Epidemiology, Pathophysiology, and Diagnosis of Endometriosis

In part 2 of this 2-part episode, Dan Martin, MD, speaks about his team's research titled "The Epidemiology of Endometriosis is Poorly Known as the Pathophysiology and Diagnosis are Unclear," including the gaps in endometriosis research, why those gaps are so problematic, and the key takeaways from their research.

Additional Resource:

• Koninckx PR, Ussia A, Adamyan L, et al. The epidemiology of endometriosis is poorly known as the pathophysiology and diagnosis are unclear. Best Pract Res Clin Obstet Gynaecol. 2021;71:14-26. doi:10.1016/j.bpobgyn.2020.08.005

Dan Martin, MD, is the scientific and medical director of the Endometriosis Foundation of America and a professor emeritus at the University of Tennessee Health Science Center (Memphis, TN). 

Listen to part 1 of this episode here.

TRANSCRIPTION:

Jessica Bard:

Hello, everyone, and welcome to another installment of Podcasts360, your go-to resource for medical news and clinical updates. I'm your moderator, Jessica Bard with Consultant360 Specialty Network. According to the Endometriosis Foundation of America, endometriosis is one of the leading causes in infertility, and on average, there is a seven to 10-year delay in diagnosis. Dr Dan Martin is here to speak with us today about his team's research, "the epidemiology of endometriosis is poorly known as the pathophysiology and diagnosis is unclear." Dr Martin has more than 50 years of experience in the study of endometriosis. He's the Scientific and Medical Director of the Endometriosis Foundation of America and a professor emeritus at the University of Tennessee Health Science Center in Memphis, Tennessee. Thank you for joining us today, Dr. Martin. What are the gaps in the research of endometriosis?

Dr Dan Martin:

Yeah, there are lots of gaps. Due to the many different ways that endometriosis comes in clinically, the many presentations, it takes large studies to do multi-variant analysis to correct for all the confounding factors and the overlapping presentations. That includes long-term focus and funding, just like we have in cancer and diabetic research, and a lot of the research we have in endometriosis is more short-term and related to follow-ups with 6 in 1 and 2 years. We probably need studies with seven and ten or fifteen years of follow-up to get a good idea of what the history is.

It's difficult to study the natural history, because we don't have ways to determine what's going on without doing surgery itself, creates an inflammatory response and a stress response that may affect the natural history. Theoretically, although retrograde menstruation can explain the distribution of pelvic and abdominal endometriosis, it doesn't explain pulmonary or skin endometriosis or endometriosis in men. Venous dissemination and congenital arrest can help explain those, but don't explain a lot of the things that retrograde menstruation explains.

In addition, retrograde menstruation occurs in almost all women. So the normal clearance mechanisms, the immune system, are needed to have problems of control of the tissue that comes from this retrograde menstruation so that we don't get normal clearance and normal immune activity and the endometriosis can grow. That possibility offers a therapeutic target for early treatment that might decrease the growth, morbidity, and the need for surgery.

There are lots of factors that contribute to that, which include the level of the centers doing research. Since most comes from tertiary centers, this may not be relevant in primary care populations. Most of our studies are on adult age patients, so we don't get good data or large scale data on adolescents. As an example, Knox et al. who did an adolescent study published in 2019, had the problem of numbers and not only numbers, but adolescents don't come back for visits or follow the protocols. And they only had a 47% follow-up with the mean of ten years. That low level of follow-up interferes with our ability to understand how accurate the data is going to be.

There are other problems that come in with retrospective data, how many phenotypes we have, even a definition of endometriosis, a simple surgical or pathologic definition of endometrial like lens and stroma is reasonable for clinical understanding, but it's not adequate for research. We have other markers such as fibrosis markers, stromal markers, epithelial markers, keratin markers, inflammatory markers, all sorts of markers that have to do with all the changes that go on with endometriosis. We don't have a standardized definition that uses all of those. And I think the last problem we have with that is that the animal models and our organoid models are limited in their ability to predict human behavior.

Jessica Bard: And why are those gaps so problematic?

Dr Dan Martin: Well, without knowing which specific phenotypes of endometriosis have different biologic behaviors, we don't really know how many types of endometriosis we need to study. We don't know if it's one type of endometriosis with lots of different presentations based on the environment and other factors, or that we really do have multiple different types of endometriosis. We need a better grasp of the specific types of endometriosis that need specific treatment, so that we can customize that treatment. Some of our ability to customize treatment still needs refinement. As an example of refinement, when I was in training, appendicitis was always treated with the surgery, with the saying that, "You never let the sun set on appendix." However, today we know that if we look at early appendicitis, it can be treated with antibiotics and doesn't always require surgery. If we know where a disease is in a natural course, it can be an important in terms of determining how we're going to treat a patient.

Jessica Bard: And what's next for research on this topic?

Dr Dan Martin: Well, I think our next steps are basically a continuation of the same steps we've taken over the past hundred or so years. We need to continue to look at the different facets of endometriosis, including its clinical presentations, its response to medications, its response to complementary and alternative medications and surgery, and what is its natural course without treatment. We've spent a lot of time in the past, looking at surgical aspects and medical aspects of treating endometriosis after we've had a delay of six to ten years before diagnosis. We need to spend more time looking at pain in its early phases. We need to spend more time, I think, getting away from the normalization of pain and how we treat the initial...How do we treat pain when it's initially presented in a moment?

Jessica Bard: Could you summarize the key take-home messages from your research?

Dr Dan Martin: Endometriosis is likely more than one disease, and we need more than one standardized definition and more than one or two standard treatments. Women need early proactive treatment and planning so that they can potentially limit the growth of endometriosis and avoid surgery.

Jessica Bard: Is there anything else that you'd like to add today, Dr. Martin?

Dr Dan Martin: Perhaps clinically, there are things that are more important than the epidemiology. This paper did not discuss the normalization of patients by pain. This did not discuss the normalization of pain by patients, themselves, their friends, their parents, society in general and their providers. Unless we reject that normalization of pain and understand that severe cramps are not normal, so that we use proactive treatment and planning, we don't have a chance of potentially decreasing the growth in severity of endometriosis and the need for surgery. They just suggest that some surgery can be avoided by using a specific approach that looks at when patients are going to be seen and when different testing and treatment are going to be used. We can't wait six to ten years to make a diagnosis. We need to have proactive treatment so that we can stop the cramps and potentially to decrease surgery. On the other hand, even if that's a theoretical thing that doesn't work and proactive treatment does not decrease surgery, it is still the right thing to do for pain. We can't keep normalizing pain and putting people through pain just because they're women.

Jessica Bard: Well said. Thank you very much for your research on this and for your time today. We really appreciate you being on the podcast.

Dr Dan Martin: Thank you, Jessica. It's been a pleasure being with you today.