Leslie Farland, MSc, ScD
Endometriosis: A high-risk population for major chronic diseases?
Patient Awareness Day
The Lifecycle of Endometriosis: From Diagnosis to Coping with Disease
Sunday April 17, 2016
Lenox Hill Hospital, Einhorn Auditorium
Thank you; I am honored to be here today to speak at the Endometriosis Foundation of America. As was said I am an epidemiologist at the Harvard School of Public Health. I work closely with Dr. Stacey Missmer who is also an epidemiologist at Harvard.
Today I am going to be talking about the relationship between endometriosis and chronic disease risk. I am going to be focusing my talk on cancer, cardiovascular disease and autoimmune conditions because these are the conditions we know the most about.
As epidemiologists we study relationships on the population level. Today I am going to be presenting the body of literature that we know to be existent. I wanted to start off by thinking about why it is important to study these comorbidities. The relationships between endometriosis and chronic disease risk can help us to inform public health interventions as well as screening practice. But from a research perspective understanding these relationships can strengthen our understanding of the underlying diseases. As many of you know we do not necessarily know what causes endometriosis and so understanding how endometriosis may relate to other diseases may help us target future treatments for both endometriosis and those chronic diseases.
How could endometriosis be related to chronic disease risk. We have heard of some potential mechanisms earlier today and I wanted to walk though some potential mechanisms as well. Endometriosis lesions could induce change in the body, either locally or systemically, which could alter a woman’s risk for chronic diseases. There could be shared genetics overlapping pathology between the two conditions, which make women at increased risk both for endometriosis and a specific chronic disease. And there could be shared risk factors for the two conditions. For example, we know that timing of first menstrual period is important for endometriosis risk and it is also important for some of the cancers that I am going to be talking about later today. It could be that the shared risk factor increases your risk for both endometriosis and some of the chronic diseases.
I also wanted to point out some of the things that were mentioned earlier. We know that endometriosis is an estrogen dependent condition. We have also heard a lot about inflammation and we know that women with endometriosis have an increased inflammatory state, both locally in the peritoneal fluid as well as systemically in the peripheral blood. Thinking about these mechanisms may help us understand the relationships between endometriosis and these chronic diseases.
I also wanted to highlight that the mechanism is different for each of the chronic diseases I am going to be talking about today. I am not going to go into too much detail for each disease but I am happy to discuss those more in detail later on.
The last thing I wanted to point out before we dive into these studies is that research is really challenging. It is challenging for reasons that many of you may be able to point out. Many of you may have experienced that endometriosis can be very difficult to diagnose. We heard a lot about that this morning. Globally we see around approximately a seven year diagnostic delay between symptom onset and disease diagnosis. From a research perspective that delay can influence who we are considering endometriosis cases and who we are not considering those cases. There is also important variability in endometriosis lesions. Earlier we heard about the different colors of endometriosis lesions, the staging, the locations of those lesions and the size of those lesions. You can imagine that those differences in endometriosis lesion may influence chronic disease risk. Very few studies aside from the ovarian cancer research have investigated differences in the size and location of endometriosis lesions in relation to chronic diseases.
Thinking about the diseases that I am going to be talking about today, many of the diseases are rare overall in the population so that means we have to have lots of women in our population to study these conditions. Additionally, many of these diseases occur later in adult life so we need long disease follow up from the time of the endometriosis diagnosis to the later chronic disease. And temporality of the relationship is important, so understanding which disease came first, endometriosis or the chronic diseases we are talking about. Study designs that fail to take into account these complexities may provide us with the wrong answer.
For my talk on cancer I am going to be focusing on ovarian, endometrial, breast and melanoma. These are the cancers that we know are most about at present. Here I am showing you a figure summarizing the relationship between endometriosis and ovarian cancer risk. The dots on the figure represent the size of the effect estimates. Dots to the right of the line indicate an increased risk among patients with endometriosis and dots to the left of the line indicate a decreased risk. The lines that are coming out of those dots represent our uncertainty in the estimates. If you see the two effect estimates which stick out the very last one on the bottom and there is a lot of uncertainty in those effect estimates most likely due to very small sample sizes. And that with the very small lines like the second from the bottom you can barely see the lines coming out those indicate studies of which we have a great deal of certainty in the size of those effect estimates. Overall, we see that the majority of studies indicate a modest increase risk for women with endometriosis for ovarian cancer.
Pooled data from the Okac study has found that this elevated risk was mostly associated with endometrioid and clear cell sub-types of ovarian cancer. I wanted to share with you some preliminary research from colleagues at Harvard that have found that women with endometriosis may have a lower ovarian cancer mortality among those who get the disease. I also really wanted to emphasize the absolute risk for ovarian cancer is very low in the general population. Let us pretend that each cell in this box is a woman. We have a hundred cells. The absolute risk for ovarian cancer in the general population is one in one hundred.
Now we know that women with endometriosis are at increased risk but again the absolute risk is very low, even for women with endometriosis. It is two in one hundred women.
There have been nine studies investigating the relationship between endometriosis and endometrial cancer. The body of the literature seems to indicate that endometriosis is not associated with endometrial cancer. Those studies that suggest an increased association tend to find the increase occurring when endometriosis and endometrial cancer are diagnosed at the same time. From a research perspective that seems to indicate to us that the endometriosis is not necessarily causing the endometrial cancer.
I wanted to talk briefly about the study that I work closely with because I am going to be using examples from this population. My research comes from the Nurses Health Study II, which is a prospective cohort which began in 1989 when nearly 120,000 women returned mailed questionnaires. Those women have been followed every two years subsequently to collect detailed information on a variety of exposures, outcomes and co-variate statuses over time, which allows us to prospectively investigate the relationship between endometriosis and chronic disease risk. Many of the limitations that I outlined for why this kind of research is challenging were able to be overcome in the study design of the Nurses Health Study II.
Here is data from our research group showing the relationship between endometriosis and ovarian as well as endometriosis and endometrial cancer. To orient you to the figure again the dots represent the effect estimate size and dots above the line indicate an increased risk. Here we see that similar to the body of research I showed you previously endometriosis was associated with a modest increased risk of ovarian cancer and no increased risk of endometrial cancer. These findings were consistent across the different methodologies that we used to classify endometriosis, which I think is important because that can lead to variability in our effect estimates.
Many studies have investigated the relationship between endometriosis and breast cancer with some of the earlier work indicating a potential increased risk. But remember those wide lines indicated a great deal of variability or uncertainty in the effect estimates. More recent work seems to indicate there has been no increased risk for breast cancer.
Here is data again from the Nurses Health Study II. We have over 20 years of follow up looking at breast cancer risk and we saw no increased risk of breast cancer among women of endometriosis. Here I am showing you three different models. I am showing you this because I wanted to highlight that since we were able to take into account those shared risk factors which can drive associations, as well as some of the treatments which can drive associations, when we were able to take those into account we still saw no increased risk.
Next I wanted to show you the relationships between endometriosis and melanoma. There have been 12 studies investigating this topic with six of them suggesting an increased risk. This is data from the E3N cohort, which is a cohort of teachers in Paris that I have been collaborating with colleagues at the University of Paris. These teachers have been followed for over 20 years since 1990. This is the largest study to investigate endometriosis and skin cancer risk. With over 20 years of follow up we do see an increased risk in melanoma but we see no increased risk of non-melanoma skin cancers. That is interesting from a research perspective to try and tease out the underlying etiology or connection between these two conditions, which is something we have been working on.
I wanted to highlight that the European Society of Human Reproduction as well as the World Endometriosis Society did not call for modified screening of women with endometriosis. But I also want to reinforce that all women should feel empowered and should be vigilant if anything changes in their bodies. They should feel comfortable to seek medical help if they have suggestive symptoms.
I briefly wanted to outline what those symptoms are; it is kind of a nice public health message. All women should be receiving regular pelvic exams. They should be looking out for abdominal swelling, pelvic pressure or pain, difficulty eating or pain while urinating. While the mammography guidelines vary depending on what your age is all women between the ages of 45 to 54 should receive a mammogram yearly. And everyone should remember the ABCD and Es of skin cancer screening and check themselves and their loved ones regularly.
Next I wanted to talk about endometriosis and cardiovascular disease, or diseases of the heart and blood. I am going to present research today from our cohort investigating the relationship between endometriosis and some of the big cardiovascular disease endpoints. This was recently published in Circulation. We found that women with endometriosis were at increased risk of heart attack, chest pain as well as interventions that are associated with cardiovascular disease including getting a stent. This finding was strongest among younger aged women and here I am showing you a figure showing the incidence, so new cases of cardiovascular disease per 100,000 women.
To orient you to what that number means my husband tells me that the New York Yankees stadium holds around 50,000 women so think of 100,000 women as the size of two New York Yankees stadiums. That number of incident cardiovascular disease cases is the Y axis and the X axis is age across time. Women with endometriosis represent the red line and women without endometriosis represent the blue line. Here we see that among younger age women those with endometriosis are more likely to have cardiovascular disease events. But again I want to emphasize that the absolute risk of these conditions is relatively low.
At older ages where we are most concerned about cardiovascular disease events we see no difference in the relationship between those with endometriosis and those without endometriosis. I also wanted to emphasize that of all the diseases I am talking about today we know the most about cardiovascular disease and how to prevent it.
I wanted to remind us that all women should take measures to reduce their cardiovascular disease risk by focusing on a healthy diet including fiber, lean protein, vegetables and fruit, quitting or never starting smoking, exercising for the recommended amount of 30 minutes per day and having routine medical exams where your blood pressure and cholesterol are checked.
I also wanted to take this opportunity to briefly mention that the heart attack symptoms for women are different than the ones we often think about and see on TV for men. Women can experience pain, pressure and fullness of chest. But women are also more likely than men to experience pain in the upper back, neck or jaw, indigestion or nausea and shortness of breath without chest discomfort.
The last disease that I wanted to briefly touch on today was endometriosis and autoimmune conditions. Autoimmune conditions occur when the body’s immune system targets the body’s own cells as opposed to targeting invader cells. There are more than 80 different types of autoimmune disorders. But the research on this topic has been very limited. There have been very few studies because these relationships can be very difficult to study.
Similar to endometriosis, getting a diagnosis for an autoimmune condition can take a very long time and can be very difficult to classify. I am listing here some of the autoimmune conditions that have been associated with endometriosis. But I wanted to reinforce again that the research is very limited. I also wanted to share with you studies again from the cohort of the Nurses Health Study II. Here we saw a modest increased risk for both Lupus and Rheumatoid Arthritis. These findings need to be supported by more research.
To briefly wrap up my topic I wanted to instill in you that you know your body best and you should feel empowered. If you feel like something is wrong just say something to your medical care provider. I also wanted to take this opportunity to encourage you and your loved ones and your friends and your family to participate in medical research, whether it is about endometriosis or it is about another chronic disease which you are asked to be involved in.
Lastly, I wanted to encourage all of you to reach out to your representatives and support national research funding efforts for endometriosis and these chronic disease risks.
I briefly wanted to again thank the Endometriosis Foundation of America. I wanted to thank the participants in the Nurses Health Study II who have been returning those questionnaires every two years for over 20 years, our funding sources and our collaborators who made this work possible. Thank you.