A role of estradiol withdrawal in the onset of mood disorders in some perimenopausal women has been suggested indirectly by the clustering of depressive episodes during the late menopause transition (the stage of ovarian aging associated with maximal decline of ovarian estradiol secretion) and by estradiol's antidepressant efficacy in perimenopausal depression. Nonetheless, there is no direct evidence that estradiol withdrawal precipitates depressive episodes in those women who develop depression during the perimenopause. In these studies, first we examine the effects of estradiol withdrawal and the recent onset of hypogonadism on mood symptoms in asymptomatic premenopausal women. Second, we investigate what factors influence the development of depression during estradiol withdrawal. We administered a gonadotropin releasing hormone (GnRH) agonist for two to three months to 70 regular cycling, asymptomatic, healthy, premenopausal women. Only three women (<5.0% of the sample) reported clinically significant symptoms of depression. In contrast to the relative absence of depressive symptoms in these women, we did observe the significant appearance of several symptoms including hot flushes, disturbed sleep, and diminished libido. Thus, in otherwise healthy women, the induction of neither hypogonadism nor hot flushes (with an accompanying sleep disturbance) uniformly precipitates depressive symptoms. In these studies, we also investigate two factors that could impact the appearance of depression during estradiol withdrawal - age and a previous episode of depression. We evaluate the effects of the acute withdrawal of estradiol therapy in older postmenopausal women with and those without a past perimenopausal depression. Preliminary results suggest that estradiol withdrawal induces depressive symptoms in women with a past perimenopausal depression, but not in those without such a history. In women with a past depression during the perimenopause, estradiol withdrawal is associated with a significant increase in depressive symptoms compared with those women who were maintained on estradiol therapy under double-blind conditions. Additionally, no significant depressive symptoms emerged in the women lacking a history of depression who were either withdrawn or maintained on estradiol therapy. We intend to complete this study by the end of the year. Our data are consistent with those from epidemiologic studies showing that, for a subgroup of women, the endocrine events of the late menopause transition may represent important triggers for mood destabilization and the onset of depression. Both the markers of this risk and the mechanisms underlying estradiol withdrawal-induced depressive symptoms remain to be identified. The results of the Womens Health Initiative (WHI) have deterred many women from using estrogen therapy. Although considerable controversy exists regarding the applicability of the WHIs findings to younger perimenopausal women, many women and their physicians are concerned about the long-term risks of estrogen therapy. In a previous study, we demonstrated the antidepressant effects of the short-term administration of estradiol in women with perimenopausal depression. In an ongoing study, we now are examining the effects on mood and behavior of two compounds that for many women represent alternatives to traditional estrogen therapy. Specifically, selective estrogen receptor modulators (SERMs) and phytoestrogens (plant-derived estrogen-like compounds) have become available and are reported to display both tissue-specific profiles of estrogen agonist and antagonist actions and differential affinities from estradiol for the two forms of estrogen receptor. Preliminary results demonstrate that after eight weeks of either estradiol or raloxifene, mood rating scores were significantly decreased compared with baseline scores and significantly lower than scores in women receiving placebo. Women receiving either phytoestrogen or placebo showed no significant improvement compared with their baseline scores. Recruitment for this treatment trial is approximately 75% complete and we hope to finish this protocol within the next two years. Equal efficacy to that of estradiol would provide an alternative therapeutic option with a more acceptable profile of long-term side effects. As phytoestrogens are already commonly recommended, well accepted, and widely used for the treatment of mood symptoms, further clarification of their mood effects could have significant public health implications. In future studies, we intend to investigate the behavioral relevance of estrogen receptor beta in humans. Specifically, we will examine the antidepressant/anxiolytic efficacy of selective estrogen receptor beta agonists (when available for human use) in women with perimenopausal depression. These data will not only establish the role of estrogen receptor beta in the mechanism of estradiols antidepressant action, but could identify a promising new class of therapeutic agents that are safer and more acceptable than estrogen and potentially lack the side effects or withdrawal syndromes associated with traditional psychotropics. An additional strategy that we have employed is the use of the longitudinal design to identify predictors of the onset of depression during the menopause transition. Predictors that we have examined include the following: 1) the kinetics of the menstrual cycle (example duration of menstrual cycle irregularity);2) past history of affective illness;and 3) symptom concomitants of the menopause transition (e.g., vasomotor symptoms). We also intend to investigate specific changes in reproductive hormones that may identify markers of risk for some of the physiology of the vulnerability to experience depression at this phase of a woman's life. Currently we have 100 women who have been recruited for this trial and 40 have completed their participation ranging from five to 10 years. This will be the first high-density, longitudinal study examining both menstrual cycle phase characteristics and reproductive hormones in women as they transition through the menopause. Karyotypically, normal, 46XX spontaneous (i.e., idiopathic) primary ovarian insufficiency (POI) is a condition in which ovarian failure occurs at an early age. We have completed a study of 174 women with well-characterized diagnoses of POI. We have identified that a lifetime prevalence of depression in women with POI is significantly greater than that reported in both the general population, and in gynecologic or general medical outpatient settings. Additionally, first episodes of major depression preceded the date of POI diagnosis in over 70% of women confirming previous findings by Harlow, et al. However, rather than causing POI, the episodes of depression occurred after evidence of ovarian failure began in the majority of women (i.e., after the onset of menstrual cycle irregularity). Thus, we have demonstrated that depressions occur after the onset of MCI potentially secondary to the events related to this premature menopause transition (at a time similar to the onsets of depression in the normally-time menopause transition). Both depression and POI also could be manifestations of a similar pathophysiology or genetic vulnerability, such as the fMR1 pre-mutation which is associated with both ovarian insufficiency and a late onset neurodegenerative disease. A better understanding of the nature of this association could identify candidate genes and physiological processes that may inform both our understanding of the relationship between depression and POI, as well as the association between depression and the menopause transition in the normally-timed menopause.
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