The immune system and infertility in women with endometriosis
The immune system and infertility in women with endometriosis
Hugo Verhoeven, MD: “Good afternoon, my name is Hugo Verhoeven from the Centre for Reproductive Medicine in Düsseldorf, Germany, and I’m reporting from the 12th annual meeting of the ISGE, the International Society of Gynaecologic Endoscopy, in Cancun, Mexico in April of 2003. It is a great honour for me to talk this morning with Paul Dmowski, MD, PhD, who is one of the leaders in the research, diagnosis, and treatment of endometriosis. I have known Dr. Dmowski since I was a student, at least for 25 years.
What always fascinates me is that we still do not understand exactly why endometriosis is a reason for female infertility. During your academic career, which spans more than three decades, you have held many prestigious positions at various universities and are currently Professor of Obstetrics and Gynaecology at Rush Medical College in Chicago. In 1990, you established one of the first private, entirely office-based IVF programs in the USA, the Oak Brook Fertility Center in Illinois, where you are the Medical Director.”
Paul Dmowski, MD: “Yes, we have also had the Institute for the Study and Treatment of Endometriosis for the last ten years. The Institute is a not-for-profit, independent organisation dedicated to the study of those questions, which you just mentioned. That is, what is the relationship between endometriosis and infertility, what is the pathogenesis of endometriosis, and what treatments can be performed that are more effective than those available in the past? These questions and more are being studied and, hopefully, some new information and treatments will become available. And also, perhaps a better understanding of the disease itself.”
Hugo Verhoeven, MD: “So, for our listeners, there are different forms, different sorts of endometriosis. What many people and also myself cannot understand immediately is why should a very small implant of endometriosis be the reason for infertility? Do you know the answer to this?”
Paul Dmowski, MD: “Well, maybe researchers like myself do not know all of the answers, but I think we do know some of the answers and if researchers look at endometriosis not necessarily as a disease of the female pelvis, but as a systemic disease, a disease that is associated with changes at the molecular level, I think our understanding of the interaction between endometriosis and fertility would be much more clear. Specifically, research has shown that with endometriosis, there are changes in the immune system - changes both in humoral and cell-mediated immunity.”
Hugo Verhoeven, MD: “Please explain this in more detail so the average patient can understand. What is the difference?”
Paul Dmowski, MD: “Well, our immune system responds in two different ways to the antigens that activate the immune system. One way is the humoral response and the other is cell-mediated response. Humoral response is mediated by antibodies directed against antigens. The cell-mediated response is directed by the cells of the immune system. Both responses work together in synchrony.
As far as changes in humoral immunity in women with endometriosis, our Institute, as well as other investigators, demonstrated the presence of multiple antibodies directed against different auto-antigens in women with endometriosis. Specifically, women with endometriosis have antibodies against their own endometrial tissues. They have anti-phospholipid antibodies and a high prevalence of anti-tissue and anti-organ antibodies, such as antibodies against the thyroid, basal membranes, epithelial cells, and so forth.
What is interesting is that not all women with endometriosis, only about 50 to 60%, have those autoimmune phenomena, which are abnormal auto-antibodies. However, because of the activation in the development of multiple auto-antibodies, this suggests what is called polyclonal activation of B-cells. B-cells are the cells that produce antibodies and polyclonal activation of B-cells is one of the characteristics of autoimmune diseases. This is why some investigators consider that endometriosis may be a form of an autoimmune disease.
Our Institute has been concentrating more on the changes in cell-mediated immunity. We have seen changes in cytotoxic T lymphocytes and in monocyte macrophages. Groups from Belgium, Oosterlink, and other sites have reported changes in natural killer cells.
All of these changes are characterized by a decrease in the recognition of the endometrial cells in a patient and by decreased destruction of these cells by the cells of the immune system. So according to this concept which we proposed several years ago, endometrial cells in all women are not only expelled outside during the menstrual period but are also disseminated into different parts of a woman’s body.
Some of these cells can be transported through the fallopian tubes while others can be transported through vascular channels but all end up outside of the normal physiological location, which means outside of the uterus. When endometrial cells in ectopic locations are faced with the immune cells, such as monocyte/macrophages or the natural killer cells, they are destroyed and do not implant. Therefore, in the majority of women, who are those without endometriosis, there is no implantation. In other words, there is no survival of endometriotic cells in ectopic locations and, therefore, endometriosis does not develop. But in a small percentage of women, around 10 to 15%, because of the decrease in the cytotoxic effect of the immune cells, endometrial cells are not destroyed and those endometrial cells that escape to ectopic locations are allowed to implant and develop into endometriotic lesions.
Once a microscopic endometriotic lesion develops, it stimulates the immune system. So endometriotic implants stimulate the development of auto-antibodies in about 50% to 60% of women with endometriosis. Those women who develop auto-antibodies probably have a milder disease because auto-antibodies prevent progression of the endometriosis. However, because of the auto-antibodies, and here I am answering one of your first questions, because of these auto antibodies, we see interference with fertility and changes in the uterine endometrium which can result in decreased implantation of the embryo and perhaps increased frequency of miscarriages.
Again, that happens only in a certain percentage of women. The remaining 50% of women do not develop auto-antibodies. Faced by antigens, we respond differently depending on our immune response. Some women produce antibodies very readily, some do not. In those women who do not produce antibodies against the endometriotic implants, endometriosis is progressing more rapidly; larger cysts tend to develop along with more extensive disease, but at the same time, their fertility may be less impaired than the fertility in women who do have auto-antibodies.
So auto-antibodies are one of the factors - but only one of the factors. Because of the activation of the immune system in endometriosis, research data shows a variety of factors that are produced not only locally in the peritoneal cavity of women with endometriosis but also systemically. We have shown that circulating blood cells (monocytes) in women with endometriosis produce much higher levels of Interleukin 6, 8, and 10, but most importantly - much higher levels of TNF-alpha. And TNF-alpha, we believe, is a crucial factor, which on one hand, plays a role in the pathogenesis of endometriosis and on the other hand, also interferes with fertility.
So coming back to your question, what is the reason for infertility? It is known that in women with endometriosis, there is an increased amount of peritoneal fluid and in that fluid, there are a variety of substances, including different types of cytokines including TNF-alpha, different types of growth factors, and different types of reactive oxygen species - all of which have an adverse effect on the reproductive system. I did not mention prostaglandins, which are also a very important factor that interferes with the reproductive function. So, concentrations of these substances in the peritoneal fluid, and therefore in the reproductive system, determine the effect on fertility and because the amount of peritoneal fluid and the concentration of these substances varies, infertility is not a consistent symptom of endometriosis.”
Hugo Verhoeven, MD: “So let us talk about the consequences of that point of view for the treatment of endometriosis. What is the significance of surgery on what you say and the traditional medical treatments with progesterone and GnRH analogues? This would be very interesting to us.”
Paul Dmowski, MD: “I have to say that none of the treatments we have had so far aim at the cause of endometriosis.”
Hugo Verhoeven, MD: “That’s what I wanted to hear.”
Paul Dmowski, MD: “Our most recent studies that are dealing with molecular events in endometriosis give us some quite fascinating results. What we find is that on the one hand, the women with endometriosis produce much higher levels of different cytokines but primarily TNF-alpha. So TNF-alpha is increased in circulation, peritoneal fluid, and the reproductive system in general.”
Hugo Verhoeven, MD: “This is a consequence of patients who already have endometriosis?”
Paul Dmowski, MD: “This is a consequence of activation of the immune system. Is the activation of the immune system the primary event or is it the consequence, as you say? We do not have the answer to this question. What we know, however, is very interesting and may tell us what is first and what is second (the chicken or the egg story). When the endometrium of women with endometriosis is examined, it is quite different than the endometrium of women without endometriosis. If I take a biopsy from inside of the uterus from a patient with endometriosis and one from a subject who definitely has no endometriosis and add TNF-alpha (synthetic recombinant TNF-alpha), I get very different results in women without endometriosis, I see suppression of proliferation, increased apoptosis, and increased cell lysis.
If I take the same cells from a patient with endometriosis, the same TNF-alpha will cause increased proliferation, decreased apoptosis, and decreased cell lysis. Our concept is as follows - during the first part of the menstrual cycle, there is proliferation of the endometrial cells. This proliferation is activated by TNF-alpha produced by the monocyte macrophages. TNF-alpha binds to the TNF-alpha receptor and activates sphingomyelinase. Sphingomyelin is then hydrolysed to ceramide. Ceramide is a substance that can on one hand activate the cascade that leads to proliferation but, on the other hand, it can also activate the cascade that leads to apoptosis. So in all women during the first part of the cycle, there is activation of the cascade leading to proliferation so endometrial cells proliferate.
During the second part of the menstrual cycle, the secretory phase, if pregnancy and implantation does not take place, there is a switch of the signal from proliferation to apoptosis. So now cells inside the uterus of healthy women are programmed to die. The apoptosis is increased. So during the menstrual period, if the cells are expelled outside or remain inside the body, it does not matter as they are all programmed to die – there is no implantation, no survival, and there is no endometriosis. In women with endometriosis, there is no change in the TNF-alpha signal, proliferation continues, and the apoptosis is decreased. When these cells are misplaced to ectopic locations, they will survive and result in endometriosis. This, we believe, is one of the primary factors which determines the development of endometriosis. Obviously, once we know the mechanisms which control development of endometriosis, the disease can be treated much more successfully in the future than it has been to date.”
Hugo Verhoeven, MD: “That is the future?”
Paul Dmowski, MD: “That is the future. Clinical studies with TNF-alpha inhibitors are beginning and I believe that in the near future, we will be able to control not only the symptoms of endometriosis, but also the disease itself. Such laboratory experimental studies in baboons have already been done by
Dr. Thomas D'Hooghe. We feel that now is the right time to get involved in studies at the molecular level which can reverse endometriosis and changes of endometriosis that lead to infertility.”
Hugo Verhoeven, MD: “So TNF is tumor necrosis factor?”
Paul Dmowski, MD: “Tumor necrosis factor-alpha, yes.”
Hugo Verhoeven, MD: “So that means that a lot of new therapeutic consequences are on the way?”
Paul Dmowski, MD: “Yes, if we think about the current treatment of endometriosis - surgical removal of endometriotic implants or a resection of endometriomas – these could be compared to the debulking of the cancerous lesions. The same applies to endometriosis. If endometriotic cysts are removed surgically, yes, that helps the patient but it does not change the basic pattern of the progression of the disease. The same applies to medical treatment. Medical treatment lowers estrogens. If estrogens are not present, the endometriosis improves and there is no progression of the disease. But none of the available treatments so far have been able to address the very cause of endometriosis and the cause of infertility associated with endometriosis.”
Hugo Verhoeven, MD: “Well, I think we have a lot of new information on the cause of endometriosis and the consequences for therapy and, well, hopefully for a better pregnancy rate. Paul, thank you very much for talking with us.”
Paul Dmowski, MD: “Thank you very much. I hope this was informative to the audience of this program.”
Hugo Verhoeven, MD: “I’m certain it will be. Thank you very much.”
Paul Dmowski, MD: “Thank you.”
I applaud Dr. Dmowski's scientific approach towards understanding endometriosis. Dr. Verhoeven's interview should be sent to all OB/GYNs. Endo is systemic, not a "pelvic disease"; thinking about endo as pelvic disease only lengthens the time it takes to understand and find the cause of the condition as well as frustrates patients by denying the full spectrum of symptoms. It should not be concluded, however, that TNFalpha is the answer; it is an important factor.
Dr. Arielle Whubbus, USA
After harrowing periods and debilitating pain, I have had a laproscopy and a laparotomy for this wretched disease. I am currently in menopause via Lupron, because I may have more endometriosis in another cavity--which was not caught in my laparotomy just a few months ago. (I have been in chronic pain since December of 2002...even without a period.)
Thank God Dr. Dmowski is looking at the root cause of this disease. Treating symptoms will not cure it. Treating the pain, and not the underlying conditions, will not ease the suffering of other women just like me.
I pray for a cure.
G. Summer Scarbough, USA
I have been to 3 well know RE in the past 7 years. Still no baby and still have severe endometriosis. I have been trying to tell them I have a problem with implantation. They just don't listen. I need a different protocol from everyone else for IVF. I was so happy to find this site and see that there is someone trying to help women like me. Thank you.
Maria Neglia MA, USA