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Yale Medicine Magazine, Spring 2024 (Issue 172) Women's Health Special Report
by Isabella Backman


Changing the trajectory of a painful systemic disease.

Even though endometriosis—a condition in which tissue similar to that lining the uterus grows outside the uterus—is among the most common gynecological conditions, it remains one of the most misunderstood and misdiagnosed.

Time and again, as far back as the age of Hippocrates, physicians have failed to recognize endometriosis as a real disease with underlying physical causes and often blamed women for the debilitating symptoms they experienced.

“The now-discredited mystery disorder, presumed for centuries to be psychological in origin, was most likely endometriosis in the majority of cases,” wrote Ceana Nezhat, MD, and his colleagues in a 2012 article in Fertility and Sterility. “If so, then this would constitute one of the most colossal mass misdiagnoses in human history, one that over the centuries has subjected women to murder, madhouses, and lives of unremitting physical, social, and psychological pain. The number of lives that may have been affected by such centuries-long misdiagnoses is staggering to consider, likely involving figures in the multiple millions.”

While one might assume that the ancient perspective on endometriosis and chronic pelvic pain is a relic of the past, that’s not necessarily true. Researchers estimate that over 10% of all women of childbearing age live with endometriosis—over 190 million adults worldwide. While initial complaints often include painful periods and/or infertility, in reality the disease has a vast number of other symptoms, many of which extend beyond the pelvis to other regions of the body. For some women, the pain correlates with their menstrual cycle; for others, symptoms are constant. And too many patients with endometriosis suffer severe, debilitating symptoms that drastically reduce their quality of life.

Unfortunately, the dismissive and demeaning attitudes of some physicians toward endometriosis is not just something that used to happen; it remains prevalent today. On average, it takes women 10 years to receive an accurate diagnosis of endometriosis, and many see at least four or five doctors before their pain is taken seriously.

Now, emerging research has demonstrated that endometriosis is a chronic, systemic disease with multiple manifestations affecting the entire body. At Yale School of Medicine (YSM), Hugh Taylor, MD, Anita O’Keeffe Young Professor of Obstetrics, Gynecology, and Reproductive Sciences and professor of molecular, cellular, and developmental biology, and department chair, specializes in identifying the dozens of symptoms of endometriosis, explaining why these symptoms occur, and advocating for recognition of the severe pain caused by the disease.

“Menstrual cramps are the only pain that we as human beings accept as normal,” says Taylor. “Any other pain would prompt one to seek medical attention, but here we have pain that we’ve normalized. Thus, the pain of endometriosis is too often underappreciated and underrecognized by physicians, other health care providers, and even by patients and their families.”

Misplaced endometrial cells

Researchers currently think that most cases of endometriosis result from what they call “retrograde menstruation.” This condition occurs when cells from the uterus and other menstrual debris flow backward out of the fallopian tubes and settle in the abdomen, where they implant and grow.

The pain of the disease may be caused by several different mechanisms. The cells may implant around nerves, irritating or compressing them. The endometrial cells may also produce inflammatory molecules that irritate and inflame the surrounding tissue. Over the long term, this inflammation can lead to scarring and adhesions, which create further pain. “Endometriosis can eventually lead to the pulling and twisting of tissues,” says Taylor. “This distorted anatomy can also cause pain.”

Sometimes, physicians even find endometrial cells outside the abdominal cavity, lodged within the lungs or even in the brain, for example. Taylor’s lab was the first to describe that some cases of endometriosis may also originate from stem cells. Usually, stem cells are mobilized to repair areas of inflammation or injury in the body. His group has found, however, that they also deliver certain molecules that promote the growth of endometriosis lesions. “The lesions of endometriosis may be perceived by the body like an injury,” says Taylor. “The stem cells are drawn there to repair the body, but in reality, they’re helping to promote the endometriosis.”

New research is revealing that endometriosis is not just a gynecologic disease, but rather a widespread inflammatory disorder. Taylor’s lab has found that the disorder communicates with the body in numerous ways. The disease, for example, secretes small RNA molecules called microRNAs that travel to organs beyond the pelvis, where they can alter gene expression. Endometriosis can also activate macrophages and other immune cells that induce whole-body inflammation. Based on these insights, Taylor’s team is currently exploring new anti-inflammatory therapies, including repurposing drugs used for other inflammatory conditions.

Genetics: complex and poorly understood

Studies on twins show that genetic factors account for approximately 50% of a woman’s risk of developing endometriosis. But the disease itself can’t be attributed to a single gene or two. “There’s certainly a familial tendency toward endometriosis. But it’s not like breast cancer where you can find a gene such as BRCA—which causes breast cancer in a large percentage of women living with it—and identify who is going to develop it,” says Taylor. “We believe endometriosis is polygenic with multiple genes that all have a net contribution.” In future studies, Taylor hopes to better understand the multitude of genes that interact to cause endometriosis so that his team can identify targets for potential therapy, “but we’re not there yet,” he says.

Furthermore, studying the genetics of endometriosis may also help researchers better understand its association with comorbid conditions. For example, a January 2023 JAMA Network Open publication has identified gene aberrations in women with endometriosis that overlap with psychiatric conditions. In other words, genetic commonalities may partially explain why endometriosis patients also have higher incidences of depression, anxiety, and eating disorders. “The epidemiological associations between endometriosis and these psychiatric traits are not only due to experiencing chronic pain, but also underlying biological and genetic mechanisms,” says Dora Koller, PhD, a postdoctoral fellow at YSM and first author of the study.

Symptoms extend far beyond the pelvis

Endometriosis typically begins to manifest as extremely painful periods. This pain, however, may extend to the intervals between periods and occur in places outside the uterus. Symptoms may include pelvic pain, back pain, bladder pain and frequent urination, painful bowel movements and other gastrointestinal issues, and fatigue. But doctors often fail to consider endometriosis when women seek help for their specific range of symptoms. For instance, a urologist or gastroenterologist may not immediately associate their patients’ bladder or digestive symptoms with endometriosis. “It’s like the blind men with the elephant analogy,” says Taylor. “Everyone looks at their own aspect of the disease rather than the big picture.”

Endometriosis is also linked to depression and anxiety. Unfortunately, many doctors blame the pain women experience on these mental symptoms. However, when Taylor’s laboratory team induced endometriosis in mice, the animals shortly developed depression and anxiety. “Depression and anxiety are directly caused by the disease,” he emphasizes.

In some women, the first sign of endometriosis is difficulty getting pregnant; they experience no pain, but infertility brings them to a doctor who ultimately diagnoses endometriosis as the reason they’ve been unable to conceive or carry a child. In other cases, women who had been previously dismissed when they go to the doctor with painful symptoms finally receive a diagnosis of endometriosis when they struggle with infertility down the road. “Many times, women only get taken seriously when they are unable to get pregnant,” says Koller.

New research is now revealing that endometriosis causes more health challenges than initially thought. Studies show that having endometriosis is linked to a greater risk of heart disease later in life. Other research has found that the disease can cause changes in metabolism, including difficulty maintaining a healthy weight. While these associations were already known, women themselves were once again often blamed, rather than the disease.

“Physicians used to say that being thin was a risk factor for developing endometriosis,” says Taylor. But his lab was the first to prove by using mouse models that the disease caused mice to be thinner, not the other way around. Furthermore, doctors used to attribute heart disease to the hormonal medications that endometriosis patients take and the surgeries they often undergo. Once again, Taylor’s lab disproved this assumption. “We induce endometriosis in mice, and they develop heart disease,” he says. “It’s cause and effect.”

Women wait years for a diagnosis

Unfortunately, women spend years seeing doctor after doctor for their symptoms, and often, says Taylor, they are dismissed or initially misdiagnosed. This delay is due, in part, to the old clinical standard for diagnosis being laparoscopic surgery. “Although that is still the definitive way to identify it, we can have a very good idea if someone has endometriosis just by her symptoms alone and start some easier treatments to alleviate the pain,” says Taylor. But he also blames the delay on sexist attitudes that are still common among physicians. “I often hear demeaning, horrible comments from doctors who believe that women with endometriosis are just anxious and complain too much, or are overly sensitive to pain.”

This lack of early intervention has tragic consequences, especially because the disease often first strikes when women are in school or in the early stages of their career. “The debilitating pain can change their life trajectory,” says Taylor. “At times, it keeps them from performing well or forces them to miss work or school. It holds them back, and you just don’t get a ‘do-over’ on your early education.”

Treatments: hormones and surgery

The majority of available treatments for endometriosis today are hormonal therapies. The standard first-line treatment is a class of synthetic hormones called progestins, typically in the form of birth control pills. This treatment, however, fails to relieve pain in a third of patients, while others will experience adverse side effects, including weight gain, mood changes, nausea, and irregular bleeding. In total, hormonal therapy is not optimal in about half of patients.

When medications fail, women may also choose to undergo laparoscopic surgery. “The only way to obtain a definitive diagnosis is through surgery, which is unheard of for such a common disease,” says Koller. This procedure involves removing the endometrial lesions, and it can be very effective in reducing pain. Surgical excision, however, is not a cure—it does not prevent reoccurrence of the lesions, among other downsides. “The decision to perform surgery often means that one has waited until they feel bad enough that they want to undergo a surgical procedure,” says Taylor. “It’s not a good option for early recognition and treatment of the disease.”

Another treatment is a GnRH agonist called leuprolide acetate (Lupron®). The injectable drug works by suppressing estrogen levels to zero and putting a patient in temporary menopause. Once administered, it doesn’t take effect for several weeks. “Lupron is an extreme therapy,” says Taylor. Physicians typically offer their patients supplemental hormones to mitigate the side effects, including hot flashes and fatigue. But unlike taking a pill that can be discontinued immediately, if a patient decides the side effects aren’t worth the benefits, she must wait months for the drug to wear off.

Over the past few years, researchers have developed an alternative to Lupron called GnRH antagonists. These oral therapies target the same receptor and have numerous benefits. They start lowering estrogen levels in the body in as little as 24 hours, and the doses can be titrated. This allows doctors to prescribe smaller doses that avoid full-blown menopause. “These have been a game changer because they are so much gentler, kinder, easier to use, and just as effective as the old-fashioned medications,” says Taylor, who was the leader of the clinical trial published in The New England Journal of Medicine that led to the approval of elagolix (Orilissa®), the first GnRH antagonist in the United States. These drugs have become the most commonly used second-line therapy when birth control pills fail.

The future of endometriosis care

Taylor and his team are working hard in the lab to improve the diagnosis of endometriosis, including developing a diagnostic blood test that looks for molecular biomarkers of the disorder, such as microRNAs, as a way to prevent the need for surgery. “Our goal is to recognize this disease early enough that we don’t ever need to do surgery to diagnose it,” he says. “And if we recognize it early enough, before the scarring and adhesions form, we may never need surgical therapy.”

As researchers continue to learn more about the molecular biology and pathophysiology of endometriosis, Taylor also hopes to see more treatment options beyond hormonal medications. Because research shows that inflammation plays a significant role in the disease, his team is interested in repurposing drugs currently used for such inflammatory conditions as Crohn’s disease and rheumatoid arthritis to see whether they also relieve the symptoms of endometriosis. Other key options include targeting the circulating microRNAs secreted by the disease by using specific microRNA inhibitors. Animal models are already showing promising results in both these areas of research.

Exciting progress is already being made, but half the battle will be convincing the medical community and beyond to recognize endometriosis as the complex disease that it is. “The more we understand and embrace that complexity, the sooner we’re going to get to better therapies that treat the entire disease,” says Taylor. “That requires getting people to start taking women’s pain seriously, being unafraid to talk about menstrual cramps, and treating endometriosis sooner before it gets to a stage where a woman needs surgery.”

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