Sex differences in the association of endogenous sex hormone levels and glucose tolerance status in older men and women.

OBJECTIVE: Some evidence suggests an inverse association between type 2 diabetes and androgens in men and a positive association between type 2 diabetes and androgens in women. The purpose of this community-based study was to evaluate sex differences in the association between endogenous total and bioavailable estrogen and testosterone levels and glucose tolerance status. RESEARCH DESIGN AND METHODS: We included in this study 775 men and 633 postmenopausal non-estrogen-using women, all > or =55 years of age (mean ages 72 and 75 years, respectively). A 75-g oral glucose tolerance test (OGTT) was administered to fasting subjects from 1984 to 1987, when sera were frozen for measurement of total and bioavailable hormone levels. Total testosterone and estradiol levels were measured by radioimmunoassay, and bioavailable hormone levels were determined using a modified ammonium-sulfate precipitation method. The association between steroid hormones and glucose tolerance status was tested. RESULTS: In sex-specific age- and BMI-adjusted analyses, men with impaired glucose tolerance (IGT) had significantly lower total testosterone levels. Women with IGT or type 2 diabetes had significantly higher bioavailable testosterone and total and bioavailable estradiol levels than those with normal glucose tolerance. Total testosterone and fasting plasma glucose were inversely associated in men (P = 0.0001), whereas bioavailable testosterone and estradiol were positively associated with fasting plasma glucose in women (P = 0.0001 and 0.001, respectively). CONCLUSIONS: Additional studies are needed to further develop the hormone-diabetes connection.

Sex hormone-binding globulin and glucose tolerance in postmenopausal women. The Rancho Bernardo Study.

OBJECTIVE: Sex hormone-binding globulin (SHBG) has been shown to be associated with several diabetes risk factors, including total body fat, central obesity, and hyperinsulinemic insulin resistance. We examined the cross-sectional association between SHBG and impaired glucose tolerance (IGT) and NIDDM. RESEARCH DESIGN AND METHODS: We conducted a cross-sectional study including 657 postmenopausal women, aged > or = 50 years, who were not using hormone replacement therapy. Blood for SHBG and fasting plasma glucose was obtained concurrently in the morning; all women had a 75-g oral glucose tolerance test and measurement of BMI and waist-to-hip ratio (WHR). RESULTS: SHBG was significantly associated with age, BMI, and WHR but not with smoking, physical activity, or alcohol intake. In these women, SHBG was significantly and independently inversely associated with IGT and with NIDDM. CONCLUSIONS: These data strongly support an association between SHBG, or androgenicity, and diabetes in postmenopausal women. Because of the cross-sectional nature of this study, however, the directionality of the association is uncertain.

Gender differences in insulin-like growth factor and bone mineral density association in old age: the Rancho Bernardo Study.

Insulin-like growth factor-I (IGF-I) clearly plays a role in bone metabolism and maintenance, as evidenced by in vitro and animal studies. In clinical studies, the age-related decrease in IGF-I parallels the age-related decrease in bone mineral density (BMD), but several age-adjusted cross-sectional studies show no consistent association of IGF-I and BMD. We report here a cross-sectional study of serum IGF-I and BMD levels in 483 men and 455 postmenopausal women not using estrogen; subjects were 55 years of age and older, community-dwelling, ambulatory, and unselected for bone density. IGF-I was measured by a highly specific radioimmunoassay. BMD was measured at the lumbar spine and hip using dual-energy X-ray absorptiometry. Men had higher IGF-I and BMD levels than women. In age-adjusted and age-stratified models, IGF-I was associated with BMD only in women (test for interaction, p < 0.0001). Gender differences persisted in gender-specific multiple regression analyses adjusted for age, body mass index, thiazide diuretic use, current smoking, alcohol intake, physical activity, and weight change; IGF-I was significantly associated with BMD at the spine (p = 0.0001) and hip (p = 0.02) in women, but not in men (p's > 0.6). Circulating estradiol levels were not associated with IGF-I levels in either gender, testosterone was inversely associated with IGF-I and only in men. This striking gender difference has not been described previously. Its etiology is unknown. The answer could lead to improved understanding of gender differences in osteoporosis and in response to treatment with IGF-I or growth hormone.

A prospective study of sex hormone-binding globulin and fatal cardiovascular disease in Rancho Bernardo men and women.

Sex hormone-binding globulin (SHBG) has been shown to be associated with several cardiovascular disease (CVD) risk factors. We examined the prospective association between SHBG and the risk of CVD and ischemic heart disease (IHD) death in 760 men and 624 women, aged 50-82 yr, who were free of heart disease at baseline. Health status and cause of death were determined annually for 99.9% of the cohort for 19 yr. SHBG correlated negatively with body mass index in both sexes and increased with age in men. After adjusting for age and body mass index, SHBG correlated negatively with fasting plasma glucose in men and women and with total cholesterol and triglycerides in men. There were 235 CVD and 134 IHD deaths in men and 153 CVD and 80 IHD deaths in women over the 19-yr follow-up. The quintile of baseline SHBG was unrelated to CVD or IHD mortality rate. No association was found in sex-specific, multiply-adjusted Cox proportional hazard models. All risk ratios were close to 1, and 95% confidence intervals were narrow and included 1. Although associated with several strong heart disease risk factors, the SHBG level does not predict CVD or IHD mortality in men or women.

Effect of replacement estrogen on insulin-like growth factor-I in postmenopausal women: the Rancho Bernardo Study.

Insulin-like growth factor-I (IGF-I) is associated with protein, carbohydrate, and bone metabolism. Results of previous studies examining the effect of exogenous estrogen on levels of IGF-I have been inconsistent. We examined the cross-sectional association between serum IGF-I levels and hormone replacement therapy (HRT) use in 672 postmenopausal women aged 50 yr and older. The mean age-adjusted IGF-I level was highest in the 415 women who reported never or past HRT use (126.8 micrograms/L), lowest in the 128 women who reported using estrogen alone (99.3 micrograms/L), and intermediate in the 115 women who reported using combination estrogen and progesterone (112.4 micrograms/L). A significant linear decline in mean age-adjusted IGF-I levels by duration of HRT use among all current users was seen. The decrease in serum IGF-I with current use of HRT is not consistent with the fact that both HRT and increased levels of IGF-I have been associated with improved glucose and bone metabolism and lipid profile. Further research is needed to evaluate the effect of the addition of a progestin to oral HRT on IGF-I-induced changes in GH levels.

Endogenous sex hormones and cognitive function in older men.

The objective of this study was to determine whether endogenous sex hormone levels predict cognitive function in older men. Our study design was an exploratory analysis in a population-based cohort in Rancho Bernardo, California. The study participants were 547 community-dwelling men 59-89 yr of age at baseline who were not using testosterone or estrogen therapy. Between 1984 and 1987, sera were collected for measurement of endogenous total and bioavailable testosterone and estradiol levels. Between 1988 and 1991, 12 standard neuropsychological instruments were administered, including two items from the Blessed Information-Memory-Concentration (BIMC) Test, three measures of retrieval from the Buschke-Fuld Selective Reminding Test, a category fluency test, immediate and delayed recall from the Visual Reproduction Test, the Mini-Mental State Examination with individual analysis of the Serial Sevens and the "World" Backwards components, and the Trail-Making Test Part B. In age- and education-adjusted analyses, men with higher levels of total and bioavailable estradiol had poorer scores on the BIMC Test and Mini-Mental State Examination. Men with higher levels of bioavailable testosterone had better scores on the BIMC Test and the Selective Reminding Test (long-term storage). Five associations were U-shaped: total testosterone and total and bioavailable estradiol with the BIMC Test; bioavailable testosterone with the "World" test; and total estradiol with the Trail-Making Test. All associations were relatively weak but independent of age, education, body mass index, alcohol use, cigarette smoking and depression. In these older men, low estradiol and high testosterone levels predicted better performance on several tests of cognitive function. Linear and nonlinear associations were also found, suggesting that an optimal level of sex hormones may exist for some cognitive functions.

Cognitive function and endogenous sex hormones in older women.

OBJECTIVE: To determine if endogenous hormone levels predict cognitive function in older women. DESIGN: A longitudinal, population-based study. SETTING: Rancho Bernardo, California PARTICIPANTS: A total of 393 community-dwelling women aged 55 to 89 years who were not using replacement estrogen. METHODS: Between 1984 and 1987, sera were collected for measurement of total and bioavailable testosterone, total and bioavailable estradiol, and estrone. Between 1988 and 1991, 12 standard neuropsychological tests were administered, including two items from the Blessed Information-Memory-Concentration Test, three measures of retrieval from the Buschke-Fuld Selective Reminding Test, a category fluency test, immediate and delayed recall from the Visual Reproduction Test, the Mini-Mental State Examination (MMSE) with individual analysis of the Serial 7's and the "World" Backwards components, and the Trail-Making Test part B (Trails B). The association between the five hormones and the 12 cognitive function tests was tested in age- and education-adjusted analyses using linear regression, partial correlation, quintile and categorical analyses. RESULTS: Women with better MMSE scores (>23) had significantly higher adjusted mean total and bioavailable testosterone levels (P = .009; P = .02, respectively). Using linear regression, the mean total testosterone was significantly associated with better performance on the World component of the MMSE (b = .12; P = .08). With regard to estrogen, the only statistically significant (P = .02) association was better performance on one test in women with very low levels of estradiol. CONCLUSIONS: In these older women, higher endogenous estrogen levels were not associated with significantly better performance on any cognitive function test. In contrast, higher levels of testosterone predicted better categorical performance on the MMSE and the World component of the MMSE. These novel findings warrant further research.

Ability of fat and fat-free mass percentages to predict functional disability in older men and women.

OBJECTIVES: Previous studies suggest an association between body composition and declining functional ability in older people. This study examined the relation between functional disability and percentage of fat mass (FM) and percentage of fat-free mass (FFM) in older men and women. DESIGN: Cross-sectional and prospective. SETTING: Rancho Bernardo, California. PARTICIPANTS: Subjects consisted of 1,051 ambulatory, community-dwelling Caucasian men and women, age 55 to 92, who attended a clinic visit between 1988 and 1992 and a subsequent clinic visit between 1992 and 1996. MEASUREMENTS: Measured at both visits, percentage of fat mass and percentage of lean body mass were estimated by bioelectric impedance analysis and functional disability was ascertained by self-administered questionnaire. Functional disability was dichotomized into those having any difficulty with a set of tasks versus those having no difficulty with the tasks. Two measures of functional disability were used: "lower body" disability, consisting of two lower motor tasks (walking 2-3 blocks and climbing up 10 stairs) and "overall" disability, consisting of nine tasks representing upper and lower body function and mobility. RESULTS: Compared with men, women were more likely to report both lower body and overall functional disability (P=.001). Cross-sectionally, a significant positive association was shown between fat mass and overall functional disability and a significant negative association was shown between FFM and overall functional disability in both men and women. Prospectively, increased percentage of body fat and decreased percentage of FFM were significantly associated with decreased functional ability in both women and men. All results were adjusted for age, smoking, alcohol use, physical activity, current estrogen use, depression, chronic disease, and education. CONCLUSION: Increased percentage of fat mass and decreased percentage of FFM are associated with greater functional disability in older men and women. Further research is needed to assess the relative importance of decreasing fat percentage or increasing fat-free percentage to preserve or improve functional ability in older people.

The epidemiology of DHEAS and cardiovascular disease.

In 1986 we reported that high levels of plasma dehydroepiandrosterone sulfate (DHEAS) reduced the risk of fatal cardiovascular disease (CVD) in 242 men and increased the risk in 289 women from the Rancho Bernardo cohort who were followed up for 12 years. We report here an update on the epidemiology of DHEAS and CVD based on a 19-year follow-up of 1,029 men and 942 women aged 30-88 years from the same cohort. In cross-sectional analyses, DHEAS levels decreased with age in both sexes and were lower in women than men. Men who were overweight were more likely to have low DHEAS levels; women who had hypercholesterolemia or hypertension or were nonusers of estrogen therapy had higher DHEAS levels. Alcohol intake and cigarette smoking were associated with higher DHEAS levels in both sexes. All differences were no longer statistically significant after adjusting for alcohol intake. All participants were followed for vital status. After 19 years there were 254 CVD deaths in men and 199 CVD deaths in women. DHEAS was not associated with CVD or ischemic heart disease (IHD) deaths in age-adjusted analyses where the comparison group was individuals without CVD or IHD death. In contrast, when the comparison group was survivors, multiply adjusted models showed a statistically significant, modestly reduced risk of fatal CVD (RR = 0.85) in men and a nonsignificant increased risk of fatal CVD (RR = 1.11) in women.

Prospective study of endogenous sex hormones and fatal cardiovascular disease in postmenopausal women.

OBJECTIVES: To examine the association between androstenedione, total and bioavailable testosterone, oestrone, and total and bioavailable oestradiol concentrations and the risk of death from cardiovascular and ischaemic heart disease. DESIGN: 19 year old population based prospective study with 99.9% follow up. SETTING: Rancho Bernardo, California. SUBJECTS: 651 postmenopausal women, none taking oestrogen. MAIN OUTCOME MEASURES: Concentrations of plasma sex hormones measured by radioimmunoassay in an endocrinology research laboratory. Cardiovascular and ischaemic heart disease deaths assessed by death certificate; 85% of 30% sample validated by record review. RESULTS: Age adjusted concentrations of sex hormones did not differ significantly in women with and without a history of heart disease at baseline and did not predict cardiovascular death or death from ischaemic heart disease. Most 95% confidence intervals for the age adjusted relative risk of cardiovascular death or death from ischaemic heart disease were narrow, and all included one. Endogenous oestrogen concentrations were not associated with significantly more favourable risk factors for heart disease, and testosterone was not associated with less favourable risk factors. CONCLUSION: These prospective data do not support a causal or preventive role for endogenous oestrogens or androgens and cardiovascular mortality in older women.

Dehydroepiandrosterone sulfate does not predict cardiovascular death in postmenopausal women. The Rancho Bernardo Study.

BACKGROUND: High levels of dehydroepiandrosterone sulfate (DHEAS) appear to be associated with a reduced risk of fatal cardiovascular disease (CVD) in men. We examined the association between baseline DHEAS levels and the 19-year CVD and ischemic heart disease (IHD) mortality rates in 942 postmenopausal women free of known heart disease at baseline. METHODS AND RESULTS: The 199 CVD deaths and 102 IHD deaths were not related to baseline DHEAS levels. DHEAS was not related to body mass index, fasting plasma glucose, or family history of coronary heart disease, but significantly higher DHEAS levels were found in women who had elevated total or HDL cholesterol or blood pressure, were current smokers, or were nonusers of estrogen replacement therapy. After we adjusted for age, cholesterol, blood pressure, smoking, estrogen replacement therapy, obesity, fasting plasma glucose, and family history of heart disease, the relative risk of fatal CVD and IHD was 1.11 (95% confidence interval, 0.81 to 1.23) and 0.92 (95% confidence interval, 0.85 to 1.17), respectively, for a 50-microgram/dL decrease in DHEAS. CONCLUSIONS: Although higher DHEAS levels were associated with several major CVD risk factors, they were unrelated to the risk of fatal CVD in women.

Total but not bioavailable testosterone is a predictor of central adiposity in postmenopausal women.

OBJECTIVE: In pre and postmenopausal women low levels of sex hormone binding globulin (SHBG) have been shown to be associated with a large waist-hip ratio (WHR), a measure of visceral adiposity. Previous studies of WHR and testosterone, however, have been inconclusive. DESIGN: We examined the prospective association between endogenous total and bioavailable testosterone and SHBG levels at baseline with WHR measured 12-15 years later in a community-based cohort of older women. SETTING: Rancho Bernardo, California. SUBJECTS: 334 postmenopausal women. MAIN OUTCOME MEASURES: Endogenous total and bioavailable testosterone and SHBG levels and WHR. RESULTS: Only age-adjusted SHBG levels and the testosterone/SHBG ratio were associated with BMI. Age-adjusted SHBG levels and total testosterone decreased with increasing WHR. Neither measured nor estimated (testosterone/SHBG ratio) bioavailable testosterone was associated with WHR before or after adjustment for age, BMI, and cigarette smoking. CONCLUSION: These prospective data confirm the reported cross-sectional association between SHBG and WHR, but show no association with measured bioavailable testosterone or the testosterone/SHBG ratio. These findings do not support the premise that androgens cause visceral adiposity in postmenopausal women.

Epidemiology of insulin-like growth factor-I in elderly men and women. The Rancho Bernardo Study.

Insulin-like growth factor-I (IGF-I) is abundant in the circulation and has been shown to have a wide array of biologic effects. The authors carried out a cross-sectional community-based study of 420 men and 419 nonestrogen-using postmenopausal women aged 50-97 years to ascertain the within-person and laboratory reliability of IGF-I measurements, and the association of IGF-I with common epidemiologic confounders. There was no evidence of seasonal or diurnal variation. IGF-I decreased linearly with age in both sexes, with significantly higher levels in men than women (134.1 microg/liter vs. 126.9 microg/liter; p = 0.03) [corrected]. In age-adjusted analyses, IGF-I was not associated with height, total or central body fat, lean body mass, current smoking, physical activity, or commonly used medications. By contrast, in both men and women who reported any alcohol use, IGF-I levels were significantly higher compared with those in men and women who reported no alcohol use, and alcohol as a continuous variable showed a significant positive linear trend in men (p = 0.0007). The authors conclude that IGF-I varied significantly only with age, sex, and alcohol use. The minimal number of confounding variables, good reliability, and little intraindividual variation suggest that IGF-I should be suitable for epidemiologic research.

Sex differences in measures of body fat and body fat distribution in the elderly.

This study describes sex differences in obesity and body fat distribution using commonly used assessment methods in 140 men and 245 women age 65-96 years from Rancho Bernardo, California. Significant correlations were shown among all obesity measures. The waist/hip ratio was more strongly correlated with the truncal fat/leg fat ratio in women than in men. The waist/hip ratio correlated significantly with the subscapular/ triceps skinfold ration in women only. In both sexes, waist circumference was more strongly correlated with body mass index and the percentage of body fat by bioelectric impedance analysis and dual-energy X-ray absorptiometry than with the waist/hip ratio. In those aged over 80 years, age stratification showed that the waist/hip ration was not correlated with any other measurement of obesity or fat distribution in men and correlated only with subscapular skinfolds in women. Waist circumference, however, correlated significantly with almost all other measures of central obesity in older and younger men and women. Estimates of upper body (central) fat distribution appear to be age specific. After age 80, the waist/hip ratio is a poor method of assessing central or visceral adiposity, and waist circumference is a better measure of body fat distribution.

The Prevalence of von Willebrand disease in women with abnormal uterine bleeding.

Although a common symptom of von Willebrand disease is menorrhagia or metrorrhagia, the prevalence of this inherited bleeding disorder in women with heavy bleeding is not known. This pilot study compared the prevalence rate of von Willebrand disease in women with dysfunctional uterine bleeding with the prevalence rate in the general population. On average, these women bled for 11.5 days per month and experienced heavy bleeding for >16 years. Over 60% had been treated previously for heavy bleeding. One woman was diagnosed with type 1 von Willebrand disease (5% prevalence rate). Larger studies are needed to confirm this increased rate of von Willebrand disease in women with abnormal uterine bleeding.

Usual dietary isoflavone intake is associated with cardiovascular disease risk factors in postmenopausal women.

Intervention data suggest a cardioprotective role for supplemental isoflavones; however, few studies have examined the cardiovascular disease (CVD) benefit of usual dietary isoflavone intake. This cross-sectional study examined the association between usual dietary isoflavone intake and CVD risk factors, including lipids and lipoproteins, body mass index (BMI) and fat distribution, blood pressure, glucose and insulin. Subjects were postmenopausal women (n = 208) aged 45-74 y, who attended screening and baseline visits for a randomized, double-blind, placebo-controlled trial examining the effects of isoflavone use. At screening, total cholesterol, triglycerides, HDL cholesterol and LDL cholesterol were measured, and demographic, behavioral and menopausal characteristics were assessed. One month later, dietary intake over the past year was assessed with a standardized questionnaire. Anthropometric measurements and blood pressure were obtained, and a 75-g oral glucose tolerance test was administered. Isoflavone consumption did not vary by age, exercise, smoking, education or years postmenopausal. Women with high genistein intake had a significantly lower BMI (P-trend = 0.05), waist circumference (P-trend = 0.05) and fasting insulin (P-trend = 0.07) than those with no daily genistein consumption. In adjusted analyses, genistein, daidzein and total isoflavone intake were each positively associated with HDL cholesterol (P = 0.05) and inversely associated with postchallenge insulin (P = 0.05). These data suggest a protective role for dietary soy intake against CVD in postmenopausal women.

The effect of postmenopausal estrogen therapy on the risk of non-insulin-dependent diabetes mellitus.

OBJECTIVES: This study examined the effect of postmenopausal estrogen replacement therapy on the incidence of non-insulin-dependent diabetes in women. METHODS: Postmenopausal women aged 50 through 70 years (n=848) without diagnosed diabetes at baseline were followed for 10 to 15 years for incident diabestes. RESULTS: Over the average 11.5 year follow-ip, there were 105 new cases of diabetes. The age-adjusted relative-risk for development of diabetes was nonsignificantly lower for women with continuous estrogen replacement therapy use than for never users. After adjustment for major covariates, a nonsignificant linear trend with increasing duration of estrogen replacement therapy was reversed. CONCLUSIONS: This study suggests that previous results showing a reduced risk of diabetes in women using estrogen may have been due to selection bias regarding who is prescribed estrogen, confounding factors, or differential diagnostic efforts.

Cumulative duration of breast-feeding influences cortisol levels in postmenopausal women.

Cortisol levels dramatically increase during pregnancy, peak at birth, and subsequently decline. However, all previous studies examined women during pregnancy and early postpartum. None examined the long-term association of parity and lactation with cortisol levels. We examined the relation of reproductive history to cortisol levels in postmenopausal women. Subjects were 749 women, aged 50-89, who were not using estrogen in 1984-1987 when morning cortisol was measured. Parity was not significantly associated with cortisol. However, women who breast-fed for >12 months had significantly higher cortisol levels than women who breast-fed for shorter durations or not at all (p = 0.003). This association was stronger among women with three or more births. Duration of breast-feeding is a determinant of cortisol levels in postmenopausal women. Because both increased cortisol and increased duration of breast-feeding may play protective roles in certain autoimmune diseases, such as rheumatoid arthritis, we suggest that the beneficial effect of lactation on the course of these diseases may be mediated by cortisol.