The protocols involved in this project are as follows: 02-M-0120, 03-M-0175, 88-M-0131, 92-M-0174. This report includes work arising from the following protocols: NCT00030147, NCT00060736, NCT00001231, and NCT00001322. In addition to the established increased risk of first onset depression during the perimenopause, there is preliminary evidence of estradiols antidepressant efficacy in perimenopausal depression (PMD). Indeed, observational studies report the emergence of depressive symptoms after the discontinuation of estradiol therapy (ET) in 5-10% of women. The role of estradiol -either declining or low levels - in the precipitation of PMD is unknown, largely due to the associational and indirect nature of the evidence linking ovarian function and depression. Correlative studies with plasma FSH or response to ET do provide indirect evidence of the relevance of changes in reproductive hormones to mood disturbances. However, even prospective epidemiological studies cannot test the estradiol withdrawal hypothesis since perimenopausal changes in the secretion of several hormonal and metabolic factors could confound the effects of estradiol withdrawal. In other studies of the role of ovarian steroids in affective disturbance, changes in ovarian steroids (in the context of otherwise normal levels) have been shown to directly trigger depression, but only in a subset of women with histories of mood disorders linked to reproductive function. In this study, we directly examined the hypothesis that declining ovarian function estradiol withdrawal - underpins depression occurring during the perimenopause. We further sought to examine whether the response to estradiol withdrawal differed in women with a past PMD compared with those without any past depression. In this second study, we determined if sudden, blinded withdrawal of ET would precipitate depressive symptoms and if it would do so differentially in those with a history of PMD. Our findings support both predictions. Estradiol withdrawal precipitated depression in women with a history of PMD, but no depressive symptoms were seen after estradiol withdrawal in women with no past history of PMD. Further, depressive symptoms did not emerge in those women with past PMD who were maintained on ET. Importantly, the recurrence of depressive symptoms in women with past PMD occurred in the absence of differences in several measures that could influence mood, including baseline clinical characteristics (other than PMD), the severity of daytime/nighttime hot-flushes, and plasma hormone levels after withdrawal. The lack of depressive symptoms in the control women despite identical hormone manipulation (and similar levels of hot-flushes and plasma estradiol levels) demonstrates that estradiol withdrawal differentially impacts CNS function in some women so as to render them susceptible to depression. This suggests that perimenopausal changes in estradiol can trigger depression, but only in the susceptible subgroup. These observations, in the context of similar plasma reproductive hormone levels, suggest that normal changes in ovarian estradiol secretion can trigger an abnormal behavioral state in susceptible women. There are several mechanisms by which changes in estradiol might mediate the observed effects on mood. First, estradiol modulates the activity of virtually every system implicated in the pathogenesis of depression, including regulation of neurotransmitter synthesis and metabolism, stress axis activation, neuroplasticity (including regulation of BDNF), epigenesis, and immune system activation. Second, estradiol signaling through estrogen receptor (ER) beta reverses depressive-like behavior in animal studies. Third, reward responsiveness, which is disturbed in depression, is modulated by estradiol in both rodents and humans. Finally, of particular note, discontinuation of long term ET in postmenopausal women was accompanied by decreases in medial frontal and temporo-occipital metabolism. Thus, through local signaling or network-level dysfunction, particularly in fronto-limbic regions, estradiol withdrawal could precipitate affective dysregulation. What remains unclear is the reason for the differential susceptibility to the mood destabilizing effects of estradiol withdrawal. Of interest in this regard is the recent identification of increased sensitivity to estrogen regulation among transcripts that were differentially expressed in women who developed postpartum depression. Alternatively, basic science studies report the de novo production of estradiol from androgens in brain regions involved in mood regulation (e.g., hippocampus). Thus, it is possible that women who did not develop depressive symptoms after ET withdrawal have sufficient CNS aromatase activity to prevent the development of depressive symptom during declining estradiol secretion. The investigation of these possible mechanisms will be the focus of future studies. One possible source of the susceptibility to developing perimenopasual depression is an abnormal hypothalamic pituitary-adrenal (HPA) axis. Dysfunction of the HPA axis is a frequent accompaniment of depression, and HPA axis function is modulated by both aging and ovarian steroid secretion. To date, only a few studies have evaluated basal (but not stimulated) HPA axis function in women with perimenopause-related depression, with findings suggesting differences in adrenal androgen secretion but not basal cortisol secretion in PMD compared with controls. We examined HPA axis function in depressed and asymptomatic perimenopausal women using the combined dexamethasone-corticotropin releasing hormone (Dex/CRH) test. In contrast to recent suggestions that declining ovarian estradiol secretion (and in turn alterations in neurosteroid synthesis), preliminary results suggest that abnormalities of HPA axis function do not distinguish perimenopausal women with depression from those without depression. Thus, unlike depression in premenopausal women, HPA axis dysfunction is not a frequent accompaniment of depression during the perimenopause. These findings suggest that reproductive endocrine-related mood disorders are not uniformly associated with the HPA dysregulation and could reflect underlying pathophysiologic processes that are distinct from those reported in women with non-reproductive-related depressions. Finally, we continue our longitudinal investigation of the onset of depression during the perimenopause. Over sixty women have completed this study that involved measuring early follicular phase blood samples, daily and weekly symptom self-ratings, and formal in-person interviews every six months during the transition from regular menstrual cycle function (premenopausal) until one year postmenopause. Women participate in this study for an average of five years (range = 3-10 years). Preliminary results confirm previous observations of a clustering of depressive episodes during the late menopause transition a stage of reproductive aging associated with estradiol withdrawal. Moreover, we have observed that depression occurring during the perimenopause,( but not other events related to the perimenopause including menstrual cycle irregularity, aging, or vasomotor symptoms) is accompanied by significant declines in measures of quality of life, social support, and personal disability.
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