January 23, 2017Women's Health
By the late 1990s, investigators at the NIMH demonstrated that women who regularly experience mood disorder symptoms just prior to their periods were abnormally sensitive to normal changes in sex hormones, even though their hormone levels were normal. But the cause remained a mystery.
Subsequently it was found that in women with PMDD, experimentally turning off estrogen and progesterone eliminated PMDD symptoms, while experimentally adding back the hormones that triggered the re-emergence of symptoms. This confirmed that there was a biologically-based behavioral sensitivity to the hormones that might be reflected in cellular molecular differences.
According to an article in the journal Molecular Psychiatry (3 January 2017), molecular mechanisms have now been discovered that may underlie a woman’s susceptibility to disabling irritability, sadness, and anxiety in the days leading up to her menstrual period. Such premenstrual dysphoric disorder (PMDD) affects 2 to 5% of women of reproductive age, whereas less severe premenstrual syndrome (PMS) is much more common. The authors stated that this dysregulated expression in a suspect gene complex adds to evidence that PMDD is a disorder of cellular response to estrogen and progesterone, and that learning more about the role of this gene complex holds hope for improved treatment of such prevalent reproductive endocrine-related mood disorders.
Following up on clues — including the fact that PMS is 56% heritable — the authors studied the genetic control of gene expression in cultured white blood cell lines from women with PMDD and controls. These cells express many of the same genes expressed in brain cells — potentially providing a window into genetically-influenced differences in molecular responses to sex hormones. An analysis of all gene transcription in the cultured cell lines turned up a large gene complex in which gene expression differed conspicuously in cells from patients compared to controls. The gene complex, identified as ESC/E(Z) (Extra Sex Combs/Enhancer of Zeste) gene complex, regulates epigenetic mechanisms that govern the transcription of genes into proteins in response to the environment — including sex hormones and stressors. Results showed that more than half of the ESC/E(Z) genes were over-expressed in PMDD patients’ cells, compared to cells from controls. But paradoxically, protein expression of four key genes was decreased in cells from women with PMDD. In addition, progesterone boosted expression of several of these genes in controls, while estrogen decreased expression in cell lines derived from PMDD patients. This suggested dysregulated cellular response to the hormones in PMDD. According to the authors, for the first time, there is now cellular evidence of abnormal signaling in cells derived from women with PMDD, and there is now a plausible biological cause for their abnormal behavioral sensitivity to estrogen and progesterone. Going forward, using cutting edge disease in a dish technologies, the authors are now following up the leads discovered in blood cell lines in neurons induced from stem cells derived from the blood of PMDD patients in the hopes of gaining a more direct window into the ESC/E(Z) complex’s role in the brain.