The Potential of Non-Invasive Biomarkers for Early Diagnosis of Asymptomatic Patients with Endometriosis, 2021, Kimber-Trojnar et al.

[SNT Gatchaman]

The Potential of Non-Invasive Biomarkers for Early Diagnosis of Asymptomatic Patients with Endometriosis
Kimber-Trojnar, Żaneta; Pilszyk, Aleksandra; Niebrzydowska, Magdalena; Pilszyk, Zuzanna; Ruszała, Monika; Leszczyńska-Gorzelak, Bożena

Endometriosis is a disease that affects women of reproductive age and has a significantly negative impact on their well-being. The main symptoms are dysmenorrhoea, chronic pelvic pain and infertility. In many patients the diagnostic process is very long and can take up to 8–12 years. Laparoscopy, an invasive method, is still necessary to confirm the diagnosis. Therefore, development of more effective diagnostic markers appears to be of the utmost importance for early diagnosis of endometriosis and provision of appropriate treatment.

From a clinical point of view, detection of early-stage endometriosis in asymptomatic patients is an ideal situation since early diagnosis of endometriosis may delay the onset of symptoms as well as prevent progression and complications. In the meantime, Cancer Antigen 125 (CA-125) is still the most frequently studied and used marker. Other glycoproteins, growth factors and immune markers seem to play an important role. However, the search for an ideal endometriosis marker is still underway. Further studies into the pathogenesis of endometriosis will help to identify biomarkers or sets of biomarkers with the potential to improve and speed up the diagnostic process in a non-invasive way.

Link | PDF (Journal of Clinical Medicine)

 

[SNT Gatchaman]

Recording a couple of quotes as endometriosis and dysregulated menstrual cycles seem to be reported in ME and LC —

Activin A is a growth factor belonging to the transforming growth factor β (TGF-β) family. Physiologically, it is produced by the healthy endometrium and its expression reaches peak values in the secretory phase of the menstrual cycle. Activin A promotes the process of decidualization and is also believed to play a role in the immunological processes of the cells involved in the pathogenesis of endometriosis. It has been noticed that in endometriosis, the level of activin A increases both in the eutopic and ectopic endometria. The greatest increase was observed in ovarian endometrioma in comparison with the other types of endometriosis, but in comparison to the controls, its growth was not sufficient enough to be used as a marker.

Natural Killer (NK) cells may play an important role in the pathogenesis of endometriosis. They are believed to be responsible for the clearance of regurgitated endometrial cells from the peritoneal cavity. It has been observed that patients with endometriosis have reduced NK cell cytotoxicity. This suggests that NK cell dysfunction may allow implantation of endometrial cells into the peritoneal cavity and lead to endometriosis.

 

[Hutan]

Great to hear of some hope for early detection of endometriosis.

as endometriosis and dysregulated menstrual cycles seem to be reported in ME and LC

It's frustrating that we still don't even have decent information about this. At least I don't think we do. Do you know of anything SNT? I really must make a list of research I'd like to see done. An epidemiological study on the frequency of endometriosis in people diagnosed with ME/CFS, and vice versa, compared to all females would be relatively easy, especially with a national database of patient records like the Taiwanese one. Does anyone know of anyone who could potentially do such a study?

I'm not even sure about the NK cell story.

 

[SNT Gatchaman]

I keep seeing menstrual dysregulation and pelvic pain in patient discussions, though I think it's not talked about more widely due to social constraints. It's also common to hear that LC symptoms worsen with menses. I haven't looked to see if it's been discussed or informally polled on S4ME. I suspect it's more widespread than we realise.

The hypotheses to explain endo have never been satisfactory. The explanation has to account for spread in the peritoneal cavity - OK - that's potentially direct spread in one body compartment. But then to the chest in the pleural space (catamenial pneumothorax) - well sure sometimes there are defects in the diaphragm and you can get pleural accumulations of CSF from a ventriculoperitoneal shunt. But then actually in the lungs or brain - now you have to surmise pseudometastatic spread or stem cells.

To my mind there seems to be symptomatic overlap and co-morbiidity between ME/LC and pelvic pain, endometriosis, polycystic ovarian disease, interstitial cystitis. Then you have drug findings like metformin being used in endometriosis and PCOS. It all suggests a hidden uniting aetiology relating to metabolism and in particular immunometabolism and resulting immune dysregulation and inflammation.

And the NK cell hypofunction, well that could be causal or simply an association with endo, but it seems like a well established observation in ME.

See Endometriosis as a Comorbid Condition in Chronic Fatigue Syndrome (CFS): Secondary Analysis of Data From a CFS Case-Control Study (2019, Frontiers in Pediatrics)

which concluded —

We found more than a third of women with CFS reported endometriosis as a comorbid condition. The endometriosis comorbidity was associated with chronic pelvic pain, earlier menopause, hysterectomy, and more CFS-related symptoms. However, endometriosis in women with CFS did not appear to further impact functioning, fatigue, inflammatory markers, or other laboratory parameters. Further investigations including younger women are warranted.

 

[SNT Gatchaman]

From Wikipedia —

Upregulation of Activin A drives pluripotent stem cells into a mesoendodermal fate, and thus provides a useful tool for stem cell differentiation and organoid formation

From Transforming Growth Factor-β Induced Warburg-Like Metabolic Reprogramming May Underpin the Development of Peritoneal Endometriosis (2014) —

It is recognized that endometriosis and tumorigenesis share clear parallels. During tumorigenesis, TGF-β can induce a shift in cell metabolism from mitochondrial oxidative phosphorylation to aerobic glycolysis, known as the “Warburg effect”. Neighboring cells of tumors are also programmed to use aerobic glycolysis by TGF-β1, and this process generates lactate, which feeds adjacent tumor cells, establishing an integrated metabolic tumor microenvironment. Overproduction of lactate increases cell invasion, angiogenesis, and immune suppression, all crucial steps in the development of tumors and known regulators of endometriosis.

Would be interesting to see if EBV/HHV-6 have been implicated in endometriosis, as dUTPase-induced upregulation of activin A could relate.

 

[Hutan]

See Endometriosis as a Comorbid Condition in Chronic Fatigue Syndrome (CFS): Secondary Analysis of Data From a CFS Case-Control Study (2019, Frontiers in Pediatrics)

On endometriosis in people with ME/CFS:
Endometriosis and ME/CFS
The discussion covers the 2019 paper noted above.

 

[Midnattsol]

I keep seeing menstrual dysregulation and pelvic pain in patient discussions, though I think it's not talked about more widely due to social constraints. It's also common to hear that LC symptoms worsen with menses. I haven't looked to see if it's been discussed or informally polled on S4ME. I suspect it's more widespread than we realise.

For some of us symptoms are at their best with menses Menses and follicular phase are usually when I function the best. I know others who say the same, but also here there is a social constraint that you shouldn't talk about it, and the added "women are at their worst with menses!" social idea still being strong (at least here).

I usually just chalk it up to changes in smooth muscle and blood flow depending on hormone status.

 

[Hutan]

Isn't it ridiculous that we have no good idea if ME/CFS symptoms change reliably with phases of the menstrual cycle or with pregnancy? Perfect natural experiments that might actually tell us something about the cause, and at least would give women some ideas of what to expect.

 

[rvallee]

Isn't it ridiculous that we have no good idea if ME/CFS symptoms change reliably with phases of the menstrual cycle or with pregnancy? Perfect natural experiments that might actually tell us something about the cause, and at least would give women some ideas of what to expect.

I saw this being reported with such high frequency I couldn't imagine it wouldn't get researched. It's reported many ways: more problems, fewer problems, longer, shorter. Many changes, all over the place. Hard to study, for sure, but it's hard to imagine scientists going "meh" over this, and simply not bothering.

I clearly lack imagination about the many ways people will fuck everything up. I can only remember a single study and it was about the effect of vaccines, obviously dismissing everything as psychological. It hasn't been studied at all. No one is even keeping track, there is no recorded data anywhere on this, so it's not even possible to look back retroactively on anything.

As an information specialist, I am baffled at how much data medicine just doesn't bother looking at, don't even want to record it in the first place. And almost everything they look at is selective. There is no more investigative research anymore, it's like the entire research paradigm has ended. It feels more like theology at times, only looking at familiar words, and barely at that.

Most crap companies selling garbage products out there with decades of customer, sales and production data. Kept everything just in case. All of this is being leveraged using machine learning. Meanwhile I guess that medicine really wants to save up on disk space, or something like that. Can't have large bases of data, too long to backup, I guess.

 

[Hutan]

There are a few problems contributing to this I think.

One is that so much of medicine is hopelessly out of date. Management systems, and data management systems, customer management systems were adopted in many industries decades ago. But they have not had the same uptake in medicine.

Part of the reason for that inadequate uptake is funding. But the whole system could have been made more efficient with good systems, so it's partly also a problem of a lack of foresight. Also, I think it's a problem with the people who become decision-makers. Often it's doctors who get promoted into leadership roles. They may have been great doctors, but that doesn't mean that they are great at organisation management, or data management. I've seen research suggesting that doctors are often dismissive of the expertise of people who don't have the same training as them, and also really don't like being told what to do by administrators.

The other thing is that there are a lot of very valid privacy issues in keeping medical records, making things much more complicated.

And another thing is that extensive, really accurate records can be a problem in an industry where mistakes are buried, and where legal action, involving as it does issues of life, death and lasting disablement, can be very traumatic and expensive. In a system where doctors have been used to writing whatever they wanted in patient notes, or not recording much, having a high degree of transparency and accountability isn't comfortable.

It's the fundamental lack of accountability, isn't it. I can see that doctors have needed to be protected from accountability in some ways, as it would be very hard to function if every single decision was going to be subjected to detailed evaluation. In many other industries, the consequences of poor performance are so much lower. But, if we look at industries like aviation, when the consequences of poor performance are dire and obvious, there are ways to strengthen systems, monitor performance and to learn from mistakes without necessarily laying the blame on individuals.

 

[SNT Gatchaman]

In many other industries, the consequences of poor performance are so much lower. But, if we look at industries like aviation, when the consequences of poor performance are dire and obvious, there are ways to strengthen systems, monitor performance and to learn from mistakes without necessarily laying the blame on individuals.

From Aviation and healthcare: a comparative review with implications for patient safety (2015, J Royal Soc Med) —

Convergence and divergence of safety-related behaviours across aviation and healthcare were derived and documented. Key safety-related domains that emerged included Checklists, Training, Crew Resource Management, Sterile Cockpit, Investigation and Reporting of Incidents and Organisational Culture. We conclude that whilst healthcare has much to learn from aviation in certain key domains, the transfer of lessons from aviation to healthcare needs to be nuanced, with the specific characteristics and needs of healthcare borne in mind. On the basis of this review, it is recommended that healthcare should emulate aviation in its resourcing of staff who specialise in human factors and related psychological aspects of patient safety and staff wellbeing. Professional and post-qualification staff training could specifically include Cognitive Bias Avoidance Training, as this appears to play a key part in many errors relating to patient safety and staff wellbeing.

 

[Hutan]

There's some great observations in that table in @SNT Gatchaman's post.

 

[SNT Gatchaman]

I could post that paper in a separate thread.

ETA: https://www.s4me.info/threads/aviat...ns-for-patient-safety-2016-kapur-et-al.32716/

 

[SNT Gatchaman]

Related potential biomarkers for endometriosis —

Fibronectin Molecular Status in Plasma of Women with Endometriosis and Fertility Disorders (2021, International Journal of Molecular Sciences)

The presence of FN-fibrin complexes with a molecular mass of more than 1300 kDa in women with endometriosis and infertility and the complete absence of these complexes in healthy women may indicate an increased and chronic activation of coagulation mechanisms in these patients.

Plasma and Peritoneal Fluid Fibronectin and Collagen IV Levels as Potential Biomarkers of Endometriosis (2022, International Journal of Molecular Sciences)

The concentration of fibronectin in the plasma (329.3 ± 98.5 mg/L) and peritoneal fluid (26.8 ± 11.1 μg/L) in women with endometriosis was significantly higher than in the control group (251.2 ± 84.0 mg/L, 7.0 ± 5.9 μg/L). Fibronectin levels were independent of endometriosis stage (p = 0.874, p = 0.469). No significant differences were observed in collagen IV levels (p = 0.385, p = 0.465).

The presence of elevated levels of fibronectin may indicate abnormalities in cell–ECM signalling during the course of endometriosis, and may be a potential biomarker for early detection.

 

[SNT Gatchaman]

The presence of FN-fibrin complexes with a molecular mass of more than 1300 kDa in women with endometriosis and infertility and the complete absence of these complexes in healthy women may indicate an increased and chronic activation of coagulation mechanisms in these patients.

Fibronectin and thrombosis: Fibronectin maintains the balance between hemostasis and thrombosis (2016, Cellular and Molecular Life Sciences)

Recent studies revealed that pFn is a vital hemostatic factor that is especially crucial for hemostasis in both genetic and anticoagulant-induced deficiencies of fibrin formation. pFn may also be an important self-limiting regulator to prevent hemorrhage as well as excessive thrombus formation and vessel occlusion. In addition to pFn, cFn is found to be prothrombotic and may contribute to thrombotic complications in various diseases.

So would elevated fibronectin be associated with more likelihood of thromboembolic disease in endometriosis? There doesn't seem to be much literature on endometriosis and thrombo-embolic disease that I could find, which suggests that it hasn't been on people's radar. However, perhaps elevated fibronectin might be generally protective against venous thromboembolism, as there are subtleties in how fibronectin interacts which could make it less likely (see first paper).

Endometriosis and thrombosis: Risk of venous thromboembolism in women with endometriosis (2022, Thrombosis Research)

Which concluded no significantly increased risk.

One VTE event, a massive fatal pulmonary embolism, occurred 8 days postoperatively, yielding a VTE incidence of 0.3 per 1000 person-years [95 % CI 0.0–1.4]. This incidence rate was lower than the expected rate of 2.7 per 1000 person-years, suggesting that a diagnosis of severe endometriosis is not associated with an increased risk of VTE.

However note the methodology —

533 consecutive women with a diagnosis of severe endometriosis based on histological and surgical criteria and whom all underwent laparoscopic surgery between January 2015 and December 2019. At time of surgery, all women were using hormonal therapy for management or pain alleviation of endometriosis. Follow-up started after surgery and ended if a VTE occurred or patients were lost to follow-up.

Eleven patients with a personal VTE history before the surgery were excluded.​

Excluding those who have already demonstrated a propensity to VTE might then under-represent the risk.