Antiestrogens as chemopreventive agents in breast cancer: promise and issues in evaluation

Tamoxifen citrate, the most extensively evaluated antiestrogen, acts primarily as a cytostatic agent by binding to the estrogen receptor. In rodent mammary model systems, when tamoxifen is given continuously after exposure to a carcinogen, the majority of expected tumors do not develop. In humans, adjuvant tamoxifen therapy, particularly when given for several years, is associated with significant improvement in relapse-free, and, in some studies, absolute survival. These benefits are achieved without major clinical toxicity and have led to suggestions that the use of tamoxifen as a chemopreventive agent in breast cancer be evaluated. In considering timing, optimal study population, study design, and methods for a chemoprevention trial using tamoxifen, the need for further data on the pharmacologic, biologic, and symptomatic effects of this agent becomes clear. Studies addressing this need are in progress and combined with ancillary data developed from ongoing adjuvant studies, should provide the critical information within the next few years.     

Hormonal supplement therapy in women: effects on the cardiovascular system

Coronary heart disease develops on average 10-15 years later in women than in men and is uncommon before menopause. 17 beta-estradiol has atheroprotective properties through rapid vasodilatory effects on the endothelium by stimulating nitric monoxide production and longer-term actions by modulating changes in gene expression. Cardioprotective effects of hormone replacement therapy in postmenopausal women have been suggested by observational data but not proved in randomized trials. Recent data indicate that oestrogens have regenerative effects on the vascular wall after acute injury, like a percutaneous transluminal coronary angioplasty. As endothelial reactivity declines with age, more studies are needed to investigate the benefits of hormone replacement therapy in the younger category of postmenopausal women.     

Laboratory equipment maintenance: a critical bottleneck for strengthening health systems in sub-Saharan Africa?

Properly functioning laboratory equipment is a critical component for strengthening health systems in developing countries. The laboratory can be an entry point to improve population health and care of individuals for targeted diseases - prevention, care, and treatment of TB, HIV/AIDS, and malaria, plus maternal and neonatal health - as well as those lacking specific attention and funding. We review the benefits and persistent challenges associated with sustaining laboratory equipment maintenance. We propose equipment management policies as well as a comprehensive equipment maintenance strategy that would involve equipment manufacturers and strengthen local capacity through pre-service training of biomedical engineers. Strong country leadership and commitment are needed to assure development and sustained implementation of policies and strategies for standardization of equipment, and regulation of its procurement, donation, disposal, and replacement.     

Skeletal benefits of soy isoflavones: a review of the clinical trial and epidemiologic data

PURPOSE OF REVIEW: Osteoporosis is a worldwide problem of immense magnitude that is expected to worsen in many countries with aging populations. Consequently, there is a need to identify ways to reduce the risk of developing this disease. This is especially true in light of clinical trial data showing the long-term harm of conventional hormone therapy outweighs the benefits. It is well established that many dietary components impact the skeletal system; in this regard there is particular interest in the possible skeletal benefits of soybean isoflavones. The purpose of this review is to evaluate the clinical and epidemiologic studies relevant to the hypothesis that isoflavones promote bone health. RESULTS: Fifteen clinical trials were identified that examined the effects of isoflavones or isoflavone-rich soy protein on bone mineral density. Most trials were conducted for 1 year or less and involved relatively few (<30) participants per group. The findings from these studies are inconsistent but generally suggest that isoflavones reduce bone loss in younger postmenopausal women. Similarly, the limited epidemiologic data generally show that among Asian populations isoflavone intake is associated with higher bone mineral density. The clinical data suggest that approximately 80 mg/day isoflavones are needed to derive skeletal benefits whereas the epidemiologic data suggest lower amounts are efficacious. SUMMARY: Until more definite data are available, although soy foods and isoflavones can not be viewed as substitutes for established anti-osteoporotic medications health professionals can feel justified in encouraging postmenopausal women concerned about bone health to incorporate soyfoods into their diet.     

The benefits and costs of tamoxifen for breast cancer prevention

OBJECTIVE: To estimate the effects of key uncertainties on the effectiveness and cost-effectiveness of breast cancer prevention with tamoxifen. METHODS: The incremental cost-effectiveness ratio of tamoxifen therapy relative to placebo was estimated using decision analysis with Markov modelling of health states, outcomes and costs for a simulated cohort of women at high risk for breast cancer. Relative effects of tamoxifen's benefits and harms were estimated from meta-analyses of randomised controlled trials. Cost estimates were based on Australian treatment patterns and costs. The main outcome measure was cost per quality-adjusted life year (QALY) gained with costs and effects discounted at a 5% annual rate. RESULTS: Tamoxifen therapy over five years reduces the incidence of breast cancer by approximately 1.4%, which is offset by an increase in endometrial cancer of 0.7% and pulmonary embolism of 0.2%. If the reduction is permanent (preventing new breast cancers emerging over five years and no further treatment effect thereafter), the model estimates an increase in life expectancy of 0.057 QALYs and an extra cost of $2,193; or $38,271/QALY gained. A model assuming further treatment effects of tamoxifen preventing new breast cancers emerging for up to 10 years results in an incremental cost of $19,354/QALY. However, if five years of tamoxifen therapy merely delays when these breast cancers appear (such that by 10 years there is no longer a reduced incidence), the incremental cost per QALY saved is estimated to be $199,149. CONCLUSIONS: Tamoxifen is potentially cost-effective in preventing breast cancer in women at high risk. However, its cost-effectiveness as a preventive therapy is highly sensitive to whether these cancers are permanently prevented or their clinical presentation is only delayed. Long-term follow-up in randomised controlled trials is therefore crucial in forming health policy.     

Hormone replacement therapy: all a woman could desire?

A nurse practitioner discusses the benefits and possible disadvantages of hormone replacement therapy both for menopausal symptoms and for longer-term health. The author recommends health professionals to be aware of alternatives to hormone replacement therapy and to adopt a holistic approach to the menopausal woman.     

The effect of hormone therapy on cognitive function in patients with breast cancer

Preclinical and clinical studies suggest that oestrogens have an important role in brain functioning and cognitive ability. Given that hormone therapies for breast cancer reduce oestrogen levels or block oestrogen receptors, it is conceivable that these agents also influence cognitive function. Several small studies have been conducted to address this issue, but many of them are methodologically insufficient. The negative effects of oophorectomy and luteinising hormone-releasing hormone (LHRH) analogues on verbal memory and working memory have been demonstrated the most consistently, albeit only in small studies. Anastrozole and tamoxifen also appear to exert some negative effect on cognition, but well-designed studies are lacking. No data are available on the influence of the aromatase inhibitors exemestane and letrozole on cognitive function. Raloxifene, a drug that has no obvious advantages over tamoxifen and will likely not be developed further for breast cancer treatment, has no negative influence on cognitive functioning. It remains unclear whether the observed effects are transient or permanent, and to what extent age, menopausal status and duration of therapy influence the severity of cognitive effects.     

Dietary fibre in infancy and childhood

There is very little evidence for the effects of dietary fibre in young children and current dietary guidelines are based on assumptions and data extrapolated from studies in adults. The first years of life may be critical for the establishment of a healthy colonic microflora, as well as good eating habits. The lack of clear and well-founded guidelines for the intake of dietary fibre in childhood may hinder both factors. The fears that a high-fibre diet in children < 5 years of age will lead to growth faltering and mineral imbalance are not well supported in the literature, especially for children in the developed world. Indeed, with the rising levels of obesity, fibre intake may be of benefit in reducing energy intake. A low-fibre diet may also be implicated in the aetiology of childhood constipation and appendicitis. The latest proposals for the definition of dietary fibre include oligosaccharides, which may act as prebiotics. There are potential health benefits of including oligosaccharides in the diets of infants and children, but more research is needed to consider the long-term effects. The immature intestine of the infant may also result in a greater amount of starch entering the colon during weaning, and this starch would now be considered dietary fibre under the new definitions. Much new research is needed to allow adequate recommendations for the intake of dietary fibre in childhood based on data collected in appropriate age-groups.     

Understanding attitudes of older women toward hormone replacement therapy

BACKGROUND: Counseling women facing the decision to initiate, continue, or discontinue hormone replacement therapy represents a major challenge for providers. Women's attitudes deserve careful consideration in this context, because attitudes may influence hormone replacement therapy use and patients' satisfaction with decision-making. Little is known about factors that may explain different attitudes. METHODS: To evaluate the association between char acteristics of peri- and postmenopausal women and their attitudes toward hormone replacement therapy, we conducted a population-based, computer-assisted telephone survey of 1,076 randomly selected women, ages 50-80, at a staff-model health maintenance organization. Women with a positive or neutral attitude were compared to those with a negative attitude. We exam ined associations between attitudes and demographic and clinical characteristics, self-rated health status, physical function, personal and family history of condi tions affected by hormone replacement therapy, gyne cologic visits, provider characteristics, interactions with provider, and sources of information about hor mone replacement therapy. RESULTS: The perception of being adequately informed about the benefits of hormone replacement therapy by one's provider was associated with a tripling of the likelihood of having a positive attitude toward hormone replacement therapy. Additional fac tors associated with positive attitudes included past hormone replacement therapy use, younger age, a higher level of physical functioning, and personal history of heart disease. Relationships between these vari ables and attitudes varied among current hormone replacement therapy users and nonusers. CONCLUSIONS: The study findings reinforce the critical role of provider counseling in shaping women's atti tudes about hormone replacement therapy.     

Menopause and hormone replacement therapy

Due to the improving life expectancy of women spend third of their active life after the menopause. Estrogen deficiency can be caused by both natural and artificial menopause. The lack of estrogen can directly worsen the quality of life and epidemiological evidence suggests association with development of certain diseased states. Hormone replacement with natural estrogens has been proven to be successful for various indications: it reduces the menopausal vasomotor and psychological symptoms thus improving quality of life. It can also be used to prevent harmful effects of estrogen deficiency in various organs. Literature review supports the role of estrogen in atherosclerosis and osteoporosis prevention. Further evidence required establishing the role of estrogens in secondary prevention of coronary artery disease. Also needs to be explained why the beneficial effects of estrogen therapy in osteoporosis seem to disappear soon after cessation of therapy. Currently the relative risk increase of breast cancer during long-term hormone replacement therapy cannot be exactly measured. Nevertheless, substantial reduction of mortality in estrogen receptor positive breast cancer can also be seen with women on hormone replacement as compared to controls. Some data support the negative correlation of residual but still detectable, endogen estrogen and atherosclerosis and similarly to osteoporosis. The same residual estrogen levels seem to correlate positively with breast cancer. The recognition (and further acceptance) of the role of the residual estrogens might have influence on the indication, choice and dosage of preparation and duration of hormone replacement therapy. Overall evidence is in favor of the need medical attention for menopause: which ranges from preventive screening to long term hormone replacement therapy. The decision to treat requires the risks and benefits taken into consideration. This highly specialized care is provided in menopause clinics in Hungary. New oestrogen like agents are being developed like the selective estrogen receptor modulators, the tibolone and the phyto-estrogens. They provide tissue-specific effect acting as estrogen agonistics, sustaining the beneficial preventive and therapeutic effects of the estrogens, but in the breast and endometrial tissue they behave like estrogen antagonists avoiding the side effects of the current used oestrogens. They might play a significant role in the treatment of menopause in the future.     

Using multiple risk models with preventive interventions

An ideal preventive intervention would have negligible side effects and could be applied to the entire population, thus achieving maximal preventive impact. Unfortunately, many interventions have adverse effects and beneficial effects. For example, tamoxifen reduces the risk of breast cancer by about 50% and the risk of hip fracture by 45%, but increases the risk of stroke by about 60%; other serious adverse effects include endometrial cancer and pulmonary embolus. Hence, tamoxifen should only be given to the subset of the population with high enough risks of breast cancer and hip fracture such that the preventive benefits outweigh the risks. Recommendations for preventive use of tamoxifen have been based primarily on breast cancer risk. Age-specific and race-specific rates were considered for other health outcomes, but not risk models. In this paper, we investigate the extent to which modeling not only the risk of breast cancer, but also the risk of stroke, can improve the decision to take tamoxifen. These calculations also give insight into the relative benefits of improving the discriminatory accuracy of such risk models versus improving the preventive effectiveness or reducing the adverse risks of the intervention. Depending on the discriminatory accuracies of the risk models, there may be considerable advantage to modeling the risks of more than one health outcome. Published 2012. This article is a US Government work and is in the public domain in the USA.     

Economics and preventing hospital-acquired infection: broadening the perspective.

OBJECTIVE: To present a hypothetical model of the change in economic costs and health benefits to society that result from nosocomial infection control programs. DESIGN: We use a modeling framework to represent how 2 types of costs change with nosocomial infection control programs: costs incurred by the hospital sector and community health services, as well as the private costs to patients. We also demonstrate how to value the health benefits of nosocomial infection control programs, using quality-adjusted life years. SETTING: Hypothetical modeling to incorporate the societal perspective. SUBJECTS: A cohort of 50,000 simulated patients at risk of surgical site infection following total hip replacement. INTERVENTION(S): A total of 8 hypothetical interventions that change costs and health outcomes among the cohort by preventing cases of surgical site infection following total hip replacement. RESULTS AND CONCLUSIONS: We demonstrate that when infection control interventions reduce economic costs and increase health benefits, they should be adopted without further question. If, however, interventions increase economic costs and increase health benefits, then the trade-off between costs and benefits should be examined. Decision-makers should assess the cost per unit of health benefit from infection control programs, consider the impact on health budgets, and compare infection control with alternative uses of scarce healthcare resources.     

ALICE IN MENOPAUSELAND: THE JABBERWOCKY OF A MEDICALIZED MIDDLE AGE

Active living is being advanced in the scientific literature as an essential and effective resource to sustained health and vitality in middle-aged women, with potent benefits to biological, social, and emotional health. At the same time, menopausal women are being counseled that hormone replacement therapy (HRT) is the treatment of choice for combating symptoms and diseases that accompany female aging. Assisted by the writing of Lewis Carroll, here we gaze "through the looking glass" on women's health choices as they are relayed through current medical practice. By exploring the jabberwocky of communications experienced by women as they consider the best pathway to late life health, we show that active living is a worthy alternative-- potent for health promotion, broader than hormones in its benefits, and is the more empowering and ethical route for women's long-term health.     

Alice in menopauseland: the jabberwocky of a medicalized middle age

Active living is being advanced in the scientific literature as an essential and effective resource to sustained health and vitality in middle-aged women, with potent benefits to biological, social, and emotional health. At the same time, menopausal women are being counseled that hormone replacement therapy (HRT) is the treatment of choice for combating symptoms and diseases that accompany female aging. Assisted by the writing of Lewis Carroll, here we gaze "through the looking glass" on women's health choices as they are relayed through current medical practice. By exploring the jabberwocky of communications experienced by women as they consider the best pathway to late life health, we show that active living is a worthy alternative--potent for health promotion, broader than hormones in its benefits, and is the more empowering and ethical route for women's long-term health.     

Is routine use of estrogen indicated in postmenopausal women? An affirmative view

A study of age-adjusted all causes of mortality has shown that estrogen nonusers are three times as likely to die of all causes compared with users. The benefit of estrogen is greatest in women who have had their ovaries removed, but benefit also occurs in those who have had a hysterectomy as well as those with intact pelvic organs. A recent British study also reported that women taking estrogen were less likely to die of all causes. Because of the many benefits of estrogen replacement therapy improving both the quality and quantity of life, all women who have this postmenopausal hormone deficiency, except possibly those who are obese, should receive estrogen replacement. The beneficial effects of estrogen replacement therapy are many and there are very few adverse effects.     

Meeting report: Estimating the benefits of reducing hazardous air pollutants--summary of 2009 workshop and future considerations

Background

Quantifying the benefits of reducing hazardous air pollutants (HAPs, or air toxics) has been limited by gaps in toxicological data, uncertainties in extrapolating results from high-dose animal experiments to estimate human effects at lower doses, limited ambient and personal exposure monitoring data, and insufficient economic research to support valuation of the health impacts often associated with exposure to individual air toxics.

Objectives

To address some of these issues, the U.S. Environmental Protection Agency held the Workshop on Estimating the Benefits of Reducing Hazardous Air Pollutants (HAPs) in Washington, DC, from 30 April to 1 May 2009.

Discussion

Experts from multiple disciplines discussed how best to move forward on air toxics benefits assessment, with a focus on developing near-term capability to conduct quantitative benefits assessment. Proposed methodologies involved analysis of data-rich pollutants and application of this analysis to other pollutants, using dose–response modeling of animal data for estimating benefits to humans, determining dose-equivalence relationships for different chemicals with similar health effects, and analysis similar to that used for criteria pollutants. Limitations and uncertainties in economic valuation of benefits assessment for HAPS were discussed as well.

Conclusions

These discussions highlighted the complexities in estimating the benefits of reducing air toxics, and participants agreed that alternative methods for benefits assessment of HAPs are needed. Recommendations included clearly defining the key priorities of the Clean Air Act air toxics program to identify the most effective approaches for HAPs benefits analysis, focusing on susceptible and vulnerable populations, and improving dose–response estimation for quantification of benefits.     

Management of Advanced Breast Cancer

Breast cancer is the most common malignancy affecting women and imposes a substantial economic burden on society. Estrogen is thought to play a major role in both the initiation and promotion of hormone dependent breast cancer, and a number of well recognized risk factors for breast cancer reflect increased cumulative estrogen exposure (e.g. early menarche, late menopause).Metastatic breast cancer is an incurable condition and the goals of treatment are to relieve symptoms, improve health-related quality of life and prolong life. Women with hormone receptor-positive disease are candidates for hormonal treatment. In contrast, chemotherapy is traditionally the treatment of choice in those with hormone receptor-negative disease or symptomatic visceral disease.Anastrozole is a highly selective nonsteroidal type II aromatase inhibitor that suppresses plasma and intratumoral estrogen levels. The results of 2 multicenter, randomized, double-blind trials have shown anastrozole to be at least as effective as tamoxifen in the first-line treatment of postmenopausal women with advanced breast cancer, although survival data are lacking. In the smaller of these trials, the median time to disease progression was significantly prolonged (p = 0.005) in anastrozole, compared with tamoxifen, recipients (11.1 vs 5.6 months), although combined analysis of the 2 trials revealed no significant difference between an-astrozole and tamoxifen in terms of this end-point.Similarly, anastrozole has been shown to be at least as effective as megestrol in the second-line treatment of postmenopausal women with advanced breast cancer in 2 multicenter randomized studies. Combined analysis of the studies revealed a significant survival advantage (p < 0.025) for anastrozole 1 mg/day, compared with megestrol 40mg 4 times daily, recipients (estimated hazard ratio 0.78; 97.5% confidence interval 0.6 to <1).Tolerability is an important consideration in women with advanced breast cancer. The most common adverse events associated with anastrozole therapy were gastrointestinal disturbance, hot flushes, asthenia and pain. Anastrozole is associated with less vaginal bleeding and thromboembolic disease than tamoxifen and less bodyweight gain than megestrol. Anastrozole also appears to be a cost-effective option in the first- and second-line treatment of advanced breast cancer, although data are limited. Conclusion: Current treatment guidelines support the use of anastrozole in the second-line treatment of postmenopausal women with advanced breast cancer. Although current treatment guidelines do not yet reflect this, data from recent, well designed studies demonstrate that anastrozole is likely to be a viable alternative to tamoxifen in the first-line treatment of postmenopausal women with advanced breast cancer.     

Health insurance systems in five Sub-Saharan African countries: medicine benefits and data for decision making

Medicine benefits through health insurance programs have the potential to improve access to and promote more effective use of affordable, high quality medicines. Information is lacking about medicine benefits provided by health insurance programs in Sub-Saharan Africa. We describe the structure of medicine benefits and data routinely available for decision-making in 33 health insurance programs in Ghana, Kenya, Nigeria, Tanzania and Uganda. Most programs surveyed were private, for profit schemes covering voluntary enrollees, mostly in urban areas. Almost all provide both inpatient and outpatient medicine benefits, with members sharing the cost of medicines in all programs. Some programs use strategies that are common in high-income countries to manage the medicine benefits, such as formularies, generics policies, reimbursement limits, or price negotiation. Basic data to monitor performance in delivering medicine benefits are available in most programs, but key data elements and the resources needed to generate useful management information from the available data are typically missing. Many questions remain unanswered about the design, implementation, and effects of specific medicines policies in the emerging and expanding health insurance programs in Sub-Saharan Africa. These include questions about the most effective medicines policy choices, given different corporate and organizational structures and resources; impacts of specific benefit designs on quality and affordability of care and health outcomes; and ways to facilitate use of routine data for monitoring. Technical capacity building, strong government commitment, and international donor support will be needed to realize the benefits of medicines coverage in emerging and expanding health insurance programs in Sub-Saharan Africa.     

Large-scale hormone replacement therapy and life expectancy: results from an international comparison among European and North American populations

OBJECTIVES: An analysis was performed to determine the risks and benefits of a 10-year hormone replacement therapy regimen that had been applied to all women at 50 years of age in 8 countries. METHODS: Cumulative mortality with and without hormone replacement therapy over 20 years was estimated, with both current and predicted total and disease-specific secular mortality trends and the influence of a generational cohort effect taken into account. RESULTS: In countries with high ischemic heart disease frequency and predictable relative predominance of ischemic heart disease rates over breast cancer rates for the next 20 years, hormone replacement therapy could result in benefits with regard to overall mortality; this advantage decreases in younger-generation cohorts. In countries in which breast cancer mortality predominates over ischemic heart disease in early postmenopause and in which the predictable trends for both diseases reinforce this condition, a negative effect on overall mortality would be observed. In the United States, the effect of large-scale hormone replacement therapy would change over time. CONCLUSIONS: The long-term effect of hormone replacement therapy on life expectancy of postmenopausal women may vary among countries.