ArticleLiterature Review

Mechanisms of Cardioprotection by Estrogens

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Abstract

Strong scientific evidence suggests that estrogen therapy offers considerable protection from coronary artery disease. While earlier studies focused mainly on favorable changes in plasma lipid profiles as the mechanism of estrogen action, recent studies have documented other mechanisms of action including direct effects on vascular wall. The other mechanisms include estrogen's role as an antioxidant, its ability to protect from DNA damage, inhibition of cell proliferation, and altering vascular response to vasoactive agents. Considerable emphasis must be placed on research on individual components of the commonly used conjugated estrogens and estrogen structure/function relationship to target specific tissues and minimize undesirable effects while maintaining estrogen's cardioprotective potency.

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... E2 has been shown to act via its three known estrogen receptors (ER): ERα (11), ERβ (12), or the G-protein coupled estrogen receptor 1 (GPER1) (13). Estrogen is the most abundant female sex hormone, which activates complex pathways involving genomic targets mediated through the classical receptors, ERα and ERβ (11,12). ...
... E2 has been shown to act via its three known estrogen receptors (ER): ERα (11), ERβ (12), or the G-protein coupled estrogen receptor 1 (GPER1) (13). Estrogen is the most abundant female sex hormone, which activates complex pathways involving genomic targets mediated through the classical receptors, ERα and ERβ (11,12). The classical genomic pathways involve transcription of prosurvival genes facilitated by estrogen response elements (EREs) (14) and super-enhancers (15). ...
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Introduction: Estrogen (17β-estradiol, E2) is well-known to induce cardioprotective effects against ischemia/reperfusion (I/R) injury. We recently reported that acute application of E2 at the onset of reperfusion in vivo induces cardioprotective effects against I/R injury via activation of its non-steroidal receptor, G protein-coupled estrogen receptor 1 (GPER1). Here, we investigated the impact and mechanism underlying chronic GPER1 activation in cultured H9c2 rat cardiomyoblasts. Methods: H9c2 rat cardiomyoblasts were cultured and pretreated with the cytotoxic agent H2O2 for 24 h and incubated in the presence of vehicle (control), GPER1 agonists E2 and G1, or GPER1 agonists supplemented with G15 (GPER1 antagonist) for 48 or 96 h. After treatment, cells were collected to measure the rate of cell death and viability using flow cytometry and Calcein AM assay or MTT assay, respectively. The resistance to opening of the mitochondrial permeability transition pore (mPTP), the mitochondrial membrane potential, and ATP production was assessed using fluorescence microscopy, and the mitochondrial structural integrity was observed with electron microscopy. The levels of the phosphorylation of mammalian sterile-20-like kinase (MST1) and yes-associated protein (YAP) were assessed by Western blot analysis in whole-cell lysate, while the expression levels of mitochondrial biogenesis genes, YAP target genes, and proapoptotic genes were measured by qRT-PCR. Results: We found that after H2O2 treatment, chronic E2/G1 treatment decreased cell death effect was associated with the prevention of the S phase of the cell cycle arrest compared to control. In the mitochondria, chronic E2/G1 activation treatment preserved the cristae morphology, and increased resistance to opening of mPTP, but with little change to mitochondrial fusion/fission. Additionally, chronic E2/G1 treatment predominantly reduced phosphorylation of MST1 and YAP, as well as increased MST1 and YAP protein levels. E2 treatment also upregulated the expression levels of TGF-β and PGC-1α mRNAs and downregulated PUMA and Bim mRNAs. Except for ATP production, all the E2 or G1 effects were prevented by the cotreatment with the GPER1 antagonist, G15. Conclusion: Together, these results indicate that chronic GPER1 activation with its agonists E2 or G1 treatment protects H9c2 cardiomyoblasts against oxidative stress-induced cell death and increases cell viability by preserving mitochondrial structure and function as well as delaying the opening of mPTP. These chronic GPER1 effects are associated with the deactivation of the non-canonical MST1/YAP mechanism that leads to genetic upregulation of cell growth genes (CTGF, CYR61, PGC-1α, and ANKRD1), and downregulation of proapoptotic genes (PUMA and Bim).
... Hashimoto et al. [11] reported that endothelium-dependent vasodilatation is increased in young women during the phases of their menstrual cycles when endogenous estrogen levels are high, and pregnant women show significantly high levels of estrogen. Some studies have documented that estrogens are potent antioxidants and decrease low-density lipoprotein cholesterol (LDL-C) oxidation in vitro and in vivo [12, 13]. While estrogens decrease lipid peroxidation and formation of reactive oxygen species [14], androgens and progestins increase oxidative stress parameters [15]. ...
... Disturbances in endothelial function have an important role in the physiopathology of atherosclerosis, and several lines of evidence suggest that interventions in endothelial function could modify the progress rates of atherosclerotic disease and the risk of cardiovascular events. Some studies have documented that estrogens are potent antioxidants and decrease LDL-C oxidation in vitro and in vivo [12, 13]. Studies on the mechanism of estrogen antioxidant effects have shown that estrogen strongly inhibits superoxide formation with minor effects on hydrogen peroxide and hydroxyl radical formation [14] . ...
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It is known that menopause or lack of endogenous estrogen is a risk factor for endothelial dysfunction and CAD. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is involved inmultiple phases of vascular dysfunction. The purpose of the current study was to determine the association between soluble LOX-1 (sLOX-1) and pregnancy followed by delivery in women of reproductive age. Sixty-eight subjects with pregnancy followed by delivery (group 1) and 57 subjects with nongravidity (group 2) were included in this study. Levels of sLOX-1 were measured in serum by EL SA. Plasma levels of sLOX-1 were significantly lower in Group 1 than Group 2 in women of reproductive age (0.52 ± 0.18 ng/mL and 0.78 ± 0.13, resp., P < 0.001). There were strong correlations between sLOX-1 levels and the number of gravida (r = -0.645, P < 0.001). The levels of sLOX-1 highly correlated with the number of parous (r = -0.683, P < 0.001). Our study demonstrated that serum sLOX-1 levels were associated with pregnancy followed by delivery that might predict endothelial dysfunction. We conclude that pregnancy followed by delivery may delay the beginning and progress of arteriosclerosis and its clinical manifestations in women of reproductive age.
... Il est intéressant de constater que même si un rythme cardiaque élevé est prédicteur de risque cardiovasculaire, les femmes ont moins de risque de développer des maladies cardiovasculaires que les hommes avant la ménopause (Mosca, 2011). Ce phénomène est souvent expliqué par l'effet cardioprotecteur des oestrogènes (Subbiah, 1998). Il est plus difficile d'expliquer le fait que les femmes ont un rythme cardiaque durant le sommeil plus élevé que les hommes. ...
Thesis
Les troubles du sommeil peuvent avoir de graves conséquences sur le bien-être et la santé d'un individu. Ils sont également intimement liés aux maladies cardiovasculaires. Le manque de sommeil augmente par exemple les risques d'hypertension, d'accident vasculaire cérébral ou encore de maladie coronaire. La mesure de référence utilisée pour explorer le sommeil et le système cardiorespiratoire durant le sommeil est la polysomnographie. Cependant, cette méthode est intrusive et coûteuse. Les objets connectés offrent une alternative intéressante : ils sont bon marchés, peu ou pas intrusifs et facile d'utilisation. Cette thèse a pour but de mieux comprendre le mode de fonctionnement et d'analyser l'utilité des objets connectés pour la recherche et la surveillance des troubles du sommeil et des maladies cardiovasculaires. L'analyseur de sommeil connecté est le principal objet connecté utilisé durant cette thèse. C'est un coussin d'air connecté à un capteur de pression. Placé sous le matelas au niveau du torse, il est non-intrusif et permet de récupérer des données décrivant la qualité du sommeil du sujet (durée du sommeil, actigraphie...) ou ses données cardiorespiratoires durant le sommeil. Cet analyseur a été utilisé dans trois études. Une première étude composée de personnes apnéiques et saines a permis d'évaluer la fiabilité algorithmique de l'appareil. Une fois la précision évaluée, une deuxième étude composée d'utilisateurs réguliers de l'appareil a été mis en place. Elle a pour but d'analyser les relations entre les variables psycho-comportementales, la qualité de sommeil et les paramètres cardiorespiratoires. Pour cela, des questionnaires ont été soumis à des volontaires et leurs réponses ont été croisées aux données de l'analyseur du sommeil. D'autres objets connectés tels que les analyseurs d'activités ont également été inclus dans l'étude. Enfin, l'analyse des données brutes cardiaques de l'analyseur de sommeil a été approfondie avec la troisième étude composée de personnes saines. Ces données ont été comparées au flux sanguin mesuré par imagerie par résonance magnétique flux 4D afin de mieux comprendre leur origine. Nous avons pu montrer que les mesures de l'analyseur de sommeil étaient fiables, comparées aux mesures de référence. Nous avons montré en population d'usager, que les troubles du sommeil ainsi que les grands facteurs de risques de maladies cardiovasculaires et des maladies respiratoires (notamment l'obésité) étaient corrélés aux données physiologiques durant le sommeil. Enfin, nous avons commencé à mieux comprendre la genèse des signaux de ballistocardiographie enregistrés par l'analyseur de sommeil, ouvrant la voie à une utilisation plus approfondie pour le diagnostic des maladies cardiovasculaires. Le caractère non-intrusif de l'analyseur de sommeil, sa facilité d'utilisation ainsi que la richesse de ses signaux ont permis d'explorer le système cardiorespiratoire durant le sommeil de manière totalement inédite. Au-delà de l'effet de mode actuel, les objets connectés tels que l'analyseur de sommeil sont donc de véritables outils qui peuvent être utilisés à des fins de recherches, de prévention chez le grand public ou de suivi chez les patients.
... The possibility that certain set of comorbidities predisposes patients to developing myocarditis following either vaccination of COVID-19 infection is still to be determined since this review did not specifically line up comorbidities of one patient to the same patient's symptomatology. Lastly, if the female cases are lower than the other two populations based on female physiology, then the lower number of cases in females may suggest a cardioprotective feature in female patients [56][57]. Additionally, we recommend further investigation regarding the lack of clinical feature awareness in female cardiac patients. ...
Article
Myocarditis is an inflammatory disease of the heart muscle, with manifestations that include myocardial infarction, arrhythmia, and even sudden death. The primary etiology of myocarditis is a viral infection, with studies demonstrating that infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to myocarditis. This enzyme is involved in many body tissues, including the gastrointestinal system and the cardiac system. This enzyme is responsible for converting angiotensin I to angiotensin II in the renin-angiotensin system of our body. This review aims to characterize the symptomatology and comorbidities of males, females, and pediatric patients who developed the SARS-CoV-2-related myocarditis (SARS-CoV-2RM) or the SARS-CoV-2 vaccine-related myocarditis (SARS-CoV-2VRM). From July 10 to July 20, 2021, a PubMed database search for "SARS CoV-2 Related Myocarditis" was conducted. From July 21 to July 30, 2021, the search for "SARS CoV-2 Vaccine Related Myocarditis" was conducted. The search completed was specific for title/abstract fields using keywords "Covid-19" AND "Myocarditis" AND "Vaccine" and specifying "Males" or "Females", respectively. Inclusion criteria included articles discussing comorbidities and symptomatology. Exclusion criteria included autopsy/postmortem reports, letters to the editor, retrospective studies, and observational studies. In the end, 49 articles were found and included in this review. We found that 27 of 40 pediatric patients with SARS-CoV-2RM presented with gastrointestinal symptoms, and 12 of 40 pediatric patients had no comorbidities. In female cases, eight of 12 patients with SARS-CoV-2RM presented with noncardiac symptoms, and only four of 12 had comorbidities such as asthma, diabetes, and obesity. In male patients with SARS-CoV-2RM, 10 of 12 presented with respiratory and/or cardiac symptoms, and seven of 12 had cardiac and/or diabetic comorbidities. Furthermore, 22 of 31 male patients with SARS-CoV-2VRM presented with chest pain with no previous comorbidities; four of six females with SARS-CoV-2VRM presented with chest pain, and three of six females had no comorbidities; and seven of 11 pediatric patients with SARS-CoV-2VRM had no comorbidities, but 11 of 11 pediatric patients presented with chest pain. In conclusion, males, females, and pediatric patients with previous SARS-CoV-2VRM showed mostly chest pain with no comorbidities. Males presenting with SARS-CoV-2RM showed mostly respiratory and cardiac symptoms with cardiac and diabetic comorbidities. Females with SARS-CoV-2RM described various symptoms from flu-like, respiratory, to cardiac and had no previous comorbidities. The bulk of pediatric patients with SARS-CoV-2RM mainly presented with GI symptoms and no past comorbidities. More studies are needed to determine the clinical presentation and risk factors that lead to SARS-CoV-2RM and SARS-CoV-2VRM.
... 68,84 Also, observational studies demonstrate that estrogen may protect against cardiovascular disease in women without a history of the disease. 141 Potential risks associated with ERT/HRT are an increased risk of endometrial cancer in nonhysterectomized, long-term users of unopposed estrogens 52 that is diminished by the addition of a progestin 16,111,113 ; a higher relative risk of venous thromboembolism in the first year of use 20 ; an increased risk of gallbladder disease 112 ; and a possible increase in the risk of breast cancer in long-term users. 26 A causal relationship between ERT/HRT and breast cancer, however, remains controversial. ...
... According to numerous studies a share of males varies from 71.5 to 100 % in this cohort [10][11][12][13][14]. IHD in men manifests 7-10 years earlier than in women [15]. Women are less susceptible to developing MI at a young age due to the direct protec-tive effect of estrogens on the coronary arteries [16,17]. ...
Article
The paper focuses on examining peculiarities of risk factors causing cardiac infarction at a young age. Although cardiac infarction primarily occurs among patients older than 45, its frequency at a young age has been growing recently. Risk factors that cause cardiac infarction at a young and old age are quite different. Examining risk factors profiles in different age groups provides wider opportunities for implementing primary and secondary prevention strategies aimed at reducing frequency and negative outcomes of ischemic heart disease. 108 patients aged from 18 to 45 and 35 patients aged from 60 to 75 took part in the research; they all had confirmed cardiac infarction with or without rise in ST segment and were treated in a regional center for cardiovascular pathology treatment in a period from January 01, 2017 to January 01, 2019. Basic risk factors of cardiac infarction were assessed when a patient was admitted to a clinic for treatment. The research results indicate high prevalence of risk factors that could cause ischemic heart disease among young patients. 92.2 % young patients have dyslipidemia, 70.2 % smoke, 68.5 have low physical activity, 68.2 % suffer from overweight and obesity, 58.8 % have arterial hypertension, 7.4 % suffer from type II pancreatic diabetes, and disorders in tolerance to carbohydrates was reveled in 15.7 % cases. Such factors as male sex (85.2 vs. 37.1 %, р=0,000), smoking (70.2 vs. 20.6 %, р=0.000) and burdened heredity as per early ischemic heart disease occurrence (54.6 vs. 16.0 %, р=0.001) were significantly more frequent among young patients than among older ones. Data obtained via the present research allowed creating risk factors profile for cardiac infarction associated with cardiac infarction occurrence at a young age; this profile included such factors as male sex, early ischemic heart disease occurrence in family history, and smoking.
... Cardiovascular disease (CVD) remains the leading cause of mortality for women in the USA with an increased prevalence of the disease after menopause [1••, 2]. Historically, estrogen had been postulated to be cardioprotective in women, due in part to its beneficial effects on cardiovascular hemodynamics, lipid metabolism, and the endothelium [3]. Estrogen had been shown to decrease the levels of total and LDL cholesterol and increase the release of nitric oxide resulting in vasodilation, possibly decreasing vascular injury and development of atherosclerosis in the long term [4]. ...
Article
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Purpose of review In past decades, there has a been a paradigm shift concerning menopause, hormone therapy (HT), and cardiovascular disease (CVD). While initial observational studies suggested hormone replacement to provide a cardioprotective benefit for all menopausal women, subsequent large randomized trials have not confirmed these benefits and furthermore brought to light the risks of HT with regard to CVD, venous thrombosis, and stroke. The goal of this review is to summarize current recommendations regarding HT as it pertains to cardiovascular risk. Recent Findings Menopause HT remains the most effective treatment for vasomotor symptoms. Guidelines now suggest benefits outweigh the risk for in women with bothersome vasomotor symptoms, when initiated in early menopause (within 10 years of symptom onset or age < 60 years) without contraindications. Consideration of cardiovascular risk is necessary. For women with a moderate atherosclerotic CVD risk score, or with CVD risk modifiers, a transdermal formulation is preferred. For patients with known CVD, non-hormonal alternatives should be trialed. Current evidence does not support the use of HT for primary or secondary prevention of CVD. Summary Initiation of menopausal HT requires an individualized approach taking into account age of menopause, timing of initiation, vasomotor symptoms, and cardiovascular risk factors.
... This physiology underlies an interesting disparity in CVD epidemiology: pre-menopausal women benefit from cardioprotective effects of estrogen. Estrogen not only raises HDL-C but also acts as an antioxidant and alters vascular responses to vasoactive agents [67]. Men do not enjoy such hormonal benefits, and dyslipidemia during middle-age can increase the risk of acute myocardial infarction in men more than women [68]. ...
Article
Introduction Blood lipid screening recommendations begin at ages 9 – 11 years, despite poor adherence and evidence of fatty streaks in coronary arteries by 3-years of age. For cardiovascular disease (CVD) prevention, there may be value in earlier measurement of blood lipids. Areas covered The present systematic review examines evidence concerning total cholesterol, low-density lipoprotein, high-density lipoprotein, and triglycerides during the infant period. Included are studies examining the extent to which infant blood lipids predict later values in childhood and factors that influence their magnitude. A total of 38 articles (published from 1965 to 2013) met inclusion criteria and were examined in this review. Expert opinion Longitudinal data suggests correlative relationships in all lipid values around 6 months of age, except for TRG. Influential factors related to blood lipids in infancy include sex, race, family history, feeding, gestational length, birth weight, and maternal factors. Clinical measurement of infant lipids could perhaps provide an early marker of CVD and a target of early CVD prevention strategies. The identification of personal characteristics that associate with high or low values in each lipid could become important in the early identification of vulnerable populations and the promotion of personalized CVD prevention.
... Existing evidence suggests that oxidative stress might be linked with development of menopause-associated depression. Estradiol (E 2 ), a form of estrogen, exerts antioxidant effect through its chemical structure containing the phenolic ring [9]. Besides, E 2 can confer antioxidant activity through modulating the gene expression and function of antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase [10]; thereby, reduction in estrogen level may increase the oxidative stress. ...
Article
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Background Postmenopausal women are at higher risk of mental disorders. Oxidative stress has implication in the development of these disorders. Dietary total antioxidant capacity (DTAC) has been proposed as a tool for assessing dietary antioxidants intake. The relationship between DTAC with depression, anxiety and stress has not been investigated in postmenopausal women. Thus, we aimed to assess the association between DTAC and depression, stress and anxiety as well as oxidative stress biomarkers. Methods This cross-sectional study was carried out on 175 postmenopausal women. Data on dietary intake and mental health were collected by 147-item semi-quantitative food frequency questionnaires (FFQ) and Depression Anxiety Stress Scales (DASS-42), respectively. Dietary and serum total antioxidant capacity (TAC), malondialdehyde (MDA), oxidized-LDL, and superoxide dismutase (SOD) were measured. ANOVA test was applied to compare the mean of variables across the tertiles of DTAC. The relationship between DTAC and oxidative stress biomarkers was determined through ANCOVA method. Simple and multivariate linear regression tests were performed to measure the relationship between DTAC and mental health. Results Serum MDA level was significantly lower in the subjects at the highest tertiles of DTAC (P-value < 0.001). In addition, serum TAC level was significantly higher in subjects at the second tertile of DTAC (P-value = 0.04). DTAC was inversely and independently related to depression (β = − 0.16, P-value = 0.03) and anxiety scores (β = − 0.21, P-value = 0.007). There was no significant association between DTAC and stress score (β = − 0.10, P-value = 0.1). Conclusion An inverse relationship was found between DTAC with depression, anxiety scores and some oxidative stress biomarkers in postmenopausal women. These findings indicate DTAC may be used for developing effective dietary measures for reducing depression and anxiety in these women.
... The molecular and cellular basis of the cardiovascular gender difference has been reviewed elsewhere [104]. Scientific evidence suggests that the female sex hormone oestrogen exerts a cardioprotective effect, which also explains why postmenopausal women have a higher cardiovascular risk compared to younger females [105]. ...
Article
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Nuclear, mitochondrial and cytoplasmic signal transducer and activator of transcription 3 (STAT3) regulates many cellular processes, e.g., the transcription or opening of mitochondrial permeability transition pore, and its activity depends on the phosphorylation of Tyr705 and/or Ser727 sites. In the heterogeneous network of cardiac cells, STAT3 promotes cardiac muscle differentiation, vascular element formation and extracellular matrix homeostasis. Overwhelming evidence suggests that STAT3 is beneficial for the heart, plays a role in the prevention of age-related and postpartum heart failure, protects the heart against cardiotoxic doxorubicin or ischaemia/reperfusion injury, and is involved in many cardioprotective strategies (e.g., ischaemic preconditioning, perconditioning, postconditioning, remote or pharmacological conditioning). Ischaemic heart disease is still the leading cause of death worldwide, and many cardiovascular risk factors contribute to the development of the disease. This review focuses on the effects of various cardiovascular risk factors (diabetes, aging, obesity, smoking, alcohol, depression, gender, comedications) on cardiac STAT3 under non-ischaemic baseline conditions, and in settings of ischaemia/reperfusion injury with or without cardioprotective strategies.
... Serum lowdensity lipoprotein (LDL) cholesterol (major risk factor for CHD) was reported to decrease with increased intake of soluble fibre, plant sterols and higher intake of whole wheat [38]. In another study, it was shown that phytoestrogen in isolation, but is also present in wheat, binds to a specific intracellular receptor, which in turn protects blood vessels from atherosclerosis [39]. This hormone promotes appropriate vasodilation of coronary arteries when increased blood supply is required. ...
Article
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Wheat (Triticum aestivum L.) is one of the most commonly cultivated and consumed cereals throughout the world. Though phytochemicals and antioxidants in the cereal grains have not been studied as in fruits and vegetables, given the role of wheat in our diet plate, it is a given of primary importance to understand the chemistry of our major food, wheat. The presence of diverse polyphenols and their action against leading cause of death, including heart diseases, cancer, obesity, and diabetes, widens the scope of wheat. Phytochemicals such as phenolic acids, alkylresorcinols, flavonoids, phytosterols, and carotenoids are present in whole wheat. The majority of phytochemicals are located in the wheat bran/germ fraction, and they are the leading contributors to the health promoting activities. However, the presence of anti-nutrients and binding of phenolic acids with protein may have adverse effect on health. This review mainly focuses on studies that have been carried out in the past decade to present, emphasizing the importance of whole wheat and whole wheat based products in preventing major diseases and disease conditions, potentials threats, current lacks, and future prospects.
... Deneysel çalışmalar da OVX ile oluşturulan östrojen yoksunluğunun redoks durumunu değiştirdiğini ve bu durumda uygulanan östrojen tedavisinin oksidan stresi azalttığını düşündürmüştür (41). Ayrıca, östrojen molekülünün kimyasal yapısının da serbest radikal süpürücü olarak etki ettiği ve fenol halkasındaki A pozisyonu sayesinde oksidan hasarı engellediği öne sürülmektedir (42). Bu bulgulara dayanılarak östrojen yokluğu ile kendini gösteren menopozun oksidan stres için bir risk faktörü olduğu kabul edilmektedir (43). ...
... Female reproductive hormones have been suggested to play an important role of the protection from the development of cardiovascular disease in young women (Stampfer & Colditz, 1991;Subbiah, 1998). For instance, aging is associated with increased risk of hypertension, however, at around the age of menopause, the incidence of hypertension in women increases markedly, where rates of hypertension meet or even exceed those in men of a similar age (Burt et al., 1995;Wiinberg et al., 1995;Martins et al., 2001;Kearney et al., 2005). ...
Thesis
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Recent epidemiological studies report a consistent association between short sleep and incidence of hypertension, as well as short sleep and cardiovascular disease-related mortality. While the association between short sleep and hypertension appears to be stronger in women than men, the mechanisms underlying the relations between sleep deprivation, stress, risks of cardiovascular diseases, and sex remain unclear. We conducted two studies to investigate the underlying neural mechanisms of these relations. In study 1, we examined sympathetic neural and blood pressure responses to experimentally-induced sleep deprivation in men and women. We further investigated the influence of sleep deprivation on cardiovascular reactivity to acute stress. In study 2, we examined the neural and cardiovascular function throughout the ovarian cycle in sleep deprived women. Twenty-eight young healthy subjects (14men and 14 women) were tested twice in study 1, once after normal sleep (NS) and once after 24-h total sleep deprivation (TSD). We measured the blood pressure, heart rate (HR), muscle sympathetic nerve activity (MSNA) and forearm blood flow (FBF) during 10min baseline, 5min of mental stress (MS) and 2 min cold pressor test (CPT). We demonstrated that TSD increased resting arterial blood pressure to a similar extent in both men and women, but MSNA decreased only in men following TSD. This MSNA response was associated with altered baroreflex function in women and divergent testosterone responses to TSD between men and women. Regarding TSD and cardiovascular reactivity, TSD elicited augmented HR reactivity and delayed recovery during both MS and CPT in men and women, and responses between sexes were not statistically different. Fourteen young healthy women participated in study 2. Subjects were tested twice, once during their early follicular (EF) phase after TSD, once during their mid-luteal (ML) phase after TSD. Blood pressure, HR, MSNA, and FBF were recorded during 10min baseline, 5 min MS, and 2 min CPT. We observed an augmented resting supine blood pressure during EF compared to ML in sleep deprived women. In contrast, resting MSNA, as well as cardiovascular responses to stressors, were similar between EF and ML after TSD. In conclusion, we observed sex differences in MSNA responses to TSD that demonstrate reductions of MSNA in men, but not women. TSD elicited augmented HR reactivity and delayed HR recovery to acute stressors similarly in men and women. We also reported an augmented supine blood pressure during EF compared to ML in sleep deprived women. These novel findings provide new and valuable mechanistic insight regarding the complex and poorly understood relations among sleep deprivation, sex, stress, and risk of cardiovascular disease.
... In the present experiment, ovariectomy resulted in an increase in total and HDL cholesterol, which was reversed by estrogen treatment in line with the findings in previous studies [14,28]. Estrogen therapy is shown to induce favorable changes in plasma lipid profiles [29]. Although HDL is generally recognized as beneficial to endothelial function, the effect of estrogen may be partially due to reduced total cholesterol level which is not related to modulation of HDL level. ...
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Menopause escalates the risk of cardiovascular diseases in women. There is an unmet need for better treatment strategy for estrogen-deficiency-related cardiovascular complications. Here we investigated the impact of chronic black tea extract (BT) consumption on cardiovascular function and lipid metabolism using a rat model of estrogen deficiency. Female Sprague-Dawley rats were ovariectomized (OVX) and treated with BT (15 mg/kg/day, 4 weeks; active ingredients: theaflavins) or estrogen (E2) treatment for 4 weeks. Serum was collected for measuring cholesterol, triacylglycerol and estradiol levels. Changes in vascular reactivity were examined. The protein levels of NADPH oxidases were assessed by Western blotting. Reactive oxygen species (ROS) level was measured using dihydroethidium fluorescence imaging. The concentrations of cGMP were measured using ELISA kit. Aortic rings from control, BT-treated and E2-treated OVX rats exhibited a greater increase in Phe-induced contraction after inhibition of NO synthase compared with those from OVX rats. ACh-induced endothelium-dependent relaxations were augmented in aortae and renal arteries in BT/E2-treated OVX rats than in OVX rats. BT/E2 treatment improved flow-mediated dilatation in small mesenteric resistance arteries of OVX rats. BT/E2 treatment restored the eNOS phosphorylation level and reversed the up-regulation of NADPH oxidases and ROS overproduction in OVX rat aortae. ACh-stimulated cGMP production was significantly elevated in the aortae from BT- and E2-treated rats compared with those from OVX rats. BT/E2 treatment reduced circulating levels of total cholesterol. The present study reveals the novel benefits of chronic BT consumption to reverse endothelial dysfunction and favorably modifying cholesterol profile in a rat model of estrogen deficiency and provides insights into developing BT as beneficial dietary supplements for postmenopausal women.
... Bereits klassische Östrogene haben in der makrophagenvermittelten Lipoproteinoxidation einen Benefit. Demnach wird geschlußfolgert, daß die Oxidation von LDL und möglicherweise anderer Lipoproteine in der Pathogenese der Atherosklerose ein kritisches Ereignis darstellt, wobei LDL zu einem Produkt oxidiert wird, das durch Scavenger-Rezeptoren oder oxidierte LDL-Rezeptoren, die auf Makrophagen sitzen, aufgenommen wird und der Schadensprozeß anhand der Bildung sogenannter Schaumzellen seinen Ausdruck findet [25,26]. Dies wird in zunehmendem Maße neben den genomischen Eigenschaften mit der vorteilhaften Verstärkung nichtgenomischer Wirkungen in Zusammenhang gebracht. ...
... However, conflicting results from randomized clinical trials performed by the Women's Health Initiative (WHI) have also observed no benefit of oral BCP or HRT on cardiovascular risk 46 in some studies and protective effects in others 47 . The protective effect that has been observed is attributed to the lowering of low-density lipoprotein (LDL) cholesterol levels and the elevation of high-density lipoprotein (HDL) cholesterol levels as well as favorable changes to fibrinogen, PAI-1, enhance blood flow, and antioxidant properties [48][49][50] . Estrogen has also been associated with lowered risk of mortality among women 15 . ...
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Conflicts of Interest: SGS has received research funding from Genentech, owns equity in Pfizer, and is co-holder of a patent pending entitled "Molecular targets for modulating intraocular pressure and differentiating steroid responders versus non-responders". WKS, AA, EAP, MP-V and JLH are inventors of a patent for use in genetic diagnosis of AMD, licensed to ArcticDX.
... [77] As such, they are at heightened risk of serious complications such as decreased bone mineral density eventually leading to osteoporosis, [78] and cardiovascular disease. [79] Estrogen replacement therapy then, with its ability to preserve bone mineral density [80] and its cardioprotective properties, [81,82] has the added benefit of preventing such adverse health outcomes in female schizophrenia patients. ...
... The steroid hormone 17b-estradiol (E2) plays critical roles in the reproductive tract, mammary gland, brain, and skeletal and cardiovascular systems (Couse and Korach, 1999;Korach, 1994;Subbiah, 1998;Toran-Allerand, 1996;Hall et al., 2001). In order to bring about its effects in target cells, E2 binds to the intracellular estrogen receptor (ER) and interacts with specific DNA sequences, estrogen response elements, to modulate gene expression (Heldring et al., 2007). ...
... Estrogen has an antioxidant effect. By increasing free radical production following estrogen reduction, it can increase the production of cytokines (Subbiah, 1998). However, the mechanism of antioxidant effect of estrogen is not yet fully identified and may vary in different tissues (Mundy, 1996). ...
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... Studies have documented that estrogens are potent anti-oxidants and decrease LDL oxidation in vitro and in vivo 100,101 . This concept was raised by studies which employed pharmacological concentrations, but it has been appreciated more recently that 17β-estradiol is active even at physiological concentrations 102 . ...
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... In this sense, liver fat accumulation, along with increased intra-abdominal fat depots are important factors in the development of insulin resistance and diabetes, being considered a hepatic component of the metabolic syndrome [43] . Menopause also induces a dramatic increase in ischemic cardiac disease, suggesting that estrogen exerts a cardioprotective role [75,85] . Additionally, menopause induces structural and functional cardiac changes such as: poor cardiac function [56] , reduced ejection fraction and aortic fl ow velocity, increased peripheral resistance, decreased cardiac index [64] , and impaired diastolic function [33] . ...
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... Zudem hemmen Estrogene als Antioxidanzien die Wirkung von Sauerstoffradikalen und mindern somit u.a. das Herzinfarkt-Risiko (Subbiah 1998, Maxwell 1998). ...
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Objective Young women form a minority but an important group of patients with acute myocardial infarction (MI) as it can potentially cause devastating physical and socioeconomic impact. This study was aimed to investigate the characteristics and outcomes of young women with MI in Malaysia. Design This is a retrospective analysis of women with ST-elevation MI (STEMI) and non-STEMI (NSTEMI) from 18 hospitals across Malaysia using the Malaysian National Cardiovascular Database registry–acute coronary syndrome (NCVD-ACS). Participants Women patients diagnosed with acute MI from year 2006 to 2013 were identified and divided into young (age ≤ 45, n=292) and older women (age >45, n=5580). Primary outcome measure Comparison of demographics, clinical characteristics and in-hospital management was performed between young and older women. In-hospital and 30-day all-cause mortality were examined. Results Young women (mean age 39±4.68) made up 5% of women with MI and were predominantly of Malay ethnicities (53.8%). They have a higher tendency to present as STEMI compared with older women. Young women have significantly higher rates of family history of premature coronary artery disease (CAD) (20.5% vs 7.8% p<0.0001). The prevalence of risk factors, such as hypertension, diabetes and dyslipidaemia was high in both groups. The primary reperfusion strategy was thrombolysis with no significant differences observed in the choice of intervention for both groups. Other than aspirin, rates of prescriptions for evidence-based medications were similar with >80% prescribed statins and aspirin. The all-cause mortality rates of young women were lower for both in-hospital and 30 days, especially in those with STEMI with adjusted mortality ratio to the older group, was 1:9.84. Conclusion Young women with MI were over-represented by Malays and those with a family history of premature CAD. Preventive measures are needed to reduce cardiovascular risks in young women. Although in-hospital management was similar, short-term mortality outcomes favoured young compared with older women.
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The authors' goal is to review the current recommendations for optimizing cardiovascular health beginning in adolescent years to adulthood, and to expand on the role that pregnancy complications may have as implications for future cardiovascular health. Attention to cardiac health begins in adolescence; however, most young patients are not screened. Pregnancy, with its increased cardiovascular demands and host of antepartum cardiopulmonary complications, may provide a window into future cardiac health. The distinct shift in cardiac risk that occurs once a woman enters menopause is largely ignored in routine screening guidelines.
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Objectives: This study investigated the association between obesity type and obstructive coronary artery disease (CAD) in postmenopausal women. Methods: Study data were obtained from a nation-wide registry, composed of 659 women older than 55 years with chest pain undergoing elective invasive coronary angiography in the suspicion of CAD. Obstructive CAD was defined as angiographic findings of ≥50% diameter stenosis with any major epicardial coronary artery. Overall obesity was defined as a body mass index of ≥25 kg/m, and central obesity was defined as a waist circumference of ≥85 cm. Results: A total of 311 women (47.2%) had obstructive CAD. The incidence of overall obesity was not different between participants with and without obstructive CAD (P = 0.340), but the prevalence of obstructive CAD was significantly higher in participants with central obesity than those without (55.5% vs 41.0%, P < 0.001). There was no significant difference in body mass index between participants with and without obstructive CAD (P = 0.373). Multivariable analysis showed that central obesity was associated with obstructive CAD even after controlling for potential confounders (odds ratio, 1.61; 95% confidence interval, 1.10-2.34; P = 0.013). However, overall obesity was not associated with obstructive CAD in the same multivariable analysis (P = 0.228). Conclusions: Central obesity but not overall obesity is associated with obstructive CAD in postmenopausal women with stable chest pain undergoing invasive coronary angiography. : Video Summary: Supplemental Digital Content 1, http://links.lww.com/MENO/A440.
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Objective: Oxidized low-density lipoprotein (LDL) seems to play an important role in the etiology of atherosclerosis. To further study this, we performed two studies: (1) we determined the ability of 10 estrogen components of the drug, conjugated equine estrogen (CEE), trans-resveratrol (t-resveratrol) and quercetin (red wine components), trolox (vitamin E analog), and probucol (a serum cholesterol-lowering drug) to delay or prevent the oxidation of plasma LDL isolated from untreated postmenopausal women, and (2) we assessed the effect of long-term (>1 year) estrogen replacement therapy and hormone replacement therapy on LDL oxidation by ex vivo methods. Design: For the in vivo study, three groups of postmenopausal women were selected based on whether they were on long-term CEE therapy (group A: 0.625 mg CEE; n = 21), on combination CEE plus progestogen therapy (group B: 0.625 mg CEE + 5.0 mg medroxyprogesterone acetate, 10 days; n = 20), or not on any hormone therapy (group C; n = 37). For the in vitro study, only LDL samples obtained from group C were used. The kinetics of LDL oxidation were measured by continuously monitoring the formation of conjugated dienes followed by determination of the lag time. Results: All compounds tested protected the LDL from oxidative damage. The relative antioxidant potency of estrogen components was generally greater than that of the other compounds. The minimum dose (nmoles) required to double the lag time from the control lag time of 57 ± 2 min was 0.47 for 17β-dihydroequilenin, 17α-dihydroequilenin, Δ-estrone; 0.6 to 0.7 for Δ-17β-estradiol, equilenin, and quercetin; 0.9 for 17β-dihydroequilin and 17α-dihydroequilin; 1.3 for equilin, estrone, 17β-estradiol, 17α-estradiol; 1.4 for trolox; 1.9 for probucol; and 3.0 for t-resveratrol. The data from the in vivo study indicate that after long-term estrogen replacement therapy (group A) and hormone replacement therapy (group B), the LDL was significantly (p < 0.01) protected (higher lag time) against oxidation compared with the control (group C). There was no difference between groups A and B. Conclusions: The oxidation of LDL isolated from postmenopausal women is inhibited differentially by various estrogens and other antioxidants. The unique ring B unsaturated estrogen components of CEE were the most potent, and t-resveratrol, the red wine component, was the least potent. Long-term CEE or CEE + medroxyprogesterone acetate administration to postmenopausal women protects the LDL against oxidation to the same extent. These combined data support the hypothesis that some of the cardioprotective benefits associated with CEE therapy and perhaps red wine consumption may be due to the ability of their components to protect LDL against oxidative modifications.
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Objective:To compare the pharmacokinetics and relative bioavailabilities of key estrogen components of Premarin (Wyeth-Ayerst, Canada) with those of a generic conjugated estrogen preparation, C.E.S. (synthetic mixture of estrogens; ICN, Montreal, Canada) in healthy postmenopausal women.
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Thyroid cancer (TC) is an endocrine related cancer and is well coupled with the female reproductive hormone, 17β-estradiol (estrogen). Plenty of articles have discussed the role of tumor microenvironment (TME) with different types of tumors in a broad-spectrum but the role of female reproductive hormone, that is, involvement of estrogen in TME of TC have not been reviewed elsewhere. The aim of this review is to analyze how 17β-estradiol affects the TME of TC and also that subsequently leads to progression of cancer. This review is given a new insight on: 1) the estrogen's involvement in TME of TC; 2) how it interferes with the complex cross talk of signaling pathways established between cancer cells, host cells, and their surrounding extracellular matrix; and 3) the important factors of microenvironment comprising inflammation, hypoxia, angiogenesis, metastasis, various growth factors and fibroblasts in stromal cells. © 2015 IUBMB Life, 2015.
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The nuclear receptors (NR) are a critical superfamily of gene regulatory proteins involved in all of human physiology. Classic biochemical techniques have provided deep insights into NR function but, due to their nature as single endpoint assays derived from pooled cell populations and tissues, these approaches are intrinsically unable to address important mechanistic considerations linked to cellular heterogeneity. Androgen receptor (AR) and estrogen receptor-α (ER) are members of the Type 1 steroid receptor subfamily of NRs that contribute to sex determination. Numerous recent advances have permitted direct, quantitative visualization of AR and ER functions within a cellular context that can be combined with conventional molecular and biochemical approaches. This new approach, essentially single cell-based systems biology, now enables researchers to follow NR shuttling through subcellular compartments in response to physiologic, pathologic or pharmacologic stimuli, to quantify transcriptional activity, and to identify interacting molecules leading to induction, or repression, of transcription. Here, we discuss recent reports that have applied advanced imaging systems [high throughput microscopy (HTM), high content analysis (HCA), FRET, FRAP] to dissect the biology of ER and AR at the single cell level. First, we discuss the use of HCA to examine AR functions in genital skin fibroblasts derived from normally virilized individuals and patients with androgen insensitivity syndrome (AIS), and in prostate cancer cell lines. Second, we highlight how these imaging techniques have been applied to define compound-specific mechanisms of ER gene regulation and coregulator interactions. These methods reveal new findings about the actions of AR and ER that are overlooked by conventional methods. © 2012 Springer Science+Business Media, LLC. All rights reserved.
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Objective This cross-sectional study aimed to evaluate the behavior of blood antioxidant enzymes (superoxide dismutase (SOD), catalase and glutathione peroxidase), plasma total antioxidant capacity and oxidative damage (lipid oxidation and protein carbonyl levels) and their relationship with the serum levels of steroid hormones in premenopausal and postmenopausal women without and with estrogen alone (ET) or estrogen plus progestin therapy (EPT). Methods Blood was collected from four groups of subjects: premenopausal women (n ϭ 24), postmenopausal women without hormone therapy (n ϭ 31), postmenopausal women with ET (n ϭ 12) and postmenopausal women with EPT (n ϭ 16). Results The activities of the different SOD isoforms (CuZnSOD and MnSOD) and the plasma total antioxidant power were signifi cantly higher in the postmenopausal women under EPT than in the postmenopausal women without hormone replacement therapy (HRT). Only CuZnSOD activity was increased in women receiving ET compared to the postmenopausal women without HRT. However, no differences were observed in the levels of lipid or protein oxidation or in the non-enzymatic plasma antioxidants (uric acid and albumin) among the groups. The duration of HRT and serum estrogen levels were positively correlated to the blood CuZnSOD activity and to plasma total antioxidant power, whereas the serum progesterone levels were positively correlated to CuZnSOD activity and negatively correlated to protein carbonyl groups. Interestingly, the total antioxidant power of plasma was positively correlated to CuZnSOD and glutathione peroxidase activities. Conclusion We conclude that EPT increases blood MnSOD and CuZnSOD activity in postmenopausal women, leading to an increased plasma total antioxidant capacity. This fi nding may be relevant to the prevention of oxidative stress-related disorders in postmenopausal women.
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This study was aimed to examine the effect of ovariectomy on visceral fat, serum adiponectin levels and lipid profile. Forty-five female Sprague Dawley rats were divided into three groups (n=15 each): ovariectomized group (OVX), ovariectomized plus estrogen-treated group (OVX+E2), and sham-operated group (SHAM). Body weight, abdominal adipose tissues, serum adiponectin and lipid profile were measured and compared among the groups after three-month feeding post-surgery. Significant increases in body weight and visceral fat were found in ovariectomized rats when compared with sham-operated ones and significant increases were also observed in serum adiponectin, triglyceride and very low density lipoprotein cholesterol levels in ovariectomized rats. Body weight, visceral fat and serum adiponectin levels were profoundly reduced in OVX+E2 group as compared with OVX group. It was concluded that ovarian hormone deficiency induced by ovariectomy leads to significant increases in body weight and visceral fat, along with increased serum adiponectin, triglyceride and very low density lipoprotein cholesterol levels in rats. Attenuation in these changes can be achieved by estrogen supplementation.
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Objective: This cross-sectional study aimed to evaluate the behavior of blood antioxidant enzymes (superoxide dismutase (SOD), catalase and glutathione peroxidase), plasma total antioxidant capacity and oxidative damage (lipid oxidation and protein carbonyl levels) and their relationship with the serum levels of steroid hormones in premenopausal and postmenopausal women without and with estrogen alone (ET) or estrogen plus progestin therapy (EPT). Methods: Blood was collected from four groups of subjects: premenopausal women (n = 24), postmenopausal women without hormone therapy (n = 31), postmenopausal women with ET (n = 12) and postmenopausal women with EPT (n = 16). Results: The activities of the different SOD isoforms (CuZnSOD and MnSOD) and the plasma total antioxidant power were significantly higher in the postmenopausal women under EPT than in the postmenopausal women without hormone replacement therapy (HRT). Only CuZnSOD activity was increased in women receiving ET compared to the postmenopausal women without HRT. However, no differences were observed in the levels of lipid or protein oxidation or in the non-enzymatic plasma antioxidants (uric acid and albumin) among the groups. The duration of HRT and serum estrogen levels were positively correlated to the blood CuZnSOD activity and to plasma total antioxidant power, whereas the serum progesterone levels were positively correlated to CuZnSOD activity and negatively correlated to protein carbonyl groups. Interestingly, the total antioxidant power of plasma was positively correlated to CuZnSOD and glutathione peroxidase activities. Conclusion: We conclude that EPT increases blood MnSOD and CuZnSOD activity in postmenopausal women, leading to an increased plasma total antioxidant capacity. This finding may be relevant to the prevention of oxidative stress-related disorders in postmenopausal women.
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Background: South Asians are known to carry higher burden of cardiovascular diseases when compared with their Caucasian counterparts. Aim: This study was designed to evaluate whether vascular age is advanced for Gujarati Asian Indians as matched to their chronological age in apparently healthy, asymptomatic population. We have also assessed the contributing risk factors for premature vascular ageing. Design: It was cross-sectional study of 2483 individuals of Gujarat state in Western India having no past or present history of major illness including cardiovascular diseases. Method: The vascular age of the population was calculated using Framingham vascular age calculator. A relationship between risk factor prevalence and vascular ageing was evaluated using univariate analysis of variance. Results: The mean chronological age of the study population was 46.8 (±10.35) years whereas mean vascular age was 53.34 (±16.05) years, and the difference (6.54±9.5) between both was statistically significant (P < 0.0001). Contributory risk factors for advanced vascular age apart from chronological age (75.4%) and male gender (66.2%) were the presence of dyslipidemia (60.4%) hypertension (57.34%) and increased waist circumference (WC) (male 39.7%, female 29%). Results of regression analysis showed that vascular age progression was highly associated with blood pressure (19.9, 95% CI: 14.34–27.63), followed by smoking (15.23, 95% CI: 8.4–27.59), and blood sugar (12.97, 95% CI: 3.48–48.25). Conclusion: The Gujarati Asian Indians are subjected to premature vascular ageing and henceforth routine screening for vascular age and risk factors prevalence is strongly advocated in this ethnic group.
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Estrogen therapy has an antioxidant effect and improves quality of life. There is no report on estrogen therapy and quality of life in relation to oxidative stress. To determine the effect of estrogen hormonal therapy on quality of life and oxidative stress in postmenopausal women. We carried out a controlled clinical trial including 111 perimenopausal women (40 to 60 years old) living in Mexico City. Women were assigned into three groups: (1) control group, 39 premenopausal women; (2) 33 postmenopausal women receiving oral conjugated estrogens and medroxyprogesterone (0.625 mg/d plus medroxyprogesterone 5 mg/d for 10 days); (3) 33 postmenopausal women taking placebo pills. We measured at baseline and at six months biochemical markers of oxidative stress: lipoperoxides by TBARS assay, erythrocyte superoxide dismutase (SOD) and glutathione peroxidase (GPx) and total antioxidant status (TAS) with Randox Laboratories, Ltd. kits. We also applied the World Health Organization Quality of Life, Brief (WHOQoL-Brief). Levels of lipoperoxides were higher in postmenopausal women with low quality of life vs. premenopausal women with high quality of life (0.357 +/- 0.06 vs0.315 +/- 0.04 micromol/L, p <0.05). Plasma lipoperoxides diminished in women taking hormonal therapy with low quality of life after six months of treatment (0.357 +/- 0.06 vs. 0.293 +/- 0.08 micromol/L, p < 0.01); also, the proportion of women in therapy with basal high lipoperoxides and quality of life average-low diminished (p < 0.05). There were no differences in the other groups. Conclusion: Estrogen therapy improves quality of life and reduces lipoperoxides as oxidative stress biomarker in postmenopausal women.
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To gain a better understanding of how estrogen-responsive genes are regulated we utilized in vivo footprinting and in vitro binding assays to define cis elements and transacting factors involved in conferring estrogen responsiveness to the pS2 and PR genes in MCF-7 breast cancer cells. The consensus pS2 ERE half site was protected in the absence of hormone and both the consensus and imperfect ERE half sites were protected in the presence of estrogen. 4-hydroxytatnoxifen and ICI 182,780 elicited distinct footprinting patterns, which differed from those observed with vehicle- or with estrogen-treated cells. Footprinting patterns in and around the TATA and CAAT sequences were identical in the presence and in the absence of estrogen suggesting that the basal promoter is accessible and poised for transcription even in the absence of hormone. In vitro DNase I footprinting experiments demonstrated that the estrogen receptor bound to the pS2 ERE and that adjacent nucleotides were protected by MCF-7 nuclear proteins. The PR gene is also induced by E2 in MCF-7 cells. Although the PR gene lacks an identifiable ERE, it does contain a complex array of conserved transcription factor binding sites. We have provided evidence that two AP-l sites help to confer estrogen responsiveness to the PR gene. In addition the ER enhances Sp 1 binding to its recognition site and binds directly to an adjacent ERE half site in the PR Promoter A. Taken together, our combined studies of the pS2 and the PR gene suggest that the ER has direct and indirect effects on formation of an active transcription complex.
Article
Objective: Age-adjusted incidence of cardiovascular disease, including myocardial infarction, is significantly lower in premenopausal women than in men, which is thought to be caused by the cardioprotective effects of estrogen. However, there is a consistent increase in the incidence of coronary artery disease in postmenopausal women in comparison with premenopausal women. The protective benefit of hormone therapy has not been observed in postmenopausal women. It is unknown whether measures of platelet reactivity and clot strength contribute to the disproportionate incidence of cardiovascular disease between premenopausal and postmenopausal women. Methods: Fifty healthy volunteers, including 25 premenopausal women and 25 postmenopausal women, aged between 40 and 65 years were enrolled. Total estradiol and follicle-stimulating hormone levels were measured for confirmation of menopausal state and comparison testing. Platelet reactivity was assessed using light transmission aggregometry and P-selectin, and glycoprotein IIb/IIIa receptor expression was assessed using flow cytometry. Thrombelastography was used to measure clot strength, clotting time, and fibrinogen activity. Serum cholesterol, C-reactive protein, complete blood count, and comprehensive metabolic panel were also measured. Results: Platelet reactivity did not differ among menopausal states or hormone levels. Clotting time was increased in postmenopausal women (6.6 ± 2.0 vs. 7.8 ± 1.2 min, P = 0.013) and significantly correlated with estradiol levels (r = 0.68, P < 0.001). A significantly higher low-density lipoprotein cholesterol level was observed in postmenopausal women (P = 0.05). Mean C-reactive protein levels were numerically higher in the postmenopausal group. Conclusions: The thrombotic risk profile between premenopausal and postmenopausal women is similar. However, improved management of cholesterol may be of clinical benefit. Large-scale studies are required to validate these findings.
Article
Increasing evidence from epidemiological, preclinical and clinical studies suggests that estrogens may exert psychoprotective effects in schizophrenia. Observations of gender differences in the onset and course of schizophrenia have prompted exploration of the effects of estrogen on the CNS. The aim of this paper is to provide an overview of different applications of adjunctive estrogen as a possible treatment for symptoms of schizophrenia in both men and women. Recent trials have suggested that estrogen augmentation therapy may be able to enhance the management of schizophrenia; however, the clinical application of estrogen as a treatment has been limited by potential side effects, the most worrying being breast and uterine cancer in women, and feminization in men. Selective estrogen receptor modulators (SERMs), however, may offer therapeutic benefits for both men and women with schizophrenia without posing threat to breast and uterine tissue and without feminizing effects. The use of estrogen opens up new possibilities for both men and women in the treatment of severe mental illnesses such as schizophrenia. With further preclinical and clinical research, it is hoped that this promising field of hormone modulation can continue to evolve and eventually be translated into real therapeutic potential.
Article
In patients with atherosclerosis, fibrosclerotic focuses are induced by multiplication of vascular smooth muscle cells (VSMC), and they are regulated by cytokines and regulators. There have been few reports about the atheroprotective effect of estriol (E3). Estrone sulfate (E1-S) is the predominant estrogen of conjugated equiline estrogens, which is commonly used in hormone replacement therapy, but it should be hydrolyzed by steroid sulfatase (STS) to enter the cells of target tissues. The purpose of this study was to detect STS in VSMC and to investigate whether E3 and E1-S have atheroprotective effects like E2. First, we detected the presence of STS mRNA in VSMC by in situ hybridization. We then examined the changes in the expression of mRNAs of cytokines, namely, PDGF-A chain, IL-1, IL-6 and TGF-β, in VSMC, in the presence and absence of E3 and estrogens. As a result, the expression of PDGF-A chain, IL-1 and IL-6 mRNAs was suppressed by E3 (P<0.05 vs control) significantly like E1-S and E2, but that of TGF-β mRNA was not significantly affected by any estrogen. These results indicate that E1-S can be hydrolyzed by STS in VSMC, and that E3 may regulate the cytokines by suppressing the production of mRNAs. It is suggested that there is a possibility of E1-S and E3 having a direct effect on vessels in atherogenesis.
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The aim of this study was to determine the influence of menopause (hypoestrogenism) as a risk factor for oxidative stress. We carried out a cross-sectional study with 187 perimenopausal women from Mexico City, including 94 premenopausal (mean ± SD age, 44.9 ± 4.0 y; estrogen, 95.8 ± 65.7 pg/mL; follicle-stimulating hormone, 13.6 ± 16.9 mIU/mL) and 93 postmenopausal (mean ± SD age, 52.5 ± 3.3 y; estrogen, 12.8 ± 6.8 pg/mL; follicle-stimulating hormone, 51.4 ± 26.9 mIU/mL) women. We measured lipoperoxides using a thiobarbituric acid-reacting substance assay, erythrocyte superoxide dismutase and glutathione peroxidase activities, and the total antioxidant status with the Randox kit. An alternative cutoff value for lipoperoxide level of 0.320 μmol/L or higher was defined on the basis of the 90th percentile of young healthy participants. All women answered the Menopause Rating Scale, the Athens Insomnia Scale, and a structured questionnaire about pro-oxidant factors, that is, smoking, consumption of caffeinated and alcoholic beverages, and physical activity. Finally, we measured weight and height and calculated body mass index. The lipoperoxide levels were significantly higher in the postmenopausal group than in the premenopausal group (0.357 ± 0.05 vs 0.331 ± 0.05 μmol/L, P = 0.001). Using logistic regression to control pro-oxidant variables, we found that menopause was the main risk factor for oxidative stress (odds ratio, 2.62; 95% CI, 1.35-5.11; P < 0.01). We also found a positive correlation between menopause rating score, insomnia score, and lipoperoxides, and this relationship was most evident in the postmenopausal group (menopause scale, r = 0.327 [P = 0.001]; insomnia scale, r = 0.209 [P < 0.05]). Our findings suggest that the depletion of estrogen in postmenopause could cause oxidative stress in addition to the known symptoms.
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Les cellules dérivées de la moelle osseuse, principalement les cellules endothéliales progénitrices, sont réduites chez les patients souffrant de maladies cardiovasculaires. Leur mobilisation et leur incorporation aux sites de lésion vasculaire sont des évènements prépondérants dans l’accélération des processus de réendothélialisation. Dans un modèle murin, le 17β-estradiol favorise les processus de guérison vasculaire par la mobilisation et le recrutement des cellules endothéliales progénitrices dérivées de la moelle osseuse. Il existe présentement plusieurs stratégies afin d’augmenter la mobilisation des cellules progénitrices ainsi que leur incorporation à la paroi vasculaire. Cependant, peu d’études privilégient la livraison locale d’un nombre élevé de cellules progénitrices fonctionnelles par un véhicule biodégradable et leur maintien au site de lésion afin de favoriser la réendothélialisation ciblée. Un polymère d’intérêt pour cette application s’avère être le chitosan. Ce biopolymère non toxique et biodégradable est couramment utilisé dans l’ingénierie tissulaire et, depuis peu, est utilisé dans la guérison vasculaire. Le chitosan complexé à la phosphorylcholine voit sa solubilité s’accroître dans les solutions aqueuses ainsi que sa biocompatibilité cellulaire en condition physiologique. Le projet de ce mémoire visait donc : 1) à étudier in vitro, la capacité d’un polymère de chitosan complexé à la phosphorylcholine à influencer l’adhésion, la survie, la différenciation et la fonctionnalité cellulaire dans un modèle murin de culture mixte de cellules dérivées de la moelle osseuse et 2) de déterminer l’impact de la présence du 17β-estradiol sur ces mêmes comportements cellulaires. Nos travaux démontrent que la matrice de chitosan-phosphorylcholine s’avère compatible avec notre modèle de culture cellulaire. En effet, ce polymère est capable de promouvoir l’organisation et le développement des cellules dérivées de la moelle osseuse de façon comparable à la matrice normalement utilisée dans la croissance in vitro des cellules endothéliales progénitrices, la fibronectine. De plus, ce polymère n’a nullement compromis l’activité migratoire des cellules, laissant supposer qu’il pourrait éventuellement être un véhicule approprié pour effectuer une livraison cellulaire à un site de lésion. Il s’avère que le 17β-estradiol, lorsqu’ajouté au milieu de culture ou complexé au polymère de chitosan phosphorylcholine, est capable de moduler le comportement cellulaire, et ce, de façon différente. Le 17β-estradiol complexé au polymère de chitosan-phosphorylcholine démontre, par rapport à sa forme soluble, une plus grande aptitude à accroître le nombre de cellules hématopoïétiques ainsi que des cellules endothéliales progénitrices dérivées de la moelle osseuse in vitro. De plus, le 17β-estradiol complexé au polymère de chitosan-phosphorylcholine permet une amplification marquée des cellules endothéliales progénitrices et leur offre un support adéquat afin de favoriser la guérison vasculaire. L’ensemble de nos travaux suggère que le polymère de chitosan complexé à la phosphorylcholine en présence ou non de 17β-estradiol est une matrice compatible avec les cellules progénitrices dérivées de la moelle osseuse in vitro. Le 17β-estradiol complexé au polymère est toutefois plus efficace que sa forme soluble à promouvoir l’amplification du nombre de cellules progénitrices. Ce polymère représente un outil thérapeutique attrayant et une matrice de livraison d’agent bioactif prometteuse pour le recrutement cellulaire dans l’accélération de la guérison vasculaire. Bone marrow derived cells, including endothelial progenitor cells, are reduced in numbers in patient with cardiovascular disease or risk factors. Mobilization and incorporation of these cells at the vascular lesion site are important events in the reendothelialization process. 17β-estradiol was shown in a mouse model of injury, to favour this healing process through mechanisms which involve the mobilization and incorporation of endothelial progenitor cells derived from the bone marrow. At the moment, there are many strategies to increase endothelial progenitor cells mobilization as well as recruitment into the vascular wall. However, few studies favour local delivery of a large number of functional progenitor cells on a biodegradable scaffold and to maintain them at the lesion site in order to promote reendothelialization. An interesting biopolymer for this application is chitosan. This non toxic and biodegradable biopolymer is commonly used in tissue engineering and was recently used in vascular healing. Phosphorylcholine modified chitosan can increase the water solubility and cell biocompatibility of the biopolymer in physiological condition. This master project was thus designed to :1) evaluate, in vitro, the capacity of phosphorylcholine modified chitosan to influence cell adhesion, survival, differentiation and functionality in a mouse model of bone marrow mixed culture and 2) determine the impact of 17β-estradiol on these cell behaviours. Our results suggest an adequate biocompatibility of phosphorylcholine modified chitosan with our cell culture system. Indeed, this polymer was able to promote cell organization and development of bone marrow derived cells in the same way that fibronectin, the most commonly matrix used in the progenitor cells in vitro culture. Moreover, cell migratory activity was not compromised by the chitosan polymer. It appears that 17β-estradiol, when added to cell culture media or attached on phosphorylcholine modified chitosan is able to modulate differently cell behaviour. Our data suggest that 17β-estradiol coupled to the chitosan polymer was superior to increase the number of haematopoietic and endothelial progenitor cells derived from bone marrow in vitro compared to the soluble form. 17β-estradiol coupled to the polymer of phosphorylcholine modified chitosan allowed an increased amplification of progenitor cell number and provided adequate scaffold to favour vascular healing. We propose that phosphorylcholine modified chitosan in presence or not of 17β-estradiol is a compatible matrix with bone marrow derived progenitor cells in vitro. 17β-estradiol enhances the amplification of progenitor cell in vitro when associated to the polymer compared to its soluble form. This biopolymer may be an attractive matrix and a promising vehicle in a drug delivery therapeutic system for progenitor cells recruitment and to promote vascular healing.
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We have examined the effects of pregnancy and sex hormones on calcium-dependent and calcium-independent nitric oxide synthases (NOSs) in the guinea pig. Pregnancy (near term) caused a > 4-fold increase in the activity of calcium-dependent NOS in the uterine artery and at least a doubling in the heart, kidney, skeletal muscle, esophagus, and cerebellum. The increase in NOS activity in the cerebellum during pregnancy was inhibited by the estrogen-receptor antagonist tamoxifen. Treatment with estradiol (but not progesterone) also increased calcium-dependent NOS activity in the tissues examined from both females and males. Testosterone increased calcium-dependent NOS only in the cerebellum. No significant change in calcium-independent NOS activity was observed either during pregnancy or after the administration of any sex hormone. Both pregnancy and estradiol treatment increased the amount of mRNAs for NOS isozymes eNOS and nNOS in skeletal muscle, suggesting that the increases in NOS activity result from enzyme induction. Thus both eNOS and nNOS are subject to regulation by estrogen, an action that could explain some of the changes that occur during pregnancy and some gender differences in physiology and pathophysiology.
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We prospectively examined the use of estrogen replacement therapy in relation to breast cancer incidence in a cohort of women 30 to 55 years of age in 1976. During 367 187 person-years of follow-up among postmenopausal women, 722 incident cases of breast cancer were documented. Overall, past users of replacement estrogen were not at increased risk (relative risk, 0.98; 95% confidence interval, 0.81 to 1.18), including even those with more than 10 years of use (relative risk after adjustment for established risk factors, 0.70; 95% confidence interval, 0.45 to 1.10). However, the risk of breast cancer was significantly elevated among current users (relative risk, 1.36; 95% confidence interval, 1.11 to 1.67). Among current users, a stronger relationship was observed with increasing age but not with increasing duration of use. These data suggest that long-term past use of estrogen replacement therapy is not related to risk of breast cancer but that current use may modestly increase risk. (JAMA. 1990;264:2648-2653)
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PIP A review was made to understand how plasma binding protein might influence sex-hormone action in target tissues. Steroids are predominately bound to plasma proteins and only unbound steroids enter the cells. Sex-hormone-binding globulin (SHBG) binds to both the main circulating steroid T and E2 but changes in SHBG concentrations exert significant results. Increased SHBG levels increase estrogen production and decreases T activity; whereas, increased androgens increase T action and inhibit SHBG production. These disturbances in hormone maintenance may lead to abnormal adult sex differentiation such as hirsutism and forms of hynaecomastia. By developing SHBG concentration measurement methods-responses of hirsutism to glucocorticoid or estrogem may be assessed. In addition, the effect of thyroid hormones on SHBG may also have therapeutic implications in endocrine disease.
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MCF-7 breast tumor cells form multicellular foci in vitro when supplemented with 17beta-estradiol (E_2). In the presence of E_2 and the aryl hydrocarbon-receptor agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), MCF-7 cells grow to confluence but do not form foci. To investigate the role of E_2 metabolism in this antiestrogenic effect of TCDD, analyses were performed by capillary GC/MS. The results revealed that pretreatment of MCF-7 cultures supplemented with 10 nM E_2, the concentration of free E_2 decreased to 4 nM in the first 12 hr, followed by a slower rate of decline. After 3 days most E_2 in the medium was in conjugated form(s); 1.7 nM was present as free E_2, and 2.9 nM was released by treatment with glucuronidase/sulfatase. In TCDD-treated cultures, E_2 declined to 290 pM in 12 hr and after 2 days was not detected (
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Estrogens are potent antioxidants both in vitro and in vivo. In this study the antioxidant affect of estradiol-17β (estradiol) was compared with those of fat-soluble antioxidants (α-tocopherol and β-carotene) in terms of both fatty acid (thiobarbituric acid-reactive substances and diene conjugation) and cholesterol oxidation (oxysterols). The addition of α-tocopherol (54 μmol/L) inhibited low-density lipoprotein (LDL) oxidation by 92.6% and high-density lipoprotein (HDL) oxidation by 76.5%. In similar experiments, estradiol (54 μmol/L) inhibited LDL oxidation by 77.5% but inhibited HDL oxidation by only 55.4%. Beta-carotene had no antioxidant effect. Lag times (diene conjugation method) for α-tocopherol and β-carotene increased by 175% and 125%, respectively. Estradiol markedly reduced the maximum formation of diene conjugates as compared with results with α-tocopherol and β-carotene, and it exhibited a linear curve (no change in lag time). In terms of cholesterol oxidation, estradiol was far more effective than α-tocopherol or β-carotene in inhibiting oxysterol formation (μg/ml plasma) (control = 24.56 ± 2.31, β-carotene = 20.59 ± 3.32, α-tocopherol = 20.19 ± 1.58, estradiol = 14.38 ± 0.70). This study shows that estradiol is as effective an antioxidant as α-tocopherol in terms of fatty acid peroxidation but is far more effective than α-tocopherol in terms of cholesterol peroxidation.
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The binding of 2-hydroxyestrone (20H E1), a catecholestrogen which is the main end product of the 2-hydroxylation of estrogen, was investigated in breast cancers. 20H E1-specific bindings were found in the cytosol (Kd = 0.54 ± 0.10 nM) and in the endoplasmic reticulum (Kd = 3.36 ± 1.32 nM). The dissociation rate constants of complexes between [3H] 2OH E1 and cytosol or membrane binding sites were 3.30 h−1 and 8.30 h−1 respectively. Qualitative analysis of [3H] 2OH E1 cytosolic complexes demonstrated a specific binding component with a mol. wt of 330,000 Dallons. Specificity experiments showed that nonestrogenic hormones were unable to compete with 20H E1 for its binding sites, whereas triphenylethylene derivatives and catecholamines were potent 2OH E1 competitors. The presence of 20H E1 specific bindings suggests a potential role of catecholestrogen in breast cancer.
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The antioxidant activities of 17-β-estradiol (E2) and other steroid hormones were studied by determining their effect on copper-catalyzed (cell-free) and mononuclear cell-mediated oxidation of low-density lipoproteins (LDL), as measured by the production of thiobarbituric acid-reactive substances (TBARS). The oxidation of LDL increased linearly with copper concentrations ranging from 0 to 10 μmol/L. E2 at a concentration of 1 μmol/L inhibited LDL oxidation by 37% to 62% at the various concentrations of copper. In a time-course study, E2 at 1 μmol/L delayed the onset of LDL oxidation in the presence of 5 μmol/L copper. E2 (1 μmol/L) inhibited TBARS production catalyzed by 5 μmol/L copper by 54%, compared with 60% inhibition by 1 μmol/L butylated hydroxytoluene (BHT), a known inhibitor of lipid peroxidation. Estriol at 5 μmol/L decreased LDL oxidation by 49%. Dehydroepiandrosterone (DHEA), testosterone, and estrone had no significant effects. E2 was also an effective inhibitor of mononuclear cell (MNC)-mediated oxidation of LDL, but had no effect on superoxide production by these cells. The onset of TBARS formation from cell-mediated LDL oxidation was also delayed by incubation with 1 μmol/L E2. The results indicate that estrogen may protect against atherosclerosis by inhibiting lipoprotein oxidation.
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Considerable epidemiological evidence has accumulated regarding the effect of postmenopausal estrogens on coronary heart disease risk. Five hospital-based case-control studies yielded inconsistent but generally null results; however, these are difficult to interpret due to the problems in selecting appropriate controls. Six population-based case-control studies found decreased relative risks among estrogen users, though only 1 was statistically significant. Three cross-sectional studies of women with or without stenosis on coronary angiography each showed markedly less atherosclerosis among estrogen users. Of 16 prospective studies, 15 found decreased relative risks, in most instances, statistically significant. The Framingham study alone observed an elevated risk, which was not statistically significant when angina was omitted. A reanalysis of the data showed a nonsignificant protective effect among younger women and a nonsignificant increase in risk among older women. Overall, the bulk of the evidence strongly supports a protective effect of estrogens that is unlikely to be explained by confounding factors. This benefit is consistent with the effect of estrogens on lipoprotein subfractions (decreasing low-density lipoprotein levels and elevating high-density lipoprotein levels). A quantitative overview of all studies taken together yielded a relative risk of 0.56 (95% confidence interval 0.50–0.61), and taking only the internally controlled prospective and angiographic studies, the relative risk was 0.50 (95% confidence interval 0.43–0.56).
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1891 women given conjugated estrogens for the menopause were followed for 12 years (mean) for incidence of breast cancer. Overall, 49 cases were observed; 39.1 were expected on the basis of rates in the general population (relative risk = 1.3, P = 0.06). The relative risk increased with follow-up duration, progressing to 2.0 after 15 years (13/6.6, P = 0.01). The excess risk after 10 years was not due simply to prolonged estrogen use, since there was no clear dose-response relation to accumulated years of use. However, higher risk accrued to women using higher-dose tablets and those taking the medication on an other than daily basis. In addition, after 10 years of follow-up observation, two factors related to low risk of breast cancer, multiparity and oophorectomy, were no longer so related. Finally, estrogen use was related to an especially high risk of breast cancer among women in whom benign disease developed after they had started the drug.
Article
The bioequivalence of four conjugated estrogens tablets USP was compared by measurement of seven estrogens or estrogen metabolites in the urine during steady-state dosing in postmenopausal women. Two studies compared three generic products with the innovator's product. The urinary excretion of 17 alpha-dihydroequilin, 17 alpha-dihydroequilenin, and 17 alpha-estradiol were significantly greater in all cases with the innovator's product than with the generic products. Statistically significant differences between products were observed occasionally for other components. The generic products thus were bioinequivalent to the innovator's product, although all products essentially met current compendial specifications. A third study observed no significant differences between three batches of the innovator's product for the seven components. Total conjugated estrogens excretion of all products at the steady state was essentially equal and correlated with neither disintegration time nor dissolution half-time. Bioinequivalence between products is discussed in relation to the need for an improved USP conjugated estrogens monograph. Evidence suggesting the metabolism of a fraction of dosed estrone, equilin, and 17 alpha-dihydroequilin to 17 beta-estradiol, 17 beta-dihydorequilim, and 17 alpha-dihydroequilenin, respectively, is presented.
Article
Mean serum concentrations of oestradiol-17beta, oestrone, and oestrone sulphate in postmenopausal women were the same when measured up to six hours after treatment with either piperazine oestrone sulphate 1.5 mg or oestradiol valerate 2 mg. Maximum concentrations of oestradiol were less than those of oestrone, but oestrone sulphate reached concentrations about 30 times higher than those of oestrone. The rapid conversion of oestradiol valerate to oestrone and oestrone sulphate does not support the suggestion that in menopausal women oestradiol is less likely to be associated with a risk of endometrial carcinoma than oestrone sulphate, since the two preparations appear to become identical after ingestion.
Article
The distribution of soluble arylsulfatase (aryl-sulfate sulfohydrolases, EC 3.1.6.1) in human tissues was investigated by DEAE-cellulose chromatography, All tissues examined contained arylsulfatase A and arylsulfatase B. In addition, brain singularly contained significant quantities (15-25% of total arylsulfatase) of a minor anionic arylsulfatase from designated arylsulfatase Bm, whereas only trace amounts of arylsulfatase Bm were found in liver, kidney, testis and placenta. Arylsulfatase B and arylsulfatase Bm had equal activity toward methyl-umbelliferyl sulfate, nitrocatechol sulfate and a physiological substrate UDP-N-acetylgalactosamine 4-sulfate, but both forms were inactive toward the arylsulfatase A substrates cerebroside sulfate and ascorbic acid 2-sulfate. Purified preparations of placental arylsulfatase B, brain arylsulfatase Bm, and urinary arylsulfatase A did not hydrolyze estrone sulfate, dehydroepiandrosterone sulfate or pregnenolone sulfate. The physico-chemical properties of arylsulfatase Band arylsulfatase Bm differed with respect to thermal lability, DEAE-cellulose chromatography, polyacrylamide gel electrophoresis and isoelectric focussing. In the latter technique, utilizing thin polyacrylamide slab gels, the isoelectric point for placental arylsulfatase B was 8.2, while brain arylsulfatase Bm resolved into 3 activity bands with pI values 6.8, 7.0 and 7.2. Although the physico-chemical properties differed, arylsulfatase B and arylsulfatase Bm appear to be functionally equivalent as well as generically related.
Article
The effects of estrogens on LDL modification by copper ions, U 937 monocyte-like cells or endothelial cells was studied by determination of the lipid peroxidation product content and measurement of the relative electrophoretic mobility. The presence of estradiol, estriol and estrone inhibited LDL oxidation in a dose-dependent manner in the range of concentrations from 5 to 50 microM. In the case of oxidation by Cu2+, the decreasing order of efficiency was: estradiol, estriol, estrone. In monocyte-induced oxidation, the protective effect of estrogens was more marked, and the order of efficiency was the same, except that estrone was as active as estriol. Pretreatment of monocyte cells with estrogens also inhibited the subsequent modification of LDL by these cells, tested in the absence of the hormones. Testosterone had no effect in all the studied systems. Furthermore, the degradation by J774 macrophage like cells of LDL modified either by Cu2+ or monocytes was markedly reduced when modification has been performed in the presence of estrogens. Since oxidative modification of LDL is believed to be involved in the appearance of atherosclerotic plaques, this effect of estrogens might be related to their protective action against atherosclerosis.
Article
PIP Reduced cardiovascular mortality is evidenced in persons undergoing hormone replacement therapy (HRT). Studying the effects of gonadal steroids on lipoproteins is therefore encouraged, not only because of this important revelation, but also due to the information to be gleaned on lipoprotein metabolism, the large numbers of women taking oral contraceptives and HRT, and the rising demand for the therapy. Thus far, studies have been performed on men and animals. This paper reviews some work on estrogens and androgens, and discusses oral contraceptives, HRT, and lipoproteins. In sum, estrogen administered via any route reduces low density lipoprotein concentrations. Given that animal studies demonstrate the ability of HRT to both inhibit the development of atherosclerosis and alter vasomotor tone in atherosclerotic coronary arteries, women with confirmed coronary disease may also be likely to benefit from the therapy. Greater information should be sought on the benefits of HRT for secondary prevention, therapy effects should be monitored, and the effects of estrogen/progestogen combinations should be investigated.
Article
We conducted a meta-analysis of the literature concerning breast cancer and estrogen replacement therapy. The overall relative risk of breast cancer associated with this therapy was 1.07. However, the variation of the estimated risks among the studies was far greater than could plausibly be explained by chance alone. To explain this variation, we looked at the effects of type, duration, and dosage of treatment. Overall, women who took 0.625 mg/d or less of conjugated estrogens had a risk of breast cancer that was 1.08 times that of women who did not receive this therapy (95% confidence interval [CI], 0.96 to 1.2). The relative risks from these individual studies of low-dosage therapy did not differ significantly from each other. Women who took 1.25 mg/d or more of conjugated estrogens had a breast cancer relative risk of 2.0 or less in all studies. However, the variation in observed risks at this higher dosage was significant. This implies that other risk factors varied among these studies, making it difficult to estimate the overall risk associated with this dosage. The relative risk of breast cancer associated with estrogen replacement therapy among women with a history of benign breast disease was 1.16 (95% CI, 0.89 to 1.5). The combined results from multiple studies provide strong evidence that menopausal therapy consisting of 0.625 mg/d or less of conjugated estrogens does not increase breast cancer risk.
Article
The effect of postmenopausal estrogen therapy on the risk of cardiovascular disease remains controversial. Our 1985 report in the Journal, based on four years of follow-up, suggested that estrogen therapy reduced the risk of coronary heart disease, but a report published simultaneously from the Framingham Study suggested that the risk was increased. In addition, studies of the effect of estrogens on stroke have yielded conflicting results. We followed 48,470 postmenopausal women, 30 to 63 years old, who were participants in the Nurses' Health Study, and who did not have a history of cancer or cardiovascular disease at base line. During up to 10 years of follow-up (337,854 person-years), we documented 224 strokes, 405 cases of major coronary disease (nonfatal myocardial infarctions or deaths from coronary causes), and 1263 deaths from all causes. After adjustment for age and other risk factors, the overall relative risk of major coronary disease in women currently taking estrogen was 0.56 (95 percent confidence interval, 0.40 to 0.80); the risk was significantly reduced among women with either natural or surgical menopause. We observed no effect of the duration of estrogen use independent of age. The findings were similar in analyses limited to women who had recently visited their physicians (relative risk, 0.45; 95 percent confidence interval, 0.31 to 0.66) and in a low-risk group that excluded women reporting current cigarette smoking, diabetes, hypertension, hypercholesterolemia, or a Quetelet index above the 90th percentile (relative risk, 0.53; 95 percent confidence interval, 0.31 to 0.91). The relative risk for current and former users of estrogen as compared with those who had never used it was 0.89 (95 percent confidence interval, 0.78 to 1.00) for total mortality and 0.72 (95 percent confidence interval, 0.55 to 0.95) for mortality from cardiovascular disease. The relative risk of stroke when current users were compared with those who had never used estrogen was 0.97 (95 percent confidence interval, 0.65 to 1.45), with no marked differences according to type of stroke. Current estrogen use is associated with a reduction in the incidence of coronary heart disease as well as in mortality from cardiovascular disease, but it is not associated with any change in the risk of stroke.
Article
The present investigation was undertaken to compare the binding affinities (Ka) of the ring B unsaturated equine estrogens (equilin [Eq], equilenin [Eqn], 17 beta-dihydroequilin [17 beta-Eq], 17 beta-dihydroequilenin [17 beta-Eqn], 17 alpha-dihydroequilin [17 alpha-Eq], and17 alpha-dihydroequilenin [17 alpha-Eqn]) and the classic estrogens (estrone [E1], 17 beta-estradiol [17 beta-E2], and 17 alpha-estradiol [17 alpha-E2]) for estrogen receptors in human endometrium and rat uterus. In both species, the ring B unsaturated estrogens bind with cytosol and nuclear receptors with high affinity (Ka x 10(9) M-1). The relative binding affinities of these estrogens were measured by determining the amount of unlabeled estrogen required to reduce by 50% the specific binding of [3H]17 beta-Eq to endometrial cytosol receptors. The order of activity found was 17 beta-Eq greater than 17 beta-E2 greater than 17 beta-Eqn greater than E1 greater than Eq greater than 17 alpha-Eq greater than 17 alpha-E2 greater than 17 alpha-Eqn greater than Eqn. Essentially the same order of activity was observed when the apparent affinity constants of these estrogens for human and rat cytosol and nuclear receptors were determined by a competitive (inhibition) binding assay. Sucrose density gradient analysis indicated that these estrogens form protein complexes with cytosol and nuclear preparation that sediment at approximately 8S and 4S, respectively. The affinity constants for 17 beta-Eq were approximately two- to six-fold higher than E2 in both species. In a rat uterotropic assay, all nine estrogens were uterotropic. These data indicate that all ring B unsaturated estrogens present in conjugated equine estrogen preparations are biologically active and they express their biologic effects in the human endometrium by mechanisms similar to those described for the classic estrogens.
Article
Sixteen different steroid hormones were individually tested in equilibrium dialysis against plasma high-density, low-density and very-low-density lipoproteins (HDL, LDL, VLDL) under physiological conditions. Six steroid hormones (androstenediol (AEDOL), estradiol (E2), dehydroepiandrosterone (DHEA), dihydrotestosterone (DHT), pregnenolone (P5), and progesterone (P4)) demonstrated metabolic interaction with HDL, particularly HDL3. In four cases (AEDOL-HDL, E2-HDL, DHEA-HDL and P5-HDL) the interaction products were more lipophilic, while in the other two cases (DHT-HDL, P4-HDL) they were hydrophilic compared to the original steroid hormone substrates. The lipophilic products appeared to be long-chain fatty acid steroid hormone esters at the C-3 position of the steroid hormone. This was confirmed, in preparative incubations, for the two strongest steroid hormone reactants (DHEA and P5) by gas chromatography-mass spectroscopy (GC-MS). Naturally occurring DHEA and P5 esters were identified in normal fresh human plasma by GC-MS, and their fatty acid compositions were similar to that of native HDL3 cholesterol esters. It was deduced that lecithin-cholesterol acyl transferase enzyme was responsible for the lipophilic type conversion activity with P5 greater than DHEA greater than AEDOL greater than E2. For DHT and P4, which exhibit a fundamentally different (hydrophilic) type of metabolic conversion, a totally different form of HDL-associated metabolic activity is indicated. These newly discovered steroid hormone-lipoprotein interactions may be important for steroid hormone processing in plasma and/or steroid hormone delivery to cells.
Article
Estrogens are associated with several cancers in humans and are known to induce tumors in rodents. In this review a mechanism of carcinogenesis by estrogens is discussed which features the following key events: (1) Steroid estrogens are metabolized by estrogen 2- and 4-hydroxylases to catecholestrogens. Target organs of estrogen-induced carcinogenesis, hamster kidney or mouse uterus, contain high levels of estrogen 4-hydroxylase activity. Since the methylation of 4-hydroxyestradiol by catechol-O-methyltransferase is inhibited by 2-hydroxyestradiol, it is proposed that a build up of 4-hydroxyestrogens precedes estrogen-induced cancer. (2) The catecholestrogen or diethylstilbestrol (DES) are oxidized to semiquinones and quinones by the peroxidatic activity of cytochrome P-450. The quinones are proposed to be (the) reactive intermediates of estrogen metabolism. (3) The quinones may be reduced to catecholestrogens and DES and redox cycling may ensue. Redox cycling of estrogens has been shown to generate free radicals which may react to form the organic hydroperoxides needed as cofactors for oxidation to quinones. (4) The quinone metabolites of catechol estrogens and of DES bind covalently to DNA in vitro whereas DNA binding in vivo has only been examined for DES. When DES is administered to hamsters, the resulting DES-DNA adduct profile in liver, kidney, or other organs closely matches that of DES quinone-DNA adducts in vitro. In vitro, DES-DNA adducts are chemically unstable and are generated in incubations with organic hydroperoxide as cofactor. It is proposed that the instability of adducts and the lower sensitivity of previous assay methods contributed to the reported failures to detect adducts. Steroid estrogen-DNA adducts in vivo are currently under investigation. (5) Tumors are postulated to arise in cells rapidly proliferating due to the growth stimulus provided by the estrogenic activity of the primary estrogen or of hormonally potent metabolites such as 4-hydroxyestradiol. The covalent modification of DNA in these cells is temporary because of the chemical instability of adducts and will result in altered genetic messages in daughter cells, whereas in non-proliferating cells there may be no lasting genetic damage. The sequence of events described above is a plausible mechanism for tumor initiation by estrogens and is partially substantiated by experimental evidence obtained in vitro and/or in vivo.
Article
A kinetic study of the reaction between estrogens (female hormone) and substituted phenoxyl radical has been performed, as a model for the reactions of estrogens with lipid peroxyl radical in biological systems. The rates of reaction of estrogens (estrone 1, estradiol 2, 2-methoxyestrone 3, 3-methoxyestrone 4, and 2-hydroxyestrone 5) with substituted phenoxyl radical in benzene have been determined spectrophotometrically, using stopped-flow technique. The second-order rate constants, k2, obtained are 84 M-1.s-1 for 1, 138 M-1.s-1 for 2, 520 M-1.s-1 for 3, less than 10(-4) M-1.s-1 for 4, and 2.6 X 10(5) M-1.s-1 for 5 at 25.0 degrees C. 2-Hydroxyestrone 5 was found to be 2.9-times more active than alpha-tocopherol, which has the highest antioxidant activity among natural tocopherols. The order of magnitude of k2 value (1 less than 2 less than 3 less than alpha-Toc less than 5) is in agreement with that of in vitro tests of their antioxidant activities, as measured by the inhibition of lipid peroxidation. Further, similar measurements have been performed for the reaction between the above estrogens 1-5 and tocopheroxyl 6 in benzene solution. It was found that the estrogens having an OH group at the aromatic ring have an ability to regenerate the tocopheroxyl 6 to tocopherol. Especially, the 2-hydroxyestrone 5 showed about three orders of magnitude higher reactivity than ascorbic acid.
Article
A nonhuman primate model was developed to study the effects of oral contraceptives on lipoproteins and atherosclerosis. Cynomolgus macaques were selected because of their susceptibility to diet-induced atherosclerosis and because their reproductive physiology, menstrual cycle, and circulating sex hormone patterns are similar to those of human females. The first study compared a vaginal ring containing levonorgestrel and estradiol with an oral contraceptive containing norgestrel and ethinyl estradiol. A second study compared two oral combinations: norgestrel-ethinyl estradiol and ethynodiol diacetate-ethinyl estradiol. As predicted, use of all the contraceptives led to lowering of high-density lipoprotein cholesterol levels. However, contrary to what might be expected, use of the ethinyl estradiol-containing oral contraceptives did not lead to an increase in the prevalence or extent of atherosclerosis. We concluded that ethinyl estradiol neutralized the atherogenic influence of the progestin component of oral contraceptives.
Article
Catecholestrogens and especially 2-hydroxyestrone (2OH-E1) are estradiol metabolites locally formed in breast cancer cells. The present study demonstrates that the two parent compounds, estradiol (E2) and its metabolite 2OH-E1, exert opposite effects on hormone-sensitive breast cancer cell growth assessed by cell counts and transferrin receptor levels, and also on cell differentiation assessed by secreted proteins such as alpha-lactalbumin and gross cystic disease fluid protein (GCDFP-15). The present findings may highlight estradiol regulation in hormone-sensitive breast cancer cells.
Article
Partition coefficient analysis, equilibrium dialysis, and computer simulation were used to evaluate associations of twelve steroid hormones (androstanediol, androstenediol, androstenedione, androsterone, dehydroepiandrosterone, dihydrotestosterone, estradiol, estriol, estrone, hydroxyprogesterone, progesterone, and testosterone) with human plasma high density lipoproteins (HDL), low density lipoproteins (LDL), and very low density lipoproteins (VLDL). It was determined that partitioning of steroid hormones (SH) between the aqueous medium and the surfaces of lipoproteins (LP) was the initial (first order) SH-LP interaction. For some SH, especially dehydroepiandrosterone, significant second order interactions, which may involve chemical conversions, were detected. The first order binding values of the twelve SH with three LP were combined with the corresponding binding values of SH with sex hormone-binding globulin, corticosteroid-binding globulin, and albumin in a 6 X 12 matrix. The computer program TRANSPORT was used to analyze the matrix and determine the distribution of each SH among six different binding agents in the "normal" male. It was concluded that LP are important vehicles for SH conveyance in plasma and may also be important for SH entry into cells.
Article
Low-density lipoprotein readily undergoes lipid peroxidation that is accompanied by apoprotein fragmentation. Oxidized forms of low-density lipoprotein show altered biological behavior, including changes in receptor recognition and cytotoxicity to cells in culture. In this review, free radical mechanisms and the biological consequences of low-density lipoprotein modification are discussed.
Article
The protective effect of early menopause shows that ovarian hormones increase the risk of breast cancer: it is likely that this is because they stimulate breast cell division. The mitotic rate of breast cells is higher during the luteal phase of the menstrual cycle than during the follicular phase, suggesting either that progesterone and oestrogen together induce more mitoses than oestrogen alone (the 'oestrogen plus progestagen hypothesis') or that oestrogen alone induces breast cell mitoses in a dose-dependent manner and that progesterone has no effect (the 'oestrogen alone hypothesis'). Both hypotheses are consistent with the known effects of reproductive history, obesity, combined oral contraceptives and oestrogen replacement therapy (ERT) on breast cancer risk, but while the oestrogen alone hypothesis predicts that hormone replacement therapy with oestrogen and a progestagen (HRT) will cause the same increase in risk as ERT, the oestrogen plus progestagen hypothesis predicts that HRT will cause a greater increase in risk than ERT. Both hypotheses suggest that the risk of breast cancer could be reduced by delaying the onset of regular ovulatory menstrual cycles and by minimizing the therapeutic use of oestrogens, and possibly of progestagens, in postmenopausal women. It may be possible to design hormonal contraceptives that will decrease breast cancer risk.
Article
A cohort of 2270 white women, aged 40-69 years at baseline, were followed for an average of 8.5 years in the Lipid Research Clinics Program Follow-up Study. There were 44 deaths due to cardiovascular disease among the 1677 nonusers of estrogens and six cardiovascular disease deaths among the 593 estrogen users. The age-adjusted relative risk (RR) of cardiovascular disease deaths in users compared with nonusers was 0.34 (95% confidence limits 0.12 to 0.81). After multivariable adjustment for potential confounding factors (age, blood pressure, and smoking), the estimated RR for estrogen use was 0.37 (95% confidence limits 0.16 to 0.88). Analyses were done to explore whether these results could be due to selection bias for estrogen use. However, the prevalence of cardiovascular disease at baseline was slightly higher in estrogen users (12%) than in nonusers (10%); furthermore, the exclusion of all women with prevalent cardiovascular disease at baseline did not alter the apparent protective effect of estrogen use on cardiovascular disease mortality (RR = 0.42, 95% confidence limits 0.13 to 1.10). Additional analyses examining the complex association between estrogen use, lipoprotein levels, and cardiovascular disease mortality suggest that the protective effect of estrogen is substantially mediated through increased high-density lipoprotein levels.
Article
Epidemiologic data indicate that cigarette smoking is associated with an important anti-estrogenic effect, and increased hepatic metabolism has been suggested as a possible mechanism. We examined the hypothesis that cigarette smoking in women induces an increase in estradiol 2-hydroxylation. This irreversible metabolic pathway yields 2-hydroxyestrogens, which possess minimal peripheral estrogenic activity and are cleared rapidly from the circulation. We found a significant increase in estradiol 2-hydroxylation in premenopausal women who smoked at least 15 cigarettes per day. The extent of the reaction (mean +/- SEM) was 53.6 +/- 2.2 percent among 14 smokers and 35.1 +/- 1.8 percent among 13 nonsmoking controls--an increase of approximately 50 percent (P less than 0.001). The extent of 2-hydroxylation among five smokers did not vary during the follicular and luteal phases of their menstrual cycles. In addition, urinary excretion of estriol relative to estrone was significantly decreased among smokers (P less than 0.01), providing evidence that the smoking-induced increase in 2-hydroxylation diminishes the competing metabolic pathway involving 16 alpha-hydroxylation. This study demonstrates that smoking exerts a powerful inducing effect on the 2-hydroxylation pathway of estradiol metabolism, which is likely to lead to decreased bioavailability at estrogen target tissues. Elucidation of the mechanism responsible for smoking-induced changes in 2-hydroxylation may be useful in the development of strategies to reduce the risk of hormone-dependent tumors.
Article
A rapid capillary GLC method for the analysis of conjugated estrogen tablets and injectable formulations is described. The method involves the hydrolytic cleavage of the sodium sulfate ester conjugates by sulfatase enzyme. The free phenolic steroids are reacted sequentially with hydroxylamine hydrochloride and N,O-bis(trimethylsilyl)trifluoroacetamide. The resulting dual derivatives are analyzed on a 15-m glass capillary column wall coated with a cyanopropylmethyl silicone phase.
Article
The popularity of estrogen therapy for the menopausal woman may well be on the rise again, with new evidence on the risks and treatment of osteoporosis and the protective effect of progestin on the endometrium becoming clearer. The risks of estrogen treatment must remain a prime concern of the practitioner, and hazards may be minimized through careful patient selection, education, examination, treatment, and follow-up. The resurgence of interest in the plight of the menopausal woman has stimulated an increasing number of competent investigators to attempt to solve the mysteries that until recently have been evaluated and treated by anecdote and homeopathic ministrations.
Article
The MCRs of equilin sulfate and equilin were determined in normal postmenopausal women and a normal man by single iv injections of either [3H]equilin sulfate or [3H] equilin. After the administration of [3H]equilin sulfate, blood was drawn at various time intervals, and the plasma obtained was fractionated into the unconjugated, sulfate, and glucuronide fractions. The bulk of radioactivity was present in the sulfate fraction, and from this, [3H]equilin sulfate, [3H]17 beta-dihydro-equilin sulfate, [3H]equilenin sulfate, and [3H]17 beta-dihydroequilenin sulfate were isolated and purified, and their concentrations were measured. The disappearance of radioactivity from plasma as equilin sulfate can be described as a function that is the sum of two exponentials. The initial fast component (half-life, 5.2 +/- 1.2 min) represents distribution and transfer from a space, with a mean volume of 12.4 +/- 1.6 liters. The mean value for the rate constant of total removal from the initial volume is 163 +/- 19 U/day, of which 15.8 +/- 2% is irreversible. The mean half-life of the slower component of equilin sulfate is 190 +/- 23 min, and the mean MCR is 176 +/- 44 liters/day . m2. Similarly, after the administration of [3H]equilin to a normal postmenopausal woman and a man, the disappearance of radio-activity from plasma as equilin could be fitted by a single straight line, consistent with a one-compartment system. The half-life of equilin was approximately 19-27 min, and the MCR of equilin was calculated to be 1982 liters/day/m2 in the normal man and 3300 liters/day/m2 in the normal postmenopausal woman. The bulk of [3H]equilin was very rapidly metabolized to mainly equilin sulfate. Small amounts of 17 beta-dihydroequilin sulfate and 17 beta-dihydroequilin were also isolated from the plasma. The in vivo formation of 17 beta-dihydroequilin and its sulfate may be of importance, as this estrogen is approximately 8 times more potent as a uterotropic agent than equilin sulfate.
Article
Conjugated equine oestrogens (CEE) as in Premarin have been used for the treatment of climacteric complaints and the prevention of oestrogen deficiency symptoms since the early 1940's. The biological activity of Premarin's different components is described. Our knowledge of the pharmacokinetics of the nine structurally related oestrogen conjugates in CEE is reviewed. Particular attention is paid to the significance of the sulphate moiety. It is possible that the sulphate group is exerting a 'protective' effect against sudden oestrogenic stimulation.
Article
Treatment of nonpolar ether extracts of human female blood with mild alkali produced more immunoassayable estradiol than the unhydrolyzed extract. Analysis of the serum extracts showed that the substance which released immunoreactive estradiol after hydrolysis has chromatographic properties identical to those of fatty acid esters of estradiol esterified at carbon 17. The physiological role of these previously unknown endogenous esters might be inferred from their structural similarity to synthetic drugs used therapeutically for their prolonged estrogenic action.
Article
The oxidative metabolism of estradiol (the natural estrogen 2,3,5(10)-estratriene-3,17 beta-diol) at positions C-2 and C-16 was examined in primary cultures of chick embryo liver cells using estradiol which was labeled with 3H specifically at either the C-2 or C-16 position as the substrate. Oxidation of estradiol by the cultured liver cells was assessed by the release of 3H which accumulated as 3H2O in the culture medium; both C-2 and C-16 oxidative reactions were detectable in the liver cell cultures by this technique. When incubated with a concentration of estradiol substrate close to the Michaelis constant (Km), approximately 45.8 pmol [2-3H]estradiol and 5.0 pmol [16-3H]estradiol/mg protein per minute underwent oxidative metabolism in untreated cells. Total amounts of oxidized product formation after 2 h of incubation were 28 and 5 pmol/mg protein for C-2 and C-16 oxidation, respectively. Treatment of cultures with phenobarbital or 2-propyl-2-isopropylacetamide significantly increased oxidation at C-16 (1.9-fold and 2.6-fold greater than control values, respectively), whereas no significant change in C-16 oxidation was observed after treatment of the cultures with 3-methylcholanthrene, benzo[a]pyrene, or benz[a]anthracene. The latter chemicals, however, were found to increase the extent of oxidation at C-2 significantly (i.e., 1.5-2.2-fold increases over control values). The increase in C-2 oxidation after treatment of cultures with phenobarbital or 2-propyl-2-isopropylacetamide was significantly less than that observed for oxidation at C-16. The apparent Km values for these oxidations in control cultures were 23.5 and 30.3 microM for C-2 and C-16 oxidation, respectively; corresponding maximum velocity (Vmax) values were 119 and 11.7 pmol/mg protein per minute, respectively. These data indicate that the C-2 and C-16 oxidations of estradiol take place in cultured avian hepatocytes and that the extent of metabolism at these positions on the hormone molecule can be altered by chemicals, such as drugs and polycyclic aromatic hydrocarbons, which induce distinctive species of cytochrome P-450 in the liver.
Article
Characteristics of the processes by which steroid and thyroid hormones enter tissues, cells and membrane vesicles are reviewed. Several authors suggest that entry is by passive diffusion: the accumulation within cells is attributed to cytoplasmic binding proteins. Other authors, however, propose a membrane-mediated process of entry. The involvement of saturability, high specificity, sensitivity to temperature, sulfhydryl and cell-surface-perturbing reagents and hydrolytic enzymes support the latter view. Purified plasma-membrane vesicle preparations retain several characteristics of entry shown by intact cells. Intracellular hormone-binding protein would not contribute to processes observed with these preparations.
Article
IT is known that women who smoke have an earlier menopause than those who do not.1 , 2 Noting recent data suggesting that breast cancer might be somewhat less frequent in smokers than in non-smokers,3 4 5 we thought it would be worthwhile to compare the estrogen profiles of smokers and nonsmokers. A difference might shed light on the mechanisms whereby smoking is associated with early menopause and with a reduction in the risk of breast cancer. Smoking histories were obtained from women for whom urinary estrogen concentrations had been determined previously. As compared with nonsmokers and exsmokers, smokers had substantially and significantly lower . . .
Article
Our study demonstrates that tamoxifen, when administered to postmenopausal women at a conventional dosage, reduces LDL levels and protects LDL from oxidation. The protective effect of tamoxifen against the development of breast cancer in women considered at risk is being investigated in a placebo-controlled trial sponsored by the National Institutes of Health. Whether tamoxifen also protects against the development of cardiovascular disease in this trial is also of considerable interest.
Article
We provide here a list of 221 P450 genes and 12 putative pseudogenes that have been characterized as of December 14, 1992. These genes have been described in 31 eukaryotes (including 11 mammalian and 3 plant species) and 11 prokaryotes. Of 36 gene families so far described, 12 families exist in all mammals examined to date. These 12 families comprise 22 mammalian subfamilies, of which 17 and 15 have been mapped in the human and mouse genome, respectively. To date, each subfamily appears to represent a cluster of tightly linked genes. This revision supersedes the previous updates [Nebert et al., DNA 6, 1-11, 1987; Nebert et al., DNA 8, 1-13, 1989; Nebert et al., DNA Cell Biol. 10, 1-14 (1991)] in which a nomenclature system, based on divergent evolution of the superfamily, has been described. For the gene and cDNA, we recommend that the italicized root symbol "CYP" for human ("Cyp" for mouse), representing "cytochrome P450," be followed by an Arabic number denoting the family, a letter designating the subfamily (when two or more exist), and an Arabic numeral representing the individual gene within the subfamily. A hyphen should precede the final number in mouse genes. "P" ("p" in mouse) after the gene number denotes a pseudogene. If a gene is the sole member of a family, the subfamily letter and gene number need not be included. We suggest that the human nomenclature system be used for all species other than mouse. The mRNA and enzyme in all species (including mouse) should include all capital letters, without italics or hyphens. This nomenclature system is identical to that proposed in our 1991 update. Also included in this update is a listing of available data base accession numbers for P450 DNA and protein sequences. We also discuss the likelihood that this ancient gene superfamily has existed for more than 3.5 billion years, and that the rate of P450 gene evolution appears to be quite nonlinear. Finally, we describe P450 genes that have been detected by expressed sequence tags (ESTs), as well as the relationship between the P450 and the nitric oxide synthase gene superfamilies, as a likely example of convergent evolution.
Article
Lipoprotein metabolism is involved in atherogenesis. Female sex-hormones have substantial effects on both lipoprotein metabolism and the vessel wall. Cholesterol, one of the major lipids in lipoproteins, is both the substrate for, and the target of, the steroidal sex hormones.
Article
Oxidative modification of low-density lipoprotein (LDL) may be atherogenic. We studied the time of onset of LDL oxidation (lag) in 18 postmenopausal women before and after intraarterial infusion of 17 beta-oestradiol, after 3 weeks' patch administration in 12 of these women, and 1 month after discontinuation in 10. The lag increased from baseline after acute infusion (from 134 [SD41] to 167 [36] min, p = 0.01) and after the patch (132 [31] to 178 [45] min, p = 0.009). After discontinuation of oestradiol, the lag returned to baseline. This study shows an antioxidant effect of physiological levels of 17 beta-oestradiol, which may contribute to an anti-atherogenic action.
Article
The metabolism of 17 beta-dihydroequilin and 17 beta-dihydroequilin sulfate was investigated after intravenous administration of [3H] 17 beta-dihydroequilin and [3H] 17 beta-dihydroequilin sulfate to postmenopausal women. Urine was collected for 3 days and 46.2 +/- 10.5% and 54.5 +/- 8.7% of the injected dose of [3H] 17 beta-dihydroequilin and [17 beta-3H]dihydroequilin sulfate was excreted in the urine respectively. The estrogens present in urine were extracted and fractionated into unconjugated, sulfate, and glucuronide conjugated forms. With both precursors, the major amount (63-64%) of metabolites were excreted in the urine conjugated with glucuronic acid. From the unconjugated, sulfate, and glucuronide fraction, 17 beta-dihydroequilenin, 17 beta-dihydroequilin, equilenin, and equilin were isolated. The conversions with both precursors were similar and 17 beta-dihydroequilenin was the major metabolite isolated from all three fractions; however, the highest levels of all four metabolites were present in the glucuronide fraction. Along with these identifiable metabolites, a large amount (51-81%) of radioactivity was present in the form of metabolites which are more polar than any of the known ring-B unsaturated estrogens. These appear to be polyhydroxy 17 beta-reduced ring-B unsaturated estrogens which remain to be identified. The in-vivo formation of equilenin and 17 beta-dihydroequilenin indicates the presence of the enzyme 6.8(9) steroid dehydrogenase in humans.
Article
It has previously been proposed that redox cycling between catechol estrogens and their quinones, mediated by cytochrome P450, could lead to the generation of free radicals that would subsequently cause oxidative damage to DNA and proteins that might have a role in hormonal carcinogenesis. Alternative, non-enzymatic mechanisms involving copper have been shown to participate in the oxidation of various chemicals through processes that also result in the appearance of reactive oxygen species and subsequent site-specific oxidative DNA damage. The goal of the present study was to determine whether the 2-hydroxy-catechol of estradiol (2-OH-E2) can be oxidized by copper through a process which generates reactive oxygen species that cause oxidative DNA damage as detected by the appearance of strand breaks in phi X-174 plasmid DNA. Our results show that both single- and double-strand breaks are formed in the presence of Cu(II) plus micromolar concentrations of 2-OH-E2, and 4-OH-E2, in a concentration/time-dependent process. No strand breaks were detected in the presence of Cu(II) or 2-OH-E2 alone. The reaction of 2-OH-E2 with Cu(II) was accompanied by the reduction of Cu(II) to Cu(I), the utilization of O2, and the generation of H2O2. The utilization of O2 and the formation of strand breaks was completely blocked by the Cu(I)-specific chelator bathocuproinedisulfonic acid (BCS) at a ratio of BCS to Cu(II) of 4:1. The appearance of strand breaks was also blocked by catalase and inhibited by the singlet oxygen scavengers sodium azide and 2,2,6,6-tetramethyl-4-piperidone. In contrast the free hydroxyl radical scavengers mannitol and N-tert-butyl-alpha-phenylnitrone were not effective inhibitors; superoxide dismutase had no inhibitory effect. These results are similar to what has been observed by others for the formation of oxidative DNA damage by the H2O2/Cu(II) system and by us for the induction of strand breaks by hydroquinone/Cu(II). Since copper is known to be present in the nucleus, particularly in association with guanines in DNA, our results with 2-OH-E2/Cu(II) together with those of others with H2O2/Cu(II), discussed below, suggest an alternate site-specific mechanism for the formation of oxidative DNA damage associated with estrogen treatment. Furthermore, the results suggest that the oxidative damage results from the localized generation of singlet oxygen or a similar bound reactive entity rather than free hydroxyl radical.
Article
Oestradiol-17 beta causes relaxation of isolated coronary arteries and increases blood flow in several vascular beds in human beings and animals. Oestrogen replacement therapy is associated with a lower incidence of cardiovascular disease, but the acute effects of oestradiol-17 beta on myocardial ischaemia are unknown. We have studied the acute effect of sublingual oestradiol-17 beta on exercise-induced myocardial ischaemia in eleven women (mean age 58 [SD 8] years) with coronary artery disease. The women did two treadmill exercise tests on separate days; 40 min before the test they took sublingual oestradiol-17 beta (1 mg) or placebo, in random order. Plasma oestradiol-17 beta concentrations were confirmed to be higher after sublingual oestradiol-17 beta than after placebo (2531 [1192] vs 155 [168] pmol/L, p < 0.001). Oestradiol-17 beta increased both time to 1 mm ST depression (456 [214] vs 579 [191] s, p < 0.004; difference of medians 92 [95% CI 46-254]) and total exercise time (569 [249] vs 658 [193] s, p < 0.01; difference 54 [10-212]). Acute administration of oestradiol-17 beta therefore has a beneficial effect on myocardial ischaemia in women with coronary artery disease. This effect may be due to a direct coronary-relaxing effect, to peripheral vasodilation, or to a combination of these mechanisms. Oestradiol-17 beta may prove to be a useful adjunct to the treatment of angina in postmenopausal women with coronary heart disease.
Article
The biotransformation of the natural estrogen 17 beta-estradiol (E2) via the C16 alpha-hydroxylation pathway is elevated in patients with breast cancer, in subjects at increased risk for developing breast cancer, and in c-Ha-ras-initiated mouse mammary epithelial cells. To determine whether differences in the extent of E2 C16 alpha-hydroxylation are related to the risk of developing breast cancer, we examined the extent of biotransformation of E2 via the C16 alpha-hydroxylation pathway in the mammary terminal duct lobular units (TDLUs), epithelial organoids that are a presumptive target site of human breast carcinogenesis, and in nontarget component mammary fat tissue. Noninvolved mammary tissue was obtained from four patients undergoing reduction mammoplasty and from four undergoing mastectomy for breast cancer. A radiometric assay that measures 3H2O formation caused by stoichiometric 3H exchange from [C16 alpha-3H]E2 was utilized to compare the relative extent of C16 alpha-hydroxylation in explant cultures of TDLUs and mammary fat. The extent of E2 C16 alpha-hydroxylation was 1.83-fold higher (95% confidence interval [CI] = 1.71-1.97) in the TDLUs from reduction mammoplasty (i.e., "low-risk") patients and 7.96-fold higher (95% CI = 6.38-10.55) in the TDLUs from mastectomy (i.e., "high-risk") patients than in the corresponding values observed in the mammary fat. In the TDLUs obtained from the patients undergoing mastectomy for cancer, the extent of this metabolism was 4.56-fold higher (95% CI = 3.97-5.33) than that observed in TDLUs obtained from reduction mammoplasty patients who did not have cancer. The increase in the extent of C16 alpha-hydroxylation of E2 in the epithelial organoids of th