Development of a urine test for endometriosis
Endometriosis is an incurable, chronic condition, associated with debilitating pain and reduced fertility. It is thought to affect 190 million women worldwide and is associated with huge costs to the economy though loss of earnings and cost of health-care/treatment. Currently, diagnosis on average takes around 8 years. CLI chatted to Dr Barbara Guinn (Centre for Biomedicine, Hull York Medical School, University of Hull, Hull, UK) about the development of a rapid, non-invasive, urine test that could speed up diagnosis to around 8 days and allow timely treatment to give sufferers of the condition a vastly improved quality of life and reduce damage cause by the disease.
What is endometriosis?
Endometriosis is where tissue that is very similar to the lining of the womb (the endometrium) grows elsewhere in the body. Those locations are often within the walls of the uterus or fallopian tubes, outside the fallopian tubes, around the ovaries. The endometriotic tissue can grow in the pouch of Douglas (which is where the uterus folds down on itself). However, the tissue can also grow on the bowels and be invasive growing into the bowel tissue; it can grow on the kidney tubules and block off the blood supply to the kidney.
The tissue responds to the menstrual cycle and breaks down during a period in exactly the same way that the endometrium does. When this occurs in areas where there is nowhere for the blood to go, this causes inflammation, pain and the formation of adhesions and scar tissue. I’ve been told about patients with endometriosis in their lungs, whose lungs collapse every month, and a woman who has a nose bleed every month as the result of the endometriotic cells growing in her nasal passages, and someone who faints when she goes to the toilet during her period because there is a lot of blood loss from the bowel due to endometriosis.
Symptoms are typically dependent on the extent, location, degree of invasion and associated adhesions; however, there is no reliable correlation between the extent of disease and symptom severity. The disease is broadly divided into three categories: superficial (peritoneal); ovarian; and deep endometriosis. The condition shows a lot of similarities to cancer: the cells proliferate, invade tissue, metastasize, and cause damage by growing in parts of the body where they shouldn’t be.
How is endometriosis usually diagnosed and what are the challenges with diagnosis?
In the UK, diagnosis takes, on average, 8 years from first presentation at the GP (general practitioner) and seeking a diagnosis to the point at which the patient is referred and seen by a specialist. On average, women will see their GP 10 times in that period of time, asking for help and support. Endometriosis starts when a woman’s periods begin and often gets worse with each menstrual cycle. The GPs should be following the NICE (National Institute of Health and Care Excellence) guidelines about endometriosis [1]. The GP should be looking for certain key statements made by the patient. Also, a lot of pain around the time of the period is very common: pelvic pain, pain passing stools, pain having sex, pain passing urine, and if that is so bad it’s stopping the patient from going about their normal daily functions then that is not normal – that is abnormal amounts of pain.
One of the challenges of diagnosis is that if your mum has endometriosis that has never been diagnosed and you say to her that you have a lot of pain when you have a period, then your mum’s going to tell you that’s normal. And if your sister has a lot of pain when she has a period, she’s going say that’s normal for periods too. And so suddenly, for a lot of people, the people around them are saying that’s normal for our family, or us. That’s ‘normal’ because we don’t talk about periods openly enough and so we don’t know what normal is – we know what ‘normal for us’ is. So, yes, diagnosis can be very difficult and there are a lot of the patients, particularly with deep endometriosis, who have had to fight to get a diagnosis because they really do need the help, and they feel as if they’ve been gaslighted. That’s a word we hear an awful lot from patients, who have been going to the GP and been told that it’s a normal period, you have to learn to manage it, which is very frustrating.
The other challenge of diagnosis is that endometriosis is similar to a few other disorders, such as irritable bowel disease, polycystic ovary syndrome, those sorts of diseases that affect the pelvic area and cause pain and discomfort. So endometriosis can be quite difficult to diagnose for that reason.
Do patients have to have quite invasive tests, if differential diagnosis is needed?
There’s a very small number of sonographers that can diagnose endometriosis by ultrasound, and they are usually specialists in gynecology and particularly have an interest in endometriosis. However, they’re very few and far between. So although part of your diagnosis would be a referral for an ultrasound, there is no definitive blood test or urine test, and the gold standard way of diagnosing endometriosis has been via laparoscopy, which is keyhole surgery. The new guidelines recommend not doing laparoscopy as it is expensive and comes with potential risks, but that it’s better just to treat patients for their symptoms and if that helps, then great. The suggestion is not to get hung up on a diagnosis, but that’s not always very nice for patients – a lot of patients really do want a diagnosis.
What would treatment usually entail?
First-line treatment involves pain relief such as paracetamol and or a non-steroidal anti-inflammatory drug, alone or in combination, and hormonal treatment such as the contraceptive pill or the coil. For patients with deep endometriosis who don’t respond well to the first-line treatments in a way that makes life bearable, the next thing is a referral to an endometriosis specialist centre. Treatment with gonadotrophin-releasing hormone (GnRH) agonists is showing success, because GnRH causes anovulation and amenorrhea.
If patients want to get pregnant, which most women around the age of diagnosis do, then they should be referred to a fertility clinic to get the whole support that they need.
Are there any biomarkers that can be used for the diagnosis of endometriosis?
We recently published a paper where we had reviewed all of the literature in a systematic literature review [2]. This review indicated that there was no biomarker that could accurately allow us to detect endometriosis, and we need it to be both sensitive (so that it can tell you when you don’t have endo-metriosis) and specific (so it can tell you when you do). It’s really important to have both of those aspects to be able to find people who are truly positive for endometriosis and those who are truly negative. So we’ve been looking for urine biomarkers based on some data analysis that we did of publicly available data sets. We’ve identified a protein that is present in the urine of people with deep endometriosis, and we can use the protein to differentiate between people with deep or superficial endometriosis and those who have symptoms of endometriosis but don’t actually have that disease. I have to be honest, the test is still in development. We’re still working out the limits of the test. We know that this protein is very labile, we know that the urine needs to be collected and tested quite quickly. We know that we can freeze–thaw it, but we want to find out if it’s better if we don’t. We also want to know if there’s an effect on the test from time of day, time of the menstrual cycle and also what hormones women are taking. Because there’s early evidence that taking hormonal treatments like the contraceptive pill or GnRH analogues (that basically put you into a an early menopause) actually changed the levels of protein and bring people away from being within the deep endometriosis group and make them much more similar to people with superficial or no endometriosis. The biomarker is very specific, we know that it lets us know when women have deep endometriosis, and it’s very accurate.
The problem that we have is it’s not very good at telling us when women don’t have endometriosis, and so that is where we’re at with the test at the moment. We’re still optimizing it to find out if there’s a way to use it so that we get the clearest results possible and differentiate between patient groups and healthy donors. Currently, the test involves a single protein, but if we can’t get the sensitivity that we want, we’ll probably add in another protein and see if that improves things, but first we’re going to see if we can make the test the best it can be with a single protein.
How would the availability of such a urine test affect the diagnosis pathway?
At the moment, the process of diagnosis does take a long time. It depends partly on how aware the GP is of the possibility of endometriosis, but one of the problems with the disease is that there isn’t a clear correlation between severity of disease and pain and additionally other diseases have to be ruled out. With our test, what it would mean is that potentially a patient would go into a GP clinic, provide a urine sample and that would be tested on site and would let the doctor know very quickly which care pathway to put the patient into. Ideally, the patient might get the information there and then, or get a phone call the next day. The GP might want a bit of time to have a look properly at the results and then make a decision, or to get some advice on the results, as we do know that there are some confounders with the results, such as certain other diseases that affect the results.
What do you envisage for the future for endometriosis diagnosis/testing?
So for the longer term, I’m hoping that the work that we and others are doing will help us to understand what causes endometriosis and find better treatments for it. Some of the analogue inhibitors and the GnRH analogues work really well, and there are new versions of those where when women stop taking them, within 24 hours their fertility is back to normal for them and they are as ready as they can be for getting pregnant. For our group, I’m particularly interested in treatment strategies. I have a background in cancer biology, and I’m keen to bring in some of those strategies that we use for trying to treat cancer and applying them to endometriosis.
It would be really nice to be able to identify patients who are at risk of endometriosis and to have a treatment that can stop endometriosis before it really starts. I’m particularly interested in the genetics of the disease, which is being investigated and will probably involve multiple genes [3]. A genetic test would also help us to understand how prevalent endometriosis is, because at the moment it’s thought to be a relatively small percentage of patients that inherit it, but it may well turn out to be more prevalent that we realize. There’s a recent statistic that suggests that as many as one in nine women have endometriosis – which is slightly more frequent than diabetes – that’s over 190 million people worldwide [4]. Endometriosis costs the UK economy £8.2 billion a year, predominantly in loss of earnings and cost of health-care/treatment, which is an absolutely massive cost. A lot of the issues with endometriosis are that women with it can’t hold down a job as they have to keep taking time off for their period, they have to keep going into hospital and we’ve got some women who’ve had five, six or seven operations. Forty percent of patients after laparoscopy will actually have further problems caused by their organs sticking together through adhesions and the endometriosis coming back again. The hope is that a better understanding of this dreadful disease will mean that women who haven’t realized what they are struggling with can be treated, and that women at risk can be identified and treated before they suffer. Additionally, trans men are equally at risk of the disease: 1% of our population is trans, so if one in nine women have endometriosis, that’s a significant number of trans men, which is a population of people who have different issues engaging with health-care and endometriosis services, which is another point of current research.
References
1. NICE guideline [NG73]. Endometriosis: diagnosis and management. National Institute of Health and Care Excellence (NICE) 2017 (https://www.nice.org.uk/guidance/ng73).
2. Dolińska W, Draper H, Othman L et al. Accuracy and utility of blood and urine biomarkers for the noninvasive diagnosis of endometriosis: a systematic literature review and meta-analysis. F&S Reviews 2023;4(2):116–130 (https://bitly.ws/3ezy4)
3. Rahmioglu N, Mortlock S, Ghiasi M et al. The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions. Nat Genet 2023;55(3):423–436 (https://www.nature.com/articles/s41588-023-01323-z).
4. Ellis K, Munro D, Clarke J. Endometriosis is undervalued: a call to action. Front Glob Womens Health 2022;3:902371 (https://bitly.ws/3ezye).
The expert
Dr Barbara Guinn PhD
Centre for Biomedicine,
Hull York Medical School,
University of Hull, Hull, UK
Email: B.Guinn@hull.ac.uk
