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The Biology Everyone Should Have Been Taught In School · The LIVING Room Podcast | Inside The WNDR Lab

0:00
SPEAKER_00: Today we're going to be talking about some of the most important women's health issues that are never taught to our children.
0:07
SPEAKER_00: If you are a woman or have a woman in your life that you care about, this is the science that they should have been taught at school and need to know at all stages of life.
0:16
SPEAKER_00: Today I'm joined by the physician scientist working on something that could quite literally change women's health forever.
0:22
SPEAKER_00: How to slow down the ovarian aging clock.
0:25
SPEAKER_00: If you've ever had any questions about egg freezing, IVF, the biological clock, and why the ovary ages faster than every other organ, this is the episode for you.
0:36
SPEAKER_00: Enjoy.
0:50
SPEAKER_01: Hello, good morning.
0:51
SPEAKER_00: I'm really excited to have you here today for so many reasons.
0:55
SPEAKER_00: Um, the main one being this is a topic I don't really know much about, but I also think lots of us don't.
1:02
SPEAKER_00: Because there doesn't seem to be a curriculum, uh uh a point at which we are taught this even as kids, particularly young women, right?
1:11
SPEAKER_04: Absolutely.
1:12
SPEAKER_00: Maybe a good place to start would be you know, if you were in front of a group of young women, how would you introduce this topic of ovarian reserve, reproductive aging, what you do?
1:27
SPEAKER_01: Absolutely.
1:28
SPEAKER_01: You are 100% correct that we teach this to nobody.
1:33
SPEAKER_01: We teach young women how not to get pregnant, and um, you know, which is incredibly important, right?
1:41
SPEAKER_01: So educating about contraception is incredibly important.
1:44
SPEAKER_01: But by the time women see me, they often have been trying to get pregnant for a very long time and realize they know nothing about their biology.
1:52
SPEAKER_01: And so I will start by saying, you know, when I'm educating someone in the office, I wish they had been educated 20 years earlier.
2:00
SPEAKER_01: And I recently did that with my daughter's sixth grade class.
2:05
SPEAKER_01: I went in and spoke to all of the sixth graders about ovarian aging, the sixth grade girls and boys.
2:11
SPEAKER_01: And, you know, and we were talking about all of reproductive biology.
2:14
SPEAKER_01: So I was educating the boys about their testes and the girls about their ovaries and speaking about the ovary as, you know, not just an organ of fertility, but an organ that is critical to endocrine function.
2:26
SPEAKER_01: We understand the ovaries to be these limited resources.
2:30
SPEAKER_01: And so you've got, you know, girls who are born with two ovaries have about a million eggs at birth.
2:35
SPEAKER_01: They've already lost the majority of their eggs.
2:38
SPEAKER_01: So when they are in utero, that's when they have peak fertility, peak ovarian uh reserve.
2:44
SPEAKER_01: And so that's uh five months in utero, peak ovarian reserve, that dwindles to about a million primordial follicles at birth.
2:51
SPEAKER_01: And the primordial follicles are the functional unit, it's the the housing structure of the egg.
2:57
SPEAKER_01: And that's where these little eggs live, arrested at prophase of meiosis one.
3:00
SPEAKER_01: So they're arrested and they can live in that little follicle for decades.
3:04
SPEAKER_01: And they do.
3:04
SPEAKER_01: They live in that little structure for decades.
3:06
SPEAKER_00: You say they are rested or arrested.
3:08
SPEAKER_01: Rested.
3:09
SPEAKER_01: They're arrested.
3:10
SPEAKER_00: That makes more sense.
3:10
SPEAKER_00: They're dormant.
3:11
SPEAKER_00: Yeah.
3:11
SPEAKER_01: Yep.
3:12
SPEAKER_01: Um, and but no, they actually are arrested at prophase of meiosis one.
3:16
SPEAKER_01: So they have started meiosis and then they stop.
3:19
SPEAKER_01: And they then can get reactivated later on, but they're basically sitting at this dormant stage and they grow to become um larger follicles down the road.
3:30
SPEAKER_01: But when we talk about that primordial follicle pool, that's that resting pool, there are only 300,000 of those left at puberty and a thousand left at menopause.
3:38
SPEAKER_01: And there is this significant loss that happens over time, and that loss is different for everybody.
3:43
SPEAKER_01: And the loss essentially involves activation of these primordial follicles.
3:49
SPEAKER_01: So they're in this pool.
3:51
SPEAKER_01: And if you imagine an hourglass and you've got the upper chamber of the hourglass, and then you've got the neck of the hourglass and the bottom chamber.
3:58
SPEAKER_01: That upper chamber is where all of those primordial follicles live.
4:02
SPEAKER_01: They make their way through that neck of the hourglass.
4:04
SPEAKER_01: And once they're in that neck, they are either activated to become growing follicles where they're going to ovulate, or the majority are going to die.
4:12
SPEAKER_01: And so that upper chamber is what we care about.
4:14
SPEAKER_01: Now, when they're activated, they grow through different stages of follicle development: primary follicles, secondary follicles, antral follicles.
4:20
SPEAKER_01: Those are the follicles that you can see on ultrasound.
4:23
SPEAKER_01: So when women have an antral follicle count, an ultrasound of their ovary, we can count the follicles.
4:28
SPEAKER_01: We can't see how many follicles are at rest, but we can estimate a proxy number of follicles that remain.
4:34
SPEAKER_01: And so this is important because essentially you've got this non-renewable source of eggs that is lost over time and everyone loses them at a different pace.
4:44
SPEAKER_01: And I'm very interested in the pace of that aging.
4:47
SPEAKER_01: And that pace differs significantly.
4:50
SPEAKER_01: It differs for women who go through chemotherapy treatment and lose some or all of their eggs at once, for women who have genetic predispositions to loss, for women have who have um medical issues like endometriosis or sickle cell disease.
5:05
SPEAKER_01: There are all these different factors that cause rate of loss to be different.
5:10
SPEAKER_01: And so if I'm talking to a sixth grader and I'm educating her about, you know, her ovaries, she's got this really valuable resource.
5:19
SPEAKER_01: And most sixth graders are not concerned about their fertility in that moment.
5:23
SPEAKER_01: Um, but it resonates with them to think about, you know, I do want to maintain options to maybe have a baby one day.
5:30
SPEAKER_01: And I also want to be healthy and I want to live a long time.
5:33
SPEAKER_01: And the ovary is key to both of those things.
5:35
SPEAKER_04: Yeah.
5:36
SPEAKER_01: And so when I'm talking to a sixth grader or a 35-year-old in my office, the key is, you know, the ovary is a fertility organ, but it is so much more than that.
5:46
SPEAKER_01: It is an endocrine organ that dictates the pace of aging throughout your life.
5:50
SPEAKER_00: With the um the total number to start with, is that very similar for everyone, or is that based on, you know, any genetic predispositions as well?
5:59
SPEAKER_01: It's similar for most, but there are some genetic etiologies of rapid loss.
6:04
SPEAKER_01: So, for example, a girl who is born with one X chromosome, Turner syndrome, or mosaic Turner syndrome, can have all of her eggs lost before she's even gone through puberty or had a chance to have ovarian function.
6:18
SPEAKER_01: And so those patients will often present with primary amenorrhea.
6:22
SPEAKER_01: So these are girls who never get their period, they go to their pediatrician, and during the course of the workup, it turns out they have no secondary sex characteristics because they have no estrogen from their ovaries.
6:31
SPEAKER_01: And a karyotype reveals a monosomy X.
6:36
SPEAKER_01: And so when I'm counseling someone with monosomy X, the conversation is you know, first, it's incredibly sad to tell a 12-year-old that she likely will not have babies with her own eggs.
6:48
SPEAKER_01: Um, and it's also hard for that 12-year-old who is seeing her friends developing breasts and going through puberty and realizing that she, you know, she is going to have to do this very differently.
6:58
SPEAKER_01: And we have options to help her have a baby in the future with eggs from an egg donor, but that autologous ocyte may not be an option for her.
7:08
SPEAKER_01: Now, there are really interesting ways to think about freezing ovarian tissue.
7:12
SPEAKER_00: Before we move on, oocyte.
7:14
SPEAKER_01: Ocyte egg.
7:15
SPEAKER_01: Yes.
7:16
SPEAKER_01: I will use those interchangeably today.
7:18
SPEAKER_00: Yeah, who knew?
7:19
SPEAKER_01: Yes.
7:20
SPEAKER_01: Egg cells.
7:21
SPEAKER_00: Sorry, Carol.
7:22
SPEAKER_01: Yeah, absolutely.
7:22
SPEAKER_01: So, so, you know, there's, but you know, what's really important in that conversation with that young person with Turner syndrome is we have to think about, you know, yes, there's the conversation about how will you have a baby one day, maybe through donor eggs, but more importantly, you're not producing your own estrogen.
7:38
SPEAKER_01: You need estrogen for your heart, for your bones, for your brain, for mental health, for, you know, estrogen is a critical regulator throughout the body.
7:48
SPEAKER_01: And so we have to make sure that that young person who doesn't have estrogen circulating, either because of genetic reasons or because of loss from chemotherapy, has the estrogen she needs to support all these organ functions.
8:00
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8:05
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8:07
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8:12
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8:18
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8:20
SPEAKER_00: I really appreciate you.
8:21
SPEAKER_00: Thank you for listening and thank you for supporting.
8:23
SPEAKER_00: I have so many questions.
8:24
SPEAKER_01: Please, I can't.
8:25
SPEAKER_00: Can we start with you know, this hourglass analogy I love because that makes it easy for me to understand at least.
8:32
SPEAKER_00: Am I right in saying, you know, we're trying to figure out how to narrow the neck of the hourglass?
8:38
SPEAKER_01: Correct.
8:39
SPEAKER_01: That's exactly what I want to do.
8:41
SPEAKER_00: Okay.
8:42
SPEAKER_01: And so let's talk about things that kind of widen the neck of the hourglass and then things that narrow the neck of the hourglass.
8:49
SPEAKER_00: I love it.
8:50
SPEAKER_01: So widening the neck would be things that cause rapid activation of follicles.
8:56
SPEAKER_01: And what I study, so I'm a reproductive endocrinologist and a physician scientist, and I'm really interested in ovarian aging and the pace that the ovaries age because the ovaries are one of the first organs in the body to age decades before other organ systems.
9:11
SPEAKER_01: And one of the critical modulators of ovarian aging, or really the modulator, is that rate of follicle loss.
9:19
SPEAKER_01: And when you think about what modulates that follicle loss, mTOR is key to it.
9:25
SPEAKER_01: So there are a few signaling pathways, but mTOR is one of the most important.
9:30
SPEAKER_01: And so my research focuses on how we can understand the role of mTOR in ovarian aging.
9:37
SPEAKER_01: We know that when you activate mTOR, you get a rapid loss of follicles.
9:42
SPEAKER_01: When you inhibit mTOR, you preserve that follicle pool and narrow that that neck of the hourglass.
9:48
SPEAKER_01: When we think about other causes.
9:50
SPEAKER_00: Sorry, do you mind explaining what mTOR is?
9:53
SPEAKER_01: Absolutely.
9:53
SPEAKER_01: So mechanistic target of rapamycin, it is a kinase.
9:58
SPEAKER_01: So it is a protein that phosphorylates other proteins.
10:01
SPEAKER_01: It turns on other proteins.
10:03
SPEAKER_03: Right.
10:03
SPEAKER_01: And it is a master center, a master regulator, and really a metabolic hub.
10:09
SPEAKER_01: It sits at the center of this very complex conversation where you've got inputs from nutrients and growth factors and insulin and all of these inputs from the environment speaking to this space, speaking to the cell and saying, do we turn on or do we turn off?
10:28
SPEAKER_01: And the question is really about do we are we in a nutrient-rich environment and so we should activate and turn on and we have resources to use, or are we in a nutrient scarce environment and we should slow down?
10:42
SPEAKER_01: And so it's at the hub of a lot of processes.
10:45
SPEAKER_01: It's it's really critical across cell types.
10:47
SPEAKER_01: And so, you know, people listening to this know a lot about mTOR, I'm sure.
10:51
SPEAKER_01: And it is well studied in the longevity space.
10:54
SPEAKER_01: And of course, I'm sure we'll talk about rapamycin.
10:57
SPEAKER_01: Um, so it's very well studied in that space.
10:59
SPEAKER_01: But what's fascinating is that mTOR is a critical driver of primordial follicle activation.
11:04
SPEAKER_01: So, in the same way that, you know, input one tells mTOR to turn on and you know, you slow, you, you take resources away and mTOR slows down.
11:14
SPEAKER_01: If you have elevated insulin signaling, if you are activating because of chemotherapy, there are so many things that turn mTOR on in the ovary and cause activation of follicles from that primordial follicle state to the primary state.
11:28
SPEAKER_01: And once you are in that activated state, that follicle's destiny is determined.
11:32
SPEAKER_01: It's either going to undergo atresia, so about a thousand per month undergo atresia and just die, or it will be the one that ovulates.
11:40
SPEAKER_00: But atresure is normal, right?
11:42
SPEAKER_00: Like that, yeah.
11:43
SPEAKER_01: Normal.
11:44
SPEAKER_01: Um, the problem is when you have a, you know, when you have too many activating at once.
11:50
SPEAKER_01: And so, for example, chemotherapy is a really good example of this accelerated ovarian aging state where chemotherapy causes rapid loss of, you know, it's it's destroying rapidly dividing cells, right?
12:02
SPEAKER_01: Which is critically important for tumors, uh, for tumor cells sensitivity.
12:06
SPEAKER_01: It's also, you know, affecting the follicles in the hair, other rapidly dividing and turning over cells.
12:11
SPEAKER_01: And the follicles in the ovary are also turning over rapidly.
12:14
SPEAKER_01: And so you get an acute loss, a lot of apoptosis of these growing follicles.
12:18
SPEAKER_01: Those are those follicles that are sensitive to gnatotropin.
12:22
SPEAKER_01: So they are the antropolicles and the secondary follicles, those die off.
12:26
SPEAKER_01: The ovary wants to be in homeostasis.
12:28
SPEAKER_01: And so it senses that these follicles are dying off, estrogen is low, it activates.
12:33
SPEAKER_01: And part of this is because of AMH, anti-mularian hormone.
12:36
SPEAKER_01: So that's a hormone that is released by the granulosa cells of these growing follicles.
12:40
SPEAKER_01: You get loss of that hormone and you get mTOR activation, and then you get this widening of the neck of the hourglass and that loss of follicles.
12:48
SPEAKER_01: And if that happens to uh too great a degree, you lose that entire pool of follicles.
12:53
SPEAKER_01: And this can happen via, you know, genetic knockout.
12:56
SPEAKER_01: So if you look at mice that are knocked out for the genes that inhibit mTOR.
13:02
SPEAKER_01: So like if you look at P10 and TSC1 and two, they downregulate PI3K and AKT.
13:09
SPEAKER_01: Those are both upstream of mTOR.
13:11
SPEAKER_01: Essentially, if you knock out these genes in mice, you get rapid activation of mTOR and an ovarian insufficiency phenotype.
13:17
SPEAKER_01: So there's all these kind of parallels in mice and and humans that if you were to say, you know, anything that rapidly activates that pathway, you lose those follicles and have uh a phenotype of ovarian insufficiency.
13:30
SPEAKER_00: This might be naive, but is that the same?
13:33
SPEAKER_00: Is I I don't want to conflate the two, but is you know, is that akin to w why we lose our hair when we undergo chemotherapy?
13:40
SPEAKER_01: Exactly the same.
13:41
SPEAKER_01: Exactly the same.
13:42
SPEAKER_01: So rapid loss of follicles.
13:44
SPEAKER_01: And what I think is really interesting, and so I'm glad that we are double-clicking on this, because when we think about hair loss during chemotherapy, we have interventions for that.
13:55
SPEAKER_01: So there's scalp cooling, and there are these um, you know, cooling caps, and you'll see women going through chemotherapy for breast cancer or lymphoma, various cancers, and they are they have a cooling cap on to prevent hair loss.
14:07
SPEAKER_01: And and we know that's important, right?
14:09
SPEAKER_01: Like that has been prioritized because it's important to women.
14:13
SPEAKER_01: And yet we have the ovaries that are also going through this massive loss of follicles and this non-renewable source of eggs that is lost, and we are not protecting them.
14:25
SPEAKER_01: And so this is where I developed my strong interest in this field because I always knew I was going to be in women's health.
14:34
SPEAKER_01: And just for context, my um I, you know, I was very inspired by my the matriarchs in my family, my grandmother, who lived to 102.
14:44
SPEAKER_01: Um right.
14:45
SPEAKER_01: Um, she wanted to be a physician.
14:47
SPEAKER_01: She would have been a woman's health advocate, but in the 1930s, that was not an option.
14:52
SPEAKER_01: So she taught biology and volunteered at Planned Parenthood Before Roe in Chicago.
14:58
SPEAKER_01: She was amazing.
14:59
SPEAKER_01: Um, and then, and so I think from her I learned that this, you know, the idea of reproductive choice and autonomy is so critically important.
15:06
SPEAKER_01: And I just grew up seeing that.
15:08
SPEAKER_01: And then my mom went through cancer treatment.
15:10
SPEAKER_01: And watching that experience for her, it was clear to me I needed to be in a space that was part reproductive choice and um, and thinking about women's health through the most critical and um and challenging inflection points in our life, like you know, infertility and cancer and menopause and pregnancy.
15:30
SPEAKER_01: Um, but then thinking about that uh next to cancer.
15:33
SPEAKER_01: And I knew I needed to take care of women with cancer as well and patients.
15:36
SPEAKER_01: I'll ask you a question, though.
15:37
SPEAKER_00: Um it must be incredibly challenging on so many levels to have that conversation with a young woman who's had a cancer diagnosis to be thinking about you know ovarium reserve at that stage feels heavy.
15:54
SPEAKER_01: It's incredibly heavy.
15:55
SPEAKER_01: It is incredibly heavy.
15:56
SPEAKER_01: And this is so I um but I also love it so deeply because the conversations are so intense and so deeply human.
16:05
SPEAKER_01: And so I'm talking to someone who, you know, either they know they've always wanted to be a parent or they are very clear that they're not sure this is important to them, but they don't want the choice taken from them.
16:17
SPEAKER_01: Sure.
16:17
SPEAKER_00: Yeah, they want the agency.
16:18
SPEAKER_01: They want the agency, yes.
16:20
SPEAKER_01: And so the conversations are, you know, layered because this is someone who just yesterday had their PET scan to see if they have metastatic cancer.
16:29
SPEAKER_01: They're grappling with their mortality and they are very much in a moment where they have to prioritize and and maybe reorder their life priorities.
16:38
SPEAKER_01: Maybe they didn't want kids, but I have so many patients who say, I didn't want kids until I realized that it may not be a possibility.
16:44
SPEAKER_01: And now I deeply want that more than anything.
16:46
SPEAKER_01: And so, yes, those conversations are really tough.
16:48
SPEAKER_01: And you know, and in this brief visit, it's you know, typically I I get an hour with these patients, which is amazing, but it's not enough because I am counseling someone about their reproductive biology.
16:58
SPEAKER_01: Many, you know, don't know the don't know their biology.
17:01
SPEAKER_01: They don't know their anatomy because again, they they were not taught it in from a young age, they learned how to contracept.
17:07
SPEAKER_00: Yeah.
17:08
SPEAKER_00: Can can I ask um what will be one of many more naive questions?
17:12
SPEAKER_00: And that is, you know, given we know that the ovaries age far earlier than many of the other organs, probably all of them, right?
17:22
SPEAKER_01: Um except for it's funny, I actually um I was speaking about this at a talk at the National Academy of Medicine a couple of years ago, and I said that the ovaries aired, you know, the first organ to age, or one of the first, and someone stood up and said, actually the thymus.
17:36
SPEAKER_01: And I said, I'm so sorry, it's the thymus.
17:38
SPEAKER_01: But yes, but interestingly, yes, the thymus ages very early as well.
17:42
SPEAKER_01: But um, the ovary is one of the first organs to age, yes.
17:45
SPEAKER_00: Okay, given that we know that, and that is sort of upstream of some of the other signatures of aging.
17:52
SPEAKER_00: Is this not something that we can be taking action on much sooner?
17:56
SPEAKER_00: I'm I'm talking decades in advance, and as such, should be a much more important conversation that has uh that happens much earlier.
18:04
SPEAKER_00: But are there things that young women can be doing to build a sort of suit of armour to protect against that happening?
18:12
SPEAKER_01: So uh yes, the ovaries are aging uh much faster than most orange.
18:16
SPEAKER_00: And by the way, without sorry to interrupt, I think it's also worth double clicking on the all of the other many benefits of of protecting uh ovarian aging that that have this huge um sort of carry-on effect to other organ systems of the body.
18:34
SPEAKER_01: Yes.
18:35
SPEAKER_01: So let's talk about what happens when the ovaries age, both when they age in an accelerated way and in a physiologic way.
18:43
SPEAKER_01: So in an accelerated model of ovarian aging, so these young people with cancer or with endometriosis or with a BRACO1 mutation, there's all of these other reasons why the ovaries might age a little faster.
18:55
SPEAKER_01: You are seeing, you know, women who have to be started on hormones much younger to support the physiologic function that the ovaries, you know, are are are um critical for.
19:07
SPEAKER_01: And so you've got, you know, someone who is 30, whose ovaries aren't working, they need to be on physiologic doses of hormones because if they aren't, you look at you know, the age of menopause earlier than when they should have got.
19:23
SPEAKER_01: So I'm gonna start that over.
19:24
SPEAKER_01: Um, if you look at the you know, average age of menopause is about 51.
19:29
SPEAKER_01: And for women who go through menopause earlier than that, for every earlier year of menopause, there is a 3% greater incident risk of cardiovascular disease.
19:41
SPEAKER_01: And for every year earlier of menopause, there's a 1 to 2% greater risk of fracture.
19:46
SPEAKER_01: And for menopause that happens before 45, then there's a 50 to 100% greater risk of hip fracture.
19:54
SPEAKER_01: And so, particularly for women whose ovaries stop functioning decades earlier than the ovaries are supposed to function for, those women have a very high risk long term of bone disease, fracture, cardiovascular disease.
20:10
SPEAKER_01: And so for those women, the recommendation is to treat with hormones that would mimic what their ovaries would be producing.
20:17
SPEAKER_01: So 100 to 150 micrograms of estrogen, and typically that's given via patch, and then we protect the uterus with a progesterone or progestogen.
20:25
SPEAKER_01: And so that is really like that population of patients, the the young population whose ovaries are aging.
20:30
SPEAKER_01: But then we yeah.
20:31
SPEAKER_00: Wait, before we move on from that, you say, you know, the young population whose ovaries are aging and they don't know, how do they know?
20:38
SPEAKER_01: Gosh, that's an incredible question.
20:41
SPEAKER_01: What often happens is they present in a crisis.
20:43
SPEAKER_01: And this is what we are doing wrong in women's health.
20:47
SPEAKER_01: They present in crisis, whether that be infertility or endometrial cancer, or, you know, any of the number of things or severe pelvic pain.
20:59
SPEAKER_01: But the most common presentation of patient who I see is someone who's maybe 35 or 37.
21:06
SPEAKER_01: They've done everything right.
21:08
SPEAKER_01: They are proactive about everything in their life.
21:11
SPEAKER_01: They've gone every single year for their annual exam and they're getting their PAPSMERS regularly and they are on top of their healthcare.
21:17
SPEAKER_01: And then they come in and they've been trying to get pregnant for a year, because that's the dogma is try for a year or try for six months, and then you present for care.
21:25
SPEAKER_01: And what happens is we then do a full workup and we evaluate their ovarian reserve.
21:30
SPEAKER_01: And that is when we might identify that their ovaries have been aging much faster.
21:33
SPEAKER_01: And so they'll find out that their AMH, anti-mularian hormone, so that's that hormone that's released by those growing follicles, that AMH might be much lower than it should be at their age.
21:44
SPEAKER_01: And then that prompts the conversation of all the different opportunities to have identified that along the way.
21:52
SPEAKER_01: At that moment, I'm asking, when did your mom go through menopause?
21:56
SPEAKER_01: And they often do not know.
21:58
SPEAKER_01: And that's often when patients.
22:00
SPEAKER_01: They'll text their mom and they'll say, you know, they'll get back, you know, in the visit, they'll say, Oh, she just responded, she was 42.
22:06
SPEAKER_01: We should have known that a really long time ago because there's a very close correlation between a mom's age of menopause and her daughter's age of menopause.
22:14
SPEAKER_01: And so that conversation, if that had happened earlier, that could have prompted her to say that to her OBGYN and then to say, maybe I should think about seeking care sooner.
22:24
SPEAKER_00: Or maybe that same person, yes, should I keep is there not a way that we can be testing for levels of AMH like a decade earlier?
22:32
SPEAKER_01: Right.
22:33
SPEAKER_01: I mean, it's so that's a really good question.
22:34
SPEAKER_01: Let's get back to it.
22:35
SPEAKER_01: Okay, so that's nuanced.
22:36
SPEAKER_00: Yeah.
22:37
SPEAKER_01: Um, so then there's, you know, maybe she had pelvic pain years ago, but a lot of women who have pelvic pain and they might normalize it.
22:44
SPEAKER_01: They might say everyone has pain with their periods.
22:46
SPEAKER_01: Yeah.
22:46
SPEAKER_01: And so they're started on a birth control pill to suppress maybe endometriosis, but we don't really know what we're treating.
22:51
SPEAKER_01: And then they come in and maybe they stop their pill and they don't get a period, and we find out they've had ovarian insufficiency that has been masked with the pill, or we find out that their ovarian reserve is just really low.
23:01
SPEAKER_01: And maybe it's because their pelvic pain was endometriosis, which predisposes to low ovarian reserve.
23:07
SPEAKER_01: And so there are all of these opportunities that are missed opportunities along the way.
23:13
SPEAKER_01: And I would say we are missing, particularly in our 20-year-old patients, like this is such a prime window where there's very little preventive health care done and people feel healthy and they're, you know, they're they're busy and they are, there's nothing that we are doing to think about ovaries during that time besides don't get pregnant.
23:31
SPEAKER_03: Yeah.
23:31
SPEAKER_01: But that's a window where there's a lot of decline.
23:34
SPEAKER_01: And so, to your question, you know, why don't we just check in AMH and everyone?
23:38
SPEAKER_01: Historically, the thought has always been that AMH is a really good predictor of response to medications in an IVF cycle.
23:46
SPEAKER_01: So, in our population, in a reproductive endocrinology center where we are, you know, thinking about fertility treatments, yes, AMH is a great tool to study, you know, to evaluate how many eggs will we get in an egg-free cycle or in an IVF cycle.
24:00
SPEAKER_01: Um, but there is pretty compelling data on a population level at least that when you look at AMH, there's a relationship with time to menopause.
24:09
SPEAKER_01: And it's a good proxy for how many eggs remain in the primordial follicle pool.
24:13
SPEAKER_01: But it's a, it's really a tool of functional ovarian reserve, kind of how many of those follicles can you get to recruit in a typical cycle of fertility treatment.
24:24
SPEAKER_01: Whether it can, on an individual level, predict menopause, we're not there.
24:28
SPEAKER_01: And we need much better biomarkers and better tools.
24:31
SPEAKER_01: And there are a lot of ways to think about doing this, but that is really where, you know, that's where we have to go as a field because we are treating after the fact, we're treating once there's a crisis.
24:43
SPEAKER_01: And when we've got someone with cancer or infertility or these moments of crisis, we are we are kind of putting a band-aid on it.
24:51
SPEAKER_00: Yeah.
24:51
SPEAKER_01: But we're not doing anything to prevent the loss.
24:53
SPEAKER_00: Well, that that that can be said in so many other domains in which we're looking to protect our health spam.
25:00
SPEAKER_00: Right.
25:00
SPEAKER_00: Um it strikes me that there should be, you know, a list of things that young women can be doing upstream of this that are just educational resources.
25:12
SPEAKER_00: You know, you mentioned about knowing the age at which your mother, you know, hit menopause or or even perimenopause.
25:20
SPEAKER_00: What is there is there other are there a list of questions that a young woman listening today should be asking her mother and the and vice versa, that as a mother you should be telling your daughters.
25:34
SPEAKER_01: Yes.
25:35
SPEAKER_01: So I want to zoom out even further than that first and say, when you are in a doctor's office, you know, what is your doctor talking to you about?
25:43
SPEAKER_02: Yeah.
25:44
SPEAKER_01: And I think one of the problems that is facing our field is that, you know, when you think about all the things that an OBGYN needs to talk to their patient about, there are so many items because an OBGYN is considered a primary care doctor and also, you know, a specialist in women's health.
26:01
SPEAKER_03: Yeah.
26:01
SPEAKER_01: So there is a set of guidelines.
26:02
SPEAKER_01: It's like called the um WSPI, and they put out guidelines.
26:07
SPEAKER_01: And if you are ever in a OBGYN office, sometimes you'll see a chart on the wall.
26:10
SPEAKER_01: And it's basically by age, what should be discussed with patients.
26:15
SPEAKER_01: And, you know, it's everything from lipids to cigarette smoke to car seats or to, you know, all the fit, maybe not car seats, but to um, you know, seat belts and, you know, urinary incontinence and all of these things.
26:26
SPEAKER_01: And on there is not fertility or reproductive aging.
26:30
SPEAKER_01: And so I, you know, I wrote like an angry op-ed about this a couple of years ago because it makes me so, it infuriates me that, you know, we are, A, we we are expecting so much of that 15-minute visit with a physician.
26:44
SPEAKER_01: And there's only so much that can be covered.
26:45
SPEAKER_01: And it's a major problem with like billing and reimbursement.
26:48
SPEAKER_01: And so there's only so much that a primary care physician and uh in that 15 minutes can do.
26:52
SPEAKER_01: So, so ultimately that conversation has moved out of the physician's office.
26:57
SPEAKER_01: Um, but I do think we need better structure in terms of where patients are getting their first line information.
27:03
SPEAKER_01: And so, and we did a review of all the guidelines that help physicians know what to talk to their patients about and really all of the, you know, ACOG ASRM and Royal College and all these, you know, umbrella organizations that help create curriculum and um guide conversations with patients, we have not unified around what to talk to patients about, at what age, you know, what what conversation needs to happen when in the office.
27:28
SPEAKER_01: So there's that.
27:29
SPEAKER_01: And so conversations have moved outside of the doctor's office and they are on social media and they are everywhere but, you know, where there's you know really solid education.
27:37
SPEAKER_01: But I think to your question, you know, these conversations should start at home.
27:41
SPEAKER_01: These should happen at home.
27:43
SPEAKER_01: If if I, you know, if I am a parent of a young child, I want that child to know that they, you know, everything that happens in their in in the teens and 20s is a predictor of what's to come down the road.
27:58
SPEAKER_01: So the timing of menarchy, so the timing of their first period, whether they're getting regular periods, that's an important measure of their ovarian function.
28:06
SPEAKER_01: Someone who's not having regular periods, that can be a sign of PMOS, formerly PCOS.
28:13
SPEAKER_01: And so um it's a sign of metabolic endocrine dysfunction.
28:18
SPEAKER_01: And if you are, you know, not getting regular periods, that impacts systemic health and it can be a marker for future cardiovascular health.
28:25
SPEAKER_01: We need to understand why that's happening.
28:27
SPEAKER_01: And so there's all that prospective information that people are getting from their own medical histories.
28:32
SPEAKER_01: And in a lot of cases, you know, those people who are having irregular cycles might just go on a birth control pill.
28:37
SPEAKER_01: And I see them 20 years later when they say, actually, I don't know if I have regular periods because I was having painful periods and irregular periods when I was 13.
28:45
SPEAKER_01: So I started a birth control pill at 14.
28:47
SPEAKER_01: And I haven't stopped and I haven't stopped and now I'm 35 and now I'm coming off the pill and I don't actually know what my function is off of um this suppression.
28:56
SPEAKER_01: And so I think there's a lot we just don't understand about our physiology.
29:00
SPEAKER_01: And so I think having a clearer window into that is very helpful prospectively.
29:04
SPEAKER_01: And so, you know, as a child, I think knowing your kind of understanding that your reproductive function is a good marker and sign for your systemic health is important.
29:13
SPEAKER_01: And then also understanding what your mom went through and what your grandma went through, because your mom's age of menopause and your grandma's age of menopause will predict to a large extent your age of menopause.
29:25
SPEAKER_01: And so that also means that, you know, if that person went through menopause before 45 or before 40, A, you should be thinking about fertility much, much younger.
29:34
SPEAKER_01: And, you know, when you are having symptoms that feel like perimenopause at 30, those should be acknowledged.
29:42
SPEAKER_01: And I take care of a lot of women who they complete their families and they'll come back and say, you know, I'm I'm done having children, but I'm 38 and I'm having hot flashes.
29:53
SPEAKER_01: And, you know, this doesn't feel right.
29:55
SPEAKER_01: I don't feel like myself.
29:56
SPEAKER_01: And I've gone to three physicians, primary care doctors, or, you know, people that I trust.
30:02
SPEAKER_01: And I've been told that I'm too young to be in menopause.
30:05
SPEAKER_01: And because I'm getting periods, I shouldn't, you know, I don't need treatment.
30:09
SPEAKER_01: And that's not correct.
30:10
SPEAKER_01: You know, if someone is symptomatic, you can treat them.
30:13
SPEAKER_01: And the number of patients who are in that boat, who they have very low ovarian reserve, we know they're going to go through menopause early, you know, and you treat them and they feel better and it's safe.
30:23
SPEAKER_01: We use a lot of hormone therapy, you know, for a lot of different reasons.
30:27
SPEAKER_01: And I think we have to, as a kind of medical community, just get a lot more comfortable using these medications.
30:34
SPEAKER_01: And the problem is 20 years ago, we stopped.
30:37
SPEAKER_01: And so people weren't trained in using them.
30:39
SPEAKER_01: And so now we've got this significant need and a lot of people who aren't trained to use them.
30:46
SPEAKER_00: Is there anywhere that, you know, as a as a young woman or young person, should I say, can go and like have find these resources?
30:54
SPEAKER_00: You know, is there is there a list of questions that I can be asked that they can be asking their mother, their grandmother, and vice versa?
31:02
SPEAKER_00: Because it doesn't maybe I'm just not in that.
31:06
SPEAKER_01: No, it's a good question because you're right.
31:08
SPEAKER_01: There is, you know, I think there's so we have good resources for patient education through the ASRM, the American Society for Reproductive Medicine, through ACOG.
31:18
SPEAKER_01: So there are resources that you can, you know, identify on these organizations' websites.
31:24
SPEAKER_01: I think in terms of, you know, the main questions I would want someone to think about is are you, you know, are you doing everything you can in your lifestyle to protect your environment?
31:37
SPEAKER_01: Smoking is one of the um biggest modifiable risk factors for early menopause.
31:43
SPEAKER_01: So if I am talking to someone who is a smoker, that is the easiest first low-hanging fruit target, you know, um, because we know that it expedites follicle loss, it affects the environment of the ovary, it affects everything, obviously, as we know.
31:59
SPEAKER_01: But um, you know, for the most part, we have fewer smokers these days, thank, thank goodness.
32:04
SPEAKER_01: But, you know, so that is one lifestyle target.
32:08
SPEAKER_01: The other is before we move on from that.
32:10
SPEAKER_00: Can I just can I just ask one question on smoking in general?
32:14
SPEAKER_00: Is does that the the same downside apply to nicotine?
32:20
SPEAKER_00: Because there's a lot of people do using pouches and vaping now that maybe might feel like that is a safer alternative.
32:27
SPEAKER_01: I think the answer is we don't have enough data to say that it's not that it's not causing harm to the ovary.
32:34
SPEAKER_01: So I would I would say that there are so many downsides to the oral nicotine in terms of you know risks to the oral mucosa.
32:45
SPEAKER_01: And, you know, I'm out of my lane, so I'll let someone who's a mucosa expert speak to that.
32:50
SPEAKER_01: But the the reality is we don't have enough data.
32:52
SPEAKER_01: And so it's worth the risk.
32:54
SPEAKER_01: What?
32:54
SPEAKER_01: It's not worth the risk.
32:55
SPEAKER_01: Not worth the risk.
32:56
SPEAKER_01: Yes.
32:57
SPEAKER_01: Um, I think metabolic health is incredibly important, obviously.
33:01
SPEAKER_01: No, you agree.
33:02
SPEAKER_01: And when we think about, you know, hyperinsulinemia and elevated insulin signaling, insulin stimulates growth pathways and it stimulates mTOR.
33:13
SPEAKER_01: And so we see diminished ovarian reserve in women with obesity.
33:18
SPEAKER_01: And obesity is a risk factor for kind of most of the untoward consequences that we think about with pregnancy and reproductive health.
33:28
SPEAKER_01: And so, you know, we, you know, ideally optimizing optimized, you know, met optimizing metabolic health is a priority.
33:34
SPEAKER_01: And so that's where working closely, either in a preconception setting, if we're talking about pregnancy, but also for long-term health and understanding, you know, when we have someone who is in their 20s or 30s, and maybe their priority right now is fertility and that's what brings them in.
33:51
SPEAKER_03: Yeah.
33:51
SPEAKER_01: But that's the opportunity to say, what happens when we, when you're done with this window, this chapter of your life, and we've completed your family building.
34:01
SPEAKER_01: I care deeply about what's going to happen to you in 10 years, 15, 20 years.
34:05
SPEAKER_01: And going back to, you know, how I'm so motivated by thinking about my mother and grandmother's stories, I look at my daughters and I think, you know, we've got this generation of women who are similarly kind of right in the middle and they have priority, you know, they are have the obligation to care for their parents and and for their children.
34:26
SPEAKER_01: And if I've got a young person who's completed her family or hasn't even begun completing her family, she's young but has low ovarian reserve.
34:33
SPEAKER_01: The priority is how do we keep her healthy for longer?
34:36
SPEAKER_01: And the ovary is a lever for that.
34:38
SPEAKER_01: The ovary is a lever to think about how do we modify the trajectory of aging via modifying ovarian function.
34:45
SPEAKER_00: Yeah.
34:46
SPEAKER_00: We had Jen Jennifer Garrison on recently.
34:48
SPEAKER_00: We we double clicked on that.
34:50
SPEAKER_00: So if anyone's interested in learning more about that, that we we we went into that a lot.
34:55
SPEAKER_00: And it was very much a school day for me, as is today.
35:00
SPEAKER_00: Can can I ask you a question about um you know, people who are less at risk, you know, who are thinking about conceiving, you know, planning to start a family.
35:14
SPEAKER_00: My understanding is so much of maybe I reword this.
35:23
SPEAKER_00: So so so much of that can be far upstream of the act of having sex itself, and that there's this sort of epigenetic expression component that nine plus months before we could and should be thinking about how to not only increase the likelihood of conception, but then the health of the baby.
35:45
SPEAKER_01: Absolutely.
35:46
SPEAKER_01: Absolutely.
35:46
SPEAKER_00: Can you maybe explain that?
35:48
SPEAKER_00: Because when I read about this a few years ago, I was I was pretty shocked about the impact and and in not just that how impactful it is, but how much agency we have, but we don't know about.
36:01
SPEAKER_01: You're absolutely right.
36:02
SPEAKER_01: And you're right, the health of the oocytes and sperm preconception can impact the health of your offspring.
36:10
SPEAKER_01: And so there are all these moments of time, you know, preconception, you know, the opportunities in pregnancy to support a healthy pregnancy, and then of course postpartum.
36:20
SPEAKER_01: But the, you know, the preconception opportunities, when you look at metabolic health and optimizing, um, you know, decreasing diabetes, you know, in I would say glucose control, hemoglobin A1C control and diabetes is a really good example.
36:34
SPEAKER_01: So, you know, diabetics tend to A, have more difficulty conceiving.
36:41
SPEAKER_01: And so there, you know, there's a relationship between diabetes and poorly controlled diabetes and fibrosis in the ovary and um testicular hypofunction.
36:51
SPEAKER_01: And so that is an that is a really important goal.
36:55
SPEAKER_01: So if I am talking to someone who is thinking about planning a family and we are trying to optimize their health, if their hemolobin A1C is eight, we are not, we are not trying anything until that number is low.
37:11
SPEAKER_03: Yeah.
37:11
SPEAKER_01: Um, and part of it is because you're going to have a higher risk of chromosome abnormalities and birth defects in a baby conceived with with poorly controlled um glucose.
37:22
SPEAKER_01: And so, and that the same applies for men and women.
37:26
SPEAKER_00: Yeah.
37:27
SPEAKER_00: So the men and women can and should be like really thinking about doing everything they can to optimize their health way upstream of of intercourse, you know, of the act of conception itself.
37:42
SPEAKER_01: Absolutely.
37:43
SPEAKER_01: But I also would pause on that to say that so many of our patients already are, yeah, and it's still not working.
37:50
SPEAKER_01: And and so then to feel like you are doing everything right, and the the plea I hear from so many patients is, but I'm the healthiest I've ever been, and I exercise every day and I'm doing everything right.
38:03
SPEAKER_01: And even with optimal conditions, infertility is a disease, and it comes down to the biology, the egg and the sperm and the uterus.
38:10
SPEAKER_01: And so there's so much planning and preparation we can do.
38:13
SPEAKER_01: And I think there can also be so much pressure then to say, you know, I should be doing all of these things preconception, and it's, you know, I should be going to all of these supplemental visits and taking all of these the untested supplements.
38:29
SPEAKER_01: And so I think the risk is that we over-control.
38:33
SPEAKER_00: Yeah, and I guess the same applies the other way.
38:35
SPEAKER_00: You know, people can have perfectly healthy offspring when they're not doing all of those things right.
38:42
SPEAKER_00: And like we can only stack the deck and we shouldn't feel guilty if you know if you hadn't optimized for that and you get pregnant and something happens, right?
38:49
SPEAKER_00: Like we can't, we we don't have that full control.
38:53
SPEAKER_00: Or we can only do what we can do.
38:54
SPEAKER_01: It's so complex.
38:55
SPEAKER_01: Yeah, it is so complex.
38:56
SPEAKER_00: Uh let's get practical for for for those listening who this is top of mind for.
39:04
SPEAKER_00: You know, we we talk about lifestyle all the time, and you know, we just reference some of those things that we can be doing to optimize for metabolic health.
39:11
SPEAKER_00: Do we have any data on some of these other big pillars of lifestyle like exercise and sleep and stress management?
39:17
SPEAKER_01: So interestingly, caloric restriction.
39:19
SPEAKER_01: So let's talk about nutrients again.
39:22
SPEAKER_01: So there are really compelling data linking caloric restriction and ovarian uh, you know, follicle preservation.
39:32
SPEAKER_01: And so when we look at animals that are calorically restricted 20 to 40 percent, you see preservation of the primordial follicle pool.
39:39
SPEAKER_03: Is that right?
39:39
SPEAKER_01: Yes.
39:40
SPEAKER_01: And for the same reason that we're seeing that in rapamycin and in mTOR inhibitors, because mTOR inhibitors are dietary mimetics, and so we're really mimicking what's happening in caloric restriction, but with a medication.
39:53
SPEAKER_01: And so caloric restriction certainly is something that someone could try.
39:58
SPEAKER_01: But I would, I would warn that A humans are not very good at it.
40:03
SPEAKER_01: You know, it's a hard thing to, um, and I'm sure you have, you know, you could you could speak for hours about this, but um, you know, it's a hard thing to maintain.
40:14
SPEAKER_01: And it's also, you know, if you're also trying to optimize pre-pregnancy, probably not the best scenario to be um putting yourself in a deprivation state.
40:23
SPEAKER_01: And so it's, you know, just as with everything, this is very nuanced.
40:28
SPEAKER_01: And so, you know, mTOR and, you know, all these pathways, they're not on-off switches.
40:32
SPEAKER_01: You want to maintain function, um, but be very, you know, cautious in how heavily activated or uh or turned off it is.
40:42
SPEAKER_01: And so I would say, you know, certainly the way to think about nutrients is, you know, whole foods and healthy diets and all the things that we would otherwise tell someone to do.
40:51
SPEAKER_01: I think that the other, you know, practical advice, um, you were asking about nutrients and exercise, exercise, sleep, sleep.
41:00
SPEAKER_01: I think those core pillars apply for every organ system.
41:05
SPEAKER_01: And so the same applies for the ovary.
41:07
SPEAKER_01: And, you know, when you're in situations of extreme stress, for example, um, physically, someone is a, you know, a ballerina or in a an environment where they are um, you know, exercising potentially so much that they are amenorrhec.
41:29
SPEAKER_01: So really intense runners or dancers, you know, and you become amenorrheic, that's a signal because, you know, you that the the period isn't the problem.
41:41
SPEAKER_01: It's okay that you're not getting a period in that case.
41:44
SPEAKER_01: The problem is that it's telling us that your ovaries aren't producing estrogen and that there's not enough estrogen to thicken the lining of the uterus, and you're not ovulating to then have a withdrawal bleed.
41:55
SPEAKER_01: And so that lack of a period is a signal that your ovaries aren't producing estrogen, and that's a signal that your bones are at risk and your heart is at risk and your brain is at risk.
42:05
SPEAKER_01: And so all of those signals are important.
42:08
SPEAKER_01: And so practical advice would be, you know, are you getting regular periods?
42:13
SPEAKER_01: And, you know, if you are not because you're on a birth control pill, well, then that's probably okay because the birth control pill is giving you estrogen and protecting your uterus.
42:22
SPEAKER_01: Um, and then I think other, you know, other menstrual abnormalities are also really good reflections of what's going on.
42:29
SPEAKER_01: If someone is having uh really heavy periods, that can be, that can be a warning sign that we need to look for some other structural reason or a precancerous lesion.
42:41
SPEAKER_01: And, you know, you know, one example is, you know, endometrial hyperplasia or endometrial cancer, which happens in people who have unopposed estrogen because they aren't ovulating regularly.
42:51
SPEAKER_01: So women who have PMOS and they don't ovulate regularly, they're producing estrogen, thickening their lining of their uterus, and it can overgrow and cause cancer.
42:59
SPEAKER_01: And so again, all of these like, you know, just normal mencies is a good sign that there's some kind of clear communication happening between the brain and the ovaries and that things are happening as they're supposed to be happening.
43:14
SPEAKER_00: I I read uh a bit of take this with a pinch of salt.
43:19
SPEAKER_00: I read uh about a study of women who gave birth much later in life were much had a much higher likelihood of living to a hundred and beyond.
43:31
SPEAKER_00: Like and it was a crazy number of multiples.
43:34
SPEAKER_00: I'm assuming that is some kind of correlation and not causation, but can you speak to that maybe?
43:39
SPEAKER_01: Yes, it is real and it's so fascinating.
43:42
SPEAKER_01: It is the it is not so it is not that they had a baby when they're 45.
43:46
SPEAKER_01: So it's not that the women who now are using donor eggs at 50 are going to live longer because they have a baby at 50.
43:53
SPEAKER_01: It's in those studies, it's that those women had ovaries that were functioning for longer.
43:59
SPEAKER_00: Got it.
44:00
SPEAKER_01: And they were capable of having babies later in life.
44:03
SPEAKER_01: And so it's, it was a proxy for their long-term systemic health.
44:08
SPEAKER_04: Yeah.
44:08
SPEAKER_01: But that is why the ovary is a lever.
44:11
SPEAKER_01: You know, we, if we can think about ways to identify women at risk of, you know, early ovarian functional decline, and we find those women, and then we we don't just educate them about their options and freeze eggs, but we find them and we think about interventions that can slow the aging of the ovary and narrow that hourglass and preserve primordial follicles, then we are potentially shifting the curve.
44:37
SPEAKER_03: Yeah.
44:38
SPEAKER_01: You know, and if we shift the curve even by a few years, that would have significant implications.
44:44
SPEAKER_01: Not necessarily for longevity.
44:46
SPEAKER_01: I don't think that, you know, I don't want to overstate what we would be able to do.
44:49
SPEAKER_01: And I certainly don't want to state that we're trying to help women have babies into their 70s or 80s, but we're really thinking, you know, if we can shift the curve of ovarian function and, you know, help my 41-year-old have a baby with her own eggs and not need to use eggs from an egg donor if she wants to use her own eggs.
45:07
SPEAKER_01: But also then that same person has ovarian function at 50 when she might have stopped having function at 48.
45:14
SPEAKER_01: Those two years, even though 48 to 50 doesn't seem significant, could change the trajectory of her cardiac aging.
45:21
SPEAKER_01: Yeah, and her health span, right?
45:22
SPEAKER_00: And we're see we see this far too large a gap with quality of life for women, more so even than men, that those latter years of optimizing for health span.
45:34
SPEAKER_00: Absolutely.
45:35
SPEAKER_00: Probably a big reason for that.
45:37
SPEAKER_01: Yes.
45:37
SPEAKER_01: Women live, you know, 25% more of their lives in poor health than men.
45:42
SPEAKER_01: And I'm sure you've heard that before.
45:44
SPEAKER_01: And I think hopefully we all have heard that before now.
45:47
SPEAKER_01: I think thankfully, this is part of the conversation.
45:49
SPEAKER_01: You know, we are having these conversations more regularly.
45:52
SPEAKER_01: I think there's like a clear understanding that this is a problem and this is a gap.
45:56
SPEAKER_01: And now we have to think about how do we fill this gap?
45:59
SPEAKER_01: You know, we have opportunities to study this.
46:03
SPEAKER_01: So if we think about like the real world opportunities, you know, my clinic is a living laboratory.
46:09
SPEAKER_01: You know, my patients are all kind of a natural experiment.
46:13
SPEAKER_01: The 30-year-old with a BRACA one diagnosis who has diminished ovarian reserve.
46:19
SPEAKER_01: She's going to have to remove her ovaries at 35 to decrease her risk of ovarian cancer.
46:24
SPEAKER_01: And we have this window where we can freeze eggs or embryos to help her have a baby, but she's going to go through surgical menopause.
46:32
SPEAKER_01: You know, how do we think about a studying that ovary once it's removed and understanding the role of BRCA on ovarian decline?
46:41
SPEAKER_01: And that's work that I'm working on right now, actually, is looking at women who have BRACA mutations and looking at their ovaries.
46:46
SPEAKER_01: And I've found some really interesting markers of early fibrosis in these ovaries of BRCA-1-mutated women.
46:53
SPEAKER_01: And this suggests, you know, could there be, is are there interventions that we can apply early so that we can protect ovarian function for as long as possible?
47:03
SPEAKER_01: And, you know, this is the case with every single one of my patients, even the patient who is, you know, coming in with what seems like straightforward infertility, there is often there are layers there that we uncover.
47:14
SPEAKER_01: And, you know, and then that person is going to the IVF laboratory to retrieve eggs.
47:21
SPEAKER_01: And when we are doing an egg retrieval, we are, we are retrieving so much tissue that we can study.
47:26
SPEAKER_01: And so, in a typical egg retrieval procedure, you know, just to kind of zoom out for a second, we stimulate the ovaries for 10 to 12 days.
47:33
SPEAKER_01: We retrieve eggs in a surgical procedure.
47:36
SPEAKER_01: And it's a little needle that goes into the ovary and we suction out the fluid that contains the egg.
47:40
SPEAKER_01: And inside that fluid, you know, there's the cumulus ocyte complex.
47:43
SPEAKER_01: So it's the egg surrounded by cumulus cells.
47:45
SPEAKER_01: There are all of these other cells that we are collecting and typically discarding.
47:49
SPEAKER_01: And, you know, again, in this living laboratory that we have, we have women who are young with very low ovarian reserve, and we have women who are 44 with a really high ovarian reserve.
48:00
SPEAKER_01: And I'm really interested in these extremes.
48:02
SPEAKER_01: You know, what is driving this early ovarian aging?
48:05
SPEAKER_01: What is driving this, you know, ovarian superaging, as I like to call it?
48:09
SPEAKER_01: Because it's the this really compelling phenotype.
48:11
SPEAKER_01: And so I'm studying those, you know, the kinases that are activated in those women and and you know, potentially identifying targets because there's just there are, you know, these, these, you know, we have these tissues and we just need the funding to study this so that we can answer these questions.
48:27
SPEAKER_00: And we're I I think I'm right in saying we're really just playing catch up with the with the science for this particular field, right?
48:35
SPEAKER_00: Because it's been embarrassingly underfunded for so long.
48:38
SPEAKER_01: Yes, we are decades behind.
48:40
SPEAKER_01: And when we think about the parallels, so you know, there's for you know, focusing on the cancer question for a second, because I think it's a good model of accelerated ovarian aging.
48:52
SPEAKER_01: But if you think about all the other organ systems that you protect in someone who's going through cancer treatment, there are drugs to protect the the heart.
48:59
SPEAKER_01: So cardioprotective, there are drugs for people whose, you know, whose kidneys are at risk, there are nephroprotective drugs.
49:06
SPEAKER_01: There are so many drugs that are specifically meant to protect organ systems during the toxic effects of chemotherapy.
49:14
SPEAKER_01: And all we have for ovaries is a drug called a GNRH agonist, canatropin releasing hormone agonist.
49:20
SPEAKER_01: And it's the idea is to kind of shut down the um pituitary, you shut down the hormones to the ovary so you don't have ovary follicles growing during chemotherapy, but you're only targeting the growing follicles.
49:31
SPEAKER_01: You're not targeting that pool, that upper chamber of the hourglass.
49:34
SPEAKER_01: And so, and and that has been used for 30 years and it's still considered experimental because we we don't have enough data to say it actually makes a meaningful difference.
49:44
SPEAKER_01: And so, um, and it's a little controversial, you know, some people still, you know, still use it because maybe it's better than nothing.
49:49
SPEAKER_01: But the point is we have so much catching up to do.
49:53
SPEAKER_00: And do those drugs exist for the other organs because they affect men as well?
49:58
SPEAKER_01: I mean, I yeah, I have to think that that part of it is some research has been prioritized over others.
50:06
SPEAKER_01: And and not to make this a, you know, a conversation around, you know, sexism and research, but there's certainly when we look at funding to women's health, it's really narrow.
50:18
SPEAKER_01: And I think part of the problem is that we've called it women's health.
50:22
SPEAKER_01: And we've called it, you know, we've anything that affects women, we've just kind of lumped into women's health.
50:28
SPEAKER_04: Yeah.
50:28
SPEAKER_01: There are there are ways to kind of tease that out.
50:31
SPEAKER_01: There's, you know, disorders that only affect women.
50:33
SPEAKER_01: So endometriosis, fibroids, chronic pelvic pain related endometriosis, those specifically are women's health disorders.
50:40
SPEAKER_01: But then there's all of the other impacts, you know, in a woman's body, but women age differently.
50:47
SPEAKER_01: And cardiovascular disease is the number one killer of women, but we're not funding that in the way that we should because it's kind of lumped into women's health in this little tiny pocket.
50:59
SPEAKER_00: I it's good to see that as shifting, not quick enough, but you know, there are it is changing.
51:06
SPEAKER_01: It is changing.
51:07
SPEAKER_01: And we have, you know, generous people like Melinda Gates, who is identifying that this is a tremendous problem and that, you know, this is a priority and that is going to move the needle.
51:19
SPEAKER_01: And so I think the more we identify um, you know, partners who care deeply about this issue and recognize that this is not a fertility problem.
51:30
SPEAKER_01: This is a this is a how do we live healthier healthier for longer problem.
51:34
SPEAKER_01: For a longer problem.
51:35
SPEAKER_00: Hey, if there were any generous people listening, what would be um a question that you would love funding to answer?
51:43
SPEAKER_01: I would love to study.
51:45
SPEAKER_01: I would love to be able to prospectively study women as their ovaries are aging in real time.
51:52
SPEAKER_01: And, you know, we have all these pieces to the puzzle.
51:55
SPEAKER_01: We have the, we have phenotypes of women who we know are aging earlier than expected, their ovaries are aging earlier.
52:02
SPEAKER_01: Um, we have opportunities to look at all of these other phenotypic markers of aging.
52:08
SPEAKER_01: We are not very good yet at putting those pieces together.
52:10
SPEAKER_01: Yeah.
52:10
SPEAKER_00: Well, you're speaking about this this morning.
52:12
SPEAKER_01: Yes.
52:13
SPEAKER_01: We need to find, we need to link all these data points.
52:15
SPEAKER_01: And so we need prospective studies of women whose ovaries are aging in real time with, you know, using, you know, identifying biomarkers, using the available biomarkers, and then also using the available available tissues that we have.
52:30
SPEAKER_01: The eggs, the, you know, cumulus cells around the eggs, the ovarian tissue at the time of oophorectomy.
52:35
SPEAKER_01: We have all of these pieces and we have, you know, all of these silos and people who are operating um, you know, independently.
52:43
SPEAKER_01: And I think like this just needs to be a unified effort.
52:46
SPEAKER_01: And we're getting there.
52:47
SPEAKER_01: I think there are a lot of people who care deeply about this.
52:49
SPEAKER_01: And I'm excited.
52:50
SPEAKER_01: It really is a it's an exciting time to be in reproductive medicine.
52:54
SPEAKER_00: I agree.
52:54
SPEAKER_01: And, you know, it's not just reproductive medicine, it's an exciting time to be part of preventive health care and thinking about how do we educate our physicians better and so that we are learning in medical school, um, you know, the role of the ovary.
53:09
SPEAKER_01: Um, because I will say that that is something that, you know, having been in a medical school and a residency program that was a top residency program, you know, we use you still focus very little on the function of the ovary and the role of the ovary after menopause and what happens when the ovary is aging.
53:28
SPEAKER_01: And so these are all questions that I think need to start from the ground up.
53:31
SPEAKER_01: How do we educate physicians and scientists?
53:33
SPEAKER_01: How do we educate our children?
53:35
SPEAKER_01: Exactly.
53:35
SPEAKER_01: I know.
53:36
SPEAKER_00: Can I ask you a question on these rapologs, rapamycin specifically, because I think you know, I'd be remiss to not bring that up.
53:44
SPEAKER_00: Yeah, we we when we were chatting this morning before we came on air, I I referenced, you know, we get this question a lot.
53:52
SPEAKER_00: Uh, gyro protectors in general, and and these or seem to be very promising um molecules or therapeutics that, at least in some animal models, have shown promise for improving health span and or lifespan.
54:05
SPEAKER_00: Rapamycin, there was a there was an article not so long ago, and I won't name the publication, but the headline was Miracle Molecule Extends Lifespan by 50%.
54:16
SPEAKER_00: And I think I've referenced this on a previous episode.
54:19
SPEAKER_00: You know, if I am reading that, I want that, I want that.
54:22
SPEAKER_00: It sounds great, like I would love that.
54:25
SPEAKER_00: Um but and the reality was it did extend lifespan, but in some mice, right?
54:32
SPEAKER_00: And some of them I think went blind, some got cancer, some just died.
54:36
SPEAKER_00: You know, how far off are we from being able to say with any degree of confidence that these things could work in humans?
54:43
SPEAKER_01: I think we have to be so cautious of the hype.
54:45
SPEAKER_01: And you're absolutely right.
54:47
SPEAKER_01: I think that we are, you know, we have missed so much for so long that there are people who are trying to fill in the gaps of where we are with preclinical work versus where we want to be with translation and bringing this to clinics.
55:01
SPEAKER_01: And so in the middle, you get a lot of hype.
55:04
SPEAKER_01: And so I think the first thing is we have to we have to be cautious and and tread carefully.
55:10
SPEAKER_01: And, you know, we know that yeast and mice and rhesus macaques are not humans.
55:15
SPEAKER_04: Yeah.
55:15
SPEAKER_01: And the problem is there are, you know, there is a a big gap in in what's funded in the middle.
55:24
SPEAKER_01: Yeah.
55:24
SPEAKER_01: And so we have a lot of really compelling preclinical data in animal models and in cells.
55:30
SPEAKER_01: And we have a lot of interest in applying these things clinically, but there aren't people who are really funding those mechanisms to take something from, you know, preclinical to translating it.
55:41
SPEAKER_01: And those are really expensive studies to do.
55:42
SPEAKER_00: Yeah.
55:43
SPEAKER_00: Frighteningly.
55:44
SPEAKER_01: Yes.
55:44
SPEAKER_01: And the problem too is something like rapamycin, it's off-patent.
55:48
SPEAKER_01: There are very few people who are going to fund that study because it will likely not be very lucrative for a pharmaceutical company to fund a study of an off-patent drug.
55:59
SPEAKER_03: Yeah.
55:59
SPEAKER_01: And so, you know, then it takes identifying new molecules and, you know, creating new drugs.
56:05
SPEAKER_03: Yeah.
56:05
SPEAKER_01: And so this is where I actually get really excited about repurposing and thinking about the drugs that are available and then doing research a little bit differently.
56:13
SPEAKER_01: So thinking about drugs, not to say metformin is the, you know, is going to be the answer, but drugs like that that are clinically available and safe and, you know, and the, you know, the RAPILALGs that are used in the oncology literature and they're already clinically used and they're FDA approved.
56:29
SPEAKER_01: You know, yes, you may not get um interest from a big pharmaceutical company to fund that study, but maybe you can do it in a way that is less expensive because these drugs are just not that expensive.
56:40
SPEAKER_01: So, but we have to do the studies, you know, and this is where there is a lot of hype.
56:44
SPEAKER_01: And we're never going to know the answer until we do the studies and do it in a controlled way.
56:50
SPEAKER_01: And right now there are a lot of people doing a lot of N of one studies and taking various doses of drugs and biohacking.
56:57
SPEAKER_01: And the risk is we don't really, you know, we're not going to learn from that.
57:01
SPEAKER_01: And if it, and I think we have to know what our surrogate endpoints are.
57:05
SPEAKER_01: And I think one example of this is in ovarian aging, there's excitement about some things like platelet-rich plasma and you know, PRP.
57:14
SPEAKER_01: And, and, you know, people are using this in all sorts of organ systems, but when they're using it in the ovary, they're injecting into directly into the ovary.
57:23
SPEAKER_01: And there are a few problems with this.
57:25
SPEAKER_01: And so if you are injecting something directly into the ovary, you are mechanically stimulating that ovary.
57:31
SPEAKER_01: And it's actually activating some of those pathways we talked about.
57:35
SPEAKER_01: MTOR being one of them, but hippo signaling being another one, and you're activating follicles.
57:39
SPEAKER_01: And so maybe if you are seeing surrogate endpoints that look reassuring, like an elevated AMH, you're just activating follicles.
57:48
SPEAKER_01: And, you know, is that actually going to be useful?
57:52
SPEAKER_01: Certainly not for long-term ovarian function, because maybe you're hyperactivating follicles and will lose reserve.
58:00
SPEAKER_01: And so, and there is, I think, just to kind of make that subtle point, when we think about rapamycin and other drugs like this in the ovarian aging space, we have to be very careful because I think some people are excited and they want to just apply it to patients who are trying to get pregnant.
58:14
SPEAKER_01: If you use a drug like that and someone who's actively trying to get pregnant, often you are suppressing menses.
58:19
SPEAKER_01: Like you are going to be amenorrheic, you are shutting down follicle activation in the short term.
58:24
SPEAKER_01: And so that's actually going to be counter to your goal of someone trying to actively get pregnant.
58:29
SPEAKER_01: But I think that they, you know, the connections are a little bit more superficial that are being made.
58:35
SPEAKER_01: And so we're not thinking about what this is actually doing long term.
58:37
SPEAKER_01: And so ideally, you're doing something that can be administered at a younger age to be protective.
58:43
SPEAKER_01: And then when you are ready to use your ovaries, then you have function of the ovaries at a later time.
58:49
SPEAKER_01: But we certainly can't think about applying these in people who are actively, you know, trying to.
58:54
SPEAKER_00: Call, this is the really frustrating thing, though, is that people do.
58:57
SPEAKER_01: Right.
58:58
SPEAKER_00: Right.
58:58
SPEAKER_00: And and I I I always feel like I sound like such a killjoy when I'm because I do think there is so much promise in so many of them.
59:06
SPEAKER_00: But it's really frustrating when you see a, you know, an expert or a professional taking that leap before we have any actual real proof that it's safe, right?
59:16
SPEAKER_00: And and I think we can apply this across every domain of of health research.
59:21
SPEAKER_00: But you know, that is it's annoying for everyone because it's because we what when we look at these things as consumers, we want it to be true, right?
59:31
SPEAKER_00: I want there to be a molecule that can help add decades of healthy years to my life.
59:35
SPEAKER_00: And so it's I'm much more likely to then try it.
59:38
SPEAKER_03: Right.
59:38
SPEAKER_00: And but there's so many downstream things that could go wrong.
59:42
SPEAKER_00: And and I think we see we see these claims everywhere in media.
59:48
SPEAKER_00: And I I I think there's that one for you specifically, like ovarian rejuvenation.
59:54
SPEAKER_01: This term, like on earth.
59:58
SPEAKER_01: I could not agree with you more.
59:59
SPEAKER_01: It is harder to practice restraint.
1:00:01
SPEAKER_01: And and that is where we have to be really cautious in this field because we need to be, we need to be doubly cautious when we are thinking about something that impacts, in my mind, something that impacts the ovaries and potentially impacts future generations.
1:00:16
SPEAKER_01: Now, ovarian rejuvenation, I think, is such a misleading term because you can't rejuvenate the ovaries.
1:00:22
SPEAKER_01: There is a non-renewable source of follicles.
1:00:25
SPEAKER_01: By very definition.
1:00:26
SPEAKER_01: By very definition, you cannot rejuvenate the ovary.
1:00:29
SPEAKER_01: When you are rejuvenating the ovary using PRP or whatever is being applied, you might be activating follicles.
1:00:40
SPEAKER_01: And so, again, just getting kind of brief activation, um, but not doing anything about long-term function.
1:00:46
SPEAKER_03: Yeah.
1:00:47
SPEAKER_01: And there is risk.
1:00:48
SPEAKER_01: You're injecting something into the ovary.
1:00:50
SPEAKER_01: We have seen case reports of really severe infections from injecting PRP into the ovary.
1:00:58
SPEAKER_01: And that can compromise someone's fertility and someone's ovarian function permanently.
1:01:03
SPEAKER_01: So these are not without risk.
1:01:04
SPEAKER_01: And when you talk about something like rejuvenation, like what they are talking about is really downstream.
1:01:10
SPEAKER_01: The problem has already happened.
1:01:12
SPEAKER_01: And so you already have an ovary that has few follicles, that's fibrotic.
1:01:17
SPEAKER_01: And so anything you do at that stage will not have a tremendous impact.
1:01:21
SPEAKER_01: We really need to be thinking further upstream and preventatively.
1:01:25
SPEAKER_01: And that's where, you know, we think about these drugs to prevent follicle activation, potentially to prevent fibrosis, um, to prevent accumulation of debris in the ovary so that we are not in a position where we then need to rely on rejuvenation, because those strategies really are um very questionable.
1:01:42
SPEAKER_00: And it's so difficult, right?
1:01:43
SPEAKER_00: Because if you are desperate, then correct.
1:01:48
SPEAKER_00: I think it that I think that's where we're sort of preying on people's desperational urgency.
1:01:53
SPEAKER_00: And I think that's really unfair.
1:01:54
SPEAKER_01: It's really unfair.
1:01:55
SPEAKER_01: And I think especially in the fertility space, it's hard because there is something that is primal for people who want to start a family.
1:02:05
SPEAKER_01: And you can't explain it until you're in it.
1:02:07
SPEAKER_03: Yeah.
1:02:07
SPEAKER_01: Um, and I've been there and I've gone through all the fertility treatments and IVF, and so I know what that feels like.
1:02:12
SPEAKER_01: And, you know, patients will do anything.
1:02:15
SPEAKER_01: They are, they truly, they, they are pleading with you for anything that will help them achieve their goal.
1:02:22
SPEAKER_01: And so we have to be the ones to practice restraint and say, this is where this is what the data does tell us, and this is where we have to be hesitant.
1:02:29
SPEAKER_01: And I do not recommend this.
1:02:31
SPEAKER_01: And so, you know, but yes, there is a lot of pressure to move things forward quickly because it's, you know, there's a lot of patient interest.
1:02:39
SPEAKER_00: Yeah.
1:02:39
SPEAKER_00: It's urgent and important.
1:02:41
SPEAKER_01: Yes.
1:02:42
SPEAKER_00: Cara, on that note, is there anything that you get asked that you really wish people wouldn't have to keep asking you?
1:02:54
SPEAKER_01: That is uh that's the key question because every conversation I have with patients is that exact question.
1:03:01
SPEAKER_01: It is I I go through the biology of the ovary, the kind of the biology of reproduction.
1:03:08
SPEAKER_01: So I call it, you know, adult sex ed or reproductive biology 101.
1:03:11
SPEAKER_01: And and patients afterwards often say, gosh, this is the first time I've ever really understood my biology.
1:03:17
SPEAKER_01: And I wish I knew this because it makes so much sense.
1:03:20
SPEAKER_01: And I think that there is um a lot of fear in the unknown.
1:03:24
SPEAKER_01: And so when you understand your body, you have a little bit more agency and you can uh make some informed decisions and empower decisions.
1:03:33
SPEAKER_01: And so understanding ovarian uh function and understanding the decline of the ovary is really empowering for people when they say, Oh gosh, so I've got this limited pool of eggs and I have this window.
1:03:44
SPEAKER_01: My ovaries will fail by 51.
1:03:47
SPEAKER_01: That's the average age of menopause.
1:03:49
SPEAKER_01: And that's really best case scenario.
1:03:51
SPEAKER_01: And 10 years leading up to menopause is when women have a really difficult time getting pregnant.
1:03:56
SPEAKER_01: That's what we call perimenopause.
1:03:58
SPEAKER_01: We also call it diminished ovarian reserve.
1:04:00
SPEAKER_01: And that window, you know, that's 40 or 41.
1:04:03
SPEAKER_01: And if someone's gonna go through menopause at 38, because maybe their mom went through menopause at 48, which didn't seem like that big of a deal, but maybe 48 is their age of menopause.
1:04:12
SPEAKER_01: By 38, they're gonna have a lot of difficulty conceiving.
1:04:15
SPEAKER_01: And when I was in fellowship, was the my first year of fellowship was the year that egg freezing lost its experimental label.
1:04:23
SPEAKER_01: So we were doing, and I was at NYU, we were doing a lot of egg freezing.
1:04:26
SPEAKER_01: It was one of the early centers to really, to um, to really push egg freezing forward.
1:04:31
SPEAKER_01: And the average age of patients that we were seeing was 38.
1:04:35
SPEAKER_01: And so these are people who they are taking proactive steps, they are doing everything they can to protect what they think is protecting their fertility, and all we're getting is a small cohort of eggs and doing nothing to preserve their long-term ovarian function.
1:04:49
SPEAKER_01: And so if you have someone who is 30 or 25 and understands that they've got this window, and maybe they're gonna have a 10-year window during which they can actually conceive with their own eggs.
1:05:00
SPEAKER_01: And then they also know that after they finish building their family, their ovaries will predictably decline.
1:05:08
SPEAKER_01: They will have symptoms.
1:05:09
SPEAKER_01: This will increase their risk of heart disease and stroke, which will be their leading cause of death.
1:05:15
SPEAKER_01: And they have a risk of fracture and that might make them immobile, or they'll live the end of their life with a hip fracture.
1:05:23
SPEAKER_01: If they know all of those things prospectively, and then they know at 25 or 30 that they're at a greater risk because their ovarian reserve is lower, you better believe that person will want to do something about it.
1:05:33
SPEAKER_01: And what kills me right now is when we have that prospective view, and I can really kind of predict, and it's a lot of pattern recognition at this point to say, I see all these people and I know what's going to happen to your ovaries and um and what that's going to feel like and look like.
1:05:46
SPEAKER_01: If, you know, what's really hard is to say, but we don't actually have anything that we can do about it.
1:05:51
SPEAKER_04: Sure.
1:05:51
SPEAKER_04: Yeah.
1:05:52
SPEAKER_01: And so, you know, I will talk to my patients about the, you know, follicle activation and the research and how.
1:06:00
SPEAKER_01: We think there might be this compelling option at some point in the future, but we don't have anything now.
1:06:04
SPEAKER_01: And that's a really hard conversation to say we we actually don't have anything that we can do besides watching and waiting.
1:06:11
SPEAKER_00: Knowledge is power, right?
1:06:13
SPEAKER_00: The earlier we know we have agency.
1:06:14
SPEAKER_01: Yes.
1:06:15
SPEAKER_00: What what are some of the exciting you mentioned, you know, exciting alternatives or solutions in the future that uh are making you feel most optimistic?
1:06:26
SPEAKER_01: Yes.
1:06:26
SPEAKER_01: So um I think that there's a lot going on in basic science labs to understand the environment of the ovary.
1:06:35
SPEAKER_01: And so um things like ovarian organoids and artificial ovaries.
1:06:40
SPEAKER_01: And um, this really comes back to the question of, you know, if you've got, let's say we have a young child who is seven and they're too young to freeze eggs, there's nothing that we can do to protect their ovaries.
1:06:52
SPEAKER_01: I would love to be able to give them a drug during their treatment or during, you know, to, you know, if they're going through chemotherapy, I'd love to give them a drug to protect their ovaries, but we don't have that.
1:07:00
SPEAKER_01: But one option is ovarian tissue freezing.
1:07:02
SPEAKER_01: So you can remove an ovary.
1:07:04
SPEAKER_01: So you take out that whole ovary, you essentially fillet, for lack of a better word, open up that ovary and remove that middle section, because the middle section, the medulla of the ovary, is less important.
1:07:17
SPEAKER_01: And it's, I mean, it's not not important, but the eggs live in the outer aspect of the ovary.
1:07:21
SPEAKER_01: And you then have that ovarian cortex, the outer layer, and that's where all the egg cells live.
1:07:26
SPEAKER_01: And you can freeze those little pieces of tissue and at a later time implant those pieces of tissue back into that person when they're older, and and and potentially those ovulate and can make babies and can produce hormones and so can give them back their own endocrine function.
1:07:44
SPEAKER_01: So that is very promising.
1:07:46
SPEAKER_01: And that is, you know, that is being done clinically.
1:07:48
SPEAKER_01: And we partner with a children's hospital.
1:07:50
SPEAKER_01: And so I have a lot of kids who are who are having this done and now coming back and saying, I want to put this tissue back in.
1:07:55
SPEAKER_01: And so we're gonna learn a lot about what happens when you put that tissue back in.
1:07:59
SPEAKER_01: And Europe has been really um ahead of where we are with ovarian tissue freezing.
1:08:04
SPEAKER_01: So we have learned a lot from Europe and Israel because of all their work in this, but we are we're lagging, but hopefully we'll have some data soon too.
1:08:12
SPEAKER_01: But so there's that.
1:08:13
SPEAKER_01: But then you have some people who have ovarian tissue frozen and you can't put that ovary back into them.
1:08:18
SPEAKER_01: You can't put that tissue back into their body.
1:08:20
SPEAKER_01: What if we could grow that tissue in the laboratory and create follicles in the lab and create an ovarian endocrine environment in the lab?
1:08:27
SPEAKER_01: So there are some really interesting um, you know, directions that this could go in terms of recreating the environment of the ovary, growing follicles, growing eggs, growing the hormone-producing cells outside of the body.
1:08:44
SPEAKER_00: With pluripotent stem cells?
1:08:46
SPEAKER_01: Yep.
1:08:46
SPEAKER_01: Um, so yes, there's some interesting, yeah, stem cell work being done, um, and and these like artificial organoids to really recreate this um environment.
1:08:56
SPEAKER_01: So there's that.
1:08:57
SPEAKER_01: Um, but again, like I, you know, I really am excited about the idea of pharmacologic agents to protect the ovaries long term.
1:09:04
SPEAKER_01: I think there's, you know, we have to figure out how to target the ovary without targeting, you know, the entire system.
1:09:11
SPEAKER_01: And so, you know, potentially drugs that are directed to the ovary rather than systemically active drugs.
1:09:19
SPEAKER_01: Um, and I think that there's a lot that we are doing to educate.
1:09:24
SPEAKER_01: And I think that is going to be an important piece is just at least understanding, you know, helping people understand their biology so that they can make empowered choices.
1:09:33
SPEAKER_00: And do you think on that note that we will develop, you know, maybe uh a panel of blood-based biomarkers or you know, omics testing that could then speak to some of the um, you know, prevention upstream of these things?
1:09:48
SPEAKER_00: Because that would that combined with the education feels like the the key most realistic thing that we can do soon.
1:09:54
SPEAKER_01: Absolutely.
1:09:55
SPEAKER_01: Because right now, you know, all we have is right AMH, estrogen, FSH.
1:09:59
SPEAKER_01: And if you're measuring an FSH, follicle stimulating hormone is the hormone, and just to um, sorry, to kind of be in the same, you know, speak the same language, when you are evaluating ovarian reserve, what you're really checking is AMH, so the hormone that's produced by the ovaries, by the granulosa cells, estrogen, and follicle stimulating hormone.
1:10:16
SPEAKER_01: And follicle stimulating hormone is secreted by the pituitary and it stimulates a follicle and it causes follicles to grow.
1:10:22
SPEAKER_01: And that is gonna cause estrogen to rise.
1:10:25
SPEAKER_01: And then, you know, in a typical menstrual cycle, that rise in estrogen causes glutenizing hormone and you ovulate.
1:10:29
SPEAKER_01: And so the follicle stimulating hormone gives us a really good sense of how responsive or resistant the ovary is.
1:10:36
SPEAKER_01: And as that AMH drops and you have fewer follicles, that FSH starts to rise because the ovary is more resistant.
1:10:42
SPEAKER_01: It's not responding to the FSH, the hormone that the brain is sending out.
1:10:45
SPEAKER_01: And so we're getting these like functional markers to give us a sense of how things are working.
1:10:49
SPEAKER_03: Yeah.
1:10:49
SPEAKER_01: But that's it.
1:10:50
SPEAKER_01: That's the extent of what we can really explore right now.
1:10:54
SPEAKER_01: And so there are some studies going on at my center with some of my colleagues looking at ultrasound measurements to look at stiffness of the ovaries.
1:11:03
SPEAKER_01: But we do need, you know, serum biomarkers.
1:11:05
SPEAKER_01: And that's part of why I'm excited about understanding, you know, the kinases of reproductive young and reproductive the older ovaries.
1:11:13
SPEAKER_01: And there are some genetic mutations that we're studying.
1:11:16
SPEAKER_01: So I have a panel of patients who have these hereditary cancer syndromes.
1:11:19
SPEAKER_01: They actually seem to have extended extended ovarian function.
1:11:23
SPEAKER_01: And so looking at the cumulus cells of their ovaries and doing some sequencing, I think we're gonna, we're gonna, we're doing a lot of proxy work to figure out what is associated with early ovarian aging and accelerated ovarian aging.
1:11:36
SPEAKER_01: Um, and I think from some of that work, we can better understand, you know, how to target this.
1:11:40
SPEAKER_01: And there's some really exciting work being done looking at AMH.
1:11:44
SPEAKER_01: Um, so you know, modulating AMH to preserve ovarian function.
1:11:49
SPEAKER_01: So there's this whole kind of world of work being done to target the modifiers.
1:11:55
SPEAKER_01: Yes, there's vascular ovarian aging, there's immune therapies, there's so much, and it just needs to be funded.
1:12:01
SPEAKER_00: I'm gonna ask, there's been a question in the back of my mind since we started, and I'm and I wasn't gonna ask it, but I feel like I have to.
1:12:08
SPEAKER_01: Please do.
1:12:10
SPEAKER_00: This rapid drop in follicles that you have from you know, even pre-birth.
1:12:21
SPEAKER_00: Is there no way we can just keep hold of some of that?
1:12:24
SPEAKER_00: Is there no way we can just stop that rapid drop so that by the time you you know go through puberty that you just have a higher amount of sand in the top of that hourglass?
1:12:33
SPEAKER_01: Well, that's the million-dollar question.
1:12:36
SPEAKER_01: That's what I want to do.
1:12:38
SPEAKER_01: So that is where targeting the processes that activate from that primordial follicle stage to the primary stage, we need to cut it off before it begins.
1:12:51
SPEAKER_01: And so that's where the mTOR pathway could be a lever, because essentially you are stopping that activation.
1:12:59
SPEAKER_01: But you're absolutely right, that is what we need to do.
1:13:02
SPEAKER_00: So it wasn't a stupid question.
1:13:03
SPEAKER_01: It was a brilliant question.
1:13:04
SPEAKER_01: It's exactly the question.
1:13:06
SPEAKER_00: Just for the win.
1:13:07
SPEAKER_00: Okay, so Cara, what I like to do, uh, and particularly for this episode, I have two of these today because I like to have the audience ask some questions and because quite often what happens is I finish the episode and I'm like, damn, I didn't ask something, or someone will leave a comment reminding me how foolish it was for me not to.
1:13:28
SPEAKER_00: So I haven't seen these.
1:13:29
SPEAKER_00: Okay.
1:13:29
SPEAKER_00: And so this is gonna be me looking at them for the first time.
1:13:33
SPEAKER_00: Does freezing my eggs in my 20s or 30s actually guarantee I'll be able to have a baby later?
1:13:39
SPEAKER_00: I suspect I know the answer there, but no.
1:13:42
SPEAKER_01: And that's a but that's a great question because I think people think of this as an insurance policy.
1:13:47
SPEAKER_00: Yeah.
1:13:47
SPEAKER_01: But insurance policies, if you qualify, they you know, you get reimbursed.
1:13:52
SPEAKER_01: This is a gamble, it's a biological gamble.
1:13:55
SPEAKER_01: And it depends on how many eggs you freeze and the age at which you freeze, but we have cases where someone freezes very few eggs and has multiple children from them or freezes many and is not successful.
1:14:07
SPEAKER_01: And so we have, you know, ways to think about the attrition of the eggs, how many are going to survive, how many are going to fertilize.
1:14:12
SPEAKER_01: And we do a lot of that counseling up front.
1:14:14
SPEAKER_01: But I think the reality is that a lot of people still walk away feeling like, okay, great, now I'm I'm done and this is going to work.
1:14:21
SPEAKER_01: And it's not a guarantee.
1:14:22
SPEAKER_01: So, you know, we need we need more than just egg freezing.
1:14:25
SPEAKER_01: But, you know, it's a great tool.
1:14:26
SPEAKER_01: And we have a lot of babies who are born from frozen eggs, but it is it is a tool and it's imperfect.
1:14:32
SPEAKER_00: What's the success rate?
1:14:34
SPEAKER_01: Depends on, you know, age and and all those factors, but about two to five percent chance of live birth per frozen egg.
1:14:41
SPEAKER_01: So you need a lot of frozen eggs to have a baby.
1:14:44
SPEAKER_01: And that increases tremendously as you get older.
1:14:47
SPEAKER_01: Because if you imagine you're 35 and you freeze 10 eggs, when you come back to use them, about 80% are going to survive the thaw.
1:14:55
SPEAKER_01: And so you have eight that survive, 70% are gonna fertilize when you inject them with sperm.
1:14:59
SPEAKER_01: So you have six that fertilize, a third make it to the final blastocyst stage.
1:15:03
SPEAKER_01: So maybe you have two, and you know, about one in three are chromosomally normal at 35.
1:15:10
SPEAKER_01: And so that cohort of 10 eggs may or may not yield a baby.
1:15:13
SPEAKER_01: And even if that's a healthy, normal embryo, they implant 60 to 70% of the time.
1:15:18
SPEAKER_01: So it's inefficient, unfortunately.
1:15:21
SPEAKER_00: Yeah.
1:15:22
SPEAKER_00: And expensive, I imagine expensive.
1:15:24
SPEAKER_01: It's expensive and inefficient.
1:15:26
SPEAKER_01: And, you know, for most people who are doing this, they are, you know, the majority of people are doing this and they have maybe one opportunity to do it because it's so expensive.
1:15:35
SPEAKER_01: In some cases, they uh, you know, have coverage through their employer or they have a medical indication, in which case maybe they have coverage.
1:15:43
SPEAKER_01: Certain states have, you know, mandates for fertility preservation.
1:15:46
SPEAKER_01: But the reality is if you're doing it one time or two times and you're getting 10 or 20 eggs, maybe that gives you a chance of a child, but it's definitely not a guarantee.
1:15:55
SPEAKER_01: The younger you freeze, the higher the quantity of eggs and higher the quality of eggs.
1:16:01
SPEAKER_01: But I'm not telling everyone who's 25 to freeze their eggs.
1:16:04
SPEAKER_01: So there is a there's a little bit of a middle ground.
1:16:07
SPEAKER_01: But, you know, will I talk very seriously to my own daughters about it one day?
1:16:13
SPEAKER_01: Yes.
1:16:16
SPEAKER_00: Miracle that it's even possible.
1:16:18
SPEAKER_01: Absolutely.
1:16:19
SPEAKER_01: Right.
1:16:19
SPEAKER_01: I mean, the fact that, yes, I mean the fact that before this was an option, women were told, you know, to preserve fertility they had to freeze embryos with donor sperm.
1:16:28
SPEAKER_01: So at least we have this, you know, it's an option for reproductive choice and agency.
1:16:32
SPEAKER_00: Is there anything I should be doing in my 20s or 30s to protect my fertility with supplementation?
1:16:41
SPEAKER_01: I mean, we get that question all the time, of course.
1:16:44
SPEAKER_01: And I think that there's just so much noise with supplementation.
1:16:49
SPEAKER_01: You know, there are no supplements that can preserve and maintain ovarian function.
1:16:55
SPEAKER_01: We have no proven supplements.
1:16:57
SPEAKER_01: There are, you know, there's some preclinical data that in an IVF population, when we're looking at egg quality, CoQ10 may improve mitochondrial health of the egg cells and so may make IVF potentially more efficient in a population of diminished ovarian reserve patients.
1:17:14
SPEAKER_01: But again, this is preclinical, this is a little bit extrapolated.
1:17:17
SPEAKER_01: So I would say if you are just trying to be proactive and you're 25 or 30, we really don't have anything right now that we can do besides not smoking and um and making sure that you're kind of taking care of your health and every other aspect.
1:17:31
SPEAKER_03: Yeah.
1:17:31
SPEAKER_01: And I think one thing that we haven't talked about yet that to me is like a really important point for someone in their 20s, is know your family cancer history.
1:17:40
SPEAKER_01: Because I take care of a lot of people who have hereditary cancer syndromes and they have a BRCA mutation or a CEC2 mutation or red 50 or 51 or whatever it may be.
1:17:49
SPEAKER_01: And those mutations, if you know that early, that's the time to come in and talk about fertility preservation, A, because if you have a BRCA1 mutation, you might have diminished ovarian reserve.
1:18:00
SPEAKER_01: And so we, if we need to freeze eggs, we'll we're going to have to do more cycles to freeze enough eggs.
1:18:05
SPEAKER_01: And for anyone who has one of those syndromes, like Lynch syndrome or any of these, 50% of your eggs will be affected.
1:18:11
SPEAKER_01: And so if you want to eventually test your embryos for those mutations, you're gonna need double the number of eggs.
1:18:19
SPEAKER_01: And so for someone who knows, for example, has a BRAC a mutation, they know they're having their ovaries removed prophylactically at 35, or maybe they'll have their fallopian tubes removed first.
1:18:29
SPEAKER_01: That's one of the kind of interval steps that we can sometimes do to delay the removal of the ovaries.
1:18:34
SPEAKER_01: But regardless, they're losing their ovaries early and they may not have thought about starting their family yet.
1:18:40
SPEAKER_01: If we freeze eggs early, then they will have hopefully an opportunity to freeze many and test those for BRACA1 so that they can protect their offspring from passing it along.
1:18:50
SPEAKER_00: Question on that.
1:18:53
SPEAKER_00: Does anyone have the BRAC-a-1 mutation or any other mutation that could impact fertility, but go through life sometimes completely asymptomatic?
1:19:02
SPEAKER_01: That's a great question.
1:19:04
SPEAKER_01: There is what we call variable penetrance.
1:19:06
SPEAKER_01: So it's not always going to present, you know, not everyone with a BRACA mutation will have breast cancer or ovarian cancer.
1:19:11
SPEAKER_01: It just increases the risk substantially.
1:19:14
SPEAKER_00: On that note, then, for those people, if they were to look at their family history, if they were asymptomatic in the family, there would still maybe be an argument for them doing some sort of genomics testing or like, you know.
1:19:27
SPEAKER_01: Yes.
1:19:28
SPEAKER_01: Oh, absolutely.
1:19:29
SPEAKER_01: So it's not, you're you're right that it's not just family history.
1:19:32
SPEAKER_01: So, you know, and in some and a lot of families don't talk about their history.
1:19:36
SPEAKER_01: And so someone may have they don't know them, or they're not alive anymore.
1:19:39
SPEAKER_01: Yeah.
1:19:39
SPEAKER_01: Right, exactly.
1:19:40
SPEAKER_01: They don't have anyone.
1:19:41
SPEAKER_01: Um, and so I think that, you know, A, there are populations who should all be screened for BRACA just because of their ethnicity.
1:19:51
SPEAKER_01: And so, you know, and and this goes for a lot of the hereditary cancer syndromes.
1:19:54
SPEAKER_01: There are certain populations that are at a greater risk, and so everyone should be offered screening.
1:19:59
SPEAKER_00: Which populations?
1:20:00
SPEAKER_01: So Ashkenazi Jewish people have a one in 40 risk of BRACA mutations.
1:20:04
SPEAKER_01: And in the general population, it's more like one in a few hundred.
1:20:07
SPEAKER_01: And one in forty.
1:20:08
SPEAKER_01: One in 40.
1:20:09
SPEAKER_01: And in some cases, maybe even a higher risk than that.
1:20:13
SPEAKER_01: And so, you know, if I'm talking to someone, but but again, I think because we are all, we are all so much of everything that we no longer think about, you know, a lot of like specific ethnic screening.
1:20:24
SPEAKER_01: We think about, you know, pan-ethnic carrier screening.
1:20:27
SPEAKER_01: So if we're doing carrier screening for, you know, Tay Sachs, that used to be really limited to Ashkenazi Jews, but now it's really like we see Tay Sachs in a lot of populations because people have had families with everybody.
1:20:40
SPEAKER_01: And so it's, you know, there what we what we know is that we have to be thinking about this for everybody.
1:20:44
SPEAKER_01: Like everyone theoretically is at risk of any of these cancer syndromes or any of these mutations.
1:20:49
SPEAKER_01: And so if we can screen earlier, then we can hopefully identify people who are at risk and help them not just plan their families, but help prospectively like, you know, prolong their health span.
1:20:59
SPEAKER_03: Yeah.
1:20:59
SPEAKER_01: And identify cancer earlier, which, you know, if we're talking about like the ultimate way to preserve health span and lifespan, like don't get cancer.
1:21:05
SPEAKER_01: It's a big one.
1:21:06
SPEAKER_00: Yeah, that helps.
1:21:07
SPEAKER_00: Yes.
1:21:07
SPEAKER_00: Yeah.
1:21:08
SPEAKER_00: Okay, interesting.
1:21:10
SPEAKER_00: What's one thing about egg freezing or fertility testing that you wish more people understood before they spent money on it?
1:21:17
SPEAKER_01: I would say uh the uh the you know, the younger you are, the more effective it is.
1:21:23
SPEAKER_01: And that it is not always uh going to work.
1:21:26
SPEAKER_01: And so I think um having a healthy dose of expectations and uh understanding that this is a tool, um, but it is a limited tool.
1:21:36
SPEAKER_00: If I've already been through chemotherapy, is there anything I can do to protect my fertility now?
1:21:42
SPEAKER_01: That's a good question.
1:21:43
SPEAKER_01: And I think there's I think it depends on the great question, by the way.
1:21:47
SPEAKER_01: It is a great question.
1:21:48
SPEAKER_01: It depends on what someone's ovarian reserve is at that moment.
1:21:52
SPEAKER_01: Now, what I often will do with my patients who have a new diagnosis with cancer, we will do what we can in the moment that they're diagnosed, we preserve or we don't.
1:22:01
SPEAKER_01: And and even if they choose not to preserve fertility in that moment, they'll go through chemotherapy and then I'll ask them to come back typically in about a year after chemotherapy.
1:22:08
SPEAKER_01: And at that point, we assess their ovarian function.
1:22:10
SPEAKER_01: And so there is often a window of time post-chemotherapy, or maybe there is still some ovarian function.
1:22:16
SPEAKER_01: And for those women, that is another opportunity to think about freezing eggs or embryos and doing something to preserve fertility because maybe they didn't have time, maybe they were so sick at the time of their leukemia diagnosis, and that often is the case with some cancers like leukemia.
1:22:30
SPEAKER_01: They're so sick, they have to start chemotherapy right away.
1:22:32
SPEAKER_01: And so we can intervene a little bit later if they still have ovarian function.
1:22:37
SPEAKER_01: And so I would say, you know, kind of consistently following with someone who is part of a survivorship clinic, evaluating ovarian function, you know, post the, you know, after the fact, either you find you have some function and you can preserve, or you find that you don't have function, and that's an opportunity where you should be thinking about protecting your bones and starting some estrogen.
1:22:58
SPEAKER_00: What is one word that your patients misunderstand most about fertility and ovarian aging?
1:23:06
SPEAKER_01: That's interesting.
1:23:07
SPEAKER_00: One word or definition, I guess.
1:23:09
SPEAKER_01: Fertility preservation is a bit of a misnomer.
1:23:12
SPEAKER_01: Yeah.
1:23:13
SPEAKER_01: Because that implies that we are preserving long-term fertility when what we're really only doing is preserving gametes.
1:23:23
SPEAKER_01: We're preserving eggs or we're preserving sperm and it's not preserving the functional aspect of fertility.
1:23:30
SPEAKER_01: So that's a little bit of a Why do we call it that?
1:23:34
SPEAKER_01: I think because it's I it's historical precedent.
1:23:39
SPEAKER_00: There's a lot of that in science, isn't it?
1:23:43
SPEAKER_00: Um what is one I love this question.
1:23:46
SPEAKER_00: What is one fertility statistic that you wish every 25-year-old knew?
1:23:51
SPEAKER_01: 3% of their eggs will be chromosomally normal at 44.
1:23:55
SPEAKER_01: And that by 45, the likelihood of conceiving with your own eggs is exceptionally low.
1:24:02
SPEAKER_01: And there are always outliers.
1:24:04
SPEAKER_01: So you will always talk to someone who says, but this person conceived on their own.
1:24:09
SPEAKER_01: And and I'm I'm certain that that does happen.
1:24:11
SPEAKER_01: But for the vast majority of people, that does not happen.
1:24:14
SPEAKER_01: And ovaries are predictable.
1:24:16
SPEAKER_01: And by your mid-40s, your eggs are incredibly inefficient and and have lost competence to fertilize normally and create a healthy embryo.
1:24:29
SPEAKER_01: So I think that when people hear 44, I mean, when you're 25, 44 sounds old, but the reality is the 30s go pretty quickly.
1:24:39
SPEAKER_00: Comes around quick.
1:24:41
SPEAKER_01: And, you know, that's a really narrow window.
1:24:44
SPEAKER_01: We are all building our careers and, you know, peak of all of the really complex things happening in your lives, and you're finding a partner, or you're not, or you're building your career, and that's all happening during this very finite window.
1:24:57
SPEAKER_01: And it, and, and ovarian aging sneaks up on us.
1:25:00
SPEAKER_01: And I think what's tough is that you've got people who are otherwise at the at the pinnacle of their lives.
1:25:07
SPEAKER_01: They are healthy, they are taking the best care of themselves, they're doing everything right, but their ovaries don't care.
1:25:14
SPEAKER_01: And the ovaries are going to age predictably decades before every other organ system and often silently.
1:25:20
SPEAKER_01: And so the majority of that ovarian aging is happening in your 30s when you're not noticing it.
1:25:26
SPEAKER_01: And then when you go to use your ovaries in your 40s, if you are like the majority of people who are, you know, delaying childbearing, then you have missed your window.
1:25:38
SPEAKER_01: And so, you know, we are not doing a good job of lining up biology with the way we're living our lives.
1:25:43
SPEAKER_01: And so this is why we have to think about how to um, how to modify and how to um, you know, I identify tools to line these up better and align our goals with our biology.
1:25:57
SPEAKER_00: Yeah.
1:25:58
SPEAKER_00: What's the most common myth you correct in any single appointment?
1:26:02
SPEAKER_01: Probably what I just said, that that people say that they are healthy and they are eating well and that they are not smoking and they don't drink and they're doing everything right.
1:26:12
SPEAKER_01: And so, of course, they should be fertile.
1:26:15
SPEAKER_01: And so I think the assumption that we have control over our egg and sperm biology is unfortunately false.
1:26:24
SPEAKER_01: And, you know, this is it comes down to biology and it's a disease, and fertility is a disease, just like, you know, we can't control hypertension and diabetes, like, you know, well, maybe some modify well, there are some maybe bad examples, but there are some diseases you just can't control.
1:26:42
SPEAKER_03: Aging.
1:26:43
SPEAKER_01: Aging.
1:26:43
SPEAKER_01: Aging.
1:26:44
SPEAKER_01: Um, but I think that this is where, you know, we cannot um, you know, there are some things that we can't modify.
1:26:52
SPEAKER_01: And infertility is a disease, and we treat it with interventions like intrauterine insemination and IVF, and just like we treat other diseases.
1:27:00
SPEAKER_00: Biology is annoying, isn't it?
1:27:01
SPEAKER_00: It's annoying we don't know all the answers.
1:27:03
SPEAKER_01: Sure is.
1:27:04
SPEAKER_01: It sure is.
1:27:05
SPEAKER_01: But, you know, what was that?
1:27:09
SPEAKER_00: It's exciting too.
1:27:09
SPEAKER_01: But it's incredibly right, exactly.
1:27:11
SPEAKER_01: But there is so much opportunity, and this is why I get so energized by talking to my patients every day because every single conversation is a window into why, why don't we understand that?
1:27:24
SPEAKER_01: Like, why are your ovaries aging at this pace and hers or not?
1:27:28
SPEAKER_01: And, you know, why do we not understand that yet?
1:27:30
SPEAKER_01: And what can we do about it?
1:27:31
SPEAKER_01: And so, you know, it's a bit of a puzzle.
1:27:33
SPEAKER_01: And I think part of what I always was excited about in, you know, I thought about going into endocrinology in medical school, but I knew I wanted to do this like women's health oncology mix.
1:27:41
SPEAKER_01: But, you know, I love the puzzle of how the brain interacts with the ovaries and how the ovaries interact with the systems, you know, throughout the body, the heart and the bone.
1:27:48
SPEAKER_01: And it's all it is a complicated puzzle to put together and we have the tools.
1:27:52
SPEAKER_01: And now we just need to, you know, think about how to apply these tools.
1:27:55
SPEAKER_00: Yeah, and get all the monies as well.
1:27:57
SPEAKER_00: All the money to study these things.
1:27:58
SPEAKER_00: Exactly.
1:28:00
SPEAKER_00: What's one thing my partner can be doing to help me through this process?
1:28:05
SPEAKER_01: So I will say that's a great question.
1:28:08
SPEAKER_01: It's a good question, but it also highlights the assumption that this is a like a woman's problem and that the partner is just there for support.
1:28:17
SPEAKER_01: If we're talking about infertility, about a third to a half of infertility is male factor.
1:28:22
SPEAKER_01: And so a third to a half.
1:28:25
SPEAKER_01: And so we often uncover in the process of working up infertility.
1:28:30
SPEAKER_01: So it's like, you know, there's the question of ovarian aging and that conversation.
1:28:34
SPEAKER_01: But if we're just talking about a couple comes in to see me because they are, they've been trying for six months and they're not getting pregnant, we will off the bat do ovarian reserve testing, uterine testing, and a semen analysis.
1:28:46
SPEAKER_01: We often uncover abnormalities in the semen analysis.
1:28:49
SPEAKER_01: And that's where we escalate to our urology partners.
1:28:52
SPEAKER_01: And, you know, there is a lot that is worked up there to try to understand why that, why those semen parameters are abnormal.
1:28:57
SPEAKER_01: But sometimes we uncover azospermia.
1:28:59
SPEAKER_01: There's no sperm.
1:29:00
SPEAKER_03: Right.
1:29:00
SPEAKER_01: And, you know, that is devastating in the same way that ovarian insufficiency is devastating.
1:29:06
SPEAKER_01: And so, you know, this is a this is a problem of both partners often.
1:29:11
SPEAKER_01: But if we're talking about someone who her, you know, she herself is going through treatments and an IVF, the burden absolutely is on the female partner for most of the time, unless there is a procedure where sperm is being retrieved directly from the testicle called a TESI.
1:29:26
SPEAKER_01: Like that, you know, certainly then the burden is on both partners.
1:29:28
SPEAKER_01: But the, you know, the burden is on the female to do her injections and to go to all the appointments and she's feeling all the symptoms and it's really, really hard.
1:29:37
SPEAKER_01: And so I think, you know, just supportive partners.
1:29:40
SPEAKER_01: Yeah, be there.
1:29:41
SPEAKER_01: Um, and you know, a lot of our patients are doing this without partners.
1:29:44
SPEAKER_01: Yes, yeah.
1:29:45
SPEAKER_01: And, you know, so there's a lot of um, there's a there's, you know, there certainly are a lot of women in their late 30s or 40s who realize that their priority is building their family and they know their ovaries are aging.
1:29:56
SPEAKER_01: And so they use donor sperm and and pursue single parenthood by choice.
1:30:00
SPEAKER_01: And there are just so many ways to build a family.
1:30:02
SPEAKER_00: Carl, what's one thing that you would tell your own daughter about fertility that has nothing to do with eggs?
1:30:09
SPEAKER_01: Oh, well, it's kind of cute.
1:30:11
SPEAKER_01: It is cute.
1:30:12
SPEAKER_01: I have three daughters, and they're just the best.
1:30:14
SPEAKER_01: I also have a son who's the best.
1:30:16
SPEAKER_01: Um, and hey, I was But your three daughters are your favorites.
1:30:21
SPEAKER_01: They're all amazing.
1:30:23
SPEAKER_01: Um, but I will say, you know, and they were conceived with all of the different, you know, treatments, and my son is a little IVF baby.
1:30:29
SPEAKER_01: And so I, you know, I've I've gone through all these things.
1:30:32
SPEAKER_01: I've been there.
1:30:33
SPEAKER_01: Um, and what I will say is that, you know, I think we there's nothing more, you know, for someone who wants to build a family, there's nothing more meaningful than being able to achieve that goal.
1:30:45
SPEAKER_01: I also acknowledge that a lot of people listening are more are less interested in the fertility piece of this and more interested in the fact that their ovaries are aging and that affects their long-term health.
1:30:58
SPEAKER_01: And so when I look at my daughters and I think about my patients, I think about, and my daughters and my son, and I think about my patients.
1:31:05
SPEAKER_01: And I think about, of course, he's so little, I sometimes forget.
1:31:09
SPEAKER_01: Um, just joking.
1:31:10
SPEAKER_01: Um, so he we we think about, you know, there's how lucky I am to parent them, but also I want to be around for a really, really long time so that I'm there for them.
1:31:23
SPEAKER_03: Yeah.
1:31:24
SPEAKER_01: And the same kind of thread that brought me into this field, thinking about my mom and my grandma and all they've been through, and the fact that I got to grow up with my grandmother, she lived until my until I was pregnant with my third child.
1:31:36
SPEAKER_01: And so, you know, to have someone in your life for that long who is so important to your life, I view what this is as not just creating families to greet a family, but to be able to be there for your children for a very long time.
1:31:50
SPEAKER_01: And so when I think about the function of the ovary and what I want to do is I want to help people achieve their goal of building a family if that's what they want, but also to be there for their kids, for their grandkids, for their great grandkids.
1:32:01
SPEAKER_01: And so when we think about this continuum of healthy aging in women, it's how do we look at an 18-year-old and we know what she's up against for the next few decades, and how do we mitigate some of these risks so that she's there to achieve all these milestones with her family?
1:32:16
SPEAKER_00: On that note, I I want to add one additional question to the audience list.
1:32:20
SPEAKER_00: And you know, I always like to acknowledge that many of our listeners will now be carers for their parents or or or certainly will be soon or at some point.
1:32:31
SPEAKER_00: Um and I always feel a degree of empathy to the older generation who didn't have access to wonderful science and scientists that might be listening to this and thinking, I wish I knew that, or I wish I knew this so long ago.
1:32:46
SPEAKER_00: But for so many of these fields that we that we touch on in the episodes, like it isn't too late, right?
1:32:54
SPEAKER_00: And there are so many things we can still be doing to optimize for quality of life specifically.
1:33:00
SPEAKER_00: This is a little different, right?
1:33:02
SPEAKER_00: But but given that we know there is so much carryover from organ uh from ovarian function to the rest of our health, what what what would you say to you know to women in their latter years, you know, who are still interested, obviously, in in optimizing for independence and function and energy?
1:33:21
SPEAKER_01: Yeah.
1:33:22
SPEAKER_01: I mean, what we haven't even touched on is hormone therapy in, you know, in menopause.
1:33:27
SPEAKER_01: And so that's you know, maybe a whole nother conversation.
1:33:30
SPEAKER_01: But it's really, you know, when we think about starting estrogen for bone and heart and brain support, you know, we know in the in the young population, it's critically necessary.
1:33:41
SPEAKER_01: And it also is really important for older women if they're a good candidate for it.
1:33:45
SPEAKER_01: And there's a lot of nuance there.
1:33:47
SPEAKER_01: And I think what we, you know, what we know is that when you start earlier, it's protective and and potentially it puts you in a position where you are, you know, living better into your later years.
1:34:00
SPEAKER_01: And I know a number of women in their 70s, 80s, even 90s who have who are very well informed and have chosen to stay on it indefinitely because they feel better and they understand the benefits.
1:34:12
SPEAKER_01: And I think, you know, we there's so much nuance when we think about what was wrong with those earlier studies.
1:34:19
SPEAKER_01: The population of patients who started hormone therapy, they started way too late.
1:34:22
SPEAKER_01: We know that now, and and women should start earlier.
1:34:25
SPEAKER_01: And so I think there's so much that can be done.
1:34:27
SPEAKER_01: And if you think about someone who's, you know, at those inflection points, like, yes, that those are moments to think about.
1:34:32
SPEAKER_01: Like if you are perimenopausal or it, you know, within 10 years of menopause, that's the window to be having these conversations and potentially starting meds.
1:34:40
SPEAKER_01: And, you know, and then of course, there's all these other things that you can do down the road to maintain your strength and maintain your bone health and, you know, the all of the making sure you're getting enough from your diet in terms of calcium and vitamin D and making sure you're doing the resistance training and the strength training.
1:34:56
SPEAKER_01: And, you know, there are so many modifiable opportunities.
1:35:01
SPEAKER_01: And, you know, again, this is, you know, I certainly don't want to say that once you've, you know, you if you haven't thought about this in your 20s, you've missed the boat because that's so not the case.
1:35:09
SPEAKER_01: But it really is, you know, if we can construct a system where we're better about prospectively thinking about this, we should.
1:35:15
SPEAKER_01: But, you know, again, not to harp on this, but my grandmother, she never exercised a day in her life until she was 80.
1:35:21
SPEAKER_01: She decided it was time to start exercising.
1:35:23
SPEAKER_01: Yes.
1:35:23
SPEAKER_01: And I think that's why she lived into 102.
1:35:25
SPEAKER_03: Yeah.
1:35:25
SPEAKER_01: And so, you know, I will be.
1:35:27
SPEAKER_01: And, you know, she she bought herself a little membership at the local jam and just walked down the treadmill every day.
1:35:32
SPEAKER_01: I know.
1:35:32
SPEAKER_00: On that note, I've got two more questions for you.
1:35:36
SPEAKER_00: Is there one particular m client?
1:35:40
SPEAKER_00: And obviously, we don't need to say any personal details or story or um just something that has happened throughout your career that really sticks in your mind as like a standout moment that made you very proud to do what you do.
1:35:58
SPEAKER_01: It it I have to say, it's I feel very blessed that I'm in this field because I do have the opportunity to kind of become deeply entwined with people's families and um and and be a part of their story.
1:36:12
SPEAKER_01: And so I will say a um, you know, one that stands out and comes to mind is a patient who was sent to me because of infertility um with a um with her female partner, and they had been trying at another clinic for a very long time and were unsuccessful.
1:36:30
SPEAKER_01: And it was not um, it was, it was really not identified or acknowledged that she was a BRCA mutation carrier.
1:36:38
SPEAKER_01: And in our initial conversation, it was clear that, you know, that BRCA mutation immensely impacts what we're doing and how we need to think about family building and how we need to think about preventive health for her.
1:36:51
SPEAKER_01: So we pivoted, the plan was to, you know, transfer embryos that they had frozen elsewhere.
1:36:56
SPEAKER_01: We pivoted and started her over and started with, you know, let's test your embryos for BRCA.
1:37:02
SPEAKER_01: Let's have you see a specialist who can talk about protecting you from ovarian cancer and protecting you from breast cancer.
1:37:09
SPEAKER_01: And in the course of creating embryos, she was diagnosed with breast cancer.
1:37:13
SPEAKER_01: And I think having all of those steps in place to say, here's your, here's your path, and this is what we're going to do to kind of help you achieve your goals, totally pivoted their care.
1:37:24
SPEAKER_01: And, you know, we we switched gears and her partner carried the embryo and and they just had their baby.
1:37:31
SPEAKER_01: And I saw them in the hospital and met their beautiful baby.
1:37:34
SPEAKER_01: And, you know, seeing families go from individuals who deeply want something, they want to have a baby, but they also want to be healthy and live for as long as possible in the healthiest way possible.
1:37:47
SPEAKER_01: And then to see that story kind of coming together is so beautiful and meaningful.
1:37:51
SPEAKER_01: And that story is ongoing.
1:37:53
SPEAKER_01: And I've taken care of some other family members of theirs as well, and I'm seeing their families grow.
1:37:57
SPEAKER_01: And so seeing kind of this family tree evolve where I hope that I am part of the story that's helping them, you know, create new generations and build these beautiful families, but also keep them healthy and and protect them from disease.
1:38:13
SPEAKER_01: It's really um the the job of a lifetime.
1:38:16
SPEAKER_00: Yeah.
1:38:19
SPEAKER_00: You you are, I think you are really wonderful, Cara.
1:38:22
SPEAKER_00: Thank you.
1:38:23
SPEAKER_00: I'm so proud to have you uh involved in this business.
1:38:26
SPEAKER_00: You know, I had a message from, and I don't think she will mind me saying this, I had a message from one of our members whose daughter you helped recently, and she's just obsessed with you because of how much you changed their life.
1:38:38
SPEAKER_00: If someone were to tune in for the last 60 seconds of this episode, what would you want them to take away?
1:38:45
SPEAKER_01: I will start by saying that we are very siloed in medicine.
1:38:51
SPEAKER_01: And what I've had the gift of seeing in my career as a reproductive endocrinologist, but who also studies the biology of the ovary, is that everything we do is so deeply interconnected.
1:39:02
SPEAKER_01: And when we understand why an organ ages, in the case that I'm interested in the ovary, we can better understand how to preserve health throughout the body.
1:39:11
SPEAKER_01: And, you know, and that impacts every other organ system.
1:39:15
SPEAKER_01: There's a domino effect.
1:39:16
SPEAKER_01: And so if we can protect ovarian function from a young age, we can optimize cardiac health, bone health, and cognitive health and really change the aging trajectory for women, for people with ovaries.
1:39:29
SPEAKER_01: And so I think that the ovaries are a key regulator of aging.
1:39:35
SPEAKER_01: And mTOR is a key regulator of the ovary.
1:39:39
SPEAKER_01: And so really thinking about how to modulate mTOR to protect ovarian function and therefore protect systemic health is key to preserving ovarian function and health span.
1:39:53
SPEAKER_00: And it's coming.
1:39:54
SPEAKER_01: It's coming.
1:39:54
SPEAKER_00: It's happening already.
1:39:55
SPEAKER_00: It is Cara, it's been a real privilege and pleasure.
1:40:02
SPEAKER_00: I love this episode and I hope everyone else does too.
1:40:04
SPEAKER_01: This has been really fun.
1:40:05
SPEAKER_01: Thank you so much for it.
1:40:06
SPEAKER_00: Thank you.