Summary: Researchers report dysregulated expression of a gene complex could explain why PMDD is a disorder of cellular response to progesterone and estrogen.
Dysregulated cellular response to estrogen and progesterone suspected.
National Institutes of Health (NIH) researchers have discovered molecular mechanisms 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 percent of women of reproductive age, whereas less severe premenstrual syndrome (PMS) is much more common.
“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,” explained Peter Schmidt, M.D. of the NIH’s National Institute of Mental Health, Behavioral Endocrinology Branch. “Learning more about the role of this gene complex holds hope for improved treatment of such prevalent reproductive endocrine-related mood disorders.”
Schmidt, David Goldman, M.D., of the NIH’s National Institute on Alcohol Abuse and Alcoholism, and colleagues, report on their findings January 3, 2017 in the journal Molecular Psychiatry.
“This is a big moment for women’s health, because it establishes that women with PMDD have an intrinsic difference in their molecular apparatus for response to sex hormones – not just emotional behaviors they should be able to voluntarily control,” said Goldman.
By the late 1990s, the NIMH team had 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.
In women with PMDD, experimentally turning off estrogen and progesterone eliminated PMDD symptoms, while experimentally adding back the hormones triggered the re-emergence of symptoms. This confirmed that they had a biologically-based behavioral sensitivity to the hormones that might be reflected in molecular differences detectable in their cells.
Following up on clues – including the fact that PMS is 56 percent heritable – the NIH researchers 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. Notably, this 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.
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.
“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,” explained Schmidt.
Using cutting edge “disease in a dish” technologies, the researchers 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 hopes of gaining a more direct window into the ESC/E(Z) complex’s role in the brain.
Participate in NIMH research on PMDD. https://www.nimh.nih.gov/labs-at-nimh/research-areas/clinics-and-labs/sbe/participate-in-research/premenstrual-dysphoric-disorder.shtml
Funding: The study was funded by the NIH.
Source: Jules Asher – NIH/NMIH
Image Source: NeuroscienceNews.com image is credited to Peter Schmidt, M.D., NIMH., David Goldman, M.D., NIAAA.
Original Research: Abstract for “The ESC/E(Z) complex, an effector of response to ovarian steroids, manifests an intrinsic difference in cells from women with premenstrual dysphoric disorder” by N Dubey, J F Hoffman, K Schuebel, Q Yuan, P E Martinez, L K Nieman, D R Rubinow, P J Schmidt and D Goldman in Molecular Psychiatry. Published online January 3 2017 doi:10.1038/mp.2016.229
The ESC/E(Z) complex, an effector of response to ovarian steroids, manifests an intrinsic difference in cells from women with premenstrual dysphoric disorder
Clinical evidence suggests that mood and behavioral symptoms in premenstrual dysphoric disorder (PMDD), a common, recently recognized, psychiatric condition among women, reflect abnormal responsivity to ovarian steroids. This differential sensitivity could be due to an unrecognized aspect of hormonal signaling or a difference in cellular response. In this study, lymphoblastoid cell line cultures (LCLs) from women with PMDD and asymptomatic controls were compared via whole-transcriptome sequencing (RNA-seq) during untreated (ovarian steroid-free) conditions and following hormone treatment. The women with PMDD manifested ovarian steroid-triggered behavioral sensitivity during a hormone suppression and addback clinical trial, and controls did not, leading us to hypothesize that women with PMDD might differ in their cellular response to ovarian steroids. In untreated LCLs, our results overall suggest a divergence between mRNA (for example, gene transcription) and protein (for example, RNA translation in proteins) for the same genes. Pathway analysis of the LCL transcriptome revealed, among others, over-expression of ESC/E(Z) complex genes (an ovarian steroid-regulated gene silencing complex) in untreated LCLs from women with PMDD, with more than half of these genes over-expressed as compared with the controls, and with significant effects for MTF2, PHF19 and SIRT1 (P<0.05). RNA and protein expression of the 13 ESC/E(Z) complex genes were individually quantitated. This pattern of increased ESC/E(Z) mRNA expression was confirmed in a larger cohort by qRT-PCR. In contrast, protein expression of ESC/E(Z) genes was decreased in untreated PMDD LCLs with MTF2, PHF19 and SIRT1 all significantly decreased (P<0.05). Finally, mRNA expression of several ESC/E(Z) complex genes were increased by progesterone in controls only, and decreased by estradiol in PMDD LCLs. These findings demonstrate that LCLs from women with PMDD manifest a cellular difference in ESC/E(Z) complex function both in the untreated condition and in response to ovarian hormones. Dysregulation of ESC/E(Z) complex function could contribute to PMDD.
“The ESC/E(Z) complex, an effector of response to ovarian steroids, manifests an intrinsic difference in cells from women with premenstrual dysphoric disorder” by N Dubey, J F Hoffman, K Schuebel, Q Yuan, P E Martinez, L K Nieman, D R Rubinow, P J Schmidt and D Goldman in Molecular Psychiatry. Published online January 3 2017 doi:10.1038/mp.2016.229