Longitudinal relation between endogenous testosterone and cardiovascular disease risk factors in middle-aged men. A 13-year follow-up of former Multiple Risk Factor Intervention Trial participants.

The present study examined lifestyle and behavioral correlates of the change in total testosterone over 13 years in 66 men aged 41-61 years who were former participants of the Multiple Risk Factor Intervention Trial (MRFIT) at the Pittsburgh, Pennsylvania, center. The authors also determined in these men if changes in total testosterone are related to changes in cardiovascular disease risk factors. The mean total testosterone level was 751 (standard deviation, 248) ng/dl at baseline and decreased by 41 (standard deviation, 314) ng/dl during follow-up. The correlation between measures was r = 0.44 (p < 0.001). In multivariate analysis, higher type A coronary-prone behavior score, greater pack-years of cigarette smoking, and the MRFIT special intervention group were associated with larger decreases in total testosterone. Age, body weight, weight change, leisure time activity level, and alcohol intake were not related to the change in total testosterone. The decrease in endogenous testosterone was associated with an increase in triglycerides and a decrease in high density lipoprotein cholesterol in multivariate analysis controlling for obesity and other lifestyle covariates. There was little relation between change in testosterone and change in total and low density lipoprotein cholesterol or blood pressure. This longitudinal study confirms a gradual decline in total testosterone levels with advancing age in older men and provides evidence that lifestyle and psychosocial factors are related to this decline. Decreases in endogenous testosterone levels with age in men are associated with potentially unfavorable changes in triglycerides and high density lipoprotein cholesterol.

Semiautomated method for the quantitation of plasma or sera androstenedione, testosterone, and dihydrotestosterone in population studies.

A method is presented that analyzes quantitatively and reproducibly the androgens testosterone, androstenedione, and dihydrotestosterone from human sera or plasma. The chromatographic separation step generates an unattended throughput of one preparative separation per hour. Controls are built into the method to account for changing chromatographic conditions that otherwise result in shifts in retention characteristics. Separation factors for the three androgens are as follows (mean +/- standard deviation): alpha = 1.23 +/- 0.011 between androstenedione and testosterone and alpha = 1.38 +/- 0.025 between testosterone and dihydrotestosterone. Sensitivities of the method are androstenedione 5 pg, testosterone 3 pg, and dihydrotestosterone 14 pg. A study of procedural losses associated with initial sample processing, a validation, and application to two sample sets which demonstrates the methods utility for the analysis of hypoandrogenic populations (postmenopausal women) and hyperandrogenic groups (prostate cancer patients) is also reported. The precision for replicate aliquots of control plasma is androstenedione and testosterone = 5-11% CV and dihydrotestosterone = 10-20% CV.

Association of sex hormones and adiposity with plasma levels of fibrinogen and PAI-1 in postmenopausal women.

Blood levels of the clotting factor fibrinogen and tissue plasminogen activator inhibitor-1 (PAI-1), a primary inhibitor of fibrinolysis, have been positively linked to risk of coronary heart disease. The authors have reported previously that plasma fibrinogen appears to rise after menopause and to be reduced with use of postmenopausal hormonal therapy. There is also evidence to suggest that sex hormones may influence PAI-1. To examine whether plasma fibrinogen and PAI-1 antigen levels differ among older postmenopausal women according to use of hormone therapy and by blood level of estrogen and androgens, these variables were assessed among 277 healthy women aged 65-82 years, one half of whom were receiving therapy. The study population was drawn from the Study of Osteoporotic Fractures, Pittsburgh, Pennsylvania, during 1986-1988. Overall, results showed median PAI-1 levels to be lower on average with oral and transdermal use of hormone therapy (25.0 vs. 33.5 ng/ml, p < 0.01) and mean fibrinogen levels to be lower (279 vs. 295 mg/dl, p < 0.02) with use of oral estrogen (but not transdermal) therapy compared with women not receiving therapy. Among women not receiving therapy, PAI-1 and fibrinogen levels were not related to endogenous sex hormone levels, with the exception of a modest positive relation between PAI-1 and serum estrone concentrations (rs = 0.29). In addition, a markedly higher PAI-1 level was found for women with a preponderance of upper body fat, independent of obesity. In sum, results showed that older women receiving postmenopausal hormone therapy had more favorable plasma levels of the hemostatic factors PAI-1 and fibrinogen than did those not receiving therapy, which can be explained in large part by differences between the two groups in obesity and body fat distribution.

Epidemiologic studies of menopause: changes in risk factors and disease.

There have been important studies of changes in risk factors and psychosocial variables during peri- and postmenopause. Most of the studies have been done in whites. Studies have clearly documented changes in behavior and biological variables related to menopause. The most critical questions bear on the interrelationships between sex steroid hormone levels, life-styles, including diet, exercise, alcohol consumption, obesity, and changes in key risk factors that are associated with the major causes of morbidity and mortality among postmenopausal women. The best study designs should be longitudinal and include frequent, accurate, and reproducible measurements of biological and psychosocial variables. Importantly, studies should be done in heterogeneous populations. The most critical variables may be measures of the degree of obesity and fatness, diet, and exercise and their relationship to hormonal changes occurring during the peri- and postmenopausal period.

Black-white differences in serum sex hormones and bone mineral density.

To determine if differences in serum sex hormones contribute to racial differences in bone mass, independent of obesity, the authors compared bone mass and sex steroid hormone levels in 273 white women and 86 black women aged 65 years or older. This study was ancillary to the Study of Osteoporotic Fractures. Black women were recruited at two clinical centers in Baltimore, Maryland, and the Monongahela Valley, near Pittsburgh, Pennsylvania. An age-stratified random sample of white women was chosen from the Pittsburgh clinic. Demographic and historical information and anthropometric measurements were obtained from a clinic questionnaire, interview, and examination. Single photon absorptiometry was obtained at three sites: the distal radius, the proximal radius, and the calcaneus. Serum estrone, androstenedione, and testosterone were measured using extraction, column chromatography, and radioimmunoassay. Serum estrone concentrations were significantly higher and androstenedione levels were significantly lower in black women compared with white women. Racial differences in estrone could be explained largely by differences in the degree of obesity. Bone mass was greater in black women compared with white women within age, body mass index, (kg/m2), and estrone strata. Androgens were not related to bone mass. Within each race, bone mass increased linearly with increasing concentration of serum estrone. There was no interaction between race and serum estrone on bone mass. Each factor contributed independently and significantly to the regression model predicting bone mass. There was no attenuation of the effect of race if estrone was included in the model. In conclusion, race and serum estrone were independent determinants of bone mass.

Serum estrone concentrations and coronary artery disease in postmenopausal women.

Little is known about the relation between serum sex hormones and either coronary heart disease or the development of atherosclerosis in women. We measured serum estrone concentrations in 87 postmenopausal women (age, 50 to 81 years) who were admitted for diagnostic cardiac catheterization. None of the women were on estrogen replacement therapy. Cases (n = 62) were defined as those women who had > or = 1 coronary artery with > or = 50% occlusion. All control subjects (n = 25) had 0% to 24% occlusion of all coronary arteries. Estrone concentrations, as measured by a combination of extraction, column chromatography, and radioimmunoassay, showed little difference between cases and control subjects. A difference of 6 pg/mL in the estrone level was not associated with a significantly increased risk of coronary artery disease (odds ratio [OR], 1.85; 95% confidence intervals [CI], 0.60, 5.2). Examination of mean estrone levels on the basis of the number of occluded vessels was also not significant. The primary predictors of coronary artery disease in this population were a history of diabetes (OR, 8.8; CI, 1.5, 51.4) and age (5-year increments; OR, 2.1; CI, 1.2, 3.8). There was also some suggestion that women who reported higher lifetime physical activity levels were at a reduced risk for developing coronary artery disease (OR, 0.18; CI, 0.05, 0.65). These preliminary results do not support the hypothesis that serum estrogens are related to coronary artery disease in older women, but these findings need to be replicated in larger populations of older women.

Serum sex hormones and severity of osteoarthritis of the hand.

OBJECTIVE: To examine the relationship of endogenous sex hormones to the severity of radiographic hand osteoarthritis (ROA) in 229 white women, mean age 74 years. METHODS: Hand ROA was graded according to the Kellgren-Lawrence scale and according to individual features of OA: osteophytes, joint space narrowing, subchondral sclerosis, lateral deformity and joint collapse. Two measures of hand ROA were considered: the worst joint score assigned to any one of 10 hand joints and the sum of the scores for the 10 joints. RESULTS: Comparison of the age and obesity adjusted sex hormone concentrations by the worst Kellgren-Lawrence score or the worst score of the individual features of OA revealed little difference. There were no trends in the sex hormone concentrations with increasing severity of hand ROA. CONCLUSIONS: Our results do not support an association between endogenous hormone levels and severity of hand ROA.

Stress management training for adolescents with diabetes.

Evaluated the effects of stress management training (SMT) for adolescents with diabetes in a 9-month controlled treatment-outcome study. Nine patients were randomly assigned to a stress management group while another 10 patients served as controls and received standard outpatient treatment. The treatment program consisted of 10 sessions over 3 months, 3 additional sessions over 3 months, and a 3-month follow-up without treatment. Diabetes-specific stress decreased significantly for patients in the SMT group over the course of the intervention and follow-up. However, metabolic control, regimen adherence, coping styles, and self-efficacy about diabetes were unchanged. These findings suggest a SMT program for adolescents with diabetes may be helpful in reducing diabetes-specific stress, but additional procedures are necessary to improve adherence, coping styles, and metabolic control.

Racial differences in metabolic control of children and adolescents with type I diabetes mellitus.

OBJECTIVE: This study evaluated racial differences in the metabolic control of children and adolescents with insulin-dependent (type I) diabetes mellitus and examined the interactive effects of race with age and sex. RESEARCH DESIGN AND METHODS: Data on several demographic and clinical variables were obtained for 102 black and 108 white children, including the percentage of total HbA1, age, age at diagnosis, duration of diabetes, pubertal status, insulin dose (U.kg-1.day-1), body mass index, number of clinic visits kept and missed, number of hospitalizations for diabetic ketoacidosis (DKA) for the year, and socioeconomic status (SES). RESULTS: Black children had higher insulin dosages (P less than 0.05) and lower SESs (P less than 0.001) than white children. HbA1 was higher in black than white children (P less than 0.01) after statistically adjusting for the effects of insulin dose, diabetes duration, and SES. With HbA1-based criteria, more black than white children were in poor and fewer in good metabolic control (P less than 0.001). Older children (greater than or equal to 13 yr) had higher HbA1 levels than younger (less than 13 yr) children (P less than 0.002), but there were no differences in HbA1 between males and females nor were there interactive effects of race, sex, and age-group. Black children were hospitalized for DKA more frequently than white children (P less than 0.04). More black than white children missed clinic visits (P less than 0.01), but they did not differ in number of visits kept. CONCLUSIONS: Black youths with type I diabetes mellitus are in poorer metabolic control than white youths.

Reliability and interrelations among serum sex hormones in postmenopausal women.

Serum sex hormones may be related to the risk of several diseases in postmenopausal women including osteoporosis, heart disease, and breast and endometrial cancer. For assessment of the relation of sex hormones to disease, the measurements should be reliable, valid, and practical. In this paper, the authors evaluated the short-term (4-week) and long-term (2-year) reliability of serum sex hormones and interrelations among serum sex hormones in white postmenopausal women recruited in Pittsburgh, Pennsylvania, 1981-1986. For comparison, the authors simultaneously evaluated the short- and long-term reliability of other commonly measured risk factors, i.e., lipids, lipoproteins, and blood pressure. Serum concentrations of estrone, estradiol, testosterone, and androstenedione were measured by extraction, column chromatography, and radioimmunoassay. Reliability was estimated by calculating the intraclass correlation coefficients (R) and their 95% confidence interval. About 50% of the estradiol levels were below the sensitivity of the assay and, therefore, these results should be interpreted with some caution. The intraclass correlation coefficient for testosterone was 0.92 (95% confidence interval 1.0-0.82), suggesting that a single measure may be reliable in characterizing women for epidemiologic research. Over 4 weeks, estrone could be measured more reliably (R = 0.72) than over 2 years (R = 0.56), but the variability over the long term was similar to that observed for other biologic variables, suggesting that, in situations where the relation between estrone and disease is fairly substantial, a single measure may be used. For estradiol and androstenedione, the intraclass correlations were small, indicating poor reproducibility and the need for more measurements. Estrone concentrations were 11 pg/ml or 46% higher in women with measurable estradiol. Estrone was also positively related to androstenedione concentrations (r = 0.33, p less than 0.001). Concentrations of estradiol are extremely low in postmenopausal women, and accordingly, there is a greater possibility of laboratory error. Since the data suggest that estrone levels can be more reliably measured and are, in fact, related to estradiol levels, it is possible that estrone levels may be used to indicate the total estrogen status of postmenopausal women.

Alpha 2-HS glycoprotein phenotypes and quantitative hormone and bone measures in postmenopausal women.

It has been suggested that inherited traits play a role in the development of osteoporosis by providing a background for the modulation of gene expression. In this study, we examine the influence of the different alleles of alpha 2-HS glycoprotein (AHSG), a protein of the bone matrix, on quantitative estrogens, estrone and estradiol, and bone measures, bone area and density. Estrogens provide a protective effect against fractures in older women and were thus included in the analyses. Isoelectric focusing of AHSG from sera followed by immunoblotting was used to type 163 white postmenopausal women participating in a clinical trial of the effects of walking on bone loss. Plasma hormones were measured by a combination of extraction, column chromatography, and radioimmunoassay; bone measures on the dominant radius were determined with computerized tomography. Analysis of variance was done on estrogen and bone measures after controlling for the effects of age and body mass index. The two major alleles of AHSG result in three phenotypes, designated AHSG 1-1, AHSG 2-1, and AHSG 2-2. The AHSG 1-1 homozygote showed a decreased concentration of estradiol, the AHSG 2-2 homozygote showed an increased concentration, and the AHSG 2-1 heterozygote was intermediate (P = 0.001). Estrone demonstrated a similar pattern in residual analysis although it did not reach statistical significance.

The relation of endogenous sex steroid hormone concentrations to serum lipid and lipoprotein levels in postmenopausal women.

The relation of concentrations of endogenous estrogens and androgens to lipid and lipoprotein levels was examined in 176 white, postmenopausal women (mean age, 58 years) with an average of 9 years since the onset of menopause. All of the women were participants in a clinical trial of the effect of walking on postmenopausal bone loss. In that trial, women were randomized into either a walking group or a control group and were followed for 3 years. There were no differences in the serum hormones or lipids by randomized group, and hence, results from this study are presented for both groups combined. None of the women were on estrogen replacement therapy. Data were available from year 1 (1982-1983) of the trial for the estrogens, lipids, and lipoproteins. Information on androgens was available for 143 of these women. Hormone levels were determined by highly specific methods involving extraction, column chromatography, and radioimmunoassay. About 50% of the women had estradiol levels at or below the sensitivity level (2.5 pg/ml) of the assay; therefore, estradiol levels were viewed as dichotomous (measurable/not measurable), and the estradiol results should be interpreted with caution. There was little relation of the androgens to the lipid values. Univariate analyses suggested a direct relation between total cholesterol, low density lipoprotein cholesterol, and triglyceride levels with estradiol. An inverse relation was suggested between serum estrone and estradiol and total high density lipoprotein (HDL) cholesterol and HDL2 cholesterol, although none of these associations were statistically significant. Multiple regression analyses revealed that the primary determinant of the HDL cholesterol and triglyceride levels was the degree of obesity as estimated by the body mass index (weight (kg)/height (m)2). Addition of estrone or estradiol to the models did not contribute to the prediction of lipid levels. These results do not support the hypothesis of there being a relation between endogenous sex hormone levels and lipid levels in postmenopausal women. The results suggest that sex hormones cannot explain the sex difference in lipid levels and may not contribute to the rise in coronary heart disease that occurs in women around menopause.

Relationship of endogenous sex steroid hormones to lipids and apoproteins in postmenopausal women.

The relationships between blood levels of estrogen and lipoprotein lipids and apoproteins were evaluated in 120 women early in the climacteric. Among women who were 1-year amenorrheic, not taking hormone replacement therapy, and with follicle-stimulating hormone levels greater than 720 ng/ml, serum estradiol levels were positively related to concentrations of the high density lipoprotein 2 cholesterol (HDL2c) subfraction. There was a substantial decrease in HDL2c and apoprotein (apo) A-I in women whose estradiol levels decreased to less than or equal to 2.5 pg/ml from the first to the second postmenopausal examination. In a sample of women evaluated during the perimenopause (3-months' amenorrheic), those with the highest concentrations of estradiol or estrone showed a (nonsignificantly) higher level of HDL2c and a lower level of low density lipoprotein cholesterol (LDLc) than did those with the lowest concentration of estradiol or estrone. Estradiol levels declined dramatically between the perimenopausal and the postmenopausal examinations, and this was accompanied by a decrease in HDL2c and a nonsignificant increase in LDLc. HDL2c levels fell substantially in those women whose estradiol decreased below the sensitivity of the assay. The change, however, was not statistically significant. Estrone is the primary postmenopausal estrogen, and levels are directly related to obesity, as are levels of insulin. The interrelationship among obesity, conversion of estrone to estradiol at the tissue level, and insulin (or insulin sensitivity) is probably the primary determinant of HDLc concentration among postmenopausal women.

The epidemiology of serum sex hormones in postmenopausal women.

Serum sex hormones may be related to the risk of several diseases in postmenopausal women. In the current report, the authors examined the epidemiology of serum sex hormones in 176 healthy, white postmenopausal women (mean age 58 years) recruited from the metropolitan Pittsburgh, Pennsylvania, area. The data were collected during 1982-1983; none of the women were on estrogen replacement therapy. Serum concentrations of estrone, estradiol, testosterone, and androstenedione were measured by a combination of extraction, column chromatography, and radioimmunoassay. Neither age nor time since menopause was a significant predictor of sex hormones. The degree of obesity was a major determinant of estrone and estradiol. The estrone levels of obese women were about 40% higher than the levels of nonobese women. There was a weak relation between obesity and the androgens. Cigarette smokers had significantly higher levels of androstenedione than nonsmokers, with little difference in serum estrogens between smokers and nonsmokers. Both estrone and estradiol levels tended to decline with increasing alcohol consumption. Physical activity was an independent predictor of serum estrone. More active women had lower levels of estrone. There was a positive relation of muscle strength with estrogen levels. The data suggest interesting relations between environmental and lifestyle factors and serum sex hormones. These environmental and lifestyle factors are potentially modifiable and, hence, if associations between sex hormones and disease exist, modification of these factors could affect disease risks.

Endogenous estrogen levels and calcium intakes in postmenopausal women. Relationships with cortical bone measures.

To examine the interactions between hormone levels and calcium with cortical bone, we have attempted to combine risk factors for the development of peak skeletal mass with factors that may be related to the maintenance of bone integrity after menopause. A total of 174 postmenopausal women participated in our study. There was little relationship found between androgen hormones and radial bone density. Estrone levels were independently related to radial bone density. Examination of the relationship of calcium intake to bone revealed a protective effect solely in women who reported high "lifetime" calcium intakes. Taking calcium and estrone together revealed an additive relationship between the two factors, in that women with high estrone and high calcium levels had significantly greater bone density than women with less calcium and/or estrone. The results suggest that a lifetime of adequate calcium intake coupled with adequate levels of serum estrogens could maximize bone density after menopause.

Cigarette smoking and serum sex hormones in men.

The relation between cigarette smoking and serum sex hormone concentrations was examined in two samples of the Multiple Risk Factor Intervention Trial (MRFIT) population. One sample consisted of 121 men at the Pittsburgh, Pennsylvania MRFIT center who were followed longitudinally for four years. The other sample was drawn from the entire MRFIT cohort and consisted of 163 MRFIT participants who subsequently developed coronary heart disease and 163 matched controls. The results indicated a positive correlation between cigarette smoking and serum total androstenedione concentration. The association was independent of age, relative weight, alcohol drinking, blood pressure, and high density lipoprotein (HDL) cholesterol. Serum total and free testosterone concentrations were positively correlated with cigarette smoking among the longitudinal sample and the controls, but not for the baseline sera from the coronary heart disease cases. This positive correlation was also independent of age, relative weight, alcohol drinking, blood pressure, and HDL cholesterol. There was no association between either serum estradiol or estrone concentrations and cigarette smoking in this population. These observations may have important implications for epidemiologic studies of diseases with significant smoking relations.