You may be interested in myalgic encephalomyelitis, which had an estimated disease burden in the US of 0.7m DALYs [1], and NIH funding of $13m this year. That would put the ratio at 0.06, far below the other diseases you've listed. The disease burden estimate is pre-pandemic, and ME/CFS is one of the more common sequeala of covid, so the ratio is likely worse again.
ME/CFS is also incredibly interesting for its hallmark symptom - a highly unlinear response to exertion. Mild patients can often go about parts of their day to day life just fine, but if they hit an exertion threshold they can be bedbound for weeks. Severe patients are permanently bedbound and processing light is beyond the exertion threshold for some.
Mitochondrial dysfunction [2] is thought to be central to the disease. A large scale (n=18k) GWAS study will be reporting in the next two months [3]. Strong evidence of autoimmunity have been found in a subset of patients (hot off the press, from a recent conference [4]).
As someone who has Long Covid, I can attest to these symptoms. A few months in, I was so tired I couldn't listen to music or watch television. I spend almost the entire day staring at the ceiling. When I improved a little, I just watched this ASMR cooking channel, because that was all the stimulation I could handle. Things got better with time. In the first year, flare-ups could set me back for weeks. But weeks turned into days, which turned into hours. It's been a long, long path to recovery, but luckily, nearly five years later, I am now again almost entirely functional.
ME/CFS is so confusing that when we understand it, that will probably herald the discovery of something quite unpredicted: a new way of understanding metabolism, a cellular function we thought did one thing but actually does something else entirely, a new immune signal, a new place viruses can hide, perhaps even a new anatomical function.
They should rename it I-Notice-I-am-Confused-Disease because there's something important we are missing.
Fascinating article, thank you. I'm one of the many women who know of endometriosis, but couldn't say what it was except "tissues growing where they shouldn't" - despite having a colleague suffering from severe endometriosis and booked for surgery.
Had never heard about the similarities to cancer before. Do we ever see malignant cancers (as in life-threatening) emerge from ectopic endometrial tissue? (Apologies if this is mentioned and I missed it!)
Thank you, this is one of the clearest and most compelling accounts of endometriosis I’ve read. Your synthesis of the disease’s biology, from mutational patterns to metabolic weirdness, is not just rigorous but refreshingly readable.
What lingers most is the contrast between the complexity of the condition and the indifference it’s met with. As you show, endometriosis isn’t just “understood poorly”, it’s systemically minimised. The DALYs-to-dollars ratio is shameful, but not surprising.
One small addition: the diagnostic lag doesn’t just delay care—it undermines a person’s trust in their own body. Years of being told debilitating pain is normal leaves lasting damage. That distortion is harder to quantify, but essential to name.
Thank you for writing this! I’m quite shocked that through my whole PhD, in the Developmental, Regenerative & Stem Cell biology department no less, I never learned about endometriosis. I agree that it is extremely interesting. I’m going to be thinking about this for a while. Given its similarity to cancer, do you know if anyone is trying immunotherapy approaches to treatment?
I would imagine it’s because, in the subconscious clinical/clinical research narrative, immunotherapy is framed as Serious Business for Serious Diseases and endometriosis is framed as one of those pesky nebulous hard-to-diagnose women’s health conditions — possibly accruing negative halo effect from the presumption of somaticization associated with such conditions even though it’s obviously materially real.
The burning question for me reading this very interesting piece was — knowing what we now know, why do we not simply reclassify endometriosis as a cancer? It would obviously be a tumor on the more benign and indolent side, one on the opposite end of the aggressiveness spectrum from, say, pancreatic adeno. But there are other such diseases we do call cancer, including ones where patients generally are expected to die of something else. Splenetic marginal zone lymphoma is a cancer in good standing.
The upside: unlocking resources and directing attention to research avenues that perhaps ought to be obvious but clearly aren’t in fact obvious.
The downside: stressing out patients. No one wants to hear the C word.
If you’re considering aiming a very bright and urgent rhetorical spotlight at a disease-problem, it’s generally wise to have viable diagnostic and therapeutic approaches to that problem already teed up. In this case we do have management — nothing curative, but that’s very much par with indolent cancers tending toward chronic. Maybe a more viable diagnostic approach is what’s needed to tip the balance more decisively in favor of reclassification?
(I don’t want to ascribe the failure to reclassify to straight-up misogyny — unfortunately a genuine problem in physician-patient dialogue and underdiagnosis, but this isn’t a front-line clinical practice issue, it’s a ‘key opinion leader’ matter for the societies and guideline panels, and that’s not a level at which the sociological stuff generally feels explanatory.)
It’s probably obvious that my own gut take is let’s reclassify it already and get on with it, but I’m just a high-science/specialty marketing strategist — an adjacency that has a particularly good window into framing failures and inadequacies in the underlying disease and treatment narratives, but that, very reasonably, doesn’t get to have a direct voice in such things!
So, why don't cancer treatments work here? Or would they likely work, and just haven't been tested yet?
(And regarding surgery, codetweep on Hacker News claims (https://news.ycombinator.com/item?id=44274327) that the reason the surgery doesn't cure it is because most surgeons aren't removing enough... is this accurate?)
Some of the medications suggested (at least the ones I was prescribed) are intended for patients with prostate cancer.
Unfortunately, the majority dx with endo who will have surgeries the rest of their life. As we know, it is hard to detect even with the naked eye. The gold standard is exploratory surgery and some surgeons still miss it. DIE is deep within the tissue and is not visible to the naked eye. In some cases a pelvic MRI can indicate abnormal growth spots but that’s about it. It may continue to grow )in most cases) no matter how well surgery went, consistent PT, medications, lifestyle changes, pain management, pelvic floor surgeons and more. Why? We just don’t have that research yet. What may work with one body won’t work with all.
I have had two endometriosis excision surgeries with experts, the second with a thoracic surgeon who removed it from the pleura of my right lung and chest side of my diaphragm, where it had been giving me cyclical nerve pain for many years. Not only did excision surgery restore my fertility (I’m expecting my third baby), but I do not have pain in those spots where lesions were removed.
I think the embryonic rest theory, aka endometriosis being a birth defect, is the only one that makes sense. The reasons you list here discounting it can be attributed to hormonal states during pregnancy (ie you don’t have a cycle going, so flare ups are minimized if not prevented) and the poor quality of some surgeries (such as ablation or partial excision by lower-skill surgeons). Also, if you look at endometriosis as a disease of fibrosis (and I do) it is when the menstrual cycle begins that the damage begins, even though the cells that cause endo have been found in 6wk old fetuses.
I think looking at the disease as a birth defect would be a much better place for researchers to start than the current positioning of seeing it as a menstrual disorder. Also, if you look at it as a birth defect, it makes sense that you’d see it more often alongside other reproductive birth defects, which you mentioned is the case. I don’t think it is like cancer, because cancer cells proliferate and move. Endo just worsens in the spots where it is. If you carefully remove it from those spots, it stops the process.
One thing you also did not mention is that it is often known to run in families. So not only is it a debilitating birth defect, but a hereditary one at that. But I agree that it’s a very interesting and horrible disease, and I think we are due for a paradigm shift and a steep increase in research funding, given how many people are harmed by it.
You probably need to address the gnrh antagonists, particularly those formulated with hormonal addback like myfembree, which show best available results for management of endometriosis pain
There are two treatments I did not see mentioned for treating endometriosis,
1 - treating the area with ethanol injections
2 - treating the area with cryogenic/ freezing
Both will kill the endometriosis cells.. my wife had debilitating pain during her period post emergency C-section.. we met a lot of Drs to discuss and it was hard to find a treatment that worked. This went on for years. We found out about the ethanol treatment and had that done at the Mayo Clinic in Jacksonville 9 months ago and she has been pain free since then.
The other options (medication) or actual surgery did not seem ideal to us. Just putting this out there.
I had severe endometriosis in my 20s. It infiltrated my bladder, my colon, presacral ligaments, stomach wall, etc. After two conventional laser surgeries that didn't reduce my pain, I flew to Stanford and had surgery with Dr. Camran Nezhat and another surgical colleague who did a bowel resection. It was a four-hour laparascopic surgery, and what made it different from the previous surgeries is that Dr. Nezhat excised completely each lesion that he found. My endometriosis symptoms never returned. I've since then placed a high value on the skill of surgeons and am forever grateful to Dr. Nezhat. That was 30 years ago.
I remember being shocked by the lack of research into endometriosis when I first learned of this disease and how prevalent it is. Personally, I'm in favor of the bacteria hypothesis because of papers like Fusobacterium infection facilitates the development of endometriosis through the phenotypic transition of endometrial fibroblasts (https://www.science.org/doi/10.1126/scitranslmed.add1531 (locked behind a login wall)), especially since antibiotic treatments seem to improve mouse endometriosis. Based on the mouse results, I think approaches based on administering antibiotics should be trialed in humans.
It should not be controversial to suggest pathogens cause disease!! We are learning a lot about EBV; alzheimers response to shingles vaccines is also suggestive, I think the infectious disease physicians will win a lot of turf back from the geneticists and especially from the psychologists in the next few decades.
Thank you for the most in-depth paper that I have read about this extremely painful and devastating disease. I am 74 yrs old…but had very advanced endometriosis in my late 20’s which resulted in two emergency surgeries and finally a complete hysterectomy when I was 30. They didn’t know anything about it then and they have made very little progress in the ensuing 40+ years. My heart goes out to any woman suffering from very painful and misunderstood disease.
As a person with severe endometriosis, who has has numerous operations to separate my organs, l am grateful to read that the medical world now acknowledges the condition. It was very different 50 years ago when l was in debilitating pain as a 15 year old girl. Even at 61 years, l had to have an operation to remove the amount of scar tissue. I hope the medical world one day makes a breakthrough that prevents future suffering.
You may be interested in myalgic encephalomyelitis, which had an estimated disease burden in the US of 0.7m DALYs [1], and NIH funding of $13m this year. That would put the ratio at 0.06, far below the other diseases you've listed. The disease burden estimate is pre-pandemic, and ME/CFS is one of the more common sequeala of covid, so the ratio is likely worse again.
ME/CFS is also incredibly interesting for its hallmark symptom - a highly unlinear response to exertion. Mild patients can often go about parts of their day to day life just fine, but if they hit an exertion threshold they can be bedbound for weeks. Severe patients are permanently bedbound and processing light is beyond the exertion threshold for some.
Mitochondrial dysfunction [2] is thought to be central to the disease. A large scale (n=18k) GWAS study will be reporting in the next two months [3]. Strong evidence of autoimmunity have been found in a subset of patients (hot off the press, from a recent conference [4]).
[1] https://oatext.com/Estimating-the-disease-burden-of-MECFS-in-the-United-States-and-its-relation-to-research-funding.php
[2] https://journals.physiology.org/doi/full/10.1152/physiol.00056.2024
[3] https://www.decodeme.org.uk/
[4] https://events.mecfs-research.org/en/events/conference_2025/videos/jeroen-den-dunnen-autoimmunity-cause-mecfs
As someone who has Long Covid, I can attest to these symptoms. A few months in, I was so tired I couldn't listen to music or watch television. I spend almost the entire day staring at the ceiling. When I improved a little, I just watched this ASMR cooking channel, because that was all the stimulation I could handle. Things got better with time. In the first year, flare-ups could set me back for weeks. But weeks turned into days, which turned into hours. It's been a long, long path to recovery, but luckily, nearly five years later, I am now again almost entirely functional.
ME/CFS is so confusing that when we understand it, that will probably herald the discovery of something quite unpredicted: a new way of understanding metabolism, a cellular function we thought did one thing but actually does something else entirely, a new immune signal, a new place viruses can hide, perhaps even a new anatomical function.
They should rename it I-Notice-I-am-Confused-Disease because there's something important we are missing.
Fascinating article, thank you. I'm one of the many women who know of endometriosis, but couldn't say what it was except "tissues growing where they shouldn't" - despite having a colleague suffering from severe endometriosis and booked for surgery.
Had never heard about the similarities to cancer before. Do we ever see malignant cancers (as in life-threatening) emerge from ectopic endometrial tissue? (Apologies if this is mentioned and I missed it!)
Thank you, this is one of the clearest and most compelling accounts of endometriosis I’ve read. Your synthesis of the disease’s biology, from mutational patterns to metabolic weirdness, is not just rigorous but refreshingly readable.
What lingers most is the contrast between the complexity of the condition and the indifference it’s met with. As you show, endometriosis isn’t just “understood poorly”, it’s systemically minimised. The DALYs-to-dollars ratio is shameful, but not surprising.
One small addition: the diagnostic lag doesn’t just delay care—it undermines a person’s trust in their own body. Years of being told debilitating pain is normal leaves lasting damage. That distortion is harder to quantify, but essential to name.
A vital piece - thanks again!
Thank you for writing this! I’m quite shocked that through my whole PhD, in the Developmental, Regenerative & Stem Cell biology department no less, I never learned about endometriosis. I agree that it is extremely interesting. I’m going to be thinking about this for a while. Given its similarity to cancer, do you know if anyone is trying immunotherapy approaches to treatment?
Seems like there are strong theoretical reasons why it would work, but not seeing any active trials for it unfortunately: https://pmc.ncbi.nlm.nih.gov/articles/PMC10150018/
I would imagine it’s because, in the subconscious clinical/clinical research narrative, immunotherapy is framed as Serious Business for Serious Diseases and endometriosis is framed as one of those pesky nebulous hard-to-diagnose women’s health conditions — possibly accruing negative halo effect from the presumption of somaticization associated with such conditions even though it’s obviously materially real.
The burning question for me reading this very interesting piece was — knowing what we now know, why do we not simply reclassify endometriosis as a cancer? It would obviously be a tumor on the more benign and indolent side, one on the opposite end of the aggressiveness spectrum from, say, pancreatic adeno. But there are other such diseases we do call cancer, including ones where patients generally are expected to die of something else. Splenetic marginal zone lymphoma is a cancer in good standing.
The upside: unlocking resources and directing attention to research avenues that perhaps ought to be obvious but clearly aren’t in fact obvious.
The downside: stressing out patients. No one wants to hear the C word.
If you’re considering aiming a very bright and urgent rhetorical spotlight at a disease-problem, it’s generally wise to have viable diagnostic and therapeutic approaches to that problem already teed up. In this case we do have management — nothing curative, but that’s very much par with indolent cancers tending toward chronic. Maybe a more viable diagnostic approach is what’s needed to tip the balance more decisively in favor of reclassification?
(I don’t want to ascribe the failure to reclassify to straight-up misogyny — unfortunately a genuine problem in physician-patient dialogue and underdiagnosis, but this isn’t a front-line clinical practice issue, it’s a ‘key opinion leader’ matter for the societies and guideline panels, and that’s not a level at which the sociological stuff generally feels explanatory.)
It’s probably obvious that my own gut take is let’s reclassify it already and get on with it, but I’m just a high-science/specialty marketing strategist — an adjacency that has a particularly good window into framing failures and inadequacies in the underlying disease and treatment narratives, but that, very reasonably, doesn’t get to have a direct voice in such things!
So, why don't cancer treatments work here? Or would they likely work, and just haven't been tested yet?
(And regarding surgery, codetweep on Hacker News claims (https://news.ycombinator.com/item?id=44274327) that the reason the surgery doesn't cure it is because most surgeons aren't removing enough... is this accurate?)
Some of the medications suggested (at least the ones I was prescribed) are intended for patients with prostate cancer.
Unfortunately, the majority dx with endo who will have surgeries the rest of their life. As we know, it is hard to detect even with the naked eye. The gold standard is exploratory surgery and some surgeons still miss it. DIE is deep within the tissue and is not visible to the naked eye. In some cases a pelvic MRI can indicate abnormal growth spots but that’s about it. It may continue to grow )in most cases) no matter how well surgery went, consistent PT, medications, lifestyle changes, pain management, pelvic floor surgeons and more. Why? We just don’t have that research yet. What may work with one body won’t work with all.
Great post.
There are also rare cases of ‘cerebral endometriosis’ which can present with psychiatric symptoms https://pmc.ncbi.nlm.nih.gov/articles/PMC9738496/
I have had two endometriosis excision surgeries with experts, the second with a thoracic surgeon who removed it from the pleura of my right lung and chest side of my diaphragm, where it had been giving me cyclical nerve pain for many years. Not only did excision surgery restore my fertility (I’m expecting my third baby), but I do not have pain in those spots where lesions were removed.
I think the embryonic rest theory, aka endometriosis being a birth defect, is the only one that makes sense. The reasons you list here discounting it can be attributed to hormonal states during pregnancy (ie you don’t have a cycle going, so flare ups are minimized if not prevented) and the poor quality of some surgeries (such as ablation or partial excision by lower-skill surgeons). Also, if you look at endometriosis as a disease of fibrosis (and I do) it is when the menstrual cycle begins that the damage begins, even though the cells that cause endo have been found in 6wk old fetuses.
I think looking at the disease as a birth defect would be a much better place for researchers to start than the current positioning of seeing it as a menstrual disorder. Also, if you look at it as a birth defect, it makes sense that you’d see it more often alongside other reproductive birth defects, which you mentioned is the case. I don’t think it is like cancer, because cancer cells proliferate and move. Endo just worsens in the spots where it is. If you carefully remove it from those spots, it stops the process.
One thing you also did not mention is that it is often known to run in families. So not only is it a debilitating birth defect, but a hereditary one at that. But I agree that it’s a very interesting and horrible disease, and I think we are due for a paradigm shift and a steep increase in research funding, given how many people are harmed by it.
Thank you very much for this and your work behind it! I have at least 3 women in my direct circle of friends dealing with the desease. They sometimes joke that at least it might be over in the menopause (https://www.medicalnewstoday.com/articles/endometriosis-and-menopause).
It doesn't end with menopause. 😣
You probably need to address the gnrh antagonists, particularly those formulated with hormonal addback like myfembree, which show best available results for management of endometriosis pain
This disease has absolutely ruined my life and has me in constant pain.
I feel like a ghost, walking through the world of the living with a knife through my abdomen and no one can see it, or care.
Thank you for bringing some light to it
There are two treatments I did not see mentioned for treating endometriosis,
1 - treating the area with ethanol injections
2 - treating the area with cryogenic/ freezing
Both will kill the endometriosis cells.. my wife had debilitating pain during her period post emergency C-section.. we met a lot of Drs to discuss and it was hard to find a treatment that worked. This went on for years. We found out about the ethanol treatment and had that done at the Mayo Clinic in Jacksonville 9 months ago and she has been pain free since then.
The other options (medication) or actual surgery did not seem ideal to us. Just putting this out there.
I had severe endometriosis in my 20s. It infiltrated my bladder, my colon, presacral ligaments, stomach wall, etc. After two conventional laser surgeries that didn't reduce my pain, I flew to Stanford and had surgery with Dr. Camran Nezhat and another surgical colleague who did a bowel resection. It was a four-hour laparascopic surgery, and what made it different from the previous surgeries is that Dr. Nezhat excised completely each lesion that he found. My endometriosis symptoms never returned. I've since then placed a high value on the skill of surgeons and am forever grateful to Dr. Nezhat. That was 30 years ago.
I had my 4 hour laparoscopic surgery in San Diego 2.5 years ago. At age 30. I hope that mine never returns. I am so happy for you.
I remember being shocked by the lack of research into endometriosis when I first learned of this disease and how prevalent it is. Personally, I'm in favor of the bacteria hypothesis because of papers like Fusobacterium infection facilitates the development of endometriosis through the phenotypic transition of endometrial fibroblasts (https://www.science.org/doi/10.1126/scitranslmed.add1531 (locked behind a login wall)), especially since antibiotic treatments seem to improve mouse endometriosis. Based on the mouse results, I think approaches based on administering antibiotics should be trialed in humans.
It should not be controversial to suggest pathogens cause disease!! We are learning a lot about EBV; alzheimers response to shingles vaccines is also suggestive, I think the infectious disease physicians will win a lot of turf back from the geneticists and especially from the psychologists in the next few decades.
Thank you for the most in-depth paper that I have read about this extremely painful and devastating disease. I am 74 yrs old…but had very advanced endometriosis in my late 20’s which resulted in two emergency surgeries and finally a complete hysterectomy when I was 30. They didn’t know anything about it then and they have made very little progress in the ensuing 40+ years. My heart goes out to any woman suffering from very painful and misunderstood disease.
Are you keeping track of CTs etc? So many women I know would be willing volunteers in the space!
As a person with severe endometriosis, who has has numerous operations to separate my organs, l am grateful to read that the medical world now acknowledges the condition. It was very different 50 years ago when l was in debilitating pain as a 15 year old girl. Even at 61 years, l had to have an operation to remove the amount of scar tissue. I hope the medical world one day makes a breakthrough that prevents future suffering.