UCSF, NIH researchers set sites on diagnostic test for menopause-like condition

Primary ovarian insufficiency is a poorly understood condition with a clear lack of effective therapies, but researchers at UCSF and the NIH hope to begin turning that around by building the foundation for a test to predict a woman’s risk of developing the condition

Amy Swinderman
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SAN FRANCISCO—Researchers at the University of California,San Francisco (UCSF) and the National Institutes of Health (NIH) are laying thegroundwork for the development of a test to predict a woman's risk ofdeveloping primary ovarian insufficiency (POI), a menopause-like condition thataffects women decades before they would normally develop symptoms of actualmenopause. 
Dr. Lawrence M. Nelson, head of the Integrative ReproductiveMedicine Group at the NIH's Eunice Kennedy Shriver National Institute of ChildHealth and Human Development (NICHD), and his colleagues have long beenstudying overt POI, which is characterized by a lack of menstrual cycle, hotflashes and even reduced bone density—even in women who may be in their earlyteens and 20s. Some cases of POI appear to result from an autoimmune attack onthe ovaries.
"POI is a very common problem in the ovarian spectrum, andin the past, we called these women 'low responders,'" Nelson says. "Theseinclude women who are infertile, who have irregular menstrual cycles, who havetrouble getting pregnant or who don't respond very well to IVF."
Overt POI affects one in 100 women by age 40, but it is apoorly understood clinical condition lacking in effective treatments, Nelsonsays.
"Our data show that over half of these women have to see atleast three different doctors before they are diagnosed," he says. "Some of themore subtle forms of POI are very common, while some patients think it's notreally a problem to not have periods. This is why we need to develop a bloodtest that is an early warning indicator of the condition."
Expanding on this unmet need in the June 1 online edition ofEndocrinology, Nelson and hiscolleagues hypothesize that "understanding the targets of the autoimmuneresponse and induction of ovarian-specific tolerance would allow development offocused therapies to preserve fertility in an at-risk population."
In a study of mice, the researchers confirmed that anovarian protein MATER, or "maternal antigen that embryos require," is the maintarget of this autoimmune attack. The researchers created a condition in micethat resembles autoimmune-related POI by removing the thymuses in mice whenthey were two to four days old. The researchers observed that the T-cells inthese thymus-deficient mice failed to recognize that the ovary was part of thebody, and the T-cells instructed B-cells to make antibodies against theovaries.
In the thymus, T-cells learn that cells covered with MHCprotein complexes are part of the body and off limits to an immune attack. Theresearchers altered the animals' MHC genes so they produced parts of MATER onthe surface of their cells, along with MHC. The alteration lessened the immuneattack on the ovaries.
When the mice were six weeks old, the researchers found that94 percent of the mice without the MATER-MHC combination had developed animmune attack on the ovaries. Among the mice with the MATER-MHC combination, 56percent showed evidence of an immune attack against the ovaries.
Nelson points out that although his team's findings showthat MATER is a main target of the immune attack in these mice, it's not theonly target. Both groups of mice had antibodies to other ovarian proteins thathave not yet been identified.
He also notes that some women with POI may have antibodiesto NALP5, the protein counterpart of MATER. Thus, researchers could develop adiagnostic test to find out if some women carry this antibody. Early detectionwould give these patients the option to explore fertility-sparing options suchas frozen embryo storage, or freezing unfertilized eggs.
"For some women of childbearing age, this can be a major hiton 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 womanwho goes to the gynecologist will be able to ask if she can be tested for theseantibodies."
The researchers are working on identifying the other targetsof immune attacks in women with POI—and they have patented their findings andare "heavily seeking" a commercial partner, Nelson adds—but they are alsoheavily involved in bringing more awareness to the treating the menstrual cycleas "a trademark of overall health."
"Problems with the menstrual cycle can often be indicatorsof other medical problems," Nelson points out, "and in fact, it can sometimesbe a vital sign that a patient has a serious medical condition."
To that end, Nelson is one of several parties involved inthe formation of Rachel's Well, a multidisciplinary nonprofit organization inFairfax County, Va., dedicated to improving women's health by raising awareness,removing barriers to care and stimulating research. Other partners include theOffice of Women's Health, the U.S. Department of Health & Human ServicesOffice of Performance Improvement and the Florida Department of Health.
Co-authors on this study include first author NoriyukiOtsuka, Zhi-Bin Tong, Konstantina Venevski and Wei Tu, all of NICHD, and MickieH. Cheng of UCSF.  

Amy Swinderman

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