Is There a PMS Gene?

It's that time of the month. You're constantly on edge, have difficulty concentrating, and wish you could just go back to bed and hide under the covers all day. Is it all in your head?

Not so long ago, that's what many doctors would have told women who were bold enough to complain about these symptoms. There was little research about problems affecting women, perhaps because researchers were mostly male. The prevailing view among scientists was that women were outliers and not useful study subjects because their biology was more complex than men's. So even doctors who wanted to help wouldn't have had the knowledge to tell their women patients why their world seemed to implode every month.

But in the last two decades, basic science research has made huge advances in understanding how women's moods and emotions are affected by their hormones. It's now widely accepted that a small percentage of reproductive-age women (estimates range from 1.8 to 10 percent) may suffer from premenstrual dysphoric disorder (PMDD), a severe form of premenstrual syndrome (PMS). The most common symptoms of PMDD, says Yale University psychiatrist Kimberly Yonkers, are mood swings, irritability, fatigue, poor concentration, and headaches.

Although scientists still don't understand the precise biological mechanism behind PMDD, it's increasingly clear that the brains of women who suffer from the disorder are affected by where they are in their menstrual cycle. Pieces of this puzzle are slowly emerging. On Feb. 8, researchers at the Rockefeller University in New York reported the results of a study in mice that suggested that a particular gene may be involved. Between 20 and 30 percent of women carry a variation of this gene, called "brain-derived neurotropic factor Met," which past research has shown is a risk factor for mood disorders. The Rockefeller scientists, whose paper was published in the Proceedings of the National Academy of Sciences, showed that the behavior of the mice carrying the variant gene changed at different times in their estrous cycle.

The Rockefeller researchers tested eight mice with the variant gene and compared their actions with eight who did not have it. They found that at specific stages of their cycle, the mice with the variant gene had trouble remembering objects they had seen before (in this case, a sake cup and a similarly shaped cup made of Legos). The mice were also more anxious. Women aren't mice, of course, but because humans with this gene also are more anxious and more prone to memory problems, the Rockefeller scientists think that their work suggests that this gene plays a role in PMDD and other mood disorders related to monthly changes in hormones. "On a broader scale," says lead author Joanna Spencer, "I think that this kind of research shows that hormones do affect the brain, and they do affect behavior."

Scientists who have been studying the interplay between hormones and mood disorders say this newest gene research adds one more significant piece of evidence to the growing body of studies showing that PMS and PMDD are biologically based conditions that affect a small group of women who have an unusual mood response to monthly hormonal fluctuation. "We've struggled with the basis for that differential response," says Dr. Peter Schmidt, who pioneered this area of research at the National Institute of Mental Health. "This is the first time, in the case of PMS and PMDD, that we have very strong evidence that there may be an underlying biological variation, at the level of the genome, that may relay a differential response to a normal change in hormone levels." That doesn't mean that all women with this gene variation will go ballistic every month. But Schmidt says the Rockefeller study does indicate that there may be a "cocktail of gene variation" behind PMDD.

The newest research comes at a delicate moment in the sometimes controversial history of PMDD. As scientists like those at Rockefeller work hard to understand the biology behind it, the American Psychiatric Association is deciding whether to include PMDD as an officially recognized disorder in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders, or DSM-V, which is due to be published in 2012. The DSM is critical because it guides clinicians; officially recognizing a disorder also makes it more likely that insurance companies will pay for treatment.

The American Psychiatric Association first considered adding PMDD to an earlier edition of the manual 20 years ago, but women's health advocates protested, claiming that making PMDD an official disorder would pathologize female biology and incorrectly label women as mentally ill. As a compromise, PMDD was placed in the category of conditions proposed for further study. In the meantime, treatment options have expanded. In the last decade, the Food and Drug Administration has approved two medications to treat PMDD: the antidepressant fluoxetine (commonly known as Prozac but repackaged as Sarafem) and a birth control pill called Yaz.

Yonkers, who is on the task force charged with revising the DSM, says the group is "still reviewing the evidence," and it's too soon to say what the outcome will be. But she vigorously disagrees with critics who say that PMDD is "just some pharmaceutical company–generated diagnosis." Like Schmidt, Yonkers has been studying women's mental health disorders for many years. "When we were originally doing studies in this area, we couldn't get anybody to fund us to do treatment studies," she says. "Pharmaceutical companies didn't want to touch it … We had patients who were coming to us who really wanted some help, and they didn't know what to do. All we could tell them was to take vitamins and exercise."

The prevailing attitude was deeply frustrating, she says: "If men had PMS, don't you think we would know what caused it by now?"

The answer may not be far off. "We're a lot closer than we were a decade ago," says Schmidt. "We have more solid data, and we study a wider, larger area. More investigators are involved, and the topic enjoys more legitimacy than it did a decade ago." The attitude among women has changed as well, he says. "Women are more informed, and they are willing to stand up and say that their experience is not the same … They find that there are times in their cycle when they are extremely able, but there are other times when their symptoms become very troubling, and it limits their normal ability to function."

Yonkers says she has also seen a big change in the research world. "It's clearly better," she says. "I was like the Simone de Beauvoir of medical researchers, and now I'm mainstream." She thinks it helps that more women are involved in the research. "Scientists used to exclude a lot of very valuable information in pursuit of being 'pure' and having the perfect methodological study," she says.

Spencer, who received her Ph.D. from Rockefeller last year and is now a medical student at Cornell, says she and her peers are the beneficiaries of that change—and someday their patients will be better off as well. "In medical school, there is an emphasis on the fact that many common diseases, such as cardiovascular disease, present differently in women and have a different course in women," she says. They're also taught that PMDD is "a real thing and should not be dismissed."

Even without a cure, having science take women seriously makes that time of the month just a little easier to handle.

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