Menopause Society Research Articles

Hormone replacement therapy in postmenopause - where we stand?

Background: The findings of most relevant randomized clinical studies such as HERS, WHI and MWS, performed in the last decade have shown that hormonal replacement therapy (HRT) users are at increased risk for the development of breast cancer, stroke and pulmonary edema. On the other hand they are at a lower risk for the development of large bowel cancer and for hip and vertebral fractures; the incidences of endometrial cancer and coronary heart disease have not been proved to be significantly affected by HRT. As for the prevention of cardiovascular diseases, the findings of these studies differed from those provided by observational studies, it became an imperative to find the causes of these discrepancies. The major criticism of randomized clinical studies was aimed at the inclusion criteria, as the mean women’s age in HERS and in WHI study was 63 years. The women of that age may no longer be healthy, and are particularly exposed to cardiovascular diseases. In all studies the same type of HRT was used, i.e. conjugated equine estrogen alone or in combination with medroxyprogesterone acetate. In Europe, this combination is rarely prescribed; we do not prescribe it in Slovenia either. The same type of HRT used in randomized clinical studies was further criticized, the basic idea of HRT being an individual approach to each woman requiring HRT. For rather sensational and often misinterpreted findings of randomized studies, the largest menopause societies worldwide, the International Menopause Society (IMS), the European Menopause and Andropause Society (EMAS) and the North American Menopause Society (NAMS), have revised the guidelines for HRT use in postmenopause. These guidelines have been adopted by the Slovene Menopause Society as well. Conclusions: The indications for HRT remain to be markedly expressed and severe climacteric symptoms, prevention and treatment of osteoporosis, urogenital syndrome and premature menopause. However, the ‘safe’ window regarding the duration of HRT use has disappeared, and so have the terms ‘short-term’ and ‘long-term’ treatment. The only criterion for the duration of HRT use is to constantly assess the benefits and risks for each individual, and to adjust the dose, type and duration of HRT use accordingly.

Design of the Japan Nurses' Health Study: A Prospective Occupational Cohort Study of Women's Health in Japan

The Japan Nurses' Health Study (JNHS) is a prospective occupational cohort study investigating the effects of lifestyle and healthcare practices on women's health. It was initiated in 2001, with a six-year entry period and a proposed ten-year follow-up. Participants comprise female registered nurses, licensed practical nurses, public health nurses, and midwives, aged 25 yr or over at the baseline survey. Participants were recruited in cooperation with the Japanese Nursing Association and the Japan Menopause Society. A self-administered baseline questionnaire was distributed, requesting demographic information, lifestyle factors, pharmaceutical drug use, physical condition, reproductive health, and disease history. A total of 49,914 women from all 47 prefectures in Japan responded to the baseline survey. Among them, approximately 18,000 agreed to be followed-up, and returned signed informed-consent sheets, together with their completed baseline questionnaires. Changes in lifestyle, healthcare, incidence of disease, and health outcomes over time will now be studied. The cohort receives annual JNHS newsletters and biennial follow-up questionnaires by mail.

Osteoporosis guidelines

The Position Statement from the International Menopause Society (IMS) in 2004 recommends the use of hormone therapy for the `avoidance of bone-wasting and fractures'. It also states that `prevention, not treatment, is the most feasible goal'. In updating the Statement, this paper considers the relevance of Osteoporosis Guidelines. Relevant documents will be of two broad types. These may be consensus statements/position statements that summarize the `state of the art' for practitioners, based on the work of expert groups, or they may be formal Guidelines generated through formal `evidence-based' methodology. The former approach is generally used by Societies and can be generated through relatively efficient consensus processes. The latter approach will normally involve extensive work and cost, necessarily becomes very detailed, involving systematic review and technology appraisal and can lead to highly specific recommendations on intervention thresholds. For the revision of the general IMS Position Statement, the specific IMS Paper on Postmenopausal Osteoporosis (2005) must be a key reference document. This provides a description of the international consensus on the management of osteoporosis up to late 2004 and which remains relevant today. Additionally, other consensus statements and systematic guidelines need to be considered. Across these documents providing guidance, the substantial influence of the International Osteoporosis Foundation/National Osteoporosis Foundation Position Paper, defining a `New approach to the development of assessment guidelines for osteoporosis', can be seen. This flagged the importance of a shift from guidance, tying the diagnostic threshold to the intervention threshold, and instead advised linking the intervention threshold to estimated fracture risk probability. This moves the intervention decision away from a simple bone density threshold to a more complex, but more realistic, threshold estimate, taking into account a range of important clinical risk factors and bone mineral density. This thinking is reflected in the IMS Paper on Postmenopausal Osteoporosis (2005).

International Menopause Society — Updated Recommendations on Post-menopausal Hormone Therapy

International Menopause Society — Updated Recommendations on Post-menopausal Hormone Therapy

In Vivo exposure of lipopolysaccharide (LPS) but not estrogen decreases platelet reactivity in early postmenopausal women

Infection and oral estrogen treatments are risk factors for thrombosis. Experiments were designed to evaluate in vitro effects of priming doses of LPS and physiological doses of estrogen on platelets from healthy, newly menopausal women. Blood was collected from early postmenopausal women (42–56 years old) with a menopausal age between 6 months to 3 years into anticoagulants (citrate, hirudin and TAP). Platelet rich plasma was prepared and preincubated with LPS (ultrapure LPS from E. Coli: 10ng-1000ng/mL) and/or 17β-estradiol(10−10M/mL) Four groups were studied: control, LPS, 17β-estradiol, 17β-estradiol+LPS). Platelet aggregation was measured by lumiaggregometry. Thrombin receptor agonist peptide (TRAP 10μM) was used as an agonist. Platelet dense granules ATP secretion was measured by luciferin bioluminescence. Only the highest concentration of LPS (100ng/ml) decreased the maximum and rate of ATP secretion from dense granules and aggregation. At physiological concentrations, 17β-estradiol did not affect platelet aggregation alone or in combination with LPS. These data suggest that LPS and estrogen may not increase thrombotic risk by direct activation of platelets; effects most likely require the interaction of the platelets with other cells in the circulation. (Supported by NIH HL78638, the Mayo Foundation, Kronos Longevity Institute and Japanese Menopause Society)

Recent epidemiological evidence relevant to the clinical management of the menopause

Background The 2003 Workshop of the International Menopause Society considered the epidemiological evidence collected up to that time on the effects of female hormone therapy (HT). New evidence relevant to the clinical management of the menopause has since been published.Objectives To summarize the new evidence, to offer critiques of important recently published studies, and to consider the implications for clinical practice.Cardiovascular disease Recent evidence from two studies, the Women's Health Initiative (WHI) clinical trial, and an observational component of the WHI, suggests that combined hormone therapy (estrogen plus progestin) (CHT) initially increases the risk of coronary heart disease (CHD), stroke, and venous thromboembolism (VTE), followed by a decline. For CHD, the hazard ratio exceeds 1.0 during the first year of follow-up, followed by a progressive decline to <1.0 after >5 years. Other studies show the same trend.Breast cancer In the WHI data, recent evidence suggests that estrogen therapy (ET) reduces the overall risk of breast cancer, predominantly ductal and localized cancer. Evidence from the Million Women Study (MWS) now suggests that the previously reported association of HT with breast cancer is concentrated on tumors with lobular or tubular histology; the risk of ductal cancer is also increased, but to a lesser degree. The risks of these outcomes are higher for CHT than for ET. Other recent studies broadly accord with the MWS observations.Other outcomes Among CHT recipients, the WHI findings of reduced risks of fractures and colorectal cancer, and an increased risk of VTE, remain unchanged. Evidence from other studies now suggests that protracted exposure to CHT may increase the risk of ovarian cancer, and reduce the risk of endometrial cancer.Interpretation The recently published WHI findings for CHD and breast cancer are of major importance. For CHD, detection bias may have resulted in systematic overestimation of the duration-dependent hazard ratios. If so, there may be no initial increase in the risk, and prolonged use may be associated with a decreased risk. The hypothesized protective effect of HT may have been missed in the WHI study. For breast cancer, the WHI evidence now suggests a protective effect of ET.Tumors with lobular or tubular histology tend to be small, slow-growing, low-grade, and well differentiated. Such tumors may be more susceptible to detection bias, and that bias has not been ruled out as an alternative explanation of the higher risks among CHT recipients, observed in the MWS. The possibility of detection bias in that study, and in other observational studies, is supported by the decreased risk of breast cancer observed among ET recipients in the WHI clinical trial. Based on the present evidence, it is impossible to determine whether HT, or specific forms of HT, increase, decrease, or have no effect on the overall risk of breast cancer, or of specific types of breast cancer.Other evidence raises the possibility that prolonged CHT may increase the risk of ovarian cancer, and decrease the risk of endometrial cancer. Additional studies are needed to confirm those findings.If, as now seems possible, CHT in fact reduces the risk of CHD, and has little or no effect on the risk of breast cancer, or if ET decreases the risk, the clinical and public health implications would be major. However, the picture is confused.In view of new, but uncertain, findings concerning CHD and breast cancer, clinicians will have to continue to use clinical judgment, informed by a critical evaluation of the epidemiological evidence, in the management of the menopause.

International Menopause Society — Updated Recommendations on Post-menopausal Hormone Therapy

International Menopause Society — Updated Recommendations on Post-menopausal Hormone Therapy

Fatores associados à intensidade das ondas de calor em mulheres em climatério

To identify factors associated with the intensity of hot flashes in 334 climacteric women living in Campinas, São Paulo, Brasil. Secondary analysis of a data bank of a descriptive cross-sectional population-based study. Selection of 334 women reporting hot flashes aged 45-60 years was carried out through cluster sampling. Data were collected by home interviews using a structured, pre-tested questionnaire provided by the International Health Foundation/International Menopause Society and by the North American Menopause Society and adapted by the authors. Intensity of hot flashes was measured using the circulatory index. The variables analyzed were age, use of contraceptive methods and hormonal therapy, tubal ligation, body mass index, menopausal status, time since menopause, hysterectomy, bilateral oophorectomy and smoking. Statistical analysis was performed by using the median, absolute and relative frequencies according to the type of variable. The prevalence ratio (PR) was used to measure association. Bivariate analysis and multiple logistic regression with a 95% confidence interval (95% CI) were used to identify the factors associated with the intensity of hot flashes. Women with time since menopause of over 61 months (PR: 0.59; IC 95%: 0.39-0.88) had a significantly lower chance of presenting intense hot flashes while the antecedent of bilateral oophorectomy (PR: 1.95; IC 95%: 1.08-3.50) was significantly associated with the intensity of hot flashes. Both factors, time since menopause and bilateral oophorectomy, suggest hypoestrogenism as a common cause of more intense hot flashes. Women with these factors should receive specialized care to minimize the negative effects of hot flashes.

The role of calcium in peri- and postmenopausal women

To update the evidence-based consensus opinion published by The North American Menopause Society (NAMS) in 2001 on the role of calcium in peri- and postmenopausal women. NAMS followed the general principles established for evidence-based guidelines to create this document. A panel of clinicians and researchers acknowledged to be experts in the field of calcium and women's health was enlisted to review the previous position statement and data published since then, compile supporting statements, and make recommendations. Their advice was used to assist the NAMS Board of Trustees in publishing this position statement. Adequate calcium intake (in the presence of adequate vitamin D status) has been shown to reduce bone loss in peri- and postmenopausal women and reduce fractures in postmenopausal women older than age 60 with low calcium intakes. Adequate calcium is considered a key component of any bone-protective therapeutic regimen. Calcium has also been associated with beneficial effects in several nonskeletal disorders, primarily hypertension, colorectal cancer, obesity, and nephrolithiasis, although the extent of those effects has not been fully elucidated. The calcium requirement rises at menopause. The target calcium intake for most postmenopausal women is 1,200 mg/day. Adequate vitamin D status, defined as 30 ng/mL or more of serum 25-hydroxyvitamin D (usually achieved with a daily oral intake of at least 400 to 600 IU), is required to achieve the nutritional benefits of calcium. The best source of calcium is food, and the best food source is dairy products. High-quality calcium supplements (taken in divided doses) are alternative sources for women unable to consume enough dietary calcium. There are no reported cases of calcium intoxication from food sources, and cases associated with supplements are rare (high intake levels of 2,150 mg/day have resulted in a 17% increase in renal calculi in one recent study, but not others). Because no accurate test to determine calcium deficiency exists, clinicians should focus instead on encouraging women to consume enough calcium to meet the recommended levels. The most definitive role for calcium in peri- and postmenopausal women is in bone health, but, like most nutrients, calcium has beneficial effects in many body systems. Based on the available evidence, there is strong support for the importance of ensuring adequate calcium intake in all women, particularly those in peri- or postmenopause.

17th Annual Meeting of The North American Menopause society

17th Annual Meeting of The North American Menopause society

Management of the menopauseManagement of the menopause Margaret Rees , David W Purdie The Royal Society of Medicine Press and British Menopause Society 4th 180 £19.95 1 85315 667 1 1853156671

The intended target audience for this book is gynaecologists, GPs, doctors, nurses and allied healthcare professionals working predominantly in primary care with women experiencing the menopause.

Management of osteoporosis in postmenopausal women

To update the evidence-based position statement published by The North American Menopause Society (NAMS) in 2002 regarding the management of osteoporosis in postmenopausal women. NAMS followed the general principles established for evidence-based guidelines to create this updated document. A panel of clinicians and researchers expert in the field of metabolic bone diseases and/or women's health were enlisted to review the 2002 NAMS position statement, compile supporting statements, and reach consensus on recommendations. The panel's recommendations were reviewed and approved by the NAMS Board of Trustees. Osteoporosis, whose prevalence is especially high among elderly postmenopausal women, increases the risk of fractures. Hip and spine fractures are associated with particularly high morbidity and mortality in this population. Given the health implications of osteoporotic fractures, the primary goal of osteoporosis therapy is to prevent fractures, which is accomplished by slowing or stopping bone loss, maintaining bone strength, and minimizing or eliminating factors that may contribute to fractures. The evaluation of postmenopausal women for osteoporosis risk requires a medical history, physical examination, and diagnostic tests. Major risk factors for postmenopausal osteoporosis (as defined by bone mineral density) include advanced age, genetics, lifestyle factors (such as low calcium and vitamin D intake, smoking), thinness, and menopause status. The most common risk factors for osteoporotic fracture are advanced age, low bone mineral density, and previous fracture as an adult. Management focuses first on nonpharmacologic measures, such as a balanced diet, adequate calcium and vitamin D intake, adequate exercise, smoking cessation, avoidance of excessive alcohol intake, and fall prevention. If pharmacologic therapy is indicated, government-approved options are bisphosphonates, a selective estrogen-receptor modulator, parathyroid hormone, estrogens, and calcitonin. Management strategies for postmenopausal women involve identifying those at risk of low bone density and fracture, followed by instituting measures that focus on reducing modifiable risk factors through lifestyle changes and, if indicated, pharmacologic therapy.

Advice has changed for hormone therapy in the WHI era

Advice has changed for hormone therapy in the WHI era

Serotonergic Agents as an Alternative to Hormonal Therapy for the Treatment of Menopausal Vasomotor Symptoms

Hot flashes represent one of the most common complaints among women undergoing menopause. Despite their prevalence, the pathophysiology leading to hot flashes is only partly understood. Short-term estrogen remains the most effective treatment for hot flashes, but because of safety concerns many women are reluctant to use this treatment. Several non-hormonal pharmacologic treatments have been evaluated in randomized, prospective clinical trials. Placebo-controlled clinical trials have suggested that agents from the selective serotonin reuptake inhibitor/serotonin and norepinephrine reuptake inhibitor (SSRI/SNRI) family reduce hot flashes by 50-60%. Successful treatment of hot flashes with these compounds may also be associated with improvements in sleep, mental health, and vitality. Adverse events may cause 10-20% of individuals to withdraw from treatment. The agents should be stopped with caution to prevent a discontinuation syndrome. Given the available data, the North American Menopause Society and the American College of Obstetricians and Gynecologists have recommended that women with moderate to severe, menopause-related hot flashes, with concerns or contraindications to estrogen-containing treatments, should consider prescription progestogens, venlafaxine, paroxetine, fluoxetine, or gabapentin. Prescribing clinicians are urged to discuss the potential benefits, adverse effects, and new information that may become available for each of the treatment options. Caution should also be exercised when prescribing strong cytochrome P450 2D6 inhibitors, such as paroxetine or fluoxetine, to women who are taking tamoxifen. Further studies are required to evaluate the optimal agent and duration of SSRI/SNRI treatment in menopausal women.

Managing the menopause: British Menopause Society Council consensus statement on hormone replacement therapy

The British Menopause Society Council aims to help health professionals inform and advise women about the menopause. This guidance regarding estrogen-based hormone replacement therapy (HRT), including tibolone, which is classified in the British National Formulary as HRT, responds to the results and analysis of the randomized Women's Health Initiative studies and the observational Million Women Study. Treatment choice should be based on up-to-date information and targeted to individual women's needs. HRT still offers the potential for benefit to outweigh harm, providing the appropriate regimen has been instigated in terms of dose, route and combination.

16th Annual Meeting of The North American Menopause Society September 28 to October 1, 2005, San Diego, CA

16th Annual Meeting of The North American Menopause Society September 28 to October 1, 2005, San Diego, CA

The role of testosterone therapy in postmenopausal women: position statement of The North American Menopause Society

To create an evidence-based position statement regarding the role of exogenous testosterone in postmenopausal women. The North American Menopause Society (NAMS) enlisted a panel of clinicians and researchers acknowledged to be experts in the field of testosterone therapy to review the evidence obtained from the medical literature, compile supporting statements and conclusions, and reach consensus on recommendations. The document was reviewed and approved by the NAMS Board of Trustees. Endogenous testosterone levels have not been clearly linked to sexual function in postmenopausal women. Published evidence from randomized controlled trials, although limited, indicates that exogenous testosterone, both oral and nonoral formulations, has a positive effect on sexual function, primarily desire, arousal, and orgasmic response, in women after spontaneous or surgically induced menopause. Data are inadequate to support recommending testosterone use for any other indication, including preserving or increasing bone mineral density, reducing hot flashes, increasing lean body mass, or improving well-being. Hirsutism and acne have been associated with testosterone therapy, but the actual risks are not well defined. It is not known whether testosterone therapy increases the risk of breast cancer, cardiovascular disease, or thromboembolic events. There are few data regarding the safety and efficacy of testosterone therapy in women not using concomitant estrogen therapy or for the use of testosterone therapy for longer than 6 months. Clinically available laboratory assays do not accurately detect testosterone concentrations at the values typically found in women, and no testosterone level has been clearly linked to a clinical syndrome of hypoandrogenism or testosterone insufficiency. Postmenopausal women with decreased sexual desire associated with personal distress and with no other identifiable cause may be candidates for testosterone therapy. Testosterone treatment without concomitant estrogen therapy cannot be recommended because of a lack of evidence. When evaluating a woman for testosterone therapy, recommendations are to rule out causes not related to testosterone levels (eg, physical and psychosocial factors, medications) and to ensure that there is a physiologic cause for reduced testosterone levels (eg, bilateral oophorectomy). Laboratory testing of testosterone levels should be used only to monitor for supraphysiologic levels before and during therapy, not to diagnose testosterone insufficiency. Monitoring should also include subjective assessments of sexual response, desire, and satisfaction as well as evaluation for potential adverse effects. Transdermal patches and topical gels or creams are preferred over oral products because of first-pass hepatic effects documented with oral formulations. Custom-compounded products should be used with caution because the dosing may be more inconsistent than it is with government-approved products. Testosterone products formulated specifically for men have a risk of excessive dosing, although some clinicians use lower doses of these products in women. Testosterone therapy is contraindicated in women with breast or uterine cancer or in those with cardiovascular or liver disease. It should be administered at the lowest dose for the shortest time that meets treatment goals. Counseling regarding the potential risks and benefits should be provided before initiating therapy.

Guidelines for hormone treatment of women in the menopausal transition and beyond: Position Statement by the Executive Committee of the International Menopause Society

Recent communications regarding estrogen or estrogen+progestin treatment and clinical cardioprotection, breast cancer risk and cerebral aging have produced considerable confusion and concerns among women, care-givers and the media. The actions of the United States’ Food and Drug Administration (FDA) and other National Safety of Medicine Boards, such as the European Medicine Evaluation Agency (EMEA), in response to publication of data from the Women's Health Initiative (WHI) [1–3] and the Million Women Study (MWS) [4], have also raised concerns.

Climacteric medicine: European Menopause and Andropause Society (EMAS) 2004/2005 position statements on peri- and postmenopausal hormone replacement therapy

In women experiencing distressing climacteric symptoms during the peri- and postmenopause there is conclusive evidence from abundant randomised controlled trials that systemic hormone replacement therapy (HRT) of any type affords symptom relief, with no alternative treatment producing similar effect. Though this evidence is accumulating, the question of how to provide best clinical practice in an attempt to both alleviate the menopausal symptoms and prevent the more long-term postmenopausal degenerative diseases is still under debate. When providing climacteric medicine, the dose and regimen of HRT needs to be individualised based on the principle of choosing the lowest appropriate dose in relation to severity of symptoms and on the menopausal age. However, few long-term data on different HRT formulations exist in symptomatic women, which also account for baseline risk of cardiovascular disease (CVD), breast cancer and osteoporosis. In most cases, an individualized prescription together with life-style management will sustain possibilities for net beneficial effects on climacteric symptoms, quality of life (QoL), sexuality and osteoporosis, with only rare risk of severe adverse effects. With the perspective provided by recent epidemiological findings, not least from the estrogen only arm of the Women's Health Initiative Study (WHI), European Menopause and Andropause Society (EMAS) supports research activities in symptomatic women with new HRT formulations in order to affect positively the balance of clinical benefit and risk, including specific information on QoL and also account for the traditional differences in treatment modalities between the US and Europe, and the difference in BMI, life-style and diet. In women experiencing an early menopause (<45 year) current data support a specific overall benefit of HRT. At present, more long-term systemic HRT may be considered in women at high risk of osteoporotic fractures, in particular when alternate therapies are either inappropriate or insufficiently effective, as benefits will outweigh any risks. In contrast, urogenital symptoms may be addressed efficiently and safely with long-term local estrogen therapy.

Fatores associados às ondas de calor em mulheres climatéricas: inquérito populacional domiciliar

OBJETIVO: identificar os fatores associados à ocorrência de ondas de calor em mulheres climatéricas residentes em Campinas, São Paulo. MÉTODOS: análise secundária de banco de dados de estudo descritivo de corte transversal, de base populacional. Foram selecionadas 456 mulheres por processo de amostragem, com idade entre 45-60 anos de idade. Os dados foram coletados por meio de entrevistas domiciliares, com questionários estruturados e pré-testados, fornecidos pela Fundação Internacional de Saúde/Sociedade Internacional de Menopausa e Sociedade Norte-Americana de Menopausa e adaptados pelos autores. As variáveis analisadas foram idade, cor, uso de métodos anticoncepcionais e terapia hormonal, laqueadura tubárea, índice de massa corpórea, estado menopausal, tempo de menopausa, histerectomia e tabagismo. Foram calculados a média, desvio padrão, mediana e razão de prevalência (RP). Realizou-se análise de regressão múltipla, utilizando o processo de seleção passo a passo, com intervalo de confiança de 95% (IC 95%). RESULTADOS: na análise bivariada, mulheres na pós-menopausa (RP: 1,42; IC 95%: 1,06-1,90) e histerectomizadas (RP: 1,50; IC 95%: 1,05-2,14) apresentaram chance significativamente maior de ocorrência de ondas de calor. A análise de regressão múltipla não mostrou associação significativa entre a presença de ondas de calor e as variáveis avaliadas. CONCLUSÃO: os resultados mostraram coerência com estudos anteriores, ou seja, ainda não é possível indicar os fatores que estão associados à ocorrência de ondas de calor.