High Levels Of Endogenous Estrogens Research Articles

Investigating the Effect of Estradiol Levels on the Risk of Breast, Endometrial, and Ovarian Cancer.

BackgroundHigh levels of estrogen are associated with increased risk of breast and endometrial cancer and have been suggested to also play a role in the development of ovarian cancer. Cancerogenic effects of estradiol, the most prominent form of estrogen, have been highlighted as a side effect of estrogen-only menopausal hormone therapy. However, whether high levels of endogenous estrogens, produced within the body, promote cancer development, has not been fully established.ObjectiveWe aimed to examine causal effects of estradiol on breast, endometrial, and ovarian cancer.MethodsHere we performed a two-sample Mendelian randomization (MR) to estimate the effect of endogenous estradiol on the risk of developing breast, endometrial, and ovarian cancer, using the UK Biobank as well as 3 independent cancer cohorts.ResultsUsing 3 independent instrumental variables, we showed that higher estradiol levels significantly increase the risk for ovarian cancer (OR = 3.18 [95% CI, 1.47-6.87], P = 0.003). We also identified a nominally significant effect for ER-positive breast cancer (OR = 2.16 [95% CI, 1.09-4.26], P = 0.027). However, we could not establish a clear link to the risk of endometrial cancer (OR = 1.93 [95% CI, 0.77-4.80], P = 0.160).ConclusionOur results suggest that high estradiol levels promote the development of ovarian and ER-positive breast cancer.

A Breast Cancer in a Man in Ndola-Zambia: A Short Case Presentation

Men Breast Cancer (MBC) is uncommon and occurs after the age of 60 years. Among men Prognosis is poor as Prognosis a course of a medical condition is discovered at a late stage. where Infiltrating ductal carcinoma accounts for (70-90%) of male breast cancers. In situ but not invasive carcinoma is exclusively ductal, and it accounts only 7% of the breast cancer cases in males. It is observed that 50-75% of breast cancer cases are spread to lymph nodes. The etiology of male breast cancer is unknown. An excess risk has been associated with the testicular disorders, benign breast disease including gynecomastia, Klinefelter syndrome, etc., Preliminary evidence suggests that BRCA2 is a strong cause. The carriers of the males with BRCA2 mutation have an increased lifetime risk of breast cancer with 80-fold in it. It is also known that there is also a risk of breast cancer associated with undescended testes and it is also related to orchiectomy, orchitis, testicular injury, etc., with an increasing number of children the decreasing trend in risk was observed gradually. Where It is also known that Liver cirrhosis is associated with increased levels of estrogens possibly via high levels of endogenous estrogens.

Effect of physical activity on sex hormones in women: a systematic review and meta-analysis of randomized controlled trials.

IntroductionExposure to high levels of endogenous estrogens is a main risk factor for breast cancer in women, and in observational studies was found to be inversely associated with physical activity. The objective of the present study is to determine the effect of physical activity interventions on sex hormone levels in healthy women.MethodsElectronic databases (MEDLINE, EMBASE, CENTRAL), from inception to December 2014, and reference lists of relevant reviews and clinical trials were searched, with no language restrictions applied. Randomized controlled trials (RCTs) were included if they compared any type of exercise intervention to no intervention or other interventions, and assessed the effects on estrogens, androgens or the sex hormone binding globulin (SHBG) in cancer-free women. Following the method described in the Cochrane Handbook for Systematic Reviews of Interventions, data on populations, interventions, and outcomes were extracted, and combined using the inverse-variance method and a random-effects model. A pre-established protocol was drawn up, in which the primary outcome was the difference in circulating estradiol concentrations between the physical activity (experimental) and the control groups after intervention. Pre-specified subgroup analyses and sensitivity analysis according to the risk of bias were conducted.ResultsData suitable for quantitative synthesis were available from 18 RCTs (1994 participants) for total estradiol and from 5 RCTs (1245 participants) for free estradiol. The overall effect of physical activity was a statistically significant decrease of both total estradiol (standardized mean difference [SMD] -0.12; 95 % confidence interval [CI] -0.20 to −0.03; P = 0.01; I2 = 0 %) and free estradiol (SMD −0.20; 95 % CI −0.31 to −0.09; P = 0.0005; I2 = 0 %). Subgroup analyses suggest that this effect is independent of menopausal status and is more noticeable for non-obese women and for high intensity exercise. Meta-analysis for secondary outcomes found that physical activity induces a statistically significant decline of free testosterone, androstenedione, dehydroepiandrosterone–sulfate and adiposity markers, while a significant increase of SHBG was observed.ConclusionsAlthough the effect is relatively modest, physical activity induces a decrease in circulating sex hormones and this effect is not entirely explained by weight loss. The findings emphasize the benefits of physical activity for women.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0647-3) contains supplementary material, which is available to authorized users.

Aromatase inhibitors, tamoxifen, and endometrial cancer in breast cancer survivors

The risks of both endometrial cancer and postmenopausal breast cancer are increased by obesity and higher endogenous estrogen levels. Although aromatase inhibitors reduce breast cancer incidence, their influence on endometrial cancer is uncertain. The authors investigated this issue in a cohort of 17,064 women who were diagnosed with hormone receptor-positive breast cancer in an integrated group practice health plan. Information on demographics, comorbidities, and the receipt of adjuvant endocrine therapy was available from electronic medical records and pharmacy records, respectively. Endometrial cancer information was obtained from the health plan's Surveillance, Epidemiology, and End Results-affiliated tumor registry, and rates were compared across endocrine therapy groups (aromatase inhibitor, n = 5303; tamoxifen, n = 5155; switchers: both [n = 3787] or none [n = 2819]) using multivariable adjusted Cox proportional-hazards models. Endometrial cancer incidence was a statistically significant 48% lower in the aromatase inhibitor group versus the tamoxifen group (hazard ratio, 0.52; 95% confidence interval, 0.31-0.87; P = .01). Endometrial cancer incidence was 29% lower in the aromatase inhibitor group versus the no endocrine therapy group (hazard ratio, 0.71; 95% confidence interval, 0.37-1.35; P = .30) and 33% lower in the aromatase inhibitor group versus the tamoxifen group (hazard ratio, 0.67; 95% confidence interval, 0.42-1.06; P = .08), but neither difference was statistically significant. Associations were stronger among those with good drug adherence. In a community-based, integrated health plan setting, endometrial cancer incidence was lower in women who were receiving an aromatase inhibitor compared with those who were receiving tamoxifen. In addition, aromatase inhibitors may mitigate the incidence of tamoxifen-associated endometrial cancer. Although there were somewhat fewer endometrial cancers in the aromatase inhibitor group versus the no endocrine therapy group, further studies are needed for the definitive assessment of this potential association.

Pulmonary and Venous Thromboembolism After In Vitro Fertilization

Pregnancy raises risk for venous thromboembolism (VTE) — but does in vitro fertilization (IVF), given the high endogenous estrogen levels achieved

Higher endogenous estrogen levels in 70-year-old women and men

Reported associations between endogenous steroid hormone levels and cardiovascular disease in the older population have been contradictory. We evaluated plasma steroid concentrations in terms of the dimensions of the common carotid artery wall layers as a measure of the extent of atherosclerosis. A subgroup of 70-year-old participants (32 women and 50 men) from the Prospective Investigation of the Vasculature in Uppsala Seniors study was investigated. All participants had assessments of common carotid artery wall layer parameters (intima thickness, media thickness, and intima-media thickness [IMT] ratio; measured by high-frequency ultrasound at 22 MHz) and endogenous steroid hormone concentrations (measured by liquid chromatography-tandem mass spectrometry). Low androgen levels, high aromatase enzyme activity (estrone [E1]/androstenedione and estradiol [E2]/testosterone), high E2/E1 ratio, and high estrogen levels (E1, E2, estriol, and E2/sex hormone-binding globulin) were consistently associated (often significantly) with a more unhealthy artery wall (thick intima, thin media, and high IMT ratio) in both sexes. Consistently strong associations were found between the aromatase index E2/testosterone and intima, media, and the IMT ratio. For IMT ratio, in both men (rs = 0.52) and women (rs = 0.58), P was <0.001 for both and remained significant after adjustment for cardiovascular disease risk factors and the Framingham risk score (both P < 0.01). Low androgens, high aromatase enzyme activity, and high estrogen levels are often significantly associated with an unhealthy artery wall on ultrasound. We suggest that the steroid hormone profile of older individuals with higher estrogens most probably reflects an endogenous response to developing atherosclerosis, rather than a cause-and-effect relationship. However, the reverse causality cannot be excluded.

Circulating Sex Hormones and Mammographic Breast Density among Postmenopausal Women

The use of breast density as an intermediate or predictive marker of breast cancer risk is limited by an incomplete understanding of the etiology of breast density. High blood levels of endogenous estrogens and androgens are associated with increased risk of breast cancer among postmenopausal women. We sought to examine whether these hormones are also associated with breast density. The Wisconsin Breast Density Study enrolled 257 postmenopausal women, ages 55-70 years, with no history of postmenopausal hormone use, from mammography clinics in Madison, Wisconsin. Subjects provided a blood sample for sex hormone analysis, and breast density was measured from subjects' screening mammograms using a computer-assisted thresholding method. Numerous sex hormones were associated with breast density in age-adjusted analyses. However, further adjustment for body mass index and other potentially confounding factors substantially attenuated or eliminated these associations. In the fully adjusted model, there remained a positive association between percent breast density and serum progesterone (P=0.03), with percent density rising from 11.9% (95% CI: 9.8, 14.1%) among women in the lowest quartile of serum progesterone to 15.4% (12.9, 18.2%) among women in the highest quartile. There was also a positive association between sex hormone binding globulin and percent breast density (P=0.06). In contrast, there were no independent associations between percent breast density and estradiol (total, free, or bioavailable), estrone, estrone sulfate, or testosterone (total, free, or bioavailable). These results suggest that breast density has a hormonal etiology; however, it may differ in important ways from that of breast cancer risk.

Abstract LB-415: Polymorphisms in nucleotide excision repair genes and endometrial cancer risk

Abstract The increased risk of endometrial cancer associated with unopposed exogenous estrogens and high levels of endogenous estrogens (as are present in obesity) has been hypothesized to result, at least in part, via two possible mechanisms: 1) increased cellular proliferation, and 2) through the production of estrogen metabolites, which can result in DNA damage by directly binding to DNA and forming bulky DNA adducts, and/or indirectly through the production of reactive oxygen species. Thus, interindividual variation in the ability to repair such damage might influence a woman's risk of endometrial cancer. To test this hypothesis, we examined whether the presence of the minor alleles in 64 tag SNPs in the nucleotide excision repair genes ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, LIG1, XPA, and XPC was associated with risk of endometrial cancer in a population-based case-control study in Washington State, with 726 cases ages 50-74 years diagnosed between 1994-2005, and 736 controls frequency-matched to the cases by age. The analyses were restricted to non-Hispanic white women. Most of the genotypes that we investigated were not associated with endometrial cancer risk. However, the presence of the rs4150386 C allele (ERCC5), the rs3730865 C allele (LIG1), and the rs3731127 T allele (XPC) was associated with risk, with respective age-adjusted per-allele odds ratios (ORs) and 95% confidence intervals (CIs) of 0.68 (0.53-0.87), 1.50 (1.05-2.14) and 1.52 (1.10-2.10). The association between rs4150386 and endometrial cancer risk was considerably stronger among obese women (body mass index (BMI)≥30 kg/m2: per-C-allele OR=0.40, 95% CI 0.24-0.65) compared to women with BMI&amp;lt;30 kg/m2 (per-C-allele OR=0.86, 95% CI 0.64-1.14), while the association with rs3730865 was stronger among lighter versus heavier weight women (per-C-allele ORs and 95% CIs were: 1.69, 95% CI 1.12-2.56 for BMI&amp;lt;30 kg/m2, and 1.15, 95% CI 0.55-2.42 for BMI≥30 kg/m2). The association with rs3731127 did not vary by BMI, and the altered risk associated with the minor alleles of the three SNPs did not vary by use of long-term unopposed estrogens. Because of the multiple redundancies in DNA repair pathways and the large number of possible associations examined, there is the potential for false positive findings, both overall and in BMI subgroups. Any conclusions regarding the influence of NER genotypes on risk of endometrial cancer await the results of additional studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-415.

High Levels of Endogenous Estrogens are Associated With Death in the Critically Injured Adult

Sex hormones exhibit predictable changes in their physiologic patterns during critical illness. Endogenous estrogens are elevated in both genders as a result of the peripheral conversion of androgens to estrogens by the aromatase enzyme. Elevated endogenous estrogens have been associated with death in medical and mixed surgical intensive care unit (ICU) patients. Our objective was to determine the relationship between endogenous estrogens and outcomes in critically injured patients. A prospective cohort of injured patients remaining in the ICU for at least 48 hours at two trauma centers was enrolled. Sex hormones (estradiol, progesterone, testosterone, prolactin, and dehydroepiandrosterone-sulfate) were assayed and mortality was assessed. A logistic regression model was used to determine the association between estradiol and death. The area under the receiver operating characteristic (AUROC) curve was used to estimate the accuracy of estradiol in predicting death. Nine hundred ninety-one patients were enrolled with a 13.4% mortality rate. Despite no detectable difference in mortality among genders, estradiol was significantly elevated in nonsurvivors (16 pg/mL vs. 35 pg/mL, p < 0.001). Estradiol was a marker for injury severity with the most severely injured patients exhibiting the highest levels. The ability of estradiol to predict death (AUROC = 0.65) was comparable with Trauma and Injury Severity Score (AUROC = 0.65) and superior to Injury Severity Score (AUROC = 0.54) in this cohort. Serum estradiol is a marker of injury severity and a predictor of death in the critically injured patient, regardless of gender. Whether or not estradiol plays a causal role in outcomes is unclear, but estrogen modulation represents a potential therapy for improving outcomes in critically ill trauma patients.

Biochemical and computational insights into the anti-aromatase activity of natural catechol estrogens

High levels of endogenous estrogens are associated with increased risks of breast cancer. Estrogen levels are mainly increased by the activity of the aromatase enzyme and reduced by oxidative/conjugative metabolic pathways. In this paper, we demonstrate for the first time that catechol estrogen metabolites are potent aromatase inhibitors, thus establishing a link between aromatase activity and the processes involved in estrogen metabolism. In particular, the anti-aromatase activity of a set of natural hydroxyl and methoxyl estrogen metabolites was investigated using biochemical methods and subsequently compared with the anti-aromatase potency of estradiol and two reference aromatase inhibitors. Catechol estrogens proved to be strong inhibitors with an anti-aromatase potency two orders of magnitude higher than estradiol. A competitive inhibition mechanism was found for the most potent molecule, 2-hydroxyestradiol (2-OHE 2) and a rational model identifying the interaction determinants of the metabolites with the enzyme is proposed based on ab initio quantum–mechanical calculations. A strong relationship between activity and electrostatic properties was found for catechol estrogens. Moreover, our results suggest that natural catechol estrogens may be involved in the control mechanisms of estrogen production.

Chemoprevention of Breast Cancer for Women at High Risk

Breast cancer remains the second most common cause of cancer death in the United States. Several studies have identified cohorts of women at higher than average risk to develop this disease. These are women who are exposed to high levels of endogenous or exogenous estrogens, those with a family history of breast cancer, and those who harbor benign breast disease or genetic mutations that predispose to breast cancer. In this population group, adapting a chemoprevention strategy to decrease the risk of developing overt disease is a strong consideration. To this end, tamoxifen is the most studied agent to date. This article describes high-risk categories that predict future development of invasive breast cancer, summarizes the currently available data to support the use of tamoxifen for chemoprevention, and discusses the adverse effects of tamoxifen, as well as measures to anticipate and monitor for possible adverse outcomes.

Associations among maternal soy intake, isoflavone levels in urine and blood samples, and maternal and umbilical hormone concentrations (Japan)

In utero exposure to high levels of endogenous estrogens has been hypothesized to increase breast cancer risk in later life. A high intake of soy has been suggested to protect against breast cancer. We examined the hypothesis that maternal soy intake may be inversely associated with pregnancy hormone levels. The concentrations of hormones (estradiol, estriol, and testosterone) and isoflavones (genistein, deidzein, and equol) were measured in the maternal urine and serum, and umbilical cord blood of 194 women during pregnancy and at delivery. Soy intake during pregnancy was assessed by 5-day diet records at approximately the 29th week of pregnancy. High correlations were observed for isoflavone levels between maternal samples and umbilical cord blood, indicating that isoflavone can be transferred from the maternal to the fetal compartment. None of the hormones measured in umbilical cord blood was significantly associated with any of the isoflavones measured. There were a few significant associations between maternal hormone levels and isoflavone measures during pregnancy, but their patterns of associations varied by gestational week and differed depending on whether isoflavone exposure was measured by diet records, urine or serum. Our data contain no strong evidence showing that soy intake affects hormone levels during pregnancy.

Hepatocellular neoplasms after intrahepatic transplantation of ovarian fragments into ovariectomized rats

Intrahepatic transplantation of ovarian fragments in ovariectomized rats results in morphological abnormalities. The liver acini draining blood from ovarian grafts show alterations resembling chemically induced amphophilic hepatocellular preneoplasias. We investigated the long-term development of these estrogen-induced foci of altered hepatocytes (FAH). We divided 451 Lewis rats into one main group (MG) and 11 (7 female, 4 male) control groups and observed them for up to 30 months. MG animals were ovariectomized and received ovarian transplants into the right liver part. Different combinations of castration, transplantation of ovarian or testicular fragments, and administration of antiestrogenic toremifene were used in controls. In the MG, transplants showed signs of gonadotropic stimulation, and estrogen levels were strongly increased in the downstream liver acini. After 6 and 12 months, FAH developed in hepatocytes downstream of the transplants. After 18 months, 27% of the MG animals showed transformation of FAH into hepatocellular adenomas; this figure increased to 42% after 24 months (8/19), significantly outnumbering four spontaneous adenomas that developed between 18 and 30 months in 258 control animals. Hepatocellular carcinoma (HCC) appeared only in the MG. At 24 and 30 months, 18 HCCs developed; thus, 78% of MG animals showed at least one carcinoma. Administration of toremifene in ovariectomized and transplanted animals completely prevented hepatocarcinogenesis. Testicular grafts showed no influence on liver tissue. In conclusion, initially adaptive but preneoplastic alterations in hepatocytes downstream of intrahepatically transplanted ovarian fragments may transform into HCC, indicating a strong hepatocarcinogenic potential of high local levels of endogenous estrogens in the rat liver.

Prenatal and Perinatal Correlates of Adult Mammographic Breast Density

Adult mammographic percent density is one of the strongest known risk factors for breast cancer. In utero exposure to high levels of endogenous estrogens (or other pregnancy hormones) has been hypothesized to increase breast cancer risk in later life. We examined the hypothesis that those factors associated with higher levels of estrogen during pregnancy or shortly after birth are associated with higher mammographic breast density in adulthood. We analyzed data on 1,893 women from 360 families in the Minnesota Breast Cancer Family Study who had screening mammograms, risk factor data, over age 40, and no history of breast cancer. Prenatal and perinatal risk factor data were ascertained using a mailed questionnaire. Mammographic percent density and dense area were estimated from the mediolateral oblique view using Cumulus, a computer-assisted thresholding program. Linear mixed effects models incorporating familial correlation were used to assess the association of risk factors with percent density, adjusting for age, weight, and other breast cancer risk factors, all at time of mammography. The mean age at mammography was 60.4 years (range, 40-91 years), and 76% were postmenopausal. Among postmenopausal women, there was a positive association of birthweight with percent density (P trend <0.01), with an adjusted mean percent density of 17.1% for <2.95 kg versus 21.0% for > or = 3.75 kg. There were suggestive positive associations with gestational age (mean percent density of 16.7% for preterm birth, 20.2% for term birth, and 23.0% for late birth; P trend = 0.07), maternal eclampsia/preeclampsia (mean percent density of 19.9% for no and 14.6% for yes; P = 0.16), and being breast-fed as an infant (mean percent density of 18.2% for never and 20.0% for ever; P = 0.08). There was no association of percent density with maternal age, birth order, maternal use of alcohol or cigarettes, or neonatal jaundice. Except for being breast-fed, these associations showed similar but attenuated trends among premenopausal women, although none were statistically significant. The results for dense area paralleled the percent density results. The associations of gestational age and being breast-fed as an infant with percent density attenuated when included in the same model as birthweight. Birthweight was positively associated with mammographic breast density and dense area among postmenopausal women and more weakly among premenopausal women, suggesting that it may be a marker of this early life exposure. These results offer some support to the hypothesis that pregnancy estrogens or other pregnancy changes may play a role in breast cancer etiology, and suggest that these factors may act in part through long-term effects on breast density.

Characterization of bone mineral density (BMD) at the time of diagnosis in postmenopausal patients with operable breast cancer: Association with clinical-pathological findings

9611 Background: Estrogen is involved in the pathogenesis of breast cancer. Because bone contains estrogen receptors and is, therefore, highly sensitive to levels of circulating estrogen, bone mineral density (BMD) may be a surrogate marker of a woman’s long-term exposure to endogenous estrogen. Some studies suggest that women, especially postmenopausal women with high BMD, have an increased risk for breast cancer. Methods: In this study we evaluate the association of BMD at the time of diagnosis with clinical-pathologic findings (history of hormone replacement therapy, existence of in situ component, estrogen and progesterone receptor concentrations, tumor size, nodal status, stage, grade, existence of lympho-vascular invasion, and histology) in patients with operable postmenopausal breast cancer. 117 patients were identified as having undergone BMD measurement at the time of their breast cancer diagnosis. Lumbar spinal, total hip BMD were measured by dual-energy X-ray absorptiometry. Patients were divided into two groups based on the median BMD. The median spinal BMD was 0.93 (0.56 - 1.48) gr/cm2 and the median total hip BMD was 0.85 (0.54 - 1.23)gr/cm2 Results: Median age at diagnosis was 62 (range 49 - 83). Sixty-two patients had stage I disease and 55 had stage II disease. Patients with higher BMD were found to have low grade disease, (P=0.01 for lumbar spine BMD and P=0.09 for total hip BMD), no lymphovascular invasion (P=0.02 for lumbar spine BMD and P=0.03 for total hip BMD) and progesterone receptor-positive tumors (P=0.05 for lumbar spine BMD). Patients with low Ki-67 level also tended to have high BMD P=0.06 for lumbar spine BMD). Conclusions: In our study cohort, high BMD at the time of their breast cancer diagnosis was associated with several favorable prognostic factors. High BMD might be related to higher circulating estrogen levels in these women. Further studies with a larger patient population are needed to determine whether high endogenous estrogen levels and high BMD is also associated with favorable prognostic features and outcome in breast cancer. No significant financial relationships to disclose.

Estrogen and regulation of heat shock protein expression in female cardiomyocytes: cross-talk with NFкB signaling

Estrogen is associated with increased heat shock protein (HSP)72 and protection during hypoxia-reoxygenation in cardiomyocytes from adult male rats, as previously reported. We have also reported that female rats have more cardiac HSP72 than males. We hypothesized that, despite higher endogenous estrogen levels and higher baseline HSP72, 17β-estradiol treatment would still result in increased HSP72 and protection during hypoxia-reoxygenation in cardiomyocytes from females. Methods/Results. – Cardiac cells isolated from adult female rats were treated for 12 hr with 17β-estradiol (0.1, 10, or 50 μM), tamoxifen, (10 or 25 μM; estrogen receptor agonist/antagonist), geldanamycin (2, 5, or 10 μg/ml; inactivates HSP90, preventing interaction with HSF1), or vehicle. Western blot analyses revealed that treatment with 17β-estradiol (10 or 50 μM), tamoxifen (25 μM), and geldanamycin (all doses) resulted in significant increases in HSP72. Electromobility shift assays revealed activation of HSF1 by 2 to 3 hr, and NFкB activation by 15 min. HSP72 induction via HSF1 activation was confirmed using transcription factor decoys containing the heat shock element, which prevented the estrogen-related HSP72 induction. Estrogen pretreatment resulted in decreased LDH release during 24 hr hypoxia. This protective effect persisted despite decoy-mediated blockade of nuclear HSF1 binding. However, transfection with an NFкB decoy not only prevented an estrogen-associated increase in HSP72, but also abolished the estrogenrelated protection during hypoxia. Conclusions. – Despite higher endogenous estrogen, 17β-estradiol and the selective estrogen receptor modulator, tamoxifen, upregulate HSP72 in cardiomyocytes from adult females, and provide cytoprotection during hypoxia, independent of HSP induction. NFкB activation is necessary for the increase in HSP72, suggesting that estrogen treatment activates NFкB, with subsequent HSF1 activation. NFкB activation is critical for estrogen-associated HSP induction, and protection during hypoxia in female cardiocytes. Treatment with 17β-estradiol and tamoxifen may provide a novel means of protecting both male and female cardiac myocytes against hypoxia-induced damage. Further studies are needed to define the cross-talk between HSF1 and NFкB signaling pathways.

Differential effects of 17beta-estradiol upon stroke damage in stroke prone and normotensive rats.

We previously reported that during pro-estrus (high endogenous estrogen levels), brain damage after middle cerebral artery occlusion (MCAO) was reduced in stroke-prone spontaneously hypertensive rats (SHRSP) but not in normotensive Wistar Kyoto rat (WKY). In the present study, we examined the effect of exogenous estrogen on brain damage after MCAO in SHRSP and WKY. A 17beta-estradiol (0.025 mg or 0.25 mg, 21 day release) or matching placebo pellet was implanted into ovariectomized WKY and SHRSP (3 to 4 months old) who then underwent distal diathermy-induced MCAO 2 weeks later. Plasma 17beta-estradiol levels for placebo and 17beta-estradiol groups were as follows: WKY 0.025 mg 16.4 +/- 8.5 (pg/mL, mean +/- SD) and 25.85 +/- 12.6; WKY 0.25 mg 18.2 +/- 9.0 and 69.8 +/- 27.4; SHRSP 0.25 mg 20.7 +/- 8.8 and 81.0 +/- 16.9. In SHRSP, infarct volumes at 24 hours after MCAO were similar in placebo and 17beta-estradiol groups: SHRSP 0.025 mg 126.7 +/- 15.3 mm (n = 6) and 114.0 +/- 14.1 mm (n = 8) (not significant); SHRSP 0.25 mg 113.5 +/- 22.3 mm (n = 8) and 129.7 +/- 26.2 mm (n = 7) (not significant), respectively. In WKY, 17beta-estradiol significantly increased infarct volume by 65% with 0.025 mg dose [36.1 +/- 20.7 mm (n = 8) and 59.7 +/- 19.3 mm (n = 8) (P = 0.033, unpaired t-test)] and by 96% with 0.25 mg dose [55.9 +/- 36.4 mm (n = 8) and 109.7 +/- 6.7 mm (n = 4) (P = 0.017)]. Thus, 17beta-estradiol increased stroke damage in normotensive rats with no significant effect in stroke-prone rats. Despite being contrary to our hypothesis, our findings add substance to the recently reported negative effects of 17beta-estradiol in clinical studies.

Obesity enhances verbal memory in postmenopausal women with Down syndrome

Several lines of evidence suggest that the loss of estrogen after menopause may play a role in cognitive declines associated with Alzheimer’s disease (AD). In postmenopausal women, the principal source of estrogen is estrone, which is influenced by body mass index (BMI). Increased BMI in postmenopausal women is associated with higher levels of serum estradiol and estrone. We hypothesized that obesity could have a beneficial effect on cognition with advancing age. We compared the performance of healthy nondemented obese and non-obese women with Down syndrome (DS) on a broad spectrum of cognitive tests. Estrone levels were 66.9% higher in obese than in non-obese postmenopausal women, and 136% higher in obese than in non-obese premenopausal women. Obese postmenopausal women performed significantly better than non-obese women on measures of verbal memory and on an omnibus test of neuropsychological function, but did not differ significantly in verbal fluency, language, praxis or visuospatial functioning. Among premenopausal women, there was no difference in cognitive function between obese and non-obese women. Our results support the hypothesis that higher endogenous estrogen levels after menopause are associated with better performance on verbal memory.

Östrogenabhängige Erkrankungen der weiblichen Genitalorgane und Adipositas - der Fall eines Endometriumkarzinoms

Prolonged exposure to unopposed estrogens has a proliferative effect on the endometrium and can induce endometrial carcinoma. We describe a massively obese postmenopausal woman with high levels of endogenous estrogens who developed proliferative changes in the ovaries and the uterus in addition to endometrial hyperplasia and carcinoma. This case underlines the importance of primary prevention of gynecologic conditions and of the use of progestins in postmenopausal women.

Seasonal Variations of Vitelline Envelope Proteins, Vitellogenin, and Sex Steroids in Male and Female Eelpout (Zoarces viviparus)

The seasonal variations of vitelline envelope proteins, vitellogenin (VTG), and reproductive steroids were investigated in feral male and female eelpout, Zoarces viviparus. 17β-Estradiol was present in both sexes with a peak in prespawning fish of 2.6 ng/ml in males and 2.7 ng/ml in females. 11-Ketotestosterone peaked in June at 4.2 and 0.47 ng/ml in males and females, respectively. A surge of testosterone was seen in both sexes in August, just prior to spawning. All steroid levels were low during early pregnancy. The vitelline envelope of the eelpout is composed of two major and one minor protein with molecular weights of 50, 55, and 44 kDa, respectively. An antiserum raised against solubilized vitelline envelope from turbot (Scophthalmus maximus) cross-reacted strongly with the 50-kDa protein from the isolated vitelline envelope and a similar-sized protein in female plasma and plasma from estrogenized males. Interestingly, the 50-kDa protein was also present at low levels in males as demonstrated by ELISA and Western blotting. In males, the 50-kDa protein did not follow the seasonal changes in 17β-estradiol, but instead showed an almost perfect negative correlation with water temperature. VTG was present in female plasma as shown by Western blotting, but VTG was not detectable in male plasma despite relatively high endogenous estrogen levels. This suggests that the VTG induction by estradiol may be modulated by other factors in the eelpout.