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UCSF, NIH researchers set sites on diagnostic test for menopause-like condition
SAN FRANCISCO—Researchers at the University of California, San Francisco (UCSF) and the National Institutes of Health (NIH) are laying the groundwork for the development of a test to predict a woman's risk of developing primary ovarian insufficiency (POI), a menopause-like condition that affects women decades before they would normally develop symptoms of actual menopause.
Dr. Lawrence M. Nelson, head of the Integrative Reproductive Medicine Group at the NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and his colleagues have long been studying overt POI, which is characterized by a lack of menstrual cycle, hot flashes and even reduced bone density—even in women who may be in their early teens and 20s. Some cases of POI appear to result from an autoimmune attack on the ovaries.
"POI is a very common problem in the ovarian spectrum, and in the past, we called these women 'low responders,'" Nelson says. "These include women who are infertile, who have irregular menstrual cycles, who have trouble getting pregnant or who don't respond very well to IVF."
Overt POI affects one in 100 women by age 40, but it is a poorly understood clinical condition lacking in effective treatments, Nelson says.
"Our data show that over half of these women have to see at least three different doctors before they are diagnosed," he says. "Some of the more subtle forms of POI are very common, while some patients think it's not really a problem to not have periods. This is why we need to develop a blood test that is an early warning indicator of the condition."
Expanding on this unmet need in the June 1 online edition of Endocrinology, Nelson and his colleagues hypothesize that "understanding the targets of the autoimmune response and induction of ovarian-specific tolerance would allow development of focused therapies to preserve fertility in an at-risk population."
In a study of mice, the researchers confirmed that an ovarian protein MATER, or "maternal antigen that embryos require," is the main target of this autoimmune attack. The researchers created a condition in mice that resembles autoimmune-related POI by removing the thymuses in mice when they were two to four days old. The researchers observed that the T-cells in these thymus-deficient mice failed to recognize that the ovary was part of the body, and the T-cells instructed B-cells to make antibodies against the ovaries.
In the thymus, T-cells learn that cells covered with MHC protein complexes are part of the body and off limits to an immune attack. The researchers altered the animals' MHC genes so they produced parts of MATER on the surface of their cells, along with MHC. The alteration lessened the immune attack on the ovaries.
When the mice were six weeks old, the researchers found that 94 percent of the mice without the MATER-MHC combination had developed an immune attack on the ovaries. Among the mice with the MATER-MHC combination, 56 percent showed evidence of an immune attack against the ovaries.
Nelson points out that although his team's findings show that MATER is a main target of the immune attack in these mice, it's not the only target. Both groups of mice had antibodies to other ovarian proteins that have not yet been identified.
He also notes that some women with POI may have antibodies to NALP5, the protein counterpart of MATER. Thus, researchers could develop a diagnostic test to find out if some women carry this antibody. Early detection would give these patients the option to explore fertility-sparing options such as frozen embryo storage, or freezing unfertilized eggs.
"For some women of childbearing age, this can be a major hit on their emotional well-being," Nelson says. "There are a whole lot of ifs, ands and buts yet, but there is a possibility that at some point, every woman who goes to the gynecologist will be able to ask if she can be tested for these antibodies."
The researchers are working on identifying the other targets of immune attacks in women with POI—and they have patented their findings and are "heavily seeking" a commercial partner, Nelson adds—but they are also heavily involved in bringing more awareness to the treating the menstrual cycle as "a trademark of overall health."
"Problems with the menstrual cycle can often be indicators of other medical problems," Nelson points out, "and in fact, it can sometimes be a vital sign that a patient has a serious medical condition."
To that end, Nelson is one of several parties involved in the formation of Rachel's Well, a multidisciplinary nonprofit organization in Fairfax County, Va., dedicated to improving women's health by raising awareness, removing barriers to care and stimulating research. Other partners include the Office of Women's Health, the U.S. Department of Health & Human Services Office of Performance Improvement and the Florida Department of Health.
Co-authors on this study include first author Noriyuki Otsuka, Zhi-Bin Tong, Konstantina Venevski and Wei Tu, all of NICHD, and Mickie H. Cheng of UCSF.