Endless POFibilities -- December 1999

Ovary System;What Goes Awry in POF; Medical Concerns
presented by Larry Nelson, MD, Senior Surgeon, NICHD, NIH at The First Premature Ovarian Failure Conference held October 24, 1998

Dr. Nelson:
It’s really a pleasure to be here, to be able to talk about Premature Ovarian Failure. This is a condition that needs more attention. It’s a frustrating problem, and I don’t need to tell all of you about how frustrating it is. It’s frustrating to the women who have it. It’s frustrating to the doctors who are trying to help them and it’s also frustrating to the researchers who are trying to make more progress in understanding it. I think one of the most frustrating things about Premature Ovarian Failure that I hear from patients is they feel isolated so this is a wonderful opportunity for all of us to be at this conference.

The other thing I’d like to say, I think this is a good example of how the American system works. We’ve been hearing a lot of things about how the system doesn’t work, but this is an example of how it works. The Constitution gives us the right to assemble peaceably, and that’s what we’re doing here, and you’re doing this to bring more attention to the problem that you’re concerned about, and you can let your government know about your concern and you can make a difference. I work for the United States Public Health Service. They pay my salary and they get their money from the Congress, so that’s whom you can let know about what’s going on and what’s on your mind. They also fund the National Institutes of Health, which is the organization where I work, which is responsible for meeting the needs of the American people with regard to their health and research related to their health.

I’d like to give thanks to Vivian Pinn who couldn’t be here today because of other commitments. She asked me to say "hello." She’s the head of the Office of Research on Women’s Health. She gets her funding from Congress also.

I’d also like to thank Dr. Alexander and all of the people who work in the NICHD, who provide the money and the people and the help to be able to allow us to do research in Premature Ovarian Failure.

What I’d like to do here today, first, is to review how the normal system works, how the ovaries work to make the hormones, to release the eggs, and how that relates to fertility and the normal menstrual cycle. After that I’d like to go over how we think things go awry in some women with Premature Ovarian Failure, and as part of that we’ll go through the research effort, how that works. It’s kind of scary to be doing research on humans, but there are ways, with checks and balances, to try to make progress in understanding things and help people at the same time. Once we finish up with that, then I’d like to go over some general areas about Premature Ovarian Failure that anybody with this condition needs to know about, and then we’ll have some time for questions at the end.

Well, there are several major players that allow the normal menstrual cycle to happen. One area of the brain is called the hypothalamus. That’s behind the eyeballs. It’s like the central processing unit of the body. It measures things and sends out signals to get them working properly. Another major player is the pituitary. That’s the master gland of the body. It relays signals from the hypothalamus to other glands in the body to regulate the hormone levels, and the ovaries are the other major player, and the uterus. Now the hypothalamus, its major job, with regard to the menstrual cycle, is to measure how much estrogen is in the blood. It measures a lot of other things and controls a lot of other things, like it measures your body temperature. If your body temperature is too high, it sends out signals to the rest of your body that cause you to sweat to lower your temperature. If you’re too cold, it sends out signals that cause you to shiver so you’ll generate heat and increase your body temperature. It does that with regard to thirst, to hunger and to all different hormones, like thyroid hormone, adrenal hormone, but what we’re mainly concerned about here is the ovarian hormone. So the hormone the hypothalamus is measuring is estrogen - how much estrogen is present in the blood. If the hypothalamus, this area of the brain behinds your eyes, senses that the estrogen level is too low, it sends a signal to this master gland, to the pituitary, and the pituitary, in turn, relays a message to the ovary, to tell the ovary to make more estrogen, and it does that by sending a signal through the blood. That signal is FSH, follicle stimulating hormone. It gets its name because that’s exactly what it does. It stimulates follicles to grow. Primordial follicles are microscopic. You have to look with a microscope to see those. You need to magnify them, like 300 times, in order to see it. And that’s called a primordial follicle and it has the egg in it and is surrounded by some cells that nurture the egg called granulosa cells. Now women get all of these primordial follicles they’re going to have when they’re born. They don’t make any new ones. They get about two million of them when they’re born. It’s like getting an annuity. You get two million dollars when you’re born and you get so much every month until your age 50 and then you don’t have any more money. It’s a similar thing with the eggs. You have two million when you’re born. There’s some process that regulates how they’re used up, so on the average, women run out of these primordial follicles about age 50, and that’s what the mechanism of the normal menopause is. Now follicle stimulating hormone gets its name because it stimulates follicles to grow and it also stimulates them to make estrogen, and that’s the female sex hormone that we’re talking about. Estrogen comes from a mature follicle, a maturing follicle, and the follicle is a fluid-filled structure when it’s mature - it’s about an inch in diameter, and it also contains the egg. It also contains a lot of cells called these granulosa cells that I mentioned that play a role in making the hormone. One of these follicles matures and releases an egg a month, because humans on average have one pregnancy, a singleton, but in actuality, each month, forty or fifty or even more of these follicles start growing, and they start off microscopic, like this, and then they grow to a millimeter, a couple millimeters, half-inch, three quarters of an inch. Those forty or fifty die off and finally one goes on to ovulate. We used to think all of these follicles that were dying off were just a waste and they served no function. It looks like, from some of the research that we’re doing, these other forty or fifty are like Kamikaze pilots. They’re all going and doing things, helping this one egg work and allowing it to be released, but they actually die off and aren’t able to release their egg, and we’ll get back to this. It looks like they’re actually playing a role and the absence of this group of Kamikaze pilots, so to speak, actually impairs the ability of that one to function normally. But when this follicle gets to maturity, another hormone is released from the pituitary, called Luteinizing hormone (LH), and that causes the egg to be released and it causes the formation of a structure called the corpus luteum. That means, in Latin, "yellow body", because when you cut across these in the operating room, they actually look yellow, so that’s corpus luteum, and that makes the hormone, progesterone. And the maturing follicle, these growing follicles, are making the hormone estrogen. Now let’s get back to those primordial follicles - remember, you get all of those you’re going to have when you’re born. There has to be some process that regulates how they’re used up. Like the follicle in the middle of your right ovary might be used next year. It’s not responding to follicle stimulating hormone now. It has to be saved for working next year. Another primordial follicle might not work for twenty years. We don’t understand what’s keeping it from working now. There’s some regulatory process that we just don’t understand. Yet another follicle might work next week. And another one might work a few months from now. There’s some regulatory process.

Now the next thing we need to talk about is how this relates to the menstrual cycle, this activity in the ovary, of estrogen being made by the follicles growing up, and then progesterone being released by the corpus luteum - how does all of this relate to the normal menstrual cycle? To talk about that we need to talk about the endometrium. That’s the lining of the uterus. It means "within the uterus." The normal menstrual cycle, that’s 28 days, and normally ovulation takes place around day 14. The lining of the uterus grows each month and when you don’t have a pregnancy the lining sloughs off and you then have menstruation. Now it turns out, during the first half of the menstrual cycle, when you’re making estrogen from these growing follicles, estrogen stimulates the lining of the womb to grow. It’s like putting fertilizer on your lawn. Estrogen is to the lining of the womb like fertilizer is to your lawn. It causes it to grow up thicker. Yet this is in the building phase. It’s the construction phase. It’s building up this lining of the womb. The lining of the womb isn’t really doing its job yet. It’s building up to be able to have a pregnancy implant, but right now, it’s not functioning for that. It’s just being constructed in this first half of the cycle under the influence of estrogen. So it builds up thicker, like this, over the first two weeks of the cycle, and it’s also constructing these glands that are straight and narrow because they’re not working now. They’re just being built. So then ovulation takes place here at day 14 and this corpus luteum is formed, and then you get progesterone secretion. Progesterone means "for pregnancy." Pro means "for," gest refers to "gestation" - that’s pregnancy. So progesterone is getting this lining of the womb ready for the implantation of the embryo that shows up here later. So progesterone tells the lining of the womb to stop growing thicker. It’s already been constructed. The building’s built, now it’s time to move the people in and start getting the work done - that’s what progesterone does. So progesterone says, okay, lining of the womb should stop growing and it should change these glands so they’re working now and secreting things. So they start to fill up with materials to nourish the embryo when it shows up, so they get thicker and more tortuous. This is called secretory endometrium - it’s making the things that it’s supposed to make to be able to nourish an embryo. Well if a pregnancy shows up, it sends signals back to the ovary to keep these hormones going and you don’t have a menstrual cycle, but if a pregnancy doesn’t show up, then these hormone levels fall and the falling levels of hormones causes this menstrual lining, the endometrial lining to be swept out as the menses and the whole cycle starts over again. So this is how all these players fit together to cause the normal, regular cycle. And when you go to see your doctor, because you’re not having periods, the doctor wants to know, is the problem up here in the hypothalamus, or the pituitary? Is the problem here in the ovary, or is the problem in the uterus? And what the doctor can do to sort out this question of where the problem is that’s keeping you from having a menstrual cycle, is by measuring follicle stimulating hormone. If follicle stimulating hormone is high, that means this hypothalamus and pituitary are working okay. Let me tell you a little more about the hypothalamus and the pituitary and the ovary. The hypothalamus is kind of like the thermostat in the room. It measures the temperature and the ovary is kind of like the furnace. The furnace and the thermostat are a "feedback system" and so are the hypothalamus, pituitary and the ovary. If your thermostat senses that the temperature in the room is too low, it sends a signal to the furnace to turn on and make heat to raise the temperature, right? What happens when the temperature in the room gets up to 72? It sends a signal to the furnace to turn off and stop making heat and then the temperature falls a little bit and then the furnace comes on and makes heat and gets it up again. This is called a feedback control system. Just by keeping the temperature in this narrow range, the thermostat and the furnace regulate the temperature of the room just by turning the furnace on and off. Well a similar feedback system works with the hypothalamus and the ovary, with regard to estrogen. If the estrogen level is low, like we said to start off with, the hypothalamus sends a signal, these follicles grow and make estrogen, that raises the level of estrogen in the blood and then the hypothalamus senses that this level of estrogen in the blood is enough, so it sends the signal to the pituitary for FSH, so if the ovary can’t respond, the FSH level is going to be high, because it’s going to keep sending the signal harder and harder to try to get the ovary to work. So the doctor can tell if the problem is in the hypothalamus or the pituitary, or the problem’s in the ovary, by measuring FSH levels in the blood. If FSH level is high, that means things are working up here, okay, and it’s trying to send a signal to the ovary to get it to make estrogen, and the problem is in the ovary and the ovary’s not responding. So that’s how the normal system works and that’s how this all relates to the menstrual cycle. Are there any questions about that so far?

Speaker:
What happens with the hormones at ovulation?

Dr. Nelson:
Okay, day 14, ovulation. Up to day 14 you’ve had a follicle growing and the growing follicles make estrogen. Then when the follicle gets mature, that’s usually around day 14, the pituitary sends out this signal of Luteinizing hormone, LH. That gets its name because it causes the formation of the corpus luteum. The corpus luteum forms, from this follicle, it makes progesterone and secretes that into the blood, and progesterone going through the blood, gets to the uterus and tells the lining of the womb, okay, the eggs been released, you’d better get ready for an embryo to show up. So it tells the lining of the womb to stop growing thicker, it’s already constructed, and change...and the progesterone hormone changes the lining of the womb to get these glands working and making things, to be able to nourish the embryo, and if an embryo doesn’t show up, then the hormones fall and the normal menstrual cycle, the sloughing of this lining of the womb occurs and then the cycle starts over again in the normal menstrual cycle.

Then the next thing we need to do is talk about how this all relates to Premature Ovarian Failure. And I think it’s useful to think about Premature Ovarian Failure as occurring by two categories, and they relate to the follicles. Remember those follicles are the things that grow up and contain the egg and fluid-filled structures and they make the hormone estrogen. I think with Premature Ovarian Failure, it’s useful to think of Premature Ovarian Failure occurring by two separate major mechanisms. One is follicle depletion and the other is follicle dysfunction. Follicle depletion just means these microscopic things in the ovary, primordial follicles, have either been used up too fast or you didn’t get enough of them to begin with, or they’ve been destroyed, maybe by chemotherapy or x-ray therapy. If the follicles have all been depleted, there’s really nothing that we would expect to be able to do to get the ovary working again, because the follicle function is what releases the hormones and releases the egg. The most frustrating problem with Premature Ovarian Failure to most women is the problem with fertility as it relates to it. So, we’ve been focusing our efforts mainly on follicle dysfunction. This means there’s still some of those follicles remaining in the ovary, but something’s keeping them from working normally. There are some rare causes that can keep these follicles from working normally that relate to genetic type of defects that don’t allow the follicle to make the hormones that it should, and those are rare and I’m not going to go into those. I don’t think it would be helpful here at this point. There are two major causes of follicle dysfunction though, that might cause women to be able to have their first period and develop normally, normal breast development, and have normal, regular cycles and then have the ovaries stop working prematurely. One of those is an autoimmune attack against the follicles. And the other that we come across just as a result of our research effort is some women, we think; just have a low number of follicles. We know some women have an autoimmune attack against the ovary that’s keeping these follicles from working normally.

We all need a healthy immune system to fight off foreign invaders - bacteria and viruses. They can kill us, so we need potent weapons to recognize them and destroy them. Now it turns out our bodies are made out of the same building blocks that viruses and bacteria are, so it’s no surprise that now and then the immune system might make a mistake and send out an attack against something that is "self", and a good example of that is rheumatoid arthritis. Some people get these swollen, red joints, you know, that deforms the fingers. That’s the immune system recognizing something in the joint that’s foreign and sending out this potent attack against it. The same thing can happen in glands. Autoimmune thyroid disease is very common, especially in women. Well we know that some women that have an auto-immune attack against the ovary, and it’s really interesting how it occurs, too, because it would suggest that if we could understand it better and recognize who has it, we might be able to reverse it. Some women have an autoimmune attack...it’s not against the entire ovary. It’s just against these follicles that are trying to grow, and it’s not against these primordial follicles that are microscopic, so it seems like, in some women, the immune system is recognizing something as foreign that’s only on the follicles that are trying to work, and the follicles that are stored for use in the future are still there. In that situation, if we could recognize who those patients are, as a cause of ovarian failure and have a treatment to suppress the immune system, we might be able, just transiently, we might be able to get those primordial follicles to work just long enough for a pregnancy to occur. So that’s been the major focus of our research effort, trying to understand autoimmune ovarian failure. The major problem, the major frustrating thing about autoimmune ovarian failure is we don’t have an accurate blood test to tell us who has it, who has ovarian failure caused by auto-immunity. We have accurate blood tests for rheumatoid arthritis. We have accurate blood tests for auto-immune diseases of the thyroid, but there is not an accurate blood test to tell us who has an auto-immune attack against the ovary, and that’s been a major obstacle to making progress in the condition.

I’m going to tell you where we are right now in trying to sort out what this follicle dysfunction, what the mechanisms of follicle dysfunction is and how we can understand that better. In order to explain that to you, I’m going to explain how the research process works, because I think that’s important for you to understand...how can you do research on humans and try to help people and make progress at the same time? In order to do research we need what’s called a protocol. The NIH Clinical Center other universities around the country, medical centers, specialize in problems that we just don’t understand as well as we should. We need research effort to understand better, so what happens is, if we don’t really know what the best thing to do for a particular problem is, it’s ethical for doctors and scientists to come up with ideas of how we might be able to help the patient with a particular problem. And if we come up with an idea like that, as long as the patient understands that we don’t know whether this is going to help or not, that we don’t really know what the best thing to do is, we can try this treatment and it just might work. We don’t know. We’re trying to find out. It’s ethical to do that as long as everybody understands that that’s what’s happening. It’s not ethical to do that if the patient doesn’t understand - we don’t know whether this treatment works or not and you’re paying for it also. So, if a doctor or a scientist working at the Clinical Center at the NIH or another university across the country funded by the NIH comes up with an idea of how they might help a particular problem, they have to write a protocol, which means, it’s like writing down a recipe of exactly what you plan to do, because everybody has to understand what’s happening. It has to be approved by the different committees and things so everybody understands, and it’s out on the table, and there are checks and balances to protect everybody. So, if you come up with an idea like that, you write it down, give it to your supervisors. If they think it’s reasonable, they pass it on to what’s called an Institutional Review Board. The Institutional Review Board is kind of like a jury. It has a chairman and it has twelve or fifteen members. Some of them are doctors, some of them nurses, some scientists. There may be lay people. There may be ethicists, public health people and they read this recipe, this protocol, and they decide if it sounds reasonable and ethical, and the investigators have a chance to go to meet with this committee, explain what they are trying to do and why, and why they think it might work. The committee usually asks them a few questions, then the investigators leave and they talk about the protocol. Usually what happens after that is they make a few recommendations. "We think this is okay if you change x, y and z, then we’ll approve it." So then the protocol’s approved by the committee, then it goes on and it’s approved by the director of the institute and the scientific director of the institute. And only after all those things happen can patients come to participate in a research protocol, because everything’s written down and there’s a consent for the patient to read, to make sure the patient understands what’s happening. The thing is, though, in this research effort, it’s not enough just to try things to see if they help. The investigators are required to actually prove what they did is what helped. You know sometimes things can get just better on their own, without your treatment having any effect on it. So, in order to prove that what the doctors did is actually what helped, it means using placebos. Who can tell me briefly what a placebo is?

Speaker:
A pretend pill.

Dr. Nelson:
A pretend pill. Or it could be a pretend shot. There have to be two groups to compare, to see if your treatment is really what’s helping. There has to be the person taking the active medication, maybe as a pill or maybe as a shot, and there needs to be a person taking what looks exactly like the pill or exactly like the shot, but it isn’t. That’s really the only way you can sort out whether the medication is really what’s helping, and it’s not really just things getting better on their own. The best way to make your study look good and to make your treatment look good is to have no control group, because some people get better on their own. The body can heal itself sometimes. If you don’t have a control group, you can’t really tell if you’re doing better than the body can do on it’s own. So that’s how the research effort works. There are checks and balances, and this has been applied to this problem of Premature Ovarian Failure. When we started working on this at the NIH ten years ago, auto-immune ovarian failure was our major interest because that looks like...that’s a situation where you might be able to restore ovarian function and fertility. We didn’t have a blood test to pick out who had Premature Ovarian Failure on autoimmune basis though. So while we were working in the laboratory, trying to develop a blood test, and we still don’t have one...we’re still trying to develop that...it’s been ten years. We decided to try to make some progress in understanding this condition, let’s try some treatments to try to help women who might have auto-immune ovarian failure, even if we don’t know that’s the cause, and we’ll use some treatments that really don’t have much risk. The treatments were designed to let the ovary rest. Remember I said in the autoimmune ovarian failure, in some women, the attack is just against the growing follicles. Well if we can let the ovary rest for a few months and not have the ovary make whatever the immune system is attacking, maybe the immune attack will die down and the ovary, when we let it work again from the rest, maybe the immune attack will die down and the ovary will be able to work for a few months, maybe even a pregnancy would happen. So we wrote these protocols and we started recruiting patients and if we didn’t find any other cause of premature ovarian failure, then we just assumed this might be autoimmune, and we had placebo and control patients. Actually, in that protocol, every patient got the placebo for four months and got the medication for four months, but neither she nor the doctors knew which time she was getting which treatment. So after the four months of ovarian rest, we measured a blood test once a week, to measure estrogen and progesterone. That would tell us whether the ovary’s working again and whether the treatment helped. We did that for the two month rest period after each time, either placebo or active drug. And we also did a pelvic ultrasound at the end of that two months rest period. A pelvic ultrasound will tell us whether we can look and see whether there are structures that look like one of these follicles in the ovary. Well, we had a total of about eighty women that completed these two studies and we showed, scientifically, that the women who got...that when they were taking the drug, they did no better than if they were taking placebo. But we learned something really important from those studies. When you get a group of patients together with the same problem, you have the opportunity of observing things that people haven’t observed before. You know, if there’s one doctor in Minneapolis and one doctor in South Bend, Indiana, and these individual doctors are seeing these patients all over the place, you don’t get the added benefit of observations that you only see in aggregate that make sense. So seeing these eighty women in these two protocols, even though they didn’t help restore ovarian function, the important thing we learned is that this is not just an early menopause. That’s the major point I’d like you to take home from this whole meeting, if there was one point I thought you would take. This is not just an early menopause. And the reason I say that is, in these first studies we did, we found that half of women, their ovaries are working intermittently. We could measure estrogen levels that say there’s a follicle there growing and working. There’s not a follicle there growing and working all the time, like the normal situation, but in half of the women the follicles worked intermittently. That’s based on serum estrogen level, estrogen levels in the blood. The other important thing from that in how this differs from menopause...it didn’t seem to matter how long since the diagnosis as to whether there was a follicle there working or not, and women who had the diagnosis more than six years ago, we were just as likely to find evidence that the ovary was working intermittently, as women who had their diagnosis within the past six years. That makes this definitely different from the normal menopause. You know menopause means you’ve had your last period and you’re never going to have another period...your ovaries have stopped working and they’re not going to work again. That’s clearly not the case in patients with Premature Ovarian Failure. The ovary can work intermittently through the entire reproductive life span. There’s one case reported in the literature of a woman having the diagnosis of Premature Ovarian Failure at age 27, when it used to be called Premature Menopause, and she turned out pregnant, on her own, at age 44. This is not just an early menopause. And we have more evidence to support that. I mentioned that these first protocols we had didn’t really show any benefit to the treatment, although we learned important things about the disorder from them. The other thing that I didn’t mention that we found was in forty percent of the women with Premature Ovarian Failure that participated in this study, using pelvic ultrasound, we could see structures in their ovary that look all the world like a normal follicle that might go on to ovulate, but this is despite the fact that they were having hot flashes, they weren’t having periods, and the blood test said the ovaries weren’t working. But we could find what looked like follicles in the ovary, so at this point, since we’re interested in auto-immune ovarian failure to begin with, we were really excited about this finding, because we figured most of these follicles aren’t working because there’s an immune attack against it, but we just can’t recognize it because we don’t have a blood test, and during the time that we ran those protocols, we examined a lot of different potential blood tests and none of them turned out to be helpful. So, we were at an impasse now and we either had to make a dramatic change in our approach, or just say, "well, we’ll come back and work on this, maybe, in ten years, let’s go work on something else." Well, we decided not to go work on something else. We decided to pursue what’s keeping these follicles from working. Well, since we don’t have a blood test, we need to do an ovarian biopsy to actually get tissue and study the ovarian follicle under the microscope and do special tests to see if this is an auto-immune attack — because in order to treat an auto-immune process, you need to use medications that may have some adverse affects - a medication like Prednisone that suppresses the immune system. Although ovarian failure is a frustrating condition, it’s not a life threatening condition, and for the most part high dose long term type of treatments with Prednisone immune suppressers are for disorders that have life threatening kinds of consequences. But we talked with the people in the Arthritis Institute that use a lot of this medication, Prednisone, to get their ideas on - if we wanted to use this for a situation like ovarian failure, what we’d like to do is have a dose where it might help people if they have auto-immune ovarian failure, but it’s very unlikely to hurt anybody, and they helped us develop a dose that met that criterion, so we have a protocol now where patients that meet certain criteria can undergo an ovarian biopsy to see if there is an auto-immune attack against the ovary and if there is, then they can take this alternate day Prednisone in a dose that’s unlikely to hurt people and it’s in a controlled prospective manner so we can really tell whether the medication is what’s helping or the people are just getting better on their own. So we wrote that protocol, we got that through the system that I explained to you, and the way we started off on this first, is we had patients come to the clinical center for their baseline evaluation, and then they went back home and they got an ultrasound, maybe once a week or every so often, looking for the presence of one of these follicles that we know happens forty percent of the time in women with this condition, and when a follicle was found on ultrasound, they’d get on a plane, they’d come to the clinical center, and we’d take them to the operating room and we would excise that follicle and study it under the microscope and do special tests. Well, the first patient we did, I just couldn’t wait to see the slides because I knew it was going to be an autoimmune attack and it wasn’t. The second, the same thing happened, and it wasn’t. The third one, it wasn’t. We did six biopsies of these developing follicles and none of them were autoimmune and we had the test to really prove whether it was or not. So that seemed frustrating, but in actuality, what we did, we uncovered another mechanism for why the follicles aren’t working. It turns out all of these follicles were luteinized. Remember this corpus luteum? The corpus luteum - that means yellow body? When we cut across these follicles in the operating room, they would actually look a little yellow on the edge, like they were trying to form a corpus luteum. So, we’d do the biopsy and we found, in six women, luteinized follicles, but not only were they luteinized, they seemed lonely. Remember I said there’s forty or fifty follicles that start growing each month and only one goes on and ovulates. Well we’d do the biopsy and we’d just see this one lonely follicle there, and all these other follicles that you’d expect to find weren’t there. Normally, the ovaries are all lumpy and bumpy with these follicles in different sizes. This was a smooth ovary with just this lonely luteinized follicle. It looks like what’s happening in some women is, because they don’t have this group of buddies working, they’re unable to regulate the hormone release properly...and if you just have one of these lonely follicles trying to work, it’s like your furnace is never able to make enough heat to get back to get the temperature up to shut off the furnace. It’s inadequate feedback to shut off the thermostat. That’s what’s happening in the ovary with these lonely follicles. There’s inadequate feedback to make enough things to get back to the hypothalamus to say FSH and LH should get down to the normal range. So it looks like what’s happening in some women, you have these follicles showing up intermittently and lonely, because they don’t have this group with them, and they grow from these microscopic primordial follicles in response to the follicle stimulating hormone, and women with Premature Ovarian Failure, as we talked about, that’s high. But then when they get to a certain size, they develop the ability to respond to Luteinizing hormone, and it turns out Luteinizing hormone is high too, because these follicles have to feedback to get LH suppressed into the normal range, so this growing follicle, getting exposed to Luteinizing hormone when it’s not supposed to, impairs its ability to grow and make more estrogen and go on and ovulate. It’s like picking a green apple. It’s getting the signal to ovulate before the follicle’s really ready. So it turns out that that’s why we say low number, actually, may be a cause of the follicle dysfunction in patients with Premature Ovarian Failure, and based on what we found in the six women, statistically, we can say that that’s probably the cause in at least sixty percent of women - this low number. So we think there’s definitely some women who have autoimmune ovarian failure. We don’t have a blood test to select those out, and we’ve changed our protocol to go on and try to make more progress in understanding auto-immune ovarian failure, because that’s one place where research might allow us to select the right patients, give them the right treatment, and get the ovary working again. But this is another mechanism of follicle dysfunction, just low number. So some women, maybe instead of starting out with two million follicles when they’re born, maybe they start out with only two hundred thousand, and those two hundred thousand, but they’re timed to go off over the normal reproductive life span, so you’re not going to run out of your two hundred thousand until you’re fifty, but it’s like the annuity...you expect it to pay $3,000 a month and it’s only paying $300. You don’t have this forty or fifty coming out every month, but its still going to pay until you’re fifty years old. So, that’s what we think is happening in some women. They just have a low number of follicles. They get to the threshold below which you can’t have ready predictably cycles occur, but yet intermittently follicles might work normally. We know, another reason why I say this is not just an early menopause, we know five or ten percent of women with this condition can turn up pregnant on their own with no treatment. There’s no doubt that can happen. And nobody can tell you that there’s no follicles remaining in your ovary. You can never really prove that all of the follicles are gone. You can do an ovarian biopsy and take out a little part of the ovary and not find any follicles in that, but all you can conclude is there’s no follicles in that biopsy. There may have been a follicle one millimeter from where you took that biopsy. The only way you can prove there’s no follicles in the ovary is to take out both ovaries, slice them all up, study every section, and say, yeah, there are no follicles in the ovary. So, it looks like there’s some women that have follicles...the other thing is, we can do a blood test today - oh, you’re estrogen’s only ten. We do an ultrasound - oh, there’s no follicles. All that means is there’s no follicle working today. Remember this thing’s set up so maybe next month there would be one working. It’s just that they’re not there coming up regular, working all the time, as usual. So that’s how the research effort with Premature Ovarian Failure works, and that’s where we are right now. We still do have the protocol for auto-immunity. We’ve just changed it around a little bit. We’re trying to get an international collaboration going to try to salvage these lonely follicles, that are getting luteinized, because theoretically, what we really need is an LH antagonist. That’d be a medication that would prevent LH from acting on the follicle. So that would allow it to grow up normally under FSH, then we could give a whole lot of LH and override this antagonist and allow ovulation to occur. But we don’t have an LH antagonist, so another possible method to salvage these lonely follicles is to suppress both FSH and LH with a medication, like Lupron type of thing, and then give pure follicle stimulating hormone, injections to stimulate follicle growth, with the LH being low, because you’ve suppressed both of them, and then when a follicle gets to be mature, give an LH-like shot that would cause ovulation to take place. But that’s a hypothesis and we don’t know whether that is going to work or not. It needs to be proven in a prospective study. I wouldn’t recommend that you go talk to your doctors to try to get them to try something that’s not in a controlled study, that isn’t proven effective. And this is a difficult thing to get across because this is a frustrating problem to you. It’s a frustrating problem to your doctors, and they would like to try to do things to help. The problem is, unless we have evidence that we’re helping, we may actually be causing harm, and you can’t really tell that for sure until you have a controlled study, using drug and placebo. We always tend to think...we’re optimists, most of us, and we think, if we’re going to try something to improve fertility and get the ovary working, it must be better than doing nothing, but that’s not always true. We know the body heals itself sometimes. We know, sometimes, for reasons that we don’t fully understand, the ovary can work and ovulate and people get pregnant. We had one lady show up in our clinical center for her baseline evaluation and she was four months pregnant and didn’t know it. She had been told that she’d never ever going to be able to get pregnant, so she was actually on some medications that she shouldn’t have been on if she was pregnant. Everything turned out okay in the long run, but she had a pregnancy, just came up on her own. Her body healed itself. She got pregnant. Now if she would have gone to talk to her doctor the month before, and the doctor would have said, "Well, we don’t really know the best thing to do, but we can try this. We’ll shut down this. We’ll give you that. We’ll see what happens." It might have erased that pregnancy. That might have never happened. She wouldn’t have that baby, and she would have paid a whole lot of money and gone through a whole lot of emotional distress and had nothing to show for it. That’s a tough pill to swallow, but my advice is, unless we have evidence that we’re helping, just do the best you can with what we have that we know helps other aspects of this problem, and get on with your life, with the other ways to deal with the problem with fertility, that we’re going to hear about from our next speaker, but don’t put a lot of time and energy and emotional effort into treatments that aren’t proven safe and effective by randomized controlled studies. You’ll be better putting your efforts towards other things.

New Book: Premature Menopause