Publications

OBJECTIVE: Concern about adverse effects of progestins on mood has influenced the use of medroxyprogesterone (MPA) and other progestins. In this brief report, we examined whether the administration of MPA leads to depressive symptoms in two groups of perimenopausal and postmenopausal women randomly assigned to treatment with estrogen: one currently experiencing clinical depression and another without depression.

METHODS: Open-label MPA 10 mg/day was administered for 14 days for endometrial protection after completion of double-blinded treatment with 17β-estradiol 0.1 mg/day for 8 to 12 weeks in 40- to 60-year-old perimenopausal and postmenopausal women enrolled in two separate randomized placebo-controlled trials for treatment of cognitive problems ("nondepressed group") or clinical depression ("depressed group"). Nonparametric tests were used to compare changes in depressive symptoms on the Beck Depression Inventory (BDI) within each group and between groups during MPA therapy.

RESULTS: Of the 24 nondepressed (median BDI at baseline, 5.5; interquartile range [IQR], 2.5-8.5) and 14 depressed (median BDI at baseline, 17; IQR, 15-21) women treated with MPA, the BDI scores did not change during MPA treatment in either group (median change, 0; IQR, -2 to 0.5 and median, 0; IQR, -0.5 to 1.5, P = 0.28 and P = 0.50, respectively). Changes in BDI scores during treatment with MPA did not differ between groups (P = 0.25).

CONCLUSIONS: Among women receiving MPA for 2 weeks after discontinuation of estradiol, depressive symptoms did not emerge on MPA. These findings were consistent for both depressed and nondepressed women, suggesting that, even among women who are currently experiencing depression, brief treatment with MPA is unlikely to disrupt mood.

OBJECTIVE: The aim of this study was to examine the association of a history of major depression (MD) with menstrual problems in a multiethnic sample of midlife women.

METHODS: Participants were 934 women enrolled in the Study of Women's Health Across the Nation, a multisite study of menopause and aging. The outcomes were menstrual bleeding problems and premenstrual symptoms in the year before study entry. The Structured Clinical Interview for the Diagnosis of DSM-IV Axis I Disorders was conducted to determine recent and past psychiatric diagnoses. Covariates included sociodemographic, behavioral, and gynecologic factors.

RESULTS: One third of the participants reported heavy bleeding, 20% reported other abnormal bleeding, and 18% reported premenstrual symptoms. One third had past and 11% had recent MD. Past MD was associated with an increased likelihood of heavy bleeding (odds ratio, 1.89; 95% CI, 1.25-2.85), adjusting for recent MD, menopause status, and other covariates. Past MD was not associated with other abnormal bleeding or premenstrual symptoms in the final analysis that adjusted for recent MD.

CONCLUSIONS: Midlife women with a history of MD are more likely to report heavy bleeding.

CONTEXT: It is unknown whether a history of depression, anxiety disorders, or comorbid depression and anxiety affects subsequent health-related quality of life (HRQOL) during midlife in women when vasomotor symptoms (VMS) and sleep disturbance commonly disrupt QOL.

OBJECTIVES: To evaluate whether previous affective illness is associated with low HRQOL during midlife in the absence of current illness episodes and whether low HRQOL is explained by VMS or sleep disruption.

DESIGN: Longitudinal, community-based study.

SETTING: Western Pennsylvania.

PARTICIPANTS: A total of 425 midlife women in the Study of Women's Health Across the Nation who completed the Structured Clinical Interview for DSM-IV (SCID) and the 36-Item Short Form Health Survey (SF-36) annually during 6 years of follow-up.

MAIN OUTCOME MEASURES: Scores on the SF-36 scales of social functioning (SF), role-emotional (RE), role-physical (RP), body pain (BP), and vitality.

RESULTS: Ninety-seven women (22.8%) had comorbid affective illness histories, 162 (38.1%) had previous depression only, and 21 (4.9%) had previous anxiety only. Those with comorbid illness histories and depression alone were more likely to report low HRQOL on the SF, RE, RP, and BP domains (odds ratio [OR] = 2.31-3.54 and 1.59-2.28, respectively) than were women with neither disorder. After adjustment for VMS and sleep disturbance, the comorbid group continued to have low HRQOL on these domains (OR = 2.13-3.07), whereas the association was significant on SF and BP only for the depression-alone group (OR = 2.08 and 1.95, respectively). Compared with women with neither disorder, the anxiety-only group had low HRQOL on the RP domain (OR = 2.60). Sleep disturbance, but not VMS, was independently associated with low HRQOL on all the domains except RE.

CONCLUSIONS: A history of both depression and anxiety has the most robust negative effect on HRQOL in women during midlife, an association not explained by VMS or sleep disturbance. For the depression-alone group, sleep disturbance may partially explain the negative impact of previous affective illness on HRQOL. Sleep disturbance remains an independent correlate of low HRQOL.

CONTEXT: Emerging research suggests links between menopausal hot flashes and cardiovascular disease risk. The mechanisms underlying these associations are unclear, due to the incomplete understanding of the physiology of hot flashes. OBJECTIVE AND MAIN OUTCOME MEASURES: We examined the associations between hot flashes/night sweats and glucose and insulin resistance over 8 yr, controlling for cardiovascular risk factors and reproductive hormones.

DESIGN, SETTING, AND PARTICIPANTS: Participants in the Study of Women's Health Across the Nation (SWAN) (n=3075), a longitudinal cohort study, were ages 42-52 yr at entry. Women completed questionnaires (hot flashes, night sweats: none, 1-5 d, ≥6 d, past 2 wk), physical measures (blood pressure, height, weight), and a fasting blood draw [serum glucose, insulin, estradiol (E2), FSH] annually for 8 yr. Hot flashes/night sweats were examined in relation to glucose and the homeostasis model assessment (HOMA) in mixed models, adjusting for demographics, cardiovascular risk factors, medications, and E2/FSH.

RESULTS: Compared to no flashes, hot flashes were associated with a higher HOMAlog index [vs. none; hot flashes, 1-5 d: % difference (95% confidence interval), 2.37 (0.36-4.43), P=0.02; and ≥6 d: 5.91 (3.17-8.72), P<0.0001] in multivariable models that included body mass index. Findings persisted adjusting for E2 or FSH, and were similar for night sweats. Findings were statistically significant, yet modest in magnitude, for the outcome glucose.

CONCLUSIONS: Hot flashes were associated with a higher HOMA index, an estimate of insulin resistance, and to a lesser extent higher glucose. Metabolic factors may be relevant to understanding the link between hot flashes and cardiovascular disease risk.

CONTEXT: Hot flashes are a common side effect of adjuvant endocrine therapies (AET; leuprolide, tamoxifen, aromatase inhibitors) that reduce quality of life and treatment adherence in breast cancer patients. Because hot flashes affect only some women, preexisting neurobiological traits might predispose to their development. Previous studies have implicated the insula during the perception of hot flashes and the hypothalamus in thermoregulatory dysfunction.

OBJECTIVE: The aim of the study was to understand whether neurobiological factors predict hot flashes.

DESIGN: [18F]-Fluorodeoxyglucose (FDG) positron emission tomography (PET) brain scans coregistered with structural magnetic resonance imaging were used to determine whether metabolic activity in the insula and hypothalamic thermoregulatory and estrogen-feedback regions measured before and in response to AET predict hot flashes. Findings were correlated with CYP2D6 genotype because of CYP2D6 polymorphism associations with tamoxifen-induced hot flashes.

OUTCOME MEASURES: We measured regional cerebral metabolic rate of glucose uptake (rCMRglu) in the insula and hypothalamus on FDG-PET.

RESULTS: Of 18 women without hot flashes who began AET, new-onset hot flashes were reported by 10 (55.6%) and were detected objectively in nine (50%) participants. Prior to the use of all AET, rCMRglu in the insula (P ≤ 0.01) and hypothalamic thermoregulatory (P = 0.045) and estrogen-feedback (P = 0.007) regions was lower in women who reported developing hot flashes. In response to AET, rCMRglu was further reduced in the insula in women developing hot flashes (P ≤ 0.02). Insular and hypothalamic rCMRglu levels were lower in intermediate than extensive CYP2D6 metabolizers.

CONCLUSIONS: Trait neurobiological characteristics predict hot flashes. Genetic variability in CYP2D6 may underlie the neurobiological predisposition to hot flashes induced by AET.

BACKGROUND: In clinical samples, comorbidity between depressive and anxiety disorders is associated with greater symptom severity and elevated suicide risk. Less is known, however, regarding the long-term psychosocial impact that a lifetime history of both major depressive disorder (MDD) and one or more anxiety disorders has in community samples. This report evaluates clinical, psychological, social, and stress-related characteristics associated with a lifetime history of MDD and anxiety.

METHODS: Data from 915 women aged 42-52 who were recruited as part of the the Study of Women's Health across the Nation (SWAN) Mental Health Study were used to examine clinical and psychosocial features across groups of women with a lifetime history of MDD alone, anxiety alone, both MDD and anxiety, or neither MDD nor anxiety.

RESULTS: As compared with women with a history of either MDD or anxiety alone, women with a comorbid history were more likely to report recurrent MDD, multiple and more severe lifetime anxiety disorders, greater depressive and anxiety symptoms, diminished social support, and more past-year distressing life events. Exploratory analyses indicated that women with a comorbid history also report more childhood abuse/neglect and diminished self-esteem, as compared with women with a history of either disorder alone.

CONCLUSIONS: Midlife women with a comorbid history that includes both MDD and anxiety disorders report diminished social support, more symptomatic distress, and a more severe and recurrent psychiatric history. Future research is needed to clarify the biological and psychosocial risk factors associated with this comorobid profile, and to develop targeted interventions for this at-risk group. Depression and Anxiety 00:1-8, 2012. © 2012 Wiley Periodicals, Inc.

BACKGROUND: The antidepressant effect of estrogen in women undergoing the menopause transition is hypothesized to be mediated by central nervous system effects of increasing estradiol on mood or through a pathway involving suppression of hot flashes and associated sleep disturbance. Estrogen therapy (ET) and the hypnotic agent zolpidem were selected as interventions in a three-arm, double-blind, placebo-controlled trial to distinguish the effects of estradiol, sleep, and hot flashes on depression.

METHODS: Women with depressive disorders, hot flashes, and sleep disturbance were randomly assigned to transdermal 17β-estradiol 0.05 mg/d, zolpidem 10 mg/d, or placebo for 8 wk. Changes in serum estradiol, perceived sleep quality, objectively measured sleep, and hot flashes were examined as predictors of depression improvement [Montgomery-Åsberg Depression Rating Scale (MADRS)] using multivariate linear regression.

RESULTS: Seventy-two peri/postmenopausal women with depression disorders were randomized to 17β-estradiol (n = 27), zolpidem (n = 31), or placebo (n = 14). There was no significant difference between groups in depression improvement (overall MADRS decrease 11.8 ± 8.6). Increasing estradiol (P = 0.009) and improved sleep quality (P < 0.001) predicted improved mood in adjusted models but reduced hot flashes (P = 0.99) did not. Post hoc subgroup analyses revealed that the therapeutic effect of increasing estradiol levels on mood was seen in perimenopausal (P = 0.009), but not postmenopausal, women.

CONCLUSIONS: For women with menopause-associated depression, improvement in depression is predicted by improved sleep, and among perimenopausal women, by increasing estradiol levels. These results suggest that changes in estradiol and sleep quality, rather than hot flashes, mediate depression during the menopause transition. Therapies targeting insomnia may be valuable in treating menopause-associated depression.

OBJECTIVE: The impact of hormonal fluctuation during the menstrual cycle on the course of bipolar disorder is poorly understood. The authors determined the course of illness and time to relapse of bipolar disorder in prospectively followed women with premenstrual exacerbation.

METHOD: Participants were 293 premenopause-age women with bipolar disorder who were followed prospectively for 1 year as part of the Systematic Treatment Enhancement Program for Bipolar Disorder. Frequency of mood episodes was compared between 191 women with premenstrual exacerbation (65.2%) and 102 women without. Among 129 women who were in recovered status at baseline, time to relapse was compared between 66 women with premenstrual exacerbation (51.2%) and 63 without.

RESULTS: During follow-up, the group with premenstrual exacerbation had more episodes (primarily depressive) than did the group without, but they were not more likely to meet criteria for rapid cycling during this period. In contrast, they were more likely to report rapid cycling retrospectively. Women with premenstrual exacerbation had a shorter time to relapse and were at greater risk for relapse, but this association was not significant after adjustment for retrospectively reported rapid cycling. Women with premenstrual exacerbation had more depressive and mood elevation symptoms overall.

CONCLUSIONS: Women with bipolar disorder and premenstrual exacerbation have a worse course of illness, a shorter time to relapse, and greater symptom severity, but they are not more likely to meet criteria for rapid cycling. Premenstrual exacerbation may be a clinical marker predicting a more symptomatic and relapse-prone phenotype in reproductive-age women with bipolar disorder.

The human eye serves distinctly dual roles in image forming (IF) and non-image-forming (NIF) responses when exposed to light. Whereas IF responses mediate vision, the NIF responses affect various molecular, neuroendocrine, and neurobehavioral variables. NIF responses can have acute and circadian phase-shifting effects on physiological variables. Both the acute and phase-shifting effects induced by photic stimuli demonstrate short-wavelength sensitivity peaking ≈450-480 nm. In the current study, we examined the molecular, neuroendocrine, and neurobehavioral effects of completely filtering (0% transmission) all short wavelengths <480 nm and all short wavelengths <460 nm or partially filtering ( 30% transmission) <480 nm from polychromatic white light exposure between 2000 and 0800 in healthy individuals. Filtering short wavelengths <480 nm prevented nocturnal light-induced suppression of melatonin secretion, increased cortisol secretion, and disrupted peripheral clock gene expression. Furthermore, subjective alertness, mood, and errors on an objective vigilance task were significantly less impaired at 0800 by filtering wavelengths <480 nm compared with unfiltered nocturnal light exposure. These changes were not associated with significantly increased sleepiness or fatigue compared with unfiltered light exposure. The changes in molecular, endocrine, and neurobehavioral processes were not significantly improved by completely filtering <460 nm or partially filtering <480 nm compared with unfiltered nocturnal light exposure. Repeated light-dark cycle alterations as in rotating nightshifts can disrupt circadian rhythms and induce health disorders. The current data suggest that spectral modulation may provide an effective method of regulating the effects of light on physiological processes.

Is there evidence for a perimenopausal sleep disorder? We address this question in our presentation of the Study of Women's Health Across the Nation (SWAN) "sleep story," in which we summarize and discuss data addressing sleep quality, objective measures of sleep patterns, and sleep disorders that have been published to date by the SWAN and the ancillary SWAN Sleep Study. We describe what has been learned about sleep during the perimenopause. Analyses exploring racial/ethnic diversity and the role of hot flashes and mood disturbance in sleep-perimenopause associations are described. Implications for clinical practice are considered.