Premenstrual syndrome, or PMS, is an "abnormal response to normal hormonal changes," report National Institute of Mental Health (NIMH) researchers David Rubinow, M.D., and Peter Schmidt, M.D., in the January 22 New England Journal of Medicine. "Women with PMS have a specific susceptibility for mood problems triggered by normal monthly cycles," said the researchers.
Their study is the first to directly demonstrate the widely assumed -- yet heretofore unproven -- link between female sex hormones and PMS symptoms. PMS affects 3 to 7 percent of women, causing mood swings and physical symptoms that can interfere with work and social life.
Women with a history of the disorder experienced a reprieve from mood problems when their sex hormones were temporarily turned off, but the PMS symptoms returned when they were given either estrogen or progesterone, the major female reproductive hormones. A control group of women without PMS reported no mood shifts during the same hormonal manipulations.
The researchers compared mood ratings of 10 patients whose PMS responded to leuprolide, a drug that suppresses sex hormones in both men and women, with those of 15 women without PMS. The hormones were first removed and then reintroduced one at a time to reveal whether estrogen or progesterone alone could account for the mood changes.
Each woman was placed on month-long courses of leuprolide alone and leuprolide in combination with estrogen, progesterone and placebo. Each then rated her own severity of symptoms nightly on standardized forms that covered various aspects of mood as well as physical sensations like food craving, hot flushes and breast pain. Investigators obtained additional ratings, as well as blood for hormone assays, during biweekly visits to the NIMH clinic.
Within a week or two after either sex hormone was added back, the women with PMS began suffering typical symptoms of the disorder -- sadness, anxiety, bloating, irritability and impaired function. The control women reported no change. Yet, the NIMH researchers found no apparent differences between the two groups of women -- both groups had normal menstrual cycles in terms of hormone levels and activity.
"Although the female sex hormones need to be present to trigger PMS symptoms, the hormones themselves are not the cause of the disorder," said Rubinow.
The researchers are pursuing clues to explain what may cause the susceptibility to PMS in some women but not others. One possibility now being investigated is genetic differences in the sensitivity of receptors and related messenger systems that relay sex hormone signals within cells. Other clues include possible differences in patients' histories of other mood disorders or in serotonin function.
Studies aimed at identifying factors responsible for the differential mood responses to sex hormones are currently seeking women with perimenopausal depression, to participate in studies of the efficacy estrogen and DHEA replacement; women with PMS; women with a history of post-partum depression; and men with mid-life depression.
Also participating the current study were: Linda Adams of NIMH; Merry Danaceau, R.N., NIH Clinical Center Nursing Department; and Lynnette Nieman, M.D., National Institute on Child Health and Human Development.