#352 ‒ Female fertility: optimizing reproductive health, diagnosing and treating infertility and PCOS, and understanding the IVF process | Paula Amato, M.D.
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My guest this week is Dr. Paula Amaro. Paula is a professor of OBGYN at Oregon Health and Science University and a leading expert in reproductive endocrinology and infertility. She's been on the forefront of research and clinical practice of IVF, fertility preservation, and reproductive aging. And today we then continue our two-part series on infertility. Last week, of course,

We covered the male side of this with Dr. Paul Turek, and this week we're talking more about female infertility with Paula. In this episode, we discuss the biology of female fertility, how hormonal shifts drive the menstrual cycle and regulate ovulation, and what those patterns reveal about fertility potential, how infertility is defined, where to begin a workup, and why both partners should be evaluated early, the role of the fallopian tube in natural conception, and how infections and

and/or structural issues can lead to infertility or ectopic pregnancy, the reality of miscarriage and why most early losses are due to chromosomal abnormalities, not anything the patient is doing wrong, increasing impact of age, lifestyle, and environmental factors on fertility, especially as more people delay childbearing, causes and treatment options for polycystic ovarian syndrome , the emergence of GLP-1 agonists,

In PCOS and what we know and don't know yet about their impact on fertility and pregnancy safety, the nuances of diagnosing and treating unexplained infertility and how age and ovarian reserve shape clinical decisions, the evolution of IVF from early methods of today's technologies, including the use of pre-implantation genetic testing, and the use of pre-implantation genetic testing,

considerations around egg freezing, how timing, age, and egg quantity influence outcomes and decision-making, promise and limitations of next-gen reproductive technologies, such as mitochondrial replacement, and many other things. So without further delay, please enjoy my conversation with Dr. Paula Amato.

Hey, Paula, thank you so much for coming to Austin and sitting down to share some remarkable insights. Listeners last week will have heard us talk about all things that pertain to male fertility. And as promised, we're going to now talk about fertility, but from the female perspective. The physiology here is different, but no less complex.

And there were some pretty unique things about it. One of them being that unlike sperm, which seemed to be an infinite resource, men are constantly generating literally billions of these things. The exact opposite is the case with women. Tell us a bit about that. That's right. First, thanks for having me. Thanks for inviting me. It is true that when an embryo or fetus develops, the gonad differentiates into either a testes or an ovary. And the main difference, as you said, is that sperm is produced

Wow.

So a five-fold reduction from birth to, say, average age would be maybe 14? Yeah, 12 to 14. And we don't know why exactly that happens, but most of the eggs in the ovaries actually undergo a process we call atresia. They basically die.

So once a woman goes through puberty or a girl goes through puberty, every month, if she's not on hormonal contraception, one of those eggs grows. Actually, probably a group of eggs every month starts to grow, but then one takes over and is released from the ovary and usually finds its way into the fallopian tubes. That's the tube connecting the ovary and the uterus.

And then normally, if there's not sperm around, the egg just resorbs and there's no pregnancy and the lining of the uterus sheds and a girl or woman has a period every month. If there's sperm around, there's a chance that that egg might fertilize. And that fertilization usually happens in the fallopian tube, actually. And then that now...

zygote or embryo travels down the tube into the uterus and some of the time implants into the wall of the uterus or the lining of the uterus and establishes a pregnancy. Okay. So let's now talk about a woman in the prime of her reproductive age. She's 20 years old as an example. And

Let's talk through the cycle of what is happening and the role that hormones are playing. One of the things that to me has always been fascinating about this is the selection. With males, we don't have to think about that problem. The selection tends to be maybe more metabolic or stochastic. In other words, which sperm is the sperm that makes it isn't really predetermined.

How is it that, let's say from day zero, when a woman begins her menstrual cycle and all of a sudden everything starts to turn towards the next cycle, she's about 14 days out from ovulation, we start to see the interplay of luteinizing hormone and follicle stimulating hormone, particularly FSH. Walk me through what's happening in that period of time that ultimately leads to one and only one egg being the chosen one.

Yeah, it's a little random in women as well, actually. But it's true that the pituitary hormones, namely FSH or follicle stimulating hormone and LH, luteinizing hormone, are what drives growth of the, we call them follicles, the eggs are inside the follicles. And as I said, usually a cohort of eggs starts to grow. Tell me what grow means.

The follicles start to get bigger and the cells surrounding the eggs start to divide. And what do they look like prior to all of that happening? These are cells that only have 50% of the genetic material. They've already undergone meiosis. Yes. Meiosis, they're kind of arrested in meiosis and meiosis not completed until they actually ovulate and then in some cases are fertilized.

So we have an arrested cell that has one of each of the mother's chromosomes, including one X chromosome by definition, one of her two sex hormones.

And I don't know if this question makes sense, but is it still in its young phenotype? In other words, if the woman is 20 years old and all of the cells in her body are functionally 20 years old, is this egg prior to ovulation still basically an infant cell? As far as we know, although there's some data recently to suggest that perhaps the cells surrounding the egg are young.

metabolically active and maybe aging. Certainly, we do know that the quality of the eggs decreases, right, as women get older. So that affects how the eggs and the chromosomes ultimately divide. That's part of the reason it's harder to get pregnant as you get older. Even though you're ovulating, you may be releasing an egg every month.

but that it could be abnormal. And if it's abnormal, it likely won't fertilize. And you kind of don't want it to fertilize if it's abnormal and establish a pregnancy. But you're right. They're pretty much arrested in time. It's

certainly before puberty, and then every month a few start to develop. And then one, we don't really know how that one egg is selected. Definitely hormonal factors play a role, but it's somewhat random. One kind of grows and then eventually is released. Now, not to anthropomorphize this too much, but one would sort of assume that natural selection runs strong.

And if a woman, by the time she begins her fertility stage of life, has 400,000 eggs, just say on average, she only has a finite number of shots on goal. Let's just say 12 per year. And I don't know, let's just say if you look at peak reproductive, maybe 20 years, that's a tiny sliver of 400,000. That's true. You would have to assume...

that there is some selection that's happening to pick the best few hundred of those 400,000. Is there any evidence that that's happening?

Only in that the ones that usually result in pregnancy are chromosomally normal. So most of the embryos are chromosomally abnormal, and that's because most of the eggs are chromosomally abnormal. So there is selection in that sense. Most of the time, only the chromosomally normal embryos are the ones that implant and continue to develop.

And when you say chromosomally normal, are you referring to the egg or the zygote? The zygote, but most of the abnormalities in chromosomes that happen in a zygote are believed to be related to maternal age. And does that mean we think that the abnormality occurred...

way before ovulation? Or when do we think that that occurred? We think it occurred in the stage of meiosis that happens as the egg is developing that month. That ripening phase. So explain how that happens. If you were to sample eggs from a five-year-old girl, nowhere near reproductive age, so every one of those is in a state of frozen meiosis, how many things have to happen before it is

ready to undergo full meiosis? In other words, how does it go from that stage to... I'm sorry for using big words to the listener, and please feel free to explain what I mean by aneuploidy, but how do you go from that frozen meiotic state to an aneuploidic state? And please explain what I just said to people. Sure, sure. It's a little bit of a black box, of course, because we can't see exactly what's happening, but

The way we understand it is that the cells start off, including egg cells, as having two copies of each chromosome, but eventually has to become one copy in order to combine with a sperm that also has one copy of each chromosome. So during that process, there has to be disjunction of each of the pairs of chromosomes. So there are 23 pairs of chromosomes, including egg,

X and Y, the sex chromosomes. And during that disjunction phase is when we think most of the errors happen. Because if they don't divide evenly, like 23 and 23, you're going to get an extra one, you're going to be missing one. And then when it combines with sperm, that also has a haploid set of chromosomes, there's going to be an abnormal number, and that affects development. And that completion only occurs during...

during the 14 days leading to ovulation? Ovulation and then fertilization, yes. Okay, so that explains why, to my earlier question, there must be something, even though they are quote-unquote frozen in time,

There is either something going on with the egg or maybe the metabolic milieu around the egg from those cells that is changing the probability of success for that division of genetic material. Right. As we know that as a woman ages, the probability of successful division goes down. Right. So something changes as a woman ages.

But we don't understand exactly. But whatever it is that's going on makes those chromosome errors much more likely. Yeah. I'll tell you a very interesting story. A very close friend of mine has a son with Down syndrome.

And he's probably 20 now. So this is the story I'm telling occurred roughly 20 years ago. So when their son was born, I believe he was their third child. This is probably at a time. I don't think they knew until this was, in fact, I know that they didn't know until birth. They hadn't done amniocentesis or anything like that. They're sort of dealing with this right in the aftermath of their son's birth. And the doctor, the GYN came in and my friend says, he never forget this. The guy looked straight at his wife and

and said, "Look, it's important for you to understand that this is your fault." Oh my God. And my friend said he wanted to jump across the table and kill this guy. Yeah, I don't blame him. But then what he realized is what he was actually saying is, "This is the result of the egg releasing one too many." He had two copies of, was it 21? 21. Yeah. So two copies of 21 instead of one copy of 21 came from the egg.

It's interesting. My friend and I have talked about this many times since, and he said, I really came to appreciate what he was trying to do there, albeit in a completely clumsy way. He was just trying to explain that there is a reason for this. It is maternal and whatever. But anyway, it always stuck with me is that's a great lesson in bad bedside manner. For sure. Yeah. But he made the point. The point here being is while trisomy 21 is

a very common form of aneuploidy. It's also not lethal. There are many lethal forms of aneuploidy as well. Right, right. Trisomy 21 can be lethal, but not always. So some of those pregnancies do continue. Depending on the chromosomal abnormalities, some only develop to a certain point and then stop developing, and some are actually compatible with live birth, but usually have some abnormalities.

And do we know, for example, that if you were to look at all miscarriages that occur inside the first trimester, would you be able to hazard a guess as to what percentage of all miscarriages inside of 13 weeks are likely the result of aneuploidy? Definitely the majority of them, probably close to 90% of them. Yeah. Okay.

Okay. So in other words, maybe someone listening to this who's experienced miscarriages early in a pregnancy can take some solace in understanding that that was the body's way of correcting something that was inevitable sooner rather than later? Yeah, I think that's true. Yeah. Miscarriages are very common and that's the most common cause.

Although there are other causes, usually we don't do a whole lot of testing if it's just one miscarriage because that's very common. We just assume fetus or embryo was abnormal. But if a woman has two in a row, then that warrants some additional testing. Regardless of her age? Regardless of her age.

Obviously, the chances of finding something else goes down as a woman gets older because you don't want to miss another cause that's potentially treatable. Okay. Well, let's put a pin in that because I actually want to understand that more. But that's interesting to me that if a 40-year-old woman had successive...

miscarriages, you wouldn't just chalk it up to, well, she's 40. Of course, these are aneuploidic eggs. Yeah, that's true. I mean, that's most likely. But again, you don't want to miss, especially at 40, you don't want to miss some other treatable costs. Right, because you only have so much time. One of the lessons here, hopefully for people listening, is if a couple miscarriages, they shouldn't feel that they've done something wrong. The woman shouldn't beat herself up thinking, oh my God,

Did I have one too many cups of coffee or was I under too much stress? No. Greater than 90% chance this was a bad split and that's the way it works. Yes.

So let's go back to this process. So it's day zero. So a woman just begins her period. We're just getting ready to embark on her next fertility cycle. The pituitary gland is secreting luteinizing hormone and follicle stimulating hormone. Walk me through what is happening in the next 14 days that leads to that ovulation. So a group of eggs or follicles are starting to grow. One gets selected. We don't really understand. We don't understand why. It's random.

And that follicle, that's in a follicle, follicle is kind of a fluid-filled cyst-like structure that surrounds each egg. So that continues to grow.

And then eventually, what's happening hormonally, so those cells surrounding the eggs are producing estrogen. That estrogen is preparing, acting on the uterine lining to build up the lining to potentially support a pregnancy. And then what happens just before ovulation is there's a surge in a hormone called LH, luteinizing hormone. And that's what we think triggers ovulation or release of an egg.

So all that has to happen before an egg is released. So it busts out of the ovary, finds its way to the tube. How energetically demanding is that? We learned last week in talking with Paul that the ATP requirement for those sperm to travel all that distance is unbelievable. How passive versus active is the movement of that egg? How metabolically demanding is it?

I don't know that we understand it completely, but you would imagine that their energy is required for that to happen, certainly. So it's not passive. It's not just sort of a diffusion down the fallopian tube. Right. Prostaglandins are involved and calcium, all kinds of things have to happen for that process to occur. Okay. How long approximately, just give people a sense of how long a fallopian tube is. Probably a few centimeters, five to 10. Okay.

Everyone's probably used to seeing the image of ovaries being these little eggs and fallopian tubes having these little fingers that hug up on the eggs. What is actually in between that space? How does the egg get from an ovary into a fallopian tube? Is there an actual connection there? There is actually. They're not stuck together, but they're kind of in close proximity so that those fimbriae or finger-like projections kind of

sweep up the egg once it's released from the ovary. Got it. And it's otherwise in direct contact with the peritoneum? The ovary and the tubes. Yeah, pretty much. The space between them. Yeah. The pictures always show like the tubes out here and the eggs out here, but they're actually, everything's closer together in the pelvis.

Okay, so egg is now in fallopian tube. How long does it take to get through the length of the fallopian tube into the uterus? About five or six days. Okay, so completely different experience from the sperm, which are racing at breakneck speed and cover that distance in seconds. So what regulates the speed with which the egg travels through the fallopian tube and how does that impact fertility?

Is there a scenario whereby it happens too quickly and things don't work? I don't know about too quickly, but there are hair-like projections in the tubes, cilia, that help with motility of the egg down the fallopian tube into the uterus. The abnormalities on the female side, potential abnormalities, have to do with like scarring in the tubes or if the tubes are blocked and then it interferes with the egg encountering the sperm.

What leads to that? A number of different things. Infection probably most commonly, but also scarring from previous surgery potentially or a condition called endometriosis. So there are a number of things that can affect the tubes as well. Is the day four, assuming a woman's cycle is predictable and normal and would just say day 14 is ovulation,

That is the day that the egg leaves the ovary or that is the day that the egg reaches a certain place within the fallopian tube? Pretty much the day that the egg is released from the ovary. Yeah. And you usually encounter sperm in the fallopian tube and that's where fertilization usually happens.

And then it takes a few more days for the embryo now, or pre-embryo, to travel down the rest of the tube into the uterus and hopefully implant if it's normal. Now, one of the most interesting things here that is worth repeating, even though we talked about it last week in case anybody missed it,

How many sperm is the egg encountering at the time of fertilization? Millions. Yeah, millions. So why is it, I know the answer to this question, but it is so cool. Why is it that one and only one sperm out of millions or even less than that, but let's just say it's hundreds of thousands, why does only one get to transmit its genetic material into that egg?

Well, once an egg is fertilized, there's sort of a chemical reaction, if you will, that happens that prevents any other sperm from fertilizing the eggs, because that would be bad. You only want one sperm and one egg to combine. Yeah. There's like an electrical force field that immediately activates around the egg. I find this so fascinating. Yeah, it is fascinating. And brilliant. Okay. So now, and by the way, what is the relative size of an egg to a sperm? The egg is actually much bigger than the sperm. I

I don't know exactly in microns how big it is. I feel like I used to know this answer and it's shocking how disparate they are in size. The egg is, I believe, the biggest cell in the body potentially. I've checked on that, but I believe that's true. All right. So yeah, you have this massive egg that's basically like the sun and like this tiny little sperm, which is like the earth and colliding with it. Okay. So fertilization takes place and how long from impact?

until you have that single cell zygote that actually has a lined up pair of chromosomes? Is that a matter of hours? Yeah, within a few hours. Okay. And then what is the process that occurs for cell division for when that zygote goes from one to two to four to eight cells? So A, how long does that take? And B, at what point does it implant into the uterus?

Most of what we know actually about this is from in vitro fertilization or IVF because we can actually see that happening in the petri dish. So usually with IVF, an egg is fertilized with sperm. By the next day, we can see if it's fertilized and we know if it's fertilized because it has what we call two pronuclei. So DNA from the sperm and DNA from the egg.

And then over the course of the next couple of days, it divides into maybe six to eight cells. So about three days after fertilization, it's six to eight cells. And then by five to six days, it's about 60 to 80 cells. And that's the stage where it implants in the uterus. So five, six days after fertilization. So with that said...

Now that we have a pretty good understanding of what all needs to happen for fertilization and implantation, what is the biggest risk to

And when does it cease to become a zygote, by the way? I don't remember any of my terminology here. You have zygotes and blastospheres or blastocytes? Yeah, yeah. A zygote, I think, is still a single cell that's fertilized in egg and sperm combined. Then it starts to divide. We call it a pre-embryo. Okay. And then by two weeks, we call it an embryo. But in IVF, we call it an embryo even in the first few days. Assuming that we have...

chromosomal alignment. It's two weeks out. So we have a two week old embryo that is implanted and

What is the greatest risk that is faced by that embryo to coming to fruition as a fetus? In fact, going all the way into the third trimester. So in other words, we've taken the biggest risk off the table, which is aneuploidy. What are the other risks it faces? So once a pregnancy is established, you mean? Yes. So if it's a normal embryo, chances are pretty good that it continues to term.

So let's define normal. So normal at the macro level means chromosomally normal. What else requires normality? Any other genetic issues that get in the way here? There are other genes that play a role in embryo development. Those are less understood, but there are certainly other genes involved. So you could have a chromosomally normal embryo that fails to develop for other reasons. And then there could be uterine factors that also play a role. So an embryo may implant

But if there's some structural abnormality, for example, in the uterus, maybe that pregnancy can't continue and may result in a miscarriage. Got it. Okay. So let's talk about a patient that comes to you. They're going to say, we're having difficulty conceiving. What are the questions you have to render the diagnosis of infertility, meaning we need some intervention versus, hmm, you just need to make a few adjustments in pregnancy?

something, and I'm not willing to put the label of infertility on. Would that be the first bifurcation in thinking? Yeah. We want to take a full medical history of both partners, if it's a couple, and that includes medical history, reproductive history, psychosocial history, sexual history. All those things are important. Lifestyle factors, we ask about all those things.

And the definition of infertility is trying for about a year. So unprotected intercourse for about a year without success. That's the medical definition of infertility. But we start our testing after a year in women who are less than 35. And after six months, if a woman is older than 35, even though it may take longer to get pregnant if you're older,

If there's something wrong, you kind of want to know about it sooner rather than later. So if a couple female partners over 35 and they've been trying having time intercourse at the right time and still not pregnant, then we would initiate some preliminary investigations. On the female side, what's most important usually is we want to ask about the woman's menstrual cycles. Are they regular? Is she tracking ovulation? Does it look like she's ovulating, etc.?

The male side, we want to ask about sexual function. Have they had a semen analysis? If not, we usually order one because we're interested in the sperm concentration, the motility of the sperm, the shape of the sperm, those types of things. One of the things I was very surprised by in the podcast that we did last week on male fertility was how infrequently men are getting evaluated and how many missed opportunities. In other words, how much

wasted time is being generated because infertility is being assumed to be the responsibility of the female. Responsibility might be the wrong word, but it's just assumed that, well, that's more likely where it is. And so through no bad intention, the guy is not getting evaluated when in reality, the issue could have been with him all along and time is wasted. Right. When you look at the data, it's about a third of the time, it's a female factor, a third of the time, it's a male factor.

Another third of the time, it's some combination of male and female factors. So yes, definitely one of the first things that we do is a semen analysis on the male partner. And do you guys do that yourselves as well? We do, at the fertility clinic. Okay, great. If there is an abnormality, we usually refer that male partner to a reproductive urologist for further evaluation.

But these days, it's recommended, actually, that men, even if they're not trying to get pregnant, sometimes assess their semen analysis. And because it can be a marker of other health problems, just like a woman's menstrual cycle can be a marker of other health problems.

I should qualify that one-year timeframe. If you have some reason to believe that you have a fertility problem, I wouldn't necessarily wait a whole year and then go see a provider. If your cycles are irregular, if you think you might have polycystic ovary syndrome or something, then you definitely want to see somebody sooner than a year. Is it possible to say anything about fertility rates changing over the past 50 years? Is there any statement you can make on that? Yeah, there's some data that seems to suggest that in

infertility rates are increasing over the last several years. It's pretty common. I don't know if your listeners know, but about the lifetime risk of infertility for each person is about one in six. So that's close to 20%. In the last few years, the United States seems to be kind of a plateau of the prevalence. Let me just ask a clarifying question, Paula. So

If a woman gets pregnant in her 20s, but then in her 30s meets the criteria for infertility, would she be considered one of those one in six? Yeah. So we're going to say that the one in six means someone who wants to get pregnant at a certain point in their life can't. Exactly. Lifetime prevalence. Exactly.

As far as the reasons for the increase in infertility prevalence, it's not super well understood. Part of the reason is delayed childbearing. I was just about to say, you could make it 100% if every woman decides to have a baby when she's 70. By definition, you have 100% fertility. Exactly. Yeah. So women are waiting longer, of course, to start their families, to pursue education and careers, et cetera. Maybe they haven't found the right partner.

And so that definitely is contributing to increased rates of fertility. There's some data that show that sperm counts are decreasing globally. It's a little controversial, but that might be playing a role. Might be slight increased risk in sexually transmitted diseases as well. So all those things are probably factors. Is there an analysis that's tried to get at this by normalizing to female age?

Because it seems to me that if you could say, rather than make it lifetime prevalence, because that's going to be subject to all the problems you've stated, but what if we just said for women aged 28 to 32, 32 to 35, like if we made narrow buckets of age, we could get a better sense of whether there's a true infertility issue. Has that analysis been done?

It's definitely been looked at by age. I don't know the data off top of my head if it's been looked at by age over time, but definitely your chance of infertility is higher if you're 40 compared to if you're 20 or even. But do we know if a 30-year-old woman today has a higher rate of infertility than a 30-year-old woman 50 years ago? We think so, but I don't know that data off top of my head. If the answer there is yes...

I don't know that it would answer all our questions because it could still be explained by decreasing sperm count. It could still be explained by increasing paternal age. This would be a very difficult analysis to do. Right. Environmental factors as well.

Our exposures are different now than they were 50 years ago. Well, and then the question, of course, would be, if this is an environmental reason, what are the environmental triggers? Now, you mentioned STDs a minute ago. How do STDs and which STDs play a role in fertility? The ones most well understood are probably gonorrhea and chlamydia, which are very common sexually transmitted diseases. And on the female side, those particular infections can ascend to the fallopian tubes and cause

scarring in the fallopian tubes, which then interfere with that process that we talked about earlier, the egg and the sperm meeting and can lead to infertility.

And is that something that happens if it is left untreated, or is that something that's easy to address with antibiotics if caught early? I mean, if it's caught early, then it's usually treatable with antibiotics, or there are some issues with antibiotic resistance, especially with gonorrhea. But usually if you catch it early, it's treatable. But if it's late stage or it's unrecognized or untreated, then it's more likely to ascend to the fallopian tubes where it usually caused fertility problems.

How prevalent is gonorrhea today in the US? I think it's pretty common. I don't know. Really? Yeah. Yeah. In certain populations, it's more common than others, but unfortunately, and there's a number of reasons for that. Some of it is just lack of awareness and education about safe sex practices.

Maybe less testing as well, especially we saw that during the pandemic for sure. How does it present? In women usually with pelvic pain, fever, vaginal discharge, those are the most common symptoms. And is it equally transmissible from male to female and female to male? It's probably more transmissible from male to female. Okay.

And is it an STD where the person who has it knows, like if a male has it, does he know he has it? Not always. Presumably not if it's being transmitted this readily. Yeah, not always. What about HSV? Does that factor into fertility at all? Not as much.

And chlamydia, again, I apologize for my ignorance. I just don't remember any of this stuff since taking the USMLE exams. Tell me how chlamydia presents and how it impacts fertility. The same, actually. Yeah, very similarly. So pelvic pain, fever, usually they're both present together. And does it have the same pathology where it creates, it ascends the fallopian tubes and scars the tubes? So worst case scenario, if a woman undergoes a severe infection with one or both of these

It's not treated in time. She has completely scarred fallopian tubes. Is it still likely that she could get pregnant through IVF? Are the eggs and uterus still preserved enough to... Yes, yes. It doesn't usually affect the uterus or the eggs or the ovaries. Now, she may not know that she has blocked tubes until she...

starts trying because you wouldn't necessarily feel different if your tubes were blocked. So one of the tests we were talking earlier about what testing we might do in addition to a semen analysis and getting a menstrual history, et cetera, is we usually do an x-ray test. It's called a hysterosalpingogram or HSG for short. And it's done specifically to evaluate whether or not the tubes are open. So are you just injecting contrast? I assume you do this externally. You go into the

cervix into the, you just inject dye and take an x-ray. Exactly. And you're looking for how smooth. And so tell me, what does a normal fallopian tube look like on that test? So first the dye, so it's done in radiology facility usually by radiologists, although some gynecologists do this test as well, but usually it fills up the uterus. So you can also see the uterus.

And then the tubes are kind of like these wire-like. What's the diameter of a normal fallopian tube in that setting? Less than a centimeter. Yeah. That's pretty big. Yeah, the whole tube. But the actual opening is... No, yeah. How big is the lumen? Microns. Oh, wow. Okay. Or millimeters. I don't know. Exactly. But you can...

But you can see it, definitely see it on x-ray and you can see the- Well, if you can see it, it's probably a millimeter or more than not a micron. Yeah, for sure. Yeah. Okay. And then the dye is filling up the tubes and then spilling out the tubes. So you can see that process. The ovaries are not visualized because of the finger-like projection. So it's actually spilling dye into the peritoneum at this point. Right. Okay.

Based on that visual inspection, a trained radiologist and GYN can say that is smooth, that looks great versus that is jagged and or obstructed. Right. Now, if it's obstructed, I assume that the woman has a much bigger problem, which is every month one of those eggs comes out, it's not getting past the point. Is it just atrophy and get reabsorbed? I see. So it wouldn't necessarily cause pain. No, no.

By the way, we didn't talk about this earlier. We took it for granted. This is happening with two separate sides. Yeah. And it's just mind-boggling to me that there is one that is being selected and the one that's happening in one side, somehow that signal is making it to the other side to say, you can't do it this month. Right. How does that happen? Who knows? We don't know. We have no idea how that happens. No idea. Something to do with the receptors on the eggs and particular hormonal milieu. Maybe there's some...

nerve that plays a role. We have no idea actually, but it is on average 50% from one side and 50% from the other side. And it's a coin toss. Right. And it's not necessarily alternating, but it's on average. Right. It would be like heads is left, tails is right. If you throw it for enough times, it's 50-50, but not necessarily back to back. Exactly.

This is mind-boggling to me. Yeah, it's fascinating. It's mind-boggling if it were just one ovary, but the fact that these things are physically a foot apart, not a foot, but half a foot apart, and some signal is transmitted in this woman's body. Yep. I mean, it's... Yeah, yeah, and we don't quite understand it. That's incredible. Yeah, or whatever that egg that's being selected is.

somehow develops the appropriate receptors or whatever that only it can respond to the hormones.

It's not necessarily signaling to the other ones, but something is happening to that one that's being selected that's making it the so-called dominant follicle for that cycle. Yeah, I suppose that's a more likely and plausible scenario is that something stochastically triggers one and only one to develop a high enough receptor concentration for

FSH or LH or something so that it becomes the only one that, it's the only one that develops the radar. Right. Now, of course, when we do in vitro fertilization, we're giving much higher doses of FSH and multiple eggs are growing. So you can overcome this process and get multiple eggs to grow, but we don't totally understand physiologically what makes just one grow each month. Okay.

Let's say you do the analysis and I assume if there's scarring on one side but not the other, would you intervene or would you just say, no, we're just going to take twice as long for one to get through? Yeah, there's still a chance to get pregnant. Although whatever process caused the scarring in the one tube probably affected the other tube as well. So just because it's open doesn't mean that it's functioning normally.

Certainly can give it a few months of trying, but the other issue you have to worry about is what we call an ectopic pregnancy. If that tube is not normal, if fertilization happens, that embryo can implant in the tube. And that's kind of a very dangerous situation because obviously the tube can accommodate a pregnancy. So usually that causes pain and if it goes unrecognized... It's a surgical emergency. Yeah, exactly.

At how many weeks of gestation is a woman typically, because that's, I did my training in general surgery. So that was one of the things we were always thinking about was ectopic pregnancies for women presenting with abdominal pain. But I don't think I know the answer to this question, which is how many weeks of gestation is a woman when she's showing up in the ER complaining of abdominal pain? Usually about six,

to eight weeks of pregnancy. Two months pregnant. Right. Now, remember we time pregnancy from like two weeks before ovulation. So by the time she recognizes she's pregnant, she's already a month pregnant. So in the next month is probably the most common time where those

ectopic pregnancies present. So when a woman has an ectopic pregnancy, can that fallopian tube be salvaged? Sometimes. Sometimes if you recognize it early, it can be treated either medically or surgically and that tube can be salvaged. If you recognize it late and the tube ruptures, then oftentimes the treatment is to just remove the tube. Plus, especially if it's not functioning normally. Yeah. So when you remove that, let's just say it's a young woman, she's 25 years old,

You can't salvage the tube. You end up taking the tube. You're leaving the ovary. Right. So you still want her to have her endocrine system intact. What's happening to the eggs that come out of that tube? They just get released into the abdomen, the peritoneum and resort. So do you tell that woman your fertility rate just went down by 50%? Yeah. She can still get pregnant if she has the other tube intact. But most of the time, if the egg ovulates from the right, it's going to try and go down the right side. Although there have been cases...

where you can ovulate from the right ovary and it can travel down. It makes its way over to the other fallopian tube. It makes its way over there. Yeah, it's rare, but it could happen. What are the risks for ectopic pregnancy besides former STDs that lead to scarring in the tube? Previous surgery, pelvic surgery in particular, like a ruptured appendix or something like that, endometriosis can cause scarring of the tubes. Those are probably the most common. Okay. Okay.

Any genetic component to this? If your mom had an ectopic pregnancy or you... Not that we know of. So let's go back to our hypothetical case here. So woman comes in, let's just assume for the sake of simplicity, the workup on her male partner, totally fine. His sperm are fine. The radiograph shows that she has, at least to the eye, normal fallopian tubes. What's the next step in the workup?

So we want to assess her cycles and ovulation. So if she's ovulating regularly, then we call that sort of unexplained. And how do you know that she is? Is that determined by the fact that she has a regular period? Does that alone tell you that? Usually. Usually. It would be unusual to have regular periods and not be ovulating, but it could happen.

How stringent is your definition for a regular period? It's not 28 days necessarily. Not necessarily. Yeah. There's a range. It could be anywhere from like 21 to 35 days or so. Wow. That's a pretty big range.

Are you less concerned with the number of days of the cycle and more concerned with the fact that whatever the days are, it's just repeating over and over again? Yes. If you mean duration of the period, yeah, that's not as important as how frequently the period is happening. Even if it was 21 days, but it was always 21 days, that's better than it's 24, 28, 31. There is some normal variations. Sometimes I'll see a patient who'll say, my periods are very irregular. Sometimes they're 26 days, sometimes they're 32.

I consider that normal. It's not usually always 28 days or always 21 days. There's some normal variation. Irregular would be your skipping months or maybe you're getting a period every three months or four months. And what's happening in that situation in a young woman? There are a number of different causes. Probably the most common is something called polycystic ovary syndrome. It's a very common hormonal condition.

condition. We don't know exactly what causes it. I feel like I'm saying that a lot about women's health. We don't know exactly what causes it because we're not investing enough in women's research. Why do you think that is? This came up on another podcast on HRT, which is another one of my big rallying cries, which is how pathetic it is. Why do you think this is, given how important a subject this is? Political reasons, I think.

gender inequality, all kinds of reasons like that.

Do we have a sense objectively that there is a difference in this type of research, or do we think it's just that, well, maybe there's equal amounts of funding, but the innate problems associated with the female reproductive system or female health in general are so much more complicated that at equal funding levels, we're going to be far behind in our understanding? Yeah, no. I think it's the former. You think it's abjectly... Oh, there's good data that the funding for women's health research, it's like 10%.

Of the overall NIH budget, for example, it's very small. If you look at reproductive health, it's even smaller. So it's a huge issue.

Let's talk about polycystic ovarian syndrome. So what's the prevalence of it in, let's say, women aged, call it 15 to 30? Yeah, super common. About 6% to 8% of women will have polycystic ovary syndrome. Most common symptoms are irregular periods, also evidence of high androgen levels, and that could usually present with acne or excess hair growth. We call that hirsutism, obesity or being overweight. That's also part of the syndrome.

The androgens are specifically just testosterone, just DHEA, DHT, all of the above? Yeah, both, but typically elevated testosterone from the ovaries. Is that the cause or the effect? We don't know.

We don't know, but it's definitely seen in almost all women with PCOS that they have higher androgen levels. And why is PCOS seemingly also highly associated with insulin resistance? Again, we don't know exactly, but we think the androgens play a role. We think there might be some genetic factors that play a role.

I don't know that we understand why, but we certainly have recognized in the last several decades that most women with PCOS also happen to be insulin resistant. But we don't know the direction of causality?

No. We know that not everybody who's insulin resistant has PCOS, of course. Not all diabetics are insulin resistant. But we also know that some women with PCOS are not insulin resistant, correct? Probably on some level they are, but they're able to compensate. And certainly it's more likely if they tend to be overweight as well. So it's definitely multifactorial. And I guess it's like

We're treating PCOS now more like other complex diseases like obesity or hypertension, et cetera. There's lots of things going on. But based on what you just said, if there is any causality between them, it's more likely that the PCOS is driving the insulin resistance than the other way around, given the number of women that are insulin resistant who do not have PCOS. Yeah, that's probably true. So then the question is, what do we need to do to treat PCOS?

So depends on the goal of the patient. So if they're trying to get pregnant, there's one set of treatments. If they're not trying to get pregnant, but they have PCOS, then we usually focus on their cycles because it's generally not a good idea to go too long in between cycles because what can happen is the lining of the uterus can overgrow. If it overgrows too much, it can become what we call hyperplastic, worst case scenario, cancer. So you definitely don't want that.

So it's important to be shedding that lining or to be on hormonal suppression so that that doesn't happen.

If the goal is to treat the hyperandrogenic symptoms like the acne and the hirsutism, again, hormonal treatments usually effective for that. When you say hormonal treatments, you mean like spironolactone and things like that? We usually start with birth control pills. Birth control pills, very effective for most symptoms of PCOS. It'll regulate the cycles, decrease androgen levels, help with hirsutism and acne, et cetera. So let's talk about why. So a birth control pill is a high dose of a synthetic estrogen and propionate.

and progestin. Correct. That's given 21 days and then paused for a week, meaning you take it every day, but the last week is a placebo.

So is the reason that that helps with the hyperandrogenism because it raises sex hormone binding globulin so much that it mops up all the excess testosterone? Part of the reason. I'm impressed by your endocrinology knowledge. Yes, that's part of the reason. And by the way, you can take it that way you described where you have a bleed every month, but you don't have to. Many people take it continuously these days, so you don't have a period at all.

But then doesn't that address the issue that you were talking about? Or does the synthetic estrogen...

The synthetic progestin offset the hyperplasia and then you don't care. Right. When you take the combination of estrogen and progesterone, usually the lining becomes quite thin. Thin anyway. You don't have to worry about it. Yeah. So two mechanisms of action. When you're taking those high doses of estrogen and progesterone, it's suppressing the pituitary hormones, namely the LH and FSH. But the LH is what drives the testosterone production in the ovary. So that's one mechanism.

And the other one is the one you described. So the estrogen component of the pill will increase the sex hormone binding globulin, so you have less free testosterone around. So again, that will help with those symptoms we talked about. Okay. So a woman with PCOS doesn't want to get pregnant, just wants to reduce the androgen impact and protect her uterus.

a constant oral contraceptive is a great strategy. Great strategy. Yeah. There are others. It could be a progestin IUD. That's a hormonally active IUD. So there are a number of different ones. We're just taking progesterone every few months. That usually will help protect the lining, but probably won't decrease the androgen levels. And how often do you place women who have PCOS...

Also, with insulin resistance on metformin, do you find that or any of the other diabetic agents to be particularly useful? Occasionally, yeah. And that's an important point because women, as we said, who have PCOS are insulin resistant, which predisposes them to diabetes. So those women need to be screened periodically for diabetes. And we commonly use metformin to either treat prediabetes or to try and prevent diabetes.

Does insulin resistance and type 2 diabetes independently impair fertility, all things being equal, absent PCOS? That's a loaded question. Yeah. In some cases. I mean, there's some data that shows that metabolic diseases or chronic diseases can impact fertility. Mechanisms, again, are unclear, but probably related to both ovulation, dysfunction, and also endometrial receptivity. Okay.

So now, I assume that's the easier way to treat PCOS is the woman who does not want to get pregnant. So now let's talk about the woman with PCOS, but who is also trying to conceive. What is your playbook? So we always counsel these patients as well. I should mention whether they're trying to get pregnant or not, especially if they're overweight or obese, weight loss helps.

with all the symptoms of PCOS. So healthy diet, lifestyle, et cetera. And how much of a role are GLP-1 agonists playing in this now? How much more success are you having with treating PCOS that way? Yeah, increasingly. And they're very successful, as you know, for weight loss. And there have been some studies on PCOS patients specifically, very effective. Do you know any of those data? I'm not familiar with them. Yeah, they work really well, just like they work in people with diabetes or people with obesity without diabetes.

Problem is you can't get pregnant while you're taking them and the current recommendation is to stop for at least two months. And pardon my ignorance, why? Because we don't have any data on whether they're safe. Yeah. So FDA is saying, I forget the FDA's classification for this. There's like A, B, C, X or something like that for every drug? Yes.

I haven't looked for that one specifically, but I'm sure it's X because we have no data. That's an important message for anybody listening. If you're trying to get pregnant, you should not be on a GLP-1 agonist because we don't understand the impact of that. Right. You can be on it pre-pregnancy. Just the recommendation is to stop for at least two months.

Now, having said that, there have been lots of, you may have read about, a zempic babies, like people getting pregnant on GLP-1. So there is a registry. And so far, to my knowledge, there haven't been reported birth defects and that type of thing. But obviously, we're talking about a small number. Yeah, that's an interesting point. And now that you mention that, I now recall hearing about that. So presumably, these are women who have taken either semaglutide, trisepatide,

And presumably they get pregnant. Yes. Either intentionally or not. So that's a very interesting registry to follow. Right. Now, of course, once they find out they're pregnant, usually they stop. They're usually counseled to stop. Yeah. So we don't know what would happen if you continue. I don't think anybody wants to do that study at the moment. Yeah. It doesn't make sense. Certainly don't want women who are pregnant to not want to eat.

Okay. Understanding that a woman who's got PCOS is going to be first counseled to make these changes that effectively help her lose weight and increase her metabolic health. Let's say she is somewhat successful, but still unable to address the concern. Luckily, there are very good ovulation-inducing medications available. What we would typically recommend for someone with PCOS to help them ovulate more regularly is a medication called letrozole.

The brand name is Femara. It's just a medication you take for five days in your cycle, and then we can usually assess ovulation with ultrasound. And what does it do? Basically, it's a category of medication called aromatase inhibitors, which blocks the... Conversion of testosterone to estrogen. Right, androgens to estrogen. That lower estrogen somehow triggers the pituitary to increase secretion of FSH, and

an LH, and that stimulates the ovary to, again, get one of those follicles. And is the reason you use something like an aromatase inhibitor as opposed to clomiphene or HCG is just that it's a smaller nudge and you're starting out with it? No. We used to use Clomid first line for PCOS, but then there was a study that came out several years ago comparing the two and showed the pregnancy rates were a little bit higher with letrozole. Clomid's

perfectly good as well, but letrozole is better for PCOS. So if you have access to letrozole- That's very counterintuitive. If you think about it, when you take an aromatase inhibitor, you're going to lower estrogen, but not, I mean, I guess it depends on the dose. I guess I'm trying to think of like an astrozole, which I'm more familiar with than letrozole.

I suppose if you took a milligram of anastrozole every day for five days, you would drive estrogen down. But I didn't think that that reduction in estrogen would lead to a high enough rate

amount of gonadotropin-releasing hormone, which is effectively what has to be happening. It has to be going up to drive the secretion of LH and FSH. Right. Yeah. Yeah. Again, that's still counterintuitive to me. I would just think that giving 50 to 100 milligrams of Clomid would have a much bigger impact on that. It also works, but when they compare them, yeah. Randomized control trial, head-to-head comparison show the pregnancy rates were better for some reason with the letrozole compared to Clomid.

Okay. And does it matter when in her cycle she takes the letrozole? Usually it's recommended from day three to five. With the first day of full bleeding, we call that day one. What if the whole point of this is she's not having her period? How do you then time it? We induce a period, not a real period, but we induce a withdrawal bleed by giving progesterone typically. Okay. So you give a woman progesterone.

And then by withdrawing the progesterone, that's so cool. Yeah. You guys are so manipulative. I know. How much do you give? 200? No, 5 to 10 milligrams of methoxyprogesterone acetate, or you can give micronized progesterone for about 7 to 10 days.

Only 5 to 10 milligrams of micronized progesterone? No. Micronized progesterone, 200 milligrams. Okay. So you give the full party dose of micronized progesterone for five days. Yeah. Medroxyprogesterone acetate, 5 to 10 milligrams. So then, by the way, do you have a preference for MPA versus micronized? No, not really. Okay. Because it's such a short course. So you give the full dose of endometrial progesterone for five days. The second you take it off, it's the withdrawal of progesterone that causes the lining to shed.

And then we call that day one. And then you said on day five, we go ahead and start ripening the follicle with the aromatase inhibitor. Three to seven. Yeah. Day three to seven. For five days. Wow. Very cool. Yeah. And then we usually do an ultrasound around day 12-ish. You could see one of those follicles starting to grow. Not all patients will respond. So sometimes we have to increase the dose or sometimes we have to try a different medication. But most patients with PCOS will respond to that medication. Would

Would you say that every single woman out there with PCOS who wants to get pregnant has access to a doctor that understands what you just described and can do that for her? Or do you worry that too many women are being shunted to IVF too soon without an attempt at something like this? I definitely think there are probably not enough people who totally understand management of PCOS, especially in the context of fertility treatment.

For sure. And even in the context of non-infertility treatment, often what I hear from patients is they had irregular periods. Somebody told them to start go on the birth control pill. They never told them why. They didn't even know what they had PCOS. Happens to be the correct treatment. So great. But they've gone years now not understanding that they have PCOS and the implications of that, which as we talked about their metabolic implications, etc. So that's a problem.

But once they want to become pregnant, very few general gynecologists are set up to be able to treat patients with either Clomid or Letrozole. Some of them do, but it's not like a fertility clinic with reproductive endocrinologists because we're set up to do monitoring seven days a week and that type of thing. But not everybody has access to a fertility specialist, very dependent on where you live. A little bit better now with telehealth, but still...

Do you have to do the sonogram when you're doing this? You don't have to, but you want to know whether the woman's responding, meaning that she's actually ovulating. There are other ways to assess that. If she gets a period at the right time, then she probably ovulated, or if she gets pregnant, of course. Or you can check a progesterone level in the luneal phase, the second half of the cycle, and if it's elevated, she probably ovulated.

We just happen to use ultrasounds just easier. And how much of what you're describing is covered with typical health insurance? Kind of depends where you live. And the United States is very state dependent. Some states have infertility insurance mandates where your employer's insurance policy has to provide infertility diagnostic and treatment.

But many states, infertility is not covered. Or they might just cover the testing portion, but then not cover the treatment portion. So that's a huge problem. You're in Oregon. I'm in Oregon. What is the state there? We don't have an infertility insurance mandate yet, although we're working on it. It's actually a bill in session, this regular session now that we're trying to get passed because...

Infertility is a disease like every other disease, and we think it shouldn't matter where you live. You should have access to the appropriate treatment. So in our state, it kind of depends on your employer and whether they provide that particular insurance coverage. And so if a person has health insurance that does not cover reproductive care,

How much would be the cost of what you just described? The out-of-pocket cost? Yeah. So letrozole and Clomid are just oral medications. Yeah, they're cheap drugs. They're pretty cheap. Yeah. But then you add the ultrasound monitoring, that could be another $300 if you're paying out-of-pocket. And then if you're doing intrauterine insemination, for example, which we haven't talked about. No, let's just say just what we talked about is still a really cheap treatment, right? Relatively. Yeah, it's a few hundred dollars a month. For some people, that would be a lot. But relative to what we're about to talk about,

this is still well within the purview of out of pocket. For sure, compared to- Compared to what's coming. Yeah.

And so you kind of alluded to it, but I'm guessing you're saying, look, we would give this three tries. Would that be a fair assessment? Usually, yeah. So we'd go through three consecutive cycles of this. It's interesting. So there's two ways that this treatment could fail. The first is each time we did the ultrasound, we just didn't see an egg. Right. Not responding. We were not responding to the follicle stimulation. Right. Let's talk about what the implication is there. Alternatively, you could say-

God, three out of three months, we actually got ovulation, but we didn't get fertilization. If you were three months of that, I assume in parallel, you're doing the male workup because nothing would be a greater crime than going to all that trouble. And then you figured out the sperm was the problem. But let's assume you have that box checked. Would you be more inclined to continue that treatment for another three to six months? Yeah.

Yeah. And someone who hasn't been ovulating, they haven't tried for a year even. They haven't even met the criteria. Right. Exactly. So there's nothing magic about three months, but that's at least a check-in point where we say, hey, do we continue doing this or do we move on to something else? So if it's a young person and this is like the first time they're ovulating in their life, then yeah, we give them more time on a less invasive treatment, less expensive treatment. If they're like 38, 40, we probably move on to something else.

Okay, so let's go to the first case I described. So you get no ovulation. Okay, three times no ovulation. We're not going to waste her time anymore, but she's still young.

So what's your next step in the algorithm? Typically, so assuming we've tried higher doses and different medication like Clomid or whatever, still not responding, then we typically move on to a class of medication called gonadotropins or essentially FSH or follicle stimulating hormones, same hormone. Not LH, you don't give HCG directly? It's a little bit of combination. We do eventually give HCG to trigger ovulation. So we could either use those medications directly

with either timed intercourse or intrauterine insemination or with IVF. That middle option with timed intercourse and intrauterine insemination has kind of fallen out of favor a little bit because those medications are very expensive, require a lot of monitoring, success rate with IUI or timed intercourse is much lower than IVF. So we usually skip that and go directly to IVF. Okay. If you are going to use...

FSH and LH, give me a sense of cost. What dose are you using of HCG? So if the plan is just for time to intercourse, intrauterine insemination, we use maybe one to three ampoules of FSH in 75 units. The whole cycle, if you include the monitoring, the IUI, et cetera, could be like $3,000 or $4,000. So

So you can see- Now we're a big step up. Yeah. After a few cycles, it's almost the same cost as an IVF cycle. So you're like better off, especially if the patient wants to have, or the couple wants to have more than one child. The advantage of IVF is you can freeze embryos. So if you want to have two or three kids, might as well just do IVF and bank those embryos because otherwise you're going to have to do the same thing all over again for your second kid or your third kid. Yep.

I see. So basically, intrauterine insemination has largely fallen out of favor. Does that also mean the cost of IVF is coming down? Is that also making it more attractive? No. So IUI is very common still. I see. But we do it... We were talking specifically about the patient with PCOS who doesn't... Who's not ovulating. Right. Got it. But otherwise, and if you have a patient who is ovulating...

and has maybe unexplained infertility tubes are open. Yeah, in this case, you don't have to use a hormone to make her ovulate. You just need an ultrasound, which is relatively cheap to know when she's going to ovulate. Yeah, we still use the medication though, because we super ovulate. So normally you just make one egg. So when someone's already ovulating, the goal of the fertility medications is to get them to release more than one egg. So two eggs, three eggs, more eggs around, higher chance that one of them is going to be normal and one is going to fertilize.

What does the graph look like of number of eggs versus probability of twins, triplets, etc.? That's one of the downsides. So the risk of multiples with the oral medications like Clomid or Letrozole is about 5% to 8%, so not super high, but definitely higher than a patient were to conceive without medication. So that's something we counsel them about.

But it's very common as a first-line treatment to do oral medication with IUI, even in the context of normal sperm, I would say, although it's more important, of course, if there's a male component. And then if that didn't work in three cycles, then move on to IVF.

And with the injectables, what is the risk of multiple pregnancies? Much higher, 25 to 35%. And how many eggs are typically... It depends on the dose of the medication. So of course, when we're doing IVF, we want a lot of eggs. So it's 10 to 15 eggs. But yeah, but if we're doing IUI, it could be like three to five eggs or

It depends on the dose and depends on the age of the patient, et cetera. So what's fallen out of favor is injectables with IUI. We don't do that very much. Got it. Makes sense. Back in the day when every time you were in the grocery store and you saw the cover of the National Enquirer and there was like, this woman just had 47 babies. Like what the hell was going on in those eras? I think in the early days of IVF, well, even before IVF, when people just had access to injectables and IUI,

Most of the multiple pregnancies were not from IVF, but from injectables and IUI. Because literally there were women having eight and nine babies at a time. Yeah. That famous Octopolis case, I think that was actually an IVF case. So in the early days of IVF, when IVF was not very successful...

we had to transfer many embryos to get decent pregnancy rates. And some of the time, more than one would take. So the pregnancy rates were the multiple pregnancy rates. In that situation, they would have transferred eight and all eight took? Yeah. I'm not saying it was the right thing to do, but that's what happened. One can split into two, but in that particular case, more than the recommended number were transferred. So now there are very strict guidelines from the American Society for Reproductive Medicine, which is our professional organization.

that almost always we're transferring just one embryo these days. Unless a couple says, "I'd actually like to have twins." We kind of discourage that. Why? Because twins are riskier. They're riskier for the babies and for the mom. Riskier in an IVF setting? No, they're just riskier in general. Are IVF twins, do they pose any more risk to either fetus or mom than naturally conceived twins? Yes. There is some data that would suggest that IVF pregnancies are more complicated.

have a higher risk of complication than spontaneous pregnancies. We don't know exactly why, if it's the IVF or the fact that people who need IVF have underlying conditions that may predispose them to some of these complications. Overwhelmingly, data's reassuring that pregnancies do fine, the babies do fine, but we definitely know that twins, whether you conceive them spontaneously or with IVF, the risk of

Almost every pregnancy complication is going to be higher. So this is the risk of preeclampsia, HELP syndrome, blood clot, like anything that is a risk. Hypertension, hemorrhage, yes. Need for a C-section, all those risks. Premature delivery, all those risks are increased. So we don't intentionally like to produce twins, although it happens sometimes, obviously. Okay. Boy, this is fascinating stuff. So I'm just trying to take this in some sort of thoughtful order.

Should we now move to IVF or do you want to say a little bit more about IUI? We haven't really talked directly about IUI. By the way, I don't know what it is about when people say turkey baster. It makes me cringe like that. It's just such a gross image to me. So I am deliberately not going to say it other than that moment ago that I just said it. But just so that people know what we mean by intrauterine insemination, just to be clear, you are not using a turkey baster. Definitely not. Okay. Thank God.

Most disgusting image. I don't know why I get so grossed out by that. So can you explain how IUI is done? We've already said that with IUI, you largely favor an oral preparation. Usually, yeah. Yeah. Okay.

That means you're using an oral set of hormones so that the woman doesn't have a massive proliferation of follicles. Right. So the male ejaculates. Do you want fresh semen or do you care if it's frozen? What's the difference in success?

Same. We have single women as well and female same-sex couples who would also be doing donor insemination in that case. And we don't see any difference between fresh semen and frozen semen? No, assuming the sperm is normal. Assuming the sperm is identical. Yeah, yeah, exactly.

So the indications for IUI would be those scenarios I mentioned, single women, same-sex couples, or if there's a couple with unexplained infertility, you just can't find a reason, so you just want to try and optimize their chances. Or if there's a male factor, right? So if there's lower sperm count or lower motility.

The idea with IUI is that the female partner would typically take fertility medication to increase the number of eggs. She would track her ovulation. When she's ovulating, she would come to the clinic. The male partner would come to the clinic, produce a sperm sample. We process the sperm, which is basically collect the best sperm in a small volume, and then place that sperm directly into the uterus through the cervix. The problem that you're able to overcome on the sperm side would be number, right?

and motility.

Yeah, or morphology, like any abnormality in the semen analysis, as long as it's not very severe. So if the sperm are too few, they don't move well enough, if they're defective in most ways... IVF, more specifically ICSI, which stands for intracytoplasmic sperm injection, where we actually take a sperm and inject it directly into an egg. So for severe male factor, that would be the recommended treatment. But if the sperm's a little bit low, but it's not too bad...

Then IUI, we would try a few cycles of that first. Okay. So when in the woman's cycle, how many days before she ovulates do you want to inject those sperm into the mouth of the uterus? Essentially the day she's ovulating. So this is interesting to me because one of the things that I took away from the discussion with Paul last week was

that if you look at the probability distribution curve of when a pregnancy occurs, the ejaculate enters the uterus prior to ovulation. I forget what he said, 80% of pregnancies occur when the sperm are there prior to ovulation. And I could be wrong on this, I've already forgotten. I think only 20% occur post-ovulation. So the tail falls off much quicker.

Yes, it is true that if there's sperm around prior to ovulation, it can hang around for a while because it lives two to three days or so, whereas the lifespan of the ovulated egg is much shorter. So based on that, wouldn't it make sense to put the sperm in prior to ovulation, or is it just too risky to try and anticipate when that is?

If it's a stray couple, we'll tell them to also have intercourse every couple of days around the time of ovulation. But the pregnancy rates in these probably back early studies that have looked at this show that probably the highest pregnancy rate if you do the insemination on the day that

that you think the patient is ovulating. And are you doing that with ultrasound? Usually LH monitoring. So patient will either monitor her urine, LH, and remember LH goes up just before ovulation. We typically also do ultrasound based on the size of the follicles,

We sometimes trigger ovulation with HCG, which kind of simulates the woman's own LH surge. So if you want to be pretty precise. How big a dose of HCG do you need? Usually 5,000 units, which is... Half a vial. It's a lot, probably more than physiologic. The purpose is to cause release of the egg, and then we time the insemination to happen when we think the ovulation is happening. Okay. Do you ever do the following? This is me just thinking out the box.

get the male to bank a ton of sperm. Take weeks to get, or if she's going to a sperm bank, if it's a same-sex couple, but whatever. Just get multiple aliquots of semen. So on day one,

insert. Day two, insert. Day three, give 10,000 IU of HCG, insert, and then day four, insert. In other words, cover your bases and just have lots of semen sitting around and then force the ovulation. You could do that, or the couple could just have sex. But we then introduce another variable, right? Which is what if the count is low enough? Because if he's ejaculating every day, you're not having a chance to fully rebuild the

the supply? What if his motility is anything other than perfect? Or in the other case, what if we're dealing with same-sex couples or a single mom?

Yeah, there have been studies looking at two IUIs compared to one, specifically same-sex couples or single women, show no difference. And remember, if you're paying out of pocket for all these things, it has to be worth it. So at some point, even if what I proposed worked better, it's going to approach the cost of IVF. Right. How much better and is it worth another $400 five days now your cost of your IUI cycles all of a sudden?

$2,000. Yeah. So those are practical considerations as well. So maybe this question is too broad, so feel free to partition it. But if you look at all uses of IUI, what is the success rate? And feel free to, again, divide that up into different cases. The pregnancy success rate really depends on the age of the female partner. So if it's a young woman in her 20s, success rate might approach...

success rate for natural conception, which might be 20-25% per cycle. If it's a woman over 35, might be 10-15%. If it's a woman over 40, might only be 1-5% per cycle. Wow. And that's because, again, it's all about the quality of the egg. So even though an egg is released, maybe two eggs are released, if those eggs aren't normal, they're not going to fertilize and implant. Okay. So...

We've covered a whole lot of fertility treatments. It seems that the likelihood that a woman who's undergone some of the things we've discussed that still ends up going down to the IVF pathway is reasonably high.

Yeah, the majority of people don't need IVF. Again, it depends on the age of the female partner specifically and what the problem is. So let's just go sub 35. Okay. So of all women who present with defined infertility, which if she's under 35 means more than a year of regular sex, no pregnancy, walk through the success rate of pregnancy by modality. So under 35,

Infertility for a year, how many are successful with just an oral treatment absent IUI? Again, sort of depends on what the cause of the infertility is. Is it unexplained or is it PCOS, for example? No, let's say unexplained. Unexplained, probably less than 50% will get pregnant with IUI and have to move on to IVF. Because unexplained to me means either it's bad luck or more likely there's something going on and we just can't figure it out.

In those cases, almost always IVF is going to give you a higher chance of success. Oh, sorry. Yes. That I can understand for sure. I'm saying how many of them will need to get IVF? Are you answering that question as well? Yeah. That's what I was getting at. For PCOS, their problem was they just weren't ovulating. So probably 80% of those people will get pregnant with just ovulation induction and IUI because you're solving the problem. So hormonal therapy basically is addressing the problem. Got it. If it's very severe male factor, probably IUI.

It's not going to work. So it really kind of depends what the etiology of the infertility. And so now if we talk about, oh, age 35 to 45, and again, let's take PCOS off the table in this age group. So let's just say we're talking 35 to 45 year old women, PCOS not an issue. And let's just also assert male not an issue. That's been worked out. Unexplained infertility. So I guess now technically you would call it 60%.

six months of not getting pregnant would be sufficient, but what percentage of women will get pregnant absent an IVF strategy? So depends how long you do it for. So most of the time we're only doing it for three cycles because like I said, it's not cost effective to do it for longer. So I would say in that age group, probably the majority of women will likely need IVF if they are not successful after three months.

Theoretically, if you continue doing IUI, a lot of those people will eventually get pregnant. But we tend to stop at three months. Tell me at three months again, what percentage are going to be successful with three cycles? In that age group of unexplained infertility? Unexplained over 35? I don't know the exact number, but probably under 50%. Okay. But that could be a third potentially. Yeah. Because the success rate per cycle is something like in that age group, let's say 10 to 15%.

So you go one minus that number times three, one minus that to the third power should be about 30%. Yeah, exactly. Okay. So now let's talk a little bit about IVF. First successful IVF baby, 1978, if my memory serves correctly. That's right. Referred to as a test tube baby, which is kind of weird because I would imagine it was in a Petri dish, not a test tube. But anyway. Yeah, yeah. We've come a long way since then. We have. For historical context, I don't know anything about that girl.

But do you know anything about how that was done back in 1978? Yeah. Actually, there's a recent docudrama out called Joy. Is that her name? Her middle name, I believe, is Joy. Ah. Yes. Well, that's great. Louise Joy Brown. What's her name? Louise Brown. I believe her middle name is Joy. Got it. It's a movie about the first IVF success. Oh, that's great. Now, of course, they tried for many, many years before they had the first success. These were two doctors.

I mean, maybe this is all in the docudrama and I can't wait to check it out, but what kind of IRB approval was there? How much controversy was there around this? It must have been a huge deal. Yeah. There was a lot of controversy.

This was very freaky. Yeah, yeah. And this was done at the time primarily for women with tubal factor blocked tubes. I think, I can't remember the exact details of the couple, but I believe they had tubal disease. And IVF works great for tubal disease because, of course, you're bypassing the tubes altogether. Where was this done? In the UK and Britain. I didn't realize it wasn't done here in the US. So tell me a little bit about technologically how they accomplished it back then.

Yeah, I think the first cases, they were actually doing surgery under general anesthesia. Open surgery to harvest? Or laparoscopic, I believe. Yeah. To retrieve the eggs. Oh, wow. And then they were combining the eggs with the sperm in the test tube, Petri dish. And then I think they were transferring the embryo maybe back into the tube in those days.

Or maybe through the cervix. I can't remember the details. But yes, a lot has changed over the last 45 years or so. Wow. Despite that success in 1978, what did it look like for the next 10 years? From 1978 to 1988, how prevalent was IVF? I guess, when did it get to the point where anybody who could afford it could access it?

Much more recently, yeah. The first IVF baby in the United States was born a few years later, I think maybe 1981 or so.

In Virginia, I believe, it took probably many decades for it to become commonplace throughout the world. So now most countries, you can access IVF. Not everybody can access IVF, but in some countries more than others. But depending on how you look at it, it's kind of new, kind of not. 45 years, but in medicine, that's relatively recent development. And it's been only in the last maybe 20, 30 years that it's become standard.

Okay. So let's just walk through how IVF works and then we'll kind of dive into the ins and outs of some of the nuances. So a woman comes to you, probably she's progressed through some layers of treatment, but you've collectively come to the decision that this is hands down the best opportunity, both for success and risk. So how does the treatment go? So typically we do

A bunch of screening tests on both partners. That includes some blood tests, a semen analysis, an ultrasound to get some assessment of their egg number, the woman's egg number. And then when the cycle starts, takes about two to three months to complete a cycle of IVF. And when you say egg number, are you determining that through an AMH or through a physical examination of the ovaries? Both. So we do an ultrasound, we can count the number of follicles. How small are these things? A few millimeters.

And you have the resolution to see that on an ultrasound? Yeah. And that gives you some sense of about how many eggs that particular patient will produce with ovarian stimulation.

And we use AMH as a hormone. Explain what AMH is and how it works. Yeah. AMH is a hormone that stands for anti-malarian hormone. It's secreted by the cells that surround the egg, so it tends to correlate with egg number. It doesn't tell you anything about fertility or pregnancy rates or anything like that. Age is still the most important factor in that sense.

But it does give you an idea. Do you have a normal number of eggs for your age? Just numbers. So two women that have the same number of eggs. If one woman has high quality eggs, the other woman does not. They could still have the same AMH level on a blood test. Right. If they're different ages, their success rates can be different. Remind me of the range. So a prepubescent girl who has a billion, not a billion, but right, a million eggs, but who is not pregnant.

Does she have a high or low AMH? She has a higher AMH. We tend not to use it in that age group because it's less reliable. But a normal AMH would be about two, I think the unit's picogram per deciliter, I believe,

Less than one is considered low. So a woman who's older... But what's the difference between a 16-year-old girl who probably could get pregnant if she walked past a guy versus... That never happens, by the way. Okay, good. No, but if you have like a 16-year-old girl who is at the peak of her fertility versus...

a 30-year-old woman who's still fertile but has lost a step? Like what's the difference in AMH between them? Yeah, it's a very narrow range. So like above two, we consider that's probably normal reproductive age. Above two is two effectively. Now it can be high too in patients with PCOS, for example, have very high levels, but different thing. But above two, that's usually good number of eggs.

Less than one, low number of eggs. So this is kind of a binary test? Well, not really. You're not looking at, oh, this woman's 1.6, this woman's 1.7, this woman's... Not that. Yeah. You're not looking at it like you look at a TSH or something. Right, right. And the assay is also very variable. Depends where you have it done. Whatever just gives you an idea. Is the egg number average for your person's age? More than average, less than average. And it helps us because we can determine what dose of medication to use during IVF. And we also can give expectation to the patient

You're probably going to make five to 10 eggs, maybe not 15 to 20 and that type of thing.

When she's ready to start the cycle, everything usually starts with their period, depending on the age again. But usually the patient starts on a couple of weeks of birth control pills. What that does is kind of suppresses the ovaries because we want all the eggs to kind of grow at the same rate. Stop the pill, then you start the gonadotropins, which are the FSH. Now you go injectable. And they're injectable, just under the skin kind of injections. So meaning HCG and FSH. Not HCG, but primarily FSH with a little bit of LH. Okay.

So you're on those for about 8 to 12 days. And then every few days while you're taking those medications, you have to come into the clinic for ultrasound monitoring and estradiol levels, blood levels. And we can monitor how many follicles are growing, how big they are, etc. Usually medications are pretty well tolerated.

And what dose of LH and FSH is she injecting relative to what she would normally make? Is it a 2X, 5X, 10X? It depends on the age. Again, higher doses for women who are older, but much, much higher doses. More than 10X? Maybe not. Maybe 5X.

Typical symptoms? Most common, I would say, is bloating as the ovaries get a little more enlarged. There's a small risk of something called ovarian hyperstimulation syndrome when the ovaries get a little bit too stimulated, but that's exceedingly rare. There's signs that it's happening. We can always back down on the dose. Sometimes the patient doesn't make as many eggs as we were hoping, so sometimes we have to increase the dose or change the protocol, but usually we guess pretty right.

And then once the follicles are a certain size, that's how we know the eggs are mature. Because of course, we can't see the eggs on the ultrasound, you can only see the follicles that contain the egg. So then the patient gets HCG, which is another medication which kind of simulates her own LH surge. And the purpose of that medication, it causes the final maturation of the eggs. And if

And if we did not do an egg retrieval, she would release all those eggs. But of course, we time the egg retrieval to happen just before the woman ovulates. So that medication is very time sensitive.

And to be clear, were you only giving her FSH before or were you giving her LH as well? A little bit of LH, but mostly FSH. And why are you using LH versus HCG? Just to simulate the physiologic cycle. I didn't realize there was a difference appreciated by the body between them. They're very similar. So we use HCG for, but the body of course doesn't have HCG until the patient's pregnant, but it works well as

As a substitute for LH. So there is synthetic LH out there as a drug? Yeah. Okay. It's combined with, comes in as a combination drug. With the FSH? Yeah. Got it. I see. So...

How do you prevent her from ovulating while you are giving her FSH and LH and she is ripening multiple follicles? How are you preventing an ovulation? Good question. There's another medication that we give. It's called the GnRH antagonist. It basically blocks the LH surge from happening until we cause it. When you're giving her FSH, the LH that's attached to it is very, very low. Right.

That will prevent an ovulation. Yes, the antagonist will. Basically blocking the GnRH, which is another hormone. I'm surprised that the fact that you're giving her so much FSH with a little bit of LH isn't enough to suppress the GnRH. But anyway, clearly not, or you wouldn't be having to give her that. Okay, so you give her a GnRH antagonist. That basically puts a block between her hypothalamus and her pituitary. Right. So then now you control the switch. Right.

and the switch is in the megadose of HCG, which is an LH analog, do you harvest the follicles in the fallopian tube? In the ovaries. So the egg retrieval happens two days after the HCG trigger. Wow. Yeah. It would have taken two days? 36 hours specifically. So she usually takes it in the evening and then the retrieval... The day after in the morning.

Okay, so a woman comes into your office two days later and walk me through this. So you lay her on a table, you've got an ultrasound on her ovary, and you're literally putting a needle in there? Well, first of all, she's asleep. Fully asleep or just local sedation? Yeah, so this is done in a surgery center typically or clinic with anesthesiologists present, IV sedation. It's like a colonoscopy or dental extraction or something? Yeah, all done vaginally actually using the ultrasound.

And that day, there is a needle that's guided by the ultrasound that goes through the vagina into the ovaries. So we don't do transabdominal. Dumb question.

Don't you have a much straighter shot going through the abdomen? Not really. You just don't want to go through the peritoneum. And there's a lot of stuff between the abdomen and the ovary, like bowel. And you can't just manipulate and move the bowel out of the way or something? No, it's much easier through the vagina. They're sitting right there. So again, just pardon my ignorance of the anatomy, because again, I'm probably still locked into the image of the ovaries being like this. But you're saying, no, Peter, the ovaries are probably sitting right on top of the uterus. Right on top of the top of the vagina.

to the side of the uterus and just stick a needle on either side. So literally out of the vagina, not even going through the cervix. Yep.

That still strikes me as a very delicate, complicated procedure. I mean, it's a surgery. Yeah, relatively minor type surgery. How much do you have to dilate the vagina? What I'm thinking about is how to get your hand in there to guide the needle. You don't have to get your hand in there. Yeah, you should watch a YouTube video, but it's just the ultrasound probe and there's a needle guide. Is the needle guide inside the probe or alongside? Alongside. Okay. And the needle, it's a long needle, right? So your hand's not in the vagina. What gauge?

16, and it goes through the vagina. You're doing this under ultrasound guidance, you can see exactly. But somebody else is obviously manipulating the ultrasound for you. No, no, you have it in your hand. It's a vaginal ultrasound. Oh, that's right, that's right. Yeah, yeah, yeah. So you're doing both. So you're looking where you're going with the ultrasound, and you're using the needle to puncture the ovary, get into the follicles. The needle is attached to like a vacuum suction, and so the fluid and the follicles collected...

goes through the needle into the test tube, and then that test tube is handed off to the embryologist. They look under the microscope and try and isolate the egg.

Now, I'm just so full of dumb questions here today, Paula. How do you prevent yourself from sucking out 300 non-follicle eggs and ultimately destroy your long-term fertility risks? Well, you only go into the large follicles, which are really the only ones you can see on ultrasound. There's a gazillion of eggs in there, but you can't even see them. And you're not running the risk of sucking up those eggs? No. No, you're just going into the follicles.

How big is the ovary? The ovary is a few centimeters at that point, but each follicle is about two centimeters, I would say, and there might be 10. Whoa, whoa, whoa. How is each follicle two centimeters? In diameter. But you said the ovary is only a couple of centimeters. No, it's like maybe five, six, like a small plum or something. Okay, wait a minute. So if you have a plum or a tangerine that is the ovary, you're saying each follicle is two centimeters in diameter? Roughly.

That's huge. 1.5 to 2. I wouldn't have even thought it was one centimeter. How many follicles are in there? On average, we get 10 to 15. So maybe the ovary is bigger. Maybe it's more like an orange. I'm thinking more an unstimulated ovary is more like a plum. When it's stimulated, more like a grapefruit. Okay. I see. So you have really good resolution of where the follicles are. Yeah. Okay. So you're not running the risk of...

sucking everything out of the ovary. No. And we're just getting fluid, right? We're not touching tissue of the ovary, just the fluid and the follicles. It's only a 16 gauge needle. Does that mean you're puncturing the follicle? Each follicle. Gets punctured before it enters the needle. Yeah.

The fluid, yeah. So you do it one at a time? Yeah. You go ping into a follicle, burst it open and the egg, because a 16 gauge needle is probably only a millimeter across. Yeah. You suck out all the fluid and you don't have to take it out each time. You can go from follicle to follicle to follicle. You just have to go in typically twice, once on the right and once on the left.

Pretty interesting that that works. Yeah. It's easiest maybe to just watch a video of it and then you get the idea. I'm just thinking of all the things that could go wrong and how like the needle could get gunked up with like tissue and then you got to pull it out and put it back in. All those things can happen. You know, there's always a small risk of bleeding, small risk of infection, small risk of injury in other organs. And this is happening, you do this on both sides because presumably you're stimulating both sides. So how long does that procedure typically take?

Half an hour. And you've got the embryologist next to you and he or she is under the microscope going check, check, check, check, check. Yep. He or she is validating that you indeed are getting ripened eggs and they look different presumably.

Like those are easy to identify under a light microscope? Basically, they tell us they got eggs. We don't know if they're mature yet. We know nothing about them yet. I see. But when we get the eggs, they go to the lab and then the rest of the process happens there. So in the retrieval, we're just aspirating all the follicles, trying to get as many eggs as possible. Okay. Then let's just assume that the woman is doing this not to just freeze her eggs, but because she wants to get pregnant.

Would you then go ahead and when she wakes up, have a discussion that says, "We got this many eggs. How many would you like to fertilize? How many would you like to freeze?" That discussion has happened way upstream. Typically we're fertilizing all of them. Yeah. There's no reason not to fertilize. Right. Okay. Tell me the time course now and how you move from retrieval to fertilization. So then the eggs are sitting in the Petri dish in the lab. What's the medium? It is this proprietary medium. Is proprietary? Yes.

Meaning each lab will have its own medium? There are commercial companies that make it, but the exact components of it, not entirely known. So there are different companies that have different mediums? Yes, I believe there's more than one, but it's meant to kind of emulate the fluid in the tubes, like where fertilization would normally happen. How much of a competitive advantage is it for an embryologist? Like how many options do they have to choose from commercially?

I don't think there's that many media companies. I see. Is this a huge area of innovation in the field? It must be.

Not really. I would have guessed this would be so important. I think they got it down. Was there a day when this was a problem? I'm sure. Yeah, maybe in the early days. So the embryologist transfers this to the media? Yep. A few hours later, the eggs are inseminated. So with conventional IVF, we just put a bunch of sperm in there and let the fertilization happen by itself. With ICSI, or intracytoplasmic sperm injection, the embryologist takes a

a single sperm and injects it into each egg. And the only time again you need to do ICSI is if the sperm is so dysfunctional that it can't even on its own with no barriers make its way to fertilization when placed in direct proximity of an egg? It probably could, but maybe there's too few sperm. So anytime there's a male factor, we tend to do ICSI. Any male factor you go straight to ICSI? Any male factor, yeah. And in fact,

A lot of times it's done even when there isn't a male factor because fertilization rate is a little bit higher with ICSI compared to IVF. In very few cases, you don't get fertilization, so you don't want to find out, oh, by the way, sperm can't fertilize your egg. That's the whole problem all along because then you got to throw away the eggs. So again, for a couple listening to us now, this is something they need to be talking about with their...

fertility doc, which is, hey, do you do ICSI out of the gate no matter what? Yeah. It's a little controversial because it adds cost. How much cost? Probably another $1,000 or $2,000 or something. No, probably $1,000. So the data, to be clear, shows that ICSI and IVF have similar success rates for non-male factor.

But I'm just telling you that a lot of times we're doing it anyway because we don't want to find out small, very small percentage of cases that have zero fertilization. That's like not a good conversation. Oh, that would be just catastrophic because you've lost those eggs too. Right. Right. Right. So that's part of the reason that we do it. But technically, if you just look at the data, success rates should be the same, exceeding conventional IVF if non-male factor. But a lot of times there's sperm factor, so we're doing XC anyway.

These go into, the media sits at room temperature. I'm sorry, at body temperature. Do you put it into a 37 degree oven? Yeah, body temperature in an incubator. And then all the micromanipulations happening. What are the types of manipulations that are needed to foster the right environment? How much you're moving the fluid around? How often are you changing the media? This is like the most important cell culture experiment of all time. Pretty much, pretty much.

To be fair, it's done by the embryologists, not by me, but they strip the eggs first, which means they remove the cells around the eggs. Then a few hours later, they're injecting the sperm into each egg. And then the media these days may or may not get changed over the five or six days that we culture the embryos, trying to not have to take the embryos out of the incubator if we don't have to kind of thing.

So by the next day, usually we look at the embryos to see, or the eggs, see if they're fertilized. Usually about 70% of the eggs fertilize. So let's say we get 10 eggs. You can expect maybe seven of them will be fertilized, and now there's seven embryos.

So we discard the unfertilized eggs, continue to culture. And you can tell that grossly or are you having to move them under a microscope at this point? Under a microscope. Yeah. Yeah. And then we culture them in the Petri dish. At this point, are they all in one dish or are you separating them? They're in one like droplet of oil and there might be more than one droplet in each dish. How are embryologists trained? How does one become an embryologist?

Well, there's no clear pathway. There's not a whole bunch of embryology schools. But if I wanted to be an embryologist, what would I do? Mostly, you have an apprenticeship almost. You might start working in a fertility clinic and do some basic lab prep work initially. Most of them have some sort of undergraduate science background, but you don't have to. But anyway, you gain experience in the lab and then...

eventually you become a junior embryologist. So it's like a mentorship program. How many years would it take if I started tomorrow working as a lab tech who was doing nothing but cleaning petri dishes? How many years would it take for me to be the head embryologist in your lab? It might take four to five years. Take a while. Now there's some formal schools available as well with online programs, with some in-person components. Not to take anything away from what you do, but you could have the best experience

fertility doctor, if they don't have a good embryologist, you're not going to have great success rates. Oh, yeah, yeah. I would say the lab is almost more important than what we do because there's just more variability. But luckily, at least in the United States, labs are pretty good. But yeah, that's one of the most important things. Because I used to work in a lab, I just can think of a hundred ways that could get screwed up, contaminated, jostled, all these things that can go wrong. Super important. Yeah. So

Yeah. So most of the success rate, probably more related to what happens in the lab than anything I do or one of my physician colleague does. I guess the question is, well, let's finish the story and then I want to come back. So how many days, you go to 14 days?

No, five days, six days. And depending if we're doing a fresh transfer or freezing the embryos, or a fresh transfer, we sometimes- So you'll do both, right? We do both. Yeah. Although these days, most of the time we're freezing. Because you're doing genetic screening? Because we're doing genetic testing, right? Okay.

So let's go through that example then. Okay. So we're culturing these embryos in the Petri dish for five to six days. Then we look at them again. The ones that have made it to that stage, which is usually only half of them. So remember you're seven, now maybe there's three or four. So what explains that?

So most likely the ones that didn't make it are the chromosomally abnormal ones. Remember we talked earlier about those ones not making it. And the reason it's only half is because by definition you're doing this in women who tend to be a bit older. Not that one would do this, but just as a thought experiment, if you did this exact thing in 18-year-old girls, presumably you'd have a much higher success rate. Yeah. We call that the blastulation rate. It's a little bit higher in younger women.

Also, you have more eggs and more embryos, of course. But yes, the blastulation rate, the ones that make it to day five or six is a lower percentage, the older a woman is, because a higher proportion of those embryos are just going to be abnormal. So the ones that make it to day five or six are more likely to be normal, but not necessarily normal. So we can also do genetic testing on those embryos, which involves biopsying them. So we take a few cells from the embryo

Freeze the embryos. So yeah, let's talk about that. So how many cells do you have at five days again? Altogether, you might have like 60 to 80 cells. Okay. So you take two or three of those. Five or six. Five or six. Yeah. And they're from the perimeter. The trophoblast, not the embryo directly, but the cells surrounding the embryo. You still have full genetic material there. And so you do that for each and every egg, every embryo, sorry. And then you freeze each embryo? Yep.

Tell me what the freezing process is like. So the freezing process these days is one called vitrification, it's called. And it's like this special kind of freezing that doesn't result in ice crystals. So how do you do that? There's a process. It happens in the lab. There's a machine that does it, that lowers the temperature. So the rate at which they lower the temperature? Right. It's rapid. Okay.

Okay, so it's like a liquid nitrogen dump basically. Right, right, right. As opposed to old days when we did slow freezing. So it becomes like a glass-like state without crystals. It works really well and the survival is really high. And then you store them at what temp? Like liquid nitrogen temp? Yeah. Yep. It's not like in your freezer? No, at home. And then how long does it take typically to get the genetic results? Typically within a week or two. Okay.

What depth of genetic testing is being done here? Are you doing whole genome sequence or are you just looking at a handful of SNPs that are pre-identified as the ones that matter? So it's evolved over time. And I should say it's still very controversial because

There's always a risk of harming the embryos. You're only looking at a few cells. So is it really representative of the embryo? I mean, we do it a lot. And the data definitely shows that if you transfer a normal embryo, it has a very high chance of implanting. But the issue recently has been, are we discarding embryos that are maybe normal because we think they're abnormal based on the genetic testing, but the genetic testing is flawed?

Presumably, genetic testing is really easy to identify aneuploidy. Chromosomal analysis is trivial. Yes, it's geared up to do that, right. So most of the time we're using something called next-generation sequencing, which is very high-level sequencing, but it's not whole genome sequencing. So you're getting... Targeted. Yeah. And you're looking mostly at chromosomal abnormalities, unless you know that the couple is a carrier for some genetic mutation that you also want to screen for. Yeah, so let's say

one of the parents, well, this would be a bad example, but... Cystic fibrosis, like let's say both patients are carriers. So both of them are a carrier for CF. And so there's a one in four chance that you're going to get two copies of CF. So then you're looking directly for the CF genes. Exactly. Beta-thal, sickle cell, the standard. Yeah, there's a whole bunch of them. Right. And part of the screening, we didn't mention it, but most people doing IVF will get carrier screening to see if their carriers for

for any genetic mutations. But that's a pretty common scenario where you have two people that are CF carriers, neither of whom have CF. Most of those people would say, I'm going to do IVF because I don't want to take the chance. And then what about people who come in and say, oh, but one of us is each an APOE4 carrier. So we're each a 3-4 and we would really like to not select a 4-4 as an example. So one, are

Are you able to look at that? And two, does that start to cross an ethical line? Yeah. It's a little more controversial when you're talking about... Non-deterministic adult consequence genes. With variable penetrance, right? You may or may not get Alzheimer's or whatever it is. So it's a little more controversial, but we're kind of going in that direction, I would say. We're definitely going probably in the near future towards whole genome sequencing where we can pick up even mutations that happen to

what we call de novo, right? You might not be a carrier, but it might just happen randomly. So you could pick up some disease that way. And then what you're talking about is... Like BRCA. Well, BRCA, yeah. Often we know ahead of time, the patient's carrier, we can test for it. LPA for cardiovascular disease. Yeah, there's a whole bunch of things. So people are starting to talk about polygenic screening of embryos, but it's a little more controversial because the science isn't quite settled yet. And...

It's one thing if you're already doing IVF and we have these embryos here and we're just going to add another layer of testing, like which one of these embryos is at higher risk for like diabetes or hypertension. Whole different story if you're saying, oh, you should do IVF. Because of? Because we want to get the embryo with the lowest risk of these diseases. So we're not quite there. There's a very controversial, plus it's expensive and we already talked about cost barriers and

There are ethical issues as well. Are we now, is it a form of positive eugenics and that type of thing? So, that particular type of testing is still controversial. But anti-deploy testing, testing for chromosomal abnormalities is pretty routine, pretty standard.

Now, there was a day when people weren't doing any genetic testing and the embryo selection was just based on morphology, right? Yes. Yeah. Which is back in the days where we had to transfer more than one embryo because we didn't know. You could look at two embryos and they could look...

Both normal, but one of them is chromosomally abnormal and one's not. You can't really tell. So we had to transfer more embryos to get decent pregnancy rates. Now with genetic testing, because we know that a chromosomally normal embryo has a pretty high chance of implanting, not 100%, like maybe 70, 75%. So there's still reasons. For some reason, that's not the whole story because even chromosomally normal embryos sometimes don't implant. Yeah, that's lower than I would have guessed.

Is it? 70% to 75% for something that's chromosomally normal. I would have guessed at that stage, given all the selections taking place. What is the concordance between, let's go one step further, chromosomally genetically normal and good morphology? There's good correlation. Yeah. We use both.

If there's discordance there, which one are you relying on? Or are you discarding? Unless you have concordance that's positive for both. In reality, the ones that have poor morphology aren't even frozen or biopsied. They're discarded because we know... So we select it out. Yeah, you select it out. So there might be a little bit of difference in morphology between the ones that you've actually decided to freeze and biopsy and keep. And you presumably have the genetic testing on all of them.

You would preferentially, of course, transfer the ones that are chromosomally normal, even if the morphology grade is a little bit lower. So you have selected out bad morphology. Let's just say you harvested 15, you fertilized 10, 7 had good morphology.

Six came back genetically good. Those would be reasonable numbers. Yeah, the six out of seven is high. Yeah So five came back genetically good. Let's say a young person. Yeah, so you got one-third One-third of what you harvested you could implant you're saying each of those is 70 to 75 percent success rate And yet you would only implant one at a time. Yeah, which is interesting because if you implanted two and

Let's do the math. You're talking about- 50% chance, roughly, of twins. Yeah, which is high. Too high. We just can't take that risk. I mean, obviously, we believe in patient autonomy. Patient usually gets to make that decision, but- You're going to make the case for where that's not a great idea. You want a healthy baby in the end. You want a healthy mom. Yeah. Okay. So now let's talk about

Now it's time to implant. So how does that process work? So that process is much less complicated, but equally important. So usually it's timed. It has to happen at a certain time in the cycle. So we either use the woman's natural cycle to time it and time it at the time that

implantation would normally occur, which is the second half of the cycle, or we use what we call a controlled program cycle where we basically give the woman the hormones and then time the transfer to happen at a specific time. The actual process, kind of like a pap smear, it basically doesn't require any anesthesia or anything. We do do it under ultrasound guidance, so abdominal ultrasound. We thaw one of the embryos, draw it up in a little catheter with a little syringe on the end,

Place the speculum in the vagina and then just pass the catheter through the cervix and we're looking on the ultrasound for the placement. And where are you implanting it? One and a half centimeters to two centimeters from the top of the uterus. So a few centimeters through the cervix. How do you make sure it doesn't come out?

I mean, you can't, but it doesn't usually. You put it in there, I describe it more like peanut butter in there. It's not like you can stand up and it comes out. What's the total volume you're injecting? 50 microliters, really small. What does the inside of a uterus look like at that stage? You've timed it so that this is a uterus that doesn't have a lining yet. Does have a lining. How thick is the lining? It's about...

Seven to 10 millimeters. But it's going to get a heck of a lot thicker. This is technically only about 14 days past her period, or are you doing it artificially more into the luteal phase? So it's roughly seven days or so after ovulation, right? Ah, got it. Yes, yes, yes. So the lining is thickened already. Okay. And that's one of the things we check with ultrasound before we do the transfer to make sure the lining is- What does it actually look like?

Is it tentacle fingers or...? On the ultrasound, which is how we assess it, basically the two walls of the uterus are opposing each other. It's not like you can see the cavity. It's a potential space, not a real space. Potential space, exactly. On the ultrasound, the lining has a different echo density than muscle. The wall itself, right. Right. So we can measure the thickness.

And basically, the combined thickness of the two posing walls has to be at least seven millimeters or so. And if you get in there and do the ultrasound and it's not, are you going to come back and try to do it another day? And have you lost that egg because it's been thawed? Or can you keep that egg in the medium now? We essentially assess the lining a week before we do the transfer.

So we would not thaw the embryo unless we were sure of the lining. Until it's go time. Yeah. Because once it's thawed, I mean, you can refreeze it, but probably doesn't do as well. Not a good idea. Yeah. Okay. So I see. So once you put that egg in there. Embryo.

And then are you done or are you still doing ongoing hormone therapy? Sometimes we give supplemental progesterone. That's another hormone that helps maintain the pregnancy. And then usually 12 to 14 days later, the patient has her first pregnancy test. Hopefully she's pregnant. We usually follow the pregnancy for the first few weeks. And then she transfers to her non-IVF? Yeah. Wow.

It's just kind of amazing that this all works. Yeah. I've been doing it for 30 plus years and I still find it fascinating. Yeah. Okay. So how often does a woman go through all of this and...

for whatever reason, you can't get enough eggs or the eggs you get are not chromosomally normal and her next alternative is an egg donor? Unfortunately, more often than we would like. Again, it depends on the age of the patient, but sometimes patients do multiple cycles. Maybe they don't have any normal embryos or maybe even the normal embryos we transfer don't take or a number of different things can happen.

So the most common reason someone would need an egg donor is usually maternal age. So someone who's older and has tried to get pregnant with their own eggs, hasn't worked for whatever reason, and then now she's looking at egg donation as an option. That works really well. So usually egg donors are young women in their 20s, early 30s sometimes.

They produce multiple eggs. And then the age of the uterus doesn't seem to matter as much. So the success rate with donor egg is quite high. It's about 70, 75%. Whereas for women over 40, using their own eggs, success rate might be 10 to 20% per cycle. Per cycle? Yeah. Wow. 10 to 20% for a 40-year-old woman? Yeah. Untested embryos. Or they may not get any embryos.

normal embryos. Yeah.

I did not realize it was that low. Yeah. How many times can a young woman be an egg donor before you worry about... Is there anything you worry about if you're counseling these women? I assume the same women are coming to you as egg donors. Yes. Sometimes people do it multiple times. Sometimes they just do it once. Does it pose any risk? They're essentially undergoing the IVF process themselves, or at least the first half of it. There's the risks we talk about, ovarian hyperstimulation, which is rare, risks associated with the retrieval.

anesthesia. But is there anything that restricts her ability to get pregnant later in life? No. Barring any complications, from major complications, it does not seem to impact future fertility. What is the typical fee that's collected by an egg donor? It's usually between $5,000 and $10,000, depending on where you live. Okay. That's a lot of money. It's a lot of money for a two-week period. Yeah.

And so a woman could do that a couple times a year if she wanted to? So the guideline's up to six times. Six times a year? No, six times lifetime. Oh. Okay. So up to six times. And that's a little bit arbitrary, but the professional society has decided that's kind of a good number of times.

Most people don't do it that many times. They might just do it once or twice. And so what is, and maybe you don't do this, I don't know, but women who undergo egg donation or IVF via egg donation, what do you discuss with them about the appropriateness of timing in explaining to the children that they have a different genetic mother? Before anybody does egg donation or even before they donate eggs, we always have them meet with one of our mental

mental health therapist just as a psychoeducational visit to go over these types of questions and best practices around what to tell the child, when to tell the child. General rule is tell them early and tell them often. You basically want to normalize the thing. And you definitely want to be the ones to tell them and you don't want them to find out by some other means like somebody contacts them on 23andMe or something like that.

And early means what? Telling them before they understand reproduction? Like, what are you telling them? Yeah, I mean, again, it's a little outside my area of expertise, but when they're quite young, like it could be like four to six years of age, it might depend on the child and how mature they are, et cetera. But basically, there's different ways to introduce the concept. Obviously, if it's a same-sex couple or if it's a single person, it might happen earlier as opposed to a straight couple.

So if someone's listening to this and they're trying to figure out how to select a good IVF clinic, what are the things they should be looking for? Because I would have to assume that it's like any other field of medicine. Not all doctors and not all clinics are created equal and

Just because you see a lot of advertising doesn't tell you anything. So in other words, you're going to have to become a very, very intelligent consumer. For most people, this will be the single most expensive out-of-pocket healthcare expense they have. Yeah, that's true. And so it's not just that it's the most expensive healthcare decision they're ever going to make. It might be one of the most consequential as well.

And yet I know what I suggest to people when someone says, Peter, you know, my wife and I are thinking about getting IVF. What do you think? I just go down the rabbit hole of like, here's a hundred questions I would ask. And it usually begins with, tell me your success rate individually. I don't care about the national success rate. It means nothing to me. So how would you counsel someone who's trying to come up with their checklist of questions to ask?

These days it's a little bit easier because obviously there's the internet and there's suggested questions online you could look at. It's true there is some variability amongst clinics, although there's a lot of consolidation happening in the field as well. So a lot of the practices are becoming common to most clinics.

But some of it is practical, right? Like which clinics are close to where you live because as- You have to go in and get these ultrasounds. Yeah. You got to go in every few days. So you can't be going to another state. Most people can't. But in most major cities, you have multiple options. In most major cities, that's true.

So you're right about individual clinic success rates, although technically it's hard to use those to compare them to each other because you don't necessarily know the population, right? You don't know the patient population, right? So how do you normalize it? Right. So one thing for sure, look at the success rates. And we're one of the few fields of medicine where actually you can get clinic-specific success rates. You mean publicly it's available? Yeah, it's available. Where do you find it? Well, the CDC...

until recently. There is a law actually that says you have to report every IVF cycle in the success rate that was passed in the 90s. So because of that, the CDC tracks this. Although all the people that work in that department were fired recently. So you don't know what's going to happen with that. But also our professional organization is called Society of Assisted Reproductive Technology has a website. It's called SART.org is the URL. And all the clinics in the U.S. or most of them are

are on there and they have to report their success rates and they're published every year. There's usually like a two-year lag because the babies have to be born and everything. So I would send people to that website first, look at the clinics in your area, look at the success rates, keeping in mind that populations might be different in different clinics.

I probably would go to a clinic that does a sufficient volume. You have to do at least 100 cycles, I would say, but ideally more than that. Your clinic has how many doctors? Our clinic has about six doctors. How many total cycles do you guys do a year? We do six to 800 retrievals a year. There's a lot of variability. There's some clinics that do thousands. There are some that do like 50. So that would be one factor that I think is important, just volume.

And you have how many embryologists? We have something like nine embryologists. Yeah, there is a shortage of embryologists nationwide and reproductive endocrinologists because the demand for IVF is going up. So I would definitely look at the clinic success rates, look at the volume. The other thing with the internet, especially you can look at patient reviews.

Word of mouth. Got to take those with a grain of salt, right? Yeah. They tend to be negative selecting. Right. Not everybody who has a great experience necessarily going to post it on Reddit. But everyone who has a bad one does. Yeah. Yeah. So you have to take that with a grain of salt. But

There are objective ways. And you can also interview your doctor. Yeah, what are questions you should be asking of the doctor that are independent of the objective metrics that we might have just discussed? You can ask about their philosophy, about protocols, about things like add-ons, like genetic testing, for example. It's like, are you a clinic where everybody is encouraged to do a genetic testing? That's not necessarily the clinic I would choose.

talk to the patient about the pros and cons and you let the patient decide. And we do a lot of genetic testing, so it's not like I'm against it or anything, but you want to get a sense of the vibe of the clinic. Are they just interested in money? Not that doctors ever think like that, but you know what I mean? So sometimes it takes having a consultation with one or more clinics to see where you feel more comfortable. I'm a little bit biased towards some academic centers just because our missions include education.

education and research, et cetera. But there's several very excellent private clinics as well. What would be some red flags if you're going through this process?

How much of a delta is there in cost within a same city or did prices tend to converge within a given geography? Yeah, within a given geography, they're pretty similar and it's not cheap. Yeah. So what are we at today? Fully loaded cost. So, you know, an IVF cycle is probably around $20,000 per cycle on the EU. But that doesn't include genetic testing or does? Including genetic testing per cycle. But how does that compare to 20 years ago? Is that more or less inflation? Prices like most things have gone up.

It has? Yeah. Okay. I guess it should go up just based on the cost of labor that goes into all these things. Yeah, and there's innovations. Even though the genetic testing's coming down. Yeah, innovations and things. You're right. You think as volume goes up, eventually prices go down, but that hasn't quite happened. As new things get added, then it just tends to become more expensive. And most people are probably still paying out of pocket. Most people are not getting this covered by insurance. Again, depends where you live. Yeah, but across the country. Yeah. I

I think there are now 24 states that offer some kind of fertility coverage. About 15 of them include IVF. So you're right. Most places, they're paying out of pocket if your employer doesn't happen to offer infertility insurance coverage. Yeah. So red flags, communication with the clinic. So a lot of your experience...

is going to be communicating with nurses and coordinators. Yeah, just setting up appointments. Yeah. You want to get a sense of what that is like, because that could be stressful if it's not smooth. And oftentimes, our clinic included, sometimes it's not smooth. I mean, there've been some things we try and do like texting and apps and things to make the communication easier and

doesn't always work the way it's supposed to. You want to get time with your doctor. So some clinics, you hardly ever see the doctor and you see maybe the ultrasonographer. Not that that's bad, but it's kind of nice. Some patients prefer to have that more frequent interaction with their actual provider. So there's probably a sweet spot in volume where it's probably an inverted U-shape where if they're too low, they don't have the reps. If they're too high, it's a bit of a sweatshop and a factory and you want in the middle there.

Let's pivot now and talk about a few other things. So what's on the horizon medically for extending fertility? So there's a study going on at Columbia that's looking at the use of rapamycin to extend fertility in women. Now, I have to be honest with you, there was a day when I knew what the study was and what the inclusion criteria were. I don't at the moment. I'm assuming you are more familiar with this than I am. What is the question that is being asked and how is it being asked in this study?

So there's a lot of interest in extending fertility

Up until 100 years ago, women were basically dying at 50 in the average age of menopause. So it's a kind of recent phenomenon that we're actually living a third of our lives post-menopause. And fertility starts to decline way before you go through menopause. So there's a lot of interest in trying to extend fertility. Now, of course, egg freezing, which we haven't talked about yet, is one of the ways you can extend fertility. And it works pretty well as long as you're young when you freeze your eggs. But again, it's a relatively recent phenomenon.

You're not usually covered by insurance and it's expensive, et cetera. So it's not the answer. Because you're paying basically half the IVF cycle to harvest and then you're paying to freeze. Yeah, exactly. What's the cost of freezing? Well, $10,000 for the cycle and then about $1,000 a year for storage. And you're recommending that if a woman came to you at 20 and said, I just want to double down on my career right now, I'm

I want to do X, Y, and Z. I think I want to have kids. I at least want the optionality. When should I freeze by? Are you going to just say, do it now? Because no. I wouldn't recommend all women in their 20s freeze their eggs because most of those eggs will never be used. So you'd be doing it for nothing because most of those women will probably not need IVF and get pregnant spontaneously, right? Got it. Okay. The sweet spot we think is like early to mid 30s. That's where it makes the most sense. Okay.

Because you're about to get to the probability cliff where it starts to really decline. Right. If you think you might want to have kids, but you're not in a place in your life where you think that's going to happen in the next few years.

then doing it early to mid-30s is probably the time where it's most cost-effective. Very high likelihood that you will use them, if not for the first kid, maybe for the second kid. And it might be worth spending $10,000 and $1,000 a year. And $1,000 a year. Right. And do you freeze them, you freeze every egg you retrieve? Only the mature ones. Okay. Yeah. And what's the, for a typical 30-year-old...

you're going to get what we talked about earlier? Probably 10 to 15 per cycle, sometimes more, but that's average. And how many do you recommend a 30-year-old do? Yeah. So there's some calculators online. So the younger you are, the fewer eggs you need because more of them are going to be normal. So someone in 30, I think 10 to 20 would give you a decent chance of success. No guarantees. There's never any guarantees. But

Studies show that even if people use those eggs and then are not successful, the fact that they did something proactively, there's some psychological benefit in doing that. So even if ultimately doesn't work out or you don't end up using them. But at that age, maybe 10 to 20,

As you get closer to 40, you might need 20 to 40 or 50, which is not practical for most people because you can't do that many cycles and it's expensive and there's risks involved. So I think egg freezing is a great option for women. I also think as a society, we should try to make it easier, obviously, for women to

have kids during their peak reproductive years in their 20s and 30s. It's a whole different question, but I think having options is a good thing. So back to the rapamycin question, they're basically saying, look, is there a way that we could push that out a little bit? And so how is the study testing this? So rapamycin, as some of your listeners may know, is used in other anti-aging type contexts. There's some animal data that shows that maybe rapamycin might

extend fertility in that. Remember the egg cell death that we talked about earlier by preventing that to some degree so that the eggs last longer and you're fertile for more years. So there's some data in mice primarily. There's some data show that it's not helpful as well. So the data I would say is mixed in animal models. And the study at Columbia is actually trying to test it in humans.

I believe it's a few-month study where they're giving relatively low dose of rapamycin. I forget exactly, maybe five milligrams daily. Daily, not weekly? I think it's daily. Okay, interesting. But I'm not 100% sure. We'll pull it up and put it in the show notes. I should have known this. And then I think their outcome marker is AMH, I believe, which is that hormone. So I don't know. It's a relatively inexpensive study. They're not invasively looking at follicles.

Which you'd have to believe then is in just a period of a few months, you could pick up a signal of more or less AMH reduction. Right. And even if you can, like, what does that mean really? This study could be negative. If the study is positive, it's interesting. If it's negative, it probably doesn't tell us much if it's only three to six months. Right. To really do the study, I mean, you'd need long term. You need a few years. Right. You need pregnancy outcomes or...

at least menstrual menopause, age of menopause. So that would take for a long time and you'd have to take it for many years, probably. That's going to be a really difficult question to answer in humans. Yeah. Again, because of the animal data not being consistent. Some studies show, yeah, maybe it's helpful, but other studies show that it might be actually harmful because of the way it acts as being immunosuppressive and things. So

Certainly for any listeners trying to conceive, I would not recommend rapamycin. But yes, I'm curious about the data coming out of Columbia and other studies. Are there any other things that a woman can do to maximize her fertility beyond, we've already addressed sort of PCOS, we've already addressed the metabolic stuff, but we hear things all the time like stress, sleep. I mean, these things seem self-evident.

But what would be the most common things you would be saying to a woman who is otherwise experiencing iatrogenic, for lack of a better word, infertility? Yeah, I think all those things are important, like lifestyle factors. They're rarely the sole cause of infertility, but they can certainly exacerbate infertility as well as any other disease. So

I think the lifestyle factors that promote health are generally the same lifestyle factors that promote fertility. So healthy diet. Is there anything we can say more on that? Like what is a healthy diet as it pertains to fertility? Is it different? Does a woman who's

Getting ready to conceive, does she need more fat in her diet, for example? Yeah. Yeah. As you probably know, the data on diet is not great for anything, especially not fertility. So I would say there's very little evidence that there's a particular diet that's good for fertility that's different.

than what's good in general. So for most of my patients, I recommend the Mediterranean diet. That diet is palatable to most people and has a fair amount of evidence that it's reasonably healthy. And that's a lot of fruit and vegetables, whole grains, protein, mostly from

fish and olive oil and those types of things. It's not that different from what I would recommend for anybody. By the way, I think I said iatrogenic. I meant idiopathic, but you know what I meant. So what about supplements? I'm sure you get asked this question all the time. There's no shortage of over-the-counter supplements that people report increased fertility. I get asked these questions all the time and have blank stares because I don't know. Is there anything you can point to? And I love frameworks. So maybe one framework is

Are there supplements that correct legitimate deficiencies like vitamin D or B vitamins where we could make a case that supplementing with these things happen? I'm talking beyond just the prenatal vitamins that are obvious and necessary. We'll leave that to the side because it's so self-evident versus supplements that are kind of more grab bag mystery supplements where you're not actually correcting some obvious deficiency, but we think it might increase fertility. Yeah.

So the data around supplements, even less robust than the data around diet, I would say, yes, if you're correcting deficiencies, I think you can make a case for that. So a lot of women, reproductive age women are iron deficient, for example, and they might need to be on iron supplements.

You mentioned prenatal vitamins. Obviously, folic acid is important for anybody trying to get pregnant. People who live in Portland, Oregon, like I do, we tend to be vitamin D deficient. So I usually recommend vitamin D for people. But other supplements specifically for fertility, the ones I most commonly hear about are things like CoQ10.

Or DHEA is another one. And there's some data that it might be helpful. Again, it's not very robust. DHEA? DHEA. Which just increases endogenous testosterone production. Improves egg quality. Like, who knows how it works. Yeah. I mean, the data isn't great. Might improve libido. Maybe. I think people have studied that. It doesn't work so well.

It is a weak androgen, you're right. Yeah, the data is not very promising. But so for most of these things, the data is not there and probably will never be there, right? Because there's symptoms that aren't there to do those studies. So it probably doesn't hurt though. And so I'm relatively supportive if a patient wants to take Coquitin, there's some data around it, sure. Do you think it's just psychological where if they take it and they feel that they're doing something better, it reduces their stress around it? Because for me, I can't help but think that

stress has such a negative impact on fertility and on many aspects of health, but it's so difficult to quantify. We don't have a biomarker for stress. Even measuring cortisol doesn't actually tell you anything about the experience of stress. And so I just think so many negative health outcomes are a result of it, and therefore anything that a person can do to improve their stress. I agree with you. And if taking supplements helps with that, sure, I'm all for it. Yeah, I'm not advocating that we should be going crazy on it with no evidence, but I wonder if

Any of the efficacy of those things is mediated through that reduction of stress? Possibly, yeah. And as long as it's not harmful, that's great. And when we say the data isn't there, it's just because it doesn't mean that it doesn't work. It's just nobody's shown one way or another whether it works. So it's quite possible CoQ10 has some effect that we don't know about. And my feeling is if I don't think it's harmful and patient wants to take it, maybe helps with their stress, sure, I'm for that.

Other things, stress, almost everybody has some degree of stress in their lives, some more than others, unfortunately, but it's really hard to get rid of all the stress. Like, it's not helpful to tell a patient, well... You just need to be less stressed. You just need to be less stressed. So, like, okay, now what? But finding ways to cope with the stress is really what we're talking about. And that can be different for different people. For some people, it could be exercise.

exercise for some people. It could be meditation for some people, whatever, mindfulness, whatever it is, but definitely it's important. Same as sleep. And we talked about diet. Exercise is important. Do you caution women or do we know anything about too much exercise for women who are trying to conceive? I mean, we certainly hear stories about

college athletes and women who are doing a lot are actually having difficulty even maintaining a regular menstrual cycle. So if you're dealing with a woman, when you're taking that social history and you're trying to understand, what are some clues to you that her exercise might actually be too much and that might be impacting her fertility?

Extreme exercise can be associated with fertility issues, although I think for most patients, the benefits of exercise, as we know. Yeah. What is extreme in this case? So if it causes any change in a person's cycle, so for some of the more extreme athletes, sometimes their periods will stop altogether. There's a condition called REDS. It's relative energy deficiency in sport. And basically, the body is very smart. If it thinks...

There's not enough energy around to support a pregnancy because we're expending it all on this exercise. We're just going to shut the whole thing down and it works really well. But the patient stops menstruating. So obviously, they're going to have difficulty getting pregnant if they're not ovulating. If you're not menstruating, it means you're not ovulating. Also has other implications for things like bone health.

Because the ovary, in addition to making eggs, also makes estrogen, and estrogen is super important for bone health. So one lesson for the listeners, keep track of your... We talked about semen analysis being...

kind of a marker of other health outcomes. Your periods are also a marker. Of course, if you're on hormonal contraception, you might not know what your natural cycle is doing. But if your cycles are irregular or if you're not having them at all or if they're super painful or they're super heavy, and sometimes you don't know what's super painful or super heavy because nobody talks about anything. But thankfully, this generation of young women is talking more and there's the internet, et cetera. But don't wait till you're ready to try to get pregnant to figure that out.

There may be something important you need to know way ahead of time. And we've already talked about obituaries.

obesity, but on the other side of that, is there a certain body fat level beneath which fertility is also impacted? Yeah, there's not a cutoff, but certainly being overweight or obese can impact fertility and being severely underweight. For the underweight people, there's a similar mechanism. If your brain thinks there's just not enough. It's usually going to manifest through amenorrhea. Yeah, exactly. Exactly.

So healthy weight, healthy diet, exercise, sleep, disrupted sleep could affect ovulation and fertility. Stress, we mentioned all these things. All the things you mentioned in your book as well are all the same things that are important for fertility.

Lastly, what do you think is the most promising area of research? And if we're sitting here in 10 years and we're talking about this and we're looking back at the last decade, what do you imagine you will be most excited about from an innovation perspective? It's a very exciting field of medicine. There's always sort of innovations happening. I

I think, let's see, genetic testing will continue to evolve as we learn more about genetics. I think that'll play a bigger role. Automation in the lab, a lot of the steps we talked about earlier are like literally embryologists sitting at the microscope doing these things. But now there's some companies developing these lab-on-a-chip concepts where you put in the egg, put in the sperm.

An embryo comes out at the other end. So microfluidics or? Yeah, microfluidics, the whole process being automated. It's very interesting, right? And it could potentially improve access if you could put these labs. So do you see this as more of a cost reduction or more of a success improvement?

Maybe both because reduce error potentially. Usually the cost of things tends to go up anytime there's an innovation before it comes down. Maybe ultimately it'll come down, but imagine costs will increase. So that's kind of an exciting area. In vitro maturation, that's where the eggs are maturing in the petri dish instead of in a woman's body. So potentially in the future, a woman wouldn't have to take all these injections.

and just take the immature eggs, put them in the Petri dish, and then give the Petri dish the medications, if you will. That's in very sort of early stages, not quite as successful as conventional IVF yet, so we're not quite there. I assume because it's difficult to harvest...

Partly, and even that maturation process, we haven't quite gotten it down like it happens in the body. Other things, a real game changer would be something like in vitro gametogenesis, which is making eggs and sperm potentially from skin cells. So even if you run out of eggs, if we could take a skin biopsy and reprogram that cell to

to make an egg than potentially anybody. Where are we in that? Very early. I think we'll see it eventually. It's been done in mice. So we're probably 10 to 20 years away. What's the obstacle? Basically reprogramming skin cells, just the whole thing.

process is very complicated and not easy. People are trying, there are a couple of companies that are trying to do it. Meaning is the challenge taking the skin cell back to a stem cell and then the stem cell into- Differentiating. Yeah. And which of those two steps do we think is harder? Skin cell back to stem cell or stem cell into egg? I think they're both hard.

I don't know. There's a couple of different approaches, including we do research in this area as well, where we're taking essentially the nucleus from a skin cell and putting it- Into an egg. Into an egg. And just replacing the genetic material. Yes, exactly. So we don't have to reprogram the skin cell. And is it easy to separate the chromosomes? No. No.

Okay. I was going to say. It's very complicated because it's meiosis. It's hard for it to happen efficiently and equally, et cetera. So we're working on it, but we're probably 10, 20 years away. But that would be an alternative way to get to that. But then you need donor eggs. So that has its own limitations because it's not like donor eggs are easy to come by either. Yeah, that's true. Although I guess what it does is it helps the older woman who is

is able to make follicles, but they're just aneuploidic. Exactly. You have a solution to that problem. Yeah. Another thing we're working on is something called mitochondrial replacement therapy, where basically similar concept. You were taking, like you have an older woman, let's say,

She undergoes IVF. You have a donor that undergoes IVF, but you take the nucleus out of the older egg and you put it in a younger egg. So essentially, the cytoplasm is from the young egg, including the mitochondria. So we think part of the aging is just like other aspects of aging, you know, acquired mutations in the mitochondria. So you have young cytoplasm, young mitochondria. Maybe those eggs will do better or that nucleus will do better in that young egg.

Unfortunately, we can't do that in the United States legally, but we're doing trials in other countries. This is kind of a remarkable field. Again, it's still amazing to me how well this works. If you think about it, this is, and I don't mean this in a disparaging way at all, it's very brute force. It's very mechanical. And yet we're, as a field, I think having an enormous impact that is relatively recent when you sort of think about the timescale of this. So it seems to me that...

Early intervention is better. Your point about women who have any sort of irregularity in their cycle, if they're in their teens or 20s, if for no other reason beyond just the discomfort of it at the moment, getting this looked at now is a great way to get ahead of an infertility problem.

10 years hence. For sure. That to me is a very important takeaway that I don't think is probably appreciated enough. And while I don't think we have a high listenership of 18-year-old girls, my guess is that message through parents who are listening might make its way to potential future patients that would find themselves on your doorstep. It's also comforting to hear just how

high the probability of success is in the modern era today. And it sounds to me like we're converging on quality.

Whereas I would imagine this was a field that was a bit like the Wild West 20 years ago, where you had a bunch of charlatans out there who were, maybe not charlatans is the wrong word, but just low quality practitioners. And I'm guessing today with consolidation of groups, we're seeing less and less of that. More standardization. Yes, for sure. I'm still blown away at the concept of the embryologist and what's required to do that and how that we don't have a more formal training path.

especially given that you said that we have a shortage of such people. That seems like an incredibly rewarding career for somebody. So hopefully we can foster that. Paula, this has been great. I feel between this podcast and the podcast on male fertility, I have a much better sense of this and how to address it. Both very different problems, but completely complimentary. Related, for sure. Yeah. Appreciate your time and your expertise. Thanks for inviting me. It's been fun. Thanks for having me.

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