Leukocyte Gene Expression in Patients with Medication Refractory Depression before and after Treatment with ECT or Isoflurane Anesthesia: A Pilot Study.

Objective. To evaluate leukocyte gene expression for 9 selected genes (mRNAs) as biological markers in patients with medication refractory depression before and after treatment with ECT or isoflurane anesthesia (ISO). Methods. In a substudy of a nonrandomized open-label trial comparing effects of ECT to ISO therapy, blood samples were obtained before and after treatment from 22 patients with refractory depression, and leukocyte mRNA was assessed by quantitative PCR. Patients' mRNAs were also compared to 17 healthy controls. Results. Relative to controls, patients before treatment showed significantly higher IL10 and DBI and lower ADRA2A and ASIC3 mRNA (P < 0.025). Both ECT and ISO induced significant decreases after treatment in 4 genes: IL10, NR3C1, DRD4, and Sult1A1. After treatment, patients' DBI, ASIC3, and ADRA2A mRNA remained dysregulated. Conclusion. Significant differences from controls and/or significant changes after ECT or ISO treatment were observed for 7 of the 9 mRNAs studied. Decreased expression of 4 genes after effective treatment with either ECT or ISO suggests possible overlap of underlying mechanisms. Three genes showing dysregulation before and after treatment may be trait-like biomarkers of medication refractory depression. Gene expression for these patients has the potential to facilitate diagnosis, clarify pathophysiology, and identify potential biomarkers for treatment effects.

Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome.

OBJECTIVES: To determine mRNA expression differences in genes involved in signalling and modulating sensory fatigue, and muscle pain in patients with chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FM) at baseline, and following moderate exercise. DESIGN: Forty-eight patients with CFS only, or CFS with comorbid FM, 18 patients with FM that did not meet criteria for CFS, and 49 healthy controls underwent moderate exercise (25 min at 70% maximum age-predicted heart rate). Visual-analogue measures of fatigue and pain were taken before, during and after exercise. Blood samples were taken before and 0.5, 8, 24 and 48 h after exercise. Leucocytes were immediately isolated from blood, number coded for blind processing and analyses and flash frozen. Using real-time, quantitative PCR, the amount of mRNA for 13 genes (relative to control genes) involved in sensory, adrenergic and immune functions was compared between groups at baseline and following exercise. Changes in amounts of mRNA were correlated with behavioural measures and functional clinical assessments. RESULTS: No gene expression changes occurred following exercise in controls. In 71% of patients with CFS, moderate exercise increased most sensory and adrenergic receptor's and one cytokine gene's transcription for 48 h. These postexercise increases correlated with behavioural measures of fatigue and pain. In contrast, for the other 29% of patients with CFS, adrenergic α-2A receptor's transcription was decreased at all time-points after exercise; other genes were not altered. History of orthostatic intolerance was significantly more common in the α-2A decrease subgroup. FM-only patients showed no postexercise alterations in gene expression, but their pre-exercise baseline mRNA for two sensory ion channels and one cytokine were significantly higher than controls. CONCLUSIONS: At least two subgroups of patients with CFS can be identified by gene expression changes following exercise. The larger subgroup showed increases in mRNA for sensory and adrenergic receptors and a cytokine. The smaller subgroup contained most of the patients with CFS with orthostatic intolerance, showed no postexercise increases in any gene and was defined by decreases in mRNA for α-2A. FM-only patients can be identified by baseline increases in three genes. Postexercise increases for four genes meet published criteria as an objective biomarker for CFS and could be useful in guiding treatment selection for different subgroups.

Brain activation in multiple sclerosis: a BOLD fMRI study of the effects of fatiguing hand exercise.

BACKGROUND: Multiple sclerosis (MS) patients experience fatigue as a chronic symptom that decreases quality of life. Commonly, fatigue in MS patients is manifested as decreased motor function during or after physical activity and is associated with changes in brain metabolism. OBJECTIVE: To determine brain activation patterns in MS patients and healthy controls during a simple motor task before and after fatiguing hand-grip exercise. METHODS: Functional magnetic resonance imaging (fMRI) scans were conducted on 10 MS patients and 13 healthy controls during 4-finger flexion and extension in rested and fatigued states. RESULTS: Before the fatigue protocol, MS patients had greater activation in the contralateral primary motor cortex, insula, and cingulate gyrus than controls. Following fatiguing exercise, controls showed increased activation of precentral gyrus and insula while patients did not show any activation increases and actually decreased activity to the insula. CONCLUSION: Results indicate that before fatiguing exercise, MS patients marshaled more brain activation compared to controls, which may represent functionally adaptive changes in response to demyelination. This increased activation may suggest that patients require more effort to perform even simple motor tasks, possibly because peripheral or central signals for fatigue are chronically enhanced. When fatigued further by muscle contraction, brain activation cannot be further increased.

Stress and placental resistance measured by Doppler ultrasound in early and mid-pregnancy.

OBJECTIVES: To examine the association between self reports and biomarkers of stress and placental resistance (measured by Doppler ultrasound of the uterine and umbilical arteries), to determine if restriction of blood flow to the placenta is a mechanism by which stress might affect health during pregnancy. METHODS: Eight hundred and seventy-two women had ultrasound examinations of the uterine artery at 15-19 weeks' gestation and the uterine and umbilical arteries at 24-29 weeks, and resistance and pulsatility indices were calculated. Psychosocial stress was measured by telephone interview and self-administered questionnaire using several validated tools twice during the pregnancy. Cortisol and corticotropin-releasing hormone (CRH) were measured twice during the pregnancy. Linear and hierarchical models were used to examine the relationships among reported stress, stress hormones and placental Doppler indices. RESULTS: The umbilical artery resistance index was higher in younger women, those with less education, those who were single and those who smoked. The uterine artery pulsatility index was higher in women with pre-eclampsia, those living alone, those with high body mass index, and those who gained the least weight during pregnancy. A higher CRH level was associated with small increases in uterine artery pulsatility and umbilical artery resistance indices. Psychosocial measures of stress were not consistently associated with higher placental resistance. CONCLUSIONS: Increased CRH levels may be associated with increased placental resistance. Otherwise, these findings do not support the hypothesis that restriction of blood flow to the fetus is a major mechanism by which stress affects infant health.

Association between the blood pressure response to a change in posture and the 6-year incidence of hypertension: prospective findings from the ARIC study.

The association between the blood pressure response to a change from the supine to the standing position and the 6-year incidence of hypertension was studied in a bi-ethnic, middle-aged cohort of 6951 normotensive men and women free of coronary heart disease at baseline. Postural change in systolic blood pressure (SBP) was categorized into deciles, and the middle four deciles served as the referent (no change) group. In unadjusted analyses, the incidence of hypertension was higher among both those with SBP increases and decreases relative to those in the referent group. Associations were modestly attenuated after controlling for age, ethnicity, and gender and cardiovascular disease risk factors. However, after adjustment for baseline, seated SBP, a modest association with incident hypertension persisted only for SBP decreases. Orthostatic hypotension (upon standing) was associated with incident hypertension and isolated systolic hypertension and, unexpectedly, this increased risk was highest among those with the lowest levels of baseline, resting SBP.

Sex differences in chest pain in patients with documented coronary artery disease and exercise-induced ischemia: Results from the PIMI study.

BACKGROUND: Sex differences in the pathophysiologic course of coronary artery disease (CAD) are widely recognized, yet accurate diagnosis of coronary artery disease in women remains challenging. METHODS: To determine sex differences in the clinical manifestation of CAD, we studied chest pain reported during daily activities, exercise, and mental stress in 170 men and 26 women. All patients had documented CAD (>50% narrowing in at least 1 major coronary artery or prior myocardial infarction) and all had 1-mm ST-segment depression on treadmill exercise. We collected psychologic test results, serum samples (potassium, epinephrine, norepinephrine, cortisol, b-endorphin, and glucose), and cardiac function, sensory threshold, and autonomic function data at specified times before, during, or after exercise and mental stress tests to assess measures of depression, anxiety, and neurohormonal and thermal pain perception. RESULTS: Women reported chest pain more often than men during daily activities (P =.04) and during laboratory mental stressors (P =.01) but not during exercise. Men had lower scores than women on measures of depression, trait anxiety, harm avoidance, and reward dependence (P <.05 for all). Women had significantly lower plasma b-endorphin levels at rest (4.2 +/- 3.9 vs 5.0 +/- 2.5 pmol/L for men, P =.005) and at maximal mental stress (6.4 +/- 5.1 vs 7.4 +/- 3.5 pmol/L for men, P <.01). A higher proportion of women than men had marked pain sensitivity to graded heat stimuli applied to skin (hot pain threshold <41 degrees C, 33% vs 10%, P =.001). CONCLUSIONS: Our results reflect sex differences in the affective and discriminative aspects of pain perception and may help explain sex-related differences in clinical presentations.

Allopregnanolone levels and reactivity to mental stress in premenstrual dysphoric disorder.

BACKGROUND: This study was designed to examine basal and stress-induced levels of the neuroactive progesterone metabolite, allopregnanolone, in women with premenstrual dysphoric disorder (PMDD) and healthy control subjects. Also, because evidence suggests that allopregnanolone negatively modulates the hypothalamic-pituitary-adrenal axis, plasma cortisol levels were examined. An additional goal was to investigate the relationship between premenstrual symptom severity and luteal phase allopregnanolone levels. METHODS: Twenty-four women meeting prospective criteria for PMDD were compared with 12 controls during both the follicular and luteal phases of confirmed ovulatory cycles, counterbalancing phase at first testing. Plasma allopregnanolone and cortisol were sampled after an extended baseline period and again 17 min following the onset of mental stress. Owing to low follicular phase allopregnanolone levels, only luteal phase allopregnanolone and cortisol were analyzed. RESULTS: During the luteal phase, PMDD women had significantly greater allopregnanolone levels, coupled with significantly lower cortisol levels, during both baseline and mental stress. Moreover, significantly more controls (83%) showed the expected stress-induced increases in allopregnanolone compared with PMDD women (42%). Premenstrual dysphoric disorder women also exhibited a significantly greater allopregnanolone/progesterone ratio than control subjects, suggesting alterations in the metabolic pathways involved in the conversion of progesterone to allopregnanolone. Finally, PMDD women with greater levels of premenstrual anxiety and irritability had significantly reduced allopregnanolone levels in the luteal phase relative to less symptomatic PMDD women. No relationship between symptom severity and allopregnanolone was observed in controls. CONCLUSIONS: These results suggest dysregulation of allopregnanolone mechanisms in PMDD and that continued investigations into a potential pathophysiologic role of allopregnanolone in PMDD are warranted.

Transdermal estrogen reduces vascular resistance and serum cholesterol in postmenopausal women.

OBJECTIVE: Our aim was to compare the effects of transdermal versus oral estrogens on vascular resistance index, mean arterial pressure, serum lipid concentrations, norepinephrine, and left ventricular structure. STUDY DESIGN: Ten postmenopausal women received transdermal estradiol (0.05 mg/d) plus cyclic oral progesterone for 6 months. Responses were compared with those of 23 women receiving oral conjugated estrogens (0.625 mg/d) plus cyclic progesterone and with those of 9 subjects receiving placebo in a concurrent randomized trial. We assessed the vascular resistance index and the mean arterial pressure at rest and during behavioral stressors. RESULTS: Oral and transdermal estrogen significantly decreased the vascular resistance index, mean arterial pressure, norepinephrine, and total and low-density lipoprotein cholesterol to a similar extent. Changes in the vascular resistance index and mean arterial pressure were equally evident at rest and during stress. Although both treatments reduced left ventricular mass (-4% to -6%) and relative wall thickness (-3% to -5%), these changes were not statistically significant. CONCLUSIONS: Equivalent reductions in vascular resistance index, norepinephrine, mean arterial pressure, and cholesterol were observed with transdermal and oral estrogens. Future studies comparing novel hormone regimens with oral hormone replacement therapy should include multiple risk markers to allow better assessment of their potential impact on coronary artery health.

Hormone replacement improves hemodynamic profile and left ventricular geometry in hypertensive and normotensive postmenopausal women.

BACKGROUND: Postmenopausal estrogen replacement, with or without progestins, has been related to lower cardiovascular risks. OBJECTIVE: We investigated whether the actions of estrogen on vascular resistance contribute to this cardioprotective effect. DESIGN AND METHODS: In a 6-month double-blind study, pre- and post-treatment blood pressure, cardiac index, total vascular resistance index and plasma catecholamine responses during baseline and mental stressors were compared in 69 women (including 19 with mild hypertension but no history of heart disease). Women were randomized to receive either conjugated estrogens alone, estrogens plus medroxyprogesterone, or placebo. RESULTS: Both groups on active hormone replacement showed similar decreases in vascular resistance and modest blood pressure reductions, which differed from the unchanged responses of those on placebo (P< 0.05) after 3 and 6 months of treatment. Hypertensive women showed greater reductions in vascular resistance than normotensives (P< 0.05) and their blood pressure reductions tended to be larger. Women receiving hormone replacement showed increased stroke volume and cardiac index at 6 months, particularly among hypertensives and those receiving medroxyprogesterone (P < 0.05). Hormone replacement was also related to decreases in plasma norepinephrine. Finally, in 33 women receiving hormone replacement, significant 5 and 3% decreases in echocardiographic measures of left ventricular mass index and relative wall thickness were evident at 6 months (P < 0.05), while 20 placebo-treated women showed no reliable echocardiographic improvements (P= NS). CONCLUSIONS: These findings suggest that estrogen-mediated reductions in hemodynamic load on the heart may contribute to the reduced risk of cardiovascular events in relatively healthy postmenopausal women who use hormone replacement.

Oxytocin responsivity in mothers of infants: a preliminary study of relationships with blood pressure during laboratory stress and normal ambulatory activity.

The neuropeptide oxytocin (OT) enhances maternal behavior and decreases blood pressure (BP) and stress responses in animals. Thus, the relationship of OT responsivity to BP in 14 breast- and 11 bottle-feeding mothers of infants was examined. Laboratory BP was assessed during baseline, speech preparation, active speech, and recovery on 2 days, 1 in which baseline and speech were separated by 10 min of baby holding and the other by no baby contact. Systolic BP reactivity to speech was lower after baby contact. Plasma OT change from baseline to speech after baby contact defined OT increase, minimal OT change, and OT decrease groups. OT increase mothers were primarily breast-feeders, and they had lower BP throughout both stress sessions and after baby feeding at home than OT decrease mothers, who also had greater BP reactivity to preparation and recovery. These results suggest that oxytocin has antistress and BP-lowering effects in humans.

Stable pessimistic attributions interact with socioeconomic status to influence blood pressure and vulnerability to hypertension.

We investigated the relationship of pessimistic attributional style (specifically, stable attributions for negative events) and socioeconomic status (SES) to cardiovascular and catecholamine profiles in a biracial sample of 37 postmenopausal women (aged 39-64 years) not taking hormone replacement therapy (HRT). Blood pressure (BP) variation in response to the demands of daily life was assessed by 24-hour ambulatory monitoring on a typical workday. Subjects were classified into groups by stable pessimistic attributions (high vs. low pessimism) and by SES (high vs. low). Significant SES x pessimism interactions were found. Low SES/high pessimism women demonstrated higher systolic BP (SBP) during the day, evening, and sleep periods of 24-hour ambulatory monitoring compared with the other three groups. A greater proportion of this group was in the hypertensive range (> or = 140/90 mm Hg) compared with the other groups (57% vs. 8%-29%). Low SES/high pessimism women also reported reduced available social support compared with the other three groups.

Postmenopausal smokers show reduced hemodynamic benefit from oral hormone replacement.

With use of a randomized, placebo-controlled trial, 62 healthy, postmenopausal smokers and nonsmokers were tested for resting and stress-induced hemodynamic variables before and after 6 months of treatment with either oral hormone replacement therapy or placebo. Smokers had significantly less reduction in both resting and stress-induced vascular resistance and blood pressure after treatment with oral hormone replacement therapy than nonsmokers.

Women with eating disorder tendencies display altered cardiovascular, neuroendocrine, and psychosocial profiles.

OBJECTIVE: Cardiovascular, neuroendocrine, and psychosocial profiles were investigated in women with eating disorder tendencies, but who had never met clinical criteria for an eating disorder, and in healthy controls. METHODS: Twenty-six women who scored in the highest distribution of the Eating Disorder Inventory bulimia subscale (HEDI women) and 27 women who scored in the lowest distribution (LEDI women) completed psychosocial questionnaires, underwent a speech reactivity task for measures of blood pressure and heart rate reactivity, and also underwent 24-hour ambulatory blood pressure monitoring and urinary neuroendocrine collection. RESULTS: The HEDI women exhibited increased blood pressure and heart rate reactivity to the speech task and increased 24-hour urinary cortisol, but decreased 24-hour urinary norepinephrine compared with LEDI women. There were no overall group differences in 24-hour ambulatory blood pressure levels, but negative mood and tension were associated with greater systolic blood pressures for all women. Finally, HEDI women reported greater depressive symptoms and anxiety, lower self-esteem and sense of mastery, less social support, poor coping skills, and greater emotional impact of daily stressors relative to LEDI women. CONCLUSIONS: These results indicate that the same pattern of neuroendocrine and psychosocial profiles seen in prior studies of bulimia nervosa are also present in women with eating disorder tendencies.

Orthostatic hypotension and the incidence of coronary heart disease: the Atherosclerosis Risk in Communities study.

We examined the association between orthostatic hypotension (OH) at baseline examination (1987-1989) and the incidence of coronary heart disease (CHD) over an average of 6 years, among 12,433 black and white middle-aged men and women participating in the Atherosclerosis Risk in Communities (ARIC) study. OH was defined as a SBP decrease > or = 20 mm Hg or a DBP decrease > or = 10 mm Hg after changing from supine to standing. CHD events included definite or probable myocardial infarctions (MI), silent MI, and fatal CHD. Five percent of participants had OH. Prevalence increased with advancing age and was more common among those with cardiovascular disease (CVD)-related comorbidities and risk factors. Those with OH had an increased risk of CHD (hazard ratio [HR] = 3.49, 95% confidence interval [CI] = 2.58, 4.73). This association was attenuated after controlling for age, ethnicity, gender, comorbid conditions, and CVD risk factors (HR = 1.85, 95% CI = 1.31, 2.63).

Low hot pain threshold predicts shorter time to exercise-induced angina: results from the psychophysiological investigations of myocardial ischemia (PIMI) study.

OBJECTIVES: The purpose of this study was to test whether cutaneous thermal pain thresholds are related to anginal pain perception. BACKGROUND: Few ischemic episodes are associated with angina; symptoms have been related to pain perception thresholds. METHODS: A total of 196 patients with documented coronary artery disease underwent bicycle exercise testing and thermal pain testing. The Marstock test of cutaneous sensory perception was administered at baseline after 30 min of rest on two days and after exercise and mental stress. Resting hot pain thresholds (HPTs) were averaged for the two baseline visits and divided into two groups: 1) average HPT <41 degrees C, and 2) average HPT > or =41 degrees C, to be clearly indicative of abnormal hypersensitivity to noxious heat. RESULTS: Patients with HPT <41 degrees C had significantly shorter time to angina onset on exercise testing than patients with HPT > or =41 degrees C (p < 0.04, log-rank test). Heart rates, systolic blood pressure and rate-pressure product at peak exercise were not different for the two groups. Resting plasma beta-endorphin levels were significantly higher in the HPT <41 degrees C group (5.9+/-3.7 pmol/liter vs. 4.7+/-2.8 pmol/liter, p = 0.02). Using a Cox proportional hazards model, patients with HPT <41 degrees C had an increased risk of angina (p = 0.03, rate ratio = 2.0). These differences persisted after adjustment for age, gender, depression, anxiety and history of diabetes or hypertension (p < 0.01). CONCLUSIONS: Occurrence of angina and timing of angina onset on an exercise test are related to overall hot pain sensory perception. The mechanism of this relationship requires further study.

Potassium supplementation induces beneficial cardiovascular changes during rest and stress in salt sensitive individuals.

The typical American diet includes high salt and low potassium, a pattern linked to elevated blood pressure (BP) in cross-cultural studies. This study compared resting and stress cardiovascular responses on a high salt, low potassium diet to those observed during 2 interventions: salt restriction and potassium supplementation. Forty-seven percent of the primarily normotensive sample (n = 67 adults) were salt sensitive, showing a decrease in mean arterial pressure > or = 5 mmHg during low salt and equivalent reductions during high potassium. The equivalent benefits of the interventions were maintained, but not enhanced, during exposure to behavioral stress (i.e., no effect on reactivity). Salt resistants (SRs) exhibited no change in resting or stress BP across the diets. High salt increased cardiac index in both groups, whereas vascular tone was decreased only in the SR group. High potassium produced hemodynamic benefits similar to low salt, even with continued high salt intake.

High stress responsivity predicts later blood pressure only in combination with positive family history and high life stress.

High cardiovascular responsivity to stressors has not consistently improved prediction of later blood pressure increases beyond the predictive effects of baseline pressure. Animal models suggest that genetic susceptibility to hypertension and frequent stress exposure are important modulating factors in stress-related hypertension. Thus in 103 men originally tested at age 18 to 22 years and reassessed 10 years later, interactive effects of genetic susceptibility (defined as 1 or more hypertensive parents) with high stress responsivity (defined as top 25% on the basis of blood pressure and cardiac responses during both reaction time and cold pressor tasks) were examined in relation to follow-up systolic and diastolic levels and to change in blood pressure status from normal (diastolic<80 mm Hg) to marginally elevated (diastolic 85 to 95 mm Hg). Men with the combination of high stress response and hypertensive parents demonstrated higher systolic (P<0.05) and diastolic levels (P<0.05) at follow-up, and they showed a 7-fold increase (7.5, 95% confidence intervals 2.3, 24.3; P<0.001) in relative risk of change in blood pressure status versus men with no family history and a 3-fold increase (3.8, confidence intervals 1.5, 9.6; P<0.004) versus less stress-responsive men who also had hypertensive parents. In 65 men who also provided ratings of daily stress, family historyxstress responsivityxdaily stress interactions were significant in predicting follow-up systolic and diastolic levels (P<0.006 and 0.03, respectively), with highest pressure levels seen when high life stress was reported by high stress responders and/or men with hypertensive parents. In conclusion, results suggest that stress responsivity as a long-term predictor is modulated by both genetic and environmental factors.

Descriptive epidemiology of blood pressure response to change in body position. The ARIC study.

The epidemiology of a common measure of cardiovascular reactivity, the change in systolic blood pressure (DeltaSBP) from the supine to the standing position, is described in a cohort of 13 340 men and women aged 45 to 65 years enrolled in the Atherosclerosis Risk in Communities (ARIC) Study. The distribution of DeltaSBP was found to be symmetrical and unimodal, with a mean value near zero (-0.45 mm Hg). The range of DeltaSBP was from -63.2 to 54.3 mm Hg, and the standard deviation was 10.8. Stratification of DeltaSBP by race and gender shows a slight shift in distribution toward higher values for black men and women. DeltaSBP was categorized into deciles. Participants in the top 30% and bottom 30% of the distribution were compared with individuals in the middle 40% of the distribution, who had little or no change in SBP on standing. Participants in the bottom 30% (ie, SBP decreased on standing) were significantly older, had a greater prevalence of hypertension and peripheral vascular disease, had higher values of SBP, and had more cigarette-years of smoking. Among participants in the top 30% (ie, SBP increased on standing), a significantly larger proportion were black, mean seated SBP was higher, and the predicted risk of developing coronary heart disease after 8 years was greater. The response of SBP to change in posture showed considerable variability in a population sample of middle-aged adults. Cardiovascular morbidity, sociodemographic factors, and cigarette smoking were associated with the magnitude and direction of the postural change.

A comparison of the effect of estrogen with or without progesterone on mood and physical symptoms in postmenopausal women.

Using a randomized, placebo-controlled design, this study assessed the effects of estrogen alone (ES) or in combination with cyclic progesterone (EP) on daily ratings of mood and physical symptoms before and after 6 months of daily hormone treatment. Fifty-four postmenopausal women were recruited from the community at large and specifically selected as being asymptomatic at the time of enrollment and without significant psychiatric history. Ratings were obtained every day for 30 days prior to treatment and again every day during the last 30 days of treatment. Results revealed that when compared with pretreatment levels, women randomized to EP (n = 16) exhibited statistically significant increases in daily depression, cramping, and breast tenderness and a marginally significant increase in daily anxiety. However, these increases were mild, not clinically significant, and did not interfere with normal functioning. Women randomized to ES (n = 20) showed no significant change in daily mood measures, although they did experience an increase in breast tenderness with estrogen. A significant placebo (n = 18) effect was observed, as there was a reliable reduction in daily irritability ratings (p < 0.05) with placebo. These findings suggest that for most postmenopausal women, the use of hormones will not be associated with clinically significant changes in mood or physical symptoms, which weighs favorably into the cost-benefit ratio for women considering hormone replacement therapy.