NIH: 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
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
“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 (link is external) 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
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.