The protocols involved in this project are as follows: 00-M-0103, 03-M-0138, 03-M-0161, 04-M-0139, 05-M-0059, 81-M-0126, 90-M-0088, 92-M-0174, and 95-M-0097. This report includes work arising from the following protocols: NCT00005011, NCT00056901, NCT00059228, NCT00082043, NCT00100360, NCT00001177, NCT00001259, and NCT00001481 In our earlier studies we have developed experimental models for the triggering of symptoms in both premenstrual dysphoric disorder (PMD) and postpartum depression that we continue to employ in our efforts to identify both the underlying biology of these conditions as well as the development of new safe and effective therapies for women with these conditions. We have extended and replicated our earlier findings by demonstrating that women with PMD (n = 35), who respond to gonadotropin releasing hormone (GnRH) agonist-induced ovarian suppression experience a recurrence of PMD after the initial re-exposure to combined estradiol and progesterone. However, recurrent symptoms do not occur once hormone levels are stabilized over the subsequent two months of continuous replacement therapy. These observations are of both clinical and scientific importance, as they identify promising phenotypes and suggest the physiologic basis for the susceptibility to experience PMD and will also provide alternative hormone-based therapies for women with this condition. In addition to our studies on the behavioral effects of changes in ovarian steroids across the menstrual cycle and during the postpartum, we employ methodologies to investigate the underlying biological mechanisms of these conditions including studies investigating positron emission tomography (PET), structural magnetic resonance imaging (MRI), and functional magnetic resonance imaging (fMRI). First, our neuroimaging studies have identified both a neural substrate of risk in PMDD as well as a brain-region specific response that could underlie the differential behavioral response to ovarian steroids in this condition. We performed O15 PET and fMRI studies in women who are participating in the GnRH agonist-induced hypogonadism study. In this study, cognitive activation was achieved using the N-back test which allows us to vary the cognitive load and the effort required to perform the task. We observed that women with PMD show abnormal prefrontal recruitment, specifically greater activation than controls throughout the DLPFC bilaterally. These findings are robust and observable in both 015 PET and fMRI techniques. In both imaging modalities, significantly increased DLPFC activations in PMDD compared with controls occurred in all three hormone conditions and, therefore, were independent of hormone condition. Moreover, DLPFC activations in PMDD correlated negatively with measures of PMD functional impairment (i.e., global assessment of functional impairment GAF scores), age of onset of PMDD, and baseline (prior to Lupron) symptom severity measures the greater the over-activation, the greater the disability, the earlier age of onset, and the more severe baseline symptomatology. Our findings suggest that these persistent effects, even in the clinically asymptomatic phase of the hormone-manipulation paradigm (i.e., Lupron alone), may represent an enduring, trait-like predisposition to this hormonally-triggered disorder. By identifying the prefrontal cortex, specifically the DLPFC, as key in the pathophysiology of PMDD, these data provide insight into potential neural mechanisms contributing to this disorder. Women with PMD (n = 19) and controls (n = 32) underwent resting state PET studies during each of the three hormone conditions. We observed significant diagnosis by hormone interactions in the subgenual cingulate (BA25), medial orbital frontal cortex (mOFC), and right hippocampal/parahippocampal region. Post-hoc analyses revealed that in PMD higher resting rCBF was present during hypogonadism (when PMD symptoms are in remission) compared with estradiol or progesterone replacement (when PMD symptoms are at risk of recurring), whereas the opposite pattern (i.e., lower resting rCBF during hypogonadism compared with either estradiol or progesterone) was observed in controls who experience no change in mood across identical hormone conditions. These data demonstrate for the first time a differential pattern of rCBF within a neuroanatomical locus implicated in the process of affective adaptation. Additionally, the fact that the changes in rCBF correspond in time to the hormone state-related changes in symptoms raises the possibility that the changes in rCBF may reflect the altered mood state rather than a direct effect of hormonal state. We collaborate with Drs. Rima Kaddurah-Daouk at Duke University and Thomas Hankemeier at Leiden University to more comprehensively examine the profile of steroid and steroid metabolites with a metabolomics platform employing liquid chromatography-tandem mass spectroscopy. Our strategy is to perform metabolomic studies in women with PMD who respond to Lupron with elimination of symptoms and who experience return of symptoms during progesterone or estradiol replacement. Thus, we wish to specifically examine the effects of both estradiol and progesterone on the pattern of steroid metabolites in women with PMD and an asymptomatic comparison group. Our metabolomic and neuroimaging studies will be complemented by a new series of functional genomic studies performed in collaboration with David Goldman's laboratory at NIAAA, in which we employ lymphoid and fibroblast cell-lines obtained from women with PMD and controls who participate in our Lupron studies. We hypothesize that the capacity for phenotypic differences between women with and those without PMD will be preserved in their cellular function. These experiments allow us to explore the nature of the differential behavioral response by examining protein expression and changes in cellular behaviors associated with the exposure to physiologic levels of either estradiol or progesterone across the two different behavioral phenotypes (women with PMD who experience a remission of PMDD during ovarian suppression and a recurrence of PMDD when ovarian steroids are added back, and controls who are asymptomatic during all three hormone conditions). Preliminary results show that women with PMD express more estrogen receptor (ER) alpha (but not beta) compared with controls (consistent with our findings of differential ER alpha allele frequency in PMD compared with controls observed in a prior study). Additionally, RNA sequencing strategies investigate the response to steroid hormone exposure in immortalized lymphoid cells in these same groups of women. We observed statistically significant, quantitative and widespread differences in the PMDD transcriptome compared to a carefully selected asymptomatic control group. Our analyses identified several molecular pathways that appear to be altered in women with PMDD;one of these pathways, the chromatin modifying ESC/E(z) complex, is of particular interest as a potential candidate since it is regulated by estradiol and leads to genomic regions of transcriptional repression. The mechanism by which these pathways converge and possibly alter CNS function sufficient to manifest in PMDD will be the focus of our future studies in induced neuronal and glial cells.

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Schiller, Crystal Edler; Johnson, Sarah L; Abate, Anna C et al. (2016) Reproductive Steroid Regulation of Mood and Behavior. Compr Physiol 6:1135-60
Martinez, Pedro E; Rubinow, David R; Nieman, Lynnette K et al. (2015) 5α-Reductase Inhibition Prevents the Luteal Phase Increase in Plasma Allopregnanolone Levels and Mitigates Symptoms in Women with Premenstrual Dysphoric Disorder. Neuropsychopharmacology :
Postpartum Depression: Action Towards Causes and Treatment (PACT) Consortium (2015) Heterogeneity of postpartum depression: a latent class analysis. Lancet Psychiatry 2:59-67
Schiller, Crystal Edler; Schmidt, Peter J; Rubinow, David R (2014) Allopregnanolone as a mediator of affective switching in reproductive mood disorders. Psychopharmacology (Berl) 231:3557-67
Nevatte, Tracy; O'Brien, Patrick Michael Shaughn; Bäckström, Torbjorn et al. (2013) ISPMD consensus on the management of premenstrual disorders. Arch Womens Ment Health 16:279-91
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Steinberg, Emma M; Cardoso, Graca M P; Martinez, Pedro E et al. (2012) Rapid response to fluoxetine in women with premenstrual dysphoric disorder. Depress Anxiety 29:531-40
Epperson, C Neill; Steiner, Meir; Hartlage, S Ann et al. (2012) Premenstrual dysphoric disorder: evidence for a new category for DSM-5. Am J Psychiatry 169:465-75
Lee, Ellen E; Nieman, Lynnette K; Martinez, Pedro E et al. (2012) ACTH and cortisol response to Dex/CRH testing in women with and without premenstrual dysphoria during GnRH agonist-induced hypogonadism and ovarian steroid replacement. J Clin Endocrinol Metab 97:1887-96
Pincus, Steven M; Alam, Shaista; Rubinow, David R et al. (2011) Predicting response to leuprolide of women with premenstrual dysphoric disorder by daily mood rating dynamics. J Psychiatr Res 45:386-94

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