Researchers Uncover Cellular Pathway That May Contribute to PMDD

Premenstrual dysphoric disorder (PMDD) is a serious condition characterized by clinically distressing changes in mood and behavior that recur around the luteal phase of the menstrual cycle. The underlying biology of PMDD has been difficult to pinpoint, however, as this disorder is not a simple consequence of altered production or suppression of sex hormones.

“There’s nothing abnormal in the levels of hormones in women with PMDD; they just have an abnormal response to normal menstrual hormonal changes,” said Peter Schmidt, M.D., a principal investigator in the Behavioral Endocrinology Branch of the National Institute of Mental Health in Bethesda, Md.

In a study published January 3 in Molecular Psychiatry, Schmidt and his colleagues may have uncovered the cellular changes that underlie PMDD. This discovery is an important first step to developing treatments that can target the underlying mechanisms of PMDD.

The changes involve a protein complex called ESC/E(Z) (for Extra Sex Combs/Enhancer of Zeste), which is known to respond to reproductive hormones and environmental stress. Using cell samples obtained from women with and without PMDD, this study found that the expression of ESC/E(Z) genes is dramatically different in women with PMDD.

The research group cultured lymphoblast samples (a type of immune blood cell) from 34 women diagnosed with PMDD and 33 women without PMDD. They then compared differences between the two groups in gene expression of these cells, both in the absence or presence of the sex hormones estrogen and progesterone.

Even without exposure to sex hormones, the lymphoblast cells of women with and without PMDD differed in the expression of over 100 genes, including in 12 of the 13 genes that make up the ESC/E(Z) complex. The cells also differed in how they responded when exposed to estrogen and progesterone. In the presence of estrogen, the expression of one ESC/E(Z) gene, known as JARID2, decreased in PMDD women only, while three other ESC/E(Z) genes (EED, EZH2, and MTF2) showed increased expression following exposure to progesterone in control women only.

The finding that women with PMDD had different expression of ESC/E(Z) from those who did not have the disor-der is not surprising, as the complex has long been recognized as playing a role in adaptive behaviors, or how a person responds to changes in the environment, Schmidt explained. However, to confirm a biological role for ESC/E(Z) in the disorder and pinpoint the exact mechanism by which it alters hormonal responses will take additional work.

Schmidt noted the exact composition of proteins in the ESC/E(Z) complex varies from cell to cell, so even if the mechanism used by lymphoblasts is determined, there is no way of knowing whether this reflects a mechanism used by brain cells.

Schmidt and his colleagues hope to use stem cell technology to “make” neurons from these women with PMDD that they will then use to test the cells’ response to hormonal fluctuations.

“Future work will also look at whether the changes in the ESC/E(Z) complex contribute to the disorder or reflect some type of biological compensation mechanism to the longstanding, recurring stress experienced by women with PMDD,” he added.

Ultimately, Schmidt said he hopes to develop a new treatment that gets at the root cause of this disorder and not just the symptoms. Currently, PMDD symptoms can be managed with selective serotonin reuptake inhibitors such as fluoxetine (which need to be taken only during the periods of distress). However, about 30 percent to 40 percent of patients do not respond to medication, and those who do respond can encounter limiting side effects including loss of libido.

This study was supported by the Intramural Research Programs of the National Institute of Mental Health and National Institute on Alcohol Abuse and Alcoholism. ■

“The ESC/E(Z) Complex, an Effector of Response to Ovarian Steroids, Manifests an Intrinsic Difference in Cells From Women With Premenstrual Dysphoric Disorder” can be accessed here.