Sex and Age Differences in the Association of Blood Pressure and Hypertension with Cognitive Function in the Elderly: The Rancho Bernardo Study.

OBJECTIVES: This study examines sex and age differences in associations of systolic and diastolic blood pressure (SBP, DBP), pulse pressure and hypertension with cognitive function in a community-dwelling population. DESIGN: Cross-sectional study. SETTING: Research clinic visit in 1988-91. PARTICIPANTS: Participants were 693 men and 1022 women aged 50-97 Measurements: Blood pressure was measured and 12 cognitive function tests were administered. RESULTS: Average age was 73.8±9.9 in men and 73.2±9.3 in women; 62.6% of men and 63.4% of women were hypertensive (SBP≥140 mmHg, DBP≥90 mmHg, or antihypertensive medication use). Each 5-unit increment in SBP, DBP, or pulse pressure and categorical hypertension was associated with significantly increased odds of poor verbal fluency performance in men and poor Trails B performance in women, with strongest associations for hypertension (OR=1.97, CI:1.01,3.85 in men; OR=1.51, CI:1.01,2.26 in women). After age stratification, associations remained statistically significant in younger (<80 years ) but not older (≥80 years) participants. CONCLUSION: Blood pressure as a continuous or categorical variable was associated with poor performance on cognitive function tests, but domains varied by sex and associations were found only in those younger than 80 years. The absent associations in those aged 80 years and older could support the hypothesis that increased blood flow is required to maintain cerebral perfusion with advancing age, or could reflect a survivor effect.

Association between Dietary Sodium Intake and Cognitive Function in Older Adults.

OBJECTIVE: To examine the association of dietary sodium intake with cognitive function in community-dwelling older adults. DESIGN: Cross-sectional study. SETTING: Southern California community. PARTICIPANTS: White men (n=373) and women (n=552), aged 50-96 years from the Rancho Bernardo Study, a longitudinal study of cardiovascular disease risk factors and healthy aging. MEASUREMENTS: During the 1992-1996 research clinic visit, a food frequency questionnaire was used to determine daily sodium intake; cognitive function was assessed with Trails Making Test, part B (Trails B), Mini-Mental State Exam (MMSE), and Verbal Fluency Test (VFT); and medical, clinical and demographic information was obtained. Linear regression was used to assess the association between calorie-adjusted sodium intake and cognitive test scores with adjustment for demographic, behavioral and health measures. Logistic regression examined the odds of having cognitive impairment by sodium intake. RESULTS: Lower sodium intake was associated with poorer performance on Trails B (p=0.008) and MMSE (p=0.003) after controlling for age, sex, and education. Associations did not differ by sex, but there was a significant interaction by age for the Trails B: older (≥80 years), but not younger, adults showed worse performance with lower sodium intake (p=0.03). Associations remained significant after additional adjustment for smoking, alcohol intake, exercise, body weight, cardiovascular risk factors, kidney function, diuretic medication use, and diet quality. Lower daily sodium intake was associated with increased odds of cognitive impairment on the MMSE (score < 26; OR per SD decrease = 1.12, 95% CI 1.08, 1.16). Concluson: Lower sodium intake was associated with worse cognitive function in older community-dwelling adults. For the maintenance of cognitive health, older adults may be advised to avoid very low sodium diets.

Blood pressure trajectories in relation to cardiovascular mortality: The Rancho Bernardo Study.

The added value of blood pressure (BP) trajectories for predicting cardiovascular disease (CVD) is currently unknown. We investigated the association of systolic BP (SBP) trajectories with CVD and all-cause mortality and compared these associations with those of average SBP, taking antihypertensive medication into account. Data from 762 participants of the Rancho Bernardo Study were used. SBP from five examinations (maximum) from 1984 to 2002 was used; mortality data were obtained from 2002 to 2013. SBP trajectories were derived using group-based trajectory modelling. Cox proportional hazards analysis was used to investigate associations of trajectories and average SBP with CVD and all-cause mortality, adjusted for age, sex, cholesterol, smoking, diabetes and antihypertensive medication. Mean baseline age was 65.7 years, and 67% were women. Four trajectories were identified, in which mean SBP increased by 5-12 mm Hg during 10 years. The highest trajectories were associated with two to three times greater CVD mortality and 1.5 times greater all-cause mortality risk, compared with the lowest trajectory. Each 20 mmHg increment in average SBP was associated with 1.4 times greater CVD mortality risk and 1.2 times all-cause mortality risk. Associations were not modified by antihypertensive medication (P-interaction>0.10). SBP trajectories were not superior to average SBP in predicting CVD and all-cause mortality. In the general middle-aged and older population of the Rancho Bernardo study, SBP trajectories provided no added value to average SBP in predicting CVD and all-cause mortality. Long-term average SBP levels and trajectories were significant predictors of CVD and all-cause mortality, irrespective of prescribed antihypertensive medication (which in the 1980s-1990s mainly were diuretics and ß-blockers).

Moderate, Regular Alcohol Consumption is Associated with Higher Cognitive Function in Older Community-Dwelling Adults.

BACKGROUND: Evidence suggests that moderate alcohol consumption may protect against cognitive decline and dementia. However, uncertainty remains over the patterns of drinking that are most beneficial. OBJECTIVE: To examine associations between amount and frequency of alcohol consumption with multiple domains of cognitive function in a well-characterized cohort of older community-dwelling adults in southern California. DESIGN: Observational, cross-sectional cohort study. SETTING: A research visit between 1988-1992 in Rancho Bernardo, California. PARTICIPANTS: 1624 participants of the Rancho Bernardo Study (mean age ± SD = 73.2 ± 9.3 years). Measurements: Participants completed a neuropsychological test battery, self-administered questionnaires on alcohol consumption and lifestyle, and a clinical health evaluation. We classified participants according to average amount of alcohol intake into never, former, moderate, heavy and excessive drinkers, and according to frequency of alcohol intake, into non-drinkers, rare, infrequent, frequent and daily drinkers. We examined the association between alcohol intake and cognitive function, controlling for age, sex, education, exercise, smoking, waist-hip ratio, hypertension and self-assessed health. RESULTS: Amount and frequency of alcohol intake were significantly associated with cognitive function, even after controlling for potentially related health and lifestyle variables. Global and executive function showed positive linear associations with amount and frequency of alcohol intake, whereas visual memory showed an inverted U-shaped association with alcohol intake, with better performance for moderate and infrequent drinkers than for non-drinkers, excessive drinkers or daily drinkers. CONCLUSIONS: In several cognitive domains, moderate, regular alcohol intake was associated with better cognitive function relative to not drinking or drinking less frequently. This suggests that beneficial cognitive effects of alcohol intake may be achieved with low levels of drinking that are unlikely to be associated with adverse effects in an aging population.

Steroid hormone measurements from different types of assays in relation to body mass index and breast cancer risk in postmenopausal women: Reanalysis of eighteen prospective studies.

Epidemiological studies have examined breast cancer risk in relation to sex hormone concentrations measured by different methods: "extraction" immunoassays (with prior purification by organic solvent extraction, with or without column chromatography), "direct" immunoassays (no prior extraction or column chromatography), and more recently with mass spectrometry-based assays. We describe the associations of estradiol, estrone and testosterone with both body mass index and breast cancer risk in postmenopausal women according to assay method, using data from a collaborative pooled analysis of 18 prospective studies. In general, hormone concentrations were highest in studies that used direct assays and lowest in studies that used mass spectrometry-based assays. Estradiol and estrone were strongly positively associated with body mass index, regardless of the assay method; testosterone was positively associated with body mass index for direct assays, but less clearly for extraction assays, and there were few data for mass spectrometry assays. The correlations of estradiol with body mass index, estrone and testosterone were lower for direct assays than for extraction and mass spectrometry assays, suggesting that the estimates from the direct assays were less precise. For breast cancer risk, all three hormones were strongly positively associated with risk regardless of assay method (except for testosterone by mass spectrometry where there were few data), with no statistically significant differences in the trends, but differences may emerge as new data accumulate. Future epidemiological and clinical research studies should continue to use the most accurate assays that are feasible within the design characteristics of each study.

Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies.

BACKGROUND: Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood. METHODS: Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies. RESULTS: Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer. CONCLUSION: Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk.

Abdominal aortic diameter and vascular atherosclerosis: the Multi-Ethnic Study of Atherosclerosis.

OBJECTIVES: To gain insight into early mechanisms of aortic widening, we examined associations between the diameter of the abdominal aorta (AD) and cardiovascular disease (CVD) risk factors and biomarkers, as well as measures of subclinical atherosclerosis, in a multi-ethnic population. DESIGN: Cross-sectional cohort. METHODS: A total of 1926 participants (mean age 62, 50% women) underwent chest and abdomen scanning by computed tomography, ultrasound of the carotid arteries, and CVD risk factor assessment. AD was measured 5 cm above and at the bifurcation. RESULTS: In a model containing traditional CVD risk factors, biomarkers and ethnicity, only age (standardized ß = 0.97), male sex (ß = 1.88), body surface area (standardized ß = 0.92), current smoking (ß = 0.42), D-dimer levels (ß = 0.19) and hypertension (ß = 0.53) were independently and significantly associated with increasing AD (in mm) at the bifurcation; use of cholesterol-lowering medications predicted smaller AD (ß = -0.70) (P < 0.01 for all). These findings were similar for AD 5 cm above the bifurcation with one exception: compared to Caucasian-Americans, Americans of Chinese, African and Hispanic descent had significantly smaller AD 5 cm above the bifurcation (ß's = -0.59, -0.49, and -0.52, respectively, all P < 0.01), whereas AD at the bifurcation did not differ by ethnicity. Physical activity, alcohol consumption, diabetes and levels of IL-6, CRP and homocysteine were not independently associated with AD. Higher aortic and coronary artery calcium burden, but not common carotid artery intima-media thickness, were independently, but modestly (ß = 0.11 to 0.19), associated with larger AD. CONCLUSIONS: Incremental widening of the aortic diameter shared some, but not all, risk factors for occlusive vascular disease.

Effect of dehydroepiandrosterone supplementation on bone mineral density, bone markers, and body composition in older adults: the DAWN trial.

UNLABELLED: We present results of a randomized, placebo-controlled trial to examine the effect of 50 mg daily oral DHEA supplementation for one year on bone mineral density (BMD), bone metabolism and body composition in 225 healthy adults aged 55 to 85 years. INTRODUCTION: Dehydroepiandrosterone (DHEA) levels decline dramatically with age, concurrent with the onset of osteoporosis, suggesting a role for DHEA supplementation in preventing age-related bone loss. METHODS: We conducted a randomized, placebo-controlled trial to examine the effect of 50 mg daily oral DHEA supplementation for one year on bone mineral density (BMD), bone metabolism and body composition in 225 healthy adults aged 55 to 85 years. RESULTS: DHEA treatment increased serum DHEA and DHEA sulfate levels to concentrations seen in young adults. Testosterone, estradiol and insulin-like growth factor (IGF-1) levels increased in women (all p < 0.001), but not men, receiving DHEA. Serum C-terminal telopeptide of type-1 collagen levels decreased in women (p = 0.03), but not men, whereas bone-specific alkaline phosphatase levels were not significantly altered in either sex. After 12 months, there was a positive effect of DHEA on lumbar spine BMD in women (p = 0.03), but no effect was observed for hip, femoral neck or total body BMD, and no significant changes were observed at any site among men. Body composition was not affected by DHEA treatment in either sex. CONCLUSION: Among older healthy adults, daily administration of 50 mg of DHEA has a modest and selective beneficial effect on BMD and bone resorption in women, but provides no bone benefit for men.

Sex-specific determinants of serum adiponectin in older adults: the role of endogenous sex hormones.

OBJECTIVE: To assess the sex-specific association of adiponectin with multiple factors thought to influence its levels, with a special emphasis on endogenous sex hormones. DESIGN AND METHODS: A cross-sectional study of determinants of serum adiponectin in 873 men and 673 postmenopausal women, ages 50-92. Factors evaluated include age, body size, fat distribution, lifestyle (exercise, smoking, alcohol intake), insulin resistance, renal function and endogenous sex hormone levels (total and bioavailable testosterone and estradiol). RESULTS: Median serum adiponectin was 50% higher in women than men (P<0.001). In unadjusted analyses, adiponectin was positively related to age, alcohol intake, high-density lipoprotein (HDL) and testosterone, and negatively related to waist girth, body mass index, Homeostasis Model Assessment for Insulin Resistance (HOMA-IR), triglycerides and bioavailable estradiol in both sexes (all P<0.01). Adiponectin was positively related to blood urea nitrogen, a measure of renal function, in men only (P<0.001). Sex-specific multivariate linear regressions adjusting for HDL and triglycerides showed that only age, HOMA-IR and sex hormones independently predicted circulating adiponectin for both men and women. Higher levels of endogenous testosterone and lower bioavailable estradiol concentrations each predicted higher adiponectin; this was true for both sexes, and was not explained by differences in age, adiposity, alcohol intake, insulin resistance or lipoprotein levels. CONCLUSIONS: The association of adiponectin with the factors studied here is strikingly similar for men and women. Sex differences in circulating adiponectin levels in older adults cannot be explained by sex hormone regulation.

Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women.

BACKGROUND: Obesity is associated with increased breast cancer risk among postmenopausal women. We examined whether this association could be explained by the relationship of body mass index (BMI) with serum sex hormone concentrations. METHODS: We analyzed individual data from eight prospective studies of postmenopausal women. Data on BMI and prediagnostic estradiol levels were available for 624 case subjects and 1669 control subjects; data on the other sex hormones were available for fewer subjects. The relative risks (RRs) with 95% confidence intervals (CIs) of breast cancer associated with increasing BMI were estimated by conditional logistic regression on case-control sets, matched within each study for age and recruitment date, and adjusted for parity. All statistical tests were two-sided. RESULTS: Breast cancer risk increased with increasing BMI (P(trend) =.002), and this increase in RR was substantially reduced by adjustment for serum estrogen concentrations. Adjusting for free estradiol reduced the RR for breast cancer associated with a 5 kg/m2 increase in BMI from 1.19 (95% CI = 1.05 to 1.34) to 1.02 (95% CI = 0.89 to 1.17). The increased risk was also substantially reduced after adjusting for other estrogens (total estradiol, non-sex hormone-binding globulin-bound estradiol, estrone, and estrone sulfate), and moderately reduced after adjusting for sex hormone-binding globulin, whereas adjustment for the androgens (androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone) had little effect on the excess risk. CONCLUSION: The results are compatible with the hypothesis that the increase in breast cancer risk with increasing BMI among postmenopausal women is largely the result of the associated increase in estrogens, particularly bioavailable estradiol.

A comparison of palatal adaptation in acrylic resin denture bases using conventional and anchored polymerization techniques.

PURPOSE: The study investigated the effects of palatal depth and a resin anchoring system on the adaptation of denture base resin to the master cast after compression molding and heat polymerization. MATERIALS AND METHODS: Forty-eight virtually identical polymethyl methacrylate dentures were fabricated on master casts with either a deep or shallow palatal vault. One half of the master casts of each palate type were altered by the addition of anchoring holes along the posterior land area, as well as perpendicularly in the midsaggital area. Anchoring holes were made with a #8 round bur to a depth of 5 mm. Twenty-four hours after polymerization, the bases on their casts were sectioned at the posterior border and evaluated for degree of adaptation using a traveling microscope. Maladaptation at the interface of the denture base and master cast was measured at predetermined mediolateral locations. A split-plot analysis of variance (alpha = 0.05) was performed followed by a post-hoc Dunn Multiple Comparison Test. RESULTS: In general, depth of the palatal vault did not significantly influence denture palatal discrepancy (p =.0780), but the use of the anchoring system significantly reduced mean gap distances (p =.000). At lateral and midpalate locations, gap distances between the denture bases and their casts were reduced from approximately 0.3 mm to approximately 0.1 mm when the anchoring system was used. CONCLUSIONS: Mean gap distances for steep palate dentures were significantly less than shallow palate dentures at vestibule and lateral palate locations, and anchoring holes placed in an edentulous master cast along the posterior land area and at the midline significantly improved the adaptation of denture bases.

Cortisol circadian rhythms during the menstrual cycle and with sleep deprivation in premenstrual dysphoric disorder and normal control subjects.

BACKGROUND: In this study we extended previous work by examining whether disturbances in the circadian rhythms of cortisol during the menstrual cycle distinguish patients with premenstrual dysphoric disorder (PMDD) from normal control (NC) subjects. In addition, we tested the differential response to the effects of early and late partial sleep deprivation on cortisol rhythms. METHODS: In 15 PMDD and 15 NC subjects we measured cortisol levels every 30 min from 6:00 PM to 9:00 AM during midfollicular (MF) and late luteal (LL) menstrual cycle phases and also during a randomized crossover trial of early (sleep 3:00 AM-7:00 AM) versus late (sleep 9:00 PM-1:00 AM) partial sleep deprivation administered in two subsequent and separate luteal phases. RESULTS: In follicular versus luteal menstrual cycle phases we observed altered timing but not quantitative measures of cortisol secretion in PMDD subjects, compared with NC subjects: in the LL versus MF phase the cortisol acrophase was a mean of 1 hour earlier in NC subjects, but not in PMDD subjects. The effect of sleep deprivation on cortisol timing measures also differed for PMDD versus NC subjects: during late partial sleep deprivation (when subjects' sleep was earlier), the cortisol acrophase was almost 2 hours earlier in PMDD subjects. CONCLUSIONS: Timing rather than quantitative measures of cortisol secretion differentiated PMDD subjects from NC subjects both during the menstrual cycle and in response to early versus late sleep deprivation interventions.

Sexual dimorphism in the influence of advanced aging on adrenal hormone levels: the Rancho Bernardo Study.

In recent years, adrenal function and aging has been the subject of intense interest. This cross-sectional study examines age and gender differences in plasma levels of cortisol, dehydroepiandrosterone (DHEA), DHEA-sulfate (DHEAS), and the molar ratio of cortisol/DHEAS in 50-89-yr-old community-dwelling adults. Plasma hormone levels were assayed in samples obtained between 0730 h and 1100 h from 857 men and 735 nonestrogen-using, postmenopausal women. Hormone levels were stratified by 10-yr age groups and compared by two-factor (gender and age) ANOVA. Overall, age and BMI-adjusted DHEA and DHEAS [collectively DHEA(S)] levels were 40% lower and cortisol levels 10% higher in women than men, resulting in a 1.7-fold higher cortisol/DHEAS molar ratio for women (both, P < 0.001). Cortisol levels increased progressively (20% overall) with age in both men and women (both, P < 0.01). Although DHEA(S) levels declined 60% and the cortisol/DHEAS ratio increased 3-fold across the 40-yr age range for both men and women (all P < 0.001), the pattern of the change differed (all P < 0.01 for interaction). For men, DHEA(S) fell in a curvilinear fashion, with the degree of change decreasing with each decade. In contrast, DHEA(S) levels in women fell 40% from the 50s to 60s, were unvarying from 60-80 yr of age, and declined an additional 18% in the 80s. The cortisol/DHEAS ratio increased in a linear fashion for men, but was flat during the 60-80-yr age range for women. Despite these differences in the effect of aging, levels of DHEA(S) remained lower and cortisol and the cortisol/DHEAS ratio higher, in women than men throughout the 50-89-yr age range. These results were independent of adiposity, smoking, and alcohol consumption. In summary, among older, healthy adults DHEA(S) levels are lower and cortisol levels higher in women than men. The age-related decline in adrenal androgens persists into advanced age for both men and women, but exhibits a sexually dimorphic pattern. In contrast, cortisol levels in men and women show a parallel, linear increase with aging. These findings may have important implications for a host of age-related processes that exhibit gender differences, including brain function, bone metabolism, and cardiovascular disease.

Hysterectomy, oophorectomy, and endogenous sex hormone levels in older women: the Rancho Bernardo Study.

This study examines the cross-sectional association of hysterectomy and oophorectomy status, chronological age, and years since menopause with plasma levels of total and bioavailable testosterone and estradiol, androstenedione, estrone, and sex hormone-binding globulin (SHBG) in community-dwelling postmenopausal women who were not using estrogen replacement therapy. Six hundred and eighty-four women, aged 50-89 yr, were surveyed for hysterectomy and oophorectomy status and had plasma obtained between 1984-1987. Of these, 438 (67%) had not undergone hysterectomy or oophorectomy (intact), 123 (18%) reported hysterectomy with bilateral oophorectomy, and 123 (18%) reported hysterectomy with conservation of 1 or both ovaries. After adjustment for age and body mass index, both total and bioavailable testosterone levels were reduced by more than 40% (P < 0.001) in hysterectomized women with bilateral oophorectomy compared to those in intact women, with intermediate levels observed in hysterectomized women with ovarian conservation. Androstenedione levels were about 10% lower in hysterectomized women with or without ovarian conservation compared to those in intact women (P = 0.039). Total estradiol levels tended to be lower (P = 0.095) in bilaterally oophorectomized women. Levels of bioavailable estradiol, estrone, and SHBG did not differ by hysterectomy and oophorectomy status. Among intact women, total, but not bioavailable, testosterone levels increased with age (P = 0.015), reaching premenopausal levels for the 70-79 decade with relatively stable levels thereafter. Among oophorectomized women, total and bioavailable testosterone levels did not vary with age and were 40-50% lower than those in intact women throughout the 50-89 yr age range. Androstenedione levels decreased 27% and SHBG levels increased 30% (P < 0.001) with age in intact, but not oophorectomized, women. Levels of other hormones did not vary with age. Stratification by years since menopause or surgery yielded similar results. These results demonstrate that the postmenopausal ovary remains a critical source of androgen throughout the lifespan of older women. The clinical consequences of lower testosterone levels years after oophorectomy are unknown. Reconsideration of prophylactic oophorectomy and clinical trials to evaluate the effects of androgen replacement after oophorectomy are needed.

Low levels of estradiol are associated with vertebral fractures in older men, but not women: the Rancho Bernardo Study.

This longitudinal study included 288 postmenopausal women without estrogen use (median age, 72 yr) and 352 men (median age, 66 yr). All were community-dwelling, ambulatory, and Caucasian. Blood for hormone assays (total and bioavailable estradiol and testosterone, estrone, androstenedione, dihydrotestosterone, dehydroepiandrosterone, and dehydroepiandrosterone sulfate) was obtained in 1984-1987, and vertebral fractures were diagnosed from lateral spine radiographs obtained in 1992-1996. At least one vertebral fracture was found in 21% of women and 8% of men. Among men, age-adjusted hormone levels differed by fracture status only for total (64.1 vs. 75.4 pmol/L, P = 0.012) and bioavailable (43.0 vs. 51.4 pmol/L, P = 0.008) estradiol. There was a graded association between higher concentrations of total and bioavailable estradiol and lower fracture prevalence (trend P<0.01 for both hormones). Men with total testosterone levels compatible with hypogonadism (<7 nmol/L) were not more likely to have vertebral fractures. In women, none of the measured sex hormones was associated with vertebral fractures. There was also no increased prevalence of fractures in women with estradiol levels below the assay sensitivity (<11 pmol/L). These data suggest that estrogen plays a critical role in the skeletal health of older men and confirm other studies showing no association of postmenopausal endogenous estrogen levels with vertebral fractures in older women.

Endogenous levels of dehydroepiandrosterone sulfate, but not other sex hormones, are associated with depressed mood in older women: the Rancho Bernardo Study.

OBJECTIVE: The purpose of this study was to determine whether endogenous steroid hormone levels are associated with depressed mood in community-dwelling older women. DESIGN: A cross-sectional population-based study. SETTING: Rancho Bernardo, California PARTICIPANTS: A total of 699 non-estrogen using, community-dwelling, postmenopausal women (aged 50 to 90 years) from the Rancho Bernardo cohort who were screened for depressed mood and had plasma obtained for steroid hormone assays in 1984-1987. MEASUREMENTS: Plasma levels of total and bioavailable (non-SHBG-bound) estradiol and testosterone, estrone, androstenedione, cortisol, dehydroepiandrosterone, and (DHEA) and its sulfate (DHEAS) were measured by radioimmunoassay. Mood and depression were assessed using the Beck Depression Inventory. RESULTS: Only DHEAS levels were significantly and inversely associated with depressed mood, and the association was independent of age, physical activity, and weight change (P = .0002). Age, sedentary lifestyle, and weight loss were positively associated with depressed mood. Alcohol intake, cigarette smoking, marital status, type of menopause, and season of testing were unassociated with depressed mood. A subset of 31 women with categorically defined depression had lower DHEAS levels compared with 93 age-matched nondepressed women (1.17 +/- 1.08 vs 1.57 +/- .98 micromol/L; P = .01). CONCLUSIONS: These results add to the evidence that DHEA/S is a neuroactive steroid and point to the need for careful long-term clinical trials of DHEA therapy in older women with depressed mood.

Sleep EEG studies during early and late partial sleep deprivation in premenstrual dysphoric disorder and normal control subjects.

In this study of 23 patients with premenstrual dysphoric disorder (PMDD) and 18 normal comparison (NC) subjects, we examined sleep EEG measures during baseline midfollicular (MF) and late luteal (LL) menstrual cycle phases and after early sleep deprivation (ESD), in which subjects slept from 03.00 to 07.00 h, and late sleep deprivation (LSD), in which subjects slept from 21.00 to 01.00 h. Each sleep deprivation night was followed by a night of recovery sleep (ESD-R, LSD-R) (sleep 22.30-06.30 h) and was administered in the late luteal phase of separate menstrual cycles. During baseline studies, sleep EEG measures differed significantly by menstrual cycle phase, but not group. Both PMDD and NC groups showed longer REM latencies and less REM sleep (minutes and percent) during the luteal compared with the follicular menstrual cycle phase. PMDD subjects, however, did not show sleep architecture changes similar to those of patients with major depressive disorders. Sleep quality was better during recovery nights of sleep in PMDD compared with NC subjects. REM sleep measures changed in association with clinical improvement in responders to sleep deprivation. Both early and late sleep deprivation may help to correct underlying circadian rhythm disturbances during sleep in PMDD, although differential sleep changes during ESD vs. LSD did not correlate with clinical response. Further sleep studies addressing additional circadian variables may serve to elucidate mechanisms mediating the therapeutic effects of sleep deprivation in PMDD.

Nutritional and endocrine-metabolic aberrations in women with functional hypothalamic amenorrhea.

The development of functional hypothalamic amenorrhea (FHA) in weight-stable, nonathletic women has long been thought to be psychogenic in origin. This study was designed to gain insight into the possibility that nutritional deficits and compensatory endocrine-metabolic adaptations contribute to the development and maintenance of FHA of the psychogenic type. Nutritional intake, insulin sensitivity, and 24-h dynamics of insulin/glucose, cortisol, leptin, somatotropic, and LH axes were simultaneously assessed in eight women with FHA not associated with exercise or weight loss and in eight age- and body mass index-matched regular cycling controls (NC). The percent fat body mass was lower and lean body mass was higher in FHA than in NC (P < 0.05). The FHA subjects scored higher (P < 0.05) on two Eating Disorder Inventory subscales and had a higher (P < 0.05) Beck depression rating than NC, although all were in the subclinical range. Although daily caloric intake did not differ, FHA consumed 50% less (P < 0.001) fat, twice (P < 0.05) as much fiber, and more carbohydrate (P < 0.05) compared to NC. During the feeding phase of the day, FHA exhibited lower glucose (P < 0.05) and insulin (P < 0.01) levels than NC, and the degree of hypoinsulinemia was directly related to relative dietary fat (r = 0.73). Although 24-h mean GH levels did not differ, the pattern of GH release in FHA was distinctly altered from that in NC. GH pulse amplitude was blunted, pulse frequency was accelerated 40% (P < 0.01), and interpulse GH concentrations were elevated 2-fold (P < 0.01) throughout the day for FHA compared to NC. This distorted pattern of GH pulses was associated with a 40% decrease (P < 0.01) in GH-binding protein levels. Levels of the insulin-dependent insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1) were elevated (P < 0.001) during the feeding portion of the day in FHA and were inversely related to insulin (r = -0.50) and directly related to cortisol (r = 0.64) levels for FHA and NC groups together. Although levels of IGF-I and IGFBP-3 did not differ, the elevation of IGFBP-1 levels in FHA resulted in a reduced (P < 0.01) ratio of IGF-I/IGFBP-1, which may decrease the bioactivity and hypoglycemic effect of IGF-I. Twenty-four-hour mean leptin levels and the diurnal excursion of leptin in FHA did not differ from those in NC. LH pulse frequency was slowed 50% (P < 0.001) in FHA, with unaltered pulse amplitude, resulting in 45% lower (P < 0.01) 24-h mean LH levels for FHA compared to NC. LH pulse frequency for the two groups was related positively to insulin (r = 0.80) levels and the ratio of IGF-I/IGFBP-1 (r = 0.70) and negatively with cortisol (r = -0.61) and IGFBP-1 (r = -0.72) concentrations. In summary, we found evidence of subclinical eating disorders in weight-stable, nonathletic women with FHA accompanied by a severe restriction of dietary fat intake. Unbalanced nutrient intake in psychogenic FHA was associated with multiple endocrine-metabolic alterations. Among these, reduced levels of plasma glucose and serum GHBP, a decrease in the ratio of IGF-I/IGFBP-1, accelerated GH pulse frequency, and elevated interpulse GH levels are indicative of a hypometabolic state. In addition, the magnitude of glucoregulatory responses (increased cortisol secretion and decreased insulin/IGF-I action) were directly related to the degree of suppression of GnRH/LH pulse frequency. These results are remarkably similar to those seen in highly trained athletes with FHA(1). Thus, nutritional deficits may represent a common contributing factor to the development and maintenance of multiple neuroendocrine-metabolic aberrations underlying both psychogenic and exercise-related FHA.

Aging and the adrenal cortex.

Aging in humans is accompanied by an increase in adrenal glucocorticoid secretion and a decline in adrenal androgen synthesis and secretion. The intense interest in adrenal function in aging individuals in recent years is in large measure related to the potential impact of cortisol excess in the development of cognitive impairment and hippocampal neuronal loss, and to the desire to provide hormone replacement and healthy aging. Although the preliminary data is tantalizing, solid scientific evidence are not at hand. It is apparent that both issues are extremely complex. Dehydroepiandrosterone (DHEA) and its 3 beta-sulfate are fascinating molecules, including their synthesis and actions in the brain. Recent studies have shown that DHEA-sulfate (DHEA-S), but not DHEA, activates peroxisome proliferator-activated receptor alpha (PPAR alpha) in the liver, an intracellular receptor belonging to the steroid receptor superfamily. Thus, DHEA-S may serve as a physiological modulator of liver fatty acid metabolism and peroxisomal enzyme expression, and thereby may contribute to the anticarcinogenic and chemoprotective properties of this intriguing class of endogenous steroids. The life-sustaining role of adrenal cortisol secretion and its regulation of metabolism via catabolic actions may be modulated by its partner DHEA and DHEA-S. During the anabolic growth period (childhood and early adulthood) the body is exposed to relatively high levels of DHEA/DHEA-S but to relatively or absolutely high levels of cortisol during infancy and the aging phase. The cortisol/DHEA-S ratio during the life span follows a U-shape curve, which may be telling us to explore these two critical adrenal steroids in tandem.

Inappropriate gonadotropin secretion in polycystic ovary syndrome: influence of adiposity.

In recent years, there has been uncertainty concerning the association of inappropriate gonadotropin secretion (high LH and normal FSH) and the polycystic ovary syndrome (PCOS). In the present study, we ascertained the influence of body composition on LH pulsatile parameters in 33 PCOS and 32 normal cycling (NC) women across a wide range of body mass index (BMI, 19-42 kg/m2). Twenty four-hour pulsatile parameters for serum LH (10-min sampling) and pituitary gonadotropin responses to i.v. bolus GnRH (10 micrograms) were evaluated. Fasting (0800 h) FSH and steroid hormone concentrations and 24-h mean insulin levels were determined. Insulin sensitivity (SI) was assessed by rapid i.v. glucose tolerance test in a subset of 28 PCOS and 29 NC subjects. Our results showed that BMI, an indicator of relative adiposity, had a significant negative impact on 24-h mean LH pulse amplitude (r = -0.63, P < 0.001) and the peak increment of LH in response to GnRH stimulation (r = -0.41; P = 0.02) for PCOS but not NC women. In contrast, 24-h LH pulse frequency was uniformly increased (40%) in PCOS as compared with NC women independent of BMI. In PCOS women, the blunting of pulse amplitude with increasing BMI resulted in a decline in 24-h mean LH levels (r = -0.63, P < 0.001) and the ratio of LH/FSH (r = -0.44, P = 0.02) not seen in NC. With BMI < 30 kg/m2, 24-h mean LH values for PCOS women were greater than the normal range for NC in 95% (18/19) of cases, whereas 24-h LH levels failed to discriminate PCOS from NC women in 43% (6/14) of obese (BMI > 30 kg/m2) PCOS women. Thus, the diagnostic value of LH determinations is retained for PCOS women with BMI < 30 kg/m2. For screening purposes, the mean of two LH values in samples collected at 30-min intervals was found to have a discriminatory power equal to that of the 24-h mean. These findings suggest that 1) BMI negatively influences LH pulse amplitude in PCOS women principally by an effect at the pituitary level; 2) accelerated LH pulse frequency in PCOS women is not influenced by BMI and represents a basic component of hypothalamic dysfunction in PCOS women; and 3) BMI does not influence gonadotropin secretion in normal cycling women. Thus assessments of basal LH levels and the LH/FSH ratio in hyperandrogenic anovulatory women are clinically meaningful when BMI is taken into account. Investigations to define the factor(s) that link adiposity and the attenuation of LH pulse amplitude in PCOS women would add further understanding of this complex neuroendocrine-metabolic disorder.