Can problems in our immune system cause infertility, miscarriage, or premature birth? Today we talk with Reproductive Endocrinologist Dr. Daniel Stein, Director of RMA of New York’s Westside office and Chief of Reproductive Endocrinology at Mount Sinai West Hospital, about the impact our immune system has on our fertility.
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Welcome, everyone to creating a family talk about infertility. I'm Dawn Davenport and I am both the host of this show as well as the director of the nonprofit creating a family. And our mission is to provide unbiased medically accurate information to the patient community. So welcome. Today we're going to be talking about how the immune system affects fertility and miscarriage and we will be speaking with Dr. Daniel Stein. He is the director of RMA of New York's West Side office and chief of reproductive endocrinology and that Sinai West hospital. Dr. Stein has over 20 years of experience as a reproductive endocrinologist and fertility specialist. Welcome Dr. Stein, we are so glad to have you here. Oh, thank you so much for having me. All right. So let's start by talking about ways that our immune system and the reproductive system are linked. We don't think of them as being linked, particularly we think of them as being separate systems within our body, but in fact, they are linked. And so So how? So really good question. Yes, they are linked, in fact, very, very tightly linked, I would go as far as to say that a normal immune system can help make a pregnancy occur, and an abnormal one can certainly break apart. It's the make or break situation. The bottom line is that our immune system within our uterus, or fallopian tubes, our cervix and vagina, so forth, has a very profound effect on the ability of an embryo to grow, has a very, very profound effect on the ability for invasion of that embryo into the uterus and to gain the blood supply from the mom. So it is really very, very critically important. Well, okay, so we understand I mean, from basic biology that the immune system is, is the, is the part of our body that distinguishes self from other that that, you know, it's set up for, to to distinguish and to repel each other and to accept self. So it seems to me that that just the whole notion of pregnancy, how does that work? the fetus is other at least 50%? Other? So why doesn't the woman's body immediately reject the fetus? Because it is other? And is that part of some of the issues that happen with failed implantation or miscarriage or even even conception? So you're absolutely right, the fetus is in fact, partly other It is about 50% self to the woman because 50% come from the woman's genes, 50% of the man's genes. And so that portion that is not from the woman herself, but from the man would be considered foreign or non self and the body responds very, very aggressively against non self. And you would expect, in fact, that as soon as some of those placental cells come in contact with maternal blood supply, that there would be a very profound in reaction. But evolution is amazing. And it's been already mechanisms that have come into place to allow this to occur to allow this placenta to not be rejected by by the by the mother. And some of the methods some of those mechanisms include, first of all, some protection, or blockage of fetal blood from the placenta. So what happens is that not all the fetal blood is actually exposed to the maternal blood, in fact, it's very, very well protected through some of the mechanisms in the structure of the placenta. In addition, all of our cells in order to be recognized as self or non self, have a code of what are called antigens. an antigen really is any kind of particle microbe that is foreign to the body that will elicit an immune reaction. But we have our own antigens, sort of our own ID card. And that's called a HLA a human leukocyte antigen complex. And this essentially, it's like an ID card, it's a code on each one of our cells, so that when our cells are in our body, and circulating around our defense cells, okay, will not Garner an immune reaction against those cells. But if it recognizes something that doesn't have the proper ID card, it will destroy it. And so there have been mechanisms by which the body I would say, the pregnant woman, and the cells of the placenta, have evolutionarily developed the ability to hide and not express some of those IDs, so that they go essentially unseen. They evade recognition. And that's one of the mechanisms by which they do that. In addition, we have a bunch of immune cells called T cells. And these T cells are two T lymphocytes, which oftentimes will kill abnormal or I should say, not abnormal, but foreign cells. There are some T cells that actually
Don't do that and produce certain chemicals will help to kind of soften or lessen the immune reaction to calm it down. And then there are some other mechanisms in place called natural killer cells and sometimes will work in our favor, as well as some other topic, which I'll talk about called phospholipids. And their role in health protecting the pregnancy. So there's a lot of mechanisms is amazing, amazing evolutionary system, it does seem amazing to me, it seems. So often the more I learn about reproduction, the more amazed I am that week, any of us can carry and could get pregnant and stay pregnant, and that that children are born healthy. And of course, that is the predominant thing that happens. It's just, it's,
it is miraculous. And I certainly understand why you wanted to study that you were in medical school, it's got to be one of the best fields to be in to learn about. So we've talked about the immune system when it's functioning well, and the woman's immune system or anybody, the human immune system, being able to distinguish between self and non self. But we know we've heard of audit, we all have heard of autoimmune diseases. And that would be where the the body's self that are, we attack that which is self, our immune system attacks that which itself. So let's start by just giving lips ground people and what are some of the more common autoimmune diseases that others that people would have heard about? Right. So as you said, autoimmune immune diseases involve the body, not recognizing its own cells as self and attacking those cells. So one of the most common ones that we talk about probably the most common one overall, would be just autoimmune thyroid disease, something called hashimotos thyroiditis, which essentially is antibodies against the thyroid gland, that cause it to not function properly to cause it to make less functional hormone. And in those cases, we can of course, use hormone replacement to help patients but other ones had a far better thought about or far better known things like rheumatoid arthritis, or lupus. Very, very common very often times can be quite severe, autoimmune diseases, and they don't necessarily in most cases affect reproduction, because we do know that a lot of these diseases are in fact, passed on in a familial fashion. And so if they truly prevented reproduction from ever occurring, we wouldn't be seeing them in each generation. They were they were five phase out exactly right. They would phase out and Crohn's disease is a common one. Multiple Sclerosis is a common one. celiac disease is common, even type one diabetes. So all these are common, one that we think about most often affecting reproduction is something called endometriosis. endometriosis is a disorder where the uterine lining cells can implant in different parts of the pelvis and cause a severe immune reaction causing scarring. And sometimes affecting sperm migration and, and can really have a significant effect on on reproduction. Another one is what we call primary ovarian insufficiency, where a woman at less at the age of 40 begins to stop having a periods and about 20% of those cases, there seems to be a significant autoimmune contribution. So yeah, so these are very, very, very important. We're always very careful. And we're always, you know, very much focused on women in our practice, who have autoimmune disease, because we do know that they will have a higher chance of having miscarriage and a little bit harder chance of getting pregnant with endometriosis. What percentage of the endometriosis cases? What could be attributed to autoimmune? So some believe that all endometriosis is autoimmune, and that the reaction to the endometriosis is worse than the endometriosis itself? And so I would say that there are strong believers who 100% of it is autoimmune. Interesting. Okay. And so the as far as the treatment, and they let's talk a little bit about the, let's specifically talk about endometriosis, since we know that that has the greater potential or has a greater potential than some of the other earlier when she mentioned autoimmune diseases. Let's talk about endometriosis as far as the diagnosis and treatment, because it isn't an auto immune problem, an auto immune failure, that are disease that has the potential to impact fertility. So how is it How is it diagnosed?
So usually it's diagnosed as someone presents with some type of symptoms. So for example, it often will present with pain, particularly during menstrual cycles. It can have very, very severe cramping, you can have abdominal pain, sometimes
causing pain and even other structures nearby the bladder, even sometimes bleeding from the bladder. It could be causing pain with urination. It could be causing pain with defecation, pain with intercourse, there's a lot of different things and often also will present with infertility. But I do want people to understand that in the majority of cases of women who have endometriosis, they won't necessarily have infertility. Yeah, people don't realize right? Yeah. Oh, about what percentage are. The problem is we don't actually know the answer to this, I realized because we don't know how many women have endometriosis. But what does the research say about the percentage of women with endometriosis? That that were it causes infertility? So there were some very early studies done that suggested that approximately one in three women with endometriosis will present with infertility and two and three will not. But those are old data. I suspect that it is quite a bit lower than that, that present with infertility. I think there's many women with endometriosis who will live their entire lives never knowing that that in mitosis, because it had no clinical ramifications for them. In fact, a significant percentage of women who just go in to have their philippian tubes removed for the purpose of actually preventing further fertility have been found to have endometriosis just by incidences just seen on a laparoscopy. So and that was, I think, seven or 8% of women in that study, which was a long time ago that study, but so my feeling is that probably endometriosis is far more common than we think. But it doesn't cause clinical problems in more and most patients. In some patients, of course, it does cause very significant clinical problems. What was the more severe from the symptoms and pain being one of the primary symptoms? Is the more severe the symptoms are the more likely that it will impact pregnancy? are not well impact conception? Are? Do we know the answer to that? The answer is not necessary. There is definitely a an association between the severity of the disease and pain, the amount of pain. But the truth is many people who have mild disease have significant pain. And many people who have significant disease have minimal symptoms. So there's not really a perfect relationship. But we do know that very deep, extensive endometriosis lesions in the pelvis can be associated with significant pain. So we've talked about the diagnosis. Let's talk about the treatment. Well, we actually have it okay. So diagnosis is primarily made through symptoms and assessment of symptoms symptoms and laparoscopy was going to ask and then laparoscopy would be the the state of the art, what somebody would do to to determine whether to confirm the diagnosis. Got it. Now, treatment of endometriosis is an interesting topic now. And it seems to be one that that has been in the news in the last couple of years. Because certain celebrities were getting a particular celebrity got a hysterectomy to deal with the endometriosis and a number of fertility specialist and gynecologist. Were on the new saying this is not considered the best practice treatment for endometriosis. So let's talk about so how and obviously it wouldn't be a good treatment if you if having children was something that was a high priority for you having children without using a surrogate, so or adoption or some other alternative method. So let's talk about the treatment of individually osis as an autoimmune disease. Sure. So endometriosis, what it is, essentially, are the glands of the inner uterine lining. The inner uterine lining is called the endometrium. So the glands and the stroma, which has some supportive tissue around the glands can be found in different parts of the pelvis. And when you see both of those things together under a microscope slide that's essentially the the diagnosis of an immature osis. So these glands do respond to estrogen to hormones, and therefore, things that reduce estrogen helped to reduce the development of the disease, or at least put it sort of quiet down at least temporarily. So for example, things like using birth control pills sometimes can have some benefit for people with endometriosis. Not for all people. But for some people. What it does is it also reduces the amount dimensional flow. And if there's a reduction in menstrual flow, then there's less endometriosis tissue entering into the pelvis, medications that shut down the brain's stimulation of the ovaries so that the ovary doesn't make a lot of estrogen. One of these is called Lupron which is a medication that essentially blocks the signal or I should say turns off the signal from the brain to the ovaries. So that estrogen
levels go down certain types of progesterone. There are other medications called aromatase inhibitors, that can also go ahead and prevent the conversion of that of the androgens into estrogen so estrogen levels go down. And, and also people oftentimes we'll use a IUD like a Merino or some other progesterone IUD, which will quiet down some of the tissue within the uterus and reduce the chance of endometriosis. When you mentioned somebody having a hysterectomy, well, first of all, laparoscopic surgery is a common treatment. In most cases, it is not necessary, right? It is definitely at the minority of cases that laparoscopy is required. But laparoscopic surgery can be used to obliterate some of the lesions to cause them to cauterize them or even to strip them away. hysterectomy, I know that there were those who were very critical of hysterectomy. So the truth is, though, that people have to think about the symptoms. So I agree that hysterectomy would probably be a last ditch effort for most people with endometriosis, although not unreasonable for someone who no longer wishes to bear children, or the symptoms are too severe, just that they were willing to do anything at that point because of this. Exactly, exactly. And the truth is that if somebody has tried all the other treatments, and they are not working for them, and they no longer wish to have children, it's very hard for people to be critical of somebody making a decision to rid themselves of an organ that is causing them only harm and no good at that point in their life. So I would never be judgmental the person who decides that that is their best effort at this point in time.
Exactly. I noted that that most of the treatments, if not all of the ones you mentioned, would also prevent pregnancy. For people who are wanting with endometriosis who want to get pregnant I am assuming that they then stop the treatment for the endometriosis allow their system to reset. They would then go back to having the symptoms of endometriosis. But they could then try to conceive naturally. Is that how it was? Okay, that's exactly right. What you said is exactly obviously medications would get in the way of getting pregnant, they certainly would get in the way of ovulation. And yes, they would have to temporarily stop them while they're trying to conceive. Gotcha. Okay, another autoimmune disease that you mentioned that obviously would have direct relevance to or direct impact on fertility would be premature ovarian insufficiency, poi. So let's talk about that. And first of all, let's talk about what it is then talk about how it is diagnosed. So premature ovarian insufficiency, as you said poi is a severe loss of ovarian activity, basically, essentially loss of periods, and a substantial loss of eggs in a woman at a much younger age than would be expected. So typical menopause would be typically between 45 and 55. This would be occurring typically, and women under the age of 40. And as I said, it's estimated that in about 20% of use cases, you'll find some other concurrent hormonal disorder like significant antibodies against the adrenal gland or the thyroid gland causing some loss of function of those organs. So the diagnosis really is somebody usually will present with menstrual loss, they'll come in with long periods of time, which they haven't gotten a period, they may even present with some hot flashes, vaginal dryness, just as a result of the loss of estrogen. And then you run some hormone testing, and you look at some of the hormones that are made by the brain. And when the hormone levels, for example, follicle stimulating hormone, or luteinizing hormone, when they are very, very high. In this type of a scenario, that will generally indicate that the brain is working very hard to try to stimulate the ovaries. And that's usually a telltale sign that person has premature ovarian insufficiency. And in those cases, the most important thing for those patients is to one, help them protect their bone from bone loss and osteoporosis. And then, of course, if they want to get pregnant, sometimes they will oscillate spontaneously on their own and about probably, you know, a couple times a year, but many times these women do need the use of donor eggs in order to conceive.
Okay, so that's and so the treatment is really the treatment of preventing the what would happen to your body, if it doesn't have estrogen for a longer period of time, because you're really going into menopause at a much younger age. So you would then be so that's the treatment is to prevent the side effects of the lack of estrogen. And then then there would be treatment specifically to for the potential infertility. That's right. Got it. Okay. So, what are some of the other some of the other autoimmune diseases you've
Talk about lupus rheumatoid arthritis type one diabetes, Crohn's disease celiacs hashimotos. Is there any connection between somebody who has any of these other autoimmune diseases? Do they increase the likelihood that that person would have infertility or increase the likelihood that the person will experience a miscarriage?
Yes. So, you know, the the data with regard to these diseases around fertility isn't quite as clear. We know that many, many women who have these diseases will have no problem conceiving, and some will, what they are associated with is, in many cases, a lower number of eggs in the ovary so that their reproductive lifespan sometimes might become a little bit more limited in time. But the biggest issue, as you mentioned, is far more data on early miscarriage. And one of the causes of miscarriage or certainly have recurrent miscarriages. Are these systemic diseases that do have some significant autoimmune effect. Even things like endometriosis, as celiac disease, rheumatoid arthritis, bichette syndrome, there's a lot of different ones, lupus. So yeah, there are several different diseases, and they definitely are associated with an increased risk, particularly of early miscarriage. Okay. And, you know, we hear a lot about unexplained infertility, and we hear a lot of it because it's a frustrating diagnosis for many patients. Because if you have something to identify, and I realize you're well aware of this, but if you have something to identify as to what is wrong, it gives you a feeling, perhaps a false feeling. But it does give you a feeling of control of some sort. But unexplained is particularly frustrating because you lack even the semblance of control. So what percentage of the unexplained infertility is do you think could have some connection to our immune system or a malfunction of our immune system? So it's a wonderful question, and and anyone who would say they know would be lying?
We don't, we don't really have a clue. We don't think of unexplained infertility in general as autoimmune. Although I have no doubt that the immune system may cause reduced fertility and many people, there's no way for us to really know this. We do suspect in many cases, unexplained is involved with autoimmune dysfunction. But, you know, one of the things that we do know, for example, with unexplained infertility is that when we do in vitro fertilization, in cases of unexplained infertility as compared, for example, to tubal infertility or even malefactor infertility, we do find that a greater percentage of embryos are chromosomally abnormal, in those with the unexplained infertility than those who have these other issues. So we think that probably there is a strong genetic component to this. The autoimmune component is much more difficult if a lot of our diseases, even something like polycystic ovaries, which is a disorder in which we have a, you know, of loss of normal ovulation, sometimes an excess production of male hormones by the ovaries, as well as a very classic multicystic appearance and ultrasound, it can that can affect many, many different women and caused them to have difficulty getting pregnant. And while pcls itself is not an autoimmune disease that we know of, there's a very strong association between polycystic ovary syndrome, and things like thyroid disease. So about 25% of women who have polycystic ovary syndrome will also have a common thyroiditis, hashimotos, or low thyroid function, which is much about three times higher than what you would find in the general population. So there is obviously some significant link between some of these different disorders and autoimmune factors, but not well characterized, and not something that we know what to do with. And I always tell my patients Be very careful of those who are offering broad spectrum type massive immune treatments, because we don't even know what we're treating or if it helps in any way.
Yeah, I think and but there's a strong temptation, when you don't have any when you can't think of anything or nothing else is working to then to grasp at straws, perhaps that would say, well, let's do anything.
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all right. What is an
phospholipid syndrome APS and how does it impact fertility or miscarriage. So antiphospholipid syndrome refers to syndrome in which the body creates antibodies to the phospholipids, which are the constituents that make up the cell membranes within within human cells. So first, the lipids are very important because those lipids that are within the within the, for example, in the cells of our center, for example, what they do is they help the cells of the placenta to kind of aggregate together and to invade attached to the university to invade into the uterus and gain blood supply from the mother. For reasons are not clear, some women make antibodies against these fat phospholipids.
Some of these common ones so called the anti cardia, life and antibody, lupus anticoagulant, anti beta two glycoprotein, there's a variety of different ones, although not all of them have been shown to have any significant clinical effect. And what happens is when people do have these antibodies circulating around is that some people will develop multiple miscarriages, three or more miscarriages, typically in a first trimester although have a late fetal loss, or even have things like preeclampsia, which has high blood pressure in pregnancy or have a decreased blood supply to the baby leading to babies that are born small for gestational age. So it's a little different process. So there's a lot of possibilities. But antiphospholipid syndrome is specifically a case in which somebody has one of these significant problems, either excessive clotting, or loss of multiple pregnancies, or unexplained early fetal death, in combination, so So in other words, a major clinical phenomenon and combination with an elevation of one of these permanent antibodies. And that's antiphospholipid syndrome, and is a very, very well known and well described cause, particularly for second trimester losses, probably not nearly, you know, it is I should say, not just for a second time as losses also for first trimester losses. So it's really for both, but it's probably only about 10 15% of cases of recurrent pregnancy losses due to this. The fortunate thing is that when it is diagnosed, which can be done by by both clinical history as well as blood testing, it's treatable. And one of the ways that you treat it is by using certain types of blood thinners, because anti phospholipids, When activated, can cause small clots in some of the vessels that feed the developing embryo. And, and so some of the blood thinners may help to break up these clots, but also may have a more direct effect on even just allowing the placental cells to aggregate together and invade better.
It would seem that somebody who would have APS would be having some significant symptoms is outside of fertility because it attacks the cell membrane. So would it not attacked other cell membranes? If you have these anti phospho? lipids? Would it not attack cell membranes in other parts of the body? Or is it exclusive to the fetal cells are the placental cells?
No, actually, it can affect other cells, although many times early in someone's life, you don't have quite as many of these antibodies, but as people get older, sometimes the amount of antibodies can increase. And people who do have high antiphospholipid antibodies are more prone to heart attack and to stroke. Sure. Yeah. So absolutely. So it is not just limited to in fact, to to pregnancy is just but but that's, that's a place where it can often be seen. And maybe some of the maybe one of the earlier times because women are trying to conceive it, you know, one would assume in an earlier age before some of these long term health impacts would show. Absolutely. Yeah, that makes sense. I think you answered this question before, but in general, we've talked about autoimmune issues impacting conception, but they also have an impact on the carrying the pregnancy to term. Is that correct? Yes, absolutely. I would say the data with regard to loss of pregnancy is far greater than the data related to infertility. There's not nearly as much data to suggest that they affect fertility as much as they do for early pregnancy loss. So so when we do an evaluation for the patient who does have two or more miscarriages, particularly in those who have never had a successful live birth, one of the things that we do check for are these antiphospholipid antibodies because these are probably the best described antibodies that not only
have been linked to recurrent pregnancy loss and very good studies, but for which there is some actionable effect to take. So you can actually treat them. There's lots of times other antibodies are checked. And they may not even have been corroborated as being causes of recurrent pregnancy loss, and for which there are no treatments. So, and sometimes these are even then given treatments, like intravenous immunoglobulin, so things like that, for which there may not be any adequate data to suggest that, and it's very expensive, also, so people have to understand that they may be not being treated with evidence based medicine. Yeah, yes. And that is a real issue. Again, for people in particular, who the number of courses of IVF, a number of cycles of IVF have not been, have not been successful, or who have not been successfully able to carry a pregnancy to term. Alright, let's talk about the female's immune systems reaction to sperm. sperm is other but on the other hand, it's not it's not really becoming a part of our system per se. But it does have to enter the woman's system to get to the egg and then and then of course, the DNA then becomes part of the fetus. But so Can Can we, as women be with it, the thing that we often hear is people say I'm allergic to sperm are, I am, I am rejecting my husband's sperm. So let's talk about the, the female's immune systems reaction to sperm.
Yes. So you know, this is something we call the mucosal immune system. So the vagina, for example, has what's called a mucosal layer, just like the gastrointestinal tract does, just like the mouth does, etc. And this mucosal membranes that line the vagina, what they do is they have a certain interplay of immune factors, that's very different than the mucosal membranes and other parts of the body. Because here, it's not just about attacking nonself. And recognizing self, it's about, as you mentioned, it's about a two fold job. One is it has to attack things that shouldn't be there. But it also has, it has to have some sort of an adaptive response to things that are foreign that it wants to have there. So in the the sperm is very important because the semen itself has a seminal fluid that contains certain enzymes and antibodies and things that can actually help to make the sperm protect the sperm as it travels through the, through the vagina, into the cervix, and then into the uterus. But the mucosal immunity, the response, immune response within the uterus, within the vagina, within the fallopian tubes are all different. And all of them work well to kill things that shouldn't be there, but all work well to, to tolerate the things that shouldn't be there. And it's not fully understand all the mechanisms by which it does is some of the things are what I mentioned earlier, some of the T cell responses and hiding of antibodies hiding of our HLA antigens and things like that. But it is very, very fascinating. Now, when you talk about sperm allergies, so yes, I mean, many people come in and say I'm allergic to my husband's sperm, or my partner's sperm. So I would say that number of times, that's true is so rare, you know, but there are cases in which clearly that happens. There are people who will get a very severe inflammation
in the vagina when exposed to sperm. So we know that there's something in the not necessary in the sperm, but in the semen that can cause very significant reactions. But I have to tell you, I've seen that less than five times in my last 25 years. It's very, very unusual. So I don't think that we have great data to suggest that people were actually significantly allergic to sperm not nearly as much as people claim that they are well, okay. So, is there such a thing as anti seminal or sperm antibodies, where the woman's immune system is producing antibodies that will either kill the sperm or make it less let make injure them or make it less likely that they will be able to fertilize an egg? Yes, so anti sperm antibodies, or immunoglobulins, you know, produced by the body that attack antigens that are present on sperm. So, it recognizes that portion of the sperm is being not self and can attack it. And they can be found in men that can be found in the jack latorre fluid it can be found in the men's bloodstream, it can be found in women, it can be found in in any part of the reproductive tract and women but particularly vagina and cervix, and it can also be found in in women's bloodstream as well. And how does it get there? Yeah, it doesn't seem like it's a very effective. I mean, if the if the if the goal of the human race is
to procreate, it does seem like an antibody against sperm and the woman's body is. It's contrary to that goal. Well, it is in this country. And usually it doesn't happen because, for example, in the man, when you go to man first, he has what we call blood testes barrier. So there's a tissue barrier that generally prevents his bloodstream from ever seeing his sperm. But sometimes it does, particularly if there's testicular injury, trauma to the testicle that could expose the sperm to blood, if he's had a vasectomy, or a vasectomy, reversal of varicose seal surgery where there's an abnormal collection of veins in testicle that can then be removed. So anything that can break that barrier can expose sperm to blood and cause a man to develop antibodies. But for men, the antibodies are present in his blood probably don't have any effect on him. But the antibodies present for example, in the semen can cause the sperm to kind of aggregate and bind and clump together and make them far less capable of moving throughout the reproductive tract and actually far less capable of binding to the egg and fertilizing it. In women. Women can be exposed to this as well. Their blood can be exposed, particularly in cases of more traumatic intercourse. If there's traumatic vaginal intercourse, or you know, intercourse, or even some exposure of the oral cavity of the sperm, it can cause an immune reaction that will cause women develop some antibodies within her blood. But again, that might not be the most important thing. It's your the more the antibodies in the reproductive tract that can again cause a failure of the sperm to move well, and to penetrate the egg and to cause fertilization. And so is this a real thing? It is a real thing. But the truth is that in the era of in vitro fertilization, for example, it's just not something we we even think about because it's was something like in vitro fertilization, where we're processing the sperm and getting rid of the semen and and isolating the sperm and sometimes even injecting into eggs. These anti sperm antibodies are no longer relevant, but in regular at home, intercourse, certainly it can be effective. But But I will tell you, again, my nearly 25 years of doing this, very rare, very, very rarely effective. Okay, so it's at Mack was wondering how a woman's if a woman's vagina would develop antibodies against sperm, I could see how it could happen in her blood. But why would they? How would they get from the blood to the vagina? Because Wouldn't that be where they would need to be in order to I guess, if it could be anywhere along the reproductive track and still have a negative impact on conception? But how would the antibodies even get into the reproductive tract? Yeah, so so some of it may come from the blood, but some of it may be developed locally. So there are definitely women who will have some, some of their antibodies will recognize something on the sperm as being foreign. And because people do have a significant difference in their immune activity, some will have a very heightened immune activity and some will have a lesser immune activity. A lot of that is determined by a whole different topic here, which is very important, called the microbiome. And that's essentially all the bacterial and viral DNA within our bodies, that actually can have a very significant effect on how our immune system works. And that's a very big part. I mean, the microbiome is a fascinating topic by itself. Yeah, it is. It's an absolutely and the impact of the microbiome we have done a number of courses and resources on that. And the impact of the microbiome there in the reproductive track on fertility is absolutely fascinating in such a field of I mean, that the information that we're getting on it, it's it's fast, and it's it's new, it's such a growing body of research. So I'm, I'm absolutely fascinated by it. And and valid point about that the microbiome is a is a is an integral part of our immune system. Absolutely. It's, it's so so important to our immune system. You know, what people don't realize that in our own bodies, 90% of the genes active in our bodies don't belong to us. 90% of the genes that are active in our bodies belong to well, all the microbes that live within us.
All the critters, yeah, all the credits exactly, that have an effect within us. And they affect so many different aspects of our body from our nervous system, our gastrointestinal system, even the way our skin looks. So what happens is that the they can activate the immune system and they can really have a very significant effect on how our immune system works. In fact, there are certain bacteria we should absolutely see and some we absolutely shouldn't see.
In the uterus, it was always thought that the uterus was a sterile organ that didn't have any bacteria in it. But it's so far from sterile it has, it has certain bacteria and some bacteria are essential, for example, lactobacilli lactobacilli are, are should be present in a great, great dominance inside the female reproductive tract. If it's not, you will run into problems of reduced fertility and increase miscarriage.
Fascinating. Can we test for the microbiome in any easy way? And let me add that it's not just the uterus, it's also in the fallopian tubes, and so other other reproductive organs as well? Is it possible to test and say what the microbiome is? Or is it maybe it's possible, but is it? Is it very invasive? Well, it's not always invasive. I mean, it wouldn't be very invasive, for example, the cervix or the, or the vagina would be more so obviously, for the uterus, and and definitely much more. So for the ovaries, which you wouldn't be able to easily access. Yes, there are, you can actually, you can actually take small tissue samples from these different places. And you do what's called very specific type of RNA testing on them. So you're looking at the genetic material directly. And you can discern which you can discern how much of this RNA is from, let's say, a bacterium, versus how much is coming from the regular tissue of that organ. So you can sort of quantify it and see, and you can look at the RNA produced by different bacteria. And you can then tell what kind of bacterial species there are. So it is definitely definitely doable. It's just not easy. Yeah, it's not easy. And once it becomes really easy, I think we're going to make huge progress in our understanding of how our bodies work. Because the truth is, this microbiome is generally dramatically overlooked by medical professionals. There is a huge project called the Human Microbiome Project, which was like the Human Genome Project that tried to characterize the different genetic material from from the microbiome. But it isn't easy. You're right, it's not easy to do it.
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I want to now move to a topic that gets perhaps more attention than it should do to its name, and that is natural killer cells. I really think we need to rename these just that the name
is enough to terrify you. And it also probably draws more attention than is that it's due. However, maybe I should ask that question. Does it draw? Let's talk about the impact of natural killer cells on fertility and miscarriage. And is it truly the culprit that its name would imply or is it just suffering from a really bad title?
Yeah, I think you're right. It's a that's a tough title.
Right here is that that, especially that movie Natural Born Killers, which I think about, Yeah, me too, you know, so it's interesting about natural killer cells. What are natural killer cells? Yeah. So So most of our immune cells are T cells and B cells and macrophages and lymphocytes. What they do is, in order for them to be to function, they have what's called adaptive immunity. They see, they see something that body wants, and they take a picture of it so they can remember it. And then the next time they see it, they say, Okay, I know this guy, I'm going to attack it. Alright, so basically, they have to see this thing. First, they have to recognize it before they can attack it. natural killer cells are type of white blood cell that doesn't have to do that. They're just, they're already ready. They're ready and they smell blood and they want it so they circulate through the body, and they will destroy foreign cells. And the way they do this is a little bit different, obviously, than the other cells because again, they don't need to, they don't need to recognize this HLA coating that we talked about this ID card on these cells, but natural killer cells.
As you mentioned, very true, a very valid point, they get a bad rap because they're very important, obviously, in protecting us. And the natural killer cells that are what we call a peripheral natural killer cells, the ones that circulate through our blood are cytotoxic, they destroy cells that shouldn't be there. But people confuse those with the natural killer cells that are within the uterus, and the uterine natural killer cells. And the peripheral circulating natural killer cells are not the same. They're different populations, they act differently, they look differently. And the natural killer cells in the uterus are actually our friend, they are not our foe. In fact, they are essential for normal implantation, because they very much have a very significant ability to be able to allow the placental cells to attach and invade into the blood vessels of the uterus and to obtain blood supply. So many times people are giving very high dose treatments of immunoglobulins, for example, to kill these natural killer cells.
But it's not doing anything because what it's doing ultimately, is it's potentially having an effect on the peripheral ones not on the uterine ones, they're different population, it's the wrong treatment for the wrong issue. So they do get a bad rep. natural killer cells are essential for reproduction within the uterus. And this are the treatment that is that we hear about is attacking the are is is damaging are affecting the natural killer cells in your blood. So in essence, what it's doing is lowering your immune system in your in your blood, but it is not affecting the natural killer cells in your uterus. Am I hearing you correctly? That Yeah, well, certainly it's not affecting it in the same way. And and you wouldn't want to affect you if it did significantly reduce the ones inside the university, but have the opposite effect of what we're trying to do. Right, because we want them because they're allowing the placenta to attach. And I guess the correct term is invade but attaches.
is attached. I liked it, it seems like a kinder term. All right, yeah. So does infertility treatment, such as IVF, being the most common one, affect a woman's immune system. So the only way it would really do that is through its hormonal effects. So we know, for example, that when you use stimulation medications, and in vitro fertilization, those that stimulate the ovaries to release more eggs, and therefore cause a significant increase in estrogen for example, estrogen definitely has an effect on increasing some circulating immunoglobulins within the blood, although it can have a suppressive effect on some of the some of the T cells T lymphocytes. And also when progesterone levels are increased, from all these follicles that have ruptured, and producing progesterone or from professional supplementation that we give, that also can have a suppressive effect on the immune system, then that suppressive effect of progesterone is actually quite helpful. Because what it does oftentimes is allow for a hormonal environment, or I should say, rather an immune environment within the uterus that is more conducive to implantation. But there is no doubt that the hormones that we produce as a result of IVF can have a transient effect on our immune system. However, however, not necessarily a negative one, not necessarily a negative one in any way, it could be a very positive one. And so I would say that we don't generally do things that harm our immune system through IVF. We sometimes can help by the increase in progesterone. But no, I don't think that that's really a major issue. You know, I would say that it's, I won't say it's a non issue, certainly non non issue. But I think for the vast majority of people, that's just not going to be an adverse effect. Thank you. And thank you, Dr. Daniel Stein for being with us today to talk about the immune system and its impact on fertility and miscarriage. Thank you so much for having me and to our audience. Thanks for joining us, and I will see you next week.
Transcribed by https://otter.ai