Jeffrey A. Perlman

Effects of estrogen dose and smoking on lipid and lipoprotein levels in postmenopausal women

The joint effects of conjugated estrogen use, age, body mass index, and smoking on plasma lipid and lipoprotein levels were assessed in 585 women who used oral estrogen and 1093 women who did not who participated in the Walnut Creek Contraceptive Drug Study. Whether administered daily or cyclically, conjugated estrogen was associated with reductions in low-density lipoprotein cholesterol levels and increases in high-density lipoprotein cholesterol and triglyceride levels. The adjusted mean low-density lipoprotein cholesterol concentration was 132 mg/dl for women who used conjugated estrogen in a dose greater than or equal to 1.25 mg/day; the adjusted corresponding mean concentration was 147 mg/dl for postmenopausal women who did not use estrogen. A dose-response pattern was demonstrated between conjugated estrogen and low- and high-density lipoprotein cholesterol levels. A maximum low-density lipoprotein cholesterol level reduction was reached at a dose of 1.25 mg, suggesting a saturation phenomenon. Stepwise dose-response increases in high-density lipoprotein cholesterol levels were also found with estrogen therapy, with a maximum increase of 8 to 10 mg/dl observed with the 1.25 mg dose. Estrogen-related rises in low-density lipoprotein cholesterol levels and decreases in high-density lipoprotein cholesterol levels were offset by 2 to 3 mg/dl in women who smoked. It may be concluded, therefore, that among postmenopausal women, low-risk lipoprotein profiles as assessed by low- and high-density lipoprotein cholesterol levels are found in nonsmokers whose postmenopausal hormone therapy includes the equivalent of a conjugated estrogen dose of 1.25 mg.

Vasectomy and prostate cancer risk: Methodological review of the evidence

Two recent studies have reported a significantly elevated risk of prostate cancer among vasectomized men. To assess whether the new results conflict with earlier studies that found no significant overall association, and, if so, whether such a conflict could have a methodological basis, we reviewed the six major epidemiological studies of this topic. Statistical analysis revealed significant (p < 0.01) heterogeneity among the associations in the six studies, attributable to one of the recent studies. Scrutiny of the studies for fulfillment of eight methodological standards for scientific validity revealed that no study completely fulfilled more than four standards, and that all studies were deficient in avoiding detection bias and obtaining accurate vasectomy histories. Our review indicates that the evidence on this topic is indeed conflicting, that the quality of the evidence does not resolve the conflict, and that future studies of this topic, designed to ensure scientific credibility of results, are needed.

Cardiovascular risk factors, premature heart disease, and all-cause mortality in a cohort of northern California women.

Large prospective studies and intervention trials have identified major risk factors for premature heart disease in men, while the Framingham Heart Disease Study has provided the leading evidence of predictors of cardiovascular disease in women. We evaluated the role of these risk factors in a 13-year follow-up study of 8935 premenopausal and 2716 postmenopausal women in the Walnut Creek Contraceptive Drug Study cohort in Northern California. Elevated cholesterol levels, high blood pressure, smoking, obesity, family history of heart disease, and diabetes were investigated for their contribution to premature death due to all causes and due to cardiovascular disease. In addition, risk factor profiles were developed separately for users and nonusers of Premarin (conjugated estrogen) in the postmenopausal cohort. The results show that the strongest predictors of cardiovascular mortality among premenopausal women were smoking, high blood pressure, and diabetes, with relative risks of 2.8, 10.5, and 11.6, respectively. A disparity between high cardiovascular risk factor prevalence and low rates of premature heart disease indicates that the high relative risks will not be accompanied by large attributable risks. Nevertheless, the study reconfirms the need for screening women for heart disease risk because life-style changes can improve cardiovascular risk factors and can potentially reduce the chance of premature death even further.

Impaired glucose tolerance in women using oral contraceptives: United-States 1976-1980.

Based on 75-g oral glucose tolerance test results from the second National Health and Nutrition Examination Survey (1976-1980), women 20-44 years reporting the use of oral contraceptives (OCs) had decreased glucose tolerance compared with women not using OCs in this age group. Estimates of decreased glucose tolerance after adjustment for age and body mass index were 15.4% (95% CI, 7.6-23.2%) in OC users vs 6.3% (95% CI, 4.5-8.1%) in nonusers. Oral contraceptive use was associated with elevations in 1 and 2 hour plasma glucose concentrations. The mean adjusted difference between OC users and nonusers at 1 and at 2 hours postchallenge was 14 and 13 mg/100 ml, respectively. Characteristics of study nonrespondents vs respondents were analyzed to estimate potential bias due to nonresponse. No appreciable biases were found, but this does not rule out the possibility that some bias may exist.

The potential for hormonal prevention trials

Breast and prostate cancer are significant causes of morbidity and mortality and are very similar in etiology, epidemiology, and modalities of treatment. Investigational strategies in the prevention of these malignancies also have strong parallels. The National Cancer Institute is sponsoring several large scale clinical trials involving hormonal manipulation and cancer prevention. In the Breast Cancer Prevention Trial, 16,000 women at high risk for breast cancer are being randomized to receive the antiestrogen agent tamoxifen or placebo for 5 years in an effort to determine if breast cancer development can be inhibited. In a similar trial, the Prostate Cancer Prevention Trial, 18,000 men older than 55 years of age will be randomized to receive finasteride, a 5‐alpha‐reductase inhibitor, or placebo to determine if inhibition of dihydrotestosterone synthesis in the prostate over a prolonged period will lead to a decreased incidence of prostate cancer. Both clinical trials offer the possibility of demonstrating that a hormonal intervention can decrease an individuals risk of developing breast or prostate cancer. They also have the potential of providing critical information about cancer risk, etiology, screening, and genetics, as well as quantifying the risks and benefits of specific preventive interventions.

Cardiovascular risk status and oral contraceptive use: United States, 1976–1980☆☆☆

Data from the second National Health and Nutrition Examination Survey, conducted in 1976-1980, were analyzed for the prevalence of cardiovascular risk factors (cigarette smoking, serum cholesterol, and blood pressure) among 2,342 premenopausal women ages 20-44 years, stratified by oral contraceptive use. For oral contraceptive users and non-users, adjusted means were serum cholesterol, 205 vs 188 mg/dl (P less than 0.05); systolic blood pressure, 116 vs 113 mm Hg (P less than 0.01); and diastolic blood pressure, 74 vs 73 mm Hg (NS). The prevalence of cigarette smoking was significantly higher among oral contraceptive users (44% compared with 36% among nonusers; P less than 0.05). Using the 1984 NIH Consensus Development Conference Statement on Lowering Blood Cholesterol to define risk levels for serum cholesterol, 23% of the oral contraceptive users were at high risk compared with 12% of the nonusers, and 16% of the oral contraceptive users vs 11% of the nonusers were at moderate risk. For users and nonusers, the respective prevalence of a blood pressure at or above 140/90 mm Hg was 5.3% vs 8.8% (unadjusted) and 8.6% vs 8.0% (age adjusted). The percentage of women with multiple risk factors was also higher among oral contraceptive user; 14% of the users had two or more risk factors vs 7% of the nonusers (P less than 0.05). These cross-sectional national data support data from clinical studies regarding the effect of oral contraceptives on cholesterol and blood pressure levels. In addition, since the use of oral contraceptives is widespread in the population and users tend to see physicians more regularly than other women, the data suggest that users of the pill are a good target group among which to screen and monitor cardiovascular risk factors.

Effect of 131I on the anemia of hyperthyroidism

Data from the National Thyrotoxicosis Therapy Follow-Up Study (NTTFS) are presented here to document the existence of anemia in hyperthyroidism, a mild and reversible anemia that is simultaneously ameliorated with reversal of the hyperthyroid state. Among 20,600 women entered into the NTTF study with no previous history of hematological disorders, the prevalence of anemia was found to range from 10-15%, appearing to be higher in those selected for treatment with 131I when compared to those selected for surgery. An attempt is made to verify the recent hypothesis that thyroid hormone levels in the supraphysiologic range may suppress erythrogenesis. Two statistically significant regression models are consistent with a hypothesis of thyrotoxic bone marrow suppression. However, both associations are weak enough to suggest that some other physiologic improvement underlies the amelioration of anemia when hyperthyroidism is reversed. The degree of improvement in hematological status is similar for women in both treatment groups. Among 4464 women for whom serial hematological tests are obtained, over 3/4 of anemic patients are no longer anemic after an average 6.2 yr of follow-up. Clinicians are reassured that radioactive iodine exposure causes no further insult to the bone marrow, no matter what the cumulative dosage. The highly fractionated low dose bone marrow exposures to radiation account for the minimal hematological risks of 131I treatment.