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PMDD Linked to Gene Network

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.

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DR. PETER SCHMIDT: So many women will report experiencing feels of irritability, sadness, anxiety -- during the luteal phase, or the premenstrual phase of their cycle. As those concerns have been investigated, we've realized that perhaps two to five percent of women who experience these symptoms during the luteal phase will experience a very a very marked disability and dysfunction associated with that. And it was very clear that there was no abnormality of any reproductive hormone that distinguished a woman with Premenstrual Dysphoric Disorder from a woman who had no symptoms during her luteal phase. These women would experience a remission of their symptoms when ovarian function was turned off -- and then a recurrence of symptoms when either of the hormones was added back. Women with PMDD experienced a differential sensitivity to the mood disturbing effects of ovarian steroids. So there was no abnormality of these hormones. What was abnormal was the behavioral response to normal levels of these ovarian steroids. We essentially tried to recreate what we saw in the clinic in the laboratory.

DR. DAVID GOLDMAN: Drawing the blood from these women and making cell lines, we then have a type of -- if you will -- disease in a dish. Or a little model of the human patient in a dish that we can study molecularly. And, so then those cells were studied both at baseline and after treatment with ovarian steroids, mimicking the sort of changes that occur in a woman during the ovarian cycle. And showing that at baseline, and also after exposures, that they are intrinsically different in a pathway involved in ovarian steroid response. Some women's cells respond differently to ovarian steroids than do others. Rather than homing in on what we already know, which are receptors for ovarian steroids and some of the ovarian steroid response apparatus -- the usual suspects, if you will -- we study simultaneously the expression of thousands of genes. And then, via gene network analyses, identify the particular networks that are distinct and different in the cases versus the controls. And when this was done, it was quite exciting that a main molecular network that came up was an ovarian steroid response gene network. It had never been noted before that in women with PMDD that that pathway was systematically disturbed in any way. So the discovery was made in a genomic context, but it did lead back to a destination that we might have expected. What we're now doing is that we're improving on this lymphobastoid cell model with induced induced pluripotent stem cells made from these very women. So these are a cell line, again made from cells in peripheral blood, which are capable of becoming, capable of developing into any type of cell that we could want to study. And, in particular, we're able to take these induced pluripotent stem cells and were able to stimulate them to develop into neurons. And then these neurons will be able to study in detail and, hopefully, to confirm these sorts of findings that we've made in the lymphoblastoid cell lines.

DR. PETER SCHMIDT: So, once we identify either the mechanism where they're stimulated or their direct action on other genes, that will open up the opportunity of transforming the abnormal cellular response to steroids into a normal one. And hopefully will provide women with PMDD with some alternate therapies that may be based more directly on the cause of the condition.