Jane Morley Kotchen

The Women's Health Initiative Observational Study: Baseline Characteristics of Participants and Reliability of Baseline Measures

The Women’s Health Initiative (WHI) Observational Study (OS) was established to explore the predictors and natural history of important causes of morbidity and mortality in postmenopausal women, and to serve as a secular control for the WHI Clinical Trial (CT). It enrolled 93,676 ethnically diverse women born in four different decades, from those who came of age in the depression-era, to the first members of the baby boom. Accordingly, this cohort reflects a wide range of socio-cultural influences on opportunities and health behaviors. OS participants will contribute longitudinal data on health status, risk exposures and disease events. The followup interval will be slightly shorter than that in the clinical trial, approximately 7 years. All OS women had a physical examination at baseline and 3 years. Additional data are obtained with annual mailed questionnaires. These forms explore risk exposures, health behaviors, and the prevalence of less common diseases to provide a comprehensive view of both classical and novel risk factors, as well as secular trends in the predictors of healthy aging and disease events. Because of its size, the OS will permit exploration of factors associated with less common diseases. This article describes the demographic, reproductive, dietary, and health characteristics of the OS women by eth-

Oestrogen plus progestin and lung cancer in postmenopausal women (Women's Health Initiative trial): a post-hoc analysis of a randomised controlled trial.

BACKGROUND In the post-intervention period of the Womens Health Initiative (WHI) trial, women assigned to treatment with oestrogen plus progestin had a higher risk of cancer than did those assigned to placebo. Results also suggested that the combined hormone therapy might increase mortality from lung cancer. To assess whether such an association exists, we undertook a post-hoc analysis of lung cancers diagnosed in the trial over the entire follow-up period. METHODS The WHI study was a randomised, double-blind, placebo-controlled trial undertaken in 40 centres in the USA. 16 608 postmenopausal women aged 50-79 years with an intact uterus were randomly assigned by a computerised, stratified, permuted block algorithm to receive a once-daily tablet of 0.625 mg conjugated equine oestrogen plus 2.5 mg medroxyprogesterone acetate (n=8506) or matching placebo (n=8102). We assessed incidence and mortality rates for all lung cancer, small-cell lung cancer, and non-small-cell lung cancer by use of data from treatment and post-intervention follow-up periods. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00000611. FINDINGS After a mean of 5.6 years (SD 1.3) of treatment and 2.4 years (0.4) of additional follow-up, 109 women in the combined hormone therapy group had been diagnosed with lung cancer compared with 85 in the placebo group (incidence per year 0.16%vs 0.13%; hazard ratio [HR] 1.23, 95% CI 0.92-1.63, p=0.16). 96 women assigned to combined therapy had non-small-cell lung cancer compared with 72 assigned to placebo (0.14%vs 0.11%; HR 1.28, 0.94-1.73, p=0.12). More women died from lung cancer in the combined hormone therapy group than in the placebo group (73 vs 40 deaths; 0.11%vs 0.06%; HR 1.71, 1.16-2.52, p=0.01), mainly as a result of a higher number of deaths from non-small-cell lung cancer in the combined therapy group (62 vs 31 deaths; 0.09%vs 0.05%; HR 1.87, 1.22-2.88, p=0.004). Incidence and mortality rates of small-cell lung cancer were similar between groups. INTERPRETATION Although treatment with oestrogen plus progestin in postmenopausal women did not increase incidence of lung cancer, it increased the number of deaths from lung cancer, in particular deaths from non-small-cell lung cancer. These findings should be incorporated into risk-benefit discussions with women considering combined hormone therapy, especially those with a high risk of lung cancer. FUNDING National Heart, Lung and Blood Institute, National Institutes of Health.

Association of Adrenal Steroids With Hypertension and the Metabolic Syndrome in Blacks

Blacks have a high prevalence of hypertension and adrenal cortical adenomas/hyperplasia. We evaluated the hypothesis that adrenal steroids are associated with hypertension and the metabolic syndrome in blacks. Ambulatory blood pressures, anthropometric measurements, and measurements of plasma renin activity (PRA), aldosterone, fasting lipids, glucose, and insulin were obtained in 397 subjects (46% hypertensive and 50% female) after discontinuing antihypertensive and lipid-lowering medications. Hypertension was defined as average ambulatory blood pressure >130/85 mm Hg. Late-night and early morning salivary cortisol, 24-hour urine-free cortisol, and cortisone excretion were measured in a consecutive subsample of 97 subjects (40% hypertensive and 52% female). Compared with normotensive subjects, hypertensive subjects had greater waist circumference and unfavorable lipid profiles, were more insulin resistant, and had lower PRA and higher plasma aldosterone and both late-night and early morning salivary cortisol concentrations. Twenty-four-hour urine-free cortisol and cortisone did not differ. Overall, ambulatory blood pressure was positively correlated with plasma aldosterone (r=0.22; P<0.0001) and late-night salivary cortisol (r=0.23; P=0.03) and inversely correlated with PRA (r=−0.21; P<0.001). Plasma aldosterone correlated significantly with waist circumference, total cholesterol, triglycerides, insulin, and the insulin-resistance index. Based on Adult Treatment Panel III criteria, 17% of all of the subjects were classified as having the metabolic syndrome. Plasma aldosterone levels, but not PRA, were elevated in subjects with the metabolic syndrome (P=0.0002). The association of aldosterone with blood pressure, waist circumference, and insulin resistance suggests that aldosterone may contribute to obesity-related hypertension in blacks. In addition, we speculate that relatively high aldosterone and low PRA in these hypertensive individuals may reflect a mild variant of primary aldosteronism.

Calcium Plus Vitamin D Supplementation and Mortality in Postmenopausal Women: The Women's Health Initiative Calcium–Vitamin D Randomized Controlled Trial

BACKGROUND Calcium and vitamin D (CaD) supplementation trials including the Womens Health Initiative (WHI) trial of CaD have shown nonsignificant reductions in total mortality. This report examines intervention effects on total and cause-specific mortality by age and adherence. METHODS The WHI CaD trial was a randomized, double-blind, placebo-controlled trial that enrolled 36,282 postmenopausal women aged 51-82 years from 40 U.S. clinical centers. Women were assigned to 1,000 mg of elemental calcium carbonate and 400 IU of vitamin D(3) daily or placebo with average follow-up of 7.0 years. RESULTS The hazard ratio (HR) for total mortality was 0.91 (95% confidence interval [CI], 0.83-1.01) with 744 deaths in women randomized to CaD versus 807 deaths in the placebo group. HRs were in the direction of reduced risk but nonsignificant for stroke and cancer mortality, but near unity for coronary heart disease and other causes of death. HRs for total mortality were 0.89 in the 29,942 women younger than 70 years (95% CI, 0.79-1.01) and 0.95 in the 6,340 women aged 70 and older (95% CI, 0.80-1.12; p value for age interaction = .10). No statistically significant interactions were observed for any baseline characteristics. Treatment effects did not vary significantly by season. CONCLUSIONS In the WHI CaD trial, supplementation did not have a statistically significant effect on mortality rates but the findings support the possibility that these supplements may reduce mortality rates in postmenopausal women. These data can neither support nor refute recommendations for higher dose vitamin D supplementation to reduce cancer or total mortality.

Arterial Pressure, Left Ventricular Mass, and Aldosterone in Essential Hypertension

The purpose of the present study was to evaluate the relationship of aldosterone to blood pressure and left ventricular size in black American (n=109) and white French Canadian (n=73) patients with essential hypertension. Measurements were obtained with patients off antihypertensive medications and included 24-hour blood pressure monitoring, plasma renin activity and aldosterone, and an echocardiogram. Compared with the French Canadians, the black Americans had higher body mass indexes, higher systolic blood pressures, attenuated nighttime reduction of blood pressure, and lower serum potassium concentrations (P <0.01 for each). Left ventricular mass index, posterior wall thickness, interventricular septal thickness, and relative wall thickness were also greater (P <0.01 for each) in the black American patients. Supine and standing plasma renin activity was lower (P <0.01 and P <0.05, respectively) in the black Americans, whereas supine plasma aldosterone concentrations did not differ, and standing plasma aldosterone was greater (P <0.05) in the black Americans (9.2±0.7 ng/dL) than in the French Canadians (7.3±0.6 ng/dL). In the black Americans, supine plasma aldosterone was positively correlated with nighttime systolic (r =0.30;P <0.01) and diastolic (r =0.39;P <0.001) blood pressures and inversely correlated with the nocturnal decline of systolic (r =−0.29;P <0.01) and diastolic (r =−0.37;P <0.001) blood pressures. In the black Americans, standing plasma aldosterone was positively correlated with left ventricular mass index (r =0.36;P <0.001), posterior wall thickness (r =0.33;P <0.01), and interventricular septal thickness (r =0.26;P <0.05). When the black American patients were divided into obese and nonobese groups, significant correlations between plasma aldosterone and both blood pressure and cardiac mass were observed only in the obese. In the French Canadians, overall, plasma aldosterone did not correlate with either blood pressure or any measures of heart size. However, among obese French Canadians, supine plasma aldosterone correlated with nighttime diastolic (r =0.53, P <0.02) and systolic (r =0.44, P <0.01) blood pressures but not with cardiac mass. These results are consistent with the hypothesis that aldosterone contributes to elevated arterial pressure in obese black American and obese white French Canadian patients with essential hypertension and to the attenuated nocturnal decline of blood pressure and left ventricular hypertrophy in obese, hypertensive black Americans.

Stress Reduction in the Secondary Prevention of Cardiovascular Disease Randomized, Controlled Trial of Transcendental Meditation and Health Education in Blacks

Background—Blacks have disproportionately high rates of cardiovascular disease. Psychosocial stress may contribute to this disparity. Previous trials on stress reduction with the Transcendental Meditation (TM) program have reported improvements in cardiovascular disease risk factors, surrogate end points, and mortality in blacks and other populations. Methods and Results—This was a randomized, controlled trial of 201 black men and women with coronary heart disease who were randomized to the TM program or health education. The primary end point was the composite of all-cause mortality, myocardial infarction, or stroke. Secondary end points included the composite of cardiovascular mortality, revascularizations, and cardiovascular hospitalizations; blood pressure; psychosocial stress factors; and lifestyle behaviors. During an average follow-up of 5.4 years, there was a 48% risk reduction in the primary end point in the TM group (hazard ratio, 0.52; 95% confidence interval, 0.29–0.92; P=0.025). The TM group also showed a 24% risk reduction in the secondary end point (hazard ratio, 0.76; 95% confidence interval, 0.51–0.1.13; P=0.17). There were reductions of 4.9 mmHg in systolic blood pressure (95% confidence interval −8.3 to –1.5 mmHg; P=0.01) and anger expression (P<0.05 for all scales). Adherence was associated with survival. Conclusions—A selected mind–body intervention, the TM program, significantly reduced risk for mortality, myocardial infarction, and stroke in coronary heart disease patients. These changes were associated with lower blood pressure and psychosocial stress factors. Therefore, this practice may be clinically useful in the secondary prevention of cardiovascular disease. Clinical Trial Registration—URL: www.clinicaltrials.gov Unique identifier: NCT01299935.

Genetic Determinants of Hypertension Identification of Candidate Phenotypes

Our long-term objective is to identify genes whose expression results in hypertension and in phenotypic changes that may contribute to hypertension. The purpose of the present study was to describe evidence for the heritability of hypertension-related phenotypes in hypertensive, hyperlipidemic black sib pairs. Outpatient anthropomorphic measurements were obtained in >200 affected sib pairs. In addition, 68 of these sib pairs were studied under controlled, standardized conditions at an inpatient clinical research center while off both antihypertensive and lipid-lowering medications. Heritability was estimated on the basis of sib-sib correlations and with an association model. Higher heritability estimates for blood pressure were observed with multiple measurements averaged over 24 hours than with measurements at a single time point, and heritability estimates for nighttime blood pressures were higher than those for daytime blood pressures. Heritability estimates for several of the phenotypes were augmented by obtaining measurements in response to a standardized stimulus, including (1) blood pressure responses to the assumption of upright posture, standardized psychological stress, and norepinephrine infusion; (2) plasma renin, aldosterone, epinephrine, and cAMP and cGMP responses to the assumption of upright posture; (3) para-aminohippurate and inulin clearances in response to norepinephrine infusion; and (4) plasma arginine vasopressin in response to NaCl infusion. High heritability estimates were also observed for various measures of body size and body fat, left ventricular size, cardiac index, stroke volume, total peripheral resistance, and serum concentrations of LDL and HDL cholesterol and leptin. These heritability estimates identify the hypertension-related phenotypes that may facilitate the identification of specific genetic determinants of hypertension in blacks with hyperlipidemia.

Hyperaldosteronism and Hypertension. Ethnic Differences

The purpose of this study is to evaluate the relationship between aldosterone and blood pressure in a total of 220 normotensive and 293 essential hypertensive subjects in 2 genetically distinct populations—blacks and white French Canadians. The 24-hour blood pressure monitoring was performed under standardized conditions after discontinuing antihypertensive medications. Plasma renin activity and plasma aldosterone were measured in the supine position and after standing for 10 minutes. Plasma atrial natriuretic factor was also measured. Supine and standing plasma renin activities were lower (P≤0.01), plasma aldosterone was higher (P<0.0001), and the aldosterone/renin ratios were higher (P<0.0001) in the hypertensive subjects. Atrial natriuretic factor was also higher in the hypertensive subjects (P<0.0001). Among blacks, blood pressures did not correlate with plasma renin activity. However, both average daytime and nighttime systolic and diastolic blood pressures were correlated with supine and standing plasma aldosterone and with the aldosterone/renin ratio (P<0.005 or less). In French Canadians, blood pressures tended to be positively correlated with standing plasma renin activity and aldosterone, but not with the aldosterone/renin ratio. Correlations of blood pressure with aldosterone were more consistent and more striking in blacks than in French Canadians. In both ethnic groups, there were inconsistent correlations of blood pressure with atrial natriuretic factor. These observations are consistent with the hypothesis that aldosterone-induced volume expansion is an important contributor to hypertension, especially in blacks.

Lung cancer among postmenopausal women treated with estrogen alone in the women's health initiative randomized trial

BACKGROUND In the Womens Health Initiative (WHI) randomized controlled trial, use of estrogen plus progestin increased lung cancer mortality. We conducted post hoc analyses in the WHI trial evaluating estrogen alone to determine whether use of conjugated equine estrogen without progestin had a similar adverse influence on lung cancer. METHODS The WHI study is a randomized, double-blind, placebo-controlled trial conducted in 40 centers in the United States. A total of 10 739 postmenopausal women aged 50-79 years who had a previous hysterectomy were randomly assigned to receive a once-daily 0.625-mg tablet of conjugated equine estrogen (n = 5310) or matching placebo (n = 5429). Incidence and mortality rates for all lung cancers, small cell lung cancers, and non-small cell lung cancers in the two randomization groups were compared by use of hazard ratios (HRs) and 95% confidence intervals (CIs) that were estimated from Cox proportional hazards regression analyses. Analyses were by intention to treat, and all statistical tests were two-sided. RESULTS After a mean of 7.9 years (standard deviation = 1.8 years) of follow-up, 61 women in the hormone therapy group were diagnosed with lung cancer compared with 54 in the placebo group (incidence of lung cancer per year = 0.15% vs 0.13%, respectively; HR of incidence = 1.17, 95% CI = 0.81 to 1.69, P = .39). Non-small cell lung cancers were of comparable number, stage, and grade in both groups. Deaths from lung cancer did not differ between the two groups (34 vs 33 deaths in estrogen and placebo groups, respectively; HR of death = 1.07, 95% CI = 0.66 to 1.72, P = .79). CONCLUSION Unlike use of estrogen plus progestin, which increased deaths from lung cancer, use of conjugated equine estrogen alone did not increase incidence or death from lung cancer.

Temporomandibular disorders and associated clinical comorbidities.

ObjectiveTemporomandibular joint and muscle disorders (TMJD) are ill-defined, painful debilitating disorders. This study was undertaken to identify the spectrum of clinical manifestations based on self-report from affected patients. MethodsA total of 1511 TMJD-affected individuals were recruited through the web-based registry of patients maintained by The TMJ Association, Ltd, a patient advocacy organization, and participated in the survey as well as 57 of their nonaffected friends. Results were also compared with US population for questions in common with the National Health and Nutrition Examination Survey. ResultsThe TMJD-affected individuals were on average 41 years of age and predominantly female (90%). Nearly 60% of both men and women reported recent pain of moderate-to-severe intensity with a quarter of them indicating interference or termination of work-related activities. In the case-control comparison, a higher frequency of headaches, allergies, depression, fatigue, degenerative arthritis, fibromyalgia, autoimmune disorders, sleep apnea, and gastrointestinal complaints were prevalent among those affected with TMJD. Many of the associated comorbid conditions were over 6 times more likely to occur after TMJD was diagnosed. Among a wide array of treatments used (46 listed), the most effective relief for most affected individuals (91%) was the use of thermal therapies—hot/cold packs to the jaw area or hot baths. Nearly 40% of individuals affected with TMJD patients reported one or more surgical procedures and nearly all were treated with one or many different medications. Results of these treatments were generally equivocal. Although potentially limited to the most severe TMJD affected individuals, the survey results provide a comprehensive dataset describing the clinical manifestations of TMJD. DiscussionThe data provide evidence that TMJD represent a spectrum of disorders with varying pathophysiologies, clinical manifestations, and associated comorbid conditions. The findings underscore the complex nature of TMJD, the need for more extensive interdisciplinary basic and clinical research, and the development of outcome-based strategies to more effectively diagnose, prevent, and treat these chronic, debilitating conditions.