Postmenopausal hormone therapy and cognition

This article is part of a Special Issue "Estradiol and cognition".Prior to the publication of findings from the Women's Health Initiative (WHI) in 2002, estrogen-containing hormone therapy (HT) was used to prevent age-related disease, especially cardiovascular disease, and to treat menopausal symptoms such as hot flushes and sleep disruptions. Some observational studies of HT in midlife and aging women suggested that HT might also benefit cognitive function, but randomized clinical trials have produced mixed findings in terms of health and cognitive outcomes. This review focuses on hormone effects on cognition and risk for dementia in naturally menopausal women as well as surgically induced menopause, and highlights findings from the large-scale WHI Memory Study (WHIMS) which, contrary to expectation, showed increased dementia risk and poorer cognitive outcomes in older postmenopausal women randomized to HT versus placebo. We consider the ‘critical window hypothesis’, which suggests that a window of opportunity may exist shortly after menopause during which estrogen treatments are most effective. In addition, we highlight emerging evidence that potential adverse effects of HT on cognition are most pronounced in women who have other health risks, such as lower global cognition or diabetes. Lastly, we point towards implications for future research and clinical treatments.     

Postmenopausal hormone therapy and ductal carcinoma in situ: a population-based case-control study

Background and aim: The relationship between hormone therapy (HT) and invasive breast cancer has been extensively investigated, but the relationship between HT and in situ breast cancer has received relatively little attention. We examined the relationship between HT and ductal carcinoma in situ (DCIS) among postmenopausal women who participated in a population-based case–control study in Connecticut, USA. Methods: This analysis included 1179 post-menopausal women (603 controls and 576 cases), who comprised a subset of a population-based case–control study that included all incident cases of breast carcinoma in situ (BCIS) in Connecticut and frequency-matched controls by 5-year age intervals. Results: We found no association between DCIS and ever use of any HT (adjusted odds ratio (OR) = 0.85, 95% confidence interval (CI): 0.65–1.11); of estrogen alone (adjusted OR = 0.93; 95% CI: 0.68–1.29) or of estrogen and progesterone (adjusted OR = 0.75; 95% CI: 0.52–1.08). There was also no association between DCIS and current use of these hormones. In addition, estimated risk of DCIS did not increase with duration of use of these preparations. Conclusions: These results add to a small literature that remains inconclusive. To determine whether HT poses risk of in situ breast cancer, larger studies with greater power and precise control of important covariates (e.g., mammography screening) are needed, as are meta-analyses of available data.     

Impact of folic acid fortification on global DNA methylation and one-carbon biomarkers in the Women's Health Initiative Observational Study cohort

DNA methylation is an epigenetic mechanism that regulates gene expression and can be modified by one-carbon nutrients. The objective of this study was to investigate the impact of folic acid (FA) fortification of the US food supply on leukocyte global DNA methylation and the relationship between DNA methylation, red blood cell (RBC) folate, and other one-carbon biomarkers among postmenopausal women enrolled in the Women's Health Initiative Observational Study. We selected 408 women from the highest and lowest tertiles of RBC folate distribution matching on age and timing of the baseline blood draw, which spanned the pre- (1994–1995), peri- (1996–1997), or post-fortification (1998) periods. Global DNA methylation was assessed by liquid chromatography-tandem mass spectrometry and expressed as a percentage of total cytosine. We observed an interaction (P = 0.02) between fortification period and RBC folate in relation to DNA methylation. Women with higher (vs. lower) RBC folate had higher mean DNA methylation (5.12 vs. 4.99%; P = 0.05) in the pre-fortification period, but lower (4.95 vs. 5.16%; P = 0.03) DNA methylation in the post-fortification period. We also observed significant correlations between one-carbon biomarkers and DNA methylation in the pre-fortification period, but not in the peri- or post-fortification period. The correlation between plasma homocysteine and DNA methylation was reversed from an inverse relationship during the pre-fortification period to a positive relationship during the post-fortification period. Our data suggest that (1) during FA fortification, higher RBC folate status is associated with a reduction in leukocyte global DNA methylation among postmenopausal women and; (2) the relationship between one-carbon biomarkers and global DNA methylation is dependent on folate availability.     

Impact of folic acid fortification on global DNA methylation and one-carbon biomarkers in the Women's Health Initiative Observational Study cohort

DNA methylation is an epigenetic mechanism that regulates gene expression and can be modified by one-carbon nutrients. The objective of this study was to investigate the impact of folic acid (FA) fortification of the US food supply on leukocyte global DNA methylation and the relationship between DNA methylation, red blood cell (RBC) folate, and other one-carbon biomarkers among postmenopausal women enrolled in the Women's Health Initiative Observational Study. We selected 408 women from the highest and lowest tertiles of RBC folate distribution matching on age and timing of the baseline blood draw, which spanned the pre- (1994–1995), peri- (1996–1997), or post-fortification (1998) periods. Global DNA methylation was assessed by liquid chromatography-tandem mass spectrometry and expressed as a percentage of total cytosine. We observed an interaction (P = 0.02) between fortification period and RBC folate in relation to DNA methylation. Women with higher (vs. lower) RBC folate had higher mean DNA methylation (5.12 vs. 4.99%; P = 0.05) in the pre-fortification period, but lower (4.95 vs. 5.16%; P = 0.03) DNA methylation in the post-fortification period. We also observed significant correlations between one-carbon biomarkers and DNA methylation in the pre-fortification period, but not in the peri- or post-fortification period. The correlation between plasma homocysteine and DNA methylation was reversed from an inverse relationship during the pre-fortification period to a positive relationship during the post-fortification period. Our data suggest that (1) during FA fortification, higher RBC folate status is associated with a reduction in leukocyte global DNA methylation among postmenopausal women and; (2) the relationship between one-carbon biomarkers and global DNA methylation is dependent on folate availability.     

Anthropometric factors, physical activity, and risk of non-Hodgkin's lymphoma in the Women's Health Initiative

Background: Incidence rates of non-Hodgkin's lymphoma (NHL) increased substantially in the United States and worldwide during the latter part of the 20th century, but little is known about its etiology. Obesity is associated with impaired immune function through which it may influence the risk of NHL; other factors reflecting energy homeostasis (height, abdominal adiposity, and physical activity) may also be involved. Methods: We examined the association of anthropometric factors and physical activity with risk of NHL and its major subtypes in a large cohort of women aged 50–79 years old who were enrolled at 40 clinical centers in the United States between 1993 and 1998. Over a mean follow-up period of 11 years, 1123 cases of NHL were identified among 158,975 women. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Results: Height at baseline was positively associated with risk of all NHL and with that of diffuse large B-cell lymphoma (HRs_q4vs.q1 1.19, 95% CI 1.00–1.43 and 1.43, 95% CI 1.01–2.03, respectively). Measures of obesity and abdominal adiposity at baseline were not associated with risk. Hazard ratios for NHL were increased for women in the highest quartile of weight and body mass index at age 18 (HRs_q4vs.q1 1.29, 95% CI 1.01–1.65 and 1.27, 95% CI 1.01–1.59, respectively). Some measures of recreational physical activity were modestly associated with increased risk of NHL overall, but there were no clear associations with specific subtypes. Conclusion: Our findings regarding anthropometric measures are consistent with those of several previous reports, suggesting that early life influences on growth and immune function may influence the risk of NHL later in life.     

Study of cognitive function among the Adult Health Study (AHS) population in Hiroshima and Nagasaki

Although neuropsychological dysfunction is found among A-bomb survivors exposed in utero as it is among patients who receive central nervous system radiotherapy, neuropsychological examinations have not been conducted on the survivors. Its prevalence may be increased as a result of the increased rate of strokes reported among those exposed to a high radiation dose. In this study, we examined the effects of radiation exposure on cognitive function among adult survivors in the Adult Health Study (AHS). The study subjects were men and women born prior to September 1932 who had undergone biennial examinations during the period 1992-1996 in Hiroshima or 1993-1998 in Nagasaki. We evaluated cognitive performance for 3,113 subjects with the Cognitive Abilities Screening Instrument (CASI), and we examined the relationship between cognitive performance and potentially related factors (sex, age, city where the subjects were exposed, years of education, and radiation dose). In contrast to exposure to radiotherapy, exposure to atomic bomb radiation had no apparent effect on cognitive function. Factors that did affect cognitive function were age, sex, city and years of education. Further investigation, including examination of other neurological functions, is required before a final conclusion regarding radiation-induced neurological dysfunction can be reached.     

Evaluation of the effect of systolic blood pressure and pulse pressure on cognitive function: the Women's Health and Aging Study II

Background

Evidence suggests that elevated systolic blood pressure (SBP) and pulse pressure (PP) in midlife is associated with increased risk for cognitive impairment later in life. There is mixed evidence regarding the effects of late life elevated SBP or PP on cognitive function, and limited information on the role of female gender.

Methods/Principal Findings

Effects of SBPand PPon cognitive abilities at baseline and over a 9-year period were evaluated in 337 non-demented community-dwelling female participants over age 70 in the Women''s Health and Aging Study II using logistic and Cox proportional hazards regression analyses. Participants aged 76–80 years with SBP≥160 mmHg or PP≥84 mmHg showed increased incidence of impairment on Trail Making Test-Part B (TMT, Part B), a measure of executive function, over time when compared to the control group that included participants with normal and pre-hypertensive SBP (<120 and 120–139 mmHg) or participants with low PP (<68 mmHg) (HR = 5.05 [95%CI = 1.42, 18.04], [HR = 5.12 [95%CI = 1.11; 23.62], respectively). Participants aged 70–75 years with PP≥71 mmHg had at least a two-fold higher incidence of impairment on HVLT-I, a measure of verbal learning, over time when compared to participants with low PP (<68 mmHg) (HR = 2.44 [95%CI = 1.11, 5.39]).

Conclusions/Significance

Our data suggest that elevated SBP or PP in older non-demented women increases risk for late-life cognitive impairment and that PP could be used when assessing the risk for impairment in cognitive abilities. These results warrant further, larger studies to evaluate possible effects of elevated blood pressure in normal cognitive aging.     

The Innovative Medicine Initiative (IMI)

The Innovative Medicine Initiative (IMI) is a joint technology initiative jointly implemented by the European Commission and by the European Federation of Pharmaceutical Industries and Associations (EFPIA). The objective of IMI, officially launched on April 30th 2008, is to identify and address the bottlenecks of the drug discovery and development process. IMI will reinforce the public-private partnerships and will be focused towards critical nodes of the drug discovery such as efficacy predictivity, safety predictivity, knowledge management and education and training. This initiative will also reinforce the attractivity of Europe for biomedical science and will then lead to the discovery of novel therapeutic strategies for the patients.     

Women's Health in Post-Soviet Russia: The Politics of Intervention

Women's Health in Post-Soviet Russia: The Politics of Intervention . Michele Rivkin-Fish. Indianapolis: University of Indiana Press, 2006. 253 pp.     

Benefits and risks of hormone replacement therapy (HRT)

In western countries more than 30% of the female population are postmenopausal. Approximately 30% of postmenopausal women suffer from clinical symptoms of the climacteric such as vasomotor symptoms, associated with hot flushes, night sweat, insomnia and depressive mood. Sufficient hormonal replacement therapy (HRT) will abolish specific menopausal symptoms in over 90% of patients, unspecific symptoms such as headache respond to placebo and HRT equally well. The question of cancer risk related to HRT will be addressed in this review. In combination with progestins, estrogens are obviously protective regarding ovarian and endometrial cancer. The association between HRT and breast cancer risk is presently unclear. Epidemiological data available so far do not provide compelling evidence as to a cause and effect relationship between HRT and breast cancer risk. There seems to be an overall trend towards a slightly increased risk with increasing duration of HRT use. Guidelines for HRT use in women with a history of endometrial and breast cancer are provided in this article.     

Postmenopausal tibolone therapy: biologic principles and applied clinical practice

Although the menopause is a generic physiologic event, its biology is variable and specific to a given individual. Genetically determined distribution and polymorphism of relevant hormone receptors, enzymes, and various cofactors are the biologic mechanisms controlling an individual's clinical response to endogenous and prescribed hormones. Advances in molecular biology have led to the development of newer pharmacologic agents that are tailored to meet specific therapeutic objectives, based on the hormonal biology of relevant organs. Tibolone, an analogue of the progestin, norethynodrel, is a drug with tissue-specific effects on receptors and enzymes that influences the synthesis and metabolism of endogenous estrogen, progesterone, and androgen. This is achieved via the intestinal bioconversion of tibolone into metabolites that have tissue-specific agonistic and/or antagonistic estrogenic (3alpha and 3beta hydroxytibolone) and progestogenic/androgenic (delta4 tibolone) properties. The postmenopausal synthesis and metabolism of estrogen and androgen are briefly reviewed with particular reference to sex steroid activity in various target organs. On the basis of this hormonal physiology, the clinical utility of tibolone is reviewed as a therapeutic agent for the treatment of the symptomatic menopause. The effects of tibolone on bone health and osteoporosis, cardiovascular disease, the breast, and the endometrium are summarized, and its role in clinical practice is reviewed.     

生长激素和生长激素受体的多样性

生长激素及其受体对动物生长发育起着重要的作用。转录过程选择性剪接和存在多种降解途径可能是GH或GHR产生多样性的原因。随着GH结构形态的改变,其功能也在发生变化。GH基因的多样性对鸡的抗病选择性反应与产蛋性能有相关,GH和GHR基因的多样性会影响奶牛的产奶生产性能。GHR的分子多样性可能导致动物生长发育模式的变异,例如动物的矮小病。     

Fasting Plasma Glucose as Initial Screening for Diabetes and Prediabetes in Irish Adults: The Diabetes Mellitus and Vascular Health Initiative (DMVhi)

Objective

Type 2 diabetes has a long pre clinical asymptomatic phase. Early detection may delay or arrest disease progression. The Diabetes Mellitus and Vascular health initiative (DMVhi) was initiated as a prospective longitudinal cohort study on the prevalence of undiagnosed Type 2 diabetes and prediabetes, diabetes risk and cardiovascular risk in a cohort of Irish adults aged 45-75 years.

Research Design and Methods

Members of the largest Irish private health insurance provider aged 45 to 75 years were invited to participate in the study. Exclusion criteria: already diagnosed with diabetes or taking oral hypoglycaemic agents. Participants completed a detailed medical questionnaire, had weight, height, waist and hip circumference and blood pressure measured. Fasting blood samples were taken for fasting plasma glucose (FPG). Those with FPG in the impaired fasting glucose (IFG) range had a 75gm oral glucose tolerance test performed.

Results

122,531 subjects were invited to participate. 29,144 (24%) completed the study. The prevalence of undiagnosed diabetes was 1.8%, of impaired fasting glucose (IFG) was 7.1% and of impaired glucose tolerance (IGT) was 2.9%. Dysglycaemia increased among those aged 45-54, 55-64 and 65-75 years in both males (10.6%, 18.5%, 21.7% respectively) and females (4.3%, 8.6%, 10.9% respectively). Undiagnosed T2D, IFG and IGT were all associated with gender, age, blood pressure, BMI, abdominal obesity, family history of diabetes and triglyceride levels. Using FPG as initial screening may underestimate the prevalence of T2D in the study population.

Conclusions

This study is the largest screening study for diabetes and prediabetes in the Irish population. Follow up of this cohort will provide data on progression to diabetes and on cardiovascular outcomes.     

Differences in self-reported health in the Osteoarthritis Initiative (OAI) and Third National Health and Nutrition Examination Survey (NHANES-III)

Objective

To assess self-reported health status (SRHS) in two cohorts of participants with radiographic knee osteoarthritis (OA) and examine the extent that differences in SRHS are due to study design.

Method

We used data from the Third National Health and Nutritional Examination Survey (NHANES-III; population-based national survey) and the Osteoarthritis Initiative (OAI; prospective cohort study). Inclusion criteria for this analysis were age 60–79 and presence of radiographic knee OA. SRHS, elicited as a five-item domain (excellent, very good, good, fair, poor), was analyzed by dichotomizing the general health status measure as “fair/poor” versus all other states. We estimated the proportion of participants in fair/poor health from each study. Propensity score methodology was used to adjust for the differences in sampling strategies between the two studies.

Results

Thirty-four percent (N = 1,608) of OAI and 29% (N = 756) of NHANES-III participants satisfied inclusion criteria. The proportion in fair/poor health was higher in NHANES-III (28%) than in OAI (5%). After adjusting for the propensity score, the proportion in fair/poor health was four times higher in NHANES-III than in OAI.

Conclusion

SRHS was substantially better in OAI than in NHANES-III. Self-selection bias may contribute to overestimation of SRHS in prospective cohort studies such as OAI.     

Socioeconomic status and incident type 2 diabetes mellitus: data from the Women's Health Study

Objectives

We prospectively examined whether socioeconomic status (SES) predicts incident type II diabetes (diabetes), a cardiovascular risk equivalent and burgeoning public health epidemic among women.

Methods

Participants include 23,992 women with Hb_A1c levels <6% and no CVD or diabetes at baseline followed from February 1993 to March 2007. SES was measured by education and income while diabetes was self-reported.

Results

Over 12.3 years of follow-up, 1,262 women developed diabetes. In age and race adjusted models, the relative risk of diabetes decreased with increasing education (<2 years of nursing, 2 to <4 years of nursing, bachelor''s degree, master''s degree, and doctorate: 1.0, 0.7 [95% Confidence Interval (CI), 0.6–0.8], 0.6 (95% CI, 0.5–0.7), 0.5 (95% CI, 0.4–0.6), 0.4 (95% CI, 0.3–0.5); p_trend<0.001). Adjustment for traditional and non-traditional cardiovascular risk factors attenuated this relationship (education: p_trend = 0.96). Similar associations were observed between income categories and diabetes.

Conclusion

Advanced education and increasing income were both inversely associated with incident diabetes even in this relatively well-educated cohort. This relationship was largely explained by behavioral factors, particularly body mass index.     

The Proliferation Security Initiative (PSI) and Interdiction at Sea: A Chinese Perspective

The Proliferation Security Initiative has been surrounded by questions and criticisms pertaining to its legality since its inception. However, after nearly a decade of existence and development, it appears now that the actions conducted pursuant to the PSI have, by and large, been consistent with the principles of flag state jurisdiction, the nonuse of force, and sovereign equality and have not substantially impeded states’ maritime rights in the territorial sea, contiguous zone, exclusive economic zone, or on the high seas.     

Glycerophospholipid and Sphingolipid Species and Mortality: The Ludwigshafen Risk and Cardiovascular Health (LURIC) Study

Vascular and metabolic diseases cause half of total mortality in Europe. New prognostic markers would provide a valuable tool to improve outcome. First evidence supports the usefulness of plasma lipid species as easily accessible markers for certain diseases. Here we analyzed association of plasma lipid species with mortality in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. Plasma lipid species were quantified by electrospray ionization tandem mass spectrometry and Cox proportional hazards regression was applied to assess their association with total and cardiovascular mortality. Overall no differences were detected between total and cardiovascular mortality. Highly polyunsaturated phosphatidylcholine species together with lysophosphatidylcholine species and long chain saturated sphingomyelin and ceramide species seem to be associated with a protective effect. The predominantly circulating phosphatidylcholine-based as well as phosphatidylethanolamine-based ether species and phosphatidylethanolamine species were positively associated with total and cardiovascular mortality. Saturated and monounsaturated phosphatidylcholine species, especially phosphatidylcholine 32∶0 (most probably dipalmitoyl-phosphatidylcholine) and palmitate containing sphingomyelin and ceramide species showed together with 24∶1 containing sphingomyelin and ceramide species strongest positive association with mortality. A quotient of the sums of the six most protective species and the six species with the strongest positive mortality association indicated an almost 3-fold increased risk of mortality, which was higher than the hazard ratio for known risk factors in our cohort. Plasma lipid species levels and especially ratios of certain species may be valuable prognostic marker for cardiovascular and total mortality.