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Dr. Jones: Taking information from around the world, about 3 in 100 women will experience early loss of ovarian function due to having no more eggs, or running out of eggs and follicles in the ovary. And early means below 40. The consequences of running out of eggs include menstrual irregularities and menopausal symptoms as well as infertility.

What is Premature Ovarian Insufficiency (POI)?

Years ago, when I was teaching medical students, I would mention the few causes of premature menopause that we understood. And I would say the rest of the causes were idiot pathic. I use that word instead of the real word idiopathic, which means unknown. Idiot pathic was my word to get a smile from the medical students and to help them remember that we weren't as smart enough yet to know what all the causes were. We have a long way to go to understand the causes of this condition.

Now we know a lot more. We've come a long way for the causes of premature loss of eggs in the ovaries, and we call it now premature ovarian insufficiency. We have some evidence that there can be an increased risk of breast cancer in women with this problem.

Here in the virtual Scope studio, with me, is Dr. Corrine Welt, and she is the George E. Cartwright Presidential Endowed Chair in the Department of Internal Medicine. She's Professor and Chief of the Division of Endocrinology, Metabolism and Diabetes. Now that's a big long title for someone who knows a lot about hormones, ladies' hormones—all kinds of hormones. And she's at the Ï㽶ÊÓƵ of Utah School of Medicine.

Welcome Dr. Welt, and I'm very happy to have you join us and talk about some new research about this problem for women.

Dr. Welt: Very happy to be here today.

Why Does Early Menopause Happen?

Dr. Jones: Oh, good. So tell me a little bit about your research and your clinical practice, and how this interested you.

Dr. Welt: I have always been interested in women's health and how the menstrual cycle signals health or disease in a woman. It's been very clear for some time that when the menstrual cycles are irregular or are not present at all, there can be some health consequences for the woman whose menstrual cycles are affected. So we've always been interested in really early diagnosis of why menstrual cycles become irregular. We came into genetics as a very early way to look at the problems that can cause menstrual cycle dysfunction.

So, within this, there are women who do go through menopause early. Before the age of 40, we call, as you say, premature ovarian insufficiency. And before the age of 45, we would call it early menopause. And it's been pretty clear that about 70% of these women never know why they have this problem.

Dr. Jones: Right. Amazing.

Dr. Welt: And so that was a big empty space for us to look.

The Connection Between DNA Repair, Cancer, and Early Menopause

Dr. Jones: And it's hard for women not knowing. I mean, sometimes they have a mom that had that problem sometimes. And sometimes they know because they were treated for cancer and they got a big whopping dose of chemotherapy that nuked all their eggs. And so sometimes they know maybe they had parts of their ovaries removed for other tumors. But for most of them, when they came to see me at least, I would take a good history and I'd do the few tests I had. But now you've got a lot more. What made you think about the risk of this disease, premature ovarian insufficiency, and cancer risk?

Dr. Welt: Well, you know, it's become pretty clear in the last several years now that people are able to do genetics. You know, the price of doing sequencing of the DNA in your body has gotten very cheap. And the quickness of how you can get that done has rapidly expanded. So we were able to look at those 70% of women who never had a diagnosis and say, "Hey, is there something underlying your early loss of eggs that might explain the problem?"

So along with this ease of doing genetic sequencing, there came a big study looking at just the genetics or the DNA risk for just going through menopause slightly earlier or slightly later in women in general. In those big studies, it was shown that a lot of the genes that seem to affect age at menopause had something to do with the repair of DNA.

And then it sort of all comes together because we know that cancer risk is caused often by the inability to repair DNA breaks. So your DNA gets damaged. There are all these proteins that repair that DNA, and then the cells go on and live their lives. But if the DNA is not prepared or repaired properly, then the cells can go awry. They can have abnormal functions and can cause cancer.

So what's really interesting about that is these same genes, that repair DNA in all the cells of the body, are really important when the eggs in the ovary go through what's called meiosis. So we know that the eggs split up into four different eggs, where one becomes the functional one. And when that happens, the DNA is actually crossing and recombining and repairing itself so that there's some variability in the babies that are born later on.

So as the eggs are going through meiosis, the DNA crosses, and it breaks and it repairs itself. And these same proteins that are repairing genes that are important for all cells, repair the DNA in the oocytes. So when we thought about that, if we knew that there was a problem with DNA causing cancer, if those same proteins were affected in the eggs, it was possible that the eggs would also be affected and therefore be lost early. So that's kind of how we put it together. Cancer and DNA breaking in the eggs.

Using Family History to Understand Early Menopause

Dr. Jones: So we have these amazing DNA diagnostic abilities for individual women. But then we've got the Utah Population Database, where we can look at women who went through early menopause and maybe look at their families. And is that what, you know, you did?

Dr. Welt: Yes. So the wonderful thing about Utah is that we have this big genealogy database, where we know we can look at a woman who has problems with menopause, and then we can find all of her family members and see if they also had problems with menopause. And then we can also use that same database, and the Utah Cancer Registry, to see if those same women had cancer and whether their family members had cancer. So we could take these families of women who had early menopause and say, "Hey, do you have more cancer? And does anyone in your family have more cancer?"

Dr. Jones: Right.

Dr. Welt: And, in fact, we did see that the female family members had a higher risk of breast cancer, and both sides had risks of colon cancer. And then three generations of family members had a risk for prostate cancer as well.

What Should Women with Early Menopause Do?

Dr. Jones: So I think that having this new set of information and this new relationship to other diseases, how do you think this might change the way we talk to women who come with premature ovarian insufficiency? And how do we recommend that they take care of themselves? I mean, I don't want them to panic because what you found is an increased risk, but it's not 100% risk. Even it's not as high as the risk for women who have the BRCA genes for breast cancer, which is 25% or 50%. So it's not that high. So how do we take care of women differently now?

Dr. Welt: I think what I would like to emphasize is that this isn't even necessarily every single woman who goes through menopause early. It seems like the women that were more affected were the ones that had menopause maybe in their 30s to early 40s. What I would say is that the women that we found tended to have a very high rate of cancer in their families as well.

Assess Personal and Family Health History

So we have been thinking for a long time about what it means if you come to a fertility physician and have trouble with getting pregnant and your problem is really related to having too few eggs. Is there some risk for your future health because of that problem? And I think what we can say is that not only should you be screened for osteoporosis and watched for heart disease later in your life, but at the same time a family cancer risk history should be taken. And for those women who have a high family risk for cancer and have gone through menopause early, I think it's really important that they get genetic testing, mostly for the cancer-risk genes. But someday we will have a big panel where we can look at all the genes that might cause early menopause as well. I don't think we're there yet, but we're getting closer, I think, to figuring out which genes should be on those tests.

Screenings and Regular Check-ups

Dr. Jones: Right. So it'd be great. In probably 5 or 10 years from now, people who have premature menopause or have menopause as early as their 30s will come into their primary care doctor and say, "Oh, we're going to do the premature ovarian insufficiency panel, click." And then you can say, "Well, these are the many kinds of inherited, you know, DNA changes that you might be at risk for." I just don't want women to, you know, say bail and say, "There's nothing I can do," because, in fact, the kinds of breast cancers that women get are the kinds of breast cancers that most women get. And it's very amenable to early screening.

And so what I think for me, as a clinician, I would just say, "Here's what I think. I think you should be screened earlier and screened often." And that would be what I would say. We don't do that much prostate screening anymore, but maybe the men in your family, if they have a prostate cancer risk, should be screened earlier too. Does that sound reasonable?

Dr. Welt: It does. And I would also say I agree with you that a lot of the cancers that we saw weren't the very scary, triple-negative versions. They were often the more common hormone-sensitive cancers that are very treatable.

Explore Your Fertility Options

Dr. Jones: Yeah. So I think, first of all, it's so encouraging that your group and other groups have found more reasons that we can help women understand. And many of these women in your study had kids, right?

Dr. Welt: Yes. I think the one thing about Utah that is a very good thing for women who might go through menopause early is they tend to have their children pretty early. Maybe that's not true so much anymore. But there was only a slight decrease in the number of children if the women were able to have children with earlier menopause, one less child per woman in general.

Dr. Jones: Yeah. If I knew I had this problem and I knew I had boy children and girl children, then it would affect a little bit about how I would talk to my boy children and girl children about getting screened themselves once we get this magic little screening test. Is that something that we would help them talk to their kids about?

Dr. Welt: Absolutely. And I think it would be interesting in the future, you know, knowing how quickly technology advances, you know, you can freeze your eggs, you can freeze embryos. It's possible that girls might be diagnosed very early on and could potentially save their eggs for future use, even if they go through menopause early.

Dr. Jones: Right. So if a mom who had a girl child, let's say, went through menopause in her late or mid-30s and she did some testing, then she would say to her daughter, "You know, it's a good thing that you're going to college, and I really want you to do what you want to do. But you might want to be screened for this, and then you may make some decisions about either working on having your kids or freezing your eggs or embryos." And those are the kinds of conversations that sound kind of science-fictiony to me now, but not so much anymore. I mean, that's the kind of thing 20 years ago I would have said, "No, we're not going to really do that." And now I think we'd really do that.

Dr. Welt: We do. I think it's encouraging because I think one of the most devastating things a woman can be told is that, "You will not be able to have children," especially when a woman was expecting that that was going to be her life in that of course.

Dr. Jones: Yeah. Well, as a reproductive endocrinologist, so you do medical endocrinology with a reproductive bent, and I do reproductive endocrinology with a neuroendocrine bent. But from the IVF side, when I give people the devastating news that the reason they're not getting pregnant and their periods are irregular is that they've run almost completely out of eggs. But they can have children with other technologies, including donor eggs, and it's remarkably successful if people are open to that option.

Dr. Welt: Absolutely.

Personalized Care for Women at Ï㽶ÊÓƵ of Utah Health

Dr. Jones: And then they wouldn't necessarily pass on that gene. So I think we have so many more highly individualized options. I think the Ï㽶ÊÓƵ of Utah has kind of set itself off as very hyper-individualized medicine, meaning we will learn a lot about you, so that we can take care of just you, just the kinds of things that you need. And I'm sure you do that in your clinical practice.

Dr. Welt: Yes. I think the here at the Ï㽶ÊÓƵ of Utah is excellent and really does provide that personalized care that I cannot give as an endocrinologist, but I do look to them all the time for my patients.

Dr. Jones: Right. Because they might come to you instead of to us for their primary diagnosis. And after you give people kind of some grim news, you can say, "We have some choices for you. And they're not always easy choices, but they're out there for you and we can help."

Dr. Welt: I think you alluded to the idea that this isn't a death sentence, nor is it that every single woman who has early menopause will get breast cancer. I think there's just a small subset that this will apply to. In general, women who have later menopause tend to be the ones who get breast cancer. But I think there are just a very small proportion of women who might be at risk. And as I mentioned, the women that are maybe going through menopause in their 30s, rather than in their 20s, may be the ones to really watch out for breast cancer risk.

Dr. Jones: Well, we've come a long way, and I don't even use the word idiot pathic anymore about premature ovarian insufficiency because we just know so much more. And I'm really grateful for the work that you've done in your genetics interest and of course that you've done with the UPDB, the Utah Population Database, and your team in really expanding the way that we're going to be taking care of women and their families. And that's really important to me and probably very important to you.

Dr. Welt: Yes. And I think it's really important to have all this family information, and Utah really has the market on all this genealogy and ancestry, which is so important I think for family health.

Dr. Jones: And for everyone who's listening, who every time you go to your electronic health record and you have to fill out once again all your family history, it really matters. Please do think about your family.

And I want to thank you for coming and talking with us, Dr. Welt, and the work that you're doing. And for those of you who might have this condition or know somebody who does, I hope this has been helpful. And if you have questions about this problem, why it happens, and how you can learn more about your own health, we can help. And thanks for listening to us on The Scope.