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

27:23But in other words, how much wasted time is being generated because infertility is being assumed to be the responsibility of the female, responsibility might be the wrong word. But it's just assumed that, well, that's more likely where it is. And so, through no bad intention, the guy is not getting evaluated when in reality the issue could have been with him all along and time is wasted. Right. When you look at the data, it's about a third of the time. It's a female factor, a third of the time it's a male factor, and another third of the time at 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.

27:59And do you guys do that yourselves as well? Or do you, at the fertility class? 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 like, I'm one of those 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 my whole year and then go see a provider.

28:34If your cycles are regular, if you think you might have places to go for your syndrome or something, then you definitely want to see somebody sooner than a year. Is it possible to say anything about fertility rates changing over the past 50 years? Is there any statement you can make on that? Yeah, there are 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 one in six, 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.

29:10Let me just ask a clarifying question, Paula. So if a woman gets pregnant in her 20s, but then in her 30s meets the criteria for infertility, would she be considered one of those one in six? Yeah. So we're going to say that the one in six means someone who wants to get pregnant at a certain point in their life can't. Exactly. Lifetime prevalence. Exactly. As far as the reasons for the increase in infertility prevalence, it's not super well -understood. Part of the reason is delayed child barriers. I was just about to say you could make it 100 % if every woman decides to have a baby when she's 70.

29:46But definition you have 100 % fertility. Exactly. Exactly. Yeah. So women are waiting longer, of course, to start their families, to pursue education and career, etc. 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 plain and rural. might be slight increase risk and sexually transmitted diseases as well. So all those things are probably factors. Is there an analysis that's tried to get at this by normalizing to female age?

30:21Because it seems to me that if you could say rather than make it lifetime prevalence because that's going to be subject to all the problems you've stated. But what if we just said for women aged 28 to 32, 32 to 35? Like if we made narrow buckets of age, we could get a better sense of whether there's a true infertility issue. Has that analysis been done? It's definitely been looked at by age. I don't know the date off top of my head if it's been looked at by age over time. But definitely your chance of infertility is higher if you're 40 compared to if you're 20 or even. But do we know if a 30 -year -old woman today has a higher rate of infertility than a 30 -year -old woman 50 years ago?

31:07We think so, but I don't know that data of top of my head. If the answer there is yes, I don't know that it would answer all our questions because it could still be explained by decreasing sperm count. It could still be explained by increasing paternal age. This would be a very difficult analysis to do. Right. Environmental factors as well. are exposures are different now than they were 50 years ago. Well, and then the question of course would be, if this is an environmental reason, what are the environmental triggers? Now, you mentioned STDs a minute ago. How do STDs in which STDs play a role in fertility?

31:42The ones most well -entred are probably gone to re -enclimidia, 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 philopeontus, which then interfere with that process that we talked about earlier, the egg in the sperm, meeting, and can lead to infertility. And is that something that happens if it is left untreated or is that something that's easy to address with antibiotics if caught early? I mean, if it's caught early, then it's usually treatable with antibiotics, or there are some issues with antibiotic resistance, especially with gonorrhea, but usually if you catch it early, it's treatable, But if it's late stage or it's unrecognized or untreated, then it's more likely to ascend to the phloetian twos where it usually caused fertility problems.

32:31How prevalent is gonorrhea today in the US? I think it's pretty common, I don't know. Really? Yeah. In certain populations is 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, is maybe less testing as well, especially if we saw that during the pandemic for sure. How does it present? In women usually with pelvic pain, fever, vaginal discharge, those are the most common symptoms. And is it equally transmissible from male to female and female to male? It's probably more transmissible from male to female.

33:11Okay. And is it an STD where the person who has it knows, like if a male has it, does he know he has it, presumably not, if it's being transmitted this readily. Yeah, not always. What about HSV? Does that factor into fertility at all? Not as much. And Climidia, again, I apologize for my ignorance. I just don't remember any of this stuff since taking the USMLE exams. Tell me how Climidia presents and how it impacts fertility. The same actually. Yeah, very similarly. So pelvic pain, fever, usually they're both present together. And does it have the same pathology where it creates, it ascends the fallopian tubes and scars the tubes?

33:51Yeah. So, worst case scenario, if a woman undergoes a severe infection with one or both of these, it's not treated in time. She has completely scarred fallopian tubes. Is it still likely that she could get pregnant through IVF? Are the eggs and uterus still preserved enough to... Yes, yes. ...that 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 menstrual history, et cetera, is we usually do an x -ray test that's called a histrosal pingogram or HSG for short, and it's done specifically to evaluate whether or not the tubes are open.

34:39So are you just injecting contrast? I assume you do this externally. You go into the cervix into the you just inject dye and take an x -ray. Exactly. And you're looking for how smooth. And so tell me what is a normal phylope and tube look like on that test? So first the dye, so it's done in radiology facility usually by radiologists. Although some gynecologists do this test as well, but usually fills up the uterus. So you can also see the uterus. and then the tubes are kind of like these wire like. What's the diameter of a normal fallopian tube in that setting? Less than a centimeter. Yeah. That's pretty big.

35:13Yeah, the whole tube, but the actual opening. No, yeah. How big is the lumen? Microns. Oh, wow. Okay. Or millimeters. I don't know. Exactly. But you can see it. Definitely see it on X -ray. Well, you can see it. It's probably a millimeter or more than not a micro. Yeah, for sure. Yeah. And then the die is filling up the tubes and then spilling out the tubes. So you can see that. The ovaries are not visualized because of the finger -like projection. So it's actually spilling dye into the peritoneum at this point. Right. Okay. Based on that visual inspection, a trained radiologist and GYN can say, that is smooth, that looks great versus that is jagged and or obstructed.

35:51Right. Now, if it's obstructed, I assume that the woman has a much bigger problem, which is every month one of those eggs comes out, it's not getting past the point. Is it just atrophy and get reabsorbed? I see. So it wouldn't necessarily cause pain. No. No. No. By the way, we didn't talk about this earlier. We took it for granted. This is happening with two separate sides. Yeah. And it's just mind -boggling to me that there is one that is being selected and the one that's happening in one side, somehow that signal is making it to the other side to say, you can't do it this month. Right. How does that happen?

36:25Who knows? We don't know. We have no idea how that's happening. No idea. Something to do with the receptors on the eggs, and particular hormonal milieu, maybe there's some nerve that plays a role. We have no idea, actually. But it is on average 50 % from one side and 50 % from the other side. And it's a coin toss. Right. And it's not necessarily alternating, but it's on average. Right. It would be like heads is left, tails is right. if you throw it for enough times, it's 50 -50, but not necessarily back -to -back. Exactly. This is mind -boggling to me. Yeah, especially. It's mind -boggling if it were just one ovary, but the fact that these things are physically a foot or not a foot, but half a foot apart.

37:08And some signal is transmitted in this woman's body. Yep. I mean, it's... Yeah, yeah, we don't quite understand it. That's incredible. Yeah. Or whatever that egg that's being selected, 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 selective, that's making it the so -called dominant molecule for that cycle. Yeah, I suppose that's a more likely and plausible scenario is that something stochastically triggers one and only one to develop a high enough receptor concentration for FSH or LH or something so that it becomes the only one that it's the only one that develops the radar.

37:56Right. 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 processing at multiple eggs to grow, but we don't totally understand physiologically what makes just one grow each month. Okay. Let's say you do the analysis and I assume if there's scarring on one side but not the other, would you intervene or would you just say no? We're just going to take twice as long for one to get through. Yeah, there's still a chance to get pregnant, although whatever process caused the scarring and the one two, probably affected the other two as well.

38:34also just because it's open doesn't mean that it's functioning normally. Certainly can give it a few months of trying, but the other issue you have to worry about is what we call an ectopic pregnancy. If that tube is not normal, if fertilization happens, that embryo can implant in the tube. And that's kind of a very dangerous situation because obviously the tube can accommodate a pregnancy. So usually that causes pain. And if it goes unrecognized. It's a surgical emergency. Yeah, exactly. At how many weeks of gestation is a woman typically? Because that's, I did my training in general surgery.

39:08So that was one of the things we were always thinking about was ectopic pregnancies for women presenting with abdominal pain. But I don't think I know the answer to this question, which is how many weeks of gestation is a woman when she's showing up in the ER complaining of abdominal pain? Usually about six to eight weeks of pregnancy. Two months pregnant. Right. Now, remember, we time. Yeah. Pregnancy from like two weeks before ovulation. So by the time she recognizes that she's pregnant, she's already a month pregnant. So in the next month is probably the most common time where those ectopic pregnancy is percent.

39:43So when a woman has an ectopic pregnancy, can that fallopian tube be salvaged? Sometimes. Sometimes if you recognize it early, it can be treated either medically or surgically and that tube can be salvaged. If you recognize it late and the tube ruptures, then often time the treatment is to just remove the tube. Plus, especially if it's not functioning normally too good. 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. So you still want her to have her endocrine system intact. What's happening to the eggs that come out of that tube?

40:16They just get released into the abdomen, the parotinium, and the resort. So do you tell that woman your fertility rate just went down by 50%. Yeah, she can still get pregnant if she has the other tube intact. But most of the time, if the egg ovulates from the right, it's going to try and go down the right side. Although there have been cases where you can ovulate from the right ovary and it can travel down. It makes its way over to the other side too. It makes its way over there. Yeah, it's rare. Wow. But it could happen. What are the risks for an ectopic pregnancy besides former STDs that lead to scarring in the tube?

40:48Previous surgery, pelvic surgery in particular, like rupture appendix or something like that, endometriosis, concuss scarring of the tubes. Those are probably the most common. Okay. Any genetic component to this, if your mom had an ectopic pregnancy, or you? Not that we know of. So let's go back to our hypothetical case here. So woman comes in, let's just assume for the sake of simplicity, the workup on her male partner, totally fine. His sperm are fine. And the radiograph shows that she has at least to the eye normal philopian tubes. What's the next step in the workup? So we want to assess her cycles and ovulations.

41:29So if she's ovulating regularly, then we call that sort of unexplained. And how do you know that she is? Is that determined by the fact that she has a regular period? Is that alone telling you that? Usually, usually it would be unusual to have regular periods and not be ovulating, but what it could happen. How stringent is your definition for a regular period? It's not 28 days necessarily. Not necessarily. Yeah, there's a range could be anywhere from like 21 to 35 days or so. Wow, that's a pretty big range. Are you less concerned with the number of days of the cycle and more concerned with the fact that whatever the days are, it's just repeating over and over again?

42:07Yes, if you mean duration of the period, yeah, that's not as important as how frequently the period is happening. Even if it was 21 days, but it was always 21 days, that's better than 24, 28, 31. There is some normal variations. Sometimes all, see a patient should say, my periods are very regular. Sometimes they're 26 days. Sometimes they're 32. I consider that normal. It's not usually always 28 days or always 21 days. There's some normal variation. Irregular would be your skipping months or maybe you're getting a period every three months or four months. And what's happening in that situation in a young woman?

42:45There 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. Why do you think that is? This came up on another podcast on HRT, which is another one of my big rallying cries, which is how pathetic it is. Why do you think this is? given how important a subject this is. Political reasons, I think, gender inequality, all kinds of reasons like that.

43:22Do we have a sense objectively that there is a difference in this type of research? Or do we think it's just that, well, maybe there's equal amounts of funding, but the innate problems associated with the female reproductive system or female health in general are so much more complicated that at equal funding levels, we're going to be far behind in our understanding. Yeah, no, I think it's the fourth. You think it's an object to you? Oh, there's good data that the funding for women's health research, it's like 10 percent of the overall NIH budget. For example, it's very small. If you look at reproductive health, it's even smaller.

43:56So it's a huge issue. Let's talk about polycystic ovarian syndrome. So what's the prevalence of it in, let's say, women aged, call it 15 to 30? Yeah, super common. About 6 to 8 % of women will have polycystic every 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 it herosutism obesity or being overweight. That's also part of the syndrome. The androgens are specifically just testosterone, just DHA, DHE, all of the above. Yeah, both, but typically elevated to stosterone from the ovaries.

44:37Is that the cause or the effect? We don't know. We don't know, but it's definitely seen in almost all women with PCOS that they have higher androgen levels. And why is PCOS seemingly also highly associated with insulin resistance? Again, we don't know exactly, but we think the Androgens play a role. we think there might be some genetic factors that play a role. I don't know that we understand why, but we certainly have recognized in the last several decades that most women with PCOS also happen to be insulin resistant. But we don't know the direction of causality. No. We know that not everybody who's insulin resistant has PCOS, of course, not all diabetics are But we also know that some women with PCOS are not insulin resistant, correct?

45:27Probably on some level they are, but they're able to compensate. And certainly, it's more likely if they tend to be overweight as well. So it's definitely multifactorial. And I guess it's like we're treating PCOS now more like other complex diseases like obesity or hypertension, etc. There's lots of things going on. But based on what you just said, if there is any causality between them, it's more likely that the PCOS is driving the insulin resistance than the other way around. Given the number of women that are insulin resistant who do not have PCOS. Yeah, that's probably true. So then the question is, what do we need to do to treat PCOS?

46:06So 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, or it's 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 hyperindrogenic symptoms like the acne and the hersietism, again, hormonal treatments, usually effective for that.

46:48when you say hormonal treatments, you mean like spirulone, a lactone and things like that? We usually start with birth control pills. Birth control pills, very effective for most symptoms of PCOS. It'll regulate the cycles, decrease androgen levels, help with theorectism and acne, et cetera. So let's talk about why. So a birth control pill is a high dose of a synthetic estrogen and progestin. Correct. That's given 21 days and then paused for a week, meaning you take it every day, but the last week is a placebo. So is the reason that that helps with the hyperandrogenism because it raises sex hormone binding globulans so much that it mobs up all the excess testosterone?

47:27Part of the reason. I'm impressed by your endocrinology knowledge. Yes, that's part of the reason. And by the way, you can take it that way you described where you have a bleed every month, but you don't have to. Many people take it continuously these days so you don't have a period at all. But then doesn't that address the issue that you were talking about or does the synthetic estrogen and the synthetic progestin offset the hyperplasia, and then you don't care. Right. When you take the combination of estrogen, progestin usually the lining becomes quite thin. Then anyway, okay. You don't have to worry about it.

47:56So 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 describe. So the estrogen component of the pill will increase the sex hormone binding globial. And so you have less free testosterone around. So again, that will help with those symptoms we talked about. Okay. So women with PCOS doesn't want to get pregnant, just wants to reduce the androgen impact and protect her uterus.

48:34A constant oral contraceptive is a great strategy. A great strategy. Yeah, there are others. could be a progestin IUD, that's a hormonal reactive IUD. So there are a number of different ones who are just taking progesterone every few months that usually will help protect the lining, but probably won't decrease the antigen levels. Can how often do you place women who have PCOS also with insulin resistance on metformin? Do you find that or any of the other diabetic agents to be particularly useful? Occasionally, yeah, and that's an important point because women, as we said, who have PCOS or insulin resistant, which predispose us to diabetes.

49:12So those women need to be screened periodically for diabetes, and we commonly use metformin to either treat pre -diabetes or to try and prevent diabetes. Does insulin resistance and type 2 diabetes independently impair fertility? All things being equal? Absent PCOS, that's a loaded question. Yeah. In some cases, I mean, there's some data that shows that metabolic diseases or chronic diseases can impact fertility mechanisms again are unclear but probably related to both ovulation, dysfunction and also endometrial receptivity. Okay, so now I assume that's the easier way to treat PCOS as the woman who does not want to get pregnant.

49:56So now let's talk about the woman with PCOS but who is also trying to conceive. What is your playbook? So we always counts as 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, etc. And how much of a role are GLP1 agonists playing in this now? How much more success are you having with treating PCOS that way? Yeah, increasingly. And they're very successful, as you know, for weight loss. And there have been some studies on PCOS patients specifically very effective.

50:30Do you know any of those data I'm not familiar with? Yeah, they work really well. just like they work with people with diabetes or people who with obesity without diabetes. Probably as you can't get pregnant while you're taking them in the current recommendation is to stop for at least two months. And pardon my ignorance why? Because we don't have any data on whether they're safe. Yeah, so FDA is saying I forget the FDA's classification for this. There's like A, B, C, X or something like that for every drug. Yes, I haven't looked for that one specifically, but I'm sure it's X because we have no data.

51:01That's an important message for anybody listening. If you're trying to get pregnant, you should not be on a GLP1 agonist because we don't understand the impact of that. Right. You can be on a pre -pregnancy, just the recommendation is to stop for at least two months. Now, having said that, there have been lots of, you may have read about, a Zempic babies, like people getting pregnant on GLP1. So there is a registry, and so far, to my knowledge, there haven't been reported or defects in that type of thing, but obviously we're talking about small number. Yeah, that's an interesting point. Now that you mentioned that, I now recall hearing about that.

51:34So presumably, these are women who have taken either semi -glutite or is epitide and presumably they get pregnant, either intentionally or not. So that's a very interesting registry to follow. Right. Now of course, once they find out, they're pregnant usually. They're usually counseling the stop. Yeah. So we don't know what would happen if you continue. I don't think anybody wants to do that study at the moment. Yeah, it doesn't make sense. certainly don't want women who are pregnant to not want to eat. Okay. Understanding that a woman who's got PCOS is going to be first counseled to make these changes that effectively help her lose weight and increase her metabolic health.

52:11Let's say she is somewhat successful, but still unable to address the concern. Luckily, there are very good ovulation -inducing medications available. What we would typically recommend for someone with PCOS to help them opulate, more regularly, is a medication called letharzole. The brand name is Fomara. It's just a medication you take for five days in your cycle, and then we can usually assess ovulation with the ultrasound. And what does it do? Basically, it's a category of medication called aromatase inhibitors, which blocks the conversion of testosterone to... Right. Antergents to estrogen, that lower estrogen, some how triggers the pituitary to increase secretion of FSH and LH and that stimulates the ovary to again get one of those follicles.

53:01And is the reason you use something like an aromatase inhibitor as opposed to clomaphine or HCG is just that it's a smaller nudge and you're starting out with it? No, we used to use clomid first line for PCOS but then there was a study that came out several years ago comparing the two and show the pregnancy rates were a little bit higher with letharzole. Well, it's perfectly good as well, but letharzole is better for PCOS. So if you have access to letharzole, it's very counterintuitive. If you think about it, when you take an aromatase inhibitor, you're going to lower estrogen, but not, I mean, I guess it depends on the dose.

53:37I guess I'm trying to think of like an astrozole, which I'm more familiar with than letharzole. I suppose if you took a milligram of anastrasal 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 this accretion of LHNFSH. Right. Yeah. Again, that's still counterintuitive to me. I would just think that giving 50 to 100 milligrams of plumage would have a much bigger impact on that. It also works, but when they compared them, yeah, randomized control trial had to had comparison, show the pregnancy rates were better for some reason with the let result compared to plumage.

54:23Okay. And does it matter when in her cycle she takes the let result? Usually it's recommended from day three to five with the first day of full bleeding we call that day one. What at the point of this is she's not having her period, how do you then time it? We induce a period, not a real period, but we induce a withdrawal bleed by giving progesterone, typically. Okay, so you give a woman progesterone and then by withdrawing the progesterone, that's so cool. Yeah. You guys are so manipulative. I know. How much do you give? 200? Now, five to ten milligrams of progesterone acetate or you can give micronized progesterone for about seven to ten days.

55:03Only 5 to 10 milligrams of micronized progesterone. No. Micronized progesterone 200 milligrams. Okay. So you give the full party dose of micronized progesterone for five days. With Dr. C. progesterone, acetate, 5 to 10. Yeah. So then, by the way, do you have a preference for MPA versus micronized? No. Not really. Okay. Because it's such a short. Yes. 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 right -pening the follicle with the aromatase inhibitor.

55:39Read a seven. Yeah, day three. Five days. Wow. Very cool. Yeah, and then we usually do an ultrasound around day 12 -ish. You could see one of those follicles starting to grow. Not all patients will respond, so sometimes we have to increase the dose or sometimes we have to try a different medication, but most patients with PCOS will respond to that medication. Would 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?

56:17I definitely think they're 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 -infurtually treatment, often what I hear from patients is they had a regular period Somebody told them to start go on the birth control pill. They never told them why they didn't even know what they had PCOS Happens to be the correct treatment. So great But they've gone years now not understanding that they have PCOS and the implications of that Which as we talked about their metabolic implications, etc So that's a problem But once they want to become pregnant, very few general gynecologists are set up to be able to treat patients with either clomit or let result.

57:03Some of them do, but it's not like a fertility clinic with reproductive and ecronologist, because we're set up to do monitoring seven days a week and that type of thing. But not everybody has access to a fertility specialist, very dependent on where you live, a little bit better now with telehealth, but still. Do you have to do the sonogram when you're doing this? You don't have to, but you want to know whether the woman's responding meaning that she's actually ovulating. There are other ways to assess that. If she gets a period at the right time, that 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.

57:44We just happen to use ultrasounds just easier. And how much of what you're describing is covered with typical health insurance? It depends where you live and the United States is very state dependent. Some states have infertility insurance mandates where your employer's insurance policy has to provide infertility, diagnostic, and treatment. But many states infertility is not covered or they might just cover the testing portion but then not cover the treatment portion. So that's a huge problem. You're in Oregon. I'm an organ. What is the state there? We don't have an infertility insurance mandate yet, although we're working on it It's actually a bill in session this regular session now that we're trying to get passed because infertilities of the disease like every other disease And we think it shouldn't matter where you live you should have access to the appropriate treatment So in our state it kind of depends on your employer and whether they provide that particular insurance coverage And so if a person has health insurance that does not cover reproductive care, how much would be the cost of what you just described, the outer pocket cost?

58:52Yeah. So, let's resolve and clone mid or just oral maintenance. Yeah, the cheap drugs. They're pretty cheap. Yeah. But then you add the ultrasound monitoring. That could be another $300 if you're paying out of pocket. And then if you're doing intrauterine insemination, for example, which we haven't talked about. No, let's just say just what we talked about is still a really cheap treatment, right? Relatively. Yeah, it's a few hundred dollars a month for some people that would be a lot. But relative to what we're about to talk about, this is still well within the purview of out of pocket. For sure, compared to what's coming.

59:22Yep. For sure. And so you kind of alluded to it, but I'm guessing you're saying, look, we would give this three tries. Would that be a fair assessment? Usually. So, so we'd go through three consecutive cycles of this. It's interesting. So there's two ways that this treatment could fail. The first is each time we did the ultrasound, we just didn't see an egg. Right. Not responding. We were not responding to the follicle stimulation. 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.

59:57If 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. Right. Right. 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? Yeah. Yeah. And someone who hasn't been ovulating, they haven't tried for a year even, right? They haven't even met the criteria for two months. 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?

1:00:29So if it's the young person and this is like the first time they're ovulating in their life, then yeah, we give them more time on a less invasive treatment, less expensive treatment. If they're like 38, 40, we probably move on to something else. Okay, so let's go to the first case I described, so you get no ovulation. Okay, three times no ovulation. We're not gonna waste her time anymore, but she's still young, so what's your next step in the other of them? Typically, so assuming we've tried higher doses and different medication like clomet or whatever, and still not responding, then we typically move on to a class of medication called gonadotropins, or essentially FSH, or follicle stimulating hormone, same hormone.

1:01:10Not LH, you don't give HCG directly? It's a little bit of combination. We do eventually give HCG to trigger ovulation, so we could either use those medications with either timed intercourse or intrauterine dissemination, or with IVF. That middle option with time in a course and in some entry or in some nation is kind of fallen out of favor a little bit because those medications are very expensive, acquire a lot of monitoring, success rate with IUI or time in a course is much lower than IVF. So we usually skip that and go directly to IVF. Okay, if you are going to use FSH and LH, give me a sense of cost.

1:01:52What dose are you using of HCG? So if the plan is just for time -darenal course entry or insemination, we use maybe one to three ampules of FSH and 75 units. The whole cycle, if you include the monitoring, the IEY, et cetera, could be like $3 ,000 or $4 ,000. So you can see. That would be a big step up. Yeah. After a few cycles, it's almost the same cost as an IVF cycle. So you're like, better off, especially if the patient wants to have or the couple wants to have more than one child. The advantage of IVF is you can freeze embryos. So if you want to have two or three kids, well, 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.

1:02:37Yep. I see. So basically, intra -yudarin insemination has largely fallen out of favor. Does that also mean the cost of IVF is coming down? Is that also making it more attractive? No, so I UIs very common still. I see. But we do it. We were talking specifically about the patient with the US who's not ovulating. Right. Got it. But otherwise, and if you have a patient who is ovulating and has maybe unexplained infertility tubes are open. Yeah, in this case, you don't have to use a hormone to make her ovulate. You just need an ultrasound, which is relatively cheap to know when she's going to ovulate.

1:03:13Yeah, we still use the medication though, because we super -obulate. So normally you just make one egg. So when someone's already ovulating, the goal of the fertility medications is to get them to release more than one egg. So two eggs, three eggs, more eggs around, higher chance that one of them is going to be normal, and one is going to fertilize. What does the graph look like of number of eggs versus probability of twins, triplets, etc.? That's one of the downsides. So the risk of multiples with the oral medications like clomet or letharzoil is about 5 to 8%. So not super high, but definitely higher than patient where to conceive without medication.

1:03:52So that's something we counsel them about. But it's very common as a first line treatment to do oral medication with IUI, even in the context of normal sperm, I would say, although it's more important, of course, if there's a male component. And then if that didn't work in three cycles, then move on to IVF. And with the injectables, what is the risk of multiple pregnancies? Much higher. 25 to 35%. And how many eggs are typically? It depends on the dose of the medication. So of course, when we're doing IVF, we want a lot of eggs. So it's 10 to 15 eggs. But if we're doing IUI, it could be like 3 to 5 eggs.

1:04:32It depends on the dose and depends on the age of the patient, et cetera. So what's fallen out of favors injectables with IUI? We don't do that very much. Got it. Make sense. Back in the day when every time you were in the grocery store and you saw the cover of the national enquire and there was like, this woman just had 47 babies. Like what the hell was going on in those eras? I think in the early days of IVF, well, even before IVF when people just had access to injectables in IUI, most of the multiple pregnancies were not from IVF, but from injectables in IUI. Because literally there were women having eight and nine babies at a time.

1:05:08Yeah, 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. In that situation, they would have transferred eight and all eight took. Yeah, I'm not saying it was the right thing to do, but that's what happened. But 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 were transferring just one embryo these days.

1:05:50Unless a couple says I'd actually like to have twins. We kind of discourage that. Why? Because twins are riskier. They're riskier for the babies and for them all. Riskier in an IVF setting? No, they're just riskier in general. Are IVF twins, do they pose any more risk to either fetus or mom than naturally conceived twins? Yes, there is some data that would suggest that IVF pregnancies are more complicated. Have a higher risk of complication than spontaneous pregnancies? We don't know exactly why if it's the IVF or the fact that people who need IVF have underlying conditions that may predispose them to some of these complications.

1:06:26Well, we're well -invented data -spre assuring that pregnancies do find the babies do find, but we definitely know that twins, whether you're conceived them spontaneously or with IVF, the risk of almost every pregnancy complications is going to be higher. This is the risk of preeclampsia, helps in blood clot, like anything that is a risk. High pretension, hemorrhage, yes, need -first -e -section, all those risks. Premature delivery, all those risks are increased. We don't intentionally like to produce twins, although it happens sometimes obviously. Okay. Boy, this is fascinating stuff. So I'm just trying to take this in some sort of thoughtful order.

1:07:05Should 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 -based or it makes me cringe. Like that is just such a gross image to me. I agree. 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 inter -uterine insemination, just to be clear, you are not using a turkey baster. Definitely not. Okay. Thank God. Most disgusting image. I don't know why I have so grossed out by that. So can you explain how IUI is done?

1:07:39We've already said that with IUI, you largely favor an oral preparation. Usually, yeah. Yeah. Okay. That means you're using an oral set of hormones so that the woman doesn't have a massive proliferation of follicles. So, male ejaculates, do you want fresh semen or do carifits frozen? What's the difference in success? Same. We have single women as well and female same -sex couples who would also be doing donor insemination in that case. And we don't see any difference between fresh semen and frozen semen. No, assuming the sperm is a... The swimming is sperm is a dead body. Yeah, yeah, exactly. So the indications for IUI would be those scenarios, I mentioned single women, same sex couples, or if there's a couple with unexplained infertility, you just can't find a reason, so you just want to try and optimize their chances.

1:08:31Or 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. The problem that you're able to overcome on the sperm side would be number and motility.

1:09:07Yeah, or morphology, like any abnormality in the semen analysis as long as it's not very severe. So if the sperm are too few, they don't move well enough. If they're defective in most ways. IVF, more specifically Ixi, which stands for intracidoplasmic sperm injection, where we actually take a sperm and inject it directly into an X. So first of the year male factor, that would be the recommended treatment. But if the sperm's a little bit low, but it's not too bad, then IUI, we would try a few cycles of that first. Okay, so when in the woman's cycle, how many days before she ovulates, do you want to inject those sperm into the mouth of the uterus?

1:09:51Essentially the day she's ovulating. So this is interesting to me because one of the things that I took away from the discussion with Paul last week was that if you look at the probability distribution curve of when a pregnancy occurs, the ejaculate enters the uterus prior to ovulation. 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. Yes, it is true that if they're sperm around prior to ovulation, it can hang around for a while because it lives two to three days or so.

1:10:33that words, the life span of the ovulated egg is much shorter. So based on that, wouldn't it make sense to put the sperm in prior to ovulation? Is it just too risky to try and anticipate when that is? If it's a straight couple, we'll tell them to also have an recourse every couple 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. And are you doing that with ultrasound? Usually LH monitoring, so patient will either monitor her urine LH.

1:11:12And remember LH goes up just before ovulation. We typically also look to ultrasound based on the size of the follicles. We sometimes trigger ovulation with HCG, which kind of simulates the woman's own LH surge. So if you want to be pretty precise. How big a dose of HCG do you need? Usually 5 ,000 units, which is half a vial. It's a lot, probably more than physiologic. The purpose is to cause release of the egg and then we time the insemination to happen when we think the ovulation is happening. Okay, do you ever do the following? This is me just thinking out the box. Get the male to bank a ton of sperm.

1:11:50Take weeks to get, or if she's going to a sperm bank, if it's the same sex level, whatever, just get multiple Alliquots of Seaman. So on day one, insert, day two, insert, day three, give 10 ,000 IU of HCG, insert, and then day four, insert. In other words, cover your bases and just have lots of semen sitting around and then force the ovulation. You could do that or the couple could just upsex. 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.

1:12:29What if his motility is anything other than perfect? Or in the other case, what if we're dealing with same -sex couples or a single mom? Yeah, there have been studies looking at two IUIs compared to one. Specifically, same -sex couples or single women show no difference. And remember, if you're paying out a pocket for all these things, it has to be worth it. So at some point, even if what I proposed worked better, it's going to approach the cost of IVF. Right. How much better and is it worth another $400? Five days now your cost of your IUI cycles all of a sudden. $2000. Yes, so those are practical considerations as well.

1:13:06So maybe this question is too broad, so feel free to partition it. But if you look at all uses of IUI, what is the success rate? And feel free to again divide that up into different cases. The pregnancy success rate really depends on the age of the female partner. So if it's a young woman in her 20s, success rate might approach success rate for natural conception, which might be 20 and 25 % per cycle. If it's a woman over 35, might be 10 to 15%. If it's a woman over 40, might only be 1 to 5 % per cycle. Wow. And that's because, again, it's all about the quality of the egg. So even though an egg is released, maybe two eggs are released.

1:13:50If those eggs aren't normal, they're not going to fertilize and implant. Okay. So, we've covered a whole lot of fertility treatments. It seems that the likelihood that a woman who's undergone some of the things we've discussed that still ends up going down to the IVF pathways is reasonably high. Yeah. The majority of people don't need IVF again. It depends on the age of the female partner specifically and what the problem is. So let's just go sub 35. Okay. So of all women who present with defined infertility, which if she's under 35 means more than a year of regular sex, no pregnancy, walk through the success rate of pregnancy by modality.

1:14:33So under 35, infertility for a year, how many are successful with just an oral treatment absent IUI? Again, it sort of depends on what the cause of the infertility is. Is it unexplained or is it PCOS? No, let's say unexplained. Unexplained? Probably less than 50 percent will get pregnant with IUI and have to move on to IVF because unexplained to me means either it's bad luck or more more likely if something 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. Oh, sorry, yes. That I can understand for sure. I'm saying how many of them will need to get IVF?

1:15:12Are you answering that question as well? Yeah, that's what I was getting at. For PCOS, their problem was they just weren't ovulating. So probably 80 % of those people will get pregnant with just ovulation induction and IUI because you're solving the problem. So, one of the things that would be basically is addressing the problem. If it's very severe male factor, probably I UI, it's not going to work. So really kind of depends what the ideology of the infertility of the... And so now if we talk about 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.

1:15:48That'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 in IVF strategy? So depends how long you do it for. So most of the time, we're only doing it for three cycles. That's right. 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 a lot of those people will eventually get pregnant.

1:16:27But we tend to stop at three months. Tell me at three months again, what percentage are gonna be successful with three cycles? In that age group, unexplained infertility. Unexplained over 35. I don't know the exact number, but probably under 50%. Okay, but that could be a third, potentially. Yeah, because the success rate per cycle is something like in that age group, let's say 10 to 15%. So it's... So you go one minus that number times three. Should it turn? One minus that to the third power. Yeah, should be about 30%. Exactly. Okay. So now, let's talk a little bit about IVF. First successful IVF baby, 1978, if my memory serves correctly.

1:17:04That's right. Referred to as a test tube baby, which is kind of weird, because I would imagine it was in a peach reddish, not a test tube, but anyway. Yeah. Yeah. We've come a long way since then, for historical context, I don't know anything about that girl, but do you know anything about how that was done back in 1978? Yeah, actually there's a recent docu -drama out called joy. Is that her name? Her middle name I believe is Joy. Oh. Yes. Well that's great. Joy Brown. What's her name? Louise Brown. Louise Brown. Okay. It's a movie about the first IVF success. Oh, that's great. Now of course they tried for many, many years before they had the first success.

1:17:42These were two doctors. I mean, maybe this is all on 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. Yeah, there was a lot of controversy. Like this was very freaky. Yeah, yeah. And this was done at the time, primarily for women with tubal factor block tubes. I think camera, remember the exact details of the couple, but I believe they had tubal disease and IVF works great for tubal disease because of course you're bypassing the tubes altogether. Where was this done? In the UK and Britain.

1:18:14I didn't realize it wasn't done here in the US. So tell me a little bit about technologically how they accomplished it back then. Yeah, I think the first cases, they were actually doing surgery under general anesthesia, for leproscopic, I believe, to retrieve the eggs. Oh wow. And then they were combining the eggs with the sperm in the test tube, petri dish. And then I think they were transferring the embryo maybe back into the tube in those days, or maybe through the cervix. I can't remember the details, but yes, a lot of has changed over the last 45 years or so? Wow. Despite that success in 1978, what did it look like for the next 10 years?

1:18:57From 1978 to 1988, how prevalent was IVF? I guess when did it get to the point where anybody who could afford it could access it? Much more recently. Yeah, the first IVF baby in the United States was born a few years later, I think maybe 1981 or so. In Virginia, I believe. It took probably many decades for it to become commonplace throughout the world. So now most countries, you can access IVF, not everybody can access IVF, but in some countries more than others. But depending on how you look at it, it's kind of not 45 years, but in medicine that's relatively recent development and it's been only in the last maybe 20, 30 years that has become standard.

1:19:40Okay, so let's just walk through how IVF works and then we'll kind of dive into the ins and of some of the nuances. So a one comes to you probably she's progressed through some layers of treatment, but you've collectively come to the decision that this is hands down the best opportunity both for success and risk. So how does the treatment go? So typically we do a bunch of screening tests on both partners that include some blood tests, a semen analysis, an ultrasound to get some assessment of their egg number, the woman's egg number, and then when the cycle starts, takes about two to three months to complete a cycle of IVF.

1:20:16And when you say egg number, are you determining that through an AMH or through a physical examination of the ovaries? Both. So we do an ultrasound, we can count the number of follicles. How small are these things? A few millimeters. And you have the resolution to see that on an ultrasound? Yeah. And that gives you some sense of about how many eggs that particular patient will produce with ovarian stimulation. And we use AMH as a hormone. Explain what AMH is and how it works. Yeah, AMH is a hormone that stands for anti -malarion hormone. It's secreted by the cells that surround the egg, so it tends to correlate with egg number.

1:20:52Doesn'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 to have a normal number of eggs for your age. 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. Right. If there are different ages, their success rate is going to be different. Remind me the range. So a pre -pubescent girl who has a billion, not a billion, but right, a million eggs, but who is not fertile.

1:21:25Does she have a higher low AMH? She has a higher AMH. We tend not to use it in that age group because it's less reliable, But a normal image would be about two, I think the United's peak around predestined her, I believe, less than one is considered low. So a woman who's older. What's the difference between a 16 year old girl who probably could get pregnant if she walked past a guy versus... That never happens, by the way. Oh, okay, good. No, but if you have like a 16 year old girl who is at the peak of her fertility versus a 30 year old woman who's still fertile but has lost a step. Like what's the difference in AMA?

1:22:01Yeah, it's a very narrow range. Okay. So like above two, we consider, that's probably normal reproductive. It's two is two, effectively. Okay. 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. So this is kind of a binary test. Well, not really. You're not looking at, oh, this woman's 1 .6, this woman's 1 .7, this woman's, yeah, you're not looking at like you look at a TSH or something. Right, right. And the assays also very variable depends where you have it done.

1:22:31Whatever just gives you 90 -A 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 in 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 suppress the ovaries because we want all the eggs to kind of grow with the summary.

1:23:05Stop the pill, then you start the gonadotropins, which are the... You don't inject them. Yep, and they're injectable just under skin kind of injections. So, meaning HCG and FSH? Not at HCG, but primarily FSH with a little bit of LH. So you're on those for about 8 to 12 days. And then every few days while you're taking those medications, you have to come into the clinic for ultrasound monitoring and Estardial levels, blood levels and we can monitor how many follicles are growing, how big they are, etc. Usually the medications are pretty well tolerated. And what dose of LH and FSH is she injecting relative to what she would normally make?

1:23:45Is it a 2x, 5x, 10x? It depends on the age again, higher doses for women who are older, but much, much higher doses. More than 10X? Hmm, maybe not. Maybe five. Typical symptoms? Most common, I would say, is bloating as the ovaries get a little more enlarged. There's a small risk of something called ovarian hyperstimulation syndrome when the ovaries get a little bit too stimulated, but that's exceedingly rare. Their signs is happening. We can always back down on the dose. Sometimes, 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.

1:24:22And then once the follicles are certain size, that's how we know the eggs are mature. Because of course we can't see the eggs on the ultrasound. You can only see the follicles that contain the egg. So then the patient gets HCG, which is another medication, which kind of simulates her own LH surge. And the purpose of that medication it causes the final maturation of the eggs. And if we did not do an egg retrieval, she would release all those eggs. but of course we timed the egg retrieval to happen just before the woman obvious. So that medication is very time sensitive. And to be clear, were you only giving her FSH before or were you giving her LH as well?

1:25:00A little bit of LH, but mostly FSH. And why are you using LH versus HCG? Just to simulate the physiologic cycle. I didn't realize there was a difference appreciated by the body between them. They're very similar, so we use HCG for, but the body, of course, doesn't have HCG until the patient's pregnant, but it works well as a substitute for LH. So there is a synthetic LH out there as a drug? Yeah. Okay. It's combined with, comes as a combination drug. With the FSA? Yeah. Got it. I see. So how do you prevent her from ovulating while you are giving her FSA and LH and she is ripening multiple levels?

1:25:41Yes. Good question. There's another medication that we give. It's called the GNRH antagonist basically blocks the LH surge from happening until we cause it. When you're giving her FSH, the LH that's attached to it is very, very low. Right. That will prevent an ovulation. Yes, the antagonist will basically block in the GNRH, which is another hormone. I'm surprised that the fact that you're giving her so much FSH with a little bit of LH isn't enough to suppress the GNRH. But anyway, clearly not, or you wouldn't be having to give her that. Okay, so you give her a GNRH antagonist that basically puts a block between her hypothalamus and her pituitary.

1:26:23Right. So then now you control the switch. And the switch is in the megados of HCG, which is an LH analog. Do you harvest the follicles in the phylopean tube? In the ovaries. So the agritrival happens two days after that HCG trigger. Wow. Yeah. It would have taken two days. 36 hours specifically. So this usually takes it in the evening and then the retrieval. The day after in the morning. Okay. So a woman comes into your office two days later and walk me through this. So you layer on a table. You've got an ultrasound on her ovary and you're literally putting a needle in there. Well, first of all, she's asleep.

1:27:02Fully asleep or just woke up. A growth of fall. Yeah, so this is done in a surgery center typically or clinic with anesthesiologist present IV sedation It's like a colonoscopy or dental extract or something. Yeah, all done vaginally actually using the ultrasound and that day There's a needle that's guided by the ultrasound that goes through the vagina into the ovars So we don't do transubdomo dumb question Don't you have a much straighter shot going through the abdomen? Not really. You just don't want to go through the peritoneum and there's a lot of stuff between the abdomen and the ovary, like bowel.

1:27:35And you can't just manipulate and move the bowel out of the one or something. It's much easier through the vagina. They're sitting right there. So again, just pardon my ignorance of the anatomy because again, I'm probably still locked into the image of the ovaries being like this. But you're saying, no, Peter, the ovaries are probably sitting right on top of the Right on top of the vagina to the side of the uterus. You just stick a needle on either side and you can get it. So literally out of the vagina, not even going through the cervix. That still strikes me as a very delicate, complicated procedure.

1:28:02I mean, it's a surgery. Yeah, relatively minor type surgery. How much you have to dilate the vagina. What I'm thinking about is how to get your hand in there to guide the needle. You don't have to get your hand in there. Yeah, you should watch a YouTube video, but it's just the ultrasound probe. And there's a needle guide. Is the needle guide inside the probe or alongside? Alongside. Okay. And the needle, it's a long needle, right? So your hand's not in the vagina. What can you do? 16. And it goes through the vagina. You're doing this under ultrasound guidance. You can see exactly. But somebody else is obviously manipulating the ultrasound for you.

1:28:38No, no, you have it in your hand. It's a vaginal ultrasound. Oh, that's right, that's right. Yeah, yeah. So you're doing both. So you're looking where you are with the ultrasound and you're using the needle to puncture the ovary, get into the follicles. The needle is attached to like a vacuum suction. And so the fluid and the follicles collected goes through the needle into the test tube. And then that test tube is handed off to the embryologist. They look under the microscope and try and isolate the egg. Now, I'm just so full of dumb questions here today, Paula. How do you prevent yourself from sucking out 300 non -follicle eggs and ultimately destroy your long -term fertility risks?

1:29:21Well, you only go into the large follicles, which are really the only ones you can see on ultrasound. There's gazillion of eggs in there, but you can't even see them. And you're not running the risk of sucking up those eggs? No, no, you're just going into the follicles. How big is the ovary? The ovary is a few centimeters at that point, but each follicle is about two centimeters, I would say, and there might be tens. How is each follicle two centimeters if... End diameter. But you said the ovary is only a couple of centimeters. No, it's like maybe five, six, like a small plumb or something. Okay, wait a minute.

1:29:54So if you have a plumb or a tangerine that is the ovary, You're saying each follicle is two centimeters in diameter? Roughly. That's huge. 1 .5 to 2. I wouldn't have even thought it was one centimeter. How many follicles are in there? On average, we get 10 to 15. So maybe the overeats is bigger. Maybe it's more like an orange. I'm thinking more an unstimulated ovary is more like a plum when it's stimulated, more like a grapefruit. Okay. I see. So you have really good resolution of where the follicles are. Okay. So you're not running the risk of sucking everything out of the ovary. No, and we're just getting fluid, right?

1:30:29We're not touching tissue of the ovary. Just the fluid and the follicles. It's only a 16 gauge needle. Does that mean you're puncturing the follicle? Each follicle gets punctured before it enters the needle. Yeah, fluid. Yeah. So you do it one at a time. Yeah. You go ping into a follicle, burst it open, and the egg, because a 16 gauge needle is probably only a millimeter across. Yeah, you suck out all the fluid, and you don't have to take it out each time. You can go from follicle to follicle to follicle. You just have to go in typically twice, once on the right and once on the left. Pretty interesting that that works.

1:31:08Yeah, it's easiest maybe to just watch a video of it, and then you get the idea. I'm just thinking of all the things that could go wrong and how the needle could get gunked up with tissue, and then you gotta pull it out and put it back in. All those things can happen. You know, there's always a small risk of bleeding, small risk of infection, small risk of injury, and other organs. And this is happening. You do this on both sides, because presumably you're stimulating both sides. So how long does that procedure typically take? Half an hour. And you've got the embryologist next to you, and he or she is under the microscope going, check, check, check, check, check.

1:31:41He or she is validating that you, indeed, are getting ripeened eggs, and they look different, presumably. Like those are easy to identify under a light microscope. Basically, they tell us they got eggs. We don't know if they're mature, yet we know nothing about them yet. I see. But when we get the eggs, they go to the lab and then the rest of the process happens there. So the retrieval, we're just aspirating all the follicles, trying to get as many eggs as possible. Okay. Then, let's just assume that the woman is doing this not to just freeze her eggs, but because she wants to get pregnant. And 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?

1:32:24How many would you like to freeze? That discussion has happened way upstream. Typically we're fertilizing all of them. Yeah, there's no reason not to fertilize. Okay, tell me the time course now and how you move from retrieval to fertilization. So then the eggs are sitting in the peachy dish in the lab. What's the medium? It is this proprietary medium. Is proprietary? Yes. Yes. Meaning each lab will have its own medium. There are commercial companies that make it, but the exact components of it, not entirely known. So there are different companies that have different mediums? Yes, I believe there's more than one, but it's meant to kind of emulate the fluid in the tubes like where fertilization would normally happen.

1:33:06How much of a competitive advantage is it for an embryologist, like how many options do they have to choose from commercially? Of media? Yeah, I don't think there's that many media companies. I see. Is this a huge area of innovation in the field? It must be. Not really. I would have guessed this would be so important. I think they got it down. Was there a day when this was a problem? I'm sure. Yeah, maybe in the early days. So the embryologist transfers this to the media. Yep. A few hours later, the eggs are inseminated. So with conventional IVF, we just put a bunch of sperm in there and what the fertilization happened by itself With Xe, or intracidoplasmic sperm injection, the embryologist takes a single sperm and injects it into each egg.

1:33:50And the only time again you need to do Xe is if the sperm is so dysfunctional that it can't even on its own with no barriers make its way to fertilization when placed in direct proximity of an egg. It probably could, but maybe there's too few sperm, so anytime there's a male factor, we tend to do Xe. Any male factor you just treat to Xe? 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 XE compared to IVF in very few cases. You don't get fertilization so you don't want to bind out. Oh, by the way, sperm can't fertilize your egg.

1:34:26That's the whole problem along along because then you get to see the S. 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 XE out of the gate? no matter what. Yeah, it's a little controversial because it adds cost. How much cost? Probably another thousand dollars or two thousand or something. Probably a thousand. So the data, to be clear, shows that XC 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.

1:35:07That's like not a good conversation. That would be catastrophic. Because you've lost those eggs too. 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. Okay. See conventional IVF, if non -male factor. But a lot of times there's sperm factor, so we're doing XC anyway. These go into the media sits at room temperature. I'm sorry, at body temperature, do you put it into a 37 degree oven? body temperature in an incubator, and then all the micro manipulation is happening. What are the types of manipulations that are needed to foster the right environment?

1:35:42How much you are moving the fluid around, how often you're changing the media? This is like the most important cell culture experiment of all time. Pretty much, pretty much, to be fair, it's done by the embryologists and up by me, but they stripped the eggs first, which means they removed 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.

1:36:23Usually about 70 % of the eggs fertilize. So let's say we get 10 eggs. You can expect maybe seven of them will be fertilized and now there's seven embryos. So we discard the unfertilized eggs, continue to culture. And you can tell that grossly, or you're having to move them under a microscope, but that's not a microscope. Yeah. And then we culture them in the Petri dish. At this point, are they all in one dish, or are you separating them? They're in one like droplet of oil, and there might be more than one droplet in each dish. How are embryologists trained? How does one become an embryologist?

1:37:01Well, there's no clear pathway. There's not a whole bunch of embryology schools. But if I wanted to be an embryologist, what would I do? Mostly, I'm going to 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 And eventually you become a junior embryologist, so it's like a mentorship program. How many years would it take, if I started tomorrow working as a lab tech who was doing nothing but cleaning petri dishes, how many years would it take for me to be the head embryologist in your lab?

1:37:39It 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. 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. Oh, yeah, yeah. I would say the lab is almost more important than what we do because there's just more variability. But luckily, the United States labs are pretty good. But yeah, that's one of the most important things. I mean, I, 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.

1:38:21Super 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 colleague does. I guess the question is, well let's finish the story and then I want to come back. So how many days you go to 14 days of this? No, five days, six days. And depending if we're doing a fresh transfer or freezing the embryo, so a fresh transfer week, some time we do both. Although these days most of the time we're freezing. because you're doing genetic screening because we're doing genetic testing. Okay. So let's go through that example then.

1:38:56Okay. So we're culturing these embryos in the Petri dish for five to six days. Then we look at them again. The ones that have made it to that stage, which is usually only half of them. So remember, you're seven, now maybe there's three or four. So what explains that? So most likely the ones that didn't make it are the chromosomely abnormal ones. Remember, we talked earlier about those ones not making it. And the reason it's only half is because by definition you're doing this in women who tend to be fit 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.

1:39:33Yeah, 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 blustulation rate, the ones that make it to day five or six is a lower percentage. The older woman is because higher proportion of those embryos are just going to be abnormal. So the ones that make it to day five or six are more likely to be normal, but not necessarily normal. So we can also do genetic testing on those embryos, which involves biopsying them. So we take a few cells from the embryo, freeze the embryos. So yeah, let's talk about that.

1:40:09So how many cells do you have at five days again? All together you might have like 60 to 80 cells. Okay, so you take two or three of those. Five or six. Five or six? Yeah, and they're from the perimeter. The tropha blast, not the embryo directly, but the cells surrounding the embryo. But 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? Yeah. Tell me what the freezing process is like. So the freezing process these days is one called vitrification is called and it's like this special kind of freezing that doesn't result in ice crystals So how do you do that?

1:40:45There's a process that happens in the lab. There's a machine that does it that lowers the temperature So the rate at which they lower the temperature? Right, it's rapid. Okay, so it's like a liquid nitrogen that basically right right as opposed to all days when we did slow freezing So it becomes like a glass -like state without crystals. It works really well and the survival is really high. And then you store them at what temp? Like liquid nitrogen temp? Yeah. Yeah, it's not like in your freezer. No. Head home. And then how long does it take typically to get the genetic results? Typically within a week or two.

1:41:16Okay. What depth of genetic testing is being done here? Are you doing whole genome sequence or are you just looking at a handful of snips that that are pre -identified as the ones that matter. So it's evolved over time, and I should say it's still very controversial because there's always a risk of harming the embryos. You're only looking at a few cells. So is it really representative of the embryo? I mean, we do it a lot, and the data definitely shows that if you transfer a normal embryo, it has a very high chance of implanting, but the issue recently has been, are we discarding embryos that are maybe normal because we think they're abnormal based on the genetic testing, but the genetic testiness blood.

1:41:59Presumably genetic testing is really easy to identify aneuploidy. The chromosomal analysis is trivial. It's geared up to do that, right? So most of the time we're using something called next -generation sequencing, which is very high -level sequencing, but it's not whole genome sequencing. So you're getting targeted. Yeah. And you're looking mostly at chromosomal abnormalities, unless you know that the couple's a carrier for some genetic mutation that you also want to screenplay. Yeah, so let's say one of the parents, well, this would be a bad example, but... Sistic fibrosis, like let's say both patients are carriers.

1:42:35So both of them are a carrier for CF. And so there's a one in four chance that you're going to get two copies of CF. So then you're looking directly for the CF. Exactly. Exactly. BetaFal, sickle cell, standard. Yeah, there's a whole bunch of them. Right. And part of the screening, we didn't mention it, but most people doing IVF will get carrier screening to see if they're carriers for any genetic mutations. But that's a pretty common scenario where you have two people that are CF carriers, neither of whom have CF. Most of those people would say, I'm going to do IVF because I don't want to take the chance.

1:43:06And then what about people who come in and say, oh, but one of us is each an APOE4 carrier. So we're each a 3 -4 and we would really like to not select a 4 -4 as an example. So, one, are you able to look at that and two, does that start to cross an ethical line? Yeah, it's a little more controversial when you're talking about non -deterministic adult consequence genes. With variable penetrance, right? You may or may not get Alzheimer's or whatever it is. So, it's a little more controversial, but we're kind of going in that direction, I would say. We're definitely going probably in the near future towards whole genome sequencing where we can pick up even mutations that happen to know of what we call to know of right you might not be a carrier but it might just happen randomly.

1:43:51So you could pick up some disease that way. And then what you're talking about is like Braca. Well, Braca. Yeah. Often we know ahead of time. Yeah, patients carrier we can test for it. LPA for cardiovascular disease. Yeah, there's a whole bunch of things. So people are starting to talk about polygenic screening embryos, but it's a little more controversial because the science isn't quite settled. Yeah, and it's one thing if you're already doing IVF and we have these embryos here and we're just going to add another layer of testing like which one of these embryos is at higher risk for like diabetes or hypertension whole different story of your saying oh you should do IVF because of because we want to get the embryo with the lowest risk of these diseases so we're not quite there.

1:44:35There's a very controversial plus expensive and very talked about cost barriers and there are ethical issues as well. or we now, was it a form of positive eugenics and that type of thing? So that particular type of testing is still controversial. But an employee testing for chromosome abnormalities is pretty routine, pretty standard. Now there was a day when people weren't doing any genetic testing, and the embryo selection was just based on morphologies, right? Yes, 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 chromosomal abnormal ones, not.

1:45:16You can't really tell. So we had to transfer more embryos to get decent pregnant suites now with genetic testing because we know that a chromosomal 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 chromosomal normal embryo sometimes don't implant. Yeah, that's lower than I would have guessed. Is it 70 to 75 % for something that's chromosomally normal. I have guessed at that stage, given all the selection that's taken place, what is the concordance between, let's go one step further, chromosomally genetically normal and good morphology.

1:45:57There's good correlation. Yeah, we use both. If there's discordance there, which one are you relying on, or are you discarding, unless you have concordance that's positive for both? In reality, the ones that have poor morphology aren't even frozen or biopsy. they're discarded because we know 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 buy up seeing keep. And you presumably have the genetic testing on all of them. Do would preferentially of course transfer the ones that are chromosomeally normal, even if the morphology graded is a little bit lower.

1:46:32So you have selected out bad morphology. Let's just say you harvested 15, you fertilized 10, seven had good morphology, six came back genetically good. Those would be reasonable numbers. Yeah, the six out of seven is high. Yeah. So five came back genetically good. Let's say in a young person. Yeah, so you got one third of what you harvested, you could implant. You're saying each of those is 70 to 75 % success rate and yet you would only implant one at a time. Yeah. Which is interesting because if you implanted two, let's do the math. You're talking about... 50 % chance. That's right. We're just gonna say twins.

1:47:15Yeah, which is high. Too high. We just can't take that risk. I mean, obviously we believe in patient economy. Patient usually gets to make that decision, but... You're gonna make the case for where there's not a great idea. You want a healthy baby in the end, you want a healthy mom. Yep. Okay. So now let's talk about, now it's time to implant. So how does that process work? So that process is much less complicated but equally important. So usually it's timed. It has to happen at a certain time in the cycle. So we either use the woman's natural cycle to time it and time it at the time that implantation would normally occur, which is the second half of the cycle.

1:47:51Or we use what we call a controlled program cycle where we basically give the woman in the hormones and then time the transfer to happen in a specific time. The actual process, kind of like a pap smear. It basically doesn't require any anesthesia or anything. We do do it under ultrasound guidance, so abdominal ultrasound. We thaw one of the embryos, draw it up in a little catheter with a little syringe on the end, place the speculum in the vagina, and then just pass the catheter through the cervix and we're looking on the ultrasound for the placement. And where are you implanting it? 1 .5 centimeters to 2 centimeters from the top of the uterus.

1:48:29So a few centimeters through the cervix. How do you make sure it doesn't come out? I mean, you can't, but it doesn't usually. You put it in there and describe it more like peanut butter in there and it's not like you can stand up and it comes out. It stays in there. What's the total volume you're injecting? 50 microliters, really small. What is the inside of a uterus look like at that stage? You've timed it so that this is a uterus that doesn't have a lining yet. Does have a lining. How thick is the lining? It's about 7 to 10 millimeters. But it's going to get a heck of a lot thicker. This is technically only about 14 days past her period.

1:49:05Or are you doing it artificially more into the loodial phase? So it's roughly seven days or so after ovulation right? Oh, I got it. Yes, yes, yes. So the lining is thickened already. Yeah, okay. And that's one of the things we check with ultrasound before we do. the transfer to make sure the lining is. What does that actually look like? Is it tentacle fingers or? On the ultrasound, which is how we assess it, basically the two walls of the uterus are opposing each other. It's not like you can see the calories. It's a potential space, not a resource. Potential space, exactly. On the ultrasound, the lining has a different echo density than the mass.

1:49:42A wall itself, right? We can measure the thickness. and basically the combined thickness of the two posing walls has to be at least 7 millimeters or so. And if you get in there and do the ultrasound and it's not, are you going to come back and try to do it another day and have you lost that egg because it's been thought or can you keep that egg in the medium now? We essentially assessed the lining a week before we do the transfer. So we would not thaw the embryo unless we were sure the lining. Let's go time. Yeah. Because once it's thought, I mean, you can refuse it, but... No, I'm sure it doesn't do as well.

1:50:17Not a good idea. Yeah. Okay. So I see. So once you put that egg in there... Every. That's right, 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? Sometimes we give supplemental progesterone. That's another hormone that helps maintain the pregnancy. And then usually 12 to 14 days later, the patient has her first pregnancy test. Hopefully she's pregnant. We usually follow the pregnancy for the first few weeks. And then she transfers to her non -ivn. Oh, her good way.

1:50:48Yeah. Wow. It's just kind of amazing that this all works. Yeah. I've been doing it for 30 plus years and I still find it fascinating. Yeah. Okay. So how often does a woman go through all of this and for whatever reason, you can't get enough eggs or the eggs you get are not cromosomely normal and her next alternative is an egg donor. Unfortunately, more often than we would like. Again, it depends on the age of the patient, but sometimes patients do multiple cycles. Maybe they don't have any normal embryos or maybe even the normal embryos. We transfer don't take or number of different things can happen.

1:51:28So the most common reason someone would need an egg donor is usually Eternal age so someone who's older and is tried to get pregnant with their own eggs Hasn't worked for whatever reason and then now she's looking at egg donation as an option that works really well So usually egg donors are young women in their 20s Early 30s sometimes they produce multiple eggs and then the age of the uterus This doesn't seem to matter as much. So the success rate with donor egg is quite high. It's about 70 -75%. Whereas for women over 40, using their own eggs success rate might be 10 -20%. Per cycle? Per cycle?

1:52:11Yeah. Wow. 10 -20 % for a 40 -year -old woman. Yeah. Untested embryos. Or did they not get any embryos? Normal embryos. I did not realize it was that low. Yeah. How many times can a young woman be an egg donor before you worry about? Is there anything you worry about if you're counseling these women that assume the same women are coming to you as egg donors? Sometimes people do it multiple times, sometimes they just do it once. Does it pose any risk? They're essentially undergoing the IVF process themselves or the least the first half of it. There's the risk we talk about, ovarian hyperstimulation, which is rare, risks associated with the retrieval, anesthesia.

1:52:50But is there anything that restricts her ability to get pregnant later in life? No, barring any complications from major complications, it does not seem to impact future fertility. What is the typical fee that's collected by an egg donor? It's usually between five and ten thousand dollars depending on where you live. Okay, that's a lot of money. There's real incentive to do that. Period. Yeah. And so a woman could do that a couple times a year if she wanted to? So the guy lines up to six times. Six times a year? No, six times lifetime. So up to six times. And that's a little bit arbitrary, but the professional society has decided.

1:53:29That's kind of a good number of times. Most people don't do it that many times. They might just do it once or twice. And so what is... And maybe you don't do this. I don't know. But women who undergo egg donation, or IVFVA egg donation, What do you discuss with them about the appropriateness of timing in explaining to the children that they have a different genetic mother? Before anybody does egg donation or even before they donate eggs, we always have them meet with one of our mental health therapists. Just as a psychosocial visit to go over these types of questions and best practices around what to tell the child, when to tell the child.

1:54:08general rule is tell them early and tell them often. You basically want to normalize the thing and you definitely want to be the ones to tell them and you don't want them to find out by some other means like somebody context them on 23 of me or something like that. And early means what? Telling them before they understand reproduction like how is what are you telling them? 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, etc. But basically, there's different ways to introduce the concept.

1:54:49Obviously, if it's a same -sex couple or if it's a single person, it might happen earlier, opposed to a straight couple. So if someone's listening to this and they're trying to figure out how to select a good IVF clinic. What are the things they should be looking for? Because I would have to assume that it's like any other field of medicine. Not all doctors and not all clinics are created equal and just because you see a lot of advertising doesn't tell you anything. So in other words, you're going to have to become a very, very intelligent consumer. For most people, this will be the single most expensive out of pocket health care expense they have.

1:55:32Yeah, that's true. And so it's not just that it's the most expensive health care decision they're ever going to make. It might be one of the most consequential as well. And yet, I know what I suggest to people when someone says Peter, you know, my wife and I are thinking about getting IVF, what do you think? I just go down the rabbit hole of like, here's 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?

1:56:06These 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 look because as you have to go in and get these ultrasounds. Yeah, you got to go in every few days, so you can't be going to another state. Most people can. But in most major cities, you have multiple options.

1:56:35In most major cities, that's true. So you're right about individual clinics, success rates, although technically it's hard to use those to compare them to each other because you don't necessarily You don't know the patient population, right? So how do you normalize it? Right. So one thing for sure, look at the success rates. And we're one of the few fields of medicine where actually you can get clinic -specific success rates. You mean publicly it's available or? Yeah, it's available. Where do you find it? Well, the CDC, until recently, there is a law actually that says you have to report every IVF cycle on the success rate that was passed in the 90s.

1:57:12So because of that, the CDC tracks this. Although all the people that work in that department and we're fired recently, so I don't know what's gonna happen with that. But also our professional organizations called does Society of Assisted Reproductive Technology as 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. Look at the clinics in your area, look at the success rates, keeping in mind that populations might be different in different clinics.

1:57:52I probably would go to a clinic that does a sufficient volume. You have to do at least 100 cycles, I would say, but ideally more than that. Your clinic has how many doctors? Our clinic has about six doctors. How many total cycles do you guys do a year? We do six to 800 retrievals a year. There's a lot of variability. There's some clinics that do thousands. There are some that do like 50. So that would be one factor that I think is important just volume. And you have how many embryologists? We have something like nine embryologists. Wow. Yeah, there is a shortage of embryologists nationwide and reproductive endocrinologists because demand for IVF is going up.

1:58:34So I would definitely look at the clinic's success rates, look at the volume. The other thing with the internet, especially if you look at patient reviews, word of mouth, you've got to take those with a grain of salt, right? Yeah, they tend to be negative selecting. Right, not everybody who has a great experience necessarily going to post it on Reddit. But everyone who has a bad one does. Yeah, yeah. So you have to take that with a grain of salt, but they're objective ways. And you can also like interview your doctor. Yeah, what are questions you should be asking of the doctor that are independent of the objective metrics that we might have just discussed?

1:59:05You can ask about their philosophy about protocols, about things like add -ons, like genetic testing. For example, 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. 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.

1:59:45I'm a little bit biased towards some academic centers just because our missions include education and research, etc. But there's several very excellent private clinics as well. What would be some red flags if you're going through this process? How much of a delta is there in cost within a same city or did prices tend to converge within a given geography? Yeah, within a given geography, they're pretty similar and it's not cheap. Yeah, so what are we at today? Fully loaded cost. So an IVF cycle is probably around $20 ,000 per cycle on the yield. But that doesn't include genetic testing or does? Including genetic testing per cycle.

2:00:23But how does that compare to 20 years ago? Is that more or less inflation? prices like most things have gone up. It has. Yeah. Okay. I guess it should go up just based on the cost of labor that goes into all these things. Yeah. And there's even though the genetic testing's coming down. Yeah. Innovations and things like I, you write like you think as volume goes up eventually prices go down, but that hasn't quite happened. And as new things get out of it, then it just tends to become more expensive. And most people are probably still paying out a pocket. Most people are not getting this covered by insurance.

2:00:51Again, it depends where you live. Yeah, Yeah, but across the country. Yeah, I think there are now 24 states that offer some kind of fertility coverage about 15 of them include IVA. So you're right, in 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... Yeah, just setting up appointments. 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 opposed to you want to get time with your doctor or so some clinics You hardly ever see the doctor and you see maybe the ultrasound on a burden not that that's bad but it's kind of nice.

2:01:50Some patients prefer to have that more frequent interaction with their actual provider. So there's probably a sweet spot in volume where it's probably an inverted U shape where if they're too low, they don't have the reps. If they're too high, it's a bit of a sweatshop and a factory 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 and 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.

2:02:24I don't at the moment. I'm assuming you are more familiar with this than I am. What is the question that is being asked and how is it being asked in this study? So there's a lot of interest in extending fertility. Up until 100 years ago, women were basically dying at 50 and the average age of menopause. So it's kind of a recent phenomenon phenomenon that we're actually living a third of our lives, postmenopause. And fertility starts to decline way before you go through menopause. So there's a lot of interest in trying to extend fertility. Now of course, egg freezing, which we haven't talked about yet, is one of the ways you can extend fertility.

2:02:58And it works pretty well as long as you're young when you freeze your eggs. But again, it's a relatively recent phenomenon, you know, usually covered by insurance and it's expensive, etc. So it's not the answer. because you're paying basically half the IVF cycle to harvest and then you're paying to freeze. Yeah, exactly. What's the cost of freezing? Well, $10 ,000 for the cycle and then about $1 ,000 a year for storage. And you're recommending that if a woman came to you at 20 and said, I just want to double down on my career right now. I want to do X, Y, and Z. I think I want to have kids. I at least want the optionality.

2:03:34When should I freeze by? Are you going to just say do it now? Because No, I wouldn't recommend all women in their 20s freeze their eggs because most of those eggs will never be used So you'd be doing for nothing because most of those women probably not need IVF and get pregnant spontaneously Right got it. Okay. This weak spot we think is like early to mid 30s That's where it makes the most sense because you're about to get to the probability cliff Where it starts to really decline right if you think you might want to have kids But you're not in a place in your life where you think that's gonna happen in the next few years than doing it early to mint 30s.

2:04:09It's probably the time where it's most cost effective. Very high likelihood that you'll 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 each. That's right. And do you freeze them? You freeze every egg you retrieve? Only the mature ones. Okay. And what's the, for a typical 30 year old, you're gonna get what we talked about earlier? Probably 10 to 15 per cycle, sometimes more, but that's a lot. And how many do you recommend a 30 -year -old do? Yeah, so there's some calculators online. So the younger you are, the fewer eggs you need, because more of them are going to be normal.

2:04:48So someone 30, I think 10 to 20 would give you a decent chance of success. No guarantees, there's never any guarantees. But studies show that even if people use those eggs and they're not successful, the fact that they did something proactively, there's some psychological benefit in doing that. So even if ultimately doesn't work out or you don't end up using them. But at that age maybe 10 to 20, as you get closer to 40, you might need 20 to 40 or 50, which is not practical for most people because you can't do that many cycles and it's expensive and there's a risk and fall. So I think egg freezing is a great option for women.

2:05:25I also think as a society we should try to make it easier obviously for women to have kids during their peak reproductive years and their 20s and 30s. The whole different question, but I think having options is a good thing. So back to the rapamycin question, they're basically saying, look, is there a way that we could push that out a little bit? And so how is the study testing this? So rapamycin, as some of your listeners may know, is used in other anti -aging type contacts. 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 in your fertile for more years.

2:06:11So 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. Believe it's a few months study where they're giving relatively low dose of Rupa Mycene. I forget exactly maybe five milligrams daily. Daily, not weekly. I think it's daily, but not 100 % short. We'll pull it up and put it in the show notes. I should have known this. And then I think there are outcome markers, A -M -H. I believe it should that hormone. So I don't know. It's a relatively inexpensive study.

2:06:45They're not invasively looking at follicles. which you have to believe then is in just a period of a few months, you could pick up a signal of more or less AMH reduction. Right. And even if you can, like, what does that mean really? This study could be negative. If the study is positive, it's interesting. If it's negative, it probably doesn't tell us much. If it's only three to six months. Right. To really do the study, I mean you'd need a few years. Right, you need pregnancy outcomes or at least menstrual, menopause, age of menopause. So that would take for a long time and you'd have to take it for many years, probably.

2:07:25That's going to be a really difficult question to answer in humans. Yeah. Again, because of the animal data not being consistent, some studies show, yeah, maybe it's helpful, but other studies show that it might be actually harmful because of the way it acts as being immunosuppressive and things. So certainly for any listeners trying to conceive, I would not recommend Roba Mison. But yes, I'm curious about the data coming out of Columbia and other studies. Are there any other things that a woman can do to maximize her fertility beyond? We've already addressed her to PCOS. We've already addressed the metabolic stuff.

2:07:59But 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 a Atrogenic for lack of a better word infertility. Yeah, I think all those things are important like lifestyle factors They're rarely the sole cause of infertility because they can certainly exacerbate infertility as well as any other disease. So I think the lifestyle factors that But promote health are generally the same lifestyle factors that promote fertility. So healthy diet. Is there anything we can say more on that?

2:08:40Like, what is a healthy diet as it pertains to fertility? Is it different? Does a woman who's getting ready to conceive? Does she need more fat in her diet, for example? Yeah. Yeah. As you probably know, the data on diet is not great for anything, especially not fertility. So, I would say there's very little evidence that there's a particular diet that's good for fertility that's different than what's good in general. So, for most of my patients, I recommend a Mediterranean diet that diet is palatable, most people, and has a fair amount of evidence that it's reasonably healthy, and that's a lot of fruit and vegetables, whole grains, protein, mostly from fish, and all of oil and those types of things.

2:09:23It's not that different from what I would recommend for anybody. By the way, I think I said I had torogenic. I meant idiopathic, but you know what I meant. Yes. So what about supplements? I'm sure you get asked this question all the time. There's no shortage of over -the -counter supplements that people report, increase fertility. I get asked these questions all the time and have blank stairs because I don't know. Is there anything you can point to? And I love framework. 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's supplementing with these things happen.

2:09:59I'm talking beyond just the prenatal vitamins that are obvious and necessary, but 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. 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 it was a lot of women, reproductive age women are iron deficient, for example. And they might need to be on iron supplements.

2:10:30You 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 DHA is another one. And there's some data that it might be helpful. Again, it's not very robust. DHA? DHA. Which just increases endogenous testosterone production. Proves at quality, like who knows how it works. Interesting. Yeah, I mean, the data isn't great.

2:11:08Might improve libido. Maybe I think people have studied that. It doesn't work so well. It is a weak ender, genuinely, 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 aren't there to do those studies. So it probably doesn't hurt, though. And so I'm relatively supportive. Patient wants to take co -key 10. There's some data around it. Sure. Do you think it's just psychological where if they take it and they feel that they're doing something better, it reduces their stress around it?

2:11:38Like, because for me, I can't help but think that stress has such a negative impact on fertility. Oh, for sure. And on many aspects of health, it's so difficult to quantify. We don't have a biomarker for stress. Even measuring cortisol doesn't actually tell you anything about the experience of stress. And so I just think so many negative health outcomes are a result of it and therefore anything that a person can do to improve their stress. I agree with you and if taking supplements helps with that, sure, I'm all for it. Yeah, I'm not advocating that we should be going crazy on it with no evidence.

2:12:09But I wonder if any of the efficacy of those things is mediated through that reduction of stress. Possibly. Yeah. And as long as it's not harmful, that's great. And when we say the data is in there, it's just because it doesn't mean that it doesn't work, because just nobody's shown one way or another whether it works. So it's quite possible. Coked U10 has some effect that we don't know about. And my feeling is if I don't think it's harmful and patient wants to take it, maybe helps their stress short and for that. Other things that 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.

2:12:45Like it's not helpful to tell patient, well. You just need to be less stress. You just need to be less stress. I was like, okay, now what? But finding ways to cope with the stresses, really what we're talking about. And that can be different for different people. For some people, it could be exercise for some people. It could be meditation for some people. Whatever, mindful. That's what's important. Whatever it is. But definitely, it's important. Same as sleep. And we talked about diet. Exercise is important. Do you caution women or do we know anything about too much exercise for women who are trying to conceive?

2:13:18We 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 is some clues to you that her exercise might actually be too much and that might be impacting her fertility. Absolutely. Extreme exercise can be associated with fertility issues, although I think for most patients of benefits of exercise as we know, what is extreme in this case? So if it causes any change in a person's cycle, so for some of the more extreme athletes, sometimes their periods will stop altogether.

2:13:53There's a condition called reds, it's relative energy deficiency in sport. And basically the body is very smart. If it thinks there's not enough energy around to support a pregnancy because we're expending it all on this exercise. We're just going to shut the whole thing down and it works really well. But the patient stops menstruating. So obviously they're going to have difficulty getting pregnant. 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 super important for bone health.

2:14:25So one lesson for the listeners. Keep track of your, we talked about the semen analysis being kind of a marker of other health outcomes, your periods are also a mark. Of course, if you're on hormonal contraception, you might not know what your natural cycle is doing. But if your cycles are regular 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 no problem about anything. But thankfully, this generation of young women is talking more and they're seeing an internet, etc. But don't wait till you're ready to try to get pregnant to figure that out.

2:14:59There may be something important you need to know way ahead of time. So. 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? Yeah, there's not a cut off, but certainly being overweight or obese can impact fertility and being severely underweight. For the underweight people, similar mechanism, if your brain thinks there's just not enough. It's usually going to manifest through amenorrhea. Exactly. Exactly. So healthy way, healthy diet, exercise, sleep, disrupted sleep could affect ovulation and fertility, stress.

2:15:36We mentioned all these things, all things you mentioned in your book as well, are all the same things that are important for fertility. Lastly, what do you think is the most promising area of research? And if we're sitting here in 10 years and we're talking about this and we're looking back at the last decade. What do you imagine you will be most excited about from an innovation perspective? It's a very exciting field of medicine. There's always sort of innovations happening. I think, let's see, genetic testing will continue to evolve as we learn more about genetics. I think that'll play a bigger role.

2:16:12Automation and 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 to develop being these lab ownership concepts where like you put in the egg put in this firm Emberio comes out of the other so microfluidics or yeah microfluidics the whole process being automated It's very interesting right and it could potentially improve access if you could put these So you see this as more of a cost reduction or more of a success improvement Maybe both because reduce error potentially, usually the cost that 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.

2:16:59So 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, woman wouldn't have to take all these injections and just take the immature eggs, put them in the petri dish, and then give the petri dish the medications, if you will. That's in very sort of early stages, not quite as successful as conventional IVF yet, so we're not quite there. I assume because it's difficult to harvest unmatured particles. And even that maturation process, we haven't quite gotten it down like it happens in the body.

2:17:35other things. A real game changer would be something like in vitro gamita genesis, 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, then potentially, anywhere we in that very early. I think we'll see it eventually. It's been done in mice. So we're probably 10 to 20 years away, What's the obstacle? Basically reprogramming skin cells. The whole process is very complicated and not easy. People are trying their couple of companies to try and do this. Meaning is the challenge taking the skin cell back to a stem cell and then the stem cell in front of you?

2:18:22Different, right? Yeah. And which of those two steps do we think is harder? Skin cell back to stem cell or stem cell into egg? I think they're both hard. I don't know. There's a couple of different approaches including we work due research in this area as well, where we're taking essentially the nucleus from a skin cell and putting it into an egg, and just replacing the genetic material. Yes, exactly. So we don't have to reprogram the skin cell. And is it easy to separate the chromosomes? No. Okay. It's very complicated because it's myosis. It's hard for it to happen efficiently and equally, et cetera.

2:18:57So we're working on it, but we're probably 10, 20 years away. But that would be an alternative way to get to that. But then you need donor eggs so that has its own limitations because it's not like donor eggs are easy to come by either. Yeah, that's true. Although I guess what it does is it helps the older woman who is able to make follicules but they're just end -employed. You have a solution to that problem. Yeah. Another thing we're working on is something called mitochondrial replacement therapy where basically a similar concept you were taking like you have an older woman, let's say. She undergoes IVF.

2:19:35You 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 that 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, you can't do that in the United States legally, but we're doing trials in other countries. This is kind of a remarkable field. Again, it's still amazing to me how well this works.

2:20:12If 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, as a field, I think having an enormous impact that is relatively recent when you sort of think about the timescale of this. So it seems to me that early intervention is better. Your point about women who have any sort of irregularity in their cycle, if they're in their teens or 20s, if for no other reason, beyond just the discomfort of it at the moment, getting this looked at now is a great way to get ahead of an infertility problem 10 years hence. That to me is a very important takeaway that I don't think is probably appreciated enough.

2:20:57And 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 were 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 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.

2:21:35More standardization, yes, for sure. I'm still blown away at the concept of the embryologist and what's required to do that and how that we don't have a more formal training path, especially given that you said that we have a shortage of such people that seems like an incredibly rewarding career for somebody. So hopefully we can foster that. Paul, 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 calm. For a later, for sure. Yeah, appreciate your time and your expertise.

2:22:07Thanks for inviting me. It's been fun. Thanks for having me. Thank you for listening to this week's episode of The Drive. Head over to peteratiamd .com forward slash show notes. If you want to dig deeper into this episode, you can also find me on YouTube, Instagram, and Twitter all with the handle Peter Atia MD. 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.

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