Is trait rumination associated with affective reactivity to the menstrual cycle? A prospective analysis.

BACKGROUND: A minority of naturally cycling individuals experience clinically significant affective changes across the menstrual cycle. However, few studies have examined cognitive and behavioral constructs that may maintain or worsen these changes. Several small studies link rumination with premenstrual negative affect, with authors concluding that a tendency to ruminate amplifies and perpetuates hormone-sensitive affective symptoms. Replication in larger samples is needed to confirm the validity of rumination as a treatment target. METHOD: 190 cycling individuals (M = 30.82 years; 61.1% Caucasian) were recruited for moderate perceived stress, a risk factor for cyclical symptoms. They completed the Rumination Response Scale at baseline, then reported daily affective and physical symptoms across 1-6 cycles. Multilevel growth models tested trait rumination as a predictor of baseline levels, luteal increases, and follicular decreases in symptoms. RESULTS: The degree of affective cyclicity was normally distributed across a substantial range, supporting feasibility of hypothesis tests and validating the concept of dimensional hormone sensitivity. Contrary to prediction, higher brooding did not predict levels or cyclical changes of any symptom. In a subsample selected for luteal increases in negative affect, brooding predicted higher baseline negative affect but still did not predict affective cyclicity. CONCLUSIONS: An individual's trait-like propensity to engage in rumination may not be a valid treatment target in premenstrual mood disorders. State-like changes in rumination should still be further explored, and well-powered prospective studies should explore other cognitive and behavioral factors to inform development of targeted psychological treatments for patients with cyclical affective symptoms.

Effects of Nicotine Content and Preferred Flavor on Subjective Responses to E-cigarettes: A Randomized, Placebo-controlled Laboratory Study.

INTRODUCTION: Evidence suggests that e-liquid flavor and nicotine concentration are important factors in the initiation and maintenance of e-cigarette use (vaping). Flavors may increase the initiation and maintenance of vaping, and nicotine content is a factor in e-cigarette dependence and the efficacy of e-cigarettes for cigarette smoking cessation. Few human laboratory studies have assessed the joint and interactive effects of flavor and nicotine on subjective responses to e-cigarettes. METHODS: Regular e-cigarette users (N = 89) completed a multi-session study involving a paced vaping procedure with e-liquid cartridges containing their preferred flavor (berry, menthol, or tobacco) or no flavor, with or without nicotine (18 mg). Subjective effects of vaping (satisfaction, reward, aversion, airway sensations, and craving relief) were assessed. RESULTS: Nicotine significantly increased psychological reward and craving relief, whereas flavor significantly increased vaping satisfaction and taste. Nicotine dependence severity moderated the effect of nicotine on reward, such that those with the greatest dependence severity reported the greatest reward. CONCLUSIONS: These findings support differential and noninteractive effects of e-liquid nicotine content and flavor on reinforcing effects of e-cigarettes. IMPLICATIONS: E-liquid flavor and nicotine content have independent, non-interactive effects on subjective responses to vaping under controlled laboratory conditions. Among regular e-cigarette users, vaping a preferred flavor increased taste and satisfaction, but did not interact with nicotine to alter reward or craving. Further research on the ways in which these subjective effects may motivate vaping behavior among different populations of e-cigarette users would be useful to inform regulatory policy of ENDS products.

Perimenstrual exacerbation of symptoms in borderline personality disorder: evidence from multilevel models and the Carolina Premenstrual Assessment Scoring System.

BACKGROUND: Individuals with a borderline personality disorder (BPD) suffer from a constellation of rapidly shifting emotional, interpersonal, and behavioral symptoms. The menstrual cycle may contribute to symptom instability among females with this disorder. METHODS: Fifteen healthy, unmedicated females with BPD and without dysmenorrhea reported daily symptoms across 35 days. Urine luteinizing hormone and salivary progesterone (P4) were used to confirm ovulation and cycle phase. Cyclical worsening of symptoms was evaluated using (1) phase contrasts in multilevel models and (2) the Carolina Premenstrual Assessment Scoring System (C-PASS), a protocol for evaluating clinically significant cycle effects on symptoms. RESULTS: Most symptoms demonstrated midluteal worsening, a perimenstrual peak, and resolution of symptoms in the follicular or ovulatory phase. Post-hoc correlations with person-centered progesterone revealed negative correlations with most symptoms. Depressive symptoms showed an unexpected delayed pattern in which baseline levels of symptoms were observed in the ovulatory and midluteal phases, and exacerbations were observed during both the perimenstrual and follicular phases. The majority of participants met C-PASS criteria for clinically significant (⩾30%) symptom exacerbation. All participants met the emotional instability criterion of BPD, and no participant met DSM-5 criteria for premenstrual dysphoric disorder (PMDD). CONCLUSIONS: Females with BPD may be at elevated risk for perimenstrual worsening of emotional symptoms. Longitudinal studies with fine-grained hormonal measurement as well as hormonal experiments are needed to determine the pathophysiology of perimenstrual exacerbation in BPD.

Emotion-related impulsivity and rumination predict the perimenstrual severity and trajectory of symptoms in women with a menstrually related mood disorder.

OBJECTIVE: Women with menstrually related mood disorders (MRMDs) demonstrate clinically significant distress during the premenstrual week that remits with the onset of menses. Relatively little is known about psychosocial mechanisms of MRMDs. Given the core affective and behavioral symptoms of MRMDs, dysfunctional responses to emotion (e.g., difficulties with awareness and regulation of emotion; rumination and impulsive or maladaptive behavior in response to emotion) may be important factors to explore as cognitive and behavioral mechanisms in MRMDs. The purpose of the present study was to examine the associations of various dysfunctional responses to emotion (as measured using the Difficulties in Emotion Regulation Scale [DERS] and brooding on the Ruminative Responses Scale [RRS]) with premenstrual symptom severity and trajectory. METHOD: A total of 54 women (mean age = 38.11; 65% Caucasian) with prospectively confirmed MRMDs completed the DERS and RRS, and provided 2-4 menstrual cycles of daily symptom reports. RESULTS: Only the emotion-related impulsivity subscale of the DERS was robustly associated with premenstrual symptom severity. Brooding rumination predicted a more rapid premenstrual increase and slower postmenstrual remission of some symptoms. CONCLUSION: Both rumination and emotion-related impulsivity may be important treatment targets in cognitive behavioral interventions aimed at reducing symptom severity and cyclicity in MRMDs.

The Role of Chronic Psychosocial Stress in Explaining Racial Differences in Stress Reactivity and Pain Sensitivity.

OBJECTIVE: To examine the role of psychosocial factors in mediating the relationship between African American (AA) race and both increased pain sensitivity and blunted stress reactivity. METHODS: Participants included 133 AA and non-Hispanic white (nHW) individuals (mean [SD] age, 37 [9]) matched for age, sex, and socioeconomic status. Participants underwent mental stress testing (Trier Social Stress Test) while cardiovascular, hemodynamic, and neuroendocrine reactivity were measured. Participants completed questionnaires assessing potential sources of psychosocial stress and were tested for pain responses to cold pain and the temporal summation of heat pulses. Mediation analyses were used to determine the extent to which exposure to psychosocial stress accounted for the observed racial differences in stress reactivity and pain. RESULTS: Chronic stress exposure and reactivity to mental stress was largely similar among AAs and nHWs; however, AAs exhibited heightened pain to both cold (p = .012) and heat (p = .004). Racial differences in the relationship between stress reactivity and pain were also observed: while greater stress reactivity was associated with decreased pain among nHWs, reactivity was either unrelated to or even positively associated with pain among AAs (e.g., r = -.21 among nHWs and r = .41 among AAs for stroke volume reactivity and cold pressor intensity). Adjusting for minor racial differences in chronic psychosocial stress did not change these findings. CONCLUSIONS: Accounting for psychosocial factors eliminated racial differences in stress reactivity but not racial differences in sensitivity to experimental pain tasks. Increased exposure to chronic stress may not explain AAs' increased pain sensitivity in laboratory settings.

Treatment of premenstrual dysphoria with continuous versus intermittent dosing of oral contraceptives: Results of a three-arm randomized controlled trial.

BACKGROUND: Although traditionally dosed combined oral contraceptives (COCs) (21 days of active pills, 7 days of inactive pills) have not been demonstrated as superior to placebo for the treatment of premenstrual dysphoria (PMD), some randomized controlled trials (RCTs) indicate that oral contraceptives administered with a shortened or eliminated hormone-free interval are superior to placebo. However, results of such trials are mixed, and no existing studies have directly compared continuous and intermittent dosing schedules of the same oral contraceptive. The present study compared placebo, intermittent dosing of oral contraceptives, and continuous dosing of contraceptives for the treatment of PMD. METHODS: Fifty-five women with prospectively confirmed PMD completed a three-arm, RCT in which they were randomized to 3 months of placebo (n = 22), intermittent drospirenone/ethinyl estradiol dosed on a 21-7 schedule (n = 17), or continuous drospirenone/estradiol (n = 16) following a baseline assessment month. RESULTS: All three groups demonstrated similar, robust reductions in premenstrual symptoms over time. A marked placebo response was observed. CONCLUSIONS: The study fails to replicate a uniquely beneficial effect of continuous COC on PMD. Additional work is needed to understand the psychosocial context bolstering the placebo response in women with PMD.

Reproductive and Appetite Hormones and Bulimic Symptoms during Midlife.

Eating disorders and related symptoms occur during midlife; however, little is known about their aetiology. It has been hypothesised that perimenopause represents a window of vulnerability for the development or exacerbation of eating disorder symptomatology because, like puberty, perimenopause is a period of reproductive hormone change. We compared symptoms of bulimia nervosa (bulimic symptomatology) assessed via mean scores on a self-report questionnaire in premenopausal and perimenopausal women. We also examined the association between hormone concentrations (reproductive/appetite) and bulimic symptomatology. No mean differences in bulimic symptomatology were observed between premenopause and perimenopause. However, there was a significant positive association between leptin and binge eating. Although no significant associations between reproductive hormones and bulimic symptomatology were observed, additional research is needed to provide definitive information. It is essential to learn more about the aetiology of eating disorders and related symptomatology across the lifespan in order to develop age-relevant treatment and prevention programs. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association.

Hormone replacement therapy in the treatment of perimenopausal depression.

The menopause transition is associated with a two to fourfold increased risk in major depressive disorder (MDD) and clinical elevations in depressive symptoms. While the pathophysiological mechanisms underlying this increased risk remain uncertain, ovarian hormone fluctuation is believed to play a role. To the extent that this is the case, hormone replacement therapy (HRT), through its hormone-stabilizing effects, represents a viable antidepressant treatment. The current review summarizes the most recent literature evaluating the efficacy of HRT in treating MDD in peri- and postmenopausal women. In addition, to provide a clinical context in which to interpret this research, the endocrinology and clinical phenomenology related to depression with onset in the menopause transition (D-MT) are discussed. The available evidence suggests that HRT, specifically involving estrogen delivered through a skin patch, is a promising intervention in the treatment of D-MT. However, HRT of any form is an ineffective antidepressant in women who are well into the postmenopausal period.

Nonpharmacologic treatments for depression related to reproductive events.

There is a growing body of evidence suggesting that nonpharmacological interventions have an appropriate place in the treatment of major depressive disorders (MDDs) as both stand-alone and supplemental treatments. Because women may be reluctant to use psychotropic medications due to strong values or treatment preferences during specific reproductive events, clinicians need to be able to offer empirically based alternatives to medication. In this review, we present recent findings from studies of acupuncture, bright light therapy, electroconvulsive therapy, omega fatty acid supplementation, physical activity, and psychosocial intervention for women experiencing depressive symptoms in the contexts of menstruation, pregnancy, postpartum, and menopause.

Cyclical exacerbation of suicidal ideation in female outpatients: Prospective evidence from daily ratings in a transdiagnostic sample.

Suicide is a leading cause of death among females of reproductive age. The menstrual cycle is a plausible yet understudied trigger for acute suicide risk. Cross-sectional studies have demonstrated a greater frequency of suicide attempts and deaths in the weeks before and after the onset of menses compared to other cycle phases. Here, using prospective daily ratings, we examine the relationship between the cycle and suicidal ideation (SI) and related symptoms known to show a cyclical change in some patients (depression, hopelessness, guilt, rejection sensitivity, interpersonal conflict, anxiety, mood swings, and anger/irritability). Thirty-eight naturally cycling outpatients recruited for past-month SI reported SI severity and other symptoms across an average of 40 days. Participants were excluded for hormone use, pregnancy, irregular cycles, serious medical illness, and body mass index > 29.9 or < 18. Intraclass correlations ranged from .29 to .46, highlighting that most symptom variance lies within-person. Cyclical worsening of symptoms was evaluated using phase contrasts in multilevel models. Most symptoms, including SI, were significantly worse in the perimenstrual phase than in all other phases. Additionally, anger/irritability was higher in the midluteal than in the midfollicular phase, and several symptoms of depression were higher in the midfollicular than in the periovulatory phase. Otherwise, symptoms did not significantly differ between the midluteal, midfollicular, and periovulatory phases. Cycle phase predictors accounted for 25% of the within-person variance in SI. Females with SI may be at risk for perimenstrual worsening of SI and related symptoms. These findings highlight the importance of assessing the cycle phase for improved prediction of suicide risk. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Hormone sensitivity predicts the beneficial effects of transdermal estradiol on reward-seeking behaviors in perimenopausal women: A randomized controlled trial.

Depression is highly prevalent during the menopause transition (perimenopause), and often presents with anxious and anhedonic features. This increased vulnerability for mood symptoms is likely driven in part by the dramatic hormonal changes that are characteristic of the menopause transition, as prior research has linked fluctuations in estradiol (E2) to emergence of depressed mood in at risk perimenopausal women. Transdermal estradiol (TE2) has been shown to reduce the severity of depression in clinically symptomatic women, particularly in those with recent stressful life events. This research extends prior work by examining the relation between E2 and reward seeking behaviors, a precise behavioral indicator of depression. Specifically, the current study utilizes a randomized, double blind, placebo-controlled design to investigate whether mood sensitivity to E2 flux ("hormone sensitivity") predicts the beneficial effects of TE2 interventions on reward seeking behaviors in perimenopausal women, and whether recent stressful life events moderate any observed associations. METHOD: Participants were 66 women who met standardized criteria for being early or late perimenopausal based on bleeding patterns. Participants were recruited from a community sample; therefore, mood symptoms varied across the continuum and the majority of participants did not meet diagnostic criteria for a depressive or anxiety disorder at the time of enrollment. Hormone sensitivity was quantified over an 8-week baseline period, using within-subjects correlations between repeated weekly measures of E2 serum concentrations and weekly anxiety (State Trait Anxiety Inventory) and anhedonia ratings (Snaith-Hamilton Pleasure Scale). Women were then randomized to receive 8 weeks of TE2 (0.1 mg) or transdermal placebo, and reward-seeking behaviors were assessed using the Effort-Expenditure for Rewards Task (EEfRT). RESULTS: Participants who were randomized to receive transdermal estradiol and who demonstrated greater anxiety sensitivity to E2 fluctuations at baseline, demonstrated more reward seeking behaviors on the EEfRT task. Notably, the strength of the association between E2-anxiety sensitivity and post-randomization EEfRT for TE2 participants increased when women experienced more recent stressful life events and rated those events as more stressful. E2-anhedonia sensitivity was not associated with reward-seeking behaviors. CONCLUSION: Perimenopausal women who are more sensitive to E2 fluctuations and experienced more recent life stress may experience a greater benefit of TE2 as evidenced by an increase in reward seeking behaviors.

Hypothalamic-pituitary-thyroid axis function in women with a menstrually related mood disorder: association with histories of sexual abuse.

INTRODUCTION: We previously reported a unique hypothalamic-pituitary-thyroid (HPT) axis profile in women with a menstrually related mood disorder (MRMD) who also had a history of sexual abuse (SA). In the present study, we sought to extend that work by examining the association of an SA history with HPT-axis disturbance in both women with MRMD and women without MRMD. METHODS: Fifty-seven women met the prospective criteria for MRMD (23 with an SA history), and 52 women were non-MRMD (18 with an SA history). Thyroid-stimulating hormone, thyroxin (T4; total and free), and triiodothyronine (T3; total and free) were evaluated in serum, together with thyroid hormone ratios reflecting T4 to T3 conversion. RESULTS: Women with MRMD, compared with women without MRMD, had elevated T3/T4 ratios (p values ≤ .01; reflecting increased conversion of T4 to T3) and lower free and total T4 concentrations (p values = .01). Higher T3/T4 ratios and lower T4 concentrations predicted more severe premenstrual symptoms in all women. An SA history, irrespective of MRMD status, was associated with elevated thyroid-stimulating hormone concentrations (p = .03). However, in women with MRMD, an SA history was associated with elevated T3 concentrations (p = .049), whereas in women without MRMD, an SA history was associated with decreased T3 concentrations (p = .02). CONCLUSIONS: An MRMD and an SA history are associated with independent and interactive effects on the HPT axis. The evidence that an MRMD moderates the influence of SA on T3 concentrations contributes to a growing body of work suggesting that an SA history may identify a distinct subgroup of women with MRMD.

Personal resource profiles of individuals with a history of interpersonal trauma and their impact on opioid misuse.

OBJECTIVE: Individuals who experience interpersonal trauma (e.g., intimate partner violence, sexual assault, and adverse childhood experiences) are disproportionately affected by the opioid epidemic; however, not all will engage in opioid misuse behaviors. Personal resources, such as coping, social support, and self-efficacy, may attenuate the negative effects of trauma and foster resiliency. This study examines how personal resources affect opioid misuse among individuals with a history of interpersonal trauma. METHOD: Data were collected from a convenience sample (N = 236) through a cross-sectional, self-report survey. Latent profile analysis identified subgroups with different personal resource profiles based on coping behaviors, social support, and health-related self-efficacy. Logistic regression examined subgroup differences in sociodemographics and opioid misuse behaviors. RESULTS: Results supported a 3-class (low, moderate, and high personal resource groups) and 4-class model (low, internal, external, and high resource groups). Males, African Americans, and Hispanics were more likely to have low resource profiles. Low resource groups had the highest probability of reporting opioid misuse; however, there were no significant between-class differences after adjusting for depressive symptoms, pain intensity, sex, race/ethnicity, and age. Pain intensity and depressive symptoms largely accounted for subgroup differences in opioid misuse. CONCLUSIONS: Findings suggest that sex and race/ethnicity play an important role in the personal resource profiles of individuals with a history of interpersonal trauma. Interventions to promote resiliency and mitigate the effects of trauma on opioid misuse should consider personal resource profiles, mental health, and effective pain management. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Baseline anxiety-sensitivity to estradiol fluctuations predicts anxiety symptom response to transdermal estradiol treatment in perimenopausal women - A randomized clinical trial.

BACKGROUND: The menopausal transition (perimenopause) is associated with an increased risk of major depression, characterized by anxiety and anhedonia phenotypes. Greater estradiol (E2) variability predicts the development of perimenopausal depression, especially within the context of stressful life events (SLEs). While transdermal E2 (TE2) reduces perimenopausal depressive symptoms, the mechanisms underlying TE2 efficacy and predictors of TE2 treatment response remain unknown. This study aimed at determining relationships between E2 fluctuations, mood symptoms, and physiologic stress-reactivity (cortisol and interleukin-6) and whether differences in mood-sensitivity to E2 fluctuations predict mood responses to TE2 treatment. METHODS: This randomized, double-blind, placebo-controlled trial investigated medically healthy women (46-60 years) in the early or late menopause transition. Baseline E2-sensitivity strength was calculated from eight weekly individual correlations between week-to-week E2 change and index week anxiety (State-Trait Anxiety Inventory) and anhedonia (Snaith-Hamilton Pleasure Scale). Women then received eight weeks of TE2 or transdermal placebo. RESULTS: Analyses included 73 women (active TE2 n = 35). Greater baseline E2 fluctuations predicted greater anhedonia (p = .002), particularly in women with more SLEs. Greater E2 fluctuations also predicted higher cortisol (p = .012) and blunted interleukin-6 (p = .02) stress-responses. Controlling for baseline symptoms, TE2 was associated with lower post-treatment anxiety (p < .001) and anhedonia (p < .001) versus placebo. However, the efficacy of TE2 for anxiety (p = .007) and also for somatic complaints (p = .05) was strongest in women with greater baseline E2 sensitivity strength. CONCLUSIONS: TE2 treatment reduced perimenopausal anxiety and anhedonia. The ability of baseline mood-sensitivity to E2 fluctuations to predict greater TE2 efficacy has implications for individualized treatment of perimenopausal anxiety disorders.

Effects of acute estradiol and progesterone on perimenstrual exacerbation of suicidal ideation and related symptoms: a crossover randomized controlled trial.

Female suicide attempts peak peri-menstrually-around the onset of menses-when the ovarian steroids estradiol (E2) and progesterone (P4) fall rapidly. Given preclinical evidence that withdrawal from either E2 or P4 can provoke behaviors consistent with elevated suicide risk, we hypothesized that withdrawal from one or both of these steroids contributes to perimenstrual exacerbation of suicidal ideation (SI) and related symptoms. In a randomized, controlled, double-blind crossover experiment (NCT03720847), a transdiagnostic sample of naturally cycling, medically healthy psychiatric outpatients reporting past-month SI completed two conditions during two different 14-day experimental intervals (days 7-20 where the luteinizing hormone surge = day 0), separated by a monthlong washout cycle. In the E2 and P4 (EP) condition, participants received transdermal E2 (0.1 mg/day) plus oral micronized P4 (200 mg/day as 100 mg twice daily) to buffer perimenstrual steroid withdrawal. A matched placebo (PBO) condition allowed natural perimenstrual steroid withdrawal. Participants reported daily SI and planning (primary outcomes) and indices of depression (low mood, hopelessness), threat sensitivity (anxiety, perceived stress), executive functioning (difficulty concentrating, impulsivity), and social cognitive bias (rejection sensitivity, perceived burdensomeness). In baseline cycles, no participant met prospective criteria for DSM-5 premenstrual dysphoric disorder, but 59% met all criteria except full follicular symptom remission, and 93% showed the highest SI in the perimenstrual phase. Of 29 randomized, 28 were analyzed (14 EP-PBO, 14 PBO-EP). Experimental administration of E2 and P4 (relative to PBO) reduced perimenstrual exacerbation of SI, suicide planning, depression, hopelessness, perceived stress, rejection sensitivity, and perceived burdensomeness, particularly in the perimenstrual (natural E2 and P4 withdrawal) days. Further, delayed withdrawal from experimental E2 and P4 (but not PBO) recapitulated SI, hopelessness, and rejection sensitivity. Acute perimenstrual withdrawal from ovarian steroids may play a causal role in perimenstrual worsening of depression and SI.

Relationship of fatigue and exercise capacity with emotional and physical state in patients with coronary artery disease admitted for rehabilitation program.

BACKGROUND: The relationship between subjective fatigue, exercise capacity, and symptoms of depression and anxiety in patients with coronary artery disease (CAD) needs to be specified. METHODS: In this cross-sectional study, a total of 1,470 (64% men; mean age 57 ± 11 years) consecutive CAD patients admitted for cardiac rehabilitation after treatment of acute cardiac events were evaluated for demographic characteristics, for past and current diagnosis and treatment, for New York Heart Association (NYHA) class, for symptoms of depression and for symptoms of anxiety using the Hospital Anxiety and Depression Scale, and for subjective fatigue using the Multidimensional Fatigue Inventory. On the next day, all patients underwent exercise capacity evaluation using a standard bicycle ergometer testing procedure. RESULTS: In univariate regression analyses, there was the strongest positive association between scores on all Multidimensional Fatigue Inventory subscales and scores on the Hospital Anxiety and Depression Scale depression and anxiety subscales and between exercise capacity and NYHA class. Multivariate regression analyses revealed that symptoms of depression were the strongest positive determinants of all dimensions of subjective fatigue and, together with other significant variables, accounted for 17% to 29% of the variance. However, neither depressive nor anxious symptoms were significant determinants of exercise capacity. The association between subjective fatigue and exercise capacity and vice versa was minimal. CONCLUSION: Subjective fatigue in CAD patients is strongly related to symptoms of depression and symptoms of anxiety. In contrast, exercise capacity in CAD patients is strongly related to NYHA functional class, with no relationship to symptoms of depression and anxiety.

Hormones, heart disease, and health: individualized medicine versus throwing the baby out with the bathwater.

It is increasingly axiomatic that depression has widespread adverse physiological effects and, conversely, that a variety of physiological systems impact the risk for developing depression. This convergence of depression and altered physiology is particularly dramatic during midlife--a time during which reproductive failure presages dramatic increases in prevalence of both heart disease and depression. The potentially meaningful and illuminating links between estrogen deficiency, cardiovascular disease (CVD), and depression have largely been obscured, first by assertions, subsequently repudiated, that the perimenopause was not a time of increased risk of depression, and more recently by the denegration of hormone replacement therapy by initial reports of the Women's Health Initiative. Increasingly, however, research has led to unavoidable conclusions that CVD and depression share common, mediating pathogenic processes and that these same processes are dramatically altered by the presence or absence of estrogen (E2). This review summarizes data supporting these contentions with the intent of placing depression and estrogen therapy in their proper physiologic context.

Hormones, heart disease, and health: individualized medicine versus throwing the baby out with the bathwater.

It is increasingly axiomatic that depression has widespread adverse physiological effects, and conversely that a variety of physiological systems impact the risk for developing depression. This convergence of depression and altered physiology is particularly dramatic during midlife-a time during which reproductive failure presages dramatic increases in prevalence of both heart disease and depression. The potentially meaningful and illuminating links between estrogen (E2) deficiency, cardiovascular disease (CVD), and depression have largely been obscured, first by assertions, subsequently repudiated that the perimenopause was not a time of increased risk of depression, and more recently by the denegration of hormone replacement therapy by initial reports of the Women's Health Initiative. Increasingly, however, research has led to unavoidable conclusions that CVD and depression share common and mediating pathogenic processes and that these same processes are dramatically altered by the presence or absence of E2. This review summarizes data supporting this contention with the intent of placing depression and E2 therapy in their proper physiologic context.

Perimenopausal transdermal estradiol replacement reduces serum HDL cholesterol efflux capacity but improves cardiovascular risk factors.

BACKGROUND: The cardiovascular (CV) safety of estrogen replacement therapy (ERT) in perimenopausal women remains uncertain. Although exogenous estrogens increase HDL cholesterol (HDL-C), estrogen-mediated effects on alternative metrics of HDL that may better predict CV risk are unknown. OBJECTIVE: To determine the effects of transdermal ERT on HDL composition and cholesterol efflux capacity (CEC), as well as the relationships between these metrics and CV risk factors. METHODS: Fasting plasma samples were analyzed from 101 healthy, perimenopausal women randomized to receive either transdermal placebo or transdermal estradiol (100 µg/24 h) with intermittent micronized progesterone. At baseline and after 6 months of treatment, serum HDL CEC, HDL particle concentration, HDL protein composition, insulin resistance and brachial artery flow-mediated dilatation (FMD) were measured. RESULTS: No difference between groups was found for change in plasma HDL-C (p = 0.69). Between-group differences were found for changes in serum HDL total CEC [median change from baseline -5.4 (-17.3,+8.4)% ERT group versus +5.8 (-6.3,+16.9)% placebo group, p = 0.01] and ABCA1-specific CEC [median change from baseline -5.3 (-10.7,+6.7)% ERT group versus +7.4 (-1.5,+18.1)% placebo group, p = 0.0002]. Relative to placebo, transdermal ERT led to reductions in LDL-C (p < 0.0001) and insulin resistance (p = 0.0002). An inverse correlation was found between changes in serum HDL total CEC and FMD (ß = -0.26, p = 0.004). CONCLUSIONS: Natural menopause leads to an increase in serum HDL CEC, an effect that is abrogated by transdermal ERT. However, transdermal ERT leads to favorable changes in major CV risk factors.