman is a fetus. The most follicles in a woman's life is when she's a twenty-week fetus, then there's a large wave of follicle loss that happens and then at birth it kind of resumes a certain pace and then picks up a little at puberty, picks up a little more at perimenopause.

Dr. Thomas Flaig 

Do you want to talk any more about hormone replacement context of menopause and how it's being applied and maybe lessons learned over recent years about such therapy?

Dr. Nanette Santoro 

Well, right now it's a bit of a media frenzy I would say on hormone therapy. And a lot of it goes back to the 1960s really when Robert Wilson, a Brooklyn gynecologist, wrote a book called Feminine Forever and told women they would be dried husks of humanity if they didn't take estrogen, which was going to keep them feminine and allow them to keep their man essentially. So couldn't be more sexist or offensive. There you go. It led to a stampede for hormones. About 10 years later, the first studies finding that there was endometrial cancer associated with hormones was discovered and there was a stampede away from hormones.

Then 10 years later, epidemiologic data started coming out from the nurse's health study, which looked at women in a cohort fashion and noticed that the women that took hormones seemed to have a lower risk of heart disease. So that led to a lot of enthusiasm for using it. It did not have an FDA indication for heart disease prevention, but many physicians were using it at the time. And the Women's Health Initiative was then started to see if should  e just put hormones in the water supply? Some of the questions that we were addressing at the beginning of this. Should everyone just have them because they're going to be beneficial?

And the answer is, if there was a clear-cut signal for heart disease, they would be in the water supply right now. And the Women's Health Initiative did not show that. So it did not show evidence of benefit after about six or seven years of hormone use. If you had a uterus and you took estrogen with progesterone or if you didn't have a uterus and you took estrogen only. And now about 20 years later, there's been follow-up of the same women looking at heart disease. And again, there does not seem to be any huge benefit in one sub-analysis that was not pre-specified. Women who were 50 to 59 who took hormones seem to do best and they seem to have a decrease in heart disease.

They seem to have a decrease in Alzheimer's. But this is not a pre-specified clinical trial endpoint. It's something that remains a question. People have seized upon this as, "Aha, we told you. Estrogen's going to prevent heart disease and Alzheimer's. You just have to take it in your fifties." Now what that has done, has opened up a more liberal use of hormone therapy for women, particularly in that age group. So it goes, speaks to your question, should we just push this out another 10 years or so? Would that be beneficial? Again, not really well known. And subsequent studies that have looked at clinical trials looking at Alzheimer's don't support the use of hormone therapy to prevent it.

They typically show actual harm. The Danish prescription osteoporosis prevention study, they have the best prescription database in the world, observational data. All age groups have more Alzheimer's. So the short answer is we don't know if this is good as a preventive medicine. It sure is great for most women who can take it for symptoms. I think there's more enthusiasm in the media to give it for symptoms, which I think is very good. I think these preventive indications are still premature.

Dr. Thomas Flaig 

It's really helpful to hear that conversation because I'd say being in the medical field, but not in this particular area. I have heard more on this topic in the last few years, even the popular press. And here you talk about it, I can see your clinical role about how you maybe talk to patients about that, the nuance, the pros and the cons of going through that. I think it's a very helpful discussion.

Dr. Nanette Santoro 

And that's really where we should be now. Patients do need to talk to their doctors. There's kind of a lament because after the Women's Health Initiative, they flushed them all down the toilet, they were gone. And we've almost lost a generation of practitioners who feel comfortable prescribing them. And we also have new treatments coming out that are exciting that actually specifically treat menopausal symptoms, and that's been a godsend for women who can't take estrogen or who don't want to take it.

Dr. Thomas Flaig 

Dr. Johnson,just to build on that idea, one of the areas that you've been doing some research in is around freezing or cryopreservation ovarian tissue with the potential of re-implanting that later. Do you want to talk more about that research and the goals of that?

Dr. Joshua Johnson 

Sure. So this is a collaboration with a mathematician Dr. Sean Lawley at the University of Utah and Dr. Kutluk Oktay at Yale University. And Dr. Oktay approached Sean and I, we had been doing some modeling work seeing if we could simulate or predict how ovarian aging works in the real world. And thankfully in a project with Dr. Santoro, that turned out to be true. That simulations, if you model follicle behavior certain ways, you can get the natural patterns of ovarian aging out of the models.

And in doing so, when Dr. Oktay reached out, he said, "Could this modeling be applied to the question?" If you took ovarian tissue out of the body, let's say somewhat early in life, closer to a woman's twenties and you put it in a freezer, what would happen if you kept that tissue frozen and those follicles remained dormant and you put it back later? How might menopause be delayed? Purely on the simulation and prediction side, we published a paper together showing that indeed we'd expect menopause to be delayed and significantly so.

Dr. Thomas Flaig 

I mean it's very interesting collaboration. You have people of different specialties including mathematics, they're getting involved in that. So from that theoretical point of view, has that been translated into more of a clinical application or future clinical applications?

Dr. Joshua Johnson 

So I should back up and say quickly that this technology or the approach comes from the world of fertility preservation, treating cancer patients. And so the technique or the manipulation of tissue, taking it out surgically and freezing it is well worked out and we can expect how the follicles will behave in that tissue. And so understanding that and being able to model how it might work leads back to your question, is this being done? Could it be done and would it be likely to work in the real world? And there's some suggestion that it has worked in patients in Europe and I believe in Russia, but some of these remains unpublished and only time will tell.

Dr. Thomas Flaig 

Just going back to one thing you said there, I think you said the age of  obtaining that tissue would be ideally in the twenties. Now I can imagine for people, they may not be thinking of this issue in their twenties or so forth. Did I read that part correctly?

Dr. Joshua Johnson 

You do. And many of the patients that are reaching out to Dr. Oktay interested in such a procedure are doing so as their periods are starting to become irregular and the suspicion is it's far too late.

Dr. Thomas Flaig 

One last item on this topic. How long could you presumably delay menopause with this approach?

Dr. Joshua Johnson 

So given the large numbers of follicles in the ovarian tissue of most young women for many years, if you kept that tissue frozen and put it back into the body closer to menopausal onset, you'd expect several years of extended ovarian function.

Dr. Nanette Santoro

And I just want to point out that in the clinical setting, the way this is being used now is to permit fertility. So it's really not so much to extend reproductive life or reproductive hormones because for the most part, we can give them back and avoid some of the side effects. Because we do know unlike menopausal at age 50, menopausal at age 40 ain't so good for you. So that's not so healthy for women and they have worse health outcomes. So trying to edge those women destined for very early menopause to a later-age at menopause would really be beneficial.

Megan Lane 

So Dr. Santoro, do you ever see a world where you would recommend a cryopreservation as a preemptive treatment for menopause?

Dr. Nanette Santoro 

I think it currently involves a lot of procedures. I think we'd have to get procedurally much more adept and a much better handle on how many eggs we can actually get and preserve. As it is now, you have to take a fairly sizable chunk of ovarian tissue, you freeze it, when you thaw it you lose a lot of the viability of that tissue and then you have to do another surgical procedure to put it back. If we reached a point where this could be done, for example, with ultrasound and you could use a needle and just take the tissue out, put the tissue in, that would be far more efficient.

A lot like the way we do IVF and it would make more sense, but for now it really is probably in selected populations of people that really do not want to do procedures like IVF or freeze eggs or gametes or embryos in order to conceive.

Dr. Joshua Johnson 

I'll add that there's a lot of work in my lab and others working on that loss of follicles after surgery, handling the tissue. It's true that a minimum of 60% of follicles can be lost just for taking the tissue out and freezing it. So while freezing is effective at ensuring that there are follicles left afterward when they're thawed out and put back. The haircut you take in follicle loss is significant and that's a big problem that many labs are working on.

Dr. Thomas Flaig 

We've been talking a bit about preserving fertility in the context of, for example, cancer therapy. Are there other medical reasons to delay menopause or benefits from that?

Dr. Nanette Santoro 

Really in the case of early menopause, I think it has its biggest applicability because we don't know enough about the benefits that would happen and there may well be risks. One of the things that doesn't get thought about a lot when we talk about delaying menopause is that that would also result in having your ovary continued to function, continued fertility into your fifties, that you may well not want, continued menstrual periods, which you may well not want, especially if you have fibroids, painful periods, which many women have and continued fluctuations in your hormones, which may not be so much fun.

Megan Lane 

And in delaying menopause, I'm assuming that means women are going to have higher amounts of estrogen in their bodies for a longer amount of time. Are there any risks or downsides to this?

Dr. Nanette Santoro 

There are known risks of continuing hormone exposure after menopause. And women who have late menopause tend to have a higher risk of breast cancer and also uterine cancer. So those are the two risks. In many ways, they are healthier from a cardiovascular point of view and they're less likely to have problems with bone density later in life so that you get a little gain, but you get some negatives along with that. So it's a trade-off.

And current clinical guidelines favor for women that have early menopause prior to age 45 or 40, that's about the 95th confidence lower boundary. The confidence interval is 45. That those women do take hormones until they're around 50. 50, 51 is the median age at natural menopause. And then you would make a decision just as you would for any other patient. Do you have symptoms, do you not? Do you have health risks? That may be a factor here, but mostly we treat for symptoms.

Dr. Thomas Flaig 

So in your practices, we've been talking about some of these different techniques including the ovarian cryo preservation. Is this a question that's coming up in your clinical practice more and more or is it a limited number of patients that are interested in this approach?

Dr. Nanette Santoro 

I think at this point it's really the women with very early menopause whose fertility has been shockingly and unexpectedly truncated. And that can be a cancer diagnosis that's threatening fertility or it could just be an idiopathic case of early menopause. In those cases, we often will try just for the purposes of preserving fertility to just preserve eggs. Because if we can harvest eggs and freeze those, we know they freeze pretty well and we have a decent idea about their behavior. So it's really more for the woman who's facing many years of no hormones where you might want to give her those hormones back along with the opportunity for fertility.

Dr. Joshua Johnson 

And what Dr. Santoro was mentioning allows us to highlight for a moment the differences between ovarian function with the intention to conceive, really focused on fertility and the quality of the eggs and the mature eggs that could produce versus background ovarian function and cycling. The conversation today has allowed us to expand on that a little bit, but clearly there are differences between wanting to conceive and making sure you can conceive possibly later to fit with your family planning versus ongoing ovarian function that we talked about trade-offs for health and longevity.

Dr. Thomas Flaig 

It's an important distinction to make.

Dr. Nanette Santoro 

We tend to have a sentimental attachment to women having regular monthly menstrual cycles. But I also want to point out that may not have been the norm throughout human history because often we lived in a time where there was nutritional scarcity. So women were either pregnant, they were breastfeeding and they weren't having periods, or they were just a little too low on nutrition to be able to have regular periods. So cycling wasn't this monthly thing that happened throughout all of a woman's reproductive years. It's good to go back and remember that point when we talk about this.

Dr. Thomas Flaig 

It's a very interesting point. I'm glad you raised that. That's not one I've really heard very often. It's an interesting historic perspective of how things may have changed over time based on the environment and the situation.

Dr. Nanette Santoro 

We tend to think it's a sign of health because it means your normal weight, you're not too stressed when you're having a regular period, but it may not have been the human condition. So nature may not have actually meant for women to be cycling all the time.

Dr. Thomas Flaig 

We've been talking a bit about early menopause and some of those impacts, if we're thinking about delayed menopause, do we know the causes of that and what we learned about that for patients that may want to delay natural menopause?

Dr. Nanette Santoro 

We don't really know a lot about it. And we've tried to look at it in studies like the SWAN study, which I've participated in and looked at those women with late menopause. We've looked at their hormone patterns. Do they differ somehow? They seem to be of better cardiovascular health. That's one of the things we see. Their lipid panels are a little bit better. That may be why, but we know there are so many sort of wonky genetic reasons why your ovary stops when it does that I would hesitate to try to attribute it to anything. And we haven't found anything dominant.

Megan Lane 

It just strikes me the lack of information and knowledge and research around this phase of a woman's life. And I actually saw an NIH report that showed that the agency actually funds 10 times more studies regarding pregnancy than it does for studies related to menopause. Even though 100% of women who live into their later years will experience menopause. 

Dr. Nanette Santoro 

It's fairly shocking. Most of the work on menopause gets funded through the National Institute of Aging, and most work on women's reproductive lives is the National Institute of Child Health and Human Development. Did you hear the word women in that title? You didn't. What a surprise. It's not okay.

Megan Lane 

So what would you say are your hopes for the future of this field and this body of work and how it can help to improve the lives of women in the years to come?

Dr. Nanette Santoro 

I think we for sure need more clinical trials that are well targeted. We need to understand better what happens during the menopause transition and how we can follow all those health markers for women because it is a pretty dramatic change in hormones. And most women, 75% of them will have some symptoms, and yet we treat 2.8% with hormone therapy right now. So there's a very big gap, a very big care gap that needs to be addressed. So it's really at all levels. It's really the basic science.

Why do symptoms happen? What do they mean? What are their consequences? Some investigators have linked hot flashes with later in life heart disease. When you look in longitudinal models, does that mean that women with bad hot flashes are at high risk or does it mean that you could actually intervene and maybe reduce risk? We just don't know. Those studies are begging to be done.

Dr. Joshua Johnson 

I would say that my hopes for the future both near term and long term are matching up what we know about ovarian function and how it impacts health and then eventually longevity, right? Whether longevity impacted by disease risk and reducing deaths to particular diseases or general health and longevity. And there are scientific tools referred to as aging clocks that are also increasingly in the news. Genetic and other biomarkers in the body can give a somewhat objective measure.

How old is that body? Whether if you're seventy-years old chronologically, your aging clock given a hard life may suggest that you have a body more of an eighty-year-old, for example. So matching up ovarian aging with how it impacts the body and using tools like aging clocks, I think are really exciting and will reveal how the ovary influences overall longevity and health.

Megan Lane 

Dr. Santoro, I have another question for you. As a woman in my mid-forties, menopause and perimenopause is a frequent topic of conversation among my friend group. What would be your advice to a woman who's going into this next phase of life?

Dr. Nanette Santoro 

I think it's a good idea to take stock of symptoms. Many women will come in with menstrual irregularity and just not feeling well. They just feel some kind of a decrement in wellness. And that's not a bad time to just consult with a physician or your practitioner and just say, "Do you think this is happening now? What would you recommend for me?"

There's a lot of different ways to address symptoms, and it's also very important because there's such a focus on menopause right now, that it's important to know what is not menopause because there's other things that happen to women in their forties that really need to be addressed. And if you chase a hormone issue that isn't there, you can waste a lot of time.

Megan Lane 

Great advice.

Dr. Thomas Flaig 

Well, I think it's been a great discussion today. So wide-ranging from some basic science concepts to some historical perspectives, to the clinical implications and so forth. But as we wrap up today, I just wanted to see if there's any final or closing comments either one of you would like to make on this topic?

Dr. Nanette Santoro 

Nothing that I can think of, but Josh has an idea.

Dr. Joshua Johnson 

I can go back to the point that this area is underfunded nationally and internationally. Not enough attention is paid to women's health broadly and menopause and the menopausal transition specifically. And so if podcasts like this can attract a little attention, I'd be very pleased.

Dr. Thomas Flaig 

I'd like to thank you very much for joining us today and very much enjoyed the conversation discussion.

Dr. Nanette Santoro 

Thank you.

Dr. Joshua Johnson 

Thank you.

Megan Lane 

Thank you.