New therapeutic targets for endometriosis could be on the horizon

UB study reveals how neurotrophins and their receptors could be novel therapeutic targets for pelvic pain in endometriosis

By the University at Buffalo

New research on the connection between endometrial lesions and pain in endometriosis could lead to new therapies for this chronic, painful and poorly understood condition that affects 5% to 10% of women worldwide and costs an estimated $69 billion in medical and surgical expenses. Endometriosis is a condition where tissue similar to uterine tissue develops and grows outside of the uterus, causing chronic pain that can be severe.

Published online in May in the American Journal of Pathology and featured on the cover of the journal this month, the work was led by researchers in the department of obstetrics and gynecology in the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo, in collaboration with researchers at the University of Michigan.

Robert N. Taylor, M.D., Ph.D., senior author on the paper and professor of obstetrics and gynecology and pathology and anatomical sciences in the Jacobs School, described the drawbacks of current endometriosis treatments.

“Laparoscopic surgical removal of endometriosis lesions remains a primary mode of treatment, but it can be expensive, with attendant risks of complications, and often is associated with recurrence,” he said. “Hormonal medications have been useful, but their long-term use is associated with menopausal symptoms and side effects.”

The new research focuses on the potential connection between the presence of nerves in endometriosis lesions and pain.

“The association of pain with endometriosis has been known for a hundred years, but the relationship between the volume of lesions and the degree of pain symptoms is poorly correlated,” Taylor said.

To determine how lesions and pain are related, the UB researchers teamed up with researchers at the University of Michigan, who Taylor said are experts in the brain’s perception of pain and central sensitization or nociplastic pain, which is a quality of pain that does not arise from an identifiable injury or lesion.

The UB team of scientists has studied the biology of the uterus and endometriosis lesions for decades and now focuses on how nerves present in those tissues are peripheral generators of pelvic pain.

Only in the past 20 years has it been established that the density of nerves in endometriosis lesions and the endometrium (the inner lining of the uterus) is higher in women with endometriosis.

“This led us to propose that this phenomenon might be explained by the excessive expression of neurotrophins, proteins that stimulate the growth and migration of neurons,” Taylor said. “This paper addresses the molecular pathways that are activated in endometriosis and offer new targets for therapy.”

Using established neural biomarkers isolated from endometrial tissue biopsies obtained from eight adult women (four patients with endometriosis and four without), the researchers were looking to identify biochemical mediators of endometriosis-associated pelvic pain. They used immunofluorescence histochemistry, a technique that visualizes parts of a cell with fluorescently labeled antibodies, to confirm that neurons are present in human endometrial tissue. Endometrial stromal cells isolated from the issue expressed neurotrophins and their receptors.

The researchers propose that IL-1β, a potent inflammatory protein, activates a membrane receptor in endometrial stromal cells, predominantly through the c-Jun N-terminal kinase (JNK) pathway, to promote neurotrophin and neurotrophin receptor production and signaling. That increase, in turn, activates the development of new neurons in the brain, which can potentially create a vicious cycle of inflammation and perceived pelvic pain.

The researchers also found that tropomyosin receptor kinase A/B expression, one of the main neurotrophin receptors in endometrium, was almost twice as high in cells from patients with endometriosis than in those from control subjects, an increase that also is mediated through the JNK pathway.

“We therefore postulate that clinical trials using JNK inhibitors have the potential to reduce neuroinflammation in women with endometriosis,” Taylor said. “It is our hope that by identifying and correlating peripheral and central generators of pain, we can come up with new pharmacological approaches for treating endometriosis symptoms.”

“Targeted therapies of the future have the promise of blocking nerve growth and pain transmission, ideally without compromising endocrine function,” he said. “This is the ultimate goal of our research.”