Ovarian Hormone Deprivation Research Articles

Dynamic resistance training decreases sympathetic tone in hypertensive ovariectomized rats.

The aim of this study was to investigate the effects of resistance exercise training on hemodynamics and cardiac autonomic control in ovariectomized spontaneously hypertensive rats. Female rats were divided into 4 groups: sedentary control (SC), sedentary hypertensive (SH), sedentary hypertensive ovariectomized (SHO), and resistance-trained hypertensive ovariectomized (RTHO). Resistance exercise training was performed on a vertical ladder (5 days/week, 8 weeks) at 40-60% maximal load. Direct arterial pressure was recorded. Vagal and sympathetic tones were measured by heart rate (HR) responses to methylatropine (3 mg/kg, iv) and propranolol (4 mg/kg, iv). Ovariectomy resulted in additional increases in blood pressure in hypertensive rats and was associated with decreased vagal tone. Resistance exercise trained rats had lower mean arterial pressure than untrained rats (RTHO: 159±2.2 vs SHO: 177±3.4 mmHg), as well as resting bradycardia (RTHO: 332±9.0 vs SHO: 356±5 bpm). Sympathetic tone was also lower in the trained group. Moreover, sympathetic tone was positively correlated with resting HR (r=0.7, P<0.05). The additional arterial pressure increase in hypertensive rats caused by ovarian hormone deprivation was attenuated by moderate-intensity dynamic resistance training. This benefit may be associated with resting bradycardia and reduced cardiac sympathetic tone after training, which suggests potential benefits of resistance exercise for the management of hypertension after ovarian hormone deprivation.

Aerobic exercise training promotes additional cardiac benefits better than resistance exercise training in postmenopausal rats with diabetes.

The aim of this study was to evaluate the effects of aerobic exercise training or resistance exercise training on cardiac morphometric, functional, and oxidative stress parameters in rats with ovarian hormone deprivation and diabetes. Female Wistar rats (200-220 g) were divided into a sham-operated group (euglycemic sham-operated sedentary [ES]; n = 8) and three ovariectomized (bilateral removal of ovaries) and diabetic (streptozotocin 50 mg/kg IV) groups as follows: diabetic ovariectomized sedentary (DOS; n = 8), diabetic ovariectomized undergoing aerobic exercise training (DOTA; n = 8), and diabetic ovariectomized undergoing resistance exercise training (DOTR; n = 8). After 8 weeks of resistance (ladder) or aerobic (treadmill) exercise training, left ventricle function and morphometry were evaluated by echocardiography, whereas oxidative stress was evaluated at the left ventricle. The DOS group presented with increased left ventricle cavity in diastole and relative wall thickness (RWT), and these changes were attenuated in both DOTA and DOTR groups. Systolic and diastolic function was impaired in the DOS group compared with the ES group, and only the DOTA group was able to reverse this dysfunction. Lipoperoxidation and glutathione redox balance were improved in both trained groups compared with the DOS group. Glutathione peroxidase and superoxide dismutase were higher in the DOTA group than in the other studied groups. Correlations were observed between lipoperoxidation and left ventricle cavity in diastole (r = 0.55), between redox balance and RWT (r = 0.62), and between lipoperoxidation and RWT (r = -0.60). Aerobic exercise training and resistance exercise training promote attenuation of cardiac morphometric dysfunction associated with a reduction in oxidative stress in an experimental model of diabetes and menopause. However, only dynamic aerobic exercise training is able to attenuate systolic and diastolic dysfunction under this condition.

Aerobic physical training increases contractile response and reduces cardiac fibrosis in rats subjected to early ovarian hormone deprivation.

We investigated the effects of early ovarian hormone deprivation on the heart and the role of physical training in this condition using different approaches: cardiac autonomic tone, contractility, morphology and function, and cardiac fibrosis. Female Wistar rats (n = 48) were assigned into two groups: ovariectomized (Ovx; 10-wk-old) and control rats (Sham; 10-wk-old). Each group was further divided into two subgroups, sedentary and trained (aerobic training by swimming for 10 wk). The sedentary groups showed similar cardiac autonomic tone values; however, only the Sham group had an increase in vagal participation for the determination of the basal heart rate after physical training. The contractile responses to cardiac β-agonists of the sedentary groups were similar, including an increased response to a β1-agonist (dobutamine) observed after physical training. The Ovx sedentary group presented changes in cardiac morphology, which resulted in decreases in the ejection fraction, fractional shortening, and cardiac index compared with the Sham sedentary group. Physical training did little to alter these findings. Moreover, histology analysis showed a significant increase in cardiac fibrosis in the sedentary Ovx group, which was not observed in the trained Ovx group. We conclude that early ovarian hormone deprivation in rats impairs autonomic control, cardiac morphology, and cardiac function and increases cardiac fibrosis; however, it does not affect the contractility induced by dobutamine and salbutamol. Furthermore, this model of physical training prevented an increase in fibrosis and promoted an increase in the cardiac contractile response but had little effect on cardiac autonomic control or morphological and functional parameters.

Influência dos hormônios sexuais no consumo de oxigênio de ratos

Introdução: Achados da literatura sugerem que oscilações dos hormônios sexuais femininos podem alterar o consumo máximo de oxigênio (VO2max).Objetivo: Comparar o VO2max entre ratos machos (M, n=8), fêmeas nas fases ovulatórias (OV, n=8) ou não-ovulatórias (NOV, n=8) do ciclo estral e ooforectomizadas (OS, n=8).Métodos: A avaliação do consumo de oxigênio foi realizada em esteira rolante com caixa metabólica acoplada.Resultados: Em repouso, o VO2 foi semelhante entre os grupos estudados. O grupo M apresentou maior VO2max em relação ao grupo NOV, mas valores semelhantes ao do grupo OV. O VO2max foi menor no grupo ooforectomizado (OS: 62±3 ml.kg-1.min-1) quando comparado aos demais grupos (M: 92±2; NOV: 77±4; OV: 87±3 ml.kg-1.min-1).Conclusões: Esses achados evidenciam que a variação hormonal decorrente das diferentes fases do ciclo estral e da privação dos hormônios ovarianos pode induzir alterações no consumo máximo de oxigênio em ratos.

Cardiovascular autonomic dysfunction and oxidative stress induced by fructose overload in an experimental model of hypertension and menopause.

BackgroundMetabolic syndrome is characterized by the association of 3 or more risk factors, including: abdominal obesity associated with an excess of abdominal fat, insulin resistance, type 2 diabetes, dyslipidemia and hypertension. Moreover, the prevalence of hypertension and metabolic dysfunctions sharply increases after the menopause. However, the mechanisms involved in these changes are not well understood. Thus, the aim of this study was to assess the effects of fructose overload on cardiovascular autonomic modulation, inflammation and cardiac oxidative stress in an experimental model of hypertension and menopause.MethodsFemale SHR rats were divided into (n = 8/group): hypertensive (H), hypertensive ovariectomized (HO) and hypertensive ovariectomized undergoing fructose overload (100 g/L in drinking water) (FHO). Arterial pressure (AP) signals were directly recorded. Cardiac autonomic modulation was evaluated by spectral analysis. Oxidative stress was evaluated in cardiac tissue.ResultsAP was higher in the FHO group when compared to the other groups. Fructose overload promoted an increase in body and fat weight, triglyceride concentration and a reduction in insulin sensitivity. IL-10 was reduced in the FHO group when compared to the H group. TNF-α was higher in the FHO when compared to all other groups. Lipoperoxidation was higher and glutathione redox balance was reduced in the FHO group when compared to other groups, an indication of increased oxidative stress. A negative correlation was found between IL-10 and adipose tissue.ConclusionFructose overload promoted an impairment in cardiac autonomic modulation associated with inflammation and oxidative stress in hypertensive rats undergoing ovarian hormone deprivation.

Chronic unpredictable stress and long-term ovariectomy affect arginine-vasopressin expression in the paraventricular nucleus of adult female mice

Arginine-Vasopressin (AVP) may regulate the hypothalamic–pituitary–adrenal axis (HPA) and its effects on depressive responses. In a recent study, we demonstrated that Chronic Unpredictable Stress (CUS) depressive effects are enhanced by long-term ovariectomy (a model of post-menopause). In the present study, we investigated the effects of long-term ovariectomy and CUS on AVP expression in different subdivision of the paraventricular nucleus (PVN) of female mice. Both long-term ovariectomy and CUS affect AVP immunoreactivity in some of the PVN subnuclei of adult female mice. In particular, significant changes on AVP immunoreactivity were observed in magnocellular subdivisions, the paraventricular lateral magnocellular (PaLM) and the paraventricular medial magnocellular (PaMM), the 2 subnuclei projecting to the neurohypophysis for the hormonal regulation of body homeostasis. AVP immunoreactivity was decreased in the PaLM by both the long-term deprivation of ovarian hormones and the CUS. In contrast, AVP immunoreactivity was increased in the PaMM by CUS, whereas it was decreased by ovariectomy. Therefore, present results suggest morphological and functional differences among the PVN’s subnuclei and complex interactions among CUS, gonadal hormones and AVP immunoreactivity.

Abstract 616: Aging, Menopause And Metabolic Syndrome As Related To The Beneficial Effects Of Exercise Training

Menopause and aging are associated with increased blood pressure. High fructose may modify the development of the pathologies associated with these conditions. The objective was to investigate the effects of exercise training (ET) in aged, oophorectomy mimic of menopause fructose-fed rats. Female Wistar rats (24 months old) were ovariectomized, fed with fructose (100g/L) in drinking water and divided in 5 groups (n=8/group): control (C), ovariectomized (O), ovariectomized trained (OT, n= 8), ovariectomized fructose (OF, n= 8) and ovariectomized fructose trained (OFT, n= 8). The ET was performed on a treadmill (1 h/day; 5 days/wk for 8 wk). The metabolic results showed that ET decreased adipose tissue in both trained groups (OT: 4.3±0.5, OFT: 5.3±0.7), compared with sedentary rats (C: 6.2± 0.6, O: 9.6±1.3, OF: 10.1±0.6, g). The same findings were observed for insulin resistance (OT: 4.6±0.2, OFT: 5.5±0.6 vs C: 3.2± 0.6, O: 3.2±0.3, OF: 4.0±0.5, mg/dl/min). ET increased physical capacity (OT: 20±0.9, OFT: 17.5±0.9 vs C: 11.5± 0.5, O: 10±0.5, OF: 10.3±0.5 Min/h). The hemodynamic results showed that ET attenuated the increase in MBP (C: 109.4± 1.9, OT: 103±1.1, OFT: 107±1.1 vs O: 119.1±1.9, OF: 119.1±2.7, mmHg) and HR (C: 341.4± 8, OT: 302±1, OFT: 306.4±8 vs O: 398.17±19, OF: 378.9±17 Bpm). The sympathetic tonus was decreased in C, OT and OTF (C: 63.6± 4, OT: 62.2±3, OFT: 51.2± 7 beats/ min) when compared with O and OF (O: 102.6±12, OF: 91.9±7 beats/min) while vagal tonus was increased just in OT (OT: 44.8±5) vs (C: 24.9± 6, OFT: 22±3, O: 13±6, OF: 9±2 beats/min). The OT and OTF groups showed an increased bradycardic response to BP changes (C: -1.50±0.06 OT: -1.74±0.12, OFT: -1.77±0.15 vs O: -0.93±0.07, OF: -1.21±0.12 bpm/mmHg). ET increased the Standard deviation of the pulse interval (C: 6.7±1.1 OT: 11.6±0.8, OFT: 13.0±1.5 vs O: 7.05±0.6, OF: 9.57±0.7 ms) and decreased VARR PAS (C: 6.7±1.09 OT: 23.6±0.8, OFT: 30.7±2.6 vs O: 56.4±8.1, OF: 40.5±3.7 mmHg2) as well as representative sympathetic modulation (LF PAS) (C: 6.7±1.1 OT: 3.6±0.5, OFT: 3.7±0.4 vs O: 9.8±1.2, OF: 8.3±0.8 mmHg. In conclusion, ET effectively improved metabolic and cardiovascular parameters altered by aged or excessive fructose consumption in rats submitted to ovarian hormone deprivation.

Aerobic exercise training decreased oxidative stress in aged females rats after ovarian hormones deprivation (706.11)

The objective was to investigate the effects of aerobic exercise training on parameters of oxidative stress profile in aged females rats after ovarian hormones deprivation. Female aged ovariectomized Wistar rats (~18 wks of age) were divided into 2 groups (n=8/each) sedentary (OVXs) and trained group (OVXt). The exercise training was performed on a treadmill (8wks, 60% VO2 max). Oxidative profile was evaluated by membranes lipoperoxidation by thiobarbituric acid reactive substances (TBA), chemiluminescence (CL) and antioxidants enzymes: catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) in cardiac, muscle and renal tissues. The redox state was performed in the heart. The TBA and CL were reduced in muscle and in the cardiac tissue (101% and 68%; 46% and 93%, respectively) in OVXt group in relation to OVXs group. The levels of CAT, SOD were higher in OVXt than OVXs group in renal tissue. GPx was higher in cardiac, renal and muscle tissues in OVXt group in relation to OVXs group. The redox state was higher in OVXt (5.4±0.34 mmol/g tissue) than OVXs (2.94±0.52 mmol/g tissue) group. These results suggest a beneficial role of exercise training in oxidative stress profile in different tissues in aged rats after ovarian hormone deprivation.

Exercise training attenuates alterations in blood pressure and heart rate variability in old ovariectomized rats under fructose consumption (546.2)

The aim of the present study was to investigate the effects of exercise trainig (ET) in metabolic and cardiovascular parameters of old Wistar female under 24 months old. Female rats were ovariectomized and trained on a treadmill (1 h/day; 5 days/wk for 8 wk). The animal had free access to standard chow and fructose solution (100g/L) in drinking water and divided into 3 groups: ovariectomized (O, n= 8), ovariectomized fructose (OF, n= 8) and trained ovariectomized fructose (TOF, n= 8). Adipose tissue, insulin resistance, physical capacity, blood pressure and heart rate variability were evaluated at the end of the protocol. The metabolic results showed that ET decreased the adipose tissue in OFT (TOF: 5.28±0.6; O: 6.5±0.7 vs. OF: 10.07±0.6 g) and insulin resistance (TOF: 5.0±0.2 vs. OF: 3.2±0.6 mg/dl/min). The physical capacity was increased in (TOF: 1.8±0.1) compared with sedentary (O:1.1±0.05; OF: 1.1±0.05 Km/h). ET attenuated the increase in MBP (TOF: 107±1: O:119±2; OF:119±2 mmHg). The same behavior was observed in SBP (TOF: 129±1; O:142±2; OF:143±2 mmHg) and DBP (TOF: 89±1; O:100±2; OF:98±2; mmHg). TOF group showed increased pulse interval variance (133.3±36 ms2) when compared with O (88.3±22 ms2) and OF (114±22 ms2). The cardiac sympathetic modulation was decreased in TOF (1.95±0.4 ms2) when compared with OF (4.18±0.8ms2.) while cardiac vagal modulation was increased (TOF: 76±2.7 vs. OF: 69±3.6 n.u.). Consequently, sympatho‐vagal balance was decreased in OFT (0.33±0.04) vs. OF group (0.52±0.09). A similar behavior was observed for sympathetic modulation of blood pressure (TOF: 30±2.5 vs. O 37±3.4; OF: 40±4.1). In conclusion, exercise training effectively improves metabolic and cardiovascular parameters (blood pressure increase and heart rate variability) altered by excessive fructose consumption in aged rats submitted to ovarian hormone deprivation.

Abstract 220: Exercise Training Attenuates Hypertension and Insulin Resistance in Old Fructose-fed Ovariectomized Rats

Menopause and aging are associated with a gradual increase in systolic blood pressure. Poor eating habits through food containing fructose, have also been related to alterations in the cardiovascular system; however, there are few studies available in the literature relating exercise training (ET), menopause, aging and metabolic syndrome. The aim of the present study was to investigate the effects of ET in ovarian hormone deprivation and/or fructose consumption in old Wistar rats. Female Wistar rats (24 months old) were ovariectomized, fed with fructose (100g/L in drinking water) or normal water, and submitted to an ET protocol in treadmill (1 h/day; 5 days/wk for 8 wk, ~ 40-60% of maximum test) or kept sedentary. The groups were: ovariectomized (O, n= 8), ovariectomized trained (OT, n= 8), ovariectomized fructose (OF, n= 8) and ovariectomized fructose trained (OFT, n= 8). Glycemia, triglycerides, adipose tissue, insulin resistance, physical capacity and blood pressure (BP) were evaluated at the end of the protocol. While the glycemia values remained within the normal range (O:90.1±7.; OT:85.2±2; OF:86±2; OFT:80.6±3 mg/dl) and the triglycerides values were increased in OF group (OF:182±20 vs. O:140.3±9; OT:143.5±7;; OFT:140 ±12 mg/dl). The physical capacity was increased in both OFT (1.8±0.1 Km/h) and OF (1.6±0.07 Km/h) when compared with sedentary peers (O:1.1±0.05; OF: 1.1±0.05 Km/h). The metabolic results showed that ET decreased the adipose tissue in (OT: 6.7±0.9 and OFT: 5.28±0.6 vs. OF: 10.07±0.6 g), and insulin resistance (OT:4.8±0.2 and OFT: 5.0±0.2 vs. OF: 3.2±0.6 mg/dl/%). No differences were observed in O group (O: 6.5±0.8g and 4.5±0.2 mg/dl/min). Finally, ET attenuated the increase in mean BP in both OT and OFT rats (O:119±2; OT 110±2; OF:119±2; OFT: 107±1 mmHg). The same behavior was observed in systolic BP (O:142±2; OT 127±2; OF:143±2; OFT: 129±1 mmHg) and diastolic BP (O:100±2; OT 92±2; OF:98±2; OFT: 89±1 mmHg). In conclusion, low to moderate aerobic ET can attenuate the deleterious effects of ovarian hormone deprivation, and/or fructose consumption, especially the blood pressure increase in old female Wistar rats.

Abstract 507: Combined Exercise Training Induces Additional Cardiovascular Autonomic Benefits in Comparison to Dynamic Resistance Training in Ovariectomized Diabetic Rats

The purpose of this study was to compare the cardiovascular autonomic effects between dynamic aerobic, resistance and combined exercise training in ovariectomized diabetic female rats. Female Wistar rats (200-220g) were divided into 4 ovariectomized (bilateral ovaries removal) diabetic (streptozotocin, 50mg/kg, iv) groups: sedentary (DOS) and trained by an aerobic protocol on a treadmill (DOTA), by a resistance protocol in ladder (DOTR), or by a combined protocol in ladder+treadmill on alternate days (DOTC). After 8 weeks of training, the animals were cannulated to arterial pressure (AP) recording and baroreflex sensitivity (BS) evaluation. Heart rate (HR) and systolic AP variabilities were analyzed in the time and frequency domains. Exercise training induced an increase of 77% in the run capacity in the DOTA group (DOS: 8.6±0.6; DOTA: 15.3±0.4; DOTR: 11.5±1.6; DOTC: 15.0±0.2 min), 60% in the maximum load in DOTR group (DOS: 179.7±11.0; DOTA: 167.3±1.5; DOTR: 288.4±7.5; DOTC: 284.6±10.2 % of body weight), and increases in both exercise tests in DOTC (75% and 58%, respectively). All trained animals showed normalization of diabetic induced-resting hypotension and bradycardia, associated with increased HR variance (DOS: 39.6±2.6; DOTA: 71.2±7.2; DOTR: 70.9±12.1; DOTC: 65.7±6.1 ms2) and normalization of the LF band of pulse interval (DOS: 2.7±0.3; DOTA: 5.3±0.4; DOTR: 7.2±1.5; DOTC: 6.8±0.8 ms2) (vs. DOS). The DOTA and DOTC groups (but not DOTR) had higher BS (tachycardic and bradycardic responses), and attenuation in SAP variability (DOS: 7.4±0.8; DOTA: 12.7±1.1; DOTR: 8.9±1.0; DOTC: 13.3±1.0 mmHg2) in relation to DOS. Mortality was higher in DOS group when compared to trained group. In conclusion, the results showed that dynamic aerobic, resistance or combined exercise training induced benefits in physical capacity, hemodynamic and autonomic parameters after ovarian hormone deprivation in diabetic rats. However, the combined exercise training promoted additional effects than aerobic or resistance training in this condition.

Adipose tissue decrease by exercise training is associated with blood pressure reduction in old fructose‐fed female rats

The aim of the present study was to investigate the effects of exercise training (ET) in old female Wistar rats (24 months old). They were ovariectomized, fed with fructose (100g/L) in drinking water and divided in 2 groups (n=6): sedentary (S) or trained (T). ET was performed on a treadmill (1 h/day; 5 days/wk for 8 wk). Glycemia, triglycerides, adipose tissue, mean blood pressure (MBP), and heart rate variability were evaluated at the end of the protocol. The metabolic results showed that ET decreased only the adipose tissue (T: 3.45±0.45 vs. S: 8.43±1.23 g). ET reduced MBP (T: 106±1.4 vs. S 117±3.8 mmHg) and increased the pulse interval variance (T:42.1±11 vs. S:33.2±5.5 ms). Cardiac sympathetic modulation (LF) was decreased in T (16.0±5.6 vs. S: 31.5±6.5 n.u.) while cardiac vagal modulation (HF) was increased (T: 84±5.6 vs. S: 68±6.5 n.u). Consequently, sympatho‐vagal balance was decreased in T (0.21±0.09) vs. S rats (0.56±0.16). A similar behavior was observed for sympathetic modulation of blood pressure (T: 5.12±1.5 vs. S: 14.9±8.1 mmHg2). Finally, we observed a direct and positive correlation between adipose tissue and MBP (r2=0.8), LF of pulse interval (r2=0.45) and LF of blood pressure (r2=0.4), while HF of pulse interval was inversely correlated (r2=0.43). In conclusion, adipose tissue decrease induced by ET is a key factor to hemodynamic benefits in old fructose‐fed female rats with ovarian hormone deprivation.

Correlation between cardiovascular autonomic control dysfunction and oxidative stress in an experimental model of hypertensive and menopause submitted to fructose overload

The aim of this study was to verify the effects of fructose overload in an experimental model of hypertensive and menopause on cardiovascular autonomic control and cardiac oxidative stress. Female SHR rats were divided into (n=8/group): hypertensive (H), hypertensive ovariectomized (HO) and hypertensive ovariectomized submitted to fructose overload (100g/L in drinking water) (FHO). Arterial pressure (AP) signals were directly recorded. Cardiovascular autonomic modulation was evaluated by spectral analysis. Oxidative stress was evaluated by chemiluminescence (CL), total reactive antioxidant potential (TRAP) and redox balance of glutathione (GSH/GSSG) determinations. AP was higher in FHO group (174±4 vs. H: 146±4 HO: 164±5 mmHg) than others groups. FHO group showed reduced vagal tonus (5±3 vs. H: 23±4; HO: 35±7 bpm) and increased sympathetic tonus (91±18 vs. H: 56±11; HO: 60±3 bpm) when compared to other groups. CL was higher in FHO group than other groups. GSH/GSSG was lower in FOH group (8.94±0.80 umol/g) than HO group (13.0±1.4 umol/g). Negative correlation was obtained between VAR‐SAP and TRAP (r: −0.71, p≤0.05) and a positive correlation between RMSSD index and GSH/GSSG (r: 0.68, p≤0.05). In conclusion, fructose overload induced impairment in cardiovascular autonomic control associated with increased oxidative stress in hypertensive rats submitted to ovarian hormones deprivation.

Ovariectomy Induces a Shift in Fuel Availability and Metabolism in the Hippocampus of the Female Transgenic Model of Familial Alzheimer's

Previously, we demonstrated that reproductive senescence in female triple transgenic Alzheimer's (3×TgAD) mice was paralleled by a shift towards a ketogenic profile with a concomitant decline in mitochondrial activity in brain, suggesting a potential association between ovarian hormone loss and alteration in the bioenergetic profile of the brain. In the present study, we investigated the impact of ovariectomy and 17β-estradiol replacement on brain energy substrate availability and metabolism in a mouse model of familial Alzheimer's (3×TgAD). Results of these analyses indicated that ovarian hormones deprivation by ovariectomy (OVX) induced a significant decrease in brain glucose uptake indicated by decline in 2-[18F]fluoro-2-deoxy-D-glucose uptake measured by microPET-imaging. Mechanistically, OVX induced a significant decline in blood-brain-barrier specific glucose transporter expression, hexokinase expression and activity. The decline in glucose availability was accompanied by a significant rise in glial LDH5 expression and LDH5/LDH1 ratio indicative of lactate generation and utilization. In parallel, a significant rise in ketone body concentration in serum occurred which was coupled to an increase in neuronal MCT2 expression and 3-oxoacid-CoA transferase (SCOT) required for conversion of ketone bodies to acetyl-CoA. In addition, OVX-induced decline in glucose metabolism was paralleled by a significant increase in Aβ oligomer levels. 17β-estradiol preserved brain glucose-driven metabolic capacity and partially prevented the OVX-induced shift in bioenergetic substrate as evidenced by glucose uptake, glucose transporter expression and gene expression associated with aerobic glycolysis. 17β-estradiol also partially prevented the OVX-induced increase in Aβ oligomer levels. Collectively, these data indicate that ovarian hormone loss in a preclinical model of Alzheimer's was paralleled by a shift towards the metabolic pathway required for metabolism of alternative fuels in brain with a concomitant decline in brain glucose transport and metabolism. These findings also indicate that estrogen plays a critical role in sustaining brain bioenergetic capacity through preservation of glucose metabolism.

Ovariectomy-mediated impairment of spatial working memory, but not reference memory, is attenuated by the knockout of the dopamine D3 receptor in female mice

Memory modulation is implemented through many different factors, such as the dopaminergic system and ovarian hormones. Alterations of these factors may cause memory behavior changes. In the current study, dopamine D3 receptor mutant (D3−/−) female mice and their wild-type (WT) controls were used and randomly assigned to ovariectomized (OVX) and sham-operated (Sham) groups (four groups: WT-OVX, WT-Sham, D3−/−-OVX, and D3−/−-Sham). The possibility of co-effects of the dopamine D3 receptor and ovarian hormones on cognitive behavior was then examined. The spatial reference memory (SRM) and the motivation to escape from the water maze were not affected by either knockout of the dopamine D3 receptor or ovariectomy. Knockout of the dopamine D3 receptor had no effect on spatial working memory (SWM) in the Sham groups, but had a positive effect on SWM in the OVX groups. While an ovariectomy inhibited SWM in WT mice, it had no effect on SWM in D3−/− mice. These data suggested that ovarian hormone deprivation may induce spatial working memory decline, and blockade of D3 receptors could ameliorate this impairment. Based on our findings, there may be specific molecular changes responsible for the function of D3 receptors in modulating information processes under conditions of ovarian hormone deficit, which need to be further elucidated.

Ageing is the main determinant of haemodynamics and autonomic cardiac changes observed in post-menopausal female rats

The aim of this study was to evaluate and compare the effects of early and physiological menopause on cardiac autonomic parameters in aged female rats. To this end, female Wistar rats (22 and 82 weeks old, N=96) were divided into 4 groups: Young Sham-operated Rats, Aged Sham-operated Rats, Young Ovariectomised (OVX) Rats, and Aged OVX Rats. Young Sham-operated and OVX rats were used as controls. The cardiac autonomic parameters were investigated using different approaches: 1) pharmacological evaluation of the autonomic tonus with methylatropine and propranolol; 2) isolated cardiac contractility with β-adrenergic agonists; and 3) quantification of the mRNA and protein level expression of cardiac β-adrenergic receptors. Among the groups of aged female rats, both the Sham-operated and OVX rats showed higher basal mean arterial pressure and heart rate (HR) values compared to their respective young counterparts. The aged groups also showed a predominance of the sympathetic autonomic component in the determination of HR, whereas the young rats showed a vagal predominance. An assessment of cardiac contractility showed that aged Sham-operated and OVX rats had lower contractile responses following the administration of dobutamine compared to their respective young counterparts. In addition, the aged groups showed higher mRNA and protein expression levels of the β1-adrenergic receptors. In conclusion, our results show that haemodynamic alterations and impairment of the autonomic parameters were similar between the groups of rats subjected to early and physiological menopause. Moreover, these results seem to be due to the ageing process and not ovarian hormone deprivation.

Menopause leads to elevated expression of macrophage-associated genes in the aging frontal cortex: rat and human studies identify strikingly similar changes

BackgroundThe intricate interactions between the immune, endocrine and central nervous systems shape the innate immune response of the brain. We have previously shown that estradiol suppresses expression of immune genes in the frontal cortex of middle-aged ovariectomized rats, but not in young ones reflecting elevated expression of these genes in middle-aged, ovarian hormone deficient animals. Here, we explored the impact of menopause on the microglia phenotype capitalizing on the differential expression of macrophage-associated genes in quiescent and activated microglia.MethodsWe selected twenty-three genes encoding phagocytic and recognition receptors expressed primarily in microglia, and eleven proinflammatory genes and followed their expression in the rat frontal cortex by real-time PCR. We used young, middle-aged and middle-aged ovariectomized rats to reveal age- and ovariectomy-related alterations. We analyzed the expression of the same set of genes in the postcentral and superior frontal gyrus of pre- and postmenopausal women using raw microarray data from our previous study.ResultsOvariectomy caused up-regulation of four classic microglia reactivity marker genes including Cd11b, Cd18, Cd45 and Cd86. The change was reversible since estradiol attenuated transcriptional activation of the four marker genes. Expression of genes encoding phagocytic and toll-like receptors such as Cd11b, Cd18, C3, Cd32, Msr2 and Tlr4 increased, whereas scavenger receptor Cd36 decreased following ovariectomy. Ovarian hormone deprivation altered the expression of major components of estrogen and neuronal inhibitory signaling which are involved in the control of microglia reactivity. Strikingly similar changes took place in the postcentral and superior frontal gyrus of postmenopausal women.ConclusionsBased on the overlapping results of rat and human studies we propose that the microglia phenotype shifts from the resting toward the reactive state which can be characterized by up-regulation of CD11b, CD14, CD18, CD45, CD74, CD86, TLR4, down-regulation of CD36 and unchanged CD40 expression. As a result of this shift, microglial cells have lower threshold for subsequent activation in the forebrain of postmenopausal women.

The Effects of 17β-Oestradiol on Increased α1-Adrenergic Vascular Reactivity Induced by Prolonged Ovarian Hormone Deprivation: The Role of Voltage-Dependent L-type Ca2+ Channels

The present study investigated the hypothesis that the duration of ovarian hormone deprivation before reintroduction of oestrogen affects the role of oestrogen as a mediator of the contractile function of α₁-adrenergic receptors. Rats underwent ovariectomy (OVX) or were sham-operated, and the OVX rats were treated with vehicle (corn oil) or 17β-oestradiol (E₂) for 5 days either 10, 28 or 60 days after OVX. The OVX increased phenylephrine- and Ca²⁺-induced contractions. Interestingly, the phenylephrine-induced contractions were increased at each of the three time points, whereas the Ca²⁺-induced contractions were only increased in the 60-day group. E₂ had biphasic effects on phenylephrine- and Ca²⁺-induced contractility. Indeed, E₂ increased contractions in the 10-day group and diminished contractions in the other groups (the increased contractions were avoided by verapamil). These results indicate that E₂ controls α₁-adrenergic receptor-mediated contractility through effects on L-type Ca²⁺ channels in a way that depends on the timing in which the treatment with E₂ is initiated.

Abstract 614: Mechanism Involved In Fructose Induced Cardiovascular Risk: Evidence In An Experimental Model Of Hypertension And Menopause

The metabolic syndrome is a bunch of ordinary pathologies: abdominal obesity associated to an excess of visceral fat, insulin resistance, dyslipidemia and hypertension. Moreover, the prevalence of hypertension and metabolic dysfunctions sharply increases after the menopause. However, the mechanisms involved in these changes were not well understood. Thus, the aim of this study was to evaluate the effects of ovarian hormone deprivation (9 wks) in hypertensive (or not) female rats submitted (or not) to fructose overload on cardiovascular autonomic control and cardiac oxidative stress. Female Wistar and SHR rats were divided into (n=8/group): control (C), ovariectomized (O), hypertensive ovariectomized (HO) and hypertensive ovariectomized submitted to fructose overload (100g/L in drinking water) (FHO). The arterial pressure (AP) signals were directly recorded. The cardiovascular autonomic modulation was evaluated by pharmacological blockade and by spectral analysis. Oxidative stress profile was evaluated by chemiluminescence (CL) and redox balance of glutathione (GSH/GSSG) determinations. The AP showed increased in the O and HO groups when compared to C group. The FHO group showed increased blood glucose and tryglicerides, insulin resistance; an additional increase in mean AP (174±4 vs. C:108±1; O:121±2; HO:164±5 mmHg), resting tachycardia, reduced vagal tonus (5±3 vs. C:55±5; O:37±6; HO:35±7bpm), increased sympathetic tonus (91±18 vs. 39±10bpm in C), decreased high frequency band of the pulse interval (vagal modulation) and exacerbated increased systolic AP variance and decreased low frequency band of the pulse interval (sympathetic modulation) in relation to other groups. The CL was higher in O and HO groups than C group. FHO group showed additional increase in CL (15043±1333 vs. C: 2661±358; O: 5134±277; HO: 6514±547 cps/mgprot) when compared to other groups. The cardiac GSH/GSSG was lower in FOH group (8.94±0.80 umol/g) in relation to HO group (13.0±1.4 umol/g), indicating impaired redox balance. In conclusion, the fructose overload induced metabolic dysfunctions associated with additional impairment in cardiovascular autonomic control and oxidative stress profile in hypertensive rats submitted to ovarian hormones deprivation.

Minireview: translational animal models of human menopause: challenges and emerging opportunities.

Increasing importance is placed on the translational validity of animal models of human menopause to discern risk vs. benefit for prediction of outcomes after therapeutic interventions and to develop new therapeutic strategies to promote health. Basic discovery research conducted over many decades has built an extensive body of knowledge regarding reproductive senescence across mammalian species upon which to advance animal models of human menopause. Modifications to existing animal models could rapidly address translational gaps relevant to clinical issues in human menopausal health, which include the impact of 1) chronic ovarian hormone deprivation and hormone therapy, 2) clinically relevant hormone therapy regimens (cyclic vs. continuous combined), 3) clinically relevant hormone therapy formulations, and 4) windows of opportunity and optimal duration of interventions. Modifications in existing animal models to more accurately represent human menopause and clinical interventions could rapidly provide preclinical translational data to predict outcomes regarding unresolved clinical issues relevant to women's menopausal health. Development of the next generation of animal models of human menopause could leverage advances in identifying genotypic variations in estrogen and progesterone receptors to develop personalized menopausal care and to predict outcomes of interventions for protection against or vulnerability to disease. Key to the success of these models is the close coupling between the translational target and the range of predictive validity. Preclinical translational animal models of human menopause need to keep pace with changes in clinical practice. With focus on predictive validity and strategic use of advances in genetic and epigenetic science, new animal models of human menopause have the opportunity to set new directions for menopausal clinical care for women worldwide.