Treatment of menopausal symptoms post-Women’s Health Initiative: refinement of existing treatments and development of new therapies

Menopause is a normal life transition for women. More than 80% of women experience some symptoms at menopause and > 25% of women in western countries seek treatment for a variety of symptoms that accompany this transition. In addition, there are certain chronic disease processes that accelerate after the menopausal transition. Hormone replacement therapy (HRT) with various combinations of oestrogen and progesterone compounds has been the mainstay of treatment for menopausal symptoms, as well as theoretical reduction in acceleration of certain chronic diseases after menopause. After the publication of the results of the Women’s Health Initiative study in June 2002, the safety of HRT, as well as its effectiveness in decreasing various chronic diseases, was challenged. New formulations of hormone therapy, as well as new treatments, are evolving to aid the reduction of menopausal symptoms and long-term risks of common chronic disease processes that accelerate after the menopause.     

Hormone replacement therapy: II. A pharmacoeconomic appraisal of its role in the prevention of postmenopausal osteoporosis and ischaemic heart disease

The reduction in estrogen production that occurs at menopause is associated with several long term sequelae. There is an accelerated decrease in bone mineral density leading to an increased risk of osteoporotic fracture. Furthermore, changes in plasma lipid profiles and other cardiovascular parameters increase the risk of cardiovascular and cerebrovascular pathology. These effects are additional to the menopausal symptoms experienced by many women. The effectiveness of estrogen-based hormone replacement therapy (HRT) is well established in preventing bone mineral loss and also in ameliorating menopausal symptoms, with the addition of progestogen maintaining or possibly enhancing the bone-conserving effects. However, prolonged therapy appears to be necessary to conserve bone mineral density and prevent osteoporotic fracture, particularly in women aged greater than or equal to 75 years, and compliance with long term therapy is likely to be poor. Estrogen favourably alters plasma lipid profiles, improves coronary blood flow and inhibits the central distribution of body fat. Effects on haemostatic mechanisms and coronary vasomotor response to acetylcholine have also been suggested as mechanisms for the beneficial effects of estrogen on ischaemic heart disease. The effects of concomitant progestogens on plasma lipids are variable, and may depend on the type, dosage regimen and duration of therapy. Pharmacoeconomic analyses of HRT have used a variety of risk assumptions. Relative risk rates of osteoporotic fracture and mortality from myocardial infarction are assumed to reduce to 0.5 after greater than 5 years' therapy. Long term HRT is associated with a relative risk of approximately 1.3 for breast cancer, whereas the relative risk of endometrial cancer is 4.0 to 8.0 in women with intact uteri receiving prolonged unopposed estrogen therapy. HRT that includes progestogens is assumed to incur no added risk of endometrial cancer, and this treatment is generally recommended for women with intact uteri. Data concerning the effect of HRT on quality of life are limited and utility values for hip fracture of 0.95 to 0.36 have been assigned, depending on assumptions of disability. Cost-benefit, cost-effectiveness and cost-utility studies evaluating HRT in the prevention of osteoporotic fracture have differed widely in methodology, making comparison of results difficult. HRT appears to be most economically useful in the prevention of fracture if used in women who have undergone hysterectomy, in women with high risk of osteoporotic fracture or ischaemic heart disease, and/or in women with menopausal symptoms.(ABSTRACT TRUNCATED AT 400 WORDS)     

HRT and its impact on the menopause,osteoporosis and breast cancer

Hormone replacement therapy (HRT) is a widely used treatment for vasomotor symptoms of the menopause. In this respect, there is a wealth of randomised evidence that it is an effective and cost-effective treatment, achieving substantial quality of life gains for relatively low cost. On the other hand, potentially major health benefits lie in the prevention of chronic diseases such as osteoporosis and cardiovascular disease. Observational data strongly support the role in HRT’s ability to prevent fractures; however, there is a suggestion that this antifracture benefit is only realised if treatment is taken soon after the menopause and is soon lost after cessation of treatment. HRT also increases the risk of breast cancer, which may negate much of its health benefit.     

HRT and its impact on the menopause, osteoporosis and breast cancer

Hormone replacement therapy (HRT) is a widely used treatment for vasomotor symptoms of the menopause. In this respect, there is a wealth of randomised evidence that it is an effective and cost-effective treatment, achieving substantial quality of life gains for relatively low cost. On the other hand, potentially major health benefits lie in the prevention of chronic diseases such as osteoporosis and cardiovascular disease. Observational data strongly support the role in HRT's ability to prevent fractures; however, there is a suggestion that this antifracture benefit is only realised if treatment is taken soon after the menopause and is soon lost after cessation of treatment. HRT also increases the risk of breast cancer, which may negate much of its health benefit.     

Maximising the use of HRT: focus on hysterectomised women

Hysterectomy is one of the most common gynaecological surgical operations performed in the UK. In addition to causing the early onset of the menopause, hysterectomy can lead some women to be at increased risk of future CHD and osteoporosis owing to declining oestrogen levels. Hysterectomised women are therefore an ideal group to receive hormone replacement therapy (HRT). However, only small numbers of women receive HRT owing to a number of factors, including fear of potential complications and adverse side-effects. Of those women who do receive HRT, compliance with therapy is low. In this article, the authors weigh the benefits of HRT, in terms of relief of menopausal symptoms, and prevention of osteoporosis, Alzheimer's disease and cardiovascular disease, against the known risks. The authors suggest that compliance with HRT could be optimised by profiling patients in general practice and by educating women on the long-term benefits of HRT.     

Hormone replacement therapy: I. A pharmacoeconomic appraisal of its therapeutic use in menopausal symptoms and urogenital estrogen deficiency

Menopause and the accompanying reduction in estrogen production may cause a number of symptoms in women which include hot flushes, sweating, mood and sleep disturbances, fatigue and urogenital dysfunction. The effectiveness of estrogen-based hormone replacement therapy (HRT) in ameliorating these symptoms, and in preventing long term sequelae such as osteoporosis, is well established. Comparative trials indicate that oral conjugated estrogens 0.625mg, oral ethinyl estradiol 0.02mg and transdermal estradiol 0.05mg have equivalent efficacy in relief of mild to moderate menopausal symptoms and prevention of bone mineral loss. Concomitant progestogen therapy is usually prescribed for women with intact uteri to protect against endometrial hyperplasia and carcinoma. The addition of progestogen maintains and may even enhance the bone-conserving effects of estrogen, and continuous regimens appear to reduce the incidence of irregular menses. Adverse reactions are predominantly local skin irritation with transdermal preparations (14% of patients) and systemic effects common to most forms of HRT including breast tenderness, flushing, headache and irregular bleeding, occurring in less than or equal to 2% of patients. Data concerning the effect of HRT on quality of life are limited, but most analyses have assigned utility values of 0.99 for mild and 0.95 for severe menopausal symptoms. However, recent clinical data suggest that these utility values may underestimate the impact of menopausal symptoms on quality of life. The cost benefit and cost effectiveness of HRT in the treatment of menopausal symptoms have not been fully researched, although preliminary results suggest that conjugated estrogens and transdermal estradiol compare well with alternative therapies such as veralipride and Chinese medicines. A Swedish study using a prevalence-based approach estimated that estriol treatment in all women with urinary incontinence aged greater than or equal to 65 years resulted in monetary savings compared with treating 20% of women. Cost-utility data indicated that the change in quality-adjusted life years (QALYs) with HRT was always positive, but the degree of change was determined by the baseline assumptions. Estimated changes in QALYs with HRT ranged from 0.006 for 5 years of treatment with unopposed estrogen in women with intact uteri, to 0.5 for 10 years of the same treatment in women with severe menopausal symptoms following hysterectomy. Compliance with HRT is suboptimal as 5 to 50% of women withdraw from therapy, thereby increasing costs per year of life saved.(ABSTRACT TRUNCATED AT 400 WORDS)     

The pharmacogenomics of sex hormone metabolism: breast cancer risk in menopausal hormone therapy

With women in western countries spending nearly one-third of their lifetime beyond menopause and a substantial number of these women facing severe menopausal symptoms, the goal of sex hormone pharmacogenomics is to promote the safe use of hormone replacement therapy (HRT). This could be achieved by providing molecular predictors for the upfront stratification of women in need of relief from menopausal symptoms into those with a likely benefit from HRT and those with a contraindication due to an HRT-associated breast cancer risk or other adverse effects. An increasing knowledge base of sex hormone metabolism and its variability, HRT outcomes and breast cancer susceptibility, as well as emerging examples of pharmacogenomic predictors, underscore the potential relevance of genetic variations for HRT outcome. The genes responsible for the metabolism, signaling and action of sex hormones are at the heart of this research; however, pharmacogenomic investigation of their therapeutic effects due to the enormous complexity of the biological pathways involved is still in its infancy. This article discusses the current knowledge, challenges and potential future directions towards the goal of genotype-guided safer HRT use.     

Hormone therapy for the management of menopausal symptoms: pharmacotherapy update

Nearly 50 million women each year are projected to reach menopause by 2030. Many of these women will experience vasomotor symptoms such as night sweats and hot flashes as they enter the menopausal transition. Up until the release of the findings of the Women's Health Initiative (WHI) studies, women were frequently prescribed hormone therapy (HT) to alleviate bothersome and sometimes debilitating menopausal symptoms as well as to prevent osteoporosis and coronary heart disease (CHD). Although the WHI studies were the first large, randomized, controlled trials that contradicted what was historically believed about the benefits of HT in postmenopausal women, important limitations including baseline demographics of WHI participants and investigation of only one HT strength/dosage form exist. HT may be a reasonable pharmacotherapy option for the management of menopausal symptoms following complete patient evaluation by experienced clinicians. Updated recommendations addressing management of menopausal symptoms, a new HT product containing the spironolactone-analogue drospirenone (DRSP), and discontinuation methods of HT are also discussed in this review.     

The demise of HRT? The long-term safety of hormone replacement therapy

The role of hormone replacement therapy (HRT) in the health of middle-aged women has come a full circle. HRT has been widely accepted as the treatment of choice for the management of menopausal symptoms. However, the Women's Health Initiative (WHI) and other recent randomised controlled trials have failed to confirm beliefs of other potential benefits in reducing the risk of coronary artery disease (CAD) and stroke. Indeed, early increases in cardiac event and stroke rate have been seen in women taking combination HRT. An increased risk of breast cancer diagnosis has also been confirmed in HRT users. The use of HRT now needs to be regarded as a short-term therapy for menopausal symptom management with treatment individualised for each woman.     

Differential effects of exogenous estrogen versus a estrogen-progesterone combination on auditory evoked potentials in menopausal women

The study was undertaken to determine the differential effects of estrogen and progestin on auditory evoked responses in postmenopausal women receiving hormone replacement therapy (HRT). Forty-seven women between 45 and 70 years of age attending menopause and HRT clinic were divided into two groups. Group I included 32 women who attained natural menopause and receiving combined estrogen progestin therapy. While group II included 15 surgically menopausal women receiving only estrogen. Evoked potentials were recorded in form of auditory brainstem response (ABR), middle latency response (MLR) & slow vertex response (SVR). There was improvement of conduction in auditory pathways at the level of brainstem and thalamocortical projections as indicated by the decrease in latencies of most of the waves of ABR and/MLR after 6 months of HRT in both the groups. The conduction in association areas, as indicated by SVR, did not show a significant change. The intergroup comparison after therapy revealed a decrease in latency of wave V and I-V interpeak latency in group II indicating that only estrogen users are benefited more. Thus HRT facilitates the process of sensory conduction, which may form one of the mechanisms of improved neuropsychological functions in menopausal women on HRT. The addition of progestin to estrogen does not have a negative or potentiating effect on it.     

Acetaminophen safety and hepatotoxicity – where do we go from here?

The role of hormone replacement therapy (HRT) in the health of middle-aged women has come a full circle. HRT has been widely accepted as the treatment of choice for the management of menopausal symptoms. However, the Women’s Health Initiative (WHI) and other recent randomised controlled trials have failed to confirm beliefs of other potential benefits in reducing the risk of coronary artery disease (CAD) and stroke. Indeed, early increases in cardiac event and stroke rate have been seen in women taking combination HRT. An increased risk of breast cancer diagnosis has also been confirmed in HRT users. The use of HRT now needs to be regarded as a short-term therapy for menopausal symptom management with treatment individualised for each woman.     

Treatment of osteoporosis and reduction in risk of invasive breast cancer in postmenopausal women with raloxifene

INTRODUCTION: Raloxifene, a non-steroidal selective estrogen receptor modulator (SERM), offers a new dimension for the treatment and prevention of osteoporosis and risk reduction of invasive breast cancer in postmenopausal populations at high risk. Both osteoporosis and breast cancer are important public health issues for postmenopausal women. It is well known that estrogen and estrogen receptors play an important role in the pathogenesis of both diseases. Initially, hormone replacement therapy (HRT) was used for the purpose of preventing and treating postmenopausal osteoporosis. However, HRT significantly contributed to an increase in breast cancer risk. The SERM, raloxifene, is used for the prevention and for the treatment of postmenopausal osteoporosis and reducing the risk of invasive breast cancer in postmenopausal women. AREAS COVERED: This article reviews the emerging evidence of the efficacy of raloxifene in postmenopausal women, summarizes the results and places in perspective their therapeutic uses for women having either a high risk of osteoporosis or breast cancer. Emerging clinical evidence suggests bisphosphonates, currently used as drugs for the treatment of osteoporosis, may also reduce breast cancer risk. The status of other SERMs and bisphosphonates are included for completeness. A Medline search of raloxifene, osteoporosis, breast cancer and SERMs was used to derive a database of 355 references. EXPERT OPINION: Readers will understand the value of raloxifene to prevent osteoporosis and breast cancer in postmenopausal women. Although most women do not require pharmacotherapy for menopausal symptoms, many are severely affected by osteoporosis or breast cancer at and beyond menopause and, for such women, pharmacologic intervention is important if they are to retain an acceptable quality of life. It is reasonable to use raloxifene or bisphosphonate as an appropriate drug that targets symptom-free postmenopausal women for treatment and prevention of osteoporosis but raloxifene is proven to reduce the incidence of invasive breast cancer.     

Risks and benefits of long-term hormone replacement therapy.

Studies of long-term hormone replacement therapy (HRT) are reviewed, and treatment recommendations based on the results are advanced. HRT is a popular therapy for postmenopausal symptoms and osteoporosis prevention in women. However, women also use hormones for unlabeled indications, such as cardiovascular disease prevention. In the past, observational and case-controlled trials have suggested that HRT confers a benefit through an improvement in lipid profiles and has relatively few adverse effects. However, no randomized controlled trial had proven this before HRT became popular. More recently, the results of additional observational studies and large, double-blind, placebo-controlled trials have been published that indicate that HRT may not be as beneficial or risk free as first thought. If a woman wishes to begin or continue HRT for short-term menopausal symptoms, it is crucial to evaluate her individual risk of breast cancer, coronary heart disease, venous thromboembolism, and stroke before recommending therapy. Otherwise, HRT should not be recommended for treatment durations of more than five years, and treatment should be discontinued in women at risk of complications. Recent large, randomized, placebo-controlled trials have shown substantial risks and limited benefits in the long-term use of HRT.     

Hormone replacement therapy and health protection

Menopause is potentially a cause of concern and hormone-related diseases. Hormone replacement therapy (HRT) is considered to be an effective treatment strategy to relieve menopausal symptoms and prevent related diseases, however, knowledge on HRT and its benefits and risks is still evolving. For many climacteric women, HRT is the ideal choice to treat symptoms, prevent diseases and improve quality-of-life, while for others it can cause concerns and problems. Thus, the appropriate role of HRT has still to be fully defined. An individualized, patient-tailored approach to HRT, based on the current evidence of risk factors for hormone-related diseases and treatments, is essential to maximize the benefits and minimize the risks.     

Hormone Replacement Therapy and Breast Cancer: Revisiting the Issues

ObjectiveTo assess current ideas about the benefits and risks of estrogen and hormone replacement therapy (ERT/HRT) in post·menopausal women.Data SourcesMEDLINE searches, supplemented by various texts, of the literature on HRT, ERT, and selective estrogen receptor modulators (SERMs): tamoxifen, toremifene, and raloxifene.Data SynthesisHRT is primarily used for improving quality of life in women suffering from vasomotor symptoms associated with menopause. HRT is beneficial in postmenopausal women for preventing cardiovascular disease, osteoporosis, and Alzheimer's disease. Review of meta-analyses of clinical trials showed that ERT/HRT ever·users (patients who have ever used ERT/HRT) did not have an increased risk of breast cancer, but current users did have an increased risk, with some studies reporting increasing risk with duration of ERT. No relationship was found between dose or the addition of progestin to ERT and increased breast cancer risk. Overall breast cancer mortality rates associated with HRT were decreased in current users. In general, HRT does not increase the risk of breast cancer in women with a family history of the disease, compared with those without a family history. New HRT strategies that could potentially prevent breast cancer are now being developed. The SERMs tamoxifen and toremifene appear to have positive clinical effects on bone and serum lipids; they are currently being investigated for use as breast cancer chemopreventive agents. Raloxifene, a new SERM used for the prevention of osteoporosis, is an alternative for women who cannot tolerate HRT. Unfortunately, these SERMS have anti-estrogenic effects and thus cause vasomotor adverse effects such as hot flashes and vaginal dryness. In addition, SERMs do not protect against heart disease or prevent osteoporosis as well as does HRT.ConclusionPresently, SERMs will not become first-line HRT, as the positive effects of ERT/HRT may out·weigh any potentially increased risk of breast cancer. The development of new agents with pharmacodynamic profiles similar to that of ERT/HRT but lacking its adverse effects would be greatly beneficial for postmenopausal women.     

Postmenopausal hormone therapy: impact on menopause-related symptoms, chronic disease and quality of life

Quality of life in climacteric and postmenopausal women is often compromised. This overview addresses the many factors that may interfere with health and well-being in such women. Hormonal changes during the menopausal transition, finally resulting in estrogen deficiency, play a pivotal role in the incidence of climacteric symptoms and also in the development of chronic diseases. Such symptoms and diseases can contribute to impaired quality of life in climacteric and postmenopausal women. Postmenopausal hormone therapy (PHT) is the treatment of first choice to alleviate symptoms of estrogen deficiency. Besides effectively relieving climacteric symptoms and complaints, PHT can also protect against some chronic diseases, such as osteoporosis and colorectal cancer. Presently, available PHTs vary widely in type, estrogen and progestogen dosage, and route and duration of administration. Furthermore, the number of alternatives to treat climacteric symptoms, and/or to prevent chronic diseases, has increased. Therefore, doctors involved in the care of climacteric women in the 21st century are much more able to meet the specific needs of individual patients and improve health and quality of life.     

激素替代疗法及其安全性

目的：绝经妇女广泛使用激素替代疗法(hormone replacement therapy，HRT)，在学术界始终存在争议，其安全性令人担忧。方法：检索2000年～2002年文献，综述评价。结果：绝经妇女使用激素治疗是必须的，关键是如何安全、合理、规范使用HRT剂量，权衡HRT利与弊。结论：HRT引起绝经妇女的副作用与医生、患者错误地使用有很大关系，HRT防止心血管疾病、预防骨质疏松及对其它器官系统的益处相比，利大于弊。     

Alcohol, hormones, and postmenopausal women

Many women take supplemental estrogens after menopause, a practice called hormone replacement therapy (HRT). Moderate alcohol consumption may increase estrogen levels in women receiving HRT, potentially affecting their risk for various adverse health effects. Two recent studies, however, provide no strong evidence for an effect of alcohol on hormones in postmenopausal women. The possible association between alcohol consumption and risk of cancer of the breast does not appear to be mediated by estrogens. Both estrogens and moderate alcohol consumption have been associated with a decreased risk for cardiovascular disease; however, alcohol's beneficial effect on heart disease does not appear to involve hormonal mechanisms. Additional research is needed to define the consequences of moderate drinking on hormone levels after menopause.     

Pharmacy-based care for perimenopausal and postmenopausal women

Perimenopause and menopause represent a major physiologic and, often, psychosocial transition in the lives of women. During this time, women often experience disturbing new symptoms and develop an increased awareness of their risks for major chronic illnesses. Women in this stage of life are often highly motivated to improve their health and can benefit greatly from pharmacy-based preventive health care services. Although perimenopausal and menopausal women represent an important target market, some pharmacists may wish to offer more focused services within the broader arena of women's health. For example, a number of community pharmacies have developed niche services for these patients, such as osteoporosis screening, (46) breast cancer risk assessment, (50) or bioidentical HRT consulting and compounding. (59) Other pharmacy care services that may be targeted to women in midlife include smoking cessation, weight management, and dietary supplement consulting. Based on the experiences of the Mar-Main Pharmacy staff, a practical approach is to implement new services gradually, while focusing on providing high-quality, individualized service to a small number of patients. Using this strategy, Mar-Main Pharmacy has experienced tremendous growth in its bioidentical HRT services. This increase in demand for pharmacy services has arisen from word-of-mouth referrals from patients and physicians rather than formal marketing. Perimenopausal and menopausal women represent a growing and increasingly knowledgeable group of patients. Many of these women are seeking care that is individualized, responsive to their health beliefs, and designed to help them maintain a high quality of life. Providing pharmacy-based consulting services for these patients can be extremely rewarding, both professionally and personally.     

Sex hormones and the cardiovascular system: effects on arterial function in women

1. It has long been hypothesized that oestrogen may be cardioprotective. This hypothesis is supported by diverse and comprehensive mechanistic studies in animals and humans. Consistently, in observational studies, oestrogen use in post-menopausal women significantly reduced cardiovascular disease. Contrastingly, large interventional trials focusing on chronic disease prevention in older post-menopausal women have suggested neutral (oestrogen alone) or adverse (combined oestrogen/progestin preparations) cardiovascular effects. 2. The negative initial interpretation and extrapolation of the early randomized, controlled interventional trials, primarily the Women's Health Initiative, has recently been theoretically reconciled with the positive mechanistic and observational studies. As a new interventional literature emerges, it has been suggested that if oestrogen is used from menopause onwards it is likely to be protective, but if instituted after endothelial damage has occurred in an oestrogen-deficient post-menopausal state, the beneficial vessel wall effects are not observed and the procoagulant effects result in overall increased cardiovascular risk. 3. The present article reviews the literature on arterial function and oestrogen use in the setting of the early endothelial protection theory. This theory is generally supported by the data on oestrogen effects on arterial function. In general, in studies of premenopausal women the effects of oestrogen were positive, with similar benefits noted if oestrogen was used early after menopause. However, where hormone therapy was commenced some years after menopause, the beneficial effects on arterial function were not observed. In clinical practice, hormone therapy is primarily used at menopause for the treatment of menopausal symptoms. The data on arterial function reviewed herein, along with emerging interventional human studies, suggest that the cardiovascular effects of this practice are not adverse.