Dr. Taylor: Welcome everyone. Welcome to this Medscape Live Event. Today we're going to talk to you about personalized fertility care. Are we there yet? How we might be able to gather more information, provide more information, more monitoring for patients that let us personalize and improve their access to care. My name's Hugh Taylor. I'm [00:01:00] your moderator today. I am a reproductive endocrinologist and professor and chair of OB-GYN at the Yale School of Medicine. I'm joined by two distinguished faculty, Kate Devine, who is an assistant professor of OB-GYN at Georgetown and the executive medical director and chief research officer at US Fertility, and Nanette Santoro, yet another reproductive endocrinologist who is professor and E Stewart Taylor Chair of OB-GYN at the University [00:01:30] of Colorado. This is our agenda for this evening. First, I'll be welcoming you and giving you the introductions. Then we will give a talk on personalized fertility care, how do we evaluate fertility and how personalized really are we. Then Dr. Devine will give you a talk on assessing infertility. The standard time we usually wait for somebody to try and conceive is one year. She'll talk to you about when that's not appropriate. Then Dr. Santoro [00:02:00] will talk to you about early hormone testing. Is this clinically useful? Is this the future of way we can help enhance the information we get to our patients and improve access? Then we'll all talk about a view towards the future of fertility care, what are the implications of these increased hormone assessment. So I'll jump right into my talk to get us started. Personalized fertility care. I think most of you know the common reasons why we see fertility, but those indications are growing. Of course, male factor in fertility, low sperm counts, varicocele, congenital absence of the vas, certain medications that men may take may lower fertility. From the female side, ovulatory dysfunction, fallopian [00:03:00] tubes that are blocked, uterine anomalies, low egg count, diminished ovarian reserve. And in either partner, sexually transmitted diseases, hormonal dysfunction, not only sex hormones but thyroid and prolactin genetic disorders, environmental toxins. A lot of times we just don't know the cause of infertility. Sometimes we see unexplained infertility. But again, other than these traditional reasons, the reasons people seek fertility assistance are growing. [00:03:30] As we have more and more cancer survivors, iatrogenic infertility is becoming an issue and people see us prior to chemotherapy or radiation therapy to preserve fertility. Similarly with gender-affirming care before oophorectomy, we were often consulted about fertility services. And of course in LGBTQ individuals, they need fertility care. They need either females, donor sperm, or for men, donor [00:04:00] eggs and surrogacy. And also more and more women are deciding to become single parents, that we don't necessarily need a partner. So these broader indications for fertility services and more information is certainly needed. We think about a-third of fertility issues are male factor, about a-third female, about 15% unexplained, and a combination another maybe [00:04:30] 20%. Again, we used to define infertility as not being able to conceive after a year of unprotected intercourse. I think this definition doesn't fit though with what I just described the modern concept of who needs fertility care. There may be plenty of people who are not having unprotected intercourse but still need our help conceiving. So we need to broaden our horizons there. Somewhere around [00:05:00] 15 to 20% of couples though in the United States are infertile and seeking care. This looks at the time to conceive. Somewhere around 25 to 30% of young women will potentially conceive in their first cycle, but about 75% conceive within six months, and 85% in 12 months. It's sort of arbitrary that we set 12 months of attempting to conceive as the time that we begin an infertility evaluation. [00:05:30] Dr. Devine will talk to you a little bit later about really what is the most appropriate time to start that investigation. But you see it drops off over time. The chart or graph on the right though looks at what happens after that first year. You can see that those numbers are very small. Notice the Y-axis here only goes up to 50%. And in the best case scenario, of those 15% [00:06:00] who didn't get pregnant in the first year, over the next couple of years, only at half at most will get pregnant. And if you have some other known disease such as a tubal defect or male factor or endometriosis, that number is much, much lower. So certainly we need to do more to start sorting things out, to start identifying and personalizing care. Who can really wait that year? Who should be investigated sooner? And what are really the odds going forward after that first [00:06:30] year? We also know there's a tremendous age-related decline in infertility. It's about 15% of couples under the age of 30. But it goes up dramatically as we get older, more like 20% after the age of 30, and of course even higher percentage of infertility in those over the age of 40. Again, Dr. Devine will go into this in more detail, but if you know there is an infertility problem that you can identify, there's no need to wait that [00:07:00] full year. That's really quite an arbitrary definition. We see much earlier than that pregnancy rate starting to drop. Somebody over the age of 35, somebody has another obvious indication where you suspect that they may not be able to conceive. Irregular cycles, history of PID that you might suspect block fallopian tubes or endometriosis, or other suspicion for male factor infertility. Certainly, you don't need to wait the full year to begin infertility [00:07:30] evaluation and treatment. In terms of fertility testing, it's gotten a lot simpler. We've eliminated many unnecessary or uninformative tests. We need some indication of ovulatory status, suitable patency, sperm quality and ovarian reserve. I think those four key factors are things we need to assess in the patients were evaluating for potential fertility concerns. [00:08:00] Ovulation. In the old days we used to use the basal body temperature charting. Patients hated this. It was a nuisance. They had to take their temperature every morning first thing before they get out of bed and it wasn't that reliable. Ovulation predictor kits. The urinary tests are used commonly now and a big improvement. We'll talk about some of the limitations and alternatives now to those. And we used to measure luteal progesterone levels, good indication of ovulation, but again requires a blood test [00:08:30] and is only retrospective in nature. We get the hysterosalpingogram is shown here, but there are a lot of tests we just don't do anymore. We don't do the post-coital test. It's not really providing any useful information. Sperm antibodies aren't done. Endometrial biopsy looking for luteal phase defect does not provide any useful information. A lot of the evaluation of infertility has gotten simpler and easier and is more amenable to self-testing. [00:09:00] Again, as I mentioned, we need to get semen analysis, look for sperm count, motility, normal forms and evaluate that if it is truly abnormal. We need to look at ovulatory dysfunction. Probably about 20% of infertility is attributable to an ovulatory dysfunction. Many women with normal menstrual cycle length and regularity probably have ovulatory cycles, but there are anovulatory cycles even in the presence of [00:09:30] what appears to be or what a patient believes to be a regular cyclic menstrual cycle. Sometimes you'll get follicles that start to develop but do not mature to the point of ovulation. They're not followed by a rise in progesterone, but you may still get cyclic swings in estradiol levels that can trigger an estrogen withdrawal bleed or an estrogen breakthrough bleed that someone may misinterpret as menses when it's not. So I think we need to be more vigilant about [00:10:00] assessing ovulation. There are lots of reasons for ovulatory dysfunction and ovulation, low ovarian reserve, hypothalamic from stress or anorexia, polycystic ovary syndrome or a combination of the above, but I think assessing ovulation is one of the key things we need to do to evaluate infertility. Not only do we need to do it to evaluate infertility, but it really helps patients conceive knowing the day of ovulation. This is some data from some time ago [00:10:30] but still valid, that shows that the probability of conception is highest when intercourse occurs on the day or prior to the day of ovulation. And it drops down dramatically even at the day post ovulation. Those eggs are only viable for a very brief time hours where a sperm can survive in the female reproductive tract for several days. So timing, knowing when someone's ovulating is crucial to maximizing their chance of conception. [00:11:00] The other thing I mentioned is assessment of ovarian reserve, Anti-Mullerian hormone or AMH has largely replaced FSH. It doesn't need to be menstrual cycle specific. You used to have to time FSH on the third day of the menstrual cycle. AMH can be measured at any point in the menstrual cycle and it is produced by the very early follicles, the primary and secondary follicles by those granulosa cells when they're [00:11:30] hormone independent, FSH independent. Estradiols made later, but this isn't produced by the very early follicles, so it is an accurate predictor no matter where you are in the cycle and predicts how many of those early primary and secondary follicles you have. It's normal even in somebody with hypothalamic amenorrhea, the ovarian function is still good. So even if you don't produce hypothalamic hormones, FSH, or produce estradiol, [00:12:00] the AMH is still an accurate predictor of ovarian reserve. It can often be very high in polycystic ovary syndrome and it's often very low or it always becomes low to undetectable as we approach menopause or in somebody with diminished ovarian reserve, it may be falling. But an important measurement again that we can easily do and patients can check to determine whether diminished ovarian reserve is part of the fertility problem. [00:12:30] Another big problem for patients though is access, and this is a little bit complicated slide so I'll try and simplify it. This looks at how well patients can get in to see a physician when they're having problems with infertility, from easy on the left to very difficult on the right. Here we look at three broad categories on each of those rows. How difficult is it to take time off? How difficult is it to pay for treatment? And how difficult is it to get an appointment. It's [00:13:00] broken down the different lines, go break it down by income, race or insurance coverage. And when those lines diverge, there's a big discrepancy there. The biggest one you can see is in that second row all the way to the right. This looks at insurance coverage. People with good insurance coverage find it fairly easy to pay for their fertility treatments, to get that time off and pay for their fertility treatments. Here's another way to look at this, breaking [00:13:30] this down by age, race, poverty or insurance coverage. Looking at how often women can get access to the fertility care they need. If you're young, you see those numbers are fairly low. If you're 35 to into your 40s, it's about 15% of women come to see somebody for fertility advice. 15% roughly equivalent to the incidents of infertility in [00:14:00] the population. But if you're young, you're not getting it. Same thing if we look at race. If you're white, it's 13%. That's not quite the level of infertility in the general population, but it's approaching it. But if you're Black or Hispanic, it's half that rate. You're not getting the access. If you have a high income, similarly you get about 16% similar to the incidence of fertility in the general population. But if you're lower income, [00:14:30] you certainly don't get that access. And a huge discrepancy, again, if you have private insurance on the right, you can see that most number of patients getting access to care is similar to the incidence of fertility and fertility in the population. Yet if you're on Medicaid or uninsured, you just can't get that access. You're not getting the care you need. These disparities in access mean that we often see delays in getting [00:15:00] techniques that people need such as assisted reproductive technologies, bigger dropout, lower success rates. It's not only access that they're not getting but also potentially poor outcomes. So the ASRM has put out a statement about disparities. The ASRM Ethics Committee published this two years ago, that statement that building a family is a basic human right. This is something we all should [00:15:30] be entitled to. This is not something where access should be a huge barrier. Infertility is recognized as a disease certainly by the ASRM, but also the World Health Organization, the AMA, and many others. No one chooses to be infertile. This is a disease that deserves coverage, that deserves access. And the United States and in many other countries, economic, racial, [00:16:00] ethnic, geographic, and other disparities affect both access and treatment outcomes. We need to do better. These economic factors are chief contributors to the disparities and social cultural factors play a role as well as discrimination of disadvantaged people because of race, ethnicity, sexual orientation, gender identity. We need to make sure that people of all races, ethnicities, and sexual orientations have access to [00:16:30] fertility care. I think we can do better than we're doing now as those last two slides addressed. Finally, I want to put up this slide that looks at why people come to us seeking fertility services. Notice here the number one reason is fertility advice, and we deliver that without patients coming to the office. Fertility testing, same question. Fertility drugs, lower. Things like IUI or other procedures, IVF [00:17:00] much lower. What most patients need, the first step in access is good advice and testing. Can we deliver that in a much more patient-friendly, easily accessible way? So I'll summarize my portion of the presentation by saying that modern fertility evaluation has been made much simpler than it used to be. We certainly see a need for greater access, we need for improved ease of testing and providing better information, basic testing and guidance because patients [00:17:30] aren't getting the access they need now. I'll end my presentation here and then we'll move on to a brief patient video where a patient will describe her experience with getting this access and needed information about her fertility. Speaker 2: My husband and I hadn't actually been actively trying to conceive for long if at all, [00:18:00] trying being the operative word. Prior to our first appointment with our fertility clinic in August 2017, we really just were living our happily married lives. We married in 2013 and were both fairly career minded at the age of 29. In April 2014, I had a myomectomy to remove a grapefruit sized fibroid that my OB-GYN had easily [00:18:30] located during a routine finger exam. And then in July 2015, I decided to discontinue birth control. I went to my regular OB-GYN frequently with complaints of irregular cycles and what I considered to be extreme PMS symptoms. I was always reassured that my symptoms were signs that things were working. There were some emotional challenges when my cycles were longer because without a formal diagnosis and constantly being told that [00:19:00] everything was working as it should, I genuinely believed that I was accidentally pregnant, meaning I was just getting pregnant like everyone else and was possibly getting false negatives when my cycle would be longer than 30 or so days. Little did I know I was perimenopausal and my follicular stage was longer than 14 days. At some point, I purchased urinary ovulation strips, [00:19:30] not so that I could track my ovulation and try to get pregnant, but I got this in response to my OB-GYN at some point saying that perhaps my shorter cycles were anovulatory. When she did tell me it was anovulatory, I just thought, "Okay, well let me check to see if I'm ovulating" and I got ovulation strips. I used them maybe a handful of times before discontinuing. I didn't find [00:20:00] that it was reliable. I did not bring up my fertility concerns to my doctor. I did bring up my health concerns with my consistent bleeding. I was told that the symptoms were a sign that all was working well so I really did not think to ask about my potential fertility issues. I took some tests and found out I had diminished ovarian reserve, premature ovarian insufficiency, [00:20:30] and potentially blocked fallopian tubes. My FSH was off the charts and my AMH was super low for my age. I had to get started with IVF immediately. In terms of my journey, and this is a major fast-forward, but when I walked into the fertility clinic, I was basically told I had no chance of having my own biological child, and [00:21:00] I beat the odds. Dr. Devine: Okay, well that patient testimonial I think really does kind of put into perspective why we need to personalize fertility care and why we're all here. One of the ways that we can personalize fertility care is to make sure that we are offering that advice that Dr. Taylor mentioned, that's the number one thing that patients need at the right time and not having patients wait too long to see us. And so while one year is kind of the standard when we don't have suspicions that there might be some subfertility factors [00:22:00] there and that the patient doesn't have any number of other things going on that we want to see them, there's a lot of patients we want to see sooner. So I wanted to address that part of personalizing care. The definition of infertility, and this is [00:22:30] from both the American Medical Association and ASRM, is 12 months of regular unprotected intercourse or impairment in the capacity to reproduce. And importantly, as again Dr. Taylor stated, infertility is a disease and it's really important that we all talk about it as such so that we can help patients get access, so that we can help [00:23:00] insurance coverage grow for people who need this basic human right to build a family. And so we should always be talking about it as such. Thankfully, all of our professional societies support this designation of infertility as a disease, and we need to make sure that we also as healthcare providers are consistent in talking about it that way. Again, the recommended timing is 12 months if the female [00:23:30] partner is younger than 35. But one factor that's long been acknowledged as a reason why we might want to offer evaluation sooner is if the female partner is older. So why is it that we might want to offer an earlier evaluation? Again, as Dr. Taylor said, this is somewhat arbitrary. That said, time is very much of the essence as we get older. Egg quality and quantity are decreasing and a lot of our patients want [00:24:00] to have more than one child. And so we definitely should be encouraging our patients to seek evaluation as soon as they're worried, especially if they're over 35. And in my opinion, when patients are 40 years old or older, initiating attempts at conception, a conversation that expert advice is really warranted right away. They should not wait. That's not to say that they need or should necessarily start with IVF, but that education, that advice and some [00:24:30] evaluation is key for these patients. And so some examples of an impairment in the ability to reproduce are listed here. And so those are, as we said, if their menstrual cycles are not regular, if they've had a history of surgical sterilization, if they had pelvic surgery, iatrogenic causes, certainly having been exposed to chemotherapy or other genotoxic agents, [00:25:00] those are reasons why they should definitely have this conversation sooner, anyone that we know has an acquired or congenital anatomic abnormality or if we know that the male partner has this sperm quality or quantity issue. And so why has 35 been designated as this line in the sand? Well, we all know and call this advanced maternal age. Really this was the age at which amniocentesis was offered, right? Because it was essentially the time at which the odds of diagnosing a chromosomal abnormality in an ongoing pregnancy was a little bit more than the risk of causing damage to the pregnancy by doing that procedure. It's in many ways [00:26:00] kind of a historical artifact to be honest in the age of NIPT and the way that we currently screen for aneuploidies. And so it's important that we recognize as well that for women who are over 35, their chances of getting pregnant is half of that, of their cohort of 19 to 26 year old patients. That's very significant. And again, thankfully as [00:26:30] a field of women's healthcare providers, we're really turning our attention not just to that baby that they want to have right now, but helping families grow to achieve their desired family size. And so we don't just want to be taking into account baby number one, but the family that they hope to have and build. So for 35 to 39 year olds, 60% will conceive after one year and 85% will conceive after [00:27:00] two years. Again, we need to be thinking about growing to their full family size and acknowledge that 60% means 40% will not have conceived after one year, and that's a really valuable year that just passed. So it's never too much to try to convince this patient to go in and get advice and testing. And so again, time is of the essence, especially when thinking about the full family. [00:27:30] So repetition is excellent pedagogy. I know that you've seen this slide before. Just looking at it now in terms of who should be seen earlier than a year, when we look at this right most graph on this slide, we see that in 36 months after somebody has tried for a year, no [00:28:00] couple gets up to 50% chance of having a baby over three more years of trying. That's pretty impressive. We don't want to wait. Again, egg quality and quantity are decreasing. And then when we look at the relative decline in the probability of conceiving over those next three years and those lines below the reference, so the yellow line in the right is the reference, that those lines below are decreasing. That green dash line is if there's a male or tubal defect, so they have half the chance of getting pregnant over that 36 month period compared to the all comers who didn't conceive after one year. And then we have patients with endometriosis have a 40% of the reference. So patients who have endometriosis absolutely should not be waiting. Our younger patients and patients who have achieved [00:29:00] a prior pregnancy do a little bit better. The prior pregnancy is the red line at the very top. And then we see that the patients who have had less than 36 months of infertility leading up to it do a little bit better as well. But the take home message here is nobody gets up to better than 50%. So the idea that we should be saying, "Oh, don't worry, wait a couple more years" for these patients is really not serving them well. [00:29:30] This is a schematic out of Speroff, our favorite textbook, which essentially outlines the way in which the number of oocytes goes down over time as women age while the quality of the oocytes, which we're really talking about the rate of chromosomal abnormalities in those oocytes, rises over that same time period. So it is a double-edged sword. Both egg [00:30:00] quantity and egg quality are decreasing over this time period and we see that the rate of change is really quite pronounced in the late 30s and early 40s. And so again, yet another reason not to let these women and couples wait too long. So in terms of what is the assessment that should be done, whether it's after a year when we really have no other causes of concern or potentially earlier [00:30:30] for a lot of our patients, again, we're going to be confirming that they're ovulated. Most patients that have regular cycles are ovulating. That said, there are anomalies. We really need to take a good and careful history to make sure that those are truly regular cycles and not potentially random withdrawal bleeds that don't represent ovulation. We are going to be assessing ovarian reserve. As Dr. Taylor said, the modern assessment ovarian reserve relies much more so [00:31:00] on antral follicle count, on ultrasound, and anti-müllerian hormone than it does on the more arduous day two or three baseline testing. Thyroid disorders absolutely cause ovulatory dysfunction and infertility as well as obstetrical problems and risk. And so that's something that we need to assess for all patients who are having difficulty conceiving. I'll talk a little bit more on the next couple of slides about [00:31:30] for who we really need to be assessing the fallopian tubes. But certainly on an ultrasound we should assess the uterine anatomy for all patients who are having a difficult time conceiving and see analysis as a no-brainer, such an easy test to do and accounts for a huge portion of infertility is often missed or delayed way too long since women are seen as the primary people responsible for becoming pregnant for the couple. [00:32:00] Also very similar to a prior slide that you saw about AMH, one of the things that our patients often ask us is by doing fertility treatment, ovarian stimulation, and certainly fertility preservation, "Am I borrowing from my reproductive future?" We see here that so many follicles that we have are kind of die on the vine and are lost. We have 300 some odd ovulations in a woman's lifespan usually, [00:32:30] whereas women are born with most of them millions of eggs. So unfortunately, egg quantity is dropping rapidly and it's highly variable, the rate at which is dropping, especially in the late 30s and early 40s and we need to be testing that. I had mentioned that we'd be talking a little bit about uterine and tubal assessment. It could be a whole talk in and of itself, who should be getting their fallopian [00:33:00] tubes assessed. This is actually a paper that looked at this very question in a non-infertile population. Should we be doing an HSG on everyone even in an infertile population? But Occam's razor being what it is, if we think we know what the cause is, should we be subjecting everyone to a hysterosalpingogram? I would say probably not. But in this setting of a history of PID or sexually transmitted infections or pelvic [00:33:30] surgery, these women absolutely need to have their fallopian tubes assessed because it is certainly not in their interest to continue trying with low tech fertility treatment or natural conception with blocked fallopian tubes. And obviously, cavity distorting anatomic defects need to be managed in order to optimize probability of fertility. Again, steam analysis affects men and women equally. It gets forgotten so many times. And so [00:34:00] for our providers in the communities, to know where and how they can help their patients, male partners, get a semen analysis early in the process. You really will be serving your patient population very, very well. And there's really never a time that's too early to do a semen analysis. It's a quick, easy, pleasurable test and it's almost always covered by insurance. And worst case scenario, it's normal and we've ruled out [00:34:30] that factor. So just to get to the chase of what we mean when we say earlier evaluation is helping, patients minimize their emotional impact of the cumulative unsuccessful attempts. Oftentimes by the time a couple gets to the fertility doctor, they're pretty broken. The cumulative disappointments take a toll even before they get to you. [00:35:00] And so we can help get to their goal to heal. That's really why we're all here and why we take care of patients. We can treat the causes that are mitigatable and we can move on to fertility treatment for those who need that. We can also have a conversation about, again, what is their optimal family size? Do they need fertility preservation? If somebody is 39 and they want three kids, that's pretty [00:35:30] improbable without having some eggs or embryos stored, and that warrants a conversation. So to play the other side of the coin, that's not to say that there's no downside to sending everyone for a fertility evaluation. That's not what we're suggesting here. So this may have a potential cost for patients who don't have coverage. Some insurance will not cover this until they have [00:36:00] a clear diagnosis of infertility. There is injustice in access to care. And unfortunately, there are some patients who really do need fertility evaluation who are not considered infertile. Our LGBTQ couples oftentimes have to pay entirely out of pocket even though there's no way that they could possibly build their families without our help. Unfortunately, there's not enough of us out there. And [00:36:30] even if we want to evaluate all these patients who need our help, wait times are long. There is an extreme problem in terms of the geographic variation. There's almost no REIs in the middle of this country. OB-GYNs, we do a little bit better, but actually I think one of the things that we'll talk about a bit later in terms of who will benefit. And as time goes on and [00:37:00] home fertility testing improves, those patients that don't have geographic access to care are the ones that come to mind most for me. So we may have false positive tests. Not every test is 100% accurate. We may cause alarm unnecessarily. It's also really important that patients understand that there's no such thing as a fertility checkup, that the only way to know whether you're fertile is to try to get pregnant. We can rule out known causes of infertility, but we cannot [00:37:30] tell someone that they're fertile. So again, the people who should be evaluated earlier than six months, LGBTQ, 40 years or older, if they're in their mid 30s and they know they want a larger family, if they want kids and they don't have a partner or not in a position to try. And again, in my opinion, early 30s, that's a good time to start talking about that. And whether fertility preservation is warranted. And again, if we know of anything [00:38:00] from a history or physical perspective that would indicate that they have subfertility. So in summary, and very importantly, infertility is a disease. Everyone deserves access to the tools they need to build a family. We can only know about causes of infertility that are evident on the testing that we have. We cannot tell someone that they are fertile by evaluating them. Focused [00:38:30] evaluation before 12 months in young patients or before six months in older patients is often warranted and it may limit the emotional impact of repeated failures as well as maximizing the chances of achieving a desired family size. Dr. Santoro: Thank you. So we're going to move on to hormone testing. What tools and methods do we have to triage patients when we're looking for the people who are going to have trouble? These are things that patients can and want to do themselves if they want to get information. Are their cycle lengths normal? 25 to 35 days is normal. Anything outside of [00:39:30] that is a red flag. Shorter and long cycles may indicate reproductive dysfunction. We've talked about the day 21 progesterone, which is great if you have a 28-day cycle, but what if you don't? Day 21 might fall on the wrong day for you. If your cycle's a long cycle, you'll miss it. The normal range for women is also very wide. Most definitions consider three nanograms per mil indicative of ovulation, but they can't tell you enough about what's progesterone yesterday and [00:40:00] what is it going to be tomorrow. So how much progesterone is enough for fertility? We look with ovulation predictor kits, it's another way that we can look. It finds the day of the LH surge. And from their, normal luteal phase length is 12 to 16 days. So an ovulation predictor kit in and of itself can help detect short luteal phases, which 10 days or less. Those are associated with infertility or subfertility. And if the ovulation predictor kit never turns positive, it may [00:40:30] detect anovulation for a patient. That will also often be evident because the cycle's not normal. So the methods we have are pretty inexpensive, but they lack precision when they're good or happy. But if they're not and you are a little bit different, but you're still normal, how can you tell? So some of the tricks that we've acquired, and this is summarizing a lot of what you've just heard, is testing ovarian reserve relatively early [00:41:00] in the game, because then you can at least get ahead of the biological clock because one of the most frustrating things that I see, and I'm sure my partners to my right will say they see in the office, is a patient who's been persisting with first line fertility therapy when her ovarian reserve is dwindling and dwindling and now it's critically low. So AMH is a helpful test. It provides information on the quantity but not always the quality of follicles. So a younger woman with a low [00:41:30] AMH will do better than an older woman with a low AMH. So when it's normal, it's reassuring, but we still don't know how frequently women should be tested. I actually had a 26-year old in my office a few months ago who wanted to be tested every three months unless her ovarian reserve drop. So I really had to pull out the data to talk her out of it. Antral follicle counts are another very easy tool that we have in the office that gives us the number of available growing follicles, but it requires [00:42:00] a pelvic ultrasound, it adds expense to the workup. One of the things I think we are slowly being able to put to rest is FSH. So many of you have had this hammered into you to do FSH. Patients used to come to us as it's the menopause test. But it fluctuates cycle by cycle and it also fluctuates wildly in late reproductive age. So while a high FSH helps rule in the diagnosis of diminished ovarian reserve and you know there's a problem, [00:42:30] if it's normal that month, you can be falsely reassured. It does not rule out diminished ovarian reserve. And again, you've got the problem of what happened last month, what's going to happen next month. So that has led to a push to test entire menstrual cycles to try to forecast fertility. It's been done using daily blood sampling to establish normal data. Daily blood sampling is obviously impractical for large scale use. Having been a volunteer in many of those studies when [00:43:00] I was a fellow, I can tell you that it's also kind of a drag after about two weeks getting your blood drawn every day. And the sample handling is demanding. So there's a push towards at home methods that can reasonably reproduce serum patterns. We have body fluids that we can use. There's saliva, there's urine, and there's blood spots. So I'm going to go through some of these with you to show you a little bit of what's possible. This shows you what's going on in a normal menstrual cycle. So what are the events that you're looking for? So one is there's a rise in progesterone at the end of the cycle. So here you see menses to menses, follicle is growing right here. In the middle you have a mid-cycle surge but number three on this graph is mid-cycle surge. And that's what we call the day of luteal transition. So that's when the luteal phase begins. [00:44:00] The follicle becomes a corpus luteum. About two weeks from then if pregnancy hasn't happened, menses will occur. So estrogen rises in response to the early follicular phase rise in FSH, the event estrogen rise triggers the ovulatory surge and the corpus luteum's formed. So those are the things we want to look at. I want to just call your attention back to just the shape of that graph. So the [00:44:30] shape of the estrogen graph, it rises. It reaches a peak at mid-cycle, it goes down and then rises again. And that's exactly what you see when you look at salivary estradiol in normally cycling women. So these are women with different circumstances, some are nulliparous, some are parous. It's related to age and parity. But you can see that all of these graphs look very, very similar. When they're aligned to cycle [00:45:00] day zero, which is the day after the peak estradiol, those salivary patterns line up beautifully and really mimic what we see in an ovulatory cycle, and that mid-cycle peak is quite normal. So it's a decent reproduction of what you see in serum. You see something similar if you use urine. And I've done this for a lot of my career looking at urinary hormones. This is from Catherine O'Connor, but it looks very similar to the things that I and others have done [00:45:30] in studies over the years. So estradiol curves. So E2 is on the right in the close circles. And estrone measured in urine is the bar on the left in the open circles. You can see their overlapping and that's estrone and progesterone on the right, on bottom square, and PDG, pregnanediol glucuronide. So if you look at urine, you also get very, very good reproduction of those patterns. So can these patterns be mobilized [00:46:00] to give people an idea of what their hormones look like day to day and avoid that frustration? Here's another graph looking at salivary progesterone profile changes. These are changes that are seen with aging. So subjects are getting older as you go down on the graph and the PDG patterns are older. And that's what we also see when you look at urinary hormones. This is data just [00:46:30] from the SWAN study showing that luteal phase progesterone in the upper left gets lower across the entire luteal phase. So there we just looked at it every day. Integrated luteal phase levels gets lower as women approach their final menstrual period shown as the zero on this graph. And along with that, other things change. Obviously, FSH goes up and LH goes up. We also know as women pass [00:47:00] through their fertile years and get into perimenopause, that perimenopausal hormone patterns can be extremely erratic. And this is just a very prolonged episode of high gonadotropins. This is LH and FSH followed by a crazy high rise in estrone conjugates. This is urinary estrogen measured in a single perimenopausal woman. Notice that there was no progesterone produced in that cycle. These are the little black bumps that show you the progesterone was produced. So she had a rise in estrogen [00:47:30] that was about six to seven times as high as what a mid reproductive aged woman would do and reported a very heavy menstrual bleed after that. So typical perimenopausal, dysfunctional uterine bleeding, but the kind of pattern that is seen at this time of life and not in the mid reproductive years. So, "Hey, they're great. Let's make an app for that and let's start doing it all the time." There are some caveats. So urinary hormones can vary depending on the state [00:48:00] of conjugation of steroids so that women probably represent themselves, they compare better to themselves than they will necessarily compare to other women. There's some racial and ethnic differences in how people conjugate sulfation and glucuronide function is different. If you adjust urinary hormones to urinary creatinine, that will vary if there's problems with creatinine elevation in the urine. So it [00:48:30] may best be compared within women. So a woman can tell in one cycle if she ovulated or if she didn't in the other, but there may not be normative means. Salivary collection is dependent on how you collect. If you collect at a time when you're salivating madly, that's a problem. If you're dehydrated, it may change your concentrations. It measures free hormone but can also be contaminated by blood especially if oral health is poor. [00:49:00] So in urinary studies, you can also detect ovulation just using sex steroids. And that was in the prior graph you saw something called the DLT or the day of luteal transition. That's when the estrogen to progesterone ratio flips. So estrogen goes up, I showed you that mid-cycle peak. Then it goes down, progesterone rises, that ratio flips. And that's pretty helpful. You can also detect that rise in progesterone just looking at a moving average, which is exactly what all of your eyes [00:49:30] did when you looked at that graph and watched it stay the same and then go up into that sort of bell shaped curve. There's been multiple hierarchical criteria that have been developed by my group and others with the SWAN study and other studies. Daily collection is similar to every other day and gives you about 97% detection of ovulation if you use these criteria and you look for that change in E2/P, you look for the consistent [00:50:00] rise. So this is again showing you that algorithm. So when you look at these other non-serum hormones, first you look for that rise in progesterone. So it's low, it's low, it's low. And whoops, it goes up. And that's what you're looking at with the moving average. Then you track back, so it happened, ovulation happened, that tells you that. When did it happen/ You look for that flip in the E2/P ratio. And if you are looking at gonadotropins, you may also capture a mid-cycle surge with an ovulation [00:50:30] predictor kit and further reinforce when ovulation occurred, which is, as Dr. Taylor mentioned, good prospectively for patients who are trying to get pregnant. So what's the value of self-testing hormones for patients? It can give them a reliable determination of whether ovulation is occurring. So those women that are having slightly irregular cycles, they're not sure, they live in a remote area, it's going to take them [00:51:00] a long time to get to see a specialist. This is information they can bring to the office and it may get them directed to a subspecialist sooner or get them to their OB-GYN sooner to figure out what their condition is. It can be a reliable determination of timing of ovulation. So it can help identify those women that have a very short luteal phase that may be giving them problems with fertility. We see this in athletes, people with different sorts of fertility issues. And may also [00:51:30] help people identify some of those early reproductive aging patterns. And as reproductive aging occurs, follicular phases tend to get shorter. So a woman who is noticing this subtle change and maybe suspecting there might be something wrong, before she comes in to see you, she may do one of these tests and help establish the diagnosis. And I say this as somebody who does a lot of menopause practice and is often confronted with patients with downloaded testing off the internet [00:52:00] or something that they bought that's about this stick to look through the test. So not all tests are created equal, so something that's reliable would be helpful here. So daily hormone measurements, what they cannot do, they cannot diagnose polycystic over syndrome. They cannot diagnose diminished ovarian reserve and they can't determine if a luteal phase is adequate. You need somebody to interpret that. [00:52:30] And luteal phase deficiency, is that even a thing? The ASRM defines it as a luteal phase that's less than 10 days. But we know that abnormal endometrial biopsies, and this is a test that used to be done and is no longer done, occur in about 4% of women. So they can be random events. But if they are consistent, they may represent what's called a sub ovulatory disorder. And there's some associations with pregnancy loss and they can be empirically treated. So a patient who's doing this again and [00:53:00] again can pick that up and hopefully get to medical attention sooner. So to summarize, there's a strong consumer driven movement for people to do a lot of self-diagnosis at home. Women are interested in their fertility and would like to do self-testing and self-diagnosis privately before they visit a clinician. So it's helpful for you as a clinician to understand what home testing is useful for [00:53:30] and what it probably can't do. But for most healthy women who don't have concurrent medical conditions that might mess up the determinations, self-testing should help them be able to predict anovulation, possibly luteal phase defects and possibly reproductive aging patterns. And those are all things that are good for you to know when they walk in the door. It helps save time in their workup, which as Dr. Devine said, is important for many women. So [00:54:00] back to you. Dr. Taylor: So again, thank you all for joining us. I'm going to give a brief summary. There are some challenges that we've all talked about of assessing [00:54:30] ovulatory cycles. We learned about how we can use estradiol and progesterone patterns to assess ovulation and normal cycles. Notice there's no Y-axis here. You don't need precise units of measurement. You can identify from these patterns whether someone has a normal ovulatory cycle and learn a lot about cycle function and ovulation. We don't necessarily need phlebotomy with the long delays, but this pattern tracking could [00:55:00] really be helpful in providing a future for us to more rapidly understand what's going on with our patients, to improve access, to do some of these things at home and provide us with more information. Again, some options for tracking ovulation, we talked about basal body temperature charts. These are retrospective only. The basal body temperature doesn't rise way after ovulation. It isn't going to help anyone time ovulation. Our nuisance to do [00:55:30] aren't all that accurate. Same with cervical mucus, very inaccurate. Urinary LH strips, we use today. These urinary ovulation predictor kits for the LH surge. But sometimes they don't detect ovulation either because the timing of when someone's checking is wrong, or you may have a very low amplitude LH signal, or it may be tonically elevated sometimes in PCOS patients. Home devices that track estrogen and progesterone are something that's up and coming and may [00:56:00] help patients to get more information, give them better access, and reassure them. We have a lot of challenges now. We talked about limited access that varies by insurance coverage, that varies by race, that varies by income, that varies by geography. Not only that, but we have very limited time with our patients and a limited number of access to healthcare professionals. There aren't enough REIs in [00:56:30] this country. And long waits. So I think the type of things we need to do to address these problems are thinking about some of this in-home testing or at-home testing where we can empower our patients. They want information, they want testing and good information. They need that prior to coming to see us. It can help get them in appropriately. It can provide them the access they need and really help these disenfranchised [00:57:00] patients who aren't able to get the access they want today. I want to thank you for joining us tonight and have a pleasant evening.