Patricia W. Wahl

Effect of Estrogen/Progestin Potency on Lipid/Lipoprotein Cholesterol

We studied 374 women taking oral contraceptives, 284 women taking estrogen preparations after menopause, and 1086 women taking no hormones, to determine the relation of plasma lipids and lipoprotein cholesterol concentrations to various types of estrogen/progestin formulations. Premenopausal women, using oral contraceptives containing a relatively low dose of estrogen combined with a medium or high dose of progestin (Norlestrin, Ovral, or Demulen) had a 24 per cent higher median concentration of low-density-lipoprotein cholesterol than did those not using hormones (P less than 0.05). Women using oral contraceptives that are high in estrogen and low in progestin (Enovid or Oracon) had significantly higher concentrations of high-density-lipoprotein cholesterol than did nonusers; those using Ovral, a low-estrogen and high-progestin formulation, had significantly lower levels of high-density-lipoprotein cholesterol. In postmenopausal women the use of estrogen was associated with concentrations of low-density-lipoprotein cholesterol that were 11 to 19 per cent below the levels in postmenopausal women who did not use hormones. The effects of estrogen-progestin balance on low-density and high-density lipoproteins may underlie the increased incidence of stroke and myocardial infarction in women of childbearing age who take oral contraceptives.

Sleep Disturbance, Psychosocial Correlates, and Cardiovascular Disease in 5201 Older Adults: The Cardiovascular Health Study

OBJECTIVES: To describe the prevalence of self reported sleep disturbances in older men and women and to describe their relationships with health status and cardiovascular diseases (CVD).

Quantitation of apolipoprotein A-I of human plasma high density lipoprotein.

High density lipoproteins (HDL) may be controlled via their major apolipoprotein, A-I. To study this apolipoprotein, a simple, precise, and accurate immunodiffusion assay for A-I was developed and applied in a sample of Bell Telephone Company employees. A-I showed a slight increase with age in men (r=0.11, n=263) and women (r=0.15, n=257). A-I correlated closely with HDL cholesterol (r=0.72). It was weakly related to total triglyceride in women (r=0.24) but was inversely related in men (r=-0.17). Women on estrogen had the highest A-I levels (149 mg/dl +/- 26, x +/- S.D., n=29, p is less than 0.05), followed by women on combination oral contraceptives (141 +/- 26, n=80) whereas women on no medication had lower levels (129 +/- 25, n=99, p is less than 0.01) but men had the lowest levels (120 +/- 20, p is less than 0.01) In a separate group of 14 women given estrogen for 2 wks (1 mug/kg/day), A-I increased by 24%. Thus A-I is increased by exogenous and, most likely, endogenous estrogen, Among hyperlipidemic referral subjects, those with hypercholesterolemia (n=43) and hypertriglyceridemic women (n=33) had normal A-I levels. Among hypertriglyceridemic men both A-I and HDL cholesterol values were decreased (115 +/- 20, p is less than 0.01 and 37 +/- 3, p is less than 0.01, respectively, n=68) but were significantly lower among a group of myocardial infarction survivors (107 +/- 16, p is less than 0.01, and 27 +/- 6, p is less than 0.01, respectively, n=24). High density lipoprotein levels and the content of cholesterol in HDL associated with A-I appear to be decreased in coronary heart disease.

The Risk of Myocardial Infarction Associated With the Combined Use of Estrogens and Progestins in Postmenopausal Women

BACKGROUND While observational studies have suggested that unopposed estrogens reduce the incidence of coronary disease in postmenopausal women, there are few data on the effect of combined therapy with estrogens and progestins--a regimen adopted in recent years to minimize the risk of endometrial hyperplasia and cancer. In clinical trials, the addition of progestins has an adverse effect on serum lipid levels, and these lipid effects have raised the question of whether combined estrogen-progestin therapy increases the risk of coronary disease compared with the use of estrogen alone. METHODS We conducted a population-based, case-control study among enrollees of Group Health Cooperative of Puget Sound. Cases were postmenopausal women who sustained an incident fatal or nonfatal myocardial infarction in 1986 through 1990. Controls were a stratified random sample of female Group Health Cooperative enrollees frequency matched to the cases by age and calendar year. We reviewed the medical records of the 502 cases and 1193 controls and conducted brief telephone interviews with consenting survivors. The health maintenance organizations computerized pharmacy database was used to ascertain the use of postmenopausal hormones. For the primary analysis of current use, we classified women into one of three groups: (1) nonusers of hormones; (2) users of estrogens alone; or (3) users of combined therapy including both estrogens and progestins. Each group of hormone users was compared with nonusers. RESULTS After adjustment for potential confounding factors, the risk ratio of myocardial infarction associated with current use of estrogens alone was 0.69 (95% confidence interval, 0.47 to 1.02); and the risk ratio of myocardial infarction associated with current use of combined therapy was 0.68 (95% confidence interval, 0.38 to 1.22). Duration of combined-therapy use was relatively short, averaging less than 2 years in cases and controls. CONCLUSIONS In this case-control study, the reduced risk of myocardial infarction associated with the use of estrogens alone was consistent with previous observational studies. Although the 95% confidence interval only excluded a risk above 1.22, the current use of combined therapy was not associated with an adverse effect on the incidence of myocardial infarction in postmenopausal women.

Sex Differences in the Effect of Diabetes Mellitus on Lipoprotein Triglyceride and Cholesterol Concentrations

We studied sex differences in the serum lipid abnormalities associated with diabetes mellitus in 111 patients with insulin-dependent diabetes and 270 patients with non-insulin-dependent diabetes, who were compared with 586 nondiabetic controls. Relative to control levels, the increases in triglycerides were 17 to 34 mg per deciliter greater in diabetic women than in diabetic men. The median low-density-lipoprotein cholesterol concentration in non-insulin-dependent diabetics was 1 to 4 mg per deciliter lower than the control level in women and 16 to 22 mg per deciliter lower in men, and was 30 mg per deciliter higher than control in insulin-dependent diabetic women and similar to control in insulin-dependent diabetic men. The decrease in median high-density-lipoprotein cholesterol in non-insulin-dependent diabetics was 2 to 7 mg per deciliter greater in women than in men, and the increase in high-density-lipoprotein cholesterol in insulin-dependent diabetics was 3 mg per deciliter less in women than in men. We conclude that diabetes has a greater adverse effect on triglyceride and lipoprotein cholesterol concentrations in diabetic women than in diabetic men, and that this may explain the greater increase in risk of arteriosclerosis in diabetic women.

Inhibition of hypercholesterolemia-induced atherosclerosis in the nonhuman primate by probucol. I. Is the extent of atherosclerosis related to resistance of LDL to oxidation?

Lipoprotein oxidation is believed to play an important role in atherogenesis. To investigate whether inhibition of oxidation of low density lipoprotein (LDL) would alter atherogenesis in the nonhuman primate, we administered probucol, a potent antioxidant, to Macaca nemestrina fed a high-fat, high-cholesterol diet. Probucol was administered to half of the 16 monkeys 14 wk after starting the hypercholesterolemic diet, and was given daily until they were sacrificed after 11 mos. To evaluate the antioxidant effect of probucol, the resistance of isolated plasma LDL to in vitro oxidation was evaluated. Probucol significantly increased the resistance of LDL to oxidative modification, as shown by an increase in the lag time required for conjugated diene formation. Lesions in the probucol-treated animals appeared less mature, and increased accumulation of lipid was observed in smooth muscle cells. Comparison of all control and probucol-treated monkeys demonstrated that intimal lesion areas in the thoracic aortas of the probucol-treated monkeys were reduced by 43% (P < 0.0001), but no significant difference in lesion area was found in the abdominal aortas or in the iliac arteries. However, the lag phase of conjugated diene formation was not prolonged in 2 of the 8 probucol-treated animals. A plot of intimal lesion size versus lag phase of all 16 animals showed a trend that lesion size was inversely related to oxidation resistance for all anatomic sites. The strong inverse relationship between intimal lesion size and resistance of LDL to oxidation supports a role for lipoprotein oxidation in the development and progression of lesions of atherosclerosis. The possibility that some of the effect is due to other biological properties of probucol cannot be ruled out.

Cardiovascular disease in older adults with glucose disorders: comparison of American Diabetes Association criteria for diabetes mellitus with WHO criteria

BACKGROUND The new fasting American Diabetes Association (ADA) criteria for the diagnosis of diabetes mellitus rely mainly on fasting blood glucose concentrations and use a lower cut-off value for diagnosis than the WHO criteria. We aimed to assess the sensitivity of these criteria for the detection of cardiovascular disease, the main complication of diabetes mellitus in the elderly. METHODS We did a cross-sectional and prospective analysis of 4515 participants of the Cardiovascular Health Study, an 8 year longitudinal study designed to identify factors related to the onset and course of cardiovascular disease in adults aged at least 65 years. We calculated the prevalence and incidence of cardiovascular disease for the ADA and WHO criteria. FINDINGS There was a higher prevalence of cardiovascular disease among individuals with impaired glucose or newly diagnosed diabetes by both criteria than among those with normal glucose concentrations. However, because fewer individuals had abnormal glucose states by the fasting ADA criteria (22.3%) than by the WHO criteria (46.8%), the number of cases of cardiovascular disease attributable to abnormal glucose states was a third of that attributable by the WHO criteria (53 vs 159 cases per 10,000). For the two sets of criteria, the relative risk for incident cardiovascular disease (mean follow-up 5.9 years) was higher in individuals with impaired glucose and newly diagnosed diabetes than in those with normal glucose. Individuals classified as normal by the fasting ADA criteria had a higher absolute number of incident events (455 of 581 events) than those classified as normal by the WHO criteria (269 of 581 events). Fasting ADA criteria were therefore less sensitive than the WHO criteria for predicting cardiovascular disease among individuals with abnormal glucose (sensitivity, 28% vs 54%). INTERPRETATION The new fasting ADA criteria seem to be less predictive than the WHO criteria for the burden of cardiovascular disease associated with abnormal glucose in the elderly.

Association of Elevated Fasting C-Peptide Level and Increased Intra-Abdominal Fat Distribution With Development of NIDDM in Japanese-American Men

The Japanese-American population of King County, Washington, is known to have a high prevalence of non-insulin-dependent diabetes mellitus (NIDDM). As part of a community-based study, we reexamined 146 second-generation Japanese-American men who had been initially classified as nondiabetic. At a mean follow-up period of 30 mo, 15 men had developed NIDDM, and 131 remained nondiabetic. The variables measured at the initial visit that distinguished the 15 diabetic men from the 131 nondiabetic men were older age, higher serum glucose level at 2 h after 75 g oral glucose, higher fasting plasma C-peptide level, and increased cross-sectional intra-abdominal fat area as determined by computed tomography. Both older age and higher 2-h glucose levels are variables that have been associated with the development of NIDDM, but the association of higher fasting C-peptide level and greater intra-abdominal fat area with subsequent development of NIDDM were new observations. The elevated fasting C-peptide level persisted after adjustment for fasting serum glucose. The elevated C-peptide level represents hypersecretion of insulin and was interpreted to reflect a compensatory response to an underlying insulin-resistant state that antedates the development of NIDDM. The fasting C-peptide level was correlated with the intra-abdominal fat area, suggesting that the intra-abdominal fat area may be associated with insulin resistance. Thus, in individuals who develop NIDDM, insulin resistance, increased insulin secretion, and increased intra-abdominal fat are present before diabetic glucose tolerance can be demonstrated.

Survival with Dialysis and Transplantation in Patients with End-Stage Renal Disease

We examined the survival experience of 1038 white patients with end-stage renal disease to compare transplantation with maintenance dialysis. A mathematical model was used that permitted adjustment for the confounding effects of age and morbidity at the start of treatment as well as for the year in which treatment began. For patients with all kinds of renal disease, survival was related to age and morbidity but not to the year of starting treatment. Transplantation with a graft from a living related donor was associated with significantly better survival than either transplantation with a cadaveric graft (relative risk, 0.54) or dialysis (relative risk, 0.55). No significant difference in survival was found between treatment by dialysis and by cadaveric transplantation (relative risk, 1.01). In view of this experience, the decision about whether a patient on dialysis should receive a cadaveric transplant should be based on evaluation of the differences in complications associated with the two treatments and the potential effects of these on the patients general life style, opportunity for rehabilitation, and family and social responsibilities. Whether the use of cyclosporine will change this assessment in the future remains to be seen.

Prevalence of diabetes mellitus and impaired glucose tolerance among second-generation Japanese-American men.

We describe the initial findings from a multidisciplinary, epidemiologic study of diabetes mellitus conducted in a population of secondgeneration Japanese-American (Nisei) men born between 1910 and 1939 who reside in King County, Washington (n = 1746). From this study population, 487 volunteered, and 229 were enrolled to comprise the study sample. A random sample of Nisei men was also drawn from the population to develop a reference sample of 189 men. All subjects participated in a 75-g oral glucose tolerance test; the National Diabetes Data Group (NDDG) and World Health Organization (WHO) diagnostic criteria as well as a modification of the WHO criteria were used to classify individuals with normal glucose tolerance, impaired glucose tolerance (IGT), or diabetes. Within the study sample, 79 men were found to have normal glucose tolerance, 72 had IGT, and 78 had type II diabetes. The mean age of the study sample was 61.4 yr. Based on comparison of the study sample to the reference sample, the study sample was ascertained to be representative of Nisei men in King County. Extrapolating from our observations in the reference sample and in the study sample, we have estimated that ∼56% of Nisei men in the study population have abnormal glucose tolerance. Much of this is undiagnosed because only ∼13% of the reference sample of Nisei men reported a prior diagnosis of diabetes. Of the men who enrolled in the study as nondiabetic subjects, 11.1% had diabetes and 39.2% had IGT; i.e., 50.3% had previously unknown abnormalities in glucose tolerance. We estimate that ∼20% of Nisei men have diabetes (both previously diagnosed and undiagnosed) and ∼36% have IGT.