This report includes work arising from the following clinical protocols: NCT00005011, NCT00056901, NCT00059228, NCT00082043, NCT00100360, NCT00001177, NCT00001259, and NCT00001481. The linkage between the onset of symptoms and the luteal phase of the menstrual cycle suggests a role for ovarian steroid secretion in the pathophysiology of PMDD. Our studies have documented that PMDD symptoms are eliminated by ovarian suppression and stimulated by administration of ovarian steroids, yet appear in the context of levels of ovarian steroids indistinguishable from those in women without PMDD. We have recently more clearly defined the kinetics of the ovarian steroid event relevant to triggering PMDD symptoms. Women with PMDD who responded to treatment with gonadotropin-releasing hormone (GnRH) agonist-induced ovarian suppression (i.e., PMDD symptom remission) then were exposed to three months of combined continuous estradiol and progesterone treatment (E/P). We demonstrated that the change in levels of E/P from low to high, and not the steady state levels, was associated with the onset of PMDD symptoms. Although the mechanisms underlying the mood destabilizing effects of ovarian steroids in PMDD remain to be better characterized, as does the source of susceptibility to this trigger, our findings provide a new target on which interventions could be focused (namely increasing neurosteroid levels from the follicular to the luteal phase). To that end, we completed a pilot study evaluating (under blinded conditions) the effects of inhibiting the production of the neurosteroid, allopregnanolone (a derivative of progesterone that is implicated in the alterations of neurotransmitter function that could lead to PMDD). After successful elimination of the luteal phase increase in allopregnanolone (despite maintaining normal progesterone levels), the emergence of luteal phase affective symptoms in PMDD were prevented. These findings have led to our plans to conduct a larger placebo-controlled treatment trial investigating the effects of stabilizing neurosteroid levels in women with PMDD. Our findings to date suggest that women with PMDD have a differential behavioral response to ovarian steroids (as demonstrated in our GnRH agonist studies) and the relevance of neural differences in the response to ovarian steroids with consequent differential activation (described above) of brain networks that mediate the affective responsivity of women with PMDD. These data set the stage for the performance of in vitro cellular studies of ovarian steroid responsivity in women with PMDD. The observed differential sensitivity could be due to an as yet unrecognized aspect of hormonal signaling or a difference in cellular response. Isolating the molecular mechanism of the observed differential response is key to interventional approaches and, therefore, we have moved to cellular models in which the molecular machinery of response (i.e., ovarian steroid receptors) is present. In collaboration with Dr. David Goldman at NIAAA, we developed lymphoblastoid cell lines (LCLs) and human induced-pluripotent cell lines (h-IPSCs) from women with and without PMDD who have participated in our GnRH agonist-induced ovarian suppression studies. The behavioral outcomes observed during these protocols serve to refine the hormone-sensitive phenotype beyond simply the established clinical diagnoses. Women are selected retrospectively, based on the observed behavioral response to the hormone manipulation (i.e., occurrence of mood symptoms proximate to hormone manipulation in women with PMDD, or no changes in mood in the matched controls). Our in vitro experimental strategies attempt to recapitulate the endocrine events that trigger mood symptoms in women with PMDD. In this study, we found mRNA expression for estrogen receptor (ER) ESR1 (ERalpha) and ESR2 (ERbeta) and the progesterone membrane receptors PGRMC1 & 2. In untreated LCLs, our results overall suggest a divergence between mRNA and protein for the same genes. Pathway analyses 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 to controls. This pattern of increased ESC/E(Z) mRNA expression was confirmed in the larger replication cohort by qRT-PCR. In contrast, protein expression of ESC/E(Z) genes was decreased in untreated PMDD LCLs. Finally, mRNA expression of several ESC/E(Z) complex genes were increased by P in controls only and decreased by E in PMDD LCLs. Our findings provide the first evidence of a plausible biological substrate for the differential behavioral response to E/P in women with PMDD. Indeed, these data suggest that women with PMDD have an intrinsic abnormality in their epigenetic capacity that could manifest in an alteration in their ability to translate environmental events into long-term changes in gene expression. Several issues require future exploration: First, preliminary evidence from a whole small RNA sequencing (targeting micro-RNA expression) shows a significantly increased expression of several micro-RNAs in LCLs from women with PMDD compared to those in controls. Additionally, several of these differentially expressed micro-RNAs target the ESC/E(Z) pathway, and, therefore, could contribute to the observed dissociation between increased expression of the ESC/E(Z) pathway genes and decreased protein levels of this same pathway in PMDD. Second, we have strengthened evidence of the physiologic relevance of the observed changes in ESC/E(Z) pathway genes in LCLs by demonstrating both baseline (untreated) expression of ESC/E(Z) pathway genes and the hormone stimulated effects on gene expression in both neuroprogenitor cell lines (derived from h-IPSCs developed from these same women) and in stock neuronal cell cultures. Finally, in a data-driven re-analysis of the untreated and estradiol-stimulated whole transcriptome sequencing, we identified a pattern of differential gene expression in several genes involved in the regulation of intra-cellular calcium signaling in women with PMDD compared to control women. We are pursuing these latter findings in LCLs with both a calcium stress challenge paradigm and intra-cellular calcium imaging studies. Finally, we have initiated a new collaborative initiative (supported by an NIH Bench to Bedside award), to employ these same methods to cell lines obtained from women with and without postpartum depression (PPD) and in women with first-onset postpartum psychosis. Lastly, we examined the possibility that women with PMDD metabolize steroids differently than asymptomatic controls and, therefore, produce a different profile of neuroactive steroid metabolites that contributes to the onset of PMDD symptoms. Pharmacometabolomic studies (employing liquid chromatography-tandem mass spectroscopy) were performed in women with PMDD who respond to Lupron with elimination of symptoms and who experience return of symptoms during progesterone (P) or estradiol (E) replacement, as well as controls who experience no change in mood during the identical experimental paradigm. Importantly, no differences in the formation of P-derived neurosteroids were observed in this sample of women studied under controlled hormone. However, despite identical exposures to E and P, women with PMDD were distinguished by differences in their profiles of sulfated steroid metabolites. Relative to the Lupron condition (i.e., suppressed steroid secretion), women with PMDD were distinguished from controls by a significantly attenuated sulfotransferase activity which also could contribute to the differential steroid sensitivity in PMDD.

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