Endometriosis: New Research, New Directions

"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this 12-part journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

As endometriosis maintains its stranglehold on at least 10% of those born with a uterus worldwide, researchers are hopeful that heightened awareness of this systemic inflammatory condition will lead to routine screening, earlier diagnosis, increased research funding, and novel, non-hormonal treatments.

Wanted: A New Attitude in Education

According to Serdar Bulun, MD, chair of the Department of Obstetrics and Gynecology at Northwestern University in Chicago, medical training and textbooks need to be overhauled to address the burden of this disease.

"There's still a huge disconnect in the textbooks, with the thinking being that this is just primary dysmenorrhea of adolescence and it will magically disappear when a young woman reaches her early 20s," Bulun said. "But the probability is that a female fetus is already disposed to endometriosis in utero and if endometriosis is not recognized early, it will evolve into the full debilitating syndrome."

Another misconception in current medical training is that a bit of surgery will solve the problem. "We have to understand that endometriosis is preventable and treatable, but it is something a woman will have to live with for the rest of her life," Bulun said. "You can't just resect a few pieces of tissue and it will go way. That's what surgeons told patients back in 1980, and it has continued to trickle down into the textbooks used today."

Clinical Screening

Hugh Taylor, MD, chair of Obstetrics, Gynecology & Reproductive Sciences at Yale School of Medicine in New Haven, Connecticut, noted that targeted, endometriosis-specific questioning by doctors about menstrual periods will hasten diagnosis and should be part of every young woman's basic clinical examination.

"You can't just ask about pain, because pain is subjective and no one knows if their pain is worse than someone else's," he explained. Pointed questions should focus objectively on disability – for example, how much school, work, and social time is actually being lost to menstrual problems?

"Traditionally, there's been a terrible 10-year delay in diagnosis, and greater awareness among the public and professionals is key," Taylor continued. "We're just starting to recognize the total systemic nature of the disease so it can be correctly diagnosed. There's enough critical mass now to make a difference."

He said he agrees that the medical curriculum needs updating, but that's easier said than done as "everyone interested in change is looking to get a piece of the curriculum pie."

Biomarkers for Noninvasive Diagnosis

Many researchers are looking at genetic markers as harbingers of endometriosis. At the Feinstein Institutes for Medical Research in Manhasset, New York, the ROSE (Research Outsmart Endometriosis) group is assessing genetic markers associated with endometriosis by characterizing and comparing tissues from affected and unaffected women in hopes that such a classification will lead to a simple diagnostic tool.

Taylor said he is optimistic that the next few years will see a quick and easy blood test providing early diagnostic clarity. His team has been researching microRNAs. "There are about 20,000 of these in the circulation. They don't get translated into proteins but you can find the signatures of many diseases in them, including endometriosis," he said.

In 2020, Taylor and his Yale colleague Valerie Flores, MD, published a study in American Journal of Obstetrics & Gynecology showing that microRNA biomarkers reliably distinguished endometriosis from other gynecologic pathologies. Such a noninvasive assay could serve many women, reduce the time to diagnosis, surgical risk, decades of discomfort and lost time, disease progression, comorbidities, and healthcare costs, Taylor explained.

His team is also investigating why some patients do not respond to progesterone therapy. "Inflammation contributes to progesterone resistance, but it is not the whole story since some endometriosis remains resistant to progesterone even when we remove the inflammation in the lab," he said. Faulty precursor stem cells in the endometrium are another avenue of inquiry, and the group is targeting stem cells in animal trials.

New Treatments

The therapeutic holy grail are medications that do not involve estrogen suppression, the current mainstay of therapy. "Estrogen deprivation works, but it also deprives other organs like the brain of the estrogen they need to function properly," and it stops ovulation in women who want to become pregnant, Taylor said.

He said he foresees next-generation treatment evolving in two broad categories: immune modulators to get the immune system to reject extrauterine endometrial tissue and targeted molecular agents of the sort used in cancer therapy.

Hormone-based therapy will likely remain at the therapeutic core for this estrogen-driven disease for the foreseeable future, Bulun said. "Endometriosis is a function of ovulation and menstruation. If a drug doesn't stop that, it won't work."

He noted that risk is greater in modern women since they are exposed to far more menstrual cycles than their ancestors – with earlier menarche, fewer pregnancies, and less ovulation-suppressing breastfeeding, and longer lifespans. "The total number or menses over a woman's lifetime has increased 10-fold. But this is not a normal process from an evolutionary perspective. You don't need to have so many uninterrupted cycles," he said.

Bulun said he hopes the pharmaceutical industry can come up with strategies for interrupting ovulation/menses with minimal side effects and no impact on ovarian reserve. "The best we can do with current technology is decrease the severity of ovulation, so we need new options."

In the meantime, newer hormone-based treatments that block follicle-stimulating hormone and luteinizing hormone help decrease inflammation and pain, noted Adi Katz, MD, of Lenox Hill Hospital in New York City. "There are also several new studies looking at pain treatment with nerve-stimulating electrodes."

Alternatives to Surgery

Some women will always require the removal of unresponsive endometriotic adhesions, and minimally invasive nonsurgical procedures to do this are under investigation. Borrowing a page from the oncologist's handbook, a recent study adapted an experimental therapy called nanoparticle-mediated magnetic hyperthermia, which is used to remove cancerous tissue. The magnetic particles target vascular endothelial growth factor receptor 2, which abounds in endometriotic tissue. Delivered intravenously and targeted locally, the particles generate heat when exposed to an alternating magnetic field. At temperatures above 46°C, the endometriotic tissue dies within 20 minutes. This method appears to be safe and well-tolerated in humans and animals.

Curbing the Inflammatory Response

Controlling the systemic inflammation and associated pain of established endometriosis is another treatment goal. "Medication that goes beyond symptom management to disease treatment will likely be done with immunotherapy," Katz said.

Some researchers are homing in on a possible causative role for macrophages in endometriotic pain. For example, a U.K. team found that levels of the hormone insulin-like growth factor (IGF)-1 in pelvic cavity tissue from women with endometriosis were higher than in unaffected women and aligned with the severity of their pain scores. In cell culture experiments, the group showed that adding IGF-1 from macrophages promoted nerve cell growth and activation, and in mice with endometriosis blocking the cell receptor for IGF-1 reversed their previously observed pain behavior. Therefore, distinguishing potentially harmful macrophages from healthy ones may lead to targeted molecular treatments for pain.

A review by a Chinese team highlighted several therapeutic agents currently under investigation for application in endometriosis, including:

• Pentoxifylline, a methylxanthine with anti-inflammatory properties that acts as a phosphodiesterase inhibitor, has been proposed for treating endometriosis. This drug has long been used for cerebrovascular and peripheral vascular diseases, as well as other conditions involving defective microcirculation

• N-palmitoylethanolamine, a structural analog of anandamide, has anti-inflammatory, immunosuppressive, analgesic, neuroprotective, and antioxidant effects. It inhibits mast cell activation, blocking the crosstalk between mast cells and nociceptive nerve fibers peripherally. It downregulates microglial cell behaviors and thus reduces associated central pain hypersensitization and has successfully reduced pain due to chronic lumbosciatalgia

• Anti-angiogenic drugs used in cancer treatment to inhibit the growth of tumor-supporting blood vessels are another type under scrutiny for possible use in endometriosis. In addition, natural antioxidants such as grape-sourced resveratrol and immune-modulating biologics such as the tumor necrosis factor inhibitors used to treat psoriasis, rheumatoid arthritis, and Crohn's disease may mitigate endometriotic inflammation as well

Preliminary lab and mouse studies by a team that included Taylor and Flores found that the Janus kinase inhibitor tofacitinib (Xeljanz) reduced the burden of endometriotic lesions and might well prove effective in humans.

Rebalancing the Microbiota

Mounting evidence suggests that, as in other painful chronic diseases, the microbiota is important for proper immune function. A dysbiotic gut, and disruptions in other microbial milieus such as that of the reproductive tract, may foster the development of endometriosis, chronic pelvic pain, and subfertility.

The microbiome appears to affect estrogen regulation as modulated by the estrobolome, as well as inflammation and other endometriosis-promoting mechanisms within the genital tract.

This ecosystem also plays a role in the gut-brain axis, which mediates pain. One future option may be to manipulate colonies of bacterial, fungal, and viral microorganisms to increase strains associated with good immune function and the absence of endometriosis and reduce those linked to harmful immune-disturbing strains.

The microbiota of affected women does appear to differ. A study of human and animal microbiota found that bacteria were enriched and more diverse in endometriosis patients, although there was no consensus on which specific microbiota compositions were associated with the disease.

However, vaginosis-associated bacteria and Lactobacillus depletion in the cervicovaginal microbiome were associated with endometriosis and infertility in the majority of studies. Moreover, animal studies supported a bidirectional relationship between the gut microbiota and endometriosis onset and progression.

In other chronic pain conditions such as inflammatory bowel disease (IBD), exposure to antibiotics, artificial sweeteners, and chemical food additives have all been considered as possible contributors to immune dysfunction and the rising prevalence of IBD. A question is whether these dietary and other environmental exposures could also be immune-impacting culprits in endometriosis?

Reducing Environmental Exposures

Investigators such as Anna Pollack, PhD, MPH, of George Mason University College of Health and Human Services in Fairfax, Virginia, are seeking to clarify the possible role of different endocrine-disrupting chemicals involved in endometriosis in order to inform policies for reducing exposure and risk. Her group is comparing tissue samples from eutopic endometrium with those from ectopic endometrium, measuring for a range of chemical exposures to evaluate the dose of these chemicals in target tissue.

"Per- and polyfluorinated substances – or PFAS – are ubiquitous in many consumer products, and we found they were also ubiquitous in eutopic endometrial tissue," Pollack said. "While there was no evidence that PFAS in endometrial tissue were associated with the development of endometriosis, several were associated with the risk of more severe disease -- that is, American Society of Reproductive Medicine stages 3 or 4 versus stages 1 or 2." The next step may be to investigate if PFAS may be linked to disease subtype such as [superficial] endometriosis versus deep-infiltrating disease or endometriomas.

Other investigators are focusing specifically on diethyl hexyl phthalate, a chemical that commonly occurs in insecticides, cosmetics, and food packaging and is present in high levels in endometriosis patients.

Research Funding on the Rise

Endometriosis research has long suffered from underfunding, but that is starting to change. In 2020 Congress voted to double to $26 million the existing funding for endometriosis, which in 2019 was only $13 million, which equated to less than $1 per year for each diagnosed U.S. patient.

Increasing recognition among members of the public and the medical profession is a first essential step. "The biggest obstacle we face is still lack of awareness of this common condition," Taylor said. "About two-thirds of patients will respond to a simple birth control pill, and if we can catch endometriosis early before it evolves into the full syndrome, we can help a lot of women."

Katz is optimistic that there may even eventually be a cure for endometriosis: "If we can understand the disease process, if we can identify what causes endometriosis to grow and implant, and how the immune system responds, we can successfully block the development of endometriosis," she said.

Read the previous installments of this series:

Part 1: Endometriosis: Understanding the Pathogenesis and Pathophysiology

Part 2: Diagnosing Endometriosis

Part 3: Managing Endometriosis: Research and Recommendations

Part 4: Case Study: Endometriosis or Hernia?

Part 5: Endometriosis: Fertility and Pregnancy

Part 6: The Latest on What to Know About Managing Endometriomas

Part 7: Enhancing the Doctor-Patient Dialogue About Endometriosis

Part 8: Case Study Mystery: Swollen, Painful Belly Button During Menstruation

Part 9: Endometriosis: Why Is Research Funding So Low?

Part 10: Endometriosis's Links to Inflammatory Conditions and Other Diseases

Part 11: Endometriosis: Mitigating Risk, Progression, and Severity