8 March 2022
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The theme of International Women’s Day 2022 was “Break the Bias”, with the overarching aim of promoting gender equality. Women’s health is an area that has suffered from gender bias for years. One reason for this is that many female health conditions, such as menstruation, menopause and pregnancy, have traditionally been treated as taboo subjects. This has restricted discussion of these topics and has blocked investment and research into them, leading to persistent and widespread misunderstanding, mistreatment and misdiagnosis.

Coinciding with International Women’s Day 2022, March 2022 was also Endometriosis Awareness Month. This blog examines this common, yet often misunderstood, condition.

What is endometriosis?

Endometriosis is a condition in which tissue similar to the lining of the womb grows in other places around the body, including anywhere within the pelvic cavity (such as the ovaries and fallopian tubes), the bladder, the bowel, and even the lungs. Considering how poorly understood it is, endometriosis is shockingly common – affecting 1 in 10 women worldwide[1]. Its symptoms vary widely and can be very debilitating. These may include pelvic pain, nausea, fatigue, constipation and impaired fertility. The most common symptom is pelvic pain, which may correlate with the menstrual cycle, but can also be unpredictable and occur at any point during the cycle.

Diagnosis is often complicated by this unpredictability, as well as symptoms which overlap with other conditions, often resulting in underdiagnosis, or misdiagnosis of appendicitis or bad period pain. Additionally, severity of symptoms often has little correlation with the extent of endometrial lesions. Taken together, this means that on average, women in the UK wait 8 to 12 years for a diagnosis, by which time their condition may have progressed to such a state that drastic surgery is required. Moreover, the gold-standard for diagnosis is a laparoscopy (key-hole surgery), an invasive procedure.

Debilitating symptoms, compounded with long diagnosis times, can hugely compromise quality of life and impact the mental wellbeing of patients, leading to a high incidence of depression and anxiety. Endometriosis also presents a socio-economic burden, as the debilitating symptoms often lead to lost work productivity. In the UK alone, it is estimated that the total cost of endometriosis (in terms of lost work productivity and health care costs) is approximately £8.2 billion[2].

Causes

The precise cause of endometriosis remains unclear, although there are several theories. These include retrograde menstruation (where menstrual blood flows back through the fallopian tubes into the pelvic cavity, carrying endometrial cells with it) and cellular metaplasia (where cells change from one type to another). Endometriosis is multifactorial, and other causes may include immune system dysfunction, localised complex hormonal influences and genetics.

What are the current treatment options?

Currently there is no cure for endometriosis, and only limited treatment options. These are pain relief, hormone treatment and surgery. Although helpful for some women, these treatment avenues may have long-term complications.

Pain relief

Most endometriosis-related pain is caused by inflammation, which is in part driven by high levels of prostaglandins, such as PGE2. Non-steroidal anti-inflammatory drugs (NSAIDs) are therefore widely prescribed for endometriosis. However, clear instructions must also be provided because NSAIDs merely stop production of prostaglandins and so are only effective if taken before the pain symptoms occur. Analgesics are only a short-term treatment and do nothing to treat the underlying causes.

Hormone treatments

Endometriosis is driven by oestrogen, and so many treatments options involve hormones. These include the combined pill, the contraceptive patch, an intrauterine system (IUS) and gonadotrophin-releasing hormone (GnRH). However, these treatments are not suitable if the patient is trying to conceive. They also do not offer long-term relief and so must be taken continually.

Surgery

Surgical treatment includes cutting away endometriosis tissue to alleviate symptoms, as well as remove part or all of organs affected by tissue growth. Hysterectomy is a common route, but this irreversible surgery means the patient will no longer be able to conceive. Surgery may also be complicated by fibroids or adenomyosis, two common endometriosis comorbidities. Surgery may offer only temporary symptom relief, with a high recurrence rate of 50% after 5 years[3].

What is the Future?

Awareness of endometriosis is gaining traction. This is evidenced by a recent announcement by the EU to award 6 million euros for endometriosis research to the Finding Endometriosis Using Machine Learning (FEMaLe) project, a multidisciplinary collaboration which aims to improve endometriosis diagnosis and prevention, by identifying the biological subtypes of endometriosis using digital tools. Importantly, the project also aims to support dialogue between patients and health care professionals, to enable patients’ voices to be heard.

Treatment

A lot of treatment research is focused on discovering non-hormonal drug targets, to improve options for women of child-bearing age.

One potential target is the neuropeptide S receptor 1 (NPSR1) gene. The presence of rare variants of this gene were found to correlate with endometriosis in mice, rhesus monkeys, and humans[4]. Building on this insight, an NPSR1 inhibitor reduced inflammation and abdominal pain in animal models, making NPSR1 a potential non-hormonal drug target.

Researchers at the University of Edinburgh have discovered that human peritoneal mesothelial cells (HPMCs) recovered from the pelvic peritoneum of women with endometriosis display altered metabolism[5]. Interestingly, these changes had many parallels with the metabolic adaptations seen in cancer cells. For example, the peritoneal fluid (PF) of women with endometriosis was found to have elevated TGF-β1 and lactate. TGF-β1 drives cancer cells to switch from normal mitochondrial respiration to glycolysis, which drives increased production of lactate. Lactate is thought to contribute to cell invasion, angiogenesis, and immune suppression in tumours, all of which are implicated in endometriosis. Following on from this, the researchers found that the anti-cancer drug dichloroacetate was able to reverse glycolysis in HPMCs from endometriosis patients and to reduce endometriosis lesion size in mouse models. This is currently being investigated further in a clinical trial[6].

Diagnosis

Improved diagnostic procedures are needed, both to reduce the wait time for diagnosis, and to avoid the need for invasive diagnostic surgery. Reducing time to diagnosis will improve access to treatment, as well as improve the mental wellbeing of women by providing them with a reason for their symptoms and access to ways to control them. With this aim, researchers at Endometriosis CaRe Oxford, a University of Oxford program, are looking into non-invasive biomarker diagnostic techniques.

Summary

Awareness of endometriosis must be raised for two main reasons.

Firstly, women themselves should be educated about endometriosis and its symptoms, so that they are empowered to seek out help from medical professionals. Some women may be suffering without knowing the cause and will not seek treatment, whilst others are dismissed as having merely bad period pain and lack the confidence and knowledge to persist in seeking help.

Secondly, we must raise awareness of the impact of endometriosis on women’s lives, both in society as a whole and in the medical profession. Society’s perspective of endometriosis must be reformulated. Too often endometriosis is treated as just a fertility issue, meaning it is only considered properly when a woman is trying to conceive. Instead, the effects of this condition must be understood and addressed throughout her whole life.

Initiatives such as Wellbeing of Women and Menopause Matters are helping to break down the stigma around areas like menstruation, menopause and pregnancy, and there are encouraging signs that investment is beginning to flow towards women’s health. For example, Mirvie, a health technology platform that predicts pre-eclampsia in pregnant women, has raised $30 million in early-stage financing since 2018, as we reported recently. Other FemTech products such as Clue and Natural Cycles have been hugely successful. In addition, the UK government has recently published the Vision for Women’s Health, which, among other initiatives, appointed a Minister for Women’s Health to raise the profile of women’s health and increase awareness of previous taboo topics.

This means that now is a hugely exciting time in women’s health, and it is to be hoped that research funding and education will help the many women living with endometriosis.

 



References

  1. Zondervan KT, Becker CM, Missmer SA. Endometriosis. N Engl J Med 2020; 382:1244-56
  2. Simoens S, et al. The burden of endometriosis: costs and quality of life of women with endometriosis and treated in referral centres. Hum Reprod 2012;27:1292-9
  3. S. W. Guo, Recurrence of endometriosis and its control. Hum. Reprod. Update 15, 441–461 (2009).
  4. Tapmeier T, Rahmioglu N, et al. Neuropeptide S receptor 1 is a nonhormonal treatment target in endometriosis. Sci Transl Med 2021;13(608)
  5. Horne, A. W., Repurposing dichloroacetate for the treatment of women with endometriosis. PNAS 116 (51) 2019
  6. https://clinicaltrials.gov/ct2/show/NCT04046081?term=NCT04046081&draw=2&rank=1
Fay is a trainee patent attorney in our life sciences team. She has an undergraduate BSc degree in Biochemistry from the University of Bristol and a PhD in Biological Sciences from the University of Cambridge. During her undergraduate degree, Fay undertook a one year industry research placement in synthetic biochemistry, developing alternative protein expression systems in bacteria. Her doctoral research focused on mitochondrial dysfunction, particularly mitochondrial metabolism during ischaemia-reperfusion injury and heart transplant. Fay joined Mewburn Ellis LLP in 2019.
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