A New Nonhormonal Approach to Endometriosis Pain Treatment

Can a nonhormonal treatment work to alleviate pain and reduce health disparities for adolescents with endometriosis?

From gender discrimination to period poverty, global health inequities persist between those who menstruate and those who don’t. This divide is exemplified by treatment for endometriosis. In this chronic pain condition, tissue mimicking the endometrium spreads outside the uterus, causing lesions throughout the pelvic region — including on the fallopian tubes, ovaries and uterosacral ligaments — and, more rarely, the bowel, intestines or bladder. This tissue thickens, breaks down and bleeds with each menstrual cycle, causing inflammation and extreme pain. Half of all adolescents with chronic pelvic pain eventually receive an endometriosis diagnosis, but before that, their healthcare providers and families affirm that painful periods are normal. When the answer finally comes, endometriosis has already exacted its physical, social and emotional toll.

Testing a nonhormonal treatment for endometriosis

At Children’s Hospital Colorado, clinicians and researchers are working to break the silence on endometriosis pain. The team includes pediatric and adolescent gynecologists Tricia Huguelet, MD, and Stephen Scott, MD, along with Kendra Hutchens, PhD, Co-Director of Research for Pediatric and Adolescent Gynecology at the University of Colorado School of Medicine.

Drs. Huguelet, Scott and Hutchens are collaborating with researchers across the country to study a nonhormonal treatment option that may help alleviate the severe pain of endometriosis. “Endometriosis is another level of unrelenting pain that makes it really hard for teens to engage in school or outside activities with friends,” Dr. Huguelet says. “It can have a negative impact on emotional well-being as well as their physical health.”

The Novel Treatment for Endometriosis (NOTE) Expansion study, funded by the J. Willard and Alice S. Marriott Foundation, unites multiple institutions — including Children’s Colorado, Boston Children’s Hospital, Stanford University Hospital, Beth Israel Deaconess Medical Center and Thomas Jefferson University Hospital — to study the drug cabergoline. There is no treatment approved by the United States Food and Drug Administration (FDA) for endometriosis-associated pain in adolescents, but by recruiting participants at multiple sites, the NOTE study will confirm to researchers if this novel, nonhormonal drug could be the first.

“Endometriosis is a common condition, but many people don’t know pediatric gynecologists exist,” Dr. Huguelet says. “We’re excited to partner with other institutions because it allows us to bring attention to our field and find substantial research data that will support better treatments.”

The trial at Children’s Colorado began enrolling participants with endometriosis in summer 2024, with a focus on people assigned female at birth between the ages of 15 and 40. Individuals may be eligible if they have had a surgical diagnosis of endometriosis in the past three years, experience chronic pain from the condition and are currently using a hormonal treatment. Over six months, participants will take either a placebo or cabergoline, a dopamine receptor agonist approved by the FDA in adults to treat a variety of other hormonal conditions, including infertility that results from hyperprolactinemia (high prolactin levels). Participants will also be asked to engage in sensory tests, and to complete questionnaires and symptom diaries throughout the study’s duration.

Targeting endometriosis pain

Pain is the primary symptom of endometriosis, and the goal of this research is to help treat and reduce that pain. Currently, patients are treated with hormonal medications that regulate the menstrual cycle and slow or prevent the growth of endometrial tissue. In more serious cases, a hormone-based approach involves shutting down hormonal stimulation to induce a menopause-like state.

Both instances alter levels of estrogen — a hormone that’s essential for bone accrual during adolescence. Peak bone mass isn’t established until age 18, so interfering with this process earlier in life could have long-term implications on bone health. Furthermore, hormone therapy is not a cure for endometriosis, and pain returns when treatment is stopped.

“Unfortunately, there’s very little research in the adolescent population with regard to optimal hormonal therapy,” Dr. Huguelet says. “There also aren’t a lot of long-term studies looking at surgical intervention in adolescents, and then how that translates into long-term reproductive health and fertility outcomes for them as adults.”

Another barrier to treating endometriosis pain effectively is that the condition can only be officially diagnosed via surgery. Imaging tests may help detect lesions, but in most cases, doctors can’t see abnormalities in an adolescent on an MRI or ultrasound. This means that the main form of diagnosis results from patients self-reporting their pain to providers. Listening to teens in pain is always important, but it especially matters with endometriosis, where it’s often the lone signpost that something is wrong.

How cabergoline could further health equity

Unfortunately, a growing body of research shows that the pain of girls, women and gender expansive individuals is often dismissed, though they are more likely to experience chronic pain conditions such as endometriosis (1). This phenomenon isn’t only frustrating; it also furthers health disparities. Adolescents with endometriosis frequently experience debilitating pain that causes them to miss school, work and social activities.

“When the pain of adolescent girls, women and gender expansive patients is not taken seriously or treated aggressively, those disparities widen and have implications for patients’ immediate and long-term health and well-being,” Dr. Hutchens explains. “It is important to also consider these issues from an intersectional lens, as these disparities are often compounded by other factors. For instance, evidence from other studies shows that Black women’s pain is treated less aggressively than white women’s pain.”

Left untreated, endometrial tissue can also spread to new areas of the body, causing further pain and irreversible complications, such as infertility. It’s common for patients to grow so exasperated with the lack of effective treatment that they reach a breaking point. “A lot of patients as young adults will say, ‘I’m done. Just do a hysterectomy,’” Dr. Huguelet says. “It’s so heartbreaking that they feel that way, and a hysterectomy is not always curative, especially if there’s a late diagnosis and they already have chronic pain from lesions outside the uterus that have triggered muscle and nerve pain.”

This is why, in addition to ameliorating the pain and associated symptoms of endometriosis, Drs. Huguelet, Scott and Hutchens hope the study will draw attention to abnormal periods and put a stop to the normalization of pain for teens. “This provides us with an opportunity to reassure young people that their pain is not normal and that there are treatments available to them,” Dr. Hutchens explains. “The earlier that we can begin to treat some of these issues, the better outcomes people are going to have throughout their entire life course.”

Dr. Huguelet, who works with patients daily, says an important part of this work involves fostering healthy discussions about vaginas, sex and menstruation, and why these topics matter. “Combating the stigma around sexual and reproductive health for young people will also help us to take that more preventative approach,” she says. She hopes that someday, in addition to having better nonhormonal treatments, standard care for endometriosis will echo the multidisciplinary approach at Children’s Colorado, where chronic pain teams, pelvic floor therapists and behavioral health specialists work together with OB/GYN providers to address the full scope of the impact of living with endometriosis.

“What I’d like to see is earlier diagnosis and clear treatment regimens that are approved for adolescents,” Dr. Huguelet says, “and for this to then translate into better outcomes — long-term, their pain decreases, their fertility improves and so does their quality of life.”