WE’VE LOOKED IN great detail at how endometriosis is treated currently, and this alone has seen major advances in recent years with improved surgical techniques through laparoscopic surgery and a rapid increase in awareness, thanks largely to the internet and social media. Let’s now turn to the future, as there are still many areas of unanswered questions and so much scope for even better treatments.
The future for research in endometriosis is clearly a huge topic but we recently tried to tease out the key issues by surveying nearly 2,000 women with endometriosis, their supporters and healthcare professionals, and asking them what they felt was important.
Perhaps not surprisingly, the top priority for everyone was to find ‘a cure’, followed closely by women and clinicians wanting to find out ‘what causes endometriosis’. Clearly, these questions are inextricably linked – if we are to find a cure for endometriosis we need to find out what causes the condition to start with.
But first of all, we believe that we really need to better define endometriosis. Are there truly three subtypes – peritoneal/superficial, ovarian and deep? Secondly, if there are different subtypes – are there different mechanisms to explain why they occur? And thirdly, do these subtypes need to be treated differently?
Other ‘hot topics’ from our national survey included raising awareness of endometriosis amongst healthcare practitioners through education programmes, and improving diagnosis.
Over the last few years, researchers have made commendable attempts nationally and internationally to ensure that samples (biopsies) collected from women with endometriosis are carefully and accurately defined in a uniform way. This has included taking into account the wide-ranging symptoms experienced by women with endometriosis, as well as the appearance and location of the endometriosis lesions. We believe that this will significantly expedite the research efforts in endometriosis and enable researchers to perform large-scale, cross-continent studies to address the research questions important to women with the condition and the healthcare practitioners that treat them.
Dominic Byrne, the endometriosis surgeon we heard from earlier, says, ‘to advance research in endometriosis you need to take a certain group of patients, patients with indisputable disease so you are sure that the population you are studying is the same. Then you need to collect everything you can from them; blood and store it; a history of the observations and findings; and look at biopsies of the tissue; and then you look for patterns. Do the patients carry the same genetic code, does the histology show certain characteristics or biomarkers? This is the basic science and it needs to come alongside the surgical and the clinical experience and only then will you get breakthroughs. These types of scientific observation can develop into something that can be backed up by facts and could lead to someone saying, well actually, I can tell you why that happens; it’s because this gene is not expressing this protein and therefore the peritoneum is not responding in this patient like it does in a patient without endometriosis.’
Professor Philippa Saunders, a scientist in the field who has researched endometriosis for many years adds: ‘I think endometriosis is a disorder that is crying out for a more precise, “intelligent” approach to therapy. To me as a scientist, there is a minimum of three diseases (superficial/peritoneal, ovarian and deep) and the research community are not actually modelling all three of them in our studies. What we need is to develop new ideas focused on identifying the best treatments for each of these subtypes of endometriosis, so that the clinicians can place better emphasis on personalised care. Personalised care will be the only way forward.’
Increasingly we are learning more and more about endometriosis by considering the results from studies in cancer, which are much more numerous than those on endometriosis.
Whilst endometriosis is not a cancer, it does behave like a cancer: it can spread around the pelvis and ‘destroy’ local tissue, and is sporadic in that it affects some women and not others. We can draw some parallels in the ways cells behave in both conditions and we hope to exploit this knowledge to ‘repurpose’ drugs for endometriosis patients.
Deep endometriosis lesions isolated from women undergoing surgery for endometriosis have mutations (changes in the genetic make-up) in some genes implicated in endometrial cancer. Furthermore, for an endometriosis lesion to develop, it needs to ‘stick’, ‘invade’ and ‘form its own blood and nerve supply’ – and these are all steps that occur in cancer.
Not only are the steps in cancer replicated in endometriosis but there is new evidence to suggest that the cells lining the wall of the pelvis (‘peritoneal mesothelial cells’) are ‘metabolically’ different and can enable the steps.
Normally cells break down sugars in their mitochondria – the energy packs within the cells. Cancer cells instead switch off their mitochondria and break down sugars in the cytoplasm – the main area of the cell. This is known as the ‘Warburg effect’. The cells in the pelvis of women with endometriosis also behave in this way.
For a number of years now, cancer researchers have been trying to exploit the Warburg effect to find new potential treatments. We hope that in the future, new drug treatments in individuals might be identified using a similar approach.
Philippa adds, ‘I think the challenge is our level of understanding of how this disorder starts, why some women get it and indeed what actually is going on in terms of why this so called lesion can cause the associated problems.’
Ovarian and deep endometriosis is now increasingly diagnosed by imaging, such as ultrasound and MRI. It is the superficial/peritoneal subtype of the disease that proves the biggest challenge. We think that one of the main reasons that progress has not been made to identify a biomarker that can be used to test for endometriosis is due to the fact that, until now, many studies have been on a small-scale and involved poorly defined populations of women and samples. We are confident that we will see a change in the progress in this area, with the efforts that have been made to improve endometriosis definition. Professor Christian Becker, from the University of Oxford says: ‘The average time between the onset of symptoms and a diagnosis of endometriosis ranges between 8–12 years worldwide. Sensitive biomarkers are the key to reduce the time of suffering for millions of women. Despite increasing efforts, no clinically relevant biomarkers for endometriosis exist at the present time. Only large, multi-centre collaborative studies using standardised sample and data collection tools, will enable us to identify and validate biomarkers for a heterogenous condition such as endometriosis.’
The evidence for the benefit of surgery for endometriosis – particularly for improving painful symptoms – is, unfortunately, only based on a small number of studies, and whilst these may be of good quality, they are often studies that include women with a range of the different types of endometriosis rather than specific types.
Dominic Byrne says, ‘A lot of basic science is missing, and it’s quite hard to get basic science on surgical diseases and operations, because patients and doctors don’t welcome random allocation to one treatment or another. Yet that is the purest scientific way of demonstrating one treatment is better than another, so the data we need is quite hard to collect and probably will never fully be achieved. The same with other surgical procedures, so an element of experience drives the knowledge base, rather than pure science driving the knowledge base.’
Nevertheless, if you look at the success rates of surgery performed in endometriosis centres, it is becoming increasingly clear that symptoms associated with deep endometriosis (and probably, ovarian endometriosis) improve with appropriate surgery. It is particularly heartening that, with hindsight, some women even appear to be cured from their endometriosis.
But, we are aware that more and more clinicians are questioning whether ‘cutting out’, ‘burning’ or ‘lasering’ superficial/peritoneal disease is of benefit to women to treat the painful symptoms of endometriosis. There is good evidence to suggest that surgery for superficial/peritoneal disease increases pregnancy rates. Indeed, is it possible surgery for superficial/peritoneal disease may cause more harm than good, and puts women at risk of multiple operations and the complications that these operations could lead to? We need better evidence about whether surgery is the best way to treat this type of endometriosis. And to do so, we come back to the fundamental need to understand why it happens in the first place.
Dominic says, ‘It is actually the other end of the spectrum that’s slightly more difficult, and that is patients who have lots of symptoms, but when you look inside their pelvis or abdomen you find very little or very limited disease. It is hard to understand what can be the cause of their disease, so that’s frustrating. It may be that they have other causes for their pain, and it may be that they have endometriosis in places we haven’t even identified, but in terms of treating them, it’s relatively unfulfilling on both sides of the relationship. From my point of view, I explain to them that I think the outcome is likely to be little changed if we remove relatively minor endometriosis. Some women don’t have the surgery, and some do, and it’s about 50/50 who feel there is an improvement. But that’s sort of frustrating from a surgical side.’
We believe that improved awareness of endometriosis will increase the likelihood that it is diagnosed more quickly. Raising the awareness of endometriosis should not ‘on paper’ be difficult, but it will only be achieved by support from politicians and governments, including investment and well-thought-out strategies to inform the general public and better educate healthcare practitioners at all levels about endometriosis.
Endometriosis UK play an invaluable role in continually highlighting the condition through social media and campaigning for greater acknowledgement and a much better understanding of this common but frequently misunderstood condition.
How does Emma Cox, Chief Executive of Endometriosis UK, feel about the future? ‘I am optimistic that we will start to see diagnosis times reducing in the next few years – yes, that’s slower than I, and many others, would like, but it is going in the right direction. This will come about through improved GP training and awareness; greater understanding of what’s “normal” for the menstrual cycle through education in schools; and, of course, greater public awareness so women know what questions to ask, and aren’t dismissed as having “women’s issues”.’
We have witnessed so many unimaginable advances in science and medicine, whether it’s technology that now allows us to peer deep into the body and deliver treatment, or the multiple medicines that extend the lives of people. Think of anaesthetics that dull the pain that had long been associated with surgery, and antibiotics and vaccines that have halted communicable diseases. Think also of the announcement, over 15 years ago, that the majority of the human genome had been sequenced, housing the dawn of a new branch of medicine, medical genomics. And don’t forget progress in our methods of conducting research, like the advent of the randomised controlled trial which has given researchers an important tool in determining which treatments work, and which do not, bringing in the current era of evidence-based medicine.
So, we think that the state of medicine today is not an endpoint for women with endometriosis but that it marks a new beginning. There is the enticing promise of the next hopeful steps towards, not only a cure for endometriosis, but the means to identify women at risk of the condition and allow early intervention.
It is appropriate that we leave the last words to be the hopes of the women we interviewed. You might have imagined that all women asked for a cure, or to understand the causes of endometriosis, or even to have a much simpler diagnostic test. But these hopes, whilst very much there, often remained unspoken – women frequently looked far more pragmatically at what would make a difference here and now, to this generation of women suffering, as well as to the future.
These were less about demands on a heavily burdened health system than a plea for acknowledgement, as Sophie says: ‘I’ve been an Endometriosis UK support group leader for three years now, however, it’s sad seeing every few months the same questions repeated, the same struggles. I’d really like in the future that endometriosis is more accepted, more known about by professionals, that women are being referred to services a lot quicker than they are now, and that there is help from the beginning.’
Women hope that, with greater awareness and education amongst clinicians, the diagnosis time might be reduced, as Amy tells us: ‘I want there to be greater awareness of it, particularly within the healthcare system, obviously with GPs because it is often the first point of call, then obviously in society at large, with employers. That seven and a half years’ statistic (average length of time to diagnosis) needs to come right down. I know that it’s an invasive, complex disease, so you know it’s never going to be one of those things where everyone goes to the doctor and it’s immediately diagnosed, but seven and a half years is too long.’
Alongside this, women want to be listened to, particularly when they have hard decisions to make, so that they can own those choices, as Saskia explains: ‘I want them to have treatments that they feel okay with, they’re not forced upon them but they feel like their choices have been listened to. Even though when you’re stuck between a rock and a hard place, when you have a difficult decision to make, you feel okay that you’ve made a decision by yourself and it’s your decision.’
Few of these asks are about expensive interventions – they are mostly about human interactions and understanding. So why has this been hard? We cannot ignore how difficult it is within a complex system to ensure person-centred care takes priority, but we can, as patients and professionals, continue to work together to ensure that we are all working towards the same end: high-quality care, delivered in the right place on a timely basis. This is something that we, as ‘health citizens’, all need to own.
Women told us the sort of services they want to receive – services that some women are fortunate to receive now, but not all – and the priorities which sometimes seem far off:
‘For pain clinics to be more widely available.’ – Sophie
‘I wish there were more specialist nurses, it would really change many people’s lives.’ – Lucy
‘On a big-picture level, although I think awareness has increased, one of my biggest frustrations is that the government hasn’t taken this seriously enough, there’s still not enough investment in research.’ – Zoe
‘We need money for research because we need to know what causes this, because until you know what causes it and why it happens and how it happens, you can’t find a cure or find out what medications work best to help control it. Now it might be that there is not a cure, it might be that there is medication to control it, but that’s fairyland you know, that’s not going to happen or I’d be very surprised if it happens.’ – Poppy
Let’s hope this is not ‘fairyland’ – because all women, and all of the women that come after them – deserve better.