New drug compounds show promise against endometriosis
Two new drug compounds - one of which has already proven useful in a mouse model of multiple sclerosis - appear to be effective in treating endometriosis, a disorder that, like MS, is driven by estrogen and inflammation, scientists report in Science Translational Medicine.
The researchers hope to eventually use the new compounds and others like them to treat a variety of disorders linked to estrogen signaling and inflammation: endometriosis, multiple sclerosis, inflammatory breast cancer, liver fibrosis, and cardiovascular and metabolic problems associated with obesity, for example.
The team tested the new compounds in a mouse model of endometriosis (en-doh-mee-tree-OH-sis) and in human endometriotic cells. Both compounds interact with estrogen receptors, signaling proteins that regulate the activity of many genes. Some of these genes contribute to the body’s immune response and promote inflammation.
Endometriosis afflicts as many as 15 percent of reproductive-age women in the U.S. and millions of women around the world. The disorder can lead to scarring of the ovaries, fallopian tubes and other tissues; infertility; inflammation and chronic pain.
“The usual treatments for endometriosis are aimed at suppressing estrogen production because it’s an estrogen-driven disease,” said University of Illinois molecular and integrative physiology professor Benita Katzenellenbogen, who led the new study with chemistry professor John Katzenellenbogen. “We thought that a better approach might be to interfere with both of the main aspects of endometriosis: the growth-promoting actions and also the inflammatory aspects - both of which involve the estrogen receptor,” she said.
Current pharmaceutical treatments can suppress endometriosis, but often fail to reduce the pain and inflammation that are hallmarks of the disorder, said John Katzenellenbogen, whose laboratory developed the new compounds.
What is endometriosis?
Endometriosis, pronounced, “end-o-me-tree-o-sis” can affect girls of all ages. It is a condition that occurs when tissue similar to the inside lining of the uterus is found outside of its normal location. Endometrial implants can be found on the ovaries, fallopian tubes, and ligaments that support the uterus and tissue covering the bladder and rectum. The most common locations of endometrial implants in teens are in the cul -de - sac area (behind the uterus), and near the bladder.
What are the symptoms of endometriosis?
Endometriosis causes different symptoms in young women. Pelvic pain and/or severe period cramps are the most common symptoms. There can be pain before, during or after your period. The pain may occur at regular times in your cycle or it may occur at any time during the month. It is often referred to as “chronic” pelvic pain. The location of the endometrial implants and the way in which the lesions affect the pelvic organs contribute to the symptoms teens may have. Some teens may have pain with exercise, sex, and/or after a pelvic exam. Although not as common, some teens may have painful or frequent urination, diarrhea or constipation with pelvic pain. It’s important to remember that some teens have a lot of endometriosis and have very little pain, while others may have a small amount of endometriosis and severe pain.
“Current treatments also have side effects on other tissues through which estrogens work, and so they can’t be taken forever,” he said. “There also is unfortunately a high rate of recurrence of the disease.”
The new compounds, OBHS (oxabicycloheptene sulfonate) and CLI (chloroindazole), interact with two types of estrogen receptors (ER-alpha and ER-beta, respectively). Each drug reduced the size of endometriotic tissue or prevented its growth outside the uterus in mice. Each also reduced inflammation and suppressed the development of new neurons and blood vessels that support the misplaced tissue. The treatments did not reduce fertility or the health of young pups born to mouse mothers that had undergone the therapies.
The compounds had similar positive effects in human endometriotic cells that were grown in culture with human immune cells, called macrophages, which can contribute to the inflammation and growth of endometriotic tissue.
How many people are affected by or at risk for endometriosis?
Because some women might have endometriosis, but do not have symptoms, it is difficult to know exactly how many women have the condition. Current estimates suggest that 6% to 10% of women of reproductive age have endometriosis, or approximately 5 million women in the United States.
In 2011, the NICHD-led Endometriosis: Natural History, Diagnosis, and Outcomes study found that 11% of a group of women with no symptoms of endometriosis actually had the disorder. If this finding applies to all the women in the United States, the number of American women with endometriosis may well exceed previous estimates of 5 million.
Endometriosis is most common in women in their 30s and 40s, but it can affect any female who menstruates.
Factors that May Increase the Risk of Endometriosis
Studies show that women are at higher risk for endometriosis if their:
- Mother, sister, or daughter had endometriosis (raises the risk about sixfold)
- Periods started at an early age (before age 11)
- Monthly cycles are short (less than 27 days)
- Menstrual cycles are heavy and last more than 7 days
Factors that May Lower the Risk of Endometriosis
Studies also show that some factors may lower the risk for endometriosis, including:
- Pregnancy
- Starting menstruation late in adolescence
- Regular exercise of more than 4 hours a week
- Low amount of body fat
The research team also found that adding either of the new compounds to a common endometriosis treatment, letrazole, did a better job of suppressing endometriosis than letrazole alone.
“Inflammation is a driver of endometriosis,” Benita Katzenellenbogen said. “At some point you’ve got to turn it off, and these compounds turn it off by working through the estrogen receptors.”
In a previous study published in the Proceedings of the National Academy of Sciences, researchers found that CLI suppressed - and even reversed - the loss of brain neuron structure and function in a mouse model of MS.
While many more years of work must be done to test these new compounds in other models and, eventually, in human patients, the work demonstrates a new approach to treating endometriosis and other disorders tied to estrogen signaling and inflammation, the researchers said.
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The Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health supported this research.
Editor’s notes:
To reach Benita Katzenellenbogen, call 217-333-9769; email .(JavaScript must be enabled to view this email address).
To reach John Katzenellenbogen, call 217-333-6310; email .(JavaScript must be enabled to view this email address).
The paper, “Dual Suppression of Estrogenic and Inflammatory Activities for Targeting of Endometriosis,” is available online or from the U. of I. News Bureau.
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Diana Yates
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217-333-5802
Journal - Science Translational Medicine