Cerebrovascular reactivity after cessation of menopausal hormone treatment.
ABSTRACT: OBJECTIVE:Women who are currently using menopausal hormone therapy (MHT) have higher cerebrovascular reactivity when compared with postmenopausal women who are not taking MHT; however, the effect of cessation of MHT on cerebrovascular reactivity is not known. Given that MHT can have structural and activational effects on vascular function, this study was performed to characterize cerebrovascular reactivity following cessation of MHT in women at low risk for cerebrovascular disease. METHODS:Cerebrovascular reactivity was measured in a subset of women from the Kronos Early Estrogen Prevention Study (KEEPS) 3 years after cessation of the study drug (oral conjugated equine estrogen, transdermal 17?-estradiol, or placebo [PLA]). RESULTS:Age, body mass index, and blood pressure were comparable among groups. At rest, the middle cerebral artery velocity (MCAv), cerebrovascular conductance index, mean arterial pressure, and cerebral pulsatility index did not differ among groups. Slope-based summary measures of cerebrovascular reactivity did not differ significantly among groups. However, utilizing repeated-measures modeling, there was a significant upward shift in MCAv responses (p?=?0.029) in the combined MHT group compared with the PLA group. CONCLUSION:MHT has a marginal sustained effect on cerebrovascular reactivity when measured 3?years after cessation of hormone treatment.
Project description:High intensity interval exercise (HIIE) improves aerobic fitness with decreased exercise time compared to moderate continuous exercise. A gap in knowledge exists regarding the effects of HIIE on cerebrovascular function such as cerebral blood velocity and autoregulation. The objective of this systematic review was to ascertain the effect of HIIE on cerebrovascular function in healthy individuals. We searched PubMed and the Cumulative Index to Nursing and Allied Health Literature databases with apriori key words. We followed the Preferred Reporting Items for Systematic Reviews. Twenty articles were screened and thirteen articles were excluded due to not meeting the apriori inclusion criteria. Seven articles were reviewed via the modified Sackett's quality evaluation. Outcomes included middle cerebral artery blood velocity (MCAv) (n = 4), dynamic cerebral autoregulation (dCA) (n = 2), cerebral de/oxygenated hemoglobin (n = 2), cerebrovascular reactivity to carbon dioxide (CO2) (n = 2) and cerebrovascular conductance/resistance index (n = 1). Quality review was moderate with 3/7 to 5/7 quality criteria met. HIIE acutely lowered exercise MCAv compared to moderate intensity. HIIE decreased dCA phase following acute and chronic exercise compared to rest. HIIE acutely increased de/oxygenated hemoglobin compared to rest. HIIE acutely decreased cerebrovascular reactivity to higher CO2 compared to rest and moderate intensity. The acute and chronic effects of HIIE on cerebrovascular function vary depending on the outcomes measured. Therefore, future research is needed to confirm the effects of HIIE on cerebrovascular function in healthy individuals and better understand the effects in individuals with chronic conditions. In order to conduct rigorous systematic reviews in the future, we recommend assessing MCAv, dCA and CO2 reactivity during and post HIIE.
Project description:Exercise has been shown to induce cerebrovascular adaptations. However, the underlying temporal dynamics are poorly understood, and regional variation in the vascular response to exercise has been observed in the large cerebral arteries. Here, we sought to measure the cerebrovascular effects of a single 20-min session of moderate-intensity exercise in the one hour period immediately following exercise cessation. We employed transcranial Doppler (TCD) ultrasonography to measure cerebral blood flow velocity (CBFV) in the middle cerebral artery (MCAv) and posterior cerebral artery (PCAv) before, during, and following exercise. Additionally, we simultaneously measured cerebral blood flow (CBF) in the internal carotid artery (ICA) and vertebral artery (VA) before and up to one hour following exercise cessation using Duplex ultrasound. A hypercapnia challenge was used before and after exercise to examine exercise-induced changes in cerebrovascular reactivity (CVR). We found that MCAv and PCAv were significantly elevated during exercise (p = 4.81 × 10-5 and 2.40 × 10-4, respectively). A general linear model revealed that these changes were largely explained by the partial pressure of end-tidal CO2 and not a direct vascular effect of exercise. After exercise cessation, there was no effect of exercise on CBFV or CVR in the intracranial or extracranial arteries (all p > 0.05). Taken together, these data confirm that CBF is rapidly and uniformly regulated following exercise cessation in healthy young males.
Project description:We investigated the association between menopausal hormone therapy (MHT) and incident type 2 diabetes in postmenopausal women, and explored the potential modifying role of body fat distribution on this association.We included 2210 postmenopausal women without prevalent diabetes at recruitment (2000-2002) from the Multiethnic Study of Atherosclerosis. Cox proportional hazards models were used to examine associations of MHT and MHT types with incident diabetes, testing for variation according to body fat distribution.Over a median follow-up of 11.1 years, there were 226 incident cases of diabetes. There were no significant interactions with central or generalized body fatness. In fully adjusted models, current and past MHT use was associated with a greater risk of incident diabetes [HR: 1.66 (1.18-2.35) and 1.60 (1.11-2.30) respectively]. Estrogen only (ET) and combined progestin and estrogen (PET) formulations were similarly associated with a greater risk of incident diabetes [HR: 1.52 (1.03-2.24) and 1.77 (1.15-2.72) respectively].In our observational study of middle-aged and older, non-diabetic postmenopausal women, a current or past use of MHT was independently associated with a greater risk of incident diabetes. ET and PET are associated with similar risks of incident diabetes in postmenopausal women. The association of MHT use with incident diabetes is the same irrespective of body mass index (BMI) or waist circumference.
Project description:The augmented cerebral hemodynamic pulsatility could lead to the elevated risk of cerebrovascular disease. To determine the impact of an acute orthostatic challenge on a pulsatile component of cerebral hemodynamics, mild lower body negative pressure (LBNP, -30 mmHg) was applied to 29 men. Middle cerebral artery blood flow velocity (MCAv) was measured by transcranial Doppler technique. Stroke volume (SV) was estimated by the Modelflow method with adjustment by the Doppler ultrasound-measured SV at rest. SV, peak and pulsatile MCAv, and pulsatility index were significantly lower during the LBNP stimulation than those at the baseline (e.g., supine resting) (P < 0.05 for all), whereas mean arterial pressure and mean MCAv remained unchanged. The change in SV with the LBNP stimulation significantly correlated with corresponding changes in peak and pulsatile MCAv (r = 0.617, P < 0.001; r = 0.413, P = 0.026, respectively). These results suggest that pulsatile components of cerebrovascular hemodynamics are dampened during the transient period of orthostatic challenge (as simulated using LBNP) when compared to supine rest, and which is partly due to the modified SV.
Project description:Cardiovascular disease (CVD) is less common in premenopausal women than men of the same age or postmenopausal women, suggesting vascular benefits of estrogen. Estrogen activates estrogen receptors ER?, ER? and GPR30 in endothelium and vascular smooth muscle (VSM), which trigger downstream signaling pathways and lead to genomic and non-genomic vascular effects such as vasodilation, decreased VSM contraction and growth and reduced vascular remodeling. However, randomized clinical trials (RCTs), such as the Women's Health Initiative (WHI) and Heart and Estrogen/progestin Replacement Study (HERS), have shown little vascular benefits and even adverse events with menopausal hormone therapy (MHT), likely due to factors related to the MHT used, ER profile, and RCT design. Some MHT forms, dose, combinations or route of administration may have inadequate vascular effects. Age-related changes in ER amount, distribution, integrity and post-ER signaling could alter the vascular response to MHT. The subject's age, preexisting CVD, and hormone environment could also reduce the effects of MHT. Further evaluation of natural and synthetic estrogens, phytoestrogens, and selective estrogen-receptor modulators (SERMs), and the design of appropriate MHT combinations, dose, route and 'timing' could improve the effectiveness of conventional MHT and provide alternative therapies in the peri-menopausal period. Targeting ER using specific ER agonists, localized MHT delivery, and activation of specific post-ER signaling pathways could counter age-related changes in ER. Examination of the hormone environment and conditions associated with hormone imbalance such as polycystic ovary syndrome may reveal the causes of abnormal hormone-receptor interactions. Consideration of these factors in new RCTs such as the Kronos Early Estrogen Prevention Study (KEEPS) could enhance the vascular benefits of estrogen in postmenopausal CVD.
Project description:Low estrogen levels can contribute to development of fecal incontinence (FI) in women after menopause by altering neuromuscular continence mechanisms. However, studies have produced conflicting results on the association between menopausal hormone therapy (MHT) and risk of FI.We studied the association between MHT and risk of FI among 55,828 postmenopausal women (mean age, 73 years) who participated in the Nurses' Health Study, were enrolled since 2008, and with no report of FI. We defined incident FI as a report of at least 1 liquid or solid FI episode per month during 4 years of follow-up from self-administered, biennial questionnaires administered in 2010 and 2012. We used Cox proportional hazard models to calculate multivariate-adjusted hazard ratios and 95% confidence intervals (CIs) for FI risk in women receiving MHT, adjusting for potential confounding factors.During more than 185,000 person-years of follow-up, there were 6834 cases of incident FI. Compared with women who never used MHT, the multivariate hazard ratio for FI was 1.26 (95% CI, 1.18-1.34) for past users of MHT and 1.32 (95% CI, 1.20-1.45) for current users. The risk of FI increased with longer duration of MHT use (P trend ? .0001) and decreased with time since discontinuation. There was an increased risk of FI among women receiving MHT that contained a combination of estrogen and progestin (hazard ratio, 1.37; 95% CI, 1.10-1.70) compared with estrogen monotherapy.Current or past use of MHT was associated with a modestly increased risk of FI among postmenopausal women in the Nurses' Health Study. These results support a potential role for exogenous estrogens in the impairment of the fecal continence mechanism.
Project description:OBJECTIVE:Little is known regarding the progression of preclinical atherosclerosis upon cessation of menopausal hormone therapy (MHT). This study evaluated changes in carotid artery intima-media thickness (CIMT) in a subgroup of participants during 4 years and 3 years after the Kronos Early Estrogen Prevention Study (KEEPS). METHODS:Of the women enrolled in KEEPS at Mayo Clinic (n?=?118), a subset (n?=?76) agreed to participate in this follow-up study. KEEPS MHT assignments were placebo (PBO), n?=?33; transdermal 17?-estradiol (tE2), n?=?23; and oral conjugated equine estrogens group (oCEE), n?=?20. CIMT was measured by B-mode ultrasonography. Longitudinal analysis of CIMT was performed using all available data from pre-, on-, and post-treatment periods. RESULTS:At 7 years, median age of participants was 60.2 years; median time since menopause was 8.5 years. The mean difference in rates of increase was significantly greater over the post- than on-treatment period within the oCEE group (0.010 [0.002-0.017] mm/y), but not within the PBO (0.006 [-0.001 to 0.012] mm/y; P?=?0.072) or tE2 (0.002 [-0.005 to 0.010] mm/y; P?=?0.312) groups. There were, however, no significant treatment differences in the linear trends over those intervals (P?=?0.524). CONCLUSIONS:Cessation of MHT at the lower doses and formulations used in KEEPS did not appear to alter the trajectory of CIMT over a 3-year follow-up period. CIMT, however, increased in all groups over the entire 7-year timeframe as expected with age and timing of menopause possibly key contributors.
Project description:Epidemiological studies have shown that cardiovascular disease (CVD) is less common in pre-menopausal women (Pre-MW) compared to men of the same age or post-menopausal women (Post-MW), suggesting cardiovascular benefits of estrogen. Estrogen receptors (ERs) have been identified in the vasculature, and experimental studies have demonstrated vasodilator effects of estrogen/ER on the endothelium, vascular smooth muscle (VSM) and extracellular matrix. Several natural and synthetic estrogenic preparations have been developed for relief of menopausal vasomotor symptoms. However, whether menopausal hormone therapy (MHT) is beneficial in postmenopausal CVD remains controversial. Despite reports of vascular benefits of MHT from observational and experimental studies, randomized clinical trials (RCTs), such as the Heart and Estrogen/progestin Replacement Study (HERS) and the Women's Health Initiative (WHI), have suggested that, contrary to expectations, MHT may increase the risk of CVD. These discrepancies could be due to agerelated changes in sex hormone synthesis and metabolism, which would influence the effective dose of MHT and the sex hormone environment in Post-MW. Age-related changes in the vascular ER subtype, structure, expression, distribution, and post-ER signaling pathways in the endothelium and VSM, along with factors related to the design of RCTs, preexisting CVD condition, and structural changes in the blood vessels architecture have also been suggested as possible causes of MHT failure in CVD. Careful examination of these factors should help in identifying the causes of the changes in the vascular effects of estrogen with age. The sex hormone metabolic pathways, the active versus inactive estrogen metabolites, and their effects on vascular function, the mitochondria, the inflammatory process and angiogenesis should be further examined. Also, the genomic and non-genomic effects of estrogenic compounds should be viewed as integrated rather than discrete responses. The complex interactions between these factors highlight the importance of careful design of MHT RCTs, and the need of a more customized approach for each individual patient in order to enhance the vascular benefits of MHT in postmenopausal CVD.
Project description:BACKGROUND:Systemic blood flow in patients on extracorporeal assist devices is frequently not or only minimally pulsatile. Loss of pulsatile brain perfusion, however, has been implicated in neurological complications. Furthermore, the adverse effects of absent pulsatility on the cerebral microcirculation are modulated similarly as CO2 vasoreactivity in resistance vessels. During support with an extracorporeal assist device swings in arterial carbon dioxide partial pressures (PaCO2) that determine cerebral oxygen delivery are not uncommon-especially when CO2 is eliminated by the respirator as well as via the gas exchanger of an extracorporeal membrane oxygenation machine. We, therefore, investigated whether non-pulsatile flow affects cerebrovascular CO2 reactivity (CVR) and regional brain oxygenation (rSO2). METHODS:In this prospective, single-centre case-control trial, we studied 32 patients undergoing elective cardiac surgery. Blood flow velocity in the middle cerebral artery (MCAv) as well as rSO2 was determined during step changes of PaCO2 between 30, 40, and 50?mmHg. Measurements were conducted on cardiopulmonary bypass during non-pulsatile and postoperatively under pulsatile blood flow at comparable test conditions. Corresponding changes of CVR and concomitant rSO2 alterations were determined for each flow mode. Each patient served as her own control. RESULTS:MCAv was generally lower during hypocapnia than during normocapnia and hypercapnia (p?<?0.0001). However, the MCAv/PaCO2 slope during non-pulsatile flow was 14.4?cm/s/mmHg [CI 11.8-16.9] and 10.4?cm/s/mmHg [CI 7.9-13.0] after return of pulsatility (p?=?0.03). During hypocapnia, non-pulsatile CVR (4.3?±?1.7%/mmHg) was higher than pulsatile CVR (3.1?±?1.3%/mmHg, p?=?0.01). Independent of the flow mode, we observed a decline in rSO2 during hypocapnia and a corresponding rise during hypercapnia (p?<?0.0001). However, the relationship between ?rSO2 and ?MCAv was less pronounced during non-pulsatile flow. CONCLUSIONS:Non-pulsatile perfusion is associated with enhanced cerebrovascular CVR resulting in greater relative decreases of cerebral blood flow during hypocapnia. Heterogenic microvascular perfusion may account for the attenuated ?rSO2/?MCAv slope. Potential hazards related to this altered regulation of cerebral perfusion still need to be assessed. TRIAL REGISTRATION:The study was retrospectively registered on October 30, 2018, with Clinical Trial.gov (NCT03732651).
Project description:In women, cortical bone mass decreases significantly at menopause. By contrast, loss of trabecular bone begins in the third decade and accelerates after menopause.The aim of the study was to investigate the effects of estrogen on cortical and trabecular bone.The Kronos Early Estrogen Prevention Study is a double-blind, randomized, placebo-controlled trial of menopausal hormone treatment (MHT) in women, enrolled within 6-36 months of their final menstrual period.The study was conducted at the Mayo Clinic, Rochester, Minnesota.Subjects were treated with placebo (n = 31), or .45 mg/d conjugated equine estrogens (n = 20), or transdermal 50 ?g/d 17?-estradiol (n = 25) with pulsed micronized progesterone.Cortical and trabecular microarchitecture at the distal radius was assessed by high-resolution peripheral quantitative computed tomography.At the distal radius, cortical volumetric bone mineral density (vBMD) decreased, and cortical porosity increased in the placebo group; MHT prevented these changes. By contrast, MHT did not prevent decreases in trabecular microarchitecture at the radius. However, MHT prevented decreases in trabecular vBMD at the thoracic spine (assessed in a subset of subjects; n = 51). These results indicate that MHT prevents deterioration in radial cortical vBMD and porosity in recently menopausal women.The maintenance of cortical bone in response to estrogen likely has important clinical implications because cortical bone morphology plays an important role in bone strength. However, effects of MHT on trabecular bone at the radius differ from those at the thoracic spine. Underlying mechanisms for these site-specific effects of MHT on cortical vs trabecular bone require further investigation.