Roughly 4 decades after she first started menstruating, Elizabeth Flanagan finally underwent surgery to repair damage wreaked on her body by endometriosis. She’d spent years struggling with a variety of seemingly random symptoms, from migraines to excruciatingly painful periods to fatigue and irritable bowel syndrome. She’d worried about abnormal labs, including “extremely high” ANA, creatinine, and BUN blood test results that had been out of normal range for more than 10 years.
She was diagnosed with endometriosis in 2016, at age 47, after surgery to remove an ovarian cyst. Still, it took 5 more years before she landed in the office of a surgeon with the proper training to excise the lesions that continued to cause her so much anguish. That physician, Matthew Siedhoff, MD, at Cedars-Sinai Medical Center in Los Angeles, explained why her creatinine and BUN results were so far out of range: The endometriosis was impinging on her ureters.
The appointment left Ms. Flanagan with a range of emotions. “I was shocked that no doctor had identified this before, relieved knowing that I was finally in the hands of an expert who understood my condition, and saddened by the dearth of knowledge and proper treatment of endometriosis,” she wrote in an email.
Although the disease afflicts at least 1 out of every 10 women, endometriosis remains a conundrum for patients and their physicians. It often masquerades as other problems, from mental health issues such as anxiety and depression to physical issues such as irritable bowel syndrome. It often coexists with autoimmune conditions. Short of performing surgery, it can be a diagnosis of exclusion. And the existing, state-of-the-art treatment – hormone therapy that shuts down the reproductive system – doesn’t work for every woman every time.
“It is no wonder that it takes 10 years on average, from the time someone has symptoms of endometriosis, until they get a definitive diagnosis,” said Hugh Taylor, MD, chair of obstetrics, gynecology, and reproductive sciences at Yale University, New Haven, Conn. “It’s a combination of [physicians] not taking painful menses seriously and getting distracted by all these other manifestations of the disease throughout the whole body.”
Endometriosis, he said, “is a whole-body disease.”
But recent genetic research offers the tantalizing prospect of new diagnostic tools and treatments. In 5-10 years, scientists say, physicians may be able to diagnose the disease with a simple blood test, and treat it, for example, by preventing a gene receptor from initiating a cascade of inflammatory effects, or crafting treatments tailored to the molecular makeup of a patient’s disease.
“Tomorrow’s therapies will target specifically the molecular defects of endometriosis and be nonhormonal,” Dr. Taylor said.
Guidelines published last year by the European Society of Human Reproduction and Embryology detail the latest standards for diagnosis and treatment of endometriosis.
According to the guidelines, physicians should consider the diagnosis of endometriosis in individuals presenting with the following cyclical and noncyclical signs and symptoms: dysmenorrhea, deep dyspareunia, dysuria, dyschezia, painful rectal bleeding or hematuria, shoulder tip pain, catamenial pneumothorax, cyclical cough/hemoptysis/chest pain, cyclical scar swelling, and pain, fatigue, and infertility.
A clinical exam should be considered, as well as imaging such as ultrasound and/or MRI, the guidelines state, although negative findings should not rule out a diagnosis. Laparoscopy is also an option, particularly for patients who desire a definitive diagnosis or cannot be diagnosed any other way, “although negative histology [of endometriotic lesions] does not entirely rule out the disease,” the guidelines state.
To treat the pain associated with endometriosis, the guidelines advise, as a first-line therapy, beginning with NSAIDs and combined hormonal contraceptives (in oral, vaginal, or transdermal form). Another option is progesterone, including progesterone-only contraceptives, with a recommendation to prescribe a levonorgestrel-releasing intrauterine system or an etonogestrel-releasing subdermal implant to reduce endometriosis-associated pain.
However, progestins and low-dose oral contraceptives are “unsuccessful in a third of women,” Dr. Taylor and his coauthors wrote in a paper published in 2021 in The Lancet.
Until recently, the gold standard for second-line treatment of endometriosis was oral gonadotropin-releasing hormone (GnRH) agonists. These manage the disease by inducing medical menopause – they downregulate pituitary GnRH receptors to create a hypoestrogenic state characterized by low serum levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). GnRH agonists may be administered nasally, or through daily, monthly, or trimonthly injections. But the Food and Drug Administration advises that, when used for longer than 6 months, GnRH agonists be paired with add-back hormone replacement therapy to reduce the risk of bone loss associated with the plunge in hormone levels. Also, treatment may not be appropriate for patients who, when suddenly forced into menopause, suffer from bothersome symptoms.
The latest treatment, GnRH antagonists, are new options for patients who either do not respond adequately to progestins and low-dose contraceptives or develop progesterone resistance, and want to avoid some of the risks and/or symptoms associated with GnRH agonists. Two advantages of GnRH antagonists for patients, Dr. Taylor said, are that they have a fast onset of action and are oral rather than injectable.
“These drugs [GnRH antagonists] cause competitive blockage of the GnRH receptor and hence dose-dependently suppress production of FSH and LH and inhibit secretion of ovarian steroid hormones without inducing a flare-up effect,” Belgian physicians and researchers Jacques Donnez, MD, and Marie-Madeleine Dolmans, MD, PhD, wrote in a paper published last year in the Journal of Clinical Medicine. “The mechanism is different from that of the GnRH agonist which, after a first phase of stimulation, desensitizes GnRH receptors, leading to full suppression of LH and FSH production and subsequently to complete suppression of [estrogen] to levels similar to those observed after bilateral oophorectomy.”
Patients who took Elagolix, the first oral nonpeptide GnRH antagonist available for the treatment of moderate to severe endometriosis-associated pain, had fewer vasomotor side effects and less bone density loss than those on the GnRH agonist leuprorelin, according to a 2018 study in Obstetrics and Gynecology. However, without add-back hormone-replacement therapy, GnRH antagonist use may need to be limited to 24 months, because of loss of bone density, a study in Cell Reports Medicine reported in 2022.
Attempting to explain the pathogenesis of endometriosis, and frustrated by the shortcomings of currently available therapies, researchers have turned to genetics for insight. A team of scientists led by Thomas Tapmeier, PhD, now a senior research fellow at Monash University in Australia, and Prof. Krina Zondervan at the University of Oxford, ran genetic analyses of families with a history of endometriosis, as well as rhesus macaques that spontaneously developed endometriosis. The research, published in Science Translational Medicine, identified NPSR1, the gene encoding neuropeptide S receptor 1, as one commonly associated with endometriosis. In trials with mouse models, they found that the NPSR1 inhibitor SHA 68R was able to reduce endometriosis-related inflammation and pain.
“It’s important to stress that there is no single gene that is responsible for endometriosis,” Dr. Tapmeier said in an interview. “This gene just has a higher frequency in people with endometriosis.”
The next step, then, would be to try to find a compound that would inhibit NPSR1 at some point, or a competitor to the ligand that binds to the receptor and blocks it, he said.
“We’re currently looking at compounds that might be able to inhibit the receptor signaling,” he said.
Such a therapy could potentially reduce the symptoms of endometriosis without interfering with the menstrual cycle and without introducing hormones that cause undesirable side effects in some patients.
“This might be a way to treat the pain and inflammation that goes with endometriosis, as well as leaving the possibility of pregnancy open,” he said.
Other researchers are searching for biomarkers of the disease, both to provide a definitive, nonsurgical diagnostic tool, and for potential, individualized treatment.
In a study published in Nature Genetics, researchers at Cedars-Sinai created a “cellular atlas” of endometriosis by analyzing nearly 400,000 individual cells from 21 patients, some of whom had the disease and some of whom did not. A new technology, single-cell genomics, allowed the scientists to profile the multiple cell types contributing to the disease.
“So the initial question we wanted to ask was about understanding how the cells look in endometriosis, compared to endometrium,” said Kate Lawrenson, PhD, an associate professor in the department of obstetrics and gynecology at Cedars-Sinai, and co–senior author of the study. “We know that they resemble the cells of the womb, but we really don’t understand if they behave the same. We had a good inkling that they would behave differently.”
It turned out they did: Cells of endometriosis interacted atypically with female hormones, compared with cells in the uterus, Dr. Lawrenson said.
“That helps us understand how, even when patients take contraceptive pills, which is a commonly prescribed therapy, it doesn’t always work, or sometimes it stops working after a while,” she said. The next step for researchers, she said, will be to pinpoint the specific causes of these altered interactions.
Meanwhile, the current research also points to diagnostic possibilities. “We were quite excited to see that multiple cell types and endometriosis are upregulating the same sets of genes,” she said. “That makes us optimistic that hopefully there are some protein gene products that are being made in abundance, and hopefully we can detect them in the blood stream. It might be that we could use that information to develop new biomarkers, or even risk stratification tools.”
In the future, a simple blood test could identify signs of endometriosis in at-risk patients and get them “fast-tracked to a specialist for evaluation,” she said. “Whereas now, they might go from PCP to gynecologist to a different gynecologist over the course of 5-10 years before they get that referral.”
This discovery, that endometrial cells use genes differently and cross-talk with nearby cells differently, presents new treatment possibilities. Maybe we can physically block how cells interact with nearby cells, Dr. Lawrenson said. One model for doing that, she said, would be antibody-based therapy, similar to the therapies now changing the treatment of cancer.
What’s most exciting, looking ahead 5-10 years, is that treatment for endometriosis in the future may be significantly more individualized, and less hormone-based, than it is today.
“What we need for endometriosis is more options for patients and something that is tailored to the molecular makeup of their disease rather than a process of trial and error,” she said.