Precision Medicine May Be on the Way for Patients with Endometriosis

A new test could help people with endometriosis side-step ineffective treatments, according to Yale School of Medicine (YSM) research published March 18 in Biomarker Research.

Endometriosis is a chronic pain condition caused by uterine-like cells growing where they aren’t supposed to. People with endometriosis can develop extremely painful periods, bladder issues, and even infertility.

Most people who are diagnosed with endometriosis are first treated with progesterone-based birth control. But a third of all patients fail this therapy because it is ineffective for them while many others stop taking it due to side effects. Now, researchers at YSM are developing a test that uses epigenetic markers in white blood cells to identify which patients will likely respond to birth control—and which won’t.

This test, if confirmed, could help doctors fast-track endometriosis patients who are resistant to progesterone-based birth control to more effective treatments, says Hugh Taylor, MD, chair and Anita O’Keeffe Young Professor of Obstetrics, Gynecology, and Reproductive Sciences at YSM.

“I see patients every day and put them on birth control pills. You have to wait a couple of months to see if it works, and unfortunately, many of them fail,” he says. “I’d rather get them the best treatment right away.”

Endometriosis isn’t easy to treat. The condition affects between 10-15% of reproductive-age women. Despite its prevalence, it takes a decade on average for most people with endometriosis to be diagnosed. Even then, the hardship is far from over. Patients often try and fail many treatments to find something that works—and some never do.

Many insurance companies require patients to try and fail progesterone-based birth control before attempting other treatments. However, it isn’t the most effective endometriosis treatment, and people with the condition are particularly sensitive to the birth control’s side effects, including depression.

There is currently no way to know whether patients will fail the treatment without trying it. That means that many people end up on progesterone-based birth control for anywhere between three months to a year before being permitted to try other treatments, all while continuing to experience devastating symptoms, says Taylor.

Taylor and his colleagues wondered if there was a way to skip this step. To do this, the team decided to search for markers of progesterone resistance in blood. This is possible because endometriosis has far-reaching effects outside the pelvis. In particular, the condition causes a constant, low-grade inflammation throughout the body, mediated by white blood cells.

Yale researchers have previously looked at whether epigenetic markers in white blood cells can be used to diagnose endometriosis without surgery. This time, Taylor and his team evaluated methylation—a type of epigenetic marker where genes are silenced by adding a methyl group to DNA—in the genomes of white blood cells collected from 31 women with endometriosis, 21 of whom had progesterone-resistant endometriosis.

The researchers identified over 1,400 genes that were differentially methylated between patients who responded to progesterone and those who didn’t. Of these, three genes stood out— MMP20, NRXN1, and RNA5-8SN5—with high methylation rates in them being good predictors of progesterone-resistant endometriosis.

This was unexpected, says Taylor, because these genes aren’t thought to have any connection to progesterone signaling or receptors. However, they might be related to inflammation, he says.

Whatever the reason, it’s “very exciting” to see this signal, he says. The results will need to be validated in a larger patient cohort. If so, Taylor and his team plan to develop a commercial test that doctors can use to determine whether patients are likely to respond to progesterone-based treatments. The test would be the first example of precision medicine for endometriosis.

Ideally, any future test could help doctors provide justification to insurance companies to skip ineffective progesterone-based treatment in patients who simply don’t respond to those medications. Endometriosis patients “are people who’ve spent years suffering,” says Taylor. “To make them suffer for a few more months while undergoing trials of an often ineffective therapy just seems cruel.”