New drugs, research could offer ways to better detect and treat endometriosis

Diagnosis & Therapy

Article 1 of 10: New Drugs and Research

New drugs, research could offer ways to better detect and treat endometriosis

Promising biomarkers, increasing use of transvaginal imaging, and more rigorous assessment of pelvic pain are all shifting the field toward earlier diagnosis and individualized management.

BY CHRISTINE KILGORE

Endometriosis is a heterogeneous, often unrelenting disease that's ripe with uncertainty. It has been shown to be the most significant cause of chronic pelvic pain and a major cause of infertility. Yet it's not uncommon for the disease to go undiagnosed for 10 years or more, and treatment is far from straightforward, especially in the setting of infertility and among women with more severe disease.


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Perspectives on Endometriosis Management


"Right now there are more dilemmas than there are certainties," said Charles E. Miller, MD, who directs the Advanced IVF Institute and the Advanced Gynecologic Surgery Institute in metropolitan Chicago.

Yet for every uncertainty there are glimmers of hope. A renewed search for biomarkers, as well as efforts to better utilize imaging and to more rigorously assess pelvic pain, indicate a shift toward earlier, more thorough clinical diagnosis and better individualized management.

Medical options also are advancing. And there are global efforts to collect and share clinical, surgical, and epidemiological data on the disease - a push that is expected to help answer the many underlying and pertinent questions about the types and progression of disease.

Diagnosis: Strengthening an often-uncertain process

Over the past several decades, laparoscopy has revolutionized the ability to diagnose and treat endometriosis; even the most advanced and complicated cases can be treated laparoscopically today. However, the procedure's place as the reigning "gold standard" of definitive diagnosis, often coupled with histology, has left clinicians and patients frustrated.

While minimally invasive by surgical standards, laparoscopy still is an invasive and costly procedure with inherent risks - characteristics that deter many women from obtaining a diagnosis at all or at least until the disease has become severe, experts said.
Moreover, when laparoscopy is performed, lesions vary in appearance and can be difficult to identify - and subsequently to treat - in all but the more experienced hands.

There are even uncertainties with histology; a negative biopsy, according to current clinical guidelines, doesn't necessarily rule out the presence of disease.

"In the U.S. overall we do a lot of diagnostic laparoscopy for pelvic pain," said Dr. Miller. "But in my 30 years in the field, I'd say we're doing less diagnostic laparoscopy today than we ever have. There is more of a tendency to [manage suspected problems empirically] and to watch and observe."

Even with observation, the physician must remain vigilant, Dr. Miller added.
This stems not only from the nature of laparoscopy and its imperfections but because, for endometriosis, there's good evidence that pain associated with the disease can be eliminated or relieved with medications.

Therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) and continuous oral contraceptives (especially in young women who have dysmenorrhea) is a common front-line approach for symptom management, with laparoscopy being performed when pain persists.

In some cases, patients with persistent pain will move on to try a course of a GnRH agonist, or occasionally progestins or androgens, before undergoing laparoscopy.
Experts said that, clinically, the diagnostic process should be more proactive and rigorous than it sometimes is.

This means thoroughly assessing pain (Dr. Miller uses the Pelvic Pain Assessment Form of the International Pelvic Pain Society) and having a high index of suspicion for endometriosis when dysmenorrhea or other endometriosis-associated symptoms are more than mild.

"It's not normal for women to have so much pain that their quality of life is being impacted," said G. David Adamson, MD, who leads Palo Alto Medical Foundation Fertility Physicians of Northern California and is currently president of the World Endometriosis Research Foundation.

"If a patient has a little dysmenorrhea that's easily managed by an NSAID or oral contraceptive, it's possible but not probable that endometriosis will be a major problem for them at that time," he said. "But if she has dysmenorrhea, dyspareunia, dyschezia, or other pelvic pain that is causing a disruption in her life, whether it be school or work or physical activity or [sexual activity], it's important to have that suspicion and continue [investigating] ... with further history, physical exam, potentially [imaging], and any clinically indicated consultation."

Bruce Lessey, MD, PhD, of the Fertility Center of the Carolinas in Greenville, S.C., similarly advocates for greater awareness and suspicion of the disease. He believes that teenagers with severe dysmenorrhea "probably already have endometriosis" and maintains that endometriosis is to blame in most cases of "unexplained infertility."

Thinking beyond the "three Ds" would take diagnosis a huge step forward, he emphasizes. For instance, irritable bowel symptoms that are related to menstruation are "highly suggestive" of endometriosis and are often missed as such.

"When we look at these patients laparoscopically, they almost always have endometriosis on the posterior part of their pelvis near the bowel," said Dr. Lessey, also clinical professor of ob.gyn. at the University of South Carolina School of Medicine.

Endometriosis can masquerade as interstitial cystitis, he noted. Menstrual spotting several days before periods is another underappreciated sign of possible endometriosis; it is indicative of progesterone resistance, which is gaining increasing attention for its likely role in the pathogenesis of the disease and the development of unexplained recurrent pregnancy loss, he said.

Unarguably, the best path to a robust clinical diagnostic process would entail use of a sensitive and specific biomarker or panel of biomarkers, preferably measured through a blood test, to reliably indicate the presence of disease.

Research conducted during the 1990s was disappointing, but experts say that evolving knowledge of endometriosis, as well as new technology, give current research more promise.

"There's a push all over the world to find a marker for diagnosis. It's difficult, because endometriosis is a pelvic disease, not a systemic disease ... and we still don't know precisely the etiology of its different [phenotypes]," said Mauricio Abrao, MD, director of the endometriosis division at Sao Paulo University in Brazil. "But I think that in the next 5-10 years we may have something helpful."

As part of his research on endometriosis and infertility, Dr. Lessey, for instance, has reported that a protein called BCL6 (B-cell lymphoma protein-6) is markedly upregulated in the endometrium of women with the disease, leading to progesterone resistance, and that it appears to be superior to beta-3 integrin (a biomarker currently used in fertility clinics) in predicting endometriosis and implantation failure in IVF.

A test for BCL6 would be somewhat invasive, requiring an endometrial biopsy. Whether such a test will offer a clinical advantage in endometriosis diagnosis remains to be seen.

MicroRNAs are among other potential biomarker candidates. The short non-coding RNA molecules are "much more specific to particular tissue types [and diseases] than inflammatory biomarkers have been" and can be detected with a blood test, said Hugh S. Taylor, MD, chair of obstetrics, gynecology and reproductive sciences at Yale University, New Haven, Conn.

Researchers there have been looking for serum microRNAs that distinguish women with endometriosis from those without the condition. Thus far, it appears that one particular microRNA - microRNA 125b-5p - has potential as a single diagnostic biomarker for the disease.

While biomarker research proceeds, transvaginal ultrasound has gained an increasingly firm place in the diagnostic armamentarium, at least for moderate and severe disease. "The ubiquity of transvaginal ultrasound in the [American] ob.gyn.'s office has enabled more doctors to diagnose endometriomas," said Dr. Adamson. "And in the past 5-10 years, we've improved our ability to diagnose and quantify infiltrative endometriosis in the pelvis."

In Brazil, Dr. Abrao has been a leader in the use of transvaginal ultrasound (TVUS), training sonographers, radiologists, and ob.gyns. to use simple ultrasound with bowel preparation to diagnose and understand endometriosis. With experience, he maintains, imaging can be used to quantify the disease - to define its size and site - and to make prelaparoscopic treatment decisions about whether to proceed with surgery or wait, and about how conservative or aggressive surgery should be.

"With deep endometriosis, we can recommend precisely what should be done to reduce complications, and prepare the patient and the team," he said.

Imaging's shortfall is that it cannot detect mild or superficial peritoneal disease. Biomarkers might eventually help, but in the meantime there's a troubling gap. Dr. Lessey has begun using methylene blue dye with laparoscopy to find "subtle, almost invisible forms" of endometriosis in women who have persistent pelvic pain. A blue-stained area indicates a loss of peritoneal integrity, he believes. Removal of this tissue has eliminated pain for his patients, he said.

While some women with endometriosis remain asymptomatic over time, "others with small amounts may be affected profoundly," Dr. Lessey said.

Management: Resolving dilemmas

Surgical management of endometriosis is undoubtedly the most definitive approach. "What's very clear now is that hormones only treat symptoms. There's no evidence that [our current medications] can treat the disease," Dr. Abrao said. "In the past, many clinicians would think about hormone treatment for reducing the course of disease, the size of disease ... but there are no studies showing this is true."

The literature on surgical treatment has provided surgeons with more food for thought than evidence; it is replete with small, often poorly controlled single-center studies that offer conflicting conclusions about outcomes and best approaches.

Part of the problem, experts said, is that there's currently no system for classifying or staging endometriosis that can be used in diagnosis to predict and compare outcomes. "Right now we can't talk adequately with each other," Dr. Miller said.

It appears that deep infiltrative endometriosis (DIE) - widely regarded as one of two common phenotypes of moderate-severe disease - can be successfully treated, but surgery is complicated, especially when the bowel is involved.

There's little consensus on best approaches, and there's an ongoing debate about shaving nodules as opposed to segmental bowel resection.

What has become increasingly clear, Dr. Miller said, is that bowel surgery for endometriosis "requires a multispecialty approach involving urology and colorectal surgery."

Ovarian endometriomas, the other common phenotype of moderate to severe disease, can be particularly vexing for women who want to maintain their fertility. On one hand, these cystic structures "almost certainly reduce ovarian reserve over time by damaging the ovary," Dr. Adamson said. On the other hand, the process of removing endometriomas can also harm normal tissue and pose a risk of infertility.

In the last 5-10 years, the scale has tipped toward a more conservative approach to removal. "There's increasing recognition that, especially for smaller endometriomas, surgery poses more risk of damage to the ovary and ovarian reserve than benefit," he said. "Today, unless there's a compelling reason, we generally do not operate on 2- to 4-cm endometriomas ... and we're cautious even with the 4-cm cysts."

In the context of infertility, however, "it's not only about size," Dr. Miller said. "If the actual follicle count is quite suppressed because of the endometrioma, then surgery has to be considered."

Overall, for women who have endometriosis-related infertility, surgery can improve pregnancy rates, but decisions are individualized and multifactorial. In the absence of pain, patients and physicians work together in deciding whether to take a surgical path initially, or move forward with assisted reproduction and come back to surgery if that fails.

There is "increasing acceptance of data" showing that women who have more severe disease and are planning to undergo an IVF cycle can potentially benefit from several months of ovarian suppression prior to IVF, according to Dr. Adamson.

With respect to surgical management overall, the option of postoperative hormonal therapy is also up for consideration. While it hasn't been proven to improve surgical outcomes, there aren't any proven harms either, according to recent practice guidelines on endometriosis management from the European Society of Human Reproduction and Embryology (Hum Reprod. 2014 Mar;29[3]:400-12).

"We should do surgery with the goal of limiting subsequent recurrence, and to do that means cessation of menses," Dr. Lessey said. "Endometriosis does not come back quickly without menstrual cycles."

New oral GnRH antagonists under development may soon offer patients another option for ovarian suppression. Like GnRH agonists, the new drugs block production of ovarian-stimulating hormones, lowering estrogen and preventing menstruation.

But their anti-estrogen effect is immediate and there doesn't appear to be problems with osteopenia as there are with GnRH agonists. Moreover, the new drugs are oral rather than intramuscular.

In the future, there may be other completely different options, Dr. Taylor noted. "As we understand the biology better, we can probably start to target pathways that [reduce disease expression] without having to render someone [artificially] menopausal," he said.

Dr. Adamson is a consultant to Abbvie, Bayer, and Ferring. Dr. Lessey is a scientific adviser to Pfizer, AbbVie, and CiceroDx. Dr. Miller is a consultant for and is involved in a research study with AbbVie. Dr. Abrao served on the advisory board for Bayer Schering in 2014 and for AbbVie in 2014, and as a consultant for Olympus in 2016. Dr. Taylor is a consultant for Abbvie, ObsEva, Pfizer, Euroscreen, and OvaScience.

Christine Kilgore is a contributing writer for Ob.Gyn. News.

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