Premenstrual dysphoria tied to aberrant response to ovarian hormones
By Marilynn Larkin
NEW YORK (Reuters Health) - Premenstrual dysphoric disorder (PMDD) may be due at least in part to a dysregulation in the function of ESC/E(Z), an ovarian steroid-regulated gene silencing complex, researchers suggest.
Dr. Peter Schmidt of the U.S. National Institute of Mental Health told Reuters Health by email, "A potentially important source of biology has been identified that could explain the abnormal behavioral symptoms that emerge in women with PMDD during the luteal phase of the menstrual cycle in response to changes in ovarian steroids."
Dr. David Goldman of the U.S. National Institute on Alcohol Abuse and Alcoholism, added in the same email, "We can now say for sure that the problems with mood and irritability that PMDD women experience are not merely subjective."
About 2% to 5% of women of reproductive age have PMDD, the two authors and their colleagues say.
As reported in Molecular Psychiatry, online January 3, the research team analyzed gene expression in cultured white cell lines from women with PMDD and controls before (ovarian steroid-free) and after hormone treatment.
Pathway analysis of the cells revealed, among other changes, overexpression of ESC/E(Z)(Extra Sex Combs/Enhancer of Zeste) complex genes in untreated cells from women with PMDD. More than half of certain genes - in particular and significantly, MTF2, PHF19 and SIRT1 - were overexpressed compared with the controls.
By contrast, the untreated cells also showed decreased protein expression in the affected genes.
Treating cells with progesterone boosted messenger RNA expression in several ESC/E(Z) genes in controls only, whereas treating cells with estradiol decreased expression in PMDD cells.
"These findings demonstrate that (cell lines) 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," the authors write.
Dr. Schmidt said, "As we explore more details of the direction of the differences in the function of the ESC/E(Z) complex between women with and those without PMDD, as well as the underlying mechanisms, we hope to identify molecular systems that could represent novel targets for treatments in this condition."
Dr. Goldman noted that PMDD "is now recognized as a DSM-5 diagnosis, having clear criteria that take it beyond ordinary differences in mood that most women experience during the course of the ovarian cycle."
"This new research, pointing to molecular causation, further helps put PMDD on the same footing as other medical diseases," he said.
But, he added, "it will probably take years to use these findings to better treat or prevent PMDD. Also, it will be necessary to identify the drivers of the cellular differences that were observed in the PMDD women, and genetic differences they may have."
Dr. Barbara Parry of the University of California, San Diego told Reuters Health by email that this "landmark study" has "important theoretical and clinical implications in being able to identify targets for intervention in this recurrent but preventable condition." Dr. Parry is doing work related to PMDD but was not involved in the study.
Dr. Yvonne Bohn, an OB/GYN at Providence Saint John's Health Center in Santa Monica, California who also was not involved in the study, told Reuters Health by email that the findings "give women who suffer from PMDD some hope and understanding that their condition is biologically driven and not something that they have control of."
SOURCE: https://go.nature.com/2j1zUvD
Mol Psychiatry 2017.
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