Effects of hormone replacement therapy on magnetic resonance imaging of brain parenchyma hyperintensities in postmenopausal women.

AIM: To apply 3.0 magnetic resonance imaging (MRI) to study the effects of long-term, low dose hormone replacement therapy (HRT) on the brain parenchyma of postmenopausal women. METHODS: A total of 155 postmenopausal healthy female medical staff members from Peking Union Medical College Hospital were enrolled. The HRT group was composed of 71 subjects who had been given a low dose of HRT for over 4 years, while 84 women who had never been given HRT were enrolled in the control group. The Mini-Mental State Examination (MMSE) was used to evaluate mental state, and an Enzyme-Linked ImmunoSorbent Assay (ELISA) was used to detect plasma levels of sex hormones. In addition, all participants were subjected to an MRI, including axial T2 weighted imaging (T2WI), fluid-attenuated inversion recovery (FLAIR), T1 weighted imaging (T1WI, oblique coronal, vertical to the hippocampus, slice thickness 3 mm without gaps), and a 3D image of the whole brain. RESULTS: The ELISA showed that the plasma level of estradiol in the HRT group was significantly higher than that in the control group (P<0.05). No differences were observed in the MMSE between the two groups. In participants older than 70 years of age, the number of deep white matter hyperintensities (DWMHs) in the control group was significantly higher than that in the HRT group (P=0.0013); however, in other age subgroups, no statistical differences were observed. Finally, no significant difference in periventricular hyperintensity (PVH) between the two groups was observed. CONCLUSION: We found that a high plasma level of estradiol in postmenopausal women receiving long-term HRT was correlated with the survival of brain parenchyma.Acta Pharmacologica Sinica (2009) 30: 1065-1070; doi: 10.1038/aps.2009.81.

Effects of long-term low-dose hormone replacement therapy on the binding capacity of platelet peripheral-type benzodiazepine receptor in postmenopausal women.

The effects of long-term low-dose hormone replacement therapy (HRT) on the level of hormone in plasma and on the binding capacity of peripheral-type benzodiazepine receptor (PBR) on the platelet membranes were investigated among women. This study was a retrospective and case-controlled study where 64 women using long-term low-dose HRT for over 4 years entered the study and 99 women, age and education matched, were enrolled as control. Plasma hormone level and platelet PBR binding capacity of two groups were analyzed. A significant increase in plasma estradiol level in women using HRT was observed, compared to those in the control group. Meanwhile, women in the HRT group displayed higher platelet PBR binding capacity. Further analysis demonstrated that the binding capacity of platelet PBR was closely related to estradiol plasma level in all subjects. These results suggest that long-term low-dose HRT could relieve the decrease of estradiol level in plasma and PBR binding capacity on platelets in postmenopausal women, alleviate the endocrine imbalance process, and might be beneficial for reducing the risks of some diseases.

Protective effects of phytoestrogen alpha-zearalanol on beta amyloid25-35 induced oxidative damage in cultured rat hippocampal neurons.

Although experimental evidence has shown that the neuroprotective effect from estrogen may benefit postmenopausal women, but the clinical use of estrogen was limited by the risk of increasing the cases of mammary and endometrial cancer. This study was designed to evaluate the neuroprotective effects of a novel phytoestrogen alpha-zearalanol (alpha-ZAL), on the cultured rat hippocampal neurons. Following a 24-h exposure of the cells to amyloid beta-peptide fragment 25-35 (A beta 25-35), a significant reduction in cell survival and activities of total superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), as well as increased of malondialdehyde (MDA) were observed. Preincubation of the cells with alpha-ZAL or 17 beta-estradiol(17 beta-E2) prior to A beta 25-35 exposure elevated the cell survival and SOD and GSH-Px activities, and decreased the level of MDA. These data suggested that the phytoestrogen alpha-ZAL, like estrogen, may effectively antagonize A beta 25-35-induced cell toxicity, which might be beneficial for neurons.

Effects of long-term, low-dose sex hormone replacement therapy on hippocampus and cognition of postmenopausal women of different apoE genotypes.

AIM: To study the effects of long-term, low-dose sex hormone replacement therapy (HRT) on the volume and biochemical changes of the hippocampus in postmenopausal women carrying apolipoprotein E (apoE) gene epsilon3 or epsilon4. METHODS: Eighty-three postmenopausal women who had used a low dose of HRT for over 4 years were selected as the HRT group, and 99 postmenopausal women with matched age and education were enrolled as the control group. ApoE alleles were analyzed by PCR. Magnetic resonance imaging was performed to determine the volume of the brain hippocampus. Proton magnetic resonance spectroscopy was used to detect the biochemical changes in the anterior cingulate cortex and hippocampus in apoE epsilon4 and epsilon3 carriers. Six common cognitive tests were used to make an overall evaluation of cognitive function. RESULTS: Analysis with the apoE epsilon4 carriers showed that the volume of the hippocampus of the control group were significantly lower than those of the HRT group. The biochemical analysis showed that there was an increase of N-acetylaspartate (NAA)/total creatine (tCr) and a decrease of myoinositol (mI)/tCr in the hippocampus of apoE epsilon4 carriers in the HRT group, compared with the control group. For the apoE epsilon3 carriers, the least squares means (LSMEAN) of the HRT group was higher than that of the control group. CONCLUSION: This study showed that long-term, low dose HRT might be beneficial for reducing the risk of AD development in vulnerable postmenopausal women. Meanwhile, HRT could increase the LSMEAN of apoE epsilon3 carriers.

[Effects of long-term and low-dose hormone replacement therapy on bone mineral density in postmenopausal women].

OBJECTIVE: To observe the effects of long-term and low-dose hormone replacement therapy on bone mineral density (BMD), and the incidence of bone pain in postmenopausal women. METHODS: Totally 141 postmenopausal women were selected from the medical staff of the Peking Union Medical College Hospital. Of them, 63 women treated with low-dose sex hormone for over 5 (5-32) years were divided into hormone replacement therapy (HRT) group, and 78 never receiving HRT were divided into control group. The BMD was measured by dual energy X-ray absorptiometry (DEXA) at lumbar spine, Ward's triangle, femoral neck, trochanter, and total hip, and the incidence of bone pain was inquired. RESULTS: The BMD in the HRT group was 9.1% higher than that in the control group (P < 0.05). The incidence of bone pain was significantly lower in the HRT group (71.4%) than that in the control group (89.7%). CONCLUSION: Long-term and low-dose hormone replacement therapy can reduce bone loss and the incidence of bone pain.

Treatment with phytoestrogen alpha-zearalanol might protect neurons of hippocampus in ovariectomized rats.

Although neuroprotective effects of estrogen on postmenopausal women have been recognized, an associated increased incidence of uterine and breast tumors has jeopardized the clinical use of estrogen. This study was designed to evaluate the neuroprotective effects of a novel phytoestrogen alpha-zearalanol (alpha-ZAL), on ovariectomized (OVX) rats. Adult Wistar rats were ovariectomized or sham-operated and treatment with equivalent doses of 17beta-estradiol or alpha-ZAL for 5 wk. Uteruses have been weighted and stained by hematoxylin and eosin for morphology analysis. The expression of synaptophysin and parvalbumin in hippocampus were evaluated by immunohistochemistry assays. Our experiments indicated that the synaptophysin and parvalbumin-positive areas were significantly decreased in the OVX group compared to the sham group, alpha-ZAL or 17beta-estradiol administration can reverse the effects. Although alpha-ZAL and 17beta-estradiol treatments reconciled uterus weight loss which was induced by ovariectomy, the effect of alpha-ZAL was less than 17beta-estradiol. This result suggests that alpha-ZAL may effectively abate neurons loss in the hippocampus while slightly promoting weight gain of the uterus.

Evaluation of neuroprotective effects of long-term low dose hormone replacement therapy on postmenopausal women brain hippocampus using magnetic resonance scanner.

OBJECTIVE: To investigate the effects of long-term low dose hormone replacement therapy (HRT) on postmenopausal women in hormone level, cognition score, hippocampus volume, and magnetic resonance spectroscopy (MRS) parameters. METHODS: A total of 182 postmenopausal women aged 50-87 years were chosen at Peking Union Medical College Hospital and assigned to HRT group and control group. The volunteers of HRT group had taken low dose hormone [estradiol (E2) 0.5-1.0 mg and progesterone 0.5-2.0 mg, once a day] for 4-33 years. The concentrations of E2, progesterone, and testosterone were measured using enzyme-linked immunosorbent assay (ELISA). The gene types of apolipoprotein E (ApoE) were measured by polymerase chain reaction, and the subjects with susceptible genes (ApoE epsilon3/epsilon4) of Alzheimer's disease (AD) were screened. Their hippocampus volumes and MRS parameters were obtained through magnetic resonance imaging (MRI), and results in two groups were analyzed by statistical method. RESULTS: Compared with control group, the concentrations of E2 at each age stage in HRT group were significantly higher (P < 0.05) except the 80-89 years old subgroup; yet, there were no statistical differences in the concentrations of progesterone and testosterone between the two groups. There was no obvious difference in ApoE subtypes distribution between the two groups. The results of hippocampus MRI for the subjects with susceptible genes ApoE epsilon3/epsilon4 (HRT group 14 cases, control group 11 cases) showed that the ratio of bilateral hippocampus volume to whole brain volume in HRT group (0.406 +/- 0.028) was significantly higher than control group (0.369 +/- 0.031, P < 0.05). The results of 1H MRS for the subjects with susceptible genes ApoE epsilon3/epsilon4 (HRT group 12 cases, control group 11 cases) showed that the N-acetylaspartate/total creatine at the area of hippocampus in HRT group (1.54 +/- 0.08) were significantly higher than control group (1.45 +/- 0.13, P < 0.05). CONCLUSIONS: For postmenopausal women, long-term low dose HRT can maintain the physiological concentration of E2 in plasma. Furthermore, the hippocampus MRI performed on those with ApoE epsilon3/epsilon4 genes shows that long-term low dose HRT can prevent hippocampus atrophy, which is beneficial to maintain the brain function and prevent AD.

[Bone mineral and body composition analysis of whole body in 292 normal subjects assessed by dual X-ray absorptiometry].

OBJECTIVE: To understand whole body bone mineral and body composition changes in normal subjects, and study the relationship between body composition and bone mineral. METHODS: 292 normal subjects aged 10-79 years old, including 140 males and 152 females, were selected to be measured bone mineral content (BMC), bone mineral density (BMD) lean and fat of whole body by dual X-ray absorptiometry (DXA). Individuals were divided into age-groups by every ten years and were analyzed by statistical methods. RESULTS: In males, peak values of BMC, BMD, lean and fat were in the 30-39, 20-39, 30-39, 70-79 age-groups. In females, they were in the 30-39, 30-39, 30-49, 50-69 age-groups respectively. Peak values of BMC, BMD and lean were higher in males than that in females, but peak value of BMD was not significantly higher in males than that in females. Peak value of fat was higher in females than that in males. Loss of BMC and BMD for females were more pronounced than that for males. Loss of lean for males was more pronounced than that for females. There are significant positive correlation between lean, weight and bone mineral in males and females. Fat has significant effect on BMC in females only. CONCLUSIONS: The normal bone mineral and body composition data of whole body for males and females, and the characteristic of changes with aging are provided for analyzing the relationship between bone mineral and body composition with ease.

[Effects of sex hormones on serum levels of nitric oxide and plasma angiotensin II in postmenopausal women].

OBJECTIVE: To observe the effect of estrogen and progestin on the blood levels of nitric oxide and angiotensin II in aid of the application of hormone replacement therapy in postmenopausal women. METHODS: The serum nitric oxide and plasma angiotensin II levels in postmenopausal women were determined before and 3 months after oral intake of estradiol valerate 1 mg/day (n = 10) or estradiol valerate, 1 mg/d plus medroxyprogesterone acetate, 2 mg/d (n = 30). RESULTS: The serum nitric oxide levels of postmenopausal women were significantly increased by 3 months of oral estradiol valerate 1 mg/d (P < 0.05), whereas the plasma levels of angiotensin II tended to decrease. The positive correlation between the increases of nitric oxide and the changes of estradial 3 months after oral intake of estradiol valerate 1 mg/d was significant. Compared with the baseline, no significant changes were observed in both serum nitric oxide levels and plasma angiotensin II levels 3 months after oral intake of estradiol valerate, 1 mg/d plus medroxyprogesterone acetate, 2 mg/d (P < 0.05). CONCLUSIONS: The vascular functions can be improved through increasing the serum nitric oxide level after 3-month oral intake of estradiol valerate, 1 mg/d in postmenopausal women, and estradiol valerate plus medroxyprogesterone acetate intake may attenuate the beneficial effects.

[Right attitude towards the postmenopausal hormone replacement therapy].

We have gone through decades using hormone replacement therapy (HRT). The first problem encountered was increased endometrial cancer and solved by addition of progesterone. Now we are facing cardiovascular complications and how could we solve in the use of HRT. Research in vitro with HUAR and HUVEC and clinically seemed to show that small physiological doses might be the solution in protection of CVD.