Are we on the cusp of a breakthrough in endometriosis?

[Plantz Admin]

I copied this from an article in The Guardian, so the formatting is all over the place. But in summary, it says that Endo could be caused by bacteria called fusobacterium, and there are positive signs that anti-biotics could treat the lesions.

Original Article

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Endometriosis has long been thought of as a disease of the reproductive system, which is why up until now treatments have been limited to hormones or surgical removal. Illustration: Lilian Darmono/The Guardian

‘It’s really only the beginning’: are we on the cusp of a breakthrough in endometriosis?

Endometriosis has long been thought of as a disease of the reproductive system, which is why up until now treatments have been limited to hormones or surgical removal. Illustration: Lilian Darmono/The Guardian

After generations of inaction and very few novel ideas, researchers and activists are hopeful a new path is being charted in understanding and treating the crippling chronic condition by Gabrielle Jackson

“There’s an excitement at the moment,” says Andrew Horne. After decades of inaction, something is happening in endometriosis. Now, says the professor of gynaecology and reproductive sciences at the University of Edinburgh, “I do think things are changing. There are more people working on it, so it’s bringing in people from different disciplines with new ideas.”

In the space of a few months, from gatherings in Edinburgh and Washington DC, labs in Sydney and Japan, there is a sense that new ideas are bubbling to the surface, including a fundamental rethinking of endometriosis not as a disease of the pelvis, but rather, says Horne, “a whole-body disease”. It’s hard to pinpoint the exact moment when despair turned to hope in the research and patient community. There was no single breakthrough. No one person responsible. In March, the largest ever study on the genetics of endometriosis was published in Nature Genetics, which found genetic links to 11 other pain conditions as well as other inflammatory conditions. The study, involving DNA from more than 760,000 women, found ovarian endometriosis is genetically distinct from other types and indicated there may be a genetic predisposition to excessive inflammation in people with the condition. One of the researchers, Dr Nilufer Rahmioglu from the University of Oxford, described the data as a “treasure trove of new information”. When you talk to people and you compare ideas … that’s when you get the eureka moments Dr Susan Evans, gynaecologistWeeks later on the other side of the world, researchers from Sydney’s Royal Hospital for Women attracted international attention after they grew tissue from different types of endometriosis and compared how each responded differently to treatments. Jason Abbott, professor of obstetrics and gynaecology at the hospital, likened the development to those made in the treatment of breast cancer three decades ago. Two weeks on from the Australian discovery, Japanese researchers found a common form of bacteria may be contributing to the growth of endometriosis via inflammation. The frisson was, by then, hard to miss. Dr Susan Evans, an Australian gynaecologist, pain physician and founder of Alyra Biotech, says: “I’ve been disappointed over many years at the lack of real innovation in this space.” But as she joined 1,000 other scientists at the World Endometriosis Congress in Edinburgh in May, in the midst of this research coming out, she was impressed by the new ideas put forward and excited by the developing focus on the neuroimmune system. “That’s been slow coming, but I think it’s really only the beginning of how that’s going to make an enormous difference,” she says.

Dr Susan Evans, founder of Alyra Biotech, explains the uterus-brain axis at a seminar run by the Pelvic Pain Foundation of Australia and Labtrobe Health Assembly. Photograph: Pelvic Pain Foundation of Australia“The excitement in biotech and biopharma is where you have different skill sets that all come together. When you talk to people and you compare ideas, you think laterally and you learn new skills – that’s when you get the eureka moments. It’s not one person knowing more and more and more about one little area that does it these days.” ‘There’s been so little happening’ Endometriosis is a disease where tissue similar to the lining of the uterus grows in other parts of the body. It can cause severe pain and fatigue, painful periods, painful sex and infertility. Often people with the condition report being written off as hysterical, type A personalities, too anxious about their health or even attention-seekers. The average wait for diagnosis remains seven to 10 years. Money for research has been thin worldwide – despite affecting the same number of women as diabetes, it was receiving 5% of the funding in 2018. There is no known cause or cure. And all the while, 176 million people with the disease suffer.

An interactive diagram showing ‘What is endometriosis?’Endometriosis has been described as a disease of the reproductive system, which is why treatments up until now have been limited to hormones or surgical removal. These treatments can work for some, but not all. Scientists now know endometriosis is, in fact, a whole-body inflammatory condition that can alter a person’s nervous system and have severe quality of life impacts, reducing a person’s ability to work, maintain relationships and take part in social activities. “There’s been so little happening for so long and a lot of the new things that have supposedly come out are just rehashes of the old things, and that’s not doing it for women out there,” says Evans. “We need whole new areas of medicine to open up that actually have relevance for women’s endometriosis lesions and their pain.” This data strongly suggests that fusobacterium infection facilitates the formation of endometriosis Researcher Yutaka KondoSo when the research out of Japan hit the headlines it sent the endo community abuzz. This was the kind of whole new approach in the neuroimmune space that Evans was talking about. Simply put, the researchers found a common form of bacterium called fusobacterium – found in gum disease – was playing a role in the growth of endometriosis lesions and that it could potentially be treated with existing antibiotics. Not hormones, not surgery. The Nagoya University researchers looked at samples taken from hysterectomy in 28 women. They were stunned by the results. The endometrium (the inner lining of the uterus) and lesions in women with endometriosis, they found, contained a cell called myofibroblasts. This was absent in the endometrium of people without endometriosis. Knowing that myofibroblasts may develop as a result of chronic inflammation, they tested whether fusobacterium could cause endometriosis lesions to grow in mice models. It worked. They tested whether an existing antibiotic could shrink the lesions. It did.

Yutaka Kondo (front row wearing a tie) with other endometriosis researchers“This data strongly suggests that fusobacterium infection facilitates the formation of endometriosis,” says researcher Yutaka Kondo. But there are limitations to this study. For one, mice don’t menstruate. Secondly, the samples taken were from women who tended to be older, but endometriosis affects people from their teens. The researchers are working on methods to check for the presence of fusobacterium in people with endometriosis so they can plan a larger study testing whether antibiotics can help shrink endometriosis lesions in humans. Despite the study’s limitations, it is a new idea to explore and it has researchers talking. While Evans doubts fusobacterium would be the only contributing factor in the growth of endometriosis lesions, she acknowledges that bacteria has been discovered to cause other significant health problems before. Peptic ulcers, for example, were found by two Australian researchers to be caused primarily by the bacterium Helicobacter pylori. The discovery revolutionised treatment and researchers Barry Marshall and Robin Warren won the 2005 Nobel prize for the breakthrough. “So I was interested [in the Japanese research] because when you have an infection with a bacteria like the fusobacterium that they found, that’s going to increase inflammation,” says Evans. “And endometriosis is an inflammatory condition, and chronic pain – and all the symptoms that women get with that – is chronic inflammation.”

The ‘uterus-brain axis’ Understanding chronic inflammation and its impact on the whole body is key to understanding endometriosis and the myriad symptoms it presents in patients. It is an area Evans has been studying; she calls it the “uterus-brain axis”. She says while many people now understand the gut-brain axis and how it works to make us feel unwell – or well – via the immune system, not many people have studied how the same process may work between the uterus and brain. “I personally believe the reason why women are so much more affected by immune conditions than men is that there’s also a uterus-brain axis, and the uterus talks to the brain via inflammation,” Evans says. When we think about short-term inflammation, we might think of how we feel sick, achey and fatigued when we get the flu. We can also think about the red sore area we get in our finger when we get a splinter. These are signs of our immune system at work. Most people generally recover fairly quickly after a splinter or the flu. But, Evans says, “There’s actually a proportion of people who have a low grade of inflammation all the time, and that doesn’t work well with our central nervous system.” When this inflammation feedback loop works in uterus-brain axis it shows up in people with endometriosis or chronic pelvic pain via symptoms including irritable bowel syndrome, painful bladder syndrome, pelvic muscle spasm, chronic fatigue, poor sleep, anxiety, low mood, nausea, dizziness, feeling sweaty, headaches and brain fog.

A still from Shannon Cohn’s film about endometriorsis, Below the Belt. Photograph: Shannon CohnHorne agrees with Evans that looking at the immune system’s role in the development of endometriosis is a promising new area of study. Evans is about to start clinical trials on an intrauterine device she believes may “alter and moderate the excessive immune activation in the uterus in order to reduce symptoms”. She can’t name the drug just yet, but says it is already used in humans with few side effects. The key to this device, she says, is that it releases the drug directly into the uterus, which has its own immune environment. It’s one of a number of studies being undertaken for treatment of endometriosis with a new idea. Many trials over the past decade tested existing hormonal drugs. Horne describes Evans’ clinical trial as “exciting” and compares it to a new treatment his team in Edinburgh have been looking at with the University of Warwick that also involves treatment with an immunomodulatory drug. “This would be a drug which would be given by an intravenous infusion weekly over six weeks. And the idea behind it is that it sort of deactivates, if you like, immune cells called macrophages. And we know that these are really important for the development of endometriosis lesions,” says Horne. Their pain scores have been reduced Andrew Horne, University of Edinburgh Both Horne and Evans point to recent developments in France as promising. Different teams there have found less invasive diagnostic tools than surgery, one team with ultrasound and another using saliva. Horne’s team is also gearing up for a clinical trial on another non-hormonal treatment. He says they found that one of the chemical processes within the cells lining the pelvis – what we commonly know as metabolism – was different in people with endometriosis compared with those without the disease. Horne says the cells behave a bit like cancer cells, with many of the enzymes involved in cell metabolism producing more lactate in endo patients. Lactate is the chemical your body produces when your cells break down carbohydrates for energy. Both Horne and Kondo say that while endometriosis is not cancer, in many ways endometriosis lesions act like cancer. Lactate, for example, has been studied in cancer because it is known to increase cell proliferation. “So their ability to divide and grow, their ability to invade, their ability to to make their own blood supply – these are all steps that are really important for the development of an individual endometriosis lesion,” Horne says. His team has focused on a drug called dichloroacetate, which has been used for a number of years to treat rare metabolic disorders in children. Pre-clinical studies had success in reducing the amount of endometriosis in mice, and a later study of 30 people with the disease also showed promising results. “What we’ve seen in these patients who’ve taken dichloroacetate is that their pain scores have been reduced,” Horne says. While the study did not check surgically to see whether the overall lesions had been reduced, the pain scores involved a number of quality of life measures. Recruitment for a multi-centre double-blind trial of 100 patients will begin later this year.

Horne also describes the Japanese research as “really exciting” and says both this research and his own raise an important question, that is: why is there more fusobacterium and lactate produced in the pelvis of endometriosis patients? Getting the answer is the next frontier. ‘We had the right people’ While these trials take many years, and funding for them can be hard to come by, Horne believes research has become easier in recent years due to increased awareness around endometriosis. “Certainly you probably see it in the press, both patients, clinicians and researchers all campaigning around trying to increase the amount of research,” Horne says. Governments too, including in Australia and France, have been more willing to fund work into the area. Shannon Cohn has been at the forefront of the public awareness campaign in the United States. She has made two films about endometriosis – Endo What? in 2016 and this year launched Below the Belt, which named Hillary Clinton as an executive producer. Cohn became interested in endometriosis research about a decade ago when she realised that in the 20 years since her diagnosis, little progress had been made. The work of HIV/Aids campaigners to raise awareness and fund research in the 1980s and 1990s became a model she sought to replicate. Cohn met with Gregg Gonsalves from the Yale School of Public Health to ask him about it. “He told me: ‘We didn’t have 100 people, we had dozens of the right people.’” That meant scientists working alongside lobbyists, publicists and the people who are going to take direct action and say, “No, we’re not going to take this any more.”

‘I do feel this momentum’: film-maker Shannon Cohn.In June, in the wake of the Edinburgh buzz and the Australian and Japanese discoveries, Cohn helped organise a meeting in Washington DC, which included representatives from the Office of Research in Women’s Health, the White House Gender Policy Council, Republican and Democratic representatives of the House of Representatives and Senate, and the National Institutes of Health, the world’s largest public funder of medical research. Endometriosis advocates went to the meeting with five action items, including US$50m for endometriosis research targeted at novel studies and a national action plan based on Australia’s. They achieved a general consensus of support from those present on their aims. What if this could be a model forward for other conditions that predominantly affect women? Shannon Cohn, campaigner and film-maker While Cohn is positive about recent developments and the outcomes of her meetings, she knows it’s not enough: “We have these interesting research findings coming out and that’s great, but we need more. We need more information. We need more funding. We need more researchers. “I do feel this momentum,” she says. But, she adds there’s a long way to go, not just for endometriosis, but all of women’s health. “It’s not like it’s just endometriosis that’s underfunded, undervalued. It’s like, what if this could be a model forward for other conditions that predominantly affect women?” Horne agrees: “Women’s health conditions have always suffered from lack of funding. Women’s health is still seen as a small specialty within all the other specialties. It shouldn’t be seen in that way but unfortunately it is.” Evans is hopeful we are on the verge of change, of recognising that women are not the same as men and their symptoms are worthy of research. “Women’s health is starting to get more attention, and that’s about time,” she says. “It’s slowly coming together.”

Gabrielle Jackson is an associate news editor for audio and visual at Guardian Australia and the author of Pain and Prejudice