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Hormone replacement therapy (HRT) has profound effects on the cardiovascular system, with plausible biological mechanisms explaining both the benefits and harm. Benefits may result from oestrogen action on metabolic risk factors, such as lipids, glucose and insulin metabolism, as well as direct arterial effects, reducing atherogenesis. Harm may arise from inappropriately high starting doses causing transient increases in coagulation activation and adverse vascular remodelling. Observational studies of HRT suggest that there is a beneficial effect on the incidence of coronary heart disease (CHD). Any benefit of HRT seen in randomized clinical trials appears to be confined to those women within several years of their menopause, and it is clear from the randomized trials that age at initiation is a crucially important consideration. Women initiating HRT within 10 years of menopause onset may achieve cardiovascular benefit, particularly in terms of primary CHD prevention, whilst avoiding risks of stroke and venous thrombo-embolism.

The British Menopause Society Council is committed to provide up-to-date authoritative reviews to aid health professionals to inform and advise women about key issues in postreproductive health. This guidance refers to non-estrogen-based treatments for menopausal symptoms, such as hot flushes, symptoms of urogenital atrophy and lack of sexual desire. Treatment of choice should be based on up to-date information and targeted to individual women's needs. Non-hormonal strategies may be useful for women with estrogen-dependent disease such as breast cancer.

Observational studies have consistently shown a benefit of hormone replacement therapy (HRT) on coronary heart disease (CHD), but some randomised studies have not shown any significant effect. Thus questions still remains as to whether HRT is beneficial for CHD, and in whom this benefit might be achieved. The biological effects of oestrogen on the cardiovascular system have been extensively studied, and beneficial effects on metabolic CHD risk factors, as well as on arterial function and on surrogate clinical markers of CHD, have been demonstrated. Thus it seems implausible that HRT should not benefit CHD in postmenopausal women. Most randomised trials using clinical outcomes have studied just one dose of one HRT regimen, a dose inappropriately high with the average starting age of the participants being in their mid-60s. The observational population studies largely comprise women starting on HRT at appropriate dose around the age of menopause, i.e. early 50s. In fact, it was the older women in the randomised trials that failed to show benefit, whereas there was a trend to benefit in the younger ones for whom the starting dose of HRT was appropriate. Furthermore, a pilot study of lower dose HRT in older women did not show any cardiovascular harm. Inappropriately high doses of oestrogen could cause cardiovascular harm due to transient disturbances in thrombogenesis and vascular remodelling. Whilst the greatest CHD benefit may be seen by starting HRT in the early postmenopause, this does not exclude benefit in older women given appropriate low dose therapy.

There has been some confusion among women and health professionals since the publication of the Women's Health Initiative and Million Women studies about the management of premature ovarian failure (POF). Both studies were undertaken in women aged 50 and over, and cannot be extrapolated to their younger counterparts, who would normally be producing their endogenous estrogen, since they have functioning ovaries. Estrogen-based replacement therapy is the main stay of treatment for women with POF and is recommended at least until the average age of natural menopause (52 years in the UK). This view is endorsed by regulatory bodies such as the Committee on Safety of Medicines (now the Commission on Human Medicines) in the UK. No evidence shows that estrogen replacement increases the risk of breast cancer to a level greater than that found in normally menstruating women, and women with POF do not need to start mammographic screening early unless other risk factors are present, such as family history.

Aims: Randomized trials have not demonstrated coronary heart disease benefit from hormone replacement therapy (HRT). We hypothesized that low-dose HRT may avoid harm., Methods and Results: We studied the effects of HRT on lipids and coagulation in women with acute coronary syndromes. A total of 100 post-menopausal women >55 years were enrolled between 2 and 28 days after an acute coronary syndrome and randomized to oral oestradiol-17beta 1 mg plus norethisterone acetate 0.5 mg daily, or matching placebo, and followed for up to 12 months. Levels of lipids, lipoproteins, and haemostasis markers were measured at baseline, 3, and 6 months. There were no significant differences in lipid levels between the two groups, probably due to concomitant statin use. Antithrombin and factor VII levels were significantly lower in the HRT group, whereas fibrinogen was significantly decreased in the placebo group. No evidence of increased coagulation activation was observed, nor of adverse cardiovascular outcomes [odds ratio (OR) 0.63 (95% confidence intervals 0.31-1.31)]., Conclusion: Low-dose HRT may give cardiovascular benefit. These findings require confirmation in a full clinical trial with evaluation of cardiovascular outcomes as the primary objective.

HRT has been widely used for the relief of menopausal symptoms and the prevention and treatment of post-menopausal osteoporosis. However, following the publication of the Women's Health Initiative (WHI) and the Million Women Study (MWS), regulatory authorities issued an urgent safety restriction on HRT use in preventing post-menopausal osteoporosis, recommending that it now be considered a second-line treatment. Are such recommendations justified? Treatments for osteoporosis, in women with increased future risk for fractures but who have not yet developed the disease, should prevent all types of osteoporotic fractures. Of the available therapies, none other than HRT has been clearly demonstrated to prevent hip fractures in such women. Thus, HRT should be recommended as first-line treatment for osteoporosis prevention. Potential risks of HRT, such as increased development of breast cancer and increased thromboembolism, have long been known. The WHI showed risks in less than 0.3% of women studied, and the MWS appears to have overestimated the risk of breast cancer. Thus, no new safety issues have been identified, and the regulatory authorities may have misinterpreted the data from these recent studies. When given for the correct indications, HRT is of major benefit to many women.

Drospirenone is a new progestogen in hormone replacement therapy, with anti-mineralocorticoid activity. This anti-mineralocorticoid activity counteracts water and sodium retention, helping to reduce the likelihood of fluid retention that some women experience with hormone replacement therapy. In a post hoc analysis of women with mild hypertension, estradiol (1 mg) plus drospirenone (2 mg) was found to lower blood pressure in mildly hypertensive women. The introduction of estradiol plus drospirenone may offer the opportunity to re-evaluate the contribution of the progestogen component of hormone replacement therapy.

Osteoporosis is a common condition in postmenopausal women and is associated with significant healthcare costs, morbidity and mortality. It is clear that long-term hormone replacement therapy (HRT) has a role to play in preventing osteoporosis by increasing bone mineral density and reducing fracture rate. It is important that these benefits, as well as those on climacteric symptoms, quality of life, colorectal carcinoma and cognition, are not underestimated in the face of the postulated risks with regard to breast cancer and cardiovascular disease. In conclusion, HRT should currently be used only for women with climacteric symptoms or an increased risk of osteoporosis, and it is important that there is an individualised approach to treatment based on each woman's risk profile.

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.

Objective: To evaluate the effect on bone mineral density of vaginal rings delivering estradiol acetate at two systemic doses versus a locally active vaginal ring in healthy postmenopausal women., Design: A total of 174 postmenopausal women (younger than age 65 years) were randomly assigned to a 0.05 mg/day vaginal ring, 0.1 mg/day vaginal ring, or 0.0075 mg/day vaginal ring (active comparator), and treated for 96 weeks. Of these, 170 took a study drug; 85 taking the study drug had data at 96 weeks, and 132 women were included in the intent-to-treat analysis. Non-hysterectomized women received 1 mg of norethisterone taken on the last 12 days of each 28-day monthly cycle. The primary endpoint was change in lumbar spine bone mineral density (L2-L4); change in total hip bone mineral density was a secondary endpoint., Results: At 96 weeks, mean lumbar spine bone mineral density increased 2.7% and 3.3% from baseline, respectively, in the 0.05-mg and 0.1-mg groups (P < 0.001 for both) compared with an 0.3% increase in the 0.0075-mg group (P = 0.56). Mean total hip bone mineral density increased 1.7% and 1.8% from baseline, respectively, in both the 0.05-mg and 0.1-mg groups (P < 0.001) and decreased 1.2% in the 0.0075-mg group (P = 0.001). All vaginal ring doses were well tolerated., Conclusions: Vaginal rings delivering systemic doses of estradiol increase bone mineral density of the lumbar spine and total hip in healthy postmenopausal women. Safety and acceptability were similar to existing estradiol therapies.

Hormone replacement therapy (HRT) has profound metabolic effects which impact on the cardiovascular system. These effects include changes in lipids and lipoproteins, glucose and insulin metabolism, haemostatic factors, inflammatory markers and body composition, as well as changes in vascular function and remodelling. Observational studies have demonstrated coronary heart disease benefit with HRT use, in contrast to the outcomes from randomised clinical trials. Lack of benefit in the latter studies appears to arise from early harm caused by HRT which outweighs any later benefit. Such early harm could result from transient increases in thrombogenesis and adverse vascular remodelling, which in turn could arise from starting doses of such therapies that are inappropriately high for the women's age. This problem is avoided in observational studies because the women are much younger and those same starting doses are appropriate for their age. Later benefit could result from oestrogen action on metabolic risk factors and direct arterial effects resulting in reduced atherogenesis. It is therefore possible that more appropriate HRT regimens could be devised to provide coronary benefit without risk of stroke, even in older age groups. Such strategies need to be tested in large clinical trials. The metabolic effects of HRTs are key to providing cardiovascular benefit.

Objective: To evaluate prediction of coronary heart disease (CHD) by quantitative measures of the metabolic syndrome and inflammation in a cohort of high socio-economic status males., Methods: Incident CHD was identified in a cohort of 649 male participants in a company health programme during a mean follow-up of 10.6 years. Using factor analysis, metabolic syndrome and sub-clinical inflammation scores were derived from baseline measurements, which included an oral glucose tolerance test-derived measure of insulin resistance. Factor scores were then included as predictor variables in a Cox regression analysis of incident CHD., Results: Forty-two cases of definite CHD were identified on follow-up. The conventional risk factors, cigarette smoking, blood pressure, total cholesterol and low HDL cholesterol were clearly distinguished as significant predictors of incident CHD. Erythrocyte sedimentation rate was also an independent predictor (coefficient 0.0480, z score 2.39, p=0.017). The metabolic syndrome factor included insulin resistance, body mass index, serum triglycerides, glucose tolerance, serum uric acid and fasting plasma glucose. The inflammation factor included serum globulin, blood leukocyte count, low albumin, haemoglobin and cholesterol, but not erythrocyte sedimentation rate. The inflammation factor score was a significant predictor of CHD (coefficient 0.4601, z score 2.43, p=0.015) but the metabolic syndrome factor was not (coefficient 0.2488, z score 1.24, p=0.2)., Conclusions: Erythrocyte sedimentation rate and a factor analysis-derived measure of sub-clinical inflammation were important in the development of CHD in this relatively low-risk group, but neither metabolic syndrome factor score nor its individual components predicted CHD.

Hormone replacement therapy has profound effects on the cardiovascular system, through metabolic effects as well as direct effects on arterial function. Observational studies showing coronary heart disease benefit have appeared superficially to be at odds with the outcomes from randomized clinical trials, but the lack of benefit from the latter appears to arise from early harm caused by hormone replacement therapy that outweighs any later benefit. The early harm could arise from starting doses of such therapies that are inappropriately high for the women's age, and could therefore cause transient increases in thrombogenesis and adverse vascular remodeling. Later benefit could result from estrogen action on metabolic risk factors, such as lipids, glucose, and insulin metabolism, as well as direct arterial effects reducing atherogenesis. In contrast, this is avoided in observational studies because the women are 15 yr younger and those same starting doses of hormone replacement therapy are appropriate for their age. It is therefore possible that more appropriate hormone replacement therapy regimens, particular in terms of dose, could be devised to effect coronary benefit in older age groups. This concept needs to be tested as a priority before hormone replacement therapies are rejected as being of no cardiovascular benefit.

Hormone replacement therapy (HRT) is a collective term to include a variety of sex steroids, estrogens, and progestogens, given to postmenopausal women at various doses and administered through various routes. HRT is used for the relief of menopausal symptoms, with many women experiencing considerable improvement in their quality of life. It is also used for the prevention and treatment of osteoporosis, which is as effective as other available therapies. Other potential benefits of HRT are the prevention of cardiovascular disease and dementia. The main risks of HRT are an increased incidence of breast cancer and a transient increase in venous thromboembolism. The Women's Health Initiative is the largest randomized clinical trial of HRT to date, and has demonstrated benefits and risks of one specific HRT regimen. Skeletal benefits have been confirmed in terms of fracture reduction, as has a small risk of breast cancer development. Further studies of other HRT regimens are urgently required to clarify the cardiovascular effects.

Whether hormone replacement therapy (HRT) is beneficial for coronary heart disease (CHD) is controversial. We hypothesized that continuous combined transdermal HRT may have benefits on CHD risk markers without the potential adverse effects seen with certain other HRT regimens. Sixty apparently healthy postmenopausal women, aged 40-65 years, entered a prospective, double-blind, randomized, placebo-controlled clinical trial; 55 women completed the 6-month study. Women received either transdermal oestradiol 17beta 0.05 mg and norethisterone acetate 0.125 mg daily, or identical placebo. Circulating markers of vascular function and remodelling, forearm blood flow, lipids and lipoproteins, glucose and insulin, and haemostatic safety parameters were measured at baseline and after treatment. Compared with placebo after 6 months, HRT administration resulted in decreased E-selectin (P < 0.01), and angiotensin-converting-enzyme (ACE; P = 0.05). Cholesterol (P < 0.05), low-density lipoproteins (LDL; P < 0.05), high-density lipoprotein3 (HDL3; P < 0.05) and apolipoproteins AII (P < 0.05) and B (P < 0.05), and fasting insulin (P < 0.05) also decreased in the HRT group. Factor VII coagulation activity decreased (P < 0.01) and plasminogen activator inhibitor-1 and fibrin D-dimer increased (P < 0.05) in the HRT group, whilst prothrombin fragment 1 + 2 (P < 0.05) decreased, more so in the placebo group. There were no changes in matrix metalloproteinase (MMP)-2, or in LDL particle size. This transdermal HRT had beneficial effects on vascular function and CHD risk markers.

Objective: Levels of angiotensin I-converting enzyme (ACE) in blood are associated with variation in cardiovascular disease risk. Serum ACE activity in women may be reduced by combined oestrogen-progestogen hormone replacement therapy (HRT). However, the relative contribution of each hormonal component to this observation is uncertain. We investigated ACE activity in two groups of healthy postmenopausal women receiving HRT regimens., Design: The first group received placebo or oestrogen-only HRT randomly (oral conjugated equine oestrogens or transdermal 17 beta-oestradiol). The second group was treated with oestrogen-only HRT (oral 17 beta-oestradiol) followed by sequential oestrogen-progestogen HRT (17 beta-oestradiol and dydrogesterone)., Measurements: Assay of blood for soluble ACE activity before and whilst receiving HRT., Results: In the first group, oral conjugated equine oestrogens significantly reduced (P < 0.01) ACE activity by 18% on average relative to pretreatment whereas non-significant changes of -9% and +7% were seen with transdermal 17 beta-oestradiol or placebo treatment, respectively. In the second group oestrogen-only HRT significantly reduced (P < 0.001) ACE activity by 15% on average. The reduction during both the oestrogen-only and combined phases of sequential treatment was 12% and 19%, respectively, compared with pretreatment values (P < 0.01 and P < 0.001). ACE activity also differed significantly (P < 0.05) between the two phases of sequential treatment., Conclusions: Both oestrogen-only and oestrogen-progestogen HRT may reduce ACE activity in blood. Oestrogen and progestogen may exhibit additive effects on blood ACE activity.