Long-term Estrogen Therapy Research Articles

Effects of estrogen therapy on age-related differences in gray matter concentration

Objective Previous studies suggest that estrogen therapy (ET) either improves or has a neutral effect on the structural integrity of neural tissue in postmenopausal women. The inconsistency in the findings of previous studies is likely to be due to a variety of methodological factors. In this study, we attempted to overcome many of these factors.Method We used magnetic resonance imaging and voxel-based morphometry to study the long-term effects of ET commenced immediately postmenopause on age-related differences in (1) normalized lobar brain volumes and (2) regional gray and white matter concentrations. We included 61 healthy women: 23 young, 19 postmenopausal long-term ET users (who had started ET around the time of menopause) and 19 postmenopausal ET never-users.Results We report that ET users did not differ significantly from never-users in age, duration of menopause, general intelligence, mnemonic function or apolipoprotein E allele frequency. Compared to young women, both ET users and never-users had significantly smaller normalized volumes of whole brain and left and right frontal lobes, but ET users did not differ significantly from never-users in bulk brain volumes. Compared to young women and ET users, never-users had significantly lower gray matter concentration bilaterally in orbitofrontal cortices and cerebellum, right inferior frontal and precentral cortices, and left paracentral cortex.Conclusion These findings suggest that initiation of ET around the time of menopause may modulate age-related differences in regional gray matter concentration. The functional significance of our findings remains unknown.

What’s new in the other journals?

What’s new in the other journals?

Long-term estrogen therapy and 5-HT 2A receptor binding in postmenopausal women; a single photon emission tomography (SPET) study

Variation in estrogen level is reported by some to affect brain maturation and memory. The neurobiological basis for this may include modulation of the serotonergic system. No neuroimaging studies have directly examined the effect of extended estrogen therapy (ET), on the 5-HT 2A receptor in human brain. We investigated the effect of long-term ET on cortical 5-HT 2A receptor availability in postmenopausal women. In a cross-sectional study, we compared cortical 5-HT 2A receptor availability in 17 postmenopausal ERT-naive women and 17 long-term oophorectomised estrogen-users, age- and IQ-matched using single photon emission tomography and the selective 5-HT 2A receptor ligand 123I-5-I-R91150. Also, we used the Revised Wechsler Memory Scale to relate memory function to 5-HT 2A receptor availability. Never-users had significantly higher 5-HT 2A receptor availability than estrogen-users in hippocampus (1.17 vs. 1.11, respectively, p = 0.02), although this did not remain significant after correction for multiple comparisons. Hippocampal 5-HT 2A receptor availability correlated negatively with verbal and general memory and delayed recall ( r = − 0.45, p = 0.01; r = − 0.40, p = 0.02; r = − 0.36, p = 0.04). Right superior temporal 5-HT 2A receptor availability correlated negatively with verbal memory ( r = − 0.36, p = 0.04). In estrogen-users, receptor availability correlated negatively with verbal and general memory ( r = − 0.70, p = 0.002; r = − 0.69, p = 0.002); and in never-users, receptor availability negatively correlated with attention and concentration ( r = − 0.54, p = 0.02). Long-term ET may be associated with lower 5-HT 2A receptor availability in hippocampus. This may reflect increased activity within the serotonergic pathway leading to down-regulation of post-synaptic receptor. Also, increased availability of the 5-HT 2A receptor in hippocampus is associated with poorer memory function.

Hormone Replacement Therapy and Atherosclerosis in Postmenopausal Women

Despite the clear-cut epidemiological evidence of protective effects of endogenous estrogens in premenopausal women,1,2 the results of randomized clinical trials using conjugated equine estrogens and medroxyprogesterone acetate instead of natural hormones have led to a paradigm shift in the usefulness of hormone treatment in postmenopausal women.3,4 One of the main criticisms in addition to the types of drugs chosen for treatment was the age of the patients. Indeed, in both WHI trial and HERS study, treatment of patients was initiated in women many years beyond menopause.5 In fact, the number of years since menopause was an independent indicator for nonfatal myocardial infarction or coronary related death.5 In this context, it appears of interest that heart disease may contribute to menopausal age and that menopausal age actually may be an indicator of cardiovascular risk.6,7 See page 1782 It was noted as early as 1952 that the natural endogenous estrogen 17β-estradiol inhibits experimental atherosclerosis,8 and oral estrogens were even unsuccessfully evaluated to treat coronary artery disease in male patients.9–11 However, at the time little was known about the mechanisms by which sex steroid hormones affect vascular homeostasis and thrombogenesis. During the past 2 decades, considerable advances were made in the understanding of how natural estrogens act on the vasculature. 17β-estradiol causes rapid and endothelium-independent dilation of coronary arteries of men and women,12 and chronic treatment with 17β-estradiol inhibits experimental atherosclerosis in males and females.13,14 On the other hand, treatment with conjugated equine estrogens, which contain more than 30 different steroid compounds including testosterone and substances of still undefined vascular activity (Table), have shown less favorable effects,2–4 as has been reported for the synthetic progestin medroxyprogesterone acetate.15 With the identification of molecular targets of 17β-estradiol and other estrogens it now appears that …

Estrogen Therapy and brain muscarinic receptor density in healthy females: A SPET study

Estrogen Therapy (ET) may protect against age-related cognitive decline and neuropsychiatric disorders (e.g. Alzheimer's disease). The biological basis for this putative neuroprotective effect is not fully understood, but may include modulation of cholinergic systems. Cholinergic dysfunction has been implicated in age-related memory impairment and Alzheimer's disease. However, to date no one has investigated the effect of long-term ET on brain cholinergic muscarinic receptor aging, and related this to cognitive function. We used Single Photon Emission Tomography (SPET) and ( R, R)[ 123I]-I-QNB, a novel ligand with high affinity for m 1/m 4 muscarinic receptors, to examine the effect of long-term ET and age on brain m 1/m 4 receptors in healthy females. We included 10 younger premenopausal subjects and 22 postmenopausal women; 11 long-term ET users (all treated following surgical menopause) and 11 ET never-users (surgical menopause, n = 2). Also, verbal memory and executive function was assessed in all postmenopausal subjects. Compared to young women, postmenopausal women (ET users and never-users combined) had significantly lower muscarinic receptor density in all brain regions examined. ET users also had higher muscarinic receptor density than ET never-users in all the brain regions, and this reached statistical significance in left striatum and hippocampus, lateral frontal cortex and thalamus. Moreover, in ET users, ( R, R)[ 123I]-I-QNB binding in left hippocampus and temporal cortex was significantly positively correlated with plasma estradiol levels. We also found evidence for improved executive function in ET users as compared to ET never-users. However, there was no significant relationship between receptor binding and cognitive function within any of the groups. In healthy postmenopausal women use of long-term ET is associated with reduced age-related differences in muscarinic receptor binding, and this may be related to serum estradiol levels.

Chronic exposure to estrogen and tamoxifen regulates synaptophysin and phosphorylated cAMP response element-binding (CREB) protein expression in CA1 of ovariectomized rat hippocampus

We report here the in vivo effects of estrogen (E2) on modulation of synaptic plasticity and the agonistic (estrogen-like) role of selective estrogen receptor modulator (SERM), tamoxifen (TAM) in the CA1 of the rat hippocampus. Effects on synaptophysin (SYP), a presynaptic vesicular protein, and phosphorylated cyclic AMP responsive element- binding (p-CREB) protein, a signal transduction pathway molecule, were studied using the ovariectomized (OVX) experimental rat model. Bilateral ovariectomy was performed on 40 rats and these were divided into 4 groups based on the treatment they received (at 2 weeks post-ovariectomy, a subcutaneous injection daily for 4 weeks) viz., OVX + E2 (0.1 mg/kg body weight), OVX + TAM (0.05 mg/kg body weight), OVX + vehicle and one group served as OVX control. An additional 10 animals served as the ovary intact control group. At the end of the treatment schedule, five animals/group were used for immunohistochemical staining of SYP and p-CREB using specific antibodies with peroxidase anti-peroxidase technique on paraformaldehyde-fixed cryostat sections. Protein estimation and Western blot analysis coupled with densitometric analysis (using gel-documentation system and image analysis software) were performed on unfixed hippocampus collected from rest of the five animals/group. Serum estradiol levels were estimated with radioimmunoassay prior to sacrifice. The results revealed that ovariectomy reduced SYP and p-CREB expression whereas E2 or TAM administration resulted in their upregulation. Serum estradiol levels of E2 administered animals were comparable with the ovary intact group whereas those of TAM administered group persisted in the range of OVX controls. To conclude, long-term estrogen therapy modulates the synaptic plasticity of hippocampal neurons and presumably, the agonist biocharacter of TAM as observed in the present investigations, may in the long run have a potential in the treatment and prevention of various estrogen-related disorders.

Menopausal estrogen therapy predicts better nocturnal oxyhemoglobin saturation

Objectives The respiratory responses in the few previous studies evaluating the effects of short-term unopposed estrogen therapy on breathing in postmenopausal women have been inconsistent. We performed a study to investigate whether long-term estrogen therapy would prevent age-related decline in nocturnal arterial oxyhemoglobin saturation and whether higher serum estradiol concentration is associated with better arterial oxyhemoglobin saturation. Methods Sixty-four healthy postmenopausal women were followed-up for 5 years in a 5-year prospective open follow-up study. The women were users or non-users of estrogen therapy according to their personal preference. Results Mean overnight arterial oxyhemoglobin saturation was similar at baseline (94.3 ± 1.1%) and after follow-up (94.5 ± 1.6%). Present estrogen users had higher mean arterial oxyhemoglobin saturation (95.2 ± 1.4%) than present non-users (94.0 ± 1.5%), when adjusted for age and body mass index ( p = 0.042). The change in mean arterial oxyhemoglobin saturation during follow-up was not associated with serum estradiol concentration at baseline but associated with estradiol at follow-up ( p = 0.042), when adjusted for age and body mass index. At follow-up, women with higher serum estradiol concentration had also higher mean nocturnal arterial oxyhemoglobin saturation (Pearson r = 0.29, p = 0.019) and lower apnea-hypopnea index (Spearman r = −0.28, p = 0.031). The pooled current estrogen users spent proportionally less time with SaO 2 below 90% than non-users (ANCOVA adjusted for age and BMI, p = 0.017). Conclusions Estrogen use and especially high serum estradiol concentration predict higher mean overnight arterial oxyhemoglobin saturation. The present data suggest that estrogen therapy has favorable respiratory effects.

α1‐Adrenoceptor subtypes in isolated corporal tissue from patients undergoing gender re‐assignment

To investigate the pharmacology and functionality of alpha(1)-adrenoceptors in human corpus cavernosum, and to determine the predominant subtype. Cavernosal tissue specimens were obtained from the penises of 22 men (mean age 37.4 years) removed during gender re-assignment surgery. The men had been maintained on long-term oestrogen therapy before surgery, to aid the development of secondary feminine characteristics (oestrogen treatments were stopped 6 weeks before surgery). Corpus cavernosum strips were mounted in organ baths perfused with Krebs' solution. A control concentration-response curve (CRC) to phenylephrine (a nonselective alpha(1)-agonist) was obtained. Then the tissues were incubated with the alpha(1A) antagonist, WB4101; the alpha(1B) antagonist, chloroethylclonidine; or the alpha(1D) antagonist BMY 7378 (all at 1 microm) and the CRC to phenylephrine was repeated. The concentration producing a half-maximal response (EC(50)) and pK(B) values (logarithm of the dissociation constant, a measure of affinity) were determined. WB4101 produced a parallel rightward shift of the CRC to phenylephrine, with a pK(B) of 7.49. BMY 7378 also produced a parallel rightward shift of the CRC to phenylephrine with a pK(B) of 6.45. Chloroethylclonidine had a similar effect on the phenylephrine CRC, with a pK(B) of 5.90. Alpha(1)-adrenoceptors in human cavernosal tissue have a relatively low affinity for BMY 7378 and chloroethylclonidine, but are more sensitive to WB4101. This confirms that the predominant alpha(1)-adrenoceptor subtype in human corpus cavernosum is the alpha(1A) subtype and this might help in developing more selective antagonists and agonists for managing erectile dysfunction and priapism.

Increased longevity in older users of postmenopausal estrogen therapy: the Leisure World Cohort Study

To examine the effect of postmenopausal estrogen therapy (ET), including duration and recency of use, on all-cause mortality in older women. As part of a prospective cohort study of residents of a California retirement community begun in the early 1980s, Leisure World Cohort women (median age, 73 y) completed a postal health survey including details on ET use and were followed up for 22 years (1981-2003). Age- and multivariate-adjusted risk ratios (RR) and 95% CIs were calculated using proportional hazard regression. Of the 8,801 women, 6,626 died during follow-up (median age, 88 y). ET users had an age-adjusted mortality rate of 52.9 per 1,000 person-years compared with 56.5 among lifetime nonusers (RR = 0.91; 95% CI, 0.87-0.96). Risk of death decreased with both increasing duration of ET and decreasing years since last use (P for trend <0.001). The risk was lowest among long-term (> or =15 y) users (RR = 0.83; 95% CI, 0.74-0.93 for 15-19 y and RR = 0.87; 95% CI, 0.80-0.94 for 20+ y). For long-term users, the age-adjusted mortality rate was 50.4 per 1,000 person-years. Lower-dose users (< or =0.625 mg) had a slightly better survival rate than higher-dose users (RR = 0.84; 95% CI, 0.78-0.91 vs RR = 0.91; 95% CI, 0.83-0.97). Risk did not differ by route of administration (P = 0.56). Further adjustment for potential confounders had little effect on the observed RRs for ET. Long-term ET is associated with lower all-cause mortality in older women.

Climacteric medicine: European Menopause and Andropause Society (EMAS) 2004/2005 position statements on peri- and postmenopausal hormone replacement therapy

In women experiencing distressing climacteric symptoms during the peri- and postmenopause there is conclusive evidence from abundant randomised controlled trials that systemic hormone replacement therapy (HRT) of any type affords symptom relief, with no alternative treatment producing similar effect. Though this evidence is accumulating, the question of how to provide best clinical practice in an attempt to both alleviate the menopausal symptoms and prevent the more long-term postmenopausal degenerative diseases is still under debate. When providing climacteric medicine, the dose and regimen of HRT needs to be individualised based on the principle of choosing the lowest appropriate dose in relation to severity of symptoms and on the menopausal age. However, few long-term data on different HRT formulations exist in symptomatic women, which also account for baseline risk of cardiovascular disease (CVD), breast cancer and osteoporosis. In most cases, an individualized prescription together with life-style management will sustain possibilities for net beneficial effects on climacteric symptoms, quality of life (QoL), sexuality and osteoporosis, with only rare risk of severe adverse effects. With the perspective provided by recent epidemiological findings, not least from the estrogen only arm of the Women's Health Initiative Study (WHI), European Menopause and Andropause Society (EMAS) supports research activities in symptomatic women with new HRT formulations in order to affect positively the balance of clinical benefit and risk, including specific information on QoL and also account for the traditional differences in treatment modalities between the US and Europe, and the difference in BMI, life-style and diet. In women experiencing an early menopause (<45 year) current data support a specific overall benefit of HRT. At present, more long-term systemic HRT may be considered in women at high risk of osteoporotic fractures, in particular when alternate therapies are either inappropriate or insufficiently effective, as benefits will outweigh any risks. In contrast, urogenital symptoms may be addressed efficiently and safely with long-term local estrogen therapy.

Estrogen Therapy Fails to Alter Amyloid Deposition in the PDAPP Model of Alzheimer’s Disease

Epidemiological studies implicate estrogen deprivation as a risk factor for Alzheimer's disease and postmenopausal estrogen replacement as protective factor. One potential mechanism involves estrogen attenuation of beta-amyloid (Abeta) peptide accumulation. We examined the effect of estrogen on amyloid accumulation in female PDAPP mice, which express human amyloid precursor protein (APP) with the V717F mutation. These animals deposit Abeta 1-42 in the hippocampus and neocortex and develop Alzheimer-like neuropathology. Mice were subjected to ovariectomy, ovariectomy with estrogen replacement, or sham surgery at 3 months of age, and levels of cerebral Abeta 1-40 and 1-42 were determined after 5 months of treatment. Neither estrogen deprivation nor estrogen replacement altered Abeta accumulation in the hippocampus or neocortex. Similarly, immunoreactivity for full-length human APP and secreted APPalpha was unchanged. Estrogen status of the animals was confirmed using a variety of techniques, including uterine and pituitary weight, vaginal cytology, and plasma estradiol concentrations. There was no correlation between plasma estradiol levels and accumulation of either Abeta 1-40 or Abeta 1-42 in the brain. Our observations indicate that long-term estrogen therapy does not alter amyloid pathology in PDAPP mice, an animal model of Alzheimer's disease, and question the role of estrogen in Abeta deposition in brain.

Effect of long-term estrogen therapy on dopaminergic responsivity in post-menopausal women—a preliminary study

Females have a higher prevalence than men of neuropsychiatric disorders in which dopaminergic abnormalities play a prominent role, e.g. very late-onset schizophrenia and Parkinson’s disease (PD). The biological basis of these sex differences is unknown but may include modulation of the dopaminergic system by sex hormones, as there is preliminary evidence that estrogen modulates treatment response in these disorders. Furthermore, sex differences in dopamine-mediated cognitive decline suggest estrogen may also play a role in healthy aging. However, the effects of estrogen on the dopaminergic system are poorly understood, and nobody has examined the effect of long-term estrogen therapy (ET) on this system. We compared dopaminergic responsivity (growth hormone (GH) response to apomorphine) in post-menopausal women on ET to women who were ET-naïve. GH response to subcutaneous apomorphine (0.005 mg/kg) was measured in two groups of healthy post-menopausal women aged between 55 and 70 years: those taking ET ( n=13) and those who had never taken ET ( n=13). Neither group was taking any other medication. GH was measured at 15 min intervals from −30 min before administration of apomorphine to 90 min post-administration. GH response was measured in two ways: area under the curve (AUC) and maximum response over baseline (GH). There were no between-group differences in demographic or baseline variables. The ET treated women had a significantly greater ( p=0.03) AUC than ET naïve women (mean±S.D.; 5.3±4.7 vs. 2.6±2.3). However, (GH) did not differ significantly between groups (6.1 mU/l±6.2 vs. 2.7 mU/l±S.D.=4.1). Also, analysis of GH response over time revealed a significant main effect of time ( p<0.0005), and a group by time interaction ( p=0.004), but no significant main effect of group. Our results suggest that ET may enhance dopaminergic responsivity in post-menopausal women. Estrogen deficiency following menopause may partly explain age and gender differences in late-onset neuropsychiatric disorders.

Hot flashes in breast cancer survivors.

Hot flashes can be a major problem for patients with a history of breast cancer. The precipitation of menopause in premenopausal women who undergo chemotherapy for breast cancer can lead to the rapid onset of hot flash symptoms that are more frequent and more severe than those associated with natural menopause. In addition, tamoxifen, historically the most commonly prescribed pharmacologic agent for the treatment of breast cancer, is associated with hot flashes in more than 50% of its users. Although estrogen relieves hot flashes in 80-90% of women who initiate treatment, its use in women with a history of breast cancer is controversial, and most physicians in the community will not use this treatment modality. In addition, the results of the long-awaited Women's Health Initiative study and other recent studies suggest that long-term estrogen therapy should not be recommended for most women for a variety of reasons. However, hot flashes in breast cancer survivors should no longer be considered untreatable, as there are many pharmacologic and nonpharmacologic treatments that can help alleviate this problem. This article reviews the current strategies for the management of hot flashes in breast cancer survivors and the evidence supporting their use.

Estrogens and menopause: pharmacology of conjugated equine estrogens and their potential role in the prevention of neurodegenerative diseases such as Alzheimer’s

Menopause marks the start of a new phase in a woman’s life that is associated with a decrease in circulating estrogen levels. Although the average age of women has increased from 50 to nearly 85 years, the average age at menopause has remained essentially constant at 50 years. Thus, women now spend nearly a third of their lives in an estrogen deficient state. This normal aging process in women is associated with increasing health problems such as osteoporosis, cardiovascular disease, neurodegenerative diseases, and cancer. Estrogen replacement therapy (ERT) has been shown to play an important beneficial role in the health and well being of postmenopausal women. Several estrogen preparations are available and among these conjugated equine estrogens (CEE) are most frequently used. The drug CEE, is a complex natural urinary extract of pregnant mare’s urine and contains at least 10 estrogens in their sulfate ester form and these are the ring B saturated estrogens: estrone (E 1), 17β-estradiol (17β-E 2), 17α-estradiol (17α-E 2), and the ring B unsaturated estrogens equilin (Eq), 17β-dihydroequilin (17β-Eq), 17α-dihydroequilin (17α-Eq), equilenin (Eqn), 17β-dihydroequilenin (17β-Eqn), 17α-dihydroequilenin (17α-Eqn), and Δ 8-estrone (Δ 8-E 1). All of these estrogens in their unconjugated form are biologically active and can interact with recombinant human estrogen receptor α (ERα) and β (ERβ) with 17β-estradiol and 17β-dihydroequilin having the highest affinity for both receptors. A number of the ring B unsaturated estrogens had nearly twofold higher affinity for the ERβ. The pharmacokinetics of these estrogens in postmenopausal women indicate that the unconjugated estrogens compared to their sulfated forms are cleared more rapidly. The 17-keto estrogens are metabolized to the more potent 17β-reduced products which are cleared at a slower rate. In postmenopausal women, the extent of 17β-activation is much higher with the ring B unsaturated estrogens than with ring B saturated estrogens. Oxidized LDL and oxidative stress are thought to contribute to both atherosclerosis and neurodegenerative disorders. Neurons in particular are at a high risk from damage resulting from oxidative stress. In vivo and in vitro studies indicate that the oxidation of LDL isolated from postmenopausal women was inhibited differently by various estrogens and other antioxidants. The unique ring B unsaturated estrogens were the most potent while the red wine component t-resveratrol was the least potent. Studies were designed to explore the cellular and molecular mechanisms that may be involved in the neuroprotective effects of CEE components. The data indicate that the neurotoxic effects of oxidized LDL and glutamate can be inhibited by various estrogens, with the ring B unsaturated estrogens being the most active. These effects are involved in the inhibition of DNA fragmentation and up-regulation of anti-apoptotic protein Bcl-2 and down-regulation of pro-apoptotic protein Bax. These combined data suggest that some of the neuroprotective benefits associated with long-term estrogen therapy may occur by the above mechanism(s). Because estrogens such as the Δ 8-estrogens are relatively less feminizing than the classical estrogen 17β-estradiol, they may be important in the development of more neuro-specific estrogens that will be useful in the prevention of neurodegenerative diseases, such as Alzheimer’s and Parkinson disease, in both men and women.

Women’s Health Initiative Study

Menopause marks the start of a new phase in a woman’s life that is associated with a decrease in circulating estrogen levels. Although the average age of women has increased from 50 to nearly 85 years, the average age at menopause has remained essentially constant at 50 years. Thus, women now spend nearly a third of their lives in an estrogen deficient state. This normal aging process in women is associated with increasing health problems such as osteoporosis, cardiovascular disease, neurodegenerative diseases, and cancer. Estrogen replacement therapy (ERT) has been shown to play an important beneficial role in the health and well being of postmenopausal women. Several estrogen preparations are available and among these conjugated equine estrogens (CEE) are most frequently used. The drug CEE, is a complex natural urinary extract of pregnant mare’s urine and contains at least 10 estrogens in their sulfate ester form and these are the ring B saturated estrogens: estrone (E1), 17β-estradiol (17β-E2), 17α-estradiol (17α-E2), and the ring B unsaturated estrogens equilin (Eq), 17β-dihydroequilin (17β-Eq), 17α-dihydroequilin (17α-Eq), equilenin (Eqn), 17β-dihydroequilenin (17β-Eqn), 17α-dihydroequilenin (17α-Eqn), and Δ8-estrone (Δ8-E1). All of these estrogens in their unconjugated form are biologically active and can interact with recombinant human estrogen receptor α (ERα) and β (ERβ) with 17β-estradiol and 17β-dihydroequilin having the highest affinity for both receptors. A number of the ring B unsaturated estrogens had nearly twofold higher affinity for the ERβ. The pharmacokinetics of these estrogens in postmenopausal women indicate that the unconjugated estrogens compared to their sulfated forms are cleared more rapidly. The 17-keto estrogens are metabolized to the more potent 17β-reduced products which are cleared at a slower rate. In postmenopausal women, the extent of 17β-activation is much higher with the ring B unsaturated estrogens than with ring B saturated estrogens. Oxidized LDL and oxidative stress are thought to contribute to both atherosclerosis and neurodegenerative disorders. Neurons in particular are at a high risk from damage resulting from oxidative stress. In vivo and in vitro studies indicate that the oxidation of LDL isolated from postmenopausal women was inhibited differently by various estrogens and other antioxidants. The unique ring B unsaturated estrogens were the most potent while the red wine component t-resveratrol was the least potent.Studies were designed to explore the cellular and molecular mechanisms that may be involved in the neuroprotective effects of CEE components. The data indicate that the neurotoxic effects of oxidized LDL and glutamate can be inhibited by various estrogens, with the ring B unsaturated estrogens being the most active. These effects are involved in the inhibition of DNA fragmentation and up-regulation of anti-apoptotic protein Bcl-2 and down-regulation of pro-apoptotic protein Bax. These combined data suggest that some of the neuroprotective benefits associated with long-term estrogen therapy may occur by the above mechanism(s). Because estrogens such as the Δ8-estrogens are relatively less feminizing than the classical estrogen 17β-estradiol, they may be important in the development of more neuro-specific estrogens that will be useful in the prevention of neurodegenerative diseases, such as Alzheimer’s and Parkinson disease, in both men and women.

Effects of long-term hormone replacement and of tibolone on choline acetyltransferase and acetylcholinesterase activities in the brains of ovariectomized, cynomologous monkeys

We examined long-term effects of low and high doses of tibolone, conjugated equine estrogens, and conjugated equine estrogens plus medroxyprogesterone acetate on choline acetyltransferase and acetylcholinesterase activities within different regions of the brain in cynomologous monkeys. All treatments were administered for 2 years. None of the treatments produced significant increases in either choline acetyltransferase or acetylcholinesterase in any of eight brain regions analyzed. In contrast, treatment with conjugated equine estrogens plus medroxyprogesterone acetate, but not conjugated equine estrogens alone, produced significant reductions in both choline acetyltransferase and acetylcholinesterase in the medial septum/diagonal band of Broca compared with untreated controls. Treatment with tibolone also resulted in significant reductions in both choline acetyltransferase and acetylcholinesterase in the medial septum/diagonal band of Broca, and this effect was dose-related. These findings are the first to report the effects of long-term therapies used by postmenopausal women on cholinergic measures in the primate brain. The findings are consistent with recent reports in rats, and suggest that any positive effects of long-term estrogen or hormone replacement therapy on cognitive processes are probably not due to significant effects on choline acetyltransferase or acetylcholinesterase activities.

Arterial stiffness is not improved in long-term use of estrogen

Objective: The purpose of this study was to compare arterial stiffness in long-term users of estrogen who were postmenopausal, age-matched women who did not use estrogen, and women of fertile age. Study Design: In this clinical cross-sectional study, carotid, femoral, and aortic stiffness (estimated as elastic modulus and stiffness β index) were assessed by ultrasonic phase-locked echo-tracking in 17 women who were postmenopausal and who were treated with 17 β-estradiol implants (mean age, 68.8 years; mean duration of treatment, 20 years), 17 age-matched (±1 year) untreated women, and 20 women in the fertile age period. Results: Compared with women of fertile age, both postmenopausal groups had significantly higher stiffness elastic modulus and stiffness β index (carotid, P <.001; femoral, P <.05; aorta, P <.001). However, for all 3 arteries, both stiffness indices were similar in estrogen users and nonusers and did not differ significantly. These results remained after an adjustment for systolic blood pressure, body mass index, and low-density lipoprotein cholesterol levels. Conclusion: These data indicate that the arterial stiffening that is related to aging/menopause is not substantially affected by long-term estrogen therapy. (Am J Obstet Gynecol 2002;186:189-94.)

Long-term estrogen therapy worsens the behavioral and neuropathological consequences of chronic brain inflammation.

Long-term estrogen therapy worsens the behavioral and neuropathological consequences of chronic brain inflammation.

Long-term estrogen therapy worsens the behavioral and neuropathological consequences of chronic brain inflammation.

Alzheimer's disease (AD) is accompanied by chronic neuroinflammation and occurs with greater incidence in postmenopausal women. The increased incidence may be delayed by estrogen replacement therapy (ERT). The authors investigated the interaction of chronic ERT and lipopolysaccharide (LPS)-induced neuroinflammation in the female rat. Ovariectomy did not impair water maze performance; however, addition of chronic ERT or neuroinflammation resulted in an impairment that became exacerbated by the simultaneous occurrence of both conditions. Chronic LPS activated microglia, which was not reduced by ERT. Intact females receiving LPS infusion were not impaired in the water maze and had significantly fewer activated microglia. Results suggest that chronic ERT in postmenopausal women may exacerbate the memory impairment induced by the chronic neuroinflammation associated with AD.

Selective Estrogen Receptor Modulator Effects on Serum Lipoproteins and Vascular Function in Postmenopausal Women and in Hypercholesterolemic Men

Epidemiological observations, clinical mechanistic studies, and basic laboratory research suggest that estrogen therapy is associated with beneficial cardiovascular effects in postmenopausal women. Estrogen has a multitude of biological effects that may account for this apparent benefit (which remains to be proved in randomized clinical trials), including favorable effects on the lipid profile, increased endothelial nitric oxide bioactivity, and enhanced fibrinolysis. However, long-term estrogen therapy increases the risk of breast and endometrial cancers. Raloxifene, a benzothiophene derivative that binds to the estrogen receptor, is a selective estrogen receptor modulator, producing estrogen-agonist effects in some tissues (liver, bone) and estrogen-antagonistic effects in others (breast, uterus), and may prove to be an option for women with atherosclerosis or its risk factors. This review updates the current knowledge of the biological effects of selective estrogen receptor modulators of potential cardiovascular importance in postmenopausal women.