Kerry L. Hildreth

Endothelial Function Is Impaired across the Stages of the Menopause Transition in Healthy Women

CONTEXT The stages of the menopause transition are characterized by changes in ovarian hormones and increased cardiovascular disease (CVD) risk factors and vasomotor symptoms that may adversely affect vascular health. OBJECTIVE We tested the hypothesis that endothelial function, a predictor of CVD, would be reduced across the stages of the menopause transition, independent of CVD risk factors and vasomotor symptoms. DESIGN, SETTING, AND PARTICIPANTS This was a cross-sectional study of 132 healthy women from the general community aged 22-70 yr, categorized as premenopausal (n = 33, 32 ± 6 yr; mean ± SD), early perimenopausal (n = 20, 49 ± 3 yr) or late perimenopausal (n = 22, 50 ± 4 yr), or early (n = 30, 55 ± 3 yr) or late postmenopausal (n = 27, 61 ± 4 yr). MAIN OUTCOME Endothelial-dependent vasodilation was measured by brachial artery flow-mediated dilation (FMD) using ultrasound. RESULTS Brachial artery FMD was significantly different among the groups (P < 0.001). It was highest in premenopausal women (9.9 ± 2.1%) with progressive decrements in perimenopausal (early: 8.2 ± 2.5%; late: 6.5 ± 1.9%) and postmenopausal women (early: 5.5 ± 1.9%; late: 4.7 ± 1.7%). Adjustment for risk factors, vasomotor symptoms, and sex hormones did not alter the association (P < 0.001). In subgroup analyses of women aged 50-59 yr, brachial artery FMD was lower in late peri- and early and late postmenopausal compared with early perimenopausal women (P < 0.001) but was not different between late perimenopausal and either early or late postmenopausal women. CONCLUSIONS Our findings suggest that a decline in endothelial function begins during the early stages of menopause (perimenopause) and worsens with the loss of ovarian function and prolonged estrogen deficiency. These data add to the accumulating evidence that the perimenopausal window is a critical time period for adverse changes in CVD risk.

Effects of Testosterone and Progressive Resistance Exercise in Healthy, Highly Functioning Older Men With Low-Normal Testosterone Levels

CONTEXT Aging in men is associated with reduced testosterone (T) levels and physiological changes leading to frailty, but the benefits of T supplementation are inconclusive. OBJECTIVE We studied the effects of T supplementation with and without progressive resistance training (PRT) on functional performance, strength, and body composition. DESIGN, SETTING, AND PARTICIPANTS We recruited 167 generally healthy community-dwelling older men (66 ± 5 years) with low-normal baseline total T levels (200-350 ng/dL). INTERVENTION Subjects were randomized to placebo or transdermal T gel [2 doses targeting either a lower (400-550 ng/dL) or higher (600-1000 ng/dL) T range] and to either PRT or no exercise for 12 months. MAIN OUTCOME MEASURE The primary outcome was functional performance, whereas secondary outcomes were strength and body composition. RESULTS A total of 143 men completed the study. At 12 months, total T was 528 ± 287 ng/dL in subjects receiving any T and 287 ± 65 ng/dL in the placebo group. In the PRT group, function and strength were not different between T- and placebo-treated subjects, despite greater improvements in fat mass (P = .04) and fat-free mass (P = .01) with T. In the non-PRT group, T did not improve function but improved fat mass (P = .005), fat-free mass (P = .03), and upper body strength (P = .03) compared with placebo. There were fewer cardiovascular events in the T-treated groups compared with placebo. CONCLUSIONS T supplementation was well tolerated and improved body composition but had no effect on functional performance. T supplementation improved upper body strength only in nonexercisers compared with placebo.

Obesity, Insulin Resistance, and Alzheimer's Disease

Obesity has reached epidemic proportions in our society, affecting over one-third of US adults, with two-thirds overweight or obese (1). Trends toward overweight and obesity among younger age groups are alarming; 27.5% of men and 34.0% of women ages 20–39 are obese (1), and 11.3% of children 2–19 years of age are at or above the 97th percentile for 2000 BMI-for-age growth charts (2). The majority of overweight or obese individuals are also insulin resistant (3). The adverse health consequences of obesity and insulin resistance (IR) are well-documented, particularly with respect to cardiovascular disease and type 2 diabetes mellitus (T2DM). More recently, these conditions have also been linked to an increased risk of cognitive impairment and Alzheimer’s disease (AD) (4). AD is the most common cause of dementia, and the fifth leading cause of death in the United States among those 65 and older (5). The number of patients affected by AD in the United States is projected to increase from 5.3 million currently, to 16 million in 2050 as the population ages (5), imposing extraordinary monetary and non-monetary costs on patients, caregivers, and the healthcare system. Currently approved therapies for AD provide modest symptomatic benefits to some patients, but do not affect the underlying pathology. Identification of modifiable risk factors to delay or prevent progression to clinical dementia and functional impairment could have a dramatic impact on the prevalence and costs associated with AD. Although there is currently insufficient evidence to firmly link any modifiable risk factor with AD, substantial empirical evidence supports a role for several cardiovascular risk factors, including obesity, hypertension, dyslipidemia, diabetes, and IR (6). All of these factors have been implicated in the development and progression of AD, both individually and in aggregate (i.e., the metabolic syndrome) (7,8). A growing body of literature has demonstrated insulin dysregulation as a risk factor for both AD and its prodrome, mild cognitive impairment (4,9,10). Furthermore, IR represents a preclinical stage on the path to diabetes during which efforts at intervention are likely to have maximal effect. We focus here on the potential role of IR in the pathogenesis of AD, and discuss interventions that target IR as possible approaches to prevent or delay progression of AD.

Vascular Aging across the Menopause Transition in Healthy Women

Vascular aging, featuring endothelial dysfunction and large artery stiffening, is a major risk factor for developing cardiovascular disease (CVD). In women, vascular aging appears to be accelerated during the menopause transition, particularly around the late perimenopausal period, presumably related to declines in ovarian function and estrogen levels. The mechanisms underlying endothelial dysfunction and large artery stiffening with the menopause transition are not completely understood. Oxidative stress and the proinflammatory cytokine tumor necrosis factor-α contribute to endothelial dysfunction and large artery stiffening in estrogen-deficient postmenopausal women. Habitual endurance exercise attenuates the age-related increase in large artery stiffness in estrogen-deficient postmenopausal women and can reverse arterial stiffening to premenopausal levels in estrogen-replete postmenopausal women. In contrast, estrogen status appears to play a key permissive role in the adaptive response of the endothelium to habitual endurance exercise in that endothelial improvements are absent in estrogen-deficient women but present in estrogen-replete women. We review here the current state of knowledge on the biological defects underlying vascular aging across the menopause transition, with particular focus on potential mechanisms, the role of habitual exercise in preserving vascular health, and key areas for future research.

Oxidative stress contributes to large elastic arterial stiffening across the stages of the menopausal transition.

ObjectiveIt is unclear how changes in ovarian hormones during the menopausal transition contribute to age-associated arterial stiffening. We sought to evaluate differences in arterial stiffness and the role of oxidative stress across the stages of the menopausal transition in healthy women. MethodsArterial stiffness (carotid artery compliance and ultrasound) was measured during immediate infusions of saline (control) and ascorbic acid (experimental model to immediately decrease oxidative stress) in 97 healthy women (22-70 y) classified as premenopausal (n = 24; mean [SD] age, 33 [7] y), early perimenopausal (n = 21; 49 [3] y) or late perimenopausal (n = 21; 50 [4] y), or postmenopausal (n = 31; 57 [5] y). ResultsBasal carotid artery compliance was different among the groups (P < 0.001). Mean [SD] compliance was highest in premenopausal women (1.31 [0.25] mm2/mm Hg × 10−1), with progressive decrements in perimenopausal (early perimenopausal, 0.98 [0.31] mm2/mm Hg × 10−1; late perimenopausal, 0.90 [0.25] mm2/mm Hg × 10−1) and postmenopausal (0.75 [0.24] mm2/mm Hg × 10−1) women. Ascorbic acid infusion improved compliance in late perimenopausal (15% [18%] increase, P = 0.001) and postmenopausal (17% [26%] increase, P = 0.002) women but not in early perimenopausal or premenopausal women. ConclusionsArterial stiffening worsens across the stages of the menopausal transition in healthy women. This seems to be mediated, in part, by oxidative stress, particularly during the late perimenopausal and postmenopausal periods. It remains uncertain whether this is specifically caused by loss of ovarian function or aging.

Association of serum dehydroepiandrosterone sulfate and cognition in older adults: sex steroid, inflammatory, and metabolic mechanisms.

OBJECTIVE Dehydroepiandrosterone sulfate (DHEAS) levels and cognitive function decline with age, and a role for DHEAS in supporting cognition has been proposed. Higher DHEAS levels may be associated with better cognitive performance, although potential mechanisms for this relationship are not well established. METHOD We performed a cross-sectional study of the relationship between serum DHEAS and three aspects of cognition--executive function, working memory, and processing speed--in 49 men and 54 women, aged 60-88 years, with low serum DHEAS levels. We examined three potential mechanisms of DHEAS action--sex hormone sufficiency, inflammatory status, and glucose regulation. RESULTS After adjustment for multiple covariates, higher serum DHEAS levels were associated with better working memory (standardized beta coefficient 0.50, p < .05), with a trend toward better executive function (standardized beta coefficient 0.37, p < .10) in men only. There was a nonsignificant trend toward a negative association between levels of tumor necrosis factor α (TNFα) and working memory in the combined population (standardized beta coefficient -0.22, p < .10). None of the glucoregulatory measures was associated with cognitive function. CONCLUSIONS The relationship between DHEAS and cognition is complex and differs by sex and cognitive domain. This study supports the need for further investigations of the sex-specific effects of DHEAS on cognition and its underlying mechanisms of action.

Effects of Testosterone Therapy on Cognitive Function in Aging: A Systematic Review.

Endogenous testosterone in the aging man has been scrutinized extensively in regard to its effects on performance in many cognitive domains, especially verbal fluency, visuospatial and visuoperceptual abilities, memory, and executive function. Studies of testosterone supplementation have sought to identify potential cognitive improvements in men with and without baseline cognitive impairment, and have had a wide range of results. The variability in outcomes is likely related, in part, to the lack of consensus on methods for testosterone measurement and supplementation and, in part, to the disparate measures of cognitive function used in randomized controlled studies. Despite the limitations imposed by such inconsistent methods, promising associations have been found between cognition and testosterone supplementation in both eugonadal men and men with low testosterone levels, with and without baseline cognitive dysfunction. This systematic review highlights the cognitive measures used in and the outcomes of existing studies of testosterone and cognition in aging men. The review suggests that larger studies and a more standardized approach to assessment will be needed before we can fully understand and realize sustained benefits from testosterone supplementation in the elderly male population, particularly given the substantial increase in testosterone supplementation in clinical practice.

Effects of Pioglitazone or Exercise in Older Adults with Mild Cognitive Impairment and Insulin Resistance: A Pilot Study

Aims: To examine the effects of pioglitazone or endurance exercise training on cognitive function in older adults with mild cognitive impairment (MCI) and insulin resistance. Methods: Seventy-eight adults (mean age ± SD: 65 ± 7 years) with central obesity and MCI were randomized to 6 months of endurance exercise, pioglitazone or control. Results: Sixty-six participants completed the study. Exercise training did not significantly increase peak oxygen uptake compared to control (p = 0.12). Compared to control, insulin resistance improved in the pioglitazone group (p = 0.002) but not in the exercise group (p = 0.25). There was no measureable effect of pioglitazone or exercise on cognitive performance compared to control. Conclusion: In this pilot study, pioglitazone improved insulin resistance but not cognitive performance in older adults with MCI and insulin resistance.

A relative L‐arginine deficiency contributes to endothelial dysfunction across the stages of the menopausal transition

Vascular endothelial function declines across the menopause transition in women. We tested the hypothesis that reduced availability of the endothelial nitric oxide synthase [eNOS] substrate L‐arginine is an underlying mechanism to vascular endothelial dysfunction across menopause stages. Endothelial function (brachial artery flow‐mediated dilation [FMD]) and plasma markers of L‐arginine metabolism (citrulline, NG‐mono‐methyl‐ւ‐arginine [L‐NMMA] asymmetric dimethylarginine [ADMA] and NG‐N′G‐dimethyl‐l‐arginine [SDMA]), were measured in 129 women: 36 premenopausal (33 ± 7 years), 16 early‐ (49 ± 3 years) or 21 late‐ (50 ± 4 years) perimenopausal, and 21 early‐ (55 ± 3 years) or 35 late‐ (61 ± 4 years) postmenopausal. FMD was progressively reduced across menopause stages (P < 0.001). Menopause stage was associated with L‐arginine concentrations (P = 0.012), with higher levels in early postmenopausal compared to early and late perimenopausal women (P < 0.05). The methylarginine and eNOS inhibitor L‐NMMA was higher in early and late postmenopausal women compared to premenopausal and early and late perimenopausal women (all P < 0.001), and was inversely correlated with FMD (r = −0.30, P = 0.001). The L‐arginine/L‐NMMA ratio, a potential biomarker of relative L‐arginine levels, was lower in postmenopausal compared to either premenopausal or perimenopausal women (both P < 0.001), and was positively correlated with FMD (r = 0.33, P < 0.001). There were no differences in plasma citrulline, ADMA or SDMA across groups. These data suggest that a relative L‐arginine deficiency may be a mechanism underlying the decline in endothelial function with the menopause transition in women. The relative L‐arginine deficiency may be related to elevated levels of the methylarginine L‐NMMA, which would compete with L‐arginine for eNOS and for intracellular transport, reducing NO biosynthesis.

Effects of Testosterone and Progressive Resistance Exercise on Vascular Function in Older Men

The cardiovascular effects of testosterone (T) are controversial. Low T has been associated with accelerated vascular aging, characterized by large elastic artery stiffening (decreased compliance), intimal-medial thickening (IMT), and endothelial dysfunction. Endurance exercise improves vascular function, but resistance training may increase arterial stiffness. We sought to determine whether T supplementation improved markers of vascular aging in men with low-normal T, and whether T supplementation prevented arterial stiffness with resistance exercise. We studied 160 community dwelling older men (66 ± 5 years) with low-normal baseline total T levels (200-350 ng/dL). Participants were randomized to transdermal T gel targeting either a lower [400-550 ng/dL] or higher [600-1000 ng/dL] T range or to placebo gel, and to either progressive resistance training (PRT) or to no exercise for 12 months. Carotid artery stiffness (arterial compliance) and carotid IMT were measured at baseline, 6, and 12 months. Endothelial function (brachial artery flow-mediated dilation) was measured in a subset (N=86). Changes in carotid artery compliance, IMT and endothelial function with either the lower or higher range of T supplementation were not different from placebo at 6 or 12 months. There were no differences between PRT and no PRT groups, alone or with T supplementation, in changes in any of the vascular measures at either time point. Supplementation of T and PRT in older men with low-normal levels do not appear to improve or harm vascular function.