David Redwine, MD
Thank you for that introduction Tamer. It is an honor to be here, thanks for having me. I am proud to call myself an endometriosis surgeon. There have been so few of them over the years that it has been lonely. There are going to be more as time goes by.
You are probably wondering why we are here talking about asteroids and astronomy. I have been interested in astronomy ever since I could see the sky and many of the problems that astronomers have are kind of the same problems that we have in medicine as we focus more deeply and more deeply into the innards of whatever disease we are looking at. What starts out as just a myriad of possibilities you have to piece out and look in a little microscopic way to see what each part is and then fit them together.
I have a few disclosures to make. I am not a reproductive endocrinologist. I have no higher special training in endometriosis. I have no higher special training in surgery for endometriosis. I have not completed a fellowship. I am not affiliated with any industry. I work 110 miles away from the nearest interstate highway. I am not affiliated with a medical school, although I did attend medical school.
This is the cosmic microwave background. This is what happened shortly after the Big Bang, 14 and a half billion years ago. As you look through higher and higher powered telescopes you can see the most distant galaxies 12 and a half billion years old as they were forming. Nearby galaxies still hundreds of millions of light years away, and then we get into our own milky way where you have clouds of gas and stellar objects and star-forming regions of nebulae. How do you make sense of it all? Well, the ancients tried to make sense of the heavens by arranging everything into constellations, the constellations that we all know and some that we do not know. This problem of mapping the heavens is kind of particularly pertinent with respect to endometriosis when you try to map where an asteroid is. If you look in the middle of this picture you will see an asteroid moving back and forth. Can you see it? The way you map an asteroid kind of clicked in my mind many years ago as a way of possibly mapping endometriosis in the pelvis. Not using stars but using the pelvic surfaces as the road map to figure out where endometriosis occurs. The discovery of the planet Pluto was done the same way. The position on January 23, 1930 was compared with the position on January 29th and Pluto had moved that much whereas the stars in the background had not moved at all. That change in the state of one geographic area in one time zone to another state in a different time is the essence of mapping the stars and also mapping where endometriosis is in the pelvis and how it behaves. One of the reasons I started pelvic mapping is because I wanted to check out to see whether Sampson’s Theory was correct. The reason I got into endometriosis is that my first wife had the disease and I became very pissed off with how poorly it was understood, and that was 30 some odd years ago. So I wanted to figure out if one of Sampson’s Theory’s basic tenets, the dandelion spread of endometriosis, with the cells coming out of the end of the fallopian tubes each month and spreading like dandelions throughout the pelvis – I wanted to find out if that was true and there was no tool that I could use so I had to develop pelvic mapping. But instead of dividing the pelvis into a grid of squares basically I wanted just to divide it into anatomic regions because the pelvis is not a grid of squares. This became my first form of pelvic mapping. It was taken onto accounting spreadsheets with pencil and paper. Now I have digitized pelvic mapping on almost 3,000 patients with endometriosis that I have operated on. These just represent 15 to16 pelvic areas, there are four or five intestinal areas. If somebody has endometriosis in one of those areas they get a tick mark on the computer, if they have two areas, they get two tick marks, and so on. And I wanted to find out if older age groups had more endometriosis because just like dandelions seeding a pasture, the more time that has passed the more dandelions there are. So reflux menstruation predicts that as times passes the older age groups will have more and more disease. And they will have more severe disease, it is like any other thing that spreads geographically in the body, whether it is facial wrinkles, coronary artery disease, obesity, older individuals exposed to this over time have more of it and more severe of it. This is what you should see but this is what I found looking at the five areas of the pelvis that are most commonly involved. Older age groups did not have more frequent involvement than younger age groups. So I said, “Wow! That’s weird”. Sampson’s Theory predicts just the opposite. Well, I felt kind of lonely when that evidence came out, now over 20 years ago because it was so consternating to people. But a friend of mine Philippe Koenigs also did a similar study where he mapped the surface area of pelvic involvement by age groups and he found that lo and behold older age groups do not have more surface area of involvement by endometriosis. When you look at the AFS classifications system, older age groups do not have higher classifications by the AFS system, so it was like, “Okay, I’m looking for evidence to believe in Sampson’s Theory. Older age groups are supposed to have more of the disease but they do not, what is going on”? It came to pass that endometriosis revealed itself to be positionally static. It does not spread like dandelions it follows patterns in the pelvis. Why does this happen? Well normal endometrium is supposed to reflux out the end of the fallopian tube if you believe Sampson’s Theory, where it first adheres to the peritoneal surfaces and then it proliferates and invades and then you have the autotransplant disease that we call endometriosis. And because this is supposed to occur each month, it is supposed to be a recurrent disease therefore you need to treat it with hormonal therapy to stop this. This occurs by the billions because when you think about all the women that have had endometriosis over time, all the menstrual flows they have had during their life, all the tens of thousands if not millions of menstrual cells from the lining of the uterus were refluxed out, you would – this is something that is extremely common. Our textbooks should be filled with photomicrographs of reflux cells attaching and all that.
Let us consider some things about reflux menstruation. One of the things it predicts is that endometriosis is an autograft which just means that it is identical to the tissue that it came from. If you take your ear and transplant it to your forehead it does not work as an ear but it looks like an ear. Various things have been transplanted around the body. If you amputate your thumb, if you got a big toe and put it on here, it looks like a big toe but it is used as a thumb, so autografts remain identical or very similar to the tissue of origin. They remain identical with respect to structure, function, morphology, histology, biochemistry and genetics. It works for every other tissue that is transplanted therapeutically or pathologically and for years we have been told that endometriosis is identical to the endometrium. In fact, I have been able to find several similarities of endometriosis to endometrium, but the similarities are actually very rare, and when a similarity occurs, when a paper or somebody finds a similarity between endometriosis and endometrium that identical nature is a reportable case because it is so rare. There use to be dozens, now there are hundreds of differences that have been described between endometriosis and endometrium. It is not an autotransplant, it is not an autograft, and it is completely different from the endometrium lining the uterus. This process, which occurs by the billions, reflux menstruation, cells raining down like pine cones onto the forest floor, what about the evidence that that occurs? Those of you who are physicians thinking back to your medical school days basically you did not ever see that picture, did you? I never did. Well, somebody asked earlier this morning about microscopic endometriosis and I have written two papers on that, the microscopic endometriosis literature basically we were looking for normal peritoneum that would have the earliest sign of early endometriosis, whether it was attachment or whether it was proliferation and invasion. Here is the evidence from the microscopic endometriosis studies, all of them, not just my two. This is the evidence for that initial step of adherence to the peritoneal surface. Nobody found initial adherence. You could say, “Well, you know Redwine, when you have taken that tissue out and you are prepping it you know the cells are really attached and they are attached by the billions, but see all that tissue preparation washes all the cells off and that is why you do not get any evidence for initial attachment”. Okay fine, well the cells have got to proliferate and invade, you cannot wash that away. There should be billions of instances of that. Secondary invasion was not found either. It is like, hmmm, this is behaving very unlike the disease that we were taught. Okay, what about recurrence after excision of endometriosis? You are going to leave a big, broad area there that is raw, here comes more cells out the next month and it just reseeds, so even if you do reduce the disease burden to zero, over time you should see an incidence of recurrence that increases until everybody, 100 percent of those patients, have endometriosis and that is what we are taught that endometriosis is incurable.
Well, that is what we should see and here is what we do see. These are quarters after surgery and at about four to five years after surgery the risk of finding new endometriosis in the pelvis is about 19 percent. It is not like it goes up and this is the disease that is supposed to be incurable, that 100 percent of people are going to get it back. What is wrong? Is our interpretation of the disease wrong, or what? Well, let us talk about cure. You are not supposed to mention the word cure in the same sentence with endometriosis. But, if this is a positionally static disease, and if it seems to behave kind of differently than we thought, well maybe we can cure it with surgery, and of course, you all know, that we can. There have been many studies on that, each study having from dozens to hundreds of patients. These are not small studies, follow up is out to 8, 10, 11 years. These are not short-term studies like medical therapy studies but I will just review them. Sixty-six percent were cured by laparotomy excision, 57 percent cured by laparoscopy incision. The way cure was diagnosed was that these women had reoperation at some time in the future for whatever reason. They had had excision, they are being re-operated, they either have endometriosis or they do not. It is a binary type of system, very simple to understand. Fifty-seven percent were cured by laparoscopy incision. None of these studies used any post-op medical therapy routinely. If they needed contraception for birth control – great, take that. Fifty-six percent cured by laparoscopy excision, 60 percent cured by laparoscopy excision. You are seeing a trend here, these cure rates are in a very narrow zone between 56 and 66 percent. These cure rates come from all hemispheres of the earth and from two different millennia. These cure rates come from different institutions and different surgeons but they are all doing the same thing, they are all doing aggressive excision of endometriosis. In a sense we have a, it was not planned that way, we have a multi-center prospective type of study that confirms that you can cure over half the patients with one surgery. Most of the patients in this study had previous therapies, medical therapies, and surgical therapies. They had what would be classified as really resistant endometriosis. They still have disease after all these treatments, cure rates of 60 percent say on average. I just reviewed a paper for Fertility and Sterility that is going to be documenting a 100 percent cure rate in teenagers undergoing excision of endometriosis with no post-op medical therapy. One quick take home from this that right now, with all the promise there is on the horizon for this or that medical therapy or gene therapy, excision is the best treatment that we have for our patients. We have known about the cure for endometriosis of course by surgery for many years. You all are aware that ever since the 1950s people were saying, “Yes, recurrence is not frequent and cure by conservative surgery is usual”. It is a long-term theme, I am sure everybody is familiar with the concept of the cure of endometriosis by excision because it has been repeated for almost 60 years now.
Can reflux menstruation explain the origin of any type of endometriosis? No, of course not, it requires a miracle. Attachment of the cells occurs only in the dark. You see here that step one is attachment, step two proliferation and invasion, but like I said, there are no pictures of this, there are no photomicrographs. Where is the evidence? When you consider that surgery requires light, whether laparoscopic light or laparotomy light, I conclude that attachment of endometriosis must occur only in the dark because when you shine light in there the cells are photophobic and they run away. I am trying to support Sampson’s Theory here I would appreciate a little respect. But okay, maybe attachment does not occur in the dark, but I do have one of the finest cartoons to display the origin of endometriosis, because that is all we have, cartoons. And I am presenting here to you for the first time concrete evidence of the mode of attachment in step one, okay? I am going to show you the evidence for that. I am going to make a few adjustments here and try to slow that down…a little slower. Ah yes, this, I am sorry this is as good a proof of Sampson’s Theory as anything in the literature. Can I say it is ridiculous? Reflux menstruation, it has been a theory that has been around too long. It is a dangerous theory. It is very dangerous for this reason, it becomes an excuse for ineffective therapy because if you shine the light at endometriosis, if you spray the electrons at endometriosis, if you poison it with Lupron or birth control pills, and if you say it is gone but oh man your disease comes back, see it comes out the end of the fallopian tubes. Sampson’s Theory predicts failure and recurrence, 100 percent recurrence and ineffective therapy provides that failure. It is like a symbiotic relationship, if you get rid of one or the other then they both go away.
What is the origin of endometriosis? The answer lies with HOX genes. HOX is short for homeobox. They are highly conserved, we have the same HOX genes in us that dogs do and cats and many of the same HOX genes as snails and a few of the HOX genes the same as sponges. There are four HOX clusters, A, B, C and D. They control embryonic development in patterns. The human female tract is primarily formed by HOX 9, 10, 11 and 13. HOX genes are not only important in embryonic development but they stay in the areas of the body where they were laid down and that is important for conserving the regeneration of the body in that area. It is also important for the origin of scar in the endometriosis because the HOX genes are still in the area of the abdominal wall. And this is just a scheme showing – here are the adult HOX genes, and you can see the similarities down through the species, identical genes. Man is a simple animal. We want to take the easy way out. God says that man was created in his image that means that God wants the easy way out. HOX genes are the easy way out because you have this pattern that you do not have to do much to. It is tweaked a little bit by downstream genes and other processing genes but you see the same bone pattern in the fore limbs and hind limbs of mammals, etc. That is kind of the nature of what HOX genes do. The female genital system the perimysium_____ duct is composed from these HOX genes 9, 10, 11 and 13. In the adult female you see the corresponding areas of the female reproductive organ. Schematically HOXA 9 is responsible for formation of the fallopian tube, HOX 10 and 11 the uterus, HOX 11 the cervix, HOX 12 the sigmoid and HOX 13 the rectum and the vagina. We are starting to see patterns here and the same kind of patterns in the intestinal tract with a large concentration of HOX 12 genes down at the bottom. When you take the distribution of intestinal endometriosis and put it on the map of HOX genes I am not sure what it tells you but it gives it a pretty picture. Endometriosis is caused by a problem with HHOX genes, which results in abnormal differentiation and migration of cells during embryonic formation of the female reproductive tract. If that is the case, if it is embryonic should we be able to find it before puberty? Well, yes. Here is an area of glands with some surrounding stroma from the cul-de-sac of an infant with endometriosis that I published back in 1988. One out of nine of the infants that I got samples from, or 11 percent, had this finding, which is not far off from the 10 percent that is commonly quoted as the prevalence of endometriosis. Then endometriosis was found, or evidence suggestive of endometriosis, was found in four out of 36 aborted female infants in an Italian study. Also 11 percent, also very close to 10 percent quoted as the prevalence in the population. If things were off by a lot, 90 percent, five percent, it would be a little suspicious but when something is real things come together in a very similar story.
Here is what happens in the embryo as times goes by, HOX 9 operates first to form the fallopian tube analogue, 10 and 11 the lower segment and the cervix, 13 the vagina and the rectum. That is how the HOX genes are actually activated by the replication of the DNA. It is ordered numerically. If you go here and look at the days of embryonic life, looking at this genital ridge it is called, at 33 days the cells that were deposited on the surface begin to invade. There is epithelial in-growth in the genital ridge and the same epithelial in-growth at 37 days and more epithelial in-growth at 41 days. All the cells that are deposited on the coelomic epithelium begin to invade the genital ridge. This is a genital ridge that is going to form the pelvic organs. What you have is a genetic gradient set up. It is strongest on the peritoneal surface - party’s started, CY’s here. The gradient is strongest on the peritoneal surface but it is less strong deeper down except that when you have got HOX like 11 and 13 that are responsible for rectovaginal endometriosis you get deeper penetration in some areas. It is not a perfect gradient, it is somewhat hobnob and there can be other genes that are in that genital ridge, downstream genes that may modify the action of HOX genes, things like KRAS and p10. KRAS was implicated in mouse endometriosis that was induced by a metaplasia. These HOX genes are powerful, they can be called up normally by reproduction, you can call them up with chemicals and such but endometriosis is due to these susceptible field gradients or rests. That is where the endometriosis is going to occur. You may have a little bit of a different distribution than your next door neighbour but this I think is a much better model of origin of endometriosis. The location of the HOX genes 12 and 17, the HOX genes that form the female pelvis are on chromosome seven. This is kind of what it looks like when you look at the human genome online. Those are the HOX genes, there they are and just more evidence that chromosome seven is important in HOX genes and the female tract.
I think people have been saying here earlier all day that well endometriosis may be too narrow a word because you have got this and you have got that, you have got IBS symptoms, irritable bladder symptoms so we may need a broader view, something that is more inclusive than just the term endometriosis and mulleriosis is one such candidate term because the müllerian ducts are what form the female organs during embryonic life. The term mulleriosis is so overarching it predicts embryologically patterned pathology of the female pelvic organs, including things like adenomyosis and endosalpingiosis. It is more inclusive of genetic problems, associated things like immune disorders in the minority of women with endometriosis who have them and so on. It embraces a lot of things rather than just a narrow focus on endometriosis and of course mulleriosis was predicted on the basis of pelvic mapping a quarter of a century ago. That is my little term that is my baby.
What we are finally seeing is convergence. That is where different authors are arriving at the same conclusion from different directions and that relates to the embryonic origin of endometriosis. I had a publication in 1988, people thought well, that is a little out there. When you live in the sticks that is what happens. Serdar, he came to the same conclusion in a 2009 publication, and then several other authors recently have come to the realization that endometriosis is not due to Sampson’s Theory that has proven scientifically to be a dead end. The answer lies with the embryo.
The opposite of convergence is divergence, and this is what we are seeing with attempts to continue to support Sampson’s Theory. Different author’s explanations highlight increasingly large and unreconciled differences. I have been saying for 25 years I just want to see a picture of initial attachment. It is occurring by the billions show me a picture. Nobody will give me that picture. There are only two reasons they are not showing me that picture; they either have the picture and are suppressing the evidence, or the picture does not exist.
So reflux menstruation as the etiology of endometriosis has serious problems that it is supported entirely by fantasy and more recently by fabricated evidence. If you want details on that ask me later I will not publicly embarrass people. Continued support for Sampson’s Theory is a threat to science because it is clearly invalid and it is also a big threat to women with endometriosis because much of our modern therapy is based on a decrepit theory that is not operative.
So, what is in the future? More mapping, surgical mapping, chromosomal mapping of HOX and other genes, we need maps to know where to go, whether it is a chromosomal map going deeper, deeper into the chromosomes. Here is the DNA structure and what lies in there? If you go deeper the possibilities are endless of what you might find. The, as you get deeper and deeper what you will find is where we began. The stars and the pelvic maps and the diagrams, they are all related because everything has an inner-connection we just need to find it.
Thank you very much.