Estrogen-deficient Postmenopausal Women Research Articles

How to Suppress Mineral Loss and Stimulate Anabolism in Postmenopausal Bones with Appropriate Timing of Exercise and Nutrients.

Background. Bone Health and Osteoporosis Foundation (BHOF) reports that as of 2023, approximately 10 million of older Americans have osteoporosis and another 44 million have low bone density. Osteoporosis is a serious handicap for the elderly and, in particular, for estrogen-deficient postmenopausal women, as it increases the risk of debilitating bone weakness and fractures. The BHOF recommendations for prevention of osteopenia, osteoporosis and bone fractures are to perform weight-bearing and muscle-strengthening exercises and to take recommended amounts of daily calcium and vitamin D. Methods. The purpose of this review is to describe and discuss recent evidence-based research on how to effectively utilize timing of exercise and calorie intake for stimulation of postmenopausal bone anabolism, and to provide this new information in the form of specific and actionable recommendations. Results. The five evidence-based recommendations are as follows: 1. Select an appropriate circadian time of day for exercise; 2. Increase walking speed to raise the movement momentum; 3. Eat a weight-maintenance meal one or two hours before the exercise bout; 4. Sustain the duration of walking activity (impulse) for 40 to 45 min; and 5. Repeat effective exercise stimulus 7 to 8 h after the first one to double the anabolic effect. Osteogenesis can also be increased with subthreshold mechanical loading, where needed, under several special circumstances. Conclusions. This review should provide pragmatic actionable pointers on how to utilize the idiosyncratic bone responsiveness to timing of movement and meals to prevent osteoporosis and encourage research toward a better understanding of how bone detects adequacy of a mechanical stimulus and determines duration of necessary rest to recover its sensitivity to mechanical stimulation and nutrients.

Effects of regular exercise on vascular function with aging: Does sex matter?

Vascular aging, featuring endothelial dysfunction and large elastic artery stiffening, is a major risk factor for the development of age-associated cardiovascular diseases (CVDs). Vascular aging is largely mediated by an excessive production of reactive oxygen species (ROS) and increased inflammation leading to reduced bioavailability of the vasodilatory molecule nitric oxide and remodeling of the arterial wall. Other cellular mechanisms (i.e., mitochondrial dysfunction, impaired stress response, deregulated nutrient sensing, cellular senescence), termed "hallmarks" or "pillars" of aging, may also contribute to vascular aging. Gonadal aging, which largely impacts women but also impacts some men, modulates the vascular aging process. Regular physical activity, including both aerobic and resistance exercise, is a first-line strategy for reducing CVD risk with aging. Although exercise is an effective intervention to counter vascular aging, there is considerable variation in the vascular response to exercise training with aging. Aerobic exercise improves large elastic artery stiffening in both middle-aged/older men and women and enhances endothelial function in middle-aged/older men by reducing oxidative stress and inflammation and preserving nitric oxide bioavailability; however, similar aerobic exercise training improvements are not consistently observed in estrogen-deficient postmenopausal women. Sex differences in adaptations to exercise may be related to gonadal aging and declines in estrogen in women that influence cellular-molecular mechanisms, disconnecting favorable signaling in the vasculature induced by exercise training. The present review will summarize the current state of knowledge on vascular adaptations to regular aerobic and resistance exercise with aging, the underlying mechanisms involved, and the moderating role of biological sex.

Role of BH4 deficiency as a mediator of oxidative stress-related endothelial dysfunction in menopausal women.

Endothelial function (brachial artery flow-mediated dilation [FMD]) is reduced in estrogen-deficient postmenopausal women, mediated, in part, by reduced nitric oxide (NO) bioavailability, secondary to tetrahydrobiopterin (BH4) deficiency and oxidative stress. FMD is increased, but not fully restored, in postmenopausal women after acute intravenous vitamin C (VITC; superoxide scavenger) or oral BH4 supplementation. In vitro studies demonstrate that coadministration of VITC with BH4 prevents endothelial nitric oxide synthase (eNOS) uncoupling and reductions in NO by peroxynitrite. To investigate mechanisms of endothelial dysfunction in women, we assessed the separate and combined effects of VITC and BH4 to determine whether coadministration of VITC + BH4 improves FMD in healthy postmenopausal women (n = 19, 58 ± 5 yr) to premenopausal (n = 14, 36 ± 9 yr) levels, with exploratory testing in perimenopausal women (n = 8, 51 ± 3 yr). FMD was measured during acute intravenous infusions of saline (control) and VITC (∼2-3 g) ∼3 h after a single dose of oral BH4 (KUVAN, 10 mg/kg body wt) or placebo (randomized crossover, separated by ∼1 mo). Under the placebo condition, FMD was reduced in postmenopausal compared with premenopausal women during the saline infusion (5.6 ± 0.7 vs. 11.6 ± 0.9%, P < 0.001) and increased in postmenopausal women during VITC (+3.5 [1.4, 5.6]%, P = 0.001) and acute BH4 (+1.8 [0.37, 3.2]%, P = 0.01) alone. Coadministration of VITC + BH4 increased FMD in postmenopausal women (+3.0 [1.7, 4.3]%, P < 0.001), but FMD remained reduced compared with premenopausal women (P = 0.02). Exploratory analyses revealed that VITC + BH4 did not restore FMD in perimenopausal women to premenopausal levels (P = 0.045). Coadministration of VITC + BH4 does not restore FMD in menopausal women, suggesting that additional mechanisms may be involved.NEW & NOTEWORTHY Endothelial function is reduced across the menopausal stages related to increased oxidative stress associated with estrogen deficiency. In vitro studies demonstrate that coadministration of VITC with BH4 prevents endothelial nitric oxide synthase (eNOS) uncoupling and reductions in NO by peroxynitrite; however, this remains untested in humans. We demonstrate that the coadministration of BH4 + VITC does not restore endothelial function in perimenopausal and postmenopausal women to the level of premenopausal women, suggesting that other mechanisms contribute.

Inspiratory muscle strength training for lowering blood pressure and improving endothelial function in postmenopausal women: comparison with "standard of care" aerobic exercise.

Background: High blood pressure (BP), particularly systolic BP (SBP), is the major modifiable risk factor for cardiovascular diseases and related disorders of aging. SBP increases markedly with aging in women such that the prevalence of above-normal SBP (i.e., ≥120 mmHg) in postmenopausal women exceeds rates in age-matched men. This increase in SBP is associated with vascular endothelial dysfunction, mediated by excessive reactive oxygen species-induced oxidative stress and consequent reductions in nitric oxide bioavailability. Moderate-intensity aerobic exercise is a recommended lifestyle strategy for reducing SBP. However, adherence to aerobic exercise guidelines among postmenopausal women is low (<30%) and aerobic exercise does not consistently enhance endothelial function in estrogen-deficient postmenopausal women. High-resistance inspiratory muscle strength training (IMST) is a time-efficient, adherable lifestyle intervention that involves inhaling against resistance through a handheld device (30 breaths/day). Here, we present the protocol for a randomized controlled trial investigating the efficacy of 3 months of high-resistance IMST compared to guideline-based, “standard-of-care” aerobic exercise training for decreasing SBP and improving endothelial function in estrogen-deficient postmenopausal women with above-normal SBP (120–159 mmHg) at baseline (ClinicalTrials.gov Identifier: NCT05000515). Methods: A randomized, single-blind, parallel-group design clinical trial will be conducted in 72 (36/group) estrogen-deficient postmenopausal women with above-normal SBP. Participants will complete baseline testing and then be randomized to either 3 months of high-resistance IMST (30 breaths/day, 6 days/week, 75% maximal inspiratory pressure) or moderate-intensity aerobic exercise training (brisk walking 25 min/day, 6 days/week, 40–60% heart rate reserve). Outcome measures will be assessed after 3 months of either intervention. Following end-intervention testing, participants will abstain from their assigned intervention for 6 weeks, after which BP and endothelial function will be assessed to evaluate the potential persistent effects of the intervention on the primary and secondary outcomes. Discussion: This study is designed to compare the effectiveness of time-efficient, high-resistance IMST to guideline-based aerobic exercise training for lowering SBP and improving endothelial function, and interrogating potential mechanisms of action, in estrogen-deficient postmenopausal women. Clinical Trial Registration: ClinicalTrials.gov, Identifier: NCT05000515.

Blueberries Improve Endothelial Function in Postmenopausal Women With Above-Normal Blood Pressure via Reductions in Oxidative Stress

ObjectivesResearch suggests blueberries and their (poly)phenols may improve endothelial dysfunction, a major risk factor for cardiovascular disease (CVD). The objective of this study was to investigate the impact of consuming 22 g/day for 12 weeks of freeze-dried highbush blueberry powder on endothelial function and other measures of cardiovascular health, oxidative stress, and circulating (poly)phenol metabolites in postmenopausal women with above-normal blood pressure.MethodsWe performed a randomized, double-blind, placebo-controlled, parallel-arm trial in estrogen-deficient postmenopausal women aged 45–65 years with elevated blood pressure or stage 1-HTN. Endothelial function was assessed as brachial artery flow-mediated dilation (FMD) and normalized to individual shear rate area under the curve (FMD/SRAUC) to control for inter-individual variability in reactive hyperemia-induced shear stress. To assess whether improvements in FMD were mediated by reduced oxidative stress, FMD was assessed before and after intravenous infusion of a supra-physiologic dose of ascorbic acid. Blood pressure, arterial stiffness, and plasma (poly)phenol metabolites were also assessed.ResultsA total of 43 women completed the trial (n = 32 for endothelial function). Compliance in the Blueberry and Placebo groups were 93% and 91%, respectively. Mean total plasma (poly)phenol metabolite concentrations were increased at 4 (250,053 nmol/L, P < 0.05) and 8 (303,053 nmol/L, P < 0.05) weeks in the Blueberry group compared to baseline (125,798 nmol/L) with a strong trend at 12 weeks (227,971 nmol/L, P < 0.05), and no changes in Placebo. Blood pressure and arterial stiffness were unchanged with both treatments. At 12 weeks, FMD/SRAUC was increased by 96% from baseline (P < 0.05) in the Blueberry group but unchanged in Placebo, and changes in FMD/SRAUC from baseline to 12 weeks were higher (P < 0.05) than Placebo. The response in FMD/SRAUC to ascorbic acid infusion was lower (P < 0.05) at 12 weeks compared to baseline in the Blueberry group but not Placebo.ConclusionsThese findings suggest blueberries improve endothelial function, and is mediated, in part, by reduced oxidative stress in postmenopausal women with above-normal blood pressure, a high-risk population for developing CVD.Funding SourcesUS Highbush Blueberry Council and USDA National Institute of Food and Agriculture.

Objectively Measured Vigorous‐Intensity Physical Activity is Related to Endothelial Function in Midlife and Older Men but not in Estrogen‐Deficient Postmenopausal Women

BackgroundAerobic exercise training is consistently associated with enhanced vascular endothelial function via suppression of oxidative stress in midlife/older (ML/O; 50 years) men but not in estrogen‐deficient postmenopausal women (E‐PMW). It is unclear if chronic physical activity (PA) patterns assessed under free‐living conditions, including sedentary behavior and vigorous exercise, are related to endothelial function among ML/O men or E‐PMW. We investigated if objectively measured PA patterns were associated with endothelial function in ML/O adults and the potential mechanisms involved.Methods172 ML/O adults were included for analysis (67 ± 7 years; 85M/87W). Endothelium‐dependent dilation was assessed via brachial artery flow‐mediated dilation (FMDBA), a bioassay of endothelial function. PA was assessed over 3‐7 days via wrist‐worn accelerometers (GENEactiv), which measured sedentary time and light, moderate, and vigorous activity. The relations between endothelial function and PA were examined using simple and stepwise linear regression. Multiple linear regression was used to examine the correlation between endothelial function and PA when controlling for conventional cardiovascular disease risk factors. Plasma oxidized low‐density lipoprotein (OxLDL) concentrations and total antioxidant status were used as markers of oxidative stress and antioxidant defenses, respectively. Interleukin‐6, tumor necrosis factor‐α, and C‐reactive protein concentrations were examined to assess chronic low‐grade inflammation. Mediation analysis was used to determine the potential for changes in oxidative stress, antioxidant defenses, and inflammation as mechanisms mediating the relation between PA and endothelial function.ResultsIn the entire cohort of subjects, FMDBA was negatively associated with sedentary time (R2=0.04; p=0.01), not associated with light PA (R2=0.02; p=0.09), and positively associated with moderate (R2=0.03; p=0.04) and vigorous (R2=0.06; p&lt;0.01) PA. Only sedentary time (R2=0.06; p=0.02) and vigorous PA (R2=0.11; p&lt;0.01) were associated with FMDBA in ML/O men. No PA parameters were associated with FMDBA in E‐PMW (all p&gt;0.05). Stepwise linear regression revealed vigorous PA primarily mediated the effects of PA on FMDBA in ML/O men (R2=0.10; p&lt;0.01). When controlling for age, blood pressure, body mass index, triglycerides, high‐density lipoprotein, low‐density lipoprotein, and fasting glucose, vigorous PA independently predicted FMDBA in ML/O men (R2=0.05; p=0.05) but not in E‐PMW (R2=0.03; p=0.18). Plasma OxLDL concentrations mediated 13.5% of the group effect of vigorous PA on FMDBA (p&lt;0.01); no other plasma markers had a mediating effect (all p&gt;0.05).ConclusionsObjectively measured PA, primarily vigorous PA, is positively associated with endothelial function in ML/O men but not in E‐PMW. This relation is mediated, in part, by oxidative stress. These associations are consistent with findings that aerobic exercise training does not improve endothelial function in E‐PMW. Alternative strategies to improve endothelial function in E‐PMW are needed.

Role of Short-Term Estradiol Supplementation in Symptomatic Postmenopausal COVID-19 Females: A Randomized Controlled Trial.

Background:Protective role of estrogen in COVID-19 was speculated once the epidemiological studies reported increased susceptibility of estrogen-deficient population – males and postmenopausal females to severe disease category and involvement of angiotensin-converting enzyme 2 receptors and renin–angiotensin– aldosterone system in pathophysiology.Materials & Methods:An open-label randomized controlled trial was planned to assess the efficacy of short-course oral estradiol in preventing the clinical progression to severe disease and reduce case-fatality rate and the hospital stay duration in estrogen-deficient postmenopausal women. The intervention group (n = 40) received 2 mg per day of estradiol valerate per orally for 7 days along with the standard care, while the control group (n = 40) received only the standard care.Results:A significant difference was observed in the rate of reverse transcriptase–polymerase chain reaction negativization in the intervention versus control group at day 5 and day 7 of admission (42.5% vs. 15%, P = 0.007; 72.5% versus 50%, P = −0.026). No significant difference was noted in the duration of hospitalization (P = 0.213). A significant decrease was noted in the mean values of inflammatory biomarkers – D-dimer, lactate dehydrogenase, and C-reactive protein on day 5 in the intervention group. Interleukin-6 also showed a declining trend on day 5 in the intervention group, while a rising trend was noted in the control arm. Only one case (2.5%) in the intervention group while seven in the control group (17.5%) progressed to the moderate category; however, the difference was not statistically significant (P = 0.057).ConclusionOral estradiol in postmenopausal females can be a novel and efficient option for managing nonsevere COVID-19 infection.

Effects of resveratrol or estradiol on postexercise endothelial function in estrogen-deficient postmenopausal women

Regular exercise enhances endothelial function in older men, but not consistently in estrogen-deficient postmenopausal women. Estradiol treatment improves basal endothelial function and restores improvements in endothelial function (flow-mediated dilation, FMD) to aerobic exercise training in postmenopausal women; however, estradiol treatment is controversial. Resveratrol, an estrogen receptor ligand, enhances exercise training effects on cardiovascular function and nitric oxide (NO) release in animal models, but impairs exercise training effects in men. We conducted a randomized cross-over, double-blinded, placebo-controlled pilot study to determine whether acute (single dose) resveratrol (250-mg tablet) or estradiol (0.05 mg/day transdermal patch) treatment enhances FMD at rest and after a single bout of moderate-intensity aerobic exercise in healthy estrogen-deficient postmenopausal women (n = 15, 58.1 ± 3.2 yr). FMD was measured before and after (30, 60, and 120 min) a 40-min bout of moderate-intensity treadmill exercise (60-75% peak heart rate) under the respective conditions (separated by 1-2 wk). FMD was higher (P < 0.05) before exercise and at all post-exercise time points in the resveratrol and estradiol conditions compared to placebo. FMD was increased from baseline by 120 min postexercise in the estradiol condition (P < 0.001), but not resveratrol or PL conditions. Consistent with our previous findings, estradiol also enhances endothelial function in response to acute endurance exercise. Although resveratrol improved basal FMD, there was no apparent enhancement of FMD to acute exercise and, therefore, may not act as an estradiol mimetic.NEW & NOTEWORTHY The benefits of endurance exercise training on endothelial function are diminished in estrogen-deficient postmenopausal women, but estradiol treatment appears to restore improvements in endothelial function in this group. We show that basal endothelial function is enhanced with both acute estradiol and resveratrol treatments in estrogen-deficient postmenopausal women, but endothelial function is only enhanced following acute endurance exercise with estradiol treatment.

Impaired vascular function in exercising anovulatory premenopausal women is associated with low bone mineral density.

In estrogen-deficient post-menopausal women, osteoporosis shares a common link with cardiovascular disease risk, including endothelial dysfunction. The current study sought to examine associations between bone mineral density (BMD) and endothelial function in estrogen-deficient premenopausal women with exercise-associated menstrual disturbances. Recreationally trained women (24.3±0.8years; overall mean±SEM) who were estrogen deficient (amenorrheic or eumenorrheic anovulatory cycles; E2Def; n=13) or estrogen replete (eumenorrheic ovulatory cycles; E2Rep; n=14) were studied. Total body and lumbar BMD (L1-L4) were determined using dual-energy X-ray absorptiometry. Serum markers of oxidative stress (oxidized low-density lipoprotein; OxLDL), energy deficiency (triiodothyronine), and bone turnover (osteocalcin, c-telopeptide X, P1NP) were assessed. Estrogen exposure was determined by assessing daily urinary estrone-3-glucuronide (E1G) across a monitoring period. Calf blood flow (CBF), an index of endothelial function, was measured using strain-gauge plethysmography. CBF, total body and L1-L4 BMD, triiodothyronine and E1G were lower (P<0.05), and c-telopeptide crosslinks higher (P<0.05) in E2Def. Osteocalcin and OxLDL did not differ (P>0.05) between groups. L1-L4 BMD, osteocalcin, and E1G were the strongest predictors of CBF (R2 =0.615, P<0.001). CBF was the strongest predictor of L1-L4 BMD (R2 =0.478, P<0.001). L1-L4 (r=0.558, P=0.008) and CBF (r=0.534, P=0.004) were independently correlated with E1G. In young recreationally trained premenopausal women with anovulatory menstrual disturbances, low CBF predicts decreased lumbar BMD, suggesting impaired peripheral endothelial function may predict early unfavorable changes in bone metabolism. This finding may be of relevance in the early detection of cardiovascular and bone health decrements in otherwise healthy estrogen-deficient premenopausal women.

Ovarian Hormones Regulate the Production of Adipocytes From Bone Marrow-Derived Cells.

Sex differences in body fat distribution and menopause-associated shifts in regional adiposity suggest that sex hormones play an important role in regulating the differentiation and distribution of adipocytes, but the underlying mechanisms have not been fully explained. The aim of this study was to determine whether ovarian hormone status influences the production and distribution of adipocytes in adipose tissue arising from bone marrow-derived cells. Nine- to ten-week-old ovariectomized (OVX), surgery naïve (WT), and estrogen receptor alpha knockout (αERKO) mice underwent bone marrow transplantation from luciferase or green fluorescent protein expressing donors. A subset of OVX animals had estradiol (E2) added back. Eight-weeks posttransplant, whole body and gonadal fat BM-derived adipocyte production was highest in OVX and αERKO mice, which was attenuated in OVX mice by E2 add-back. All groups demonstrated the highest bone marrow derived adipocyte (BMDA) production in the gonadal adipose depot, a visceral fat depot in mice. Taken together, the loss of ovarian hormones increases the production of BMDAs. If translatable across species, production of BMDA may be a mechanism by which visceral adiposity increases in estrogen-deficient postmenopausal women.

Habitual aerobic exercise does not protect against micro- or macrovascular endothelial dysfunction in healthy estrogen-deficient postmenopausal women.

This is the first study to demonstrate that habitual aerobic exercise may not protect against age/menopause-related whole forearm microvascular endothelial dysfunction in healthy nonobese estrogen-deficient postmenopausal women, consistent with recent findings regarding macrovascular endothelial function. This is in contrast to what is observed in healthy middle-aged and older aerobic exercise-trained men.

Acute ascorbic acid infusion increases left ventricular diastolic function in postmenopausal women

ObjectivesWe tested the hypothesis that oxidative stress contributes to reductions in left ventricular diastolic (LV) function in estrogen-deficient postmenopausal women, related in part to reduced nitric oxide (NO) bioavailability. Study designLV diastolic function – recorded using transthoracic echocardiography and determined as the peak early (E) to late (A) mitral inflow velocity ratio and the E to peak early (e’) mitral annular velocity ratio – and brachial artery flow mediated dilation (FMD), a biomarker of NO bioavailability, were measured during acute systemic infusions of saline (control) and ascorbic acid (experimental model to decrease oxidative stress) in healthy premenopausal women (N=14, 18–40 years) and postmenopausal women (N=23, 45–75 years). ResultsThe E/A ratio was lower (1.16[1.06–1.33] vs 1.65[1.5–2.3]; median[interquartile range]) and the E/e’ ratio was elevated (8.8[7.6–9.9] vs. 6.6[5.5–7.3]) in postmenopausal compared with premenopausal women, indicating reduced LV diastolic function. E/A and E/e’ were correlated with FMD (r=0.54 and r=−0.59, respectively, both P<0.01). Ascorbic acid infusion improved both FMD (5.4±2.0% to 7.8±2.6%) and E/e’ (to 8.1[7.2–9.7], P=0.01) in postmenopausal women but not in premenopausal women. Ascorbic acid did not change E/A in either group. ConclusionThe current study provides evidence that oxidative stress contributes to reduced LV diastolic function in estrogen-deficient postmenopausal women, possibly by reducing the availability of NO.

Habitual Aerobic Exercise Does Not Significantly Influence Age‐related Microvascular Endothelial Dysfunction in Healthy Estrogen‐deficient Postmenopausal Women

Aging causes macro‐ and microvascular endothelial dysfunction, as assessed by endothelium‐dependent dilation (EDD), which can be prevented and reversed by habitual aerobic exercise (AE) in men. However, a beneficial effect of AE on macrovascular EDD has not been consistently shown in estrogen‐deficient postmenopausal women, and microvascular EDD has not been assessed. We determined forearm blood flow in response to incremental brachial artery infusion of acetylcholine (FBFACh), a measure of microvascular EDD, and brachial artery flow‐mediated dilation (FMD), an assessment of macrovascular EDD, in 8 premenopausal sedentary (PrS; 25.5±2 yrs; VO2max = 36.9±2.6 ml/kg/min), 28 estrogen‐deficient postmenopausal sedentary (PoS; 61.8±1 yrs; VO2max = 24.5±0.9 ml/kg/min), and 7 estrogen‐deficient postmenopausal trained (PoT; 58.6±2 yrs; VO2max = 40.6±2.4 ml/kg/min) women. Peak and area under the curve (AUC) FBFACh was lower in PoS vs. PrS (19.5±1.2 vs. 29.9 ml/100 ml tissue/min and 133.4±8.8 vs. 211.5±28.7 AUC, respectively, P&lt;0.05) women. In PoT, peak and AUC FBFACh was lower than PrS, but not different from PoS (20.1 ml/100 ml tissue/min and 102.8±21.8 AUC, respectively, P&lt;0.05 and P&gt;0.05, respectively) women. FMD was 28% and 42% lower in PoS and PoT, respectively, vs. PrS women, and there was no difference in FMD between PoS and PoT (P&gt;0.05) women. These findings suggest that habitual AE does not protect against age‐related macro‐ and microvascular endothelial dysfunction in estrogen‐deficient postmenopausal women.

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.

Essential Role of Estrogen for Improvements in Vascular Endothelial Function With Endurance Exercise in Postmenopausal Women

In contrast to age-matched men, endurance exercise training is not consistently associated with enhanced endothelial function in estrogen-deficient postmenopausal women. We determined whether endurance exercise training improves endothelial function in postmenopausal women treated with estrogen. In a substudy, we determined if oxidative stress is mechanistically linked to endothelial function adaptations to endurance exercise training. Brachial artery flow-mediated dilation (FMD) was measured in 36 sedentary, estrogen-deficient postmenopausal women (45-65 y) at study entry (baseline), after 12 weeks of either placebo, oral (1 mg/d) estradiol, or transdermal estradiol (0.05 mg/d) (randomized), and after an additional 12 weeks of continued estradiol or placebo treatment with concurrent endurance exercise training. In subgroups of women, FMD also was measured during the infusion of ascorbic acid at baseline and following estradiol/placebo plus endurance exercise training, and in seven habitually endurance-trained estrogen-deficient controls. FMD increased in the estrogen-treated groups (both P < .01) after 12 weeks and remained unchanged in placebo. FMD further increased following 12 weeks of endurance exercise training in estrogen-treated (both P < .025), but not placebo-treated women (P = .55). In the substudy, baseline FMD was similar between sedentary and endurance-trained controls. Ascorbic acid increased FMD at baseline in sedentary women and endurance-trained controls, and following endurance exercise training in placebo-treated, but not in estrogen-treated women. Estrogen status appears to play an important modulatory role in improvements in endothelial function with endurance exercise training in postmenopausal women. The restored endurance exercise training adaptation in estrogen-treated postmenopausal women may be related to mitigation of oxidative stress.

Tumor necrosis factor-α inhibition improves endothelial function and decreases arterial stiffness in estrogen-deficient postmenopausal women

ObjectiveTumor necrosis factor (TNF)-α, a pleiotropic pro-inflammatory cytokine involved in a variety of biological processes including oxidative stress, has been associated with vascular dysfunction in aged and ovariectomized animals. We determined whether acute inhibition of TNF-α improves vascular endothelial function and decreases arterial stiffness in estrogen-deficient postmenopausal women. MethodsArterial stiffness (carotid artery compliance) and endothelial function (brachial artery flow-mediated dilation [FMD]) were measured in postmenopausal women (n = 23; 57 ± 1 years, mean ± SE) before and following randomization to two days of either transdermal estradiol (0.05 mg/d, N = 12) or placebo (N = 11) alone and following a single subcutaneous injection of the TNF-α inhibitor, etanercept (25 mg), and in premenopausal (n = 9; 33 ± 2 years) before and following etanercept. Results and conclusionsBaseline carotid artery compliance and brachial artery FMD were lower in postmenopausal than premenopausal women (P < 0.0001). In postmenopausal women, carotid artery compliance (n = 12; 0.59 ± 0.05–0.78 ± 0.06 mm2/mmHg × 10−1, P < 0.001) and FMD (4.1 ± 0.6–6.0 ± 0.7%, P = 0.02) increased in response to estradiol but not placebo (n = 11). Carotid artery compliance (0.71 ± 0.06–0.81 ± 0.06 mm2/mmHg × 10−1, P = 0.02) and FMD (5.2 ± 0.7–7.5 ± 0.9%, P = 0.003) increased with etanercept in the placebo group but had no effect in postmenopausal randomized to estradiol or premenopausal women. These results suggest that TNF-α contributes to impaired endothelial-dependent vasodilation and arterial stiffening in estrogen-deficient postmenopausal women.

HIGH SERUM CONCENTRATION OF INTERLEUKINE-6 AND RANK-LIGAND AS RISK FACTORS FOR OSTEOPOROSIS IN ESTROGEN DEFICIENCY POST-MENOPAUSAL WOMEN

Osteoporosis in post-menopausal women is not merely due to deficient estrogenhormone production. The development of osteoporosis is due to increased boneresorption by osteoclasts. The osteoclast’s number and activity is controlled by activatingfactors such as IL-6 and RANK-L. The objective of this study was to determine that highIL-6 and RANK-L serum concentrations are risks for osteoporosis in estrogen deficientpost-menopausal women. The serum concentration of ß-CrossLaps (CTx) was measuredto determine bone resorption rate. This is an observational analytical study using case andcontrol design conducted at Sanglah General Hospital of Denpasar. The sample size wascalculated using the paired case-control study formula. There were 41 osteoporotic and41 non-osteoporotic (control) estrogen deficient post-menopausal women involved in thestudy.Data were analyzed by using the t-paired and McNemar tests. Mean serumconcentration of IL-6 among the osteoporotic women was significantly higher ascompared to that of the controls (3.47±1.75 pg/ml vs 2.51±1.13 pg/ml, p = 0.001). Meanserum concentration of RANK-L among the osteoporotic women was also significantlyhigher as compared to that of the controls (320.66±122.44ng/ml vs 249.94±82.41 ng/ml,p = 0.002). To qualify as risk factors for osteoporosis, the cut-off point for IL-6 was 2.17pg/ml (OR = 4, CI 95%: 1.23-14.24; p = 0.032); the cut-off point for RANK-L was275.165 ng/ml (OR = 8, CI 95%: 1.84-34.79; p = 0.001). Analysis of both high serumconcentration of IL-6 and RANK-L was associated with an odd ratio of 9 (CI 95%: 4,27-18,96, p=0,000). CTx concentration in the osteoporotic women was significantly higherthan in the controls (0.60±0.22ng/ml vs 0.46±0.16ng/ml, p = 0.004).We found that the high IL-6 and RANK-L serum concentrations were risk factorsin estrogen deficient post-menopausal women. CTx being a marker for osteoclastic boneresorption activity, increased in concentration higher in osteoporotic than in nonosteoporoticwomen. The high serum concentrations of IL-6 and RANK-L could be usedas predictors for osteoporosis in estrogen deficient post-menopausal women.

Hysterectomy is associated with large artery stiffening in estrogen-deficient postmenopausal women

Hysterectomy, with or without oophorectomy, is associated with increased cardiovascular disease (CVD) risk due, in part, to an adverse CVD risk factor profile. Large artery stiffening, a biomarker of vascular aging, increases the risk for CVD. We determined whether hysterectomy with or without bilateral oophorectomy (BLO) is associated with arterial stiffening in healthy postmenopausal women. We conducted a cross-sectional study including estrogen-deficient postmenopausal women who had a hysterectomy with ovarian preservation (n = 24; mean ± SE age, 59 ± 1 y) or with BLO (n = 21; 58 ± 2 y) and had no hysterectomy/no BLO (n = 58; 58 ± 1 y). Arterial stiffness (arterial compliance and β stiffness index) was measured by ultrasonography of the carotid artery. Carotid artery compliance was lower in women with hysterectomy alone and in women with hysterectomy with BLO compared with women with no hysterectomy (0.66 ± 0.03 and 0.71 ± 0.06 vs 0.89 ± 0.03 mm/mm Hg × 10, respectively, both P < 0.05). There were no differences in traditional CVD risk factors (ie, adiposity, blood pressure and fasted lipids and lipoproteins, glucose, and insulin) between the groups. After adjustment for age, menopause duration, previous menopausal hormone therapy duration, parity, waist-to-hip ratio, systolic blood pressure, and sex hormone-binding globulin, hysterectomy status remained a significant predictor of arterial compliance. These results indicate that hysterectomy status (with or without BLO) is associated with greater arterial stiffening in estrogen-deficient postmenopausal women. The greater arterial stiffening with hysterectomy was not related to an adverse CVD risk profile. Large artery stiffening may be an important mechanism by which hysterectomy increases the risk of CVD in postmenopausal women.

Tetrahydrobiopterin improves endothelial function and decreases arterial stiffness in estrogen-deficient postmenopausal women

The mechanisms mediating arterial stiffening with aging and menopause are not completely understood. We determined whether administration of tetrahydrobiopterin (BH(4)), a critical cofactor for endothelial nitric oxide synthase to produce nitric oxide, would increase vascular endothelial-dependent vasodilatory tone and decrease arterial stiffness in estrogen-deficient postmenopausal women. Additionally, we examined whether the beneficial effects of estrogen on vascular function were possibly related to BH(4). Arterial stiffness (carotid artery compliance) and endothelial-dependent vasodilation [brachial artery flow-mediated dilation (FMD)] were measured in postmenopausal (n = 24; 57 ± 1 yr, mean ± SE) and eumenorrheic premenopausal (n = 9; 33 ± 2 yr) women before and 3 h after the oral administration of BH(4). Subsequently, in postmenopausal women, vascular testing (before and after BH(4)) was repeated following randomization to either 2 days of transdermal estradiol or placebo. Baseline carotid artery compliance and brachial artery FMD were lower in postmenopausal than in premenopausal women (P < 0.0001). BH(4) administration increased carotid artery compliance (0.61 ± 0.05 to 0.73 ± 0.04 mm(2)·mmHg(-1)·10(-1) vs. baseline, P < 0.0001) and brachial artery FMD (P < 0.001) in postmenopausal women but had no effect in premenopausal women (P = 0.62). Carotid artery compliance (0.59 ± 0.05 to 0.78 ± 0.06 mm(2)·mmHg(-1)·10(-1), P < 0.001) and FMD increased in postmenopausal women in response to estradiol (P = 0.02) but were not further improved with the coadministration of BH(4), possibly because estrogen increased BH(4) bioavailability. Carotid artery compliance and FMD increased with BH(4) in the placebo group (P = 0.02). Although speculative, these results suggest that reduced vascular BH(4) may be an important contributor to arterial stiffening in estrogen-deficient postmenopausal women, related in part to reduced endothelial-dependent vasodilatory tone.

Leptin, Fat Mass, and Bone Mineral Density in Healthy Pre- and Postmenopausal Women

The purpose was to examine relationships between age, fat mass, and bone mineral density (BMD) with resting leptin levels in premenopausal and postmenopausal women. Young (aged 18–30 yr, n = 30) and estrogen-deficient postmenopausal (aged 55–75 yr, n = 43) women were recruited. Total body and segmental fat mass and bone-free lean body mass (BFLBM) and total body, lumbar spine, and proximal femur BMD were assessed using dual-energy X-ray absorptiometry. Serum-resting, fasted leptin levels were measured by Immunoradiometric Assay (IRMA), and leptin-to-fat mass ratios were calculated. Young and older women had similar amounts of BFLBM, but older women had greater ( p < 0.05) amounts of fat mass and 35% higher leptin levels. Age differences in leptin concentrations were no longer significant after controlling for fat mass. Older women had significantly ( p < 0.05) lower hip BMD values. Age was negatively related ( r = −0.29, p < 0.05) to leptin:trunk fat ratio. Increases in fat mass, not menopause per se, contributes to higher leptin levels in older women. Relationships between leptin and BMD may be age dependent.