#352 ‒ Female fertility: optimizing reproductive health, diagnosing and treating infertility and PCOS, and understanding the IVF process | Paula Amato, M.D.

View the Show Notes Page for This Episode https://peterattiamd.com/paulaamato/?utm_source=podcast-feed&utm_medium=referral&utm_campaign=250609-pod-paulaamato&utm_content=250609-pod-paulaamato-podfeed Become a Member to Receive Exclusive Content https://peterattiamd.com/subscribe/?utm_source=podcast-feed&utm_medium=referral&utm_campaign=250609-pod-paulaamato&utm_content=250609-pod-paulaamato-podfeed Sign Up to Receive Peter's Weekly Newsletter https://peterattiamd.com/newsletter/?utm_source=podcast-feed&utm_medium=referral&utm_campaign=250609-pod-paulaamato&utm_content=250609-pod-paulaamato-podfeed This is part two of a two-part mini-series on fertility and reproductive health. Paula Amato is a leading expert in female reproductive health and infertility, widely recognized for her contributions to advancing fertility treatment and research. In this episode, which follows last week's conversation on male fertility, Paula explores the biology of female fertility, including how hormonal changes regulate the menstrual cycle and ovulation, what those patterns reveal about fertility potential, and why both partners should be evaluated early in infertility workups. She discusses the role of the fallopian tubes, the causes of miscarriage, the impact of age and lifestyle on fertility, and treatment options for conditions like PCOS—including the emerging use of GLP-1 agonists. The episode also covers the evolution of IVF, advances in pre-implantation genetic testing, egg freezing, and the promise and limitations of next-generation reproductive technologies. We discuss: The finite nature of a woman's egg reserve, how it changes over time, and the basic process of ovulation and fertilization [3:00]; How hormones influence egg selection, and how and why chromosomal errors lead to most miscarriages [5:30]; The full journey of conception—from hormonal cues triggering ovulation, to fertilization, embryo development, implantation, and early pregnancy risks [16:30]; How infertility is defined and diagnosed, and the broader trends contributing to rising infertility rates [25:15]; Fallopian tube damage: how STDs and scarring impact fertility and raise ectopic pregnancy risk [31:30]; Unexplained infertility: how doctors evaluate ovulation and cycles—and why more research on women's health is needed [41:00]; The defining symptoms of polycystic ovary syndrome (PCOS), its hormonal characteristics, and its relationship with insulin resistance [44:00]; Managing PCOS without pregnancy: cycle regulation, androgen suppression, and insulin resistance treatment [46:00]; The treatment approach for women with PCOS who are trying to conceive: GLP-1 use, ovulation induction, and timing protocols [49:45]; Barriers to getting informed fertility care for PCOS: limited provider knowledge and access, insurance gaps, and next steps when ovulation treatments don't lead to pregnancy [55:45]; Fertility treatment for women with unexplained infertility, risk of multiple pregnancies with superovulation, and more [1:03:00]; Intrauterine insemination (IUI): process, success rates, and when in vitro fertilization (IVF) becomes the better option [1:07:00]; The history of in vitro fertilization (IVF), and how access and acceptance have evolved over time [1:16:45]; The step-by-step process of IVF [1:19:30]; The IVF lab process: egg retrieval, fertilization, embryo culture, and freezing [1:26:30]; Genetic testing and embryo selection in IVF: aneuploidy screening, polygenic traits, and ethical concerns [1:41:15]; Embryo transfer in IVF: timing, uterine preparation, and implantation support [1:47:30]; Egg donation in IVF: indications, donor guidelines, and other considerations [1:50:45]; How to choose the right IVF clinic [1:54:45]; Innovations in fertility on the horizon, advice about freezing eggs, and more [2:02:00]; Optimizing fertility through lifestyle: diet, stress management, sleep, exercise, and supplementation [2:07:45]; Promising areas of fertility research [2:15:45]; and More. Connect With Peter on Twitter https://twitter.com/PeterAttiaMD, Instagram https://www.instagram.com/peterattiamd/, Facebook https://www.facebook.com/peterattiamd/ and YouTube https://www.youtube.com/channel/UC8kGsMa0LygSX9nkBcBH1Sg

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:11Dr. Peter Attia?

  Hey everyone, welcome to the Drive Podcast. I'm your host, Peter Attia. This podcast, my website, and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, and we've established a great team of analysts to make this happen. It is extremely important to me to provide all of this content without relying on paid ads. To do this, our work is made entirely possible by our members, and in return, we offer exclusive, member-only content and benefits above and beyond what is available for free. If you want to take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of a subscription. If you

• 0:54Dr. Peter Attia?

  want to learn more about the benefits of our premium membership, head over to peterattiamd.com/subscribe.

• 1:04Dr. Peter Attia?

  My guest this week is Dr. Paula Amato. Paula is a professor of OB-GYN 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

• 1:48Dr. Peter Attia?

  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/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, PCOS, 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,

• 2:31Dr. Peter Attia?

  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, 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.

• 3:11Dr. Peter Attia?

  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.

• 3:44Speaker 01

  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 throughout a man's lifetime, whereas women are born with a finite number of eggs. Actually, the most eggs you'll ever have is when you're in your mom's womb as a fetus. And by the time you're born, there's about 2 million or so eggs. And by the time you start menstruating, you're down to maybe 400,000 or so.

• 4:18Dr. Peter Attia?

  Wow. So a five-fold reduction from birth to, say, average age would be maybe 14?

• 4:24Speaker 01

  Yeah, 12 to 14. And we don't know why exactly that happens, but most of the eggs and the ovaries actually undergo a process we call a treia. 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

• 5:09Speaker 01

  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.

• 5:32Dr. Peter Attia?

  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. So 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

• 6:14Dr. Peter Attia?

  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.

• 6:29Speaker 01

  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.

• 6:51Dr. Peter Attia?

  Tell me what grow means.

• 6:53Speaker 01

  The follicles start to get bigger and the cells surrounding the eggs start to divide.

• 7:00Dr. Peter Attia?

  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.

• 7:10Speaker 01

  Yes. Miosis, they're kind of arrested in meiosis and meiosis not completed until they actually ovulate and then, in some cases, are fertilized.

• 7:22Dr. Peter Attia?

  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?

• 7:52Speaker 01

  As far as we know, although there's some data recently to suggest that perhaps the cells surrounding the egg are 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 egg 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 your pregnancy.

• 8:33Speaker 01

  But you're right, they're pretty much arrested in time, 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.

• 8:56Dr. Peter Attia?

  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.

• 9:29Speaker 01

  That's true.

• 9:29Dr. Peter Attia?

  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?

• 9:40Speaker 01

  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.

• 10:03Dr. Peter Attia?

  And when you say chromosomally normal, are you referring to the egg or the zygote?

• 10:08Speaker 01

  The zygote, but most of the abnormalities in chromosomes that happen in a zygote are believed to be related to maternal age.

• 10:16Dr. Peter Attia?

  And does that mean we think that the abnormality occurred way before ovulation? Or when do we think that that occurred?

• 10:25Speaker 01

  We think it occurred in a stage of meiosis that happens as the egg is developing that month.

• 10:32Dr. Peter Attia?

  That ripening phase?

• 10:33Speaker 01

  Yes.

• 10:34Dr. Peter Attia?

  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 aneuploitic state? And please explain what I just said to people.

• 11:05Speaker 01

  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 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 X and Y, the sex chromosomes. And during that disjunction phase is when we think most of the errors happen.

• 11:46Speaker 01

  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.

• 12:01Dr. Peter Attia?

  And that completion only occurs during the 14 days leading to ovulation?

• 12:06Speaker 01

  Ovulation and then fertilization, yes.

• 12:09Dr. Peter Attia?

  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.

• 12:35Speaker 01

  Right.

• 12:36Dr. Peter Attia?

  As we know, that as a woman ages, the probability of successful division goes down.

• 12:41Speaker 01

  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.

• 12:50Dr. Peter Attia?

  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 said, "Look, it's important for you to understand that this is your fault."

• 13:29Speaker 01

  Oh, my God.

• 13:29Dr. Peter Attia?

  And my friend said he wanted to jump across the table and kill this guy.

• 13:34Speaker 01

  Yeah, I don't blame him.

• 13:35Dr. Peter Attia?

  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?

• 13:47Speaker 01

  21.

• 13:47Dr. Peter Attia?

  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."

• 14:01Speaker 01

  Inappropriate manner.

• 14:02Dr. Peter Attia?

  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."

• 14:11Speaker 01

  For sure.

• 14:11Dr. Peter Attia?

  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.

• 14:24Speaker 01

  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.

• 14:42Dr. Peter Attia?

  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?

• 14:57Speaker 01

  Definitely the majority of them, probably close to 90% of them, yeah.

• 15:01Dr. Peter Attia?

  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?

• 15:17Speaker 01

  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.

• 15:37Dr. Peter Attia?

  Regardless of her age?

• 15:39Speaker 01

  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.

• 15:49Dr. Peter Attia?

  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.

• 16:02Speaker 01

  Yeah, that's true. I mean, that's most likely.

• 16:04Dr. Peter Attia?

  Most likely.

• 16:05Speaker 01

  But again, you don't want to miss, especially at 40, you don't want to miss some treatable, other treatable cause.

• 16:10Dr. Peter Attia?

  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.

• 16:19Speaker 01

  Definitely not.

• 16:20Dr. Peter Attia?

  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.

• 16:30Speaker 01

  Yes.

• 16:30Dr. Peter Attia?

  And that's the way it works.

• 16:31Speaker 01

  Yes.

• 16:32Dr. Peter Attia?

  Okay. 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.

• 16:52Speaker 01

  So a group of eggs or follicles are starting to grow. One gets selected. We don't really understand.

• 16:57Dr. Peter Attia?

  We still don't know how.

• 16:58Speaker 01

  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.

• 17:41Speaker 01

  So it busts out of the ovary, finds its way to the tube.

• 17:46Dr. Peter Attia?

  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?

• 18:05Speaker 01

  I don't know that we understand it completely, but you would imagine that their energy is required for that to happen. Certainly.

• 18:12Dr. Peter Attia?

  So it's not passive? It's not just sort of a diffusion down the fallopian tube?

• 18:17Speaker 01

  Right. Prostaglandins are involved and calcium, all kinds of things have to happen for that process to occur.

• 18:24Dr. Peter Attia?

  Okay. How long approximately? Just give people a sense of how long a fallopian tube is.

• 18:29Speaker 01

  Probably a few centimeters, five to 10.

• 18:32Dr. Peter Attia?

  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?

• 18:46Speaker 01

  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.

• 18:58Dr. Peter Attia?

  Got it. And it's otherwise in direct contact with the peritoneum?

• 19:02Speaker 01

  The ovary and the tubes.

• 19:04Dr. Peter Attia?

  The space between, the space between them?

• 19:06Speaker 01

  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.

• 19:13Dr. Peter Attia?

  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?

• 19:22Speaker 01

  About five or six days.

• 19:23Dr. Peter Attia?

  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?

• 19:42Speaker 01

  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, dental 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.

• 20:06Dr. Peter Attia?

  What leads to that?

• 20:07Speaker 01

  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.

• 20:20Dr. Peter Attia?

  Is the day four, assuming a woman's cycle is predictable and normal, and we 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?

• 20:34Speaker 01

  Pretty much the day that the egg is released from the ovary. Yeah. And usually encounters 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.

• 20:56Dr. Peter Attia?

  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?

• 21:07Speaker 01

  Millions.

• 21:08Dr. Peter Attia?

  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?

• 21:26Speaker 01

  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 egg. Because that would be bad. You only want one sperm and one egg to combine.

• 21:38Dr. Peter Attia?

  Yeah, there's like an electrical force field that immediately activates around the egg. I find this so fascinating.

• 21:45Speaker 01

  Yeah, it is fascinating.

• 21:45Dr. Peter Attia?

  And brilliant. Okay, so now, and by the way, what is the relative size of an egg to a sperm?

• 21:51Speaker 01

  The egg is actually much bigger than the sperm. I don't know exactly in microns how big it is.

• 21:56Dr. Peter Attia?

  I feel like I used to know this answer, and it's shocking how disparate they are in size.

• 22:01Speaker 01

  The egg is, I believe, the biggest cell in the body, potentially. I've checked on that, but I believe that's true.

• 22:06Dr. Peter Attia?

  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?

• 22:29Speaker 01

  Yeah, within a few hours.

• 22:30Dr. Peter Attia?

  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?

• 22:45Speaker 01

  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.

• 23:28Speaker 01

  And that's the stage where it implants in the uterus. So five, six days after fertilization.

• 23:34Dr. Peter Attia?

  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 that? 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 blastoc spheres or blastocites?

• 23:54Speaker 01

  Yeah, a zygote, I think, is still a single cell that's fertilized, an egg and sperm combined. Then it starts to divide. We call it a pre-embryo.

• 24:05Dr. Peter Attia?

  Okay.

• 24:06Speaker 01

  And then by two weeks, we call it an embryo. But in IVF, we call it an embryo even in the first few days.

• 24:12Dr. Peter Attia?

  Assuming that we have chromosomal alignment, it's two weeks out. So we have a two-week-old embryo that is implanted. 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?

• 24:38Speaker 01

  So once a pregnancy is established, you mean?

• 24:41Dr. Peter Attia?

  Yes, yes.

• 24:42Speaker 01

  So if it's a normal embryo, chances are pretty good that it continues to turn.

• 24:47Dr. Peter Attia?

  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?

• 24:56Speaker 01

  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.

• 25:23Dr. Peter Attia?

  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 something and I'm not willing to put the label of infertility on. Would that be the first bifurcation in thinking?

• 25:51Speaker 01

  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 the 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.

• 26:34Speaker 01

  So if a couple female partners over 35 and they've been trying, having timed 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, et cetera? 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.

• 27:11Dr. Peter Attia?

  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.

• 27:36Speaker 01

  Cause, yeah.

• 27:36Dr. Peter Attia?

  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.

• 27:43Speaker 01

  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, and 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.

• 27:59Dr. Peter Attia?

  And do you guys do that yourselves as well?

• 28:01Speaker 01

  We do, at the fertility clinic.

• 28:02Dr. Peter Attia?

  Okay, great.

• 28:03Speaker 01

  Yeah. 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.

• 28:42Dr. Peter Attia?

  Is it possible to say anything about fertility rates changing over the past 50 years? Is there any statement you can make on that?

• 28:48Speaker 01

  Yeah, there's some data that seems to suggest that 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 1 in 6, so that's close to 20%. In the last few years in the United States, it seems to be kind of a plateau of the prevalence.

• 29:10Dr. Peter Attia?

  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 1 in 6?

• 29:23Speaker 01

  Yeah.

• 29:24Dr. Peter Attia?

  So we're going to say that the 1 in 6 means someone who wants to get pregnant at a certain point in their life can't?

• 29:29Speaker 01

  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.

• 29:40Dr. Peter Attia?

  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.

• 29:48Speaker 01

  Exactly. Yeah. So women are waiting longer, of course, to start their families, to pursue education, career, 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.

• 30:15Dr. Peter Attia?

  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 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?

• 30:45Speaker 01

  It's definitely been looked at by age. I don't know the data off the 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.

• 31:00Dr. Peter Attia?

  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?

• 31:07Speaker 01

  We think so, but I don't know that data off the top of my head.

• 31:10Dr. Peter Attia?

  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.

• 31:23Speaker 01

  Right. Environmental factors as well. Our exposures are different now than they were 50 years ago.

• 31:29Dr. Peter Attia?

  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?

• 31:42Speaker 01

  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.

• 32:04Dr. Peter Attia?

  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?

• 32:12Speaker 01

  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 causes fertility problems.

• 32:31Dr. Peter Attia?

  How prevalent is gonorrhea today in the US?

• 32:34Speaker 01

  I think it's pretty common. I don't know.

• 32:35Dr. Peter Attia?

  Really?

• 32:35Speaker 01

  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.

• 32:53Dr. Peter Attia?

  How does it present?

• 32:54Speaker 01

  In women, usually with pelvic pain, fever, vaginal discharge. Those are the most common symptoms.

• 33:02Dr. Peter Attia?

  And is it equally transmissible from male to female and female to male?

• 33:08Speaker 01

  It's probably more transmissible from male to female.

• 33:11Dr. Peter Attia?

  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?

• 33:18Speaker 01

  Not always.

• 33:18Dr. Peter Attia?

  Presumably not, if it's being transmitted this readily.

• 33:21Speaker 01

  Yeah, not always.

• 33:22Dr. Peter Attia?

  What about HSV? Does that factor into fertility at all?

• 33:26Speaker 01

  Not as much.

• 33:27Dr. Peter Attia?

  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.

• 33:37Speaker 01

  The same, actually. Yeah, very similarly. So pelvic pain, fever, usually they're both present together.

• 33:44Dr. Peter Attia?

  And does it have the same pathology where it creates, it ascends the fallopian tubes and scars the tubes?

• 33:50Speaker 01

  Yep.

• 33:51Dr. Peter Attia?

  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 in uterus still preserved enough to?

• 34:08Speaker 01

  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 histrocell pingogram, or HSG for short, and it's done specifically to evaluate whether or not the tubes are open.

• 34:39Dr. Peter Attia?

  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?

• 34:47Speaker 01

  Exactly.

• 34:47Dr. Peter Attia?

  And you're looking for how smooth, and so tell me, what does a normal fallopian tube look like on that test?

• 34:52Speaker 01

  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...

• 35:07Dr. Peter Attia?

  What's the diameter of a normal fallopian tube in that setting?

• 35:10Speaker 01

  Less than a centimeter. Yeah.

• 35:12Dr. Peter Attia?

  That's pretty big.

• 35:13Speaker 01

  Yeah, the whole tube, but the actual opening...

• 35:16Dr. Peter Attia?

  No, yeah, how big is the lumen?

• 35:17Speaker 01

  Microns.

• 35:18Dr. Peter Attia?

  Oh, wow, okay.

• 35:19Speaker 01

  Or millimeters, I don't know, exactly. But you can see it, definitely see it on x-ray and you can see.

• 35:24Dr. Peter Attia?

  Well, if you can see it, it's probably a millimeter or more than, not a micron.

• 35:27Speaker 01

  Yeah, for sure.

• 35:27Dr. Peter Attia?

  Yeah, okay.

• 35:28Speaker 01

  And then the dye is filling up the tubes and then spilling out the tubes. So you can see that.

• 35:33Dr. Peter Attia?

  Right, the ovaries are not visualized because of the finger-like projection. So it's actually spilling dye into the peritoneum at this point.

• 35:39Speaker 01

  Right.

• 35:39Dr. Peter Attia?

  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.

• 35:51Speaker 01

  Right.

• 35:51Dr. Peter Attia?

  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. Does it just atrophy and get reabsorbed?

• 36:05Speaker 01

  Yeah.

• 36:05Dr. Peter Attia?

  I see, so it wouldn't necessarily cause pain?

• 36:07Speaker 01

  No, no.

• 36:08Dr. Peter Attia?

  By the way, we didn't talk about this earlier, we took it for granted. This is happening with two separate sides.

• 36:13Speaker 01

  Yeah.

• 36:14Dr. Peter Attia?

  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.

• 36:23Speaker 01

  Right.

• 36:24Dr. Peter Attia?

  How does that happen?

• 36:24Speaker 01

  Who knows? We don't know.

• 36:26Dr. Peter Attia?

  We have no idea how that happens.

• 36:28Speaker 01

  We have no idea, 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.

• 36:44Dr. Peter Attia?

  And it's a coin toss.

• 36:45Speaker 01

  Right, and it's not necessarily alternating, but it's on average.

• 36:49Dr. Peter Attia?

  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.

• 36:56Speaker 01

  Exactly.

• 36:57Dr. Peter Attia?

  This is mind-boggling to me.

• 36:59Speaker 01

  Yeah, it's fascinating.

• 37:00Dr. Peter Attia?

  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?

• 37:12Speaker 01

  Yep.

• 37:12Dr. Peter Attia?

  I mean, it's.

• 37:13Speaker 01

  Yeah, yeah, and we don't quite understand it.

• 37:15Dr. Peter Attia?

  That's incredible.

• 37:16Speaker 01

  Yeah, or whatever that egg that's being selected.

• 37:21Speaker 01

  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.

• 37:34Dr. Peter Attia?

  Yeah.

• 37:35Speaker 01

  That's making it the so-called dominant follicle for that cycle.

• 37:39Dr. Peter Attia?

  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.

• 37:56Speaker 01

  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.

• 38:13Dr. Peter Attia?

  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?

• 38:26Speaker 01

  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.

• 39:00Dr. Peter Attia?

  It's a surgical emergency.

• 39:01Speaker 01

  Yeah, exactly.

• 39:03Dr. Peter Attia?

  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?

• 39:22Speaker 01

  Usually about six to eight weeks of pregnancy.

• 39:25Dr. Peter Attia?

  Two months pregnant.

• 39:27Speaker 01

  Right. Now, remember, we time.

• 39:29Dr. Peter Attia?

  Yeah, yeah.

• 39:30Speaker 01

  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.

• 39:43Dr. Peter Attia?

  So when a woman has an ectopic pregnancy, can that fallopian tube be salvaged?

• 39:48Speaker 01

  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.

• 40:03Dr. Peter Attia?

  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.

• 40:11Speaker 01

  Right.

• 40:11Dr. Peter Attia?

  So you still want her to have her endocrine system intact. What's happening to the eggs that come out of that tube?

• 40:16Speaker 01

  They just get released into the abdomen, the peritoneum, and resort.

• 40:20Dr. Peter Attia?

  So do you tell that woman, your fertility rate just went down by 50%?

• 40:24Speaker 01

  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.

• 40:39Dr. Peter Attia?

  It makes its way over to the other fallopian tube.

• 40:41Speaker 01

  Makes its way over there, yeah. It's rare.

• 40:42Dr. Peter Attia?

  Wow.

• 40:42Speaker 01

  But it could happen.

• 40:43Dr. Peter Attia?

  What are the risks for ectopic pregnancy besides former STDs that lead to scarring in the tube?

• 40:49Speaker 01

  Previous surgery, pelvic surgery in particular, like ruptured appendix or something like that. Endometriosis can cause scarring of the tubes. Those are probably the most common.

• 40:59Dr. Peter Attia?

  Okay. Any genetic component to this? If your mom had an ectopic pregnancy or you?

• 41:04Speaker 01

  Not that we know of.

• 41:05Dr. Peter Attia?

  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?

• 41:25Speaker 01

  So, we want to assess her cycles and ovulation. So, if she's ovulating regularly, then we call that sort of unexplained.

• 41:34Dr. Peter Attia?

  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?

• 41:40Speaker 01

  Usually, usually. It would be unusual to have regular periods and not be ovulating, but it could happen.

• 41:46Dr. Peter Attia?

  How stringent is your definition for a regular period? It's not 28 days necessarily?

• 41:51Speaker 01

  Not necessarily, yeah. There's a range. It could be anywhere from like 21 to 35 days or so.

• 41:57Dr. Peter Attia?

  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?

• 42:07Speaker 01

  Yes, if you mean duration of the period.

• 42:09Dr. Peter Attia?

  Correct.

• 42:09Speaker 01

  Yeah, that's not as important as how frequently the period is happening.

• 42:14Dr. Peter Attia?

  Even if it was 21 days, but it was always 21 days, that's better than 24, 28, 31.

• 42:21Speaker 01

  There is some normal variations. Sometimes I'll see a patient and she'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 you're skipping months or maybe you're getting a period every three months or four months.

• 42:42Dr. Peter Attia?

  And what's happening in that situation in a young woman?

• 42:45Speaker 01

  There are a number of different causes. Probably the most common is something called polycystic ovary syndrome. It's a very common hormonal 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.

• 43:02Dr. Peter Attia?

  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?

• 43:15Speaker 01

  Political reasons, I think. Gender inequality, all kinds of reasons like that.

• 43:22Dr. Peter Attia?

  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?

• 43:43Speaker 01

  Yeah, no, I think it's the former.

• 43:45Dr. Peter Attia?

  You think it's objectively?

• 43:46Speaker 01

  There's good data that the funding for women's health research is 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.

• 43:59Dr. Peter Attia?

  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?

• 44:06Speaker 01

  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.

• 44:27Dr. Peter Attia?

  The androgens are specifically just testosterone, just DHEA, DHE, all of the above?

• 44:32Speaker 01

  Yeah, both, but typically elevated testosterone from the ovaries.

• 44:37Dr. Peter Attia?

  Is that the cause or the effect?

• 44:39Speaker 01

  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.

• 44:48Dr. Peter Attia?

  And why is PCOS seemingly also highly associated with insulin resistance?

• 44:54Speaker 01

  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.

• 45:14Dr. Peter Attia?

  But we don't know the direction of causality?

• 45:17Speaker 01

  No. We know that not everybody who's insulin resistant has PCOS, of course, not all diabetics are insulin resistant.

• 45:23Dr. Peter Attia?

  But we also know that some women with PCOS are not insulin resistant, correct?

• 45:27Speaker 01

  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 my guess is like, we're treating PCOS now more like other complex diseases like obesity or hypertension, et cetera. There's lots of things going on.

• 45:46Dr. Peter Attia?

  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?

• 46:01Speaker 01

  Yeah, that's probably true.

• 46:02Dr. Peter Attia?

  So then the question is, what do we need to do to treat PCOS?

• 46:06Speaker 01

  So it 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.

• 46:48Dr. Peter Attia?

  When you say hormonal treatments, you mean like spironolactone and things like that?

• 46:51Speaker 01

  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.

• 47:02Dr. Peter Attia?

  So let's talk about why. So a birth control pill is a high dose of a synthetic estrogen and progestin.

• 47:10Speaker 01

  Correct.

• 47:10Dr. Peter Attia?

  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?

• 47:27Speaker 01

  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.

• 47:42Dr. Peter Attia?

  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?

• 47:51Speaker 01

  Right. When you take the combination of estrogen and progesterone, usually the lining becomes quite thin.

• 47:55Dr. Peter Attia?

  Thin anyway.

• 47:55Speaker 01

  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.

• 48:24Dr. Peter Attia?

  Okay. So 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.

• 48:38Speaker 01

  Great strategy, yeah. There are others. 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.

• 48:53Dr. Peter Attia?

  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?

• 49:03Speaker 01

  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.

• 49:22Dr. Peter Attia?

  Does insulin resistance and type 2 diabetes independently impair fertility? All things being equal, absent PCOS? That's a loaded question.

• 49:31Speaker 01

  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.

• 49:49Dr. Peter Attia?

  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?

• 50:03Speaker 01

  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.

• 50:15Dr. Peter Attia?

  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?

• 50:22Speaker 01

  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.

• 50:30Dr. Peter Attia?

  Do you know any of those data? I'm not familiar with them.

• 50:32Speaker 01

  Yeah, 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.

• 50:44Dr. Peter Attia?

  And pardon my ignorance, why?

• 50:46Speaker 01

  Because we don't have any data on whether they're safe.

• 50:48Dr. Peter Attia?

  Yep. 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?

• 50:55Speaker 01

  Yes. I haven't looked for that one specifically, but I'm sure it's X because we have no data.

• 51:01Dr. Peter Attia?

  That's an important message for anybody listening.

• 51:03Speaker 01

  Yes.

• 51:03Dr. Peter Attia?

  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.

• 51:09Speaker 01

  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, Ozempic 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.

• 51:30Dr. Peter Attia?

  Yeah, that's an interesting point. And now that you've mentioned that, I now recall hearing about that. So presumably, these are women who have taken either semaglutide trisepotide, and presumably they get pregnant.

• 51:41Speaker 01

  Yes.

• 51:42Dr. Peter Attia?

  Either intentionally or not. So that's a very interesting registry to follow.

• 51:47Speaker 01

  Right. Now, of course, once they find out they're pregnant, usually they stop.

• 51:50Dr. Peter Attia?

  They're usually counseled to stop.

• 51:51Speaker 01

  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.

• 51:57Dr. Peter Attia?

  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.

• 52:17Speaker 01

  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 Famara. It's just a medication you take for five days in your cycle, and then we can usually assess ovulation with ultrasound.

• 52:38Dr. Peter Attia?

  And what does it do?

• 52:39Speaker 01

  Basically, it's a category of medication called aromatase inhibitors, which blocks the-

• 52:46Dr. Peter Attia?

  Conversion of testosterone to-

• 52:47Speaker 01

  Right, androgens to estrogen. That lower estrogen somehow triggers the pituitary to increase secretion of FSH and LH, and that stimulates the ovary to, again, get one of those follicles-

• 53:01Dr. Peter Attia?

  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?

• 53:11Speaker 01

  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 that pregnancy rates were a little bit higher with Letrozole. Clomid's perfectly good as well, but Letrozole's better for PCOS. So if you have access to Letrozole-

• 53:28Dr. Peter Attia?

  That's very counterintuitive. If you think about it, when you take an aromatase inhibitor, you're gonna lower estrogen, but not, I mean, I guess it depends on the dose. I guess, I'm trying to think of like an AstraZeneca, which I'm more familiar with than Letrozole. I suppose if you took a milligram of an AstraZeneca 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 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.

• 54:03Speaker 01

  Right, yeah.

• 54:04Dr. Peter Attia?

  Yeah, that's, 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.

• 54:12Speaker 01

  Yeah, it also works, but when they compared them, yeah. Randomized controlled trial, head-to-head comparison showed that pregnancy rates were better, for some reason, with the Letrozole compared to Clomid.

• 54:23Dr. Peter Attia?

  Okay. And does it matter when in her cycle she takes the letrozole?

• 54:28Speaker 01

  Usually it's recommended from day three to five with the first day of full bleeding. We call that day one.

• 54:34Dr. Peter Attia?

  What if the whole point of this is she's not having her period? How do you then time it?

• 54:38Speaker 01

  We induce a period, not a real period, but we induce a withdrawal bleed by giving progesterone typically.

• 54:43Dr. Peter Attia?

  Okay, so you give a woman progesterone and then by withdrawing the progesterone? That's so cool.

• 54:50Speaker 01

  Yeah.

• 54:51Dr. Peter Attia?

  You guys are so manipulative.

• 54:52Speaker 01

  I know.

• 54:53Dr. Peter Attia?

  How much do you give? 200?

• 54:55Speaker 01

  No, five to 10 milligrams of midroxiprogesterone acetate, or you can give micronized progesterone for about seven to 10 days.

• 55:03Dr. Peter Attia?

  Only five to 10 milligrams of micronized progesterone?

• 55:07Speaker 01

  No, micronized progesterone, 200 milligrams.

• 55:10Dr. Peter Attia?

  Okay, okay, yeah, so you give the full party dose of micronized progesterone for five days.

• 55:13Speaker 01

  Midroxiprogesterone acetate, five to 10 milligrams.

• 55:16Dr. Peter Attia?

  So then, by the way, do you have a preference for MPA versus micronized?

• 55:19Speaker 01

  No, not really.

• 55:20Dr. Peter Attia?

  Okay.

• 55:20Speaker 01

  Because it's such a short course.

• 55:22Dr. Peter Attia?

  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.

• 55:39Speaker 01

  Three to seven, yeah, for five days.

• 55:41Dr. Peter Attia?

  Wow, very cool.

• 55:42Speaker 01

  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.

• 55:59Dr. Peter Attia?

  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?

• 56:17Speaker 01

  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, there are metabolic implications, et cetera. 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

• 57:02Speaker 01

  either Clomid or Lutrisol. 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.

• 57:21Dr. Peter Attia?

  Do you have to do the sonogram when you're doing this?

• 57:24Speaker 01

  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 luteal phase, the second half of the cycle. And if it's elevated, she probably ovulated. We just happen to use ultrasounds just easier.

• 57:47Dr. Peter Attia?

  And how much of what you're describing is covered with typical health insurance?

• 57:53Speaker 01

  Kind of depends where you live. In the United States, it's 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.

• 58:15Dr. Peter Attia?

  You're in Oregon.

• 58:16Speaker 01

  I'm in Oregon.

• 58:16Dr. Peter Attia?

  What is the state there?

• 58:18Speaker 01

  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.

• 58:43Dr. Peter Attia?

  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?

• 58:52Speaker 01

  Yeah, so letrozole and Clomid are just oral medications.

• 58:55Dr. Peter Attia?

  Yeah, they're cheap drugs.

• 58:56Speaker 01

  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.

• 59:07Dr. Peter Attia?

  No, let's just say just what we talked about is still a really cheap treatment, right?

• 59:10Speaker 01

  Relatively, yes. A few hundred dollars a month. For some people, that could be a lot.

• 59:14Dr. Peter Attia?

  But relative to what we're about to talk about, this is still well within the purview of out-of-pocket.

• 59:19Speaker 01

  For sure, compared to.

• 59:21Dr. Peter Attia?

  Compared to what's coming.

• 59:21Speaker 01

  Yeah, for sure.

• 59:23Dr. Peter Attia?

  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?

• 59:29Speaker 01

  Usually.

• 59:30Dr. Peter Attia?

  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.

• 59:42Speaker 01

  Right, not responding.

• 59:43Dr. Peter Attia?

  We were not responding to the follicle stimulation.

• 59:46Speaker 01

  Right.

• 59:47Dr. Peter Attia?

  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.

• 1:00:06Speaker 01

  Right.

• 1:00:06Dr. Peter Attia?

  And then you didn't, 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?

• 1:00:14Speaker 01

  Yeah, yeah. And someone who hasn't been ovulating, they haven't tried for a year even.

• 1:00:19Dr. Peter Attia?

  They haven't even met the criteria.

• 1:00:20Speaker 01

  Right, 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.

• 1:00:44Dr. Peter Attia?

  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?

• 1:00:55Speaker 01

  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 hormone, same hormone.

• 1:01:10Dr. Peter Attia?

  Not LH? You don't give HCG directly?

• 1:01:12Speaker 01

  It's a little bit of combination. We do eventually give HCG to trigger ovulation. So we could either use those medications 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.

• 1:01:46Dr. Peter Attia?

  Okay, if you are going to use FSH and LH, give me a sense of cost. What dose are you using of HCG?

• 1:01:55Speaker 01

  So if the plan is just for timed intercourse, intrauterine insemination, we use maybe one to three ampules of FSH and 75 units. The whole cycle, if you include the monitoring, the IUI, et cetera, could be like $3,000 or $4,000. So you can see.

• 1:02:12Dr. Peter Attia?

  Now we're a big step up.

• 1:02:13Speaker 01

  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.

• 1:02:37Dr. Peter Attia?

  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?

• 1:02:48Speaker 01

  No. So IUI is very common still.

• 1:02:50Dr. Peter Attia?

  I see.

• 1:02:51Speaker 01

  But we do it, we were talking specifically about the patient with PCOS.

• 1:02:56Dr. Peter Attia?

  Who's not ovulating.

• 1:02:56Speaker 01

  Right.

• 1:02:57Dr. Peter Attia?

  Got it.

• 1:02:57Speaker 01

  But otherwise, and if you have a patient who is ovulating and has maybe unexplained infertility tubes are open.

• 1:03:04Dr. Peter Attia?

  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.

• 1:03:13Speaker 01

  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.

• 1:03:30Dr. Peter Attia?

  What does the graph look like of number of eggs versus probability of twins, triplets, et cetera?

• 1:03:38Speaker 01

  That's one of the downsides. So the risk of multiples with the oral medications like Clomid or Letrizol is about five to eight percent. So not super high, but definitely higher than 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.

• 1:04:10Dr. Peter Attia?

  And with the injectables, what is the risk of multiple pregnancies?

• 1:04:15Speaker 01

  Much higher, 25 to 35%.

• 1:04:18Dr. Peter Attia?

  And how many eggs are typically?

• 1:04:20Speaker 01

  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.

• 1:04:41Dr. Peter Attia?

  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?

• 1:04:52Speaker 01

  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.

• 1:05:05Dr. Peter Attia?

  Because literally, there were women having eight and nine babies at a time.

• 1:05:08Speaker 01

  Yeah, that famous octoplets 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.

• 1:05:27Dr. Peter Attia?

  In that situation, they would have transferred eight and all eight took?

• 1:05:30Speaker 01

  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.

• 1:05:50Dr. Peter Attia?

  Unless a couple says, I'd actually like to have twins.

• 1:05:52Speaker 01

  We kind of discourage that.

• 1:05:54Dr. Peter Attia?

  Why?

• 1:05:54Speaker 01

  Because twins are riskier. They're riskier for the babies and for the mom.

• 1:05:58Dr. Peter Attia?

  Riskier in an IVF setting?

• 1:06:01Speaker 01

  No, they're just riskier in general.

• 1:06:02Dr. Peter Attia?

  Are IVF twins, do they pose any more risk to either fetus or mom than naturally conceived twins?

• 1:06:08Speaker 01

  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, the data is reassuring that pregnancies do fine, the babies do fine. But we definitely know that twins, whether you're, conceived them spontaneously or with IVF, the risk of almost every pregnancy complication is going to be higher.

• 1:06:39Dr. Peter Attia?

  So this is the risk of preeclampsia, HELPS syndrome, blood clot, like anything that is a risk?

• 1:06:46Speaker 01

  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.

• 1:06:58Dr. Peter Attia?

  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 is just such a gross image to me.

• 1:07:17Speaker 01

  I agree.

• 1:07:18Dr. Peter Attia?

  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?

• 1:07:29Speaker 01

  Definitely not.

• 1:07:30Dr. Peter Attia?

  Okay, thank God. Most disgusting image. I don't know why I get so grossed out by that.

• 1:07:35Speaker 01

  Yes.

• 1:07:35Dr. Peter Attia?

  So can you explain how IUI is done? We've already said that with IUI, you largely favor an oral preparation.

• 1:07:44Speaker 01

  Usually, yeah.

• 1:07:46Dr. Peter Attia?

  Yeah, okay. That means you're using an oral set of hormones so that the woman doesn't have a massive proliferation of follicles.

• 1:07:55Speaker 01

  Right.

• 1:07:55Dr. Peter Attia?

  So the male ejaculates. Do you want fresh semen? Or do you care if it's frozen? What's the difference in success?

• 1:08:02Speaker 01

  Same. We have single women as well, and female same-sex couples who would also be doing donor insemination in that case.

• 1:08:10Dr. Peter Attia?

  And we don't see any difference between fresh semen and frozen semen?

• 1:08:14Speaker 01

  No, assuming the sperm is normal.

• 1:08:16Dr. Peter Attia?

  Assuming the sperm is identical.

• 1:08:17Speaker 01

  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 the 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.

• 1:09:00Dr. Peter Attia?

  The problem that you're able to overcome on the sperm side would be number and motility.

• 1:09:07Speaker 01

  Yeah, or morphology, like any abnormality in the semen analysis, as long as it's not very severe.

• 1:09:14Dr. Peter Attia?

  It's not chromosomal. So if the sperm are too few, they don't move well enough, if they're defective in most ways.

• 1:09:21Speaker 01

  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.

• 1:09:40Dr. Peter Attia?

  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?

• 1:09:51Speaker 01

  Essentially, the day she's ovulating.

• 1:09:53Dr. Peter Attia?

  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. You have a, 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.

• 1:10:24Speaker 01

  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.

• 1:10:37Dr. Peter Attia?

  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?

• 1:10:46Speaker 01

  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 you think the patient is ovulating.

• 1:11:03Dr. Peter Attia?

  And are you doing that with ultrasound?

• 1:11:05Speaker 01

  Usually LH monitoring, so patient will either monitor her urine LH. And remember LH goes up just before ovulation. We typically also look, 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.

• 1:11:27Dr. Peter Attia?

  How big a dose of HCG do you need?

• 1:11:28Speaker 01

  Usually 5,000 units, which is.

• 1:11:31Dr. Peter Attia?

  Half a vial.

• 1:11:32Speaker 01

  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.

• 1:11:43Dr. Peter Attia?

  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, 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.

• 1:12:16Speaker 01

  You could do that, or the couple could just have sex.

• 1:12:19Dr. Peter Attia?

  But we then introduce another variable, right? Which is what if the semen, what if the count is low enough? Because if he's ejaculating every day, you're not having a chance to fully rebuild 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?

• 1:12:36Speaker 01

  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 of these things, it has to be worth it.

• 1:12:48Dr. Peter Attia?

  So at some point, even if what I proposed worked better, it's going to approach the cost of IVF.

• 1:12:54Speaker 01

  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.

• 1:13:06Dr. Peter Attia?

  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.

• 1:13:18Speaker 01

  The pregnancy success rate really depends on the age of the female partner. So if it's a young woman in her twenties, success rate might approach success rate for natural conception, which might be 20, 25% per cycle. If it's a woman over 35, it might be 10 to 15%. If it's a woman over 40, it might only be 1 to 5% per cycle.

• 1:13:42Dr. Peter Attia?

  Wow.

• 1:13:43Speaker 01

  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 an implant.

• 1:13:54Dr. Peter Attia?

  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.

• 1:14:08Speaker 01

  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.

• 1:14:16Dr. Peter Attia?

  So let's just go sub 35.

• 1:14:18Speaker 01

  Okay.

• 1:14:18Dr. Peter Attia?

  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?

• 1:14:41Speaker 01

  Again, sort of depends on what the cause of the infertility is. Is it unexplained or is it PCOS?

• 1:14:47Dr. Peter Attia?

  No, let's say unexplained.

• 1:14:48Speaker 01

  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, if something's going on, we just can't figure it out. In those cases, almost always IVF is going to give you a higher chance of success.

• 1:15:06Dr. Peter Attia?

  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?

• 1:15:13Speaker 01

  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.

• 1:15:24Dr. Peter Attia?

  So hormonal therapy basically is addressing the problem. Got it.

• 1:15:27Speaker 01

  If it's very severe male factor, probably IUI is not going to work. So it really kind of depends what the etiology of the infertility.

• 1:15:35Dr. Peter Attia?

  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 six months of not getting pregnant would be sufficient, but what percentage of women will get pregnant absent an IVF strategy?

• 1:16:01Speaker 01

  So depends how long you do it for. So most of the time, we're only doing it for three cycles.

• 1:16:07Dr. Peter Attia?

  That's right.

• 1:16:07Speaker 01

  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.

• 1:16:26Dr. Peter Attia?

  But we tend to stop at three months.

• 1:16:28Speaker 01

  Yeah.

• 1:16:28Dr. Peter Attia?

  Tell me at three months again, what percentage are going to be successful with three cycles?

• 1:16:32Speaker 01

  In that age group?

• 1:16:33Dr. Peter Attia?

  Yes.

• 1:16:33Speaker 01

  Unexplained infertility?

• 1:16:35Dr. Peter Attia?

  Unexplained over 35?

• 1:16:36Speaker 01

  I don't know the exact number, but probably under 50%.

• 1:16:39Dr. Peter Attia?

  Okay, but that could be a third, potentially.

• 1:16:41Speaker 01

  Yeah, because the success rate per cycle is something like in that age group, let's say 10 to 15%. So it's...

• 1:16:49Dr. Peter Attia?

  So you go one minus that number times three.

• 1:16:51Speaker 01

  To the third.

• 1:16:52Dr. Peter Attia?

  One minus that to the third power.

• 1:16:53Speaker 01

  Yeah.

• 1:16:53Dr. Peter Attia?

  Should be about 30%.

• 1:16:55Speaker 01

  Exactly.

• 1:16:55Dr. Peter Attia?

  Okay. So now, let's talk a little bit about IVF. First successful IVF baby, 1978, if my memory serves correctly?

• 1:17:03Speaker 01

  That's right. That's right.

• 1:17:04Dr. Peter Attia?

  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.

• 1:17:10Speaker 01

  Yeah, yeah.

• 1:17:12Dr. Peter Attia?

  We've come a long way since then.

• 1:17:13Speaker 01

  We have.

• 1:17:14Dr. Peter Attia?

  For historical context, I don't know anything about that girl, but do you know anything about how that was done back in 1978?

• 1:17:21Speaker 01

  Yeah, actually, there's a recent docu-drama out called Joy.

• 1:17:24Dr. Peter Attia?

  Is that her name?

• 1:17:25Speaker 01

  Her middle name, I believe, is Joy.

• 1:17:27Dr. Peter Attia?

  Ah.

• 1:17:27Speaker 01

  Yes.

• 1:17:28Dr. Peter Attia?

  Well, that's great.

• 1:17:28Speaker 01

  Louise Joy Brown.

• 1:17:30Dr. Peter Attia?

  What's her name?

• 1:17:30Speaker 01

  Louise Brown. I believe her middle name is Joy.

• 1:17:33Dr. Peter Attia?

  Got it.

• 1:17:34Speaker 01

  It's a movie about the first IVF success.

• 1:17:37Dr. Peter Attia?

  Oh, that's great.

• 1:17:38Speaker 01

  Now, of course, they tried for many, many years before they had the first success. These were two doctors.

• 1:17:44Dr. Peter Attia?

  I mean, maybe this is all in the docu-drama, 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.

• 1:17:51Speaker 01

  Yeah, there was a lot of controversy, like... This was very freaky.

• 1:17:56Dr. Peter Attia?

  Yeah.

• 1:17:56Speaker 01

  Yeah. And this was done at the time primarily for women with tubal factor blocked tubes. I think, 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.

• 1:18:11Dr. Peter Attia?

  Where was this done?

• 1:18:12Speaker 01

  In the UK in Britain.

• 1:18:14Dr. Peter Attia?

  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.

• 1:18:21Speaker 01

  Yeah, I think the first cases, they were actually doing surgery under general anesthesia.

• 1:18:26Dr. Peter Attia?

  Open surgery to harvest?

• 1:18:27Speaker 01

  Leposcopic, I believe.

• 1:18:28Dr. Peter Attia?

  Yeah.

• 1:18:29Speaker 01

  To retrieve the eggs.

• 1:18:30Dr. Peter Attia?

  Oh, wow.

• 1:18:31Speaker 01

  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 of has changed over the last 45 years or so.

• 1:18:50Dr. Peter Attia?

  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?

• 1:19:06Speaker 01

  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.

• 1:19:40Dr. Peter Attia?

  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?

• 1:19:59Speaker 01

  So typically, we do a bunch of screening tests on both partners. That includes some blood tests, semen analysis, an ultrasound to get some assessment of their egg number, the woman's egg number. And then when the cycle starts, it takes about two to three months to complete a cycle of IVF.

• 1:20:16Dr. Peter Attia?

  And when you say egg number, are you determining that through an AMH or through a physical examination of the ovaries?

• 1:20:23Speaker 01

  Both. So we do an ultrasound. We can count the number of follicles.

• 1:20:26Dr. Peter Attia?

  How small are these things?

• 1:20:28Speaker 01

  A few millimeters.

• 1:20:29Dr. Peter Attia?

  And you have the resolution to see that on an ultrasound?

• 1:20:32Speaker 01

  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.

• 1:20:42Dr. Peter Attia?

  Explain what AMH is and how it works.

• 1:20:44Speaker 01

  Yeah. AMH is a hormone. It stands for anti-malarian hormone. It's secreted by the cells that surround the egg, so it tends to correlate with egg number. 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?

• 1:21:03Dr. Peter Attia?

  Just number. 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?

• 1:21:12Speaker 01

  Right. If they're different ages, their success rates can be different.

• 1:21:16Dr. Peter Attia?

  Remind me the range. So a prepubescent girl who has a billion, not a billion, but right, a million eggs, but who is not fertile, does she have a high or low AMH?

• 1:21:26Speaker 01

  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 peak around per deciliter, I believe. Less than one is considered low. So a woman who's older...

• 1:21:41Dr. Peter Attia?

  But what's the difference between a 16-year-old girl who probably could get pregnant if she walked past a guy versus...

• 1:21:48Speaker 01

  That never happens, by the way.

• 1:21:50Dr. Peter Attia?

  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 is still fertile but has lost a step, like what's the difference in AMH?

• 1:22:01Speaker 01

  Yeah, it's a very narrow range.

• 1:22:02Dr. Peter Attia?

  Okay.

• 1:22:03Speaker 01

  So like above two, we consider that's probably normal reproductive age.

• 1:22:06Dr. Peter Attia?

  Above two is two effectively, okay.

• 1:22:08Speaker 01

  Now, it can be high, too, and 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.

• 1:22:19Dr. Peter Attia?

  So this is kind of a binary test.

• 1:22:20Speaker 01

  Well, not really.

• 1:22:21Dr. Peter Attia?

  You're not looking at, oh, this woman's 1.6, this woman's 1.7.

• 1:22:25Speaker 01

  No, not that.

• 1:22:25Dr. Peter Attia?

  Yeah, you're not looking at like you look at a TSH or something.

• 1:22:28Speaker 01

  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 cycle, everything usually starts with her 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.

• 1:23:08Dr. Peter Attia?

  Now you go injectable.

• 1:23:09Speaker 01

  Yep, and they're injectable, they're just under skin kind of injections.

• 1:23:12Dr. Peter Attia?

  So meaning HCG and FSH?

• 1:23:15Speaker 01

  Not HCG, but primarily FSH with a little bit of LH. So you're on those for about eight 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, et cetera. Usually medications are pretty well tolerated.

• 1:23:40Dr. Peter Attia?

  And what dose of LH and FSH is she injecting relative to what she would normally make? Is it a 2X, 5X, 10X?

• 1:23:47Speaker 01

  It depends on the age again, higher doses for women who are older, but much, much higher doses.

• 1:23:53Dr. Peter Attia?

  More than 10X?

• 1:23:54Speaker 01

  Hmm, maybe not, maybe five.

• 1:23:57Dr. Peter Attia?

  Typical symptoms?

• 1:23:58Speaker 01

  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 are signs of it 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.

• 1:24:40Speaker 01

  And the purpose of that medication, it causes the final maturation of the eggs. 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.

• 1:24:56Dr. Peter Attia?

  And to be clear, were you only giving her FSH before, or were you giving her LH as well?

• 1:25:00Speaker 01

  A little bit of LH, but mostly FSH.

• 1:25:02Dr. Peter Attia?

  And why are you using LH versus HCG?

• 1:25:04Speaker 01

  Just to simulate the physiologic cycle.

• 1:25:08Dr. Peter Attia?

  I didn't realize there was a difference appreciated by the body between them.

• 1:25:12Speaker 01

  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 a substitute for LH.

• 1:25:23Dr. Peter Attia?

  So there is synthetic LH out there as a drug?

• 1:25:24Speaker 01

  Yeah.

• 1:25:25Dr. Peter Attia?

  Okay.

• 1:25:25Speaker 01

  It's combined with, comes in as a combination drug.

• 1:25:28Dr. Peter Attia?

  With the FSH?

• 1:25:29Speaker 01

  Yeah.

• 1:25:30Dr. Peter Attia?

  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?

• 1:25:42Speaker 01

  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.

• 1:25:54Dr. Peter Attia?

  When you're giving her FSH, the LH that's attached to it is very, very low.

• 1:25:58Speaker 01

  Right.

• 1:25:59Dr. Peter Attia?

  That will prevent an ovulation.

• 1:26:01Speaker 01

  Yes, the antagonist will, basically blocking the GnRH, which is another hormone.

• 1:26:06Dr. Peter Attia?

  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.

• 1:26:23Speaker 01

  Right.

• 1:26:24Dr. Peter Attia?

  So then now you control the switch and the switch is in the mega dose of HCG, which is an LH analog. Do you harvest the follicles in the fallopian tube?

• 1:26:34Speaker 01

  In the ovaries. So the egg retrieval happens two days after that HCG trigger.

• 1:26:41Dr. Peter Attia?

  Wow.

• 1:26:41Speaker 01

  Yeah.

• 1:26:42Dr. Peter Attia?

  It would have taken two days.

• 1:26:44Speaker 01

  Thirty six hours specifically. So she usually takes it in the evening and then the retrieval.

• 1:26:49Dr. Peter Attia?

  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?

• 1:27:00Speaker 01

  Well, first of all, she's asleep.

• 1:27:02Dr. Peter Attia?

  Fully asleep or just?

• 1:27:03Speaker 01

  Prophylaxis. Yeah. So this is done in a surgery center typically or clinic with anesthesiologist present, IV sedation.

• 1:27:13Dr. Peter Attia?

  It's like a colonoscopy or dental extraction or something?

• 1:27:16Speaker 01

  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 trans-abdominal.

• 1:27:26Dr. Peter Attia?

  Dumb question. Don't you have a much straighter shot going through the abdomen?

• 1:27:30Speaker 01

  Not really.

• 1:27:30Dr. Peter Attia?

  You just don't want to go through the perineum?

• 1:27:32Speaker 01

  And there's a lot of stuff between the abdomen and the ovary.

• 1:27:35Dr. Peter Attia?

  And you can't just manipulate and move the bowel out of the way or something?

• 1:27:37Speaker 01

  It's much easier through the vagina. They're sitting right there.

• 1:27:40Dr. Peter Attia?

  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.

• 1:27:51Speaker 01

  Right on top of the top of the vagina, to the side of the uterus. You just stick a needle on either side.

• 1:27:55Dr. Peter Attia?

  So literally out of the vagina, not even going through the cervix?

• 1:27:58Speaker 01

  Yep.

• 1:27:59Dr. Peter Attia?

  That still strikes me as a very delicate, complicated procedure.

• 1:28:03Speaker 01

  I mean, it's a surgery. Yeah, relatively minor type surgery.

• 1:28:08Dr. Peter Attia?

  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.

• 1:28:13Speaker 01

  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.

• 1:28:20Dr. Peter Attia?

  Is the needle guide inside the probe or alongside?

• 1:28:23Speaker 01

  Alongside.

• 1:28:24Dr. Peter Attia?

  Okay.

• 1:28:24Speaker 01

  And the needle, it's a long needle, right? So your hand's not in the vagina? 16 and it goes through the vagina. You're doing this under ultrasound guidance. You can see exactly.

• 1:28:35Dr. Peter Attia?

  But somebody else is obviously manipulating the ultrasound for you.

• 1:28:38Speaker 01

  No, no, you have it in your hand. It's a vaginal ultrasound.

• 1:28:40Dr. Peter Attia?

  That's right. Yeah, yeah, yeah.

• 1:28:42Speaker 01

  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 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.

• 1:29:07Dr. Peter Attia?

  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?

• 1:29:21Speaker 01

  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.

• 1:29:29Dr. Peter Attia?

  And you're not running the risk of sucking up those eggs?

• 1:29:32Speaker 01

  No, no, you're just going into the follicles.

• 1:29:34Dr. Peter Attia?

  How big is the ovary?

• 1:29:36Speaker 01

  The ovary is a few centimeters at that point, but each follicle is about two centimeters, I would say, and there might be tent.

• 1:29:43Dr. Peter Attia?

  Whoa, whoa, whoa. How is each follicle two centimeters?

• 1:29:45Speaker 01

  In diameter.

• 1:29:46Dr. Peter Attia?

  But you said the ovary is only a couple of centimeters.

• 1:29:48Speaker 01

  No, it's like maybe five, six, like a small plum or something.

• 1:29:53Dr. Peter Attia?

  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?

• 1:30:01Speaker 01

  Roughly.

• 1:30:02Dr. Peter Attia?

  That's huge.

• 1:30:03Speaker 01

  1.5 to two.

• 1:30:04Dr. Peter Attia?

  I wouldn't have even thought it was one centimeter. How many follicles are in there?

• 1:30:08Speaker 01

  On average, we get 10 to 15. So maybe the ovary is bigger.

• 1:30:13Dr. Peter Attia?

  Maybe it's more like an orange.

• 1:30:14Speaker 01

  I'm thinking more an unstimulated ovary is more like a plum. When it's stimulated, more like a grapefruit.

• 1:30:19Dr. Peter Attia?

  Okay, I see. So you have really good resolution of where the follicles are?

• 1:30:23Speaker 01

  Yeah.

• 1:30:24Dr. Peter Attia?

  Okay, so you're not running the risk of sucking everything out of the ovary?

• 1:30:28Speaker 01

  No, and we're just getting fluid, right? We're not touching tissue of the ovary, just the fluid and the follicles.

• 1:30:34Dr. Peter Attia?

  It's only a 16-gauge needle. Does that mean you're puncturing the follicle?

• 1:30:40Speaker 01

  Each follicle.

• 1:30:41Dr. Peter Attia?

  Gets punctured before it enters the needle?

• 1:30:42Speaker 01

  Yeah. The fluid, yeah.

• 1:30:45Dr. Peter Attia?

  So you do it one at a time?

• 1:30:46Speaker 01

  Yeah.

• 1:30:46Dr. Peter Attia?

  You go ping into a follicle, burst it open and the egg, because a 16 gauge needle is probably only a millimeter across.

• 1:30:56Speaker 01

  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.

• 1:31:07Dr. Peter Attia?

  Pretty interesting that that works.

• 1:31:08Speaker 01

  Yeah, it's easiest maybe to just watch a video of it and then you get the idea.

• 1:31:12Dr. Peter Attia?

  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 gotta pull it out and put it back in.

• 1:31:20Speaker 01

  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.

• 1:31:27Dr. Peter Attia?

  And this is happening, you do this on both sides because presumably you're stimulating both sides.

• 1:31:30Speaker 01

  Yeah.

• 1:31:31Dr. Peter Attia?

  So how long does that procedure typically take?

• 1:31:33Speaker 01

  Half an hour.

• 1:31:34Dr. Peter Attia?

  And you've got the embryologist next to you and he or she is under the microscope going check, check, check, check, check.

• 1:31:41Speaker 01

  Yep.

• 1:31:41Dr. Peter Attia?

  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.

• 1:31:52Speaker 01

  Basically they tell us they got eggs. We don't know if they're mature yet. We know nothing about them yet.

• 1:31:56Dr. Peter Attia?

  I see.

• 1:31:57Speaker 01

  But as long as we get the eggs, they go to the lab and then the rest of the process happens there. So with the retrieval, we're just aspirating all the follicles, trying to get as many eggs as possible.

• 1:32:08Dr. Peter Attia?

  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?

• 1:32:25Speaker 01

  That discussion has happened way upstream. Typically, we're fertilizing all of them.

• 1:32:30Dr. Peter Attia?

  Yeah, there's no reason not to fertilize.

• 1:32:32Speaker 01

  Right.

• 1:32:32Dr. Peter Attia?

  Okay. Tell me the time course now and how you move from retrieval to fertilization.

• 1:32:37Speaker 01

  So then the eggs are sitting in the Petri dish in the lab.

• 1:32:41Dr. Peter Attia?

  What's the medium?

• 1:32:42Speaker 01

  It is this proprietary medium.

• 1:32:44Dr. Peter Attia?

  Is proprietary?

• 1:32:45Speaker 01

  Yes.

• 1:32:46Dr. Peter Attia?

  Meaning each lab will have its own medium?

• 1:32:49Speaker 01

  There are commercial companies that make it, but the exact components of it, not entirely known.

• 1:32:54Dr. Peter Attia?

  So there are different companies that have different mediums?

• 1:32:56Speaker 01

  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.

• 1:33:06Dr. Peter Attia?

  How much of a competitive advantage is it for an embryologist? Like, how many options do they have to choose from commercially?

• 1:33:14Speaker 01

  Of media? I don't think there are that many media companies.

• 1:33:17Dr. Peter Attia?

  I see. Is this a huge area of innovation in the field? It must be.

• 1:33:21Speaker 01

  Not really.

• 1:33:22Dr. Peter Attia?

  I would have guessed this would be so important.

• 1:33:24Speaker 01

  I think they got it down.

• 1:33:25Dr. Peter Attia?

  Was there a day when this was a problem?

• 1:33:27Speaker 01

  I'm sure.

• 1:33:27Dr. Peter Attia?

  Okay.

• 1:33:28Speaker 01

  Yeah, maybe in the early days.

• 1:33:29Dr. Peter Attia?

  So the embryologist transfers this to the media.

• 1:33:31Speaker 01

  Yep. Few hours later, the eggs are inseminated. So with conventional IVF, 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 single sperm and injects it into each egg.

• 1:33:50Dr. Peter Attia?

  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?

• 1:34:02Speaker 01

  It probably could, but maybe there's too few sperm. So anytime there's a male factor, we tend to do ICSI.

• 1:34:08Dr. Peter Attia?

  Any male factor, you go straight to ICSI?

• 1:34:10Speaker 01

  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.

• 1:34:30Dr. Peter Attia?

  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?

• 1:34:40Speaker 01

  Yeah, it's a little controversial because it adds cost.

• 1:34:44Dr. Peter Attia?

  How much cost?

• 1:34:45Speaker 01

  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.

• 1:35:09Dr. Peter Attia?

  Oh, that would be just catastrophic because you've lost those eggs, too.

• 1:35:12Speaker 01

  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. Exe and conventional IVF, if non-male factor. But a lot of times there's sperm factor, so we're doing exe anyway.

• 1:35:26Dr. Peter Attia?

  These go into, the media sits at room temperature, I'm sorry, at body temperature? Do you put it into a 37-degree oven?

• 1:35:33Speaker 01

  Yeah, body temperature in an incubator and then all the micromanipulation's happening.

• 1:35:38Dr. Peter Attia?

  What are the types of manipulations that are needed to foster the right environment? How much you're moving the fluid around? How often you're changing the media? This is like the most important cell culture experiment of all time.

• 1:35:48Speaker 01

  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.

• 1:36:33Speaker 01

  So we discard the unfertilized eggs, continue to culture.

• 1:36:37Dr. Peter Attia?

  And you can tell that grossly or are you having to move them under a microscope?

• 1:36:40Speaker 01

  Under a microscope.

• 1:36:41Dr. Peter Attia?

  Yeah.

• 1:36:42Speaker 01

  And then we culture them in the Petri dish.

• 1:36:45Dr. Peter Attia?

  At this point, are they all in one dish or are you separating them?

• 1:36:49Speaker 01

  They're in one like droplet of oil and there might be more than one droplet in each dish.

• 1:36:57Dr. Peter Attia?

  How are embryologists trained? How does one become an embryologist?

• 1:37:01Speaker 01

  Well, there's no clear pathway. There's not a whole bunch of embryology schools.

• 1:37:06Dr. Peter Attia?

  But if I wanted to be an embryologist, what would I do?

• 1:37:08Speaker 01

  Mostly, I've got 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.

• 1:37:29Dr. Peter Attia?

  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?

• 1:37:39Speaker 01

  It might take four to five years. Take a while. Now, there's some formal schools available as well that with online programs, with some in-person components.

• 1:37:49Dr. Peter Attia?

  Not to take anything away from what you do, but you could have the best fertility doctor. If they don't have a good embryologist, you're not going to have great success rates.

• 1:37:59Speaker 01

  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 the United States labs are pretty good. But yeah, that's one of the most important things.

• 1:38:12Dr. Peter Attia?

  I mean, because I used to work in a lab. I just think, I just can think of a hundred ways that could get screwed up. Contaminated, jostled, all these things that can go wrong.

• 1:38:21Speaker 01

  Super important. 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 colleagues does.

• 1:38:31Dr. Peter Attia?

  I guess the question is, well, let's finish the story and then I'll come back. So how many days? You go to 14 days of this?

• 1:38:37Speaker 01

  No, five days, six days. And depending if we're doing a fresh transfer or freezing the embryos, or a fresh transfer, we sometimes.

• 1:38:46Dr. Peter Attia?

  So you'll do both, right?

• 1:38:47Speaker 01

  We do both.

• 1:38:47Dr. Peter Attia?

  Yeah.

• 1:38:48Speaker 01

  Although these days, most of the time, we're freezing.

• 1:38:51Dr. Peter Attia?

  Because you're doing genetic screening?

• 1:38:52Speaker 01

  Because we're doing genetic testing, right?

• 1:38:54Dr. Peter Attia?

  So let's go through that example then.

• 1:38:56Speaker 01

  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.

• 1:39:08Dr. Peter Attia?

  So what explains that?

• 1:39:10Speaker 01

  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.

• 1:39:18Dr. Peter Attia?

  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.

• 1:39:33Speaker 01

  Yeah, we call that the blastulation rate is 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.

• 1:40:07Dr. Peter Attia?

  So yeah, let's talk about that. So how many cells do you have at five days again?

• 1:40:11Speaker 01

  Altogether, you might have like 60 to 80 cells.

• 1:40:14Dr. Peter Attia?

  Okay, so you take two or three of those.

• 1:40:16Speaker 01

  Five or six.

• 1:40:17Dr. Peter Attia?

  Five or six.

• 1:40:17Speaker 01

  Yeah, and they're from

• 1:40:19Dr. Peter Attia?

  The perimeter.

• 1:40:19Speaker 01

  The trophoblast, not the embryo directly, but the cells surrounding the embryo.

• 1:40:23Dr. Peter Attia?

  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?

• 1:40:32Speaker 01

  Yep.

• 1:40:32Dr. Peter Attia?

  Tell me what the freezing process is like.

• 1:40:34Speaker 01

  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.

• 1:40:44Dr. Peter Attia?

  So how do you do that?

• 1:40:45Speaker 01

  There's a process, it happens in the lab, there's a machine that does it, that lowers the temperature.

• 1:40:50Dr. Peter Attia?

  So the rate at which they lower the temperature?

• 1:40:53Speaker 01

  Right, it's rapid.

• 1:40:54Dr. Peter Attia?

  Okay, so it's like a liquid nitrogen dump, basically.

• 1:40:57Speaker 01

  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.

• 1:41:06Dr. Peter Attia?

  And then you store them at what temp? Like liquid nitrogen temp?

• 1:41:09Speaker 01

  Yeah.

• 1:41:10Dr. Peter Attia?

  Yep, it's not like in your freezer?

• 1:41:11Speaker 01

  No. Head home.

• 1:41:12Dr. Peter Attia?

  And then how long does it take typically to get the genetic results?

• 1:41:15Speaker 01

  Typically, within a week or two.

• 1:41:16Dr. Peter Attia?

  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?

• 1:41:30Speaker 01

  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 is 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.

• 1:41:59Dr. Peter Attia?

  Presumably genetic testing is really easy to identify aneuploidy. Chromosomal analysis is trivial.

• 1:42:06Speaker 01

  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

• 1:42:15Dr. Peter Attia?

  Targeted.

• 1:42:16Speaker 01

  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.

• 1:42:26Dr. Peter Attia?

  Yeah. So let's say one of the parents, well, this would be a bad example, but

• 1:42:32Speaker 01

  Cystic fibrosis, like let's say both patients are carriers.

• 1:42:35Dr. Peter Attia?

  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.

• 1:42:42Speaker 01

  Right.

• 1:42:42Dr. Peter Attia?

  So then you're looking directly for the CF genes.

• 1:42:44Speaker 01

  Exactly, exactly.

• 1:42:45Dr. Peter Attia?

  Beta foul, sickle cell, the standard.

• 1:42:47Speaker 01

  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 they're carriers for any genetic mutations.

• 1:42:57Dr. Peter Attia?

  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 three, four, and we would really like to not select a four, four as an example. So one, are you able to look at that? And two, does that start to cross an ethical line?

• 1:43:23Speaker 01

  Yeah, it's a little more controversial when you're talking about

• 1:43:25Dr. Peter Attia?

  Non-deterministic adult consequence genes.

• 1:43:28Speaker 01

  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 Nova, what we call to Nova, 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

• 1:43:56Dr. Peter Attia?

  Like BRCA.

• 1:43:57Speaker 01

  Well, BRCA, yeah. Often we know ahead of time, the patient's carrier, we can test for it.

• 1:44:01Dr. Peter Attia?

  LPA for cardiovascular disease.

• 1:44:03Speaker 01

  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 hypotension, whole different story if you're saying, oh, you should do IVF.

• 1:44:29Dr. Peter Attia?

  Because of?

• 1:44:30Speaker 01

  Because we want to get the embryo with the lowest risk of these diseases. So we're not quite there. It's 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 antipoly testing, testing for chromosomal abnormalities is pretty routine, pretty standard.

• 1:44:56Dr. Peter Attia?

  Now, there was a day when people weren't doing any genetic testing and the embryo selection was just based on morphology, right?

• 1:45:04Speaker 01

  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, and 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.

• 1:45:38Dr. Peter Attia?

  Yeah, that's lower than I would have guessed.

• 1:45:40Speaker 01

  Is it?

• 1:45:41Dr. Peter Attia?

  Seventy to seventy-five percent for something that's chromosomally normal?

• 1:45:44Speaker 01

  Yeah.

• 1:45:44Dr. Peter Attia?

  I would have guessed at that stage, given all the selections taking place.

• 1:45:47Speaker 01

  Yeah.

• 1:45:47Dr. Peter Attia?

  What is the concordance between, let's go one step further, chromosomally genetically normal and good morphology?

• 1:45:57Speaker 01

  There's good correlation, yeah. We use both.

• 1:46:00Dr. Peter Attia?

  If there's discordance there, which one are you relying on? Or are you discarding, unless you have concordance that's positive for both?

• 1:46:07Speaker 01

  In reality, the ones that have poor morphology aren't even frozen or biopsied. They're discarded because we know.

• 1:46:13Dr. Peter Attia?

  So we selected out?

• 1:46:14Speaker 01

  Yeah, you're selected 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.

• 1:46:33Dr. Peter Attia?

  So you have selected out bad morphology. Let's just say you harvested fifteen, you fertilized ten. Seven had good morphology. Six came back genetically good. Those would be reasonable numbers?

• 1:46:48Speaker 01

  Yeah, the six out of seven is high.

• 1:46:50Dr. Peter Attia?

  Yeah, okay. So five came back genetically good.

• 1:46:53Speaker 01

  Let's say, in a young person.

• 1:46:54Dr. Peter Attia?

  Yeah, so you've got one-third, one-third of what you harvested, you could implant. You're saying each of those is seventy to seventy-five percent success rate?

• 1:47:03Speaker 01

  Yeah.

• 1:47:03Dr. Peter Attia?

  And yet you would only implant one at a time?

• 1:47:05Speaker 01

  Yeah.

• 1:47:06Dr. Peter Attia?

  Which is interesting, because if you implanted two,

• 1:47:10Dr. Peter Attia?

  let's do the math, you're talking about?

• 1:47:12Speaker 01

  Fifty percent chance, roughly, of twins. Yeah, which is high.

• 1:47:16Dr. Peter Attia?

  Too high. We just can't take that risk.

• 1:47:18Speaker 01

  I mean, obviously, we believe in patient autonomy. Patient usually gets to make that decision, but.

• 1:47:24Dr. Peter Attia?

  You're gonna make the case for why that's not a great idea.

• 1:47:26Speaker 01

  You want to help the baby. In the end, you want a healthy mom.

• 1:47:29Dr. Peter Attia?

  Yep. Okay, so now let's talk about, now it's time to implant. So how does that process work?

• 1:47:33Speaker 01

  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

• 1:48:14Speaker 01

  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.

• 1:48:22Dr. Peter Attia?

  And where are you implanting it?

• 1:48:23Speaker 01

  One and a half centimeters to two centimeters from the top of the uterus. So a few centimeters through the cervix.

• 1:48:31Dr. Peter Attia?

  How do you make sure it doesn't come out?

• 1:48:34Speaker 01

  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.

• 1:48:41Dr. Peter Attia?

  What's the total volume you're injecting?

• 1:48:43Speaker 01

  Fifty microliters, really small.

• 1:48:46Dr. Peter Attia?

  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.

• 1:48:54Speaker 01

  Does have a lining.

• 1:48:55Dr. Peter Attia?

  How thick is the lining?

• 1:48:56Speaker 01

  It's about seven to 10 millimeters.

• 1:49:01Dr. Peter Attia?

  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?

• 1:49:08Speaker 01

  So it's roughly seven days or so after ovulation, right?

• 1:49:13Dr. Peter Attia?

  I got it. Yes, yes, yes.

• 1:49:15Speaker 01

  So the lining is thickened already.

• 1:49:16Dr. Peter Attia?

  Yeah, okay.

• 1:49:17Speaker 01

  And that's one of the things we check with ultrasound before we do the transfer to make sure the lining is.

• 1:49:22Dr. Peter Attia?

  What does that, I mean, what does it actually look like? Is it tentacle fingers or?

• 1:49:26Speaker 01

  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.

• 1:49:35Dr. Peter Attia?

  It's a potential space, not a real space.

• 1:49:36Speaker 01

  Potential space, exactly. On the ultrasound, the lining has a different echo density than.

• 1:49:42Dr. Peter Attia?

  The wall itself, right?

• 1:49:43Speaker 01

  Right, so we can measure the thickness. And basically, the combined thickness of the two opposing walls has to be at least seven millimeters or so.

• 1:49:53Dr. Peter Attia?

  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?

• 1:50:04Speaker 01

  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.

• 1:50:12Dr. Peter Attia?

  Until it's go time.

• 1:50:13Speaker 01

  Yeah. Because once it's thawed, I mean, you can refreeze it, but.

• 1:50:15Dr. Peter Attia?

  No, I'm sure.

• 1:50:16Speaker 01

  Probably doesn't do as well.

• 1:50:17Dr. Peter Attia?

  Not a good idea.

• 1:50:18Speaker 01

  Yeah.

• 1:50:19Dr. Peter Attia?

  Okay, so I see. So once you put that egg in there.

• 1:50:21Speaker 01

  Embryo.

• 1:50:22Dr. Peter Attia?

  Sorry, that embryo in there closer to the top of the uterus, it's largely being held in place by the opposition of the wall. And then are you done or are you still doing ongoing hormone therapy?

• 1:50:31Speaker 01

  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.

• 1:50:45Dr. Peter Attia?

  And then she transfers to her non IVF?

• 1:50:48Speaker 01

  Or midway, yeah.

• 1:50:49Dr. Peter Attia?

  Wow. It's just kind of amazing that this all works.

• 1:50:51Speaker 01

  Yeah. I've been doing it for 30 plus years and I still find it fascinating. Yeah.

• 1:50:57Dr. Peter Attia?

  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?

• 1:51:13Speaker 01

  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 twenties, early thirties sometimes. They produce multiple eggs. And then the age of the uterus doesn't

• 1:51:55Speaker 01

  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%.

• 1:52:09Dr. Peter Attia?

  Per?

• 1:52:10Speaker 01

  Cycle.

• 1:52:10Dr. Peter Attia?

  Per cycle?

• 1:52:11Speaker 01

  Yeah.

• 1:52:12Dr. Peter Attia?

  Wow. 10 to 20% for a 40-year-old woman?

• 1:52:15Speaker 01

  Yeah. Untested embryos or they may not get any embryos, normal embryos. Yeah.

• 1:52:21Dr. Peter Attia?

  I did not realize it was that low.

• 1:52:22Speaker 01

  Yeah.

• 1:52:23Dr. Peter Attia?

  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.

• 1:52:33Speaker 01

  Yes, sometimes people do it multiple times. Sometimes they just do it once.

• 1:52:37Dr. Peter Attia?

  Does it pose any risk?

• 1:52:38Speaker 01

  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.

• 1:52:50Dr. Peter Attia?

  But is there anything that restricts her ability to get pregnant later in life?

• 1:52:54Speaker 01

  No, barring any complications from major complications, it does not seem to impact future fertility.

• 1:53:01Dr. Peter Attia?

  What is the typical fee that's collected by an egg donor?

• 1:53:04Speaker 01

  It's usually between $5,000 and $10,000, depending on where you live.

• 1:53:08Dr. Peter Attia?

  Okay, that's a lot of money.

• 1:53:10Speaker 01

  It's a lot of money for two weeks.

• 1:53:13Dr. Peter Attia?

  Yeah.

• 1:53:13Speaker 01

  Period. Yeah.

• 1:53:15Dr. Peter Attia?

  And so a woman could do that a couple of times a year if she wanted to?

• 1:53:17Speaker 01

  So the guideline's up to six times.

• 1:53:19Dr. Peter Attia?

  Six times a year?

• 1:53:20Speaker 01

  No, six times lifetime.

• 1:53:21Dr. Peter Attia?

  Oh.

• 1:53:23Speaker 01

  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.

• 1:53:35Dr. Peter Attia?

  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?

• 1:53:53Speaker 01

  Before anybody does egg donation, or even before they donate eggs, we always have them meet with one of our mental health therapists, just as a cycle educational 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.

• 1:54:14Speaker 01

  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.

• 1:54:27Dr. Peter Attia?

  And early means what? Telling them before they understand reproduction? Like, what are you telling them?

• 1:54:33Speaker 01

  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.

• 1:54:57Dr. Peter Attia?

  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.

• 1:55:32Speaker 01

  Yeah, that's true.

• 1:55:33Dr. Peter Attia?

  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.

• 1:55:42Dr. Peter Attia?

  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 100 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?

• 1:56:06Speaker 01

  These days is 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-

• 1:56:26Dr. Peter Attia?

  You have to go in and get these ultrasounds.

• 1:56:28Speaker 01

  Yeah, you gotta go in every few days, so you can't be going to another state. Most people can't.

• 1:56:32Dr. Peter Attia?

  But in most major cities, you have multiple options.

• 1:56:35Speaker 01

  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

• 1:56:48Dr. Peter Attia?

  You don't have the patient population, right? So how do you normalize it?

• 1:56:50Speaker 01

  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.

• 1:56:59Dr. Peter Attia?

  You mean publicly it's available?

• 1:57:01Speaker 01

  Yeah, it's available.

• 1:57:02Dr. Peter Attia?

  Where do you find it?

• 1:57:03Speaker 01

  Well, the CDC, until recently, there is a law actually that says you have to report every IVF cycle and 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 US, or most of them, 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.

• 1:57:44Speaker 01

  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.

• 1:58:01Dr. Peter Attia?

  Your clinic has how many doctors?

• 1:58:03Speaker 01

  Our clinic has about six doctors.

• 1:58:06Dr. Peter Attia?

  How many total cycles do you guys do a year?

• 1:58:08Speaker 01

  We do 600 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.

• 1:58:21Dr. Peter Attia?

  And you have how many embryologists?

• 1:58:23Speaker 01

  We have something like nine embryologists.

• 1:58:26Dr. Peter Attia?

  Wow.

• 1:58:27Speaker 01

  Yeah, there is a shortage of embryologists nationwide and reproductive endocrinologists because of 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?

• 1:58:45Dr. Peter Attia?

  Yeah, they tend to be negative selecting.

• 1:58:47Speaker 01

  Right. Not everybody who has a great experience necessarily going to post it on Reddit.

• 1:58:51Dr. Peter Attia?

  But everyone who has a bad one does.

• 1:58:52Speaker 01

  Yeah. Yeah. So you have to take that with a grain of salt, but there are objective ways. And you can also like interview your doctor.

• 1:58:58Dr. Peter Attia?

  Yeah. What are questions you should be asking of the doctor that are independent of the objective metrics that we might have just discussed?

• 1:59:05Speaker 01

  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. You 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

• 1:59:46Speaker 01

  towards some academic centers just because our missions include education and research, et cetera. But there's several very excellent private clinics as well.

• 1:59:58Dr. Peter Attia?

  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?

• 2:00:08Speaker 01

  Yeah, within a given geography, they're pretty similar and it's not cheap.

• 2:00:12Dr. Peter Attia?

  Yeah. So what are we at today? Fully loaded cost?

• 2:00:14Speaker 01

  So, you know, an IVF cycle is probably around $20,000 per cycle.

• 2:00:18Dr. Peter Attia?

  But that doesn't include genetic testing or does?

• 2:00:20Speaker 01

  Including genetic testing per cycle.

• 2:00:23Dr. Peter Attia?

  But how does that compare to 20 years ago? Is that more or less inflation?

• 2:00:26Speaker 01

  Prices, like most things, have gone up.

• 2:00:28Dr. Peter Attia?

  It has?

• 2:00:29Speaker 01

  Yeah.

• 2:00:29Dr. Peter Attia?

  Okay. I guess it should go up just based on the cost of labor that goes into all these things?

• 2:00:34Speaker 01

  Yeah, and there's innovations.

• 2:00:35Dr. Peter Attia?

  Even though the genetic testing's coming down?

• 2:00:36Speaker 01

  Yeah, innovations and things like, you're right, like 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.

• 2:00:47Dr. Peter Attia?

  And most people are probably still paying out of pocket. Most people are not getting this covered by insurance.

• 2:00:51Speaker 01

  Again, depends where you live.

• 2:00:52Dr. Peter Attia?

  Yeah, yeah, but across the country.

• 2:00:53Speaker 01

  Yeah. I think there are now Twenty-four 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

• 2:01:20Dr. Peter Attia?

  Yeah, just setting up appointments.

• 2:01:21Speaker 01

  Coordinators, 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.

• 2:01:54Dr. Peter Attia?

  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.

• 2:02:02Speaker 01

  It can be, yeah.

• 2:02:03Dr. Peter Attia?

  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?

• 2:02:33Speaker 01

  So there's a lot of interest in extending fertility. Up until 100 years ago, women were basically dying at 50 is 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. 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.

• 2:03:09Dr. Peter Attia?

  Because you're paying basically half the IVF cycle to harvest and then you're paying to freeze.

• 2:03:15Speaker 01

  Yeah, exactly.

• 2:03:16Dr. Peter Attia?

  What's the cost of freezing?

• 2:03:17Speaker 01

  Well, $10,000 for the cycle and then about $1,000 a year for storage.

• 2:03:22Dr. Peter Attia?

  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 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?

• 2:03:37Speaker 01

  No.

• 2:03:37Dr. Peter Attia?

  Because, no.

• 2:03:38Speaker 01

  I wouldn't recommend all women in their twenties 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 probably not need IVF and get pregnant spontaneously, right?

• 2:03:49Dr. Peter Attia?

  Got it, okay.

• 2:03:49Speaker 01

  The sweet spot, we think, is like early to mid 30s. That's where it makes the most sense.

• 2:03:55Dr. Peter Attia?

  Because you're about to get to the probability cliff where it starts to really decline.

• 2:04:00Speaker 01

  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 then $1,000 a year.

• 2:04:21Dr. Peter Attia?

  A thousand bucks a year. And do you freeze them? You freeze every egg you retrieve?

• 2:04:26Speaker 01

  Only the mature ones.

• 2:04:28Dr. Peter Attia?

  Okay.

• 2:04:28Speaker 01

  Yeah.

• 2:04:29Dr. Peter Attia?

  And what's the, for a typical 30-year-old, you're going to get what we talked about earlier?

• 2:04:35Speaker 01

  Probably 10 to 15 per cycle, sometimes more, but that's average.

• 2:04:38Dr. Peter Attia?

  And how many do you recommend a 30-year-old do?

• 2:04:41Speaker 01

  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 30, I think 10 to 20 would give you decent chances 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, 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

• 2:05:23Speaker 01

  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 twenties and thirties. A whole different question, but I think having options is a good thing.

• 2:05:37Dr. Peter Attia?

  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 this study testing this?

• 2:05:46Speaker 01

  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 like 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 months study where they're giving relatively low dose of rapamycin. I forget exactly, maybe five milligrams daily.

• 2:06:31Dr. Peter Attia?

  Daily, not weekly?

• 2:06:32Speaker 01

  I think it's daily.

• 2:06:33Dr. Peter Attia?

  Okay.

• 2:06:34Speaker 01

  But I'm not 100% sure.

• 2:06:35Dr. Peter Attia?

  We'll pull it up and put it in the show notes. I should have known this.

• 2:06:37Speaker 01

  And then I think their outcome marker is AMH, I believe is that hormone. So I don't know.

• 2:06:43Dr. Peter Attia?

  It's a relatively inexpensive study. They're not invasively looking at follicles. What 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.

• 2:06:57Speaker 01

  Right. And even if you can, like, what does that mean really?

• 2:07:01Dr. Peter Attia?

  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.

• 2:07:09Speaker 01

  Right. To really do the study, I mean, you'd need long term.

• 2:07:12Dr. Peter Attia?

  You need a few years.

• 2:07:13Speaker 01

  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.

• 2:07:25Dr. Peter Attia?

  That's going to be a really difficult question to answer in humans.

• 2:07:28Speaker 01

  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.

• 2:07:50Dr. Peter Attia?

  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?

• 2:08:17Speaker 01

  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.

• 2:08:38Dr. Peter Attia?

  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?

• 2:08:50Speaker 01

  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 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.

• 2:09:28Dr. Peter Attia?

  By the way, I think I said iatrogenic, I meant idiopathic, but you know what I meant.

• 2:09:31Speaker 01

  Yes.

• 2:09:32Dr. Peter Attia?

  So what about supplements? I'm sure you get asked this question all the time.

• 2:09:35Speaker 01

  Yeah.

• 2:09:35Dr. Peter Attia?

  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.

• 2:09:44Speaker 01

  Yeah.

• 2:09:44Dr. Peter Attia?

  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.

• 2:10:02Speaker 01

  Right.

• 2:10:02Dr. Peter Attia?

  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.

• 2:10:13Speaker 01

  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.

• 2:10:58Dr. Peter Attia?

  DHEA?

• 2:10:59Speaker 01

  DHEA.

• 2:11:00Dr. Peter Attia?

  Which just increases endogenous testosterone production.

• 2:11:03Speaker 01

  Improves egg quality, like who knows?

• 2:11:06Dr. Peter Attia?

  Interesting.

• 2:11:06Speaker 01

  Yeah, I mean, the data isn't great.

• 2:11:08Dr. Peter Attia?

  Might improve libido.

• 2:11:09Speaker 01

  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 CoQ10. There's some data around it, sure.

• 2:11:32Dr. Peter Attia?

  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? Like, because for me, I can't help but think that stress has such a negative impact on fertility.

• 2:11:44Speaker 01

  Oh, for sure.

• 2:11:45Dr. Peter Attia?

  And on many aspects of health.

• 2:11:46Speaker 01

  For sure.

• 2:11:46Dr. Peter Attia?

  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.

• 2:12:02Speaker 01

  I agree with you. And if taking supplements helps with that, sure, I'm all for it.

• 2:12:06Dr. Peter Attia?

  Yeah, I'm not advocating that we should be going crazy on it.

• 2:12:08Speaker 01

  Right, right.

• 2:12:08Dr. Peter Attia?

  With no evidence. But I wonder if any of the efficacy of those things is mediated through that reduction of stress.

• 2:12:14Speaker 01

  Possibly, yeah. And as long as it's not harmful.

• 2:12:16Dr. Peter Attia?

  Yeah.

• 2:12:16Speaker 01

  That's great. And when we say the data is in there, it's just because, 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 it helps 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.

• 2:12:47Dr. Peter Attia?

  You just need to be less stressed.

• 2:12:48Speaker 01

  You just need to be less stressed. I'm 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 peoples. For some people, it could be exercise. For some people, it could be meditation. For some people, whatever, mindfulness.

• 2:13:02Dr. Peter Attia?

  Social support, yoga.

• 2:13:04Speaker 01

  Whatever it is. But definitely, it's important. Same as sleep. And we talked about diet. Exercise is important.

• 2:13:12Dr. Peter Attia?

  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?

• 2:13:35Speaker 01

  Extreme exercise can be associated with fertility issues, although I think for most patients, the benefits of exercise, as we know.

• 2:13:43Dr. Peter Attia?

  Yeah. What is extreme in this case?

• 2:13:45Speaker 01

  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's 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 gonna shut the whole thing down. And it works really well. But the patient stops menstruating. So obviously, they're gonna have difficulty getting pregnant if they're not ovulating. If you're not menstruating, 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's super important for bone health. So, one

• 2:14:26Speaker 01

  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.

• 2:14:50Dr. Peter Attia?

  It's all the norm.

• 2:14:51Speaker 01

  But thankfully, this generation of young women is talking more, and there's the internet, etc. 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. So.

• 2:15:03Dr. Peter Attia?

  And we've already talked about obesity. But on the other side of that, is there a certain body fat level beneath which fertility is also impacted?

• 2:15:11Speaker 01

  Yeah, there's not a cutoff, but certainly being overweight or obese can impact fertility and being severely underweight. For the underweight people, it's a similar mechanism. If your brain thinks there's just not enough.

• 2:15:23Dr. Peter Attia?

  It's usually gonna manifest through amenorrhea.

• 2:15:26Speaker 01

  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.

• 2:15:45Dr. Peter Attia?

  Lastly, what do you think is the most promising area of research? And if we're sitting here in 10 years

• 2:15:50Speaker 01

  Yeah.

• 2:15:50Dr. Peter Attia?

  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?

• 2:16:00Speaker 01

  It's a very exciting field of medicine. There's always sort of innovations happening. 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 like you put in the egg, put in the sperm, an embryo comes out.

• 2:16:29Dr. Peter Attia?

  So microfluidics or?

• 2:16:30Speaker 01

  Yeah, microfluidics, the whole process being automated. It's very interesting, right? And it could potentially improve access if you could put these labs.

• 2:16:41Dr. Peter Attia?

  So do you see this as more of a cost reduction or more of a success improvement?

• 2:16:46Speaker 01

  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.

• 2:17:26Dr. Peter Attia?

  I assume because it's difficult to harvest un-mature follicles?

• 2:17:30Speaker 01

  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 like a skin biopsy and reprogram that cell. To make an egg than potentially anybody.

• 2:17:56Dr. Peter Attia?

  Where are we in that?

• 2:17:58Speaker 01

  Very early. I think we'll see it eventually. It's been done in mice. So we're probably 10 to 20 years away.

• 2:18:05Dr. Peter Attia?

  What's the obstacle?

• 2:18:06Speaker 01

  Basically reprogramming skin cells, just the whole process is very complicated and not easy. People are trying, there are a couple of companies that are trying to do.

• 2:18:17Dr. Peter Attia?

  Is the challenge taking the skin cell back to a stem cell and then the stem cell into?

• 2:18:22Speaker 01

  Differentiating it.

• 2:18:22Dr. Peter Attia?

  Yeah. And which of those two steps do we think is harder? Skin cell back to stem cell or stem cell into egg?

• 2:18:29Speaker 01

  I think they're both hard. I don't know. There's a couple of different approaches, including we work, do research in this area as well, where we're taking essentially the nucleus from a skin cell and putting it.

• 2:18:40Dr. Peter Attia?

  Into an egg and just replacing the genetic material?

• 2:18:43Speaker 01

  Exactly. So we don't have to reprogram the skin cell.

• 2:18:46Dr. Peter Attia?

  And is it easy to separate the chromosomes?

• 2:18:49Speaker 01

  No.

• 2:18:50Dr. Peter Attia?

  Okay, I was gonna say.

• 2:18:52Speaker 01

  It's very complicated because it's myosis. 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.

• 2:19:11Dr. Peter Attia?

  Yeah, that's true. Although I guess what it does is it, it helps the older woman who is able to make follicles, but they're just aneuploidic.

• 2:19:20Speaker 01

  Exactly.

• 2:19:21Dr. Peter Attia?

  You have a solution to that problem?

• 2:19:22Speaker 01

  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.

• 2:20:07Dr. Peter Attia?

  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 twenties, 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.

• 2:20:52Speaker 01

  For sure.

• 2:20:53Dr. Peter Attia?

  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.

• 2:21:35Speaker 01

  More standardization, yes, for sure.

• 2:21:37Dr. Peter Attia?

  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.

• 2:22:04Speaker 01

  Related, for sure.

• 2:22:05Dr. Peter Attia?

  Yeah. Appreciate your time and your expertise.

• 2:22:07Speaker 01

  Thanks for inviting me. It's been fun. Thanks for having me.

• 2:22:10Dr. Peter Attia?

  Thank you for listening to this week's episode of The Drive. Head over to peterattiamd.com/shownotes if you want to dig deeper into this episode. You can also find me on YouTube, Instagram, and Twitter, all with the handle Peter AtiyahMD. You can also leave us a review on Apple Podcasts or whatever podcast player you use. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. No doctor-patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical

• 2:22:54Dr. Peter Attia?

  advice, diagnosis, or treatment. Users should not disregard or delay in obtaining medical advice from any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take all conflicts of interest very seriously. For all of my disclosures and the companies I invest in or advise, please visit peterattiamd.com/about, where I keep an up-to-date and active list of all disclosures.