Premenstrual mood changes linked to abnormalities in gene network

Many women of reproductive age experience premenstrual syndrome, or PMS, which is characterized by mood changes in the days before menstruation. While some studies have linked PMS to hormonal changes that occur during the menstrual cycle, the exact causes remain unclear. Now, researchers have discovered a dysregulated gene network that might be behind a more severe form of PMS - premenstrual dysphoric disorder.

In a new study, researchers found that women with premenstrual dysphoric disorder (PMDD) experience an abnormal expression of genes in the Extra Sex Combs/Enhancer of Zeste network, or the ESC/E(Z) network. This network regulates gene expression in response to sex hormones.

Such abnormalities in gene expression may increase women's sensitivity to the sex hormones progesterone and estrogen, which might contribute to changes in emotional behaviors.

Study co-author Dr. Peter Schmidt - of the Behavioral Endocrinology Branch of the National Institute of Mental Health (NIMH), a part of the National Institutes of Health (NIH) - and colleagues recently published their findings in the journal Molecular Psychiatry.

PMS is a common complaint among women who menstruate, but around 1 in 20 women regularly experience severe symptoms in the 7-10 days before their monthly period, adversely affecting their everyday lives. Symptoms include abdominal pain, headache, bloating, breast tenderness, sadness, and irritability.

While symptoms of PMDD are similar to those of PMS, they are even more severe; some women with PMDD experience anxiety and depression.

PMDD cell lines showed abnormalities in ESC/E(Z) gene network

Previous research has shown that women who regularly experience mood changes just before their menstrual cycle are hypersensitive to normal changes in sex hormones, but the reasons behind this have been unclear.

Dr. Schmidt and colleagues note that PMS is 56 percent heritable, suggesting that genetics might play a role in the condition. For the new study, the team sought to find out whether this is the case.

To reach their findings, the researchers analyzed the gene expression of white blood cell lines derived from women aged 18-48 with PMDD. These cell lines were compared with those derived from healthy women of the same age without PMDD (the control group). Both groups of women had regular menstrual cycles.

The researchers found that gene expression cell lines from women with PMDD differed significantly to those from the control group.

In particular, they found that more than half of genes in the ESC/E(Z) network were overexpressed in cell lines from women with PMDD, compared with those of the controls. Interestingly, the team also identified four key genes in the ESC/E(Z) network in which protein expression was reduced in PMDD cell lines.

In other words, genes were both underexpressed and overexpressed in PMDD cell lines.

Additionally, the team uncovered evidence of abnormal cellular response to sex hormones in PMDD; progesterone was found to increase the expression of several genes within the ESC/E(Z) network of cell lines from controls, while estrogen reduced gene expression in cell lines derived from women with PMDD.

Evidence that PMDD is a 'disorder of cellular response to sex hormones'

According to the researchers, taken together, their findings provide evidence of a molecular mechanism that may increase women's susceptibility to PMDD.

"For the first time, we now have cellular evidence of abnormal signaling in cells derived from women with PMDD, and a plausible biological cause for their abnormal behavioral sensitivity to estrogen and progesterone," notes Dr. Schmidt.

"We found dysregulated expression in a suspect gene complex which adds to evidence that PMDD is a disorder of cellular response to estrogen and progesterone.

Learning more about the role of this gene complex holds hope for improved treatment of such prevalent reproductive endocrine-related mood disorders."

Dr. Peter Schmidt

The researchers want to gain a better understanding of how the ESC/E(Z) gene network affects the brain in PMDD. They plan to reach this goal by analyzing nerve cells induced from stem cells that are derived from the blood of women with PMDD.

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