Expert Interview

Multifactorial Effects of Endometriosis as a Chronic Systemic Disease

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Can you talk about your research thus far and what your overall lab work has shown regarding endometriosis as a chronic systemic disease?

Dr. Flores: Endometriosis has traditionally been characterized by its pelvic manifestation however, it is important to understand that it is profoundly more than a pelvic disease—it is a chronic, systemic disease with multifactorial effects throughout the body.

We and other groups have found increased expression of several inflammatory cytokines in women with endometriosis. Our lab has found that compared to women without endometriosis, women with endometriosis not only have certain inflammatory cytokines elevated but also have altered expression of microRNAs. MicroRNAs are small noncoding RNAs that bind to and modulate translation of mRNA. To help determine whether these miRNAs were involved in mediating increased expression of inflammatory cytokines in women with endometriosis, we then transfected these miRNAs into a macrophage cell line, and again found altered inflammatory cytokine expression. We and others have also found a role for stem cells (from bone marrow and other sources) in the pathogenesis of endometriosis. In addition, we have found that in endometriosis, women have a low body-mass index and altered metabolism, which is related to induction of induction of hepatic (anorexigenic) gene expression and microRNA-mediated changes in adipocyte (metabolic) gene expression. Furthermore, we have found altered gene expression in regions of the brain associated with anxiety and depression and altered pain sensitization. Taken together, this work helps provide support for the systemic nature of endometriosis.

How can your findings in this space help us in diagnosing clinically and ultimately avoid diagnostic delay?

Dr. Flores: It’s about understanding that endometriosis is not just a pelvic disease and understanding that endometriosis is leading to inflammation and altered expression of miRNAs which allows endometriosis to have long-range effects. For example, women with endometriosis commonly have anxiety and depression and low BMI. As mentioned earlier, we have found that in a murine model of endometriosis, there is altered gene expression in regions of the brain associated with anxiety and depression and altered metabolism in a murine model of endometriosis. Other groups have also found changes in brain volume in these same areas in women with endometriosis, and we have seen low BMI in women with endometriosis. In fact, a common misconception was that being thin was a risk factor for endometriosis, however we have found that the endometriosis itself, is causing women alteration in genes associated with metabolism.

With respect to the endometrium, in addition to being a pelvic pain disorder, we also see that women with endometriosis have a higher likelihood of having infertility. And we think that's in part because one, just like the lesions can be resistant to progesterone, the endometrium of these women can also be resistant to progesterone. Progesterone is necessary for decidualization/implantation. We have also seen that stem cells can be recruited and ultimately incorrectly incorporated into the endometrium, which may also contribute to infertility in women with endometriosis.

If we can understand this multifactorial nature of endometriosis, I think this will help us not only shift toward diagnosing endometriosis clinically, but also avoid diagnostic delay. If we can understand that endometriosis is not just a pelvic disorder, but that It can also involve altered mood, bowel/bladder symptoms, inflammation, altered metabolism and/or cause infertility, I think that will ultimately help us to diagnosing earlier.

In addition, we can also utilize pelvic pain symptomatology to help with diagnosis as well. We can ask about cyclic pelvic pain that's been getting progressively worse over the years, not responding to non-steroidal anti-inflammatory medications. Also, in understanding that endometriosis can affect other organs, asking about cyclic pain/symptoms in other areas, such as cyclical bowel or bladder symptoms.

Thinking about the fact that if you do have a patient like that, you're seeing that they have altered mood symptoms, or alterations in inflammatory markers. Maybe that will help us shift from a disease that was typically only considered to be diagnosed by surgery, by switching to a clinical diagnosis for endometriosis. Doing that will hopefully help avoid diagnostic delay.

If we understand that while we typically describe endometriosis as causing cyclic pain symptoms, sometimes because of the existing diagnostic delay, ultimately women can present with chronic pelvic pain. Thus, it's also important to ask patients presenting with chronic pelvic pain what the symptoms were like beforehand (i.e., was the pain cyclic and progressively worsening over the years/before it became chronic) doing so will also help in terms of diagnosing sooner.

Lastly, circulating miRNAs have been considered promising biomarker candidates because they are stable in circulation and have highly specific expression profiles. We have found that the combination of several miRNAs reliably distinguished endometriosis patients from controls, and a prospective, blinded study showed that the combination of several miRNAs could be used to accurately identify patients with endometriosis, with an area under the receiver operating characteristic curve of 0.93.

Roughly 11%, or more than 6.5 million, women in the United States between the ages of 15–44 years, may have endometriosis. Is this disease more common in any particular age range or ethnicity?

Dr. Flores: We’re actually actively investigating that right now. And I think what makes it challenging, especially with respect to the age range, is now we're -- I think in part because of so much more awareness and more research is being done looking at this disease as a chronic systemic disease-- we're now starting to see/diagnose adolescents with endometriosis.

I think as we start gathering more information about these individuals, we'll be able to better say if there is a particular age range. Right now, we usually say it's in the reproductive years, however for some women it may be later if they were not diagnosed earlier. Conversely, some who are hopefully reading this, and also who conduct research on endometriosis, may be able to diagnose someone earlier that may have been missed until they were in their 30s or 40s, for example.

With respect to ethnicity, I'm the task force leader for diversity, equity, and inclusion in research and recruitment. This is something that I'm actively starting to work on, as are other groups. I don't have the answer for that yet, but as we continue to collect more data, we will have more information on this.

What are some of the existing hormonal therapies you rely upon as well as the biomarkers in predicting response to treatment, and are there any new research or treatments on the horizon?

Dr. Flores: I'll first start by telling you a bit about our existing treatment regimens, and then how I decide who would benefit from a given one. First line has always been progestin-based therapy, either in the form of a combined oral contraceptive pill or as progesterone only pills. However, up to 1/3 of women fail progestin-based therapy—this is termed progesterone resistance.

When progestin-based therapies fail, we then rely on other agents that are focused more on estrogen deprivation because, while we don't know the complete etiology of endometriosis, we do know that it is estrogen-dependent. There are two classes— gonadotropin releasing hormone (GnRH) agonists and GnRH antagonists. The agonist binds to the GnRH receptors, and initially can cause a flare effect due to its agonist properties, initially stimulate release of estradiol, and ultimately the GnRH receptor becomes downregulated and estradiol is decreased to the menopausal range. As a result we routinely provided add-back therapy with norethindrone to help prevent hot flashes and ensure bone protection.

Within the past three years, there has been a new oral GnRH receptor antagonist approved for treating endometriosis. The medication is available as a once a day or twice a day dosing regimen. As this is a GnRH antagonist, upon binding to the GnRH receptor, it blocks receptor activity, thus avoiding the flare affect; essentially, within 24 hours, there is a decrease in estradiol production.

As two doses are available, you can tailor how much you dial down estrogen for a given patient. The low dose lowers estradiol to a range of 40 picograms while the high (twice a day) dosing lowers your estrogen to about 6 picograms. Also, although it was not studied originally in terms of giving add-back therapy for the higher dose, given the safety (and effectiveness) of add-back therapy with GnRH agonists we are using the same norethindrone add-back therapy for women who are taking the GnRH receptor antagonist.

The next question is, how do we decide which medication a given patient receives? To answer that, I will tell you a bit about my precision-based medicine research. As mentioned before, while progestin-based therapy is first-line, failure rates are high, and unfortunately, we previously have not been able to identify who will or will not respond to first-line therapy. As such, I decided to assess progesterone receptor expression in endometriotic lesions from women who had undergone surgery for endometriosis, and determine whether progesterone receptor expression levels in lesions could be used to predict response to progestin-based therapy. I found that in women that had high levels of the progesterone receptor, they responded completely to progestin-based therapy-- there was a 100% response rate to progestin-based therapy. This is in sharp contrast to women who had low PR expression, where there was only a 6% response rate to progestin-based therapy.

While this is great with respect to being able to predict who will or will not respond to first line therapy, the one limitation is that would mean that women have to undergo surgery in order to determine progesterone receptor status/response to progestin-based therapy. However, given that within two to five years following surgery, up to 50% of women will have recurrence of pain symptoms, where I see my test coming into play is postoperatively. This is because many times , women who had pain, or who were failing a given agent, are placed back on that same medical therapy they were failing after surgery. Usually that was a progestin. Therefore, instead of putting them on that same therapy that they were failing, we can use my test to place them on an alternative therapy (such as a GnRH analogue) that more specifically targets estradiol production.

In terms of future directions with respect to treatment, there is a microRNA that has been found to be low in women with endometriosis—miRNALet-7b. In a murine model of endometriosis, we have found that if we supplement with Let-7, there is decreased inflammation and decreased lesion size of endometriosis. We have also found that supplementing miRNA Let-7b in human endometriotic lesions results in decreased inflammation in cell culture.

That would be future directions in terms of focusing on microRNAs and seeing how we can manipulate those to essentially block inflammation and lesion growth. Furthermore, such treatment would be non-hormonal, which would be a novel therapeutic approach.

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